Compound containing heterocyclic dihydrophthalazine

Abstract

Provided are a compound containing heterocyclic dihydrophthalazine, a preparation method therefor, a pharmaceutical composition containing said compound, and the use thereof in treating a related disease.

Description

Compounds containing heterocyclic dihydrophthalazines

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This disclosure claims priority to and the benefits of Chinese Patent Application Nos. 202311609862.X, 202410161637.2, 202411062342.6, and 202411686593.1, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure belongs to the field of medicinal chemistry and relates to a compound containing heterocyclic dihydrophthalazine, a preparation method thereof, a pharmaceutical composition containing the compound, and use thereof in treating related diseases (such as cancer). Background Art

[0004] Protein arginine N-methyltransferase (PRMT5) is a type II arginine methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the omega-nitrogen of the guanidino moiety of L-arginine residues in proteins (omega monomethylation) and transfers a second methyl group to the other omega-nitrogen, generating symmetric dimethylarginine (sDMA). PRMT5 forms a complex with MEP50 (methylosome protein 50), which is required for substrate recognition and targeting, as well as for PRMT5's catalytic histone 2A and histone 4 methyltransferase activities. Homozygous deletions of p16 / CDKN2a are common in cancer, and these mutations often involve co-deletions of adjacent genes, including the gene encoding methylthioadenosine phosphorylase (MTAP). It is estimated that approximately 15% of human cancers harbor homozygous deletions of the MTAP gene. Cells lacking MTAP activity have elevated levels of the MTAP substrate methylthioadenosine (MTA), a potent inhibitor of PRMT5. Inhibition of PRMT5 activity leads to reduced methylation activity and increases the sensitivity of cell proliferation to PRMT5 depletion or loss of activity. Therefore, the loss of MTAP activity reduces the methylation activity of PRMT5, making cells selectively dependent on PRMT5 activity. Therefore, in cancers in which MTAP is deleted, MTA synergistically inhibits PRMT5 activity and will provide therapeutic benefits for a variety of cancers. The compounds disclosed herein provide such therapeutic benefits as MTA synergistic PRMT5 inhibitors, which negatively regulate the activity of MTA-bound PRMT5 in cells, particularly MTAP-deficient cells, or are used to treat various forms of MTAP-related cancers. It is necessary to develop new MTA synergistic PRMT5 inhibitors that can inhibit PRMT5 activity when MTA concentrations are elevated, particularly in MTAP-deficient cells.

[0005] Detailed Description of the Invention

[0006] The present disclosure relates to compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII, stereoisomers thereof, or pharmaceutically acceptable salts thereof,

[0007] in,

[0008] Ring A is selected from 6-10 membered aryl groups (i.e., C 6-10 aryl) or 5-10 membered heteroaryl;

[0009] R and R' are independently selected from H, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl;

[0010] R s and R t are independently selected from H, deuterium, C 1-10 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl,

[0011] or R s and R t Connect to form C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted by one or more cycloalkyl groups selected from OH, NH2, CN, halogen or C 1-3 Alkyl radical substitution;

[0012] R 2a and R 2b are independently selected from H, OH, NH2, CN, halogen, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1- 10 Alkyl)2N-, C 3-10Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more groups selected from deuterium, OH, NH2, CN or halogen;

[0013] R 2c Selected from OH, NH2, CN, halogen, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more groups selected from deuterium, OH, NH2, CN or halogen;

[0014] R 4 Selected from C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -NR e R f 、-OR e or -SR e , the C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl are optionally substituted with one or more of the following groups: deuterium, OH, NH2, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl O-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl NHC(O)-, (C 1-6 Alkyl) 2NC(O)-, C 1-6Alkyl C(O)NH-, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl OS(O)-, C 1-6 Alkyl S(O)O-, C 1-6 Alkyl OS(O)2-, C 1-6 Alkyl S(O)2O-, C 1-6 Alkyl NHS(O)-, C 1-6 Alkyl S(O)NH-, C 1-6 Alkyl NHS(O)2- or C 1-6 Alkyl S(O)2NH-;

[0015] R e and R f are independently selected from H, or optionally substituted by one or more R c1 Substituted with the following groups: C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl;

[0016] Or, R e and R f The N atom to which they are attached forms a 3-10 membered heterocycloalkyl group, wherein the 3-10 membered heterocycloalkyl group is optionally substituted by one or more R c2 replace;

[0017] R c1 and R c2 are independently selected from OH, NH2, CN, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 3-10 Cycloalkyl-O-, 3-10 membered heterocycloalkyl-O-, C 3-10 Cycloalkyl-NH-, 3-10 membered heterocycloalkyl-NH-, C 3-10 Cycloalkyl-C(O)- or 3-10 membered heterocycloalkyl-C(O)-, wherein the C 1- 10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10Alkyl)2N-, C 3-10 Cycloalkyl-O-, 3-10 membered heterocycloalkyl-O-, C 3-10 Cycloalkyl-NH-, 3-10 membered heterocycloalkyl-NH-, C 3-10 Cycloalkyl-C(O)- or 3-10 membered heterocycloalkyl-C(O)- is optionally substituted by one or more radicals selected from OH, NH2, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl group substituted (or, the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 3-10 Cycloalkyl-O- or C 3-10 Cycloalkyl-C(O)- optionally substituted with one or more groups selected from OH, NH2, CN or halogen);

[0018] R 6 Selected from H, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted by one or more groups selected from OH, NH2, CN or halogen;

[0019] R a and R b are independently selected from H, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, C 3-10 Cycloalkyl, -COC 1-10 Alkyl or -S(O)2C 1-10 Alkyl; the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, C 3-10 Cycloalkyl, -COC 1-10 Alkyl or -S(O)2C1-10 The alkyl group is optionally substituted with one or more groups selected from OH, NH2, CN, halogen, CHO or COOH;

[0020] R 3 are independently selected from OH, NH2, CN, halogen, or optionally substituted by one or more R 5 Substituted with the following groups: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 1-12 Alkyl NHC(O)-, (C 1-12 Alkyl) 2NC(O)-, C 1-12 Alkyl C(O)NH-, C 1-12 Alkyl OC(O)-, C 1-12 Alkyl C(O)O-, C 1-12 Alkyl OS(O)-, C 1-12 Alkyl S(O)O-, C 1-12 Alkyl OS(O)2-, C 1-12 Alkyl S(O)2O-, C 1-12 Alkyl NHS(O)-, C 1-12 Alkyl S(O)NH-, C 1-12 Alkyl NHS(O)2-, C 1-12 Alkyl S(O)2NH-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl;

[0021] R 5 Selected from OH, NH2, CN, halogen, or optionally one or more R d Substituted with the following groups: C 1-10 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl S-, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 3- 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl;

[0022] R d Selected from OH, NH2, CN, COOH, CHO, halogen, C 1-10Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl S-, C 1-10 Alkyl NH- or (C 1-10 Alkyl) 2N-, the C 1-10 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl S-, C 1-10 Alkyl NH- or (C 1-10 alkyl) 2N- optionally substituted by one or more groups selected from OH, NH2, CN or halogen;

[0023] n is selected from 0, 1, 2, 3, 4 or 5;

[0024] R 1 Selected from H, halogen, CN, OH, C 1-10 Alkyl, halogenated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, -NHR a or -NR a R b (Or, R 1 Selected from H, halogen, CN, OH, C 1-10 Alkyl, halogenated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, halogenated C 1-10 Alkoxy, C 1-10 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, -NHR a or -NR a R b ;)

[0025] R 1a Selected from H, halogen, CN, OH, C 1-10 Alkyl, halogenated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, -NHR a、-NR a R b or C optionally substituted by halogen 1-10 alkoxy;

[0026] R 3a Selected from optionally one or more R 5 Substituted C 2-12 alkenyl;

[0027] R 3b Selected from OH, NH2, CN, halogen, or optionally one or more R 5 Substituted with the following groups: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 1- 12 Alkyl NHC(O)-, (C 1-12 Alkyl) 2NC(O)-, C 1-12 Alkyl C(O)NH-, C 1-12 Alkyl OC(O)-, C 1-12 Alkyl C(O)O-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl;

[0028] p is selected from 0, 1, 2, 3 or 4;

[0029] R 3c Selected from optionally one or more R 5a Substituted C 2-12 Alkynyl;

[0030] The R 5a Selected from 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; the 3-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more groups selected from the group consisting of halogen, CN, OH, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, -NHR a 、-NR a R b 、C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, -NHR a 、-NR a R b 、C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more groups selected from OH, NH2, CN or halogen;

[0031] R 3d Selected from optionally substituted C 2-12 Alkenyl or C 2-12 Alkynyl (or R 3d Selected from optionally one or more R 5 Substituted C 2-12 Alkenyl or C 2-12 alkynyl).

[0032] In some embodiments, Ring A is selected from C 6-10 Aryl.

[0033] In some embodiments, Ring A is selected from phenyl or C 10 In some embodiments, ring A is selected from phenyl or naphthyl. In some embodiments, ring A is selected from phenyl.

[0034] In some embodiments, R and R' are independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl.

[0035] In some embodiments, R and R' are independently selected from H, C 1-6 Alkyl or C 3-8 Cycloalkyl.

[0036] In some embodiments, R and R' are independently selected from H, C 1-3 Alkyl or C 3-6 Cycloalkyl.

[0037] In some embodiments, R and R' are independently selected from H or C 1-3 In some embodiments, R and R' are independently selected from H or methyl. In some specific embodiments, R and R' are selected from H.

[0038] In some embodiments, R is selected from H, C 1-3 Alkyl or C 3-6 Cycloalkyl; R' is selected from C1-3 Alkyl or C 3- 6-cycloalkyl.

[0039] In some embodiments, R is selected from H or C 1-3 Alkyl; R' is selected from C 1-3 In some embodiments, R is selected from H or methyl; R' is selected from H or methyl.

[0040] In some embodiments, R s and R t are independently selected from H, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl,

[0041] or R s and R t Connect to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by one or more cycloalkyl groups selected from OH, NH2, CN, halogen or C 1-3 Alkyl groups are substituted.

[0042] In some embodiments, R s and R t are independently selected from H, deuterium, C 1-6 Alkyl or C 3-6 Cycloalkyl, or R s and R t Connect to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

[0043] In some embodiments, R s and R t are independently selected from H, deuterium, or C 1-4 Alkyl, or R s and R t Connect to form C 3-4 Cycloalkyl.

[0044] In some embodiments, R s and R t are independently selected from H, deuterium, or methyl, or R s and R t are connected to each other to form a cyclopropyl group. In some embodiments, R s and R t are independently selected from H or deuterium.

[0045] In some embodiments, R 2a and R 2bare independently selected from H, OH, NH2, CN, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more groups selected from deuterium, OH, NH2, CN or halogen.

[0046] In some embodiments, R 2a and R 2b are independently selected from H, OH, NH2, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more groups selected from deuterium, OH, NH2, CN or halogen.

[0047] In some embodiments, R 2a and R 2b are independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more groups selected from deuterium, OH, NH2, CN or halogen.

[0048] In some embodiments, R 2a and R 2b are independently selected from H, C 1-4 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl, the C 1-4 Alkyl, C 3-4The cycloalkyl or 3-4 membered heterocycloalkyl is optionally substituted with one or more groups selected from deuterium, OH, NH2, CN or halogen.

[0049] In some embodiments, R 2b Selected from H.

[0050] In some embodiments, R 2a Selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-4 The cycloalkyl or 3-4 membered heterocycloalkyl is optionally substituted with one or more groups selected from deuterium, OH, NH2, CN or halogen.

[0051] In some embodiments, R 2a Selected from C 1-6 Alkyl or C 3-6 Cycloalkyl, the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with one or more groups selected from deuterium, OH, NH2, CN or halogen.

[0052] In some embodiments, R 2a Selected from C 1-3 Alkyl or C 3-4 Cycloalkyl, the C 1-3 Alkyl or C 3-4 The cycloalkyl groups are optionally substituted with one or more deuterium, F, Cl or Br.

[0053] In some embodiments, R 2a is selected from methyl or cyclopropyl, said methyl or cyclopropyl being optionally substituted by one or more deuterium or F.

[0054] In some embodiments, R 2a is selected from CH3, CD3, CF3, CHF2 or cyclopropyl. In some embodiments, R 2a is selected from CH3, CD3 or CHF2. In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a Selected from CHF2.

[0055] In some embodiments, R 2c Selected from OH, NH2, CN, halogen, C 1-6 Alkyl, C1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more groups selected from deuterium, OH, NH2, CN or halogen.

[0056] In some embodiments, R 2c Selected from C 1-3 Alkyl or C 3-4 Cycloalkyl, the C 1-3 Alkyl or C 3-4 Cycloalkyl is optionally substituted with one or more deuterium, F, Cl, or Br. In some embodiments, R 2c is selected from methyl or cyclopropyl, said methyl or cyclopropyl being optionally substituted by one or more deuterium or F.

[0057] In some embodiments, R 2c is selected from CH3, CD3, CF3, CHF2 or cyclopropyl. In some embodiments, R 2c Selected from CD3 or CHF2.

[0058] In some embodiments, R 4 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, -NR e R f 、-OR e or -SR e , the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10Aryl, 5-6 membered heteroaryl are optionally substituted with one or more of the following groups: deuterium, OH, NH2, CN, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkyl O-, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 1-3 Alkyl NHC(O)-, (C 1-4 Alkyl) 2NC(O)-, C 1-4 Alkyl C(O)NH-, C 1-4 Alkyl OC(O)- or C 1-4 Alkyl C(O)O-.

[0059] In some embodiments, R 4 Selected from C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl, -NR e R f 、-OR e or -SR e , the C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl or 5-6 membered heteroaryl is optionally substituted with one or more of the following groups: deuterium, OH, NH2, CN, halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0060] In some embodiments, R 4 Selected from C 6-8 Aryl, 5-6 membered heteroaryl, -NR e R f OR e .

[0061] In some embodiments, R 4 Selected from phenyl, 6-membered heteroaryl, -NR e R f OR e In some embodiments, R 4 Selected from phenyl, pyridyl, -NR e R f OR e In some embodiments, R 4 Selected from-NR e R f OR e .

[0062] In some specific embodiments, R 4 Selected from C 6-8 Aryl, 5-6 membered heteroaryl or -NR e R f .

[0063] In some specific embodiments, R 4 Selected from phenyl, 6-membered heteroaryl or -NR e R f In some embodiments, R 4 Selected from phenyl, pyridyl or -NR e R f In some embodiments, R 4 Selected from-NR e R f .

[0064] In some embodiments, R e and R f are independently selected from H, or optionally substituted by one or more R c1 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-8 membered heteroaryl;

[0065] Or, R e and R f The N atom to which they are attached forms a 3-8 membered heterocycloalkyl group, wherein the 3-8 membered heterocycloalkyl group is optionally substituted by one or more R c2 replace.

[0066] In some embodiments, R e and R f are independently selected from H, or optionally substituted by one or more R c1 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-8 membered heteroaryl;

[0067] Or, R e and R f The N atom to which they are attached forms a 3-8 membered heterocycloalkyl group, wherein the 3-8 membered heterocycloalkyl group is optionally substituted by one or more R c2 replace.

[0068] In some embodiments, R e and R f are independently selected from H, or optionally substituted by one or more R c1 Substituted with the following groups: C 1-4 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl;

[0069] Or, R e and R f Together with the N atom to which they are attached, they form a 3-6 membered heterocycloalkyl group, which is optionally substituted by one or more R c2 replace.

[0070] In some embodiments, R e and R f are independently selected from H, or optionally substituted by one or more R c1 Substituted with the following groups: C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl;

[0071] Or, R e and R f The N atom to which they are attached forms a 4-5 membered heterocycloalkyl group, which is optionally substituted by one or more R c2 replace.

[0072] In some embodiments, R e and R f are independently selected from H, or optionally substituted by one or more R c1 Substituted with the following groups: C 1-3 Alkyl, C 3-6 Cycloalkyl or 6-7 membered heterocycloalkyl;

[0073] Or, R e and R f The N atom to which they are attached forms a 4-5 membered heterocycloalkyl group, which is optionally substituted by one or more R c2 replace.

[0074] In some embodiments, R f Selected from H, R e Selected from optionally one or more R c1 Substituted with the following groups: C 1-3 Alkyl, C 3-6 Cycloalkyl or 6-7 membered heterocycloalkyl;

[0075] Or, R e and R fThe N atom to which they are attached forms a 4-5 membered heterocycloalkyl group, which is optionally substituted by one or more R c2 replace.

[0076] In some embodiments, R e and R f are independently selected from H, or optionally substituted by one or more R c1 substituted with the following groups: methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or monoazaspiroheptyl,

[0077] Or, R e and R f are linked to each other and to the N atom to which they are attached to form an azetidinyl or pyrrolidinyl group, which is optionally substituted by one or more R c2 replace.

[0078] In some embodiments, R f Selected from H, R e Selected from optionally one or more R c1 substituted with the following groups: methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or monoazaspiroheptyl,

[0079] Or, R e and R f are linked to each other and to the N atom to which they are attached to form an azetidinyl or pyrrolidinyl group, which is optionally substituted by one or more R c2 replace.

[0080] In some embodiments, R e and R f are independently selected from H, or optionally substituted by one or more R c1 Substituted groups: methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, azetidinyl, pyrrolidinyl or monoazaspiroheptyl,

[0081] Or, R e and R f are linked to each other and to the N atom to which they are attached to form an azetidinyl or pyrrolidinyl group, which is optionally substituted by one or more R c2 replace.

[0082] In some embodiments, R c1 and R c2 are independently selected from OH, NH2, CN, halogen, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-8 Cycloalkyl-O-, 3-8 membered heterocycloalkyl-O-, C 3-8 Cycloalkyl-NH-, 3-8 membered heterocycloalkyl-NH-, C 3-8 Cycloalkyl-C(O)- or 3-8 membered heterocycloalkyl-C(O)-, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-8 Cycloalkyl-O-, 3-8 membered heterocycloalkyl-O-, C 3-8 Cycloalkyl-NH-, 3-8 membered heterocycloalkyl-NH-, C 3-8 Cycloalkyl-C(O)- or 3-8 membered heterocycloalkyl-C(O)- is optionally substituted by one or more radicals selected from OH, NH2, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-10 The cycloalkyl group or the 3-10 membered heterocycloalkyl group is substituted.

[0083] In some embodiments, R c1 and R c2 are independently selected from OH, NH2, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-8 Cycloalkyl-O- or C 3-8 Cycloalkyl-C(O)-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-8 Cycloalkyl-O- or C 3-8 Cycloalkyl-C(O)- is optionally substituted by one or more radicals selected from OH, NH2, CN, halogen or C1-6 Alkoxy groups are substituted.

[0084] In some embodiments, R c1 and R c2 are independently selected from OH, NH2, CN, F, Cl, Br, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 3-6 Cycloalkyl-O- or C 3-6 Cycloalkyl-C(O)-, the C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 3-6 Cycloalkyl-O- or C 3-6 Cycloalkyl-C(O)- is optionally substituted by one or more radicals selected from OH, NH2, CN, halogen or C 1-3 Alkoxy groups are substituted.

[0085] In some embodiments, R c1 and R c2 are independently selected from OH, NH2, CN, F, Cl, Br, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl-O- or C 3-6 Cycloalkyl-C(O)-, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl-O- or C 3-6 Cycloalkyl-C(O)- is optionally substituted by one or more radicals selected from OH, NH2, CN, halogen or C 1-3 Alkoxy groups are substituted.

[0086] In some embodiments, R c1 and R c2 are independently selected from OH, NH2, CN, F, Cl, Br, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-4 Cycloalkyl-O- or C 5-6 Cycloalkyl-C(O)-, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-4 Cycloalkyl-O- or C5-6 Cycloalkyl-C(O)- is optionally substituted by one or more radicals selected from OH, NH2, CN, halogen or C 1-3 Alkoxy groups are substituted.

[0087] In some embodiments, R c1 and R c2 Each is independently selected from OH, F, cyclopropyl-O-, cyclopentyl-C(O)-, methoxy, isopropyloxy, CH3OCH2CH2O-, methyl, CHF2 or CF3.

[0088] In other embodiments, R c1 and R c2 are independently selected from OH, NH2, CN, F, Cl, Br, C 1-3 Alkoxy, C 3-4 Cycloalkyl-O- or C 5-6 Cycloalkyl-C(O)-, the C 1-3 Alkoxy, C 3-4 Cycloalkyl-O- or C 5-6 Cycloalkyl-C(O)- is optionally substituted by one or more radicals selected from OH, NH2, CN, halogen or C 1-3 Alkoxy groups are substituted.

[0089] In other embodiments, R c1 and R c2 Each is independently selected from OH, F, cyclopropyl-O-, cyclopentyl-C(O)-, methoxy, isopropyloxy or CH3OCH2CH2O-.

[0090] In other embodiments, R c1 and R c2 are independently selected from OH, NH2, CN, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 3-10 Cycloalkyl-O-, 3-10 membered heterocycloalkyl-O-, C 3-10 Cycloalkyl-NH-, 3-10 membered heterocycloalkyl-NH-, C 3-10 Cycloalkyl-C(O)- or 3-10 membered heterocycloalkyl-C(O)-, wherein the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 3-10 Cycloalkyl-O- or C 3-10Cycloalkyl-C(O)- is optionally substituted with one or more groups selected from OH, NH2, CN or halogen.

[0091] In other embodiments, R c1 and R c2 are independently selected from OH, NH2, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-8 Cycloalkyl-O-, 3-8 membered heterocycloalkyl-O-, C 3-8 Cycloalkyl-NH-, 3-8 membered heterocycloalkyl-NH-, C 3-8 Cycloalkyl-C(O)- or 3-8 membered heterocycloalkyl-C(O)-, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-8 Cycloalkyl-O-, 3-8 membered heterocycloalkyl-O-, C 3-8 Cycloalkyl-NH-, 3-8 membered heterocycloalkyl-NH-, C 3-8 Cycloalkyl-C(O)- or 3-8 membered heterocycloalkyl-C(O)- is optionally substituted with one or more groups selected from OH, NH2, CN or halogen.

[0092] In other embodiments, R c1 and R c2 are independently selected from OH, NH2, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-8 Cycloalkyl-O- or C 3-8 Cycloalkyl-C(O)-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-8 Cycloalkyl-O- or C 3-8Cycloalkyl-C(O)- is optionally substituted with one or more groups selected from OH, NH2, CN or halogen.

[0093] In other embodiments, R c1 and R c2 are independently selected from OH, NH2, CN, F, Cl, Br, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 3-6 Cycloalkyl-O- or C 3- 6 cycloalkyl-C(O)-, the C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 3-6 Cycloalkyl-O- or C 3-6 Cycloalkyl-C(O)- is optionally substituted with one or more groups selected from OH, NH2, CN or halogen.

[0094] In other embodiments, R c1 and R c2 are independently selected from OH, NH2, CN, F, Cl, Br, C 1-3 Alkyl, C 3-6 Cycloalkyl-O- or C 3-6 Cycloalkyl-C(O)-, the C 1-3 Alkyl, C 3-6 Cycloalkyl-O- or C 3-6 Cycloalkyl-C(O)- is optionally substituted with one or more groups selected from OH, NH2, CN or halogen.

[0095] In other embodiments, R c1 and R c2 are independently selected from OH, NH2, CN, F, Cl, Br, C 3-4 Cycloalkyl-O- or C 5-6 Cycloalkyl-C(O)-, the C 3-4 Cycloalkyl-O- or C 5-6 Cycloalkyl-C(O)- is optionally substituted with one or more groups selected from OH, NH2, CN or halogen. c1 and R c2 Each is independently selected from OH, F, cyclopropyl-O- or cyclopentyl-C(O)-.

[0096] In some embodiments, R e and R f are independently selected from H, methyl, ethyl, isopropyl, Cyclopropyl, cyclobutyl, cyclopentyl, In some embodiments, R e and R f are independently selected from

[0097] Or, R e and R f Connected to each other and to the N atoms to form

[0098] In some embodiments, R 4 Selected from -O-cyclopropyl, In some embodiments, R 4 Selected from In some specific embodiments, R 4 In some embodiments, R 4 Selected from -O-cyclopropyl.

[0099] In some embodiments, R 6 Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more groups selected from OH, NH2, CN or halogen.

[0100] In some embodiments, R 6 Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

[0101] In some embodiments, R6 Selected from H, C 1-4 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl.

[0102] In some embodiments, R 6 Selected from H, C 1-3 Alkyl or C 3-4 Cycloalkyl.

[0103] In some embodiments, R 6 In some embodiments, R 6 Selected from H.

[0104] In some specific embodiments, R 6 Selected from C 1-4 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl.

[0105] In some specific embodiments, R 6 Selected from C 1-3 Alkyl or C 3-4 Cycloalkyl.

[0106] In some specific embodiments, R 6 Selected from ethyl or cyclopropyl.

[0107] In some embodiments, R a and R b are independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, -COC 1-6 Alkyl or -S(O)2C 1-6 Alkyl; the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, -COC 1-6 Alkyl or -S(O)2C 1-6 The alkyl group is optionally substituted with one or more groups selected from OH, NH2, CN, halogen, CHO or COOH.

[0108] In some embodiments, R a and R b are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, -COC 1-6 Alkyl or -S(O)2C 1-6alkyl.

[0109] In some embodiments, R a and R b are independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, -COC 1-4 Alkyl or -S(O)2C 1-4 alkyl.

[0110] In some embodiments, R a and R b are independently selected from H, C 1-3 Alkyl, C 3-5 Cycloalkyl, -COC 1-3 Alkyl or -S(O)2C 1-3 alkyl.

[0111] In some embodiments, R a and R b are independently selected from H or C 1-3 In some embodiments, R a and R b are independently selected from H, methyl, ethyl or isopropyl. a and R b are independently selected from H or methyl.

[0112] In some specific embodiments, R a and R b All are selected from H.

[0113] In some specific embodiments, R a Selected from H, C 1-3 Alkyl, C 3-5 Cycloalkyl, -COC 1-3 Alkyl or -S(O)2C 1-3 Alkyl; R b Selected from C 1-3 Alkyl, C 3-5 Cycloalkyl, -COC 1-3 Alkyl or -S(O)2C 1-3 alkyl.

[0114] In some specific embodiments, R a Selected from H or C 1-3 Alkyl; R b Selected from C 1-3 In some embodiments, R a and R b R are independently selected from H, methyl, ethyl or isopropyl; b is selected from methyl, ethyl or isopropyl.

[0115] In some specific embodiments, R a and R b Not selected from H at the same time.

[0116] In some embodiments, R and R' are independently selected from H, R s and R t are independently selected from H, R 2b Selected from H, R 2a is selected from C optionally substituted by halogen (such as F, Cl, Br or I) 1-3 Alkyl (such as methyl), R 4 Select from -OR e , R e Selected from C 3-6 Cycloalkyl (e.g. cyclopropyl), R 6 Selected from H, R a and R b are independently selected from H or methyl.

[0117] In some embodiments, R 3 are independently selected from OH, NH2, CN, halogen, or optionally substituted by one or more R 5 Substituted with the following groups: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl S-, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 1-10 Alkyl NHC(O)-, (C 1-10 Alkyl) 2NC(O)-, C 1-10 Alkyl C(O)NH-, C 1-10 Alkyl OC(O)-, C 1-10 Alkyl C(O)O-, C 1-6 Alkyl OS(O)-, C 1-6 Alkyl S(O)O-, C 1-6 Alkyl OS(O)2-, C 1-6 Alkyl S(O)2O-, C 1-6 Alkyl NHS(O)-, C 1-6 Alkyl S(O)NH-, C 1-6 Alkyl NHS(O)2-, C 1-6 Alkyl S(O)2NH-, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl.

[0118] In some embodiments, R3 are independently selected from OH, NH2, CN, halogen, or optionally substituted by one or more R 5 Substituted with the following groups: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl.

[0119] In some embodiments, R 3 are independently selected from OH, NH2, CN, halogen, or optionally substituted by one or more R 5 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-10 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl or 5-6 membered heteroaryl.

[0120] In some embodiments, R 3 are independently selected from OH, NH2, CN, halogen, or optionally substituted by one or more R 5 Substituted with the following groups: C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl.

[0121] In some embodiments, R 3 are independently selected from OH, NH2, CN, halogen, or optionally substituted by one or more R 5 Substituted with the following groups: C 1-4 Alkyl, C 2-3 Alkenyl, C 2-6 Alkynyl, C 3-4 Cycloalkyl or 3-membered heterocycloalkyl.

[0122] In some embodiments, R 3 are independently selected from OH, NH2, CN, F, Cl, Br, I, or optionally substituted by one or more R 5 Substituted: methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, propenyl, ethynyl, propynyl, butynyl, dimethylbutynyl (e.g., 3,3-dimethylbutynyl), methylpentynyl (e.g., 4-methylpentynyl), cyclopropyl, or oxirane.

[0123] In other embodiments, R3 are independently selected from OH, NH2, CN, halogen, or optionally substituted by one or more R 5 Substituted with the following groups: C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or 3-4 membered heterocycloalkyl.

[0124] In other embodiments, R 3 are independently selected from OH, NH2, CN, halogen, or optionally substituted by one or more R 5 Substituted with the following groups: C 1-3 Alkyl, C 2-3 Alkenyl, C 2-6 Alkynyl or 3-membered heterocycloalkyl.

[0125] In other embodiments, R 3 are independently selected from OH, NH2, CN, F, Cl, Br, I, or optionally substituted by one or more R 5 Substituted groups include methyl, ethyl, vinyl, propenyl, ethynyl, propynyl, butynyl, dimethylbutynyl (such as 3,3-dimethylbutynyl), methylpentynyl (such as 4-methylpentynyl), or oxirane.

[0126] In some specific embodiments, R 3 are independently selected from OH, NH2, CN, halogen, or optionally substituted by one or more R 5 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-8 Alkynyl.

[0127] In some specific embodiments, R 3 are independently selected from OH, NH2, CN, halogen, C 2-6 Alkenyl or C 2-8 Alkynyl, the C 2-6 Alkenyl or C 2-8 Alkynyl is optionally substituted with one or more R 5 replace.

[0128] In some specific embodiments, R 3 are independently selected from OH, NH2, CN, halogen, C 2-3 Alkenyl or C 2-6 Alkynyl, the C 2-3 Alkenyl or C 2-6 Alkynyl is optionally substituted with one or more R 5 In some embodiments, R 3are independently selected from OH, NH2, CN, halogen, C 2-3 Alkenyl or C 2-4 Alkynyl, the C 2-3 Alkenyl or C 2-4 Alkynyl is optionally substituted with one or more R 5 In some embodiments, R 3 are independently selected from OH, NH2, CN, halogen, vinyl, ethynyl or propynyl, wherein the vinyl, ethynyl or propynyl is optionally replaced by one or more R 5 In some embodiments, R 3 are independently selected from CN, F, vinyl or propynyl, the vinyl or propynyl being optionally substituted by one or more R 5 In some embodiments, R 3 Each is independently selected from CN, F, vinyl or propynyl, the vinyl being optionally substituted with one or more F groups.

[0129] In some embodiments, R 5 Selected from OH, NH2, CN, halogen, or optionally one or more R d Substituted with the following groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 1-8 Alkyl S-, C 1-8 Alkyl NH-, (C 1- 8 alkyl) 2N-, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-8 aryl or 5-8 membered heteroaryl.

[0130] In some embodiments, R 5 Selected from OH, NH2, CN, halogen, or optionally one or more R d Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1- 6 alkyl) 2N-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl or 5-6 membered heteroaryl.

[0131] In some embodiments, R 5 Selected from OH, NH2, CN, halogen, or optionally one or more R dSubstituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl S-, C 1-4 Alkyl NH-, (C 1-4 Alkyl)2N-, C 2-4 Alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl.

[0132] In some embodiments, R 5 Selected from OH, NH2, CN, F, Cl, Br, or optionally one or more R d Substituted with the following groups: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl.

[0133] In some embodiments, R 5 Selected from OH, NH2, CN, F, chlorine, bromine, or optionally one or more R d Substituted with the following groups: C 1-2 Alkyl, C 1-2 Alkoxy, C 3-6 cycloalkyl, phenyl or 5-6 membered heteroaryl.

[0134] In some embodiments, R 5 selected from OH, NH2, CN, F, Cl, Br, optionally with one or more R d Substituted from the following groups: methyl, -OCH3, -OCH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, piperidinyl, dioxane, piperazinyl, morpholinyl, tetrahydropyranyl, phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, pyridazinyl, pyrimidinyl, pyrazinyl or pyridyl.

[0135] In some embodiments, R 5 Selected from OH, F, or optionally one or more R d Substituted from the following groups: methyl, OCH3, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, furyl, thienyl, pyrazolyl, pyrimidinyl, pyrazinyl or pyridyl.

[0136] In some embodiments, R 5 Selected from OH, F, OCH3, Cyclopropyl, cyclopentyl, cyclohexyl, phenyl, Pyrrolyl, furyl, thienyl, pyrazolyl, pyrimidinyl, pyrazinyl or pyridyl.

[0137] In some embodiments, R 5 Selected from CN, F, Cl or Br.

[0138] In some embodiments, R d Selected from OH, NH2, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1- 6 alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH- or (C 1-6 Alkyl) 2N-, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl S-, C 1-6 Alkyl NH- or (C 1-6 alkyl)2N- is optionally substituted by one or more groups selected from OH, NH2, CN or halogen.

[0139] In some embodiments, R d Selected from OH, NH2, CN, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy.

[0140] In some embodiments, R d Selected from OH, NH2, CN, F, Cl, Br, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 In some embodiments, R d Selected from CN, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Alkoxy.

[0141] In some embodiments, R d is selected from OH, NH2, CN, F, Cl, Br, methyl, ethyl, CF3 or OCH3.

[0142] In some embodiments, R d Selected from CN, methyl, CF3 or OCH3.

[0143] In some embodiments, R 3 are independently selected from OH, CN, F, Cl, acetylene, propynyl, butynyl, Vinyl, methyl, In some embodiments, R 3 are independently selected from CN, F, Cl, acetylene, propynyl, butynyl, vinyl, In some embodiments, R 3 are independently selected from CN, F or propynyl. 3 Each independently selected from CN, F or

[0144] In some embodiments, R 3 are independently selected from CN, F, Cl, methyl, propynyl,

[0145] In some embodiments, n is selected from 1, 2, or 3. In some embodiments, n is selected from 2 or 3.

[0146] In some embodiments, R 1 Selected from H, halogen, CN, OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -NHR a or -NR a R b .

[0147] In some embodiments, R 1 Selected from H, halogen, CN, OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -NHR a or -NR a R b .

[0148] In some embodiments, R 1 Selected from H, halogen, CN, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-4 Cycloalkyl, -NHR a or -NRa R b .

[0149] In some embodiments, R 1 Selected from H, halogen, CN, OH, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-4 Cycloalkyl, -NHR a or -NR a R b .

[0150] In some embodiments, R 1 Selected from H, C 2-3 Alkenyl, -NHR a or -NR a R b .

[0151] In some embodiments, R 1 Selected from H, halogen, C 2-6 Alkenyl, -NHR a or -NR a R b .

[0152] In some embodiments, R 1 Selected from H, halogen, C 2-6 Alkenyl, -NH2, -NHC 1-6 Alkyl or -N(C 1-6 Alkyl)2.

[0153] In some embodiments, R 1 Selected from H, F, Cl, Br, C 2-3 Alkenyl, -NH2, -NHC 1-3 Alkyl or -N(C 1-3 Alkyl)2.

[0154] In some embodiments, R 1 is selected from H, Cl, vinyl, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3 or -NHCH(CH3)2.

[0155] In some specific embodiments, R 1 Selected from H, -NH2, -NHC 1-6 Alkyl or -N(C 1-6 Alkyl)2.

[0156] In some specific embodiments, R 1 Selected from H, -NH2, -NHC 1-3 Alkyl or -N(C 1-3 Alkyl)2.

[0157] In some specific embodiments, R 1 is selected from H, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3 or -NHCH(CH3)2.

[0158] In some specific embodiments, R 1 In some embodiments, R 1 Selected from -NH2.

[0159] In some embodiments, R 1a Selected from H, halogen, CN, OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -NHR a 、-NR a R b or C optionally substituted by halogen 1-6 Alkoxy.

[0160] In some embodiments, R 1a Selected from H, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2 or C optionally substituted by halogen 1-6 In some embodiments, R 1a is selected from H, -NH2 or C optionally substituted by F 1-3 In some embodiments, R 1a Selected from H, -NH2 or -OCH2CF3.

[0161] In some embodiments, R 3a Selected from optionally one or more R 5 Substituted C 2-6 Alkenyl.

[0162] In some embodiments, R 3a Selected from optionally one or more R 5 Substituted C 2-4 Alkenyl.

[0163] In some embodiments, R 3a Selected from optionally one or more R 5 Replaced vinyl.

[0164] In some embodiments, R 3aSelected from vinyl groups optionally substituted with one or more of the following groups: halogen, CN, OH, NH2, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally substituted with one or more of the following groups: OH, NH2, CN, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Alkoxy.

[0165] In some embodiments, R 3a Selected from vinyl optionally substituted by one or more of the following groups: halogen, CN, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally substituted with one or more of the following groups: OH, NH2, CN, halogen, C 1-3 Alkyl, C 1- 3 haloalkyl or C 1-3 Alkoxy.

[0166] In some embodiments, R 3a is selected from vinyl optionally substituted with one or more of the following groups: halogen, CN, phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted with one or more of the following groups: OH, NH2, CN, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0167] In some embodiments, R 3a is selected from vinyl optionally substituted with one or more of the following groups: halogen, pyrrolyl or pyrazinyl, wherein the pyrrolyl or pyrazinyl is optionally substituted with one or more of the following groups: OH, NH2, CN, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0168] In some embodiments, R 3a is selected from vinyl optionally substituted with one or more of the following groups: halogen, pyrrolyl or pyrazinyl, said pyrrolyl or pyrazinyl being optionally substituted with one or more C 1-3 Alkyl substitution.

[0169] In some specific embodiments, R 3a is selected from C optionally substituted by one or more of the following groups 2-4 Alkenyl: C3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally substituted with one or more of the following groups: OH, NH2, CN, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Alkoxy.

[0170] In some specific embodiments, R 3a is selected from C optionally substituted by one or more of the following groups 2-3 Alkenyl: phenyl or 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally substituted with one or more of the following groups: OH, NH2, CN, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Alkoxy.

[0171] In some specific embodiments, R 3a is selected from vinyl optionally substituted by one or more of the following groups: phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted by one or more of the following groups: OH, NH2, CN, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0172] In some specific embodiments, R 3a Selected from vinyl optionally substituted with one or more of the following groups: pyrrolyl or pyrazinyl, said pyrrolyl or pyrazinyl optionally substituted with one or more of the following groups: OH, NH2, CN, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0173] In some specific embodiments, R 3a is selected from vinyl optionally substituted with one or more of the following groups: pyrrolyl or pyrazinyl, the pyrrolyl or pyrazinyl being optionally substituted with one or more C 1-3 In some embodiments, R 3a is selected from vinyl optionally substituted with one or more halogens; in some embodiments, R 3a is selected from vinyl optionally substituted by one or more F.

[0174] In some embodiments, R 3a Selected from vinyl, In some embodiments, R3a Selected from vinyl, In some embodiments, R 3a Selected from

[0175] In some embodiments, R 3b Selected from OH, NH2, CN, halogen, or optionally one or more R 5 Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1- 6 alkyl) 2N-, C 1-6 Alkyl NHC(O)-, (C 1-6 Alkyl) 2NC(O)-, C 1-6 Alkyl C(O)NH-, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl C(O)O-, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl.

[0176] In some embodiments, R 3b Selected from OH, NH2, CN, halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0177] In some embodiments, R 3b Selected from OH, NH2, CN, halogen, C 1-4 Alkyl or C 3-4 Cycloalkyl.

[0178] In some embodiments, R 3b Selected from OH, NH2, CN, halogen, C 1-4 In some embodiments, R 3b In some embodiments, R 3b is selected from CN, F, Cl, methyl, cyclopropyl, isopropyl or tert-butyl.

[0179] In some embodiments, R 3b Selected from OH, NH2, CN, halogen or C 1-4 alkyl.

[0180] In some embodiments, R 3b is selected from OH, NH2, CN or halogen. In some embodiments, R 3bIn some embodiments, R 3b Selected from CN or F.

[0181] In some embodiments, p is selected from 0, 1, or 2. In some embodiments, p is selected from 1 or 2.

[0182] In some embodiments, R 3c Selected from optionally one or more R 5a Substituted C 2-8 Alkynyl.

[0183] In some embodiments, R 3c Selected from optionally one or more R 5a Substituted C 2-6 Alkynyl.

[0184] In some embodiments, R 3c Selected from optionally one or more R 5a Substituted C 2-3 Alkynyl.

[0185] In some embodiments, R 3c Selected from optionally one or more R 5a Substituted ethynyl.

[0186] In some embodiments, the R 5a Selected from 3-6 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl; the 3-6 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl is optionally substituted by one or more groups selected from the group consisting of halogen, CN, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, -NHR a 、-NR a R b 、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C 6-10 Aryl or 5-6 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C 6-10 The aryl or 5-6 membered heteroaryl is optionally substituted with one or more groups selected from OH, NH2, CN or halogen.

[0187] In some embodiments, the R 5aphenyl or 5-6 membered heteroaryl; the phenyl or 5-6 membered heteroaryl is optionally substituted by one or more groups selected from the following: halogen, CN, OH or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more groups selected from OH, NH2, CN or halogen.

[0188] In some embodiments, the R 5a is selected from phenyl, pyrrolyl, pyrazolyl, furanyl, thienyl, pyrazolyl, pyrimidinyl, pyrazinyl or pyridinyl; the phenyl, pyrrolyl, pyrazolyl, furanyl, thienyl, pyrimidinyl, pyrazinyl or pyridinyl is optionally substituted with one or more groups selected from the following: F, Cl, Br, CN, OH, CH3 or CF3.

[0189] In some embodiments, R 5a Selected from phenyl, Pyrrolyl, furyl, thienyl, pyrazolyl, pyrimidinyl, pyrazinyl or pyridyl.

[0190] In some embodiments, R 3c Selected from

[0191] In some embodiments, R 3d is selected from C optionally substituted by halogen (such as F, Cl, Br or I) 2-6 Alkenyl or C 2-6 In some embodiments, R 3d Selected from C 2-3 Alkynyl or C optionally substituted by F 2-3 In some embodiments, R 3d Selected from vinyl or propynyl.

[0192] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from Specifically, the group With adjacent groups The corresponding connections form the structural parts The group With adjacent groups The corresponding connections form the structural parts Other groups such as The connection method is the same as above. In some specific embodiments, R 3 are independently selected from C 2-3 Alkenyl or C 2-4 Alkynyl, the C 2-3 Alkenyl or C 2-4 Alkynyl is optionally substituted with one or more R 5 In some embodiments, the R 3 is selected from vinyl or propynyl, the vinyl being optionally substituted with one or more F groups.

[0193] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from Specifically, the group With adjacent groups such as The corresponding connections form the structural parts The group With adjacent groups such as The corresponding connections form the structural parts Other groups such as The connection method is the same as above.

[0194] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from Specifically, the group With adjacent groups such as The corresponding connections form the structural parts The group With adjacent groups such as The corresponding connections form the structural parts Other groups such as The connection method is the same as above.

[0195] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from Specifically, the group With adjacent groups such as The corresponding connections form the structural parts The group With adjacent groups such as The corresponding connections form the structural parts Other groups such as The connection method is the same as above.

[0196] In some embodiments, the compound of Formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is selected from the compound of Formula IA, Formula IA-1, or Formula IA-2, its stereoisomers, or pharmaceutically acceptable salts thereof,

[0197] Among them, R, R', R s 、R t 、R 2a 、R 2b 、R a 、R b 、R 3 、R 4 and R 6 is as defined in this disclosure;

[0198] R 31 and R 32 are independently selected from OH, NH2, CN, halogen, or optionally replaced by one or more R 5 Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1- 6 alkyl) 2N-, C 1-6 Alkyl NHC(O)-, (C 1-6 Alkyl) 2NC(O)-, C 1-6 Alkyl C(O)NH-, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl C(O)O-, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl.

[0199] In some embodiments, R 31 and R 32 are independently selected from OH, NH2, CN, halogen or C optionally substituted by halogen 1-4 Alkyl or C 3-4 Cycloalkyl.

[0200] In some embodiments, R 31 and R 32 are independently selected from OH, NH2, CN, halogen, C 1-4 Alkyl or cyclopropyl.

[0201] In some embodiments, R 31 and R 32 are independently selected from CN, halogen, C 1-4 Alkyl or cyclopropyl.

[0202] In some embodiments, R 31 and R 32 are independently selected from CN, F, Cl, methyl, isopropyl, tert-butyl or cyclopropyl.

[0203] In some embodiments, R 31 and R 32 are independently selected from OH, NH2, CN, halogen or C optionally substituted by halogen 1-4 alkyl.

[0204] In some embodiments, R 31 and R 32 are independently selected from OH, NH2, CN or halogen.

[0205] In some embodiments, R 31 and R 32 are independently selected from CN or halogen.

[0206] In some embodiments, R 31 and R 32 are independently selected from CN or F.

[0207] In some embodiments, R 31 Selected from CN, C 1-3 In some embodiments, R 31 is selected from CN, methyl, isopropyl, tert-butyl or cyclopropyl.

[0208] In some embodiments, R 31 In some embodiments, R 32 Selected from F.

[0209] In some embodiments, R 3 Selected from optionally one or more R 5 Substituted with the following groups: C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl.

[0210] In some embodiments, R 3 Selected from optionally one or more R 5 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-10 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl or 5-6 membered heteroaryl.

[0211] In some embodiments, R 3 Selected from optionally one or more R 5 Substituted with the following groups: C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or 3-4 membered heterocycloalkyl.

[0212] In some embodiments, R 3 Selected from optionally one or more R 5 Substituted with the following groups: C 1-3 Alkyl, C 2-3 Alkenyl, C 2-6 Alkynyl or 3-membered heterocycloalkyl.

[0213] In some embodiments, R 3 Selected from optionally one or more R 5 Substituted: methyl, ethyl, oxirane, vinyl, ethynyl, propynyl, butynyl, dimethylbutynyl (eg, 3,3-dimethylbutynyl), or methylpentynyl (eg, 4-methylpentynyl).

[0214] In some specific embodiments, R 3 Selected from C 2-6 Alkenyl or C 2-8 Alkynyl, the C 2-6 Alkenyl or C 2-8 Alkynyl is optionally substituted with one or more R 5 replace.

[0215] In some specific embodiments, R 3 Selected from C 2-3 Alkenyl or C 2-6 Alkynyl, the C 2-3 Alkenyl or C 2-6 Alkynyl is optionally substituted with one or more R 5 In some embodiments, R3 Selected from C 2-3 Alkenyl or C 2-4 Alkynyl, the C 2-3 Alkenyl or C 2-4 Alkynyl is optionally substituted with one or more R 5 In some embodiments, R 3 Selected from optionally one or more R 5 In some embodiments, R 3 is selected from propynyl or vinyl optionally substituted by F.

[0216] In some embodiments, the R 5 The definition of is as described in this disclosure.

[0217] In some embodiments, the compound of formula IV, its stereoisomers, or pharmaceutically acceptable salts thereof is selected from the compound of formula IVA, formula IVA-1, or formula IVA-2, its stereoisomers, or pharmaceutically acceptable salts thereof,

[0218] Among them, R, R', R 2a 、R 2b 、R 1 、R 3 、R 31 、R 32 、R 4 and R 6 The definition of is as described in this disclosure.

[0219] In some embodiments, the compound of formula V, its stereoisomers, or pharmaceutically acceptable salts thereof is selected from the compound of formula VA, formula VA-1, or formula VA-2, its stereoisomers, or pharmaceutically acceptable salts thereof,

[0220] Among them, R, R', R s 、R t 、R 2b 、R 1 、R 3 、R 31 、R 32 、R 4 and R 6 The definition of is as described in this disclosure.

[0221] In some embodiments, the moiety Selected from

[0222] In some embodiments, the moiety Selected from

[0223] In some embodiments, the moiety Selected from

[0224] In some embodiments, the compound of Formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is selected from the compound of Formula IIA, Formula IIA-1, or Formula IIA-2, its stereoisomers, or pharmaceutically acceptable salts thereof.

[0225] Among them, R, R', R s 、R t 、R 2a 、R 2b 、R 1 、R 3a 、R 3b 、R 4 and R 6 The definition of is as described in this disclosure.

[0226] In some embodiments, the moiety Selected from

[0227] In some embodiments, the moiety Selected from

[0228] In some embodiments, the moiety Selected from

[0229] In some embodiments, the compound of Formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is selected from the compound of Formula IIIA, Formula IIIA-1, or Formula IIIA-2, its stereoisomers, or pharmaceutically acceptable salts thereof,

[0230] Among them, R, R', R s 、R t 、R 2a 、R 2b 、R 1 、R 3c 、R 3b 、R 4 and R 6 The definition of is as described in this disclosure.

[0231] In some embodiments, the moiety Selected from

[0232] In some embodiments, the moiety Selected from

[0233] In some embodiments, the moiety Selected from

[0234] In some embodiments, the compound of Formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is selected from the compound of Formula VIA, Formula VIA-1, or Formula VIA-2, its stereoisomers, or pharmaceutically acceptable salts thereof,

[0235] Among them, R, R', R s 、R t 、R 2b 、R 3 、R 31 、R 32 、R 3 、R 4 and R 6 The definition of is as described in this disclosure.

[0236] It is to be understood that any of the embodiments of the compounds of the present disclosure as described above and the specific R, R', R s 、R t 、R 2a 、R 2b 、R 1 、R a 、R b , Ring A, R 3 、R 3a 、R 3b 、R 3c 、R 5 、R d ,n,p,R 4 、R e 、R f 、R c1 、R c2 、R 5a 、R 6 、R 31 、R 32 , structural part Structural part Structural part Any specific substituent described can be independently combined with other embodiments of the present disclosure and / or substituents of compounds to form embodiments of the present disclosure not specifically described above. In addition, any specific R, R', R s 、R t 、R 2a 、R 2b 、R1 、R a 、R b , Ring A, R 3 、R 3a 、R 3b 、R 3c 、R 5 、R d ,n,p,R 4 、R e 、R f 、R c1 、R c2 、R 5a 、R 6 、R 31 、R 32 , structural part Structural part Structural part Substituents Where a range of substituents is disclosed, it is understood that one or more substituents can be deleted from the range and the remaining range of substituents is also considered an embodiment of the disclosure.

[0237] In some embodiments, when R 3 Selected from vinyl, propynyl or R a 、R b 、R 6 , R, R', R s and R t Not H, and / or R at the same time 4 Not cyclopropyl O-.

[0238] In some embodiments, when R 3a Selected from vinyl or F substituted vinyl, R a 、R b 、R 6 , R, R', R s and R t Not H, and / or R at the same time 4 Not cyclopropyl O-.

[0239] In some embodiments, heterocycloalkyl and heterocycloalkenyl each independently contain 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, heterocycloalkyl and heterocycloalkenyl each independently contain 1 or 2 heteroatoms independently selected from N and O.

[0240] In some embodiments, the heteroaryl group contains 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0241] In some embodiments, the heterocyclyl contains 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocyclyl contains 1 or 2 heteroatoms independently selected from N and O.

[0242] In some embodiments, the halo is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo is selected from fluoro.

[0243] In some embodiments, the C 1-10 Selected from C 1-9 、C 1-8 、C 1-7 、C 1-6 、C 1-4 、C 1-3 , or C 1-2 In some embodiments, C 1-6 Selected from C 1-4 、C 1-3 , or C 1-2 In some embodiments, the C 1-4 is selected from C4, C3, C2, or C1. In some embodiments, the C 1-3 Selected from C3, C2, or C1.

[0244] In some embodiments, the C 2-10 Selected from C 2-8 、C 2-6 、C 2-5 、C 2-4 、C 2-3 In some embodiments, the C 2-6 Selected from C 2-4 , or C 2-3 In some embodiments, the C 2-4 Selected from C4, C3, or C2.

[0245] In some embodiments, the C 3-6 Selected from C 3-5 、C 3-4 、C 4-6 、C 4-5 , or C 5-6 In some embodiments, the C 6-10 Selected from C 6-9 、C 6-8 、C 6-7 、C 7-10 、C 7-9 、C 7-8 、C 8-10 、C 8-9 , or C 9-10 In some embodiments, the C3-10 Selected from C 3-9 、C 3-8 、C 3-7 、C 3-6 、C 3-5 、C 3-4 、C 4-10 、C 4-9 、C 4-8 、C 4-7 、C 4-6 、C 4-5 、C 5-10 、C 5-9 、C 5-8 、C 5-7 、C 5-6 、C 6-10 、C 6-9 、C 6-8 、C 6-7 、C 7-12 、C 7-10 、C 7-9 、C 7-8 、C 8-12 、C 8-10 、C 8-9 、C 9-12 , or C 9-10 In some embodiments, the C 3-15 Selected from C 3-12 or C 3-10 In some embodiments, the C 3-12 Selected from C 3-10 In some embodiments, the C 6-12 Selected from C 6-10 .

[0246] In some embodiments, the 3-6 yuan is selected from 3-5 yuan, 3-4 yuan, 4-6 yuan, 4-5 yuan, or 5-6 yuan. In some embodiments, the 5-10 yuan is selected from 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6-9 yuan, 6-8 yuan, 6-7 yuan, 7-10 yuan, 7-9 yuan, 7-8 yuan, 8-10 yuan, 8-9 yuan, and 9-10 yuan. In some embodiments, the 3-10 yuan is selected from 3-9 yuan, 3-8 yuan, 3-7 yuan, 3-6 yuan, 3-5 yuan, 3-4 yuan, 4-10 yuan, 4-9 yuan, 4-8 yuan, 4-7 yuan, 4-6 yuan, 4-5 yuan, 5-10 yuan, 5-9 yuan, 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6-9 yuan, 6-8 yuan, 6-7 yuan, 7-10 yuan, 7-9 yuan, 7-8 yuan, 8-10 yuan, 8-9 yuan, 9-10 yuan. In some embodiments, the 3-15 yuan is selected from 3-12 yuan or 3-10 yuan. In some embodiments, the 3-12 yuan is selected from 3-10 yuan. In some embodiments, the 5-12 yuan is selected from 5-10 yuan.

[0247] In some embodiments, optionally, the compound described herein, its stereoisomer or pharmaceutically acceptable salt thereof (such as a compound of Formula I, Formula IA, Formula IA-1, Formula IA-2, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII or Formula VIII) is selected from or not selected from (preferably, not selected from) the following compounds:

[0248] In some embodiments, optionally, the compound described herein, its stereoisomer or pharmaceutically acceptable salt thereof (such as a compound of Formula I, Formula II, Formula IIA, Formula IIA-1, Formula IIA-2, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII or Formula VIII) is selected from or not selected from (preferably not selected from) the following compounds:

[0249] In some embodiments, optionally, the compound described herein, its stereoisomer or pharmaceutically acceptable salt thereof (such as a compound of Formula I, Formula II, Formula III, Formula IIIA, Formula IIIA-1, Formula IIIA-2, Formula IV, Formula V, Formula VI, Formula VII or Formula VIII) is selected from or not selected from (preferably, not selected from) the following compounds:

[0250] The present disclosure relates to the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0251] The present disclosure also relates to the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0252] The present disclosure also relates to the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0253] Alternatively, the following compound, its stereoisomer or a pharmaceutically acceptable salt thereof:

[0254] On the other hand, the present disclosure relates to a pharmaceutical composition, which contains the above-mentioned compound of the present disclosure, its stereoisomer or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition of the present disclosure further includes a pharmaceutically acceptable excipient.

[0255] In another aspect, the present disclosure relates to the use of the above-mentioned compound or its pharmaceutically acceptable salt, its stereoisomer or its pharmaceutical composition in the preparation of a medicament for preventing or treating a disease.

[0256] In another aspect, the present disclosure relates to a method for treating or preventing a disease in a mammal, comprising administering a therapeutically effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt, stereoisomer thereof, or pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0257] In another aspect, the present disclosure relates to use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a pharmaceutical composition thereof in preventing or treating a disease.

[0258] In another aspect, the present disclosure relates to the above-mentioned compound or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a pharmaceutical composition thereof for preventing or treating a disease.

[0259] In some embodiments, the disease is selected from PRMT5-related diseases. In some embodiments, the disease is selected from cancer.

[0260] In some specific embodiments, the above-mentioned PRMT5-related diseases are selected from disorders that can be treated by degrading or inhibiting PRMT5 protein; in some specific embodiments, the above-mentioned PRMT5-related diseases are selected from cancer; in some more specific schemes, the above-mentioned PRMT5-related diseases are selected from colon cancer.

[0261] In some aspects, the present disclosure comprises the above-defined variables and embodiments thereof, and any combination thereof.

[0262] Technical Effects

[0263] The disclosed compounds exhibit excellent in vitro protein binding activity, including binding to hPRMT5 and hMEP50 (with MTA). They exhibit MTA-synergistic PRMT5 inhibition, exhibit proliferation inhibition against HCT116 MTAP- / - cells, and exhibit selective inhibition of HCT116 MTAP- / - cells compared to HCT116 WT cells. They exhibit stable in vitro metabolism and good in vivo pharmacokinetic properties and efficacy.

[0264] definition

[0265] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

[0266] In some embodiments, the "one or more" is selected from one, two, three, four, five, or six. In some embodiments, the "one or more" is selected from one, two, or three. In some embodiments, the "one or more" is selected from one, or two.

[0267] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0268] The term "optionally" or "optionally" means that the event or circumstance described subsequently may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0269] Non-limiting examples of “substituents” as described herein include —OH, —SH, halogen, —NH 2 , nitro, nitroso, —CN, an azide group, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, a carboxaldehyde group, an imine group, an alkyl group, a halo-alkyl group, a cycloalkyl group, a halo-cycloalkyl group, an alkenyl group, a halo-alkenyl group, a cycloalkenyl group, a halo-cycloalkenyl group, an alkynyl group, a halo-alkynyl group, a cycloalkynyl group, a halo-cycloalkynyl group, a heteroalkyl group, a halo- heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group and ester group, etc., The group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, aryl, arylalkyl, or aryloxy.

[0270] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0271] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. For example, if a group contains two R's, each R has an independent option.

[0272] When a bond crosses two atoms in a ring (including a monocyclic, fused, or spirocyclic ring), the bond may be bonded to any atom in the ring (including a monocyclic, fused, or spirocyclic ring).

[0273] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0274] The term "hydroxy" refers to an -OH group.

[0275] The term "amino" refers to a -NH2 group.

[0276] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6 The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.

[0277] The term "heteroalkyl" is a straight or branched chain alkyl group consisting of a certain number of carbon atoms and at least one heteroatom, preferably having 1 to 14 carbons, more preferably 1 to 10 carbons, even more preferably 1 to 6 carbons, and most preferably 1 to 3 carbons in the chain, wherein the heteroatoms are preferably selected from S, O and N heteroatoms, and the number is preferably 1, 2 or 3. The nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heteroatom or heteroatom group can be located at any internal position of the heteroalkyl group, including the position where the hydrocarbon group is attached to the rest of the molecule. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkylamines, amides, sulfides, etc., including alkoxy, alkylthio, alkylamino; unless otherwise specified, C 1-6 Heteroalkyl groups include C1, C2, C3, C4, C5 and C6 heteroalkyl groups, such as C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino.

[0278] The term "alkoxy" refers to an -O-alkyl group.

[0279] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0280] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1,3-butadiynyl (-C≡C≡CH), and the like.

[0281] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bicyclic bridged ring or spirocycle. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 20-membered ring or a 3 to 10-membered ring (e.g., a 4 to 8-membered ring). Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc.

[0282] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically 3 to 20 rings, 3 to 12 rings, or 3 to 10 rings (e.g., 5 to 8 rings). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, etc.

[0283] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 20-membered ring, a 3 to 15-membered ring, a 3 to 7-membered ring, a 3 to 6-membered ring or a 3 to 5-membered ring containing 1 to 3 heteroatoms (preferably 1, 2 or 3 heteroatoms) independently selected from boron, sulfur, oxygen and / or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and cyclonitroethane; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, azetidinyl, oxetanyl, and thietanyl; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl; examples of 7-membered heterocycloalkyl groups include, but are not limited to, azaspiroheptane, azepanyl, oxetanyl, and thiepanyl. Preferably, the heterocycloalkyl group is a monocyclic group having 5 or 6 ring atoms.

[0284] The term "heterocycloalkenyl" includes cycloalkenyl groups in which up to 3 carbon atoms, or up to 2 carbon atoms, or 1 carbon atom are independently replaced by boron, oxygen, S(O) or nitrogen, provided that at least one cycloalkenyl carbon-carbon double bond is retained. Cyclic groups may exist as monocyclic, bridged or spirocyclic rings and may be 3 to 20-membered rings or 3 to 13-membered rings (e.g., 5 to 13-membered rings, 5 to 8-membered rings).

[0285] Term " heterocyclic radical " refers to the non-aromatic ring that is fully saturated or partially undersaturated (but not fully undersaturated heteroaromatic) and can exist with monocycle, bridged ring or spirocycle.Unless otherwise indicated, this heterocycle is generally 3 to 20 yuan (or 3 to 17 yuan or 3 to 13 yuan or 3 to 7 yuan) ring containing 1 to 3 heteroatoms (preferably 1, 2 or 3 heteroatoms) independently selected from boron, sulphur, oxygen and / or nitrogen.The limiting examples of heterocyclic radical include but not limited to oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc.Heterocyclic radical can be for example heterocycle alkenyl, heterocycloalkyl or benzoheterocycle alkenyl (not fully saturated heteroaromatic).

[0286] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene.

[0287] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from nitrogen, oxygen, S, with the remaining ring atoms being C and having at least one aromatic ring. Preferred heteroaryl groups have single 4 to 8-membered rings, especially 5 to 8-membered rings, or multiple fused rings containing 6 to 14, especially 6 to 20, or 6 to 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

[0288] The term "treating" means administering a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0289] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0290] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0291] The term "prevention" means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0292] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0293] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0294] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0295] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0296] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0297] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0298] Unless otherwise specifically stated, singular terms encompass plural terms and plural terms encompass the singular. Unless otherwise specifically stated, the words "a" or "an" mean "at least one" or "at least one." Unless otherwise specified, the use of "or" means "and / or."

[0299] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0300] Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0301] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicates the relative configuration of stereocenters; Indicates that the configuration is not confirmed, which can be or Or Z configuration or E configuration.

[0302] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary groups are cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then the pure enantiomers are recovered. In addition, separation of enantiomers and diastereoisomers is typically accomplished using chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., to form carbamates from amines).

[0303] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0304] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0305] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0306] In addition, the use of heavier isotopes such as deuterium (i.e. 2H)) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

[0307] The compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. Certain compounds of the present application may exist as atropisomers. This occurs when rotation around a single bond in a molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule. The compounds of the present disclosure may include all atropisomers, either as pure individual atropisomers, or enriched in one of the atropisomers, or as a non-specific mixture of each. If the rotational potential around the single bond is high enough and the interconversion between conformations is slow enough, separation of the isomers may be permitted. The bond | indicates that the stereo orientation of that side is outward. For example Atropisomer 1 exists and atropisomer 2 This disclosure shows and etc. all represent the same configuration, specifically the same as the configuration of the above-mentioned isomer 1 compound, Adjacent structural parts Connect into the following structure or Adjacent structural parts Connect into the following structure Other structural parts are similar. and etc. all represent the same configuration, i.e. the same configuration as the above-mentioned isomer 2 compound. Adjacent structural parts Connect into the following structure The connection of other structural parts to adjacent structural parts is similar to the above. The compounds containing asymmetric carbon atoms disclosed herein can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0308] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0309] Typical routes of administration of the disclosed compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0310] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0311] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0312] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0313] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0314] In all methods of administration described herein, the compounds of formula I are administered at a dosage of 0.01 to 200 mg / kg body weight per day in single or divided doses.

[0315] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0316] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0317] An important consideration in synthetic route planning in this field is the selection of appropriate protecting groups for reactive functional groups (such as the amino groups in the present disclosure). For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0318] The compounds disclosed herein can be prepared by the following routes in combination with techniques known in the art:

[0319] Wherein, halogen represents halogen; proc represents a protecting group, such as Boc or Piv;

[0320] When R 31 and R 32 Replace with R 3b , R 3 Replace with R 3a or R 3c , that is, corresponding to the compound of formula IIA or IIIA, respectively, the corresponding compound can be prepared by a similar preparation route as above;

[0321] R s 、R t 、R 2a 、R 2b 、R 3 、R 31 、R 32 、R 3a 、R 3c 、R 3b and R 4 Definitions are as described in this disclosure.

[0322] This disclosure uses the following abbreviations:

[0323] NIS represents N-iodosuccinimide; NBS represents N-bromosuccinimide; EA represents ethyl acetate; LDA represents lithium diisopropylamide; BuOK represents potassium tert-butoxide; THF represents tetrahydrofuran; Pd(dtbpf)Cl2 represents 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride; DMF represents N,N-dimethylformamide; Boc represents tert-butyloxycarbonyl; Bu represents tert-butyl; Piv represents pivaloyl; HATU represents 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; DIPEA represents diisopropylethylamine; HFIP represents 1,1,1,3,3,3-hexafluoro-2-propanol; Meotf represents methyl trifluoromethanesulfonate; TMSCL represents trimethylchlorosilane; DCE represents dichloroethane; DMSO represents dimethyl sulfoxide; cataCXium A Pd G3 represents [(di(1-adamantyl)butylphosphino)-2-(2iuamino-1,1(2-biphenyl)]palladium(II) methanesulfonate; P(t-Bu)2(n-Bu)Pd G3 represents [2'-(amino-κN)[1,1'-biphenyl]-2-yl-κC][butylbis(1,1-dimethylethyl)phosphine](mesylate-κO)palladium; Pd(dppf)Cl2*CH2Cl2 represents 1,1-bis(diphenylphosphino)ferrocene dichloropalladium dichloromethane complex; Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. DETAILED DESCRIPTION

[0324] For the sake of clarity, the present disclosure is further illustrated with examples, but the examples do not limit the scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0325] Example 1: Preparation of Compound 1

[0326] (1) Preparation method of compound A1:

[0327] 5-Bromophthalide (80.0 g) and potassium tert-butoxide (4.2 g) were dissolved in N,N-dimethylformamide dimethyl acetal (2880.0 g). The reaction mixture was stirred at 110°C under a nitrogen atmosphere for approximately 20 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The resulting product was first slurried with petroleum ether and then with ethyl acetate at 80°C to obtain compound A1 (60.0 g). ESI-MS: m / z = 267.9 [M+H] + .

[0328] (2) Preparation method of compound B1:

[0329] Compound A1 (60.0 g) and hydrazine hydrate (18.6 mL) were dissolved in 1.0 L of ethanol. The reaction mixture was stirred at 70°C under a nitrogen atmosphere for approximately 12 h. After the reaction was completed, compound B1 (55.0 g) was filtered and used directly in the next reaction. ESI-MS: m / z = 282.0 [M+H] + .

[0330] (3) Preparation method of compound C1:

[0331] Compound B1 (55.0 g) was dissolved in 680 mL of tetrahydrofuran. Under a nitrogen atmosphere, isobutyl chloroformate (32.0 g) was slowly added at 0°C. After the addition, the reaction flask was stirred at room temperature for 6 h. After the reaction, the reaction flask was placed in an ice-water bath and 920 mL of 0.5 M hydrogen chloride solution was added to quench the reaction. The mixture was filtered and the filter cake was dried under reduced pressure to obtain compound C1 (45.0 g). This was used directly in the next reaction. ESI-MS: m / z = 272.9 [M+H] + .

[0332] (4) Preparation method of compound D1:

[0333] Compound C1 (45.0 g) and potassium phthalimide (31.3 g) were dissolved in 890 mL of DMF and stirred at room temperature for approximately 1.5 h. After completion of the reaction, 550 mL of 0.5 M hydrogen chloride solution was added to the reaction system to quench the reaction, followed by filtration. The resulting product was slurried in ethanol at 70°C to obtain compound D1 (48.0 g), which was used directly in the next reaction. ESI-MS: m / z = 383.9 [M+H] + .

[0334] (5) Preparation method of compound E1:

[0335] Compound D1 (48.0 g) and hydrazine hydrate (25.6 mL) were dissolved in 100 mL of ethanol and stirred at 80°C for 2 h. After the reaction, the reaction system was concentrated to dryness, and the resulting product was dissolved in ethyl acetate and slurried to obtain compound E1 (30.0 g), which was used directly in the next reaction. ESI-MS: m / z = 253.9 [M+H] + .

[0336] (6) Preparation method of compound F1:

[0337] Compound E1 (30.0 g), di-tert-butyl dicarbonate (51.5 g), and triethylamine (35.8 g) were dissolved in 630 mL of dichloromethane. The reaction was stirred at room temperature for 2 h. After completion of the reaction, the mixture was filtered and the resulting filter cake was slurried in dichloromethane to obtain compound F1 (55.0 g), which was used directly in the next reaction. ESI-MS: m / z = 354.0 [M+H] + .

[0338] (7) Preparation method of compound G1:

[0339] Compound F1 (25.0 g), pinacol diboronate (20.2 g), Pd(dtbpf)Cl2 (3.9 g), and potassium acetate (15.6 g) were dissolved in 1.0 L of 1,4-dioxane. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for approximately 2 h. After the reaction, the mixture was cooled to room temperature and filtered. The resulting filter cake was slurried in a mixture of petroleum ether and ethyl acetate to obtain compound G1 (20.0 g). ESI-MS: m / z = 402.27 [M+H] + .

[0340] (8) Preparation method of compound H1:

[0341] Dissolve 4-chloro-2,5-difluorobenzonitrile (93.5 g) and cyclopropanol (31.3 g) in 935 mL of tetrahydrofuran and cool to -25 to -15°C. Add BuOK-THF (594 mL, 594 mmol) dropwise over 30 minutes and allow to react at the same temperature for 2 hours until the reaction is complete. After completion, quench the reaction by adding purified water (935 mL) at 0 to 10°C. Extract with EA, wash with saturated brine, dry, and concentrate to obtain compound H1 (113 g). ESI-MS: m / z = 212 [M+H] + .

[0342] (9) Preparation method of compound I1:

[0343] Compound H1 (110 g) was dissolved in tetrahydrofuran (1650 mL). After N2 substitution, the temperature was lowered to -80 to -70°C. A 2N solution of LDA in tetrahydrofuran (390 mL, 780 mmol) was added dropwise over 20 minutes. A solution of I2 (264 g, 1040 mmol) in tetrahydrofuran (1650 mL) was added dropwise over 30 minutes. The temperature was raised to 20 to 30°C and the reaction was allowed to proceed for at least 1 hour until the reaction was complete. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with EA. The mixture was washed with saturated brine, dried, and purified by column chromatography to obtain compound I1 (105 g).

[0344] (10) Preparation method of compound J1:

[0345] Compound I1 (134.75 g), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (95.74 g), potassium fluoride (58.1 g) and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (14.16 g) were dissolved in dioxane-water (1484 / 244 mL). After N2 replacement, the temperature was raised to 80°C and reacted for more than 5 h. After the reaction was completed, the temperature was cooled to room temperature and concentrated to dryness. 1600 mL of water and 2 L of EA were added and stirred. The organic phase was separated, washed with saturated brine, dried and concentrated to dryness. The concentrate was dissolved in 780 mL of ethanol, 1 L of water was added dropwise, and the mixture was slurried to obtain compound J1 (89 g). ESI-MS: m / z=292 [M+H] + .

[0346] (11) Preparation method of compound K1:

[0347] Compound J1 (40 g) and NIS (61.8 g) were dissolved in glacial acetic acid (800 mL) and heated to 80°C for more than 2 h until the reaction was complete. After the reaction was completed, the mixture was cooled to room temperature, concentrated to dryness, and extracted with water and EA. The organic phase was separated and washed with saturated sodium bicarbonate solution and saturated brine, dried, and concentrated. Compound K1 (43 g) was purified by column chromatography. ESI-MS: m / z = 418 [M+H] + .

[0348] (12) Preparation method of compound L1:

[0349] Compound K1 (17.3 g), compound G1 (20 g), sodium carbonate (17.6 g), and tetrakistriphenylphosphine palladium (7.19 g) were dissolved in dioxane-water (5:1) (1730 mL). After N2 displacement, the temperature was raised to 85°C and the reaction was allowed to proceed for 1 h. After the reaction, the temperature was cooled to room temperature, concentrated to dryness, and extracted with water and EA. The organic phase was separated, washed with water and saturated brine, dried, and concentrated to obtain compound L1 (25.5 g). ESI-MS: m / z = 565 [M+H] + .

[0350] (13) Preparation method of compound M1:

[0351] Compound L1 (282 mg), tributyl vinyl tin (475.5 mg), tetrakistriphenylphosphine palladium (100 mg), and cesium fluoride (380 mg) were stirred in dioxane (15 mL) and reacted at 100°C under nitrogen. After completion of the reaction, the reaction solution was filtered and concentrated under reduced pressure to obtain compound M1 (500 mg), which was directly used for the next step. LC-MS: m / z 557.18 (M+H) + .

[0352] (14) Preparation method of compound N1:

[0353] Compound M1 (668 mg), 3-iodo-1-methylpyrazole (300 mg), bis(triphenylphosphine)palladium dichloride (168 mg), and triethylamine (480 mg) were dissolved in N,N-dimethylformamide (20 mL). After nitrogen substitution, the mixture was reacted at 120°C for 6 h. After completion of the reaction, the reaction solution was filtered, and the filtrate was added with water and ethyl acetate. The organic phase was separated and washed sequentially with water and saturated brine. The organic phase was dried, filtered, and the filtrate was concentrated to obtain 810 mg of compound N1. ESI-MS: m / z = 537.33 [M-Boc+2H] + .

[0354] (15) Preparation method of compound 1:

[0355] Compound N1 (810 mg) was dissolved in a 4 M solution of hydrogen chloride in ethyl acetate (10 mL). The reaction was allowed to proceed at room temperature for approximately 2 h. After completion of the reaction, the filtrate was concentrated and purified by preparative liquid chromatography (HPLC conditions: column: YMC TA C18, 30*250 mm, 10 μm; A: 30 mM ammonium acetate (containing 0.1% acetic acid), B: acetonitrile; gradient: 20% B to 80% B (0-60 min), λ: 254 nm, V: 30 mL / min) to obtain compound 1.

[0356] Compound 1 was subjected to chiral resolution (resolution conditions: column: CHIRALPAK IG, 20*250mm5μm; A: n-hexane, B: ethanol; gradient: 85% B isocratic, wavelength 254nm, v=10ml / min, 1-2a: rt 31.0min, 1-2b: rt 41.7min) to obtain Example 1-2a (77mg) and Example 1-2b (61mg).

[0357] Example 1-2a ESI-MS: m / z=537.33 [M+H] + .

[0358] 1 H NMR(500MHz,DMSO-d6)δ12.43(s,1H),8.27(s,1H),8.17-8.13(m,1H),8.0 4(d,J=5.9Hz,1H),7.77-7.68(m,3H),7.59(d,J=16.5Hz,1H),7.26(d,J=16 .5Hz,1H),6.68(d,J=2.3Hz,1H),4.25(tt,J=6.1,2.9Hz,1H),3.86(s,3H) ,3.78(s,3H),3.75(d,J=3.9Hz,2H),0.98-0.90(m,2H),0.82-0.78(m,2H).

[0359] Example 1-2b ESI-MS: m / z=537.31 [M+H] + .

[0360] 1 H NMR (500MHz, DMSO-d6) δ12.43(s,1H),8.27(s,1H),8.16(d,J=8.8Hz,1H),8.07-8.04(m,1H),7.78-7.68(m,3H),7.60(d,J=16.5Hz,1H),7.30-7.17 (m,1H),6.69(d,J=2.3Hz,1H),4.30-4.23(m,1H),3.87(s,3H),3.79(s,3 H), 3.74 (d, J = 3.9 Hz, 2H), 0.94 (dd, J = 6.1, 2.1 Hz, 2H), 0.86-0.73 (m, 2H).

[0361] Example 2: Preparation of Compounds 2-1, 2-2, 2-2a, and 2-2b:

[0362] (1) Preparation method of compound A2:

[0363] Methyl 2-methyl-3-amino-5-bromobenzoate (80 g) and triethylamine (50 mL) were added to tetrahydrofuran (800 mL). After cooling to 0°C, pivaloyl chloride (44 mL) was added dropwise. The mixture was stirred at room temperature for 5 h. After the reaction was complete, water was added to the reaction system to quench the reaction, and ethyl acetate was added for extraction. The resulting organic phase was then washed with water and saturated brine. The resulting organic phase was concentrated to dryness to obtain compound A2 (117 g). ESI-MS: m / z = 328.17 [M+H] + .

[0364] (2) Preparation method of compound B2:

[0365] Compound A2 (117 g) was dissolved in tetrahydrofuran (400 mL). A solution of sodium hydroxide (57 g) in water (100 mL) was added dropwise at room temperature and stirred overnight at room temperature. After the reaction was complete, the mixture was concentrated and adjusted to pH 5-6 by adding 1N hydrochloric acid. The resulting filter cake was filtered to obtain compound B2 (120 g). ESI-MS: m / z = 314.17 [M+H] + .

[0366] (3) Preparation method of compound C2:

[0367] Compound B2 (120 g), dimethylhydroxylamine hydrochloride (56 g), HATU (175 g), and DIPEA (99 g) were added to N,N-dimethylformamide (1.5 L). After stirring at room temperature for 2 h, water was added to the reaction system to quench the reaction, and ethyl acetate was added for extraction. The resulting aqueous phase was extracted with ethyl acetate, and the resulting organic phases were combined and washed with water and saturated brine. The resulting organic phase was concentrated to dryness to obtain compound C2 (90 g). ESI-MS: m / z = 357.23 [M+H] + .

[0368] (4) Preparation method of compound D2:

[0369] Methylmagnesium bromide (3M, 253 mL) was dissolved in tetrahydrofuran solution (0.8 L). Compound C2 (90 g) in tetrahydrofuran solution (0.2 L) was slowly added to the reaction system under a nitrogen atmosphere at 0°C. After the addition, the mixture was stirred at room temperature for 3 h, the reaction was stopped, water was added to quench the reaction, and ethyl acetate was added for extraction. The resulting organic phase was washed with water and saturated brine. The resulting organic phase was concentrated to dryness to obtain compound D2 (75 g). ESI-MS: m / z = 312.16 [M+H] + .

[0370] (5) Preparation method of compound E2:

[0371] Compound D2 (75 g), potassium carbonate (66 g), and potassium permanganate (265 g) were added to water (0.8 L) and stirred at 50°C for 5 h before stopping the reaction. A saturated sodium thiosulfate solution was added to quench the reaction and the mixture was filtered. The resulting organic phase was adjusted to pH 2 with 2N HCl, and a mixture of ethyl acetate and tetrahydrofuran (v:v = 10:1, 1.2 L) was added. The combined organic phases were washed with saturated brine. The resulting organic phase was concentrated to dryness to yield Compound E2 (47 g).

[0372] (6) Preparation method of compound F2:

[0373] Compound E2 (47 g) and hydrazine hydrate (7.7 g) were added to ethanol (470 mL), stirred at 75° C. for 5 h, and then the reaction was stopped. The reaction system was cooled and filtered to obtain a filter cake, namely compound F2 (10 g).

[0374] (7) Preparation method of compound G2:

[0375] Compound F2 (10 g) and a methanol solution of hydrogen chloride (4 M, 136 mL) were added to methanol (136 mL). The mixture was stirred at 70°C for 36 h. The reaction system was concentrated to dryness and water (35 mL) was added. The pH was adjusted to 8 with 1N NaOH solution. The mixture was stirred for 0.5 h and filtered. The filter cake was washed with water and ethanol to obtain compound G2 (11 g).

[0376] (8) Preparation method of compound H2:

[0377] Compound G2 (4 g) was added to ethanol (60 mL), and sodium borohydride (740 mg) was added in portions at 0°C, followed by calcium chloride (1.3 g). After the addition, the reaction system was returned to room temperature and stirred for 1 h before stopping the reaction. Saturated ammonium chloride solution was added to quench the reaction. The ethanol in the reaction system was then concentrated to dryness, diluted with water, and filtered. The filter cake was washed with water, slurried with methanol, and filtered. The resulting filter cake was compound H2 (3 g).

[0378] (9) Preparation method of compound I2:

[0379] Compound H2 (3 g) was added to thionyl chloride (33 mL), and the reaction was stopped after stirring at 70° C. for 2 h. The reaction system was concentrated to dryness, and petroleum ether was added to slurry to obtain compound I2 (2.8 g).

[0380] (10) Preparation method of compound J2:

[0381] Bis(tert-butyloxycarbonyl)amine (1.7 g) was dissolved in tetrahydrofuran (46 mL) and lithium bis(trimethylsilyl)amide (1 M, 8.5 mL) was slowly added at -30°C. After stirring at the same temperature for 10 min, the mixture was heated to 0°C and stirred for 30 min. A tetrahydrofuran solution of I2 (2.8 g) (50 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature. After 5 h, the reaction was complete and quenched with a saturated solution of ammonium chloride. The mixture was extracted with ethyl acetate and the resulting organic phase was washed sequentially with pure water and saturated brine. The resulting organic phase was concentrated to dryness to obtain compound J2 (3.0 g). ESI-MS: m / z = 575.12 [M+Na] + .

[0382] (11) Preparation method of compound K2:

[0383] Compound J2 (2.9 g), pinacol diboron (2.0 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (370 mg), and potassium acetate (1.6 g) were stirred in dioxane (170 mL) and reacted at 100°C under nitrogen for 5 h. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The concentrate was slurried with a mixture of petroleum ether and ethyl acetate to obtain compound K2 (4.1 g). ESI-MS: m / z = 623.31 [M+Na] + .

[0384] (12) Preparation method of compound L2:

[0385] Compound K2 (3.3 g), compound K1 (2.1 g), tetrakis(triphenylphosphine)palladium (867 mg), and sodium carbonate (2.1 g) were stirred in a mixture of dioxane (60 mL) and water (12 mL) and reacted at 85°C under nitrogen for 6 h. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain compound L2 (3.1 g). ESI-MS: m / z = 608.25 [M-Boc- t Bu+2H] + .

[0386] (13) Preparation method of compound M2:

[0387] Compound L2 (3.1 g) was dissolved in hydrogen chloride / methanol (4 M, 16 mL) and refluxed at 80°C with stirring for 48 h. After the reaction was complete, the mixture was concentrated to dryness and the resulting product was slurried with a mixture of dichloromethane and methanol to obtain compound M2 (1.8 g).

[0388] (14) Preparation method of compound N2:

[0389] 1-Methyl-3-ethynyl-1H-pyrazole (2493 mg) was dissolved in tetrahydrofuran (50 mL) and cooled to -78°C under a nitrogen atmosphere. A solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1 mol / L, 6.2 mL) was added dropwise, and the mixture was stirred at the same temperature for 0.5 h. Tributyltin chloride (9349 mg) was added dropwise, and the mixture was reacted at the same temperature for 4 h. After completion of the reaction, the mixture was quenched with saturated aqueous ammonium chloride solution, extracted with n-hexane, and the organic phase was separated and washed with brine. After drying, the filtrate was filtered and rinsed, and the resulting filtrate was concentrated to obtain 9320 mg of compound N2.

[0390] (15) Preparation method of compounds 2-1 and 2-2:

[0391] Compound M2 (768 mg), compound N2 (1192 mg), tetrakistriphenylphosphine palladium (556 mg), and sodium carbonate (1020 mg) were dissolved in a 1,4-dioxane-water (5:1) mixed solvent (22 mL). The reaction mixture was reacted in a CEM microwave reactor (130°C, 100 W) under a nitrogen atmosphere for 1 h. After the reaction was complete, the filtrate was filtered and concentrated. The concentrate was dissolved in dichloromethane and then washed with water and saturated brine. The separated organic phase was dried, concentrated, and purified by preparative liquid phase (YMC AQ C18, size 50*250mm, 10*25 mobile phase: A: 30mM ammonium acetate (containing 0.1% acetic acid), B: acetonitrile; gradient: 30%-80% B-50min, wavelength 254nm, v=60ml / min, 2-1: rt 13.4min; 2-2: rt 14.7min) to obtain compounds 2-1 and 2-2, respectively. 2-1 and 2-2: ESI-MS: m / z=552.27 [M+H] + .

[0392] (16) Preparation method of compounds 2-2a and 2-2b:

[0393] Compound 2-2 was subjected to chiral separation (YMC SA, size 30*250 mm, 10*25 mobile phase: A: n-hexane, B: 0.25% diethylamine ethanol; gradient: 50%-80% B over 30 min, wavelength 254 nm, v = 30 ml / min, 2-2a: rt 31.0 min; 2-2b: rt 41.7 min) to obtain compounds 2-2a and 2-2b. 2-2a and 2-2b: m / z = 552.29 [M+H] + .

[0394] Example 3: Preparation of Compound 3

[0395] (1) Preparation method of compound A3:

[0396] Referring to step (14) of Example 2, 1-methyl-3-ethynyl-1H-pyrazole was replaced with 2-alkynepyrazine. After the reaction was completed, n-hexane was replaced with ethyl acetate for extraction to finally obtain 3.40 g of compound A3.

[0397] (2) Preparation method of compound B3:

[0398] Compound L1 (226 mg), compound A3 (1350 mg), tetrakistriphenylphosphine palladium (144 mg), and sodium carbonate (255 mg) were dissolved in a 1,4-dioxane-water (5:1) mixed solvent (17 mL). The reaction solution was reacted in a CEM microwave reactor (130 rpm, 100 W) under a nitrogen atmosphere for 1 h. After completion of the reaction, the mixture was filtered, concentrated, and ethyl acetate was added. The mixture was washed with water and saturated brine, dried, and concentrated to obtain 320 mg of compound B3. ESI-MS: m / z = 635.31 [M+H] + .

[0399] (3) Preparation method of compound 3:

[0400] Compound B3 (320 mg) and trifluoroacetic acid (3.0 mL) were dissolved in dichloromethane (9.0 mL). The reaction was allowed to proceed at 10-30°C for 4.0 h. After the reaction was complete, the filtrate was concentrated and purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.05% trifluoroacetic acid aqueous solution (20%-70% / 0-60 min gradient elution); acetonitrile-0.1% ammonia aqueous solution (20%-70% / 0-60 min gradient elution) to obtain compound 3. ESI-MS: m / z = 535.31 [M+H] + .

[0401] 1 H NMR(500MHz,DMSO-d6)δ12.43(s,1H),8.89(s,1H),8.70(t,J=2.0Hz,1H),8.60 (d,J=2.6Hz,1H),8.28(s,1H),8.16(dd,J=7.5,3.3Hz,2H),7.94(d,J=16.2Hz,1 H),7.81(d,J=16.2Hz,1H),7.73(d,J=6.2Hz,2H),4.25(tt,J=6.1,3.0Hz,1H),3 .80 (s, 3H), 3.74 (d, J = 3.5Hz, 2H), 0.96 (p, J = 7.1Hz, 2H), 0.85 (d, J = 7.1Hz, 2H).

[0402] Example 4: Preparation of Compound 4

[0403] (1) Preparation of Compound A4:

[0404] Compound M2 (3.10 g), tributyltin propynyl (5.43 g), tetrakistriphenylphosphine palladium (954 mg), and sodium carbonate (2.32 g) were dissolved in a 1,4-dioxane-water (5:1) mixed solvent (357 mL). The reaction mixture was reacted at 85-90°C under a nitrogen atmosphere for 7 h. After the reaction was complete, the mixture was filtered and concentrated. The concentrate was added with ethyl acetate to dissolve the clear solution, then washed with water and saturated brine. The organic phase was separated, dried, and concentrated to obtain compound A4. ESI-MS: m / z = 484.28 [M+H] + .

[0405] (2) Preparation method of compound B4:

[0406] Compound A4 (966 mg), di-tert-butyl dicarbonate (480 mg), and triethylamine (210 mg) were dissolved in tetrahydrofuran (357 mL) and reacted at 10-30°C for 2 h. After the reaction was complete, the mixture was concentrated to dryness and slurried with petroleum ether to obtain compound B4. ESI-MS: m / z = 584.29 [M+H] + .

[0407] (3) Preparation method of compound C4:

[0408] Compound B4 (150 mg, 0.25 mmol) and HFIP (5.0 mL) were added dropwise to Meotf (90 μL, 0.80 mmol) in an ice bath at 0°C. After 3 h, compound B4 was detected to be completely reacted. The solvent was evaporated and column chromatography was performed to obtain compound C4. ESI-MS: m / z = 598.35 [M+H] + .

[0409] (4) Preparation method of compound 4

[0410] Compound C4 and 10 M hydrochloric acid in ethanol (3.0 mL) were added sequentially to a 10 mL reaction vial. The reaction was stirred at room temperature for 10 min, and the reaction was confirmed to be complete. The reaction was quenched with saturated sodium bicarbonate solution, and the ethanol / water solvent was evaporated to dryness. The product was then purified by preparative liquid chromatography (HPLC conditions: Waters ACQUITY UPLC BEH C18 column (1.7 μm, 2.1 x 50 mm), mobile phase: A: 5 mM ammonium acetate (0.1% acetic acid)-acetonitrile (95:5), B: acetonitrile; gradient: 5% B to 90% B (0-4.5 min), wavelength 254 nm, v = 60 mL / min; column temperature: 40°C, rt - 1.765 min) to yield 19 mg of compound 4. ESI-MS: m / z = 498.35 [M+H] + .

[0411] 1H NMR (500MHz, DMSO-d6) δ12.22(s,1H),8.77(d,J=5.2Hz,1H),8.26(s,1H),7.80(d,J=5.7Hz,1H),6.75(d,J=1.5Hz,1H),6.43(d,J=1.5H z,1H),4.17(dt,J=6.0,3.1Hz,1H),3.75(s,3H),3.69(s,2H),2.64(d,J=5.0Hz,3H),2.18(s,3H),0.93-0.78(m,2H),0.78-0.68(m,2H).

[0412] Example 5: Preparation of Compound 5

[0413] (1) Preparation method of compound A5:

[0414] Compound B4 (150 mg, 0.25 mmol) and HFIP (5.0 mL) were added dropwise to Meotf (90 μL, 0.80 mmol) in an ice bath at 0°C. After 3 h, compound B4 was detected to be completely reacted. The solvent was evaporated and column chromatography was performed to obtain compound A5. ESI-MS: m / z = 612.36 [M+H] + .

[0415] (2) Preparation method of compound 5

[0416] With reference to step (4) of Example 4, compound A5 was substituted for compound C4, and preparative liquid phase purification (liquid phase conditions: column Waters ACQUITY UPLC BEH C18 (1.7.93-0.78 (m, mobile phase: A: 5 mM ammonium acetate (0.1% acetic acid)-acetonitrile (95:5), B: acetonitrile; gradient: 5% B-90% B (0-4.5 min), wavelength 254 nm, v = 60 ml / min; column temperature: 40 rt-1.677 min) was performed to obtain compound 5. ESI-MS: m / z = 512.36 [M + H] + .

[0417] 1 H NMR(500MHz,DMSO-d6)δ11.96(s,1H),8.28(s,1H),7.80(d,J=5.6Hz,1H),7.17(s,1H),6.81(s,1H),4.43-3.99(m ,1H),3.75(s,3H),3.73(s,2H),2.67(s,3H),2.17(s,3H),1.88(s,3H),0.90(d,J=5.6Hz,2H),0.85-0.67(m,2H).

[0418] Example 6: Preparation of Compound 6

[0419] (1) Preparation method of compound A6:

[0420] Compound B4 (58.3 mg, 0.1 mmol), acetone (15 uL, 0.2 mmol), TMSCl (25 uL, 0.2 mmol), BH3·THF (200 uL, 0.2 mmol), and DMF (1.0 mL) were added to the reaction flask and allowed to react at room temperature for 2 h. The reaction was confirmed to be complete. The product was evaporated to dryness and concentrated to afford compound A6. ESI-MS: m / z = 626.34 [M+H] + .

[0421] (2) Preparation method of compound 6:

[0422] Referring to step (4) of Example 4, Compound A6 was substituted for Compound C4, and the product was purified by preparative liquid phase (liquid phase conditions: column Waters ACQUITY UPLC BEH C18 (1.7 μm, 2.1*50 mm), mobile phase: A: 5 mM ammonium acetate (0.1% acetic acid)-acetonitrile (95:5), B: acetonitrile; gradient: 5% B-90% B (0-4.5 min), wavelength 254 nm, v = 60 ml / min; column temperature: 40°C). 10 mg of Compound 6 was obtained. ESI-MS: m / z = 526.34 [M+H] + .

[0423] 1 H NMR (500MHz, DMSO-d6) δ12.48(s,1H),8.87(d,J=7.2Hz,1H),8.33(s,1H),8.30(s,1H),7.81(d,J=5.6Hz,1H),6.93(s,1H),6.27(s,1H),4.69-4 .05(m,3H),3.75(s,2H),3.14(q,J=6.4Hz,1H),2.19(s,3H),1.03(dd,J=11.8,6.2Hz,6H),0.92(d,J=6.2Hz,2H),0.70(dt,J=10.1,2.9Hz,2H).

[0424] Example 7: Preparation of Compound 7

[0425] (1) Preparation method of compound A7:

[0426] Compound B4 (58.3 mg, 0.1 mmol), acetaldehyde tetrahydrofuran solution (150 uL, 0.15 mmol, 5 mol / L), TMSCL (25 uL, 0.2 mmol), BH3 . THF (200 μL, 0.2 mmol) and DMF (1.0 mL) were added to the reaction system and reacted at room temperature for 2 h. The reaction was complete after detection. Concentration gave compound A7. ESI-MS: m / z = 612.31 [M+H] +

[0427] (2) Preparation method of compound 7:

[0428] Referring to step (4) of Example 4, Compound A7 was used in place of Compound C4 to obtain 12 mg of Compound 7. ESI-MS: m / z=512.31 [M+H] + .

[0429] Example 8: Preparation of Compound 8

[0430] (1) Preparation method of compound A8:

[0431] Compound B4 (150 mg, 0.25 mmol) and HFIP (5.0 mL) were added dropwise with Meotf (90 uL, 0.80 mmol) in an ice bath at 0°C. After 3 h, compound B4 was detected to be completely reacted. The solvent was evaporated and the reaction mixture was purified by column chromatography to obtain compound A8.

[0432] ESI-MS: m / z = 612.45 [M+H] + .

[0433] (2) Preparation method of compound 8

[0434] Referring to step (4) of Example 4, Compound A8 was substituted for Compound C4, and preparative liquid phase purification (liquid phase conditions: column Waters ACQUITY UPLC BEH C18 (1.7 μm, 2.1*50 mm), mobile phase: A: 5 mM ammonium acetate (0.1% acetic acid)-acetonitrile (95:5), B: acetonitrile; gradient: 5% B-90% B (0-4.5 min), wavelength 254 nm, v = 60 ml / min; column temperature: 40°C, rt - 1.292 min) was performed to obtain Compound 8. ESI-MS: m / z = 512.33 [M+H] + .

[0435] 1H NMR (500MHz, DMSO-d6) δ12.38(s,1H),9.44(s,1H),8.91(q,J=5.1Hz,1H),7.94(d,J=5.7Hz,1H),6.80(s,1H),6.46(s,1H),4.35(s, 3H), 4.26-4.11 (m, 1H), 4.08 (s, 3H), 3.67 (s, 2H), 2.68 (d, J = 5.1Hz, 3H), 2.20 (s, 3H), 0.91 (d, J = 6.5Hz, 2H), 0.76 (q, J = 11.1Hz, 2H).

[0436] Example 9: Preparation of Compound 9

[0437] (1) Preparation method of compound A9:

[0438] Compound B4 (150 mg, 0.25 mmol) and HFIP (5.0 mL) were added dropwise to Meotf (90 μL, 0.80 mmol) in an ice bath at 0°C. After 3 h, the reaction was complete. The solvent was evaporated and the compound A9 was isolated by column chromatography. ESI-MS: m / z = 598.35 [M+H] + .

[0439] (2) Preparation method of compound 9

[0440] Referring to step (4) of Example 4, Compound A9 was substituted for Compound C4, and the product was purified by preparative liquid phase (liquid phase conditions: column Waters ACQUITY UPLC BEH C18 (1.7 μm, 2.1*50 mm), mobile phase: A: 5 mM ammonium acetate (0.1% acetic acid)-acetonitrile (95:5), B: acetonitrile; gradient: 5% B-90% B (0-4.5 min), wavelength 254 nm, v = 60 ml / min; column temperature: 40°C. Retention time -1.168 min) to obtain Compound 9. ESI-MS: m / z = 498.35 [M+H] + .

[0441] 1 H NMR(500MHz,DMSO-d6)δ12.24(s,1H),9.30(s,1H),7.90(d,J=5.7Hz,1H),7.49(s,2H),6.77(s,1H),6.63(s,1H),4 .34(s,3H),4.23-4.13(m,1H),4.04(s,3H),3.68(s,2H),2.19(s,3H),0.90(d,J=6.1Hz,2H),0.78(q,J=3.4Hz,2H).

[0442] Example 10: Preparation of Compound 10

[0443] (1) Preparation method of compound A10:

[0444] Compound B4 (60 mg), iodoethane (12 uL), K2CO3 (20 mg), and DMF (1.0 mL) were added to the reaction flask in sequence and stirred at room temperature for 2 h. After completion of the reaction, the mixture was concentrated to obtain compound A10. ESI-MS: m / z = 612.26 [M+H] + .

[0445] (2) Preparation method of compound 10:

[0446] Referring to step (4) of Example 4, Compound A10 was used in place of Compound C4 to obtain 32 mg of Compound 10. ESI-MS: m / z=512.26 [M+H] + .

[0447] 1 H NMR(500MHz,DMSO-d6)δ8.05(s,1H),7.75(d,J=5.6Hz,1H),7.35(s,2H),6.69(s,1H),6.63(s,1H),4.17-4.10(m,1H),3 .90(s,2H),3.72(d,J=6.1Hz,2H),2.17(s,3H),1.89(s,3H),1.25(t,J=7.1Hz,3H),0.89(d,J=6.3Hz,2H),0.79(s,2H).

[0448] Example 11: Preparation of Compound 11

[0449] (1) Preparation method of compound A11:

[0450] Compound B4 (58 mg, 0.1 mmol), 2,2-bipyridine (16 mg, 0.1 mmol), DCE (1.0 ml), cyclopropylboronic acid (18 mg), copper acetate (19 mg, 0.1 mmol), and sodium carbonate (24 mg, 0.22 mmol) were added to a single-necked flask under nitrogen atmosphere. The mixture was heated to 80°C and allowed to react for 12 h. The reaction was then checked for completion. The solution was then concentrated to afford compound A11.

[0451] (2) Preparation method of compound 11:

[0452] Referring to step (4) of Example 4, Compound A11 was used in place of Compound C4 to obtain 10 mg of Compound 11. ESI-MS: m / z = 524.22 [M+H] + .

[0453] 1 H NMR(500MHz,DMSO-d6)δ8.03(s,1H),7.75(d,J=5.4Hz,1H),7.37(s,2H),6.72(s,1H),6.57(s,1H),4.13(s,1H) ,3.84(s,1H),3.72(s,3H),3.60(s,2H),2.17(s,3H),1.23(s,2H),1.00(s,2H),0.97-0.82(m,2H),0.79(s,2H).

[0454] Example 12: Preparation of Compound 12

[0455] (1) Preparation method of compound 12:

[0456] Compound M2 (168 mg), compound B12 (1173 mg), tetrakistriphenylphosphine palladium (122 mg), and sodium carbonate (223 mg) were dissolved in a 1,4-dioxane-water (5:1) mixed solvent (17 mL). The reaction solution was reacted in a CEM microwave reactor (130°C, 100W) under a nitrogen atmosphere for 1 h. After completion of the reaction, the product was filtered and concentrated. The concentrate was added with dichloromethane and washed with water and saturated brine. The organic phase was separated, dried, concentrated, and purified by preparative liquid chromatography to obtain compound 12. ESI-MS: m / z = 526.23 [M+H] + .

[0457] 1 H NMR (500MHz, DMSO-d6) δ12.10(s,1H),8.06(s,1H),7.68(d,J=5.6Hz,1H),7.30(s,2H),6.66(d ,J=14.5Hz,2H),3.71(d,J=7.4Hz,6H),1.32(s,9H),0.90(d,J=6.1Hz,2H),0.84-0.76(m,2H).

[0458] (2) Preparation of Compound B12

[0459] 3,3-Dimethyl-1-butyne (1642 mg) was dissolved in tetrahydrofuran (197 mL), the atmosphere was replaced with nitrogen, and the temperature was lowered to -78°C. A 2.5 M n-butyllithium solution in n-hexane (8.0 mL) was added dropwise, and the reaction was continued at the same temperature for 1 h. Tributyltin chloride (6522 mg) was added dropwise, and the reaction was continued for 2 h. After the reaction was complete, saturated aqueous ammonium chloride (150 mL) was added to quench the reaction, and the mixture was extracted with n-hexane. The organic phase was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness at 45-55°C to obtain 7230 mg of compound B12.

[0460] (3) Preparation method of compounds 12a and 12b:

[0461] Compound 12 was subjected to chiral separation (CHIRALPAK IG, 20 x 250 mm, 50 x 2 mobile phase: A: n-hexane, B: ethanol; gradient: 30%-90% B over 60 min, wavelength 254 nm, v = 10 ml / min) to afford compounds 12a and 12b. ESI-MS: m / z = 526.23 [M+H] + .

[0462] Example 13: Preparation of Compound 13

[0463] (1) Preparation method of compound A13:

[0464] Referring to step (1) of Example 12, Compound B13 was substituted for Compound B12 to obtain 120 mg of Compound A13. ESI-MS: m / z=542.29 [M+H] + .

[0465] (2) Preparation method of compound 13:

[0466] Compound A13 (120 mg) and a tetrahydrofuran solution of tetrabutylammonium fluoride (1N, 1.35 mg) were added to tetrahydrofuran (11 mL). The mixture was allowed to react at 10-30°C for approximately 2 h. After the reaction was complete, the filtrate was concentrated and purified by column chromatography and preparative liquid chromatography to obtain compound 13. ESI-MS: m / z = 470.27 [M+H] + .

[0467] Example 14: Preparation of Compounds 14-1 & 14-2

[0468] (1) Preparation method of compound A14:

[0469] Dissolve 4-chloro-2,5-difluorobenzonitrile (80 g), NBS (164 g), p-toluenesulfonic acid monohydrate (44 g), and palladium acetate (7.6 g) in 560 mL of 1,2-dichloroethane and stir at 75°C for at least 5 h. Cool the reaction mixture to room temperature, filter, and concentrate the filtrate to dryness at 40-50°C. Purify by column chromatography to obtain compound A14.

[0470] (2) Preparation method of compound B14:

[0471] Compound A14 (1 g), 3-hydroxypyrrolidine (696 mg), potassium carbonate (2.21 g), and N-methylpyrrolidone (20 mL) were heated to 75°C for reaction. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The separated organic phase was washed with saturated brine, dried, and concentrated to dryness at 40-50°C. The organic phase was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain compound B14.

[0472] (3) Preparation method of compound C14:

[0473] Compound B14 (1 g), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (811 mg), potassium fluoride (435 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (213 mg), and 1,4-dioxane / water (60 / 12 mL) were heated to 80°C under a nitrogen atmosphere for reaction. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was separated, washed with water and saturated brine, dried, and concentrated at 40-50°C. It was then separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain compound C14. ESI-MS: m / z = 321.15 [M+H] + .

[0474] (4) Preparation method of compound D14:

[0475] Compound C14 (400 mg), NIS (562 mg), and trifluoroacetic acid (285 mg) were dissolved in acetonitrile (8 mL) and heated to 80°C for reaction. After completion of the reaction, sodium bisulfite solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was separated, washed with water and saturated brine, dried, and concentrated. Compound D14 was obtained by separation and purification via silica gel column chromatography (petroleum ether / ethyl acetate). ESI-MS: m / z = 447.06 [M+H] + .

[0476] (5) Preparation method of compound E14:

[0477] Referring to step (12) of Example 1, Compound D14 was substituted for Compound K1, and Compound K2 was substituted for Compound G1. Compound E14 was obtained by separation and purification by silica gel column chromatography (petroleum ether / ethyl acetate). ESI-MS: m / z = 815.37 [M+Na] + .

[0478] (5) Preparation method of compound F14:

[0479] Compound E14 (400 mg) was dissolved in methanol (8 mL) and a 10 M hydrogen chloride / ethanol solution (8 mL) was added dropwise at room temperature. The temperature was raised to 80°C for reaction. After the reaction, the reaction mixture was concentrated at 40-50°C to obtain compound F14. ESI-MS: m / z = 509.23 [M+H] + .

[0480] (6) Preparation method of compound 14:

[0481] Referring to step (1) of Example 12, Compound F14 (254 mg) was substituted for Compound M2, and tributyl propargyl stannane was substituted for Compound B12. Purification was performed by preparative liquid phase (column: YMC AQ C18 250*50 mm, 10 μm; mobile phase: A: 10 mM ammonium acetate, C: methanol, gradient: 30% C-60% C (0-60 min); flow rate: 50 ml / min; wavelength: 254 nm, fractions were collected, desalted with 0.1% formic acid, and then spin-dried to obtain Compounds 14-1 (rt-40 min) and 14-2 (rt-47 min). ESI-MS: m / z = 513.26 [M+H]+.

[0482] 14-1:H NMR (500MHz, DMSO-d6) δ12.24(s,1H),8.32(s,1H),8.06(s,1H),7.34(s,2H),7.03(d,J=5.9Hz,1H),6.69(s,2H),3.88(s,2H),3.80- 3.61(m,6H),3.55(dt,J=9.3,4.7Hz,1H),3.39(d,J=10.6Hz,1H),2.11(s,3H),1.99(dtd,J=12.9,8.2,3.8Hz,1H),1.95-1.86(m,1H).

[0483] 14-2: 1H NMR (500MHz, DMSO-d6) δ12.24(s,1H),8.33(s,2H),8.06(s,1H),7.35(s,2H),7.04(d,J=5.9Hz,1H),6.72(dd,J=33.9,1.4Hz,2H),3.85(s,2H),3. 77-3.65(m,6H),3.48(td,J=8.9,3.3Hz,1H),3.31(d,J=10.5Hz,1H),2.1 2(s,3H),1.99(dtd,J=12.6,8.0,4.1Hz,1H),1.89(tt,J=8.9,3.3Hz,1H).

[0484] Example 15: Preparation of Compound 15

[0485] (1) Preparation method of compound A15:

[0486] Compound A14 (10 g), 5-boronic acid pyrazole (17 g), cesium carbonate (39.1 g) and 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (8.4 g) were dissolved in dioxane-water (5:1) (500 mL). After N2 replacement, the temperature was raised to 85°C and reacted for more than 5 h. After cooling to room temperature, the mixture was concentrated to dryness, extracted with water and EA, and the organic phase was separated and washed with water and saturated brine, dried and concentrated. The mixture was purified by column chromatography to obtain compound A15 (7 g, ESI-MS: m / z=254.00 [M+H] + .

[0487] (2) Preparation method of compound B15:

[0488] Referring to step (11) of Example 1, compound A15 was used to replace J1 to obtain compound B15 (4.8 g), ESI-MS: m / z=379.89 [M+H] + .

[0489] (3) Preparation method of compound C15:

[0490] Isopropanol (160 mg) was dissolved in tetrahydrofuran (10 mL). Sodium hydride (125 mg) was added under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes, then at room temperature for 15 minutes. Compound B15 (1 g) was added, and the mixture was allowed to react at room temperature for 2 hours. After completion, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was separated, washed with water and saturated brine, dried, filtered, and the filtrate concentrated to yield 915 mg of compound C15. ESI-MS: m / z = 419.95 [M+H] + .

[0491] (4) Preparation method of compound D15:

[0492] Compound C15 (800 mg), compound K2 (1376 mg), and Pd(dppf)Cl2 (70.4 mg) were dissolved in 1,2-dichloroethane (11.2 mL). Aqueous sodium carbonate solution (2 mol / L, 11.2 mL) was added, and the atmosphere was purged with nitrogen. The temperature was raised to 90°C and the reaction was allowed to proceed for 2.5 h. After the reaction was complete, the mixture was filtered, and the filtrate was added with water and dichloromethane. The organic phase was separated and washed with saturated brine. After drying, the mixture was filtered, and the filtrate was concentrated to dryness to obtain 300 mg of compound D15. ESI-MS: m / z = 610.12 [M-Boc- t Bu+3H] + .

[0493] (5) Preparation of Compound E15:

[0494] Compound D15 (300 mg) was dissolved in methanol (4 mL), and a hydrogen chloride-ethanol solution (4 mL) was added to the solution. The reaction was then incubated at 80°C under a nitrogen atmosphere for 60 h. After the reaction was complete, the reaction mixture was concentrated, sodium bicarbonate solution was added to adjust the pH to 7-8, and ethyl acetate was added for extraction. The organic phase was separated and washed with water and saturated brine. After drying, the filtrate was filtered and concentrated to dryness to obtain 130 mg of compound E15. ESI-MS: m / z = 482.09 [M+H] + .

[0495] (6) Preparation method of compound 15:

[0496] Referring to step (1) of Example 12, Compound M2 (130 mg) was replaced with Compound E15, and Compound B12 was replaced with tributyl propynylstannane. 64 mg of Compound 15 was obtained by preparative liquid phase purification. ESI-MS: m / z = 486.14 [M+H] + .

[0497] 1 H NMR (500MHz, DMSO) δ12.07(s,1H),8.03(s,1H),7.61(d,J=5.6Hz,1H),7.30(s,2H),6.71(d,J=1.5Hz,1H),6.59(d ,J=1.6Hz,1H),4.87(p,J=6.0Hz,1H),3.73(s,2H),3.62(s,2H),2.54(s,2H),1.88(s,4H),1.31(t,J=5.8Hz,6H).

[0498] Example 16: Preparation of Compound 16

[0499] (1) Preparation method of compound A16:

[0500] Compound B15 (500 mg), trans-3-fluorocyclobutaneamine (330 mg), and DIPEA (512 mg) were dissolved in DMSO (5 mL) and reacted at 80°C for 4 h. After completion of the reaction, water was added to the reaction system and extracted with ethyl acetate. The separated organic phase was washed with saturated brine and dried, filtered, and the filtrate was concentrated to obtain 551 mg of compound A16. ESI-MS: m / z = 448.94 [M+H] + .

[0501] (2) Preparation method of compound B16:

[0502] Referring to step (4) of Example 15, Compound A16 was used in place of Compound C15 to obtain 115 mg of Compound B16. ESI-MS: m / z = 795.37 [M+H] + .

[0503] (3) Preparation method of compound C16:

[0504] Referring to step (5) of Example 15, compound D15 was replaced with compound B16 to obtain 100 mg of compound C16. ESI-MS: m / z=511.08 [M+H] + .

[0505] (4) Preparation method of compound 16:

[0506] Referring to step (6) of Example 15, compound E15 was replaced with compound C16 and purified by preparative liquid phase to obtain 20 mg of compound 16. ESI-MS: m / z=515.16 [M+H] + .

[0507] Example 17: Preparation of Compound 17

[0508] (1) Preparation method of compound A17:

[0509] Compound B15 (1 g), cyclobutanol (190 mg), and cesium carbonate (1.7 g) were dissolved in acetonitrile (10 mL) and reacted at 50°C for 10 h. After completion of the reaction, the reaction solution was concentrated and extracted with water and ethyl acetate. The separated organic phase was washed with saturated brine and dried, filtered, and the filtrate was concentrated to obtain 750 mg of compound A17. ESI-MS: m / z = 431.97 [M+H] + .

[0510] (2) Preparation method of compound B17:

[0511] Referring to step (4) of Example 15, Compound A17 was used in place of Compound C15 to obtain 295 mg of Compound B17. ESI-MS: m / z = 778.35 [M+H] + .

[0512] (3) Preparation method of compound C17:

[0513] Referring to step (5) of Example 15, compound D15 was replaced with compound B17 to obtain 200 mg of compound C17. ESI-MS: m / z=494.07 [M+H] + .

[0514] (4) Preparation method of compound 17:

[0515] Referring to step (6) of Example 15, compound E15 was replaced with compound C17 and purified by preparative liquid phase to obtain 89 mg of compound 17. ESI-MS: m / z=498.16 [M+H] + .

[0516] 1 H NMR (500MHz, DMSO) δ12.25(s,1H),8.24(s,1H),8.08(s,1H),7.33(d,J=5.5Hz,2 H),6.67(d,J=1.6Hz,1H),6.60(d,J=1.5Hz,1H),4.93(p,J=7.1Hz,1H),3.88(d,J =1.8Hz,1H),3.72(s,2H),2.16(s,2H),2.10(dt,J=9.7,2.3Hz,1H),1.54(dd,J= 9.1, 6.3Hz, 2H), 1.27 (d, J = 7.3Hz, 2H), 1.05-1.02 (m, 2H), 0.85 (t, J = 7.3Hz, 4H).

[0517] Example 18: Preparation of Compound 18

[0518] (1) Preparation method of compound A18:

[0519] Compound B15 (1 g), 3,3-difluorocyclobutylamine hydrochloride (756 mg), N,N-diisopropylethylamine (1 g), and dimethyl sulfoxide (21 mL) were heated to 95°C for reaction. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was separated, washed with saturated brine, dried, and concentrated to dryness at 40-50°C to obtain compound A18. ESI-MS: m / z = 466.99 [M+H] + .

[0520] (2) Preparation method of compound B18:

[0521] Referring to the preparation method of L1 in step (12) of Example 1, Compound A18 was substituted for Compound K1, and Compound K2 was substituted for Compound G1. The mixture was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain Compound B18. ESI-MS: m / z = 835.40 [M+Na] + .

[0522] (3) Preparation method of compound C18:

[0523] Compound B18 (350 mg) was dissolved in methanol (8 mL). A 10 M hydrogen chloride / ethanol solution (8 mL) was added dropwise at room temperature. The mixture was heated to 80°C for reaction. After completion of the reaction, the reaction mixture was concentrated to obtain compound C18. ESI-MS: m / z = 529.19 [M+H]+.

[0524] (4) Preparation method of compound 18:

[0525] Referring to step (6) of Example 15, compound E15 was replaced with compound C18, and compound 18 was obtained after purification by preparative liquid phase. ESI-MS: m / z=533.28 [M+H] + .

[0526] 1 H NMR(500MHz,DMSO-d6)δ12.22(s,1H),8.27(s,2H),8.06(s,1H),7.33(s,2H ),7.01(d,J=5.8Hz,1H),6.74(d,J=6.4Hz,1H),6.71(d,J=1.5Hz,1H),6.62( d,J=1.6Hz,1H),3.96(dd,J=10.5,4.0Hz,1H),3.82(d,J=5.3Hz,2H),3.71( s,3H),3.12-2.97(m,2H),2.73(dtd,J=17.5,13.8,6.9Hz,2H),2.14(s,3H).

[0527] Example 19: Preparation of Compound 19

[0528] (1) Preparation method of compound A19:

[0529] To 3-ethynylpyridine (1 g) and tetrahydrofuran (100 mL) under a nitrogen atmosphere at -78°C, potassium bis(trimethylsilyl)amide (1 M, 11 mL) was slowly added dropwise. The mixture was allowed to react at the same temperature for 1 h. After completion, tri-n-butyltin methoxide (3.9 g) was slowly added dropwise. The reaction was allowed to warm to room temperature and allowed to react overnight. After completion, the reaction was quenched by addition of saturated ammonium chloride solution in an ice bath. The mixture was extracted with water and n-hexane. The organic phase was separated, washed with water and saturated brine, dried, and concentrated to dryness at 40-50°C to yield compound A19.

[0530] (2) Preparation method of compound B19:

[0531] Referring to step (1) of Example 12, Compound L1 was substituted for Compound M2, and Compound A19 was substituted for Compound B12 to obtain Compound B19. ESI-MS: m / z = 632.36 [M+H] + .

[0532] (3) Preparation method of compound 19:

[0533] Compound B19 (500 mg), trifluoroacetic acid (2 mL), and dichloromethane (7 mL) were reacted at room temperature. After the reaction, the mixture was concentrated under reduced pressure and purified by preparative liquid phase separation to obtain compound 19. ESI-MS: m / z = 532.33 [M+H] + .

[0534] 1 H NMR (500MHz, DMSO-d6) δ12.45(s,1H),8.84(dd,J=2.2,0.9Hz,1H),8.67(dd,J=4.9,1.7Hz,1H ),8.28(s,1H),8.17(d,J=8.3Hz,1H),8.08(dt,J=7.9,1.9Hz,1H),8.01(d,J=5.5Hz,1H),7.7 7(d,J=1.7Hz,1H),7.71(dd,J=8.3,1.7Hz,1H),7.52(ddd,J=7.9,4.9,0.9Hz,1H),4.21(tt,J =6.1, 2.9Hz, 1H), 3.80 (s, 5H), 0.93 (qd, J = 6.3, 5.8, 3.3Hz, 2H), 0.84 (dt, J = 5.1, 2.9Hz, 2H).

[0535] Example 20: Preparation of Compound 20

[0536] (1) Preparation method of compound A20:

[0537] Compound L1 (564 mg), 2-pyridineacetylene (206 mg), bis(acetonitrile)palladium dichloride (26 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (95 mg), and cesium carbonate (978 mg) were added to acetonitrile (12 mL) and heated with stirring at 85°C under nitrogen for 6 h. After the reaction was complete, the mixture was filtered and concentrated. The concentrate was dissolved in ethyl acetate and then washed with water and saturated brine. The organic phase was separated, dried, and concentrated to yield 800 mg of compound A20. ESI-MS: m / z = 632.32 [M+H] + .

[0538] (2) Preparation method of compound 20:

[0539] Compound A20 (800 mg) was dissolved in a 4 M solution of hydrogen chloride in ethyl acetate (12 mL). The reaction was allowed to proceed at room temperature for 2 h. After the reaction was complete, the filtrate was concentrated and purified by preparative liquid chromatography to obtain 8 mg of compound 20. ESI-MS: m / z = 532.28 [M+H] + .

[0540] 1 H NMR (500MHz, DMSO-d6) δ12.45 (s, 1H), 8.67 (d, J = 4.8Hz, 1H), 8.28 (s, 1H), 8. 17(d,J=8.3Hz,1H),8.02(d,J=5.5Hz,1H),7.92(td,J=7.8,1.8Hz,1H),7.77( s,1H),7.76-7.68(dd,J=23.8,8.3Hz,2H),7.51(dd,J=7.8,4.9Hz,1H),4.27- 4.13(m,1H),3.81(s,3H),3.62(s,2H),0.97-0.89(m,2H),0.86-0.80(m,2H).

[0541] Example 21: Preparation of Compound 21

[0542] (1) Preparation method of compound A21:

[0543] Compound J1 (650 mg), (1-fluorovinyl)methyldiphenylsilane (1 g), bis(triphenylphosphine)palladium dichloride (154 mg), cuprous iodide (42 mg) and cesium fluoride (1 g) were dissolved in 1,3-dimethyl-2-imidazolidinone (80 mL), replaced with nitrogen, and reacted at 50° C. for 5 h.

[0544] After the reaction was completed, water and ethyl acetate were added for extraction; the organic phase was separated and washed with water and saturated brine; after drying, it was filtered and the filtrate was concentrated to obtain 750 mg of compound A21. ESI-MS: m / z = 302.09 [M+H] + .

[0545] (2) Preparation method of compound B21:

[0546] Compound A21 (650 mg) and NBS (887 mg) were dissolved in acetonitrile (13 mL) and reacted at room temperature for 10 h until complete. Water was added and the mixture was extracted with ethyl acetate. The organic phase was separated and washed with saturated brine. After drying, the filtrate was filtered and concentrated to yield 570 mg of compound B21. ESI-MS: m / z = 380.11 [M+H] + .

[0547] (3) Preparation method of compound C21:

[0548] Referring to step (4) of Example 15, Compound B21 was used to replace Compound C15 to obtain 180 mg of Compound C21. ESI-MS: m / z=618.31 [M-Boc- t Bu+3H] + .

[0549] (4) Preparation method of compound 21:

[0550] Referring to step (5) of Example 15, compound C21 was substituted for compound D15, and the mixture was purified by preparative liquid phase (liquid phase conditions: column YMC*GEL ODS-AQ-C18, size 50*250, 10 μm, mobile phase: A: 0.1% acetic acid / water, B: methanol; gradient: 30% B-85% B (0-50 min), wavelength 254 nm, v = 60 ml / min) to obtain 40 mg of compound 21. ESI-MS: m / z = 490.24 [M+H] + .

[0551] 1 H NMR (500MHz, DMSO-d6) δ12.06(s,1H),8.06(s,1H),7.79(d,J=5.9Hz,1H),7.29(s,2H),6.71(d,J=1.5Hz,1H),6.62(d,J=1.6Hz,1 H),5.63(d,J=4.3Hz,1H),5.53(ddt,J=13.8,6.4,3.3Hz,2H),4.22(tt,J=6.1,2.9Hz,1H),3.74(s,4H),3.61(s,2H),1.88(s,4H).

[0552] Compound 21 (70 mg) was subjected to chiral separation (column YMC*Cellulose-SB, size 30*250, 10 μm, mobile phase: A: 0.2% diethylamine / ethanol, B: n-hexane; gradient: 0% B-50% B (0-50 min), wavelength 254 nm, v = 30 ml / min; 21a-rt 32.3 min; 21b-rt 39.8 min) to afford compounds 21a and 21b, respectively. ESI-MS: m / z = 490.24 [M+H] + .

[0553] Example 22: Preparation of Compound 22

[0554] (1) Preparation method of compound A22:

[0555] 1-Methyl-1H-pyrazole acetylene (1485 mg) was dissolved in tetrahydrofuran (40 mL) and cooled to -78°C under a nitrogen atmosphere. A 2.5N solution of n-butyllithium in hexane (6.2 mL) was added dropwise, and the mixture was stirred at this temperature for 0.5 h. Tributyltin chloride (4792 mg) was added dropwise, and the mixture was stirred at this temperature for 4 h. The temperature was then raised to 20-30°C for 20 h. After completion, the reaction was quenched with saturated aqueous ammonium chloride. The mixture was extracted with n-hexane, and the organic phase was washed with brine. After drying, filtration, and concentration were performed to yield 5.55 g of compound A22.

[0556] (2) Preparation method of compound 22:

[0557] Referring to the preparation method of compound 12 in step (1) of Example 12, compound A22 was substituted for compound B12, and the mixture was purified by preparative liquid phase (liquid phase conditions: column: Unips-300-10, 30*150mm 30μm; A: 0.1% formic acid, B: acetonitrile; gradient: 90% A-10% B to 30% A-70% B (0-60min); λ: 254nm, V: 30mL / min) to obtain compound 22. ESI-MS: m / z = 550.35 [M+H] + .

[0558] 1H NMR (500MHz, DMSO-d6) δ12.05(s,1H),8.22(s,1H),8.06(s,1H),7.84(d,J=5.6Hz,1H),7.81(s,1H),7.31(s,2H),6.72(d,J=1.5Hz,1H), 6.65(d,J=1.5Hz,1H),4.19(dt,J=6.0,3.1Hz,1H),3.88(s,3H),3.76(s,3H),3.62(s,2H),0.92(d,J=6.4Hz,2H),0.83(d,J=3.8Hz,2H).

[0559] (3) Preparation of Compounds 22a and 22b:

[0560] Compound 22 was subjected to chiral separation (LC conditions: column: YMC-Cellulose-SB, 50*250mm 10μm; A: CO2, B: 0.1% diethylamine / ethanol; gradient: 45% B isocratic; λ: 254nm, V: 60mL / min; rt 7.5min-22a and rt 9.0min-22b) to afford compounds 22a and 22b. 22a and 22b: ESI-MS: m / z = 550.35 [M+H] + .

[0561] Example 23: Preparation of Compound 23

[0562] (1) Preparation method of compound 23:

[0563] Compound M2 (192 mg), compound N2 (298 mg), tetrakistriphenylphosphine palladium (139 mg), and sodium carbonate (255 mg) were dissolved in a 1,4-dioxane-water (5:1) mixture (17 mL). The reaction mixture was allowed to react in a CEM microwave reactor (130°C, 100 W) under a nitrogen atmosphere for 1 h. After completion of the reaction, the mixture was filtered and concentrated. The concentrate was added with dichloromethane and washed with water and saturated brine. The organic phase was separated, dried, concentrated, and purified by preparative liquid chromatography (column: Diasol PFP, 30*250 mm, 10*25 mm, mobile phase: A: 30 mM ammonium acetate (containing 0.1% acetic acid), B: methanol; gradient: 30%-80% B over 50 min, wavelength 254 nm, v = 30 mL / min, rt 27.8 min) to obtain compound 23. ESI-MS: m / z = 550.35 [M+H] + .

[0564] 1H NMR(500MHz,DMSO-d6)δ12.04(s,1H),8.05(s,1H),7.93-7.80(m,2H),7.29(s,2H),6.70(s,1H),6. 64(s,2H),4.19(s,1H),3.89(s,3H),3.75(s,3H),3.62(s,2H),0.92(d,J=6.6Hz,2H),0.82(s,2H).

[0565] (2) Preparation of Compounds 23a and 23b:

[0566] Compound 23 was subjected to chiral separation (column: YMC SB, dimensions 30 x 250 mm, 10 μm, mobile phase: A: n-hexane, B: 0.1% diethylamine ethanol; gradient: 70%-90% B over 60 min, wavelength 254 nm, v = 30 ml / min, rt 19.2 min-23b & rt 24.2 min-23b) to afford compounds 23a and 23b. ESI-MS: m / z = 550.35 [M+H] + .

[0567] Example 24: Preparation of Compound 24

[0568] (1) Preparation method of compound 24:

[0569] Referring to the preparation method of compound 12 in step (1) of Example 12, compound A19 was substituted for compound B12, and the mixture was purified by preparative liquid phase (column YMC AQ C18, size 50*250, 10 μm, mobile phase: A: 0.05% acetic acid / water, B: acetonitrile; gradient: 10% B-70% B (0-60 min), wavelength 254 nm, v = 50 ml / min) to obtain compound 24. ESI-MS: m / z = 547.31 [M+H] + .

[0570] 1H NMR (500MHz, DMSO-d6) δ12.45(s,1H),8.84(dd,J=2.2,0.9Hz,1H),8.67(dd,J=4.9,1.7Hz,1H ),8.28(s,1H),8.17(d,J=8.3Hz,1H),8.08(dt,J=7.9,1.9Hz,1H),8.01(d,J=5.5Hz,1H),7.7 7(d,J=1.7Hz,1H),7.71(dd,J=8.3,1.7Hz,1H),7.52(ddd,J=7.9,4.9,0.9Hz,1H),4.21(tt,J =6.1, 2.9Hz, 1H), 3.80 (s, 5H), 0.93 (qd, J = 6.3, 5.8, 3.3Hz, 2H), 0.84 (dt, J = 5.1, 2.9Hz, 2H).

[0571] (2) Preparation of Compounds 24a and 24b:

[0572] Compound 24 was subjected to chiral separation (LC conditions: column YMC AQ C18, size 30*250, 10 μm, mobile phase: A: 0.05% acetic acid / water, B: methanol; gradient: 20% B-80% B (0-60 min), wavelength 254 nm, v = 30 ml / min; separation conditions: YMC SC, size 30*250, 10 μm, mobile phase: A: n-hexane: dichloromethane = 3:1, B: 0.1% diethylamine-methanol; gradient: 10% B-70% B (0-60 min), wavelength 254 nm, v = 30 ml / min, 24a-rt 33.2 min & 24b-rt 37.2 min) to give compounds 24a and 24b. 24a and 24b: ESI-MS: m / z = 547.31 [M+H] + .

[0573] Example 25: Preparation of Compound 25

[0574] (1) Preparation method of compound A25:

[0575] 1-Ethynylcyclopentan-1-ol (1.1 g) and tributyl(methoxy)stannane (12 mL) were reacted at 120° C. under a nitrogen atmosphere. After the reaction, the mixture was cooled to room temperature and purified by flash column chromatography (petroleum ether / ethyl acetate) to obtain compound A25.

[0576] (2) Preparation method of compound 25:

[0577] Refer to the preparation method of compound 12 in step (1) of Example 12, replacing compound B12 (190 mg) with compound A25, and purifying by preparative liquid phase to obtain compound 25. ESI-MS: m / z=554.32 [M+H] + .

[0578] 1 H NMR (500MHz, DMSO-d6) δ12.13(s,1H),8.06(s,1H),7.72(d,J=5.7Hz,1H),7.40-7.20(br,2H),6.68-6.62(m,2H),4.18(tt,J= 6.1, 2.9Hz, 1H), 3.73 (s, 5H), 2.00-1.86 (m, 7H), 1.79-1.65 (m, 4H), 0.90 (qd, J = 5.9, 1.8Hz, 2H), 0.82 (dt, J = 5.3, 3.0Hz, 2H).

[0579] Example 26: Preparation of Compound 26

[0580] (1) Preparation method of compound A26:

[0581] Compound B15 (380 mg), 2,2-difluorocyclobutaneamine hydrochloride (300 mg), triethylamine (300 mg), and dimethyl sulfoxide (8 mL) were heated to 60°C for reaction. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain compound A26. ESI-MS: m / z = 465.01 [MH] - .

[0582] (2) Preparation method of compound B26:

[0583] The preparation method of L1 in step (12) of reference example 1 was followed by replacing compound K1 with compound A26 and replacing compound G1 with compound K2. Compound B26 was obtained by separation and purification by silica gel column chromatography (petroleum ether / ethyl acetate). ESI-MS: m / z = 835.43 [M+Na] + .

[0584] (3) Preparation method of compound C26:

[0585] Compound B26 (300 mg) was dissolved in methanol (8 mL), and a 10 M hydrogen chloride / ethanol solution (8 mL) was added dropwise at room temperature. The temperature was raised to 80°C for reaction. After the reaction, the reaction solution was concentrated to obtain compound C26. ESI-MS: m / z = 529.16 [M+H] + .

[0586] (4) Preparation method of compound 26:

[0587] Compound C26 (254 mg), tributylstannane (495 mg), tetrakistriphenylphosphine palladium (173 mg), and sodium carbonate (318 mg) were dissolved in dioxane-water (5:1, v / v) (17 mL) and sparged with nitrogen for 3 min. The reaction was then microwaved at 130°C and 120W for 1 h. After completion of the reaction, the mixture was cooled to room temperature and filtered. The filtrate was concentrated and extracted with water and ethyl acetate. The organic phase was washed with water and saturated brine, dried, and concentrated. After purification by preparative liquid chromatography (column: YMC AQ C18, size 30*250 mm, 10 μm; mobile phase: A: 0.1% acetic acid in water, B: acetonitrile; gradient: 10%-70% B-60 min; wavelength 254 nm, v = 30 ml / min; rt 23 min-26-1, rt 25 min-26-2), compounds 26-1 and 26-2 were obtained. ESI-MS: m / z = 533.30 [M+H] + .

[0588] Example 27: Preparation of Compound 27

[0589] (1) Preparation method of compound A27:

[0590] 2-Hydroxyethyl methylsulfone (2.48 g) was added to N,N-dimethylformamide (100 mL), and sodium hydride (0.80 g) was added portionwise at 0°C. After stirring at the same temperature for 0.5 h, compound A15 (2.53 g) was added. After the addition, the reaction was stopped by stirring at room temperature for 5 h. After the reaction was completed, water was added to quench the reaction, and ethyl acetate was added to extract the aqueous phase. 1M hydrochloric acid solution was added to adjust the pH to 2-3, and then ethyl acetate was added to extract the aqueous phase. The organic phases were combined, washed with water, and the organic phase was concentrated under reduced pressure to obtain compound A27 (2.3 g). ESI-MS: m / z = 252.02 [M+H] + .

[0591] (2) Preparation method of compound B27:

[0592] Compound A27 (1.1 g) was added to dichloromethane (20 mL), and pyridine (1.4 g) was added at 0°C. After stirring at the same temperature for 5 minutes, trifluoromethanesulfonic anhydride (1.9 g) was added. After the addition, the mixture was stirred at room temperature for 3 hours to stop the reaction. After the reaction was completed, water (20 mL) was added for washing and extraction. The obtained organic phase was directly concentrated and purified by column chromatography to obtain compound B27 (1.0 g. ESI-MS: m / z=383.94 [M+H] + .

[0593] (3) Preparation method of compound C27:

[0594] Compound B27 (766 mg), phenylboronic acid (244 mg), tetrakis(triphenylphosphine)palladium (346 mg), and sodium carbonate (848 mg) were added to a mixed solvent of 1,4-dioxane (10 mL) and water (2 mL). The mixture was stirred at 85°C under nitrogen for 3 h before the reaction was stopped. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated and purified by column chromatography to obtain 0.8 g of compound C27. ESI-MS: m / z = 312.01 [M+H] + .

[0595] (4) Preparation method of compound D27:

[0596] Referring to the preparation method of K1 in step (11) of Example 1, compound C27 was used to replace compound J1 to obtain 0.8 g of compound D27. ESI-MS: m / z = 437.94 [M+H] + .

[0597] (5) Preparation method of compound E27:

[0598] Referring to the preparation method of L1 in step (12) of Example 1, Compound G1 (360 mg) was replaced with Compound K2, and Compound K1 was replaced with Compound D27. Compound E27 (160 mg) was purified by column chromatography. ESI-MS: m / z = 684.32 [M-Boc+2H] + .

[0599] (6) Preparation method of compound F27:

[0600] Refer to the preparation method of compound 12 in step (1) of Example 12, replacing compound M2 with compound E27 and compound B12 with tributyl propynyl stannane, and purifying by column chromatography to obtain compound F27 (130 mg). ESI-MS: m / z = 688.42 [M-Boc+2H] + .

[0601] (7) Preparation method of compound 27:

[0602] Compound F27 (130 mg) was added to a mixture of hydrogen chloride / ethanol (10 M, 2 mL) and methanol (2 mL) and stirred at 80°C for 3 days before stopping the reaction. After the reaction was complete, the filtrate was concentrated and purified by preparative liquid chromatography to obtain compound 27. ESI-MS: m / z = 504.15 [M+H] + .

[0603] Example 28: Preparation of Compound 28

[0604] To 4-methyl-1-pentyne (820 mg) and tetrahydrofuran (100 mL) under a nitrogen atmosphere at -78°C, n-butyllithium (2.5 M, 4 mL) was slowly added dropwise. The reaction was allowed to proceed for 1 h. After completion, tributyltin chloride (3.25 g) was slowly added dropwise. The temperature was raised to room temperature and the reaction was allowed to proceed overnight. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction under an ice bath. Water was added, and the mixture was extracted with n-hexane. The organic phase was separated, washed with water and saturated brine, dried, and concentrated to dryness at 40-50°C to yield compound A28.

[0605] Refer to the preparation method of compound 12 in step (1) of Example 12, replacing compound B12 with compound A28, and purification by preparative liquid phase gave compound 28. ESI-MS: m / z=526.28 [M+H] + .

[0606] 1 H NMR(500MHz,DMSO-d6)δ12.39(s,1H),8.14(s,1H),7.73(d,J=5.7Hz,1H),7.45-7.24(b r,2H),6.74(d,J=1.5Hz,1H),6.53(d,J=1.4Hz,1H),4.17(tt,J=6.1,2.9Hz,1H),4.09(d ,J=2.0Hz,2H),3.72(s,3H),2.89(s,1H),2.73(s,1H),2.45(d,J=6.5Hz,2H),1.94-1.85 (m,1H),1.00(d,J=6.6Hz,6H),0.91(dd,J=6.2,3.0Hz,2H),0.81(dt,J=5.7,2.8Hz,2H).

[0607] Example 29:

[0608] (1) Preparation method of compound 29:

[0609] Compound M1 (500 mg) was dissolved in 4 mol / L hydrogen chloride / ethyl acetate (10 mL) and reacted at room temperature. After completion of the reaction, the product was concentrated under reduced pressure and purified by preparative liquid chromatography (HPLC conditions: column: Novasep C18 250*50 mm, 10 μm; mobile phase: A: 0.05% formic acid-water, C: acetonitrile, gradient: 10% C-40% C (0-60 min); flow rate: 50 mL / min; wavelength: 254 nm, retention time: 24.09 min) to obtain compound 29 (90 mg). LC-MS: m / z 457.30 (M+H). + . 1H NMR(500MHz,DMSO-d6)δ12.67(s,1H),8.31(d,J=7.9Hz,2H),8.15(d,J=8.3Hz ,1H),7.93(d,J=5.8Hz,1H),7.78(s,1H),7.58(d,J=8.3Hz,1H),6.94(dd,J=1 7.6,11.2Hz,1H),6.30(d,J=17.6Hz,1H),5.77(d,J=11.2Hz,1H),4.23(d,J=2 .6Hz,1H),4.06(s,2H),3.77(s,3H),1.02-0.88(m,2H),0.81(d,J=6.6Hz,2H).

[0610] (2) Preparation of Compounds 29a and 29b:

[0611] Compound 29 was further chiral resolved using the following liquid chromatography conditions: column: YMC Cellulose-SC, 30*250 mm, 10 μm; column A: 0.05% diethylamine (dichloromethane:n-hexane = 1:1), column B: 0.1% diethylamine-methanol; gradient: 20-80°C-40 min; λ = 254 nm, V = 30 mL / min) to afford compounds 29a and 29b, respectively.

[0612] Example 30: Preparation of Compounds 30a and 30b

[0613] Compound A4 (also known as compound 30) was purified by preparative liquid chromatography (YMC Cellulose-SC 5 μm 30*250 column; 0.1% diethylamineethanol-n-hexane:dichloromethane = 3:1 (10%-50% / 0-40 min)) to give compound 30a and compound 30b, respectively.

[0614] 30a: LC-MS: m / z 484.19 (M+H) + , 1 H NMR (500MHz, DMSO-d6) δ12.10(s,1H),8.06(s,1H),7.77(d,J=5.6Hz,1H),7.32(s,2H),6.66(dd,J=4 0.5, 1.6Hz, 2H), 4.16 (tt, J = 6.0, 2.9Hz, 1H), 3.70 (d, J = 42.7Hz, 5H), 2.19 (s, 3H), 0.95-0.78 (m, 4H).

[0615] 30b: LC-MS: m / z 484.19 (M+H) + , 1H NMR (500MHz, DMSO-d6) δ12.08(s,1H),8.05(s,1H),7.77(d,J=5.7Hz,1H),7.31(s,2H),6.66(dd,J=4 8.7, 1.5Hz, 2H), 4.15 (tt, J = 6.1, 2.9Hz, 1H), 3.68 (d, J = 57.1Hz, 5H), 2.19 (s, 3H), 0.94-0.78 (m, 4H).

[0616] Example 31: Preparation of Compound 31

[0617] (1) Preparation method of compound A5-1:

[0618] Methyl 4-bromo-2-chloro-6-methylbenzoate (45.05 g), N-bromosuccinimide (36.74 g), and benzoyl peroxide (75% wt purity) (10.42 g) were dissolved in carbon tetrachloride (450 mL). The reaction mixture was reacted at 85°C under a nitrogen atmosphere for 12 h. After the reaction was complete, water (450 mL) and dichloromethane (900 mL) were added for extraction. The organic phase was separated and washed with water and saturated brine. The resulting organic phase filtrate was concentrated to dryness to obtain 67 g of compound A5-1.

[0619] (2) Preparation method of compound B5-1:

[0620] Compound A5-1 (63.0 g) and calcium carbonate (111 g) were dissolved in a dioxane-water (1:1) mixed solvent (2500 mL); the mixture was reacted at 90°C for 12 h. After the reaction, the mixture was filtered and the filter cake was washed with a dioxane-water (1:1) mixed solvent (400 mL); the mixture was concentrated at 50-60°C until no liquid flowed out, and then extracted with dichloromethane. The combined organic phases were washed with water and saturated brine, dried, and concentrated to obtain 32.1 g of compound B5-1.

[0621] (3) Preparation method of compound C5-1:

[0622] Compound B5-1 (32.0 g) was dissolved in N,N-dimethylformamide dimethyl acetal (112 mL), and potassium tert-butoxide (1459 mg) was added. The reaction was allowed to proceed at 105-110°C for 5 h. After completion of the reaction, the reaction solution was concentrated at 50-60°C until no liquid flowed out. The concentrate was added with petroleum ether (56 mL) and stirred at room temperature for 30 minutes. The liquid was filtered off. The filter cake was added with ethyl acetate (112 mL) and stirred at 80°C for 5 h. The temperature was then cooled and filtered to obtain 16.60 g of compound C5-1. ESI-MS: m / z = 301.96 [M+H] + .

[0623] (4) Preparation method of compound D5-1:

[0624] Compound C5-1 (15.80 g) was dissolved in anhydrous ethanol (160 mL), and hydrazine hydrate (6.4 mL) was added. After nitrogen substitution, the mixture was reacted at 80°C for 10 h. After the reaction, the mixture was stirred at room temperature for 1 h, then at -10 to 0°C for 4 h, and filtered to obtain 13.14 g of compound D5-1. ESI-MS: m / z = 315.99 [M+H] + .

[0625] (5) Preparation method of compound E5-1:

[0626] Compound D5-1 (11.34 g) was dissolved in tetrahydrofuran (114 mL), purged with nitrogen, and cooled to -5-0°C. Isobutyl chloroformate (7.37 g) was added at the same temperature, and the temperature was raised to 25°C for 5 h. After the reaction, the reaction solution was concentrated to dryness and slurried with 0.5 M hydrochloric acid (100 mL) and water (144 mL), respectively, and filtered to obtain 7.27 g of compound E5-1. ESI-MS: m / z = 306.89 [M+H] + .

[0627] (6) Preparation method of compound F5-1:

[0628] Dissolve bis(tert-butyloxycarbonyl)amine (4790 mg) in tetrahydrofuran (129 mL), replace the atmosphere with nitrogen, cool to -30°C, add lithium bis(trimethylsilyl)amide (1N, 23.1 mL) dropwise, and stir at the same temperature for 30 minutes. Add a tetrahydrofuran solution of compound E5-1 (6424 mg dissolved in 129 mL tetrahydrofuran) dropwise, raise the temperature to 25°C, and react for 3 hours. After the reaction is complete, quench with saturated ammonium chloride solution (100 mL), extract with ethyl acetate, and combine the organic phases, wash with saturated brine, dry, and concentrate to obtain 9.96 g of compound F5-1. ESI-MS: m / z = 488.14 [M+H] + .

[0629] (7) Preparation method of compound G5-1:

[0630] Compound F5-1 (9300 mg) was dissolved in acetonitrile (158 mL), magnesium perchlorate hexahydrate (1266 mg) was added, the atmosphere was replaced with nitrogen, the temperature was raised to 50°C, and the reaction was continued for 5 h. After the reaction was completed and the temperature was lowered to room temperature, water (158 mL) was added, and the mixture was stirred for 10 minutes. The mixture was then filtered, and the filter cake was washed with water, acetonitrile, and petroleum ether, respectively. The resulting filter cake was dried under reduced pressure to obtain 6.16 g of compound G5-1. ESI-MS: m / z = 388.08 [M+H] + .

[0631] (8) Preparation method of compound H5-1:

[0632] Compound G5-1 (2322 mg), pinacol diboron (2286 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (219.6 mg) and potassium acetate (1767 mg) were dissolved in 1,4-dioxane (140 mL), replaced with nitrogen, and heated to 1000°C for 6 h.

[0633] After the reaction was complete, the temperature was lowered and the mixture was filtered; the filtrate was concentrated to dryness to obtain a concentrate; ethyl acetate (25 mL) was added and stirred to dissolve, water (25 mL) was added and stirred for 10 minutes, and the mixture was filtered. The filter cake was rinsed with petroleum ether to obtain 1830 mg of compound H5-1, ESI-MS: m / z = 354.12 [M-80] + .

[0634] (9) Preparation method of compound I5-1:

[0635] Compound H5-1 (1559 mg), compound K1 (1251 mg), tetrakistriphenylphosphine palladium (520 mg), and sodium carbonate (1272 mg) were dissolved in a 1,4-dioxane-water (5:1) mixed solvent (144 mL). The reaction mixture was reacted at 85-90°C under a nitrogen atmosphere for 2 h. After the reaction was complete, the mixture was filtered and concentrated at 45-55°C until no liquid flowed out. The concentrate was added with ethyl acetate (50 mL) to dissolve the solution, then washed with water and saturated brine. The separated organic phase was dried and concentrated at 45-55°C until no liquid was present. Purification by column chromatography yielded 1060 mg of compound I5-1. ESI-MS: m / z = 599.08 [M+H] + .

[0636] (10) Preparation method of compound A10-1:

[0637] Compound I5-1 (200 mg), tributyl vinyl tin (916 mg), tetrakistriphenylphosphine palladium (112 mg), and sodium carbonate (408 mg) were dissolved in a 1,4-dioxane-water (v:v = 5:1) mixed solvent (35 mL). The reaction solution was reacted at 85-90°C under a nitrogen atmosphere for 8 h. After the reaction was complete, the solution was filtered and concentrated at 45-55°C until no liquid flowed out. The concentrate was added with ethyl acetate (20 mL) to dissolve the solution, then washed with water and saturated brine. The organic phase was separated, dried, and concentrated at 45-55°C until no liquid was present, yielding 280 mg of compound A10-1. ESI-MS: m / z = 591.31 [M+H] + .

[0638] (11) Preparation method of compound 31:

[0639] Compound A10-1 (280 mg) and trifluoroacetic acid (1.6 mL) were dissolved in dichloromethane (20 mL). The reaction was allowed to proceed at 10-30°C for approximately 2 h. After the reaction was complete, the filtrate was concentrated at 35-50°C until no liquid flowed out. Dichloromethane (15 mL) was then added and the mixture was evaporated to dryness. This was repeated four times (each time under high vacuum for at least 30 minutes). The product was purified by preparative liquid chromatography (HPLC conditions: column: Novasep C18 50*250 mm 10 μm; A: 0.05% aqueous ammonia, B: acetonitrile; gradient: 40% B-70% B (0-60 min); λ: 254 nm, V: 50 mL / min) to obtain compound 31. ESI-MS: m / z = 491.32 [M+H] + .

[0640] Example 32: Preparation of Compound 32

[0641] (1) Preparation method of compound A11-1:

[0642] Compound I5-1 (200 mg), tributyl vinyl tin (916 mg), tetrakistriphenylphosphine palladium (112 mg), and sodium carbonate (408 mg) were dissolved in a 1,4-dioxane-water (5:1) mixed solvent (35 mL). The reaction solution was reacted at 85-90°C under a nitrogen atmosphere for 8 h. After the reaction was complete, the solution was filtered and concentrated at 45-55°C until no liquid flowed out. The concentrate was added with ethyl acetate (20 mL) to dissolve the solution, then washed with water and saturated brine. The organic phase was separated, dried, and concentrated at 45-55°C until no liquid was present, yielding 280 mg of compound A11-1. ESI-MS: m / z = 583.35 [M+H] + .

[0643] (2) Preparation method of compound 32:

[0644] A11-1 (280 mg) and trifluoroacetic acid (1.6 mL) were dissolved in dichloromethane (20 mL). The reaction was allowed to proceed at 10-30°C for approximately 2 h. After the reaction was complete, the filtrate was concentrated at 35-50°C until no liquid flowed out. Dichloromethane (15 mL) was added and the mixture was evaporated to dryness. This was repeated four times (each time under high vacuum for at least 30 minutes). Compound 32 was then purified by preparative liquid chromatography (HPLC conditions: column: Novasep C18 50*250 mm 10 μm; A: 0.05% ammonia water, B: acetonitrile; gradient: 40% B-70% B (0-60 min); λ: 254 nm, V: 50 mL / min). ESI-MS: m / z = 483.35 [M+H] + .

[0645] 1H NMR(500MHz,DMSO-d6)δ12.34(s,1H),8.39(s,1H),8.14(dd,J=17.6,10.9Hz,1H),7.9 6(d,J=5.8Hz,1H),7.76-7.70(m,1H),7.64(s,1H),6.97(dd,J=17.6,11.3Hz,1H),6.31 (d,J=17.6Hz,1H),5.79(d,J=11.1Hz,1H),5.33(dd,J=28.5,14.3Hz,2H),4.25(dt,J= 6.1, 3.1Hz, 1H), 3.77 (d, J = 19.6Hz, 5H), 0.94 (d, J = 5.6Hz, 2H), 0.75 (d, J = 13.3Hz, 2H).

[0646] Example 33: Preparation of Compound 33

[0647] (1) Preparation method of compound A12-1:

[0648] Compound J1 (1.5 g), tributyl vinyl tin (4.8 g), tetrakis(triphenylphosphine palladium) (1.2 g), and cesium fluoride (2.3 g) were stirred in a mixture of dioxane (20 mL) and water (4 mL) and reacted at 100°C under nitrogen. After the reaction, the reaction solution was filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 1.1 g of pure A12-1.

[0649] LC-MS: m / z 284.14 (M+H) + .

[0650] (2) Preparation method of compound B12-1:

[0651] Compound A12-1 (1.1 g) and N-bromosuccinimide (1.4 g) were stirred in acetonitrile (20 mL) at room temperature overnight. After the reaction, water (10 mL) and ethyl acetate (20 mL) were added. The combined organic phases were washed sequentially with saturated sodium bicarbonate (20 mL) and saturated sodium chloride (20 mL). The resulting organic phase was concentrated to dryness and purified by column chromatography to obtain 1.4 g of compound B12-1.

[0652] LC-MS: m / z 361.96 (M+H) + .

[0653] (3) Preparation method of compound C12-1:

[0654] Compound G14 (600 mg), B12-1 (434 mg), tetrakis(triphenylphosphine palladium) (208 mg), and sodium carbonate (730 mg) were stirred in a mixture of dioxane (20 mL) and water (4 mL) and reacted at 110°C under nitrogen. After the reaction, the reaction solution was filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 110 mg of compound C12-1.

[0655] LC-MS: m / z 678.35 (M+Na) + .

[0656] (4) Preparation method of compound 33:

[0657] Compound C12-1 was dissolved in hydrochloric acid / methanol (10 mL) and refluxed at 80° C. with stirring for 48 h. After the reaction was complete, the mixture was directly concentrated to dryness and purified by preparative liquid separation to obtain compound 33 (49 mg).

[0658] LC-MS: m / z 472.22 (M+H) + .

[0659] 1 H NMR (500MHz, DMSO-d6) δ12.22(s,1H),8.28(s,2H),8.08(s,1H),7.89(d,J=5.9Hz,1H),7.31(s,2H),6.94(dd,J=17.7,11.2Hz,1H), 6.28(d,J=17.7Hz,1H),5.76(d,J=11.3Hz,1H),4.25-4.17(m,1H),3.81(s,2H),3.72(s,3H),0.95-0.91(m,2H),0.84-0.79(m,2H).

[0660] Example 34: Preparation of Compound 34

[0661] (1) Preparation method of compound A13-1:

[0662] 3-Ethynylthiazole (2700 mg), tri-n-butyl methoxytin (9640 mg), and zinc bromide (282 mg) were dissolved in tetrahydrofuran (27 mL) and reacted at 20-30°C for 27 h. After completion of the reaction, water (40 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine (60 mL), dried, and filtered. The filtrate was concentrated to dryness at 45-55°C to obtain 8.10 g of compound A13-1.

[0663] (2) Preparation method of compound B13-1:

[0664] Compound L1 (248 mg), compound A13-1 (2532 mg), tetrakistriphenylphosphine palladium (152.4 mg), and sodium carbonate (280 mg) were dissolved in a 1,4-dioxane-water (v:v = 5:1) mixed solvent (14.9 mL). The reaction solution was reacted in a microwave reactor (130°C, 100W) under a nitrogen atmosphere for 1 h. After the reaction was complete, the solution was filtered and concentrated at 45-55°C. The concentrate was dissolved in ethyl acetate (20 mL) and then washed with water and saturated brine. The organic phase was separated, dried, and concentrated at 45-55°C to obtain 280 mg of compound B13-1. ESI-MS: m / z = 637.26 [M+H] + .

[0665] (3) Preparation method of compound 34:

[0666] B13-1 (280 mg) and trifluoroacetic acid (1.2 mL) were dissolved in dichloromethane (15.2 mL). The reaction was allowed to proceed at 10-30°C for approximately 3.5 h. After the reaction was complete, the filtrate was concentrated at 35-50°C until no liquid flowed out. Dichloromethane (15 mL) was then added and the mixture was evaporated to dryness. This was repeated four times (each time under high vacuum for at least 30 minutes). The product was purified by preparative liquid chromatography (HPLC column: YMC AQ C18, 50*250 mm, 10 μm, mobile phase: A: acetonitrile; B: 0.1% FA, elution gradient: 17-47A-60 min; λ = 254 nm; V = 60 mL / min) to obtain 72 mg of compound 34. ESI-MS: m / z = 537.17 [M+H] + .

[0667] 1 H NMR(500MHz,DMSO-d6)δ12.43(s,1H),8.27(s,1H),8.21-7.98(m,2H),7.92(d,J=5.5Hz,1H),7.82-7.6 1(m,3H),7.34(d,J=5.0Hz,1H),4.20(dq,J=6.0,3.0Hz,1H),3.79(d,J=4.8Hz,5H),1.03-0.75(m,4H).

[0668] Example 35: Preparation of Compound 35

[0669] (1) Preparation method of compound A14-1:

[0670] Dissolve phenylacetylene (2529 mg) in tetrahydrofuran (46 mL), replace the atmosphere with nitrogen, and cool to -78°C. Add 1N lithium (trimethylsilyl)amide in tetrahydrofuran (30.5 mL) dropwise, stirring for 1 hour. Add tributyltin chloride (9946 mg) dropwise, and heat to 20-30°C for 1.5 hours. After completion, quench the reaction with saturated aqueous ammonium chloride (50 mL). Extract with ethyl acetate, separate the organic phase, wash with brine, dry, filter, and concentrate at 45-55°C to yield 9.80 g of compound A14-1.

[0671] (2) Preparation method of compound B14-1:

[0672] Compound L1 (282 mg), compound A14-1 (2940 mg), tetrakistriphenylphosphine palladium (173.4 mg), and sodium carbonate (318 mg) were dissolved in a 1,4-dioxane-water (v:v = 5:1) mixed solvent (14.1 mL). The reaction mixture was reacted in a microwave reactor (130°C, 100W) under a nitrogen atmosphere for 1 h. After completion of the reaction, the mixture was filtered and concentrated at 45-55°C. The concentrate was dissolved in ethyl acetate (20 mL) and then washed with water and saturated brine. The separated organic phase was dried and concentrated at 45-55°C to obtain 350 mg of compound B14-1. ESI-MS: m / z = 631.29 [M+H] + .

[0673] (3) Preparation method of compound 35:

[0674] Dissolve B14-1 (350 mg) and trifluoroacetic acid (3.3 mL) in dichloromethane (9.5 mL) and react at 10-30°C for 5.0 h. After the reaction was complete, the filtrate was concentrated at 35-50°C, dichloromethane (15 mL) was added, and the mixture was rotary evaporated to dryness. This was repeated four times (each time under high vacuum for more than 30 minutes). The product was then purified by preparative liquid chromatography (chromatographic column: YMC AQ C18, 50*250 mm, 10 μm, mobile phase: A: acetonitrile; B: 0.1% FA, elution gradient: 15-45 Å-60 min; λ = 254 nm; V = 60 mL / min; desalting: chromatographic column: YMC, TA-C18, 30*250 mm, 10 μm, mobile phase: A: acetonitrile; B: 0.1% aqueous ammonia, elution gradient: 5-5 Å-20 min-95-40 min; λ = 254 nm; V = 40 mL / min) to give 32 mg of compound 35. ESI-MS: m / z = 531.29 [M+H] + .

[0675] 1H NMR(500MHz,DMSO-d6)δ12.44(s,1H),8.36-8.09(m,2H),7.96(d,J=5.4Hz,1H),7.84- 7.57(m,4H),7.49(q,J=8.1,6.9Hz,3H),4.21(s,1H),3.80(s,5H),0.98-0.78(m,4H).

[0676] Example 36: Preparation of Compound 36

[0677] (1) Preparation method of compound A20-1:

[0678] 1-Methyl-1H-pyrazoleacetylene (1485 mg) was dissolved in tetrahydrofuran (40 mL), replaced with nitrogen, and cooled to -78°C. A 2.5N solution of n-butyllithium in hexane (6.2 mL) was added dropwise, and the mixture was stirred for 0.5 h. Tributyltin chloride (4792 mg) was added dropwise, and the reaction was continued for 4 h. The reaction was then heated to 20-30°C for 20 h. After completion of the reaction, saturated aqueous ammonium chloride (50 mL) was added to quench the reaction. The mixture was extracted with n-hexane, and the organic phase was washed with brine (150 mL). After drying, the filtrate was filtered, and the filtrate was concentrated to dryness at 45-55°C to obtain 5.55 g of compound A20-1.

[0679] (2) Preparation method of compound B20-1:

[0680] Compound L1 (226 mg), compound A20-1 (1036 mg), tetrakistriphenylphosphine palladium (138 mg), and sodium carbonate (255 mg) were dissolved in a 1,4-dioxane-water (v:v = 5:1) mixed solvent (17 mL). The reaction mixture was reacted in a microwave reactor (130°C, 100W) under a nitrogen atmosphere for 1 h. After completion of the reaction, the mixture was filtered and concentrated at 45-55°C. The concentrate was dissolved in ethyl acetate (20 mL) and then washed with water and saturated brine. The organic phase was separated, dried, filtered, and the filtrate was purified by silica gel column chromatography to obtain 278 mg of compound B20-1. ESI-MS: m / z = 635.37 [M+H] + .

[0681] (3) Preparation method of compound 36:

[0682] Compound B20-1 (278 mg) and trifluoroacetic acid (3.2 mL) were dissolved in dichloromethane (7.5 mL). The reaction was allowed to proceed at 10-30°C for 5 h. After completion of the reaction, the filtrate was concentrated at 35-50°C, dichloromethane (15 mL) was added, and the mixture was evaporated to dryness. This was repeated four times (each time under high vacuum for at least 30 minutes). The product was then purified by preparative liquid chromatography (HPLC conditions: column YMC*GEL ODS-AQ-HG, size 50*250, 10 μm, mobile phase: A: 0.1% formic acid / water, B: acetonitrile; gradient: 5% B to 65% B (0-60 min), wavelength 254 nm, v = 60 ml / min) to yield 47 mg of compound 36. ESI-MS: m / z = 535.26 [M+H] + .

[0683] 1 H NMR (500MHz, DMSO-d6) δ12.64(s,1H),8.30(s,1H),8.25(s,2H),8.23-8.13(m,2H),7.85(d,J=5.6Hz,1H),7.79 (d,J=1.8Hz,2H),7.59(dd,J=8.4,1.6Hz,1H),4.05(d,J=2.4Hz,2H),3.83(d,J=44.2Hz,7H),0.97-0.77(m,4H).

[0684] Example 37: Preparation of Compound 37

[0685] (1) Preparation of Compound C21-1:

[0686] Compound B21 (570 mg), compound G1 (374 mg), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (327 mg), and cesium fluoride (1.37 g) were dissolved in dioxane-water (5:1, v / v) (40 mL) and heated to 85°C under a nitrogen atmosphere for reaction. After completion of the reaction, the mixture was cooled to room temperature, water was added, and extraction was performed with EA. The organic phase was separated, washed with water and saturated brine, and concentrated to dryness at 40-50°C to obtain compound C21-1. ESI-MS: m / z = 575.29 [M+H] +

[0687] (4) Preparation method of compound 37:

[0688] Compound C21-1 (1 g), trifluoroacetic acid (2 mL), and dichloromethane (10 mL) were reacted at room temperature. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by preparative liquid phase separation (HPLC conditions: column TMC AQ C18 50*250 mm 10 μm; mobile phase: A: 0.1% formic acid in water, B: acetonitrile; gradient: 10% B to 80% B (0-60 min)) to obtain compound 37. ESI-MS: m / z = 475.22 [M+H] + .

[0689] 1 H NMR(500MHz DMSO-d6)δH 12.89(s,1H),8.37(s,3H),8.35(s,1H,),8.15(d,J=8.3Hz,1H),7.84(d,J=1.2Hz,1H),7.81(d,J=6.0Hz,1H),7.48(dd,J=8 .3,1.2Hz,1H),5.69-5.60(m,1H),4.50-4.28(m,2H),4.30-4.20(m,1H),3.78(s,3H),0.99-0.85(2H,m),0.85-0.61(m,2H).

[0690] Example 38: Preparation of Compound 38

[0691] (1) Preparation method of compound B23:

[0692] Referring to the preparation method of compound 12 in step (1) of Example 12, compound B12 was replaced with compound N2, and compound M2 was replaced with compound L1 to obtain 780 mg of compound B23-1. ESI-MS: m / z=635.37 [M+H] + .

[0693] (2) Preparation method of compound 38:

[0694] Compound 38 was prepared by referring to the preparation method of compound 3 in step (3) of Example 3, substituting compound B23-1 for compound B3. Preparative liquid phase purification conditions: Column: YMC AQ C18, dimensions 50 x 250 mm, 10 x 2, mobile phase: A: 30 mM ammonium acetate, B: acetonitrile; gradient: 20%-80% B over 60 min, wavelength 254 nm, v = 60 ml / min. ESI-MS: m / z = 535.26 [M+H] + .

[0695] 1H NMR (500MHz, DMSO-d6) δ12.87(s,1H),8.34(s,1H),8.17(d,J=8.3Hz,1H),7.93(d,J=5.5Hz,1H),7.86(t,J=2.2Hz,2H),7.55-7.4 7(m,1H),6.64(d,J=2.4Hz,1H),4.37(q,J=16.1Hz,2H),3.90(s,3H),3.81(s,3H),0.94(td,J=5.9,2.8Hz,2H),0.88-0.79(m,2H).

[0696] (3) Preparation of Compounds 38a and 38b:

[0697] Compound 38 was subjected to chiral separation (LC conditions (separation): CHIRALPAK IG column, size 20*250, 5 μm, mobile phase: A: n-hexane, B: ethanol; gradient: 10% B-70% B (0-60 min), wavelength 254 nm, v = 10 ml / min) to afford compounds 38a and 38b. 38a and 38b: ESI-MS: m / z = 535.26 [M+H] + .

[0698] Example 39: Preparation of Compound 39

[0699] (1) Preparation method of compound A24-1:

[0700] Referring to the preparation method of A22 in step (1) of Example 22, 5-alkyne pyrimidine was used to replace 1-methyl-1H-pyrazole ethynylene to obtain 5910 mg of compound A24-1.

[0701] (2) Preparation method of compound B24-1:

[0702] Referring to the preparation method of compound 12 in step (1) of Example 12, compound A24-1 was substituted for compound B12, and compound L1 was substituted for compound M2 to obtain 300 mg of compound B24-1. ESI-MS: m / z=633.29 [M+H] + .

[0703] (3) Preparation method of compound 24:

[0704] Referring to the preparation method of compound 3 in step (3) of Example 3, compound B24-1 was substituted for compound B3 to prepare compound 39. Purification by preparative liquid phase (HPLC conditions: column: YMC-Triart Prep C18-S, 50*250mm 10μm; A: 0.1% aqueous ammonia, B: acetonitrile; gradient: 90% A-10% B to 10% A-70% B (0-60min); λ: 254nm, V: 50mL / min, rt 40min). ESI-MS: m / z = 533.28 [M+H] + .

[0705] 1 H NMR(500MHz,DMSO-d6)δ12.45(s,1H),9.28(s,1H),9.11(s,2H),8.28(s,1H),8.17(d,J=8.4H z,1H),8.03(d,J=5.4Hz,1H),7.81-7.67(m,2H),4.21(s,1H),3.80(s,4H),0.95-0.83(m,4H).

[0706] Example 40: Preparation of Compound 40

[0707] (1) Preparation method of compound A25-1:

[0708] Refer to the preparation method of A22 in step (1) of Example 22, replacing 1-methyl-1H-pyrazoleacetylene with 4-ethynylbenzonitrile to obtain 5668 mg of compound A25-1.

[0709] (2) Preparation method of compound B25-1:

[0710] Referring to the preparation method of compound 12 in step (1) of Example 12, compound A25-1 was substituted for compound B12, and compound L1 was substituted for compound M2 to obtain compound B25-1. ESI-MS: m / z=656.31 [M+H] + .

[0711] (3) Preparation method of compound 40:

[0712] Compound 40 was prepared by referring to the preparation method of compound 3 in step (3) of Example 3, substituting compound B25-1 for compound B3. Preparative liquid phase purification conditions: Column: YMC-Triart Prep C18-S 30*250mm 10μm; A: 0.1% formic acid, B: acetonitrile; Gradient: 90% A-10% B to 20% A-80% B (0-60 min); λ: 254 nm, V: 30 mL / min. ESI-MS: m / z = 556.31 [M+H] + .

[0713] 1 H NMR(500MHz,DMSO-d6)δ12.89(s,1H),8.40(s,3H),8.35(s,1H),8.15(d,J =8.3Hz,1H),8.02(d,J=5.5Hz,1H),7.98-7.94(m,2H),7.87(d,J=1.7Hz,1H ),7.84-7.80(m,2H),7.47(dd,J=8.3,1.7Hz,1H),4.45-4.35(m,2H),4.20 (tt,J=6.1,2.9Hz,1H),3.79(s,3H),0.96-0.91(m,2H),0.87-0.81(m,2H).

[0714] Example 41: Preparation of Compound 41

[0715] (1) Preparation method of compound A26-1:

[0716] Refer to the preparation method of A22 in step (1) of Example 22, replacing 1-methyl-1H-pyrazoleacetylene with p-trifluoromethylphenylacetylene to obtain 8.3 g of compound A26-1.

[0717] (2) Preparation method of compound B26:

[0718] Referring to the preparation method of compound 12 in step (1) of Example 12, compound A26-1 was substituted for compound B12, compound L1 was substituted for compound M2, and cesium fluoride was substituted for sodium carbonate to obtain 623 mg of compound B26-1. ESI-MS: m / z = 699.34 [M+H] + .

[0719] (3) Preparation method of compound 26:

[0720] Compound B26-1 (623 mg) was dissolved in a 4 M solution of hydrogen chloride in ethyl acetate (10 mL). The reaction was allowed to proceed at room temperature for 2 h. After the reaction was complete, the filtrate was concentrated at 35-50°C until no liquid flowed out. The product was then purified by preparative liquid chromatography (HPLC conditions: column: YMC AQ C18 30*250mm 10 μm; A: 20 mM ammonium acetate; B: acetonitrile; gradient: 15% B-60% B (0-70 min). Desalting: A: 0.1% acetic acid; B: acetonitrile; gradient: 15% B-60% B (0-70 min); λ: 254 nm, V: 40 mL / min) to afford compound 41 (54 mg). ESI-MS: m / z = 599.32 [M+H] + .

[0721] 1 H NMR (500MHz, DMSO-d6) δ12.47(s,1H),8.29(s,1H),8.17(d,J=8.2Hz,1H),8.03(d,J=5.5Hz,1H),7.87(t,J=6.0Hz,4H),7.77(d,J=1 .7Hz,1H),7.73-7.68(m,1H),4.26-4.16(m,1H),3.82(s,3H),3.80(s,2H),0.94(dt,J=6.3,3.6Hz,2H),0.84(dt,J=5.8,3.2Hz,2H).

[0722] Example 42: Preparation of Compound 42

[0723] (1) Preparation method of compound A27-1:

[0724] Trimethylsilyldiazomethane (2M, 6mL) and tetrahydrofuran (80mL) were slowly added dropwise to potassium bis(trimethylsilyl)amide (1M, 11mL) at -78°C under a nitrogen atmosphere. The mixture was allowed to react at the same temperature for 30 minutes. After completion, a solution of 3-furfural (1g) in tetrahydrofuran (20mL) was slowly added dropwise. The mixture was heated to an ice bath with stirring. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction in an ice bath. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was separated, washed with saturated brine, dried, and concentrated to dryness at 40-50°C to yield compound A27-1.

[0725] (2) Preparation method of compound B27-1:

[0726] Referring to the preparation method of A22 in step (1) of Example 22, compound A27-1 was used to replace 1-methyl-1H-pyrazole ethyne to obtain compound B27-1.

[0727] (3) Preparation method of compound C27-1:

[0728] Referring to the preparation method of compound 12 in step (1) of Example 12, compound B27-1 was substituted for compound B12, and compound L1 was substituted for compound M2 to obtain compound C27-1. ESI-MS: m / z = 621.33 [M+H] + .

[0729] (4) Preparation method of compound 42:

[0730] Compound 42 was prepared by referring to the preparation method of compound 3 in step (3) of Example 3, replacing compound B3 with compound C27-1. Preparative liquid phase separation (liquid phase conditions: chromatographic column: YMC TA C18 (30*250mm 10μm) mobile phase A: 0.05% ammonia water B: acetonitrile elution gradient: 0-5 min 15% B, 5-10 min 15%-40% B, 10-85 min 40%-65% B) was performed to obtain compound 42. ESI-MS: m / z = 521.30 [M+H] + .

[0731] Example 43: Preparation of Compound 43

[0732] (1) Preparation method of compound 28:

[0733] 5-Chloro-1-pentyne (1.02 g) was dissolved in tetrahydrofuran (25 mL), the atmosphere was replaced with nitrogen, and the temperature was lowered to -30°C. A 2.5 M n-butyllithium solution in n-hexane (8.2 mL) was added dropwise, increasing the temperature to 10 drops. The mixture was allowed to react for 1 hour. Tributyltin chloride (3.26 g) was added, and the temperature was raised to 65°C for 4 hours. After the reaction, ethyl acetate (150 mL) and saturated sodium bicarbonate solution (30 mL) were added for washing. The organic phase was separated, washed with saturated brine, dried, and concentrated to dryness at 45-55°C to obtain 3250 mg of compound A7-1.

[0734] Referring to the preparation method of Compound 12 in Step (1) of Example 12, Compound A7-1 was substituted for Compound B12 to obtain Compound 43. Preparative liquid phase purification conditions: Novasep C18 250*50mm, 10um column; methanol-0.1% formic acid aqueous solution (10%-50%-90% / 0-60-100min gradient elution, 8mg Rt 63min). ESI-MS: m / z = 510.25 [M+H] + .

[0735] 1H NMR (500MHz, DMSO-d6) δ12.25(s,1H),8.30(s,2H),8.09(s,1H),7.71(d,J=5.6Hz,1H),6.63(d,J=41.5Hz,2H),4.14(tt ,J=6.2,3.0Hz,2H),3.79(d,J=85.2Hz,6H),1.68(tt,J=8.4,5.0Hz,1H),0.98(dq,J=6.8,3.9Hz,2H),0.91-0.77(m,6H).

[0736] Example 44: Preparation of Compound 44

[0737] (1) Preparation method of compound A37-1:

[0738] Compound J1 (2.9 g), pinacol diboronate (3.0 g), Pd(dppf)Cl2 (2.1 g), and potassium acetate (2.9 g) were added to 1,4-dioxane (60 mL). After nitrogen displacement, the reaction was allowed to proceed at 100°C for 5 h. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to dryness and subjected to column chromatography to obtain 3.1 g of compound A37-1. ESI-MS: m / z = 302.08 [M+H] + .

[0739] (2) Preparation method of compound B37-1:

[0740] Compound A37-1 (3.0 g), 2,2-difluorovinyl 4-methylbenzenesulfonate (3.5 g), Pd(dppf)Cl2 (2.9 g), sodium iodide (3.0 g), and sodium carbonate (3.2 g) were added to a 120 mL mixture of tetrahydrofuran and water (5:1). The reaction mixture was stirred at 70°C under a nitrogen atmosphere for 2.5 h. After the reaction was complete, the mixture was filtered and concentrated at 35-45°C until no liquid was present. The mixture was then purified by column chromatography to yield 1.1 g of compound B37-1. ESI-MS: m / z = 320.13 [M+H] + .

[0741] (3) Preparation method of compound C37-1:

[0742] Referring to the preparation method of K1 in step (11) of Example 1, compound B37-1 was substituted for compound J1 to obtain compound C37-1 (830 mg). ESI-MS: m / z = 446.03 [M+H] + .

[0743] (4) Preparation method of compound D37-1:

[0744] Compound C37-1 (670 mg), compound G1 (780 mg), cataCXium A Pd G3 (109 mg), and cesium fluoride (1368 mg) were added to a 1,4-dioxane-water (5:1) solvent mixture (40 mL). The reaction mixture was incubated at 60°C for 3 h under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered, concentrated at 35-45°C, and purified by column chromatography to yield 1.1 g of compound D37-1. ESI-MS: m / z = 593.32 [M+H] + .

[0745] (5) Preparation method of embodiment 44:

[0746] Compound D37-1 (830 mg) was dissolved in a 4 M solution of hydrogen chloride in ethyl acetate (15 mL). The reaction was allowed to proceed at room temperature for 2 h. After the reaction was complete, the filtrate was concentrated at 35-45°C until no liquid outflowed. The product was then purified by preparative liquid chromatography (HPLC conditions: column: YMC AQ C18, 50*250 mm 10 μm; A: acetonitrile; B: 0.05% aqueous acetic acid; gradient: 15% A-45% A (0-60 min). λ: 254 nm, V: 60 mL / min). The resulting eluate was added with hydrochloric acid (2 M, 20 mL) and concentrated to dryness to obtain compound 44. ESI-MS: m / z = 493.24 [M+H] + .

[0747] Example 45: Preparation of Compound 45

[0748] (1) Preparation method of compound A38-1:

[0749] Compound A37-1 (3.0 g), iodotrifluoroethylene (3.2 g), Pd(dppf)Cl2 (1.5 g), and sodium carbonate (2.6 g) were added to a 10 mL mixture of tetrahydrofuran and water (5:1). The reaction mixture was stirred at 70°C under a nitrogen atmosphere for 3.5 h. After completion of the reaction, the mixture was filtered, concentrated at 35-45°C, and purified by column chromatography to obtain 1.6 g of compound A38-1. ESI-MS: m / z = 338.14 [M+H] + .

[0750] (2) Preparation method of compound B38-1:

[0751] Referring to the preparation method of step (11) K1 in Example 1, compound A38-1 was used to replace compound J1 to obtain compound B38-1 (320 mg).

[0752] (3) Preparation method of compound C38-1:

[0753] Referring to the preparation method of D37-1 in step (4) of Example 44, compound B38-1 (463 mg) was substituted for compound C37-1 to obtain 50 mg of compound C38-1. Preparative liquid phase purification conditions: Column: YMC AQ C18, 50 x 250 mm, 10 μm; A: 0.05% acetic acid in water; B: acetonitrile; Gradient: 35% B to 70% B (0-60 min). λ: 254 nm, V: 60 mL / min. ESI-MS: m / z = 611.40 [M+H] + .

[0754] (4) Preparation method of Example 45:

[0755] Compound C38-1 (10 mg) was dissolved in a 4 M solution of hydrogen chloride in ethyl acetate (2 mL). The reaction was allowed to proceed at room temperature for approximately 2 h. After the reaction was complete, the mixture was concentrated to dryness to obtain compound 45. ESI-MS: m / z = 511.20 [M+H] + .

[0756] 1 H NMR (500MHz, DMSO-d6) δ12.88(s,1H),8.60(d,J=5.9Hz,3H),8.40(s,1H),8.14(d,J=8.3Hz,1H),7.93(d,J=5.4Hz,1H),7.82(d,J=1.6H z,1H),7.50(dd,J=8.3,1.6Hz,1H),4.32(dd,J=5.9,2.6Hz,2H),4.27-4.20(m,1H),3.79(s,3H),0.95-0.90(m,2H),0.88-0.78(m,2H).

[0757] Example 46: Preparation of Compound 46

[0758] (1) Preparation of Compound A15-1

[0759] Refer to the preparation method of step (2) B12 in Example 12, replacing 3,3-dimethyl-1-butyne with methyl propargyl ether to obtain 9.00 g of compound A15-1.

[0760] (2) Preparation of Compound 46

[0761] Refer to the preparation method of compound 12 in step (1) of Example 12, replace B12 with compound A15-1, and purify by preparative liquid phase to obtain compound 46. ESI-MS: m / z=514.29 [M+H] + .

[0762] Example 47: Preparation of Compounds 47, 47a & 47b

[0763] (1) Preparation of Compound A47:

[0764] Compound G2 (40 g) was added to ethanol (600 mL), followed by sodium borodeuteride (740 mg) at 0°C and calcium chloride (13 g). After addition, the reaction system was returned to room temperature and stirred for 1 h before quenching. Saturated ammonium chloride solution (2 L) was added to quench the reaction. The ethanol in the reaction system was then concentrated to dryness, diluted with water (2 L), and filtered. The filter cake was washed with additional water, and methanol (2 L) was added to slurry for 10 h. Filtered to obtain 30 g of compound A47. ESI-MS: m / z = 356.09 [M+H]. + .

[0765] (2) Preparation of Compound B47:

[0766] Compound A47 (30 g) was added to ethyl acetate (200 mL), followed by thionyl chloride (200 mL). After stirring for 5 min, N,N-dimethylformamide (3 mL) was added and stirred at 70°C for 0.5 h until the reaction was complete. The reaction system was concentrated to dryness, stirred with petroleum ether for 0.5 h, and then filtered to obtain 28 g of compound B47. ESI-MS: m / z = 372.18 [MH] - .

[0767] (3) Preparation method of compound C47:

[0768] Bis(tert-butyloxycarbonyl)amine (5.7 g) was added to tetrahydrofuran (150 mL). Lithium bis(trimethylsilyl)amide (1 M, 28 mL tetrahydrofuran solution) was slowly added at -30°C. After stirring at the same temperature for 10 minutes, the mixture was heated to 0°C and stirred for 30 minutes. A tetrahydrofuran solution of B47 (9.3 g) (150 mL) was then added. The mixture was added dropwise and stirred at room temperature for 5 hours before stopping the reaction. After completion of the reaction, a saturated solution of ammonium chloride (200 mL) was added to quench the reaction. Ethyl acetate was added for washing and extraction. The resulting organic phase was washed with pure water and saturated brine in sequence. The organic phase was concentrated to dryness to obtain 10 g of compound C47. ESI-MS: m / z = 578.96 [M+Na] + .

[0769] (4) Preparation method of compound D47:

[0770] Compound C47 (3.8 g), pinacol diboronate (2.6 g), Pd(dppf)Cl2*CH2Cl2 (486 mg), and potassium acetate (2.0 g) were stirred in dioxane (200 mL) and reacted at 100°C under nitrogen for 5 h. After the reaction, the reaction solution was filtered, concentrated under reduced pressure, and slurried with a mixture of petroleum ether and ethyl acetate for 1 h. Filtration afforded 4.1 g of compound D47. ESI-MS: m / z = 421.22 [M-Boc-diisopropyl+3H] + .

[0771] (5) Preparation of Compound E47:

[0772] Compound J1 (3.0 g), tributyl propargyl stannane (9.8 g), tetrakis(triphenylphosphine palladium) (2.4 g), and cesium fluoride (4.6 g) were stirred in a mixture of dioxane (40 mL) and water (8 mL) and reacted at 100°C under nitrogen. After the reaction, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain J1-1 (2.8 g). LC-MS: m / z 296.15 (M+H). + .

[0773] Compound J1-1 (2.8 g) and N-iodosuccinimide (4.2 g) were stirred in acetic acid (30 mL) and reacted at 80°C under nitrogen for 3 hours. After the reaction, the reaction system was concentrated to dryness, and water (20 mL) and ethyl acetate (40 mL x 2) were added. The organic phases were combined and washed sequentially with saturated sodium bicarbonate and saturated sodium chloride solutions. The resulting organic phases were concentrated to dryness and purified by column chromatography to obtain compound F47 (2.4 g). LC-MS: m / z 422.13 (M+H) + .

[0774] Compound D47 (3.3 g), compound F47 (2.1 g), tetrakis(triphenylphosphine)palladium (867 mg), and sodium carbonate (2.1 g) were stirred in a mixture of dioxane (60 mL) and water (12 mL) and reacted at 85°C under nitrogen for 5 h. After the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain 3.1 g of compound E47. ESI-MS: m / z = 614.22 [M-Boc- t Bu+3H] + .

[0775] (6) Preparation of Compounds 47, 47a & 47b:

[0776] Compound E47 (3.1 g) was added to hydrogen chloride / methanol (4 M, 16 mL) and stirred at reflux at 80°C for 48 h. After completion of the reaction, the mixture was concentrated to dryness and slurried with a mixture of dichloromethane (10 mL) and methanol (1 mL) for 1 h. The mixture was filtered, and the filter cake was washed sequentially with saturated sodium bicarbonate solution and purified water. After drying, it was purified by preparative liquid chromatography (HPLC conditions: YMC TA C18, size 30*250 mm, 10 μm, mobile phase: A: 0.1% formic acid, B: acetonitrile; gradient: 20%-60% B-60 min, wavelength 254 nm, v = 30 ml / min, rt 26 min) to obtain 1.8 g of compound 47. ESI-MS: m / z = 486.21 [M+H] + .

[0777] 1 H NMR (500MHz, DMSO) δ12.22(s,1H),8.31(s,1H),8.08(d,J=2.5Hz,1H),7.75(dd,J=5.7,2.4Hz,1H),7.32(s,1H),6.67 -6.60(m,2H),3.73(d,J=2.4Hz,3H),2.17(d,J=2.4Hz,3H),2.05-1.91(m,1H),0.94-0.87(m,2H),0.84-0.75(m,2H).

[0778] Compound 47 was subjected to chiral separation (separation conditions: column YMC SA, dimensions 30 x 250 mm, 10 μm, mobile phase: A: n-hexane, B: 0.1% ethanolamine / ethanol; gradient: 20% B to 80% B (0-60 min), wavelength 254 nm, v = 40 ml / min; 47a - rt 23 min & 47b - rt 28 min) to afford 12 mg of compound 47a and 15 mg of compound 47b. 47a: ESI-MS: m / z = 486.20 [M+H] + &47b:ESI-MS:m / z=486.20[M+H] + .

[0779] Example 48: Preparation of Compounds 48-1, 48-2, 48-2a & 48-2b

[0780] (1) Preparation method of compound A48:

[0781] Referring to step (10) of Example 1, Compound A48A was used to replace 1-methyl-1H-pyrazole-5-boronic acid pinacol ester to obtain 10 g of Compound A48. ESI-MS: m / z = 278.12 [M+H-THP] +.

[0782] (2) Preparation method of compound B48:

[0783] Compound A48 (10 g) was added to methanol (150 mL) and concentrated hydrochloric acid (231 μL) was added dropwise at room temperature. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the reaction system was concentrated to dryness, and the concentrate was slurried in methanol for 1 h. The mixture was then filtered to obtain 6 g of compound B48. ESI-MS: m / z = 278.01 [M+H] + .

[0784] (3) Preparation method of compound C48:

[0785] Compound B48 (3.4 g) and NBS (2.4 g) were added to N,N-dimethylformamide (80 mL) and stirred at room temperature for 6 h. After the reaction, ethyl acetate (100 mL) and water (100 mL) were added for extraction. The resulting organic phase was washed sequentially with water and saturated brine, and concentrated to dryness to yield 6.5 g of compound C48. ESI-MS: m / z = 355.96 [M+H] + .

[0786] (4) Preparation method of compounds D48-1 and D48-2:

[0787] Compound C48 (5.6 g), potassium fluoride (2.4 g), and diethyl bromofluoromethylphosphonate (6.4 g) were added to acetonitrile (120 mL) and stirred at room temperature for 24 h. After the reaction was completed, ethyl acetate (100 mL) and water (100 mL) were added for extraction. The resulting organic phase was washed with water and saturated brine in sequence. The resulting organic phase was concentrated to dryness and purified by column chromatography to obtain 5.2 g of a mixture of compounds D48-1 and D48-2. ESI-MS: m / z = 405.98 [M+H] + .

[0788] (5) Preparation of Compounds E48-1 and E48-2:

[0789] In step (12) of Reference Example 2, the mixture of compound D48-1 and compound D48-2 was substituted for compound K1 to obtain 3 g of a mixture of compound E48-1 and compound E48-2. ESI-MS: m / z = 644.13 [M-Boc- t Bu+3H] + 、ESI-MS:m / z=644.13[M-Boc- t Bu+3H] + .

[0790] (6) Preparation method of compounds F48-1 and F48-2:

[0791] Referring to step (15) of Example 2, a mixture of compound E48-1 and compound E48-2 was substituted for compound M2, and tributyl propargyl stannane was substituted for compound N2. After the reaction, 400 mg of compound F48-1 and 410 mg of compound F48-2 were obtained by column chromatography. F48-1: ESI-MS: m / z = 648.18 [M-Boc- t Bu+3H] + . F48-2:ESI-MS:m / z=648.17[M-Boc- t Bu+3H] + .

[0792] (7) Preparation methods of compounds 48-1, 48-2, 48-2a and 48-2b:

[0793] Referring to step (13) of Example 2, compound F48-1 was used to replace compound L2, and the product was purified by preparative liquid phase (liquid phase conditions: column: YMC TA C18, 30*250mm 10μm; A: 0.1% ammonia water, B: acetonitrile; gradient: 15%-55% B (0-80min). λ: 254nm, V: 30mL / min. rt 71min) to obtain 36mg of compound 48-1.

[0794] Referring to step (13) of Example 2, compound F48-2 was used to replace compound L2, and the mixture was purified by preparative liquid phase (liquid phase conditions: column: TAC18, 50*250mm 10μm; A: acetonitrile, B: 0.1% ammonia water; gradient: 50%-80% (0-60min). λ: 254nm, V: 50mL / min. rt 44min) to obtain 27mg of compound 48-2.

[0795] Compound 48-1 ESI-MS: m / z = 520.27 [M+H] + .

[0796] 1 H NMR (500MHz, DMSO-d6) δ12.13(s,1H),8.44(s,1H),7.82(t,J=56.8Hz,1H),7.79(d,J=5.6Hz,1H),7 .39(s,2H),6.71(d,J=10.4Hz,2H),4.23-4.07(m,1H),3.65(s,2H),2.18(s,3H),1.09-0.66(m,4H).

[0797] Compound 48-2 ESI-MS: m / z = 520.26 [M+H] + .

[0798] 1 H NMR (500MHz, DMSO-d6) δ12.22(s,1H),8.46(s,1H),7.82(d,J=51.7Hz,1H),7.79(d,J=5.7Hz,1H),7 .40(s,2H),6.70(d,J=23.8Hz,2H),4.21-4.09(m,1H),3.76(s,2H),2.18(s,3H),0.98-0.73(m,4H).

[0799] The racemate of compound 48-2 was subjected to chiral resolution (resolution conditions: YMC SA, size 30*250 mm, 10 μm, mobile phase: A: n-hexane, B: 0.1% ethanolamine ethanol; gradient: 25% B isocratic, λ: 254 nm, V: 40 ml / min, to give compound 48-2a, rt 14 min, compound 48-2b, 17 min) to give 11 mg of compound 48-2a, ESI-MS: m / z = 520.20 [M+H] + ; 15 mg compound 48-2b, ESI-MS: m / z=520.21[M+H] + .

[0800] Compound 48-2b:

[0801] 1H NMR(500MHz,DMSO-d6)δ8.49(s,1H),8.32(s,2H),8.00-7.53(m,2H),6.75(s,1H),6.60(s ,1H),4.19-4.07(m,1H),3.98(s,2H),2.15(s,3H),0.96-0.84(m,2H),0.83-0.72(m,2H).

[0802] Example 49: Preparation of Compounds 49-1 and 49-2

[0803] (1) Preparation method of compounds A49-1 and A49-2:

[0804] 1H-pyrazole-3-boronic acid pinacol ester (9.7 g), deuterated iodomethane (10.9 g), and cesium carbonate (16.3 g) were added to acetonitrile (100 mL) and stirred at room temperature for 12 h. After the reaction was completed, the mixture was filtered with suction, and the filtrate was concentrated to dryness. Methyl tert-butyl ether (50 mL) was added and the mixture was stirred for 2 h. The mixture was filtered with suction, and the filtrate was concentrated to dryness to obtain 10 g of a mixture of compound A49-1 and compound A49-2.

[0805] (2) Preparation method of compounds B49-1 and B49-2:

[0806] Referring to step (10) of Example 1, a mixture of compound A49-1 and compound A49-2 was used to replace 1-methyl-1H-pyrazole-5-boronic acid pinacol ester to obtain 6 g of a mixture of compound B49-1 and compound B49-2. ESI-MS: m / z = 295.03 [M+H] + 、ESI-MS:m / z=295.04[M+H] +

[0807] (3) Preparation method of compounds C49-1 and C49-2:

[0808] In step (11) of Reference Example 1, a mixture of compound B49-1 and compound B49-2 was used to replace compound J1 to obtain 3 g of a mixture of compound C49-1 and compound C49-2. ESI-MS: m / z = 420.97 [M+H] + 、ESI-MS:m / z=420.98[M+H] + .

[0809] (4) Preparation method of compounds D49-1 and D49-2:

[0810] In step (12) of reference example 2, the mixture of compound C49-1 and compound C49-2 was substituted for compound K1 to obtain 3 g of a mixture of compound D49-1 and compound D49-2. ESI-MS: m / z=611.13 [M-Boc- t Bu+3H] + 、ESI-MS:m / z=611.13[M-Boc- t Bu+3H] + .

[0811] (5) Preparation of Compounds E49-1 and E49-2:

[0812] In step (15) of Example 2, a mixture of compound D49-1 and compound D49-2 was substituted for compound M2, and tributyl propynyl stannane was substituted for compound N2. Column chromatography was performed to obtain 200 mg of compound E49-1 and 230 mg of compound E49-2. E49-1: ESI-MS: m / z = 615.18 [M-Boc- t Bu+3H] + . E49-2: ESI-MS:m / z=615.17[M-Boc- t Bu+3H] + .

[0813] (6) Preparation method of compounds 49-1 and 49-2:

[0814] Referring to step (13) of Example 2, compound E49-1 was used to replace compound L2, and the product was purified by preparative liquid phase (liquid phase conditions: column: YMC AQ C18, 30*250mm 10μm; A: 0.1% acetic acid, B: acetonitrile; gradient: 10%-50% B (0-80min). λ: 254nm, V: 30mL / min. rt 34min) to obtain 20mg of compound 49-1.

[0815] Referring to step (13) of Example 2, compound E49-2 was used to replace compound L2, and the product was purified by preparative liquid phase (liquid phase conditions: column: YMC AQ C18, 30*250mm 10μm; A: 0.1% acetic acid, B: acetonitrile; gradient: 10%-50% B (0-80min). λ: 254nm, V: 30mL / min. rt 34min) to obtain 28mg of compound 49-2.

[0816] Compound 49-1 ESI-MS: m / z = 487.27 [M+H] + .

[0817] 1 H NMR(500MHz,DMSO-d6)δ12.08(s,1H),8.04(s,1H),7.75(d,J=5.6Hz,1H),7.30(s,2H),6.70 -6.67(m,1H),6.60(s,1H),4.16-4.10(m,1H),3.63(s,2H),2.17(s,3H),0.96-0.76(m,4H).

[0818] Compound 49-2 ESI-MS: m / z = 487.26 [M+H] + .

[0819] 1 H NMR(500MHz,DMSO-d6)δ12.11(s,1H),8.05(s,1H),7.76(d,J=5.6Hz,1H),7.31(s,2H),6.68(s,1H ),6.61(s,1H),4.19-4.10(m,1H),3.67(s,2H),2.17(s,3H),0.95-0.86(m,2H),0.83-0.77(m,2H).

[0820] Example 50: Preparation of Compound 50

[0821] (1) Preparation method of compound B50:

[0822] Compound J1 (291 mg), (1-fluorovinyl)methyldiphenylsilane (448 mg), lithium triphenylpalladium dichloride (70.1 mg), cuprous iodide (20 mg), and cesium fluoride (456 mg) were added sequentially to a reaction flask. 1.3-Dimethyl-2-imidazolidinone (20 mL) was added as solvent. Under a nitrogen atmosphere, the reaction was started at 50°C until completion. The mixture was filtered and purified by column chromatography to obtain 180 mg of compound B50. ESI-MS: m / z = 302.14 [M+H] + .

[0823] (2) Preparation method of compound C50:

[0824] Compound B50 (30.1 mg), acetic acid (1.0 mL), and iodosuccinimide (45 mg) were added sequentially to a 20 mL reaction flask. The reaction was allowed to complete at 80°C under a nitrogen atmosphere. The reaction was quenched with saturated sodium carbonate, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography to yield 24 mg of compound C50. ESI-MS: m / z = 428.08 [M+H] + .

[0825] (3) Preparation method of compound D50:

[0826] Compound C50 (21 mg), compound D47 (30 mg), tetrakis(triphenylphosphine)palladium (8 mg), and sodium carbonate (19 mg) were stirred in a mixture of dioxane (0.5 mL) and water (0.1 mL) and reacted at 85°C under nitrogen for 5 h. After completion, the filtrate was filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 12 mg of compound D50. ESI-MS: m / z = 620.21 [M-Boc- t Bu+3H] + .

[0827] (4) Preparation method of compound 50:

[0828] Compound D50 (10 mg) was added to hydrogen chloride / methanol (4 M, 0.3 mL) and stirred at reflux at 80°C for 48 h. After completion of the reaction, the mixture was concentrated to dryness and slurried with a mixture of dichloromethane (1 mL) and methanol (1 mL) for 1 h. The mixture was filtered and the filter cake was washed sequentially with saturated sodium bicarbonate solution and purified with water. After drying, it was purified by preparative liquid chromatography (HPLC conditions: (YMC AQ C18, size 30*250 mm, 10 μm, mobile phase: A: 0.1% acetic acid, B: acetonitrile; gradient: 10%-50% B (0-80 min), wavelength 254 nm, v = 30 ml / min, rt 40 min) to give 4 mg of compound 50. ESI-MS: m / z = 492.19 [M+H]+.

[0829] Example 51: Preparation of Compound 51

[0830] (1) Preparation method of compound A51:

[0831] In step (1) of Reference Example 21, B49 was used to replace J1 to obtain 1 g of compound A51. ESI-MS: m / z=305.06 [M+H] + .

[0832] (2) Preparation method of compound B51:

[0833] Referring to step (11) of Example 1, compound J1 was replaced with A51 to obtain 380 mg of compound B51. ESI-MS: m / z=431.03 [M+H] + .

[0834] (3) Preparation method of compound C51:

[0835] Referring to step (12) of Example 1, compound K1 was replaced with B51 to obtain 300 mg of compound C51. ESI-MS: m / z=578.15 [M+H] + .

[0836] (4) Preparation method of compound 51:

[0837] Referring to step (15) of Example 1, compound N1 was replaced with C51, and the resulting product was purified by preparative liquid phase (liquid phase conditions: column: YMC TA C18, 30*250mm 10μm; A: 0.1% formic acid in water; B: acetonitrile; gradient: 10%-70% B (0-60min). λ: 254nm, V: 40mL / min. rt 23.1min) to give 50mg of compound 51, ESI-MS: m / z=478.17 [M+H] + .

[0838] 1 H NMR (500MHz, DMSO-d6) δ12.60(s,1H),8.31(s,1H),8.15(d,J=8.3Hz,1H),7.81(d,J=5.9Hz,1H),7.77(d,J=1.6Hz,1H),7.63(dd,J=8.3,1 .5Hz,1H),5.65-5.55(m,1H),5.53-5.51(m,1H),4.24(tt,J=5.9,2.9Hz,1H),3.98(s,2H),0.91(dd,J=5.8,3.2Hz,2H),0.86-0.80(m,2H).

[0839] Example 52: Preparation of Compound 52

[0840] (1) Preparation method of compound A52:

[0841] Compound I1 (6780 mg), compound A52A (5618 mg), P(t-Bu)2(n-Bu)Pd G3 (1144 mg), and potassium phosphate (9551 mg) were dissolved in 505 mL of a mixture of 1,4-dioxane and water (v:v 5:1). The reaction mixture was stirred at 80°C for 2 h under a nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature and filtered. The filtrate was concentrated to dryness at 50-60°C, and ethyl acetate (150 mL) was added. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 3220 mg of compound A52. ESI-MS: m / z = 318.07 [M+H]. + .

[0842] (2) Preparation method of compound B52:

[0843] Compound A52 (302 mg) and N-iodosuccinimide (428 mg) were added to 18 mL of glacial acetic acid and stirred at 80°C under a nitrogen atmosphere for 2 h. After completion, the reaction was concentrated to dryness at 55-60°C, and ethyl acetate (15 mL) and water (15 mL) were added. The aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phases were washed with saturated sodium bicarbonate solution and saturated brine. Purification by column chromatography afforded 420 mg of compound B52. ESI-MS: m / z = 443.99 [M+H] + .

[0844] (3) Preparation method of compound C52:

[0845] Referring to step (12) of Example 2, compound B52 was used to replace compound K1 to obtain 345 mg of compound C52. ESI-MS: m / z=634.2 [M-Boc- t Bu+3H] + .

[0846] (4) Preparation method of compound 52:

[0847] C52 (201 mg) was added to anhydrous methanol (4.0 mL) and a 10 M solution of hydrogen chloride in ethyl acetate (3 mL). The reaction was heated to 80°C for 24 h. After completion of the reaction, the filtrate was concentrated to dryness and purified by preparative liquid chromatography (YMC AQ C18, size 50*250 mm, 10 μm, mobile phase: A: 0.1% formic acid, B: acetonitrile; gradient: 10%-50% B over 60 min, wavelength 254 nm, v = 50 ml / min, rt 44.1 min) to afford 12 mg of compound 52. ESI-MS: m / z = 506.22 [M+H]+ .

[0848] 1 H NMR(500MHz,DMSO-d6)δ12.19(s,1H),8.03(s,1H),7.96(d,J=5.9Hz,1H),7.29(s,2H),6.64(s,1H),6.59(s,1H ), 4.16 (s, 2H), 3.47 (td, J = 7.4, 3.8Hz, 2H), 1.20 (s, 2H), 1.00-0.96 (m, 2H), 0.88 (d, J = 7.1Hz, 2H), 0.79 (s, 2H).

[0849] Example 53: Preparation of Compound 53

[0850] Referring to step (1) of Example 4, M2 was replaced with compound 52, and the product was purified by preparative liquid phase (YMC AQ C18, size 50*250 mm, 10 μm, mobile phase: A: 0.1% formic acid, B: acetonitrile; gradient: 20%-60% B-60 min, wavelength 254 nm, v = 50 ml / min, rt 30.4 min) to obtain 10 mg of compound 53. ESI-MS: m / z = 510.29 [M+H] + .

[0851] 1 H NMR (500MHz, DMSO-d6) δ12.22(s,1H),8.29(s,1H),7.74(d,J=5.6Hz,1H),7.31(s,2H),6.63(d,J=1.6Hz,1H),6.60(d,J=1.5Hz,1H),4.15(dd,J =6.0,2.9Hz,1H),3.83(s,2H),3.45(tt,J=7.3,3.7Hz,1H),2.15(s,3H) ,0.98(p,J=2.6Hz,2H),0.90-0.85(m,4H),0.79(dt,J=6.1,2.9Hz,2H).

[0852] Example 54: Preparation of Compound 54:

[0853] (1) Preparation method of compound A54:

[0854] Compound C52 (320 mg), methylboronic acid (120 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (28 mg), and potassium carbonate (166 mg) were added to 1,4-dioxane (4 mL) and reacted at 100°C until complete. Water (20 mL) and ethyl acetate (20 mL) were added to the reaction solution, stirred for 10 min, and the layers were separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 365 mg of compound A54. ESI-MS: m / z = 792.30 [M+Na] + .

[0855] (2) Preparation method of compound 54:

[0856] Referring to step (3) of Example 26, Compound A54 was substituted for Compound B26, and the mixture was purified by preparative HPLC (HPLC conditions: column YMC AQ C18, size 30*250, 10 μm, mobile phase: A: acetonitrile, B: 0.1% acetic acid aqueous solution, gradient: 10% B-50% B (0-80 min), wavelength 254 nm, v = 60 mL / min, rt 32 min) to obtain 89 mg of Compound 54. ESI-MS: m / z = 486.17 [M+H] + .

[0857] 1 H NMR (500MHz, DMSO-d6) δ12.22-12.06(br,1H),7.99(s,1H),7.70(d,J=5.9Hz,1H),7.45-7.15(br,2H),6.73(d,J=1.5Hz,1H),6.57(d,J=1.5Hz,1H),4 .12-4.07(m,1H),3.67(s,3H),3.45-3.39(m,2H),2.45(d,J=2.0Hz,3H),1 .08-1.02(m,1H),1.02-0.95(m,1H),0.92-0.84(m,4H),0.83-0.76(m,2H).

[0858] Example 55: Preparation of Compound 55

[0859] (1) Preparation method of compound A55:

[0860] Referring to step (1) of Example 21, Compound A52 was used to replace Compound J1 to obtain 230 mg of Compound A55, ESI-MS: m / z=328.15 [M+H] + .

[0861] (2) Preparation method of compound B55:

[0862] Referring to step (2) of Example 52, Compound A52 was replaced with Compound A55 to obtain 300 mg of Compound B55. ESI-MS: m / z = 454.08 [M+H] + .

[0863] (3) Preparation method of compound C55:

[0864] Referring to step (12) of Example 1, compound K1 was replaced with compound B55 to obtain 270 mg of compound C55, ESI-MS: m / z=601.35 [M+H] + .

[0865] (4) Preparation method of compound 55:

[0866] Referring to step (3) of Example 3, compound C55 was substituted for compound B3, and the product was purified by preparative liquid phase (YMC AQ C18, size 50*250 mm, 10 μm, mobile phase: A: 0.1% formic acid, B: acetonitrile; gradient: 30%-70% B-60 min, wavelength 254 nm, v = 50 ml / min, rt 17.2 min) to obtain 48 mg of compound 55, ESI-MS: m / z = 501.35 [M+H] + .

[0867] 1 H NMR(500MHz,DMSO-d6)δ12.84(s,1H),8.29(s,1H),8.15(d,J=8.1Hz,2H),7.8 2(d,J=5.9Hz,2H),7.51(d,J=8.4Hz,1H),5.55(d,J=18.8Hz,2H),4.31(d,J=8. 6Hz, 2H), 4.25 (dt, J=6.2, 3.0Hz, 1H), 3.55 (dd, J=7.3, 3.7Hz, 1H), 1.15 (t, J= 7.2Hz, 3H), 1.07 (dd, J = 9.2, 4.9Hz, 1H), 1.03-0.99 (m, 1H), 0.86-0.79 (m, 3H).

[0868] Example 56: Preparation of Compound 56

[0869] (1) Preparation method of compound A56:

[0870] Referring to step (12) of Example 2, compound B55 was used in place of compound K1 to obtain 130 mg of compound A56. ESI-MS: m / z = 644.35 [M-Boc-tBu+3H] + .

[0871] (2) Preparation method of compound 56:

[0872] Referring to step (4) of Example 52, Compound A56 was used to replace Compound C52, and the product was purified by preparative liquid phase (YMC TA C18, size 30*250 mm, 10 μm, mobile phase: A: 0.1% acetic acid, B: acetonitrile; gradient: 10%-70% / 0-45 min, wavelength 254 nm, v = 40 ml / min, rt 24.5 min) to obtain 14 mg of Compound 56, ESI-MS: m / z = 516.21 [M+H] + .

[0873] 1 H NMR (500MHz, DMSO-d6) δ12.11(s,1H),8.03(s,1H),7.80(d,J=5.8Hz,1H),7.31(s,2H),6.70(s,1H),6.63(s,1H),5.65-5.50(m,2H),4.24(tt,J= 5.9,2.9Hz,1H),3.66(s,2H),1.24(s,1H),1.06(d,J=10.2Hz,1H),1.00 (dt,J=10.2,4.0Hz,1H),0.89(dt,J=9.4,4.9Hz,4H),0.85-0.81(m,2H).

[0874] Example 57: Preparation of Compound 57

[0875] (1) Preparation of Compound B57:

[0876] Compound B37-1 (160 mg) was added to tetrahydrofuran (5 mL), and lithium aluminum tetrahydride (0.5 mL, 0.5 mmol) was added dropwise at room temperature. The reaction was stirred for 5 h. After completion, methanol and water were added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined, concentrated, and purified by column chromatography to obtain 100 mg of compound B57. ESI-MS: m / z = 302.11 [M+H] + .

[0877] (2) Preparation of Compound C57:

[0878] Compound B57 (30.1 mg), acetic acid (0.5 ml), and iodosuccinimide (45 mg) were added sequentially to a 10 mL reaction vial. The reaction was allowed to complete at 80°C under a nitrogen atmosphere. The reaction was quenched with saturated sodium carbonate, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography to afford 24 mg of compound C57. ESI-MS: m / z = 428.12 [M+H] + .

[0879] (3) Preparation of Compound D57:

[0880] Compound C57 (21 mg), compound G1 (32 mg), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (4 mg), and cesium fluoride (45 mg) were added to dioxane (0.5 mL) and water (0.1 mL), stirred, and reacted at 85°C under nitrogen for 5 h. After the reaction, the filtrate was filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 12 mg of compound D57. ESI-MS: m / z = 575.27 [M+H] + .

[0881] (4) Preparation method of compound 57:

[0882] Compound D57 (10 mg) was added to hydrogen chloride / methanol (4 M, 0.3 mL) and stirred at reflux at 80°C for 48 h. After completion of the reaction, the mixture was concentrated to dryness and slurried with a mixture of dichloromethane (0.5 mL) and methanol (0.5 mL) for 1 h. The resulting filter cake was then filtered and washed sequentially with saturated sodium bicarbonate solution and purified with water. After drying, it was purified by preparative liquid chromatography (HPLC conditions: YMC AQ C18, size 30*250 mm, 10 μm, mobile phase: A: 0.1% acetic acid, B: acetonitrile; gradient: 10%-50% B 0-80 min, wavelength 254 nm, v = 30 ml / min, rt 33 min) to give 3.5 mg of compound 57. ESI-MS: m / z = 475.27 [M+H] + .

[0883] 1H NMR(500MHz,DMSO)δ12.57(s,1H),8.34-8.24(m,1H),8.21-8.07(m,1H),7.87( dd,J=8.6,5.2Hz,1H),7.73(s,1H),7.68-7.61(m,1H),7.60-7.46(m,1H),7.43 -7.31(m,1H),7.21(d,J=5.4Hz,1H),6.73(dd,J=20.8,11.4Hz,1H),4.16-4.10 (m,1H),3.91(s,2H),3.83-3.68(m,3H),0.96-0.84(m,2H),0.83-0.73(m,2H).

[0884] Example 58: Preparation of Compound 58

[0885] (1) Preparation of Compound A58:

[0886] Compound B37-1 (319 mg) was added to a mixed solvent of tetrahydrofuran (10 mL) and methanol (1 mL). Cuprous chloride (100 mg), Xantphos (50 mg), bipyralidoborane (300 mg), and sodium hydride (100 mg) were added to the reaction flask in that order. Under a nitrogen atmosphere, the mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was filtered and purified by column chromatography to obtain 150 mg of compound A58. ESI-MS: m / z = 302.10 [M+H] + .

[0887] (2) Preparation of Compound B58:

[0888] Compound A58 (30.1 mg), acetic acid (0.5 ml), and iodosuccinimide (45 mg) were added sequentially to a 10 mL reaction vial. The reaction was continued at 80°C under a nitrogen atmosphere until complete. The reaction was quenched with saturated sodium carbonate and extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography to yield 24 mg of compound B58. ESI-MS: m / z = 428.12 [M+H] + .

[0889] (3) Preparation method of compound C58:

[0890] Compound B58 (21 mg), compound G1 (32 mg), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (4 mg), and cesium fluoride (45 mg) were added to dioxane (0.5 mL) and water (0.1 mL), stirred, and reacted at 85°C under nitrogen for 5 h. After the reaction, the reaction solution was filtered, and the resulting filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 12 mg of compound C58. ESI-MS: m / z = 575.27 [M+H] + .

[0891] (4) Preparation method of compound 58:

[0892] Compound C58 (10 mg) was dissolved in hydrogen chloride / methanol (4 M, 0.3 mL) and stirred at reflux at 80°C for 48 h. After completion of the reaction, the mixture was concentrated to dryness and slurried with a mixture of dichloromethane (0.5 mL) and methanol (0.5 mL) for 1 h. The mixture was filtered and the filter cake was washed sequentially with saturated sodium bicarbonate solution and purified with water. After drying, it was purified by preparative liquid chromatography (HPLC conditions: YMC AQ C18, size 30*250 mm, 10 μm, mobile phase: A: 0.1% acetic acid, B: acetonitrile; gradient: 10%-50% B 0-80 min, wavelength 254 nm, v = 30 ml / min, rt 34 min) to give 3.2 mg of compound 58. ESI-MS: m / z = 475.27 [M+H] + .

[0893] 1 H NMR(500MHz,DMSO)δ12.82(s,1H),8.33(s,1H),8.15(s,1H),8.14(s,1H), 7.98(d,J=5.7Hz,1H),7.83(s,1H),7.49(d,J=8.1Hz,1H),7.37(d,J=5.4Hz ,1H),7.21(d,J=5.4Hz,1H),6.18(d,J=5.2Hz,1H),6.09(d,J=5.3Hz,1H), 4.18-4.08(m,2H),3.76(s,3H),0.93-0.88(m,2H),0.82(d,J=10.5Hz,2H).

[0894] Example 59: Preparation of Compound 59

[0895] (1) Preparation of Compound B59:

[0896] Compound C57 (210 mg), compound K2 (600 mg), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (40 mg), and cesium fluoride (450 mg) were added to dioxane (5 mL) and water (1 mL), stirred, and reacted at 85°C under nitrogen for 5 h. After the reaction, the filtrate was filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 120 mg of compound B59. ESI-MS: m / z = 796.45 [M+Na] + .

[0897] (2) Preparation method of compound 59:

[0898] Compound B59 (100 mg) was added to hydrogen chloride / methanol (4 M, 3 mL) and stirred at reflux at 80°C for 48 h. After completion of the reaction, the product was concentrated to dryness and slurried with a mixture of dichloromethane (3 mL) and methanol (1 mL) for 1 h. The product was filtered and the filter cake was washed sequentially with saturated sodium bicarbonate solution and purified with water. After drying, the product was purified by preparative liquid chromatography (HPLC conditions: YMC AQ C18, size 30*250 mm, 10 μm, mobile phase: A: 0.1% acetic acid in water, B: acetonitrile; gradient: 20%-80% B-60 min, wavelength 254 nm, v = 40 ml / min, rt 30.1 min) to give 20 mg of compound 59. ESI-MS: m / z = 490.24 [M+H]+.

[0899] Example 60: Preparation of Compound 60

[0900] (1) Preparation method of compound A60:

[0901] Referring to step (1) of Example 4, M2 was replaced by L1, and tributyl(trimethylsilylalkynyl)tin was substituted for tributylpropynyltin to obtain 137 mg of compound A60, ESI-MS: m / z=627.36 [M+H] + .

[0902] (2) Preparation method of compound B60:

[0903] A60 (130 mg) and potassium carbonate (38 mg) were added to anhydrous methanol (6 mL) and reacted at 10-30°C for 3 h. After completion of the reaction, water (30 mL) was added and the mixture was extracted with ethyl acetate (12 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to obtain 100 mg of compound B60. ESI-MS: m / z = 555.28 [M+H] + .

[0904] (3) Preparation method of compound 60:

[0905] Referring to step (3) of Example 3, compound B60 was substituted for compound B3, and the product was purified by preparative liquid phase (column: YMC AQ C18, size 50*250 mm, 10 μm, mobile phase: A: 30 mM ammonium acetate, B: acetonitrile; gradient: 20%-80% B-60 min, wavelength 254 nm, v = 60 ml / min, rt = 39.2 min) to obtain 10 mg of compound 60, ESI-MS: m / z = 455.27 [M+H] + .

[0906] Example 61: Preparation of Compound 61

[0907] (1) Preparation method of compound A61:

[0908] Referring to step (2) of Example 4, Compound A4 was replaced with Compound M2 to obtain 750 mg of Compound A61, ESI-MS: m / z=580.20 [M+H] + .

[0909] (2) Preparation method of compound B61:

[0910] Referring to step (1) of Example 60, compound A61 was used to replace compound L1 to obtain 750 mg of compound B61, ESI-MS: m / z=642.41 [M+H] + .

[0911] (3) Preparation method of compound C61:

[0912] Compound B61 (257 mg), paraformaldehyde (72 mg), TMSCL (103 μL), and a 1 mol / L boron trifluoride solution in tetrahydrofuran (800 μL) were added to N,N-dimethylformamide (11 mL). The reaction was carried out at 20-30°C for 16 h until completion. The mixture was quenched with water and extracted with EA. The organic phase was washed with saturated sodium carbonate solution, and the aqueous phase was extracted with EA. All organic phases were combined and washed with saturated brine. The mixture was stirred and dried over anhydrous sodium sulfate. After suction filtration, the filtrate was concentrated to obtain 200 mg of compound C61. ESI-MS: m / z = 656.23 [M+H] + .

[0913] (4) Preparation method of compound D61:

[0914] Referring to step (3) of Example 3, compound B3 was replaced by C61 to obtain 150 mg of compound D61, ESI-MS: m / z=556.23 [M+H] + .

[0915] (5) Preparation method of compound 61:

[0916] Compound D61 (120 mg) and a 1 mol / L tetrabutylammonium fluoride solution in tetrahydrofuran (120 μL) were added to tetrahydrofuran (5 mL), and the mixture was reacted at 20-30°C for 6 h until completion. The mixture was concentrated to dryness at 40-50°C, and dichloromethane (20 mL) was added. The mixture was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness and purified by preparative liquid chromatography (YMC AQ C18, size 50*250 mm, 10 μm, mobile phase: A: 0.1% acetic acid, B: acetonitrile; gradient: 10%-40% B-60 min, wavelength 254 nm, v = 60 ml / min, rt 49.2 min) to give 12 mg of compound 61. ESI-MS: m / z = 484.14 [M+H] + .

[0917] Example 62: Preparation of Compound 62

[0918] (1) Preparation method of compound A62:

[0919] Referring to step (1) of Example 16, pyrrolidine hydrochloride was used to replace trans-3-fluorocyclobutaneamine to obtain 520 mg of compound A62, ESI-MS: m / z=431.02 [M+H] + .

[0920] (2) Preparation method of compound B62:

[0921] Referring to step (12) of Example 2, compound A62 was used to replace compound K1 to obtain 272 mg of compound B62, ESI-MS: m / z=621.28 [M-Boc-tBu+3H] + .

[0922] (3) Preparation method of compound 62:

[0923] Referring to step (4) of Example 52, compound B62 was substituted for compound C52, and the product was purified by preparative liquid phase (YMC AQ C18, size 30*250 mm, 10 μm, mobile phase: A: 0.1% acetic acid / water, B: acetonitrile; gradient: 5%-65% B-60 min, wavelength 254 nm, v=40 ml / min, rt=24 min) to obtain 11 mg of compound 62, ESI-MS: m / z=493.24 [M+H] + .

[0924] 1H NMR (500MHz, DMSO-d6) δ12.05(s,1H),8.03(s,1H),7.31(s,2H),7.21(d,J=6.3Hz,1H),6.77( s,1H),6.69(s,1H),3.74(s,3H),3.64(s,2H),3.57-3.53(m,4H),1.94(h,J=4.1,3.0Hz,4H).

[0925] Example 63: Preparation of Compound 63

[0926] (1) Preparation method of compound 63:

[0927] Referring to step (1) of Example 4, compound 62 was substituted for compound M2, and the product was purified by preparative liquid phase purification (YMC AQ C18, size 30*250mm, 10*25 mobile phase: A: containing 0.1% acetic acid / water, B: acetonitrile; gradient: 5%-65% B-60min, wavelength 254nm, v=40ml / min, rt=26min) to obtain 10mg of compound 63, ESI-MS: m / z=497.28 [M+H] + .

[0928] 1 H NMR (500MHz, DMSO-d6) δ12.07(s,1H),8.01(s,1H),7.31(s,2H),7.04(d,J=5.9Hz,1H),6.76(d,J=1.5Hz, 1H), 6.66 (d, J = 1.5Hz, 1H), 3.72 (s, 4H), 3.65 (s, 2H), 3.54-3.49 (m, 3H), 2.11 (s, 3H), 1.94-1.91 (m, 4H).

[0929] Example 64: Preparation of Compounds 64, 64a and 64b

[0930] (1) Preparation method of compound A64:

[0931] Referring to step (1) of Example 16, 3-methoxypyrrolidine was used to replace trans-3-fluorocyclobutaneamine to obtain compound A64 (455 mg). ESI-MS: m / z = 460.97 [M+H] + .

[0932] (2) Preparation method of compound B64:

[0933] Referring to step (4) of Example 15, Compound A64 was substituted for Compound C15 to obtain Compound B64 (383 mg). ESI-MS: m / z = 651.20 [M-Boc- t Bu+3H] + .

[0934] (3) Preparation method of compound C64:

[0935] Referring to step (15) of Example 2, compound M2 was replaced by compound B64 and N2 was replaced by tributyl propynyl stannane to obtain compound C64 (200 mg). ESI-MS: m / z=655.25 [M-Boc- t Bu+3H] + .

[0936] (4) Preparation method of compound 64a or compound 64b:

[0937] Referring to step (5) of Example 15, compound D15 was replaced by compound C64, and the product was purified by preparative liquid phase (conditions: column YMC-AQ-C18, specification 50*250, 10 μm, mobile phase: A: acetonitrile, B: 0.1% trifluoroacetic acid-aqueous solution; gradient: 15% B-35% B (0-60 min), wavelength 254 nm, v=30 ml / min; retention time: 64a-37 min; 64b-40 min) to obtain compound 64a (83 mg) and compound 64b (40 mg).

[0938] 64a: ESI-MS: m / z=527.31[M+H] + ;64b: ESI-MS: m / z=527.24[M+H] + .

[0939] Example 65: Preparation of Compound 65

[0940] (1) Preparation method of compound A65:

[0941] Referring to step (5) of Example 15, compound K2 was substituted for compound D15 to obtain compound A65. ESI-MS: m / z = 235.11 [M+H] + .

[0942] (2) Preparation method of compound B65:

[0943] Referring to step (3) of Example 15, 2-hydroxyethyl methylsulfone was used instead of isopropanol to obtain 266 mg of compound B65. ESI-MS: m / z=377.92 [M+H] + .

[0944] (3) Preparation method of compound C65:

[0945] Referring to step (1) of Example 17, Compound B65 was substituted for Compound B15, and 4-methylbenzenesulfonic acid 2-cyclopropyloxyethyl ester was substituted for cyclobutanol to obtain 240 mg of Compound C65. ESI-MS: m / z = 461.97 [M+H] + .

[0946] (4) Preparation method of compound D65:

[0947] Referring to step (12) of Example 1, Compound C65 was substituted for Compound K1, and Compound A65 was substituted for Compound G1 to obtain 240 mg of Compound D65. ESI-MS: m / z=524.14 [M+H] + .

[0948] (5) Preparation method of compound 65:

[0949] Referring to step (15) of Example 2, compound M2 was replaced with compound D65, and compound N2 was replaced with tributyl propargyl stannane. The mixture was purified by preparative liquid phase (conditions: column YMC-AQ-C18, size 50*250, 10 μm, mobile phase: A: acetonitrile, B: ammonium acetate-water solution; gradient: 20% B-60% B (0-60 min), wavelength 254 nm, v = 30 ml / min; retention time: 50 min) to obtain 5 mg of compound 65. ESI-MS: m / z = 528.14 [M+H] + .

[0950] Example 66: Preparation of Compound 66

[0951] (1) Preparation method of compound A66:

[0952] Referring to step (1) of Example 16, 2-cyclopropyloxyethylamine was used in place of trans-3-fluorocyclobutylamine to obtain 530 mg of compound A66. ESI-MS: m / z = 460.96 [M+H] + .

[0953] (2) Preparation method of compound B66:

[0954] Referring to step (12) of Example 1, Compound A66 was substituted for Compound K1, and Compound A65 was substituted for Compound G1 to obtain 300 mg of Compound B66. ESI-MS: m / z=523.16 [M+H] + .

[0955] (3) Preparation method of compound 66:

[0956] Referring to step (15) of Example 2, Compound M2 was replaced with Compound B66, and Compound N2 was replaced with tributyl propargyl stannane. The mixture was purified by preparative liquid phase (conditions: column YMC-AQ-C18, size 30*250, 10 μm, mobile phase: A: 0.1% acetic acid-water solution, B: acetonitrile; gradient: 10% B-70% B (0-60 min), wavelength 254 nm, v = 40 ml / min; retention time: 14.8 min) to obtain 9 mg of Compound 66. ESI-MS: m / z = 527.18 [M+H] + .

[0957] Example 67: Preparation of Compound 67

[0958] (1) Preparation method of compound A67:

[0959] Referring to step (1) of Example 16, azetidin-3-ol was used to replace trans-3-fluorocyclobutaneamine to obtain 600 mg of compound A67. ESI-MS: m / z=432.96 [M+H] + .

[0960] (2) Preparation method of compound B67:

[0961] Referring to step (12) of Example 1, Compound A67 was substituted for Compound K1, and Compound A65 was substituted for Compound G1 to obtain 300 mg of Compound B67. ESI-MS: m / z=495.15 [M+H] + .

[0962] (3) Preparation method of compound 67:

[0963] Referring to step (15) of Example 2, compound M2 was replaced with compound B67, and compound N2 was replaced with tributyl propargyl stannane. The mixture was purified by preparative liquid phase (conditions: column YMC-AQ-C18, size 30*250, 10 μm, mobile phase: A: methanol, B: 0.1% acetic acid-water solution; gradient: 15% B-50% B (0-70 min), wavelength 254 nm, v = 30 ml / min; retention time: 43 min) to obtain 6 mg of compound 67. ESI-MS: m / z = 499.22 [M+H] + .

[0964] Example 68: Preparation of Compound 68

[0965] (1) Preparation method of compound A68:

[0966] Referring to step (1) of Example 16, 3-methoxyazetidine was used to replace trans-3-fluorocyclobutaneamine to obtain compound A68 (418 mg). ESI-MS: m / z=446.98 [M+H] + .

[0967] (2) Preparation method of compound B68:

[0968] Referring to step (12) of Example 1, Compound A68 was substituted for Compound K1, and Compound A65 was substituted for Compound G1 to obtain 144 mg of Compound B68. ESI-MS: m / z=509.14 [M+H] + .

[0969] (3) Preparation method of compound 68:

[0970] Referring to step (15) of Example 2, Compound M2 was replaced with Compound B68, and Compound N2 was replaced with tributyl propargyl stannane. The mixture was purified by preparative liquid phase (conditions: column YMC-AQ-C18, size 30*250, 10 μm, mobile phase: A: methanol, B: 0.1% formic acid-water solution; gradient: 20% B-80% B (0-60 min), wavelength 254 nm, v = 30 ml / min; retention time: 37 min) to obtain Compound 68 (20 mg). ESI-MS: m / z = 513.18 [M+H] + .

[0971] Example 69: Preparation of Compound 69

[0972] (1) Preparation method of compound A69:

[0973] Compound A67 (300 mg) was added to DMF (5 mL) and stirred for 10 minutes. Sodium hydride (20 mg) was added to the reaction system at 0°C and stirred for 15 minutes. 2-Bromoethyl methyl ether (240 mg) was then added to the reaction system and allowed to react at room temperature for 5 hours. After the reaction was complete, water (10 mL) was added to the reaction solution at 0°C and stirred for 10 minutes. The mixture was extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 190 mg of compound A69. ESI-MS: m / z = 490.96 [M+H] + .

[0974] (2) Preparation method of compound B69:

[0975] Referring to step (12) of Example 1, Compound A69 was substituted for Compound K1, and Compound A65 was substituted for Compound G1 to obtain 53 mg of Compound B69. ESI-MS: m / z=553.08 [M+H] + .

[0976] (3) Preparation method of compound 69:

[0977] Referring to step (15) of Example 2, compound M2 was replaced with compound B69, and compound N2 was replaced with tributyl propargyl stannane. The product was purified by preparative liquid phase (conditions: column YMC-TA-C18, size 30*250, 10 μm, mobile phase: A: acetonitrile, B: 0.1% formic acid-water solution; gradient: 10% B-60% B (0-60 min), wavelength 254 nm, v = 30 ml / min; retention time: 26.3 min) to obtain 5 mg of compound 69. ESI-MS: m / z = 557.19 [M+H] + .

[0978] Example 70: Preparation of Compound 70

[0979] (1) Preparation method of compound A70:

[0980] Referring to step (1) of Example 16, 3-isopropoxyazetidine was used in place of trans-3-fluorocyclobutane to obtain 267 mg of compound A70. ESI-MS: m / z=474.99 [M+H] + .

[0981] (2) Preparation method of compound B70:

[0982] Referring to step (12) of Example 1, Compound A70 was substituted for Compound K1, and Compound A65 was substituted for Compound G1 to obtain 40 mg of Compound B70. ESI-MS: m / z=537.27 [M+H] + .

[0983] (3) Preparation method of compound 70:

[0984] Referring to step (15) of Example 2, Compound M2 was replaced with Compound B70, and Compound N2 was replaced with tributyl propargyl stannane. The product was purified by preparative liquid phase (conditions: column YMC-AQ-C18, size 50*250, 10 μm, mobile phase: A: acetonitrile, B: 0.1% formic acid-water solution; gradient: 15% B-40% B (0-60 min), wavelength 254 nm, v = 30 ml / min; retention time: 47 min) to obtain 12 mg of Compound 70. ESI-MS: m / z = 541.20 [M+H] + .

[0985] Example 71: Preparation of Compound 71

[0986] (1) Preparation method of compound A71:

[0987] Referring to step (1) of Example 16, 3-cyclopropyloxyazetidine was used in place of trans-3-fluorocyclobutaneamine to obtain 428 mg of compound A71. ESI-MS: m / z=472.96 [M+H] + .

[0988] (2) Preparation method of compound B71:

[0989] Referring to step (12) of Example 1, Compound A71 was substituted for Compound K1, and Compound A65 was substituted for Compound G1 to obtain 60 mg of Compound B71. ESI-MS: m / z=535.14 [M+H] + .

[0990] (3) Preparation method of compound 71:

[0991] Referring to step (15) of Example 2, Compound M2 was replaced with Compound B71, and Compound N2 was replaced with tributyl propargyl stannane. The mixture was purified by preparative liquid phase (conditions: column YMC-TA-C18, size 30*250, 10 μm, mobile phase: A: 0.1% ammonia solution, B: acetonitrile; gradient: 10% B-70% B (0-60 min), wavelength 254 nm, v = 40 ml / min; retention time: 46.6 min) to obtain 5 mg of Compound 71. ESI-MS: m / z = 539.17 [M+H] + .

[0992] Example 72: Preparation of Compound 72

[0993] (1) Preparation method of compound A72:

[0994] Referring to step (1) of Example 16, 3,3-difluoroazetidine hydrochloride was used to replace trans-3-fluorocyclobutaneamine to obtain 1250 mg of compound A72, ESI-MS: m / z=327.10 [M+H] + .

[0995] (2) Preparation method of compound B72:

[0996] Referring to step (11) of Example 1, compound A72 was used to replace compound J1 to obtain 1350 mg of compound B72, ESI-MS: m / z=452.98 [M+H] + .

[0997] (3) Preparation method of compound C72:

[0998] Referring to step (12) of Example 1, compound K1 was replaced with compound B72 to obtain 1150 mg of compound C72, ESI-MS: m / z=600.19 [M+H] + .

[0999] (4) Preparation method of compound 72:

[1000] Referring to step (3) of Example 3, compound C72 was substituted for compound B3, and the product was purified by preparative liquid phase (column: YMC AQ C18, size 50*250 mm, 10 μm, mobile phase: A: 30 mM ammonium acetate, B: acetonitrile; gradient: 10%-70% B-60 min, wavelength 254 nm, v = 60 ml / min, rt = 45.8 min); 19 mg of compound 72 was obtained, ESI-MS: m / z = 500.19 [M+H] + .

[1001] 1 H NMR(500MHz,DMSO-d6)δ12.44(s,1H),8.28(s,1H),8.16(d,J=8.3Hz,1H),7.81(s,1H),7 .70(d,J=8.4Hz,1H),7.29(d,J=6.2Hz,1H),4.69-4.58(m,4H),3.83(s,2H),3.78(s,3H).

[1002] Example 73: Preparation of Compound 73

[1003] (1) Preparation method of compound A73:

[1004] Referring to step (1) of Example 21, Compound A72 was used to replace Compound J1 to obtain 438 mg of Compound A73, ESI-MS: m / z=337.16 [M+H] + .

[1005] (2) Preparation method of compound B73:

[1006] A73 (390 mg), iodosuccinimide (319 mg), and bis(trifluoromethylsulfonyl)imide)zinc (219 mg) were added to dichloromethane, and the temperature was raised to 50°C for 2 h until the reaction was complete. The mixture was concentrated to dryness. Ethyl acetate was added to the concentrate, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 244 mg of compound B73. ESI-MS: m / z = 463.04 [M+H] + .

[1007] (3) Preparation method of compound C73:

[1008] Referring to step (12) of Example 1, compound K1 was replaced with compound B73 to obtain 133 mg of compound C73, ESI-MS: m / z=610.33 [M+H] + .

[1009] (4) Preparation method of compound 73:

[1010] Referring to step (3) of Example 3, compound B3 was replaced with compound C73, and the product was purified by preparative liquid phase (column: YMC AQ C18, size 50*250 mm, 10 μm, mobile phase: A: 30 mM ammonium acetate, B: acetonitrile; gradient: 10%-70% B-60 min, wavelength 254 nm, v = 60 ml / min, rt 48.9 min) to obtain 29 mg of compound 73, ESI-MS: m / z = 510.23 [M+H] + .

[1011] 1 H NMR (500MHz, DMSO-d6) δ12.44(s,1H),8.29(s,1H),8.15(d,J=8.2Hz,1H),7.79(s,1H),7.72(d,J=8.3Hz ,1H),7.06(d,J=6.0Hz,1H),5.58-5.40(m,2H),4.66(dq,J=21.9,11.5Hz,4H),3.80(s,2H),3.77(s,3H).

[1012] Example 74: Preparation of Compound 74

[1013] (1) Preparation method of compound A74:

[1014] Referring to step (2) of Example 4, Compound A4 was replaced with Compound A65 to obtain 150 mg of Compound A74, ESI-MS: m / z=335.14 [M+H] + .

[1015] (2) Preparation method of compound B74:

[1016] Referring to step (12) of Example 2, Compound K2 was replaced by Compound A74, and Compound K1 was replaced by Compound B72 to obtain 92 mg of Compound B74, ESI-MS: m / z=615.27 [M+H] + .

[1017] (3) Preparation method of compound C74:

[1018] Referring to step (1) of Example 4, compound M2 was replaced with compound B74 to obtain 87 mg of compound C74, ESI-MS: m / z=619.34 [M+H] + .

[1019] (4) Preparation method of compound 74:

[1020] Referring to step (3) of Example 3, compound C74 was substituted for compound B3, and the product was purified by preparative liquid phase (YMC AQ C18, size 30*250mm, 10*25 mobile phase: A: 0.1% acetic acid, B: acetonitrile; gradient: 10%-50% B / 0-80min, wavelength 254nm, v=30ml / min, rt 38min) to give 33mg of compound 74, ESI-MS: m / z=519.27 [M+H] + .

[1021] 1 H NMR(500MHz,DMSO-d6)δ12.11(s,1H),8.02(s,1H),7.28(s,2H),7.04(d,J=5.8Hz,1H), 6.64(dd,J=12.7,1.5Hz,2H),4.59-4.50(m,4H),3.74(s,2H),3.68(s,3H),2.09(s,3H).

[1022] Example 75: Preparation of Compound 75

[1023] (1) Preparation method of compound 75:

[1024] Referring to step (3) of Example 3, compound B74 was substituted for compound B3, and the product was purified by preparative liquid phase (YMC AQ C18, size 30*250 mm, 10 μm, mobile phase: A: 0.1% acetic acid, B: acetonitrile; gradient: 10%-50% B / 0-80 min, wavelength 254 nm, v = 30 ml / min, rt 37 min) to obtain 28 mg of compound 75, ESI-MS: m / z = 515.21 [M+H] + .

[1025] 1H NMR (500MHz, DMSO-d6) δ12.08(s,1H),8.06(s,1H),7.30-7.27(m,1H),6.70(d,J=6.1Hz,2H),4.62(q,J=13.4,12.9Hz,4H),3.74(s,3H),3.71(s,2H).

[1026] Example 76: Preparation of Compound 76

[1027] (1) Preparation method of compound A76:

[1028] Referring to step (12) of Example 2, Compound K2 was replaced by Compound A74, and Compound K1 was replaced by Compound B73 to obtain 131 mg of Compound A76, ESI-MS: m / z=625.27 [M+H] + .

[1029] (2) Preparation method of compound 76:

[1030] Referring to step (3) of Example 3, compound A76 was substituted for compound B3, and the product was purified by preparative liquid phase (YMC AQ C18, size 30*250 mm, 10 μm, mobile phase: A: 0.1% acetic acid, B: acetonitrile; gradient: 10%-50% B / 0-80 min, wavelength 254 nm, v = 30 ml / min, rt 41 min) to give 11 mg of compound 76, ESI-MS: m / z = 525.26 [M+H] + .

[1031] 1 H NMR (500MHz, DMSO-d6) δ12.05(s,1H),8.06(s,1H),7.24(d,J=53.5Hz,2H),7.04(d,J=5.9Hz, 1H), 6.71 (d, J = 29.9Hz, 2H), 5.58-5.31 (m, 2H), 4.71-4.57 (m, 4H), 3.74 (s, 3H), 3.64 (s, 2H).

[1032] Example 77: Preparation of Compound 77a or Compound 77b

[1033] (1) Preparation of Compound A77:

[1034] Compound A15 (1.0 g), 3,3-difluorocyclopentylamine (754 mg), and triethylamine (2.0 mL) were added to dimethyl sulfoxide (40 mL) and reacted at 80°C under a nitrogen atmosphere for 6 h until the reaction was complete. The mixture was extracted with ethyl acetate and water, and the organic phase was concentrated under reduced pressure and purified by column chromatography to obtain 654 mg of compound A77. ESI-MS: m / z = 355.16 [M+H] + .

[1035] (2) Preparation of Compound B77:

[1036] Compound A77 (354 mg), acetic acid (0.5 ml), and iodosuccinimide (22 mg) were added sequentially to a reaction flask. The reaction was allowed to complete at 80°C under a nitrogen atmosphere. The reaction was quenched with saturated sodium carbonate and extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography to afford 300 mg of compound B77. ESI-MS: m / z = 481.08 [M+H] + .

[1037] (3) Preparation of Compound C77:

[1038] Referring to step (12) of Example 2, compound K1 was replaced with compound B77 to obtain 308 mg of compound C77, ESI-MS: m / z=671.23 [M-Boc- t Bu+3H] + .

[1039] (4) Preparation method of compound D77:

[1040] Referring to step (1) of Example 4, compound C77 was used to replace compound M2 to obtain 50 mg of D77, ESI-MS: m / z=675.35 [M-Boc- t Bu+3H] + .

[1041] (5) Preparation of Compound E77:

[1042] Compound D77 (40 mg) was added to hydrogen chloride / methanol (4 M, 1 mL) and stirred at reflux at 80°C for 48 h. After the reaction was complete, the mixture was concentrated to dryness and slurried with a mixture of dichloromethane (1 mL) and methanol (0.3 mL) for 1 h. The mixture was filtered and the filter cake was washed sequentially with saturated sodium bicarbonate solution and pure water. After drying, 32 mg of compound E77 was obtained. ESI-MS: m / z = 547.30 [M+H] + .

[1043] (6) Preparation of Compound 77a / 77b:

[1044] Compound 77a and compound 77b were obtained by chiral separation of compound E77. 77a: ESI-MS: m / z = 547.30 [M+H] + , 77b: ESI-MS: m / z=547.27[M+H] + .

[1045] Separation conditions: Purification by preparative liquid phase (Waters Xbridge C18, size 30*250 mm, 5 μm, mobile phase: A: 30 mM ammonium acetate (containing 0.1% acetic acid), B: methanol; gradient: 40%-90% B-60 min, wavelength 254 nm, v=15 ml / min, 77a: rt 33.8 min; 77b: rt 35.3 min) gave 10 mg of compound 77a and 11 mg of compound 77b, respectively.

[1046] 1 H NMR(500MHz,DMSO)δ12.05(s,1H),8.00(s,1H),7.30(s,1H),7.14(d,J=5.7Hz ,1H),6.79(s,1H),6.58(s,1H),6.33(d,J=7.6Hz,1H),4.15(d,J=7.5Hz,1H),3 .71(s,2H),3.59(s,3H),2.68-2.56(m,1H),2.21(ddd,J=25.5,17.0,9.8Hz,2 H), 2.14 (s, 2H), 2.06 (dq, J = 22.7, 7.0Hz, 1H), 1.89 (s, 3H), 1.84-1.75 (m, 1H).

[1047] 1 H NMR (500MHz, DMSO) δ12.04(s,1H),8.00(s,1H),7.30(s,1H),7.15(d,J=5.7Hz,1H),6.81(s,1H),6.56(s,1H),6.33(d,J=7.7Hz,1H) ,4.15(q,J=7.6Hz,1H),3.71(s,2H),3.57(s,3H),2.22(dd,J=15.8,8.3Hz,3H),2.14(s,2H),1.90(s,1H),1.76(s,3H),1.24(s,1H).

[1048] Example 78: Preparation of Compounds 78-1 and 78-2

[1049] (1) Preparation method of compound A78:

[1050] Referring to step (1) of Example 21, compound C14 was used to replace compound J1 to obtain 54 mg of compound A78. ESI-MS: m / z=331.17 [M+H] + .

[1051] (2) Preparation method of compound B78:

[1052] Referring to step (2) of Example 73, Compound A78 was used to replace Compound A73 to obtain 64 mg of Compound B78. ESI-MS: m / z=457.14 [M+H] + .

[1053] (3) Preparation method of compound C78:

[1054] Referring to step (12) of Example 1, compound B78 was used to replace compound K1 to obtain 54 mg of compound C78. ESI-MS: m / z=604.22 [M+H] + .

[1055] (4) Preparation method of compound 78-1 & 78-2:

[1056] Referring to step (15) of Example 1, compound C78 was substituted for compound N1 to obtain 77 mg of crude product. The crude product was purified by preparative liquid chromatography (column: YMC AQ C18, size 30*250 mm, 10 μm, mobile phase: A: 0.1% acetic acid, B: acetonitrile; gradient: 10%-35% B 0-75 min, wavelength 254 nm, v = 30 ml / min) to give compounds 78-1 (rt 38 min, 3 mg) and 78-2 (rt 42 min, 2 mg).

[1057] Compound 78-1, ESI-MS: m / z=504.21 [M+H] + ;

[1058] Compound 78-2, ESI-MS: m / z=504.21 [M+H] + .

[1059] Example 79: Preparation of Compound 79

[1060] (1) Preparation of Compound A79:

[1061] In step (5) of Reference Example 2, 2-methyl-5-bromoacetophenone was used to replace compound D2 to obtain 23 g of compound A79. ESI-MS: m / z = 270.89 [MH] - .

[1062] (2) Preparation of Compound B79:

[1063] In step (6) of reference example 2, compound A79 was substituted for compound E2 to obtain 8.6 g of compound B79. ESI-MS: m / z = 266.95 [MH] - .

[1064] (3) Preparation of Compound C79:

[1065] In step (7) of Reference Example 2, Compound B79 was substituted for Compound F2 to obtain 6.5 g of Compound C79. ESI-MS: m / z = 280.96 [MH] - .

[1066] (4) Preparation of Compound D79:

[1067] In step (8) of Example 2, compound C79 was substituted for compound G2, and sodium borohydride was substituted for sodium borodeuteride to obtain 3.8 g of compound D79. ESI-MS: m / z = 256.94 [M+H] + .

[1068] (5) Preparation of Compound E79:

[1069] In step (9) of Reference Example 2, compound D79 was used to replace compound H2 to obtain 3.9 g of compound E79. ESI-MS: m / z = 274.86 [M+H] + .

[1070] (6) Preparation of Compound F79:

[1071] In step (10) of Example 2, compound E79 was used to replace compound I2 to obtain 3.0 g of compound F79. ESI-MS: m / z = 456.23 [M+H] + .

[1072] (7) Preparation of Compound G79:

[1073] Referring to step (11) of Example 2, compound F79 was used to replace compound J2 to obtain 2.8 g of compound G79. ESI-MS: m / z=422.20 [M-C6H 10 +H] + .

[1074] (8) Preparation of Compound H79:

[1075] In step (12) of Example 2, compound K2 was replaced by compound C50, and K1 was replaced by G79 to obtain 100 mg of compound H79. ESI-MS: m / z=677.18 [M+H] + .

[1076] (9) Preparation of Compound 79:

[1077] Referring to step (13) of Example 2, compound H79 was substituted for compound L2, and the mixture was purified by preparative liquid phase (YMC AQ C18, size 30*250 mm, 10 μm, mobile phase: A: 0.1% acetic acid in water, B: acetonitrile; gradient: 20%-80% B-60 min, wavelength 254 nm, v = 40 ml / min, rt 30.1 min) to obtain 18 mg of compound 79. ESI-MS: m / z = 477.11 [M+H] + .

[1078] Example 80: Preparation of Compounds 80-1 and 80-2

[1079] (1) Preparation method of compounds A80-1 and A80-2:

[1080] A mixture of compounds B49-1 and B49-2 (600 mg), tributyl stannane (1.2 g), tetrakistriphenylphosphine palladium (416 mg), and sodium carbonate (764 mg) were dissolved in dioxane-water (5:1, v / v) (34 mL), bubbling nitrogen for 3 min, and microwaved at 130°C, 120W for 1.5 h. After the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated under reduced pressure until no liquid flowed out. The crude product was added with water and extracted with EA. The organic phase was separated and washed with water and saturated brine, dried, and concentrated at 40-50°C. The concentrate was separated by column chromatography to obtain a mixture of compounds A80-1 and A80-2 (700 mg in total). ESI-MS: m / z = 299.13 [M+H] + .

[1081] (2) Preparation method of compounds B80-1 and B80-2:

[1082] Referring to step (11) of Example 1, the mixture of compounds A80-1 and A80-2 was substituted for compound J1 to obtain a mixture of compounds B80-1 and B80-2 (700 mg in total). ESI-MS: m / z = 425.04 [M+H] + .

[1083] (3) Preparation method of compounds C80-1 and C80-2:

[1084] A mixture of compounds B80-1 and B80-2 (400 mg), compound D47 (1.03 g), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (208 mg), potassium trimethylsilanol (146 mg), trimethyl borate (296 mg), and dioxane-water (5:1, v / v) (46 mL) were reacted at 85°C. After the reaction was complete, water (40 mL) and ethyl acetate (40 mL) were added to the reaction mixture, stirred for 10 minutes, and the layers were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and concentrated. The concentrate was separated by column chromatography to afford a mixture of compounds C80-1 and C80-2 (130 mg total). ESI-MS: m / z = 795.33 [M+Na] + .

[1085] (4) Preparation method of compounds 80-1 and 80-2:

[1086] Referring to step (13) of Example 2, compound L2 was replaced with a mixture of compounds C80-1 and C80-2, and the resulting crude product was purified by preparative liquid phase (liquid phase conditions: column: YMC AQC18 250*50mm, 10μm; mobile phase: A: 50nm ammonium acetate, C: acetonitrile gradient: 40% C-80% C (0-60min); flow rate: 50mL / min; wavelength: 254nm, secondary purification: A: 0.05% formic acid-water, C: acetonitrile, gradient: 30% C-70% C (0-60min); flow rate: 50mL / min; wavelength: 254nm, retention time: 30min to obtain 80-2, retention time: 35min to obtain 80-1) to give 20mg of compound 80-1, ESI-MS: m / z=489.20 [M+H] + &7mg compound 80-2, ESI-MS: m / z=489.20[M+H] + .

[1087] Example 82: Preparation of Compound 82

[1088] (1) Preparation method of compound A82:

[1089] Referring to the preparation process of compound E47 in step (5) of Example 47, compound A62 was used to replace compound F47 to obtain 88 mg of compound A82. ESI-MS: m / z=627.30 [M-Boc- t Bu+3H] + .

[1090] (2) Preparation method of compound 82:

[1091] Compound A82 (88 mg) was added to hydrogen chloride / ethanol (10 M, 2.8 mL) and anhydrous methanol (3.6 mL), and the mixture was stirred at reflux at 80°C for 48 h. After completion of the reaction, the mixture was concentrated to dryness and purified by preparative liquid chromatography (column: YMC AQ C18, dimensions 50 x 250 mm, 10 μm, mobile phase: A: 0.1% formic acid, B: acetonitrile; gradient: 10%-45% B over 60 min, wavelength 254 nm, v = 60 ml / min, rt 42 min) to afford 10 mg of compound 82. ESI-MS: m / z = 499.26 [M+H] + .

[1092] Example 83: Preparation of Compound 83

[1093] (1) Preparation method of compound A83:

[1094] The operation of step (2) of reference example 82 was performed, and compound A82 was replaced by compound D47. After the reaction was completed, the reaction solution was concentrated to dryness to obtain 82 mg of compound A83. ESI-MS: m / z = 237.18 [M+H] + .

[1095] (2) Preparation method of compound B83:

[1096] Compound A83 (82 mg) and di-tert-butyl dicarbonate (93 mg) were added to triethylamine (0.20 mL) and tetrahydrofuran (4 mL) and reacted at room temperature for 3 h. After completion of the reaction, the mixture was concentrated to dryness and then slurried in a mixed solvent of petroleum ether and ethyl acetate to obtain 85 mg of compound B83. ESI-MS: m / z = 337.26 [M+H] + .

[1097] (3) Preparation method of compound C83:

[1098] Reference Example 47, step (5) Preparation of Compound E47: Compound D47 was replaced with Compound B83, and Compound F47 was replaced with Compound B72 to obtain 60 mg of Compound C83. ESI-MS: m / z = 617.05 [M+H] + .

[1099] (4) Preparation method of compound D83:

[1100] Refer to the preparation procedure of compound 1 in step (15) of Example 1, replacing compound N1 with compound C83 to obtain 44 mg of compound D83. ESI-MS: m / z=517.17 [M+H] + .

[1101] (5) Preparation method of compound 83:

[1102] The procedure of step (1) of Example 4 was followed, except that compound D83 was used instead of compound M2. After the reaction, the product was purified by preparative liquid chromatography (column: YMC AQ C18, size 50*250 mm, 10 μm, mobile phase: A: 0.1% formic acid, B: acetonitrile; gradient: 10%-50% B-60 min, wavelength 254 nm, v = 60 ml / min, rt 38 min) to obtain 5 mg of compound 83. ESI-MS: m / z = 521.19 [M+H] + .

[1103] Example 84: Preparation of Compound 84

[1104] (1) Preparation method of compound A84:

[1105] Compound A15 (5 g) and methylcyclopropanol (1.5 g) were added to tetrahydrofuran (150 mL). Potassium tert-butoxide / tetrahydrofuran solution (30 mL, 1 M) was slowly added dropwise at -20°C and stirred at the same temperature for 2 h before stopping the reaction. After the reaction was completed, EA (200 mL) and water (200 mL) were added for extraction. The resulting organic phase was washed sequentially with water and saturated brine. The resulting organic phase was concentrated to dryness and then column chromatography was performed to obtain compound A48 (5 g). ESI-MS: m / z = 306.08 [M+H] + .

[1106] (2) Preparation method of compound B84:

[1107] In step (1) of Reference Example 4, compound A84 was used to replace compound M2 to obtain 2 g of compound B84.

[1108] (3) Preparation method of compound C84:

[1109] Referring to step (11) of Example 1, compound B84 was substituted for compound J1 to obtain 2.5 g of compound C84. ESI-MS: m / z = 436.03 [M+H] + .

[1110] (3) Preparation method of compound D84:

[1111] In step (12) of Reference Example 2, Compound C84 was used to replace Compound K1 to obtain 500 mg of Compound D84. ESI-MS: m / z=626.23 [M-Boc- t Bu+3H] + .

[1112] (4) Preparation method of compound 84:

[1113] Referring to step (13) of Example 2, compound D84 was substituted for compound L2. Purification by preparative liquid chromatography (HPLC conditions: column: YMC AQ C18, 30*250 mm, 10 μm; mobile phase: A: 0.1% acetic acid in water, B: acetonitrile; gradient: 20%-80% B (0-60 min). λ: 254 nm, V: 40 mL / min, rt 12 min) afforded compound 84 (20 mg). ESI-MS: m / z = 498.26 [M+H] + .

[1114] 1 H NMR (500 MHz, DMSO-d 6 )δ12.11(s,1H),8.04(s,1H),7.57(d,J=5.6Hz,1H),7.31(s,2H),6.70(d,J=1.5Hz,1H),6.57( d,J=1.6Hz,1H),3.37(s,3H),3.64(s,2H),2.17(s,3H),1.57(s,3H),1.02(s,2H),0.89(s,2H).

[1115] Example 85: Preparation of Compound 85

[1116] (1) Preparation method of compound A85:

[1117] In step (12) of reference example 2, compound C84 was substituted for compound K1, and compound D47 was substituted for compound K2 to obtain 300 mg of compound A85. ESI-MS: m / z=628.30 [M-Boc- t Bu+3H] + .

[1118] (2) Preparation method of compound 85:

[1119] Referring to step (13) of Example 2, Compound A85 was substituted for Compound L2. Purification by preparative liquid chromatography (HPLC conditions: column: YMC AQ C18, 30*250 mm, 10 μm; mobile phase: A: 0.1% acetic acid in water, B: acetonitrile; gradient: 20%-80% B (0-60 min). λ: 254 nm, V: 40 mL / min, rt 12.1 min) afforded Compound 85 (23 mg). ESI-MS: m / z = 500.26 [M+H] + .

[1120] 1 H NMR (500 MHz, DMSO-d 6)δ12.09(s,1H),8.04(s,1H),7.57(d,J=5.5Hz,1H),7.30(s,2H),6.71(d,J=1.8Hz,1H), 6.56(d,J=1.5Hz,1H),3.73(s,3H),2.17(s,3H),1.57(s,3H),1.03(s,2H),0.89(s,2H).

[1121] Example 86: Preparation of Compounds 86-1 and 86-2

[1122] (1) Preparation method of compound A86:

[1123] Compound A14 (5 g), compound A86-1 (6.6 g), potassium fluoride (3.5 g), and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (0.7 g) were added to dioxane-water (5:1) (200 mL). The reaction was continued at 85° C. for 5 h under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filtrate was washed with water and ethyl acetate. The organic phase obtained by extraction was washed with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The concentrate was subjected to column chromatography to obtain compound A86 (6 g). ESI-MS: m / z = 240.04 [M-THP+2H] + .

[1124] (2) Preparation method of compound B86:

[1125] In step (1) of Reference Example 84, Compound A86 was substituted for Compound A15 to obtain 5.2 g of Compound B86. ESI-MS: m / z = 292.17 [M-THP+2H] + .

[1126] (3) Preparation method of compound C86:

[1127] In step (1) of Reference Example 4, Compound B86 was substituted for Compound M2 to obtain 5.2 g of Compound C86. ESI-MS: m / z = 296.23 [M-THP+2H] + .

[1128] (4) Preparation method of compound D86:

[1129] In step (2) of Reference Example 48, Compound C86 was substituted for Compound A48 to obtain 4 g of Compound D86. ESI-MS: m / z = 296.21 [M+H] + .

[1130] (5) Preparation method of compound E86:

[1131] In step (3) of Reference Example 48, Compound D86 was substituted for Compound B48 to obtain 2.5 g of Compound E86. ESI-MS: m / z = 374.13 [M+H] + .

[1132] (6) Preparation method of compounds F86-1 and F86-2:

[1133] In step (4) of Reference Example 48, Compound E86 was used in place of Compound C48 to obtain 1.5 g of a mixture of Compounds F86-1 and F86-2. ESI-MS: m / z = 424.12 [M+H] + .

[1134] (7) Preparation method of compounds G86-1 and G86-2:

[1135] In step (5) of Reference Example 48, the mixture of compounds F86-1 and F86-2 was substituted for the mixture of compounds D48-1 and D48-2 to obtain 1.7 g of a mixture of compounds G86-1 and G86-2. ESI-MS: m / z = 662.28 [M-Boc- t Bu+3H] + .

[1136] (8) Preparation method of compounds 86-1 and 86-2:

[1137] The reaction was carried out in step (13) of Example 2, except that compound L2 was replaced by a mixture of compounds G86-1 and G86-2. The mixture was purified by preparative liquid phase purification (YMC AQ C18, 50*250mm 10μm; A: 0.1% formic acid, B: acetonitrile; gradient: 30%-90% B (0-60min). λ: 254nm, V: 50mL / min. Compound 86-1: rt 26min; compound 86-2: rt 28min were obtained in sequence.

[1138] Compound 86-1: 20 mg. ESI-MS: m / z = 534.21 [M+H] + .

[1139] 1 H NMR (500 MHz, DMSO-d 6 )δ12.31(s,1H),8.49(s,1H),7.81(d,J=56.8Hz,1H),7.62(d,J=5.8Hz,1H),7.42(s,2H),6.74(s ,1H),6.66(s,1H),3.87(s,2H),2.19(s,3H),1.57(s,3H),1.13-0.97(m,2H),0.96-0.83(m,2H).

[1140] Compound 86-2: 40 mg. ESI-MS: m / z = 534.20 [M+H] + .

[1141] 1 H NMR (500 MHz, DMSO-d 6 )δ12.30(s,1H),8.97(s,1H),7.98(d,J=58.8Hz,1H),7.50(d,J=5.6Hz,1H),7.37(s,2H),6.8 4(s,1H),6.64-6.62(m,1H),3.93(s,2H),2.13(s,3H),1.58(s,3H),1.03(s,2H),0.90(s,2H).

[1142] Example 87: Preparation of Compound 87

[1143] (1) Preparation method of compound A87:

[1144] Referring to step (3) of Example 15, 1-methylcyclopropanol was used instead of isopropanol to obtain 515 mg of compound A87. ESI-MS: m / z=432.09 [M+H] + .

[1145] (2) Preparation method of compound B87:

[1146] Referring to step (12) of Example 1, Compound A87 was used in place of Compound K1 to obtain 260 mg of Compound B87. ESI-MS: m / z = 579.29 [M+H] + .

[1147] (3) Preparation method of compound C87:

[1148] Referring to step (13) of Example 1, compound B87 was used to replace compound L1 to obtain 93 mg of compound C87. ESI-MS: m / z=571.31 [M+H] + .

[1149] (4) Preparation method of compound 87:

[1150] Referring to step (15) of Example 1, compound C87 was substituted for compound N1, and the mixture was purified by preparative liquid phase (column: YMC AQ C18, size 30*250 mm, 10 μm, mobile phase: A: 0.1% acetic acid, B: acetonitrile; gradient: 10%-50% B-60 min, wavelength 254 nm, v = 25 ml / min, rt 31.54 min) to obtain 30 mg of compound 87, ESI-MS: m / z = 471.31 [M+H] + .

[1151] Example 88: Preparation of Compound 88

[1152] (1) Preparation method of compound A88:

[1153] Referring to step (11) of Example 1, Compound A84 was used in place of Compound J1 to obtain 453 mg of Compound A88. ESI-MS: m / z = 432.06 [M+H] + .

[1154] (2) Preparation method of compound B88:

[1155] Referring to step (12) of Example 2, compound A88 was used to replace compound K1 to obtain 375 mg of compound B88. ESI-MS: m / z=622.28 [M-Boc- t Bu+3H] + .

[1156] (3) Preparation method of compound C88:

[1157] Referring to step (13) of Example 1, compound B88 was used to replace compound L1 to obtain 93 mg of compound C88. ESI-MS: m / z = 670.37 [M-Boc+2H] + .

[1158] (4) Preparation method of compound 88:

[1159] Referring to step (13) of Example 2, compound L2 was replaced with compound C88 and purified by preparative liquid phase (column: YMC AQ C18, size 30*250 mm, 10 μm, mobile phase: A: 0.1% acetic acid, B: acetonitrile; gradient: 10%-50% B 0-80 min, wavelength 254 nm, v = 30 ml / min, rt 34 min) to obtain 25 mg of compound 88, ESI-MS: m / z = 486.27 [M+H] + .

[1160] Example 89: Preparation of Compounds 89-1 and 89-2

[1161] (1) Preparation method of compounds A89-1 and A89-2:

[1162] In step (5) of reference example 48, compounds F86-1 and F86-2 were substituted for the mixture of compounds D48-1 and D48-2, and K2 was substituted for D47 to obtain 500 mg of a mixture of compounds A89-1 and A89-2. ESI-MS: m / z = 664.27 [M-Boc- t Bu+3H] + .

[1163] (2) Preparation method of compounds 89-1 and 89-2:

[1164] Referring to step (13) of Example 2, compound L2 was replaced with a mixture of compounds A89-1 and A89-2, and the mixture was purified by preparative liquid phase (YMC AQ C18, 50*250mm 10μm; A: acetonitrile, B: 0.05% acetic acid aqueous solution; gradient: 20%-60% A (0-60min). λ: 254nm, V: 60mL / min. Compound 89-1: rt 24min; compound 89-2: rt 27min were obtained in sequence.

[1165] Compound 89-1 was obtained: 20 mg. ESI-MS: m / z = 536.16 [M+H] + .

[1166] 1 H NMR (500 MHz, DMSO-d 6 )δ12.15(s,1H),8.44(s,1H),7.82(t,J=56.8Hz,1H),7.61(d,J=5.7Hz,1H),7.39(s,2H),6.75(t,J =1.4Hz,1H),6.66(t,J=1.6Hz,1H),2.18(s,3H),1.56(s,3H),1.06-0.98(m,2H),0.93-0.86(m,2H).

[1167] Compound 89-2 was obtained: 40 mg. ESI-MS: m / z = 536.13 [M+H] + .

[1168] 1 H NMR (500 MHz, DMSO-d 6)δ12.14(s,1H),8.94(s,1H),7.97(t,J=58.8Hz,1H),7.50(d,J=5.6Hz,1H),7.35(s,2H),6.79(d,J =1.5Hz,1H),6.66(d,J=1.5Hz,1H),2.13(s,3H),1.57(s,3H),1.07-0.97(m,2H),0.95-0.84(m,2H).

[1169] Example 90: Preparation of Compound 90

[1170] (1) Preparation method of compound B90:

[1171] Compound A90 (30 g), trifluoroethanol (24.3 g), and cesium carbonate (79.2 g) were added to dimethyl sulfoxide (600 mL) and heated to 80°C for reaction. After the reaction, the temperature was cooled to room temperature, and water (600 mL) and ethyl acetate (600 mL) were added to the reaction solution. The mixture was stirred for 10 minutes and separated. The aqueous phase was extracted with ethyl acetate, and the resulting organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated by column chromatography to obtain compound B90 (34.83 g).

[1172] (2) Preparation method of compound C90:

[1173] Compound B90 (34 g), dibenzoyl peroxide (2.6 g), and N-bromosuccinimide (21 g) were added to carbon tetrachloride (400 mL) and the temperature was raised to 80°C for reaction. After the reaction, the temperature was cooled to room temperature, and water (400 mL) was added to the reaction solution. The mixture was stirred for 10 minutes and separated. The aqueous phase was extracted with dichloromethane, and the resulting organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated by column chromatography to obtain compound C90 (21.6 g).

[1174] (3) Preparation method of compound D90:

[1175] Compound C90 (21.6 g), 1,4-dioxane (217 mL), and water (72 mL) were mixed and heated to 100°C for reaction. After the reaction, the mixture was cooled to room temperature and concentrated to obtain compound D90 (16.1 g). ESI-MS: m / z = 311.03 [M+H] + .

[1176] (4) Preparation method of compound E90:

[1177] Compound D90 (16.1 g) and potassium tert-butoxide (575 mg) were added to N,N-dimethylformamide dimethyl acetal (43 mL) and the temperature was raised to 110°C for reaction. After the reaction, the temperature was lowered to room temperature, and water (40 mL) and ethyl acetate (40 mL) were added to the reaction solution. The mixture was stirred for 10 minutes and separated. The aqueous phase was extracted with ethyl acetate. The resulting organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated by column chromatography to obtain compound E90 (13 g). ESI-MS: m / z = 366.07 [M+H] + .

[1178] (5) Preparation method of compound F90:

[1179] Compound E90 (13 g) and hydrazine hydrate (4.48 g) were added to ethanol (140 mL) and the temperature was raised to 70°C for reaction. After the reaction, the mixture was cooled to room temperature and concentrated. 100 mL of petroleum ether was added to the concentrate and the mixture was beaten for 1 hour. The mixture was filtered and the filter cake was dried at 40°C to obtain compound F90 (14 g). ESI-MS: m / z = 380.14 [M+H] + .

[1180] (6) Preparation method of compound G90:

[1181] Compound F90 (13 g) and cyanuric chloride (2.37 g) were added to dichloromethane (370 mL) and the temperature was raised to reflux for reaction. After the reaction, the temperature was lowered to room temperature and concentrated. The concentrate was separated by column chromatography to obtain compound G90 (13 g). ESI-MS: m / z = 371.04 [M+H] + .

[1182] (7) Preparation method of compound H90:

[1183] Referring to step (10) of Example 2, compound I2 was replaced with compound G90 to obtain compound H90 (3.86 g). ESI-MS: m / z = 552.21 [M+H] + .

[1184] (8) Preparation method of compound I90:

[1185] Referring to step (11) of Example 2, compound J2 was replaced with compound H90 to obtain compound I90 (3.86 g). ESI-MS: m / z = 600.27 [M+H] + .

[1186] (9) Preparation method of compound J90:

[1187] Referring to step (12) of Example 2, compound I90 was substituted for compound K2, and compound B12-1 was substituted for compound K1 to obtain compound J90 (86 mg). ESI-MS: m / z=755.53 [M+H] + .

[1188] (10) Preparation method of compound 90:

[1189] Referring to step (15) of Example 1, Compound J90 was substituted for Compound N1, and the product was purified by preparative liquid phase (liquid phase conditions: column: YMC TA C18 30*250 mm, 10 μm; mobile phase: A: 0.1% formic acid-water, B: acetonitrile, gradient: 10% C-70% C (0-60 min); flow rate: 30 mL / min; wavelength: 254 nm) to obtain Compound 90. ESI-MS: m / z = 555.34 [M+H] + .

[1190] 1 H NMR (500MHz, DMSO) δ12.34(s,1H),8.38(s,1H),8.25(s,1H),7.94(d,J=6.0Hz ,1H),7.41(d,J=1.5Hz,1H),7.17(d,J=1.4Hz,1H),6.94(dd,J=17.7,11.2Hz,1 H),6.28(d,J=17.7Hz,1H),5.77(d,J=11.3Hz,1H),4.69(q,J=8.9Hz,2H),4.24 -4.19(m,1H),3.84(s,2H),3.76(s,3H),0.98-0.88(m,2H),0.88-0.73(m,2H).

[1191] Example 91: Preparation of Compound 91

[1192] (1) Preparation method of compounds A91-1 and A91-2:

[1193] In step (4) of Reference Example 48, compound B48 was substituted for compound C48 to obtain 2.1 g of a mixture of compounds D91-1 and D91-2. ESI-MS: m / z = 328.11 [M+H] + .

[1194] In step (1) of Reference Example 4, M2 was replaced by a mixture of compounds D91-1 and D91-2 to obtain 3.2 g of a mixture of compounds E91-1 and E91-2. ESI-MS: m / z = 332.12 [M+H] + .

[1195] In step (3) of Reference Example 48, a mixture of compounds E91-1 and E91-2 was used in place of B48 to obtain 3.3 g of a mixture of compounds C91-1 and C91-2. ESI-MS: m / z = 410.13 [M+H] + .

[1196] Referring to step (12) of Example 2, the mixture of compounds C91-1 and C91-2 was substituted for compound K1, and compound G79 was substituted for compound K2 to obtain 400 mg of a mixture of compounds A91-1 and A91-2. ESI-MS: m / z = 551.07 [M-Boc- t Bu+3H] + .

[1197] (2) Preparation method of compounds 91-1 and 91-2:

[1198] Referring to step (15) of Example 1, compound N1 was replaced with a mixture of compounds A91-1 and A91-2, and the mixture was purified by preparative liquid phase (YMC AQ-C18, specification 30*250 mm, 10 μm, mobile phase: A: 0.1% acetic acid aqueous solution B: acetonitrile; gradient: 10%-60% B / 0-45 min, wavelength 254 nm, v = 40 ml / min) to give compound 91-1 (rt 23.2 min, 5 mg) and compound 91-2 (rt 24.7 min, 26 mg) in sequence.

[1199] Compound 91-1: ESI-MS: m / z=507.23 [M+H] + .

[1200] 1 H NMR (500 MHz, DMSO-d 6 )δ12.50(s,1H),8.65(s,1H),8.21(d,J=8.3Hz,1H),7.86(t,J=56.7Hz,1H),7.84(s,1H),7.82(d,J=5.9Hz, 1H), 7.73 (d, J = 8.4Hz, 1H), 4.22-4.08 (m, 1H), 2.18 (s, 3H), 0.93-0.85 (m, 2H), 0.78 (dd, J = 6.3, 3.1Hz, 2H).

[1201] Compound 91-2: ESI-MS: m / z=507.22 [M+H] + .

[1202] 1 H NMR (500 MHz, DMSO-d 6)δ12.52(s,1H),9.13(s,1H),8.19(d,J=8.3Hz,1H),8.02(t,J=55.9Hz,1H),7.92(d,J=1.7Hz,1H),7.70(d,J=5.6H z,1H),7.66(dd,J=8.3,1.7Hz,1H),4.16(tt,J=6.0,2.9Hz,1H),2.12(s,3H),0.92-0.86(m,2H),0.83-0.70(m,2H).

[1203] Example 92: Preparation of Compound 92:

[1204] (1) Preparation method of compound A92:

[1205] Referring to step (12) of Example 2, compound I90 was substituted for compound K2, and compound F47 was substituted for compound K1 to obtain compound A92 (184 mg). ESI-MS: m / z = 767.53 [M+H] + .

[1206] (2) Preparation method of compound 92:

[1207] Referring to step (15) of Example 1, Compound A92 was substituted for Compound N1, and the resulting crude product was purified by preparative liquid phase (liquid phase conditions: column: YMC*GEL ODS-AQ-HG 30*250 mm, 10 μm; mobile phase: A: 0.1% acetic acid-water, C: acetonitrile, gradient: 15% C-75% C (0-60 min); flow rate: 40 mL / min; wavelength: 254 nm, retention time: 34 min) to obtain Compound 92. ESI-MS: m / z = 567.33 [M+H] + .

[1208] 1 H NMR (500MHz, DMSO) δ12.48(s,1H),8.37(s,1H),7.80(d,J=5.6Hz,1H),7.40(d,J=1.6Hz,1H),7.10(d,J=1.5Hz,1H),4.69( q,J=8.9Hz,2H),4.17-4.11(m,1H),4.02(d,J=3.0Hz,2H),3.76(s,3H),2.18(s,3H),0.95-0.87(m,2H),0.83-0.72(m,2H).

[1209] Example 93: Preparation of Compound 93

[1210] (1) Preparation method of compound A93:

[1211] Compound A15 (253 mg) and methyl 1-hydroxycyclopropanecarboxylate (233 mg) were added to anhydrous tetrahydrofuran (6.5 mL). Under a nitrogen atmosphere, the temperature was lowered to -5-5°C, and 60% sodium hydride (88 mg) was slowly added. After the addition, the temperature was raised to 20-30°C and the reaction was allowed to proceed for 2 h. After the reaction was complete, saturated ammonium chloride solution (10 mL) was added to quench the reaction. After extraction with ethyl acetate twice, the organic phase was separated and dried over anhydrous sodium sulfate, then concentrated to dryness at 50-60°C. Column chromatography afforded 340 mg of compound A93, ESI-MS: m / z = 350.22 [M+H]. + .

[1212] (2) Preparation method of compound B93:

[1213] Preparation of LDBBA: Mix tert-butyl alcohol (752 mg) and anhydrous tetrahydrofuran (7.5 mL), replace the atmosphere with nitrogen, cool to -5-0°C, add dropwise a 2.5 M solution of n-butylamine in n-hexane (4.1 mL), and react at the same temperature for 1 h. Add dropwise a 1 M solution of diisobutylaluminum hydride in tetrahydrofuran (10.1 mL), and react at 0-10°C for 2 h to obtain LDBBA.

[1214] Under a nitrogen atmosphere, A93 (2360 mg) and anhydrous tetrahydrofuran (24 mL) were mixed and cooled to -70 to -65°C. The LDBBA prepared above was slowly added dropwise. The mixture was allowed to react at the same temperature for 2 h. After the reaction was complete, saturated ammonium chloride solution (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness at 45 to 55°C. Column chromatography afforded 1220 mg of compound B93. ESI-MS: m / z = 320.18 [M+H] + .

[1215] (3) Preparation method of compound C93:

[1216] Compound B93 (1100 mg) and anhydrous dichloromethane (30 mL) were mixed and cooled to -5-0°C under a nitrogen atmosphere. Diethylaminosulfur trifluoride (1389 mg) was then slowly added. After addition, the temperature was raised and the reaction was allowed to react for 5 h. After completion of the reaction, purified water (30 mL) was added to quench the reaction. The aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated at 30-40°C to obtain 1100 mg of compound C93. ESI-MS: m / z = 342.19 [M+H] + .

[1217] (4) Preparation method of compound D93:

[1218] Referring to step (1) of Example 33, compound C93 was substituted for compound J1 to obtain 305 mg of compound D93. ESI-MS: m / z=334.23 [M+H] + .

[1219] (5) Preparation method of compound E93:

[1220] Referring to step (2) of Example 73, compound A73 was replaced with compound D93 to obtain 100 mg of compound E93, ESI-MS: m / z=460.03 [M+H] + .

[1221] (6) Preparation method of compound F93:

[1222] Referring to step (12) of Example 2, compound E93 was substituted for compound K1 to obtain 50 mg of compound F93. ESI-MS: m / z=650.23 [M-Boc- t Bu+3H] + .

[1223] (7) Preparation method of compound 93:

[1224] Referring to step (13) of Example 2, compound F93 was substituted for compound L2, and the mixture was purified by preparative liquid phase (column: YMC AQ C18, size 50*250 mm, 10 μm, mobile phase: A: 0.1% formic acid, B: acetonitrile; gradient: 25%-55% B-60 min, wavelength 254 nm, v = 50 ml / min, rt 29.5 min) to obtain 9 mg of compound 93, ESI-MS: m / z = 522.19 [M+H] + .

[1225] Example 94: Preparation of Compound 94

[1226] (1) Preparation method of compound A94:

[1227] Referring to step (12) of Example 1, compound E93 was used in place of compound K1 to obtain 60 mg of compound A94. ESI-MS: m / z = 607.24 [M+H] + .

[1228] (2) Preparation method of compound 94:

[1229] Referring to step (15) of Example 1, compound A94 was substituted for compound N1, and the mixture was purified by preparative liquid phase (column: YMC AQ C18, size 30*250 mm, 10 μm, mobile phase: A: 30 mM ammonium acetate aqueous solution, B: methanol; gradient: 20%-75% / 0-45 min, wavelength 254 nm, v = 40 ml / min, rt 32.2 min) to obtain 6 mg of compound 94, ESI-MS: m / z = 507.20 [M+H] + .

[1230] Example 95: Preparation of Compound 95

[1231] (1) Preparation method of compound A95:

[1232] Refer to the preparation method of compound J-1 in step (5) of Example 47, replacing compound J1 with compound C93 to obtain 639 mg of compound A95. ESI-MS: m / z=346.25 [M+H] + .

[1233] (2) Preparation method of compound B95:

[1234] Referring to step (2) of Example 73, Compound A73 was replaced with Compound A95 to obtain 584 mg of Compound B95, ESI-MS: m / z=472.13 [M+H] + .

[1235] (3) Preparation method of compound C95:

[1236] Referring to step (12) of Example 2, compound B95 was used to replace compound K1 to obtain 170 mg of compound C95. ESI-MS: m / z=662.24 [M-Boc- t Bu+3H] + .

[1237] (4) Preparation method of compound 95:

[1238] Referring to step (13) of Example 2, compound L2 was replaced with compound C95, and the product was purified by preparative liquid phase (column: YMC*GEL ODS-AQ-HG 30*250 mm, 10 μm; mobile phase: A: 0.1% acetic acid-water, C: acetonitrile, gradient: 10% C-70% C (0-60 min); wavelength: 254 nm; v = 40 ml / min, rt 28.0 min) to obtain 19 mg of compound 95, ESI-MS: m / z = 534.16 [M+H] + .

[1239] Example 96: Preparation of Compound 96

[1240] (1) Preparation method of compound A96:

[1241] Referring to step (12) of Example 1, compound E93 was substituted for compound K1, and compound I90 was substituted for compound G1 to obtain 55 mg of compound A96. ESI-MS: m / z=805.31 [M+H] + .

[1242] (2) Preparation method of compound 96:

[1243] Referring to step (15) of Example 1, compound A96 was substituted for compound N1, and the mixture was purified by preparative liquid phase (column: YMC AQ C18, size 50*250 mm, 10 μm, mobile phase: A: 0.1% formic acid, B: methanol; gradient: 30%-40% B-60 min, wavelength 254 nm, v = 50 ml / min, rt 22 min) to obtain 4 mg of compound 96, ESI-MS: m / z = 605.17 [M+H] + .

[1244] Example 97: Preparation of Compound 97

[1245] (1) Preparation method of compound A97:

[1246] Compound A16 (1185 mg) was added to 2,4-dimethoxybenzylamine (3.6 mL) and N,N-dimethylacetamide (40 mL), and the temperature was raised to 90°C for 4 h. After the reaction, a chloroform:ethyl acetate (5:1) mixed solvent (120 mL) was added to dilute the reaction solution, and the solution was washed three times with 2N hydrochloric acid. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness at 45-55°C to obtain 1800 mg of compound A97. ESI-MS: m / z = 401.14 [M+H] + .

[1247] (2) Preparation method of compound B97:

[1248] Compound A97 (1800 mg) was added to triethylamine (1.8 mL) and dichloromethane (38 mL) and reacted at room temperature for 2 h. After the reaction, the mixture was concentrated at 30-40°C to obtain 1105 mg of compound B97. ESI-MS: m / z = 251.05 [M+H] + .

[1249] (3) Preparation method of compound C97:

[1250] Mix tert-butyl nitrite (2.1 mL), copper bromide (3810 mg), and acetonitrile (144 mL), replace the atmosphere with nitrogen, and heat to 80°C for 10 min. Add a solution of compound B97 (1100 mg) in acetonitrile (24 mL) dropwise, and react at the same temperature for 1 h. After the reaction is complete and cooled to room temperature, saturated ammonium chloride solution (150 mL) is added to quench the mixture. Extract with dichloromethane, separate the aqueous phase, and back-extract with dichloromethane. Combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. The filtrate is concentrated and purified by column chromatography to yield 717 mg of compound C97. ESI-MS: m / z = 314.02 [M+H] + .

[1251] (4) Preparation method of compound D97:

[1252] Compound C97 (520 mg), 1-trifluoromethylcyclopropylamine hydrochloride (534 mg), bis(dibenzylideneacetone)palladium (188 mg), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (412 mg), and cesium carbonate (2704 mg) were added to toluene (50 mL). After nitrogen replacement, the temperature was raised to 100°C and the reaction was allowed to proceed for 24 hours. After the reaction, the temperature was cooled to room temperature, concentrated to dryness, and extracted with water and ethyl acetate. The organic phase was separated, washed with water and saturated brine, dried, and concentrated. 100 mg of compound D97 was obtained by column chromatography. ESI-MS: m / z = 359.12 [M+H] + .

[1253] (5) Preparation method of compound E97:

[1254] Referring to the preparation method of compound J-1 in step (5) of Example 47, compound D97 was used to replace compound J1 to obtain 92 mg of compound E97. ESI-MS: m / z=363.15 [M+H] + .

[1255] (6) Preparation method of compound F97:

[1256] Referring to step (2) of Example 73, compound A73 was replaced with compound E97 to obtain 77 mg of compound F97, ESI-MS: m / z=489.01 [M+H] + .

[1257] (7) Preparation method of compound G97:

[1258] Referring to step (12) of Example 2, compound F97 was used to replace compound K1 to obtain 40 mg of compound G97. ESI-MS: m / z=735.25 [M-Boc+2H] + .

[1259] (8) Preparation method of compound 97:

[1260] Referring to step (13) of Example 2, compound L2 was replaced with compound G97, and the mixture was purified by preparative liquid phase (column: YMC AQ C18, size 30*250 mm, 10 μm, mobile phase: A: 0.1% formic acid, B: acetonitrile; gradient: 20%-80% B-60 min, wavelength 254 nm, v = 30 ml / min, rt 21.2 min) to obtain 6 mg of compound 97, ESI-MS: m / z = 551.17 [M+H] + .

[1261] Example 98: Preparation of Compounds 98-1 and 98-2

[1262] (1) Preparation method of compound A98:

[1263] Referring to step (13) of Example 1, compound B86 was used to replace compound L1 to obtain 10 g of compound A98. ESI-MS: m / z = 284.23 [M-THP+2H] + .

[1264] (3) Preparation method of compound B98:

[1265] Compound A98 (10 g) was added to methanol (250 mL), and concentrated hydrochloric acid (370 uL) was added dropwise at room temperature. After the addition, the mixture was stirred at room temperature for 4 h.

[1266] After the reaction was completed, the reaction system was concentrated to dryness, the concentrate was added with methanol (90 mL) and slurried for 1 hour, and filtered to obtain 6 g of compound B98. ESI-MS: m / z = 284.21 [M+H] + .

[1267] (4) Preparation method of compound C98:

[1268] Compound B98 (6 g) and NBS (5.0 g) were added to N,N-dimethylformamide (75 mL), and the mixture was stirred at room temperature for 6 h before stopping the reaction.

[1269] After the reaction was complete, ethyl acetate (75 mL) and water (50 mL) were added for extraction and washing. The resulting organic phase was washed with water and then saturated brine, and the resulting organic phase was concentrated to dryness to obtain compound C98, 5.6 g in total. ESI-MS: m / z = 362.09 [M+H] + .

[1270] (5) Preparation method of compounds D98-1 and D98-2:

[1271] Compound C98 (1.5 g), potassium tert-butoxide (940 mg), and diethyl bromofluoromethylphosphonate (1.6 g) were added to acetonitrile (60 mL), and the mixture was stirred at room temperature for 12 h before stopping the reaction.

[1272] After the reaction was completed, ethyl acetate (30 mL) and water (30 mL) were added for extraction. The resulting organic phase was washed sequentially with water and saturated brine. The resulting organic phase was concentrated to dryness and then purified by column chromatography to obtain a crude mixture of compound D98-1 and compound D98-2. This mixture was further purified by preparative liquid chromatography (HPLC conditions: column: YMC AQ C18, size 30*250 mm, 10 μm, mobile phase: A: 0.1% acetic acid, B: methanol; gradient: 30% B 0-3 min, 30-75% B 3-5 min, 75-100% B 5-55 min; wavelength 254 nm, v = 30 ml / min) to obtain D98-1 (rt 21 min, 175 mg) and D98-2 (rt 23 min, 396 mg), respectively. ESI-MS: m / z = 412.09 [M+H] + .

[1273] (6) Preparation of Compounds E98-1 and E98-2:

[1274] Referring to step (12) of Example 2, Compounds D98-1 and D98-2 were used to replace Compound K1, and Compound G1 was used to replace K2, to obtain 100 mg of Compound E98-1 and 120 mg of Compound E98-2, respectively. Compounds E98-1 and E98-2: ESI-MS: m / z = 607.21 [M-Boc+2H] + .

[1275] (7) Preparation method of compounds 98-1 and 98-2:

[1276] Referring to step (13) of Example 2, compound L2 was replaced by compound E98-1 and E98-2, respectively, to obtain 80 mg of compound 98-1 and 105 mg of compound 98-2, respectively.

[1277] The crude compound 98-1 prepared above was purified by preparative liquid chromatography (YMC-AQ-C18, 10 μm, 50*250 column; acetonitrile-0.1% acetic acid aqueous solution (10%-70% / 0-60 min gradient elution), collecting the main peak at 23.5 min, and then purified by methanol-0.1% acetic acid aqueous solution (10%-70% / 0-60 min gradient elution, collecting the main peak at 35 min, to obtain 10 mg of compound 98-1, ESI-MS: m / z=507.19 [M+H] + .

[1278] The crude compound 98-2 prepared above was purified by preparative liquid chromatography (YMC-AQ-C18, 10 μm, 50*250 column; acetonitrile-0.1% acetic acid aqueous solution (10%-70% / 0-60 min gradient elution)), collecting the main peak at 24 min, and then purified by acetonitrile-0.1% acetic acid aqueous solution (10%-70% / 0-60 min gradient elution, collecting the main peak at 24 min, to obtain 13 mg of compound 98-2, ESI-MS: m / z=507.19 [M+H] + .

[1279] Compound 98-1: 1 H NMR (500MHz, DMSO) δ12.51(s,1H),8.65(s,1H),8.21(d,J=8.1Hz,1H),7.86(s,1H),7.82-7.76(m,2H),7.74(d,J=5.8Hz,1H),6.96(dd,J=17.7 ,11.3Hz,1H),6.23(d,J=17.7Hz,1H),5.78(d,J=11.3Hz,1H),1.59(s,3H),1.29-1.22(m,2H),1.09-0.95(m,2H),0.91(dd,J=5.5,3.5Hz,2H).

[1280] Compound 98-2: 1 H NMR (500MHz, DMSO) δ12.51 (s, 1H), 9.14 (s, 1H), 8.18 (d, J = 8.3Hz, 1H), 8.02 ( s,1H),7.92-7.86(m,1H),7.72(dd,J=8.3,1.7Hz,1H),7.64(d,J=5.8Hz,1H) ,6.86(dd,J=17.7,11.3Hz,1H),6.13(d,J=17.7Hz,1H),5.69(d,J=11.3Hz,1 H), 1.60 (s, 3H), 1.24 (d, J = 3.4Hz, 2H), 1.07-1.01 (m, 2H), 0.93-0.82 (m, 2H).

[1281] Example 99: Preparation of Compounds 99-1 and 99-2

[1282] (1) Preparation method of compounds A99-1 and A99-2:

[1283] Referring to step (12) of Example 2, compound K1 was replaced by compound D98-1 and D98-2, respectively, to obtain 33 mg of compound A99-1 and 23 mg of compound A99-2, respectively. Compounds A99-1 and A99-2: ESI-MS: m / z = 650.35 [M-Boc- t Bu+3H] + .

[1284] (2) Preparation method of compounds 99-1 and 99-2:

[1285] Referring to step (13) of Example 2, compound L2 was replaced by compound A99-1 and A99-2, respectively, to obtain 29 mg of compound 99-1 and 25 mg of compound 99-2, respectively.

[1286] The crude compound 99-1 prepared above was purified by preparative liquid chromatography (column: YMC-AQ-C18, 10 μm, 30*250 column; acetonitrile-0.1% acetic acid aqueous solution (10%-70% / 0-60 min gradient elution), collecting the main peak at 18 min, and then purified by methanol-0.1% acetic acid aqueous solution (10%-70% / 0-60 min gradient elution, collecting the main peak at 35 min, to obtain 10 mg of compound 99-1, ESI-MS: m / z=522.25 [M+H] + .

[1287] The crude compound 99-2 prepared above was purified by preparative liquid chromatography (column: YMC-AQ-C18, 10 μm, 30*250 column; acetonitrile-0.1% acetic acid aqueous solution (10%-70% / 0-60 min gradient elution), collecting the main peak at 20 min, and then purified by acetonitrile-0.1% acetic acid aqueous solution (10%-70% / 0-60 min gradient elution, collecting the main peak at 24 min, to obtain 13 mg of compound 99-2, ESI-MS: m / z=522.25 [M+H] + .

[1288] Compound 99-1: 1 H NMR (500MHz, DMSO) δ12.18(s,1H),8.44(s,1H),8.30(s,1H),7.71(d,J=6.0Hz,1H),6.96(dd,J=17.7,11.3Hz,1H),6.79(d,J=1.5Hz,1H ),6.66(d,J=1.6Hz,1H),6.22(d,J=17.6Hz,1H),5.77(d,J=113Hz,1H),3.65(s,2H),1.59(s,3H),1.08-0.99(m,2H),0.95-0.86(m,2H).

[1289] Compound 99-2: 1 H NMR (500MHz, DMSO) δ12.20(s,1H),8.96(s,1H),8.31(s,1H),7.62(d,J=5.8Hz,1H),7.35(s,2H),6.87(dd,J=17.7,11.3Hz,1H),6.78(s,1H) ,6.70(d,J=1.4Hz,1H),6.13(d,J=17.6Hz,1H),5.69(d,J=11.4Hz,1H),3.77(s,2H),1.60(s,3H),1.04(q,J=5.2Hz,2H),0.97-0.87(m,2H).

[1290] Example 100: Preparation of Compound 100

[1291] (1) Preparation method of compound A100:

[1292] Compound A48 (5300 mg), tributyl vinyl tin (13960 mg), tetrakistriphenylphosphine palladium (3390 mg), and potassium phosphate (9330 mg) were added to a mixture of 1,4-dioxane and water (200 mL, v:v 5:1). The reaction mixture was stirred at 85°C under a nitrogen atmosphere for 9 hours. After the reaction, the mixture was cooled to room temperature and filtered. The filtrate was added with ethyl acetate (150 mL), washed with water and saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 3840 mg of compound A100. ESI-MS: m / z = 270.22 [M-THP+2H] + .

[1293] (2) Preparation method of compound B100:

[1294] Compound A100 (3830 mg) was added to methanol (115 mL), and concentrated hydrochloric acid (2.17 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 3 h. After the reaction was complete, the reaction system was concentrated to dryness, and the concentrate was added to methanol (10 mL) and slurried for 1 h. The mixture was then filtered to obtain 2 g of compound B100. ESI-MS: m / z = 270.15 [M+H] + .

[1295] (3) Preparation method of compound C100:

[1296] Compound B100 (2000 g) and NBS (1455 mg) were added to N,N-dimethylformamide (35 mL) and stirred at room temperature for 1 h before stopping the reaction. After completion of the reaction, ethyl acetate (50 mL) and water (50 mL) were added for extraction. The resulting organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 1200 mg of compound C100. ESI-MS: m / z = 348.05 [M+H] + .

[1297] (4) Preparation method of compound D100:

[1298] Compound C100 (1000 g), potassium tert-butoxide (645 mg), and diethyl bromofluoromethylphosphonate (1154 mg) were added to acetonitrile (20 mL) and stirred at room temperature overnight to terminate the reaction. After the reaction was completed, ethyl acetate (20 mL) and water (20 mL) were added for extraction. The resulting organic phase was washed with water and then saturated brine. The resulting organic phase was concentrated to dryness and purified by preparative liquid chromatography (column: YMC AQ C18, 50*250 mm 10 μm; A: 0.1% formic acid, B: acetonitrile; gradient: 20%-60% B (0-60 min), λ: 254 nm, V: 50 mL / min, rt 33 min) to obtain 220 mg of compound D100. ESI-MS: m / z = 398.07 [M+H] + .

[1299] (5) Preparation method of compound E100:

[1300] Compound D100 (102 mg), compound I90 (200 mg), cataCXium A Pd G3 (37 mg), and cesium fluoride (156 mg) were added to a mixture of 1,4-dioxane and water (25 mL, v:v 5:1). The reaction mixture was stirred at 85°C under a nitrogen atmosphere for 1 h. After the reaction, the mixture was cooled to room temperature and filtered. The filtrate was added with ethyl acetate (25 mL), washed with water and saturated brine, and dried over anhydrous sodium sulfate to obtain 150 mg of compound E100. ESI-MS: m / z = 791.54 [M+H] + .

[1301] (5) Preparation method of compound 100:

[1302] Compound E100 (140 mg) was added to dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was added dropwise at room temperature. After the addition, the mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction system was concentrated to dryness and then purified by preparative liquid phase (column: YMC AQ C18, 50*250mm 10μm; A: 0.1% formic acid, B: acetonitrile; gradient: 10%-60% B (0-60 min). λ: 254 nm, V: 50 mL / min. rt 32 min) to obtain 80 mg of compound 100. ESI-MS: m / z = 591.54 [M+H] + .

[1303] Example 101: Preparation of Compound 101

[1304] (1) Preparation method of compound A101:

[1305] 1-Methylcyclopropanol (720 mg), compound A15 (2.53 g), and tetrahydrofuran (20 mL) were mixed and cooled to -20°C under N2 protection with stirring. Potassium tert-butoxide / tetrahydrofuran (1 M, 12 mL) was slowly added dropwise to the reaction system and allowed to react for 2 h (the temperature was not higher than -15°C). After the reaction was complete, water (20 mL) was added to the reaction solution at 0°C and stirred for 10 min. The mixture was extracted with ethyl acetate, and the resulting organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous Na2SO4, filtered, and concentrated to yield 2.2 g of compound A101. ESI-MS: m / z = 306.20 [M+H] + .

[1306] (2) Preparation method of compound B101:

[1307] Referring to step (13) of Example 1, L1 (1.5 g) was replaced with A101 to obtain 800 mg of compound B101. ESI-MS: m / z = 298.25 [M+H] + .

[1308] (3) Preparation method of compound C101:

[1309] Compound B101 (400 mg), NIS (363 mg), bis(trifluoromethylsulfonyl)imide)zinc (253 mg), and dichloromethane (24 mL) were mixed and reacted at 50°C for 3 h under N2 protection. After the reaction was complete, the reaction solution was concentrated, and water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution. The mixture was stirred for 0.5 h and separated. The aqueous phase was extracted with ethyl acetate. The resulting organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated by column chromatog...

Claims

1. A compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII or formula VIII, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl; R and R' are independently selected from H, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl; R s and R t are independently selected from H, deuterium, C 1-10 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, or R s and R t Connect to form C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more selected from OH, NH2, CN, halogen or C 1-3 Alkyl radical substitution; R 2a and R 2b are independently selected from H, OH, NH2, CN, halogen, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1- 10 Alkyl)2N-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more groups selected from deuterium, OH, NH2, CN or halogen; R 2c Selected from OH, NH2, CN, halogen, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more groups selected from deuterium, OH, NH2, CN or halogen; R 4 Selected from C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -NR e R f 、-OR e or -SR e , the C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl are optionally substituted with one or more of the following groups: deuterium, OH, NH2, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl O-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl NHC(O)-, (C 1-6 Alkyl)2NC(O)-, C 1-6 Alkyl C(O)NH-, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl OS(O)-, C 1-6 Alkyl S(O)O-, C 1-6 Alkyl OS(O)2-, C 1-6 Alkyl S(O)2O-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, C 1-6 AlkylNHS(O)2- or C 1-6 Alkyl S(O)2NH-; R e and R f are independently selected from H, or optionally one or more R c1 Substituted with the following groups: C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; Or, R e and R f The N atom to which they are connected forms a 3-10 membered heterocycloalkyl group, wherein the 3-10 membered heterocycloalkyl group is optionally substituted by one or more R c2 replace; R c1 and R c2 are independently selected from OH, NH2, CN, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 3-10 Cycloalkyl-O-, 3-10 membered heterocycloalkyl-O-, C 3-10 Cycloalkyl-NH-, 3-10 membered heterocycloalkyl-NH-, C 3-10 Cycloalkyl-C(O)- or 3-10 membered heterocycloalkyl-C(O)-, wherein the C 1- 10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 3-10 Cycloalkyl-O-, 3-10 membered heterocycloalkyl-O-, C 3-10 Cycloalkyl-NH-, 3-10 membered heterocycloalkyl-NH-, C 3-10 Cycloalkyl-C(O)- or 3-10 membered heterocycloalkyl-C(O)- is optionally substituted by one or more selected from OH, NH2, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-10 Substitution with a cycloalkyl or 3-10 membered heterocycloalkyl group; R 6 Selected from H, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted by one or more groups selected from OH, NH2, CN or halogen; R a and R b are independently selected from H, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, C 3-10 Cycloalkyl, -COC 1-10 Alkyl or -S(O)2C 1-10 Alkyl; the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, C 3-10 Cycloalkyl, -COC 1-10 Alkyl or -S(O)2C 1-10 The alkyl group is optionally substituted with one or more groups selected from OH, NH2, CN, halogen, CHO or COOH; R 3 are independently selected from OH, NH2, CN, halogen, or optionally substituted by one or more R 5 Substituted with the following groups: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 1-12 Alkyl NHC(O)-, (C 1-12 Alkyl)2NC(O)-, C 1-12 Alkyl C(O)NH-, C 1-12 Alkyl OC(O)-, C 1-12 Alkyl C(O)O-, C 1-12 Alkyl OS(O)-, C 1-12 Alkyl S(O)O-, C 1-12 Alkyl OS(O)2-, C 1-12 Alkyl S(O)2O-, C 1-12 AlkylNHS(O)-, C 1-12 Alkyl S(O)NH-, C 1-12 AlkylNHS(O)2-, C 1-12 Alkyl S(O)2NH-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl; R 5 is selected from OH, NH2, CN, halogen, or optionally substituted by one or more R d Substituted with the following groups: C 1-10 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl S-, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 3- 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; R d Selected from OH, NH2, CN, COOH, CHO, halogen, C 1-10 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl S-, C 1-10 Alkyl NH- or (C 1-10 Alkyl) 2N-, the C 1-10 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl S-, C 1-10 Alkyl NH- or (C 1-10 alkyl)2N- is optionally substituted by one or more groups selected from OH, NH2, CN or halogen; n is selected from 0, 1, 2, 3, 4 or 5; R 1 Selected from H, halogen, CN, OH, C 1-10 Alkyl, halogenated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, halogenated C 1-10 Alkoxy, C 1-10 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, -NHR a or -NR a R b ; R 1a Selected from H, halogen, CN, OH, C 1-10 Alkyl, halogenated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, -NHR a 、-NR a R b or C optionally substituted by halogen 1-10 Alkoxy; R 3a Selected from optionally one or more R 5 Substituted C 2-12 alkenyl; R 3b is selected from OH, NH2, CN, halogen, or optionally substituted by one or more R 5 Substituted with the following groups: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 1- 12 Alkyl NHC(O)-, (C 1-12 Alkyl)2NC(O)-, C 1-12 Alkyl C(O)NH-, C 1-12 Alkyl OC(O)-, C 1-12 Alkyl C(O)O-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl; p is selected from 0, 1, 2, 3 or 4; R 3c Selected from optionally one or more R 5a Substituted C 2-12 Alkynyl; The R 5a is selected from 3-12 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; the 3-12 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl is optionally substituted by one or more groups selected from the group consisting of halogen, CN, OH, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, -NHR a 、-NR a R b , C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Heteroalkyl, -NHR a 、-NR a R b , C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted by one or more groups selected from OH, NH2, CN or halogen; R 3d Selected from optionally one or more R 5 Substituted C 2-12 Alkenyl or C 2-12 Alkynyl.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from C 6-10 Aryl; or, Ring A is selected from phenyl or C 10 Aryl; Alternatively, ring A is selected from phenyl or naphthyl; alternatively, ring A is selected from phenyl.

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R and R' are independently selected from H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl; Alternatively, R and R' are independently selected from H, C 1-6 Alkyl or C 3-8 Cycloalkyl; Alternatively, R and R' are independently selected from H, C 1-3 Alkyl or C 3-6 Cycloalkyl; Alternatively, R and R' are independently selected from H or C 1-3 alkyl; Alternatively, R and R' are independently selected from H or methyl; Alternatively, said R and R' are selected from H.

4. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R s and R t are independently selected from H, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, or R s and R t Connect to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more selected from OH, NH2, CN, halogen or C 1-3 Alkyl radical substitution; Or, R s and R t are independently selected from H, deuterium, C 1-6 Alkyl or C 3-6 Cycloalkyl, or R s and R t Connect to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; Or, R s and R t are independently selected from H, deuterium, or C 1-4 Alkyl, or R s and R t Connect to form C 3-4 Cycloalkyl; Or, R s and R t are independently selected from H, deuterium, or methyl, or R s and R t They are linked to each other to form a cyclopropyl group; Or, R s and R t are independently selected from H or deuterium.

5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are independently selected from H, OH, NH2, CN, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by one or more groups selected from deuterium, OH, NH2, CN or halogen; Or, R 2a and R 2b are independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by one or more groups selected from deuterium, OH, NH2, CN or halogen; Or, R 2a and R 2b are independently selected from H, C 1-4 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl, the C 1- 4 alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl is optionally substituted by one or more groups selected from deuterium, OH, NH2, CN or halogen; Optionally, R 2b Selected from H; Optionally, R 2a Selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl is optionally substituted by one or more groups selected from deuterium, OH, NH2, CN or halogen; Or, R 2a Selected from C 1-6 Alkyl or C 3-6 Cycloalkyl, the C 1-6 Alkyl or C 3-6 Cycloalkyl is optionally substituted with one or more groups selected from deuterium, OH, NH2, CN or halogen; Or, R 2a Selected from C 1-3 Alkyl or C 3-4 Cycloalkyl, the C 1-3 Alkyl or C 3-4 Cycloalkyl is optionally substituted with one or more deuterium, F, Cl or Br; Or, R 2a is selected from methyl or cyclopropyl, said methyl or cyclopropyl being optionally substituted by one or more deuterium or F; Or, R 2a Selected from CH3, CD3, CF3, CHF2 or cyclopropyl; Or, R 2a Selected from CH3, CD3 or CHF2; Or, R 2a Selected from CH3; or, R 2a Selected from CD3; or, R 2a is selected from cyclopropyl; Optionally, R 2c Selected from C 1-3 Alkyl or C 3-4 Cycloalkyl, the C 1-3 Alkyl or C 3-4 Cycloalkyl is optionally substituted with one or more deuterium, F, Cl or Br; Or, R 2c is selected from methyl or cyclopropyl, said methyl or cyclopropyl being optionally substituted by one or more deuterium or F; Or, R 2c Selected from CH3, CD3, CF3, CHF2 or cyclopropyl; Or, R 2c Selected from CD3 or CHF2.

6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, -NR e R f 、-OR e or -SR e , the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl are optionally substituted by one or more of the following groups: deuterium, OH, NH2, CN, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkyl O-, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 1-3 Alkyl NHC(O)-, (C 1-4 Alkyl)2NC(O)-, C 1-4 Alkyl C(O)NH-, C 1-4 Alkyl OC(O)- or C 1-4 Alkyl C(O)O-; R e and R f are independently selected from H, or optionally one or more R c1 Substituted with the following groups: C 1-6 Alkyl, C 1- 6 heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-8 membered heteroaryl; Or, R e and R f The N atom to which they are connected forms a 3-8 membered heterocycloalkyl group, wherein the 3-8 membered heterocycloalkyl group is optionally substituted by one or more R c2 replace; Optionally, R 4 Selected from C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl, -NR e R f 、-OR e or -SR e , the C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6- 8-membered aryl or 5-6-membered heteroaryl is optionally substituted by one or more of the following groups: deuterium, OH, NH2, CN, halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl; Or, R 4 Selected from C 6-8 Aryl, 5-6 membered heteroaryl, -NR e R f OR e ; Or, R 4 Selected from phenyl, 6-membered heteroaryl, -NR e R f OR e ; Or, R 4 Selected from phenyl, pyridyl, -NR e R f OR e ; Or, R 4 Selected from -NR e R f OR e ; Optionally, R e and R f are independently selected from H, or optionally one or more R c1 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-8 membered heteroaryl; Or, R e and R f The N atom to which they are connected forms a 3-8 membered heterocycloalkyl group, wherein the 3-8 membered heterocycloalkyl group is optionally substituted by one or more R c2 replace; Or, R e and R f are independently selected from H, or optionally one or more R c1 Substituted with the following groups: C 1-4 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl; Or, R e and R f The N atom to which they are connected forms a 3-6 membered heterocycloalkyl group, wherein the 3-6 membered heterocycloalkyl group is optionally substituted by one or more R c2 replace; Or, R e and R f are independently selected from H, or optionally one or more R c1 Substituted with the following groups: C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; Or, R e and R f The N atom to which they are connected forms a 4-5 membered heterocycloalkyl group, wherein the 4-5 membered heterocycloalkyl group is optionally substituted by one or more R c2 replace; Or, R e and R f are independently selected from H, or optionally one or more R c1 Substituted with the following groups: C 1-3 Alkyl, C 3-6 Cycloalkyl or 6-7 membered heterocycloalkyl; Or, R e and R f The N atom to which they are connected forms a 4-5 membered heterocycloalkyl group, wherein the 4-5 membered heterocycloalkyl group is optionally substituted by one or more R c2 replace; Or, R e and R f are independently selected from H, or optionally one or more R c1 substituted with the following radicals: methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or monoazaspiroheptyl, Or, R e and R f are connected to each other and to the N atom to which they are attached to form an azetidinyl or pyrrolidinyl group, wherein the azetidinyl or pyrrolidinyl group is optionally substituted by one or more R c2 replace; Or, R f Selected from H, R e Selected from optionally one or more R c1 Substituted with the following groups: C 1-3 Alkyl, C 3-6 Cycloalkyl or 6-7 membered heterocycloalkyl; Or, R e and R f The N atom to which they are connected forms a 4-5 membered heterocycloalkyl group, wherein the 4-5 membered heterocycloalkyl group is optionally substituted by one or more R c2 replace; Or, R f Selected from H, R e Selected from optionally one or more R c1 substituted with the following radicals: methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or monoazaspiroheptyl, Or, R e and R f are connected to each other and to the N atom to which they are attached to form an azetidinyl or pyrrolidinyl group, wherein the azetidinyl or pyrrolidinyl group is optionally substituted by one or more R c2 replace; Or, R e and R f are independently selected from H, or optionally one or more R c1 Substituted with the following groups: methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, Cyclohexyl, azetidinyl, pyrrolidinyl or monoazaspiroheptyl, Or, R e and R f are connected to each other and to the N atom to which they are attached to form an azetidinyl or pyrrolidinyl group, wherein the azetidinyl or pyrrolidinyl group is optionally substituted by one or more R c2 replace; Optionally, R c1 and R c2 are independently selected from OH, NH2, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-8 Cycloalkyl-O-, 3-8 membered heterocycloalkyl-O-, C 3-8 Cycloalkyl-NH-, 3-8 membered heterocycloalkyl-NH-, C 3-8 Cycloalkyl-C(O)- or 3-8 membered heterocycloalkyl-C(O)-, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-8 Cycloalkyl-O-, 3-8 membered heterocycloalkyl-O-, C 3-8 Cycloalkyl-NH-, 3-8 membered heterocycloalkyl-NH-, C 3-8 Cycloalkyl-C(O)- or 3-8 membered heterocycloalkyl-C(O)- is optionally substituted with one or more selected from OH, NH2, CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-10 Substitution with a cycloalkyl or 3-10 membered heterocycloalkyl group; Or, R c1 and R c2 are independently selected from OH, NH2, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-8 Cycloalkyl-O- or C 3-8 Cycloalkyl-C(O)-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-8 Cycloalkyl-O- or C 3-8 Cycloalkyl-C(O)- is optionally substituted by one or more alkyl radicals selected from OH, NH2, CN, halogen or C 1-6 Alkoxy group substitution; Or, R c1 and R c2 are independently selected from OH, NH2, CN, F, Cl, Br, C 1-3 Alkyl, C 2-3 Alkenyl, C 2- 3 alkynyl, C 1-3 Alkoxy, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 3-6 Cycloalkyl-O- or C 3-6 Cycloalkyl-C(O)-, the C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkyl NH-, (C 1-3 Alkyl)2N-, C 3-6 Cycloalkyl-O- or C 3-6 Cycloalkyl-C(O)- is optionally substituted by one or more alkyl radicals selected from OH, NH2, CN, halogen or C 1-3 Alkoxy group substitution; Or, R c1 and R c2 are independently selected from OH, NH2, CN, F, Cl, Br, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl-O- or C 3-6 Cycloalkyl-C(O)-, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl-O- or C 3-6 Cycloalkyl-C(O)- is optionally substituted by one or more alkyl radicals selected from OH, NH2, CN, halogen or C 1-3 Alkoxy group substitution; Or, R c1 and R c2 are independently selected from OH, NH2, CN, F, Cl, Br, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-4 Cycloalkyl-O- or C 5-6 Cycloalkyl-C(O)-, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-4 Cycloalkyl-O- or C 5-6 Cycloalkyl-C(O)- is optionally substituted by one or more alkyl radicals selected from OH, NH2, CN, halogen or C 1-3 Alkoxy group substitution; Or, R c1 and R c2 Each is independently selected from OH, F, cyclopropyl-O-, cyclopentyl-C(O)-, methoxy, isopropyloxy, CH3OCH2CH2O-, methyl, CHF2 or CF3; Or, R c1 and R c2 are independently selected from OH, NH2, CN, F, Cl, Br, C 1-3 Alkoxy, C 3-4 Cycloalkyl-O- or C 5-6 Cycloalkyl-C(O)-, the C 1-3 Alkoxy, C 3-4 Cycloalkyl-O- or C 5-6 Cycloalkyl-C(O)- is optionally substituted by one or more alkyl radicals selected from OH, NH2, CN, halogen or C 1-3 Alkoxy group substitution; Or, R c1 and R c2 Each is independently selected from OH, F, cyclopropyl-O-, cyclopentyl-C(O)-, methoxy, isopropyloxy or CH3OCH2CH2O-; Optionally, R c1 and R c2 are independently selected from OH, NH2, CN, F, Cl, Br, C 1-3 Alkyl, C 3-6 Cycloalkyl-O- or C 3-6 Cycloalkyl-C(O)-, the C 1-3 Alkyl, C 3-6 Cycloalkyl-O- or C 3-6 Cycloalkyl-C(O)- is optionally substituted by one or more groups selected from OH, NH2, CN or halogen; Or, R c1 and R c2 Each is independently selected from OH, F, cyclopropyl-O- or cyclopentyl-C(O)-; Or, R e and R f are independently selected from H, methyl, ethyl, isopropyl, Cyclopropyl, cyclobutyl, cyclopentyl, Or, R e and R f Connected to each other and to the N atoms connected to form 7. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from H, C 1- 6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 2- 6-alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by one or more groups selected from OH, NH2, CN or halogen; Or, R 6 Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; Or, R 6 Selected from H, C 1-3 Alkyl or C 3-4 Cycloalkyl; Or, R 6 is selected from H, ethyl or cyclopropyl; Or, R 6 Selected from H.

8. The compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R a and R b are independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, -COC 1-6 Alkyl or -S(O)2C 1- 6 alkyl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, -COC 1-6 Alkyl or -S(O)2C 1- 6Alkyl is optionally substituted with one or more groups selected from OH, NH2, CN, halogen, CHO or COOH; Or, R a and R b are independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, -COC 1-6 Alkyl or -S(O)2C 1-6 alkyl; Or, R a and R b Each is independently selected from H, methyl, ethyl or isopropyl; Or, R a and R b Each independently selected from H or methyl; Or, R a and R b Selected from H.

9. The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 3 are independently selected from OH, NH2, CN, halogen, or optionally substituted by one or more R 5 Substituted with the following groups: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkyl S-, C 1-10 Alkyl NH-, (C 1-10 Alkyl)2N-, C 1-10 Alkyl NHC(O)-, (C 1-10 Alkyl)2NC(O)-, C 1-10 Alkyl C(O)NH-, C 1-10 Alkyl OC(O)-, C 1-10 Alkyl C(O)O-, C 1-6 Alkyl OS(O)-, C 1-6 Alkyl S(O)O-, C 1-6 Alkyl OS(O)2-, C 1-6 Alkyl S(O)2O-, C 1-6 AlkylNHS(O)-, C 1-6 Alkyl S(O)NH-, C 1-6 AlkylNHS(O)2-, C 1-6 Alkyl S(O)2NH-, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; R 5 is selected from OH, NH2, CN, halogen, or optionally substituted by one or more R d Substituted with the following groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 1-8 Alkyl S-, C 1-8 Alkyl NH-, (C 1-8 Alkyl)2N-, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-8 Aryl or 5-8 membered heteroaryl; R d Selected from OH, NH2, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH- or (C 1-6 Alkyl) 2N-, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl S-, C 1-6 Alkyl NH- or (C 1-6 alkyl)2N- is optionally substituted by one or more groups selected from OH, NH2, CN or halogen; Or, R 3 are independently selected from OH, NH2, CN, halogen, or optionally substituted by one or more R 5 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-10 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6- 10 Aryl or 5-6 membered heteroaryl; Or, R 3 are independently selected from OH, NH2, CN, halogen, or optionally substituted by one or more R 5 Substituted with the following groups: C 1-3 Alkyl, C 2-3 Alkenyl, C 2-6 Alkynyl or 3-membered heterocycloalkyl; Or, R 3 are independently selected from OH, NH2, CN, halogen, or optionally substituted by one or more R 5 Substituted with the following groups: C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-4 Cycloalkyl or 3-4 membered heterocycloalkyl; Or, R 3 are independently selected from OH, NH2, CN, F, Cl, Br, I, or optionally substituted by one or more R 5 Substituted groups: methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, propenyl, ethynyl, propynyl, butynyl, dimethylbutynyl (such as 3,3-dimethylbutynyl), methylpentynyl (such as 4-methylpentynyl), cyclopropyl or oxirane; Or, R 3 are independently selected from CN, F, vinyl or propynyl, the vinyl or propynyl being optionally substituted by one or more R 5 Replace; or, R 3 are independently selected from CN, F, vinyl or propynyl, the vinyl being optionally substituted with one or more F; Optionally, R 5 is selected from OH, NH2, CN, halogen, or optionally substituted by one or more R d Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl or 5-6 membered heteroaryl; Or, R 5 is selected from OH, NH2, CN, F, chlorine, bromine, or optionally substituted by one or more R d Substituted with the following groups: C 1-2 Alkyl, C 1-2 Alkoxy, C 3-6 Cycloalkyl, phenyl or 5-6 membered heteroaryl; Or, R 5 is selected from OH, F, or optionally one or more R d Substituted from the following: methyl, OCH3, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, pyrimidinyl, pyrazinyl or pyridyl; Or, R 5 Selected from OH, F, OCH3, Cyclopropyl, cyclopentyl, cyclohexyl, phenyl, Pyrrolyl, furanyl, thienyl, pyrazolyl, pyrimidinyl, pyrazinyl or pyridinyl; Or, R 5 is selected from CN, F, Cl or Br; Optionally, R d Selected from CN, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Alkoxy; Or, R d Selected from CN, methyl, CF3 or OCH3; Or, R 3 are independently selected from OH, CN, F, Cl, acetylene, propynyl, butynyl, Vinyl, methyl, Cyclopropyl, isopropyl or tert-butyl; Or, R 3 are independently selected from CN, F, Cl, methyl, propynyl, 10. The compound according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from H, halogen, CN, OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -NHR a or -NR a R b ; Or, R 1 Selected from H, halogen, CN, OH, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-4 Cycloalkyl, -NHR a or -NR a R b ; Or, R 1 Selected from H, halogen, C 2-3 Alkenyl, -NHR a or -NR a R b ; Or, R 1 Selected from H, Cl, vinyl, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3 or -NHCH(CH3)2; Optionally, R 1a Selected from H, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2 or C optionally substituted by halogen 1-6 Alkoxy Or, R 1a is selected from H, -NH2 or C optionally substituted by F 1-3 Alkoxy; or, R 1a Selected from H, -NH2 or -OCH2CF3.

11. The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 3a Selected from optionally one or more R 5 Substituted C 2-6 Alkenyl; R 3b is selected from OH, NH2, CN, halogen, or optionally substituted by one or more R 5 Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 1-6 Alkyl NHC(O)-, (C 1-6 Alkyl)2NC(O)-, C 1-6 Alkyl C(O)NH-, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl C(O)O-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl; Or, R 3a is selected from vinyl optionally substituted by one or more of the following groups: halogen, CN, OH, NH2, C 1- 3 alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, the C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl are optionally substituted with one or more of the following groups: OH, NH2, CN, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Alkoxy; Or, R 3a is selected from vinyl optionally substituted with one or more of the following groups: halogen, pyrrolyl or pyrazinyl, the pyrrolyl or pyrazinyl being optionally substituted with one or more C 1-3 Alkyl substitution; Or, R 3a is selected from vinyl optionally substituted by one or more halogens; or, R 3a is selected from vinyl optionally substituted with one or more F; Or, R 3a Selected from vinyl, Or, R 3b Selected from OH, NH2, CN, halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; Or, R 3b Selected from CN or halogen; Or, R 3b is selected from CN, F, Cl, methyl, cyclopropyl, isopropyl or tert-butyl; Or, R 3b is selected from OH, NH2, CN or halogen; Or, R 3b Selected from CN or F.

12. The compound according to any one of claims 1 to 11, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 3c Selected from optionally one or more R 5a Substituted C 2-8 Alkynyl; R 5a is selected from 3-6 membered heterocyclic group, C 6-10 aryl or 5-6 membered heteroaryl; the 3-6 membered heterocyclic group, C 6-10 The aryl or 5-6 membered heteroaryl is optionally substituted by one or more groups selected from the group consisting of halogen, CN, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, -NHR a 、-NR a R b , C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C 6-10 Aryl or 5-6 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C 6-10 The aryl or 5-6 membered heteroaryl is optionally substituted by one or more groups selected from OH, NH2, CN or halogen; Or, R 3c Selected from optionally one or more R 5a Substituted C 2-6 Alkynyl; Or, R 3c Selected from optionally one or more R 5a Substituted ethynyl groups; Optionally, R 5a phenyl or 5-6 membered heteroaryl; the phenyl or 5-6 membered heteroaryl is optionally substituted by one or more groups selected from the following: halogen, CN, OH or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more groups selected from OH, NH2, CN or halogen; Or, R 5a Selected from phenyl, Pyrrolyl, furanyl, thienyl, pyrazolyl, pyrimidinyl, pyrazinyl or pyridinyl; Or, R 3c Selected from Optionally, R 3d is selected from C optionally substituted by halogen 2-6 Alkenyl or C 2-6 Alkynyl; Or, R 3d Selected from C 2-3 Alkynyl or C optionally substituted by F 2-3 alkenyl; Or, R 3d Selected from vinyl or propynyl.

13. The compound according to any one of claims 1 to 12, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein n is selected from 1, 2 or 3; or, n is selected from 2 or 3; Optionally, p is selected from 0, 1 or 2; or, p is selected from 1 or 2.

14. The compound according to any one of claims 1 to 13, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula IA, formula IA-1, or formula IA-2, its stereoisomer or a pharmaceutically acceptable salt thereof, R 31 and R 32 are independently selected from OH, NH2, CN, halogen, or optionally substituted by one or more R 5 Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1- 6 alkyl) 2N-, C 1-6 Alkyl NHC(O)-, (C 1-6 Alkyl)2NC(O)-, C 1-6 Alkyl C(O)NH-, C 1-6 Alkyl OC(O)-, C 1-6 Alkyl C(O)O-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C6 aryl or 5-6 membered heteroaryl; Or, R 31 and R 32 are independently selected from OH, NH2, CN, halogen or C optionally substituted by halogen 1-4 Alkyl or C 3-4 Cycloalkyl; Or, R 31 and R 32 are independently selected from CN, F, Cl, methyl, isopropyl, tert-butyl or cyclopropyl; Or, R 31 is selected from CN, methyl, isopropyl, tert-butyl or cyclopropyl; Or, R 31 Selected from CN; Or, R 32 Selected from F; Optionally, R 3 Selected from optionally one or more R 5 Substituted with the following groups: C 1-10 Alkyl, C 1-10 Alkoxy, C 2- 10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; Or, R 3 Selected from optionally one or more R 5 Substituted with the following groups: C 1-3 Alkyl, C 2-3 Alkenyl, C 2-6 Alkynyl or 3-membered heterocycloalkyl; Or, R 3 Selected from optionally one or more R 5 Substituted from the following: methyl, ethyl, oxirane, vinyl, ethynyl, propynyl, butynyl, dimethylbutynyl or methylpentynyl; Or, R 3 Selected from C 2-3 Alkenyl or C 2-4 Alkynyl, the C 2-3 Alkenyl or C 2-4 The alkynyl group is optionally substituted with one or more R 5 Replace; or, R 3 Selected from optionally one or more R 5 Substituted from the following: vinyl, propenyl, ethynyl or propynyl; Alternatively, the compound of formula IV, its stereoisomer or a pharmaceutically acceptable salt thereof is selected from a compound of formula IVA, formula IVA-1 or formula IVA-2, its stereoisomer or a pharmaceutically acceptable salt thereof, Alternatively, the compound of formula V, its stereoisomer or a pharmaceutically acceptable salt thereof is selected from a compound of formula VA, formula VA-1, or formula VA-2, its stereoisomer or a pharmaceutically acceptable salt thereof, Optionally, the structural part Selected from Or, the structural part Selected from Or, the structural part Selected from 15. The compound according to any one of claims 1 to 14, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula IIA, formula IIA-1, or formula IIA-2, its stereoisomer or a pharmaceutically acceptable salt thereof, Optionally, the structural part Selected from Or, the structural part Selected from Or, the structural part Selected from 16. The compound according to any one of claims 1 to 15, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof is selected from a compound of formula IIIA, formula IIIA-1, or formula IIIA-2, its stereoisomer or a pharmaceutically acceptable salt thereof, Optionally, the structural part Selected from Or, the structural part Selected from Or, the structural part Selected from 17. The compound according to any one of claims 1 to 16, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula VIA, formula VIA-1, or formula VIA-2, its stereoisomer or a pharmaceutically acceptable salt thereof, 18. The following compound, its stereoisomer or its pharmaceutically acceptable salt: Alternatively, the following compound, its stereoisomer or a pharmaceutically acceptable salt thereof: Alternatively, the following compound, its stereoisomer or a pharmaceutically acceptable salt thereof: Alternatively, the following compound, its stereoisomer or a pharmaceutically acceptable salt thereof:

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18, its stereoisomer or a pharmaceutically acceptable salt thereof, and optionally, further comprising a pharmaceutically acceptable excipient.

20. Use of the compound according to any one of claims 1 to 18, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of a medicament for preventing or treating cancer.

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