Nitrogen-containing heterocyclic compound as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a nitrogen-containing heterocyclic compound as well as a pharmaceutical composition and application thereof. The invention provides a nitrogen-containing heterocyclic compound as shown in a formula I, and pharmaceutically acceptable salts, prodrugs, stereoisomers, tautomers or isotope compounds thereof. According to the present invention, the nitrogen-containing heterocyclic compound has good inhibition effects on a variety of mutations such as KRASG12C, KRASG12D, KRASG12V, KRASQ61H and the like, and the wild type cells amplified by KRAS, and is expected to be used for treating and / or preventing a variety of Ras-related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a nitrogen-containing heterocyclic compound, a pharmaceutical composition and application thereof. Background Art

[0002] Ras (Rat sarcoma viral oncogene) was first discovered in rat sarcoma. The mammalian ras gene family consists of three members: H-ras (HRAS), K-ras (KRAS), and N-ras (NRAS). K-ras has two variants, A and B, in its fourth exon. Ras genes are widely present in eukaryotic organisms, including mammals, fruit flies, fungi, nematodes, and yeast, with varying levels of expression in different tissues. H-Ras is primarily expressed in the skin and skeletal muscle, K-Ras in the colon and thymus, and N-Ras at high levels in the testes. Ras proteins act as molecular switches in cellular signaling, regulating signal transduction by switching between GTP / GDP binding, thereby regulating vital processes such as cell proliferation, differentiation, aging, and apoptosis.

[0003] RAS mutations are closely associated with the development and progression of human tumors, occurring in approximately 30% of human tumors. KRAS mutations are the most common, accounting for approximately 85%, followed by NRAS and HRAS, which account for 12% and 3%, respectively. KRAS mutations are predominant in pancreatic, colorectal, and lung cancers, while NRAS mutations are more common in melanoma and acute myeloid leukemia, and HRAS mutations are more common in bladder and head and neck cancers. Ras proto-oncogene mutations primarily occur through point mutations. Over 150 different Ras point mutations have been identified, with glycine at positions 12 and 13 and glutamine at position 61 being the most common.

[0004] For decades, people have been committed to the development of small molecule inhibitors that directly target RAS. Scientists have always hoped to develop GTP competitive inhibitors that act directly on RAS proteins. However, due to the extremely strong affinity between GTP and RAS (pmol / L level), the high GTP concentration in cells (0.5mM), and the lack of pockets in the RAS protein structure that are conducive to small molecule binding, they have not been successful. In recent years, people have used KRAS G12C Some progress has been made in drug development for allosteric sites of mutants. In 2013, a research group reported that KRAS G12C The discovery of small molecule inhibitors (Nature, 2013, 503, 548-551). G12CA novel binding pocket located below the molecular switch II region was identified in the mutant. These inhibitors bind to this allosteric pocket and form a covalent bond with the nearby cysteine ​​Cys12, thereby selectively inhibiting KRAS. G12C Other researchers have reported that KRAS with cellular activity G12C Inhibitors (Science, 2016, 351, 604-608).

[0005] KRAS, one of the most important cancer-driving genes, has a G12C mutation that opens the door to the design of irreversible covalent small molecule drugs. Following breakthroughs in related research, the development of corresponding drugs has quickly become a hot topic in the global development of new anti-cancer drugs. In May 2021, Amgen's KRAS G12C inhibitor, Lumakras, received accelerated approval from the US FDA, achieving a major breakthrough in the "undruggability" of KRAS.

[0006] Despite significant breakthroughs in the research of KRAS G12C inhibitors, current clinical studies have shown that these inhibitors have limited efficacy and are prone to drug resistance. Furthermore, there is a lack of effective treatments for numerous other mutations, including cancers harboring KRAS G12D, G12V, G13D, G12R, G12S, and G12A, as well as cancers with wild-type KRAS amplification. Therefore, the search for drugs targeting KRAS mutations is urgent.

[0007] In short, after decades of unremitting efforts, people have gradually deepened their understanding of Ras. To date, drugs targeting KRASG12C mutations have been launched on the market. However, there are no particularly effective treatments for other different mutations. Finding compounds with better inhibitory effects on Ras remains a research hotspot and difficulty in the field of new drug development. Summary of the Invention

[0008] The technical problem to be solved by the present invention is the lack of effective drugs in the prior art as Ras inhibitors for clinical treatment. To this end, the present invention provides a nitrogen-containing heterocyclic compound, a pharmaceutical composition and application thereof, which is expected to be used to treat and / or prevent various diseases related to Ras.

[0009] The present invention solves the above technical problems through the following technical solutions.

[0010] The present invention provides a nitrogen-containing heterocyclic compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof:

[0011]

[0012] in, represents a single bond or a double bond;

[0013] is phenyl, "a 5-7 membered heterocycloalkenyl group containing 1 to 3 heteroatoms, which are independently selected from O, S and N", "a 5-7 membered heteroaryl group containing 1 to 3 heteroatoms, which are independently selected from O, S and N" or a 5-7 membered cycloalkenyl group; wherein, D 1 is C, CH or N; D2 is wherein Z1 and Z2 are independently a linker, CH, CH2, O, S, N or NH;

[0014] r is 0, 1, 2, 3, or 4;

[0015] R 5 are independently deuterium, halogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, C 3-10 Cycloalkyl, hydroxyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, amino, C 1-6 Alkyl-NH-, C 2-6 Alkenyl, nitro or C 3-10 Cycloalkyl-O-;

[0016] X 1 and X 2 Independently for CR b or N, and X 1 and X 2 Not CR at the same time b ;

[0017] Y 1 O, S, NH, CH2 or

[0018] Y 2 NR 2 , O or S;

[0019] m1, m2 and n are independently 0, 1, 2, 3 or 4;

[0020] R b is hydrogen, halogen or cyano;

[0021] R 1 C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", one or more R 1-1 Substituted C 6-20 Aryl, or, with one or more R 1-2Substituted "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0022] R 1-1 and R 1-2 are independently deuterium, halogen, -OR c , cyano, azido, -C(=O)R 11 、-NR 12 R 13 、-C(=O)OR 14 、-C(=O)NR 15 R 16 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -B(OR x )(OR y ), "a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from O, S and N", C 6-20 Aryl, "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", 1-1-1 Substituted C 1-6 Alkyl, one or more R 1-1-2 Substituted C 1-6 Alkyl-O-, one or more R 1-1-3 Substituted C 3-10 Cycloalkyl, one or more R 1-1-4 Substituted "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms, which are independently selected from O, S and N", 1-1-5 Substituted C 6-20 Aryl, or one or more R 1-1-6 Substituted "5-7 membered heteroaryl containing 1 or 2 heteroatoms, which are independently selected from O, S and N"; when there are multiple substituents, they are the same or different; or, when R 1-1 or R 1-2 When there are multiple R, any two R 1-1 or two R 1-2 connected to form, independently, a 3- to 8-membered cyclic olefin together with the atoms to which they are connected;

[0023] R 2 、R c 、R 12 and R 13 are independently hydrogen, C 1-6 Alkyl, -C(=O)R c1 、-C(=O)OR c2 、-C(=O)NRc3 R c4 、-SO2R c5 、 or by one or more R c10 Substituted C 1-6 alkyl;

[0024] R c1 、R c2 、R c3 、R c4 、R c5 、R c6 、R c7 、R c8 and R c9 are independently hydrogen, C 1-20 Alkyl, C 3-10 Cycloalkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N", C 6-20 Aryl, "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", 4-1-1 Substituted C 1-20 Alkyl, one or more R 4-1-2 Substituted C 3-10 Cycloalkyl, one or more R 4-1-3 Substituted "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms, which are independently selected from O, S and N", 4-1-4 Substituted C 6-20 Aryl, "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", 4-1-5 Substituted "5-7 membered heteroaryl containing 1 or 2 heteroatoms, which are independently selected from O, S and N", -NR c51 R c52 、-(C 1-6 Alkylene-O) p -C 1-6 alkyl, p is 1, 2, 3, or 4;

[0025] R 1-1-1 、R 1-1-2 、R 1-1-3 、R 1-1-4 、R 1-1-5 、R 1-1-6 、R 4-1-1 、R 4-1-2 、R 4-1-3 、R 4-1-4 and R 4-1-5 are independently cyano, halogen, hydroxy, nitro, C 1-6Alkyl-O-, C 1-6 Alkyl, one or more R 31 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N", C 6-20 Aryl, "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", -B(OR x )(OR y ),-C(=O)R 21 、-NR 22 R 23 、-OC(=O)R 24 、-OC(=O)R 32 、-C(=O)NR 25 R 26 、-COOH、-C(=O)OR 27 OR-OC(=O)OR 28 ;

[0026] R c10 C 1-6 Alkyl-O-, hydroxyl, C 1-6 Alkyl substituted By one or more -B(OR x )(OR y ) substituted C 6-20 Aryl, one or more R c10-1 Substituted "5-7 membered heteroaryl containing 1 or 2 heteroatoms, which are independently selected from O, S and N", or -OC(=O)R 29 ; R c10-1 Independently C 1-6 Alkyl or nitro;

[0027] Alternatively, optional R 2 and R b , optional R 2 and R 5 Respectively with the atoms to which they are connected form a "5-12 membered heterocycloalkenyl containing 2 to 4 heteroatoms, two of which are N, and the other heteroatoms are independently selected from O, S and N", or, a Substituted "5- to 12-membered heterocycloalkenyl containing 2 to 4 heteroatoms, two of which are N, and the other heteroatoms are independently selected from O, S and N";

[0028] R x and R y are independently hydrogen or C 1-6 Alkyl, or R x and Ry Formed with the connected oxygen atoms by one or more C 1-6 an alkyl-substituted five-membered ring;

[0029] R 4 are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, one or more R 4-1 Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-O-, one or more R 4-2 Substituted C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, one or more R 4-3 Substituted C 1-6 Alkyl-S-, O=, C 3-10 Cycloalkyl-O-, -C(=O)R 4a 、-NR 4b1 R 4b2 、-C(=O)OR 4c or -C(=O)NR 4d1 R 4d2 ; or, when n is 2, 3 or 4, any two R 4 connected, independently forming a 3-8 membered carbon ring with the atoms to which they are connected, and surrounded by one or more R 4-4 substituted 3-8 membered carbon ring, "a 4-8 membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N", or one or more R 4-5 Substituted "4-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N";

[0030] R 4-1 、R 4-2 、R 4-3 、R 4-4 、R 4-5 and R a are independently halogen, C 1-6 Alkyl, C 2-6 Alkenyl, cyano, hydroxyl, C 1-6 Alkyl-O-, -NR 4i R 4j 、-C(=O)OR 4e or -C(=O)NR 4f1 R 4f2 ; or, R 4-5 For O =;

[0031] R 4a 、R4b1 、R 4b2 、R 4c 、R 4d1 、R 4d2 、R 4e 、R 4f1 、R 4f2 、R 4i and R 4j are independently hydrogen, C 2-6 Alkenyl or C 1-6 alkyl;

[0032] L1 is the connecting key, C 1-6 Alkylene, -C(=O)-, -O(R L-1 ) n1 -、-S(R L-2 ) n2 -or-NR L-3 (R L-4 ) n3 -;R L-1 、R L-2 and R L-4 Independently C 1-6 Alkylene or C substituted by one or more deuterium 1-6 Alkylene; R L-3 is hydrogen or C 1-6 Alkyl; n1, n2 and n3 are independently 0 or 1;

[0033] R 3 C 3-12 Cycloalkyl, one or more R 3-1 Substituted C 3-12 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 3-2 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms, which are independently selected from O, S and N", C 1-6 Alkyl, one or more R 3-3 Substituted C 1-6 Alkyl, one or more R 3-4 Substituted C 2-6 Alkenyl, -OR d 、-SR d1 、-NR e1 R e2 , or -C(=O)NR e3 R e4 ; When there are multiple substituents, they are the same or different;

[0034] R 3-1 、R 3-2 、R 3-3 and R 3-4 Independently C1-6 Alkyl, one or more R 3-1-1 Substituted C 1-6 Alkyl, one or more R 3-1-5 Substituted C 6-20 Aryl, hydroxyl, azido, Ar, C 1-6 Alkyl-O-, -CH2-O-Ar, halogen, O=, -NR e5 R e6 、-C(=O)NR e7 R e8 or Ar is replaced by one or more R 3-1-4 Substituted "5-12 membered heteroaryl containing 1-3 heteroatoms, which are independently selected from O, N and S";

[0035] Or, R 3-1 and R 3-2 Independently -L2-M; L2 is -L 21 -L 22 -L 23 -L 24 -L 25 -L 26 ;L 21 、L 23 and L 25 are independently a linker, O, S, NH, C(O)NH or C 1-6 Alkylene; L 22 and L 24 Independently for the connecting bond, C 3-10 Cycloalkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N", C 6-20 Aryl, or "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N"; L 26 is a connecting bond, O, S, NH or C(O)NH;

[0036] M is

[0037] R 4g 、R 4h 、R e17 and R e18 are independently hydrogen, halogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, cyano, -C(=O)R e171 、-C(=O)OR e172 or -C(=O)NR e173 R e174 ; or, R 4g and R 4h 、Re17 and R e18 , together with the atoms to which they are attached, form a 3- to 8-membered carbocyclic ring, or a 4- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N;

[0038] R d 、R d1 、R e1 、R e2 、R e3 and R e4 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, "4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", or, 3-1-2 Substituted C 1-6 alkyl;

[0039] R 3-1-1 、R 3-1-2 、R 3-1-5 and R 3-1-4 are independently deuterium, cyano, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkyl-O-, C substituted by one or more halogens 1-6 Alkyl-O-, C substituted by one or more halogens 1-6 Alkyl, -C(=O)R e9 、-NR e10 R e11 、-C(=O)OR e12 、-C(=O)NR e13 R e14 、-OC(=O)NR e15 R e16 、"a 4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N" or、one or more R 3-1-1-1 Substituted "4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; or, any two R 3-1-5 connected to form one or more R 3-1-1-2 Substituted "4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N";

[0040] R 3-1-1-1 and R 3-1-1-2 Independently Halogen, C 1-6 Alkyl or one or more R 3-1-1-1-1 Substituted C 6-20 Aryl; R 3-1-1-1-1is halogen or C substituted by one or more halogens 1-6 alkyl;

[0041] R e5 、R e6 、R e7 、R e8 、R e9 、R e10 、R e11 、R e12 、R e13 、R e14 、R e15 、R e16 、R e171 、R e172 、R e173 and R e174 are independently hydrogen or C 1-6 alkyl;

[0042] Or, R 12 and R 13 、R 15 and R 16 、R c3 and R c4 、R 22 and R 23 、R 25 and R 26 、R 4b1 and R 4b2 、R 4d1 and R 4d2 、R 4f1 and R 4f2 、R 4i and R 4j 、R e1 and R e2 、R e3 and R e4 、R e5 and R e6 、R e7 and R e8 、R e10 and R e11 、R e13 and R e14 、R e15 and R e16 、R e173 and R e174 Respectively form with the N atom to which it is connected "a 4-12 membered heterocycloalkyl containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N", or, 3-1-3 Substituted "4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S, and N"; R3-1-3 are independently deuterium, cyano, halogen, hydroxyl, C 1-6 Alkyl-O-, C 1-6 Alkyl, one or more R 33 Substituted C 1-6 Alkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N" or -C(=O)OR 30 ;

[0043] R c51 、R c52 、R 11 、R 21 、R 14 、R 15 、R 16 、R 24 、R 25 、R 26 、R 27 、R 28 and R 30 are independently hydrogen or C 1-6 alkyl;

[0044] R 29 For hydrogen, C 1-6 Alkyl or -NR m R n ;

[0045] R 31 For hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, -NR m R n 、-OC(=O)R 32 or -C(=O)OC 1-6 alkyl;

[0046] R 32 and R 33 Independently -OC 1-6 Alkyl or one or more -NR m R n Substituted C 1-6 Alkyl; R 22 、R 23 、R m and R n are independently hydrogen, C 1-6 Alkyl or Boc.

[0047] In a certain embodiment, the nitrogen-containing heterocyclic compound as shown in Formula I, its pharmaceutically acceptable salt, its prodrug, its stereoisomer, its tautomer or its isotope compound,

[0048] in, represents a single bond or a double bond;

[0049] is phenyl, "a 5- to 7-membered heterocycloalkenyl group containing 1 to 3 heteroatoms, which are independently selected from O, S and N", or "a 5- to 7-membered heteroaryl group containing 1 to 3 heteroatoms, which are independently selected from O, S and N"; wherein D 1 is C, CH or N; D2 is wherein Z1 and Z2 are independently a linker, CH, CH2, O, S, N or NH;

[0050] r is 0, 1, or 2;

[0051] R 5 are independently halogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, hydroxyl, C 1-6 Alkyl-O-, C 2-6 alkenyl or nitro;

[0052] Y 1 O, NH, CH2 or

[0053] Y 2 O or NR 2 ;

[0054] m1, m2 and n are independently 0, 1, 2, 3 or 4;

[0055] X 1 and X 2 All are N;

[0056] R 1 C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", one or more R 1-1 Substituted C 6-20 Aryl, or, with one or more R 1-2 Substituted "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0057] R 1-1 and R 1-2 are independently halogen, -OR c , cyano, -NR 12 R 13 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -B(OR x )(OR y ) or by one or more R1-1-1 Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0058] R 2 、R c 、R 12 and R 13 are independently hydrogen, C 1-6 Alkyl, -C(=O)R c1 、-C(=O)OR c2 、-C(=O)NR c3 R c4 、-SO2R c5 、 or by one or more R c10 Substituted C 1-6 alkyl;

[0059] R c1 、R c2 、R c3 、R c4 、R c5 、R c6 、R c7 、R c8 and R c9 are independently hydrogen, C 1-20 Alkyl, C 3-10 Cycloalkyl, one or more R 4-1-1 Substituted C 1-20 Alkyl, one or more R 4-1-4 Substituted C 6-20 Aryl, "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", 4-1-5 Substituted "5-7 membered heteroaryl containing 1 or 2 heteroatoms, which are independently selected from O, S and N", -NR c51 R c52 、-(C 1-6 Alkylene-O) p -C 1-6 alkyl, or, p is 1, 2, 3 or 4; when there are multiple substituents, they are the same or different;

[0060] R 1-1-1 、R 4-1-1 、R 4-1-4 and R 4-1-5 are independently halogen, hydroxy, C 1-6 Alkyl-O-, one or more R 31 Substituted C 1-6Alkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N", C 6-20 Aryl, -C(=O)R 21 、-NR 22 R 23 、-OC(=O)R 24 、-OC(=O)R 32 、-COOH、-C(=O)OR 27 OR-OC(=O)OR 28 ;

[0061] R c10 C 1-6 Alkyl-O-, C 1-6 Alkyl substituted By one or more -B(OR x )(OR y ) substituted C 6-20 Aryl, one or more R c10-1 Substituted "5-7 membered heteroaryl containing 1 or 2 heteroatoms, which are independently selected from O, S and N", or -OC(=O)R 29 ; R c10-1 Independently C 1-6 Alkyl or nitro;

[0062] Alternatively, optional R 2 and R 5 Respectively form with the atoms to which they are attached a "5- to 12-membered heterocycloalkenyl group containing 2 to 4 heteroatoms, two of which are N, and the other heteroatoms are independently selected from O, S and N";

[0063] R x and R y are independently hydrogen, or R x and R y Formed with the connected oxygen atoms by one or more C 1-6 an alkyl-substituted five-membered ring;

[0064] R 4 are independently deuterium, halogen, hydroxyl, C 1-6 Alkyl, O= or -C(=O)R 4a ; or, when n is 2, 3 or 4, any two R 4 connected to form a group of atoms surrounded by one or more R 4-5 Substituted "4-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N";

[0065] R 4-5 For O =;

[0066] R 4a C 2-6 Alkenyl or C 1-6 alkyl;

[0067] L1 is a connecting bond or -O(R L-1 ) n1 -;R L-1 C 1-6 Alkylene or C substituted by one or more deuterium 1-6 Alkylene; n1 is 1;

[0068] R 3 For one or more R 3-1 Substituted C 3-12 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 3-2 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms, which are independently selected from O, S and N", or, 3-4 Substituted C 2-6 Alkenyl; when there are multiple substituents, they may be the same or different;

[0069] R 3-1 、R 3-2 and R 3-4 Independently C 1-6 Alkyl, one or more R 3-1-1 Substituted C 1-6 Alkyl, one or more R 3-1-5 Substituted C 6-20 Aryl, Ar, C 1-6 Alkyl-O-, -CH2-O-Ar, halogen, or Ar is replaced by one or more R 3 -1-4 Substituted "5-12 membered heteroaryl containing 1-3 heteroatoms, which are independently selected from O, N and S";

[0070] R 3-1-1 、R 3-1-5 and R 3-1-4 are independently halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C substituted by one or more halogen 1-6 Alkyl-O-, C substituted by one or more halogens 1-6 Alkyl, -C(=O)R e9 、-NR e10 R e11 、-OC(=O)NR e15 R e16、"a 4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N" or、one or more R 3 -1-1-1 Substituted "4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", or any two R 3-1-5 connected to form one or more R 3-1-1-2 Substituted "4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N";

[0071] R 3-1-1-1 and R 3-1-1-2 are independently halogen, C 1-6 Alkyl or one or more R 3-1-1-1-1 Substituted C 6-20 Aryl; R 3-1-1-1-1 C is independently halogen or substituted by one or more halogens 1-6 alkyl;

[0072] Or, R 3-1 and R 3-2 Independently -L2-M; L2 is -L 21 -L 22 -L 23 -L 24 -L 25 -L 26 ;L 21 、L 23 and L 25 are independently a linker, O, S, NH, C(O)NH or C 1-6 Alkylene; L 22 and L 24 Independently for the connecting bond, C 3-10 Cycloalkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N", C 6-20 Aryl, or "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N"; L 26 is a connecting bond, O, S, NH or C(O)NH;

[0073] M is

[0074] R e17 and R e18 are independently hydrogen or halogen;

[0075] R e9 、R e10 、R e11 、R e15 and R e16are independently hydrogen or C 1-6 alkyl;

[0076] Or, R c3 and R c4 Respectively form with the N atom to which it is connected "a 4-12 membered heterocycloalkyl containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N", or, 3-1-3 Substituted "4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S, and N"; R 3 -1-3 Independently by one or more R 33 Substituted C 1-6 Alkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N" or -C(=O)OR 30 ;

[0077] R c51 、R c52 、R 24 、R 27 、R 28 and R 30 are independently hydrogen or C 1-6 alkyl;

[0078] R 29 For hydrogen, C 1-6 Alkyl or -NR m R n ;

[0079] R 31 For hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, -NR m R n 、-OC(=O)R 32 or -C(=O)OC 1-6 alkyl;

[0080] R 32 and R 33 Independently -OC 1-6 Alkyl or one or more -NR m R n Substituted C 1-6 Alkyl; R 21 、R 22 、R 23 、R m and R n are independently hydrogen, C 1-6 Alkyl or Boc.

[0081] In a certain embodiment, the nitrogen-containing heterocyclic compound as shown in Formula I, its pharmaceutically acceptable salt, its prodrug, its stereoisomer, its tautomer or its isotope compound,

[0082] represents a single bond or a double bond;

[0083] is phenyl, "a 5- to 7-membered heterocycloalkenyl group containing 1 to 3 heteroatoms, which are independently selected from O, S and N" or "a 5- to 7-membered heteroaryl group containing 1 to 3 heteroatoms, which are independently selected from O, S and N"; wherein, D 1 is C or N; D2 is wherein Z1 and Z2 are independently a linker, CH, CH2, N or NH;

[0084] r is 0, 1, or 2;

[0085] R 5 are independently halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, hydroxyl or C 2-6 alkenyl;

[0086] Y 1 O, NH, CH2 or

[0087] Y 2 O or NR 2 ; R 2 For hydrogen, C 1-6 Alkyl, -C(=O)R c1 or -C(=O)OR c2 ; R c1 For one or more R 4-1-1 Substituted C 1-20 Alkyl; R c2 C 1-6 Alkyl; R 4-1-1 are independently halogen;

[0088] m1 and m2 are independently 0 or 1;

[0089] n is 0, 1, or 2;

[0090] R 4 is halogen, hydroxyl or C 1-6 alkyl;

[0091] X 1 and X 2 is N;

[0092] R 1 C 6-20Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", one or more R 1-1 Substituted C 6-20 Aryl, or, with one or more R 1-2 Substituted "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different;

[0093] R 1-1 and R 1-2 are independently halogen, -OR c , cyano, -NR 12 R 13 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -B(OR x )(OR y ) or by one or more R 1-1-1 Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different;

[0094] R c is hydrogen, -C(=O)R c1 、-C(=O)NR c3 R c4 or by one or more R c10 Substituted C 1-6 Alkyl; R c10 are independently -OC(=O)R 29 ; R 29 -NR m R n ; R m and R n C 1-6 alkyl;

[0095] R c1 、R c3 and R c4 are independently hydrogen, C 1-20 Alkyl, C 3-10 Cycloalkyl, -(C 1-6 Alkylene-O) p -C 1-6 Alkyl, one or more R 4-1-1 Substituted C 1-20 Alkyl or one or more R 4-1-4 Substituted C 6-20 Aryl; p is 1, 2 or 3;

[0096] R 4-1-1 For-OC 1-6 Alkyl, -C(=O)R21 、-NR 22 R 23 , -COOH or "a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from O, S and N"; R 21 C 1-6 Alkyl; R 22 and R 23 are independently hydrogen, C 1-6 Alkyl or Boc;

[0097] R 4-1-4 is a halogen;

[0098] Or, R c3 and R c4 Respectively form with the N atom to which it is connected "a 4-12 membered heterocycloalkyl containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N", or, 3-1-3 Substituted "4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S, and N"; R 3 -1-3 Independently by one or more R 33 Substituted C 1-6 Alkyl or "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N"; R 33 For-OC 1-6 alkyl;

[0099] R 12 and R 13 are independently hydrogen;

[0100] R x and R y are independently hydrogen;

[0101] R 1-1-1 is a halogen;

[0102] L1 is a connecting bond or -O(R L-1 ) n1 -;R L-1 C 1-6 Alkylene or C substituted by one or more deuterium 1-6 Alkylene; n1 is 1;

[0103] R 3 For one or more R 3-1 Substituted C 3-12 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 3-2Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 3-4 Substituted C 2-6 Alkenyl; when there are multiple substituents, they may be the same or different;

[0104] R 3-1 For one or more R 3-1-1 Substituted C 1-6 Alkyl; R 3-1-1 are independently -NR e10 R e11 , "a 4-10 membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S and N", or one or more R 3-1-1-1 Substituted "4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N"; R e10 and R e11 Independently C 1-6 Alkyl; R 3-1-1-1 Independently C 1-6 alkyl, or by one or more R 3-1-1-1-1 Substituted C 6-20 Aryl; R 3-1-1-1-1 are independently halogen;

[0105] R 3-2 Halogen, C 1-6 Alkyl, one or more R 3-1-1 Substituted C 1-6 Alkyl, Ar, -CH2-O-Ar or one or more R 3-1-5 Substituted C 6-20 Aryl; Ar is substituted by one or more R 3-1-4 Substituted "5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S"; R 3-1-1 Halogen, C 2-6 Alkenyl or -OC(=O)NR e15 R e16 ; R e15 and R e16 Independently C 1-6 Alkyl; R 3-1-4 and R 3-1-5 Independently C 1-6 Alkyl, halogen, C substituted by one or more halogens 1-6 Alkyl-O- or C substituted by one or more halogen 1-6 Alkyl; or, any two R 3-1-5 connected to form one or more R 3-1-1-2Substituted "4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N"; R 3-1-1-2 are independently halogen;

[0106] Or, R 3-1 -L2-M; L2 is -L 21 -L 22 -L 23 -L 24 -L 25 -L 26 ;L 21 、L 23 and L 25 are independently a linker, O, S, NH, C(O)NH or C 1-6 Alkylene; L 22 and L 24 Independently for the connecting bond, C 3-10 Cycloalkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N", C 6-20 Aryl, or "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N"; L 26 is a connecting bond, O, S, NH or C(O)NH;

[0107] M is

[0108] R 3-4 is halogen, or is replaced by one or more R 3-1-1 Substituted C 1-6 Alkyl; R 3-1-1 -NR e10 R e11 or “a 4- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S and N”; R e10 and R e11 Independently C 1-6 alkyl;

[0109] R e17 and R e18 are independently hydrogen or halogen.

[0110] In a certain embodiment, in the nitrogen-containing heterocyclic compound as shown in Formula I, its pharmaceutically acceptable salt, its prodrug, its stereoisomer, its tautomer or its isotope compound, certain groups have the following definitions, and the definitions of the unmentioned groups are as described in any embodiment of the present invention (this paragraph is hereinafter referred to as "in a certain embodiment").

[0111] In one scenario, two R 4 form Or, any two R4 Forming a 3-8 membered carbon ring.

[0112] In one scenario, D 1 C or N.

[0113] In one embodiment, in D2, either Z1 or Z2 is CH, CH2 or N, and the other is a connecting bond.

[0114] In one embodiment, r is 0, 1 or 2.

[0115] In one scenario, R 5 Halogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, hydroxyl, C 1-6 Alkyl-O-, C 2-6 alkenyl or nitro.

[0116] In one scheme, when r is 1, for

[0117] In one scenario, X 1 and X 2 is independently N.

[0118] In one scenario, R 1-1 are independently halogen, -OR c 、C 1-6 Alkyl, -NR 12 R 13 、C 2-6 Alkynyl or one or more R 1-1-1 Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different; R 1-1-1 are independently halogen.

[0119] In one scenario, R 1-2 are independently halogen, cyano, C 2-6 Alkenyl or -NR 12 R 13 .

[0120] In one scenario, R 12 and R 13 independently hydrogen, -SO2R c5 or -C(=O)OR c2 ; R c2 C 1-6 alkyl.

[0121] In one scenario, R c is hydrogen, -C(=O)R c1 、-C(=O)OR c2、-C(=O)NR c3 R c4 、-SO2R c5 、 or by one or more R c10 Substituted C 1-6 Alkyl; R c10 C 1-6 Alkyl-O-, C 1-6 Alkyl substituted By one or more -B(OR x )(OR y ) substituted C 6-20 Aryl, one or more R c10-1 Substituted "5-7 membered heteroaryl containing 1 or 2 heteroatoms, which are independently selected from O, S and N", or -OC(=O)R 29 ; R c10-1 Independently C 1-6 Alkyl or nitro; R c1 、R c2 、R c3 、R c4 、R c5 、R c6 、R c7 、R c8 and R c9 are independently hydrogen, C 1-20 Alkyl, C 3-10 Cycloalkyl, one or more R 4-1-1 Substituted C 1-20 Alkyl, one or more R 4-1-4 Substituted C 6-20 Aryl, "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", 4-1-5 Substituted "5-7 membered heteroaryl containing 1 or 2 heteroatoms, which are independently selected from O, S and N", -NR c51 R c52 、-(C 1-6 Alkylene-O) p -C 1-6 alkyl, p is 1, 2, 3 or 4; when there are multiple substituents, they are the same or different; R 1-1-1 、R 4 -1-1 、R 4-1-4 and R 4-1-5 are independently halogen, hydroxy, C 1-6 Alkyl-O-, C 1-6 Alkyl, one or more R 31 Substituted C 1-6Alkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N", C 6-20 Aryl, "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", -NR 22 R 23 、-OC(=O)R 24 、-OC(=O)R 32 、-COOH、-C(=O)OR 27 OR-OC(=O)OR 28 ; R x and R y are independently hydrogen, or R x and R y Formed with the connected oxygen atoms by one or more C 1-6 Alkyl-substituted five-membered ring.

[0122] In a certain scheme, when p is greater than 1, each C 1-6 The alkylene-O groups may be the same or different.

[0123] In one scenario, R c3 and R c4 The N atom to which it is connected forms a "4-12 membered heterocycloalkyl containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N", or is surrounded by one or more R 3-1-3 Substituted "4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S, and N"; R 3-1-3 Independently by one or more R 33 Substituted C 1-6 Alkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N" or -C(=O)OR 30 ; R 30 is hydrogen or C 1-6 Alkyl; R 33 Independently -OC 1-6 Alkyl or one or more -NR m R n Substituted C 1-6 Alkyl; R m and R n are independently hydrogen, C 1-6 Alkyl or -Boc.

[0124] In a certain scheme, when R 1 For one or more R 1-1 Substituted C 6-20 In the case of an aryl group, the plurality is two or three.

[0125] In one scenario, Y 1 O, NH, CH2 or

[0126] In one embodiment, m1, m2 and n are independently 0, 1 or 2.

[0127] In one scenario, Y 2 O or NR 2 .

[0128] In one scenario, R 2 For hydrogen, C 1-6 Alkyl, -C(=O)R c1 or -C(=O)OR c2 ; R c1 C 1-20 Alkyl or one or more R 4-1-1 Substituted C 1-20 Alkyl; R c2 C 1-6 Alkyl or one or more R 4-1-1 Substituted C 1-6 Alkyl; R 4-1-1 are independently halogen, C 6-20 Aryl or -OC(=O)R 24 ; or, optionally, R 2 and R 5 They respectively form with the atoms to which they are connected a "5- to 12-membered heterocycloalkenyl group containing 2 to 4 heteroatoms, two of which are N, and the other heteroatoms are independently selected from O, S and N".

[0129] In one scenario, R c1 In, R 4-1-1 are independently halogen.

[0130] In one scenario, R c2 In, R 4-1-1 Independently C 6-20 Aryl or -OC(=O)R 24 .

[0131] In one scenario, R 24 C 1-6 alkyl.

[0132] In one scenario, R 4 are independently hydroxy, halogen, deuterium, -C(=O)R 4a , oxo or C 1-6 Alkyl; R 4a C 1-6 Alkyl or C 2-6 Alkenyl.

[0133] In one embodiment, L1 is a linker or -O(R L-1 ) n1 -;R L-1 Independently C 1-6 Alkylene or C substituted by one or more deuterium 1-6 Alkylene; n1 is 1.

[0134] In one scenario, R 3 For one or more R 3-1 Substituted C 3-12 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 3-2 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 3-4 Substituted C 2-6 Alkenyl; when there are multiple substituents, they may be the same or different.

[0135] In one scenario, R 3-1 Independently by one or more R 3-1-1 Substituted C 1-6 Alkyl; R 3-1-1 -NR e10 R e11 、"a 4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N" or、one or more R 3-1-1-1 Substituted "4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N"; R e10 and R e11 Independently C 1-6 Alkyl; R 3-1-1-1 C 1-6 alkyl, or by one or more R 3-1-1-1-1 Substituted C 6-20 Aryl; R 3-1-1-1-1 C is independently halogen or substituted by one or more halogens 1-6 Alkyl; R e17 and R e18 are independently hydrogen or halogen; or, R 3-1 Independently -L2-M; L2 is -L 21 -L 22 -L 23 -L 24 -L 25 -L 26 ;L 21 、L 23 and L 25 are independently a linker, O, S, NH, C(O)NH or C1-6 Alkylene; L 22 and L 24 Independently for the connecting bond, C 3-10 Cycloalkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N", C 6-20 Aryl, or "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N"; L 26 is a connecting bond, O, S, NH or C(O)NH;

[0136] M is

[0137] In one scenario, R 3-2 are independently halogen, C 1-6 Alkyl, one or more R 3-1-1 Substituted C 1-6 alkyl, By one or more R 3-1-5 Substituted C 6-20 Aryl, -CH2-O-Ar or Ar; Ar is replaced by one or more R 3-1-4 Substituted "5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S"; R 3-1-1 are independently halogen, -OC(=O)NR e15 R e16 or C 2-6 Alkenyl; R e15 and R e16 Independently C 1-6 Alkyl; R e17 and R e18 are independently hydrogen or halogen; R 3-1-4 and R 3-1-5 are independently halogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl-O- or C substituted by one or more halogen 1-6 Alkyl; or, any two R 3-1-5 connected to form one or more R 3-1-1-2 Substituted "4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N"; R 3-1-1-2 are independently halogen.

[0138] In one scenario, R 3-4 is independently halogen, or is replaced by one or more R 3-1-1 Substituted C 1-6 Alkyl; R 3-1-1 -NR e10 R e11or “a 4- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S and N”; R e10 and R e11 Independently C 1-6 alkyl.

[0139] In one scenario, R e17 and R e18 are independently hydrogen or halogen.

[0140] In one embodiment, when the group R 5 、R b 、R 1-1 、R 1-2 、R 1-1-1 、R 1-1-2 、R 1-1-3 、R 1-1-4 、R 1-1-5 、R 1-1-6 、R 4 -1-1 、R 4-1-2 、R 4-1-3 、R 4-1-4 、R 4-1-5 、R 4 、R 4-1 、R 4-2 、R 4-3 、R 4-4 、R 4-5 、R a 、R 3-1 、R 3-2 、R 3-3 、R 3-4 、R 3-1-1 、R 3-1-2 、R 3-1-3 、R 3-1-5 、R 3-1-4 、R 4g 、R 4h 、R e17 、R e18 、R 3-1-1-1 and R 3-1-1-1-1 When halogen is mentioned, the halogen is fluorine, chlorine, bromine or iodine.

[0141] In one embodiment, when the group R 1 、R 1-1 、R 1-2 、R c1 、R c2 、R c3 、R c4 、R c5 、R c6 、R c7 、R c8 、R c9 、R1-1-1 、R 1 -1-2 、R 1-1-3 、R 1-1-4 、R 1-1-5 、R 1-1-6 、R 4-1-1 、R 4-1-2 、R 4-1-3 、R 4-1-4 、R 4-1-5 、R c10 、R 3-1 、R 3-2 、R 3-3 、R 3-4 and R 3 -1-1-1 The definition of C 6-20 When the C 6-20 Aryl is phenyl, naphthyl or anthracenyl.

[0142] In one embodiment, when the group R 5 、R 1-1 、R 1-2 、R 2 、R c 、R 12 、R 13 、R c10 、R c10-1 、R 1-1-1 、R 1-1-2 、R 1-1-3 、R 1 -1-4 、R 1-1-5 、R 1-1-6 、R 4-1-1 、R 4-1-2 、R 4-1-3 、R 4-1-4 、R 4-1-5 、R c51 、R c52 、R 11 、R 21 、R 22 、R 23 、R 14 、R 24 、R 15 、R 25 、R 16 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R x 、R y 、R4 、R 4-1 、R 4-2 、R 4-3 、R 4-4 、R 4-5 、R a 、R 4a 、R 4b1 、R 4b2 、R 4c 、R 4d1 、R 4d2 、R 4e 、R 4f1 、R 4f2 、R 4i 、R 4j 、R L-3 、R 3 、R 3-1 、R 3-2 、R 3-3 、R 3-4 、R 4g 、R 4h 、R e17 、R e18 、R d 、R d1 、R e1 、R e2 、R e3 、R e4 、R 3-1-1 、R 3-1-2 、R 3-1-5 、R 3-1-4 、R 3-1-1-1 、R 3-1-1-1-1 、R e5 、R e6 、R e7 、R e8 、R e9 、R e10 、R e11 、R e12 、R e13 、R e14 、R e15 、R e16 、R e171 、R e172 、R e173 、R e174 and R 3-1-3 The definition of C 1-6 When alkyl, the C 1-6 Alkyl is C 1-4 Alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0143] In one embodiment, when the group R c1 、Rc2 、R c3 、R c4 、R c5 、R c6 、R c7 、R c8 and R c9 Independently C 1-20 When alkyl, the C 1-20 Alkyl is C 1-12 Alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0144] In one embodiment, when the group R 1-1 、R 1-2 and R 4 The definition of C 2-6 When the alkynyl group, the C 2-6 Alkynyl is C 2-3 Alkynyl, for example ethynyl, propynyl or propargyl.

[0145] In one embodiment, when the group R 5 、R 1-1 、R 1-2 、R 4 、R 4-1 、R 4-2 、R 4-3 、R 4-4 、R 4-5 、R a 、R 4a 、R 4b1 、R 4b2 、R 4c 、R 4d1 、R 4d2 、R 4e 、R 4f1 、R 4f2 、R 4i 、R 4j 、R 3 、R 3-1-1 、R 3-1-2 、R 3-1-5 and R 3-1-4 The definition of C 2-6 When alkenyl, the C 2-6 Alkenyl is C 2-3 Alkenyl, for example, ethenyl, propenyl or allyl.

[0146] In one embodiment, when m1 is 0 and m2 is 1, or m1 is 1 and m2 is 0, n is 1 or 2.

[0147] In one embodiment, when m1 and m2 are both 1, n is 0.

[0148] In a certain scheme, when R 1 For one or more R 1-2 When the substituted “5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms which are independently selected from O, S and N” is used, the “5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms which are independently selected from O, S and N” is “8- to 10-membered heteroaryl group containing 1 heteroatom which is independently selected from O, S or N”, for example, benzothienyl.

[0149] In one embodiment, when Ar is replaced by one or more R 3-1-4 When the substituted “5-12 membered heteroaryl group containing 1-3 heteroatoms which are independently selected from O, N and S”, the “5-12 membered heteroaryl group containing 1-3 heteroatoms which are independently selected from O, N and S” is a “5-10 membered heteroaryl group containing 1-2 heteroatoms N”, for example, pyridazinyl or pyrimidinyl.

[0150] In a certain scheme, when R 3-1-1 、R 3-1-5 and R 3-1-4 are independently C substituted by one or more halogens 1-6 When alkyl, the C 1-6 Alkyl is a C substituted with two or three fluorine 1-2 alkyl.

[0151] In one embodiment, the R 4 are independently methyl, fluoro, deuterium, oxo, or hydroxyl groups.

[0152] In one plan, for

[0153] In one plan, for

[0154] In one embodiment, the R 5 For -F, -OH, -Cl, -CF3, -NO2, -OEt or -OMe, or R 2 and R 5 form In one embodiment, the R 1 for

[0155]

[0156]

[0157]

[0158]

[0159] In one plan, for

[0160] In one embodiment, L1 is a linking bond, -OCH2- or -OCD2-.

[0161] In one embodiment, the R 3 for

[0162]

[0163] In one plan, for

[0164]

[0165] In one embodiment, the for

[0166]

[0167] In one embodiment, the nitrogen-containing heterocyclic compound shown in Formula I is any of the following structures:

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182] The present invention also provides a compound, the structure of which is shown below:

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190] The present invention also provides a pharmaceutical composition comprising substance A and pharmaceutical excipients; the substance A is a therapeutically effective amount of the above-mentioned nitrogen-containing heterocyclic compound represented by Formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof.

[0191] The present invention also provides a use of a substance A in the preparation of a RAS inhibitor, wherein the substance A is the nitrogen-containing heterocyclic compound represented by Formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof.

[0192] In the use of the substance A in the preparation of a RAS inhibitor, the RAS is a wild-type RAS or a mutant RAS. The wild-type RAS may be a wild-amplified KRAS. The mutant RAS is, for example, mutant KRAS, mutant HRAS or mutant NRAS, wherein the mutant KRAS may be mutant G12, G13, Q61, such as KRAS G12C, KRAS G12D, KRAS G12S, KRAS G12A, KRAS G12V or KRAS G13D, and further such as KRAS G12C, KRAS G12D or KRASG12V; the mutant HRAS may be G12, G13, Q61, such as mutant HRAS G12C, HRAS G12D, HRAS G12S, HRAS G12A, HRAS G12V or HRAS G13D; the mutant NRAS may be mutant G12, G13, Q61, such as NRASG12C, NRAS G12D, NRAS G12S, NRAS G12A, NRAS G12V or NRAS G13D.

[0193] The present invention also provides a use of a substance A in the preparation of a drug, wherein the drug is used to treat or prevent RAS-related diseases; the substance A is the nitrogen-containing heterocyclic compound represented by Formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof.

[0194] In the use of the substance A in preparing a drug, the RAS is a wild-type RAS or a mutant RAS. The wild-type RAS may be a wild-amplified KRAS. The mutant RAS is, for example, mutant KRAS, mutant HRAS or mutant NRAS, wherein the mutant KRAS may be mutant G12, G13, Q61, such as KRAS G12C, KRAS G12D, KRAS G12S, KRAS G12A, KRAS G12V or KRAS G13D, and further such as KRAS G12C, KRAS G12D or KRAS G12V; the mutant HRAS may be G12, G13, Q61, such as mutant HRAS G12C, HRAS G12D, HRAS G12S, HRAS G12A, HRAS G12V or HRAS G13D; the mutant NRAS may be mutant G12, G13, Q61, such as NRAS G12C, NRAS G12D, NRAS G12S, NRAS G12A, NRAS G12V or NRAS G13D.

[0195] In the use of the substance A in the preparation of a medicament, the RAS-related disease is, for example, cancer. The cancer is, for example, one or more of colon cancer, appendiceal cancer, pancreatic cancer, MYH-related polyposis, blood cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia, and melanoma.

[0196] The present invention also provides a use of a substance A in the preparation of a medicament, wherein the medicament is used to treat or prevent cancer; the substance A is the nitrogen-containing heterocyclic compound represented by Formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof. The cancer is, for example, one or more of colon cancer, appendix cancer, pancreatic cancer, MYH-related polyposis, blood cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, gastric cancer, thyroid cancer, bladder cancer, lymphoma, leukemia, and melanoma.

[0197] The term "plurality" refers to 2, 3, 4 or 5.

[0198] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acid includes organic acids, including but not limited to acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0199] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms or groups of atoms in a molecule in the same order of interconnection, such as cis-trans isomers, optical isomers, or atropisomers. These stereoisomers can be separated, purified, and enriched by asymmetric synthesis or chiral separation methods (including but not limited to thin-layer chromatography, rotary chromatography, column chromatography, gas chromatography, and high-pressure liquid chromatography). They can also be obtained by chiral resolution through bonding (chemical bonding, etc.) or salification (physical bonding, etc.) with other chiral compounds.

[0200] The term "tautomer" refers to functional group isomers that result from the rapid shift of an atom between two positions in a molecule. For example, acetone and 1-propen-2-ol can be interconverted by the rapid shift of a hydrogen atom between an oxygen and an α-carbon.

[0201] The term "isotopic compound" refers to a compound in which one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2H, 3H, 13C, 14C, 15N, 18O, 17O, 18F, 35S, and 36Cl). The isotopic compounds of the present invention can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent according to the methods described herein.

[0202] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0203] The term "alkyl" refers to a straight or branched chain alkyl group having the specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0204] The term "alkylene" refers to a connecting group between two other groups, which can also be straight or branched. Examples include but are not limited to -CH2-, -CH2CH2-, -CH2CH2CH2CH(CH3)-, -CH2CH(CH2CH3)CH2-.

[0205] The term "alkoxy" refers to the group -OR X , where R X is an alkyl group as defined above.

[0206] The terms "cycloalkyl" and "carbocycle" refer to a saturated cyclic group consisting solely of carbon atoms, having a specified number of carbon atoms (e.g., C3-C6), and being monocyclic, bridged, or spirocyclic. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0207] The term "aryl" refers to an aromatic group consisting of carbon atoms, with each ring having aromatic properties, such as phenyl or naphthyl.

[0208] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which is monocyclic or polycyclic, and at least one ring is aromatic (in accordance with Huckel's rule). The heteroaryl group is connected to other fragments in the molecule through an aromatic ring or a non-aromatic ring. Heteroaryl includes, but is not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.

[0209] The term "heterocyclyl," "heterocycle," or "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 3 to 8 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which is monocyclic, bridged, or spirocyclic, and each ring is saturated. Heterocycloalkyl groups include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.

[0210] The term "hydroxy" refers to an -OH group.

[0211] The term "cyano" refers to a -CN group.

[0212] The term "oxo" refers to a =0 group.

[0213] Unless otherwise specified, The two hydrogen atoms on the same carbon atom are Substitution, for example, occurs when a carbon atom is replaced by After substitution, the formation structure.

[0214] Similarly, we can define

[0215] The "C" that determines the carbon number range x1 -C y1 " substituents (x1 and y1 are integers), such as "C x1 -C y1 "Alkyl, "C x1 -C y1 "Cycloalkyl", "C x1 -C y1 "Cycloalkenyl", "C x1 -C y1 "alkoxy", "C x1 -C y1 "Alkenyl, "C x1 -C y1 "Alkynyl, "C x1 -C y1 "Aryl, "C x1 -C y1"heteroaryl or "C x1 -C y1 "Heterocyclic group" refers to the number of carbon atoms not including substituents, for example, C1-C6 alkyl refers to C1-C6 alkyl not including substituents.

[0216] In the present invention, when R 12 and R 13 、R 15 and R 16 、R c3 and R c4 、R 22 and R 23 、R 25 and R 26 、R 4b1 and R 4b2 、R 4d1 and R 4d2 、R 4i and R 4j 、R 4f1 and R 4f2 、R 4i and R 4j 、R e1 and R e2 、R e3 and R e4 、R e5 and R e6 、R e7 and R e8 、R e10 and R e11 、R e13 and R e14 、R e15 and R e16 、R e173 R e174 Respectively form with the N atom to which it is connected "a 4-12 membered heterocycloalkyl containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N", or, 3-1-3 When the substituted "4- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S, and N" is used, the "4- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S, and N" and the "4- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S, and N" are replaced by one or more R 3-1-3 The heteroatom combination of the substituted “4- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N” in the “4- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N” is (N), (N and O), (N and S) or (N, O and S).

[0217] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0218] The reagents and raw materials used in the present invention are commercially available.

[0219] The positive progress of the present invention is that the nitrogen-containing heterocyclic compound represented by Formula I has a good inhibitory effect on various mutations such as KRASG12C, KRAS G12D, KRAS G12V, KRAS Q61H, as well as wild-type cells with KRAS amplification, and is expected to treat and / or prevent various Ras-related diseases. DETAILED DESCRIPTION

[0220] The present invention is further illustrated below by way of examples, but the present invention is not limited to the scope of the examples described. The experimental methods for which specific conditions are not specified in the following examples shall be carried out in accordance with conventional methods and conditions, or selected in accordance with the product instructions. The solvents involved in the following examples are all analytically pure or chromatographically pure. When the solvents involved in the following examples are mixed solvents, unless otherwise stated, they are all volume ratios. In the present invention, room temperature refers to ambient temperature, which is 10°C-35°C. Overnight refers to 8-15 hours. Reflux refers to the reflux temperature of the solvent under normal pressure.

[0221] The following is a list of abbreviations used in the examples:

[0222] DMF N,N-dimethylformamide

[0223] DMAc N,N-dimethylacetamide

[0224] DIPEA Diisopropylethylamine

[0225] TIPS triisopropylsilyl

[0226] THF Tetrahydrofuran

[0227] MOM Methoxymethyl

[0228] DCM dichloromethane

[0229] EA Ethyl acetate

[0230] DMSO dimethyl sulfoxide

[0231] PE petroleum ether

[0232] MeOH methanol

[0233] cataCXium A Pd G3 methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium(II)

[0234] Pd(DPEphos)Cl2Bis(diphenylphosphinophenyl ether)palladium(II) dichloride

[0235] PdCl2(dtbpf) Dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)

[0236] DABCO 1,4-diazabicyclo[2.2.2]octane

[0237] Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride

[0238] Pd2(dba)3 Trisdibenzylideneacetone Dipalladium

[0239] TFA trifluoroacetic acid

[0240] Boc tert-butyloxycarbonyl

[0241] Cbz benzyloxycarbonyl

[0242] NBS N-bromosuccinimide

[0243] TMSOTf Trimethylsilyl trifluoromethanesulfonate

[0244] TBSOTf tert-Butyldimethylsilyl trifluoromethanesulfonate

[0245] Example 1 Synthesis route of compound 1

[0246]

[0247] Synthesis of compound 1-j

[0248] 2-(tert-butyl)hydrazine-1,2-dicarboxylic acid-1-benzyl ester (1000 mg, 3.76 mmol) and DMF (10 mL) were added to the reaction flask at room temperature. Nitrogen replacement protection was applied, and the mixture was cooled in an ice-water bath. NaH (60%, 376 mg, 9.40 mmol) was added in batches. Stir for 5 minutes after the addition. 3-bromopropylene (1000 mg, 8.27 mmol) was slowly added dropwise and the mixture was completed in half an hour. After the addition was completed, the mixture was naturally warmed to room temperature and reacted for another 3 hours. 100 mL of water and 100 mL of ethyl acetate were added to the reaction solution. The liquid was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, dried, and concentrated. Compound 1-j (1200 mg, 92%) was obtained. LC-MS (ESI): m / z 247.2 (M-Boc+H) + .

[0249] Synthesis of compound 1-i

[0250] To the reaction flask at room temperature were added 1-j (1200 mg, 3.46 mmol), DCM (180 mL), and phenylmethylenebis(tricyclohexylphosphine)ruthenium dichloride (285 mg, 0.35 mmol). The atmosphere was replaced with nitrogen, heated to 45°C, and the reaction was allowed to proceed overnight. The reaction solution was concentrated and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 10 / 1) to afford compound 1-i (970 mg, 88%). LC-MS (ESI): m / z 219.1 (M-Boc+H). + .

[0251] Synthesis of compound 1-h

[0252] 1-i (970 mg, 3.05 mmol) and THF (10 mL) were added to the reaction flask at room temperature. The atmosphere was replaced with nitrogen and cooled in an ice-water bath. A solution of borane in tetrahydrofuran (1 M, 10 mL, 10.00 mmol) was added dropwise. After completion of the addition, the mixture was allowed to react overnight at room temperature. Hydrogen peroxide (30 wt %, 10 mL) was added dropwise, and NaOH (61 mg, 1.53 mmol) was added and the mixture was allowed to react for 1 hour. The reaction solution was concentrated under reduced pressure at room temperature to remove tetrahydrofuran, extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 1-h (910 mg, 89%). LC-MS (ESI): m / z 236.9 (M-Boc+H) + .

[0253] Synthesis of compound 1-g

[0254] 1-h (900 mg, 2.68 mmol), DCM (20 mL), and Dess-Martin reagent (2837 mg, 6.69 mmol) were added to the reaction flask at room temperature. The atmosphere was replaced with nitrogen and the reaction was allowed to react overnight at room temperature. 100 mL of dichloromethane was added to the reaction solution, which was washed with a saturated aqueous sodium bicarbonate solution, then with a saturated aqueous sodium bisulfite solution, washed with water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 4 / 6) to obtain compound 1-g (700 mg, 78%). LC-MS (ESI): m / z 235.1 (M-Boc+H) + .

[0255] Synthesis of compound 1-f

[0256] Methylmagnesium bromide in tetrahydrofuran (1M, 8.2mL, 8.20mmol) and THF (10mL) were added to the reaction flask at room temperature. N2 displacement protection was applied and the mixture was cooled in an ice-water bath. A solution of 1-g (2100mg, 6.28mmol) in THF (10mL) was added dropwise. After completion of the addition, the mixture was reacted at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution to quench the mixture, extracted with DCM, and the organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 5 / 5) to obtain compound 1-f (1500mg, 68%). LC-MS (ESI): m / z 251.2 (M-Boc+H) + .

[0257] Synthesis of compounds 1-e-1 and 1-e-2

[0258] To a reaction flask at room temperature, 1-f (700 mg, 2.00 mmol) and acetonitrile (20 mL) were added. The reaction was replaced with N₂ and cooled in an ice-water bath. A 1 M solution of hydrogen chloride in 1,4-dioxane (4 mL, 4.00 mmol) was added. The reaction mixture was allowed to react at room temperature for 5 hours. The reaction solution was concentrated, adjusted to alkalinity by adding 7 M ammonia in methanol, and concentrated. Water was added, and the mixture was extracted with a 10:1 solution of DCM:MeOH. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase column chromatography (mobile phase: water (0.01 M NH₄HCO₃) / acetonitrile 10:0 to 7:3) to afford compounds 1-e-1 (250 mg, 50%) and 1-e-2 (180 mg, 36%).

[0259] Compound 1-e-1 (250 mg, 50%). LC-MS (ESI): m / z 251.2 (M+H) + ; 1 H NMR (400MHz, CDCl3): δ7.43-7.30 (5H, m), 5.22 (2H, s), 3.82 (1H, d, J = 12.0Hz), 3.28 -3.14(2H,m),2.95-2.86(1H,m),1.76-1.64(2H,m),1.26(3H,s).

[0260] Compound 1-e-2 (180 mg, 36%). LC-MS (ESI): m / z 251.2 (M+H) + ; 1 H NMR (400MHz, CDCl3): δ7.45-7.31 (5H, m), 5.20 (2H, s), 4.05 (1H, d, J = 13.2Hz), 3.45 -3.25(1H,m),2.87-2.70(2H,m),1.70-1.60(2H,m),1.23(3H,s).

[0261] Synthesis of compound 1-d

[0262] 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (303 mg, 1.20 mmol) and DCM (15 mL) were added to the reaction flask at room temperature. Nitrogen was purged and the temperature was lowered to -78°C. DIPEA (258 mg, 2.00 mmol) was added dropwise, and a solution of 1-e-1 (250 mg, 1.00 mmol) in THF (5 mL) was added. After the addition, the temperature was naturally raised to room temperature and the reaction was allowed to proceed overnight. The reaction solution was added with water and extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 6 / 4) to give compound 1-d (300 mg, 64%). LC-MS (ESI): m / z 466.5 (M+H) + .

[0263] Synthesis of compound 1-c

[0264] To the reaction flask at room temperature were added 1-d (300 mg, 0.64 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (123 mg, 0.77 mmol), 1,4-dioxane (7 mL), and DIPEA (208 mg, 1.61 mmol). The atmosphere was replaced with nitrogen and the reaction was heated to 90°C overnight. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 1-c (290 mg, 77%). LC-MS (ESI): m / z 589.6 (M+H) + .

[0265] Synthesis of compound 1-b

[0266] 1-c (200 mg, 0.34 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (148 mg, 0.41 mmol), cataCXiumA PdG3 (22 mg, 0.03 mmol), potassium phosphate (217 mg, 1.02 mmol), 1,4-dioxane (2 mL), and water (0.5 mL) were added to a microwave tube at room temperature. The mixture was purged with N2, sealed, and heated to 80°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 1-b (140 mg, 52%). LC-MS (ESI): m / z 787.2 (M+H) + .

[0267] Synthesis of compound 1-a

[0268] 1-b (140 mg, 0.18 mmol) and acetonitrile (5 mL) were added to the reaction flask at room temperature. The reaction mixture was replaced with N2 and cooled to 0°C. A 1,4-dioxane solution of hydrogen chloride (4.0 M, 1 mL) was added. The mixture was stirred at 0°C for 3 hours. The reaction mixture was concentrated at low temperature to obtain crude compound 1-a (132 mg). LC-MS (ESI): m / z 743.7 (M+H) + .

[0269] Synthesis of compound 1

[0270] Crude product 1-a (132 mg, 0.18 mmol), methanol (13 mL), and 10% Pd / C (130 mg) were added to a reaction flask at room temperature. The reaction mixture was replaced with H2 and allowed to react overnight at room temperature. The reaction mixture was filtered, the filtrate was concentrated, and purified by column chromatography (mobile phase: DCM / MeOH(NH3) 10 / 0 to 10 / 1) to obtain compound 1 (49 mg, 45%). LC-MS (ESI): m / z 609.7 (M+H) + .

[0271] Synthesis of compounds 1-1 and 1-2

[0272]

[0273] Compound 1 (39 mg, 0.064 mmol) was purified by chiral separation to give compound 1-1 (16 mg, 41%), LC-MS (ESI): m / z 609.6 (M+H) + Compound 1-2 (15 mg, 38%), LC-MS (ESI): m / z 609.6 (M+H) + .

[0274]

[0275] Example 2 Synthesis route of compound 2

[0276]

[0277] Synthesis of compound 2-d

[0278] 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (217 mg, 0.86 mmol) and DCM (15 mL) were added to the reaction flask at room temperature. Nitrogen was purged and the temperature was lowered to -78°C. DIPEA (186 mg, 1.44 mmol) was added, and a solution of 1-e-2 (180 mg, 0.72 mmol) in THF (5 mL) was added dropwise. After the addition, the temperature was naturally raised to room temperature and the reaction was allowed to proceed overnight. Water was added to the reaction solution, extracted with DCM, the organic phases were combined, dried, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 6 / 4) to give compound 2-d (200 mg, 60%). LC-MS (ESI): m / z 466.5 (M+H) + .

[0279] Synthesis of compound 2-c

[0280] To the reaction flask at room temperature were added 2-d (200 mg, 0.43 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (82 mg, 0.52 mmol), 1,4-dioxane (6 mL), and DIPEA (138 mg, 1.07 mmol). The atmosphere was replaced with nitrogen and the reaction was heated to 90°C overnight. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 2-c (230 mg, 91%). LC-MS (ESI): m / z 589.6 (M+H) + .

[0281] Synthesis of compound 2-b

[0282] 2-c (230 mg, 0.39 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (169 mg, 0.47 mmol), cataCXiumA PdG3 (29 mg, 0.04 mmol), potassium phosphate (248 mg, 1.17 mmol), 1,4-dioxane (2 mL), and water (0.5 mL) were added to a microwave tube at room temperature. The mixture was purged with N2, sealed, and heated to 80°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 2-b (220 mg, 72%). LC-MS (ESI): m / z 787.7 (M+H) + .

[0283] Synthesis of compound 2-a

[0284] 2-b (220 mg, 0.28 mmol) and acetonitrile (5 mL) were added to the reaction flask at room temperature. The reaction mixture was replaced with N2 for protection. The temperature was lowered to 0°C, and a solution of hydrogen chloride in 1,4-dioxane (4.0 M, 1 mL) was added. The mixture was stirred at 0°C for 3 hours. The reaction mixture was concentrated at low temperature to obtain crude compound 2-a (208 mg). LC-MS (ESI): m / z 743.7 (M+H) + .

[0285] Synthesis of compound 2

[0286] Crude product 2-a (208 mg, 0.28 mmol), methanol (20 mL), and 10% Pd / C (200 mg) were added to a reaction flask at room temperature. The reaction mixture was replaced with H2 and allowed to react overnight at room temperature. The reaction mixture was filtered, the filtrate was concentrated, and purified by column chromatography (mobile phase: DCM / MeOH(NH3) 10 / 0 to 10 / 1) to obtain compound 2 (93 mg, 55%). LC-MS (ESI): m / z 609.7 (M+H) + .

[0287] Synthesis of compounds 2-1 and 2-2

[0288]

[0289] Compound 2 (79 mg, 0.13 mmol) was purified by chiral separation to give compound 2-1 (27 mg, 34%), LC-MS (ESI): m / z 609.6 (M+H) + ; 1 H NMR (400MHz, DMSO-d6): δ10.39-10.29(1H,d,J=7.2Hz),9.92(1H,s),7.81-7.71(1H,dd,J=8.8,6 .0Hz),7.40-7.28(2H,m),7.06-6.94(1H,m),5.55-5.40(1H,m),5.41-5.18(1H,d,J=54.4Hz),4.9 1-4.74 (1H, m), 4.27-3.91 (2H, m), 3.30-2.94 (5H, m), 2.92-2.57 (2H, m), 2.44-1.95 (6H, m), 1.94-1.57 (5H, m), 1.27-1.14 (3H, m), 0.80-0.64 (3H, t, J = 7.2 Hz); Compound 2-2 (28 mg, 35%), LC-MS (ESI): m / z 609.6 (M+H) + .

[0290]

[0291]

[0292] Example 3 Synthesis route of compound 3

[0293]

[0294] Synthesis of compound 3-c

[0295] To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (300 mg, 1.19 mmol) in dichloromethane (30 mL) was added tert-butyl 1,2-diazepine-1-carboxylate (238 mg, 1.19 mmol) and N,N-diisopropylethylamine (461 mg, 3.56 mmol) under a dry ice acetone bath. The mixture was allowed to react at this temperature for 1 hour. The reaction mixture was allowed to warm to room temperature and continue to react for 1 hour. Water was then added and the mixture was extracted with dichloromethane (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spun down to give 3-c (490 mg, 99%). LC-MS (ESI): m / z 416.0 (M+H). + .

[0296] Synthesis of compound 3-b

[0297] To a solution of 3-c (490 mg, 1.18 mmol) in dichloromethane (20 mL) was added ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (281 mg, 1.77 mmol) in an ice-water bath, followed by the slow addition of sodium tert-butoxide (226 mg, 2.35 mmol). The mixture was reacted at this temperature for 2 hours. Water was then added, and the mixture was extracted with dichloromethane (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was purified by flash column chromatography (mobile phase: dichloromethane:methanol = 10:1 / dichloromethane, 0-50%) to afford 3-b (561 mg, 88%). LC-MS (ESI): m / z 539.4 (M+H). + .

[0298] Synthesis of compound 3-a

[0299] To a 10 mL microwave tube was added 3-b (70 mg, 0.13 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (70 mg, 0.20 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (9 mg, 0.013 mmol), potassium phosphate (83 mg, 0.39 mmol), tetrahydrofuran (5 mL), and water (1 mL). The microwave tube was purged with nitrogen several times, sealed, and heated to 65°C for overnight reaction. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was purified by flash column chromatography (mobile phase: methanol / dichloromethane, 0-100%) to give 3-a (74 mg, 77%). LC-MS (ESI): m / z 737.8 (M+H) + .

[0300] Synthesis of compound 3

[0301] To a solution of 3-a (74 mg, 0.1 mmol) in acetonitrile (15 mL) was added a 4 M solution of 1,4-dioxane hydrogen chloride (3 mL) in an ice-water bath. The temperature was slowly raised to room temperature, and the mixture was reacted at this temperature overnight. Saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by prep-HPLC to yield compound 3 (13.5 mg, 23%). LC-MS (ESI): m / z 593.3 (M+H). + .

[0302] Example 4 Synthesis route of compound 4

[0303]

[0304] Synthesis of compound 4-b

[0305] To a 30 mL microwave tube was added 3-b (150 mg, 0.28 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (171 mg, 0.33 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (20 mg, 0.028 mmol), potassium phosphate (177 mg, 0.83 mmol), tetrahydrofuran (15 mL), and water (3 mL). The microwave tube was sealed, the atmosphere was replaced with nitrogen several times, and the reaction was heated to 65°C overnight. Water was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was purified by flash silica gel column chromatography (mobile phase: methanol / dichloromethane, 0-20%) to give 4-b (244 mg, 99%). LC-MS (ESI): m / z 889.9 (M+H) + .

[0306] Synthesis of compound 4-a

[0307] To a solution of 4-b (244 mg, 0.27 mmol) in N,N-dimethylformamide (10 mL) at room temperature was added cesium fluoride (417 mg, 2.74 mmol). The mixture was allowed to react at room temperature for 1 hour. Water was added and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed twice with water and twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to afford 4-a (200 mg, 99%). LC-MS (ESI): m / z 733.8 (M+H) + .

[0308] Synthesis of compound 4

[0309] To a solution of 4-a (200 mg, 0.27 mmol) in acetonitrile (15 mL) was added a 4 M solution of 1,4-dioxane hydrogen chloride (5 mL) in an ice-water bath. The temperature was slowly raised to room temperature, and the mixture was allowed to react overnight at this temperature. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by prep-HPLC to yield 4 (120 mg, 75%). LC-MS (ESI): m / z 589.3 (M+H). + ; 1H NMR (400MHz, CDCl3): δ10.15(1H,d,J=34.8Hz),7.55-7.46(1H,m),7.25(1H,dd,J =38.4,1.6Hz),7.15-7.07(1H,m),7.02(1H,s),5.31(1H,d,J=54.0Hz),4.43-4.31 (1H,m),4.30–4.16(2H,m),4.06–3.92(2H,m),3.41–3.07(4H,m),3.06–2.96(2H,m ),2.79(1H,d,J=4.4Hz),2.46–2.10(4H,m),2.03–1.85(4H,m),1.78–1.57(4H,m).

[0310] Example 5 Synthesis route of compound 5

[0311]

[0312] Synthesis of compound 5

[0313] To a solution of 4 (20 mg, 0.034 mmol) in dichloromethane (8 mL) was slowly added acetyl chloride (13 mg, 0.17 mmol) and N,N-diisopropylethylamine (44 mg, 0.34 mmol) in an ice-water bath, and the mixture was reacted at 0°C for 2 hours. The mixture was dried by rotary evaporation, dissolved in methanol (6 mL), potassium carbonate (94 mg, 0.68 mmol) was added, and the mixture was reacted at room temperature for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate (30 mL*2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was purified by prep-HPLC to give 5 (8.8 mg, 41%). LC-MS (ESI): m / z 631.3 (M+H) + .

[0314] Example 6 Synthesis route of compound 6

[0315]

[0316] Synthesis of compound 6-f

[0317] To the reaction flask were added tert-butyl 1,2-diazepine-1-carboxylate (200 mg, 0.999 mmol), methanol (20 mL), paraformaldehyde (270 mg, 2.997 mmol), and sodium cyanoborohydride (188 mg, 2.996 mmol). The mixture was stirred at room temperature overnight under nitrogen. The next day, the reaction mixture was dried and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether 0 / 100 to 20 / 80) to obtain compound 6-f (189 mg, 88%). LC-MS (ESI): m / z = 215.2 (M+H) + .

[0318] Synthesis of compound 6-e

[0319] To the reaction flask, 6-f (188 mg, 0.877 mmol), acetonitrile (20 mL), and 4 M 1,4-dioxane hydrochloride (2 mL) were added and stirred at room temperature overnight under nitrogen. The next day, the reaction solution was directly dried to obtain compound 6-e (132 mg, 99.9%), which was used directly in the next step without purification. LC-MS (ESI): m / z = 115.2 (M+H) + .

[0320] Synthesis of compound 6-d

[0321] To the reaction flask were added 6-e (140 mg, 0.929 mmol), dichloromethane (30 mL), and diisopropylethylamine (0.461 mL, 2.788 mmol). 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (235 mg, 0.929 mmol) was added under dry ice and acetone cooling. The mixture was stirred under nitrogen for 1 hour. The mixture was quenched with water and extracted with dichloromethane (40 mL x 2). The organic phase was dried, spin-dried, and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether 0 / 100 to 30 / 70) to obtain compound 6-d (127 mg, 41%). LC-MS (ESI): m / z = 330.7 (M+H). + .

[0322] Synthesis of compound 6-c

[0323] To a reaction flask, 6-d (120 mg, 0.363 mmol), dichloromethane (20 mL), and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (87 mg, 0.544 mmol) were added. Sodium tert-butoxide (87 mg, 0.909 mmol) was added under an ice-water bath and stirred for 3 hours. ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (87 mg, 0.544 mmol) and sodium tert-butoxide (87 mg, 0.909 mmol) were added, and stirring continued for 2 hours. The reaction mixture was quenched with water and extracted with dichloromethane (40 mL x 2). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography (mobile phase: ammonia methanol / dichloromethane 0 / 100 to 6 / 94) to afford compound 6-c (80 mg, 49%). LC-MS (ESI): m / z = 453.6 (M+H) + .

[0324] Synthesis of compound 6-b

[0325] To a microwave tube were added 6-c (120 mg, 0.265 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (204 mg, 0.397 mmol), tetrahydrofuran (12 mL), water (1.2 mL), potassium phosphate (169 mg, 0.795 mmol), and cataCXium A Pd G3 (19 mg, 0.026 mmol). The atmosphere was purged with nitrogen three times, the tube was sealed, and stirred at 65°C overnight. The next day, the reaction solution was dried and purified by column chromatography (mobile phase: methanol / dichloromethane 0 / 100 to 6 / 94) to give compound 6-b (199 mg, 94%). LC-MS (ESI): m / z = 803.8 (M+H) + .

[0326] Synthesis of compound 6-a

[0327] To the reaction flask were added 6-b (199 mg, 0.248 mmol), DMF (10 mL), cesium fluoride (376 mg,

[0328] The reaction mixture was quenched with water and extracted with ethyl acetate (40 mL x 2). The organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, and spin-dried to obtain compound 6-a (169 mg), which was used directly in the next step without purification. LC-MS (ESI): m / z = 647.7 (M+H) + .

[0329] Synthesis of compound 6

[0330] To the reaction flask were added 6-a (169 mg, 0.261 mmol), acetonitrile (20 mL), and 4 M 1,4-dioxane hydrochloride (2 mL, 8 mmol), and stirred at room temperature for 2 hours. The reaction solution was dried by vortexing, methanol (10 mL) was added, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was dried by vortexing and purified by column chromatography (mobile phase: methanol / dichloromethane 0 / 100 to 6 / 94) to obtain compound 6 (90 mg, 57%). LC-MS (ESI): m / z = 603.7 (M+H) + ; 1 H NMR (400M, CD3OD) δ: 10.18 (1H, d, J = 10.0Hz), 7.90-7.80 (1H, m), 7.38-7.27 (2 H,m),7.22(1H,s),5.34(1H,d,J=54.0Hz),4.59(1H,d,J=14.4Hz),4.39-4.21 (2H,m),3.68-3.57(1H,m),3.54-3.31(3H,m),3.13-3.01(1H,m),2.86-2.76( 1H,m),2.73(3H,s),2.45-2.10(3H,m),2.09-1.75(7H,m),1.64-1.22(4H,m).

[0331] Example 7 Synthesis route of compound 7

[0332]

[0333] Synthesis of compound 7-g

[0334] DMF (20 mL) was added to the reaction flask at room temperature. The atmosphere was purged with nitrogen and cooled in an ice-water bath. NaH (60%, 751 mg, 18.78 mmol) was added. After stirring for 15 minutes, a solution of 1-benzyl 2-(tert-butyl)hydrazine-1,2-dicarboxylate (2000 mg, 7.51 mmol) in DMF (5 mL) was added dropwise. After the addition was complete, the mixture was warmed to room temperature and stirred for 1 hour. The mixture was then cooled in an ice-water bath and a solution of 2,2'-dichlorodiethyl ether (1149 mg, 8.04 mmol) in DMF (5 mL) was added dropwise. After the addition was complete, the mixture was naturally warmed to room temperature and allowed to react overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 10 / 3) to yield compound 7-g (1300 mg, 51%). LC-MS (ESI): m / z 237.1 (M-Boc+H) + .

[0335] Synthesis of compound 7-f

[0336] 7-g (1300 mg, 3.86 mmol), DCM (10 mL), and trifluoroacetic acid (4467 mL, 39.18 mmol) were added to a reaction flask at room temperature. The reaction was allowed to react at room temperature for 3 hours. The reaction solution was concentrated and adjusted to alkalinity by adding a 7 M solution of ammonia in methanol. The residue was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 7-f (400 mg, 44%). LC-MS (ESI): m / z 237.2 (M+H). + .

[0337] Synthesis of compound 7-e

[0338] To a reaction flask at room temperature, add 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (256 mg, 1.01 mmol) and DCM (15 mL). The atmosphere was replaced with nitrogen and the temperature was cooled to -78°C in a dry ice-acetone bath. DIPEA (274 mg, 2.12 mmol) and 7-f (200 mg, 0.85 mmol) were added. After addition, the mixture was allowed to warm to room temperature and react overnight. Water was added to the reaction solution, which was extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 6 / 4) to afford compound 7-e (300 mg, 78%).

[0339] Synthesis of compound 7-d

[0340] To the reaction flask at room temperature were added 7-e (300 mg, 0.66 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (137 mg, 0.86 mmol), 1,4-dioxane (10 mL), and DIPEA (214 mg, 1.65 mmol). The mixture was purged with nitrogen and heated to 90°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 7-d (240 mg, 63%). LC-MS (ESI): m / z 575.5 (M+H) + .

[0341] Synthesis of compound 7-c

[0342] 7-d (130 mg, 0.23 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (139 mg, 0.27 mmol), cataCXium A Pd G3 (16 mg, 0.02 mmol), potassium phosphate (144 mg, 0.68 mmol), THF (2 mL), and water (0.5 mL) were added to a microwave tube at room temperature. The mixture was replaced with N2, sealed, and heated to 65°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 7-c (150 mg, 72%). LC-MS (ESI): m / z 925.4 (M+H) + .

[0343] Synthesis of compound 7-b

[0344] At room temperature, 7-c (130 mg, 0.14 mmol) and acetonitrile (5 mL) were added to the reaction flask. The reaction mixture was replaced with N2 for protection. The temperature was lowered to 0°C, and a solution of hydrogen chloride in 1,4-dioxane (4.0 M, 1 mL) was added. The mixture was stirred at 0°C for 3 hours. The reaction mixture was concentrated at low temperature to obtain crude compound 7-b (150 mg). LC-MS (ESI): m / z 881.4 (M+H) + .

[0345] Synthesis of compound 7-a

[0346] Crude product 7-b (150 mg, 0.14 mmol), methanol (14 mL), and 10% Pd / C (120 mg) were added to the reaction flask at room temperature. H2 was used for displacement protection and the reaction was allowed to proceed overnight at room temperature. The reaction solution was filtered and the filtrate was concentrated to obtain crude product 7-a (105 mg). LC-MS (ESI): m / z 747.4 (M+H) + .

[0347] Synthesis of compound 7

[0348] Crude product 7-a (105 mg, 0.14 mmol), DMF (3 mL), and cesium fluoride (107 mg, 0.70 mmol) were added to the reaction flask at room temperature. The mixture was replaced with nitrogen and reacted at 60°C for 5 hours. The reaction solution was filtered and the filtrate was purified by prep-HPLC to obtain compound 7 (12 mg, 14%). LC-MS (ESI): m / z 591.6 (M+H) + .

[0349] Example 8 Synthesis route of compound 8

[0350]

[0351] Synthesis of compound 8-b

[0352] 7-d (100 mg, 0.17 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (75 mg, 0.21 mmol), cataCXium A PdG3 (13 mg, 0.02 mmol), potassium phosphate (111 mg, 0.52 mmol), THF (2 mL) and water (0.5 mL) were added to a microwave tube at room temperature. The mixture was replaced with N2, sealed, and heated to 65°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 8-b (110 mg, 82%). LC-MS (ESI): m / z 773.8 (M+H) + .

[0353] Synthesis of compound 8-a

[0354] 8-b (110 mg, 0.14 mmol) and acetonitrile (5 mL) were added to the reaction flask at room temperature. The reaction mixture was replaced with N2 and cooled to 0°C. A 1,4-dioxane solution of hydrogen chloride (4.0 M, 1 mL) was added. The mixture was stirred at 0°C for 3 hours. The reaction mixture was concentrated at low temperature to obtain crude compound 8-a (104 mg). LC-MS (ESI): m / z 729.7 (M+H) + .

[0355] Synthesis of compound 8

[0356] Crude product 8-a (104 mg, 0.14 mmol), methanol (10 mL), and 10% Pd / C (100 mg) were added to a reaction flask at room temperature. H₂ was used for displacement protection and the reaction was allowed to proceed overnight at room temperature. The reaction solution was filtered, the filtrate was concentrated, and purified by prep-HPLC to afford compound 8 (18 mg, 21%). LC-MS (ESI): m / z 595.7 (M+H) + ; 1H NMR (400MHz, DMSO-d6): δ10.31(1H,s),9.97(1H,s),7.82-7.70(1H,dd,J=9.2,6.4Hz ),7.42-7.27(2H,m),7.06-6.99(1H,d,J=2.0Hz),6.25-6.15(1H,t,J=6.0Hz),5.40- 5.16(1H,d,J=53.6Hz),4.43-3.89(6H,m),3.86-3.68(2H,t,J=4.4Hz),3.23-2.94(5 H,m),2.89-2.76(1H,m),2.43-2.24(1H,m),2.23-1.64(7H,m),0.72(3H,t,J=7.2Hz).

[0357] Example 9 Synthesis route of compound 9

[0358]

[0359] Synthesis of compound 9-f

[0360] Potassium tert-butoxide (2243 mg, 20.00 mmol) and THF (40 mL) were added to the reaction flask at room temperature. Nitrogen was purged for protection. N-tert-Butyloxycarbonylhydroxylamine (1331 mg, 10.00 mmol) was added in batches. After the addition, the mixture was reacted at room temperature for 1 hour. A solution of 1,5-dibromopentane (2299 mg, 10.00 mmol) in THF (10 mL) was added dropwise. After the addition was complete, the mixture was heated to 75°C and reacted overnight. 100 mL of water and 100 mL of ethyl acetate were added to the reaction solution. The liquid was separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 10 / 1) to obtain compound 9-f (900 mg, 45%). LC-MS (ESI): m / z 146.2 (Mt-Bu+H) + .

[0361] Synthesis of compound 9-e

[0362] 9-f (200 mg, 0.99 mmol) and acetonitrile (5 mL) were added to the reaction flask at room temperature. The reaction mixture was replaced with N2 and cooled to 0°C. A 1,4-dioxane solution of hydrogen chloride (4.0 M, 1 mL) was added. The mixture was stirred at 0°C for 3 hours. The reaction mixture was concentrated at low temperature, and water and ethyl acetate were added. The liquid phases were separated, and the aqueous phase was lyophilized to obtain compound 9-e (65 mg, 48%). LC-MS (ESI): m / z 102.2 (M-HCl+H) + .

[0363] Synthesis of compound 9-d

[0364] To a reaction flask at room temperature, add 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (143 mg, 0.57 mmol) and DCM (10 mL). The atmosphere was purged with nitrogen and the temperature was cooled to -78°C in a dry ice-acetone bath. DIPEA (183 mg, 1.42 mmol) and 9-e (65 mg, 0.47 mmol) were added. After addition, the mixture was allowed to warm to room temperature and react overnight. Water was added to the reaction solution, which was extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 6 / 4) to afford compound 9-d (90 mg, 60%). LC-MS (ESI): m / z 317.5 (M+H).

[0366] Synthesis of compound 9-c

[0367] To a reaction flask at room temperature were added 9-d (90 mg, 0.28 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (68 mg, 0.43 mmol), 1,4-dioxane (5 mL), and DIPEA (110 mg, 0.85 mmol). The atmosphere was replaced with nitrogen and the reaction was heated to 90°C overnight. The reaction mixture was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to afford compound 9-c (80 mg, 64%).

[0368] Synthesis of compound 9-b

[0369] 9-c (50 mg, 0.11 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (70 mg, 0.14 mmol), cataCXium A Pd G3 (8 mg, 0.01 mmol), potassium phosphate (72 mg, 0.34 mmol), THF (2 mL), and water (0.5 mL) were added to a microwave tube at room temperature. The mixture was replaced with N2, sealed, and heated to 65°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 9-b (55 mg, 61%). LC-MS (ESI): m / z 790.8 (M+H) + .

[0370] Synthesis of compound 9-a

[0371] 9-b (55 mg, 0.07 mmol) and acetonitrile (5 mL) were added to the reaction flask at room temperature. The reaction mixture was replaced with N2 and cooled to 0°C. A 1,4-dioxane solution of hydrogen chloride (4.0 M, 1 mL) was added. The mixture was stirred at 0°C for 3 hours. The reaction mixture was concentrated at low temperature to obtain crude compound 9-a (60 mg). LC-MS (ESI): m / z 746.8 (M+H) + .

[0372] Synthesis of compound 9

[0373] Crude product 9-a (60 mg, 0.07 mmol), DMF (3 mL), and cesium fluoride (106 mg, 0.70 mmol) were added to the reaction flask at room temperature. The mixture was replaced with nitrogen and reacted at 60°C for 3 hours. The reaction solution was filtered and the filtrate was purified by prep-HPLC to obtain compound 9 (8 mg, 19%). LC-MS (ESI): m / z 590.2 (M+H) + .

[0374] Example 10 Synthesis route of compound 10

[0375]

[0376] Synthesis of compound 10-a

[0377] 9-c (15 mg, 0.03 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15 mg, 0.04 mmol), cataCXium A PdG3 (3 mg, 0.01 mmol), potassium phosphate (22 mg, 0.10 mmol), THF (2 mL), and water (0.5 mL) were added to a microwave tube at room temperature. The mixture was replaced with N2, sealed, and heated to 65°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 10-a (15 mg, 69%). LC-MS (ESI): m / z 638.8 (M+H) + .

[0378] Synthesis of compound 10

[0379] 10-a (15 mg, 0.02 mmol) and acetonitrile (2 mL) were added to the reaction flask at room temperature. The reaction mixture was replaced with N2 and cooled to 0°C. A 4.0 M solution of hydrogen chloride in 1,4-dioxane (0.3 mL) was added. The mixture was stirred at 0°C for 3 hours. The reaction mixture was concentrated and purified by prep-HPLC to obtain compound 10 (1.3 mg, 9%). LC-MS (ESI): m / z 594.7 (M+H). + .

[0380] Example 11 Synthesis route of compound 11

[0381]

[0382] Synthesis of compound 11-b

[0383] To a 30 mL microwave tube was added 3-b (50 mg, 0.093 mmol), ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (46 mg, 0.10 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (7 mg, 0.009 mmol), potassium phosphate (59 mg, 0.28 mmol), tetrahydrofuran (6 mL), and water (1.5 mL). The microwave tube was purged with nitrogen several times, sealed, and heated to 65°C for overnight reaction. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by flash column chromatography (mobile phase: dichloromethane:methanol=10:1 / dichloromethane, 0-30%) to give 11-b (61 mg, 79%).

[0384] Synthesis of compound 11-a

[0385] To a solution of 11-b (61 mg, 0.074 mmol) in DMF (8 mL) was added cesium fluoride (112 mg, 0.74 mmol) at room temperature. The reaction mixture was allowed to react overnight at room temperature. Water was added and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to give 11-a (49 mg, 99%). LC-MS (ESI): m / z 673.8 (M+H) + .

[0386] Synthesis of compound 11

[0387] To a solution of 11-a (49 mg, 0.073 mmol) in acetonitrile (8 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was dried and the crude product was purified by Prep-HPLC to afford 11 (7.5 mg, 18%). LC-MS (ESI): m / z 573.3 (M+H). + .

[0388] Example 12 Synthesis route of compound 12

[0389]

[0390] Synthesis of compound 12-a

[0391] To a 10 mL microwave tube was added 3-b (50 mg, 0.093 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (64 mg, 0.10 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (7 mg, 0.009 mmol), potassium phosphate (59 mg, 0.28 mmol), tetrahydrofuran (2.5 mL), and water (0.5 mL). The microwave tube was purged with nitrogen several times, sealed, and heated to 65°C for overnight reaction. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by flash column chromatography (mobile phase: methanol / dichloromethane, 0-100%) to give 12-a (89 mg, 96%).

[0392] Synthesis of compound 12

[0393] To a solution of 12-a (89 mg, 0.089 mmol) in DMF (8 mL) was added cesium fluoride (68 mg, 0.45 mmol) at room temperature, and the reaction mixture was allowed to react overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was spin-dried. The crude product was purified by Prep-HPLC to yield 12 (35 mg, 57%). LC-MS (ESI): m / z 689.3 (M+H) + ; 1H NMR (400MHz, CDCl3): δ9.20–9.10(1H,m),7.64–7.55(1H,m),7.27–7.10(3H,m),5.30(1H,d,J=54.0Hz),4.37–4.14(4H, m),3.99–3.83(1H,m),3.35–3.10(4H,m),3.04–2.95(1H,m),2.87–2.74(1H,m),2.36–1.58(13H,m),1.61–1.41(9H,m).

[0394] Example 13 Synthetic routes of compounds 13 and 14

[0395]

[0396] Synthesis of compound 13-c

[0397] To a solution of 3-c (150 mg, 0.36 mmol) in dichloromethane (15 mL) was added {1-[(dimethylamino)methyl]cyclopropyl}methanol (70 mg, 0.54 mmol) and sodium tert-butoxide (69 mg, 0.72 mmol) in an ice bath. The temperature was slowly raised to room temperature and the reaction was allowed to proceed overnight. Water was added to the reaction solution, which was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was spin-dried. The crude product was purified by flash column chromatography (mobile phase: DCM:MeOH = 10:1 / DCM, 0-50%) to give 13-c (140 mg, 76%). LC-MS (ESI): m / z 509.5 (M+H) + .

[0398] Synthesis of compound 13-b

[0399] To a 10 mL microwave tube was added 13-c (140 mg, 0.28 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (169 mg, 0.33 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl)palladium(II) cataCXiumA Pd G3 (20 mg, 0.028 mmol), potassium phosphate (175 mg, 0.83 mmol), tetrahydrofuran (2.5 mL), and water (0.5 mL). The microwave tube was purged with nitrogen several times, sealed, and heated to 65°C for overnight reaction. The reaction mixture was dried by rotary evaporation, and the crude product was purified by flash column chromatography (mobile phase: DCM:MeOH=10:1 / DCM, 0-100%) to give 13-b (230 mg, 97%). LC-MS (ESI): m / z 860.2 (M+H) + .

[0400] Synthesis of compound 13-a

[0401] To a solution of 13-b (230 mg, 0.27 mmol) in DMF (6 mL) was added cesium fluoride (203 mg, 1.34 mmol) at room temperature. The reaction mixture was allowed to react overnight at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate (50 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was spin-dried to afford 13-a (172 mg, 91%). LC-MS (ESI): m / z 703.9 (M+H).

[0403] Synthesis of compounds 13, 14

[0404] Under an ice-water bath, a solution of 13-a (100 mg, 0.14 mmol) in acetonitrile (15 mL) was added with a 1,4-dioxane solution of hydrogen chloride (4 M, 2.5 mL). The reaction mixture was reacted at this temperature for 1 hour. The temperature was raised to room temperature and the reaction was continued for another 3 hours. Saturated aqueous sodium bicarbonate solution was added for neutralization, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by Prep-HPLC to obtain 13 (19 mg, 24%) and 14 (12.2 mg, 13%). Compound 13: LC-MS (ESI): m / z 559.3 (M+H) + ; 1H NMR (400MHz, CDCl3): δ10.15(1H,s),7.54(1H,dd,J=9.6,5.6Hz),7.24(1H,s),7.09(1H,t,J= 8.8Hz),7.02(1H,s),4.61–4.50(1H,m),4.50–4.41(1H,d,J=10.8Hz),4.18(1H,d,J=10.4Hz), 4.08–3.92 (2H, m), 3.19–3.02 (2H, m), 2.77 (1H, s), 2.74–2.65 (1H, m), 2.39 (6H, s), 1.97–1.91 (3H, m), 1.76–1.66 (5H, m), 0.73 (2H, s), 0.56 (2H, dd, J=16.0, 9.6 Hz); Compound 14: LC-MS (ESI): m / z 659.3 (M+H) + .

[0405] Example 14 Synthesis route of compound 15

[0406]

[0407] Synthesis of compound 15-f

[0408] To a solution of 1-benzyl 2-(tert-butyl)hydrazine-1,2-dicarboxylate (2 g, 7.51 mmol) in DMF (60 mL) was added portionwise sodium hydride (60%, 0.75 g, 18.78 mmol) in an ice bath. The mixture was reacted in an ice bath for 30 min, then at room temperature for 1 hour. The mixture was then cooled to 0°C in an ice-water bath, and 1,6-dichlorohexane (1.16 g, 7.51 mmol) was slowly added. After the addition, the mixture was slowly warmed to room temperature and allowed to react overnight. Saturated aqueous ammonium chloride was added to the reaction solution, which was then extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed twice with water and twice with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether, 0-10%) to afford 15-f (0.86 g, 33%). LC-MS(ESI):m / z 249.3(M-100+H)+.

[0410] Synthesis of compound 15-e

[0411] To a solution of 15-f (860 mg, 2.47 mmol) in ethyl acetate (25 mL) was added Pd / C (10%, 200 mg, 1.88 mmol) at room temperature. The reaction solution was purged with a hydrogen balloon several times and allowed to react overnight at room temperature. The reaction solution was filtered to remove palladium on carbon, and the filtrate was dried to give 15-e (530 mg, 100.00%). LC-MS (ESI): m / z 159.2 (M-56+H). + .

[0412] Synthesis of compound 15-d

[0413] To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (100 mg, 0.396 mmol) in dichloromethane (20 mL) was added 15-e (93 mg, 0.44 mmol) and N,N-diisopropylethylamine (154 mg, 1.19 mmol) under a dry ice acetone bath. The mixture was reacted at this temperature for 2 hours. Water was added to the reaction solution, which was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether, 0-10%) to afford 15-d (169 mg, 99%). LC-MS (ESI): m / z 430.4 (M+H). + .

[0414] Synthesis of compound 15-c

[0415] To a solution of 15-d (169 mg, 0.39 mmol) in dichloromethane (15 mL) was added ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (188 mg, 1.18 mmol) in an ice-water bath, followed by the slow addition of sodium tert-butoxide (151 mg, 1.57 mmol). The mixture was reacted at this temperature for 5 hours. Water was then added, and the mixture was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was purified by flash column chromatography (mobile phase: dichloromethane:methanol = 10:1 / dichloromethane, 0-50%) to afford 15-c (154 mg, 70%). LC-MS (ESI): m / z 553.6 (M+H). + .

[0416] Synthesis of compound 15-b

[0417] To a 10 mL microwave tube was added 15-c (154 mg, 0.28 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (209 mg, 0.334 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (20 mg, 0.028 mmol), potassium phosphate (177 mg, 0.84 mmol), tetrahydrofuran (2.5 mL), and water (0.5 mL). The microwave tube was purged with nitrogen several times, sealed, and heated to 65°C for overnight reaction. Water was added to the reaction solution, extracted with ethyl acetate (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried to give 15-b (280 mg, 99%). The product was used directly in the next reaction without purification.

[0418] Synthesis of compound 15-a

[0419] To a solution of 15-b (280 mg, 0.28 mmol) in DMF (8 mL) was added cesium fluoride (209 mg, 1.38 mmol) at room temperature, and the reaction mixture was allowed to react overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was purified by flash column chromatography (mobile phase: dichloromethane:methanol = 10:1 / dichloromethane, 0-50%) to afford 15-a (166 mg, 86%). LC-MS (ESI): m / z 703.8 (M+H). + .

[0420] Synthesis of compound 15

[0421] To a solution of 15-a (166 mg, 0.24 mmol) in acetonitrile (10 mL) was added a 1,4-dioxane solution (4 M, 1.5 mL) of hydrogen chloride at room temperature. The reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added for neutralization, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by Prep-HPLC to give 15 (69 mg, 49%). LC-MS (ESI): m / z 603.3 (M+H) + ; 1H NMR (400MHz, CDCl3): δ10.14(1H,d,J=35.6Hz),7.54-7.38(1H,m),7.25(1H ,d,J=46.4,Hz),7.14-7.00(2H,m),5.29(1H,dd,J=53.6,13.2Hz),4.62(1H ,s),4.25–4.11(2H,m),4.10–3.77(2H,m),3.34–3.06(5H,m),3.02–2.93(1 H,m),2.75(1H,s),2.43–2.04(5H,m),2.02–1.86(4H,m),1.73–1.40(6H,m).

[0422] Example 15 Synthesis route of compounds 16 and 17

[0423]

[0424] Synthesis of compound 16-d

[0425] Tetrahydropyridazine-1(2H)-carboxylic acid tert-butyl ester (148 mg, 0.792 mmol), dichloromethane (30 mL), and diisopropylethylamine (0.393 mL, 2.377 mmol) were added to the reaction flask, and 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine was added under cooling in a dry ice acetone bath.

[0426] (200 mg, 0.792 mmol), the reaction solution was stirred under nitrogen for 1 hour. The reaction solution was quenched with water and extracted with dichloromethane (50 mL*2). The organic phase was dried, spin-dried, and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether 0 / 100 to 10 / 90) to obtain compound 16-d (270 mg, 85%). LC-MS (ESI): m / z = 402.1 (M+H) + .

[0427] Synthesis of compound 16-c

[0428] To the reaction flask, 16-d (100 mg, 0.249 mmol), dichloromethane (30 mL), and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (47 mg, 0.298 mmol) were added. Sodium tert-butoxide (60 mg, 0.622 mmol) was then added under ice-water bath. After the addition, the reaction mixture was stirred under ice-water bath for half an hour. Sodium tert-butoxide (60 mg, 0.622 mmol) was added and stirring continued for another half an hour. Sodium tert-butoxide (60 mg, 0.622 mmol) was then added and stirring continued for another half an hour. Sodium tert-butoxide (60 mg, 0.622 mmol) was then added again and stirring continued for another half an hour. The reaction mixture was quenched with water and extracted with dichloromethane (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, spun down, and purified by column chromatography (mobile phase: ammonia methanol / dichloromethane 0 / 100 to 6 / 94) to give compound 16-c (114 mg, 87%). LC-MS (ESI): m / z = 525.8 (M+H) + .

[0429] Synthesis of compound 16-b

[0430] To a microwave tube were added 16-c (114 mg, 0.217 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (167 mg, 0.326 mmol), tetrahydrofuran (15 mL), water (1.5 mL), potassium phosphate (138 mg, 0.651 mmol), and cataCXium A Pd G3 (16 mg, 0.022 mmol). The atmosphere was replaced with nitrogen three times, the reaction mixture was sealed, and the reaction mixture was stirred at 65°C overnight. The next day, the reaction mixture was dried and purified by column chromatography (mobile phase: methanol / dichloromethane 0 / 100 to 2 / 98) to obtain compound 16-b (198 mg, 100%). LC-MS (ESI): m / z = 875.7 (M+H) + .

[0431] Synthesis of compound 16-a

[0432] To the reaction flask were added 16-b (198 mg, 0.226 mmol), DMF (10 mL), cesium fluoride (343 mg,

[0433] The reaction mixture was quenched with water and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and dried by spin drying. The mixture was purified by column chromatography (mobile phase: methanol / dichloromethane 0 / 100 to 5 / 95) to obtain compound 16-a (127 mg, 78%). LC-MS (ESI): m / z = 719.9 (M+H) + .

[0434] Synthesis of compounds 16 and 17

[0435] 16-a (127 mg, 0.177 mmol) and formic acid (10 mL) were added to the reaction flask and stirred at room temperature for 10 hours. The reaction solution was dried, purified by prep-HPLC (ammonium bicarbonate), and lyophilized to obtain compounds 16 (25 mg, 25%) and 17 (5 mg, 4%).

[0436] Compound 16, LC-MS (ESI): m / z=575.2 (M+H) + ; 1 H NMR(400M,DMSO-d6)δ10.29(1H,s),10.14(1H,s),8.00-7.92(1H,m),7.46(1H,t,J=8.8Hz),7.38(1H,d,J=2.4Hz),7.16(1H,d,J=2.0Hz), 5.63(1H,t,J=6.4Hz),5.28(1H,d,J=53.6Hz),4.29-3.95(4H,m),3.92(1H,s),3.15-2.96(5H,m),2.88-2.76(1H,m),2.16-1.65(10H,m).

[0437] Compound 17, LC-MS (ESI): m / z=675.3 (M+H) + .

[0438] Example 16 Synthesis route of compound 18

[0439]

[0440] Synthesis of compound 18-d

[0441] To the reaction flask, tert-butyl pyrazolidine-1-carboxylate (136 mg, 0.79 mmol), dichloromethane (30 mL), and diisopropylethylamine (0.393 mL, 2.38 mmol) were added. 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (200 mg, 0.79 mmol) was added under a dry ice acetone bath. The reaction solution was stirred under nitrogen for 1 hour. The reaction solution was quenched with water and extracted with dichloromethane (50 mL*2). The organic phase was dried and spin-dried to give compound 18-d (307 mg, 100%), which was used directly in the next reaction without purification. LC-MS (ESI): m / z = 388.1 (M+H) + .

[0442] Synthesis of compound 18-c

[0443] To the reaction flask, 18-d (307 mg, 0.79 mmol), dichloromethane (30 mL), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl)methanol (126 mg, 0.79 mmol) were added, and sodium tert-butoxide (190 mg, 1.977 mmol) was added under ice-water bath and stirred for 1 hour. Sodium tert-butoxide (190 mg, 1.977 mmol) was added and stirring continued for 1 hour; sodium tert-butoxide (190 mg, 1.977 mmol) was added and stirring continued for 1 hour; sodium tert-butoxide (190 mg, 1.977 mmol) was added and stirring continued for 1 hour.

[0444] The reaction mixture was quenched with water and extracted with dichloromethane (80 mL x 2). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography (mobile phase: methanol / dichloromethane 0 / 100 to 3 / 97) to obtain compound 18-c (217 mg, 54%). LC-MS (ESI): m / z = 511.5 (M+H) + .

[0445] Synthesis of compound 18-b

[0446] To a microwave tube were added 18-c (217 mg, 0.42 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (326 mg, 0.637 mmol), tetrahydrofuran (15 mL), water (1.5 mL), potassium phosphate (270 mg, 1.274 mmol), cataCXium A Pd G3 (31 mg, 0.042 mmol), the atmosphere was purged with nitrogen three times, the tube was sealed, and stirred at 65°C overnight. The next day, the reaction solution was dried and purified by column chromatography (mobile phase: methanol / dichloromethane 0 / 100 to 4 / 96) to give compound 18-b (396 mg, 100%). LC-MS (ESI): m / z = 861.7 (M+H)+ .

[0447] Synthesis of compound 18-a

[0448] To the reaction flask were added 18-b (396 mg, 0.46 mmol), DMF (10 mL), cesium fluoride (699 mg,

[0449] The reaction mixture was quenched with water and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and dried by column chromatography (mobile phase: methanol / dichloromethane 0 / 100 to 5 / 95) to obtain compound 18-a (236 mg, 73%). LC-MS (ESI): m / z = 705 (M+H) + .

[0450] Synthesis of compound 18

[0451] 18-a (100 mg, 0.14 mmol) and formic acid (10 mL) were added to the reaction flask and stirred at room temperature overnight. The next day, the reaction solution was spin-dried, prepared with ammonium bicarbonate, and lyophilized to obtain compound 18 (19 mg, 24%). LC-MS (ESI): m / z = 561.3 (M+H) + ; 1 H NMR (400M, DMSO-d6): δ10.19 (1H, d, J = 9.2Hz), 10.04 (1H, d, J = 44.8Hz), 8.03-7 .92(1H,m),7.76-6.05(1H,m),7.46(1H,t,J=8.8Hz),7.41-7.35(1H,m),7.20- 7.10(1H,m),5.28(1H,d,J=55.2Hz),4.23-3.96(3H,m),3.92(1H,d,J=8.0Hz), 3.83(1H,t,J=7.2Hz),3.23-2.98(5H,m),2.88-2.78(1H,m),2.21-1.70(8H,m).

[0452] Example 17 Synthesis route of compound 19

[0453]

[0454] Synthesis of compound 19

[0455] Compound 4 (40 mg, 0.068 mmol), dichloromethane (15 mL), and diisopropylethylamine (56 uL, 0.34 mmol) were added to the reaction flask. Methylamine chloroformyl chloride (14 mg, 0.134 mmol) was added under an ice-water bath. After the addition, the reaction solution was stirred at room temperature overnight. The next day, the mixture was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (50 mL*2), dried over anhydrous sodium sulfate, spin-dried, prepared with trifluoroacetic acid, and lyophilized to obtain compound 19 (26 mg, 59%). LC-MS (ESI): m / z = 646.3 (M+H) + .

[0456] Example 18 Synthesis route of compound 20

[0457]

[0458] Synthesis of compound 20-d

[0459] To the reaction flask were added 3-b (290 mg, 0.54 mmol), acetonitrile (20 mL), and 1,4-dioxane hydrochloride (4 M, 2 mL). The mixture was stirred at room temperature overnight under nitrogen. The next day, the reaction solution was dried by vortexing, 20 mL of methanol was added, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was vortexed and redissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered, and vortexed to obtain compound 20-d (288 mg, 100%), which was used directly in the next step without purification. LC-MS (ESI): m / z = 439.6 (M+H) + .

[0460] Synthesis of compound 20-c

[0461] To a microwave tube were added 20-d (280 mg, 0.64 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (490 mg, 0.957 mmol), tetrahydrofuran (12 mL), water (1.2 mL), potassium phosphate (406 mg, 1.914 mmol), cataCXium A Pd G3 (93 mg, 0.128 mmol), the atmosphere was purged with nitrogen three times, the tube was sealed, and stirred at 65°C overnight. The next day, the reaction solution was dried and purified by column chromatography (mobile phase: methanol / dichloromethane 0 / 100 to 10 / 90) to give compound 20-c (380 mg, 75%). LC-MS (ESI): m / z = 789.9 (M+H) + .

[0462] Synthesis of compound 20-b

[0463] 20-c (380 mg, 0.48 mmol), DMF (10 mL), cesium fluoride (732 mg,

[0464] The reaction mixture was quenched with water and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and spin-dried to obtain compound 20-b (323 mg, 100%), which was used directly in the next step without purification. LC-MS (ESI): m / z = 633.8 (M+H) + .

[0465] Synthesis of compound 20-a

[0466] To the reaction flask were added 20-b (50 mg, 0.079 mmol), dichloromethane (20 mL), DIPEA (0.131 mL,

[0467] The mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL x 2). The organic phase was dried and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether 0 / 100 to 50 / 50) to obtain compound 20-a (50 mg, 90%). LC-MS (ESI): m / z = 705.4 (M+H) + .

[0468] Synthesis of compound 20

[0469] To the reaction flask were added 20-a (50 mg, 0.071 mmol), acetonitrile (10 mL), and 1,4-dioxane hydrochloride (4 M, 1 mL, 4 mmol) and stirred at room temperature for 2 hours. The reaction solution was dried by rotary evaporation at room temperature, methanol (20 mL) was added, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was dried by rotary evaporation, purified by column chromatography (mobile phase: methanol / dichloromethane 0 / 100 to 6 / 94), then prepared (ammonium bicarbonate), and lyophilized to obtain compound 20 (6 mg, 13%). LC-MS (ESI): m / z = 661.3 (M+H) + .

[0470] Example 19 Synthesis route of compound 21

[0471]

[0472] Synthesis of compound 21-e

[0473] At room temperature, difluoromethyl (2-pyridyl) sulfone (4118 mg, 21.32 mmol) and DMF (50 mL) were added to the reaction flask. The atmosphere was purged with nitrogen and the temperature was lowered to -50°C. A solution of ethyl 2,5-dioxohexahydro-1H-pyrrolizine-7a-carboxylate (5000 mg, 23.67 mmol) in DMF (50 mL) was added dropwise. The temperature was maintained below -45°C. After addition, the mixture was allowed to warm to room temperature and react for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL), followed by concentrated hydrochloric acid (37% wt, 18 mL) and stirred at room temperature for 1 hour. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (mobile phase: PE / DCM 10 / 0 to 0 / 10) to obtain compound 21-e (1000 mg, 19%). LC-MS (ESI): m / z 246.2 (M+H) + .

[0474] Synthesis of compound 21-d

[0475] At room temperature, a tetrahydrofuran solution of lithium aluminum hydride (1M, 6.52 mL) was added to the reaction flask. Nitrogen was replaced and the temperature was lowered to 0°C. A solution of 21-e (800 mg, 3.26 mmol) in THF (5 mL) was added dropwise. After the addition, the reaction solution was heated to 65°C for 3 hours. The reaction solution was cooled to room temperature and quenched with methanol (30 mL) under nitrogen protection. About 3 g of sodium sulfate decahydrate was added, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered and the filter cake was washed with methanol. The filtrates were combined, concentrated, and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 21-d (130 mg, 23%). LC-MS (ESI): m / z 172.2 (M+H) + .

[0476] Synthesis of compound 21-c

[0477] To a reaction flask at room temperature were added 3-c (379 mg, 0.91 mmol), 21-d (130 mg, 0.76 mmol), 1,4-dioxane (10 mL), and DIPEA (294 mg, 2.27 mmol). The reaction mixture was purged with nitrogen and heated to 90°C overnight. The reaction mixture was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to afford compound 21-c (140 mg, 33%). LC-MS (ESI): m / z 551.8 (M+H).

[0479] Synthesis of compound 21-b

[0480] At room temperature, 21-c (140 mg, 0.25 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (156 mg, 0.30 mmol), cataCXium A Pd G3 (19 mg, 0.03 mmol), potassium phosphate (162 mg, 0.76 mmol), THF (2 mL), and water (0.5 mL) were added to a microwave tube. The mixture was replaced with N2, sealed, and heated to 65°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 21-b (90 mg, 39%). LC-MS (ESI): m / z 902.0 (M+H) + .

[0481] Synthesis of compound 21-a

[0482] At room temperature, 21-b (90 mg, 0.10 mmol) and acetonitrile (5 mL) were added to the reaction flask. The reaction mixture was replaced with N2 and cooled to 0°C. A 1,4-dioxane solution of hydrogen chloride (4.0 M, 1 mL) was added. The reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was concentrated at low temperature to obtain crude compound 21-a (130 mg). LC-MS (ESI): m / z 757.5 (M+H) + .

[0483] Synthesis of compound 21

[0484] At room temperature, crude product 21-a (130 mg, approximately 0.10 mmol), DMF (3 mL), and cesium fluoride (76 mg, 0.50 mmol) were added to the reaction flask. The reaction solution was purged with nitrogen and reacted at 60°C for 1 hour. The reaction solution was filtered, and the filtrate was purified by prep-HPLC to obtain compound 21 (4 mg, 7%). LC-MS (ESI): m / z 601.6 (M+H) + .

[0485] Example 20 Synthesis route of compound 22

[0486]

[0487] Synthesis of compound 22-c

[0488] At room temperature, 3-c (200 mg, 0.48 mmol), (2-(difluoromethylene)tetrahydro-1H-pyrrolazin-7A(5H)-yl)methanol (118 mg, 0.62 mmol), 1,4-dioxane (10 mL), and DIPEA (186 mg, 1.44 mmol) were added to the reaction flask. Nitrogen was replaced and the mixture was heated to 90°C and reacted overnight. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 22-c (140 mg, 51%). LC-MS (ESI): m / z 569.8 (M+H) + .

[0489] Synthesis of compound 22-b

[0490] At room temperature, 22-c (140 mg, 0.25 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (164 mg, 0.32 mmol), cataCXium A Pd G3 (18 mg, 0.03 mmol), potassium phosphate (157 mg, 0.74 mmol), THF (2 mL), and water (0.5 mL) were added to a microwave tube. The mixture was replaced with N2 and heated to 65°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 22-b (190 mg, 84%). LC-MS (ESI): m / z 919.7 (M+H) + .

[0491] Synthesis of compound 22-a

[0492] At room temperature, 22-b (190 mg, 0.21 mmol) and acetonitrile (5 mL) were added to the reaction flask. The reaction mixture was replaced with N2 and cooled to 0°C. A 1,4-dioxane solution of hydrogen chloride (4.0 M, 1 mL) was added. The reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was concentrated at low temperature to obtain crude compound 22-a (230 mg). LC-MS (ESI): m / z 775.5 (M+H) + .

[0493] Synthesis of compound 22

[0494] At room temperature, crude product 22-a (230 mg, 0.21 mmol), DMF (3 mL), and cesium fluoride (159 mg, 1.05 mmol) were added to the reaction flask. The reaction solution was purged with nitrogen and reacted at 60°C for 1 hour. The reaction solution was filtered and the filtrate was purified by prep-HPLC to obtain compound 22 (23 mg, 18%). LC-MS (ESI): m / z 619.5 (M+H) + .

[0495] Comparative synthetic route of compound 1′

[0496]

[0497] Synthesis of compound 1′-d

[0498] At room temperature, 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (400 mg, 1.58 mmol) and DCM (20 mL) were added to the reaction flask. Nitrogen was purged and the temperature was lowered to -78°C in a dry ice acetone bath. DIPEA (614 mg, 4.75 mmol) and cycloheximide (141 mg, 1.42 mmol) were added. After the addition, the temperature was naturally raised to room temperature and the reaction was allowed to proceed overnight. Water was added to the reaction solution, and the mixture was extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 6 / 4) to obtain compound 1′-d (390 mg, 78%). LC-MS (ESI): m / z 315.4 (M+H) + .

[0499] Synthesis of compound 1′-c

[0500] At room temperature, 1′-d (400 mg, 1.27 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl)methanol (404 mg, 2.54 mmol), 1,4-dioxane (10 mL), and DIPEA (656 mg, 5.08 mmol) were added to the reaction flask. Nitrogen was replaced with protection and the reaction was heated to 90°C overnight. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 1′-c (450 mg, 81%). LC-MS (ESI): m / z 438.2 (M+H) + .

[0501] Synthesis of compound 1′-b

[0502] At room temperature, 1′-c (200 mg, 0.46 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (281 mg, 0.55 mmol), cataCXium A Pd G3 (33 mg, 0.05 mmol), potassium phosphate (291 mg, 1.37 mmol), THF (2 mL), and water (0.5 mL) were added to a microwave tube. The mixture was replaced with N2 and heated to 65°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 1′-b (230 mg, 64%). LC-MS (ESI): m / z 789.0 (M+H) + .

[0503] Synthesis of compound 1′-a

[0504] At room temperature, 1′-b (230 mg, 0.29 mmol) and acetonitrile (5 mL) were added to the reaction flask. The reaction mixture was replaced with N2 and cooled to 0°C. A 1,4-dioxane solution of hydrogen chloride (4.0 M, 1 mL) was added. After the addition, the reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was concentrated at low temperature to obtain crude compound 1′-a (270 mg). LC-MS (ESI): m / z 745.0 (M+H) + .

[0505] Synthesis of comparative compound 1′

[0506] At room temperature, crude product 1′-a (270 mg, 0.29 mmol), DMF (3 mL), and cesium fluoride (220 mg, 1.45 mmol) were added to the reaction flask. The mixture was purged with nitrogen and reacted at 60°C for 1 hour. The reaction solution was filtered, and the filtrate was purified by prep-HPLC to obtain compound 1′ (69 mg, 40%). LC-MS (ESI): m / z 588.7 (M+H) + .

[0507] Example 21 Synthesis route of compound 23

[0508]

[0509] Synthesis of compound 23-a

[0510] To compound 12 (50 mg, 0.073 mmol) in dichloromethane (10 mL) was added isobutyryl chloride (16 mg, 0.146 mmol) and N,N-diisopropylethylamine (28 mg, 0.219 mmol) under ice-water bath conditions. The reaction solution was reacted at this temperature for 1 hour. Water was added to the reaction solution and extracted with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried to give 23-a (55 mg, 100%). The crude product was used directly in the next reaction without purification. LC-MS (ESI): m / z 759.9 (M+H) + .

[0511] Synthesis of compound 23

[0512] To a solution of 23-a (55 mg, 0.072 mmol) in acetonitrile (8 mL) was added a 1,4-dioxane solution of hydrogen chloride (4 M, 1 mL) at room temperature, and the reaction mixture was allowed to react overnight at this temperature. The reaction mixture was neutralized by adding a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by Prep-HPLC to give 23 (10.6 mg, 22%). LC-MS (ESI): m / z 659.3 (M+H) + .

[0513] Example 22 Synthesis route of compound 24

[0514]

[0515] Synthesis of compound 24-c

[0516] To a solution of 3-b (160 mg, 0.38 mmol) in dichloromethane (15 mL) was added (2-methylenehexahydro-1H-pyrrolizin-7a-yl)methanol (88 mg, 0.58 mmol) in an ice-water bath, followed by the slow addition of sodium tert-butoxide (111 mg, 1.15 mmol). The mixture was reacted at this temperature for 3 hours. Water was added to the reaction solution, which was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was purified by flash column chromatography (mobile phase: dichloromethane:methanol = 10:1 / dichloromethane, 0-50%) to afford 24-c (93 mg, 45%). LC-MS (ESI): m / z 533.8 (M+H). + .

[0517] Synthesis of compound 24-b

[0518] To a 10 mL microwave tube was added 24-c (93 mg, 0.17 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (131 mg, 0.21 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (13 mg, 0.017 mmol), potassium phosphate (111 mg, 0.52 mmol), tetrahydrofuran (2.5 mL), and water (0.5 mL). The microwave tube was purged with nitrogen several times, sealed, and heated to 65°C for overnight reaction. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried to give 24-b (170 mg, 98%). The crude product was used directly in the next reaction without purification. LC-MS (ESI): m / z 996.7 (M+H) + .

[0519] Synthesis of compound 24-a

[0520] To a solution of 24-b (170 mg, 0.17 mmol) in N,N-dimethylformamide (8 mL) at room temperature was added cesium fluoride (130 mg, 0.85 mmol), and the mixture was allowed to react overnight at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate (30 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by flash column chromatography (mobile phase: DCM:MeOH = 10:1 / DCM, 0-50%) to afford 24-a (70 mg, 60%). LC-MS (ESI): m / z 683.4 (M+H). + .

[0521] Synthesis of compound 24

[0522] To a solution of 24-a (70 mg, 0.103 mmol) in acetonitrile (10 mL) at room temperature was added 1,4-dioxane (4 M, 1 mL), and the reaction mixture was allowed to react overnight at this temperature. Saturated aqueous sodium bicarbonate was added to the reaction mixture for neutralization, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by Prep-HPLC to yield 24 (8 mg, 13%). LC-MS (ESI): m / z 583.3 (M+H). + .

[0523] Example 23 Synthesis of Compound 25

[0524]

[0525] Referring to the synthetic routes of compounds 3 and 4, hexahydro-1H-pyrrolazin-7a-ylmethanol was used instead of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methanol to obtain compound 25. LC-MS (ESI): m / z 571.2 (M+H) + .

[0526] Example 24 Synthesis route of compound 26

[0527]

[0528] Synthesis of compound 26-d

[0529] To a solution of 2,4-dichloro-7-bromoquinazoline (280 mg, 1.01 mmol) in tetrahydrofuran (15 mL) was added tert-butyl 1,2-diazepine-1-carboxylate (202 mg, 1.01 mmol) and N,N-diisopropylethylamine (390 mg, 3.02 mmol) at room temperature. The reaction solution was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate (30 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether, 0-30%) to give 26-d (440 mg, 99%). LC-MS (ESI): m / z 441.1 (M+H) + .

[0530] Synthesis of compound 26-c

[0531] To a solution of 26-d (440 mg, 0.10 mmol) in toluene (10 mL) was added ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (238 mg, 1.49 mmol) and sodium tert-butoxide (287 mg, 2.99 mmol) in an ice-water bath. The reaction temperature was slowly raised to room temperature and allowed to react overnight. The reaction solution was evaporated to dryness, water was added, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by flash column chromatography (mobile phase: dichloromethane:methanol = 10:1 / dichloromethane, 0-100%) to afford 26-c (538 mg, 96%). LC-MS (ESI): m / z 564.2 (M+H). + .

[0532] Synthesis of compound 26-b

[0533] To a 10 mL microwave tube was added 26-c (100 mg, 0.18 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (133 mg, 0.21 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (13 mg, 0.018 mmol), potassium phosphate (113 mg, 0.53 mmol), tetrahydrofuran (2.5 mL), and water (0.5 mL). The microwave tube was purged with nitrogen several times, sealed, and heated to 65°C for overnight reaction. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried to give 26-b (215 mg). The crude product was used directly in the next step without purification. LC-MS (ESI): m / z 826.9 (M+H) + .

[0534] Synthesis of compound 26-a

[0535] To a solution of 26-b (215 mg, 0.26 mmol) in N,N-dimethylformamide (10 mL) at room temperature was added cesium fluoride (395 mg, 2.60 mmol), and the mixture was allowed to react overnight at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate (30 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by flash column chromatography (mobile phase: DCM:MeOH = 10:1 / DCM, 0-100%) to afford 26-a (83 mg, 48%). LC-MS (ESI): m / z 670.9 (M+H). + .

[0536] Synthesis of compound 26

[0537] To a solution of 26-a (83 mg, 0.12 mmol) in acetonitrile (10 mL) was added a 4 M solution of 1,4-dioxane hydrogen chloride (0.5 mL) at room temperature, and the reaction mixture was allowed to react overnight at this temperature. Saturated aqueous sodium bicarbonate was added to the reaction mixture for neutralization, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by Prep-HPLC to yield 26 (17.1 mg, 24%). LC-MS (ESI): m / z 570.2 (M+H). + ; 1H NMR (400MHz, CDCl3): δ8.89(1H,dd,J=26.8,8.8Hz),7.64–7.55(2H,m),7.32(1H,s),7.22–7.05(3H,m),7.03(1H,d,J=7.2 Hz),5.43–5.20(1H,m),4.26–3.93(5H,m),3.35–2.97(6H,m),2.78(1H,d,J=4.4Hz),2.01–1.88(6H,m),1.78–1.62(5H,m).

[0538] Example 25 Synthesis route of compound 27

[0539]

[0540] Synthesis of compound 27-b

[0541] To a solution of 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 1.39 mmol) in acetonitrile (15 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (1.5 mL) under ice-cooling conditions. The mixture was reacted at this temperature for 1 hour, then dried by spin drying. The crude product was purified by flash column chromatography (mobile phase: EA / PE, 0-40%) to afford 27-b (436 mg, 99%). LC-MS (ESI): m / z 317.0 (M+H) + .

[0542] Synthesis of compound 27-a

[0543] To a 10 mL microwave tube were added 26-c (70 mg, 0.12 mmol), 27-b (78 mg, 0.25 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (9 mg, 0.012 mmol), potassium phosphate (79 mg, 0.37 mmol), tetrahydrofuran (2.5 mL), and water (0.5 mL). The microwave tube was purged with nitrogen several times, sealed, and heated to 65°C for overnight reaction. Water was added to the reaction solution, which was extracted with ethyl acetate (30 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by flash column chromatography (mobile phase: DCM:MeOH = 10:1 / DCM, 0-100%) to afford 27-a (79 mg, 95%). LC-MS (ESI): m / z 674.9 (M+H) + .

[0544] Synthesis of compound 27

[0545] To a solution of 27-a (79 mg, 0.12 mmol) in acetonitrile (10 mL) was added a 4 M solution of 1,4-dioxane hydrogen chloride (0.5 mL) at room temperature, and the reaction mixture was allowed to react overnight at this temperature. Saturated aqueous sodium bicarbonate was added to the reaction mixture for neutralization, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by Prep-HPLC to yield 27 (26.1 mg, 39%). LC-MS (ESI): m / z 574.2 (M+H). + .

[0546] Example 26 Synthesis route of compound 28

[0547]

[0548] Synthesis of compound 28-a

[0549] To a 10 mL microwave tube were added 13-c (50 mg, 0.098 mmol), 27-b (47 mg, 0.15 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (7 mg, 0.01 mmol), potassium phosphate (63 mg, 0.30 mmol), tetrahydrofuran (2.5 mL), and water (0.5 mL). The microwave tube was purged with nitrogen several times, sealed, and heated to 65°C for overnight reaction. Water was added to the reaction solution, which was extracted with ethyl acetate (30 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by flash column chromatography (mobile phase: DCM:MeOH = 10:1 / DCM, 0-100%) to afford 28-a (56 mg, 86%). LC-MS (ESI): m / z 663.9 (M+H) + .

[0550] Synthesis of compound 28

[0551] To a solution of 28-a (56 mg, 0.084 mmol) in acetonitrile (10 mL) was added a 4 M solution of 1,4-dioxane hydrogen chloride at room temperature. The reaction mixture was allowed to react at this temperature for 3 hours. Saturated aqueous sodium bicarbonate was added for neutralization, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by Pre-HPLC to yield 28 (4.2 mg, 9%). LC-MS (ESI): m / z 563.2 (M+H). + .

[0552] Example 27 Synthesis route of compound 29

[0553]

[0554] Synthesis of compound 29-c

[0555] To a solution of 3-c (200 mg, 0.48 mmol) in dichloromethane (20 mL) was added (1-(morpholinomethyl)cyclopropyl)methanol (165 mg, 0.96 mmol) under ice-cooling conditions, followed by the slow addition of sodium tert-butoxide (231 mg, 2.40 mmol). The temperature was slowly raised to room temperature, and the reaction was allowed to proceed overnight. Water was added, and the mixture was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was purified by flash column chromatography (mobile phase: dichloromethane:methanol = 10:1 / dichloromethane, 0-100%) to afford 29-c (260 mg, 98%). LC-MS (ESI): m / z 551.8 (M+H). + .

[0556] Synthesis of compound 29-b

[0557] To a 10 mL microwave tube was added 29-c (100 mg, 0.18 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (136 mg, 0.22 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (13 mg, 0.018 mmol), potassium phosphate (116 mg, 0.54 mmol), tetrahydrofuran (2.5 mL), and water (0.5 mL). The microwave tube was purged with nitrogen several times, sealed, and heated to 65°C for overnight reaction. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried to give crude product 29-b (180 mg, 98%). The crude product was used directly in the next reaction without purification. LC-MS (ESI): m / z 1013.9 (M+H) + .

[0558] Synthesis of compound 29-a

[0559] To a solution of 29-b (180 mg, 0.18 mmol) in N,N-dimethylformamide (8 mL) was added cesium fluoride (270 mg, 1.78 mmol) at room temperature, and the mixture was allowed to react overnight at room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by flash column chromatography (mobile phase: MeOH / DCM, 0-100%) to obtain 29-a (40 mg, 32%). LC-MS (ESI): m / z 701.9 (M+H) + .

[0560] Synthesis of compound 29

[0561] To a solution of 29-a (40 mg, 0.057 mmol) in acetonitrile (10 mL) was added a 4 M solution of 1,4-dioxane hydrogen chloride (0.5 mL) at room temperature, and the reaction mixture was allowed to react at this temperature for 3 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture for neutralization, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by Prep-HPLC to yield 29 (1.1 mg, 3%). LC-MS (ESI): m / z 601.3 (M+H). + .

[0562] Example 28 Synthesis route of compound 30

[0563]

[0564] Synthesis of compound 30-a

[0565] To a 10 mL microwave tube was added 20-d (50 mg, 0.11 mmol), 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine (59 mg, 0.13 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (8 mg, 0.011 mmol), potassium phosphate (73 mg, 0.34 mmol), tetrahydrofuran (2.5 mL), and water (0.5 mL). The microwave tube was purged with nitrogen several times, sealed, and heated to 65°C for overnight reaction. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was purified by flash column chromatography (mobile phase: methanol / dichloromethane, 0-100%) to give 30-a (61 mg, 72%). LC-MS (ESI): m / z 744.5 (M+H) + .

[0566] Synthesis of compound 30

[0567] To a solution of 30-a (61 mg, 0.082 mmol) in N,N-dimethylformamide (8 mL) was added cesium fluoride (125 mg, 0.82 mmol) at room temperature. The mixture was reacted at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by Prep-HPLC to obtain 30 (17 mg, 35%). LC-MS (ESI): m / z 588.2 (M+H). + .

[0568] Example 29 Synthesis route of compound 31

[0569]

[0570] Synthesis of compound 31-e

[0571] 2-(6-Bromo-2,3-difluorophenyl)acetonitrile (400 mg, 1.72 mmol) was dissolved in N,N-dimethylformamide (10 mL), and potassium tert-butoxide (203 mg, 1.81 mmol) was added thereto under nitrogen protection. The resulting mixture was stirred at room temperature for 30 minutes, and then ethoxycarbonyl isothiocyanate (237 mg, 1.81 mmol) was added dropwise thereto. After the addition was completed, stirring was continued at room temperature for 1 hour, and then heated to 100 ° C and stirred for 1 hour. The reaction solution was poured into 50 mL of water, stirred for 10 minutes, and the solid was collected by filtration and dried to obtain 31-e (550 mg, 93%). LC-MS (ESI): m / z 340.8 (MH) - ; 1 H NMR (400MHz, DMSO-d6): δ12.10(1H,s),7.68(1H,dd,J=8.8,4.8Hz), 7.21(1H,t,J=8.8Hz), 4.30(2H,q,J=7.2Hz), 1.31(3H,t,J=7.2Hz).

[0572] Synthesis of compound 31-d

[0573] 31-e (300 mg, 0.87 mmol) was dissolved in dimethyl sulfoxide (9 mL), and then a 5 M aqueous sodium hydroxide solution (9 mL, 45 mmol) was added. The reaction was heated to 130°C and allowed to react at this temperature for 2 hours. The reaction solution was poured into water, and a solid precipitated. The solution was stirred at room temperature for 30 minutes and allowed to stand overnight. The next day, the solid was collected by filtration and dried to obtain 31-d (220 mg, 93%). LC-MS (ESI): m / z 268.9 (MH)- .

[0574] Synthesis of compound 31-c

[0575] To a solution of 31-d (220 mg, 0.81 mmol) in tetrahydrofuran (20 mL) were added di-tert-butyl dicarbonate (531 mg, 2.43 mmol), N,N-diisopropylethylamine (524 mg, 4.06 mmol), and 4-dimethylaminopyridine (10 mg, 0.081 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography (mobile phase: EA / PE, 0-20%) to obtain 31-c (232 mg, 77%). LC-MS (ESI): m / z 369.0 (MH) - .

[0576] Synthesis of compound 31-b

[0577] To a 30 mL microwave tube was added 31-c (50 mg, 0.13 mmol), bis-pinacol boronate (171 mg, 0.67 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (10 mg, 0.013 mmol), potassium acetate (66 mg, 0.673 mmol), and 1,4-dioxane (8 mL). The microwave tube was purged with nitrogen several times, sealed, and heated to 100°C under microwave conditions for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by column chromatography (mobile phase: EA / PE, 0-20%) to afford 31-b (50 mg, 89%). LC-MS (ESI): m / z 417.1 (MH) - .

[0578] Synthesis of compound 31-a

[0579] To a 10 mL microwave tube at room temperature were added 3-b (100 mg, 0.19 mmol), 31-b (86 mg, 0.21 mmol), dichloro[bis(diphenylphosphinophenyl)ether]palladium(II) (13 mg, 0.019 mmol), cesium carbonate (121 mg, 0.37 mmol), and toluene (4 mL). The microwave tube was purged with nitrogen several times, sealed, heated to 100°C, and reacted for 2 hours. The reaction mixture was dried by rotary evaporation, water was added, and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was purified by flash column chromatography (mobile phase: dichloromethane:methanol = 10:1 / dichloromethane, 0-100%) to afford 31-a (75 mg, 51%). LC-MS (ESI): m / z 795.9 (M+H).+ .

[0580] Synthesis of compound 31

[0581] To a solution of 31-a (75 mg, 0.094 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (2 mL) at room temperature, and the reaction mixture was allowed to react at this temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture for neutralization, and the mixture was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was purified by reverse phase chromatography (mobile phase: 5%-95%, water (10 mmol ammonium bicarbonate):acetonitrile) and Prep-TLC (developing solvent: dichloromethane:methanol = 10:1) to obtain 31 (15 mg, 27%). LC-MS (ESI): m / z 595.2 (M+H). + .

[0582] Example 30 Synthesis route of compound 32

[0583]

[0584] Synthesis of compound 32

[0585] Compound 30 (60 mg, 0.102 mmol) was dissolved in ethyl acetate (15 mL) and methanol (2 mL). 10% palladium on carbon (100 mg) was added and the mixture was replaced with hydrogen several times. The reaction mixture was allowed to react at room temperature for 4 hours. The palladium on carbon was removed by filtration, and the organic phase was dried by spin drying. The crude product was purified by Prep-HPLC to yield 32 (5.5 mg, 9%). LC-MS (ESI): m / z 592.2 (M+H) + .

[0586] Example 31 Synthesis route of compound 33

[0587]

[0588] Synthesis of compound 33-g

[0589] At room temperature, compound 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (1.0 g, 3.57 mmol) was dissolved in anhydrous DMAc (10 mL), and anhydrous methanol (2 mL) and sodium methoxide (386 mg, 7.14 mmol) were added sequentially. The reaction mixture was stirred at 50°C under nitrogen for 2 hours. The reaction solution was cooled in an ice-water bath, the pH was adjusted to 3 with 1 M hydrochloric acid solution, and then 20 mL of water was added, resulting in the precipitation of a large amount of solid. The mixture was filtered, and the filter cake was washed with water (10 mL * 3). The solid was collected and freeze-dried overnight to obtain compound 33-g (930 mg, 95%). LC-MS (ESI): m / z = 276.1 [M+H] + .

[0590] Synthesis of compound 33-f

[0591] At room temperature, compound 33-g (930 mg, 3.37 mmol) was dissolved in 20 mL of anhydrous acetonitrile, and DIPEA (4.18 mL, 25.30 mmol) and phosphorus oxychloride (4.15 mL, 44.53 mmol) were added. The reaction mixture was stirred at 80°C under nitrogen for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by a flash column (EA / PE = 0-30%) to obtain compound 33-f (775 mg, 78%). LC-MS (ESI): m / z = 293.9 [M+H] + .

[0592] Synthesis of compound 33-e

[0593] At room temperature, compound 33-f (775 mg, 2.63 mmol) was dissolved in 50 mL of dichloromethane, and DIPEA (1.31 mL, 7.91 mmol) and tert-butyl 1,2-diazepine-1-carboxylate (528 mg, 2.64 mmol) were added thereto under an ice-water bath. The mixture was warmed to room temperature and stirred for 1 hour. 50 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL*2). The organic phase was washed with 10% sodium bisulfate solution (100 mL*2) and saturated sodium bicarbonate (100 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by a rapid separation column (PE / EA=2:1) ​​to obtain compound 33-e (980 mg, 81%). LC-MS (ESI): m / z=458.2[M+H] + .

[0594] Synthesis of compound 33-d

[0595] At room temperature, compound 33-e (980 mg, 2.14 mmol) was dissolved in 30 mL of ethyl acetate, and m-chloroperbenzoic acid (1.13 g, 5.56 mmol) was added. The reaction mixture was stirred at room temperature under nitrogen for 1 hour. 100 mL of saturated sodium bicarbonate solution was added to the reaction solution, extracted with ethyl acetate (150 mL), and the organic phase was washed with saturated sodium bicarbonate (100 mL) and saturated brine (100 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by a rapid separation column (PE / EA=2:1) ​​to obtain compound 33-d (479 mg, 46%). LC-MS (ESI): m / z=490.2[M+H] + .

[0596] Synthesis of compound 33-c

[0597] At room temperature, compound 33-d (200 mg, 0.41 mmol) was dissolved in 20 mL of dichloromethane, and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (78 mg, 0.49 mmol) was added. Sodium tert-butoxide (98 mg, 1.02 mmol) was added under ice-water bath, and the reaction mixture was stirred under ice-water bath for 2 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by flash column chromatography (EA / PE = 0-100%) to obtain compound 33-c (128 mg, 55%). LC-MS (ESI): m / z = 569.5 [M+H] + .

[0598] Synthesis of compound 33-b

[0599] At room temperature, compound 33-c (128 mg, 0.22 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (211 mg, 0.34 mmol), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) (33 mg, 0.045 mmol), potassium phosphate (143 mg, 0.68 mmol), THF (2.5 mL), and water (0.5 mL) were added to a microwave tube, and the mixture was replaced with nitrogen three times, sealed, and stirred at 65°C for 18 hours. The mixture was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by flash column chromatography (PE / EA, then DCM / MeOH = 10:1) to obtain compound 33-b (53 mg, 23%). LC-MS (ESI): m / z = 1031.4 [M+H] + .

[0600] Synthesis of compound 33-a

[0601] At room temperature, compound 33-b (53 mg, 0.051 mmol) was dissolved in 5 mL of DMF, cesium fluoride (156 mg, 1.03 mmol) was added, and the mixture was stirred at room temperature under nitrogen for 8 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL*2). The organic phase was washed with saturated brine (100 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by flash column chromatography (DCM / MeOH = 10:1) to obtain compound 33-a (30 mg, 82%). LC-MS (ESI): m / z = 719.0 [M+H] + .

[0602] Synthesis of compound 33

[0603] Compound 33-a (30 mg, 0.042 mmol) was dissolved in 5 mL of formic acid at room temperature, and the mixture was stirred under nitrogen for 3 hours. The reaction mixture was concentrated under reduced pressure, and 20 mL of dichloromethane was added to the residue, and the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by Prep-HPLC (NH4HCO3) to obtain compound 33 (8.9 mg, 34%). LC-MS (ESI): m / z = 619.3 [MS+H] + .

[0604] Example 32 Synthesis route of compound 34

[0605]

[0606] Synthesis of compound 34-e

[0607] At room temperature, compound 3-c (500 mg, 1.20 mmol) was dissolved in 30 mL of dichloromethane, and [3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (377 mg, 1.32 mmol) was added. Sodium tert-butoxide (289 mg, 3.00 mmol) was added under ice-water bath, and the reaction mixture was stirred under ice-water bath for 3 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by flash column chromatography (DCM / MeOH = 10:1) to obtain compound 34-e (700 mg, 88%).

[0608] Synthesis of compound 34-d

[0609] At room temperature, compound 34-e (700 mg, 1.05 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran. Under an ice-water bath, a solution of tetrabutylammonium fluoride in tetrahydrofuran (2.10 mL, 2.10 mmol, 1 M) was added, and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 100 mL of ethyl acetate, washed sequentially with water (100 mL) and saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dried under vacuum overnight. Compound 34-d (579 mg, 100%) was obtained. LC-MS (ESI): m / z = 551.1 [M+H] + .

[0610] Synthesis of compound 34-c

[0611] Compound 34-d (460 mg, 0.83 mmol) was dissolved in 30 mL of anhydrous tetrahydrofuran at room temperature. p-Nitrophenyl chloroformate (505 mg, 2.50 mmol) and triethylamine (406 uL, 2.92 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 1 hour. Additional p-Nitrophenyl chloroformate (505 mg, 2.50 mmol) and triethylamine (406 uL, 2.92 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Additional p-Nitrophenyl chloroformate (505 mg, 2.50 mmol) and triethylamine (406 uL, 2.92 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. A solution of dimethylamine in tetrahydrofuran (8.35 mL, 16.70 mmol, 2 M) was added to the reaction solution, and the mixture was stirred for 18 hours. Then, a tetrahydrofuran solution of dimethylamine (5 mL) was added every hour until the reaction was complete, with a total of three additions of the tetrahydrofuran solution of dimethylamine. 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by a flash column (DCM / MeOH = 30:1 to 10:1) to obtain compound 34-c (240 mg, 47%). LC-MS (ESI): m / z = 622.3

[0612] [M+H] + .

[0613] Synthesis of compound 34-b

[0614] At room temperature, compound 34-c (240 mg, 0.39 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (362 mg, 0.58 mmol), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) (56 mg, 0.077 mmol), potassium phosphate (246 mg, 1.16 mmol), THF (5 mL), and water (1 mL) were added to a microwave tube, and the mixture was replaced with nitrogen three times, sealed, and stirred at 65°C for 18 hours. The mixture was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by flash column chromatography (DCM / MeOH = 10:1) to obtain crude compound 34-b (418 mg, as a mixture). LC-MS (ESI): m / z = 928.4 [M+H, de-TIPS] + ;LC-MS(ESI):m / z=1084.5[M+H]+ .

[0615] Synthesis of compound 34-a

[0616] At room temperature, compound 34-b (418 mg, 0.39 mmol) was dissolved in 30 mL of DMF, cesium fluoride (1.17 g, 7.71 mmol) was added, and the mixture was stirred at room temperature under nitrogen for 3.5 hours. 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL * 5), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by flash column chromatography (DCM / MeOH = 10:1) to obtain compound 34-a (266 mg, 88%). LC-MS (ESI): m / z = 772.4 [M+H] + .

[0617] Synthesis of compound 34

[0618] At room temperature, compound 34-a (100 mg, 0.13 mmol) was dissolved in 15 mL of formic acid, and the mixture was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was concentrated under reduced pressure, and 50 mL of saturated sodium bicarbonate was added to the residue. The mixture was extracted with dichloromethane (50 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by flash column chromatography (DCM / MeOH = 10:1) to obtain compound 34 (25 mg, 29%). LC-MS (ESI): m / z = 672.2 [MS+H] + .

[0619] Example 33 Synthesis route of compound 35

[0620]

[0621] Synthesis of compound 35-a

[0622] 3-b (150 mg, 0.28 mmol), 2-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (146 mg, 0.42 mmol), cataCXium A Pd G3 (20 mg, 0.03 mmol), potassium phosphate (177 mg, 0.83 mmol), THF (2 mL), and water (0.5 mL) were added to a sealed tube at room temperature. The mixture was replaced with N2 and heated to 65°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 35-a (160 mg, 79%). LC-MS (ESI): m / z 725.8 (M+H)+ .

[0623] Synthesis of compound 35

[0624] 35-a (130 mg, 0.18 mmol) and acetonitrile (5 mL) were added to the reaction flask at room temperature. The reaction mixture was replaced with N2 and cooled to 0°C. A 4.0 M solution of hydrogen chloride in 1,4-dioxane (1 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated at room temperature and purified by preparative HPLC to obtain compound 35 (16 mg, 15%). LC-MS (ESI): m / z 581.7 (M+H). + .

[0625] Example 34 Synthesis route of compound 36

[0626]

[0627] Synthesis of compound 36-b

[0628] To a sealed tube was added 3-b (200 mg, 0.37 mmol), triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (275 mg, 0.55 mmol), cataCXium A Pd G3 (54 mg, 0.07 mmol), potassium phosphate (236 mg, 1.11 mmol), THF (2 mL), and water (0.5 mL) at room temperature. The mixture was replaced with N2 and heated to 65°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 36-b (300 mg, 93%). LC-MS (ESI): m / z 871.9 (M+H) + .

[0629] Synthesis of compound 36-a

[0630] 36-b (140 mg, 0.16 mmol), DMF (2 mL), cesium fluoride (244 mg,

[0631] The reaction mixture was stirred for 1 hour at 60°C. Water was added to the reaction solution and extracted with ethyl acetate. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated to give crude compound 36-a (115 mg). LC-MS (ESI): m / z 715.8 (M+H) + .

[0632] Synthesis of compound 36

[0633] Crude product 36-a (115 mg, 0.16 mmol) and acetonitrile (5 mL) were added to the reaction flask at room temperature. The reaction mixture was replaced with N2 for protection, cooled to 0°C, and a solution of hydrogen chloride in 1,4-dioxane (4.0 M, 1 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with aqueous sodium bicarbonate solution and extracted with DCM. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to obtain compound 36 (11 mg, 12%). LC-MS (ESI): m / z 571.6 (M+H) + ; 1 H NMR (400MHz, DMSO-d6): δ10.24(1H,s),10.12(1H,m),7.92-7.81(1H,d,J=8. 0Hz),7.49-7.36(2H,m),7.36-7.26(1H,d,J=2.4Hz),7.14-7.04(1H,d,J=2.0 Hz),5.92-5.78(1H,t,J=6.0Hz),5.40-5.13(1H,d,J=54.0Hz),4.18-3.88(4 H,m),3.56(1H,s),3.17-2.95(5H,m),2.90-2.75(1H,m),2.19-1.54(12H,m).

[0634] Example 35 Synthesis route of compound 37

[0635]

[0636] Synthesis of compound 37-c

[0637] To the reaction flask at room temperature were added 3-c (400 mg, 0.96 mmol), (2,2-difluoro-hexahydro-1H-pyrrolizin-7a-yl)methanol (255 mg, 1.44 mmol), 1,4-dioxane (10 mL), and DIPEA (373 mg, 2.89 mmol). The mixture was purged with nitrogen and heated to 90°C overnight. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 37-c (300 mg, 56%). LC-MS (ESI): m / z 557.7 (M+H). + .

[0638] Synthesis of compound 37-b

[0639] To a sealed tube were added 37-c (300 mg, 0.54 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (505 mg, 0.81 mmol), cataCXium APd G3 (78 mg, 0.11 mmol), potassium phosphate (343 mg, 1.62 mmol), THF (2 mL), and water (0.5 mL) at room temperature. The mixture was purged with N2 and heated to 65°C overnight. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 37-b (460 mg, 84%).

[0640] Synthesis of compound 37-a

[0641] 37-b (460 mg, 0.45 mmol), DMF (2 mL), cesium fluoride (684 mg,

[0642] The reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution and extracted with EA. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated to give crude compound 37-a (500 mg). LC-MS (ESI): m / z 707.7 (M+H) + .

[0643] Synthesis of compound 37

[0644] Crude product 37-a (500 mg, 0.45 mmol), DCM (10 mL), and TFA (3 mL) were added to the reaction flask at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized with aqueous sodium bicarbonate and extracted with a 10:1 solution of DCM:MeOH. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to obtain compound 37 (4.5 mg, 2%). LC-MS (ESI): m / z 607.5 (M+H) + .

[0645] Example 36 Synthesis route of compound 38

[0646]

[0647] Synthesis of compound 38-g

[0648] To a reaction flask at room temperature were added NBS (2150 mg, 12.08 mmol), acetonitrile (28 mL), water (7 mL), and 5-bromo-1-pentene (1500 mg, 10.07 mmol). The reaction was allowed to react at room temperature for 36 hours. 90 mL of water was added to the reaction solution, and the mixture was extracted three times with DCM. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 10 / 2) to afford compound 38-g (800 mg, 32%).

[0649] Synthesis of compound 38-f

[0650] 2-(tert-Butyl)hydrazine-1,2-dicarboxylic acid-1-benzyl ester (780 mg, 2.93 mmol) and DMF (25 mL) were added to the reaction flask at room temperature. Under nitrogen purge protection, NaH (60%, 234 mg, 5.85 mmol) was added portionwise in an ice-water bath. After addition, the mixture was warmed to room temperature and stirred for 1 hour. A solution of 38-g (800 mg, 3.25 mmol) in DMF (10 mL) was then added dropwise in an ice-water bath. After addition, the mixture was warmed to room temperature and allowed to react overnight. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, washed with water, dried, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 10 / 2) to obtain compound 38-f (500 mg, 49%). LC-MS (ESI): m / z 351.2 (M+H) + .

[0651] Synthesis of compounds 38-e-1 and 38-e-2

[0652] To the reaction flask at room temperature were added 38-f (1000 mg, 2.85 mmol), EA (100 mL), and palladium on carbon (10%, 200 mg). The mixture was replaced with hydrogen and allowed to react at room temperature for 2 hours. The reaction mixture was filtered, the filtrate concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 1 / 1) to afford compounds 38-e-1 (350 mg, 57%) and 38-e-2 (180 mg, 29%). LC-MS (ESI): m / z 217.1 (M+H). + .

[0653] Synthesis of compound 38-d

[0654] To a reaction flask at room temperature, add 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2066 mg, 8.18 mmol) and DCM (30 mL). The atmosphere was replaced with nitrogen and the temperature was cooled to -78°C in a dry ice-acetone bath. DIPEA (2116 mg, 16.37 mmol) and 38-e-1 (590 mg, 2.73 mmol) were added. After addition, the mixture was allowed to warm to room temperature and react overnight. Water was added to the reaction mixture, which was extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 7 / 3) to afford compound 38-d (620 mg, 53%).

[0655] Synthesis of compound 38-c

[0656] To the reaction flask at room temperature were added 38-d (300 mg, 0.69 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (221 mg, 1.39 mmol), 1,4-dioxane (10 mL), and DIPEA (269 mg, 2.08 mmol). The mixture was purged with nitrogen and heated to 90°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 38-c (220 mg, 57%). LC-MS (ESI): m / z 555.9 (M+H). + .

[0657] Synthesis of compound 38-b

[0658] To a sealed tube were added 38-c (220 mg, 0.40 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (372 mg, 0.60 mmol), cataCXium APd G3 (58 mg, 0.08 mmol), potassium phosphate (252 mg, 1.19 mmol), THF (2 mL), and water (0.5 mL) at room temperature. The mixture was replaced with N2 and heated to 65°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 38-b (230 mg, 57%). LC-MS (ESI): m / z 1018.0 (M+H) + .

[0659] Synthesis of compound 38-a

[0660] 38-b (230 mg, 0.23 mmol), DMF (2 mL), cesium fluoride (343 mg,

[0661] The reaction mixture was purged with nitrogen and reacted at room temperature for 2 hours. Water was added to the reaction solution and extracted with EA. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated to give crude compound 38-a (300 mg). LC-MS (ESI): m / z 705.9 (M+H) + .

[0662] Synthesis of compound 38

[0663] Crude product 38-a (300 mg, 0.23 mmol), DCM (6 mL), and TFA (2 mL) were added to the reaction flask at room temperature. The mixture was stirred at room temperature for 1.5 hours. The reaction solution was neutralized with aqueous sodium bicarbonate and extracted with a 10:1 solution of DCM:MeOH. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to obtain compound 38 (27 mg, 20%). LC-MS (ESI): m / z 605.5 (M+H) + .

[0664] Example 37 Synthesis route of compound 39

[0665]

[0666] Synthesis of compound 39-d

[0667] To a reaction flask at room temperature, add 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1471 mg, 5.83 mmol) and DCM (30 mL). The atmosphere was replaced with nitrogen and the temperature was cooled to -78°C in a dry ice-acetone bath. DIPEA (1506 mg, 11.65 mmol) and 38-e-2 (420 mg, 1.94 mmol) were added. After addition, the mixture was allowed to warm to room temperature and react overnight. Water was added to the reaction mixture, which was extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 7 / 3) to afford compound 39-d (600 mg, 71%).

[0668] Synthesis of compound 39-c

[0669] To the reaction flask at room temperature were added 39-d (300 mg, 0.69 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (221 mg, 1.39 mmol), 1,4-dioxane (10 mL), and DIPEA (359 mg, 2.78 mmol). The atmosphere was replaced with nitrogen and the reaction was heated to 90°C overnight. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 39-c (250 mg, 65%). LC-MS (ESI): m / z 555.9 (M+H) + .

[0670] Synthesis of compound 39-b

[0671] To a sealed tube were added 39-c (250 mg, 0.45 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (422 mg, 0.68 mmol), cataCXium APd G3 (66 mg, 0.09 mmol), potassium phosphate (287 mg, 1.35 mmol), THF (2 mL), and water (0.5 mL) at room temperature. The mixture was replaced with N2 and heated to 65°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 39-b (260 mg, 57%). LC-MS (ESI): m / z 1017.9 (M+H) + .

[0672] Synthesis of compound 39-a

[0673] 39-b (260 mg, 0.26 mmol), DMF (2 mL), cesium fluoride (388 mg,

[0674] The reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution and extracted with EA. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated to give crude compound 39-a (400 mg). LC-MS (ESI): m / z 705.9 (M+H) + .

[0675] Synthesis of compound 39

[0676] Crude product 39-a (400 mg, 0.26 mmol), DCM (6 mL), and TFA (2 mL) were added to the reaction flask at room temperature. The mixture was stirred at room temperature for 1.5 hours. The reaction solution was neutralized with aqueous sodium bicarbonate and extracted with a 10:1 solution of DCM:MeOH. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to obtain compound 39 (36 mg, 23%). LC-MS (ESI): m / z 605.8 (M+H) + .

[0677] Example 38 Synthesis route of compound 40

[0678]

[0679] Synthesis of compound 40-f

[0680] To a solution of 1-benzyl 2-(tert-butyl)hydrazine-1,2-dicarboxylate (2 g, 7.51 mmol) in DMF (60 mL) was added portionwise 60% sodium hydroxide (0.75 g, 18.78 mmol). After addition, the mixture was stirred at room temperature for 1 hour. A solution of tert-butyl N,N-bis(2-chloroethyl)carbamate (1.82 g, 7.51 mmol) in DMF (6 mL) was then added dropwise. The mixture was reacted at 80°C for 72 hours. The reaction mixture was cooled to room temperature, quenched with ice water, and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. Purification by column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-20%) afforded 40-f (0.7 g, 21%). LC-MS (ESI): m / z 453.3 (M+NH4). + .

[0681] Synthesis of compound 40-e

[0682] To a solution of 40-f (850 mg, 1.95 mmol) in ethanol (50 mL) was added 10% palladium on carbon (208 mg, 0.19 mmol), the mixture was replaced with hydrogen three times, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, the filtrate was dried, and purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0-30%) to obtain 40-e (506 mg, 86%). LC-MS (ESI): m / z 302.2 (M+H) + .

[0683] Synthesis of compound 40-d

[0684] To a solution of 40-e (500 mg, 1.66 mmol) and N,N-diisopropylethylamine (643 mg, 4.98 mmol) in dichloromethane (50 mL) was added 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (628 mg, 2.49 mmol) under a dry ice acetone bath. The mixture was allowed to warm to room temperature and stirred overnight. The next day, water was added to the reaction mixture, and the mixture was extracted with dichloromethane (80 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried by spin drying. Purification by column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-20%) afforded 40-d (742 mg, 86%). LC-MS (ESI): m / z 517.4 (M+H). + .

[0685] Synthesis of compound 40-c

[0686] To a solution of 40-d (740 mg, 1.43 mmol) in dichloromethane (15 mL) was added ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (273 mg, 1.72 mmol) in an ice-water bath, followed by the slow addition of sodium tert-butoxide (344 mg, 3.58 mmol). The mixture was allowed to react at this temperature for 1 hour. Water was then added, and the mixture was extracted with dichloromethane (80 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was purified by column chromatography (mobile phase: dichloromethane:methanol = 10:1 / dichloromethane, 0-30%) to afford 40-c (751 mg, 82%). LC-MS (ESI): m / z 640.8 (M+H). + .

[0687] Synthesis of compound 40-b

[0688] To a microwave tube were added 40-c (100 mg, 0.16 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (146 mg, 0.23 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (11 mg, 0.016 mmol), potassium phosphate (99 mg, 0.47 mmol), tetrahydrofuran (10 mL) and water (1 mL), sealed, replaced with nitrogen three times, heated to 65°C, and reacted overnight. The reaction solution was dried by rotary evaporation, and the crude product was purified by column chromatography (mobile phase: dichloromethane:methanol=10:1 / dichloromethane, 0-50%) to obtain 40-b-1 (123 mg, 71%), LC-MS (ESI): m / z 1103.0 (M+H) +, and 40-b-2 (40 mg, 27%, partially removed TIPS), LC-MS (ESI): m / z 946.4 (M+H) + .

[0689] Synthesis of compound 40-a

[0690] To a mixture of 40-b-1 and 40-b-2 (163 mg, 0.15 mmol) was added formic acid (10 mL) at room temperature, and the mixture was allowed to react overnight at room temperature. The reaction solution was dried by rotary evaporation, saturated sodium bicarbonate was added, and extraction with ethyl acetate (50 mL x 2) was performed. The organic phase was dried and rotary evaporation to afford 40-a (117 mg, 140%), which was used directly in the next step without purification. LC-MS (ESI): m / z 746.4 (M+H) + .

[0691] Synthesis of compound 40

[0692] To a solution of 40-a (117 mg, 0.16 mmol) in N,N-dimethylformamide (10 mL) was added cesium fluoride (238 mg, 1.57 mmol) at room temperature, and the mixture was allowed to react overnight at room temperature. A large amount of water was poured into the reaction solution, and the mixture was extracted with ethyl acetate (50 mL*2). The organic phase was washed with saturated brine (50 mL*3), dried by spin drying, and purified by preparative HPLC (ammonium bicarbonate) to obtain compound 40 (23 mg, 25%). LC-MS (ESI): m / z 590.2 (M+H) + .

[0693] Example 39 Synthesis route of compound 41

[0694]

[0695] Synthesis of compound 41-d

[0696] To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (1 g, 3.03 mmol) and N,N-diisopropylethylamine (1173 mg, 9.08 mmol) in tetrahydrofuran (50 mL) was added tert-butyl 1,2-diazepine-1-carboxylate (606 mg, 3.03 mmol) under an ice-water bath. The mixture was allowed to warm to room temperature and stirred overnight. The next day, water was added to the reaction solution and extracted with ethyl acetate (100 mL*2). The combined organic phases were washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, dried by spin drying, and purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0-10%) to obtain compound 41-d (1350 mg, 90%). LC-MS (ESI): m / z 493.1 (M+H) + .

[0697] Synthesis of compound 41-c

[0698] To a solution of 41-d (300 mg, 0.61 mmol) in dichloromethane (30 mL) was added ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (232 mg, 1.46 mmol) in an ice-water bath, followed by the slow addition of sodium tert-butoxide (146 mg, 1.52 mmol). The mixture was allowed to react at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane (80 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0-100%) to afford 41-c (176 mg, 47%). LC-MS (ESI): m / z 616.2 (M+H). + .

[0699] Synthesis of compound 41-b

[0700] To a microwave tube were added 41-c (80 mg, 0.13 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (162 mg, 0.26 mmol), tetrakistriphenylphosphine palladium (15 mg, 0.013 mmol), sodium carbonate (41 mg, 0.39 mmol), 1,4-dioxane (15 mL), and water (1.5 mL). The atmosphere was replaced with nitrogen three times, the tube was sealed, and the reaction was heated to 100°C overnight. The reaction solution was dried by rotary evaporation, and the crude product was purified by column chromatography (mobile phase: dichloromethane:methanol = 10:1 / dichloromethane, 0-100%) to give 41-b (40 mg, 35%). LC-MS (ESI): m / z 878.3 (M+H) + .

[0701] Synthesis of compound 41-a

[0702] To a solution of 41-b (40 mg, 0.046 mmol) in N,N-dimethylformamide (6 mL) at room temperature was added cesium fluoride (69 mg, 0.46 mmol), and the mixture was allowed to react at room temperature for 1 hour. A large amount of water was poured into the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (30 mL x 3), dried, and purified by column chromatography (mobile phase: dichloromethane:methanol = 10:1 / dichloromethane, 0-100%) to obtain 41-a (13 mg, 40%). LC-MS (ESI): m / z 722.3 (M+H). + .

[0703] Synthesis of compound 41

[0704] To 41-a (13 mg, 0.018 mmol) was added formic acid (6 mL) at room temperature, and the mixture was allowed to react overnight. The reaction solution was dried at room temperature, purified (with ammonium bicarbonate), and lyophilized to afford 41 (2.5 mg, 22%). LC-MS (ESI): m / z 622.2 (M+H) + .

[0705] Example 40 Synthesis route of compound 42

[0706]

[0707] Synthesis of compound 42-a

[0708] To a microwave tube were added 41-c (100 mg, 0.16 mmol), tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (197 mg, 0.49 mmol), bis(diphenylphosphinophenyl ether)palladium(II) dichloride (12 mg, 0.016 mmol), cesium carbonate (264 mg, 0.81 mmol), and toluene (15 mL). The atmosphere was replaced with nitrogen three times, sealed, and heated to 100°C for 1.5 hours. The reaction mixture was dried by rotary evaporation, and the crude product was purified by column chromatography (mobile phase: dichloromethane:methanol = 10:1 / dichloromethane, 0-60%) to afford compound 42-a (153 mg, 96%). LC-MS (ESI): m / z 828.5 (M+H). + .

[0709] Synthesis of compound 42

[0710] To a solution of 42-a (50 mg, 0.060 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was spin-dried, purified by preparative HPLC (ammonium bicarbonate), and lyophilized to afford compound 42 (9 mg, 24%). LC-MS (ESI): m / z 628.5 (M+H) + ; 1 H NMR(400M,CD3OD)δ9.56(1H,d,J=1.6Hz),7.21-7.15(1H,m),7.02(1H,t,J=9.2Hz),5.40-5.21(1H,m),4.60(3H,bs) ,4.32-4.06(4H,m),3.39-2.96(6H,m),2.42-2.08(3H,m),2.05-1.94(4H,m),1.94-1.84(1H,m),1.82-1.67(4H,m).

[0711] Example 41 Synthesis route of compound 43

[0712]

[0713] Synthesis of compound 43-a

[0714] To a microwave tube were added 42-a (140 mg, 0.17 mmol), (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-3-yl)palladium(II) methanesulfonate (53 mg, 0.068 mmol), potassium phosphate (194 mg, 0.91 mmol), 1,4-dioxane (12 mL), and water (2 mL). The atmosphere was replaced with nitrogen three times, sealed, and vinylboronic acid pinacol ester (135 mg, 0.88 mmol) was added via syringe. The mixture was heated to 150°C in a microwave oven for 45 minutes. The reaction solution was dried by spin drying, and the crude product was purified by column chromatography (mobile phase: dichloromethane:methanol = 10:1 / dichloromethane, 0-100%) to afford compound 43-a (110 mg, 79%) as a mixture of two Boc groups, one Boc group, and one Boc group.

[0715] Synthesis of compound 43

[0716] To a solution of 43-a (70 mg, 0.085 mmol) in dichloromethane (9 mL) was added trifluoroacetic acid (3 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was dried by rotary evaporation, dissolved in methanol, and neutralized to pH 8 with saturated sodium bicarbonate solution. The solution was dried by rotary evaporation and purified by column chromatography (mobile phase: ammonia methanol: dichloromethane = 0-10%) to obtain compound 43 (30 mg, 57%). LC-MS (ESI): m / z 620.5 (M+H)

[0717] Example 42 Synthesis route of compound 44

[0718]

[0719] Synthesis of compound 44

[0720] To a solution of 43 (25 mg, 0.040 mmol) in ethanol (20 mL) was added 10% palladium on carbon (22 mg, 0.020 mmol) at room temperature, and the atmosphere was replaced with hydrogen three times. The mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered, the filtrate was dried, purified by preparative HPLC (ammonium bicarbonate), and lyophilized to afford 44 (9 mg, 36%). LC-MS (ESI): m / z 622.8 (M+H) + ; 1H NMR(400M,CD3OD)δ9.29(1H,s),7.18-7.11(1H,m),7.05-6.97(1H,m),5.41-5.21(1H,m),4.32 -4.05(4H,m),3.39-2.97(6H,m),2.56-2.09(5H,m),2.06-1.66(9H,m),1.07(3H,t,J=7.6Hz).

[0721] Example 43 Synthesis route of compound 45

[0722]

[0723] Synthesis of compound 45-a

[0724] To a reaction flask were added 42-a (100 mg, 0.12 mmol), potassium hydroxide (339 mg, 6.04 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (10 mg, 0.012 mmol), 1,4-dioxane (20 mL), and water (10 mL). The atmosphere was replaced with nitrogen three times, heated to 100°C, and reacted for 2 days. The reaction solution was dried and the crude product was purified by column chromatography (mobile phase: dichloromethane:methanol = 10:1 / dichloromethane, 0-100%) to afford 45-a (17 mg, 17%). LC-MS (ESI): m / z 810.4 (M+H). + .

[0725] Synthesis of compound 45

[0726] To a solution of 45-a (17 mg, 0.021 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was spin-dried, purified by preparative HPLC (ammonium bicarbonate), and lyophilized to afford 45 (2 mg, 17%). LC-MS (ESI): m / z 610.3 (M+H) + .

[0727] Example 44 Synthesis route of compound 46

[0728]

[0729] Synthesis of compound 46-a

[0730] To the reaction flask, 29-c (160 mg, 0.29 mmol) and formic acid (10 mL) were added and stirred at room temperature overnight. The reaction solution was dried by rotary evaporation, dichloromethane was added, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (40 mL x 2). The organic phase was dried by rotary evaporation and purified by column chromatography (mobile phase: methanol:dichloromethane = 0-10%) to obtain compound 46-a (97 mg, 74%). LC-MS (ESI): m / z 451.2 (M+H) + .

[0731] Synthesis of compound 46

[0732] To a microwave tube were added 46-a (45 mg, 0.10 mmol), 27-b (47 mg, 0.15 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (7 mg, 0.01 mmol), potassium phosphate (106 mg, 0.50 mmol), tetrahydrofuran (15 mL), and water (1.5 mL). The atmosphere was replaced with nitrogen three times, sealed, heated to 65°C, and reacted overnight. Water was added to the reaction solution, extracted with ethyl acetate (50 mL*2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried. Purification by preparative HPLC twice (first with trifluoroacetic acid, then with ammonium bicarbonate) was performed, and lyophilization was performed to obtain 46 (5 mg, 8%). LC-MS (ESI): m / z 605.3 (M+H) + .

[0733] Example 45 Synthesis route of compound 47

[0734]

[0735] Synthesis of compound 47-d

[0736] To the reaction flask, add [1-(aminomethyl)cyclopropyl]methanol (1 g, 9.89 mmol), acetonitrile (30 mL), 1,5-dibromopentane (2.39 g, 10.38 mmol), and potassium carbonate (3.56 g, 25.70 mmol) and stir at room temperature overnight. The mixture was spin-dried and purified by column chromatography (mobile phase: ammonia methanol: dichloromethane = 0-10%) to obtain compound 47-d (1 g, 60%). LC-MS (ESI): m / z 170.2 (M+H). + .

[0737] Synthesis of compound 47

[0738] Referring to the synthetic route of compound 29, compound 47 (11 mg, 13%) was synthesized using 3-c as the starting material and 47-d as the replacement for (1-(morpholinomethyl)cyclopropyl)methanol. LC-MS (ESI): m / z 599.3 (M+H)+ .

[0739] Example 46 Synthesis route of compound 48

[0740]

[0741] Synthesis of compound 48-c

[0742] To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-(trifluoromethyl)quinazoline (1 g, 2.75 mmol) and N,N-diisopropylethylamine (1065 mg, 8.24 mmol) in tetrahydrofuran (50 mL) was added tert-butyl 1,2-diazepine-1-carboxylate (550 mg, 2.75 mmol) under an ice-water bath. The mixture was allowed to warm to room temperature and stirred overnight. The next day, water was added and the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. Purification by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0-10%) afforded compound 48-c (1270 mg, 88%). LC-MS (ESI): m / z 527.1 (M+H). + .

[0743] Synthesis of compound 48-b

[0744] To a mixed solution of 48-c (1200 mg, 2.27 mmol) in tetrahydrofuran (25 mL) and N,N-dimethylformamide (25 mL) were added ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (1086 mg, 6.82 mmol), cesium carbonate (2223 mg, 6.82 mmol), and DABCO (1020 mg, 9.10 mmol) at room temperature. The mixture was allowed to react overnight at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography (mobile phase: methanol:dichloromethane = 0-10%) to yield 48-b (649 mg, 44%). LC-MS (ESI): m / z 650.3 (M+H). + .

[0745] Synthesis of compound 48-a

[0746] To a microwave tube were added 48-b (60 mg, 0.092 mmol), tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (75 mg, 0.18 mmol), bis(diphenylphosphinophenyl ether)palladium(II) dichloride (7 mg, 0.0092 mmol), cesium carbonate (150 mg, 0.46 mmol), and toluene (10 mL). The atmosphere was replaced with nitrogen three times, sealed, and heated to 100°C for 1.5 hours. The reaction solution was dried and the crude product was purified by column chromatography (mobile phase: methanol:dichloromethane = 0-10%) to give compound 48-a (60 mg, 75%). LC-MS (ESI): m / z 862.6 (M+H) + .

[0747] Synthesis of compound 48

[0748] To a solution of 48-a (60 mg, 0.070 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction solution was spin-dried, purified by preparative HPLC (ammonium bicarbonate), and lyophilized to afford compound 48 (14 mg, 30%). LC-MS (ESI): m / z 662.2 (M+H) + ; 1 H NMR(400M,CD3OD)δ9.93(1H,s),7.22-7.15(1H,m),7.03-6.95(1H,m),5.41-5.19(1H,m),4.60(1H,bs ),4.27(1H,d,J=10.4Hz),4.23-4.06(3H,m),3.27-2.95(5H,m),2.41-2.08(3H,m),2.06-1.67(9H,m).

[0749] Example 47 Synthesis route of compound 49

[0750]

[0751] Synthesis of compound 49-d

[0752] 7-Bromo-2,4-dichloro-6,8-difluoroquinazoline (400 mg, 1.27 mmol), tetrahydrofuran (100 mL), DIPEA (444 mg, 3.44 mmol), and tert-butyl 1,2-diazepine-1-carboxylate (383 mg, 1.91 mmol) were added to the reaction flask and stirred at this temperature for 12 hours. The reaction solution was concentrated at room temperature, and saturated sodium bicarbonate solution (100 mL) was added to the residue and extracted with dichloromethane (100 mL*3). The organic phase was concentrated and purified by column chromatography (PE / EA=10 / 1) to give compound 49-d (396 mg, 65%). LC-MS (ESI): m / z=477.6 (M+H) + .

[0753] Synthesis of compound 49-c

[0754] To the reaction flask were added 49-d (400 mg, 0.84 mmol), tetrahydrofuran (15 mL), DABCO (376 mg, 3.35 mmol), DMF (15 mL), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl)methanol (400 mg, 2.51 mmol), and cesium carbonate (818 mg, 2.51 mmol), respectively, and stirred under nitrogen overnight. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL*3). The organic phase was concentrated and purified by column chromatography (MeOH / DCM=1 / 10) to give compound 49-c (380 mg, 76%). LC-MS (ESI): m / z=600.1 (M+H) + .

[0755] Synthesis of compound 49-b

[0756] To the reaction flask were added 49-c (100 mg, 0.17 mmol), 1,4-dioxane (3 mL), water (0.5 mL), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (208 mg, 0.33 mmol), sodium carbonate (53 mg, 0.50 mmol), and tetrakistriphenylphosphine palladium (38 mg, 0.03 mmol). The atmosphere was purged with nitrogen three times and the mixture was stirred in an oil bath preheated to 100°C for 12 hours. The reaction solution was dried and purified by column chromatography (mobile phase: methanol / dichloromethane = 1 / 30; 1 / 10) to give compound 49-b (79 mg, 55%). LC-MS (ESI): m / z = 862.5 (M+H) + .

[0757] Synthesis of compound 49-a

[0758] To the reaction flask were added 49-b (79 mg, 0.09 mmol), DMF (6 mL), and cesium fluoride (230 mg, 1.51 mmol), and the mixture was stirred at room temperature for 6 hours. Water (50 mL) was added to the reaction solution, filtered, and the filter cake was dried to obtain compound 49-a (59 mg, 91%). LC-MS (ESI): m / z = 706.3 (M+H) + .

[0759] Synthesis of compound 49

[0760] To the reaction flask, 49-a (59 mg, 0.08 mmol) and formic acid (5 mL) were added and stirred at room temperature for 12 hours. The reaction solution was concentrated at room temperature, and saturated sodium bicarbonate (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phase was concentrated and purified by preparative HPLC to give compound 49 (20.6 mg, 41%). LC-MS (ESI): m / z 606.3 (M+H) + ; 1 H NMR (400MHz, DMSO-d6): δ10.21(1H,s),9.08(1H,d,J=12.4Hz),7.98(1H,t,J =6.4Hz),7.48(1H,t,J=9.2Hz),7.40(1H,s),7.15(1H,s),5.68(1H,t,J=6.0H z),5.29(1H,d,J=54.8Hz),4.16-3.90(4H,m),3.94(1H,s),3.18–2.95(5H,m) ,2.93–2.78(1H,m),2.25–2.00(4H,m),1.98–1.74(5H,m),1.73–1.60(3H,m).

[0761] Example 48 Synthesis route of compound 50

[0762]

[0763] Synthesis of compound 50-c

[0764] To a reaction flask were added 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1000 mg, 2.27 mmol), 1,4-dioxane (12 mL), water (3 mL), ((Z)-1-propenyl)-boronic acid pinacol ester (500 mg, 2.98 mmol), potassium phosphate (1700 mg, 8.01 mmol), and PdCl2(dppf)CH2Cl2 (170 mg, 0.21 mmol). The atmosphere was purged with nitrogen three times and the mixture was stirred in an oil bath preheated to 100°C for 3 hours. The reaction mixture was dried and purified by column chromatography (mobile phase: PE / EA = 100 / 0; 100 / 5) to afford compound 50-c (380 mg, 47%).

[0765] Synthesis of compound 50-b

[0766] 50-c (360 mg, 1.01 mmol) and tetrahydrofuran (10 mL) were added to the reaction flask and stirred at -78°C for 10 minutes. n-Butyl lithium solution (2.5 M, 0.6 mL, 1.50 mmol) was slowly added dropwise to the reaction solution. After the addition was complete, the mixture was stirred at the same temperature for 30 minutes. Isopropyl pinacol borate (283 mg, 1.52 mmol) was slowly added to the reaction solution and stirred at -78°C for 60 minutes. Saturated ammonium chloride (30 mL) was added to the reaction solution and extracted with ethyl acetate (20 mL*3). The organic phase was concentrated and purified by column chromatography (PE / EA=100 / 0; 100 / 3) to give compound 50-b (210 mg, 52%). LC-MS (ESI): m / z 403.1 (M+H) + .

[0767] Synthesis of compound 50-a

[0768] To the reaction flask were added 49-c (149 mg, 0.25 mmol), 1,4-dioxane (10 mL), water (2 mL), 50-b (100 mg, 0.25 mmol), cesium fluoride (113 mg, 0.75 mmol), and PdCl2(dtbpf) (30 mg, 0.05 mmol). The atmosphere was replaced with nitrogen three times and the mixture was stirred in an oil bath preheated to 100°C for 2 hours. The reaction solution was dried and purified by column chromatography (mobile phase: MeOH / DCM = 1 / 100; 1 / 10) to give compound 50-a (180 mg, 91%). LC-MS (ESI): m / z = 796.4 (M+H) + .

[0769] Synthesis of compound 50

[0770] To the reaction flask, 50-a (80 mg, 0.10 mmol), dichloromethane (3 mL), and trifluoroacetic acid (1 mL) were added and stirred at room temperature for 3 hours. The reaction solution was spin-dried, saturated sodium bicarbonate (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phase was concentrated and purified by column chromatography (mobile phase: DCM / MeOH = 30 / 1; 10 / 1) to obtain compound 50 (27.8 mg, 45%). LC-MS (ESI): m / z = 612.5 (M+H) + .

[0771] Example 49 Synthesis route of compound 51

[0772]

[0773] Synthesis of compound 51-g

[0774] To the reaction flask were added tert-butyl 4-(benzyloxy)-2-(methylsulfonyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (840 mg, 2.00 mmol), toluene (30 mL), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (383 mg, 2.40 mmol), and sodium tert-butoxide (289 mg, 3.00 mmol). The mixture was stirred at 0°C under nitrogen for 1 hour and then at room temperature for 1 hour. The reaction solution was added to a silica gel column and purified by column chromatography (mobile phase: methanol / dichloromethane 1 / 30 to 1 / 10) to obtain compound 51-g (561 mg, 56%). LC-MS (ESI): m / z 499.8 (M+H). + .

[0775] Synthesis of compound 51-f

[0776] 51-g (560 mg, 1.12 mmol), toluene (6 mL), and trifluoroacetic acid (0.86 mL, 11.23 mmol) were added to the reaction flask under nitrogen protection. The mixture was stirred at room temperature for 2 hours. Sodium hydroxide (2 M, 10 mL) was added to the reaction solution to react, the pH was adjusted to 9.5-10, and the mixture was extracted with EA (10 mL*3). The organic phase was concentrated and purified on a reverse phase column under alkaline conditions to give compound 51-f (371 mg, 83%). LC-MS (ESI): m / z 399.7 (M+H) + .

[0777] Synthesis of compound 51-e

[0778] To the reaction flask were added 51-f (500 mg, 1.25 mmol), ethanol (30 mL), Pd / C 10% (100 mg, 10% content), and hydrogen (1000 mL), and stirred at room temperature for 3 hours. The reaction solution was filtered, washed with ethanol (10 mL), and the filtrate was concentrated to give compound 51-e (260 mg, 67%). LC-MS (ESI): m / z 309.3 (M+H) + .

[0779] Synthesis of compound 51-d

[0780] 51-e (180 mg, 0.58 mmol), toluene (15 mL), ((8-bromo-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane (331 mg, 0.72 mmol), sodium tert-butoxide (280 mg, 2.92 mmol), and BINAP (73 mg, 0.12 mmol) were added to the reaction flask and stirred at room temperature under nitrogen for 2 minutes. Pd2(dba)3 (53 mg, 0.06 mmol) was added to the reaction solution, and the mixture was stirred at 110°C under nitrogen for 3 hours. The reaction solution was added to a silica gel column and directly purified by column chromatography (mobile phase: methanol / dichloromethane = 1 / 30, 1 / 10) to give compound 51-d (232 mg, 57%). LC-MS (ESI): m / z 693.6 (M+H) + .

[0781] Synthesis of compound 51-c

[0782] To the reaction flask, 51-d (90 mg, 0.13 mmol), DMF (15 mL), and cesium fluoride (395 mg, 2.60 mmol) were added and stirred at room temperature for 3 hours. The reaction solution was filtered and washed with DMF (15 mL). The resulting DMF solution of 51-c was directly used in the next reaction. LC-MS (ESI): m / z 537.5 (M+H) + .

[0783] Synthesis of compound 51-b

[0784] The filtrate of 51-c, 10% Pd / C (12 mg, 10% content), and hydrogen (1000 mL) were added to the reaction flask and stirred at room temperature for 3 hours. The reaction solution was filtered, quenched with water (50 mL), and extracted with ethyl acetate (30 mL*3). The organic phase was concentrated and purified by column chromatography (MeOH / DCM = 1 / 100; 1 / 10) to obtain compound 51-b (57 mg, total yield for two steps 81%). LC-MS (ESI): m / z 541.5 (M+H) + .

[0785] Synthesis of compound 51-a

[0786] To a reaction flask, 51-b (59 mg, 0.11 mmol), DMSO (5 mL), DIPEA (70 mg, 0.55 mmol), and N-bis(trifluoromethanesulfonyl)aniline (117 mg, 0.33 mmol) were added and stirred at room temperature for 2 hours. 1,2-Diazepine dihydrochloride (50 mg, 0.29 mmol) and DIPEA (70 mg, 0.55 mmol) were then added to DMSO (5 mL) and stirred for 30 minutes. This reaction mixture was then added to the previous mixture. Under nitrogen, the mixture was stirred at 50°C for 5 hours. The reaction mixture was concentrated and water (30 mL) was added. The mixture was filtered, and the filter cake was purified by column chromatography (MeOH / DCM = 1 / 100; 1 / 10) to afford compound 51-a (50 mg, 74%). LC-MS (ESI): m / z 623.4 (M+H).

[0788] Synthesis of compound 51

[0789] 51-a (45 mg, 0.07 mmol) and dichloromethane (5 mL) were added to the reaction flask and stirred in an ice-water bath for 10 minutes. 2,2-bipyridine (200 mg, 0.82 mmol) and TMSOTf (200 mg, 0.90 mmol) were added to the reaction solution. Formic acid (5 mL) was slowly added dropwise to the mixture, and the reaction solution was warmed to room temperature under nitrogen protection and stirred for 12 hours. The reaction solution was concentrated at room temperature, saturated sodium bicarbonate solution (30 mL) was added, and extracted with dichloromethane (30 mL*2). The organic phase was concentrated and purified by column chromatography (MeOH / DCM=1 / 10) to give compound 51 (7.1 mg, 17%), LC-MS (ESI): m / z 579.5 (M+H) + .

[0790] Example 50 Synthesis route of compound 52

[0791]

[0792] Synthesis of compound 52

[0793] Referring to the synthetic route of compound 29, compound 52 was synthesized using 3-c as the starting material and (1-((4-methylpiperazin-1-yl)methyl)cyclopropyl)methanol instead of (1-(morpholinomethyl)cyclopropyl)methanol. LC-MS (ESI): m / z 614.3 (M+H) + .

[0794] Example 51 Synthesis route of compound 53

[0795]

[0796] Synthesis of compound 53

[0797] Referring to the synthetic route of compound 29, compound 53 was synthesized using 3-c as the starting material and (1-(pyrrolidin-1-ylmethyl)cyclopropyl)methanol instead of (1-(morpholinomethyl)cyclopropyl)methanol. LC-MS (ESI): m / z 585.3 (M+H) + .

[0798] Example 52 Synthesis route of compound 54

[0799]

[0800] Synthesis of compound 54-b

[0801] To a microwave tube were added 48-b (160 mg, 0.25 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (461 mg, 0.74 mmol), Pd(DPEphos)Cl2 (35 mg, 0.049 mmol), cesium carbonate (401 mg, 1.23 mmol), and toluene (15 mL). The tube was sealed and replaced with nitrogen three times. The microwave was heated to 150°C for 6 hours. The reaction solution was dried and purified by column chromatography (mobile phase: methanol:dichloromethane = 0-5%) to give 54-b (60 mg, 23%). LC-MS (ESI): m / z 1068.5 (M+H) + .

[0802] Synthesis of compound 54-a

[0803] To a solution of 54-b (60 mg, 0.056 mmol) in N,N-dimethylformamide (10 mL) was added cesium fluoride (85 mg, 0.56 mmol) at room temperature, and the mixture was allowed to react overnight at room temperature. A large amount of water was poured into the reaction solution, and the mixture was extracted with ethyl acetate (50 mL*2). The organic phase was washed with saturated brine (30 mL*3), dried by spin drying, and purified by column chromatography (mobile phase: dichloromethane:methanol:dichloromethane = 0-7%) to obtain compound 54-a (15 mg, 35%). LC-MS (ESI): m / z 756.7 (M+H) + .

[0804] Synthesis of compound 54

[0805] A mixture of 54-a (15 mg, 0.020 mmol) and formic acid (6 mL) was stirred at room temperature overnight. The reaction solution was dried by rotary evaporation at room temperature, purified by preparative HPLC (ammonium bicarbonate), and lyophilized to afford 54 (3 mg, 23%). LC-MS (ESI): m / z 656.2 (M+H) + .

[0806] Synthesis route of compound 55

[0807]

[0808] Synthesis of compound 55-b

[0809] To a sealed tube were added 2-c (230 mg, 0.39 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (366 mg, 0.59 mmol), cataCXium APd G3 (28 mg, 0.04 mmol), potassium phosphate (249 mg, 1.17 mmol), THF (2 mL), and water (0.5 mL) at room temperature. The mixture was purged with N2 and heated to 65°C overnight. The reaction mixture was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 55-b (280 mg, 68%).

[0810] Synthesis of compound 55-a

[0811] To the reaction flask at room temperature were added 55-b (280 mg, 0.27 mmol), EA (30 mL), and palladium on carbon (10%, 200 mg). The mixture was replaced with hydrogen and allowed to react at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to afford compound 55-a (190 mg, 78%). LC-MS (ESI): m / z 917.9 (M+H) + .

[0812] Synthesis of compound 55

[0813] 55-a (190 mg, 0.21 mmol), DMF (3 mL), and cesium fluoride (315 mg, 2.07 mmol) were added to the reaction flask at room temperature. The mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC to obtain compound 55 (55 mg, 44%). LC-MS (ESI): m / z 605.8 (M+H) + .

[0814] Synthesis of compounds 55-1 and 55-2

[0815]

[0816] Compound 55 (55 mg) was purified by chiral resolution to give compounds 55-1 (15 mg, 27%) and 55-2 (19 mg, 35%).

[0817]

[0818] Synthesis route of compound 56

[0819]

[0820] Synthesis of compound 56-g

[0821] Diethyl 2,2-difluoroglutarate (1000 mg, 4.46 mmol) and THF (10 mL) were added to the reaction flask at room temperature. The mixture was replaced with N2 for protection, cooled to 0°C, and a solution of lithium aluminum hydride in tetrahydrofuran (1 M, 11 mL, 11.00 mmol) was added dropwise. After the addition was complete, the reaction solution was naturally warmed to room temperature and reacted overnight. Methanol (100 mL) was added to the reaction solution to quench the reaction, sodium sulfate decahydrate (5 g) was added, and the mixture was stirred for 1 hour. The reaction solution was filtered through celite and the filtrate was concentrated. Ethyl acetate was added to precipitate a solid, which was filtered and the filtrate was concentrated to obtain compound 56-g (550 mg, 88%).

[0822] Synthesis of compound 56-f

[0823] 56-g (550 mg, 3.93 mmol), DCM (30 mL), triethylamine (1589 mg, 15.70 mmol), and p-toluenesulfonyl chloride (2245 mg, 11.78 mmol) were added to the reaction flask at room temperature. The mixture was replaced with N2 for protection and reacted at room temperature overnight. Water was added to the reaction solution and extracted with DCM. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 6 / 4) to obtain compound 56-f (960 mg, 55%). LC-MS (ESI): m / z 466.7 (M+NH4) + .

[0824] Synthesis of compound 56-e

[0825] To a reaction flask at room temperature were added 56-f (500 mg, 1.12 mmol), acetonitrile (30 mL), 2-(tert-butyl)hydrazine-1,2-dicarboxylic acid-1-benzyl ester (297 mg, 1.12 mmol), and cesium carbonate (1816 mg, 5.57 mmol). The mixture was replaced with nitrogen and heated to 65°C for 36 hours. The reaction mixture was filtered, the filtrate was concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 7 / 3) to obtain compound 56-e (230 mg, 56%). LC-MS (ESI): m / z 388.4 (M+NH4) + .

[0826] Synthesis of compound 56-d

[0827] To the reaction flask at room temperature were added 56-e (230 mg, 0.62 mmol), EA (25 mL), and palladium on carbon (10%, 100 mg). The mixture was replaced with hydrogen and allowed to react at room temperature for 4 hours. The reaction mixture was filtered, the filtrate was concentrated, and acetonitrile (10 mL) and a solution of hydrogen chloride in 1,4-dioxane (1 M, 2 mL, 2.00 mmol) were added. The mixture was replaced with nitrogen and allowed to react at room temperature for 2 hours. The reaction mixture was concentrated to give the crude product 56-d (150 mg). LC-MS (ESI): m / z 137.2 (M+H) + .

[0828] Synthesis of compound 56-c

[0829] 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (313 mg, 1.24 mmol), DCM (15 mL), and crude compound 56-d (150 mg, 0.62 mmol) were added to the reaction flask at room temperature. The mixture was replaced with N2 for protection, cooled to 0°C, and DIPEA (481 mg, 3.72 mmol) was added. The mixture was naturally warmed to room temperature and reacted overnight. Water was added to the reaction solution and extracted with DCM. The organic phases were combined, dried, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 6 / 4) to obtain compound 56-c (110 mg, 50%). LC-MS (ESI): m / z 352.1 (M+H) + .

[0830] Synthesis of compound 56-b

[0831] To the reaction flask were added 56-c (110 mg, 0.31 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (99 mg, 0.62 mmol), 1,4-dioxane (5 mL), and DIPEA (162 mg, 1.25 mmol) at room temperature. The mixture was replaced with N2 and heated to 90°C overnight. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 56-b (80 mg, 54%). LC-MS (ESI): m / z 475.9 (M+H) + .

[0832] Synthesis of compound 56-a

[0833] To a sealed tube were added 56-b (80 mg, 0.17 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (158 mg, 0.25 mmol), cataCXium APd G3 (25 mg, 0.03 mmol), potassium phosphate (107 mg, 0.50 mmol), THF (2 mL), and water (0.5 mL) at room temperature. The mixture was purged with N2 and heated to 65°C overnight. The reaction mixture was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 56-a (150 mg, 95%).

[0834] Synthesis of compound 56

[0835] 56-a (150 mg, 0.16 mmol), DMF (3 mL), cesium fluoride (243 mg,

[0836] The mixture was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was purified by reverse phase column (mobile phase: water (0.01M NH4HCO3) / acetonitrile 10 / 0 to 1 / 9) to obtain compound 56 (69 mg, 69%). LC-MS (ESI): m / z 625.4 (M+H) + .

[0837] Comparative synthetic route of compound 2′

[0838]

[0839] Synthesis of compound 2′-c

[0840] To a reaction flask at room temperature, add 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (330 mg, 1.31 mmol) and DCM (20 mL). The atmosphere was replaced with nitrogen and the temperature was cooled to -78°C in a dry ice-acetone bath. DIPEA (338 mg, 2.62 mmol) and piperidine (134 mg, 1.57 mmol) were added. After addition, the mixture was allowed to warm to room temperature and react overnight. Water was added to the reaction solution, and the mixture was extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 6 / 4) to yield compound 2′-c (320 mg, 81%).

[0841] Synthesis of compound 2′-b

[0842] To the reaction flask at room temperature were added 2′-c (320 mg, 1.06 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (338 mg, 2.12 mmol), 1,4-dioxane (10 mL), and DIPEA (549 mg, 4.25 mmol). The atmosphere was replaced with nitrogen and the reaction was heated to 90°C overnight. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 2′-b (350 mg, 78%). LC-MS (ESI): m / z 424.4 (M+H) + .

[0843] Synthesis of compound 2′-a

[0844] To a sealed tube were added 2′-b (50 mg, 0.12 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (111 mg, 0.18 mmol), cataCXium A Pd G3 (9 mg, 0.01 mmol), potassium phosphate (75 mg, 0.35 mmol), THF (2 mL), and water (0.5 mL) at room temperature. The mixture was purged with N2 and heated to 65°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 2′-a (67 mg, 64%).

[0845] Synthesis of compound 2′

[0846] 2′-a (67 mg, 0.08 mmol), DMF (2 mL), and cesium fluoride (115 mg, 0.76 mmol) were added to the reaction flask at room temperature. The atmosphere was replaced with nitrogen and the reaction was carried out at 60°C for 1 hour. The reaction solution was filtered and the filtrate was purified by preparative HPLC to obtain compound 2′ (29 mg, 67%). LC-MS (ESI): m / z 574.8 (M+H) + .

[0847] Synthesis route of compound 57

[0848]

[0849] Synthesis of compound 57-f

[0850] Compound 3-[[tert-Butyl(dimethyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (1.5 g, 0.0053 mol) was dissolved in 1,2-dichloroethane (10 mL). Triethylamine (0.8 g, 0.0079 mol), 4-dimethylaminopyridine (60 mg, 0.49 mmol), and triphenylmethane (1.6 g, 0.0058 mol) were added. The reaction solution was purged with nitrogen and stirred at 65°C for 2 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, PE / EA 3 / 1) to obtain compound 57-f (2.6 g, 94%). LC-MS (ESI): m / z 528.2 (M+H) + .

[0851] Synthesis of compound 57-e

[0852] Compound 57-f (2.6 g, 4.93 mmol) was dissolved in tetrahydrofuran (10 mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (1 M, 19.7 mL, 19.7 mmol) was added. The mixture was stirred at 50°C for 2 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 mL). The organic phase was washed four times with water (100 mL), washed with saturated brine (50 mL), and dried over sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (mobile phase, DCM / MeOH 10 / 1) to obtain compound 57-e (1.06 g, 52%). LC-MS (ESI): m / z 414.5 (M+H) + .

[0853] Synthesis of compound 57-d

[0854] Compound 57-e (1.06 g, 2.56 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium tert-butoxide (430 mg, 3.83 mmol) was added under ice-cooling and stirred for 30 minutes. 3-Chloro-5-(trifluoromethyl)pyrazine (560 mg, 3.07 mmol) was then added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Saturated ammonium chloride solution (1 mL) and water (50 mL) were added, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was dissolved in ethyl acetate (4 mL) and 1,4-dioxane hydrochloride (4 M, 1 mL) was added. The reaction solution was stirred at room temperature for 1 hour, concentrated under reduced pressure, neutralized with 7 M ammonia methanol solution, and concentrated to obtain a crude product. The crude product was purified by column chromatography (mobile phase, DCM / MeOH 10 / 1) to obtain compound 57-d (520 mg, 64%). LC-MS (ESI): m / z 318.1 (M+H) + .

[0855] Synthesis of compound 57-c

[0856] Compound 3-c (614 mg, 1.47 mmol) and 57-d (520 mg, 1.64 mmol) were dissolved in dichloromethane (10 mL). Sodium tert-butoxide (236 mg, 2.46 mmol) was added thereto under ice bath, and the reaction was stirred under ice bath for 2 hours. Saturated ammonium chloride solution was added to the reaction solution for neutralization, water (100 mL) was added, and the mixture was extracted with dichloromethane (100 mL). The organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain compound 57-c (565 mg, 55%). LC-MS (ESI): m / z 697.4 (M+H) + .

[0857] Synthesis of compound 57-b

[0858] Compound 57-c (150 mg, 0.22 mmol) and 7-fluoro-8-[(triisopropylsilyl)ethynyl]naphthalene-1-boronic acid pinacol ester (102 mg, 0.23 mmol) were dissolved in tetrahydrofuran (4 mL) and water (1 mL) in a microwave tube. [n-Butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (16 mg, 0.021 mmol) and anhydrous potassium phosphate (183 mg, 0.86 mmol) were added. The reaction solution was purged with nitrogen for 1 minute and stirred at 65°C for 12 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain compound 57-b (200 mg, 94%). LC-MS (ESI): m / z 988.0 (M+H) + .

[0859] Synthesis of compound 57-a

[0860] Compound 57-b (200 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (5 mL), cesium fluoride (308 mg, 2.03 mmol) was added thereto, and the reaction solution was stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain compound 57-a (125 mg, 74%). LC-MS (ESI): m / z 831.6 (M+H) + .

[0861] Synthesis of compound 57

[0862] Compound 57-a (120 mg, 0.14 mmol) was dissolved in acetonitrile (3 mL), and a 1,4-dioxane hydrochloride solution (4 M, 0.3 mL) was added thereto. The reaction solution was stirred at room temperature for 12 hours. Saturated sodium bicarbonate solution was added to the reaction solution for neutralization, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (alkaline conditions) to obtain compound 57 (32 mg, 30%). LC-MS (ESI): m / z 731.0 (M+H) + .

[0863] Synthesis route of compound 58

[0864]

[0865] Synthesis of compound 58-b

[0866] Compound 57-c (177 mg, 0.25 mmol) and 7-fluoro-8-[(triisopropylsilyl)ethynyl]-3-[(triisopropylsilyl)oxy]-1-naphthyl]boronic acid pinacol ester (175 mg, 0.28 mmol) were dissolved in tetrahydrofuran (4 mL) and water (1 mL) in a microwave tube. [n-Butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (37 mg, 0.051 mmol) and anhydrous potassium phosphate (216 mg, 1.02 mmol) were added. The reaction solution was purged with nitrogen for 1 minute and stirred at 65°C for 12 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to give compound 58-b (260 mg, 88%).

[0867] Synthesis of compound 58-a

[0868] Compound 58-b (260 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (5 mL), cesium fluoride (341 mg, 2.24 mmol) was added thereto, and the reaction solution was stirred at room temperature for 4 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain compound 58-a (150 mg, 79%). LC-MS (ESI): m / z 847.2 (M+H) + .

[0869] Synthesis of compound 58

[0870] Compound 58-a (150 mg, 0.18 mmol) was dissolved in acetonitrile (3 mL), and a 1,4-dioxane hydrochloride solution (4 M, 0.3 mL) was added thereto. The reaction solution was stirred at room temperature for 12 hours. Saturated sodium bicarbonate solution was added to the reaction solution for neutralization, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (alkaline conditions) to obtain compound 58 (50 mg, 38%). LC-MS (ESI): m / z 747.6 (M+H) + ; 1 HNMR (400MHz, DMSO-d6): δ10.23(1H,s),10.13(1H,s),9.30(1H,s),8.00-7.94(1 H,m),7.74(1H,s),7.49-7.42(1H,m),7.38(1H,s),7.19-7.16(1H,m),5.88-5.83 (1H,m),4.48-4.35(2H,m),4.16-4.90(4H,m),3.94-3.90(1H,m),3.21-3.12(1H, m),3.08-2.95(3H,m),2.81-2.73(1H,m),2.15-2.02(2H,m),1.95-1.60(12H,m).

[0871] Synthesis route of compound 59

[0872]

[0873] Synthesis of compound 59-d

[0874] Compound 57-e (310 mg, 0.75 mmol) was dissolved in tetrahydrofuran (10 mL), potassium tert-butoxide (126 mg, 1.12 mmol) was added thereto under ice bath and stirred for 30 minutes, then 4-chloro-6-trifluoromethylpyrimidine (164 mg, 0.90 mmol) was added thereto under ice bath, and the reaction was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction solution and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in ethyl acetate (2 mL), 1,4-dioxane hydrochloride (4 M, 0.5 mL) was added thereto, and the reaction solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, neutralized with 7M methanolic ammonia solution, and concentrated to obtain a crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 10 / 1) to give compound 59-d (228 mg, 96%). LC-MS (ESI): m / z 318.3 (M+H) + .

[0875] Synthesis of compound 59-c

[0876] Compound 3-c (299 mg, 0.72 mmol) and 59-d (228 mg, 0.72 mmol) were dissolved in dichloromethane (10 mL). Sodium tert-butoxide (173 mg, 1.80 mmol) was added thereto under ice bath, and the reaction was stirred under ice bath for 3 hours. Saturated ammonium chloride solution was added to the reaction solution for neutralization, water (100 mL) was added, and the mixture was extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain compound 59-c (142 mg, 28%). LC-MS (ESI): m / z 697.4 (M+H) + .

[0877] Synthesis of compound 59-b

[0878] Compound 59-c (140 mg, 0.20 mmol) and 7-fluoro-8-[(triisopropylsilyl)ethynyl]naphthalene-1-boronic acid pinacol ester (136 mg, 0.30 mmol) were dissolved in tetrahydrofuran (4 mL) and water (1 mL) in a microwave tube. [n-Butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (29 mg, 0.040 mmol) and anhydrous potassium phosphate (171 mg, 0.81 mmol) were added. The reaction solution was purged with nitrogen for 1 minute and stirred at 65°C for 12 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain compound 59-b (110 mg, 56%). LC-MS (ESI): m / z 988.1 (M+H) + .

[0879] Synthesis of compound 59-a

[0880] Compound 59-b (140 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (5 mL), cesium fluoride (215 mg, 1.42 mmol) was added thereto, and the reaction solution was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain compound 59-a (100 mg, 85%). LC-MS (ESI): m / z 831.8 (M+H) + .

[0881] Synthesis of compound 59

[0882] Compound 59-a (100 mg, 0.12 mmol) was dissolved in acetonitrile (2 mL), and a 1,4-dioxane hydrochloride solution (4 M, 0.2 mL) was added thereto. The reaction solution was stirred at room temperature for 12 hours. The reaction solution was neutralized with a saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (alkaline conditions) to obtain compound 59 (50 mg, 57%). LC-MS (ESI): m / z 731.0 (M+H) + .

[0883] Synthesis route of compound 60

[0884]

[0885] Synthesis of compound 60-b

[0886] Compound 59-c (190 mg, 0.27 mmol) and 7-fluoro-8-[(triisopropylsilyl)ethynyl]-3-[(triisopropylsilyl)oxy]-1-naphthyl]boronic acid pinacol ester (255 mg, 0.41 mmol) were dissolved in tetrahydrofuran (4 mL) and water (1 mL) in a microwave tube. [n-Butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (40 mg, 0.055 mmol) and anhydrous potassium phosphate (231 mg, 1.09 mmol) were added. The reaction solution was purged with nitrogen for 1 minute and stirred at 65°C for 12 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain compound 60-b (200 mg, 63%). LC-MS (ESI): m / z 1159.9 (M+H) + .

[0887] Synthesis of compound 60-a

[0888] Compound 60-b (200 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), cesium fluoride (362 mg, 1.72 mmol) was added thereto, and the reaction solution was stirred at room temperature for 4 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain compound 60-a (120 mg, 82%). LC-MS (ESI): m / z 847.7 (M+H) + .

[0889] Synthesis of compound 60

[0890] Compound 60-a (120 mg, 0.14 mmol) was dissolved in acetonitrile (4 mL), and a 1,4-dioxane hydrochloride solution (4 M, 0.4 mL) was added thereto. The reaction solution was stirred at room temperature for 12 hours. The reaction solution was neutralized with a saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (alkaline conditions) to obtain compound 60 (50 mg, 47%). LC-MS (ESI): m / z 747.3 (M+H) + .

[0891] Synthesis route of compound 61

[0892]

[0893] Synthesis of compound 61-d

[0894] Compound 40-c (200 mg, 0.31 mmol) was dissolved in acetonitrile (10 mL), and 1,4-dioxane hydrochloride (4 M, 1 mL) was added thereto under ice bath, and the reaction was stirred under ice bath for 2 hours. Saturated sodium bicarbonate solution was added thereto for neutralization, water (10 mL), and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, DCM / 7M ammonia methanol 10 / 1) to obtain compound 61-d (110 mg, 65%). LC-MS (ESI): m / z 540.3 (M+H) + .

[0895] Synthesis of compound 61-c

[0896] Compound 61-d (110 mg, 0.21 mmol) and acetic anhydride (31 mg, 0.30 mmol) were dissolved in dichloromethane (3 mL), 4-dimethylaminopyridine (37 mg, 0.30 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. Water (50 mL) was added thereto, and the mixture was extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain compound 61-c (110 mg, 93%). LC-MS (ESI): m / z 582.6 (M+H) + .

[0897] Synthesis of compound 61-b

[0898] Compound 61-c (110 mg, 0.19 mmol) and 7-fluoro-8-[(triisopropylsilyl)ethynyl]-3-[(triisopropylsilyl)oxy]-1-naphthyl]boronic acid pinacol ester (130 mg, 0.21 mmol) were dissolved in tetrahydrofuran (4 mL) and water (1 mL) in a microwave tube. Methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (28 mg, 0.038 mmol) and anhydrous potassium phosphate (160 mg, 0.75 mmol) were added. The reaction solution was purged with nitrogen for 1 minute and stirred at 65°C for 12 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL), washed with saturated brine (50 mL), and dried over sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain compound 61-b (130 mg, 77%). LC-MS (ESI): m / z 888.8 (M+H) + .

[0899] Synthesis of compound 61-a

[0900] Compound 61-b (130 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cesium fluoride (222 mg, 1.46 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain compound 61-a (90 mg, 84%). LC-MS (ESI): m / z 732.3 (M+H)+.

[0902] Synthesis of compound 61

[0903] Compound 61-a (90 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), and tert-butyldimethylsilyl trifluoromethanesulfonate (33 mg, 0.12 mmol) was added thereto. The reaction solution was stirred at room temperature for 5 hours. Saturated sodium bicarbonate solution (10 mL) was added to the reaction solution and continued to stir for 1 hour, then extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (alkaline conditions) to obtain compound 61 (12 mg, 16%). LC-MS (ESI): m / z 632.3 (M+H) + .

[0904] Synthesis route of compound 62

[0905]

[0906] Synthesis of compound 62-a

[0907] Compound 40-b-2 (140 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (4 mL), cesium fluoride (225 mg, 1.48 mmol) was added thereto, and the reaction solution was stirred at room temperature for 4 hours. Water (100 mL) was added to the reaction solution and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to give an intermediate product. After dissolving it in acetonitrile (3 mL), 1,4-dioxane hydrochloride (4 M, 0.3 mL) was added under ice bath, and the reaction solution was stirred under ice bath for 2 hours. The reaction solution was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), dried over sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give 62-a (80 mg, 78%). LC-MS (ESI): m / z 690.5 (M+H) + .

[0908] Synthesis of compound 62

[0909] Compound 62-a (80 mg, 0.12 mmol) was dissolved in dichloromethane (4 mL), diisopropylethylamine (30 mg, 0.23 mmol) was added, acryloyl chloride (13 mg, 0.14 mmol) was added thereto, and the reaction solution was stirred at room temperature for 1 hour. Water (50 mL) was added to the reaction solution and extracted with dichloromethane (50 mL). The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (mobile phase, DCM / MeOH 20 / 1) to obtain an intermediate product, which was then dissolved in formic acid (2 mL) and the reaction solution was stirred at room temperature for 36 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (alkaline conditions) to obtain compound 62 (17 mg, 23%). LC-MS (ESI): m / z 644.3 (M+H) + .

[0910] Synthesis route of compound 63

[0911]

[0912] Synthesis of compound 63-a

[0913] At room temperature, compound 12 (100 mg, 0.15 mmol) was dissolved in 20 mL of dichloromethane, TEA (40 uL, 0.29 mmol) was added, and palmitoyl chloride (120 mg, 0.44 mmol) was added under ice-water bath. The reaction solution was warmed to room temperature and stirred for 1 hour. 1 mL of methanol was added to the reaction solution and stirred for 20 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by flash column chromatography (DCM / MeOH = 20:1) to obtain crude compound 63-a (134 mg). LC-MS (ESI): m / z = 927.3 [M+H] + .

[0914] Synthesis of compound 63

[0915] At room temperature, compound 63-a (134 mg, 0.14 mmol) was dissolved in 5 mL of DCM. Tert-butyldimethylsilyl trifluoromethanesulfonate (270 μL, 1.18 mmol) was added under ice-water bath, and the reaction mixture was stirred under ice-water bath for 1 hour. A 10% sodium bisulfate solution (10 mL) was added to the reaction mixture at room temperature and stirred for 30 minutes. Saturated sodium bicarbonate solution was then added to adjust the pH to alkaline. The mixture was extracted with DCM (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by flash column chromatography (DCM / MeOH = 10:1) to afford compound 63 (50 mg, 43%). LC-MS (ESI): m / z = 827.4 [M+H] + .

[0916] Synthesis route of compound 64

[0917]

[0918] Synthesis of compound 64-c

[0919] At room temperature, compound 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (400 mg, 0.85 mmol) was dissolved in 20 mL of anhydrous acetonitrile, and SelectFluor II (1-fluoro-4-methyl-1,4-diazabicyclo[2.2.2]octane tetrafluoroborate) (410 mg, 1.28 mmol) was added. The reaction mixture was stirred at 80°C under nitrogen for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by flash column chromatography (PE / EA = 3:1) to obtain compound 64-c (145 mg, 35%). LC-MS (ESI): m / z = 487.3 [M+H] + .

[0920] Synthesis of compound 64-b

[0921] At room temperature, 3-b (80 mg, 0.15 mmol), 64-c (79 mg, 0.16 mmol), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2′-amino-1,1′-biphenyl-2-yl)palladium(II) (22 mg, 0.03 mmol), potassium phosphate (95 mg, 0.45 mmol), THF (2.5 mL), and water (0.5 mL) were added sequentially to a microwave tube. The reaction system was purged with nitrogen three times and then stirred at 60°C for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by flash column chromatography (DCM / MeOH = 20:1) to obtain compound 64-b (66 mg, 51%). LC-MS (ESI): m / z = 863.4 [M+H] + .

[0922] Synthesis of compound 64-a

[0923] At room temperature, compound 64-b (66 mg, 0.076 mmol) was dissolved in 3 mL of DMF, and cesium fluoride (209 mg, 1.38 mmol) was added. The mixture was stirred at room temperature under nitrogen for 2 hours. 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL*2). The organic phase was washed with saturated brine (100 mL*5), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 64-a (47 mg, 87%). LC-MS (ESI): m / z = 707.3 [M+H] + .

[0924] Synthesis of compound 64

[0925] At room temperature, compound 64-a (47 mg, 0.067 mmol) was dissolved in 6 mL of dichloromethane, and tert-butyldimethylsilyl trifluoromethanesulfonate (200 uL, 0.87 mmol) was added under ice-water bath, and the reaction mixture was stirred under ice-water bath for 30 minutes. 50 mL of saturated sodium bicarbonate solution was added to the reaction solution, diluted with 30 mL of dichloromethane, and the mixture was stirred at room temperature for 6 hours. The reaction solution was extracted with dichloromethane (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by Prep-HPLC (alkali method, NH4HCO3) to obtain compound 64 (10.8 mg, 26%). LC-MS (ESI): m / z = 607.3 [M+H] + .

[0926] Synthesis route of compound 65

[0927]

[0928] Synthesis of compound 65

[0929] At room temperature, compound 4 (50 mg, 0.085 mmol) was dissolved in 5 mL of dichloromethane, and NCS (N-chlorosuccinimide) (17 mg, 0.13 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by a flash column (DCM / MeOH = 10:1) to obtain a crude product. The crude product was then separated and purified by Prep-HPLC (alkaline method, NH4HCO3 system) to obtain compound 65 (3 mg, 5.7%). LC-MS (ESI): m / z = 623.2 [M+H] + .

[0930] Synthesis route of compound 66

[0931]

[0932] Synthesis of compound 66-a

[0933] To a microwave tube was added 3-b (100 mg, 0.19 mmol), 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (97 mg, 0.28 mmol), potassium phosphate (118 mg, 0.56 mmol), cataCXium A Pd G3 (14 mg, 0.019 mmol), tetrahydrofuran (10 mL), and water (1 mL). The tube was sealed, replaced with nitrogen three times, and heated to 65°C for overnight reaction. The reaction solution was dried and purified by column chromatography (mobile phase: methanol:dichloromethane = 0-5%) to obtain 66-a (107 mg, 79%).

[0934] Synthesis of compound 66

[0935] To 66-a (30 mg, 0.041 mmol) was added formic acid (4 mL) at room temperature, and the mixture was allowed to react at 35°C overnight. The reaction solution was spin-dried, purified by preparative HPLC (ammonium bicarbonate), and lyophilized to afford 66 (9 mg, 37%). LC-MS (ESI): m / z 583.3 (M+H) + .

[0936] Synthesis route of compound 67

[0937]

[0938] Synthesis of compound 67-f

[0939] To the reaction flask, tert-butyl carbazate (2 g, 15.13 mmol), ethanol (80 mL), and methyl 5-oxopentanoate (1.97 g, 15.14 mmol) were added and stirred at room temperature overnight under nitrogen. 10% palladium on carbon (1.6 g, 1.51 mmol) was added, the atmosphere was replaced with hydrogen three times, and the mixture was stirred at room temperature overnight. The reaction solution was filtered through celite, the filtrate was dried, and purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0-50%) to give compound 67-f (1.35 g, 36%). LC-MS (ESI): m / z 247.2 (M+H) + .

[0940] Synthesis of compound 67-e

[0941] To the reaction flask, 67-f (300 mg, 1.22 mmol) and dichloromethane (40 mL) were added. 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (307 mg, 1.22 mmol) was added under dry ice acetone cooling. The mixture was stirred at room temperature under nitrogen for 2 hours. The reaction solution was dried and purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0-30%) to obtain compound 67-e (293 mg, 52%). LC-MS (ESI): m / z 462.1 (M+H) + .

[0942] Synthesis of compound 67-d

[0943] To the reaction flask were added 67-e (293 mg, 0.63 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (303 mg, 1.90 mmol), 1,4-dioxane (20 mL), and DIPEA (410 mg, 3.17 mmol). The atmosphere was replaced with nitrogen three times and stirred at 90°C for three days. The reaction solution was dried and purified by column chromatography (mobile phase: methanol:dichloromethane = 0-5%) to obtain compound 67-d (348 mg, 94%). LC-MS (ESI): m / z 585.3 (M+H) + .

[0944] Synthesis of compound 67-c

[0945] To the reaction flask, 67-d (348 mg, 0.595 mmol), acetonitrile (20 mL), and 1,4-dioxane hydrochloride solution (4 M, 2 mL, 8 mmol) were added and stirred at room temperature overnight. The reaction solution was spin-dried to obtain compound 67-c (crude product), which was used directly in the next reaction without purification. LC-MS (ESI): m / z 485.3 (M+H) + .

[0946] Synthesis of compound 67-b

[0947] To a reaction flask, 67-c (crude product, 0.59 mmol), methanol (10 mL), tetrahydrofuran (32 mL), water (3 mL), and lithium hydroxide (249 mg, 5.94 mmol) were added and stirred at room temperature for 2 hours. The pH was adjusted to 4 with 1M hydrochloric acid, and the water was removed by rotary evaporation. The mixture was dehydrated twice with ethanol and then acetonitrile. Acetonitrile (100 mL), HOBt (401 mg, 2.97 mmol), EDCI (683 mg, 3.56 mmol), and DIPEA (0.982 mL, 5.94 mmol) were added to the residue and stirred at room temperature under nitrogen overnight. Additional HOBt (401 mg, 2.97 mmol), EDCI (683 mg, 3.56 mmol), and DIPEA (0.982 mL, 5.94 mmol) were added and stirred at room temperature under nitrogen overnight. The acetonitrile was removed by rotary evaporation, and the mixture was extracted with water and ethyl acetate (80 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spun down, and purified by column chromatography (mobile phase: methanol: dichloromethane = 0-10%) to obtain compound 67-b (40 mg, 15%). LC-MS (ESI): m / z 453.2 (M+H) + .

[0948] Synthesis of compound 67-a

[0949] To a microwave tube were added 67-b (40 mg, 0.088 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (83 mg, 0.13 mmol), potassium phosphate (94 mg, 0.44 mmol), cataCXium A Pd G3 (6 mg, 0.009 mmol), tetrahydrofuran (10 mL), and water (1 mL). The tube was sealed, replaced with nitrogen three times, heated to 65°C, and reacted overnight. The reaction solution was dried and purified by column chromatography (mobile phase: methanol:dichloromethane = 0-10%) to give compound 67-a (40 mg, 49%). LC-MS (ESI): m / z 915.4 (M+H) + .

[0950] Synthesis of compound 67

[0951] DMF (3 mL) and cesium fluoride (66 mg, 0.44 mmol) were added to 67-a (40 mg, 0.044 mmol) at room temperature, and the mixture was allowed to react overnight at room temperature. The reaction solution was filtered, purified by preparative HPLC (ammonium bicarbonate), and immediately lyophilized to obtain compound 67 (6 mg, 23%). LC-MS (ESI): m / z 603.3 (M+H) + .

[0952] Synthesis route of compound 68

[0953]

[0954] Synthesis of compound 68

[0955] To a solution of compound 4 (125 mg, 0.21 mmol) in dichloromethane (10 mL) was added triethylamine (64 mg, 0.63 mmol) in an ice-water bath, followed by the slow addition of trifluoroacetic anhydride (66 mg, 0.32 mmol). The mixture was allowed to warm to room temperature and react for 2 hours. After completion of the reaction, the organic solvent was removed by concentration under reduced pressure at low temperature. The crude product was purified by column flash chromatography (mobile phase: methanol / dichloromethane, 0-10%) to afford 68 (75 mg, 52%). LC-MS (ESI): m / z 685.7 [M+H] + ; 1 H NMR(DMSO-d6,400MHz): δ10.19(1H,d,J=7.2Hz),8.67(1H,s),7.95-8.04(1H,m),7.44-7.52(1H,m),7.41(1H,s),7.16-7.28(1 H,m),5.30(1H,d,J=54.4Hz),4.04-4.66(4H,m),3.51-3.98(3H,m),2.96-3.23(3H,m),2.77-2.93(1H,m),1.50-2.29(12H,m).

[0956] Synthesis route of compound 69

[0957]

[0958] Synthesis of compound 69

[0959] To a solution of compound 4 (180 mg, 0.31 mmol) in dichloromethane (50 mL) was added pyridine (242 mg, 3.06 mmol) in an ice-water bath, followed by the slow addition of n-octyl isocyanate (66 mg, 0.32 mmol). The mixture was allowed to warm to room temperature and allowed to react for 3 hours. After completion of the reaction, the organic solvent was removed by concentration under reduced pressure at low temperature. The mixture was first purified by column flash chromatography (mobile phase: methanol / dichloromethane, 0-10%) to obtain a crude product, which was then purified by Prep-HPLC to yield product 69 (60 mg, 26%). LC-MS (ESI): m / z 744.4 [M+H] + ; 1HNMR (400MHz, CDCl3): δ10.25 (1H, s), 7.60-7.90 (1H, m), 7.79 (1H, d, J = 2.0Hz), 7.40-7. 50(1H,m),7.31(1H,t,J=8.8Hz),5.30(1H,d,J=53.6Hz),5.12(1H,t,J=6.0Hz),4.01-4. 39(5H,m),3.10-3.52(7H,m),2.95-3.05(1H,m),2.86(1H,m),2.13-2.41(3H,m),1.85-2 .09(5H,m),1.68-1.85(5H,m),1.52-1.64(3H,m),1.18-1.43(8H,m),0.82-0.94(3H,m).

[0960] Synthetic routes of compounds 70 and 71

[0961]

[0962] Synthesis of compound 70-b

[0963] Compound 41-c (200 mg, 0.32 mmol), 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalene-2-amine (227 mg, 0.49 mmol), tetrakistriphenylphosphine palladium (38 mg, 0.032 mmol), sodium carbonate (103 mg, 0.97 mmol), 1,4-dioxane (15 mL) and water (1.5 mL) were added to a microwave tube. The tube was sealed, replaced with nitrogen three times, heated to 100°C, and reacted overnight. The reaction solution was dried and the crude product was purified by column chromatography (mobile phase: methanol / dichloromethane, 0-10%) to obtain compound 70-b (200 mg, 70%). LC-MS (ESI): m / z 877.1 (M+H) + ; m / z 721.3 (M+H) + .

[0964] Synthesis of compound 70-a

[0965] To a solution of compound 70-b (200 mg, 0.23 mmol) in N,N-dimethylformamide (4 mL) was added cesium fluoride (346 mg, 2.28 mmol) at room temperature, and the mixture was allowed to react at room temperature for 1 hour. A large amount of water was poured into the reaction solution, and the mixture was extracted with ethyl acetate (50 mL*2). The organic phase was washed with saturated brine (30 mL*3), dried by spin drying, and purified by column chromatography (mobile phase: methanol / dichloromethane, 0-10%) to obtain a mixture of two isomers, 70-a (140 mg, 85%). LC-MS (ESI): m / z 721.6 (M+H) + .

[0966] Synthesis of compounds 70 and 71

[0967] To a solution of compound 70-a (140 mg, 0.19 mmol) in dichloromethane (4 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (205 mg, 0.77 mmol) at room temperature, and the mixture was reacted at room temperature for 1 hour. A saturated sodium bicarbonate solution (10 mL) was added to quench the reaction, and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was extracted with dichloromethane (15 mL*2), the organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by Prep-HPLC (alkaline method) and lyophilized to obtain two products. Compound 70 (30 mg, 25%), LC-MS (ESI): m / z 621.3 (M+H) + Compound 71 (40 mg, 33%), LC-MS (ESI): m / z 621.3 (M+H) + .

[0968] Synthesis route of compound 72

[0969]

[0970] Synthesis of compound 72-c

[0971] To a solution of compound 3-c (100 mg, 0.24 mmol) in dichloromethane (15 mL) was added (S)-(-)-1-methyl-2-pyrrolidinemethanol (55 mg, 0.48 mmol) in an ice bath, followed by the slow addition of sodium tert-butoxide (115 mg, 1.20 mmol). After the addition, the reaction temperature was slowly raised to room temperature and allowed to react overnight. Water was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was purified by flash column chromatography (mobile phase: dichloromethane:methanol = 10:1 / dichloromethane, 0-100%) to afford 72-c (70 mg, 59%). LC-MS (ESI): m / z 495.4 (M+H). + .

[0972] Synthesis of compound 72-b

[0973] To a 10 mL microwave tube was added 72-c (70 mg, 0.14 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (106 mg, 0.17 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (10 mg, 0.014 mmol), potassium phosphate (90 mg, 0.42 mmol), tetrahydrofuran (2.5 mL), and water (0.5 mL). The microwave tube was sealed, replaced with nitrogen several times, and heated to 65°C for overnight reaction. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by flash column chromatography (mobile phase: dichloromethane:methanol = 10:1 / dichloromethane, 0-100%) to give 72-b (60 mg, 53%). LC-MS (ESI): m / z 801.7 (M+H) + .

[0974] Synthesis of compound 72-a

[0975] To a solution of 72-b (60 mg, 0.075 mmol) in N,N-dimethylformamide (8 mL) was added cesium fluoride (95 mg, 0.63 mmol) at room temperature, and the mixture was allowed to react overnight at room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to give 72-a (40 mg, 83%). LC-MS (ESI): m / z 645.5 (M+H) + .

[0976] Synthesis of compound 72

[0977] To a solution of 72-a (40 mg, 0.062 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL) at room temperature, and the reaction mixture was allowed to react at this temperature for 4 hours. The reaction mixture was spin-dried, neutralized by adding saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by Prep-HPLC to yield 72 (3 mg, 9%). LC-MS (ESI): m / z 545.3 (M+H) + .

[0978] Synthesis route of compound 73

[0979]

[0980] Synthesis of compound 73-a

[0981] To a solution of compound 12 (100 mg, 0.15 mmol) in N,N-dimethylformamide (6 mL) was added 1-chloroformyl-4-piperidinylpiperidine hydrochloride (194 mg, 0.73 mmol) and potassium carbonate (201 mg, 1.45 mmol) at room temperature. The reaction solution was heated to 40°C and stirred for one hour. LCMS showed that the reaction was complete. Water was added to the reaction solution and extracted with ethyl acetate (60 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to give compound 73-a (119 mg, 93%). The crude product was used directly in the next reaction without purification. LC-MS (ESI): m / z 883.8 (M+H) + .

[0982] Synthesis of compound 73

[0983] To a solution of compound 73-a (119 mg, 0.13 mmol) in dichloromethane (10 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (0.06 mL) in an ice-water bath. The reaction mixture was allowed to react at this temperature for 1 hour, followed by addition of saturated aqueous sodium bicarbonate solution and overnight reaction at room temperature. The reaction mixture was extracted with dichloromethane (30 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by Prep-HPLC to yield compound 73 (23 mg, 22%). LC-MS (ESI): m / z 783.4 (M+H). + .

[0984] Synthesis route of compound 74

[0985]

[0986] Synthesis of compound 74

[0987] To a solution of compound 4 (100 mg, 0.17 mmol) in DCM (2 mL) was added triethylamine (0.047 mL, 0.340 mmol) and p-nitrophenyl chloroformate (34 mg, 0.17 mmol) in an ice-salt bath under nitrogen. The reaction mixture was allowed to react at this temperature for 10 min. (S)-2-(Methoxymethyl)pyrazolidine (20 mg, 0.17 mmol) was then added, and the temperature was slowly raised to room temperature. The reaction mixture was allowed to react overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by Prep-HPLC to yield 74 (81 mg, 65%). LC-MS (ESI): m / z 730.3 (M+H). + .

[0988] Synthesis route of compound 75

[0989]

[0990] Synthesis of compound 75

[0991] To a solution of compound 4 (100 mg, 0.17 mmol) in DCM (2 mL) was added triethylamine (0.047 mL, 0.340 mmol) and p-nitrophenyl chloroformate (34 mg, 0.17 mmol) in an ice-salt bath under nitrogen. The reaction mixture was allowed to react at this temperature for 10 minutes. Tert-butyl 2-piperidinylcarboxylate (31 mg, 0.17 mmol) was then added, and the temperature was slowly raised to room temperature. The reaction mixture was allowed to react overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by Pre-HPLC to yield compound 75 (73 mg, 54%). LC-MS (ESI): m / z 800.3 (M+H). + .

[0992] Synthesis route of compound 76

[0993]

[0994] Synthesis of compound 76-e

[0995] Di-tert-butyl azide (2000 mg, 8.61 mmol), DMF (60 mL), cis-1,4-dichloro-2-butene (1076 mg, 8.61 mmol), and cesium carbonate (8416 mg, 25.83 mmol) were added to the reaction flask at room temperature. The mixture was replaced with N2 for protection and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was added with water and extracted with EA. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 8 / 2) to obtain compound 76-e (2000 mg, 82%). LC-MS (ESI): m / z 302.2 (M+NH4) + .

[0996] Synthesis of compound 76-d

[0997] To the reaction flask at room temperature were added 76-e (500 mg, 1.76 mmol), acetonitrile (20 mL), and a 1 M solution of hydrogen chloride in 1,4-dioxane (5 mL). The mixture was protected with nitrogen and allowed to react at room temperature for 3 hours. The reaction mixture was concentrated at room temperature to yield crude compound 76-d (430 mg).

[0998] Synthesis of compound 76-c

[0999] To a reaction flask at room temperature were added 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (533 mg, 2.11 mmol), DCM (15 mL), and crude compound 76-d (430 mg, 1.76 mmol). The mixture was purged with N2 and cooled to 0°C. DIPEA (1136 mg, 8.79 mmol) was added. The reaction mixture was allowed to warm to room temperature and react overnight. Water was added to the reaction mixture, and the mixture was extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 8 / 2) to afford compound 76-c (430 mg, 81%).

[1000] Synthesis of compound 76-b

[1001] To the reaction flask were added 76-c (430 mg, 1.43 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (342 mg, 2.15 mmol), 1,4-dioxane (5 mL), and DIPEA (741 mg, 5.73 mmol) at room temperature. The mixture was replaced with N2 and heated to 90°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to obtain compound 76-b (600 mg, 99%). LC-MS (ESI): m / z 423.3 (M+H) + .

[1002] Synthesis of compound 76-a

[1003] To a sealed tube were added 76-b (150 mg, 0.35 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (266 mg, 0.43 mmol), cataCXium A Pd G3 (52 mg, 0.07 mmol), potassium phosphate (226 mg, 1.07 mmol), THF (2 mL), and water (0.5 mL) at room temperature. The mixture was replaced with N2 and heated to 65°C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 76-a (220 mg, 70%).

[1004] Synthesis of compound 76

[1005] To the reaction flask were added 76-a (220 mg, 0.25 mmol), DMF (3 mL), and cesium fluoride (377 mg, 2.48 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was filtered, and the filtrate was purified by reverse phase column chromatography (mobile phase: water (0.01 M NH4HCO3) / acetonitrile 10 / 0 to 1 / 9) to obtain compound 76 (50 mg, 35%). LC-MS (ESI): m / z 573.4 (M+H). + ; 1 H NMR (400MHz, CD3OD): δ10.46(1H,s),10.04(1H,s),7.91-7.80(2H,m),7.43-7.18(4H,m),5.60-5.54(1H,m),5.30(1H,d,J=53. 2Hz),4.39-4.19(3H,m),3.40(2H,t,J=6.0Hz),3.33(1H,d,J=3.2Hz),3.27-3.13(3H,m),3.09-2.96(1H,m),2.50-1.80(7H,m).

[1006] Synthesis route of compound 77

[1007]

[1008] Synthesis of compound 77-f

[1009] To a reaction flask at room temperature were added 5-bromo-2-fluoro-1-methyl-3-nitrobenzene (2500 mg, 10.68 mmol), ethanol (80 mL), water (40 mL), iron powder (5965 mg, 106.83 mmol), and ammonium chloride (5714 mg, 106.83 mmol). The mixture was purged with nitrogen and heated to 100°C for 2 hours. The reaction mixture was concentrated to remove ethanol, and water and EA were added. The mixture was filtered, and the filtrate was extracted with EA. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 8 / 2) to yield compound 77-f (1900 mg, 87%).

[1010] Synthesis of compound 77-e

[1011] To a reaction flask at room temperature, add 77-f (1900 mg, 9.31 mmol) and DMF (15 mL). The mixture was purged with N2 and cooled to 0°C. NaH (60%, 1490 mg, 37.25 mmol) was added, stirred for half an hour, and 4-methoxybenzyl chloride (PMBCl) (4375 mg, 27.94 mmol) was added. The reaction mixture was allowed to warm to room temperature and react for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with EA. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 8 / 2) to yield compound 77-e (3600 mg, 87%).

[1012] Synthesis of compound 77-d

[1013] To a reaction flask at room temperature were added 77-e (3600 mg, 8.10 mmol), acetic acid (25 mL), and NIS (N-iodosuccinimide) (1823 mg, 8.10 mmol). The mixture was purged with N2 and allowed to react at room temperature for 1 hour. The reaction solution was concentrated, neutralized with aqueous sodium bicarbonate, and extracted with EA. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 9 / 1) to afford compound 77-d (1900 mg, 41%).

[1014] Synthesis of compound 77-c

[1015] To the reaction flask at room temperature were added 77-d (1900 mg, 3.33 mmol), methyl fluorosulfonyldifluoroacetate (3200 mg, 16.66 mmol), DMAc (20 mL), and CuI (3173 mg, 16.66 mmol). The mixture was replaced with N2 and heated to 90°C for 2 hours. The reaction solution was cooled to room temperature, added with water, and extracted with EA. The organic phases were combined, dried, concentrated, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 10 / 1) to obtain compound 77-c (1300 mg, 76%). LC-MS (ESI): m / z 512.1 (M+H) + .

[1016] Synthesis of compound 77-b

[1017] To a reaction flask at room temperature were added 77-c (1300 mg, 2.54 mmol), pinacol diboronate (1933 mg, 7.61 mmol), Pd(dppf)Cl2 (371 mg, 0.51 mmol), potassium acetate (996 mg, 10.15 mmol), and 1,4-dioxane (10 mL). The mixture was purged with nitrogen and heated to 100°C for 3 hours. The reaction solution was concentrated and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 10 / 1) to afford compound 77-b (1300 mg, 92%). LC-MS (ESI): m / z 560.3 (M+H). + .

[1018] Synthesis of compound 77-a

[1019] To the reaction flask at room temperature were added 77-b (1300 mg, 2.32 mmol) and TFA (10 mL). The mixture was purged with N2 and allowed to react at room temperature for 3 hours. The reaction solution was concentrated at room temperature, basified by adding methanolic ammonia, concentrated, and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to afford compound 77-a (450 mg, 61%).

[1020] Synthesis of compound 77

[1021] To a sealed tube were added 77-a (200 mg, 0.63 mmol), 20-d (330 mg, 0.75 mmol), cataCXiumA Pd G3 (46 mg, 0.06 mmol), potassium phosphate (399 mg, 1.88 mmol), THF (4 mL), and water (1 mL) at room temperature. The mixture was replaced with N2 and heated to 65°C for 3 hours. The reaction solution was concentrated, dissolved in methanol, filtered, and the filtrate was purified by preparative HPLC to obtain compound 77 (56 mg, 15%). LC-MS (ESI): m / z 596.6 (M+H) + .

[1022] Synthesis route of compound 78

[1023]

[1024] Synthesis of compound 78-b

[1025] 3-c (200 mg, 0.48 mmol), (S)-4-N-tert-butyloxycarbonyl-2-methylpiperazine (192 mg, 0.96 mmol), 1,4-dioxane (10 mL), and DIPEA (248 mg, 1.92 mmol) were added to the reaction flask at room temperature. The mixture was replaced with N2 and heated to 90°C overnight. The reaction solution was concentrated and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 1 / 1) to obtain compound 78-b (230 mg, 83%). LC-MS (ESI): m / z 580.4 (M+H) + .

[1026] Synthesis of compound 78-a

[1027] To a microwave tube at room temperature were added 78-b (100 mg, 0.17 mmol), tert-butyl 3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (108 mg, 0.26 mmol), bis(diphenylphosphinophenyl ether)palladium(II) dichloride (25 mg, 0.03 mmol), cesium carbonate (112 mg, 0.34 mmol), and toluene (2 mL). The mixture was replaced with N2 and microwave-heated at 100°C overnight. The reaction mixture was concentrated and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 0 / 10) to afford compound 78-a (70 mg, 49%). LC-MS (ESI): m / z 836.5 (M+H). + .

[1028] Synthesis of compound 78

[1029] To the reaction flask at room temperature were added 78-a (70 mg, 0.08 mmol), acetonitrile (15 mL), and a 1 M solution of hydrogen chloride in 1,4-dioxane (4 mL). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated at room temperature, basified by adding a methanolic ammonia solution, and concentrated. The mixture was dissolved in methanol and subjected to preparative HPLC to afford compound 78 (11 mg, 25%). LC-MS (ESI): m / z 536.4 (M+H). + .

[1030] Synthesis route of compound 79

[1031]

[1032] Synthesis of compound 79-b

[1033] To the reaction flask at room temperature were added 3-c (200 mg, 0.48 mmol), (S)-tert-butyl 3-methyl-1,4-diazepane-1-carboxylate (206 mg, 0.96 mmol), 1,4-dioxane (10 mL), and DIPEA (248 mg, 1.92 mmol). The mixture was replaced with N2 and heated to 90°C overnight. The reaction solution was concentrated and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 1 / 1) to obtain compound 79-b (240 mg, 84%). LC-MS (ESI): m / z 594.3 (M+H). + .

[1034] Synthesis of compound 79-a

[1035] To a microwave tube at room temperature were added 79-b (100 mg, 0.17 mmol), tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (204 mg, 0.50 mmol), bis(diphenylphosphinophenyl ether)palladium(II) chloride (24 mg, 0.03 mmol), cesium carbonate (165 mg, 0.51 mmol), and toluene (2 mL). The mixture was protected by nitrogen displacement and microwave-heated at 120°C for 48 hours. The reaction mixture was concentrated and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 0 / 10) to afford compound 79-a (80 mg, 56%).

[1036] Synthesis of compound 79

[1037] To the reaction flask at room temperature were added 79-a (80 mg, 0.09 mmol), acetonitrile (15 mL), and a 1 M solution of hydrogen chloride in 1,4-dioxane (4 mL). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated at room temperature, basified by adding a methanolic ammonia solution, and concentrated. The mixture was dissolved in methanol and subjected to preparative HPLC to afford compound 79 (8 mg, 15%). LC-MS (ESI): m / z 550.3 (M+H). + .

[1038] Synthesis route of compound 80

[1039]

[1040] Synthesis of compound 80-c

[1041] To the reaction flask at room temperature, add (S)-tert-butyl 3-methyl-1,4-diazepane-1-carboxylate (400 mg, 1.87 mmol) and THF (10 mL). The mixture was replaced with N2 for protection, cooled to 0°C, and a solution of lithium aluminum hydride in tetrahydrofuran (1 M, 5.6 mL) was added dropwise. The reaction was allowed to react at room temperature for 48 hours. Sodium sulfate decahydrate was added to the reaction solution and stirred for 1 hour. The mixture was filtered and the filter cake was washed with THF. The filtrate was concentrated to give crude compound 80-c (300 mg). LC-MS (ESI): m / z 128.8 (M+H) + .

[1042] Synthesis of compound 80-b

[1043] To a reaction flask at room temperature were added 3-c (388 mg, 0.93 mmol), 80-c (150 mg, 0.93 mmol), 1,4-dioxane (10 mL), and DIPEA (482 mg, 3.73 mmol). The mixture was purged with nitrogen and heated to 90°C overnight. The reaction mixture was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to afford compound 80-b (150 mg, 32%). LC-MS (ESI): m / z 508.4 (M+H).

[1045] Synthesis of compound 80-a

[1046] To a microwave tube at room temperature were added 80-b (150 mg, 0.30 mmol), tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (358 mg, 0.89 mmol), bis(diphenylphosphinophenyl ether)palladium(II) chloride (42 mg, 0.06 mmol), cesium carbonate (289 mg, 0.89 mmol), and toluene (3 mL). The mixture was replaced with N2 and microwave-heated at 120°C for 48 hours. The reaction mixture was concentrated and purified by column chromatography (mobile phase: DCM / MeOH 10 / 0 to 10 / 1) to give compound 80-a (70 mg, 31%). LC-MS (ESI): m / z 764.9 (M+H). + .

[1047] Synthesis of compound 80

[1048] To the reaction flask at room temperature were added 80-a (70 mg, 0.09 mmol), acetonitrile (15 mL), and a 1 M solution of hydrogen chloride in 1,4-dioxane (4 mL). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated at room temperature, basified by adding a methanolic ammonia solution, and concentrated. The mixture was dissolved in methanol and subjected to preparative HPLC to afford compound 80 (2.7 mg, 5%). LC-MS (ESI): m / z 564.4 (M+H). + .

[1049] Synthesis route of compound 81

[1050]

[1051] Synthesis of compound 81-c

[1052] To the reaction flask, tert-butyl 3-bromo-5-chloro-4-trifluoromethylaniline formate (1 g, 2.67 mmol), dichloromethane (9 mL), and trifluoroacetic acid (3 mL, 40.04 mmol) were added and stirred at room temperature for 1 hour. The reaction solution was spin-dried and diluted with dichloromethane / methanol (10:1, 10 mL). Saturated aqueous ammonium bicarbonate was added to neutralize the pH to 8-9. The layers were separated and the aqueous phase was extracted with dichloromethane / methanol (10:1, 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 0-20%) to obtain 81-c (397 mg, 54%). LC-MS (ESI): m / z 273.9 (M+H) + .

[1053] Synthesis of compound 81-b

[1054] To a reaction flask under an ice-water bath were added 81-c (394 mg, 1.44 mmol), pinacol diboron (1.094 g, 4.31 mmol), potassium acetate (423 mg, 4.31 mmol), Pd(dppf)Cl2·CH2Cl2 (59 mg, 0.072 mmol), and 1,4-dioxane (6 mL). The mixture was purged with nitrogen three times, heated to 90°C, and reacted for 2 hours. Pd(dppf)Cl2·CH2Cl2 (59 mg, 0.072 mmol) was added to the reaction solution, and the atmosphere was purged with nitrogen three times, heated to 90°C, and reacted for 1.5 hours. The reaction solution was dried and purified by column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-20%) to afford 81-b (275 mg, 60%). LC-MS (ESI): m / z 321.9 (M+H). + .

[1055] Synthesis of compound 81-a

[1056] To a microwave tube, 3-b (100 mg, 0.19 mmol), 81-b (78 mg, 0.24 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (27 mg, 0.04 mmol), potassium phosphate (118 mg, 0.56 mmol), tetrahydrofuran (1.0 mL), and water (0.2 mL) were added. The tube was sealed, purged with nitrogen three times, and heated to 65°C for 1 hour. Dichloromethane (2 mL) and water (1 mL) were added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with dichloromethane (2 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. Purification was performed on a column (mobile phase: ethyl acetate:petroleum ether = 0-20%) to afford 81-a (62 mg, 48%). LC-MS (ESI): m / z 698.2 (M+H) + .

[1057] Synthesis of compound 81

[1058] To a solution of 81-a (70 mg, 0.10 mmol) in dichloromethane (2.4 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (398 mg, 1.50 mmol) under ice-cooling, and the mixture was reacted at 0-5°C for 0.5 h. Saturated aqueous sodium bicarbonate (4 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 20 min. The mixture was extracted with dichloromethane / methanol (10:1) (5 mL*2), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was purified by column chromatography (mobile phase: methanol:dichloromethane = 0-12%), concentrated, and lyophilized to obtain 81 (38 mg, 63%). LC-MS (ESI): m / z 598.3 (M+H). + ; 1H NMR (400MHz, d6-DMSO) δ10.22(s,1H),6.88(d,J=2.3Hz,1H),6.48(d,J=2.3Hz,1H),6.32(s,2H),5.89(t,J=6.1Hz,1H),5. 32(d,J=54.3Hz,1H),4.33–3.83(m,4H),3.04(t,J=59.2Hz,6H),2.22–1.99(m,3H),1.97–1.76(m,5H),1.75–1.59(m,4H).

[1059] Synthesis route of compound 82

[1060]

[1061] Synthesis of compound 82-d

[1062] To the reaction flask was added (2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid methyl ester (400 mg, 2.14 mmol). Tetrahydrofuran (10 mL) was placed in an ice-water bath for 10 minutes. Lithium aluminum deuteride (126 mg, 2.99 mmol) was added, and the reaction solution was stirred at room temperature for 12 hours. Sodium sulfate decahydrate was added to the reaction solution to quench the reaction until no bubbles were released. The solution was filtered, and the filtrate was concentrated and purified by column chromatography (MeOH / DCM = 0 / 100, 1 / 10) to give compound 82-d (260 mg, 75%). LC-MS (ESI): m / z = 162.2 (M+H) + .

[1063] Synthesis of compound 82-c

[1064] To the reaction flask were added 82-d (260 mg, 1.61 mmol), dichloromethane (20 mL), 3-c (700 mg, 1.68 mmol), and sodium tert-butoxide (162 mg, 1.68 mmol), respectively, and stirred at 0°C under nitrogen for 3 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL*3). The organic phase was concentrated and purified by column chromatography (MeOH / DCM = 1 / 10) to give compound 82-c (560 mg, 64%). LC-MS (ESI): m / z = 541.1 (M+H) + .

[1065] Synthesis of compound 82-b

[1066] To the reaction flask were added 82-c (320 mg, 0.59 mmol), tetrahydrofuran (18 mL), water (2 mL), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (554 mg, 0.89 mmol), potassium phosphate (439 mg, 2.07 mmol), and cataCXiumA Pd G3 (2.48 mg, 0.003 mmol). The atmosphere was purged with nitrogen three times and the mixture was stirred in an oil bath preheated to 60°C for 12 hours. The reaction solution was spin-dried and purified by column chromatography (mobile phase: methanol / dichloromethane = 0 / 100; 1 / 10) to give compound 82-b (270 mg, 54%).

[1067] Synthesis of compound 82-a

[1068] To the reaction flask were added 82-b (270 mg, 0.32 mmol), DMF (20 mL), and cesium fluoride (800 mg, 5.27 mmol), and stirred at room temperature for 6 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL*3). The organic phase was concentrated and purified by column chromatography (MeOH / DCM = 0 / 100, 1 / 10) to afford compound 82-a (170 mg, 77%).

[1069] Synthesis of compound 82

[1070] 82-a (170 mg, 0.25 mmol) and formic acid (20 mL) were added to the reaction flask and stirred at room temperature for 6 hours. The reaction solution was concentrated at room temperature and purified by preparative HPLC to give compound 82 (32 mg, 22%). LC-MS (ESI): m / z 591.3 (M+H) + .

[1071] Synthesis route of compound 83

[1072]

[1073] Synthesis of compound 83-h

[1074] Diethyl glutarate (3000 mg, 15.94 mmol) and tetrahydrofuran (60 mL) were added to the reaction flask and placed in an ice-water bath for 10 minutes. Lithium aluminum deuteride (1200 mg, 28.59 mmol) was then added. The reaction mixture was stirred at room temperature for 12 hours. Solid sodium sulfate decahydrate was added to the reaction mixture to quench the reaction until no bubbles were released. The mixture was filtered and the organic phase was concentrated to afford compound 83-h (1320 mg, 77%), which was directly used in the next reaction. 1H NMR (400MHz, CDCl3): δ2.29(s,2H),1.62-1.53(m,4H),1.49-1.40(m,2H).

[1075] Synthesis of compound 83-g

[1076] To the reaction flask were added 83-h (1300 mg, 12.02 mmol), dichloromethane (40 mL), triethylamine (4864 mg, 48.07 mmol), and p-toluenesulfonyl chloride (6873 mg, 36.05 mmol), respectively, and stirred under nitrogen overnight. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL*3). The organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 83-g (4036 mg, 81%). LC-MS (ESI): m / z = 434.7 (M+NH4) + .

[1077] Synthesis of compound 83-f

[1078] To the reaction flask were added 83-g (4000 mg, 9.60 mmol), acetonitrile (100 mL), 2-(tert-butyl)hydrazine-1,2-dicarboxylic acid-1-benzyl ester (2711 mg, 10.18 mmol), and cesium carbonate (15644 mg, 48.02 mmol). The atmosphere was purged with nitrogen three times and the mixture was placed in an oil bath preheated to 65°C and stirred for 36 hours. The reaction mixture was filtered, the organic phase was dried, and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 3) to give compound 83-f (2650 mg, 82%). LC-MS (ESI): m / z = 356.4 (M+NH4) + .

[1079] Synthesis of compound 83-e

[1080] To the reaction flask were added 83-f (2650 mg, 7.83 mmol), ethyl acetate (150 mL), and palladium on carbon (700 mg, 10%). The atmosphere was replaced with hydrogen three times and stirred at room temperature for 12 hours. The reaction mixture was filtered and the organic phase was concentrated to obtain compound 83-e (1400 mg, 88%). LC-MS (ESI): m / z = 205.3 (M+H) + .

[1081] Synthesis of compound 83-d

[1082] 83-e (700 mg, 3.43 mmol), dichloromethane (30 mL), DIPEA (1329 mg, 10.28 mmol), and 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (865 mg, 3.43 mmol) were added to the reaction flask and stirred at this temperature for 12 hours under nitrogen protection. The mixture was quenched with saturated sodium bicarbonate (100 mL) and extracted with dichloromethane (100 mL*2). The organic phase was concentrated and purified by column chromatography (PE / EA=10 / 1) to give compound 83-d (1400 mg, 97%). LC-MS (ESI): m / z=420.3 (M+H) + .

[1083] Synthesis of compound 83-c

[1084] 83-d (800 mg, 1.90 mmol), dichloromethane (30 mL), sodium tert-butoxide (366 mg, 3.81 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl)methanol (333 mg, 2.09 mmol) were added to the reaction flask, stirred under nitrogen protection in an ice-water bath for 3 hours, and then stirred at room temperature overnight. Water (20 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane (50 mL*3). The organic phase was concentrated and purified by column chromatography (MeOH / DCM=1 / 10) to give compound 83-c (890 mg, 86%). LC-MS (ESI): m / z=543.7 (M+H) + .

[1085] Synthesis of compound 83-b

[1086] To the reaction flask were added 83-c (290 mg, 0.53 mmol), tetrahydrofuran (10 mL), water (1 mL), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (500 mg, 0.80 mmol), potassium phosphate (397 mg, 1.87 mmol) and cataCXiumA Pd G3 (78 mg, 0.11 mmol). The atmosphere was replaced with nitrogen three times and the mixture was placed in an oil bath preheated to 65°C and stirred for 12 hours. The reaction solution was spin-dried and purified by column chromatography (mobile phase: methanol / dichloromethane = 0 / 100; 1 / 10) to give compound 83-b (460 mg, 86%). LC-MS (ESI): m / z = 1005.5 (M+H) + .

[1087] Synthesis of compound 83-a

[1088] To the reaction flask were added 83-b (460 mg, 0.46 mmol), DMF (5 mL), and cesium fluoride (695 mg, 4.58 mmol), and stirred at room temperature for 6 hours. Water (60 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL*3). The organic phase was concentrated and purified by column chromatography (MeOH / DCM = 0 / 100, 1 / 10) to afford compound 83-a (270 mg, 85%).

[1089] Synthesis of compound 83

[1090] 83-a (200 mg, 0.29 mmol) and formic acid (10 mL) were added to the reaction flask and stirred at room temperature for 12 hours under nitrogen. The reaction solution was concentrated at room temperature and purified by preparative HPLC to give compound 83 (50 mg, 29%). LC-MS (ESI): m / z 593.5 (M+H) + .

[1091] Synthesis route of compound 84

[1092]

[1093] Synthesis of compound 84-h

[1094] To a reaction flask at room temperature, add 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (2500 mg, 8.93 mmol), phosphorus oxychloride (10 mL), and DIPEA (3461 mg, 26.78 mmol). Place the mixture in an oil bath preheated to 85°C and stir for 3 hours. The reaction mixture was vortexed to dryness, and the crude product was added to ice water, extracted with dichloromethane (100 mL x 3), and dried over sodium sulfate. Filter and concentrate the organic phase to yield compound 84-h (1890 mg, 71%).

[1095] Synthesis of compound 84-g

[1096] To the reaction flask at room temperature were added tert-butyl 1,2-diazoheptane-1-carboxylate (2730 mg, 13.63 mmol), 2-tert-butyldimethylsilyloxyacetaldehyde (4900 mg, 28.11 mmol), and methanol (80 mL). Sodium cyanoborohydride (4900 mg, 77.98 mmol) was slowly added under an ice-water bath, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated, and water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL*3). The organic phase was concentrated and purified by column chromatography (PE / EA=20 / 1) to give compound 84-g (3910 mg, 80%). LC-MS (ESI): m / z=359.4 (M+H) + .

[1097] Synthesis of compound 84-f

[1098] 84-g (800 mg, 2.23 mmol) and acetonitrile (10 mL) were added to the reaction flask respectively, and stirred under nitrogen in an ice-water bath for 10 minutes. 1,4-dioxane hydrochloride (4 M, 1 mL, 4.00 mmol) was slowly added dropwise to the reaction solution, and stirred under an ice-water bath for 4 hours. Ammonia methanol (2 mL, 14.00 mmol, 7 M) was added to the reaction solution under an ice-water bath. Concentration and purification by column chromatography (MeOH / DCM=0 / 100, 1 / 10) gave compound 84-f (70 mg, 12%). LC-MS (ESI): m / z=259.3 (M+H) + .

[1099] Synthesis of compound 84-e

[1100] 84-h (196 mg, 0.66 mmol), dichloromethane (20 mL), and DIPEA (255 mg, 1.97 mmol) were added to the reaction flask, and the mixture was stirred at -78°C for 10 minutes. 84-f (170 mg, 0.66 mmol) was then added to the reaction flask, stirred at -78°C for half an hour, and stirred at room temperature for 2 hours. The reaction solution was concentrated at room temperature, and saturated sodium bicarbonate solution (30 mL) was added to the residue, and extracted with dichloromethane (30 mL*2). The organic phase was concentrated and purified by column chromatography (PE / EA=10 / 1) to give compound 84-e (249 mg, 73%). LC-MS (ESI): m / z=520.3 (M+H) + .

[1101] Synthesis of compound 84-d

[1102] 84-e (249 mg, 0.48 mmol), DMF (5 mL), and cesium fluoride (220 mg, 1.45 mmol) were added to the reaction flask and stirred at 55°C for 3 hours under nitrogen. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL*3). Column chromatography (MeOH / DCM = 0 / 100, 1 / 10) gave compound 84-d (143 mg, 81%). LC-MS (ESI): m / z = 370.2 (M+H) + .

[1103] Synthesis of compound 84-c

[1104] 84-d (140 mg, 0.38 mmol), ethyl acetate (20 mL), and m-chloroperbenzoic acid (192 mg, 0.95 mmol, 85%) were added to the reaction flask at room temperature and stirred at 0°C for 2 hours, then at room temperature for another hour. Saturated sodium bicarbonate solution (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL*2). The organic phase was concentrated and purified by column chromatography (PE / EA=3 / 1, 0 / 100) to give compound 84-c (130 mg, 85%). LC-MS (ESI): m / z=402.1 (M+H) + .

[1105] Synthesis of compound 84-b

[1106] To the reaction flask were added ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (68 mg, 0.43 mmol), 84-c (130 mg, 0.32 mmol), toluene (10 mL), and sodium tert-butoxide (50 mg, 0.52 mmol), respectively, and stirred at room temperature under nitrogen for 3 hours. The reaction solution was directly added to silica gel and purified by column chromatography (MeOH / DCM = 0 / 100, 1 / 10) to give compound 84-b (96 mg, 62%). LC-MS (ESI): m / z = 481.3 (M+H) + .

[1107] Synthesis of compound 84-a

[1108] To a reaction flask were added 84-b (96 mg, 0.20 mmol), tetrahydrofuran (6 mL), potassium phosphate (169 mg, 0.80 mmol), water (0.8 mL), cataCXium APd G3 (44 mg, 0.06 mmol), and ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (249 mg, 0.40 mmol). The atmosphere was purged with nitrogen three times and the mixture was stirred in an oil bath preheated to 65°C for 12 hours. The reaction mixture was dried and purified by column chromatography (mobile phase: methanol / dichloromethane = 0 / 100; 1 / 10) to give compound 84-a (110 mg, 58%).

[1109] Synthesis of compound 84

[1110] 84-a (90 mg, 0.10 mmol), DMF (5 mL), and cesium fluoride (145 mg, 0.95 mmol) were added to the reaction flask and stirred at room temperature for 6 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL*2). The mixture was concentrated and purified by preparative HPLC to give compound 84 (39 mg, 65%). LC-MS (ESI): m / z = 631.3 (M+H) + ; 1 H NMR (400MHz, DMSO-d6): δ10.15(1H,brs),7.99-7.92(1H,m),7.49-7.42(1H,m),7.38-7.33(1H,m),7.26-7.04(1H,m),5.28(1H, d,J=54.0Hz),4.60-3.93(6H,m),3.59-3.33(3H,m),3.18–2.95(5H,m),2.93–2.73(2H,m),2.25–1.93(4H,m),1.90–1.63(7H,m).

[1111] Synthesis route of compound 85

[1112]

[1113] Synthesis of compound 85-d

[1114] Synthesized according to the method of patent CN116891488A.

[1115] Synthesis of compound 85-c

[1116] To a reaction flask at room temperature were added 85-d (170 mg, 0.63 mmol), dichloromethane (20 mL), 3-c (391 mg, 0.94 mmol), and sodium tert-butoxide (121 mg, 1.25 mmol), respectively. The mixture was stirred at 0°C under nitrogen for 3 hours. Saturated ammonium chloride (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phase was concentrated and purified by column chromatography (PE / EA = 10 / 1, 3 / 1) to afford compound 85-c (290 mg, 71%).

[1117] Synthesis of compound 85-b

[1118] 85-c (170 mg, 0.26 mmol), tetrahydrofuran (6 mL), water (0.8 mL), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (326 mg, 0.52 mmol), potassium phosphate (166 mg, 0.78 mmol) and cataCXiumA Pd G3 (57 mg, 0.08 mmol) were added to a microwave tube. The atmosphere was replaced with nitrogen three times and the mixture was placed in an oil bath preheated to 65°C and stirred for 8 hours. The reaction solution was concentrated and purified by column chromatography (PE / EA=5 / 1, 1 / 1) to give compound 85-b (226 mg, 78%). LC-MS (ESI): m / z=1113.4 (M+H) + .

[1119] Synthesis of compound 85-a

[1120] To the reaction flask were added 85-b (230 mg, 0.21 mmol), DMF (5 mL), and cesium fluoride (1300 mg, 8.56 mmol), and the mixture was stirred at room temperature under nitrogen for 10 hours. Ammonium chloride (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL*3). The organic phase was concentrated and purified by column chromatography (PE / EA=100 / 0, 3 / 1) to obtain compound 85-a (133 mg, 80%). LC-MS (ESI): m / z=801.4 (M+H) + .

[1121] Synthesis of compound 85

[1122] 85-a (130 mg, 0.16 mmol) and dichloromethane (6 mL) were added to the reaction flask and stirred in an ice-water bath for 10 minutes. TBSOTf (20 mg, 0.08 mmol) was slowly added and the reaction solution was stirred in an ice-water bath for 1 hour. Saturated aqueous sodium bicarbonate solution (50 mL) was added to the reaction solution and stirred at room temperature for 17 hours. The product was extracted with dichloromethane (20 mL*3). The organic phase was concentrated and purified by preparative HPLC to give compound 85 (68 mg, 60%). LC-MS (ESI): m / z 701.1 (M+H) + .

[1123] Synthesis route of compound 86

[1124]

[1125] Synthesis of compound 86-d

[1126] Synthesized according to the method of patent CN116891488A.

[1127] Synthesis of compound 86-c

[1128] 86-d (120 mg, 0.44 mmol), dichloromethane (20 mL), 3-c (276 mg, 0.66 mmol), and sodium tert-butoxide (164 mg, 0.66 mmol) were added to the reaction flask at room temperature and stirred at 0°C for 3 hours under nitrogen. Saturated ammonium chloride (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL*2). The organic phase was concentrated and purified by column chromatography (DCM / MeOH=100 / 0, 20 / 1) to give compound 86-c (159 mg, 55%). LC-MS (ESI): m / z=651.1 (M+H) + .

[1129] Synthesis of compound 86-b

[1130] 86-c (159 mg, 0.24 mmol), tetrahydrofuran (6 mL), water (0.8 mL), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (305 mg, 0.49 mmol), potassium phosphate (156 mg, 0.73 mmol) and cataCXium A Pd G3 (53 mg, 0.07 mmol) were added to a microwave tube. The atmosphere was replaced with nitrogen three times and the mixture was placed in an oil bath preheated to 65°C and stirred for 8 hours. The reaction mixture was concentrated and purified by column chromatography (DCM / MeOH = 100 / 0, 20 / 1) to give compound 86-b (196 mg, 72%). LC-MS (ESI): m / z = 1113.4 (M+H) + .

[1131] Synthesis of compound 86-a

[1132] To the reaction flask were added 86-b (196 mg, 0.18 mmol), DMF (5 mL), and cesium fluoride (1300 mg, 8.56 mmol), and the mixture was stirred at room temperature under nitrogen for 10 hours. Ammonium chloride (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL*3). The organic phase was concentrated and purified by column chromatography (DCM / MeOH = 100 / 0, 10 / 1) to give compound 86-a (134 mg, 95%). LC-MS (ESI): m / z = 801.6 (M+H) + .

[1133] Synthesis of compound 86

[1134] To the reaction flask, 86-a (90 mg, 0.11 mmol) and dichloromethane (6 mL) were added, and the mixture was stirred in an ice-water bath for 10 minutes. TBSOTf (20 mg, 0.08 mmol) was slowly added, and the reaction mixture was stirred in an ice-water bath for 1 hour. Saturated aqueous sodium bicarbonate solution (50 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 17 hours. The mixture was extracted with dichloromethane (20 mL*3), and the organic phase was concentrated and purified by preparative HPLC to give compound 86 (40 mg, 51%). LC-MS (ESI): m / z 701.3 (M+H) + .

[1135] Synthesis route of compound 87

[1136]

[1137] Synthesis of compound 87-f

[1138] To a reaction flask, add 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(1H)-one (2 g, 7.14 mmol) and acetonitrile (30 mL). Phosphorus oxychloride (1.31 g, 8.57 mmol) and N,N-diisopropylethylamine (3.0 mL, 17.14 mmol) were added under nitrogen, and stirred at 85°C for 1 hour. The reaction solution was cooled to -10°C, and a solution of tert-butyl 1,2-diazoheptyl-1-carboxylate (1.43 g, 7.14 mmol) in acetonitrile (10 mL) and N,N-diisopropylethylamine (0.55 g, 4.28 mmol) were added. The mixture was spin-dried to dryness, and stirred at room temperature for 1 hour. Water (30 mL) was added, stirred for 15 minutes, and extracted with ethyl acetate (30 mL). The aqueous phase was then extracted with ethyl acetate (20 mL). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 0-20%) to obtain 87-f (2.89 g, 87%). LC-MS (ESI): m / z 461.9 (M+H) + .

[1139] Synthesis of compound 87-e

[1140] To a reaction flask were added 87-f (500 mg, 1.08 mmol), potassium ethylene trifluoroborate (188 mg, 1.41 mmol), sodium bicarbonate (218 mg, 2.60 mmol), tetrakis(triphenylphosphine)palladium (125 mg, 0.11 mmol), and ethanol (5 mL). The atmosphere was replaced with nitrogen three times, heated to 80°C, and reacted for 5 hours. Dichloromethane (20 mL) and water (20 mL) were added to the reaction solution, the phases were separated, and the aqueous phase was extracted with dichloromethane (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and purified by column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-80%) to obtain 87-e (210 mg). LC-MS (ESI): m / z 454.4 (M+H). + .

[1141] Synthesis of compound 87-d

[1142] To the reaction flask, 87-e (210 mg, 0.19 mmol, 40% purity), trifluoroacetic acid (2 mL) and dichloromethane (2 mL) were added and stirred at room temperature for 1 hour. The organic solvent was evaporated to dryness, and dichloromethane (10 mL) and water (10 mL) were added to the reaction solution. The solution was neutralized with saturated sodium bicarbonate to pH 8-9, the phases were separated, and the aqueous phase was extracted with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried and purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0-80%) to give 87-d (50 mg, 13% for two-step reaction). LC-MS (ESI): m / z 354.1 (M+H) + .

[1143] Synthesis of compound 87-c

[1144] To the reaction flask, 87-d (240 mg, 0.68 mmol) and dichloromethane (2 mL) were added. m-Chloroperbenzoic acid (151 mg, 0.75 mmol) was added under ice-water bath and stirred at 0-5°C for 1 hour. Saturated sodium bicarbonate was added to the reaction solution to pH 9-10, followed by dichloromethane (10 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (10 mL). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to give 87-c (260 mg, 100%). LC-MS (ESI): m / z 370.1 (M+H) + .

[1145] Synthesis of compound 87-b

[1146] To a solution of sodium tert-butoxide (81 mg, 0.85 mmol) in anhydrous toluene (1 mL) at -10 to -5°C was added dropwise a solution of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (124 mg, 0.78 mmol) in anhydrous tetrahydrofuran (2.5 mL). The mixture was stirred at -10°C for 30 minutes. A solution of 87-c (250 mg, 0.68 mmol) in anhydrous tetrahydrofuran (10 mL) was then added dropwise. The reaction mixture was stirred at -10 to -5°C for 1 hour. The mixture was quenched by the addition of saturated sodium chloride solution (5 mL), stirred for 10 minutes, and extracted twice with ethyl acetate (10 mL). The organic phases were combined, filtered, and the filtrate was dried by spin drying. The mixture was purified by column chromatography (mobile phase: methanol:dichloromethane = 0-5%) to afford compound 87-b (153 mg). LC-MS (ESI): m / z 464.9 (M+H). + .

[1147] Synthesis of compounds 87-a-1 and 87-a-2

[1148] To a microwave tube was added 87-b (60 mg, 0.13 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (97 mg, 0.16 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (14 mg, 0.02 mmol), potassium phosphate (82 mg, 0.39 mmol), tetrahydrofuran (2.0 mL), and water (0.4 mL). The tube was sealed, purged with nitrogen three times, and heated in a microwave oven at 90°C for 6 hours. The reaction solution was extracted twice with dichloromethane (5 mL), the organic phases were combined, filtered, the filtrate was dried, and purified by column chromatography (mobile phase: ethyl acetate:petroleum ether = 10-100%; methanol:dichloromethane = 0-8%) to obtain 87-a-1 (45 mg) and 87-a-2 (89 mg, purity 42%) after removal of TIPS. 87-a-1: LC-MS (ESI): m / z 927.3 (M+H) + .87-a-2:LC-MS(ESI):m / z 771.2(M+H) + .

[1149] Synthesis of compound 87

[1150] To a solution of 87-a-1 (45 mg, 0.05 mmol) in tetrahydrofuran (2.4 mL) was added tetrabutylammonium fluoride trihydrate (39 mg, 0.13 mmol) and the mixture was stirred at room temperature for 2 hours. To a solution of 87-a-2 (89 mg, 42% purity, 0.05 mmol) in tetrahydrofuran (2 mL) was added tetrabutylammonium fluoride trihydrate (39 mg, 0.13 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixtures were combined, and dichloromethane (10 mL) and water (10 mL) were added to the reaction mixture. The phases were separated, and the aqueous phase was extracted with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was purified by column chromatography (mobile phase: methanol:dichloromethane = 0-8%), concentrated, and lyophilized to obtain 87 (43 mg). LC-MS (ESI): m / z 615.7 (M+H) + .

[1151] Synthesis route of compound 88

[1152]

[1153] Synthesis of compound 88-e

[1154] To a reaction flask were added N-Boc-piperazine (2.23 g, 11.96 mmol), 3,5-difluoro-4-trifluoromethylbenzene bromide (2.23 g, 8.54 mmol), tris(dibenzylideneacetone)dipalladium (780 mg, 0.85 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazole chloride (730 mg, 1.71 mmol), sodium tert-butoxide (1.23 g, 12.81 mmol), and toluene (22 mL). The atmosphere was replaced with nitrogen three times and the reaction was heated to 100°C for 2 hours. The reaction mixture was cooled to room temperature, and water (50 mL) and ethyl acetate (50 mL) were added. The phases were separated, and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The filtrate was purified by column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-10%) to afford compound 88-e (2.30 g, 73%). LCMS (ESI): m / z 367.1 (M+H) + .

[1155] Synthesis of compound 88-d

[1156] 88-e (3.00 g, 8.19 mmol), dichloromethane (30 mL), and trifluoroacetic acid (14.00 g, 123 mmol) were added to the reaction flask and stirred at room temperature for 3 hours. The reaction solution was concentrated and dissolved in dichloromethane (50 mL). The pH was adjusted to 9-10 with saturated aqueous sodium carbonate solution. The organic phase was concentrated to give compound 88-d (2.00 g, 92%). LCMS (ESI): m / z 267.1 (M+H)+ .

[1157] Synthesis of compound 88-c

[1158] To the reaction flask were added 3-c (2 g, 4.80 mmol), 1,1-cyclopropane dimethanol (2.14 g, 20.95 mmol), N,N-dimethylformamide (10 mL), and tetrahydrofuran (10 mL). The reaction system was heated to 50°C, and cesium carbonate (5.4 g, 16.57 mmol) and DABCO (0.054 g, 0.48 mmol) were added. The reaction was stirred at 50°C for 1 hour. The reaction solution was cooled to room temperature, and water (100 mL) was added. A large amount of solid precipitated. The mixture was kept in a slurry state at room temperature for 30 minutes, filtered, and the filter cake was dried to obtain 88-c (2.00 g, 86%). LCMS (ESI): m / z 482.1 (M+H). + .

[1159] Synthesis of compound 88-b

[1160] To a reaction flask under ice-water bath, add 88-c (800 mg, 1.66 mmol), dichloromethane (10 mL), and triethylamine (504 mg, 4.98 mmol). Add a solution of methanesulfonyl chloride (190 mg, 1.66 mmol) in dichloromethane (2 mL) d...

Claims

1. A nitrogen-containing heterocyclic compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotopic compound thereof: in, represents a single bond or a double bond; is phenyl, "a 5-7-membered heterocycloalkenyl group containing 1 to 3 heteroatoms selected from O, S and N", "a 5-7-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S and N" or a 5-7-membered cycloalkenyl group; wherein D 1 is C, CH or N; D2 is wherein Z1 and Z2 are independently a linker, CH, CH2, O, S, N or NH; r is 0, 1, 2, 3, or 4; R 5 are independently deuterium, halogen, C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl, C 3-10 Cycloalkyl, hydroxyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, amino, C 1-6 Alkyl-NH-, C 2-6 Alkenyl, nitro or C 3-10 Cycloalkyl-O-; X 1 and X 2 Independently for CR b or N, and X 1 and X 2 Not CR at the same time b ; Y 1 O, S, NH, CH2 or Y 2 NR 2 , O or S; m1, m2 and n are independently 0, 1, 2, 3 or 4; R b is hydrogen, halogen or cyano; R 1 C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", 1-1 Substituted C 6-20 Aryl, or, with one or more R 1-2 Substituted "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different; R 1-1 and R 1-2 are independently deuterium, halogen, -OR c , cyano, azido, -C(=O)R 11 、-NR 12 R 13 、-C(=O)OR 14 、-C(=O)NR 15 R 16 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -B(OR x )(OR y ), "a 4-7 membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from O, S and N", C 6-20 Aryl, "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", 1-1-1 Substituted C 1-6 Alkyl, with one or more R 1-1-2 Substituted C 1-6 Alkyl-O-, with one or more R 1-1-3 Substituted C 3-10 Cycloalkyl, with one or more R 1-1-4 Substituted "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N", 1-1-5 Substituted C 6-20 Aryl, or one or more R 1-1-6 Substituted "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they are the same or different; or, when R 1-1 or R 1-2 When there are multiple R, any two R 1-1 or two R 1-2 connected, independently forming a 3- to 8-membered cycloolefin together with the atoms to which they are connected; R 2 , R c , R 12 and R 13 are independently hydrogen, C 1-6 Alkyl, -C(=O)R c1 、-C(=O)OR c2 、-C(=O)NR c3 R c4 、-SO2R c5 , or by one or more R c10 Substituted C 1-6 alkyl; R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are independently hydrogen, C 1-20 Alkyl, C 3-10 Cycloalkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N", C 6-20 Aryl, "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", one or more R 4-1-1 Substituted C 1-20 Alkyl, with one or more R 4-1-2 Substituted C 3-10 Cycloalkyl, with one or more R 4-1-3 Substituted "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N", 4-1-4 Substituted C 6-20 Aryl, "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", one or more R 4-1-5 Substituted "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", -NR c51 R c52 、-(C 1-6 Alkylene-O) p -C 1-6 alkyl, p is 1, 2, 3 or 4; R 1-1-1 , R 1-1-2 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-6 , R 4-1-1 , R 4-1-2 , R 4-1-3 , R 4-1-4 and R 4-1-5 are independently cyano, halogen, hydroxyl, nitro, C 1-6 Alkyl-O-, C 1-6 Alkyl, with one or more R 31 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N", C 6-20 Aryl, "a 5- to 7-membered heteroaryl group containing 1 or 2 heteroatoms independently selected from O, S and N", -B(OR x )(OR y ), -C(=O)R 21 、-NR 22 R 23 、-OC(=O)R 24 、-OC(=O)R 32 、-C(=O)NR 25 R 26 , -COOH, -C(=O)OR 27 OR-OC(=O)OR 28 ; R c10 C 1-6 Alkyl-O-, hydroxyl, C 1-6 Alkyl substituted By one or more -B(OR x )(OR y ) substituted C 6-20 Aryl, one or more R c10-1 Substituted "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", or -OC(=O)R 29 ; R c10-1 Independently for C 1-6 Alkyl or nitro; Or, optional R 2 and R b , optional R 2 and R 5 The atoms to which they are connected form a "5-12 membered heterocycloalkenyl group containing 2 to 4 heteroatoms, two of which are N, and the other heteroatoms are independently selected from O, S and N", or one or more R a Substituted "5- to 12-membered heterocycloalkenyl containing 2 to 4 heteroatoms, two of which are N, and the other heteroatoms are independently selected from O, S and N"; R x and R y are independently hydrogen or C 1-6 Alkyl, or R x and R y Formed with the oxygen atom to which it is connected one or more C 1-6 an alkyl-substituted five-membered ring; R 4 are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, with one or more R 4-1 Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-O-, with one or more R 4-2 Substituted C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, with one or more R 4-3 Substituted C 1-6 Alkyl-S-, O=, C 3-10 Cycloalkyl-O-, -C(=O)R 4a 、-NR 4b1 R 4b2 、-C(=O)OR 4c or -C(=O)NR 4d1 R 4d2 ; or, when n is 2, 3 or 4, any two R 4 connected, independently forming a 3-8 membered carbon ring with the atoms to which they are connected, and surrounded by one or more R 4-4 substituted 3-8 membered carbocyclic ring, "4-8 membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N", or, 4-5 Substituted "4-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N"; R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 and R a are independently halogen, C 1-6 Alkyl, C 2-6 Alkenyl, cyano, hydroxyl, C 1-6 Alkyl-O-, -NR 4i R 4j 、-C(=O)OR 4e or -C(=O)NR 4f1 R 4f2 or, R 4-5 is O=; R 4a , R 4b1 , R 4b2 , R 4c , R 4d1 , R 4d2 , R 4e , R 4f1 , R 4f2 , R 4i and R 4j are independently hydrogen, C 2-6 Alkenyl or C 1-6 alkyl; L1 is the connecting key, C 1-6 Alkylene, -C(=O)-, -O(R L-1 ) n1 -、-S(R L-2 ) n2 -or-NR L-3 (R L-4 ) n3 -; R L-1 , R L-2 and R L-4 Independently for C 1-6 Alkylene or C substituted by one or more deuterium 1-6 Alkylene; R L-3 is hydrogen or C 1-6 Alkyl; n1, n2 and n3 are independently 0 or 1; R 3 C 3-12 Cycloalkyl, with one or more R 3-1 Substituted C 3-12 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 3-2 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", C 1-6 Alkyl, with one or more R 3-3 Substituted C 1-6 Alkyl, with one or more R 3-4 Substituted C 2-6 Alkenyl, -OR d 、-SR d1 、-NR e1 R e2 , or -C(=O)NR e3 R e4 ; When there are multiple substituents, they are the same or different; R 3-1 , R 3-2 , R 3-3 and R 3-4 Independently for C 1-6 Alkyl, with one or more R 3-1-1 Substituted C 1-6 Alkyl, with one or more R 3-1-5 Substituted C 6-20 Aryl, Hydroxyl, Azide, Ar, C 1-6 Alkyl-O-, -CH2-O-Ar, halogen, O=, -NR e5 R e6 、-C(=O)NR e7 R e8 or Ar is replaced by one or more R 3-1-4 Substituted "5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S"; Or, R 3-1 and R 3-2 Independently -L2-M; L2 is -L 21 -L 22 -L 23 -L 24 -L 25 -L 26 ; L 21 , L 23 and L 25 are independently a linker, O, S, NH, C(O)NH or C 1-6 Alkylene; L 22 and L 24 Independently for the connecting bond, C 3-10 Cycloalkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N", C 6-20 Aryl, or "a 5- to 7-membered heteroaryl group containing 1 or 2 heteroatoms independently selected from O, S and N"; L 26 is a linking bond, O, S, NH or C(O)NH; M is R 4g , R 4h , R e17 and R e18 are independently hydrogen, halogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, cyano, -C(=O)R e171 、-C(=O)OR e172 or -C(=O)NR e173 R e174 or, R 4g and R 4h , R e17 and R e18 , together with the atoms to which it is attached, form a 3- to 8-membered carbocyclic ring, or a 4- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N; R d , R d1 , R e1 , R e2 , R e3 and R e4 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, "4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", or, one or more R 3-1-2 Substituted C 1-6 alkyl; R 3-1-1 , R 3-1-2 , R 3-1-5 and R 3-1-4 are independently deuterium, cyano, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkyl-O-, C substituted by one or more halogens 1-6 Alkyl-O-, C substituted by one or more halogens 1-6 Alkyl, -C(=O)R e9 、-NR e10 R e11 、-C(=O)OR e12 、-C(=O)NR e13 R e14 、-OC(=O)NR e15 R e16 , "a 4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", or, one or more R 3-1-1-1 Substituted "4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; or, any two R 3-1-5 connected to form one or more R 3-1-1-2 Substituted "4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; R 3-1-1-1 and R 3-1-1-2 Independently Halogen, C 1-6 Alkyl or one or more R 3-1-1-1-1 Substituted C 6-20 Aryl; R 3-1-1-1-1 is halogen or C substituted by one or more halogens 1-6 alkyl; R e5 , R e6 , R e7 , R e8 , R e9 , R e10 , R e11 , R e12 , R e13 , R e14 , R e15 , R e16 , R e171 , R e172 , R e173 and R e174 are independently hydrogen or C 1-6 alkyl; Or, R 12 and R 13 , R 15 and R 16 , R c3 and R c4 , R 22 and R 23 , R 25 and R 26 , R 4b1 and R 4b2 , R 4d1 and R 4d2 , R 4f1 and R 4f2 , R 4i and R 4j , R e1 and R e2 , R e3 and R e4 , R e5 and R e6 , R e7 and R e8 , R e10 and R e11 , R e13 and R e14 , R e15 and R e16 , R e173 and R e174 The N atom to which it is connected forms a "4-12 membered heterocycloalkyl group containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N", or one or more R 3-1-3 Substituted "4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N"; R 3-1-3 are independently deuterium, cyano, halogen, hydroxyl, C 1-6 Alkyl-O-, C 1-6 Alkyl, with one or more R 33 Substituted C 1-6 Alkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N" or -C(=O)OR 30 ; R c51 , R c52 , R 11 , R 21 , R 14 , R 15 , R 16 , R 24 , R 25 , R 26 , R 27 , R 28 and R 30 are independently hydrogen or C 1-6 alkyl; R 29 For hydrogen, C 1-6 Alkyl or -NR m R n ; R 31 For hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, -NR m R n 、-OC(=O)R 32 or -C(=O)OC 1-6 alkyl; R 32 and R 33 Independently for -OC 1-6 Alkyl or one or more -NR m R n Substituted C 1-6 Alkyl; R 22 , R 23 , R m and R n are independently hydrogen, C 1-6 Alkyl or Boc.

2. The nitrogen-containing heterocyclic compound as shown in Formula I according to claim 1, its pharmaceutically acceptable salt, its prodrug, its stereoisomer, its tautomer or its isotope compound, characterized in that: in, represents a single bond or a double bond; is phenyl, "a 5-7 membered heterocycloalkenyl group containing 1 to 3 heteroatoms selected from O, S and N", or "a 5-7 membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S and N"; wherein D 1 is C, CH or N; D2 is wherein Z1 and Z2 are independently a linker, CH, CH2, O, S, N or NH; r is 0, 1, or 2; R 5 are independently halogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl, hydroxyl, C 1-6 Alkyl-O-, C 2-6 Alkenyl or nitro; Y 1 O, NH, CH2 or Y 2 O or NR 2 ; m1, m2 and n are independently 0, 1, 2, 3 or 4; X 1 and X 2 All are N; R 1 C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", 1-1 Substituted C 6-20 Aryl, or, with one or more R 1-2 Substituted "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different; R 1-1 and R 1-2 are independently halogen, -OR c , cyano, -NR 12 R 13 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -B(OR x )(OR y ) or by one or more R 1-1-1 Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different; R 2 , R c , R 12 and R 13 are independently hydrogen, C 1-6 Alkyl, -C(=O)R c1 、-C(=O)OR c2 、-C(=O)NR c3 R c4 、-SO2R c5 , or by one or more R c10 Substituted C 1-6 alkyl; R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are independently hydrogen, C 1-20 Alkyl, C 3-10 Cycloalkyl, with one or more R 4-1-1 Substituted C 1-20 Alkyl, with one or more R 4-1-4 Substituted C 6-20 Aryl, "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", 4-1-5 Substituted "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", -NR c51 R c52 、-(C 1-6 Alkylene-O) p -C 1-6 alkyl, or, p is 1, 2, 3 or 4; when there are multiple substituents, they are the same or different; R 1-1-1 , R 4-1-1 , R 4-1-4 and R 4-1-5 are independently halogen, hydroxyl, C 1-6 Alkyl-O-, with one or more R 31 Substituted C 1-6 Alkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N", C 6-20 Aryl, -C(=O)R 21 、-NR 22 R 23 、-OC(=O)R 24 、-OC(=O)R 32 , -COOH, -C(=O)OR 27 OR-OC(=O)OR 28 ; R c10 C 1-6 Alkyl-O-, C 1-6 Alkyl substituted By one or more -B(OR x )(OR y ) substituted C 6-20 Aryl, one or more R c10-1 Substituted "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", or -OC(=O)R 29 ; R c10-1 Independently for C 1-6 Alkyl or nitro; Or, optional R 2 and R 5 Respectively with the atoms to which they are connected, they form a "5- to 12-membered heterocycloalkenyl group containing 2 to 4 heteroatoms, two of which are N, and the other heteroatoms are independently selected from O, S and N"; R x and R y are independently hydrogen, or R x and R y Formed with the oxygen atom to which it is connected one or more C 1-6 an alkyl-substituted five-membered ring; R 4 are independently deuterium, halogen, hydroxyl, C 1-6 Alkyl, O= or -C(=O)R 4a ; or, when n is 2, 3 or 4, any two R 4 connected to form a 4-5 Substituted "4-8 membered heterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, S and N"; R 4-5 is O=; R 4a C 2-6 Alkenyl or C 1-6 alkyl; L1 is a connecting bond or -O(R L-1 ) n1 -; R L-1 C 1-6 Alkylene or C substituted by one or more deuterium 1-6 Alkylene; n1 is 1; R 3 For one or more R 3-1 Substituted C 3-12 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 3-2 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", or, substituted by one or more R 3-4 Substituted C 2-6 Alkenyl; when there are multiple substituents, they may be the same or different; R 3-1 , R 3-2 and R 3-4 Independently for C 1-6 Alkyl, with one or more R 3-1-1 Substituted C 1-6 Alkyl, with one or more R 3 -1-5 Substituted C 6-20 Aryl, Ar, C 1-6 Alkyl-O-, -CH2-O-Ar, halogen, or Ar is replaced by one or more R 3-1-4 Substituted "5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S"; R 3-1-1 , R 3-1-5 and R 3-1-4 are independently halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C substituted by one or more halogen 1-6 Alkyl-O-, C substituted by one or more halogens 1-6 Alkyl, -C(=O)R e9 、-NR e10 R e11 、-OC(=O)NR e15 R e16 , "a 4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", or, one or more R 3-1-1-1 Substituted "4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", or any two R 3-1-5 connected to form one or more R 3-1-1-2 Substituted "4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; R 3-1-1-1 and R 3-1-1-2 are independently halogen, C 1-6 Alkyl or one or more R 3-1-1-1-1 Substituted C 6-20 Aryl; R 3-1-1-1-1 is independently halogen or C substituted by one or more halogens 1-6 alkyl; Or, R 3-1 and R 3-2 Independently -L2-M; L2 is -L 21 -L 22 -L 23 -L 24 -L 25 -L 26 ; L 21 , L 23 and L 25 are independently a linker, O, S, NH, C(O)NH or C 1-6 Alkylene; L 22 and L 24 Independently for the connecting bond, C 3-10 Cycloalkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N", C 6-20 Aryl, or "a 5- to 7-membered heteroaryl group containing 1 or 2 heteroatoms independently selected from O, S and N"; L 26 is a linking bond, O, S, NH or C(O)NH; M is R e17 and R e18 are independently hydrogen or halogen; R e9 , R e10 , R e11 , R e15 and R e16 are independently hydrogen or C 1-6 alkyl; Or, R c3 and R c4 The N atom to which it is connected forms a "4-12 membered heterocycloalkyl group containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N", or one or more R 3-1-3 Substituted "4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N"; R 3-1-3 Independently for one or more R 33 Substituted C 1-6 Alkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N" or -C(=O)OR 30 ; R c51 , R c52 , R 24 , R 27 , R 28 and R 30 are independently hydrogen or C 1-6 alkyl; R 29 For hydrogen, C 1-6 Alkyl or -NR m R n ; R 31 For hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, -NR m R n 、-OC(=O)R 32 or -C(=O)OC 1-6 alkyl; R 32 and R 33 Independently for -OC 1-6 Alkyl or one or more -NR m R n Substituted C 1-6 Alkyl; R 21 , R 22 , R 23 , R m and R n are independently hydrogen, C 1-6 Alkyl or Boc.

3. The nitrogen-containing heterocyclic compound as shown in formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof as claimed in claim 1 or 2, characterized in that: represents a single bond or a double bond; is phenyl, "a 5-7 membered heterocycloalkenyl group containing 1 to 3 heteroatoms selected from O, S and N" or "a 5-7 membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S and N"; wherein D 1 is C or N; D2 is Wherein Z1 and Z2 are independently a linker, CH, CH2, N or NH; r is 0, 1, or 2; R 5 are independently halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl, hydroxyl or C 2-6 alkenyl; Y 1 O, NH, CH2 or Y 2 O or NR 2 ; R 2 For hydrogen, C 1-6 Alkyl, -C(=O)R c1 OR -C(=O)OR c2 ; R c1 For one or more R 4-1-1 Substituted C 1-20 Alkyl; R c2 C 1-6 Alkyl; R 4-1-1 are independently halogen; m1 and m2 are independently 0 or 1; n is 0, 1 or 2; R 4 is halogen, hydroxyl or C 1-6 alkyl; X 1 and X 2 is N; R 1 C 6-20 Aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", 1-1 Substituted C 6-20 Aryl, or, with one or more R 1-2 Substituted "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N"; when there are multiple substituents, they may be the same or different; R 1-1 and R 1-2 are independently halogen, -OR c , cyano, -NR 12 R 13 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -B(OR x )(OR y ) or by one or more R 1-1-1 Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different; R c is hydrogen, -C(=O)R c1 、-C(=O)NR c3 R c4 or by one or more R c10 Substituted C 1-6 Alkyl; R c10 are independently -OC(=O)R 29 ; R 29 For-NR m R n ; R m and R n C 1-6 alkyl; R c1 , R c3 and R c4 are independently hydrogen, C 1-20 Alkyl, C 3-10 Cycloalkyl, -(C 1-6 Alkylene-O) p -C 1-6 Alkyl, with one or more R 4-1-1 Substituted C 1-20 Alkyl or one or more R 4-1-4 Substituted C 6-20 Aryl; p is 1, 2 or 3; R 4-1-1 For-OC 1-6 Alkyl, -C(=O)R 21 、-NR 22 R 23 , -COOH or "a 4-7 membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from O, S and N"; R 21 C 1-6 Alkyl; R 22 and R 23 are independently hydrogen, C 1-6 Alkyl or Boc; R 4-1-4 is a halogen; Or, R c3 and R c4 The N atom to which it is connected forms a "4-12 membered heterocycloalkyl group containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N", or one or more R 3-1-3 Substituted "4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N"; R 3-1-3 Independently for one or more R 33 Substituted C 1-6 Alkyl or "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N"; R 33 For-OC 1-6 alkyl; R 12 and R 13 are independently hydrogen; R x and R y are independently hydrogen; R 1-1-1 is a halogen; L1 is a connecting bond or -O(R L-1 ) n1 -; R L-1 C 1-6 Alkylene or C substituted by one or more deuterium 1-6 Alkylene; n1 is 1; R 3 For one or more R 3-1 Substituted C 3-12 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 3-2 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 3-4 Substituted C 2-6 Alkenyl; when there are multiple substituents, they may be the same or different; R 3-1 Independently for one or more R 3-1-1 Substituted C 1-6 Alkyl; R 3-1-1 Independently -NR e10 R e11 , "a 4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", or one or more R 3-1-1-1 Substituted "4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; R e10 and R e11 Independently for C 1-6 Alkyl; R 3-1-1-1 Independently for C 1-6 alkyl, or one or more R 3-1-1-1-1 Substituted C 6-20 Aryl; R 3-1-1-1-1 are independently halogen; R 3-2 are independently halogen, C 1-6 Alkyl, with one or more R 3-1-1 Substituted C 1-6 Alkyl, Ar, -CH2-O-Ar or one or more R 3-1-5 Substituted C 6-20 Aryl; Ar is substituted by one or more R 3-1-4 Substituted "5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S"; R 3-1-1 For halogen, C 2-6 Alkenyl or -OC(=O)NR e15 R e16 ; R e15 and R e16 Independently for C 1-6 Alkyl; R 3-1-4 and R 3-1-5 Independently for C 1-6 Alkyl, halogen, C substituted by one or more halogens 1-6 Alkyl-O- or C substituted by one or more halogen 1-6 Alkyl; or, any two R 3-1-5 connected to form one or more R 3-1-1-2 Substituted "4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; R 3-1-1-2 are independently halogen; Or, R 3-1 -L2-M; L2 is -L 21 -L 22 -L 23 -L 24 -L 25 -L 26 ; L 21 , L 23 and L 25 are independently a linker, O, S, NH, C(O)NH or C 1-6 Alkylene; L 22 and L 24 Independently for the connecting bond, C 3-10 Cycloalkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N", C 6-20 Aryl, or "a 5- to 7-membered heteroaryl group containing 1 or 2 heteroatoms independently selected from O, S and N"; L 26 is a linking bond, O, S, NH or C(O)NH; M is R 3-4 are independently halogen, or are replaced by one or more R 3-1-1 Substituted C 1-6 Alkyl; R 3-1-1 For-NR e10 R e11 or "a 4- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S and N"; R e10 and R e11 Independently for C 1-6 alkyl; R e17 and R e18 are independently hydrogen or halogen.

4. The nitrogen-containing heterocyclic compound as shown in Formula I according to claim 1, its pharmaceutically acceptable salt, its prodrug, its stereoisomer, its tautomer or its isotope compound, characterized in that: D 1 C or N; and / or, in D2, any one of Z1 and Z2 is CH, CH2 or N, and the other is a connecting bond; and / or, r is 0, 1 or 2; and / or, R 5 are independently halogen, C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl, hydroxyl, C 1-6 Alkyl-O-, C 2-6 Alkenyl or nitro; and / or, X 1 and X 2 All are N; and / or, R 1-1 are independently halogen, -OR c , C 1-6 Alkyl, -NR 12 R 13 , C 2-6 Alkynyl or one or more R 1-1-1 Substituted C 1-6 Alkyl; when there are multiple substituents, they may be the same or different; R 1-1-1 are independently halogen; and / or, R 1-2 are independently halogen, cyano, C 2-6 Alkenyl or -NR 12 R 13 ; and / or, R 12 and R 13 independently hydrogen, -SO2R c5 , or -C(=O)OR c2 ; R c2 C 1-6 alkyl; and / or, R c is hydrogen, -C(=O)R c1 、-C(=O)OR c2 、-C(=O)NR c3 R c4 、-SO2R c5 , or by one or more R c10 Substituted C 1-6 Alkyl; R c10 Independently for C 1-6 Alkyl-O-, C 1-6 Alkyl substituted By one or more -B(OR x )(OR y ) substituted C 6-20 Aryl, one or more R c10-1 Substituted "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", or -OC(=O)R 29 ; R c10-1 Independently for C 1-6 Alkyl or nitro; R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 are independently hydrogen, C 1-20 Alkyl, C 3-10 Cycloalkyl, with one or more R 4-1-1 Substituted C 1-20 Alkyl, with one or more R 4-1-4 Substituted C 6-20 Aryl, "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", 4-1-5 Substituted "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", -NR c51 R c52 、-(C 1-6 Alkylene-O) p -C 1-6 alkyl, p is 1, 2, 3 or 4; when there are multiple substituents, they are the same or different; R 1-1-1 , R 4-1-1 , R 4-1-4 and R 4-1-5 are independently halogen, hydroxyl, C 1-6 Alkyl-O-, C 1-6 Alkyl, with one or more R 31 Substituted C 1-6 Alkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N", C 6-20 Aryl, "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O, S and N", -NR 22 R 23 、-OC(=O)R 24 、-OC(=O)R 32 , -COOH, -C(=O)OR 27 OR-OC(=O)OR 28 ; R x and R y are independently hydrogen, or R x and R y Formed with the oxygen atom to which it is connected one or more C 1-6 an alkyl-substituted five-membered ring; Or, R c3 and R c4 The N atom to which it is connected forms a "4-12 membered heterocycloalkyl group containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N", or, 3-1-3 Substituted "4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N"; R 3-1-3 Independently for one or more R 33 Substituted C 1-6 Alkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N" or -C(=O)OR 30 ; R 30 is hydrogen or C 1-6 Alkyl; R 33 Independently for -OC 1-6 Alkyl or one or more -NR m R n Substituted C 1-6 Alkyl; R m and R n are independently hydrogen, C 1-6 Alkyl or -Boc; and / or, when R 1 For one or more R 1-1 Substituted C 6-20 When it is an aryl group, the plurality is two or three; and / or, Y 1 O, NH, CH2 or and / or, m1, m2 and n are independently 0, 1 or 2; and / or, Y 2 O or NR 2 ; and / or, R 2 For hydrogen, C 1-6 Alkyl, -C(=O)R c1 OR -C(=O)OR c2 ; R c1 C 1-20 Alkyl or one or more R 4-1-1 Substituted C 1-20 Alkyl; R c2 C 1-6 Alkyl or one or more R 4-1-1 Substituted C 1-6 Alkyl; R 4-1-1 are independently halogen, C 6-20 Aryl or -OC(=O)R 24 ; or, optionally, R 2 and R 5 Respectively with the atoms to which they are connected, they form a "5- to 12-membered heterocycloalkenyl group containing 2 to 4 heteroatoms, two of which are N, and the other heteroatoms are independently selected from O, S and N"; and / or, R 24 C 1-6 alkyl; and / or, R 4 are independently hydroxy, halogen, deuterium, -C(=O)R 4a , oxo or C 1-6 Alkyl; R 4a C 1-6 Alkyl or C 2-6 alkenyl; and / or, L1 is a linking bond or -O(R L-1 ) n1 -; R L-1 Independently for C 1-6 Alkylene or C substituted by one or more deuterium 1-6 Alkylene; n1 is 1; and / or, R 3 For one or more R 3-1 Substituted C 3-12 Cycloalkyl, "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 3-2 Substituted "4-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", 3-4 Substituted C 2-6 Alkenyl; when there are multiple substituents, they may be the same or different; and / or, R 3-1 Independently for one or more R 3-1-1 Substituted C 1-6 Alkyl; R 3-1-1 Independently -NR e10 R e11 , "a 4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N", or, one or more R 3-1-1-1 Substituted "4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; R e10 and R e11 Independently for C 1-6 Alkyl; R 3-1-1-1 C 1-6 alkyl, or one or more R 3-1-1-1-1 Substituted C 6-20 Aryl; R 3-1-1-1-1 is independently halogen or C substituted by one or more halogens 1-6 Alkyl; R e17 and R e18 are independently hydrogen or halogen; or, R 3-1 Independently -L2-M; L2 is -L 21 -L 22 -L 23 -L 24 -L 25 -L 26 ; L 21 , L 23 and L 25 are independently a linker, O, S, NH, C(O)NH or C 1-6 Alkylene; L 22 and L 24 Independently for the connecting bond, C 3-10 Cycloalkyl, "4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O, S and N", C 6-20 Aryl, or "a 5- to 7-membered heteroaryl group containing 1 or 2 heteroatoms independently selected from O, S and N"; L 26 is a linking bond, O, S, NH or C(O)NH; M is and / or, R 3-2 are independently halogen, C 1-6 Alkyl, with one or more R 3-1-1 Substituted C 1-6 alkyl, By one or more R 3-1-5 Substituted C 6-20 Aryl, -CH2-O-Ar or Ar; Ar is 3-1-4 Substituted "5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S"; R 3-1-1 Halogen, -OC(=O)NR e15 R e16 or C 2-6 Alkenyl; R e15 and R e16 Independently for C 1-6 Alkyl; R e17 and R e18 are independently hydrogen or halogen; R 3-1-4 and R 3-1-5 are independently halogen, C 1-6 Alkyl, C substituted by one or more halogens 1-6 Alkyl-O- or C substituted by one or more halogen 1-6 Alkyl; or, any two R 3-1-5 connected to form one or more R 3-1-1-2 Substituted "4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N"; R 3-1-1-2 are independently halogen; and / or, R 3-4 are independently halogen or are replaced by one or more R 3-1-1 Substituted C 1-6 Alkyl; R 3-1-1 Independently -NR e10 R e11 or "a 4- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S and N"; R e10 and R e11 Independently for C 1-6 alkyl.

5. The nitrogen-containing heterocyclic compound as shown in Formula I, its pharmaceutically acceptable salt, its prodrug, its stereoisomer, its tautomer or its isotope compound as claimed in claim 1, characterized in that: When r is 1, for and / or, m1 and m2 are independently 0 or 1; and / or, R e17 and R e18 are independently hydrogen or halogen; and / or, when the group R 5 , R b , R 1-1 , R 1-2 , R 1-1-1 , R 1-1-2 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-6 , R 4-1-1 , R 4-1-2 , R 4-1-3 , R 4-1-4 , R 4-1-5 , R 4 , R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 , R a , R 3-1 , R 3-2 , R 3-3 , R 3-4 , R 3-1-1 , R 3-1-2 , R 3-1-3 , R 3-1-5 , R 3 -1-4 , R 4g , R 4h , R e17 , R e18 , R 3-1-1-1 and R 3-1-1-1-1 When the definition of halogen is mentioned, the halogen mentioned is fluorine, chlorine, bromine or iodine; and / or, when the group R 1 , R 1-1 , R 1-2 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 , R c9 , R 1-1-1 , R 1-1-2 , R 1-1-3 , R 1 -1-4 , R 1-1-5 , R 1-1-6 , R 4-1-1 , R 4-1-2 , R 4-1-3 , R 4-1-4 , R 4-1-5 , R c10 , R 3-1 , R 3-2 , R 3-3 , R 3-4 and R 3-1-1-1 The definition of C 6-20 When the C 6-20 Aryl is phenyl, naphthyl or anthracenyl; and / or, when the group R 5 、R 1-1 、R 1-2 、R 2 、R c 、R 12 、R 13 、R c10 、R c10-1 、R 1-1-1 、R 1-1-2 、R 1-1-3 、R 1-1-4 、R 1-1-5 、R 1 -1-6 、R 4-1-1 、R 4-1-2 、R 4-1-3 、R 4-1-4 、R 4-1-5 、R c51 、R c52 、R 11 、R 21 、R 22 、R 23 、R 14 、R 24 、R 15 、R 25 、R 16 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R x 、R y 、R 4 、R 4-1 、R 4-2 、R 4-3 、R 4-4 、R 4-5 、R a 、R 4a 、R 4b1 、R 4b2 、R 4c 、R 4d1 、R 4d2 、R 4e 、R 4f1 、R 4f2 、R 4i 、R 4j 、R L-3 、R 3 、R 3-1 、R 3-2 、R 3-3 、R 3-4 、R 4g , R 4h , R e17 , R e18 , R d , R d1 , R e1 , R e2 , R e3 , R e4 , R 3-1-1 , R 3-1-2 , R 3-1-5 , R 3-1-4 , R 3-1-1-1 , R 3-1-1-1-1 , R e5 , R e6 , R e7 , R e8 , R e9 , R e10 , R e11 , R e12 , R e13 , R e14 , R e15 , R e16 , R e171 , R e172 , R e173 , R e174 and R 3-1-3 The definition of C 1-6 When the C 1-6 Alkyl is C 1-4 Alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; and / or, when the group R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R c7 , R c8 and R c9 Independently for C 1-20 When the C 1-20 Alkyl is C 1-12 Alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; and / or, when the group R 1-1 , R 1-2 and R 4 The definition of C 2-6 When the C 2-6 Alkynyl is C 2-3 Alkynyl, for example ethynyl, propynyl or propargyl; and / or, when the group R 5 , R 1-1 , R 1-2 , R 4 , R 4-1 , R 4-2 , R 4-3 , R 4-4 , R 4-5 , R a , R 4a , R 4b1 , R 4b2 , R 4c , R 4d1 , R 4d2 , R 4e , R 4f1 , R 4f2 , R 4i , R 4j , R 3 , R 3-1-1 , R 3-1-2 , R 3-1-5 and R 3-1-4 The definition of C 2-6 When alkenyl, the C 2-6 Alkenyl is C 2-3 Alkenyl, for example, ethenyl, propenyl or allyl.

6. The nitrogen-containing heterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof according to claim 1, characterized in that: The R 4 are independently methyl, fluoro, deuterium, oxo, or hydroxyl; and / or, for and / or, the R 5 are independently -F, -OH, -Cl, -CF3, -NO2, -OEt or -OMe, or, R 2 and R 5 form and / or, the R 1 for And / or, L1 is a connecting bond, -OCH2- or -OCD2-; and / or, the R 3 for 7. The nitrogen-containing heterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof according to claim 1, characterized in that: for and / or, for and / or, for 8. The nitrogen-containing heterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof according to claim 1, characterized in that: The nitrogen-containing heterocyclic compound shown in Formula I is any of the following structures:

9. A compound having the structure shown below:

10. A pharmaceutical composition comprising substance A and a pharmaceutical excipient; the substance A is a therapeutically effective amount of a nitrogen-containing heterocyclic compound as shown in formula I according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof.

11. Use of a substance A in the preparation of a RAS inhibitor, wherein the substance A is a nitrogen-containing heterocyclic compound as shown in formula I as described in any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof; the RAS is a wild-type amplified RAS and a mutant RAS; the wild-type RAS may be a wild-type amplified KRAS; the mutant RAS is, for example, a mutant KRAS, a mutant HRAS or a mutant NRAS.

12. Use of a substance A in the preparation of a drug, wherein the drug is used to treat or prevent RAS-related diseases; the substance A is a nitrogen-containing heterocyclic compound as shown in formula I as described in any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof; the RAS is a wild-type amplified RAS and a mutant RAS; the wild-type RAS may be a wild-type amplified KRAS; the mutant RAS is, for example, a mutant KRAS, a mutant HRAS or a mutant NRAS.

13. Use of a substance A in preparing a drug, wherein the drug is used to treat or prevent cancer; the substance A is a nitrogen-containing heterocyclic compound as shown in formula I as described in any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, a prodrug thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof; the cancer is, for example, one or more of colon cancer, appendix cancer, pancreatic cancer, MYH-related polyposis, blood cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, gastric cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.

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