CN113286794A

CN113286794A - KRAS mutein inhibitors

Info

Publication number: CN113286794A
Application number: CN202080008063.5A
Authority: CN
Inventors: 李阿敏; 李素静; 王鹏; 党超杰; 刘丹
Original assignee: Jacobio Pharmaceuticals Co Ltd
Current assignee: Jacobio Pharmaceuticals Co Ltd
Priority date: 2019-11-04
Filing date: 2020-08-18
Publication date: 2021-08-20
Anticipated expiration: 2040-08-18
Also published as: CN113286794B; WO2021088458A1

Abstract

Provided herein are KRAS mutein inhibitors of formula (I), compositions containing the inhibitors and uses thereof.

Description

KRAS mutein inhibitors

Technical Field

The invention relates to a KRAS mutein inhibitor represented by formula (I), a composition containing the inhibitor and application thereof.

Background

RAS represents a set of 189 amino acid monomeric globular proteins (21kDa molecular weight) that are closely related to the plasma membrane and which bind either GDP or GTP. RAS functions as a molecular switch. When the RAS contains bound GDP, it is in the dormant or off position and is "inactive". When cells are exposed to certain growth-promoting stimuli, RAS is induced to exchange its bound GDP for GTP. In the case of bound GTP, RAS is "turned on" and is able to interact with and activate other proteins (their "downstream targets"). The inherent ability of RAS proteins to hydrolyze GTP back to GDP, thereby turning themselves off, is very low. Shutting down RAS requires a foreign protein called Gtpase Activator Protein (GAP), which interacts with RAS and greatly accelerates conversion of GTP to GDP. Any mutation in RAS that affects its ability to interact with GAPs or convert GTP back to GDP will result in prolonged activation of the protein and thus signal the cell to continue growth and division. Because these signals lead to cell growth and division, hyperactive RAS signaling may ultimately lead to cancer.

Structurally, RAS proteins contain a G domain that is responsible for the enzymatic activity of RAS-guanine nucleotide binding and hydrolysis (gtpase reaction). It also contains a C-terminal extension called CAAX box, which can be post-translationally modified and is responsible for targeting proteins to the cell membrane. The G domain is about 21-25kDa in size and it contains a phosphate binding loop (P loop). The P-loop represents the pocket in which nucleotides bind in proteins, and this is a rigid part of the domain with conserved amino acid residues that are essential for nucleotide binding and hydrolysis (glycine 12, threonine 26 and lysine 16). The G domain also contains the so-called switch I (residues 30-40) and switch II (residues 60-76) regions, both of which are dynamic parts of the protein, which are often denoted as "spring-loaded" mechanisms because they are able to switch between the resting and loaded states. The key interaction is the hydrogen bond formed by threonine-35 and glycine-60 with the gamma-phosphate of GTP, which maintains the switch 1 and switch 2 regions in their active conformations, respectively. After GTP hydrolysis and phosphate release, both relax into the inactive GDP conformation.

The most well-known members of the RAS subfamily are HRAS, KRAS and NRAS, primarily because of their involvement in many types of cancer. Mutations in any of the three major subtypes of the RAS gene (HRAS, NRAS or KRAS) are the most common events in human tumorigenesis. About 30% of all human tumors were found to carry some mutations in the RAS gene. Notably, KRAS mutations were detected in 25-30% of tumors. In contrast, the incidence of oncogenic mutations in NRAS and HRAS family members is much lower (8% and 3%, respectively). The most common KRAS mutations are found at residues G12 and G13 and at residue Q61 in the P loop.

G12C is a frequent mutation of the KRAS gene (glycine-12 to cysteine). This mutation has been found in about 13% of carcinogenesis, about 43% of lung cancer occurrences, and in almost 100% of MYH-related polyposis (familial colon cancer syndrome). However, targeting this gene with small molecules is challenging.

Thus, despite advances in this field, there remains a need in the art for improved compounds and methods for treating cancer, for example, by inhibiting KRAS, HRAS or NRAS. The present invention fulfills this need and provides further related advantages.

Disclosure of Invention

In one aspect, the present invention provides a compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof:

wherein the content of the first and second substances,

R₁is selected from 4R₁₁substituted-C_6-10Aryl or by 4R_HSubstituted 5-10 membered heteroaryl, each heteroaryl independently containing at each occurrence 1, 2, 3, or 4 substituents selected from the group consisting of N, O, S, S ═ O or S (═ O)₂A heteroatom of (a);

each R₁₁Independently at each occurrence, is selected from halogen, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, -C_1-6Alkylene- (halogen)_1-3Hetero atom C_2-6Alkyl, -CN, -OR₈、-C_1-6Alkylene- (OR)₈)_1-3、-O-C_1-6Alkylene- (halogen)_1-3、-SR₈、-S-C_1-6Alkylene- (halogen)_1-3、-NR₈R₉、-C_1-6alkylene-NR₈R₉、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈、-NR₈SO₂R₉、-SO₂R₈、-S(＝O)₂NR₈R₉、-C_3-6Carbocyclyl, 3-6 membered heterocyclyl, -C_6-10Aryl, or 5-10 membered heteroaryl, each heterocyclyl and heteroaryl independently at each occurrence contains 1, 2, 3 or 4 substituents selected from the group consisting of N, O, S, S ═ O or S (═ O)₂Each R is₁₁Independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C_1-6Alkyl, -C_1-6Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

R₂₁or R₂₂Independently selected from hydrogen, halogen, -C_1-6Alkyl, -C_1-6Alkylene- (halogen) _1-3Hetero atom C_2-6Alkyl, -CN, -OR₈、-C_1-6Alkylene- (OR)₈)_1-3、-NR₈R₉、-C_1-6alkylene-NR₈R₉、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉or-C_3-6Carbocyclyl radical, each R₂₁Or R₂₂Independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C_1-6Alkyl, -C_1-6Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

R₃is selected from-C_1-14Alkyl, -C_2-14Alkenyl, -C_2-14Alkynyl, -C_6-10Aryl radical, -C_1-6alkylene-C_6-10Aryl, 5-10 membered heteroaryl, -C_1-6Alkylene- (5-to 10-membered heteroaryl), 3-to 14-membered heterocyclyl, -C_1-6Alkylene- (3-to 14-membered heterocyclyl), -C_3-14Carbocyclyl, -C_1-6alkylene-C_3-14A carbocyclic group,

Each C ring is independently selected at each occurrence from C_3-14A carbocyclic ring or a 3-14 membered heterocyclic ring, each D ring is independently at each occurrence selected from C_6-10An aromatic ring or a 5-10 membered heteroaromatic ring, each heterocyclyl and heteroaryl independently containing at each occurrence 1, 2, 3 or 4 substituents selected from the group consisting of N, O, S, S ═ O or S (═ O)₂Each R is₃Optionally substituted at each occurrence with 1, 2, 3, 4, 5 or 6R₃₁Substituted or unsubstituted;

each R₃₁Independently at each occurrence, is selected from halogen, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, -C_1-6Alkylene- (halogen)_1-3Hetero atom C_2-6Alkyl, -CN, -C_1-6alkylene-CN, -OR₈、-C_1-6Alkylene- (OR)₈)_1-3、-O-C_1-6Alkylene- (halogen)_1-3、-NR₈R₉、-C_1-6alkylene-NR₈R₉、-O-C_1-6alkylene-NR ₈R₉、-C(＝O)R₈、-C_1-6alkylene-C (═ O) R₈、-C(＝O)OR₈、-C_1-6alkylene-C (═ O) OR₈、-OC(＝O)R₈、-C_1-6alkylene-OC (═ O) R₈、-C(＝O)NR₈R₉、-C_1-6alkylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈、-C_1-6alkylene-NR₈C(＝O)R₈、-SO₂R₈、-C_1-6alkylene-SO₂R₈、-S(＝O)₂NR₈R₉、-C_1-6alkylene-S (═ O)₂NR₈R₉、-PO(R₈)₂、-C_1-6alkylene-PO (R)₈)₂、-C_3-6Carbocyclyl or 3-6 membered heterocyclyl, each heterocyclyl independently at each occurrenceContaining 1, 2, 3 or 4 substituents selected from the group consisting of N, O, S, S ═ O or S (═ O)₂Each R is₃₁Optionally substituted at each occurrence with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C_1-6Alkyl, -C_1-6Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

L₄selected from the group consisting of absence, (CR)₅R₆)_m、C(＝O)、O、NR₈S, S (═ O) or S (═ O)₂；

R₄Is selected from

Each one of which is

Independently optionally substituted by 1R₄₂2R₄₂3R₄₂4, R₄₂5R₄₂Or 6R₄₂Substituted or unsubstituted;

each G₁、G₂、G₃And G₄Independently at each occurrence is selected from N or CR₅；

Each n1, n2, n3, n4, n5 is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, or 6, provided that n1 and n2 are not simultaneously 0 and n3 and n4 are not simultaneously 0;

each R₄₁Independently at each occurrence is selected from

Each Q is independently selected at each occurrence from C (═ O), NR₈C(＝O)、S(＝O)₂Or NR₈S(＝O)₂；

Is selected from

Or

When in use

Is selected from

When each R is_4a、R_4bAnd R_4cIndependently at each occurrence, is selected from absent, hydrogen, halogen, -C_1-6Alkyl, -C_1-6Alkylene- (halogen) _1-3Hetero atom C_2-6Alkyl, -CN, -OR₈、-C_1-6Alkylene- (OR)₈)_1-3、-NR₈R₉、-C_1-6alkylene-NR₈R₉、-NR₈-C_1-6alkylene-OR₈、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-C_1-6alkylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈、-C_1-6alkylene-NR₈C(＝O)R₈、-C_1-6alkylene-O-C_1-6Aryl, -S (═ O)₂NR₈R₉、-C_3-10Carbocyclyl, 3-10 membered heterocyclyl, -C_1-6Alkylene- (3-to 10-membered heterocyclyl); each R_4a、R_4bOr R_4cIndependently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C_1-6Alkyl, -C_1-6Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted; or R_4bAnd R_4cTogether with the carbon atoms to which they are both attached form C_3-10Carbocyclic or 3-10 membered heterocyclic ring; or R_4aAnd R_4cTogether with the carbon atoms to which they are respectively attached form C_3-10A carbocycle or a 3-10 membered heterocycle, each heterocyclyl containing at each occurrence 1, 2 or 3 substituents selected from N, O, S, S ═ O or S (═ O)₂And said C is_3-10The carbocycle or said 3-10 membered heterocycle is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C_1-6Alkyl, -C_1-6Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted; or

When in use

Is selected from

When each R is_4aIs selected from absent, and R_4bAnd R_4cIs absent, R_4bAnd R_4cIs selected from hydrogen, halogen, -C_1-6Alkyl, -C_1-6Alkylene- (halogen)_1-3Hetero atom C_2-6Alkyl, -CN, -OR₈、-C_1-6Alkylene- (OR)₈)_1-3、-NR₈R₉、-C_1-6alkylene-NR₈R₉、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-C_1-6alkylene-C (═ O) NR ₈R₉、-NR₈C(＝O)R₈、-C_1-6alkylene-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉or-C_3-10A carbocyclic group; each R_4aIndependently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C_1-6Alkyl, -C_1-6Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

each R_4dIndependently at each occurrence, is selected from halogen;

each R₄₂Independently at each occurrence, is selected from halogen, oxo, -C_1-6Alkyl, -C_1-6Alkylene- (halogen)_1-3Hetero atom C_2-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, -OR₈、-C_1-6Alkylene- (OR)₈)_1-3、-NR₈R₉、-C_1-6alkylene-NR₈R₉、-CN、-C_1-6alkylene-CN, -C (═ O) R₈、-C_1-6alkylene-C (═ O) R₈、-C(＝O)OR₈、-C_1-6alkylene-C (═ O) OR₈、-OC(＝O)R₈、-C_1-6alkylene-OC (═ O) R₈、-C(＝O)NR₈R₉、-C_1-6alkylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈、-C_1-6alkylene-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉、-C_1-6alkylene-S (═ O)₂NR₈R₉、-SO₂R₈、-C_1-6Alkylene SO₂R₈、-NR₈SO₂R₈or-C_1-6alkylene-NR₈SO₂R₈(ii) a Each R₄₂Independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C_1-6Alkyl, -C_1-6Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted; or

Two R₄₂Together with the atoms to which they are both attached or the atoms to which they are attached respectively form C_3-6A carbocycle or a 3-6 membered heterocycle, each said heterocycle independently containing 1, 2 or 3 heteroatoms selected from N or O, each C_3-6The carbocycle or 3-6 membered heterocycle is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C_1-6Alkyl, -C_1-6Alkoxy, oxo, -OR ₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

each R₅And R₆Independently at each occurrence, selected from hydrogen, halogen, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉or-C_3-10A carbocyclic group; each R₅Or R₆Optionally substituted at each occurrence with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, oxo, -C_1-6Alkyl, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

each R₈And R₉Independently at each occurrence, selected from hydrogen, -C_1-6An alkyl group; or

R₈And R₉Together with the N atom to which they are both attached form a 3-10 membered heterocyclic ring, said 3-10 membered heterocyclic ring optionally including 1, 2, 3 or 4 substituents selected from the group consisting of N, O, S, S (═ O) or S (═ O)₂And said 3-10 membered heterocycle is independently optionally substituted with 1, 2, 3, 4, 5 or 6 heteroatoms selected from halogen, oxo, -C_1-6Alkyl, -C_1-6Alkylene- (halogen)_1-3Hetero atom C_2-6Alkyl, -CN, -OH, -OC_1-6Alkyl, -C_1-6Alkylene- (OH)_1-3、-C_1-6Alkylene- (OC)_1-6Alkyl radical)_1-3、-NH₂、-NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、-C_1-6alkylene-NH₂、-C_1-6alkylene-NHC_1-6Alkyl, -C_1-6alkylene-N (C)_1-6Alkyl radical)₂、-C(＝O)C_1-6Alkyl, -C (═ O) OC_1-6Alkyl, -OC (═ O) C_1-6Alkyl, -C (═ O) NH₂、-C(＝O)NHC_1-6Alkyl, -C (═ O) N (C)_1-6Alkyl radical)₂、-NHC(＝O)C_1-6Alkyl, -N (C)_1-6Alkyl) C (═ O) C_1-6Alkyl, -S (═ O)₂NH₂、-S(＝O)₂NH(CH₃)、-S(＝O)₂NHC_1-6Alkyl, -S (═ O)₂N(C_1-6Alkyl) or-C _3-6Substituted or unsubstituted carbocyclyl;

m is selected from 1, 2, 3, 4, 5 or 6.

In some embodiments, R₁Is selected from 4R₁₁Substituted phenyl, substituted by 4R₁₁Substituted naphthyl, by 4R₁₁Substituted 5-membered heteroaryl, substituted with 4R₁₁Substituted 6-membered heteroaryl, substituted with 4R₁₁Substituted 7-membered heteroaryl, substituted with 4R₁₁Substituted 8-membered heteroaryl, substituted with 4R₁₁Substituted 9-membered heteroaryl or substituted with 4R₁₁Substituted 10-membered heteroaryl, each heteroaryl independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O or S.

In some embodiments, R₁Is selected from 4R₁₁Substituted phenyl, substituted by 4R₁₁Substituted naphthyl, by 4R₁₁Substituted 6-membered heteroaryl or substituted by 4R₁₁Substituted 9-membered heteroaryl, each heteroaryl independently at each occurrence comprising 1 or 2 heteroatoms selected from N.

In some embodiments, R₁Is selected from 4R₁₁Substituted byPhenyl, is substituted by 4R₁₁Substituted naphthyl, by 4R₁₁Substituted pyridines substituted by 4R₁₁Substituted benzo [ d ]]Oxazolyl group, substituted by 4R₁₁Substituted benzo [ d ]]Thiazolyl, substituted by 4R₁₁Substituted pyrroles [2, 3-c]Pyridine, quilt 4R₁₁Substituted pyrazoles [3, 4-c]Pyridine, quilt 4R₁₁Substituted pyrazoles [1, 5-a ]]Pyridine, quilt 4R ₁₁Substituted imidazoles [1, 2-a ]]Pyridine, quilt 4R₁₁Substituted 2-oxo-indolyl substituted by 4R₁₁Substituted pyrimidinyl, substituted with 4R₁₁Substituted indolyl substituted by 4R₁₁Substituted indazolyl radical, substituted by 4R₁₁Substituted benzo [ d ]]Imidazolyl group by 4R₁₁Substituted pyrazoles [3, 4-b ]]Pyridine, quilt 4R₁₁Substituted 2(3H) -oxo-oxazoles [4, 5-b]Pyridine or pyridine substituted by 4R₁₁Substituted isoquinolinyl groups.

In some embodiments, R₁Is selected from 4R₁₁Substituted phenyl, substituted by 4R₁₁Substituted naphthyl, by 4R₁₁Substituted pyridines or substituted by 4R₁₁A substituted indazolyl group.

In some embodiments, R₁Selected from:

each R₁Independently at each occurrence by 4R₁₁And (4) substitution.

In some embodiments, R₁Independently selected from:

each R₁Independently at each occurrence by 4R₁₁And (4) substitution.

In some embodiments, R₁Selected from:

each R₁Independently at each occurrence by 4R₁₁And (4) substitution.

In some embodiments, each R is₁₁Independently at each occurrence is selected from-F, -Cl, -Br, oxo, -C_1-3Alkyl, -C_2-3Alkenyl, -C_2-3Alkynyl, -C_1-3Alkylene- (halogen)_1-3Hetero atom C_2-3Alkyl, -CN, -OR₈、-C_1-3Alkylene- (OR)₈)_1-3、-O-C_1-3Alkylene- (halogen)_1-3、-SR₈、-S-C_1-3Alkylene- (halogen)_1-3、-NR₈R₉、-C_1-3alkylene-NR₈R₉、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉、-C_3-6Carbocyclyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; each R ₁₁Independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, -Br, -C_1-3Alkyl, -C_1-3Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

each R₁₁In (R)₈Or R₉) Independently at each occurrence, is selected from hydrogen or-C_1-3An alkyl group.

In some embodiments, each R is₁₁Independently at each occurrence is selected from-F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, -methylene- (halogen)_1-3-ethylene- (halogen)_1-3-propylene- (halogen)_1-3Hetero-ethyl, hetero-propyl, -CN, -OR₈-methylene- (OR)₈)_1-3-yaEthyl- (OR)₈)_1-3-propylene- (OR)₈)_1-3-O-methylene- (halogen)_1-3-O-ethylene- (halogen)_1-3-O-propylene- (halogen)_1-3、-SR₈-S-methylene- (halogen)_1-3-S-ethylene- (halogen)_1-3-S-propylene- (halogen)_1-3、-NR₈R₉-methylene-NR₈R₉-ethylene-NR₈R₉-propylene-NR₈R₉、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, phenyl, 5-membered heteroaryl or 6-membered heteroaryl; each heterocyclyl and heteroaryl independently at each occurrence contains 1, 2, or 3 heteroatoms selected from N, O or S, each R ₁₁Independently optionally substituted with 1, 2, 3, 4, 5 OR 6 substituents selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

each R₁₁In (R)₈Or R₉) Independently at each occurrence is selected from hydrogen, methyl, ethyl, propyl or isopropyl.

In some embodiments, each R is₁₁Independently at each occurrence is selected from-F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, -CH₂F、-CHF₂、-CF₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃、-CH₂OCH₃、-CH₂CH₂OCH₃、-CN、-OH、-OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)₂、-CH₂OH、-CH₂CH₂OH、-CH₂CH₂CH₂OH、-OCH₂F、-OCHF₂、-OCF₃、-OCH₂CH₂F、-OCH₂CHF₂、-OCH₂CF₃、-OCH₂CH₂CH₂F、-OCH₂CH₂CHF₂、-OCH₂CH₂CF₃、-SH、-SCH₃、-SCH₂CH₃、-SCH(CH₃)₂、-SCH₂F、-SCHF₂、-SCF₃、-SCH₂CH₂F、-SCH₂CHF₂、-SCH₂CF₃、-SCH₂CH₂CH₂F、-SCH₂CH₂CHF₂、-SCH₂CH₂CF₃、-NH₂、-NHCH₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-N(CH₃)₂、-N(CH₃)CH₂CH₃、-N(CH₃)CH₂CH₂CH₃、-N(CH₃)CH(CH₃)₂、-CH₂NH₂、-CH₂CH₂NH₂、-CH₂CH₂CH₂NH₂、-CH₂N(CH₃)₂、-CH₂CH₂N(CH₃)₂、-CH₂CH₂CH₂N(CH₃)₂、-C(＝O)CH₃、-C(＝O)OCH₃、-C(＝O)OCH₂CH₃、-C(＝O)OCH₂CH₂CH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃)、-S(＝O)₂N(CH₃)₂3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, phenyl, 5-membered heteroaryl or 6-membered heteroaryl; each heterocyclyl and heteroaryl independently at each occurrence contains 1 or 2 heteroatoms selected from N or O, each R₁₁Independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH₂、-NHCH₃、-N(CH₃)₂、-CN、-C(＝O)CH₃、-C(＝O)OCH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃) or-S (═ O)₂N(CH₃)₂Substituted or unsubstituted.

In some embodiments, each R is₁₁Independently at each occurrence is selected from-F, -Cl, oxo, -OH, -NH ₂CN, -methyl, ethyl, propyl, isopropyl,

Methoxy, ethoxy, propoxy, isopropoxy, -CF₃、-OCF₃、-NH(CH₃)、-N(CH₃)₂、-CH₂F、-CHF₂、-CF₃、-CH₂OH、-SO₂NH₂、-CONH₂、

In some embodiments, each R is₁₁Independently at each occurrence is selected from-F, -Cl, -OH, -NH₂Methyl, methoxy, -OCF₃、-CHF₂、-CF₃Or

In some embodiments, each R is₁₁Independently at each occurrence, is selected from halogen; -C_1-6An alkyl group; by halogen, -NH₂-CN or-OH substituted-C_1-6An alkyl group; -OH; -O-C_1-6An alkyl group; by halogen, -NH₂-CN or-OH substituted-O-C_1-6An alkyl group; -NH₂；-NH(C_1-6alkly)；-N(C_1-6Alkyl radical)₂；-NHCOC_1-6An alkyl group; -N (C)_1-6Alkyl) COC_1-6An alkyl group; -NHSO₂C_1-6An alkyl group; -N (C)_1-6Alkyl) SO₂C_1-6An alkyl group; -SO₂(C_1-6Alkyl groups); -SO₂NH₂；-SO₂NHC_1-6An alkyl group; -SO₂N(C_1-6Alkyl radical)₂or-C_3-6A carbocyclic group.

In some embodiments, each R is₁₁Is independently selected at each occurrence from-F; -Cl; -Br; -C_1-3An alkyl group; -C substituted by-F or-Cl_1-3An alkyl group; -OH; -O-C_1-3An alkyl group; -O-C substituted by-F or-Cl_1-3An alkyl group; -NH₂；-NH(C_1- ₃alkly)；-N(C_1-3Alkyl radical)₂；-NHCOC_1-3An alkyl group; -N (C)_1-3Alkyl) COC_1-3An alkyl group; -NHSO₂C_1-3An alkyl group; -N (C)_1-3Alkyl) SO₂C_1-3An alkyl group; -SO₂(C_1-3Alkyl groups); -SO₂NH₂；-SO₂NHC_1-3An alkyl group; -SO₂N(C_1-3Alkyl radical)₂or-C_3-6A carbocyclic group.

In some embodiments, each R is₁₁Is independently selected at each occurrence from-F; -Cl; -Br; -C_1-3An alkyl group; -C substituted by-F or-Cl_1-3An alkyl group; -OH; -O-C _1-3An alkyl group; -O-C substituted by-F or-Cl_1-3An alkyl group; -NH₂；-NH(C_1- ₃alkly)；-N(C_1-3Alkyl radical)₂；-NHCOC_1-3An alkyl group; -N (C)_1-3Alkyl) COC_1-3An alkyl group; -NHSO₂C_1-3An alkyl group; -N (C)_1-3Alkyl) SO₂C_1-3An alkyl group; -SO₂(C_1-3Alkyl groups); -SO₂NH₂；-SO₂NHC_1-3An alkyl group; -SO₂N(C_1-3Alkyl radical)₂or-C_3-6A carbocyclic group.

In some embodiments, each R is₁₁Is independently selected at each occurrence from-F; -Cl; a methyl group; an ethyl group; propyl; isopropyl group; -F-substituted methyl; -an F-substituted ethyl group; -F-substituted propyl; -F-substituted isopropyl; -OH; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; -F-substituted methoxy; -an F-substituted ethoxy group; -F-substituted propoxy; -F-substituted isopropoxy; -NH₂；-NHCH₃；-NHCH₂CH₃；-NH(CH₂CH₂CH₃)；-NH(CH(CH₃)₂)；-N(CH₃)₂；-N(CH₂CH₃)₂；-N(CH₃)(CH₂CH₃)；-NHCOCH₃；-NHCOCH₂CH₃；-NHCOCH₂CH₂CH₃；-N(CH₃)COCH₃；-N(CH₃)COCH₂CH₃；-N(CH₃)COCH₂CH₂CH₃；-NHSO₂CH₃；-NHSO₂CH₂CH₃；-NHSO₂CH₂CH₂CH₃；-N(CH₃)SO₂CH₃；-N(CH₃)SO₂CH₂CH₃；-N(CH₃)SO₂CH₂CH₂CH₃；-SO₂CH₃；-SO₂CH₂CH₃；-SO₂CH₂CH₂CH₃；-SO₂(CH(CH₃)₂)；-SO₂NH₂；-SO₂NHCH₃；-SO₂NHCH₂CH₃；-SO₂NHCH₂CH₂CH₃；-SO₂N(CH₃)₂；-SO₂N(CH₂CH₃)₂；-SO₂N(CH₂CH₂CH₃)₂(ii) a A 3-membered carbocyclic group; a 4-membered carbocyclic group; 5-membered carbocyclyl or 6-membered carbocyclyl.

In some embodiments, each R is₁₁Independently at each occurrence is selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, -CH₂F、-CHF₂、-CF₃-OH, methoxy, ethoxy, propoxy, isopropoxy, -OCF₃、-NH₂、-NHCH₃、-NHCH₂CH₃、-NH(CH₂CH₂CH₃)、-NH(CH(CH₃)₂)、-N(CH₃)₂、-N(CH₂CH₃)₂、-N(CH₃)(CH₂CH₃)、-NHCOCH₃、-N(CH₃)COCH₃、-NHSO₂CH₃、-N(CH₃)SO₂CH₃、-SO₂CH₃、-SO₂CH₂CH₃、-SO₂CH₂CH₂CH₃、-SO₂(CH(CH₃)₂)、-SO₂NHCH₃、-SO₂N(CH₃)₂3-membered, 4-membered, 5-membered or 6-membered carbocyclyl.

In some embodiments, each R is₁₁Independently at each occurrence is selected from-F, -Cl, -CH₃、-CF₃、-OH、-OCH₃、-OCF₃、-NH₂、-NHCH₃、-NHCOCH₃、-NHSO₂CH₃、-SO₂CH₃or-SO₂NHCH₃。

In some embodiments, each R is₁₁Independently at each occurrence is selected from-F, -Cl, -OH or-NH ₂。

In some embodiments, R₁Selected from:

in some embodiments, R₁Selected from:

in some embodiments, R₂₁Or R₂₂Independently selected from hydrogen, -F, -Cl, -Br, -C_1-3Alkyl, -C_1-3Alkylene- (halogen)_1-3Hetero atom C_2-3Alkyl, -CN, -OR₈、-C_1-3Alkylene- (OR)₈)_1-3、-NR₈R₉、-C_1-3alkylene-NR₈R₉、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉3-, 4-, 5-or 6-membered carbocyclyl; each R₂₁Or R₂₂Independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, -Br, -C_1-3Alkyl, -C_1-3Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

each (R)₂₁Or R₂₂) In (R)₈Or R₉) Independently at each occurrence, is selected from hydrogen or-C_1-3An alkyl group.

In some embodiments, R₂₁Or R₂₂Independently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH₂F、-CHF₂、-CF₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃、-CH₂OCH₃、-CH₂CH₂OCH₃、-CN、-OH、-OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)₂、-CH₂OH、-CH₂CH₂OH、-CH₂CH₂CH₂OH、-CH₂CH₂CH₂OCH₃、-NH₂、-NHCH₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-N(CH₃)₂、-N(CH₃)CH₂CH₃、-N(CH₃)CH₂CH₂CH₃、-N(CH₃)CH(CH₃)₂、-CH₂NH₂、-CH₂CH₂NH₂、-CH₂CH₂CH₂NH₂、-CH₂N(CH₃)₂、-CH₂CH₂N(CH₃)₂、-CH₂CH₂CH₂N(CH₃)₂、-C(＝O)CH₃、-C(＝O)OCH₃、-C(＝O)OCH₂CH₃、-C(＝O)OCH₂CH₂CH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃)、-S(＝O)₂N(CH₃)₂3-, 4-, 5-or 6-membered carbocyclyl; each (R)₂₁Or R₂₂) Independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH₂、-N(CH₃)₂、-CN、-C(＝O)CH₃、-C(＝O)OCH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃) or-S (═ O)₂N(CH₃)₂Substituted or unsubstituted.

In some embodiments, R₂₁Or R₂₂Independently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH ₂F、-CHF₂、-CF₃、-OH、-OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)₂、-CH₂OH、-CH₂CH₂OH、-CH₂CH₂CH₂OH、-NH₂、-NHCH₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂Or

In some embodiments, R₂₁Selected from-F, -Cl or

And R22 is selected from hydrogen.

In some embodiments, R₂₁Independently selected from hydrogen; halogen; -C_1-6An alkyl group; by halogen, -NH₂-CN or-OH substituted-C_1-6An alkyl group; -C_2-6Alkenyl or-C_3-6A carbocyclic group;

R₂₂selected from hydrogen, halogen or-C_1-6An alkyl group.

In some embodiments, R₂₁Selected from hydrogen; -F; -Cl; -Br; -C_1-3An alkyl group; -C substituted by-F or-Cl_1-3An alkyl group; -C_2-3Alkenyl or-C_3-6A carbocyclic group.

In some embodiments, R₂₁Selected from hydrogen, -F; -Cl; a methyl group; an ethyl group; propyl; isopropyl group; methyl substituted by-F; ethyl substituted with-F; propyl substituted with-F; isopropyl substituted with-F; vinyl radical(ii) a A propenyl group; a 3-membered carbocyclic group; a 4-membered carbocyclic group; 5-membered carbocyclyl or 6-membered carbocyclyl.

In some embodiments, R₂₁Selected from-F, -Cl, -CF₃、

In some embodiments, R₂₁is-F or-Cl.

In some embodiments, R₂₂Selected from hydrogen, -F, -Cl, -Br or-C_1-3An alkyl group.

In some embodiments, R₂₂Selected from hydrogen, -F, -Cl, methyl, ethyl, propyl or isopropyl.

In some embodiments, R₂₂Is hydrogen or-CH₃。

In some embodiments, R₂₂Is hydrogen.

In some embodiments, R ₃Is selected from-C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, -C_6-10Aryl radical, -C_1-3Alkylene radical C_6-10Aryl, 5-10 membered heteroaryl, -C_1-3Alkylene- (5-10 membered heteroaryl), 3-6 membered heterocyclyl, -C_1-3Alkylene- (3-6 membered heterocyclyl), -C_3-6Carbocyclyl, -C_1-3alkylene-C_3-6A carbocyclic group,

Each ring C is independently selected at each occurrence from C_3-6A carbocyclic ring or a 3-6 membered heterocyclic ring, each ring D is independently selected at each occurrence from C_6-10An aromatic ring or a 5-10 membered heteroaryl, each heterocyclyl and heteroaryl independently containing at each occurrence 1, 2 or 3 heteroatoms selected from N, O or S, each R₃Optionally substituted at each occurrence with 1, 2, 3, 4, 5 or 6R₃₁And (4) substitution.

In some embodiments, R₃Is selected from-C_1-3Alkyl, -C_2-3Alkenyl, -C_2-3Alkynyl, phenyl, naphthyl, -methylene-C_6-10Aryl, -ethylene-C_6-10Aryl, -propylene-C_6-10Aryl, -isopropylidene-C_6-10Aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, -methylene- (5-10-membered heteroaryl), -ethylene- (5-10-membered heteroaryl), -propylene- (5-10-membered heteroaryl), -isopropylene- (5-10-membered heteroaryl), 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, -methylene- (3-6-membered heterocyclyl), -ethylene- (3-6-membered heterocyclyl), -propylene- (3-6-membered heterocyclyl), -isopropylene- (3-6-membered heterocyclyl), 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, -methylene-C _3-6Carbocyclyl, -ethylene-C_3-6Carbocyclyl, -propylene-C_3-6Carbocyclyl, -isopropylidene-C_3-6A carbocyclic group,

Each ring C is independently selected at each occurrence from a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring, each ring D is independently selected at each occurrence from a phenyl ring, a 5-membered heteroaromatic ring, or a 6-membered heteroaromatic ring, each heterocyclic, heteroaromatic, or heteroaryl ring independently comprises at each occurrence 1, 2, or 3 heteroatoms selected from N, O or S, each R is independently selected from R₃Optionally substituted at each occurrence with 1, 2, 3, 4, 5 or 6R₃₁Substituted or unsubstituted.

In some embodiments, R₃Selected from the group consisting of methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, phenyl, naphthyl, -methylene-phenyl, -ethylene-phenyl, -propylene-phenyl, -isopropylidene-phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, -methylene- (5-10-membered heteroaryl), -ethylene- (5-10-membered heteroaryl), -propylene- (5-10-membered heteroaryl), -isopropylidene- (5-10-membered heteroaryl), 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, -methylene- (3-6-membered heterocyclyl), -ethylene- (3-6-membered heterocyclyl), -propylene- (3-6 membered heterocyclyl), -isopropylene- (3-6 membered heterocyclyl), 3-membered carbocyclyl, 4-membered carbocyclyl Cyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, -methylene-C_3-6Carbocyclyl, -ethylene-C_3-6Carbocyclyl, -propylene-C_3-6Carbocyclyl, -isopropylidene-C_3-6A carbocyclic group,

In some embodiments, R₃Is selected from-C_6-10Aryl or 5-10 membered heteroaryl, each 5-10 membered heteroaryl independently at each occurrence containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, each-C_6-10Aryl or 5-10 membered heteroaryl is independently optionally substituted at each occurrence with 1R₃₁2R₃₁3R₃₁4, R₃₁5R₃₁Or 6R₃₁Substituted or unsubstituted.

In some embodiments, R₃Selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl independently at each occurrence comprising 1, 2, or 3 heteroatoms selected from N or O, each phenyl, naphthyl, or heteroaryl independently at each occurrence optionally substituted with 1R ₃₁2R₃₁3R₃₁4, R₃₁5R₃₁Or 6R₃₁Substituted or unsubstituted.

In some embodiments, R₃Selected from phenyl or 6-membered heteroaryl, said 6-membered heteroaryl comprising 1 or 2 heteroatoms selected from N, each phenyl or 6-membered heteroaryl in each occurrence independently optionally substituted with 1R₃₁2R₃₁3R₃₁4, R₃₁5R₃₁Or 6R₃₁Substituted or unsubstituted.

In some embodiments, R₃Selected from:

each R₃Independently optionally substituted by 1R₃₁2R₃₁3R₃₁4, R₃₁5R₃₁Or 6R₃₁Substituted or unsubstituted.

In some embodiments, R₃Selected from:

In some embodiments, each R is₃₁Independently at each occurrence is selected from-F, -Cl, -Br, -C_1-3Alkyl, -C_2-3Alkenyl, -C_2-3Alkynyl, -C_1-3Alkylene- (halogen)_1-3Hetero atom C_2-3Alkyl, -CN, -C_1-3alkylene-CN, -OR₈、-C_1-3alkylene-OR₈、-O-C_1-3Alkylene- (halogen)_1-3、-NR₈R₉、-C_1-3alkylene-NR₈R₉、-O-C_1-3alkylene-NR₈R₉、-C(＝O)R₈、-C_1-3alkylene-C (═ O) R₈、-C(＝O)OR₈、-C_1-3alkylene-C (═ O) OR₈、-OC(＝O)R₈、-C_1-3alkylene-OC (═ O) R₈、-C(＝O)NR₈R₉、-C_1-3alkylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈、-C_1-3Alkylene radical-NR₈C(＝O)R₈、-SO₂R₈、-C_1-3alkylene-SO₂R₈、-S(＝O)₂NR₈R₉、-C_1-3alkylene-S (═ O)₂NR₈R₉、-PO(R₈)₂、-C_1-3alkylene-PO (R)₈)₂、-C_3-6Carbocyclyl or 3-6 membered heterocyclyl, each heterocyclyl independently at each occurrence containing 1, 2 or 3 heteroatoms selected from N, O or S, each R ₃₁Independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, -Br, -C_1-3Alkyl, -C_1-3Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

R₃₁in (R)₈Or R₉) Independently at each occurrence, is selected from hydrogen or-C_1-3An alkyl group.

In some embodiments, each R is₃₁Independently at each occurrence is selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, -methylene- (halogen)_1-3-ethylene- (halogen)_1-3-propylene- (halogen)_1-3-isopropylidene- (halogen)_1-3Heteroethyl, heteropropyl, -CN, -methylene-CN, -ethylene-CN, -propylene-CN, -isopropylidene-CN, -OR₈-methylene-OR₈-ethylene-OR₈-propylene-OR₈-isopropylidene-OR₈-O-methylene- (halogen)_1-3-O-ethylene- (halogen)_1-3-O-propylene- (halogen)_1-3-O-isopropylidene- (halogen)_1-3、-NR₈R₉-methylene-NR₈R₉-ethylene-NR₈R₉-propylene-NR₈R₉-isopropylidene-NR₈R₉-O-methylene-NR₈R₉-O-ethylene-NR₈R₉-O-propylene-NR₈R₉-O-isopropylidene-NR₈R₉、-C(＝O)R₈-methylene-C (═ O) R₈-ethylene-C (═ O) R₈-propylene-C (═ O) R₈-isopropylidene-C (═ O) R₈、-C(＝O)OR₈-methylene-C (═ O) OR ₈-ethylene-C (═ O) OR₈-propylene-C (═ O) OR₈-isopropylidene-C (═ O) OR₈、-OC(＝O)R₈-methylene-OC (═ O) R₈-ethylene-OC (═ O) R₈-propylene-OC (═ O) R₈-isopropylidene-OC (═ O) R₈、-C(＝O)NR₈R₉-methylene-C (═ O) NR₈R₉-ethylene-C (═ O) NR₈R₉-propylene-C (═ O) NR₈R₉-isopropylidene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈-methylene-NR₈C(＝O)R₈-ethylene-NR₈C(＝O)R₈-propylene-NR₈C(＝O)R₈-isopropylidene-NR₈C(＝O)R₈、-SO₂R₈-methylene-SO₂R₈-ethylene-SO₂R₈-propylene-SO₂R₈-isopropylidene-SO₂R₈、-S(＝O)₂NR₈R₉-methylene-S (═ O)₂NR₈R₉-ethylene-S (═ O)₂NR₈R₉-propylene-S (═ O)₂NR₈R₉-isopropylidene-S (═ O)₂NR₈R₉、-PO(R₈)₂-methylene-PO (R)₈)₂-ethylene-PO (R)₈)₂-propylene-PO (R)₈)₂-isopropylidene-PO (R)₈)₂3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl; each heterocyclyl independently at each occurrence contains 1 or 2 heteroatoms selected from N or O; each R₃₁Independently optionally is covered1. 2, 3, 4, 5 OR 6 groups selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

R₃₁in (R) ₈Or R₉) Independently at each occurrence is selected from hydrogen, methyl, ethyl, propyl or isopropyl.

In some embodiments, each R is₃₁Independently at each occurrence is selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, -CH₂F、-CHF₂、-CF₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃、-CH(CH₃)(CF₃)、-CH₂OCH₃、-CH₂CH₂OCH₃、-CN、-CH₂CN、-CH₂CH₂CN、-CH₂CH₂CH₂CN、-OH、-OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)₂、-CH₂OH、-CH₂CH₂OH、-CH₂CH₂CH₂OH、-CH₂CH₂CH₂OCH₃、-OCF₃、-OCH₂CF₃、-OCH₂CH₂CF₃、-NH₂、-NHCH₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-N(CH₃)₂、-N(CH₃)CH₂CH₃、-N(CH₃)CH₂CH₂CH₃、-N(CH₃)CH(CH₃)₂、-CH₂NH₂、-CH₂CH₂NH₂、-CH₂CH₂CH₂NH₂、-CH₂N(CH₃)₂、-CH₂CH₂N(CH₃)₂、-CH₂CH₂CH₂N(CH₃)₂、-OCH₂NH₂、-OCH₂CH₂NH₂、-OCH₂CH₂CH₂NH₂、-C(＝O)CH₃、-CH₂C(＝O)CH₃、-CH₂CH₂C(＝O)CH₃、-CH₂CH₂CH₂C(＝O)CH₃、-C(＝O)OCH₃、-CH₂C(＝O)OCH₃、-CH₂CH₂C(＝O)OCH₃、-CH₂CH₂CH₂C(＝O)OCH₃、-OC(＝O)CH₃、-CH₂OC(＝O)CH₃、-CH₂CH₂OC(＝O)CH₃、-CH₂CH₂CH₂OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-CH₂C(＝O)N(CH₃)₂、-CH₂CH₂C(＝O)N(CH₃)₂、-CH₂CH₂CH₂C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-CH₂NHC(＝O)CH₃、-CH₂CH₂NHC(＝O)CH₃、-CH₂CH₂CH₂NHC(＝O)CH₃、-SO₂CH₃、-CH₂SO₂CH₃、-CH₂CH₂SO₂CH₃、-CH₂CH₂CH₂SO₂CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃)、-S(＝O)₂N(CH₃)₂、-CH₂S(＝O)₂N(CH₃)₂、-CH₂CH₂S(＝O)₂N(CH₃)₂、-CH₂CH₂CH₂S(＝O)₂N(CH₃)₂、-PO(CH₃)₂、-CH₂PO(CH₃)₂、-CH₂CH₂PO(CH₃)₂、-CH₂CH₂CH₂PO(CH₃)₂、

Each R₃₁Independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH₂、-N(CH₃)₂、-CN、-C(＝O)CH₃、-C(＝O)OCH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃) or-S (═ O)₂N(CH₃)₂Substituted or unsubstituted.

In some embodiments, each R is₃₁Independently at each occurrence is selected from-Cl, -CH₃、-CH₂CH₃、-CH(CH₃)₂、-CN、-OCH₂CH₂NH₂、-SO₂CH₃、-PO(CH₃)₂、

Each R₃₁Independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from-F, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH₂、-N(CH₃)₂or-CN or unsubstituted.

In some embodiments, each R is₃₁Independently at each occurrence is selected from-CH₃、-CH(CH₃)₂Or

In some embodiments, each R is₃₁Independently at each occurrence, is selected from halogen, -C_1-6Alkyl, -CN, -OH, -O-C _1-6Alkyl, -NH₂、-NH(C_1-6Alkyl), -N (C)_1-6Alkyl radical)₂or-C_3-6A carbocyclic group.

In some embodiments, each R is₃₁Independently at each occurrence is selected from-F, -Cl, -Br, -C_1-3Alkyl, -CN, -OH, -O-C_1-3Alkyl, -NH₂、-NH(C_1-3Alkyl), -N (C)_1-3Alkyl radical)₂or-C_3-6A carbocyclic group.

In some embodiments, each R is₃₁Independently at each occurrence is selected from the group consisting of-F, -Cl, methyl, ethyl, propyl, isopropyl, -CN, -OH, methoxy, ethoxy, propoxy, isopropoxy, -NH₂、-NHCH₃、-NHCH₂CH₃、-NH(CH₂CH₂CH₃)、-NH(CH(CH₃)₂)、-N(CH₃)₂、-N(CH₂CH₃)₂、-N(CH₃)(CH₂CH₃) 3-membered, 4-membered, 5-membered or 6-membered carbocyclyl.

In some embodiments, each R is₃₁Independently at each occurrence is selected from methyl or isopropyl.

In some embodiments, R₃Selected from:

in some embodiments, each R is₃Independently at each occurrence is selected from:

in some embodiments, R₃Is selected from

In some embodiments, L₄Selected from the group consisting of absence, (CR)₅R₆)_mOr NR₅；

L₄Each of (R)₅Or R₆) Independently at each occurrence, selected from hydrogen, methyl, ethyl, propyl or isopropyl;

L₄m in (1) is selected from 1, 2 or 3.

In some embodiments, L₄Selected from absent or NH.

In some embodiments, L₄Independently selected from absent, O or NH or N (C)_1-6Alkyl groups).

In some embodiments, L₄Independently selected from absent, O, NH, N (CH)₃)、N(CH₂CH₃) Or N (CH)₂CH₂CH₃)。

In some embodiments, L₄Independently selected from absent or NH.

In some embodiments, L₄Independently selected from absent.

In some embodiments, R4 is selected from

Each one of which is

Optionally substituted at each occurrence with 1R₄₂2R₄₂3R₄₂4, R₄₂5R₄₂Or 6R₄₂Substituted or unsubstituted.

In some embodiments, R4 is selected from

Independently optionally substituted by 1R₄₂2R₄₂3R₄₂4, R₄₂5R₄₂Or 6R₄₂Substituted or unsubstituted.

In some embodiments, each G is₁And G₂Independently at each occurrence is selected from N or CR₅；

(G₁Or G₂) Each R in (1)₅Independently at each occurrence is selected from hydrogen, methyl, ethyl, propyl or isopropyl.

In some embodiments, each G is₁Independently at each occurrence, selected from N or CH, and each G₂Independently at each occurrence is selected from N or CH.

In some embodiments, each n1, n2, n3, n4, n5 is independently selected at each occurrence from 0, 1, 2, or 3, provided that n1 and n2 are not simultaneously 0 and n3 and n4 are not simultaneously 0.

In some embodiments, n1 is selected from 1, 2, or 3; n2 is selected from 1, 2 or 3.

In some embodiments, n1 is selected from 1 or 2; n2 is selected from 1 or 2.

In some embodiments, R₄Is selected from

Each one of which is

In some embodiments, R₄Is selected from

Said

Independently optionally substituted by 1R₄₂2R₄₂3R₄₂Or 4R₄₂Substituted or unsubstituted.

In some embodiments, R₄Is selected from

Said

Optionally substituted by 1R₄₂2R₄₂3R₄₂4, R₄₂5R₄₂Or 6R₄₂Substituted or unsubstituted.

In some embodiments, each R is₄₁Independently at each occurrence is selected from

Each Q, at each occurrence, is independently selected from-C (═ O) -, -NHC (═ O) -or-N (CH)₃)C(＝O)-。

In some embodiments, when

Is that

When R is_4a、R_4bOr R_4cIndependently at each occurrence, is selected from hydrogen, -F, -Cl, -Br, -C_1-3Alkyl, -C_1-3Alkylene- (halogen)_1-3Hetero atom C_2-3Alkyl, -CN, -OR₈、-C_1-3Alkylene- (OR)₈)_1-3、-NR₈R₉、-C_1-3alkylene-NR₈R₉、-NR₈-C_1-6alkylene-OR₈、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-C_1-3alkylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈、-C_1-3alkylene-NR₈C(＝O)R₈、-C_1-3alkylene-O-C_1-6Aryl, -S (═ O)₂NR₈R₉、-C_3-6Carbocyclyl, 3-6 membered heterocyclyl, -C_1-3Alkylene- (3-6 membered heterocyclyl), each R_4a、R_4bOr R_4cIndependently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, -Br, -C _1-3Alkyl, -C_1-3Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted; or R_4bAnd R_4cTogether with the carbon atoms to which they are both attached form C_3-6A carbocyclic ring or a 3-6 membered heterocyclic ring; or R_4aAnd R_4cTogether with the carbon atoms to which they are respectively attached form C_3-6A carbocyclic ring or a 3-6 membered heterocyclic ring; each heterocycle contains at each occurrence 1, 2 or 3 substituents selected from N, O, S or S (═ O)₂Each carbocyclic or heterocyclic ring being optionally substituted by 1, 2, 3, 4, 5 or 6 heteroatoms selected from-F, -Cl, -Br, -C_1-3Alkyl, -C_1-3Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

when in use

Is that

When each R is_4aIs absent, and R_4bAnd R_4cOne of which is absent, R_4bAnd R_4cOne of the others is selected from hydrogen, -F, -Cl, -Br, oxo, -C_1-3Alkyl, -C_1-3Alkylene- (halogen)_1-3Hetero atom C_1-3Alkyl, -CN, -OR₈、-C_1-3Alkylene- (OR)₈)_1-3、-NR₈R₉、-C_1-3alkylene-NR₈R₉、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-C_1-3alkylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈、-C_1-3alkylene-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉or-C_3-6A carbocyclic group; each R_4bOr R_4cIndependently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, -Br, -C_1-3Alkyl, -C_1-3Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

(R_4a、R_4bor R_4c) Each of (R)₈Or R₉) Independently at each occurrence, is selected from hydrogen or-C_1-3An alkyl group;

each R_4dIndependently at each occurrence is selected from-F, -Cl or-Br.

In some embodiments, when

Is selected from

When R is_4a、R_4bOr R_4cIndependently at each occurrence, is selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -methylene- (halogen)_1-3-ethylene- (halogen)_1-3-propylene- (halogen)_1-3Hetero-ethyl, hetero-propyl, -CN, -OR₈-methylene- (OR)₈)_1-3-ethylene- (OR)₈)_1-3-propylene- (OR)₈)_1-3、-NR₈R₉-methylene-NR₈R₉-ethylene-NR₈R₉-propylene-NR₈R₉、-NR₈-methylene-OR₈、-NR₈-ethylene-OR₈、-NR₈-propylene-OR₈、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉-methylene-C (═ O) NR₈R₉-ethylene-C (═ O) NR₈R₉-propylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈-methylene-NR₈C(＝O)R₈-ethylene-NR₈C(＝O)R₈-propylene-NR₈C(＝O)R₈-methylene-O-phenyl, -ethylene-O-phenyl, -propylene-O-phenyl, -S (═ O)₂NR₈R₉3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, -methylene- (3-6 heterocyclyl), -ethylene- (3-6 heterocyclyl) or-propylene- (3-6 heterocyclyl); each R_4a、R_4bOr R_4cIndependently optionally substituted with 1, 2, 3, 4, 5 OR 6 substituents selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted; or R _4bAnd R_4cTaken together with the carbon atoms to which they are both attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring; or R_4aAnd R_4cTogether with the carbon atom to which they are each attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring; each heterocycle or heterocyclyl contains at each occurrence 1 or 2 substituents selected from N, O or S (═ O)₂And each carbocyclic, heterocyclic OR heterocyclic group is optionally substituted with 1, 2, 3, 4, 5 OR 6 heteroatoms selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyl, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted with one substituent;

when in use

Is selected from

When each R is_4aIs absent, and R_4bAnd R_4cOne of which is absent, R_4bAnd R_4cIs selected from hydrogen, -F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -methylene- (halogen)_1-3-ethylene- (halogen)_1-3-propylene- (halogen)_1-3Hetero-ethyl, hetero-propyl, -CN, -OR₈-methylene- (OR)₈)_1-3-ethylene- (OR)₈)_1-3-propylene- (OR)₈)_1-3、-NR₈R₉-methylene-NR₈R₉-ethylene-NR₈R₉-propylene-NR ₈R₉、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉-methylene-C (═ O) NR₈R₉-ethylene-C (═ O) NR₈R₉-propylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈-methylene-NR₈C(＝O)R₈-ethylene-NR₈C(＝O)R₈-propylene-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉3-, 4-, 5-or 6-membered carbocyclyl; each R_4bOr R_4cIndependently optionally substituted with 1, 2, 3, 4, 5 OR 6 substituents selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

(R_4a、R_4bor R_4c) Each of (R)₈Or R₉) Independently at each occurrence, selected from hydrogen, methyl, ethyl, propyl or isopropyl;

each R_4dIndependently at each occurrence is selected from-Cl or-Br.

In some embodiments, when

Is that

When R is_4a、R_4bOr R_4cIndependently at each occurrence, is selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH₂F、-CHF₂、-CF₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃、-CH₂OCH₃、-CH₂CH₂OCH₃、-CH₂CH₂CH₂OCH₃、-CN、-OH、-OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)₂、-CH₂OH、-CH₂CH₂OH、-CH₂CH₂CH₂OH、-NH₂、-NHCH₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-N(CH₃)₂、-N(CH₃)CH₂CH₃、-N(CH₃)CH₂CH₂CH₃、-N(CH₃)CH(CH₃)₂、-CH₂NH₂、-CH₂CH₂NH₂、-CH₂CH₂CH₂NH₂、-CH₂N(CH₃)₂、-CH₂NHCH₃、-CH₂CH₂N(CH₃)₂、-CH₂CH₂CH₂N(CH₃)₂、-NHCH₂OH、-NHCH₂CH₂OH、-NHCH₂CH₂CH₂OH、-C(＝O)CH₃、-COOH、-C(＝O)OCH₃、-C(＝O)OCH₂CH₃、-C(＝O)OCH₂CH₂CH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-CH₂C(＝O)N(CH₃)₂、-CH₂CH₂C(＝O)N(CH₃)₂、-CH₂CH₂CH₂C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-CH₂NHC(＝O)CH₃、-CH₂CH₂NHC(＝O)CH₃、-CH₂CH₂CH₂NHC(＝O)CH₃、

-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃)、-S(＝O)₂N(CH₃)₂3-membered, 4-membered, 5-membered, 6-membered, etc,

Each R_4a、R_4bOr R_4cIndependently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH₂、-NHCH₃、-N(CH₃)₂、-CN、-C(＝O)CH₃、-C(＝O)OCH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃) or-S (═ O)₂N(CH₃)₂Substituted or unsubstituted; or R_4bAnd R_4cTogether with the carbon atom to which they are both attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, A 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring; or R_4aAnd R_4cTogether with the carbon atom to which they are each attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring; each heterocycle or heterocyclyl contains at each occurrence 1 or 2 substituents selected from N, O or S (═ O)₂And each carbocyclic, heterocyclic or heterocyclic group is optionally substituted with 1, 2, 3, 4, 5 or 6 heteroatoms selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH₂、-NHCH₃、-N(CH₃)₂、-CN、-C(＝O)CH₃、-C(＝O)OCH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃) or-S (═ O)₂N(CH₃)₂Substituted with the substituent(s); or

When in use

Is that

When each R is_4aIs absent, and R_4bAnd R_4cOne of which is absent, R_4bAnd R_4cIs selected from hydrogen, -F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -CH₂F、-CHF₂、-CF₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃、-CH₂OCH₃、-CH₂CH₂OCH₃、-CH₂CH₂CH₂OCH₃、-CN、-OH、-OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)₂、-CH₂OH、-CH₂CH₂OH、-CH₂CH₂CH₂OH、-NH₂、-NHCH₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-N(CH₃)₂、-N(CH₃)CH₂CH₃、-N(CH₃)CH₂CH₂CH₃、-N(CH₃)CH(CH₃)₂、-CH₂NH₂、-CH₂CH₂NH₂、-CH₂CH₂CH₂NH₂、-CH₂N(CH₃)₂、-CH₂CH₂N(CH₃)₂、-CH₂CH₂CH₂N(CH₃)₂、-C(＝O)CH₃、-C(＝O)OCH₃、-C(＝O)OCH₂CH₃、-C(＝O)OCH₂CH₂CH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-CH₂C(＝O)N(CH₃)₂、-CH₂CH₂C(＝O)N(CH₃)₂、-CH₂CH₂CH₂C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-CH₂NHC(＝O)CH₃、-CH₂CH₂NHC(＝O)CH₃、-CH₂CH₂CH₂NHC(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃)、-S(＝O)₂N(CH₃)₂3-, 4-, 5-or 6-membered carbocyclyl; each R_4a、R_4bOr R_4cIndependently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH₂、-NHCH₃、-N(CH₃)₂、-CN、-C(＝O)CH₃、-C(＝O)OCH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃) or-S (═ O)₂N(CH₃)₂Substituted or unsubstituted;

Each R_4dIndependently at each occurrence is selected from-Br.

In some embodiments, R_4a、R_4bOr R_4cIndependently at each occurrence, is selected from hydrogen, -F, -Cl, -CH₃、-CH₂CH₃、CF₃、-CH₂CHF₂、-CH₂CH₂OCH₃、-CN、-CH₂OH、-N(CH₃)₂、-CH₂N(CH₃)₂、-CH₂NHCH₃、-CH₂CH₂NH₂、-NHCH₂CH₂OH、-COOH、-NHCOCH₃、

Or R_4aAnd R_4cTogether with the carbon atoms to which they are respectively attached form

Each R_4dIndependently at each occurrence is selected from-Br.

In some embodiments, R₄₁Is selected from

R_4a、R_4b、R_4cOr R_4eIndependently at each occurrence, selected from hydrogen, halogen, -C_1-6Alkyl or-C_1-6alkylene-N (C)_1-6Alkyl radical)₂。

In some embodiments, R_4a、R_4b、R_4cOr R_4eIndependently selected from hydrogen, -F, -Cl, -Br, -C_1-3Alkyl or-C_1-3alkylene-N (C)_1-3Alkyl radical)₂。

In some embodiments, R_4a、R_4b、R_4cOr R_4eIndependently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH₂-N(CH₃)₂、-CH₂-N(CH₂CH₃)₂or-CH₂-N(CH₃)(CH₂CH₃)。

In some embodiments, R_4a、R_4b、R_4cOr R_4eIndependently selected from hydrogen, -F, methyl or-CH₂-N(CH₃)₂。

In some embodiments, R_4aSelected from hydrogen or-F; r_4bIs hydrogen; r_4cSelected from hydrogen or-CH₂-N(CH₃)₂；R_4eIs methyl.

In some embodiments, each R is₄₁Independently at each occurrence is selected from:

In some embodiments, R₄Is independently selected from

Each one of which is

Optionally substituted at each occurrence with 1R ₄₂2R₄₂3R₄₂4, R₄₂5R₄₂Or 6R₄₂Substituted or unsubstituted.

In some embodiments, each R is₄₂Selected from-F, -Cl, -Br, oxo, -C_1-3Alkyl, -C_1-3Alkylene- (halogen)_1-3Hetero atom C_2-3Alkyl, -C_2-5Alkenyl, -C_2-5Alkynyl, -OR₈、-C_1-3Alkylene- (OR)₈)_1-3、-NR₈R₉、-C_1-3alkylene-NR₈R₉、-CN、-C_1-3alkylene-CN, -C (═ O) R₈、-C_1-3alkylene-C (═ O) R₈、-C(＝O)OR₈、-C_1-3alkylene-C (═ O) OR₈、-OC(＝O)R₈、-C_1-3alkylene-OC (═ O) R₈、-C(＝O)NR₈R₉、-C_1-3alkylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈、-C_1-3alkylene-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉、-C_1-3alkylene-S (═ O)₂NR₈R₉、-SO₂R₈、-C_1-3alkylene-SO₂R₈、-NR₈SO₂R₈or-C_1-3alkylene-NR₈SO₂R₈(ii) a Each R₄₂Independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, -Br, -C_1-3Alkyl, -C_1-3Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted; or

Two R₄₂Together with their co-or respectively-bound atoms form C_3-6Carbocycle or 3-6 membered heterocycle, each said heterocycle independently containing 1 or 2 heteroatoms selected from N or O, each carbocycle or heterocycle optionally substituted with 1, 2, 3, 4, 5 or 6 heteroatoms selected from halogen, -C_1-3Alkyl, -C_1-3Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

R₄₂each of (R)₈Or R₉) Independently at each occurrence, is selected from hydrogen or-C_1-3An alkyl group.

In some embodiments, each R is₄₂Selected from-F, -Cl, -Br, oxo, -C _1-3Alkyl, -C_1-3Alkylene- (halogen)_1-3Hetero atom C_2-3Alkyl, -C_2-5Alkenyl, -C_2-5Alkynyl, -OR₈、-C_1-3Alkylene- (OR)₈)_1-3、-NR₈R₉、-C_1-3alkylene-NR₈R₉、-CN、-C_1-3alkylene-CN, -C (═ O) R₈、-C_1-3alkylene-C (═ O) R₈、-C(＝O)OR₈、-C_1-3alkylene-C (═ O) OR₈、-OC(＝O)R₈、-C_1-3alkylene-OC (═ O) R₈、-C(＝O)NR₈R₉、-C_1-3alkylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈、-C_1-3alkylene-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉、-C_1-3alkylene-S (═ O)₂NR₈R₉、-SO₂R₈、-C_1-3alkylene-SO₂R₈、-NR₈SO₂R₈or-C_1-3alkylene-NR₈SO₂R₈(ii) a Each R₄₂Independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, -Br, -C_1-3Alkyl, -C_1-3Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted; or

Two R₄₂Together with the atoms to which they are both attached or are attached respectively, form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring, each heterocyclic ring independently containing 1 or 2 heteroatoms selected from N or O, each carbocyclic or heterocyclic ring optionally being substituted with 1, 2, 3, 4, 5 or 6 heteroatoms selected from-F, -Cl, -Br, -C_1-3Alkyl, -C_1-3Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

In some embodiments, each R is₄₂Selected from-F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -methylene- (halogen) _1-3-ethylene- (halogen)_1-3-propylene- (halogen)_1-3Heteroethyl, heteropropyl, ethenyl, propenyl, butenyl, pentenyl, ethynyl, propynyl, butynyl, pentynyl, -OR₈-methylene- (OR)₈)_1-3-ethylene- (OR)₈)_1-3-propylene- (OR)₈)_1-3、-NR₈R₉-methylene-NR₈R₉-ethyleneradical-NR₈R₉-propylene-NR₈R₉-CN, -methylene-CN, -ethylene-CN, -propylene-CN, -C (═ O) R₈-methylene-C (═ O) R₈-ethylene-C (═ O) R₈-propylene-C (═ O) R₈、-C(＝O)OR₈-methylene-C (═ O) OR₈-ethylene-C (═ O) OR₈-propylene-C (═ O) OR₈、-OC(＝O)R₈-methylene-OC (═ O) R₈-ethylene-OC (═ O) R₈-propylene-OC (═ O) R₈、-C(＝O)NR₈R₉-methylene-C (═ O) NR₈R₉-ethylene-C (═ O) NR₈R₉-propylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈-methylene-NR₈C(＝O)R₈-ethylene-NR₈C(＝O)R₈-propylene-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉-methylene-S (═ O)₂NR₈R₉-ethylene-S (═ O)₂NR₈R₉-propylene-S (═ O)₂NR₈R₉、-SO₂CH₃-methylene-SO₂CH₃-ethylene-SO₂CH₃-propylene-SO₂CH₃、-NHSO₂CH₃、-N(CH₃)SO₂CH₃-methylene-NHSO₂CH₃-ethylene-NHSO₂CH₃or-propylene-NHSO₂CH₃(ii) a Each R₄₂Independently optionally substituted with 1, 2, 3, 4, 5 OR 6 substituents selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR ₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted; or

Two R₄₂Connected together or separatelyThe atoms taken together form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, OR a 6-membered heterocyclic ring, each heterocyclic ring independently containing 1 OR 2 heteroatoms selected from N OR O, each carbocyclic OR heterocyclic ring optionally substituted with 1, 2, 3, 4, 5, OR 6 heteroatoms selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

R₄₂each of (R)₈Or R₉) Independently at each occurrence is selected from hydrogen, methyl, ethyl, propyl or isopropyl.

In some embodiments, each R is₄₂Selected from-F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -CH₂F、-CH₂Cl、-CHF₂、-CF₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃、-CH₂OCH₃、-CH₂CH₂OCH₃、-CH₂CH₂CH₂OCH₃Ethenyl, propenyl, butenyl, pentenyl, ethynyl, propynyl, butynyl, pentynyl, -OH, -OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)₂、-CH₂OH、-CH₂CH₂OH、-CH₂CH₂CH₂OH、-C(OH)(CH₃)₂、-NH₂、-NHCH₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-N(CH₃)₂、-N(CH₃)CH₂CH₃、-N(CH₃)CH₂CH₂CH₃、-N(CH₃)CH(CH₃)₂、-CH₂NH₂、-CH₂CH₂NH₂、-CH₂CH₂CH₂NH₂、-CH₂N(CH₃)₂、-CH₂CH₂N(CH₃)₂、-CH₂CH₂CH₂N(CH₃)₂、-CN、-CH₂CN、-CH₂CH₂CN、-CH₂CH₂CN、-C(＝O)CH₃、-CH₂C(＝O)CH₃、-CH₂CH₂C(＝O)CH₃、-CH₂CH₂CH₂C(＝O)CH₃、-COOH、-CH₂COOH、-CH₂CH₂COOH、-C(＝O)OCH₃、-CH₂C(＝O)OCH₃、-CH₂CH₂C(＝O)OCH₃、-CH₂CH₂CH₂C(＝O)OCH₃、-C(＝O)OCH₂CH₃、-C(＝O)OCH₂CH₂CH₃、-OC(＝O)CH₃、-CH₂OC(＝O)CH₃、-CH₂CH₂OC(＝O)CH₃、-CH₂CH₂CH₂OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-CH₂C(＝O)N(CH₃)₂、-CH₂CH₂C(＝O)N(CH₃)₂、-CH₂CH₂CH₂C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-CH₂NHC(＝O)CH₃、-CH₂CH₂NHC(＝O)CH₃、-CH₂CH₂CH₂NHC(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃)、-S(＝O)₂N(CH₃)₂、-CH₂S(＝O)₂N(CH₃)₂、-CH₂CH₂S(＝O)₂N(CH₃)₂、-CH₂CH₂CH₂S(＝O)₂N(CH₃)₂、-SO₂CH₃、-CH₂SO₂CH₃、-CH₂CH₂SO₂CH₃、-CH₂CH₂CH₂SO₂CH₃、-NHSO₂CH₃、-CH₂NHSO₂CH₃、-CH₂CH₂NHSO₂CH₃or-CH₂CH₂CH₂NHSO₂CH₃(ii) a Each R₄₂Independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH₂、-NHCH₃、-N(CH₃)₂、-CN、-C(＝O)CH₃、-C(＝O)OCH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃) or-S (═ O)₂N(CH₃)₂Substituted or unsubstituted; or

Two R₄₂Together with the atoms to which they are both or separately attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring, each heterocyclic ring independently containing 1 or 2 heteroatoms selected from N or O.

In some embodiments, each R is₄₂Is selected from-F, ═ O and-CH₃、-CH₂CH₃、-CH(CH₃)₂、-CHF₂、-CH₂Cl、-CF₃、-CH₂CF₃、

-CH₂OH、-C(OH)(CH₃)₂、-CN、-CH₂CN、-CH₂N(CH₃)₂、-COOH、-CH₂COOH、-CONH₂、

Or

Two R₄₂Together with their co-or separately-bound atoms

In some embodiments, each R is₄₂Independently at each occurrence is selected from-C_1-6An alkyl group; -C_1-6alkylene-CN or by halogen, -NH₂-CN or-OH substituted-C_1-6An alkyl group.

In some embodiments, each R is₄₂Independently at each occurrence is selected from-C_1-3An alkyl group; -C_1-3alkylene-CN or-C substituted by-F or-Cl_1-3An alkyl group.

In some embodiments, each R is₄₂Independently at each occurrence is selected from methyl; an ethyl group; propyl; isopropyl group; -methylene-CN; -ethylene-CN; -propylene-CN; methyl substituted by-F or-Cl; ethyl substituted with-F or-C1; propyl substituted with-F or-C1; or isopropyl substituted with-F or-C1.

In some embodiments, each R is₄₂Independently at each occurrence is selected from methyl; an ethyl group; -methylene-CN or methyl substituted by-F.

In some embodiments, each R is₄₂Independently at each occurrence is selected from-CH₃、-CH₂CH₃、-CH₂CN、-CHF₂or-CF₃。

In some embodiments, R₄Selected from:

in some embodiments, R₄Selected from:

in some embodiments, R₄Selected from:

in some embodiments, R₄-L₄-is selected from:

in some embodiments, the compound is selected from:

in another aspect, the present invention provides an intermediate of formula (II), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:

wherein the content of the first and second substances,

R₄' is selected from

Said

PG is a protecting group of N atom; preferably PG is

(R₁、R₂₁、R₂₂、R₃、L₄、R₄、n1、n2、n3、n4、G₁、G₂、G₃Or R₄₂) As defined in any one of claims 1 to 102.

In some embodiments, the intermediate is selected from the group consisting of:

in another aspect, the present invention provides an intermediate, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, wherein said intermediate is selected from the group consisting of:

In another aspect, the present invention provides a method of treating a compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof, the method comprising the following step a or step B:

step A:

and B:

in the step A, the R is₁' selected from the group consisting of 1R₁₁2R₁₁Or 3R₁₁substituted-C_6-10Aryl or by 1R₁₁2R₁₁Or 3R₁₁Substituted 5-10 membered heteroaryl; preferably, R is₁' is 2R₁₁Substituted phenyl; in step A, (R)₂₁、R₂₂、R₃、L₄、R₄、R₁Or R₁₁) Is as defined in any one of claims 1 to 101; in the step A, R in the intermediate A0 is reacted₁' halogenation to obtain the compound of formula (I), preferably the halogenating agent is NCS or NBS;

in step B, R is₁' selected from the group consisting of 1R₁₁2R₁₁Or 3R₁₁substituted-C_6-10Aryl or by 1R₁₁2R₁₁Or 3R₁₁Substituted 5-10 membered heteroaryl; preferably, R is₁' is 2R₁₁Substituted phenyl; said R₄' is R with a protecting group for the N atom₄Such as N-Boc piperazinyl; in step B1, the intermediate B0 is prepared by reacting R₁' halogenation to obtain intermediate B1, preferably the halogenating agent is NCS or NBS; in step B2, the intermediate B1 is prepared by reacting R ₄' deprotection and subsequent acylation of the N atom affords said compound of formula (I).

In some embodiments, R in step A or step B is₁' is selected from:

in step B, -L₄-R₄' is selected from:

in another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula (I) as described herein, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the weight ratio of the compound to the excipient ranges from about 0.0001 to about 10. In some embodiments, the weight ratio of said compound to said excipient ranges from about 0.01 to about 0.8. In some embodiments, the weight ratio of said compound to said excipient ranges from about 0.02 to about 0.2. In some embodiments, the weight ratio of said compound to said excipient ranges from about 0.05 to about 0.15.

In a further aspect, the present invention provides a compound of formula (I) as described herein, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof; or the use of a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of a disease or disorder associated with a KRAS mutein. In some embodiments, the disease or disorder associated with KRAS mutein is a disease or disorder associated with KRAS G12C mutein. In some embodiments, the disease or disorder associated with KRAS mutein is a cancer associated with KRAS G12C mutein. In some embodiments, the cancer is selected from hematologic cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, or lung cancer. In some embodiments, the hematological cancer is selected from acute myelogenous leukemia or acute lymphatic leukemia; the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

In yet another aspect, the present invention provides a method of treating a patient having a disease or disorder associated with KRAS mutein comprising administering to said patient a therapeutically effective amount of at least one compound of formula (I) as described herein, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof; or said pharmaceutical composition of the invention. In some embodiments, the disease or disorder associated with a KRAS mutein is a disease or disorder associated with a KRAS G12C mutein. In some embodiments, the disease or disorder associated with KRAS mutein is a cancer associated with KRAS G12C. In some embodiments, the cancer is selected from hematologic cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, or lung cancer. In some embodiments, the hematological cancer is selected from acute myelogenous leukemia or acute lymphocytic leukemia; the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

In a further aspect, the present invention provides a compound of formula (I) as described herein, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof or a pharmaceutically acceptable salt of an atropisomer thereof, for use as a medicament; or a pharmaceutical composition according to the invention.

Definition of

The term "halogen" as used herein, unless otherwise indicated, refers to fluorine, chlorine, bromine or iodine. Preferred halo groups include-F, -Cl and-Br. More preferably halogen is-F or-Cl.

The term "alkyl" as used herein, unless otherwise specified, includes saturated monovalent hydrocarbon radicals having a straight or branched chain. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-methylpentyl and cyclohexyl. Similarly, C_1-6C in alkyl_1-6Is defined as a group having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.

The term "alkylene" refers to a radical obtained by removing a hydrogen atom from an alkyl radical as defined aboveIs bifunctional. For example, methylene (i.e., -CH)₂-), ethylene (i.e. -CH₂-CH₂-or-CH (CH)₃) -) and propylene (i.e., -CH₂-CH₂-CH₂-、-CH(-CH₂-CH₃) -or-CH₂-CH(CH₃)-)。

The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds, typically 2 to 20 carbon atoms in length. For example, "C_2-6Alkenyl "contains 2 to 6 carbon atoms. For example, alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

The term "alkynyl" refers to a straight or branched chain hydrocarbon radical containing one or more triple bonds, typically from 2 to 20 carbon atoms in length. For example, "C_2-6Alkynyl "contains 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

The term "alkoxy" group is an oxygen ether formed from the aforementioned alkyl groups.

The term "aryl" as used herein, unless otherwise specified, refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing carbon ring atoms. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.

The term "heterocyclyl" or "heterocycle" as used herein, unless otherwise specified, refers to unsubstituted and substituted monocyclic or polycyclic non-aromatic ring systems containing one or more (e.g., 2, 3, 4, 5, or 6) heteroatoms, including monocyclic heterocycles (groups), bicyclic heterocycles (groups), bridged heterocycles (groups), fused heterocycles (groups), and spirocycles. Preferred heteroatoms include N, O and S, including N-oxides, sulfur oxides, and dioxides. Preferably, the ring is a three to ten membered ring which is fully saturated or has one or more unsaturations. This definition includes heterocyclic groups or heterocycles having multiple degrees of substitution, preferably one, two or three degrees of substitution. Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, or oxadiazolyl.

As used herein, unless otherwise indicated, the term "heteroaryl" or "heteroaromatic ring" refers to an aromatic ring system containing carbon and at least one heteroatom. The heteroaryl or heteroaromatic ring may be monocyclic or polycyclic, substituted or unsubstituted. Monocyclic heteroaryl groups may have 1 to 4 heteroatoms in the ring, while polycyclic heteroaryl groups may contain 1 to 10 heteroatoms. The polycyclic heteroaryl ring may contain a fused, spiro, or bridged ring combination, e.g., bicyclic heteroaryl is polycyclic heteroaryl. A bicyclic heteroaryl ring may contain 8 to 12 member atoms. Monocyclic heteroaryl rings can contain 5 to 8 member atoms (carbon and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenine, quinolinyl, or isoquinolinyl.

The term "carbocycle" refers to a substituted or unsubstituted monocyclic, bicyclic, or polycyclic non-aromatic saturated ring, which optionally includes an alkylene linker through which a cycloalkyl group may be attached. Exemplary "carbocyclyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "oxo" means that oxygen is formed together with the carbon atom to which it is attached

A group.

The term "-C_1-6alkylene-C_6-10Aryl "means C as defined above_6-10aryl-substituted-C_1-6An alkyl group.

The term "-C_1-6Alkylene- (5-to 10-membered heteroaryl) "means-C substituted with 5-to 10-membered heteroaryl as defined above_1-6An alkyl group.

The term "-C_1-6Alkylene- (3-to 10-membered heterocyclic) "means-C substituted by a 3-to 10-membered heterocyclic group as defined above_1-6An alkyl group.

The term "-C_1-6alkylene-C_3-10Carbocyclyl "means C as defined above_3-10Carbocyclyl substituted-C_1-6An alkyl group.

The term "-C_1-6Alkylene- (halogen)_1-3"means C substituted by 1, 2 or 3 halogens as defined above_1-6An alkyl group.

The term "hetero C_2-6Alkyl "means-C as defined above_2-6A group wherein one or more carbon atoms in the chain of the alkyl group is replaced by a heteroatom selected from O, S or N, preferably the heteroatom is O.

The term "-C_1-6Alkylene- (OR)₈)_1-3By "is meant a compound which is substituted by 1, 2 OR 3 OR₈substituted-C_1-6Alkyl radical, wherein R₈As defined above, preferred R₈Selected from hydrogen, methyl, ethyl or propyl.

The term "-C_1-6Alkylene- (SR)₈)_1-3By "is meant a radical substituted by 1, 2 or 3 SR₈substituted-C_1-6Alkyl radical, wherein R₈As defined above, preferred R₈Selected from hydrogen, methyl, ethyl or propyl.

The term "-O-C_1-6Alkylene- (halogen)_1-3"refers to-C as defined above_1-6Alkylene- (halogen)_1-3An oxygen ether of (a).

The term "-S-C_1-6Alkylene- (halogen)_1-3"refers to-C as defined above_1-6Alkylene- (halogen)_1-3The S ether of (1).

The term "-C_1-6alkylene-NR₈R₉"means by-NR₈R₉substituted-C_1-6Alkyl, wherein said R is₈And R₉Is as defined above, preferablyGround R₈、R₉Selected from hydrogen, methyl, ethyl or propyl.

The term "-C_1-6alkylene-C (═ O) R₈By "means a substituted or unsubstituted aryl group, -O₈substituted-C_1-6Alkyl, wherein said R is₈Is as defined above, preferably R₈Selected from hydrogen, methyl, ethyl or propyl.

The term "-C_1-6alkylene-C (═ O) OR₈"means substituted by-C (═ O) OR₈substituted-C_1-6Alkyl, wherein said R is₈Is as defined above, preferably R₈Selected from hydrogen, methyl, ethyl or propyl.

The term "-C_1-6alkylene-OC (═ O) R₈By "means of a substituted or unsubstituted carbonyl group-OC (═ O) R₈substituted-C_1-6Alkyl, wherein said R is₈Is as defined above, preferably R₈Selected from hydrogen, methyl, ethyl or propyl.

The term "-C_1-6alkylene-C (═ O) NR₈R₉By "means a substituted or unsubstituted aryl or heteroaryl group₈R₉substituted-C_1-6Alkyl, wherein said R is₈And R₉Is as defined above, preferably R₈、R₉Selected from hydrogen, methyl, ethyl or propyl.

The term "-C _1-6alkylene-NR₈C(＝O)R₈"means by-NR₈C(＝O)R₈substituted-C_1-6Alkyl, wherein said R is₈Is as defined above, preferably R₈Selected from hydrogen, methyl, ethyl or propyl.

The term "-C_1-6alkylene-S (═ O)₂NR₈R₉"means by-S (═ O)₂NR₈R₉substituted-C_1-6Alkyl, wherein said R is₈、R₉Is as defined above, preferably R₈、R₉Selected from hydrogen, methyl, ethyl or propyl.

The term "-C_1-6alkylene-CN "means-C substituted by-CN_1-6An alkyl group.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the invention as active ingredients and processes for preparing the compounds of the invention are also part of the invention.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compounds of the present invention are acidic, their corresponding salts may be conveniently prepared from pharmaceutically acceptable non-toxic bases including inorganic and organic bases. When the compounds of the present invention are basic, their corresponding salts may be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds of formula (I) are intended for pharmaceutical use, they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% by weight).

The present invention includes within its scope prodrugs of the compounds of the present invention. In general, such prodrugs are functional derivatives of the compounds that are readily converted in vivo to the desired compounds. Thus, in the methods of treatment of the present invention, the term "administering" shall include treating the various conditions described with a specifically disclosed compound, or with a compound that may not be specifically disclosed, but which converts to the specific compound in vivo upon administration to a subject. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in "prodrug Design" ("Design of Prodrugs", ed.h. bundgaard, Elsevier, 1985.).

The definition of any substituent or variable at a particular position in a molecule is intended to be independent of the definition of substituents or variables at other positions in the molecule. It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to provide chemically stable compounds, and can be readily synthesized by techniques known in the art and by the methods set forth herein.

The invention includes that the compounds may contain one or more asymmetric centers and thus may give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

The present invention includes all stereoisomers of the compounds and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. The products of these processes may be mixtures of stereoisomers during the course of the synthetic procedures used to prepare these compounds, or during the course of using racemization or epimerization procedures known to those skilled in the art.

The term "stereoisomer" as used herein refers to isomers of molecules in which atoms or groups of atoms are bonded in the same order but in different spatial arrangements, and includes configurational isomers and conformational isomers, wherein configurational isomers include geometric isomers and optical isomers, and optical isomers include mainly enantiomers and diastereomers.

Certain compounds provided herein can exist as atropisomers, which are conformational stereoisomers that occur when rotation about a single bond in a molecule is prevented or greatly slowed due to steric interaction with other parts of the molecule. The compounds provided herein include all atropisomers, including pure individual atropisomers, enriched atropisomers of each or non-specific mixtures of each. If the spin barrier around a single bond is high enough and the interconversion between conformations is slow enough, separation of atropisomers may be allowed.

The present invention is intended to include all atomic isotopes present in the compounds of the invention. Isotopes are atoms having the same atomic number but different mass numbers. By way of general example, and not limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of hydrogen can be represented as¹H (hydrogen) is selected from the group consisting of,²h (deuterium) and³h (tritium). They are also commonly denoted as D (deuterium) and T (tritium). In this application, CD₃Represents a methyl group in which all hydrogen atoms are deuterium. Isotopes of carbon include¹³C and¹⁴C. book (I)Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.

Unless otherwise indicated, when tautomers of compounds of formula (I) exist, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

When the compounds of formula (I) and pharmaceutically acceptable salts thereof are present in solvate or polymorphic form, the invention includes any possible solvates and polymorphs. The type of the solvent forming the solvate is not particularly limited as long as the solvent is pharmacologically acceptable.

The pharmaceutical composition of the present invention comprises a compound represented by formula (I) (a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other adjuvants. Although the most suitable route in any given case will depend on the particular host, and the nature and severity of the condition for which the active ingredient is being administered to treat it, the compositions include compositions suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration. The pharmaceutical compositions may conveniently be presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

In practice, the compounds represented by formula I of the present invention or prodrugs or metabolites thereof or pharmaceutically acceptable salts thereof may be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for the route of administration, e.g., oral or parenteral (including intravenous) routes of administration. Thus, the pharmaceutical compositions of the present invention may be presented as discrete units suitable for oral administration, for example, capsules, cachets (cachets) or tablets each containing a predetermined amount of the active ingredient. Furthermore, the composition may be present in powder form, in particulate form, in solution form, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil emulsion. In addition to the above-described conventional dosage forms, the compound represented by formula I or a pharmaceutically acceptable salt thereof may also be administered via a controlled release device and/or a delivery device. The composition may be prepared by any pharmaceutical method. Generally, these methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more required ingredients. Generally, compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired pattern.

Accordingly, the pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable carrier and a compound of formula I or a pharmaceutically acceptable salt.

The pharmaceutical carrier used may be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical medium may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units wherein solid pharmaceutical carriers are employed. Optionally, the tablets may be coated by standard aqueous or non-aqueous techniques.

Tablets containing the composition of the invention may be prepared by compression or moulding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05mg to about 5g of active ingredient, and each cachet or capsule preferably contains from about 0.05mg to about 5g of active ingredient. For example, formulations for oral administration to humans may contain from about 0.5mg to about 5g of the active agent, in admixture with a suitable and convenient amount of carrier material which may comprise from about 0.05% to about 95% of the total composition. Unit dosage forms typically contain from about 0.01mg to about 2g of the active ingredient, typically 0.01mg, 0.02mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, 1000mg, 1500mg or 2000 mg.

Pharmaceutical compositions of the invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compound in water. Suitable surfactants, such as hydroxypropyl cellulose, may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. In addition, preservatives may be included to prevent the unwanted growth of microorganisms.

Pharmaceutical compositions of the invention suitable for injectable use include sterile aqueous solutions or dispersions. In addition, the compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid to facilitate injection. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; therefore, it is preferable that preservation should be prevented from contamination by microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

The pharmaceutical compositions of the present invention may be in a form suitable for topical use, such as aerosols, creams, ointments, lotions, dusting powders and the like. In addition, the composition may be in a form suitable for use in a transdermal device. Using the compounds of formula I of the present invention, or pharmaceutically acceptable salts thereof, these formulations can be prepared by conventional processing methods. For example, a cream or ointment is prepared by mixing a hydrophilic material and water with about 0.05 wt% to about 10 wt% of the compound to produce a cream or ointment having a desired consistency.

The pharmaceutical compositions of the present invention may be in a form suitable for rectal administration wherein the carrier is a solid. Preferably the mixture is formed into unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by first mixing the composition with the softened or molten carrier, followed by cooling and shaping in a mould.

In addition to the above-mentioned carrier ingredients, the above-mentioned pharmaceutical preparations may suitably comprise one or more additional carrier ingredients, such as diluents, buffers, flavouring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like. In addition, other adjuvants may be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof may also be prepared in the form of a powder or liquid concentrate.

Typically, dosage levels of about 0.001mg/kg to about 150mg/kg body weight per day are useful for treating the above conditions, or about 0.05mg to about 7g per patient per day.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

These and other aspects will become apparent from the following written description of the invention.

Drawings

FIG. 1 shows a graph of tumor volume as a function of days post cell inoculation in mice in experiments in which compound 11 was used to inhibit tumor growth.

FIG. 2 is a graph showing the change in body weight of mice with days after cell inoculation in a safety search experiment using Compound 11B.

Detailed Description

The compounds of the invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. Examples of specific synthetic routes and the following general schemes are intended to provide guidance to the synthetic chemist in the art, who will readily understand that solvents, concentrations, reagents, protecting groups, order of synthetic steps, times, temperatures, and the like, may be modified as needed within the skill and judgment of the artisan. For example, the compounds of the present invention may be prepared according to the following general synthetic scheme.

The following examples are provided to better illustrate the invention. Unless otherwise expressly indicated, all parts and percentages are by weight and all temperatures are in degrees Celsius. The following abbreviations in table 1 are used in the examples:

TABLE 1

General synthetic scheme

Scheme I:

in scheme I, X₁Represents a leaving group such as halogen, for example, Cl, Br, I; x₂Represents a leaving group such as halogen, for example Cl; br; i; LG represents a leaving group, e.g., Cl, OTf; y is₁Represents H or a leaving group; r₄' represents R4 with a protecting group, such as N-Boc piperazinyl; the definition of the other substituents or groups in scheme I is as defined above.

INT-A route

Compounds of formula (I) disclosed herein can be prepared as described in scheme IAnd (4) synthesizing. In step 1, the purchased or synthetically obtained starting material 1 is condensed with INT-A (INT-A route) in a condensing agent such as HATU or EDCI/HOBT, or an acid chloride (prepared from compound 1) to give compound 2. The coupling reaction may be carried out in the presence of a base (such as triethylamine or Hunig's base) in a solvent (such as dichloromethane or DMF). In

step

2, 2 can be treated with a suitable base (e.g., LiHMDS or NaH) to obtain the intramolecular ring closure product compound 3. In step 3, the monooxygroup of the pyridone (compound 3) is converted to a leaving group by the action of an activating reagent, including but not limited to acid chloride, triflic anhydride, phosphorus oxychloride, and phosphorus pentachloride, to form compound 4. In step 4, the leaving group is Y-substituted in a solvent (e.g. acetonitrile) and a base (e.g. DIPEA) ₁-L₄-R₄' of L₄-R₄' substitution gives compound 5. In step 5, compound 5 is deprotected under the action of TFA/DCM or methanolic hydrogen chloride and reacted with an acylating agent to obtain compound 6, and the specific conditions include: acylating agent such as acryloyl chloride, solvent such as DCM or THF, base such as TEA, DIEA or K₃PO₄An aqueous solution. Step 6 Compound 6 with the corresponding Compound Z₁-R₁Coupling introduction of R₁To obtain the compound of formula (I), the reagent used may be a combination of catalysts such as Pd₂(dba)₃X-Phos, a solvent such as dioxane, a base such as cesium carbonate or sodium carbonate. In some cases R₁And R₃There may be protecting groups which may be removed in subsequent synthetic steps.

The compound can be purified in all the above steps by common purification means such as column chromatography, crystallization purification, reversed phase column HPLC or Pre-TLC. The enantiomeric compound (I) can be resolved and purified by well-known purification means such as chiral SFC or HPLC to give enantiomers or atropisomers, if necessary.

Scheme II:

in scheme II, X₁Represents a leaving group such as a halogen or the like,such as Cl, Br, I; x₂Represents a leaving group such as halogen, for example, Cl, Br, I; LG represents a leaving group, e.g., Cl, OTf; y is₁Represents H or a leaving group; r ₄' represents R with a protecting group₄Such as N-Boc piperazinyl; the definition of the other substituents or groups in scheme II is as defined above.

INT-A route:

the compounds of formula (I) disclosed herein can be synthesized as described in scheme II. In step 1, the starting material 1, purchased or synthesized, is mixed with a condensing agent such as: under the action of HATU or EDCI/HOBT, or the compound 1 firstly forms acyl chloride and then is condensed with INT-A (INT-A route) to obtain a compound 2. The solvent used for condensation can be dichloromethane or DMF, and the base used can be TEA or DIEA. Compound 2 in step 2 can be prepared in the presence of a base such as: compound 3 is formed by intramolecular ring closure under the action of LiHMDS or NaH. In step 3, the hydroxyl group is reacted with an activating reagent to form compound 4, the activating reagent including, but not limited to, acid chloride, trifluoromethanesulfonic anhydride, phosphorus oxychloride, and phosphorus pentachloride. Leaving group activated in step 4 is reacted with Y in a solvent such as acetonitrile, a base such as DIPEA₁-L₄-R₄' of L₄-R₄' substitution gives compound 5. Step 5 Compound 5 with the corresponding Compound Z₁-R₁Coupling introduction of R₁To obtain compound 6, the reagent used may be a catalyst combination such as Pd₂(dba)₃X-Phos, a solvent such as dioxane, a base such as cesium carbonate or sodium carbonate. Deprotection of compound 6 in step 6 by TFA/DCM or hydrogen chloride in methanol and reaction with an acylating agent affords compounds of formula (I). The specific conditions include: acylating agents such as acryloyl chloride, solvents such as DCM or THF, bases such as TEA, DIEA or K ₃PO₄An aqueous solution. In some cases R₁And R₃There may be protecting groups which may be removed in subsequent synthetic steps.

Scheme III:

in scheme III, X₁Represents a leaving group such as halogen, for example, Cl, Br, I; x₂Represents a leaving group such as halogen, for example, Cl, Br, I; LG represents a leaving group, e.g., Cl, OTf; y is₁Represents H or a leaving group; r₄' represents R with a protecting group₄Such as N-Boc piperazinyl; r₁' represents a group represented by 1R₁₁2R₁₁Or 3R₁₁substituted-C_6-10Aryl or by 1R₁₁2R₁₁Or 3R₁₁Substituted 5-10 membered heteroaryl. The definition of the other substituents or groups in scheme III is as defined above.

INT-A route:

the compounds of formula (I) disclosed herein can be synthesized as described in scheme III. In step 1, the starting material 1, purchased or synthesized, is mixed with a condensing agent such as: under the action of HATU or EDCI/HOBT, or the compound 1 firstly forms acyl chloride and then is condensed with INT-A (INT-A route) to obtain a compound 2. The solvent used for condensation can be dichloromethane or DMF, and the base used can be TEA or DIEA. Compound 2 in step 2 can be prepared in the presence of a base such as: compound 3 is synthesized by intramolecular cyclization under the action of LiHMDS or NaH. In step 3, the hydroxyl group is reacted with an activating reagent to form compound 4, the activating reagent including, but not limited to, acid chloride, trifluoromethanesulfonic anhydride, phosphorus oxychloride, and phosphorus pentachloride. Leaving group activated in step 4 is reacted with Y in a solvent such as acetonitrile, a base such as DIPEA ₁-L₄-R₄' of L₄-R₄' substitution gives compound 5. In the step 5, the compound 5 is deprotected under the action of TFA/DCM or methanol solution of hydrogen chloride and reacts with an acylating agent to obtain a compound 6, and the specific conditions comprise: acylating agents such as acryloyl chloride, solvents such as DCM or THF, bases such as TEA, DIEA or K₃PO₄An aqueous solution. Step 6 Compound 6 with the corresponding Compound Z₁-R₁' coupling introduction of R₁' obtaining Compound 7, the reagent used may be a combination of catalysts such as Pd₂(dba)₃X-Phos, a solvent such as dioxane, a base such as cesium carbonate or sodium carbonate. Compound 7 may be halogenated in step 7 to give a compound of formula (I) using reagents such as NCS/AcOH. In some cases R₁′、R₁And R₃There may be protecting groups which are removed in subsequent synthetic steps.

Scheme IV:

in scheme IV, X₁Represents a leaving group such as halogen, for example, Cl, Br, I; x₂Represents a leaving group such as halogen, for example, Cl, Br, I; LG represents a leaving group, e.g., Cl, OTf; y is ₁Represents H or a leaving group; r₄' represents R with a protecting group₄Such as N-Boc piperazinyl; r₁' represents a group represented by 1R₁₁2R₁₁Or 3R₁₁substituted-C_6-10Aryl or by 1R₁₁2R₁₁Or 3R₁₁Substituted 5-10 membered heteroaryl. The definition of the other substituents or groups in scheme Iv is as defined above.

INT-A route:

the compounds of formula (I) disclosed herein can be synthesized as described in scheme III. In step 1, the starting material 1, purchased or synthesized, is mixed with a condensing agent such as: under the action of HATU or EDCI/HOBT, or the compound 1 firstly forms acyl chloride and then is condensed with INT-A (INT-A route) to obtain a compound 2. The solvent used for condensation can be dichloromethane or DMF, and the base used can be TEA or DIEA. Step 2 may be carried out in the presence of a base such as: compound 3 is formed by intramolecular ring closure under the action of LiHMDS or NaH. In step 3, the hydroxyl group is reacted with an activating reagent to form compound 4, the activating reagent including, but not limited to, acid chloride, trifluoromethanesulfonic anhydride, phosphorus oxychloride, and phosphorus pentachloride. Leaving group activated in step 4 is reacted with Y in a solvent such as acetonitrile, a base such as DIPEA₁-L₄-R₄' of L₄-R₄' substitution gives compound 5. Step 5 Compound 5 with the corresponding Compound Z₁-R₁' coupling introduction of R₁' obtaining Compound 6, the reagent used may be a combination of catalysts such as Pd ₂(dba)₃Step 6 Compound 6 can be halogenated with a halogenating agent such as NCS/AcOH to give Compound 7. Deprotection of compound 7 in step 7 with TFA/DCM or hydrogen chloride in methanol and reaction with an acylating agent affords compounds of formula (I). The specific conditions include: acylating agents such as acryloyl chloride, solvents such as DCM or THF, bases such as TEA, DIEA or K₃PO₄An aqueous solution. In some cases R₁′，R₁And R₃There may be protecting groups which may be removed in subsequent synthetic steps.

Example 1

4- (4-Acryloylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 1")

Step 1.4-methyl-2- (prop-1-en-2-yl) pyridin-3-amine.

2-bromo-4-methylpyridin-3-amine (BD, APL099) (15.01g, 80.25mmol), 4, 5, 5-tetramethyl-2- (prop-1-en-2-yl) -1, 3, 2-dioxaborolan (13.62g, 81.05mmol), Pd (dppf) Cl ₂(5.95g，8.03mmol)、K₂CO₃(33.52g, 240mmol), dioxane (150mL), and water (20mL) were added to a 350-mL sealed tube purged and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at 100 ℃ for 8 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was applied to a silica gel column eluted with EA/n-hexane (v: v ═ 2: 3). This gave 11.2g (94%) of 4-methyl-2 (prop-1-en-2-yl) pyridin-3-amine as a yellow oil. LCMS: 149[ M +1 ] M/z]⁺。

Step 2.2-isopropyl-4-methyl-3-pyridylamine (intermediate A)

4-methyl 2 (prop-1-en-2-yl) pyridin-3-amine (11.2g, 75.67mmol), MeOH (100mL) was added to a 250-mL round bottom flask purged and maintained with a nitrogen inert atmosphere and Pd/C (2.81g) was added in three portions. The mixture was evacuated under reduced pressure and treated with H₂The ball was purged three times. The reaction mixture was stirred at 25 ℃ for 3 h. The resulting solution was filtered to give a filtrate, which was then concentrated under reduced pressure. This gives 11g (crude) of 2-isopropyl-4-methylpyridin-3-amine used directly. LCMS: m/z 151[ M +1 ]]⁺。

Step 3.2-cyano-aza- (2-isopropyl-4-methylpyridin-3-yl) acetamide.

2-cyanoacetic acid (3g, 35.27mmol), DCM (40mL) was placed in a 100-mL round bottom flask purged and maintained under a nitrogen inert atmosphere, and oxalyl chloride (6.2g, 48.85mmol) was added dropwise. After the addition was complete, DMF (0.1mL) was added. The resulting mixture was stirred at 25 ℃ for 3 h. The resulting solution was concentrated under reduced pressure, whereby 3.10g (crude product) of 2-cyanoacetyl chloride was obtained as it was.

2-isopropyl-4-methylpyridin-3-amine (2.00g, 13.31mmol), TEA (5.40g, 53.36mmol), DCM (40mL) was added to a 100-mL round bottom flask purged and maintained with a nitrogen inert atmosphere and stirred. The resulting mixture was cooled to 0 ℃ and then 2-cyanoacetyl chloride (3.10g, crop) was added dropwise. The resulting solution was stirred at room temperature for 2 h. The reaction was quenched by addition of 100 mL. The resulting solution was extracted with dichloromethane (3X 50mL), and the combined organic phases were washed with saturated brine (50mL), dried over anhydrous Na₂SO₄The residue obtained after drying and concentration under reduced pressure was applied to a silica gel column eluted with EA/n-hexane (v: v ═ 3: 2). This gave 1.00g (34%) of 2-cyano-N- (2-isopropyl-4-methylpyridine-3-cyanoacetamide as a yellow solid LCMS: M/z 218[ M +1 ═]⁺。

Step 4.2-cyano-3- (2, 6-dichloro-5-fluoropyridin-3-yl) -N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxopropanamide.

2, 6-dichloro-5-fluoronicotinic acid (3g, 14.28mmol), thionyl chloride (30mL) was added to a 100-mL round bottom flask purged and maintained with a nitrogen atmosphere. The resulting mixture was heated to 80 ℃ and stirred for 1 h. The resulting solution was concentrated under reduced pressure. This gave 3.10g (crude) of 2, 6-dichloro-5-fluoronicotinoyl chloride which was used directly in the next step.

2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) acetamide (650mg, 2.99mmol) and THF (10mL) were added to a 50-mL round-bottom flask and the resulting mixture was stirred at 0 ℃. NaH (250mg, 6.25mmol) was added in three portions. The resulting mixture was stirred at 0 ℃ for a further 40 min. 2, 6-dichloro-5-fluoronicotinoyl chloride (820mg, 3.59mmol) in THF (5mL) was then added dropwise. The resulting reaction mixture was stirred at 25 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The crude product thus obtained is further purified by using ACN/H₂C eluted O (v: v ═ 3: 7)₁₈And (5) purifying by using a column. This gives 1.00g (82%) of 2-cyano-3- (2, 6-dichloro-5-fluoropyridin-3-yl) -N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxopropanamide as a yellow solid. LCMS: m/z is 409[ M +1 ]]⁺。

Step 5.7-chloro-6-fluoro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (intermediate B).

2-cyano-3- (2, 6-dichloro-5-fluoropyridin-3-yl) -N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxopropanamide (1.10g, 2.68mmol), THF (20mL) was placed in a 50-mL round bottom cake purged and maintained with a nitrogen atmosphere and stirred at room temperature. NaH (530mg, 13.25mmol) was added. The resulting mixture was stirred at 50 ℃ for 12 h. The reaction was concentrated under reduced pressure. The resulting residue was dissolved in 40mL of water and the pH was adjusted to 7 with acetic acid. The resulting solid was filtered and dried under reduced pressure to give 0.80g (88%) of 7-chloro-6-fluoro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m/z 373[ M +1 ] ]⁺。

Step 6.4- (7-chloro-3-cyano-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

7-chloro-6-fluoro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (389mg, 1.04mmol), phosphorus oxychloride (552mg, 3.60mmol), DIEA (651mg, 5.04mmol), and acetonitrile (15mL) were placed in a 50-mL round-bottomed flask. The resulting mixture was stirred at 80 ℃ for 1 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The resulting crude product of 4, 7-dichloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile was dissolved in acetonitrile (15mL), and DIEA (480mg, 3.71mmol) and tert-butylpiperazine-1-carboxylate (233mg, 1.25mmol) were then added. The reaction mixture was stirred at rt for 0.5 h. After the reaction was complete, the reaction was quenched by addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3X 50mL), the organic phases were combined and washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column of silica gel eluting with EA/n-hexane (V/V-2/1). This gave 0.45g (79%) of tert-butyl 4- (7-chloro-3-cyano-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate as a yellow solid. LCMS: m/z 541[ M +1 ] ]⁺。

Step 7.4- (7- (2-amino-6-fluorophenyl) -3-cyano-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

Tert-butyl 4- (7-chloro-3-cyano-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate (155mg, 0.29mmol), 3-fluoro-2- (4, 4, 5.5-tetramethyl-1, 3, 2-dioxaboron-2-yl) aniline (206mg, 0.87mmol), Pd (PPh)₃)₄(50mg, 0.04mmol), sodium carbonate (107mg, 1.01mmol), dioxane (2mL), and water (0.2mL) were placed in a 20-mL sealed tube purged and maintained under an inert atmosphere of nitrogen. The resulting reaction mixture was stirred at 80 ℃ for 1 h. The reaction cloudy mixture was filtered and concentrated under reduced pressure. The residue was purified by column on silica eluting with EA/n-hexane (2/1 (v: v)). This gave 187mg (crude) of tert-butyl 4- (7- (2-amino-6-fluorophenyl) -3-cyano-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate as a yellow solid. LCMS: 616[ M +1 ] M/z]⁺。

Step 8.4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -3-cyano-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

Tert-butyl 4- (7- (2-amino-6-fluorophenyl) -3-cyano-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate (150mg, 0.24mmol), AcOH (4mL), NCS (72mg, 0.54mmol) were placed in a 50-mL round bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting mixture was stirred at room temperature for 2 days. The reaction was quenched with water (50mL), the resulting solution was extracted with ethyl acetate (3X 50mL), and the combined organic phases were washed with saturated brine (1X 50mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This gave 150mg (90%) of tert-butyl 4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -3-cyano-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate as a yellow solid. LCMS: 684[ M +1 ] M/z]⁺。

Step 9.4- (4-Acryloylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 1")

Tert-butyl 4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -3-cyano-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate (100mg, 0.15mmol), DCM (10mL), TFA (2mL) were placed in a 20-mL round bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. In a 25-mL round-bottom flask, the resulting residue was dissolved with DCM (3mL) and DIEA (82mg, 0.64mmol) was added. The resulting reaction mixture was cooled to 0 ℃ and acryloyl chloride (15mg, 0.15mmol) was added dropwise. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (20mL) and extracted with ethyl acetate (3X 50 mL). The combined organic phases were washed with brine (1X 50mL) and anhydrous Na ₂SO₄Dried, filtered and concentrated under reduced pressure. The residue obtained is subjected to Prep-HPLC (CH)₃CN/H₂O6/4 (v: v)). This gave 22mg (23% two-step yield) of 4- (4-acryloylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (compound 1) as a yellow solid. LCMS: 638[ M +1 ] M/z]⁺。

¹HNMR(400MHz，CD₃OD)δ8.67(d，J＝5.7Hz，1H)，8.42(d，J＝9.1Hz，1H)，7.82(d，J＝5.7Hz，1H)，7.47(d，J＝7.4Hz，1H)，6.90(dd，J＝16.7，10.6Hz，1H)，6.34(d，J＝16.8Hz，1H)，5.87(d，J＝10.6Hz，1H)，4.30-3.85(m，8H)，3.13-2.96(m，1H)，2.28(s，3H)，1.32(d，J＝6.9Hz，3H)，1.15(d，J＝6.8Hz，3H)。

Example 2

4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (3, 5-dichloro-2-fluoro-6-hydroxyphenyl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 2")

Step 1.4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

Mixing 7-chloro-6-fluoro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (389mg, 1.04mmol), POCl₃(552mg, 3.60mmol), DIEA (651mg, 5.04mmol), and acetonitrile (15mL) were placed in a 50-mL round bottom flask, purged and maintained with a nitrogen inert atmosphere. The reaction mixture was stirred at 80 ℃ for 1 h. The reaction was cooled to room temperature and concentrated under reduced pressure. Crude 4, 7-dichloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile was dissolved in acetonitrile (15mL), followed by the addition of DIEA (480mg, 3.71mmol) and 2- (piperazin-2-yl) acetonitrile (169mg, 1.35 mmol). The resulting reaction mixture was stirred at room temperature for 0.5 h. The resulting reaction mixture was cooled to 0 ℃ and acryloyl chloride (120mg, 1.33mmol) was added. The reaction was stirred for 1 h. After the reaction was complete, the reaction was quenched by addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3X 50mL), the organic phases were combined and washed with saturated brine (50mL), anhydrous Na ₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by column on silica eluting with EA/n-hexane (2/1 (v: v)). This gave 0.55g (98% yield in two steps) of 4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a pale yellow solid. LCMS: 534[ M +1 ] M/z]⁺。

Step 2.4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

To an 8-mL flask, 4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (232mg, 0.43mmol), 2-fluoro-6-hydroxyphenylboronic acid (299mg, 1.92mmol, 4.41eq), Pd (PPh) were added under a nitrogen atmosphere₃)₄(218mg，0.19mmol，0.43eq)、Na₂CO₃(308mg, 2.91mmol, 6.69eq), dioxane (5mL) and water (2 mL)mL). The resulting mixture was stirred at 90 ℃ for 2.5 h. The resulting reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column on silica eluting with EA/n-hexane (7/3 (v: v)). This gave 62mg (crude) of 4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: 610[ M +1 ] M/z ]⁺。

Step 3.4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (3, 5-dichloro-2-fluoro-6-hydroxyphenyl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 2")

4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (62mg, 0.10mmol), NCS (27mg, 0.20mmol, 2.00eq), and AcOH (4mL) were placed in a 20-mL reaction flask. The resulting reaction mixture was stirred at room temperature for 36 h. The reaction was quenched by addition of water (4 mL). The resulting solution was extracted with ethyl acetate (3X 10ml), and the organic layers were combined and concentrated in vacuo. The residue obtained is subjected to Prep-HPLC (CH)₃CN/H₂O3/2 (v: v)). This gave 13mg of 4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (3, 5-dichloro-2-fluoro-6-hydroxyphenyl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("compound 2") as a yellow solid. LCMS: 678[ M +1 ] M/z]⁺.

¹HNMR(400MHz，CD₃OD)δ8.83(s，1H)，8.43(d，J＝5.0Hz，1H)，7.54(d，J＝7.8Hz，1H)，7.29(t，J＝4.7Hz，1H)，6.91(s，1H)，6.36(d，J＝16.5Hz，1H)，5.90(d，J＝10.9Hz，1H)，4.28-3.94(m，4H)，3.80-3.40(m，3H)，3.08-2.96(m，1H)，2.91-2.77(m，1H)，2.71-2.54(m，1H)，2.15-2.90(m，3H)，1.19(dd，J＝16.1，6.7Hz，3H)，1.01(dd，J＝19.9，6.8Hz，3H)。

Example 3

4- ((s) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6-chloro-7- (3, 5-dichloro-2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 3")

Step 1.2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) acetamide.

2-cyanoacetic acid (3g, 35.27mmol), DCM (40mL) was placed in a 100-mL round bottom flask purged and maintained with a nitrogen inert atmosphere. Oxalyl chloride (6.2g, 48.85mmol) was added dropwise. After the addition was complete, DMF (0.1mL) was added. The resulting mixture was stirred at 25 ℃ for 3 h. The resulting reaction solution was concentrated under reduced pressure. This gives 3.10g (crude) of 2-cyanoacetyl chloride, which can be used as such.

2-isopropyl-4-methylpyridin-3-amine (2.00g, 13.31mmol), TEA (5.40g, 53.36mmol), DCM (40mL) was added to a 100-mL round bottom flask purged and maintained with a nitrogen inert atmosphere and stirred. The resulting mixture was cooled to 0 ℃ and then 2-cyanoacetyl chloride (3.10g, crop) was added dropwise. The resulting solution was stirred at room temperature for 2 h. The reaction was quenched by addition of water (100 mL). The resulting mixed solution was extracted with dichloromethane (3X 50mL), the organic phases were combined and washed with saturated brine (50mL), anhydrous Na₂SO₄And (5) drying. The residue obtained by concentration under reduced pressure was applied to a silica gel column eluted with EA/n-hexane (v: v ═ 3: 2). This gave 1.00g (34%) of 2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) acetamide as a yellow solid. LCMS: 218[ M +1 ] M/z ]⁺。

Step 2.2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxo-3- (2, 5, 6-trichloropyridin-3-yl) propionamide

2, 5, 6-trichloronicotinic acid (5.01g, 22.12mmol), thionyl chloride (30mL) was placed in a 100-mL round bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting mixture was heated to 80 ℃ and stirred for 2 h. The resulting solution was concentrated under reduced pressure. This gives 5.10g (crude) of 2, 5, 6-trichloronicotinoyl chloride, which can be used directly in the next step.

2-cyano N- (2-isopropyl-4-methylpyridin-3-yl) acetamide (3.01g, 13.85mmol) and tetraTetrahydrofuran (40mL) was placed in a 250-mL round-bottom flask and the resulting mixture was stirred at 0 ℃. NaH (1.16g, 28.99mmol) was added in three portions. The resulting mixture was stirred at 0 ℃ for a further 40 min. Then 2, 5, 6-trichloronicotinoyl chloride (3.19g, 13.03mmol) dissolved in tetrahydrofuran (10mL) was added dropwise. The resulting reaction mixture was stirred at 25 ℃ for 2 h. The resulting reaction mixture was concentrated under reduced pressure. The crude product obtained is further processed by using ACN/H₂Reversed phase C eluted with O (0% -30%)₁₈And (5) column purification. This gives 5.89g (crude) of 2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxo-3- (2, 5, 6-trichloropyridin-3-yl) propionamide as a yellow solid. LCMS: 425[ M +1 ] M/z ]⁺。

Step 3.6, 7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (intermediate C).

2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxo-3- (2, 5, 6-trichloropyridin-3-yl) propionamide (5.89g, 13.83mmol), tetrahydrofuran (70mL) was placed in a 250-mL round bottom flask purged and maintained under an inert atmosphere of nitrogen and stirred at room temperature. NaH (2.73g, 68.25mmol) was added. The resulting mixture was stirred at 50 ℃ for 2 h. The reaction was concentrated under reduced pressure. The residue was dissolved in 100mL of water and the pH was adjusted to 7 with AcOH. The resulting solid was filtered and dried under reduced pressure, thereby obtaining 5.85g (two-step yield 108%) of 6, 7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m/z 389[ M +1 ]]⁺。

¹HNMR(400MHz，DMSO-d₆)68.77(d，J＝5.7Hz，1H)，8.38(s，1H)，7.89(d，J＝5.4Hz，1H)，3.01-2.88(m，1H)，2.19(s，3H)，1.21(d，J＝6.9Hz，3H)，1.14(d，J＝6.9Hz，3H).

(s) -3- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester.

A solution of 1-benzyl-4- (tert-butyl) (S) -2- (cyanomethyl) piperazine-1, 4-carbonate (2.99g, 8.32mmol) in tetrahydrofuran (40mL) was treated with 10% Pd/C (1.03g) with hydrogen at atmospheric pressure for 2h at room temperature. The catalyst was filtered and the filtrate was concentrated under reduced pressure. Thus, 2.3g of (S) -3- (cyanomethyl) was obtained Yl) piperazine-1-carboxylic acid tert-butyl ester, which is a colorless oil. LCMS: 226[ M +1 ] M/z]⁺。

(S) -2- (piperazin-2-yl) acetonitrile.

Tert-butyl (S) -3- (cyanomethyl) piperazine-1-carboxylate (2.3g, 10.21mmol), HCl/dioxane (10mL), dioxane (10mL) was placed in a 100-mL round bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. This gave 1.8g (crude) of (S) -2- (piperazin-2-yl) acetonitrile as a white solid. LCMS: 126[ M +1 ] M/z]⁺。

¹HNMR(400MHz，DMSO-d₆)610.10(s，2H)，4.07-3.82(m，1H)，3.80-3.41(m，4H)，3.41-2.93(m，4H)。

(S) -4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

Mixing 6, 7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (2.51g, 6.45mmol) and POCl₃(3.12g, 20.34mmol), DIEA (3.21g, 24.84mmol) and acetonitrile (30mL) were placed in a 100-mL round bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting mixture was stirred at 80 ℃ for 1 h. The reaction was cooled to room temperature and concentrated under reduced pressure. 4, 6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (2.63g, 6.45mmol), acetonitrile (30mL), DIEA (3.24g, 20.05mmol), and (S) -2- (piperazin-2-yl) acetonitrile (1.272g, 7.87mmol) were placed in a 100-mL round-bottomed flask purged and maintained with a nitrogen inert gas atmosphere. The reaction mixture was stirred at rt for 0.5 h. The reaction mixture was cooled to 0 ℃ and acryloyl chloride (602mg, 6.65mmol) was added. The reaction mixture was stirred at room temperature for further 0.5h and concentrated under reduced pressure. The residue was purified by column of silica gel eluting with EA/n-hexane 3/2 (v: v). This gave 1.45g (41% of three-step yield) of (S) -4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a pale yellow solid. LCMS: m/z is 550[ ] M+1]⁺。

¹HNMR(400MHz，CD₃OD)δ8.50(d，J＝3.9Hz，2H)，7.37-7.24(m，1H)，6.87(s，1H)，6.33(d，J＝16.6Hz，1H)，5.87(d，J＝10.8Hz，1H)，4.43-3.89(m，5H)，3.77-3.36(m，2H)，3.13(s，1H)，3.02-2.89(m，1H)，2.85-2.47(m，1H)，2.08-1.92(m，3H)，1.20-0.98(m，6H)。

Step 7.4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

(S) -4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (204mg, 0.37mmol), 3-fluoro-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (83mg, 0.53mmol), Pd (dppf) Cl₂(58mg, 0.08mmol), sodium carbonate (140mg, 1.32mmol), dioxane (5mL), and water (1mL)25-mL were added to the round bottom flask. The resulting mixture was stirred at 80 ℃ for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue is obtained by reacting with CH₃CN/H₂O(0.05％NH₄HCO₃) Prep-HPLC purification eluted at 3/2 (v: v). This gave 32mg (41%) of 4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: 626[ M +1 ] M/z]。

¹HNMR(400MHz，DMSO-d₆)δ10.15(d，J＝10.1Hz，1H)，8.52(s，1H)，8.41(d，J＝4.7Hz，1H)，7.29-7.15(m，2H)，6.94(s，1H)，6.80-6.54(m，2H)，6.24(d，J＝16.5Hz，1H)，5.82(d，J＝10.6Hz，1H)，5.31-4.44(m，2H)，4.32-3.83(m，4H)，3.68-3.37(m，2H)，3.08-2.88(m，1H)，2.84-2.63(m，1H)，1.98-1.78(m，3H)，1.23-0.99(m，3H)，0.97-0.75(m，3H).

Step 8.4- ((s) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6-chloro-7- (3, 5-dichloro-2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 3")

4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (124mg, 0.20mmol), NCS (48mg, 0.36mmol), glacial acetic acid (5mL) was placed in a 25-mL round bottom flask. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was filtered and concentrated under reduced pressure. The residue was passed through Prep-HPLCCH₃CN/H₂O(0.05％NH₄HCO₃) 2/1. This gave 8mg (6%) of 4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6-chloro-7- (3, 5-dichloro-2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("compound 3") as a yellow solid. LCMS: 694[ M +1 ] M/z]⁺。

¹HNMR(400MHz，CD₃OD)δ8.55(s，1H)，8.43(d，J＝4.8Hz，1H)，7.51(s，1H)，7.27(s，1H)，6.94(s，1H)，6.36(d，J＝16.4Hz，1H)，5.90(d，J＝10.5Hz，1H)，5.39-5.11(m，1H)，4.36-3.86(m，4H)，3.82-3.37(m，2H)，3.10-2.75(m，2H)，2.74-2.45(m，1H)，2.14-1.90(m，3H)，1.26-1.12(m，3H)，1.09-0.84(m，3H).

Example 4

4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 4")

Step 1.4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile.

(S) -4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (101mg, 0.36mmol) ) 3-fluoro-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (149mg, 1.01mmol), palladium tetratriphenylphosphine (69mg, 0.12mmol), sodium carbonate (92mg, 1.36mmol), dioxane (8mL), and water (2mL) were placed in a 50-mL sealed tube purged and maintained under an inert atmosphere of nitrogen. The reaction mixture was stirred at 80 ℃ for 4 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue is passed through with ACN/H₂C18 column eluted with O (0.5%) HCl ═ 7/3. This gave 29mg (13%) of 4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: 625[ M +1 ] M/z]⁺。

¹HNMR(400MHz，CD₃OD)δ8.60(dd，J＝10.0，5.6Hz，2H)，7.75-7.65(m，1H)，7.18-6.84(m，2H)，6.52(d，J＝8.3Hz，1H)，6.43-6.32(m，2H)，5.91(d，J＝10.7Hz，1H)，5.44-5.16(m，1H)，4.40-3.95(m，5H)，3.64(s，2H)，3.15-2.90(m，2H)，2.40-2.10(m，3H)，1.45-1.00(m，6H).

Step 2.4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("compound 4").

4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (157mg, 0.25mmol), NCS (65mg, 0.49mmol), and glacial acetic acid (6mL) were placed in a 50-mL round bottom flask purged and maintained under a nitrogen inert atmosphere. The resulting mixture was stirred at room temperature for 48 h. The reaction was quenched with water (100mL), the resulting solution was extracted with ethyl acetate (2X 100mL), the organic phases were combined and washed with saturated brine (10mL), anhydrous Na ₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC (ACN/H)₂O(0.5％)NH₄HCO₃7/3 (v: v)). Thus, 22mg (two-step yield 13%) of 4- ((S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-)Methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 4") as a yellow solid. LCMS: m/z 693[ M +1 ]]⁺。¹HNMR(400MHz，CD₃OD)68.64-8.56(m，1H)，8.45(t，J＝4.9Hz，1H)，7.46-7.25(m，2H)，6.91(s，1H)，6.37(d，J＝16.8Hz，1H)，5.86(d，J＝10.7Hz，1H)，5.48-5.08(m，2H)，4.35-3.95(m，4H)，3.61(s，1H)，3.10-2.50(m，3H)，2.16-1.88(m，3H)，1.23-1.13(m，3H)，1.12-0.93(m，3H).

Example 5

4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 5")

Step 1. tert-butyl (S) -4- (6, 7-dichloro-3-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylate

6, 7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (3.68g, 9.46mmol), phosphorus oxychloride (4.52g, 29.50mmol), DIEA (5.21g, 40.29mmol), and acetonitrile (40mL) were placed in a 100-mL round-bottomed flask purged and maintained under a nitrogen inert atmosphere. The mixture was stirred at 80 ℃ for 0.5 h. The reaction was cooled to room temperature and concentrated under reduced pressure. 4, 6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (3.84g, 9.46mmol), acetonitrile (30mL), DIEA (5.29g, 40.93mmol), and tert-butyl (S) -3-methylpiperazine-1-carboxylate (2.034g, 10.17mmol) were placed in a 100-mL round-bottomed flask purged and maintained under an inert atmosphere of nitrogen. The reaction mixture was stirred at rt for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column of silica gel eluting with EA/n-hexane 3/2 (v: v). This gives 2.24g (two-stage yield 41%) (S) -4- (6, 7-dichloro-3-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -3-methylpiperazine Tert-butyl oxazine-1-carboxylate as a pale yellow solid. LCMS: 571[ M +1 ] M/z]⁺。

Step 2.(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

Tert-butyl (S) -4- (6, 7-dichloro-3-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylate (2.24g, 3.92mmol), trifluoroacetic acid (3mL) and dichloromethane (15mL) were placed in a 100-mL round bottom flask purged and maintained with a nitrogen inert atmosphere. The reaction mixture was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure.

(S) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (1.84g, 3.92mmol), dichloromethane (20mL), DIEA (1.872g, 14.48mmol), and acryloyl chloride (0.442g, 4.88mmol) were placed in a 100-mL round-bottomed flask purged and maintained under an inert atmosphere of nitrogen. The reaction mixture was stirred at rt for 0.5 h. By H₂The reaction was quenched with O (100mL), extracted three times with dichloromethane (100mL), washed with saturated brine (100mL), anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by column of silica gel eluting with EA/n-hexane 3/2 (v: v). This gave 1.87g (91% yield in two steps) of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a pale yellow solid. LCMS: 525[ M +1 ] M/z ]⁺。

¹HNMR(400MHz，CD₃OD)δ8.50(d，J＝5.0Hz，1H)，8.44(s，1H)，7.34-7.28(m，1H)，6.94-6.76(m，1H)，6.32(d，J＝17.2Hz，1H)，5.87-5.79(m，1H)，4.51-4.37(m，2H)，4.01-3.75(m，1H)，3.60(d，J＝12.4Hz，2H)，2.86-2.72(m，1H)，2.72-2.62(m，1H)，2.62-2.47(m，1H)，2.02(d，J＝9.4Hz，3H)，1.21-1.15(m，3H)，1.15-1.07(m，3H)，1.04-1.02(m，3H)。

Step 3.4- ((s) -4-acryloyl-2-methylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

25-mL of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (0.305g, 0.78mmol), 3-fluoro-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (0.524g, 2.21mmol), tetrakistriphenylphosphine palladium (0.105g, 0.09mmol), sodium carbonate (0.325g, 3.07mmol), dioxane (8mL), and water (1mL) were placed in a 20-mL round bottom flask, which was purged and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at 80 ℃ for 1 h. By H₂The reaction mixture was quenched with O (50mL), extracted three times with dichloromethane (50mL), washed with saturated brine (50mL), anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by column of silica gel eluting with EA/n-hexane 3/2 (v: v). This gave 269mg (57%) of 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: 600[ M +1 ] M/z ]⁺。

Step 4.4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 5")

4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (182mg, 0.30mmol), NCS (89mg, 0.67mmol), HOAc (5mL) were placed in a 25-mL round-bottomed flask. The reaction mixture was stirred at room temperature for 2 days. The reaction was quenched with water (50mL), extracted three times with dichloromethane (50mL), washed with 50mL saturated sodium bicarbonate (50mL) and saturated brine (50mL), and passed over anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by Prep-HPLC (CH)₃CN/H₂O(0.05％NH₄HCO₃) 2/1. This gave 8mg (6%) of 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 5 ") as a yellow solid. LCMS: 668[ M +1 ] M/z]⁺。

¹HNMR(400MHz，CD₃OD)δ8.75-8.25(m，2H)，7.58-7.14(m，2H)，7.05-6.70(m，1H)，6.36(d，J＝15.7Hz，1H)，5.90(d，J＝10.5Hz，1H)，4.73-3.95(m，5H)，3.85-3.50(m，2H)，2.95-2.50(m，1H)，2.25-1.80(m，3H)，1.50-0.70(m，9H)。

Example 6

4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 6")

(P) -4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

(M) -4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

Step 1.2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxo-3- (2, 5, 6-trichloropyridin-3-yl) propionamide

2, 5, 6-trichloronicotinic acid (99.63g, 439.98mmol), thionyl chloride (500mL) was placed in a 1000-mL round bottom flask purged and maintained with a nitrogen inert atmosphere. The mixture was heated to 80 ℃ and stirred for 3 h. The solution was concentrated under reduced pressure. 100.97 (93.68%, yield) of 2, 5, 6-trichloronicotinoyl chloride was thus obtained, which was used directly in the next step.

2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) acetamide (15.08g, 69.40mmol) and tetrahydrofuran (150mL) were placed in a 500-mL round-bottom flask and the mixture was stirred at 0 ℃. NaH (6.05g, 151.25mmol) was added in three portions. The mixture was stirred at 0 ℃ for a further 1 h. Then dropwise adding the mixture to dissolve in THF (50mL) 2, 5, 6-trichloronicotinoyl chloride (15.43g, 63.01 mmol). The reaction mixture was stirred at 0 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting crude product was poured into 5% aqueous acetic acid (200mL) and stirred for 30 min. The resulting solid was filtered and dried in vacuo to give 21.98g (74%) of 2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxo-3- (2, 5, 6-trichloropyridin-3-yl) propionamide as a yellow solid. LCMS: 425[ M +1 ] M/z]⁺。

Step 2.6, 7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxo-3- (2, 5, 6-trichloropyridin-3-yl) propionamide (20.08g, 47.17mmol), acetonitrile (200mL) was placed in a 500-mL round bottom flask purged and maintained with a nitrogen inert atmosphere and stirred at room temperature. Cesium carbonate (72.32g, 221.96mmol) was added. The mixture was stirred at 50 ℃ for 1 h. The reaction was filtered and the mother liquor was concentrated in vacuo. The residue was dissolved in 100mL of water and the pH was adjusted to 6 with AcOH. The resulting solid was filtered and dried in vacuo, thereby yielding 15g (82% yield) of 6, 7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m/z 389[ M +1 ] ]⁺。

Step 3.4- ((3R, 5S) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

A500-mL eggplant-shaped bottle was charged, maintaining a nitrogen atmosphere, with 6, 7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (6.21g, 15.95mmol), phosphorus oxychloride (6.88g, 48.87mmol), DIEA (6.80g, 52.61mmol), and acetonitrile (100mL) placed in a 500-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. The mixture was stirred at 80 ℃ for 2 h. The reaction was cooled to room temperature and concentrated under vacuum. This gives 4, 6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile, which is used directly in the next step.

Another 500-mL eggplant-shaped bottleTo a 500-mL round bottom flask purged and maintained with a nitrogen inert atmosphere was added 4, 6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (crude), DIEA (6.80g, 52.61mmol), acetonitrile (100mL), (2S, 6R) -2, 6-dimethylpiperazine (2.17g, 19.00 mmol). The mixture was stirred at room temperature for 1 h. LCMS monitored the reaction for completion. Acryloyl chloride (2.61g, 28.83mmol) was added to the reaction solution. The mixture was stirred at room temperature for 1 h. The resulting solution was concentrated under vacuum and applied to a silica gel column eluted with EA/n-hexane. This gives 4.30g (50% yield) of 4- ((3R, 5S) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: 539[ M +1 ] M/z ]⁺。

Step 4.4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (289mg, 0.54mmol), 3-fluoro-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (281mg, 1.19mmol, 2.2leq), Pd (dppf) Cl₂(73mg, 99.77umol, 0.19eq), sodium carbonate (193mg, 1.82mmol, 3.40eq), dioxane (4mL), and water (1mL) were placed in an 8-mL sealed tube purged and maintained with a nitrogen inert atmosphere. The reaction mixture was stirred at 80 ℃ for 1.5 h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by column on silica eluting with EA/n-hexane (7/3 (v: v)). This gave 282mg (crude) of 4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: 614[ M +1 ] M/z]⁺。

Step 5.4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 6")

4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (282mg, 0.46mmol), NCS (125mg, 0.94mmol), and AcOH (20mL) were placed in a 500-mL reaction flask. The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was warmed to 50 ℃ and stirring was continued for 3 h. The reaction mixture was quenched with water (40 mL). The resulting solution was extracted with ethyl acetate (3X 30mL), the organic phases were combined and concentrated in vacuo. The residue was purified by Prep-HPLC (CH)₃CN/H₂O3/2 (v: v)). This gave 31mg (9.88%) of 4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("compound 6") as a yellow solid. LCMS: m/z 682[ M +1 ]]⁺。

¹HNMR(400MHz，CD₃OD)δ8.83(s，1H)，8.43(d，J＝5.0Hz，1H)，7.39(dd，J＝7.5，2.3Hz，1H)，7.27(d，J＝4.9Hz，1H)，6.88(dd，J＝16.7，10.7Hz，1H)，6.32(dd，J＝16.7，2.0Hz，1H)，5.83(dd，J＝10.6，1.9Hz，1H)，4.78(s，2H)，4.06-3.92(m，2H)，3.90-3.74(m，2H)，2.70-2.63(m，1H)，2.10-1.92(m，3H)，1.66(t，J＝6.1Hz，6H)，1.22-1.11(m，3H)，1.06(d，J＝6.8Hz，1H)，0.96(d，J＝6.8Hz，2H).

A mixture of 4- ((3R, 5S) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (150mg, "compound 6") was purified by Chiral-Prep-HPLC according to the following conditions: column, ChiralpakIBN, 0.46cmi.d. × 15 cmL; mobile phase: MeOH (100% MeOH for 6 min); detection wavelength: UV 254 nm. Isolation gave 61mg (41%) of 4- ((3R, 5S) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (first eluate, "compound 6A", M or P atropisomers) as a yellow solid;

¹HNMR(400MHz，CD₃OD)δ8.73(s，1H)，8.33(d，J＝5.0Hz，1H)，7.29(dd，J＝7.4，2.8Hz，1H)，7.19-7.14(m，1H)，6.88-6.72(m，1H)，6.23(d，J＝16.6Hz，1H)，5.74(d，J＝10.7Hz，1H)，4.67(s，2H)，3.96-3.84(m，2H)，3.81-3.67(m，2H)，2.73-2.52(m，1H)，2.01-1.83(m，3H)，1.56(t，J＝5.9Hz，6H)，1.07(dd，J＝10.1，6.9Hz，3H)，0.89-0.76(m，3H)；

And 47mg (31%) of 4- ((3R, 5S) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (second eluate, "compound 6B", P or M atropisomers) as a yellow solid;

¹HNMR(400MHz，CD₃OD)δ8.73(s，1H)，8.34(d，J＝5.0Hz，1H)，7.29(dd，J＝7.5，2.6Hz，1H)，7.17(d，J＝5.0Hz，1H)，6.89-6.72(m，1H)，6.23(d，J＝16.6Hz，1H)，5.74(d，J＝10.6Hz，1H)，4.67(s，2H)，3.98-3.85(m，2H)，3.78-3.65(m，2H)，2.71-2.53(m，1H)，2.02-1.82(m，3H)，1.56(t，J＝5.8Hz，6H)，1.12-1.01(m，3H)，1.00-0.83(m，3H).

example 7

4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6-chloro-7- (3, 5-dichloro-2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 7")

Step 4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl)Yl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (150mg, 0.28mmol), 3-fluoro-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaboropyran-2-yl) phenol (83mg, 0.53mmol), Pd (dppf) Cl₂(22mg, 0.03mmol), sodium carbonate (152mg, 1.55mmol), dioxane (5mL), and water (1mL) were placed in a 25-mL round bottom flask. The reaction mixture was stirred at 80 ℃ for 1 h. The reaction mixture was quenched with water (50mL), extracted three times with DCM (50mL), washed with saturated brine (50mL), anhydrous Na ₂SO₄Dried and concentrated under vacuum. The residue was purified by Prep-HPLC for CH₃CN/H₂O(0.05％NH₄HCO₃) 3/2 (v: v). This gave 47mg (26%) of 4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: 615[ M +1 ] M/z]⁺。

¹HNMR(400MHz，CD₃OD)δ8.82(s，1H)，8.66(d，J＝5.4Hz，1H)，7.87(s，1H)，7.25(d，J＝7.2Hz，1H)，6.97-6.83(m，1H)，6.75-6.53(m，2H)，6.35(d，J＝16.6Hz，1H)，5.86(d，J＝10.7Hz，1H)，4.79(s，2H)，4.05(d，J＝13.0Hz，2H)，3.89(s，2H)，3.20-3.05(m，1H)，2.30(s，3H)，1.67(d，J＝6.0Hz，6H)，1.34(d，J＝6.6Hz，3H)，1.19(d，J＝6.4Hz，3H)。

Step 2.4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6-chloro-7- (3, 5-dichloro-2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 7")

4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (358mg, 0.35mmol), NCS (104mg, 0.78mmol), HOAc (5mL) was placed in a 25-mL round-bottomed flask. The reaction mixture was stirred at room temperature for 2 days. By H₂The reaction mixture was quenched with O (50mL), extracted three times with DCM (50mL), and saturated NaHCO₃Washed with aqueous solution (50mL) and saturated brine (50mL) and dried over anhydrous Na₂SO₄And (5) drying. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by Prep-HPLC CH₃CN/H₂O(0.05％NH₄HCO₃) Purification was carried out at 1/1 (v: v). This gave 70mg (28%) of 4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6-chloro-7- (3, 5-dichloro-2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("compound 7") as a yellow solid. LCMS: m/z 683[ M +1 ] ]⁺。

¹HNMR(400MHz，CD₃OD)δ8.81(s，1H)，8.43(d，J＝5.1Hz，1H)，7.54(d，J＝7.7Hz，1H)，7.30(s，1H)，6.89(dd，J＝16.7，10.6Hz，1H)，6.32(dd，J＝16.7，1.9Hz，1H)，5.83(dd，J＝10.6，1.8Hz，1H)，4.77(s，2H)，4.07-3.93(m，2H)，3.91-3.75(m，2H)，2.83-2.67(m，1H)，2.04(s，3H)，1.71-1.59(m，6H)，1.18(d，J＝6.8Hz，3H)，1.01(d，J＝6.8Hz，3H)。

Example 8

4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -6-chloro-7- (3, 5-dichloro-2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 8")

Step 1.(R) -4- (6, 7-dichloro-3-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester

6, 7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (1.05g, 2.71mmol), phosphorus oxychloride (2.04g, 13.27mmol), DIEA (3.09g, 23.93mmol), and acetonitrile (20mL) were placed in a 50-mL round-bottomed flask purged and maintained under a nitrogen inert atmosphere. The mixture was stirred at 80 ℃ for 2 h. The reaction was cooled to room temperature and concentrated under vacuum. This gives 4, 6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile, which is used directly in the next step.

4, 6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (crude) and acetonitrile (10mL) were placed in a 100-mL round-bottomed flask purged and maintained under a nitrogen inert atmosphere. DIEA (3.09g, 23.93mmol) and (R) -tert-butyl 2-methylpiperazine-1-carboxylate (507mg, 2.53mmol) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction was then quenched by addition of water (50 mL). Extraction with ethyl acetate (3X 50mL), combining the organic phases and washing with saturated brine (50mL), anhydrous Na ₂SO₄Dried, filtered and concentrated under vacuum. The residue was purified by a silica gel column eluted with EA/n-hexane (V/V ═ 5/4), whereby 0.95g (65% yield in two steps) of tert-butyl (R) -4- (6, 7-dichloro-3-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylate was obtained as a red solid. LCMS: 571[ M +1 ] M/z]⁺。

¹HNMR(400MHz，CD₃OD)δ8.55-8.45(m，2H)，7.38-7.28(m，1H)，4.48(s，1H)，4.20-4.08(m，2H)，3.99-3.81(m，2H)，3.74-3.51(m，2H)，2.78-2.50(m，1H)，2.10-1.98(m，3H)，1.59-1.44(m，9H)，1.34(dd，J＝14.7，7.2Hz，3H)，1.22-1.01(m，6H)。

Step 2.(R) -4- (4-acryloyl-3-methylpiperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

(R) -4- (6, 7-dichloro-3-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (2.58g, 4.51mmol), DCM (60mL), trifluoroacetic acid (23.10g, 202.59mmol) were placed in a 250mL round bottom flask. The reaction was allowed to react at room temperature for 1 h. The reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (40mL), followed by the addition of triethylamine (2.91g, 28.78mmol) at room temperature and the addition of acryloyl chloride (0.644g, 7.12mmol) between 0 and 10 deg.C, and the reaction was carried out at room temperature for 30 min. The reaction mixture was concentrated under vacuum and applied to a silica gel column, eluting with EA/Hex (0% to 45% V/V). The eluate was collected and concentrated in vacuo. Thus was obtained (1.69g, 3.22mmol, 7) 1.29%) of 6, 7-dichloro-1- (2-isopropyl-4-methyl-3-pyridinyl) -4- [ (3R) -3-methyl-4-prop-2-enoyl-piperazin-1-yl]-2-oxo-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: 525[ M +1 ] M/z]⁺。

Step 3.4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

(R) -4- (4-acryloyl-3-methylpiperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (401mg, 0.76mmol), (2-fluoro-6-hydroxyphenyl) boronic acid (568mg, 3.64mmol), palladium tetratriphenylphosphine (123mg, 0.11mmol), sodium carbonate (320mg, 3.02mmol), dioxane (5mL), and water (2mL) were placed in an 8-mL sealed tube purged with and maintained under an inert atmosphere of nitrogen. The reaction mixture was stirred at 80 ℃ for 1.5 h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by column on silica eluting with EA/n-hexane (7/3 (v: v)). This gave 213mg (crude) of 4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: 601[ M +1 ] M/z ]⁺。

Step 4.4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -6-chloro-7- (3, 5-dichloro-2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 8")

4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (147mg, 0.24mmol), NCS (77mg, 0.58mmol), and AcOH (4mL) were placed in a 25-mL round-bottomed flask. The reaction mixture was stirred at room temperature for 1 h. The temperature was raised to 50 ℃ and the mixture was stirred for a further 3 h. The reaction mixture was quenched by addition of water (20 mL). The resulting solution was extracted with ethyl acetate (3X 20mL), the organic phases were combined and concentrated in vacuo. The residue was purified by Prep-HPLC (CH)₃CN/H₂O3/2 (v: v)). This gave 12mg of 4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -6-chloro-7- (3, 5-dichloro-2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("compound 8") as a yellow solid. LCMS: m/z 669[ M +1 ]]⁺。

Example 9

4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 9")

(P) -4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

(M) -4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

Step 1.4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile.

(R) -4- (4-acryloyl-3-methylpiperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (403mg, 0.77mmol), (2-amino-6-fluorophenyl) boronic acid (569mg, 2.40mmol), palladium tetrakistriphenylphosphine (260mg, 0.23mmol), sodium carbonate (438mg, 4.13mmol), dioxane (8mL), and water (2mL) were placed in a 25-mL sealed tube purged with and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at 80 ℃ for 4 h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by Prep-HPLC (CH)₃CN/H₂O4/6 (v: v)). This gave 50mg (11%) of 4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: 600 m/z [M+1]⁺。

¹HNMR(400MHz，CD₃OD)δ8.62-8.52(m，1H)，8.45(dd，J＝12.2，5.0Hz，1H)，7.36-7.22(m，1H)，7.17-7.06(m，1H)，6.87(dd，J＝16.8，10.7Hz，1H)，6.57-6.47(m，1H)，6.43-6.26(m，2H)，5.85(d，J＝10.7Hz，1H)，4.76-3.82(m，6H)，3.66(s，1H)，2.90-2.55(m，1H)，2.20-1.85(m，3H)，1.53-1.41(m，3H)，1.23-1.12(m，3H)，1.10-0.88(m，3H)。

Step 2.4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 9")

4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (255mg, 0.42mmol), NCS (125mg, 0.84mmol), and AcOH (4mL) were placed in a 50-mL round-bottomed flask purged and maintained with a nitrogen inert atmosphere. The mixture was stirred at room temperature for 2 days. The reaction was then quenched with water (50mL) and extracted with ethyl acetate (3X 50 mL). The organic phases were combined and washed with saturated brine (50mL) and anhydrous Na₂SO₄Dried, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC (CH)₃CN/H₂O-6/4 (v: v)). This gave 60mg (21%) of 4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("compound 9") as a yellow solid. LCMS: 668[ M + I ] M/z]⁺。

¹HNMR(400MHz，CD₃OD)δ8.63-8.53(m，1H)，8.49-8.41(m，1H)，7.43-7.37(m，1H)，7.32-7.24(m，1H)，6.86(dd，J＝16.7，10.6Hz，1H)，6.30(dd，J＝16.7，1.7Hz，1H)，5.84(dd，J＝10.6，1.7Hz，1H)，4.50-4.16(m，2H)，4.14-3.84(m，3H)，3.79-3.50(m，2H)，2.90-2.50(m，1H)，2.19-1.89(m，3H)，1.55-1.35(m，3H)，1.25-1.13(m，3H)，1.12-0.92(m，3H)。

The atropisomeric mixture of 4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (600mg, "compound 9") was purified by Chiral-Prep-HPLC using the following conditions: column, ChiralpakIBN, 0.46cmi.d. × 15 cmL; mobile phase, n-hexane/EtOH 50/50 (V/V); detection wavelength, UV254 nm. This gave 262mg (43.7%) of 4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (first eluate, compound 9A ", M or P atropisomer) as a yellow solid;

¹HNMR(400MHz，CD₃OD)δ8.46(d，J＝5.7Hz，1H)，8.39-8.26(m，1H)，7.33-7.22(m，1H)，7.24-7.15(m，1H)，6.88-6.66(m，1H)，6.20(d，J＝16.7Hz，1H)，5.73(dd，J＝10.7，1.8Hz，1H)，4.16(d，J＝12.6Hz，2H)，4.05-3.70(m，3H)，3.69-3.30(m，2H)，2.75-2.63(m，1H)，1.96-1.83(m，3H)，1.38-1.25(m，3H)，1.12-0.85(m，6H)；

And 272mg (45.3%) of 4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (second eluate, "compound 9B", P or M atropisomers) as a yellow solid.

¹HNMR(400MHz，CD₃OD)δ8.47(s，1H)，8.35-8.28(m，1H)，7.33-7.22(m，1H)，7.19-7.10(m，1H)，6.88-6.66(m，1H)，6.20(d，J＝16.7，1.8Hz，1H)，5.73(dd，J＝10.6，1.8Hz，1H)，4.14(d，J＝13.2Hz，2H)，4.00-3.76(m，3H)，3.69-3.30(m，2H)，2.64-2.40(m，1H)，2.02-1.88(m，3H)，1.40-1.31(m，3H)，1.05(dd，J＝10.8，6.8Hz，3H)，0.96-0.83(m，3H)。

Example 10

7- (2-amino-3, 5-dichloro-6-fluorophenyl) -4- (4- (2-butynoyl) piperazin-1-yl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 10")

Step 1.4- (7- (2-amino-6-fluorophenyl) -6-chloro-3-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

Tert-butyl 4- (6, 7-dichloro-3-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate (183.00g, 328.27mmol), 3-fluoro-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (235.77g, 994.48mmol), PdCl₂(dppf)₂(25.14g, 34.36mmol), sodium carbonate (105.32g, 993.69mmol), water (900mL), 1, 4-dioxane (3600mL) was placed in a 10L three-neck round bottom flask purged and maintained under a nitrogen inert atmosphere. The reaction was stirred at 89 ℃ for 12 hours. The reaction was filtered and concentrated under vacuum. The residue was applied to a silica gel column eluted with n-hexane/ethyl acetate (20% -60% V/V). The eluate was collected and concentrated in vacuo. The crude product was slurried with n-hexane/ethyl acetate (V/V-10/1) and the mixture was filtered. This gave (154.39g, 244.24mmol, 74.40% yield) 4- [7- (2-amino-6-fluoro-py-nzy 1) -6-chloro-3-cyano-1- (2-isopropyl-4-methyl-3-pyridyl) -2-oxo-1, 8-naphthyridin-4-yl ]Piperazine-1-carboxylic acid tert-butyl ester as yellow solid.

Step 2.4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-3-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

Tert-butyl 4- [7- (2-amino-6-fluoro-phenyl) -6-chloro-3-cyano-1- (2-isopropyl-4-methyl-3-pyridine) -2-oxo-1, 8-naphthyridin-4-yl ] piperazine-1-carboxylate (0.933g, 1.48mmol), NCS (0.451g, 3.38mmol), acetic acid (20mL) were added to a 100mL three-necked flask, reacted at 25 ℃ for 12 hours, and then heated to 50 ℃ for 2.5 hours. The reaction was quenched with saturated sodium carbonate (aq) (150mL), extracted with ethyl acetate (80 mL. times.3), and the organic phase was collected, washed with water (100mL) and saturated brine (100mL), and dried over anhydrous sodium sulfate. The reaction was concentrated under vacuum. This gave (0.98g, 1.40mmol, yield 94.62%) tert-butyl 4- [7- (2-amino-3, 5-dichloro-6-fluoro-phenyl-1) -6-chloro-3-cyano-1- (2-isopropyl-4-methyl-3-pyridine) -2-oxo-1, 8-naphthyridin-4-yl ] piperazine-1-carboxylate as a yellow solid.

Step 3.7- (2-amino-3, 5-dichloro-6-fluorophenyl) -4- (4- (2-butynoyl) piperazin-1-yl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 10").

Tert-butyl 4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-3-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate (271mg, 0.39mmol), trifluoroacetic acid (0.5mL), dichloromethane (2mL) were placed in a 50-mL round bottom flask purged and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated under vacuum. The residue was dissolved in MeCN (3mL), followed by the addition of DIEA (3.0mL, 21.58mmol), HATU (179mg, 0.47mmol), 2-butynoic acid (33mg, 0.39 mmol). The reaction was stirred at room temperature for 0.5 h. The reaction was quenched by addition of water (30 mL). Extract with ethyl acetate (3 × 20mL), combine the organic phases and wash with saturated brine (30mL), dry over sodium sulfate, filter and concentrate under vacuum. The residue was purified by Prep-HPLC (acetonitrile/water 0% -60%). This gave 64mg (yield 25%) of 7- (2-amino-3, 5-dichloro-6-fluorophenyl) -4- (4- (2-butynoyl) piperazin-1-yl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("compound 10") as a yellow solid. LCMS: 666[ M +1 ] M/z]⁺。

¹HNMR(400MHz，Methanol-d₄)68.53(d，J＝2.2Hz，1H)，8.43(d，J＝5.0Hz，1H)，7.38(dd，J＝7.5，2.5Hz，1H)，7.29-7.23(m，1H)，4.19-4.09(m，2H)，4.04-3.81(m，6H)，2.84-2.70(m，1H)，2.12-1.93(m，6H)，1.22-1.12(m，3H)，1.00(dd，J＝42.8，6.7Hz，3H)。

Example 11

4- (4-Acryloylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 11")

(P) -4- (4-acryloylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

(M) -4- (4-acryloylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

Step 1.4, 6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

6, 7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (980mg, 2.51mmol), phosphorus oxychloride (1150mg, 7.50mmol), DIEA (1.32g, 10.21mmol), and acetonitrile (12mL) were placed in a 50-mL round-bottomed flask purged and maintained under a nitrogen inert atmosphere. The mixture was stirred at 80 ℃ for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. This gives 4, 6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile, which is used directly in the next step.

Step 2.4- (6, 7-dichloro-3-cyano-1- (2-isopropyl-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

4, 6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (1.20g, crude) and acetonitrile (20mL), DIEA (660mg, 5.10mmol) and tert-butylpiperazine-1-carboxylate (0.57g, 3.06mmol) were placed in a 100-mL round-bottomed flask purged and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3X 50mL), and the organic phases were combined and washed with saturated brine (50mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by washing with ethyl acetate/n-hexane (30% -70%) of silica gel column. This gave 0.92g (65% yield in two steps) of tert-butyl 4- (6, 7-dichloro-3-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate as a yellow solid. LCMS: m/z 557[ M +1 ]]⁺。

Step 3.4- (4-Acryloylpiperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

Tert-butyl 4- (6, 7-dichloro-3-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate (920mg, 1.65mmol), trifluoroacetic acid (4mL), dichloromethane (15mL) were placed in a 50-mL round bottom flask purged and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (15mL) in a 50mL round-bottom flask, followed by the addition of DIEA (1.02g, 10.08 mmol). The reaction mixture was cooled to 0 ℃ and acryloyl chloride (190mg, 2.09mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction was quenched by addition of water (30 mL). The resulting solution was extracted with ethyl acetate (3 × 50mL), the organic phases were combined and washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by a silica gel column eluted with ethyl acetate/n-hexane (V/V ═ 40% to 80%). This gives 0.86g (crude) of 4- (4-acryloylpiperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m/z 511[ M +1 ] ]⁺。

Step 4.4- (4-Acryloylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 11-4")

4- (4-Acryloylpiperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (99mg, 0.19mmol), 3-fluoro-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaboropyran-2-yl) aniline (78mg, 0.33mmol), tetratriphenylphosphine palladium (44mg, 0.03mmol), sodium carbonate (65mg, 0.61mmol), dioxane (4-acryloylpiperazin-1-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (78mg, 0.19mmol), sodium carbonate (65mg, 0.61mmol), and4mL) and water (1mL) were placed in a 20-mL sealed tube purged and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at 90 ℃ for 2 hours. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by Prep-HPLC (acetonitrile/water-1/1 (v: v)). This gave 12mg (10%) of 4- (4-acryloylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("compound 11-4") as a yellow solid. LCMS: 586[ M +1 ] M/z]⁺。

¹HNMR(400MHz，CD₃OD)δ8.52(s，1H)，8.46(d，J＝5.0Hz，1H)，7.29(d，J＝4.7Hz，1H)，7.11(d，J＝6.6Hz，1H)，6.89(dd，J＝16.7，10.6Hz，1H)，6.56-6.49(m，1H)，6.38-6.30(m，2H)，5.90-5.81(m，1H)，4.18-3.84(m，8H)，2.82-2.70(m，1H)，2.08-1.98(m，3H)，1.19(t，J＝7.1Hz，3H)，1.10-0.93(m，3H)。

Step 5.4- (4-acryloylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

4- (4-Acryloylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 11-4") (104mg, 0.18mmol), NCS (56mg, 0.42mmol), and acetic acid (3mL) were placed in an 8-mL sealed tube purged and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at 25 ℃ overnight. The reaction mixture was directly concentrated in vacuo and purified by Prep-HPLC (acetonitrile/water ═ 4/1.) thus yielding 11mg (9.46%) of 4- (4-acryloylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("compound 11") as a yellow solid. LCMS: 654M +1]⁺。

¹HNMR(400MHz，CD₃OD)δ8.57(s，1H)，8.45(d，J＝4.8Hz，1H)，7.41(d，J＝7.1Hz，1H)，7.29(s，1H)，6.90(dd，J＝16.7，10.7Hz，1H)，6.33(dd，J＝16.4Hz，1H)，5.86(d，J＝10.7Hz，1H)，4.14-3.88(m，8H)，2.82-2.63(m，1H)，2.15-1.95(m，3H)，1.23-0.95(m，6H)。

An atropisomer mixture of 4- (4-acryloylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile atropisomer (150mg) was purified by Chiral-Prep-HPLC according to the following conditions: column, ChiralpakIBN, 0.46cmi.d. × 15 cmL; mobile phase, n-hexane/ethanol 50/50 (V/V); detection wavelength, UV254 nm). This gave 61mg (41%) of 4- (4-acryloylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (first eluate, "compound 11A", M or P atropisomer) as a yellow solid;

¹HNMR(400MHz，CD3OD)δ8.54(d，J＝1.2Hz，1H)，8.41(d，J＝5.0Hz，1H)，7.39-7.33(m，1H)，7.31-7.17(m，1H)，6.87(dd，J＝16.8，10.6Hz，1H)，6.30(dd，J＝16.8，1.9Hz，1H)，5.83(dd，J＝10.6，1.9Hz，1H)，4.04-3.85(m，8H)，2.92-2.60(m，1H)，2.10-1.88(m，3H)，1.18-1.14(m，3H)，1.09-0.93(m，3H)。

And 47mg (31%) of 4- (4-acryloylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (second eluate, "compound 11B", P or M atropisomers) as a yellow solid;¹HNMR(400MHz，CD₃OD)δ8.54(d，J＝1.3Hz，1H)，8.41(d，J＝5.0Hz，1H)，7.39-7.33(m，1H)，7.28-7.19(m，1H)，6.87(dd，J＝16.8，10.6Hz，1H)，6.31(dd，J＝16.8，1.8Hz，1H)，5.84(dd，J＝10.6，1.8Hz，1H)，4.10-3.84(m，8H)，2.84-2.62(m，1H)，2.08-1.94(m，3H)，1.18-1.13(m，3H)，1.09-0.93(m，3H)。

example 12

4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 12")

7-chloro-6-fluoro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (389mg, 1.04mmol), phosphorus oxychloride (552mg, 3.60mmol), DIEA (651mg, 5.04mmol), and acetonitrile (15mL) were placed in a 50-mL round bottom flask purged and maintained under a nitrogen inert atmosphere. The mixture was stirred at 80 ℃ for 1 hour. The reaction was cooled to room temperature and concentrated in vacuo.

4, 7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (480mg, 3.71mmol), acetonitrile (20mL), DIEA (480mg, 3.71mmol) and 2- (piperazin-2-yl) acetonitrile (169mg, 1.35mmol) were placed in a 100-mL round-bottomed flask purged and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was cooled to 0 ℃ and acryloyl chloride (120mg, 1.33mmol) was added. The reaction was quenched by addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3 × 50mL), the organic phases were combined and washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column on silica eluting with ethyl acetate/n-hexane (2/1 (v: v)). This gave 0.55g (86% yield in two steps) of 4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a pale yellow solid. LCMS: 534[ M +1 ] M/z ]⁺。

Step 2.4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (61mg, 0.11 mmo)l), 3-fluoro-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (63mg, 0.27mmol), palladium tetratriphenylphosphine (21mg, 0.02mmol), sodium carbonate (81mg, 0.76mmol), dioxane (1mL), and water (0.1mL) were placed in a 20-mL sealed tube purged and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at 80 ℃ for 1 hour. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by Prep-HPLC (CH)₃CN/H₂O5/4 (v: v)). This gave 16mg (23%) of 4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: 609[ M +1 ] M/z]⁺。

¹HNMR(400MHz，CD₃OD)δ8.69(d，J＝5.5Hz，1H)，8.38(d，J＝9.2Hz，1H)，7.91-7.72(m，1H)，7.30-7.04(m，1H)，6.91(s，1H)，6.53(d，J＝8.2Hz，1H)，6.47-6.28(m，2H)，5.90(d，J＝10.5Hz，1H)，5.29(s，1H)，4.45-3.84(m，4H)，3.49(d，J＝74.7Hz，2H)，3.30-2.88(m，3H)，2.43-2.05(m，3H)，1.45-1.21(m，3H)，1.21-1.00(m，3H)。

Step 3.4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (86mg, 0.14mmol), NCS (39mg, 0.29mmol), acetic acid (2mL) was placed in a 20-mL round bottom flask. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under vacuum. The residue was purified by Prep-HPLC CH₃CN/H₂O(0.05％NH₄HCO₃) (V/V-2/1)). This gave 14mg (17%) of 4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("compound 12") as a yellow solid. LCMS: 677[ M +1 ] M/z]⁺。

¹HNMR(400MHz，DMSO)δ8.62-8.42(m，2H)，7.62(d，J＝7.8Hz，1H)，7.24(t，J＝5.1Hz，1H)，6.25(d，J＝16.4Hz，1H)，5.83(d，J＝12.1Hz，1H)，5.64(d，J＝11.1Hz，1H)，5.35-4.90(m，2H)，4.53(s，1H)，3.80-4.25(m，5H)，3.04-2.88(m，1H)，2.83-2.69(m，1H)，2.04-1.84(m，3H)，1.05(dd，J＝13.0，6.6Hz，3H)，0.91(dd，J＝24.1，6.6Hz，3H)。

Example 13

4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 13")

Step 1.4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile.

6, 7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (1.02g, 2.63mmol), phosphorus oxychloride (2.81g, 18.29mmol), DIEA (3.90g, 30.18mmol), and acetonitrile (20mL) were placed in a 50-mL round-bottomed flask purged and maintained under a nitrogen inert atmosphere. The mixture was stirred at 80 ℃ for 1 hour. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was used directly in the next step.

4, 7-dichloro-6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (crude), acetonitrile (20mL), DIEA (1mL), and 2- (piperazin-2-yl) acetonitrile (586mg, 2.96mmol) were placed in a 100-mL round-bottomed flask purged and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was cooled to 0 ℃ and acryloyl chloride (297mg, 3.28mmol) was added. The reaction was quenched with water (50mL), the resulting solution extracted with ethyl acetate (3X 50mL), the organic phases combined and washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column on silica eluting with ethyl acetate/n-hexane (7/3 (v: v)). This gave (0.686g, 1.25mmol, yield 47.37%) 4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a light yellow solid. LCMS: m/z 550[ M +1 ]]⁺。

Step 2.4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (453mg, 822.98umol), 3-fluoro-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (748mg, 3.16umol), tetratriphenylphosphine palladium (279mg, 241.44umol), sodium carbonate (390mg, 3.68mmol), dioxane (10mL), and water (2mL) were placed in a 25-mL sealed tube purged and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at 80 ℃ for 1 hour. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by silica gel column (EA/n-hexane (3/1 (v: v)) to thereby obtain (0.413g, 660.70umol, yield 80.28%) 4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow solid]⁺。

Step 3.4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (307mg, 0.49mmol), NCS (148mg, 1.11mmol), acetic acid (6mL) were placed in a 20-mL round bottom flask. The reaction mixture was stirred at room temperature for 16 hours. The reaction was then warmed to 50 ℃ and reacted for 1 hour. With 50mL saturated NaHCO ₃(aqueous solution) quenching reactionThe mixture was extracted with ethyl acetate (30mL × 3) and concentrated in vacuo. The residue was purified by Prep-HPLC CH₃CN/H₂O(0.05％NH₄HCO₃) (V/V-2/1). This gave (compound 13, 80mg, 115.276umol, yield 23.47%) 7- (2-amino-3, 5-dichloro-6-fluoro-phenyl) -6-chloro-4- [3- (cyanomethyl) -4-prop-2-enoyl-piperazin-1-yl]-1- (2-isopropyl-4-methyl-3-pyridine) -2-oxo-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m/z 693[ M +1 ]]⁺。

¹HNMR(400MHz，CD₃OD)δ8.55(d，J＝4.3Hz，1H)，8.46(dd，J＝14.0，5.0Hz，1H)，7.27(dd，J＝14.7，4.9Hz，1H)，7.11(dt，J＝14.7，6.1Hz，1H)，6.52(d，J＝8.1Hz，1H)，6.44-6.30(m，1H)，5.90(dd，J＝10.6，1.8Hz，1H)，5.30(s，1H)，4.31-3.91(m，4H)，3.59-3.51(m，2H)，3.07-2.94(m，1H)，2.92-2.78(m，1H)，2.75-2.51(m，1H)，2.16-1.90(m，3H)，1.26-1.12(m，3H)，1.10-0.87(m，3H)。

Example 14

4- (4-Acryloylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 14")

Step 1.4- (6, 7-dichloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

6, 7-dichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -4-hydroxy-2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (2.931g, 7.007mmol), phosphorus oxychloride (3.239g, 21.124mmol), DIEA (3.982g, 30.810mmol), and acetonitrile (35mL) were placed in a 50-mL round bottom flask purged and maintained under a nitrogen inert atmosphere. The mixture was stirred at 80 ℃ for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. This gives 4, 6, 7-trichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile, which is used directly in the next step.

4, 6, 7-trichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (crude) and acetonitrile (35mL) were placed in a 100-mL round-bottomed flask purged and maintained under a nitrogen inert atmosphere. DIEA (3.982g, 30.810mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.157g, 6.212mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3 × 50mL), the organic phases were combined and washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by a silica gel column eluted with ethyl acetate/n-hexane (V/V ═ 2/8). This gave 1.422g (23% yield in two steps) of tert-butyl 4- (6, 7-dichloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate. LCMS: 586[ M +1 ] M/z]⁺。

Step 2. tert-butyl 4- (7- (2-amino-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate

Tert-butyl 4- (6, 7-dichloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate (0.502g, 0.86mmol), (2-amino-6-fluorophenyl) boronic acid (0.452g, 1.907mmol), tetrakistriphenylphosphine palladium (0.099g, 0.086mmol), sodium carbonate (0.170g, 1.604mmol), dioxane (10mL), and water (3mL) were placed in a 25-mL sealed tube purged with and maintained under a nitrogen inert atmosphere. The reaction mixture was reacted at 90 ℃ for 4 hours. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by a silica gel column eluted with ethyl acetate/n-hexane (V/V ═ 2/1). This gave 600mg (95%) of tert-butyl 4- (7- (2-amino-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate as a yellow solid. LCMS: m/z 661[ M +1 ═ ]⁺。

Step 3.4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

Tert-butyl 4- (7- (2-amino-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate (0.598g, 0.91mmol), NCS (0.261g, 1.955mmol), and acetic acid (8mL) were placed in a 20-mL round bottom flask purged and maintained under a nitrogen inert atmosphere. The mixture was stirred at room temperature for 2 days. The reaction was quenched by addition of water (10 mL). The resulting solution was extracted with ethyl acetate (3x10mL), the organic phases were combined and washed with saturated brine (1x50mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by a silica gel column eluted with EA/n-hexane (V/V-7/3). This gave 470mg (71%) of tert-butyl 4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate as a yellow solid. LCMS: m/z 729[ M +1 ]]⁺。

Step 4.4- (4-Acryloylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

Tert-butyl 4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate (0.468g, 0.64mmol), trifluoroacetic acid (4mL) and dichloromethane (20mL) were placed in a 20-mL round bottom flask purged and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum. In a 25-mL round-bottom flask, the residue was dissolved with DCM (3 mL). DIEA (1.107g, 8.57mmol) was added. The reaction mixture was cooled to 0 ℃ and acryloyl chloride (0.063g, 0.70mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction was quenched by addition of water (10 mL). The resulting solution was extracted with ethyl acetate (3x50mL), the organic phases were combined and washed with saturated brine (1x50mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (CH)₃CN/H₂O (V/V ═ 6/4)). This gave 156mg (36% yield in two steps) of 4- (4-acryloylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-l-methyl-phenyl-l-methyl-amide1, 8-naphthyridine-3-carbonitrile ("Compound 14") as a yellow solid. LCMS: m/z 683[ M +1 ] ]⁺。

¹HNMR(400MHz，CD₃OD)δ9.08(s，1H)，8.58(s，1H)，7.41(d，J＝7.5Hz，1H)，6.89(dd，J＝16.8，10.6Hz，1H)，6.33(dd，J＝16.7，1.5Hz，1H)，5.86(dd，J＝10.6，1.5Hz，1H)，4.14-3.85(m，8H)，2.89-2.74(m，1H)，2.73-2.57(m，1H)，1.24-1.14(m，6H)，1.10(d，J＝6.7Hz，3H)，0.99(d，J＝6.7Hz，3H)。

Example 15

4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 15")

Step 1.(R) -tert-butyl 4- (6, 7-dichloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylate

6, 7-dichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -4-hydroxy-2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (3.586g, 8.57mmol), phosphorus oxychloride (3.961g, 25.83mmol), DIEA (4.768g, 36.89mmol), and acetonitrile (45mL) were placed in a 50-mL round-bottomed flask purged and maintained under a nitrogen inert atmosphere. The mixture was stirred at 80 ℃ for 2 h. The reaction was cooled to room temperature and concentrated in vacuo. This gives 4, 6, 7-trichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile, which is used directly in the next step.

4, 6, 7-trichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (crude) and acetonitrile (45mL) were placed in a 100-mL round-bottomed flask purged and maintained under a nitrogen inert atmosphere. DIEA (4.768g, 36.89mmol) and (R) -tert-butyl 2-methylpiperazine-1-carboxylate (1.911g, 9.57mmol) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched by addition of water (50 mL). The obtained solution is treated with acetic acid B The esters were extracted (3 × 50mL), the organic phases were combined and washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by a silica gel column eluted with EA/n-hexane (V/V-2/8). This gave 2.152g (two-step yield 42%) of tert-butyl (R) -4- (6, 7-dichloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylate as a yellow solid. LCMS: 600[ M +1 ] M/z]⁺。

Step 2 tert-butyl (2R) -4- (7- (2-amino-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylate.

Tert-butyl (R) -4- (6, 7-dichloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylate (0.504g, 0.84mmol), (2-amino-6-fluorophenyl) boronic acid (0.427g, 1.801mmol), palladium tetrakistriphenylphosphine (0.114g, 0.098mmol), sodium carbonate (0.163g, 1.54mmol), dioxane (10mL), and water (3mL) were placed in a 20-mL sealed tube purged and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at 90 ℃ for 4 h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by a silica gel column eluted with EA/n-hexane (V/V-2/1). This gave 500mg (88%) of tert-butyl (2R) -4- (7- (2-amino-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylate as a yellow solid. LCMS: 675[ M +1 ] M/z ]⁺。

Step 3 tert-butyl (2R) -4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylate

Tert-butyl (2R) -4- (7- (2-amino-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylate (0.510g, 0.76mmol), NCS (0.225g, 1.685mmol) and acetic acid (8mL) were placed in a 25-mL round bottom flask purged and maintained under a nitrogen inert atmosphere. The mixture was stirred at room temperature for 2 days. The reaction was quenched by addition of water (10 mL).The resulting solution was extracted with ethyl acetate (3x10mL), the organic phases were combined and washed with saturated brine (1x50mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by a silica gel column eluted with (EA/n-hexane (V/V-7/3)). This gave 410mg (73%) of tert-butyl (2R) -4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylate as a yellow solid. LCMS: 743[ M +1 ] M/z]⁺。

Step 4.4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile.

Tert-butyl (2R) -4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylate (0.408g, 0.55mmol), trifluoroacetic acid (4mL), dichloromethane (20mL) were placed in a 50-mL round bottom flask purged and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum. In a 25-mL round-bottom flask, the residue was dissolved with dichloromethane (3 mL). DIEA (0.963g, 7.45mmol) was added. The reaction mixture was cooled to 0 ℃ and acryloyl chloride (0.052g, 0.57mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. The reaction was quenched by addition of water (10 mL). The resulting solution was extracted with ethyl acetate (3x50mL), the organic phases were combined and washed with saturated brine (1x50mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (CH)₃CN/H₂O-6/4). This gave 89mg (two-step yield 23%) of 4- ((R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("compound 15") as a yellow solid. LCMS: m/z 697[ M +1 ] ]⁺。

¹HNMR(400MHz，CD₃OD)δ9.08(s，1H)，8.60(d，J＝4.2Hz，1H)，7.41(d，J＝7.5Hz，1H)，6.87(dd，J＝16.7，10.7Hz，1H)，6.32(d，J＝16.5Hz，1H)，5.85(d，J＝11.0Hz，1H)，4.34-4.22(m，1H)，4.12-3.91(m，3H)，3.82-3.48(m，2H)，2.95-2.50(m，3H)，1.53-1.41(m，3H)，1.25-1.20(m，3H)，1.19-1.15(m，3H)，1.14-1.06(m，3H)，1.05-0.92(m，3H).

Example 16

4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 16")

Step 1.4, 6-2 (prop-1-en-2-yl) pyrimidin-5-amine

4, 6-dichloropyrimidin-5-amine (50.61g, 308.61mmol), 4, 4, 5, 5-tetramethyl-2-allyl-1, 3, 2-dioxaborolan (154.16g, 917.40mmol), Pd (dppf) Cl₂(21.00g, 28.31mmol), potassium carbonate (132.11g, 955.90mmol), dioxane (500mL), and water (10mL) were placed in a 1000-mL sealed tube purged and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at 90 ℃ overnight. The reaction mixture was filtered and concentrated under vacuum. The residue was applied to a silica gel column eluted with (EA/n-hexane (0% -5%)). This gives 56.19g (crude) of 4, 6-2 (prop-1-en-2-yl) pyrimidin-5-amine as a yellow oil. LCMS: m/z 176[ M +1 ]]⁺。

¹HNMR(400MHz，Methanol-d₄)δ8.37(s，1H)，5.59-5.54(m，2H)，5.44-5.36(m，2H)，2.13(s，6H)。

Step 2.4, 6-diisopropylpyrimidin-5-amine

4, 6-2 (prop-1-en-2-yl) pyrimidin-5-amine (56.19g, 320.66mmol), methanol (500mL), Pd/C (11.04g) were placed in a 1000-mL round bottom flask. The mixture was degassed under vacuum and then purged three times with a hydrogen balloon. The mixture was stirred at room temperature for 6.5 h. The resulting solution was filtered and concentrated under vacuum. This gives 41.68g (crude) of 4, 6-diisopropylpyrimidin-5-amine, which can be used directly in the next step. LCMS: m/z 180[ M +1 ] ]⁺。

¹HNMR(400MHz，Methanol-d₄)δ8.33(s，1H)，3.28-3.13(m，2H)，1.25(d，J＝6.8Hz，12H)。

Step 3.2-cyano-N- (4, 6-diisopropylpyrimidin-5-yl) acetamide

4, 6-diisopropylpyrimidin-5-amine (41.68g, 232.51mmol), 2-cyanoacetic acid (36.33g, 427.10mmol), HATU (133.82g, 351.95mmol), DMF (500mL), DIEA (96.99, 351.95mmol) were placed in a 1000-mL round bottom flask purged and maintained under a nitrogen inert atmosphere. The mixture was stirred at room temperature for 1.5 h. The reaction was quenched by addition of water (500 mL). The resulting solution was extracted with ethyl acetate (3 × 200mL), the organic phases combined and washed with saturated brine (500mL), dried over anhydrous sodium sulfate, concentrated under vacuum to give a residue and applied to a silica gel column eluted with EA/n-hexane (0% to 40%). This gave 37g (yield 65%) of 2-cyano-N- (4, 6-diisopropylpyrimidin-5-yl) acetamide as a white solid. LCMS: m/z 247[ M +1 ═ M]⁺。

¹HNMR(400MHz，Methanol-d₄)δ8.95(s，1H)，3.88(s，2H)，3.283.17(m，2H)，1.23(d，J＝6.8Hz，13H).

Step 4.6, 7-dichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -4-hydroxy-2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

2-cyano N- (2-isopropyl-4-methylpyridin-3-yl) acetamide (2.016g, 8.18mmol), cesium carbonate (5.416g, 16.62mmol), acetonitrile (25mL) were placed in a 500-mL round bottom flask and the mixture was stirred at 20 ℃ for 0.5 h. 2, 5, 6-trichloronicotinoyl chloride (2.00g, 8.18mmol) dissolved in acetonitrile (10mL) was then added dropwise. The reaction mixture was stirred at 20 ℃ for 3 h. The reaction mixture was stirred at 80 ℃ for 1 h. The reaction was then quenched by addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3X 50mL), and the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate and concentrated in vacuo. This gives 3.15g (crude) of 6, 7-dichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -4-hydroxy-2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: 418[ M +1 ] M/z ]⁺。

¹HNMR(400MHz，CD₃OD)δ9.07(s，1H)，8.49(s，1H)，2.76-2.66(m，2H)，1.21(d，J＝7.2Hz，6H)，1.05(d，J＝6.8Hz，6H)。

Step 5.4- ((3R, 5S) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6, 7-dichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

6, 7-dichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -4-hydroxy-2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (3.15g, 7.53mmol), phosphorus oxychloride (3.50g, 22.83mmol), DIEA (4.13g, 31.92mmol), and acetonitrile (30mL) were placed in a 100-mL round bottom flask purged and maintained under a nitrogen inert atmosphere. The mixture was stirred at 80 ℃ for 0.5 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in acetonitrile (30mL), followed by the addition of DIEA (2.4mL, 14.49mmol), (2S, 6R) -2, 6-dimethylpiperazine (0.868g, 7.60 mmol). The resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was cooled to 0 ℃ and acryloyl chloride (0.71g, 7.89mmol) was added. The resulting mixture was stirred at room temperature for a further 0.5 h. The resulting solution was concentrated under vacuum and applied to a silica gel column eluted with (EA/n-hexane (0% to 40%)). This gave 1.33g (51% yield) of 4- ((3R, 5S) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6, 7-dichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a red solid. LCMS: 568[ M +1 ] M/z ]⁺。

¹HNMR(400MHz，CD₃OD)δ9.14(s，1H)，8.73(s，1H)，6.87(dd，J＝16.7，10.6Hz，1H)，6.36-6.19(m，1H)，5.90-5.77(m，1H)，4.74(s，2H)，3.96(d，J＝13.0Hz，2H)，3.87-3.74(m，2H)，2.78-2.61(m，2H)，1.66-1.57(m，6H)，1.21-1.14(m，6H)，1.07(d，J＝6.7Hz，6H).

Step 6.4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6, 7-dichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-diHydrogen-1, 8-naphthyridine-3-carbonitrile (0.284g, 1.20mmol), 3-fluoro-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaboropyran-2-yl) aniline (0.224g, 0.39mmol), palladium tetrakistriphenylphosphine (0.164g, 0.14mmol), sodium carbonate (0.140g, 1.32mmol), dioxane (10mL), and water (2mL) were placed in a 20-mL sealed tube purged and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at 80 ℃ for 4 h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by flash Column (CH)₃CN/H₂O, V/V-1/1). This gave 150mg of 4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: 643[ M +1 ] M/z]⁺。

Step 7.4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (0.178g, 0.277mmol), NCS (0.06g, 0.45mmol), and acetic acid (10mL) were placed in a 20-mL sealed tube purged and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at 25 ℃ for 4 h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by Prep-HPLC (CH)₃CN/H₂O, V/V ═ 1/1). This gave 22mg of 4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("compound 16") as a yellow solid. LCMS: 711[ M +1 ] M/z]⁺。

¹HNMR(400MHz，MeOD)δ9.09(s，1H)，8.86(s，1H)，7.42(d，J＝7.5Hz，1H)，6.91(dd，J＝16.7，10.5Hz，1H)，6.35(d，J＝16.7Hz，1H)，5.86(d，J＝10.7Hz，1H)，4.80-4.83(m，2H)，4.01-4.05(m，2H)，3.84-3.87(m，2H)，2.80-2.82(m，1H)，2.65-2.67(m，1H)，1.66-1.68(m，6H)，1.19(dd，J＝10.6，6.8Hz，6H)，1.11(d，J＝6.6Hz，3H)，1.00(d，J＝6.6Hz，3H)。

The compounds listed in table 2 can be synthesized by analogous methods to those listed in the examples above:

TABLE 2

Amgen 6

4- (4-Acryloylpiperazin-1-yl) -6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Amgen 6")

Step 1.4- (4-Acryloylpiperazin-1-yl) -6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

4- (4-Acryloylpiperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (75mg, 0.15mmol), (2-fluorophenyl) boronic acid (56mg, 0.40mmol), Pd (dppf) Cl₂(25mg, 34.17umol), sodium carbonate (69mg, 0.65mmol), dioxane (1mL), and water (0.2mL) were placed in an 8-mL sealed tube purged and maintained under a nitrogen inert atmosphere. The reaction mixture was stirred at 90 ℃ for 2 h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by column of silica gel eluting with EA/n-hexane (7/3). The eluate was collected and concentrated in vacuo. The residue was purified by Prep-HPLC (CH)₃CN/H₂O-3/2). This gave 22mg of 4- (4-acryloylpiperazin-1-yl) -6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Amgen 6") as a yellow solid. LCMS: 571[ M +1 ] M/z]⁺。

¹HNMR(400MHz，CD₃OD)δ8.52(s，lH)，8.43(d，J＝5.0Hz，1H)，7.54-7.46(m，1H)，7.32-7.13(m，4H)，6.89(dd，J＝16.7，10.6Hz，1H)，6.33(d，J＝16.7Hz，1H)，5.86(d，J＝10.6Hz，1H)，4.15-3.90(m，8H)，2.79-2.65(m，1H)，2.04(s，3H)，1.19(d，J＝6.8Hz，3H)，1.00(d，J＝6.7Hz，3H)。

The atropisomer mixture of 4- (4-acryloylpiperazin-1-yl) -6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (1.59g) was purified by Chiral-Prep-HPLC according to the following procedure: column, CHIRALCellulose-SB, 3cm × 25cm, 5 um; mobile phase, CO ₂IPA and ACN are 1: 1; detection wavelength, UV 254 nm. This gave 739mg (46%) of 4- (4-acryloylpiperazin-1-yl) -6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (first eluate) as a yellow solid; LCMS: 571[ M +1 ] M/z]⁺。

And 709mg (45%) of 4- (4-acryloylpiperazin-1-yl) -6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (second eluate) as a yellow solid. LCMS: 571[ M +1 ] M/z]⁺。

¹HNMR(400MHz，CD₃OD)δ8.50(s，1H)，8.41(d，J＝5.0Hz，1H)，7.52-7.37(m，1H)，7.30-7.08(m，4H)，6.87(dd，J＝16.8，10.6Hz，1H)，6.38-6.24(m，1H)，5.83(dd，J＝10.6，1.8Hz，1H)，4.09-3.82(m，8H)，2.78-2.63(m，1H)，2.02(s，3H)，1.16(d，J＝6.8Hz，3H)，0.98(d，J＝6.8Hz，3H)。

Amgen6.3

4- (4-Acryloylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Amgen 6.3")

Step 1.7- (2-amino-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-4- (piperazin-1-yl) -1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

Tert-butyl 4- (7- (2-amino-6-fluorophenyl) -6-chloro-3-cyano-l- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate (5.39g, 8.15mmol), trifluoroacetic acid (5mL) and dichloromethane (50mL) were placed in a 100-mL round bottom flask. The reaction mixture was stirred at room temperature for 1 h. After the reaction is complete, the solution is dried under vacuum to give 4.36g of 7- (2-amino-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-4- (piperazin-1-yl) -1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow oil.

Step 2.4- (4-Acryloylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

7- (2-amino-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-4- (piperazin-1-yl) -1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (4.36g, 7.77mmol), potassium phosphate (7.401g, 34.87mmol), tetrahydrofuran (40mL) and water (20mL) were placed in a 100-mL round-bottomed flask. Acryloyl chloride (0.65g, 7.14mmol) was added dropwise to the reaction mixture at 0 ℃ and stirred at room temperature for 1 h. When the reaction was complete, the solution was evaporated to dryness and purified by pre-HPLC to give 1.168g of 4- (4-acryloylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("amgen 6.3") as a yellow solid. LCMS: 615[ M +1 ] M/z]⁺。

¹HNMR(400MHz，DMSO-d6)δ9.09(s，1H)，8.48(s，1H)，7.05(q，J＝7.8Hz，1H)，6.93(dd，J＝16.6，10.4Hz，1H)，6.44(d，J＝8.3Hz，1H)，6.31(t，J＝8.9Hz，1H)，6.21(dd，J＝16.7，2.4Hz，1H)，5.77(dd，J＝10.4，2.4Hz，1H)，5.08(s，2H)，3.90(m，8H)，2.90-2.74(m，1H)，2.70-2.55(m，1H)，1.07(dd，J＝12.2，6.7Hz，6H)，1.00(d，J＝6.6Hz，3H)，0.86(d，J＝6.7Hz，3H)。

Amgen7.3

4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Amgen 7.3")

Step 1.4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile

4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (109mg, 0.20mmol), ((2-fluorophenyl) boronic acid (110mg, 0.79mmol), palladium tetrakistriphenylphosphine (85mg, 0.073mmol), sodium carbonate (69mg, 0.65mmol), dioxane (6mL) and water (2mL) were placed in a 20-mL sealed tube purged with nitrogen inert atmosphere and maintained, the reaction mixture was stirred at 80 ℃ for 4 h. Water (100mL) was added to quench the reaction, the resulting solution was extracted with ethyl acetate (3X100mL), the organic phases were combined and washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (CH)₃CN/H₂O (V/V ═ 1/1)). This gave 31mg (two-step yield 26%) of 4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("amgen 7.3") as a yellow solid. LCMS: 599[ M +1 ] M/z]⁺.

¹HNMR(400MHz，CD₃OD)δ8.80(s，1H)，8.44(d，J＝5.0Hz，1H)，7.48(dd，J＝8.4，4.6Hz，1H)，7.40-7.22(m，4H)，6.98-6.85(m，1H)，6.35(d，J＝16.5Hz，1H)，5.86(d，J＝10.6Hz，1H)，4.79(s，2H)，4.14-3.79(m，4H)，2.80-2.74(m，1H)，2.05(s，3H)，1.68(d，J＝7.0Hz，6H)，1.19(d，J＝6.8Hz，3H)，1.01(d，J＝6.7Hz，3H).

The atropisomeric mixture of 4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (1.48g) was purified by Chiral-Prep-HPLC according to the following conditions: column, CHIRALCellulose-SB, 3cm × 25cm, 5 um; mobile phase, Hex/EtOH 50/50 (V/V); detection wavelength, UV254 nm. This gave 625mg (42%) of 4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (first eluate) as a yellow solid; LCMS: 599[ M +1 ] M/z ]⁺，

¹HNMR(400MHz，CD₃OD) δ 8.68(S, 1H), 8.32(d, J ═ 5.0Hz, 1H), 7.42-7.30(m, 1H), 7.23-7.01(m, 4H), 6.78(dd, J ═ 16.7, 10.6Hz, 1H), 6.22(dd, J ═ 16.7, 1.9Hz, 1H), 5.73(dd, J ═ 10.6, 1.9Hz, 1H), 4.66(S, 2H), 3.99-3.83(m, 2H), 3.74-3.72(m, 2H), 2.63-2.61(m, 1H), 1.93(S, 3H), 1.55(d, J ═ 7.0Hz and 669mg (45%) of 4- ((3S, 5R) -4-acryloyl-3, 5-dimethylpiperazine-1- (1-chloro-2-propyl) -2- (1H) -4- ((1.7-chloro-2-propyl) -2- ((1.6-methyl-2-propyl) -1- (1H), 2-dihydro-1, 8-naphthyridine-3-carbonitrile (second eluate) as a yellow solid. LCMS: 599[ M +1 ] M/z]⁺。

¹HNMR(400MHz，CD₃OD)δ8.80(s，1H)，8.43(d，J＝5.0Hz，1H)，7.57-7.41(m，1H)，7.37-7.07(m，4H)，6.90(dd，J＝16.7，10.6Hz，1H)，6.34(dd，J＝16.7，1.9Hz，1H)，5.85(dd，J＝10.6，1.9Hz，1H)，4.78(s，2H)，4.07-3.98(m，2H)，3.86-3.84(m，2H)，2.76-2.74(m，1H)，2.05(s，3H)，1.68-1.66(m，6H)，1.12-1.10(m，3H)，0.91-0.89(m，3H)。

Pharmacological experiments

SOS 1-catalyzed guanylic acid exchange experiment

HIS-KRAS (G12C, aa 2-185, Sino biological) was first diluted to 5. mu.M with EDTA buffer (20mM HEPES, pH 7.4, 50mM NaCl, 10mM EDTA, 0.01% (v/v) Tween-20) and incubated at 25 ℃ for 30 minutes. Then assay buffer (25mM HEPES, pH 7.4, 120mM NaCl, 5mM MgCl)₂GDP-KRAS (G12C) was prepared by diluting EDTA-pretreated HIS-KRAS (G12C) to 12nM with 1mM DTT, 0.01% (v/v) Tween 20, 0.1% (w/v) BSA) and incubating with 120nM GDP and 6HIS-Tb cryptate Gold (Cisbio) at 25 ℃ for 60 minutes. After pre-incubation of GDP-KRAS (G12C) with diluted compounds in 384-well plates for 1 hour, SOS1 ExD (Flag tag, aa 564-one 1049) and BODIPY were added ^TMFL GTP (Invitrogen) initiates the exchange reaction (reaction: 3nM HIS-KRAS (G12C), 2. mu.M SOS1 ExD, 80nM BODIPY^TMFL GTP, 21ng/mL MAb Anti 6HIS-Tb cryptate Gold), placed at 25 ℃ for reaction for 4 hours. The TR-FRET signal was measured using a Tecan Spark plate reader with the following detection parameters: f486 excitation wavelength 340(35) nm, absorption wavelength 486(10) nm, delay time 100 mus, integration time 200 mus; f515: excitation wavelength 340(35) nm, absorption wavelength 515(10) nm, delay time 100 μ s, integration time 200 μ s. The TR-FRET ratio for each well was calculated by the equation TR-FRET ratio ═ (F515 signal/F486 signal) × 10000. The data was then analyzed using a four parameter logistic model to calculate IC₅₀The value is obtained. The results of the SOS 1-catalyzed nucleotide exchange experiments are shown in Table 3 below:

TABLE 3

As can be seen from table 3, the example compounds of the present invention have strong inhibitory activity in the SOS1 catalyzed nucleotide exchange experiment.

2. Intracellular phospho-ERK 1/2(THR202/TYR204) protein level detection (HTRF)

NCI-H358 cells expressing KRAS G12C were incubated in RPMI1640 medium (Gibco) containing 10% fetal bovine serum (Gibco). Cells in the medium were seeded at a concentration of 40000 cells/well in 96-well plates and allowed to adhere overnight. The next day The medium was removed and compounds diluted with assay medium (RPMI 1640+ 0.1% FBS) were added. At a temperature of 37 ℃ with 5% CO₂After 2 hours incubation in the cell incubator of (1), the assay medium was removed, then 50 μ L of 1 × supplemented lysis buffer was added and the well plate was incubated at 25 ℃ for 45 minutes with shaking. Cell lysis of 10. mu.L was also transferred from 96-well plates to a well containing 2.5. mu.L/well

Pre-mixed antibodies (Cisbio 64 aerphe) in 384-well plates (Greiner). Incubation was carried out at 25 ℃ for 4 hours and then HTRF values were read in a Tecan Spark plate reader. Data analysis and IC calculation with a four parameter logistic model₅₀The value is obtained. The results of Phospho-ERK1/2(THR202/TYR204) HTRF experiments are shown in Table 4 below:

TABLE 4

Compound (I)	p-ERK IC₅₀(nM)	Compound (I)	p-ERK IC₅₀(nM)
				Compound 1	56.15	Compound 10	244.9
Compound 2	235.3	Compound 11-4	14.18
				Compound 3	407.6	Compound 11	10.36
Compound 4	12.25	Compound 11A	60.63
				Compound 5	42.07	Compound 11B	11.69
Compound 6	38.11	Compound 12	16.92
				Compound 6A	34.26	Compound 13	14.92
Compound 6B	57.91	Compound 14	18.51
				Compound 7	17.66	Compound 15	73.33
Compound 8	220.1	Compound 16	101.3
				Compound 9	28.8	Amgen-6	29.9
Compound 9A	69.54	Amgen-6.3	20.1
				Compound 9B	23.9	Amgen-7.3	44.5

As can be seen from Table 4, the compounds of the examples of the present invention have strong inhibitory activity in Phospho-ERK1/2(THR202/TYR204) HTRF experiments.

3. Cell proliferation inhibition assay

NCI-H358 cells expressing KRAS G12C were cultured in RPMI1640 medium (Gibco) containing 10% fetal bovine serum (Gibco). Cells in the medium were seeded at a concentration of 3000 cells/well (100 μ L/well) in 96-well plates and allowed to adhere overnight. The next day, compounds were diluted in medium and added to the well plates. At a temperature of 37 ℃/5% CO₂After 6 days of incubation in the cell incubator of (1), the medium was removed and 100. mu.L of 1X CCK-8(MCE) in the medium was added to each well. Orifice plate at 37 deg.C/5% CO₂Is incubated in the cell culture chamber for 1.5-2 hours. OD450 signals were read with a Tecan Spark multi-modal microplate reader and analyzed using a 4-parameter logistic model and ICsa values were calculated. The results are as followsShown in Table 5:

TABLE 5

As can be seen from Table 5, the compounds of the examples of the present invention have strong inhibitory activity against NCI-H358 cells expressing KRAS G12C mutant protein.

4. Mouse PK assessment

The purpose of this experiment was to evaluate the PK profile of compounds following a single administration in Balb/c mice (male). Prior to dosing, mice were fasted overnight with free access to water. Mice for each compound were divided into 2 groups (n-3/group). Group A mice were given a single 3mg/kg dose of compound (iv). Group B mice were given a single 10mg/kg dose of compound (po). For group a mice, blood samples were collected at 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, 24h before and after dosing. For group B mice, blood samples were collected at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 24h before and after dosing. Blood samples were placed on ice until centrifuged to obtain plasma. Plasma samples were stored at-80 ℃ until analysis. The concentration of the compound in the plasma sample was determined by LC-MS/MS method. The results are shown in Table 6:

TABLE 6

As can be seen from the results of the pharmacokinetic testing of the mice shown in table 6: preferred compounds 6 and 11 of the invention have pharmacokinetic parameters in mice superior to those of the control compounds 11-4, Amgen 6 and Amgen 6.3. The exposure of compound 6 can be more than 10 times the exposure of the control compound Amgen 6 and more than 6 times the exposure of the control compound Amgen 6.3. The exposure of the compound 11 can reach more than 6 times of that of a control compound Amgen 6, more than 3 times of that of the control compound Amgen 6.3 and more than 30 times of that of a control compound 11-4; at the same time, the half-lives of compound 6 and compound 11 were also greatly extended. Therefore, it is more consistent with the requirements of administration.

5. Beagle PK assessment

The purpose of this experiment was to evaluate PK properties of compounds following a single administration in beagle dogs. Before dosing, dogs were fasted overnight with free access to water. Dogs corresponding to each compound were divided into 2 groups (one male and one female per group). Group A dogs were given a single 1mg/kg dose of compound (iv). Group B dogs were given a single 10mg/kg dose of compound (po). For group a dogs, blood samples were collected at 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, 24h before and after dosing. For group B dogs, blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 24h before and after dosing. Blood samples were placed on ice until centrifuged to obtain plasma. Plasma samples were stored at-80 ℃ until analysis. The concentration of the compound in the plasma sample was determined by LC-MS/MS method. The results obtained are shown in Table 7:

TABLE 7

As can be seen from table 7, the preferred compounds of the invention, compound 9, compound 11 and compound 11B, have superior pharmacokinetic parameters in male or female dogs and their exposure is significantly higher than the control compounds, compared to the control compounds Amgen 6, Amgen 6 (second eluent) and Amgen 6.3, especially compound Amgen 6.3, which is hardly absorbed by male dogs. For example, compound 11B is exposed 5.8-11.2 times more than compound Amgen 6 and 3.4-4.2 times more than compound Amgen 6 (second eluent). Therefore, it is more consistent with the requirements of administration.

Validation experiments in MIA PaCa-2 xenograft model

A mixture of MIAPaCa-2 cells (1.0E +07 cells) and corning (corning) was injected subcutaneously on the right side of female BALB/c mice (6-8 weeks). Mice were monitored daily and caliper measurements were started when tumors became visible. The volume of the tumor was calculated by measuring two perpendicular diameters using the following formula: (L W)²) [ 2 ] wherein L and W areThe length and width of the tumor diameter. When the average tumor volume reaches 200mm³When mice were grouped (n-6/group) and given compound. During the dosing period (-3 weeks), tumor volume and mouse weight were measured 2 times per week. By the formula TGI% (1- (Vt-Vt)) ₀)/(Vc-Vc₀) 100%) of the tumor growth inhibition rate, where Vc and Vt are the mean tumor volumes of the control group and the administration group at the end of the experiment, Vc₀And Vt₀Mean tumor volumes of the control group and the administration group at the beginning. The results are shown in Table 8, and the tumor volume of the mice as a function of the number of days after cell inoculation is shown in FIG. 1.

TABLE 8

As can be seen from table 8 and fig. 1, compound 11 has good activity of inhibiting tumor growth.

Security exploration in the NCI-H1373 xenograft model

A mixture of NCI-H1373 cells (5.0E +06 cells) and Corning (Corning) was injected subcutaneously on the right side of female BALB/c mice (6-8 weeks). Mice were monitored daily and caliper measurements were started when tumors became visible. The volume of the tumor was calculated by measuring two perpendicular diameters using the following formula: (L W)²) And/2, wherein L and W refer to the length and width, respectively, of the tumor diameter. After grouping mice, we used the remaining mice (n ═ 8) to explore safety. Mice were dosed with compound 11B (po, QD) at a dose of 4000mg/kg for 15 days, and the body weight of the mice was measured 2 times per week during dosing. The body weight of the mice as a function of the days after cell inoculation is shown in FIG. 2.

As can be seen from fig. 2, compound 11B has good safety.

It should be understood that if the present invention refers to any prior art publication, it should be understood that: such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art in any country. Although the foregoing invention has been described in some detail by way of illustration for purposes of clarity of understanding, certain minor variations and modifications will become apparent to those skilled in the art. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

1. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:

wherein the content of the first and second substances,

R₁is selected from 4R₁₁substituted-C_6-10Aryl or by 4R₁₁Substituted 5-10 membered heteroaryl, each heteroaryl independently containing at each occurrence 1, 2, 3, or 4 substituents selected from the group consisting of N, O, S, S ═ O or S (═ O)₂A heteroatom of (a);

each R₁₁Independently at each occurrence, is selected from halogen, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, -C_1-6Alkylene- (halogen)_1-3Hetero atom C_2-6Alkyl, -CN, -OR₈、-C_1-6Alkylene- (OR)₈)_1-3、-O-C_1-6Alkylene- (halogen)_1-3、-SR₈、-S-C_1-6Alkylene- (halogen)_1-3、-NR₈R₉、-C_1-6alkylene-NR ₈R₉、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈、-NR₈SO₂R₉、-SO₂R₈、-S(＝O)₂NR₈R₉、-C_3-6Carbocyclyl, 3-6 membered heterocyclyl, -C_6-10Aryl, or 5-10 membered heteroaryl, each heterocyclyl and heteroaryl independently at each occurrence contains 1, 2, 3 or 4 substituents selected from the group consisting of N, O, S, S ═ O or S (═ O)₂Hetero atom of (A)Each R₁₁Independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C_1-6Alkyl, -C_1-6Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

R₂₁or R₂₂Independently selected from hydrogen, halogen, -C_1-6Alkyl, -C_1-6Alkylene- (halogen)_1-3Hetero atom C_2-6Alkyl, -CN, -OR₈、-C_1-6Alkylene- (OR)₈)_1-3、-NR₈R₉、-C_1-6alkylene-NR₈R₉、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉or-C_3-6Carbocyclyl radical, each R₂₁Or R₂₂Independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C_1-6Alkyl, -C_1-6Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

Each one of which isC Ring at each occurrence is independently selected from C_3-14A carbocyclic ring or a 3-14 membered heterocyclic ring, each D ring is independently at each occurrence selected from C_6-10An aromatic ring or a 5-10 membered heteroaromatic ring, each heterocyclyl and heteroaryl independently containing at each occurrence 1, 2, 3 or 4 substituents selected from the group consisting of N, O, S, S ═ O or S (═ O) ₂Each R is₃Optionally substituted at each occurrence with 1, 2, 3, 4, 5 or 6R₃₁Substituted or unsubstituted;

each R₃₁Independently at each occurrence, is selected from halogen, -C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, -C_1-6Alkylene- (halogen)_1-3Hetero atom C_2-6Alkyl, -CN, -C_1-6alkylene-CN, -OR₈、-C_1-6Alkylene- (OR)₈)_1-3、-O-C_1-6Alkylene- (halogen)_1-3、-NR₈R₉、-C_1-6alkylene-NR₈R₉、-O-C_1-6alkylene-NR₈R₉、-C(＝O)R₈、-C_1-6alkylene-C (═ O) R₈、-C(＝O)OR₈、-C_1-6alkylene-C (═ O) OR₈、-OC(＝O)R₈、-C_1-6alkylene-OC (═ O) R₈、-C(＝O)NR₈R₉、-C_1-6alkylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈、-C_1-6alkylene-NR₈C(＝O)R₈、-SO₂R₈、-C_1-6alkylene-SO₂R₈、-S(＝O)₂NR₈R₉、-C_1-6alkylene-S (═ O)₂NR₈R₉、-PO(R₈)₂、-C_1-6alkylene-PO (R)₈)₂、-C_3-6Carbocyclyl or 3-6 membered heterocyclyl, each heterocyclyl independently containing at each occurrence 1, 2, 3 or 4 substituents selected from N, O, S, S ═ O or S (═ O)₂Each R is₃₁Optionally substituted at each occurrence with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C_1-6Alkyl, -C_1-6Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

R₄Is selected from

Each one of which is

Each R₄₁Independently at each occurrence is selected from

Is selected from

When in use

Is selected from

When each R is_4a、R_4bAnd R_4cIndependently at each occurrence, is selected from absent, hydrogen, halogen, -C_1-6Alkyl, -C_1-6Alkylene- (halogen)_1-3Hetero atom C_2-6Alkyl, -CN, -OR₈、-C_1-6Alkylene- (OR)₈)_1-3、-NR₈R₉、-C_1-6alkylene-NR₈R₉、-NR₈-C_1-6alkylene-OR₈、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-C_1-6alkylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈、-C_1-6alkylene-NR₈C(＝O)R₈、-C_1-6alkylene-O-C_1-6Aryl, -S (═ O)₂NR₈R₉、-C_3-10Carbocyclyl, 3-10 membered heterocyclyl, -C_1-6Alkylene- (3-to 10-membered heterocyclyl); each R_4a、R_4bOr R_4cIndependently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C_1-6Alkyl, -C_1-6Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted; or R_4bAnd R_4cTogether with the carbon atoms to which they are both attached form C_3-10Carbocyclic or 3-10 membered heterocyclic ring; or R_4aAnd R_4cTogether with the carbon atoms to which they are respectively attached form C_3-10A carbocycle or a 3-10 membered heterocycle, each heterocyclyl containing at each occurrence 1, 2 or 3 substituents selected from N, O, S, S ═ O or S (═ O)₂Of (2)Atom, and said C_3-10The carbocycle or said 3-10 membered heterocycle is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C_1-6Alkyl, -C_1-6Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted; or

When in use

Is selected from

When each R is_4aIs selected from absent, and R_4bAnd R_4cIs absent, R_4bAnd R_4cIs selected from hydrogen, halogen, -C_1-6Alkyl, -C_1-6Alkylene- (halogen)_1-3Hetero atom C_2-6Alkyl, -CN, -OR₈、-C_1-6Alkylene- (OR)₈)_1-3、-NR₈R₉、-C_1-6alkylene-NR₈R₉、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-C_1-6alkylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈、-C_1-6alkylene-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉or-C_3-10A carbocyclic group; each R_4aIndependently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from halogen, -C_1-6Alkyl, -C_1-6Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

each R_4dIndependently at each occurrence, is selected from halogen;

Two R₄₂Together with the atoms to which they are both attached or the atoms to which they are attached respectively form C _3-6A carbocycle or a 3-6 membered heterocycle, each said heterocycle independently containing 1, 2 or 3 heteroatoms selected from N or O, each C_3-6A carbocyclic ring or 3-6 membered heterocyclic ring independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from halogen,-C_1-6Alkyl, -C_1-6Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

R₈And R₉Together with the N atom to which they are both attached form a 3-10 membered heterocyclic ring, said 3-10 membered heterocyclic ring optionally including 1, 2, 3 or 4 substituents selected from the group consisting of N, O, S, S (═ O) or S (═ O)₂And said 3-10 membered heterocycle is independently optionally substituted with 1, 2, 3, 4, 5 or 6 heteroatoms selected from halogen, oxo, -C_1-6Alkyl, -C_1-6Alkylene- (halogen)_1-3Hetero atom C_2-6Alkyl, -CN, -OH, -OC_1-6Alkyl, -C_1-6Alkylene- (OH)_1-3、-C_1-6Alkylene- (OC)_1-6Alkyl radical)_1-3、-NH₂、-NHC_1-6Alkyl, -N (C)_1-6Alkyl radical) ₂、-C_1-6alkylene-NH₂、-C_1-6alkylene-NHC_1-6Alkyl, -C_1-6alkylene-N (C)_1-6Alkyl radical)₂、-C(＝O)C_1-6Alkyl, -C (═ O) OC_1-6Alkyl, -OC (═ O) C_1-6Alkyl, -C (═ O) NH₂、-C(＝O)NHC_1-6Alkyl, -C (═ O) N (C)_1-6Alkyl radical)₂、-NHC(＝O)C_1-6Alkyl, -N (C)_1-6Alkyl) C (═ O) C_1-6Alkyl, -S (═ O)₂NH₂、-S(＝O)₂NH(CH₃)、-S(＝O)₂NHC_1-6Alkyl, -S (═ O)₂N(C_1-6Alkyl) or-C_3-6Substituted or unsubstituted carbocyclyl;

m is selected from 1, 2, 3, 4, 5 or 6.

2. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 1, wherein:

R₁is selected from 4R_nSubstituted phenyl, substituted by 4R₁₁Substituted naphthyl, by 4R₁₁Substituted 5-membered heteroaryl, substituted with 4R₁₁Substituted 6-membered heteroaryl, substituted with 4R₁₁Substituted 7-membered heteroaryl, substituted with 4R₁₁Substituted 8-membered heteroaryl, substituted with 4R₁₁Substituted 9-membered heteroaryl or substituted with 4R₁₁Substituted 10-membered heteroaryl, each heteroaryl independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O or S.

3. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 1, wherein:

R₁Is selected from 4R₁₁Substituted phenyl, substituted by 4R₁₁Substituted naphthyl, by 4R₁₁Substituted 6-membered heteroaryl or substituted by 4R₁₁Substituted 9-membered heteroaryl, each heteroaryl independently at each occurrence comprising 1 or 2 heteroatoms selected from N.

4. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-3, wherein:

R₁is selected from 4R₁₁Substituted phenyl, substituted by 4R₁₁Substituted naphthyl, by 4R₁₁Substituted pyridines substituted by 4R₁₁Substituted benzo [ d ]]Oxazolyl group, substituted by 4R₁₁Substituted benzo [ d ]]Thiazolyl, substituted by 4R₁₁Substituted pyrroles [2, 3-c]Pyridine, quilt 4R₁₁Substituted pyrazoles [3, 4-c]Pyridine, quilt 4R₁₁Substituted pyrazoles [1, 5-a ]]Pyridine, quilt 4R₁₁Substituted imidazoles [1, 2-a ]]Pyridine, quilt 4R₁₁Substituted 2-oxo-indolyl substituted by 4R₁₁Substituted pyrimidinyl, substituted with 4R₁₁Substituted indolyl substituted by 4R₁₁Substituted indazolyl radical, substituted by 4R₁₁Substituted benzo [ d ]]Imidazolyl group by 4R₁₁Substituted pyrazoles [3, 4-b ]]Pyridine, quilt 4R₁₁Substituted 2(3H) -oxo-oxazoles [4, 5-b ]Pyridine or pyridine substituted by 4R₁₁Substituted isoquinolinyl groups.

5. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-4, wherein:

R₁is selected from 4R₁₁Substituted phenyl, substituted by 4R₁₁Substituted naphthyl, by 4R₁₁Substituted pyridines or substituted by 4R₁₁A substituted indazolyl group.

6. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-5, wherein:

R₁selected from:

each R₁Independently at each occurrence by 4R₁₁And (4) substitution.

7. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to claims 1-6, wherein:

R₁independently selected from:

each R₁Independently at each occurrence by 4R₁₁And (4) substitution.

8. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-7, wherein:

R₁Selected from:

each R₁Independently at each occurrence by 4R₁₁And (4) substitution.

9. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-8, wherein:

each R₁₁Independently at each occurrence is selected from-F, -Cl, -Br, oxo, -C_1-3Alkyl, -C_2-3Alkenyl, -C_2-3Alkynyl, -C_1-3Alkylene- (halogen)_1-3Hetero atom C_2-3Alkyl, -CN, -OR₈、-C_1-3Alkylene- (OR)₈)_1-3、-O-C_1-3Alkylene- (halogen)_1-3、-SR₈、-S-C_1-3Alkylene- (halogen)_1-3、-NR₈R₉、-C_1-3alkylene-NR₈R₉、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉、-C_3-6Carbocyclyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; each R₁₁Independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, -Br, -C_1-3Alkyl, -C_1-3Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

10. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-9, wherein:

Each R₁₁Independently at each occurrence is selected from-F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, -methylene- (halogen)_1-3-ethylene- (halogen)_1-3-propylene- (halogen)_1-3Hetero-ethyl, hetero-propyl, -CN, -OR₈-methylene- (OR)₈)_1-3-ethylene- (OR)₈)_1-3-propylene- (OR)₈)_1-3-O-methylene- (halogen)_1-3-O-ethylene- (halogen)_1-3-O-propylene- (halogen)_1-3、-SR₈-S-methylene- (halogen)_1-3-S-ethylene- (halogen)_1-3-S-propylene- (halogen)_1-3、-NR₈R₉-methylene-NR₈R₉-ethylene-NR₈R₉-propylene-NR₈R₉、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, phenyl, 5-membered heteroaryl or 6-membered heteroaryl; each heterocyclyl and heteroaryl independently at each occurrence contains 1, 2, or 3 heteroatoms selected from N, O or S, each R₁₁Independently optionally substituted with 1, 2, 3, 4, 5 OR 6 substituents selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

11. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-10, wherein:

each R₁₁Independently at each occurrence is selected from-F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, -CH₂F、-CHF₂、-CF₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃、-CH₂OCH₃、-CH₂CH₂OCH₃、-CN、-OH、-OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)₂、-CH₂OH、-CH₂CH₂OH、-CH₂CH₂CH₂OH、-OCH₂F、-OCHF₂、-OCF₃、-OCH₂CH₂F、-OCH₂CHF₂、-OCH₂CF₃、-OCH₂CH₂CH₂F、-OCH₂CH₂CHF₂、-OCH₂CH₂CF₃、-SH、-SCH₃、-SCH₂CH₃、-SCH(CH₃)₂、-SCH₂F、-SCHF₂、-SCF₃、-SCH₂CH₂F、-SCH₂CHF₂、-SCH₂CF₃、-SCH₂CH₂CH₂F、-SCH₂CH₂CHF₂、-SCH₂CH₂CF₃、-NH₂、-NHCH₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-N(CH₃)₂、-N(CH₃)CH₂CH₃、-N(CH₃)CH₂CH₂CH₃、-N(CH₃)CH(CH₃)₂、-CH₂NH₂、-CH₂CH₂NH₂、-CH₂CH₂CH₂NH₂、-CH₂N(CH₃)₂、-CH₂CH₂N(CH₃)₂、-CH₂CH₂CH₂N(CH₃)₂、-C(＝O)CH₃、-C(＝O)OCH₃、-C(＝O)OCH₂CH₃、-C(＝O)OCH₂CH₂CH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃)、-S(＝O)₂N(CH₃)₂3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, phenyl, 5-membered heteroaryl or 6-membered heteroaryl; each heterocyclyl and heteroaryl independently at each occurrence contains 1 or 2 heteroatoms selected from N or O, each R₁₁Independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH₂、-NHCH₃、-N(CH₃)₂、-CN、-C(＝O)CH₃、-C(＝O)OCH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃) or-S (═ O)₂N(CH₃)₂Substituted or unsubstituted.

12. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-11, wherein:

Each R₁₁Independently at each occurrence is selected from-F, -Cl, oxo, -OH, -NH₂CN, -methyl, ethyl, propyl, isopropyl,

13. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-12, wherein:

each R₁₁Independently at each occurrence is selected from-F, -Cl, -OH, -NH₂Methyl, methoxy, -OCF₃、-CHF₂、-CF₃Or

14. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-8, wherein:

each R₁₁Independently at each occurrenceIs selected from halogen; -C_1-6An alkyl group; by halogen, -NH₂-CN or-OH substituted-C_1-6An alkyl group; -OH; -O-C_1-6An alkyl group; by halogen, -NH₂-CN or-OH substituted-O-C_1-6An alkyl group; -NH₂；-NH(C_1-6alkly)；-N(C_1-6Alkyl radical)₂；-NHCOC_1-6An alkyl group; -N (C)_1-6Alkyl) COC_1-6An alkyl group; -NHSO₂C_1-6An alkyl group; -N (C)_1-6Alkyl) SO₂C_1-6An alkyl group; -SO ₂(C_1-6Alkyl groups); -SO₂NH₂；-SO₂NHC_1-6An alkyl group; -SO₂N(C_1-6Alkyl radical)₂or-C_3-6A carbocyclic group.

15. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 14, wherein:

each R₁₁Is independently selected at each occurrence from-F; -Cl; -Br; -C_1-3An alkyl group; -C substituted by-F or-Cl_1-3An alkyl group; -OH; -O-C_1-3An alkyl group; -O-C substituted by-F or-Cl_1-3An alkyl group; -NH₂；-NH(C_1-3alkly)；-N(C_1-3Alkyl radical)₂；-NHCOC_1-3An alkyl group; -N (C)_1-3Alkyl) COC_1-3An alkyl group; -NHSO₂C_1-3An alkyl group; -N (C)_1-3Alkyl) SO₂C_1-3An alkyl group; -SO₂(C_1-3Alkyl groups); -SO₂NH₂；-SO₂NHC_1-3An alkyl group; -SO₂N(C_1-3Alkyl radical)₂or-C_3-6A carbocyclic group.

16. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 14 or 15, wherein:

each R₁₁Is independently selected at each occurrence from-F; -Cl; -Br; -C_1-3An alkyl group; -C substituted by-F or-Cl_1-3An alkyl group; -OH; -O-C_1-3An alkyl group; -O-C substituted by-F or-Cl_1-3An alkyl group; -NH₂；-NH(C_1-3alkly)；-N(C_1-3Alkyl radical)₂；-NHCOC_1-3An alkyl group; -N (C)_1-3Alkyl) COC_1-3An alkyl group; -NHSO ₂C_1-3An alkyl group; -N (C)_1-3Alkyl) SO₂C_1-3An alkyl group; -SO₂(C_1-3Alkyl groups); -SO₂NH₂；-SO₂NHC_1-3An alkyl group; -SO₂N(C_1-3Alkyl radical)₂or-C_3-6A carbocyclic group.

17. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 14-16, wherein:

each R₁₁Is independently selected at each occurrence from-F; -Cl; a methyl group; an ethyl group; propyl; isopropyl group; -F-substituted methyl; -an F-substituted ethyl group; -F-substituted propyl; -F-substituted isopropyl; -OH; a methoxy group; an ethoxy group; a propoxy group; an isopropoxy group; -F-substituted methoxy; -an F-substituted ethoxy group; -F-substituted propoxy; -F-substituted isopropoxy; -NH₂；-NHCH₃；-NHCH₂CH₃；-NH(CH₂CH₂CH₃)；-NH(CH(CH₃)₂)；-N(CH₃)₂；-N(CH₂CH₃)₂；-N(CH₃)(CH₂CH₃)；-NHCOCH₃；-NHCOCH₂CH₃；-NHCOCH₂CH₂CH₃；-N(CH₃)COCH₃；-N(CH₃)COCH₂CH₃；-N(CH₃)COCH₂CH₂CH₃；-NHSO₂CH₃；-NHSO₂CH₂CH₃；-NHSO₂CH₂CH₂CH₃；-N(CH₃)SO₂CH₃；-N(CH₃)SO₂CH₂CH₃；-N(CH₃)SO₂CH₂CH₂CH₃；-SO₂CH₃；-SO₂CH₂CH₃；-SO₂CH₂CH₂CH₃；-SO₂(CH(CH₃)₂)；-SO₂NH₂；-SO₂NHCH₃；-SO₂NHCH₂CH₃；-SO₂NHCH₂CH₂CH₃；-SO₂N(CH₃)₂；-SO₂N(CH₂CH₃)₂；-SO₂N(CH₂CH₂CH₃)₂(ii) a A 3-membered carbocyclic group; a 4-membered carbocyclic group; 5-membered carbocyclyl or 6-membered carbocyclyl.

18. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 14-17, wherein:

each R₁₁Independently at each occurrence is selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, -CH ₂F、-CHF₂、-CF₃-OH, methoxy, ethoxy, propoxy, isopropoxy, -OCF₃、-NH₂、-NHCH₃、-NHCH₂CH₃、-NH(CH₂CH₂CH₃)、-NH(CH(CH₃)₂)、-N(CH₃)₂、-N(CH₂CH₃)₂、-N(CH₃)(CH₂CH₃)、-NHCOCH₃、-N(CH₃)COCH₃、-NHSO₂CH₃、-N(CH₃)SO₂CH₃、-SO₂CH₃、-SO₂CH₂CH₃、-SO₂CH₂CH₂CH₃、-SO₂(CH(CH₃)₂)、-SO₂NHCH₃、-SO₂N(CH₃)₂3-membered, 4-membered, 5-membered or 6-membered carbocyclyl.

19. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 14-18, wherein:

each R₁₁Independently at each occurrence is selected from-F, -Cl, -CH₃、-CF₃、-OH、-OCH₃、-OCF₃、-NH₂、-NHCH₃、-NHCOCH₃、-NHSO₂CH₃、-SO₂CH₃or-SO₂NHCH₃。

20. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 14-19, wherein:

each R₁₁Independently at each occurrence is selected from-F, -Cl, -OH or-NH₂。

21. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 14-20, wherein:

R₁selected from:

22. a compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-21, wherein:

R₁Selected from:

23. a compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-22, wherein:

R₂₁or R₂₂Independently selected from hydrogen, -F, -Cl, -Br, -C_1-3Alkyl, -C_1-3Alkylene- (halogen)_1-3Hetero atom C_2-3Alkyl, -CN, -OR₈、-C_1-3Alkylene- (OR)₈)_1-3、-NR₈R₉、-C_1-3alkylene-NR₈R₉、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉3-, 4-, 5-or 6-membered carbocyclyl; each R₂₁Or R₂₂Independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, -Br, -C_1-3Alkyl, -C_1-3Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

24. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-23, wherein:

R₂₁or R₂₂Independently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH ₂F、-CHF₂、-CF₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃、-CH₂OCH₃、-CH₂CH₂OCH₃、-CN、-OH、-OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)₂、-CH₂OH、-CH₂CH₂OH、-CH₂CH₂CH₂OH、-CH₂CH₂CH₂OCH₃、-NH₂、-NHCH₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-N(CH₃)₂、-N(CH₃)CH₂CH₃、-N(CH₃)CH₂CH₂CH₃、-N(CH₃)CH(CH₃)₂、-CH₂NH₂、-CH₂CH₂NH₂、-CH₂CH₂CH₂NH₂、-CH₂N(CH₃)₂、-CH₂CH₂N(CH₃)₂、-CH₂CH₂CH₂N(CH₃)₂、-C(＝O)CH₃、-C(＝O)OCH₃、-C(＝O)OCH₂CH₃、-C(＝O)OCH₂CH₂CH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃)、-S(＝O)₂N(CH₃)₂3-, 4-, 5-or 6-membered carbocyclyl; each (R)₂₁Or R₂₂) Independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH₂、-N(CH₃)₂、-CN、-C(＝O)CH₃、-C(＝O)OCH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃) or-S (═ O)₂N(CH₃)₂Substituted or unsubstituted.

25. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-24, wherein:

R₂₁or R₂₂Independently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH₂F、-CHF₂、-CF₃、-OH、-OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)₂、-CH₂OH、-CH₂CH₂OH、-CH₂CH₂CH₂OH、-NH₂、-NHCH₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂Or

26. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-25, wherein:

R₂₁selected from-F, -Cl or

And is

R₂₂Selected from hydrogen.

27. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-23, wherein:

R₂₁Independently selected from hydrogen; halogen; -C_1-6An alkyl group; by halogen, -NH₂-CN or-OH substituted-C_1-6An alkyl group; -C_2-6Alkenyl or-C_3-6A carbocyclic group;

R₂₂selected from hydrogen, halogen or-C_1-6An alkyl group.

28. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 27, wherein:

R₂₁selected from hydrogen; -F; -Cl; -Br; -C_1-3An alkyl group; -C substituted by-F or-C1_1-3An alkyl group; -C_2-3Alkenyl or-C_3-6A carbocyclic group.

29. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 27 or 28, wherein:

R₂₁selected from hydrogen, -F; -Cl; a methyl group; an ethyl group; propyl; isopropyl group; methyl substituted by-F; ethyl substituted with-F; propyl substituted with-F; isopropyl substituted with-F; a vinyl group; a propenyl group; a 3-membered carbocyclic group; a 4-membered carbocyclic group; 5-membered carbocyclyl or 6-membered carbocyclyl.

30. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 27-29, wherein:

R₂₁Selected from-F, -Cl, -CF₃、

31. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to claims 27-30, wherein:

R₂₁is-F or-Cl.

32. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to claims 27-31, wherein:

R₂₂selected from hydrogen, -F, -Cl, -Br or-C_1-3An alkyl group.

33. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 27-32, wherein:

R₂₂selected from hydrogen, -F, -Cl, methyl, ethylPropyl or isopropyl.

34. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 27-33, wherein:

R₂₂Is hydrogen or-CH₃。

35. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 27-34, wherein:

R₂₂is hydrogen.

36. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-35, wherein:

R₃is selected from-C_1-6Alkyl, -C_2-6Alkenyl, -C_2-6Alkynyl, -C_6-10Aryl radical, -C_1-3Alkylene radical C_6-10Aryl, 5-10 membered heteroaryl, -C_1-3Alkylene- (5-10 membered heteroaryl), 3-6 membered heterocyclyl, -C_1-3Alkylene- (3-6 membered heterocyclyl), -C_3-6Carbocyclyl, -C_1-3alkylene-C_3-6A carbocyclic group,

Each ring C is independently selected at each occurrence from C_3-6A carbocyclic ring or a 3-6 membered heterocyclic ring, each ring D is independently selected at each occurrence from C_6-10An aromatic ring or a 5-10 membered heteroaryl, each heterocyclyl and heteroaryl independently containing at each occurrence 1, 2 or 3 heteroatoms selected from N, O or S, each R₃Optionally 1, 2, 3, 4 independently at each occurrence 5 or 6R₃₁And (4) substitution.

37. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-36, wherein:

R₃is selected from-C_1-3Alkyl, -C_2-3Alkenyl, -C_2-3Alkynyl, phenyl, naphthyl, -methylene-C_6-10Aryl, -ethylene-C_6-10Aryl, -propylene-C_6-10Aryl, -isopropylidene-C_6-10Aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, -methylene- (5-10-membered heteroaryl), -ethylene- (5-10-membered heteroaryl), -propylene- (5-10-membered heteroaryl), -isopropylene- (5-10-membered heteroaryl), 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, -methylene- (3-6-membered heterocyclyl), -ethylene- (3-6-membered heterocyclyl), -propylene- (3-6-membered heterocyclyl), -isopropylene- (3-6-membered heterocyclyl), 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, -methylene-C_3-6Carbocyclyl, -ethylene-C_3-6Carbocyclyl, -propylene-C_3-6Carbocyclyl, -isopropylidene-C_3-6A carbocyclic group,

Each ring C is independently selected at each occurrence from a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring, each ring D is independently selected at each occurrence from a phenyl ring, a 5-membered heteroaromatic ring, or a 6-membered heteroaromatic ring, each heterocyclic, heteroaromatic, or heteroaryl ring independently comprises at each occurrence 1, 2, or 3 heteroatoms selected from N, O or S, each R is independently selected from R ₃Optionally substituted at each occurrence with 1, 2, 3, 4, 5 or 6R₃₁Substituted or unsubstituted.

38. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-37, wherein:

R₃selected from the group consisting of methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, phenyl, naphthyl, -methylene-phenyl, -ethylene-phenyl, -propylene-phenyl, -isopropylidene-phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, -methylene- (5-10-membered heteroaryl), -ethylene- (5-10-membered heteroaryl), -propylene- (5-10-membered heteroaryl), -isopropylidene- (5-10-membered heteroaryl), 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, -methylene- (3-6-membered heterocyclyl), -ethylene- (3-6-membered heterocyclyl), -propylene- (3-6 membered heterocyclyl), -isopropylene- (3-6 membered heterocyclyl), 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, -methylene-C_3-6Carbocyclyl, -ethylene-C _3-6Carbocyclyl, -propylene-C_3-6Carbocyclyl, -isopropylidene-C_3-6A carbocyclic group,

39. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-38, wherein:

R₃is selected from-C_6-10Aryl or 5-10 membered heteroaryl, each 5-10 membered heteroaryl independently at each occurrence containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, each-C_6-10Aryl or 5-10 membered heteroaryl is independently optionally substituted at each occurrence with 1R₃₁2R₃₁3R₃₁4, R₃₁5R₃₁Or 6R₃₁Substituted or unsubstituted.

40. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-39, wherein:

R₃selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl independently at each occurrence comprising 1, 2, or 3 heteroatoms selected from N or O, each phenyl, naphthyl, or heteroaryl independently at each occurrence optionally substituted with 1R₃₁2R₃₁3R₃₁4, R₃₁5R₃₁Or 6R₃₁Substituted or unsubstituted.

41. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-40, wherein:

R₃selected from phenyl or 6-membered heteroaryl, said 6-membered heteroaryl comprising 1 or 2 heteroatoms selected from N, each phenyl or 6-membered heteroaryl in each occurrence independently optionally substituted with 1R₃₁2R₃₁3R ₃₁4, R₃₁5R₃₁Or 6R₃₁Substituted or unsubstituted.

42. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-41, wherein:

R₃selected from:

43. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-42, wherein:

R₃selected from:

44. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-43, wherein:

each R₃₁Independently at each occurrence is selected from-F, -Cl, -Br, -C _1-3Alkyl, -C_2-3Alkenyl, -C_2-3Alkynyl, -C_1-3Alkylene- (halogen)_1-3Hetero atom C_2-3Alkyl, -CN, -C_1-3alkylene-CN, -OR₈、-C_1-3alkylene-OR₈、-O-C_1-3Alkylene- (halogen)_1-3、-NR₈R₉、-C_1-3alkylene-NR₈R₉、-O-C_1-3alkylene-NR₈R₉、-C(＝O)R₈、-C_1-3alkylene-C (═ O) R₈、-C(＝O)OR₈、-C_1-3alkylene-C (═ O) OR₈、-OC(＝O)R₈、-C_1-3alkylene-OC (═ O) R₈、-C(＝O)NR₈R₉、-C_1-3alkylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈、-C_1-3alkylene-NR₈C(＝O)R₈、-SO₂R₈、-C_1-3alkylene-SO₂R₈、-S(＝O)₂NR₈R₉、-C_1-3alkylene-S (═ O)₂NR₈R₉、-PO(R₈)₂、-C_1-3alkylene-PO (R)₈)₂、-C_3-6Carbocyclyl or 3-6 membered heterocyclyl, each heterocyclyl independently at each occurrence containing 1, 2 or 3 heteroatoms selected from N, O or S, each R₃₁Independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, -Br, -C_1-3Alkyl, -C_1-3Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

45. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-44, wherein:

each R₃₁Independently at each occurrence is selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, -methylene- (halogen) _1-3-ethylene- (halogen)_1-3-propylene- (halogen)_1-3-isopropylidene- (halogen)_1-3Heteroethyl, heteropropyl, -CN, -methylene-CN, -ethylene-CN, -propylene-CN, -isopropylidene-CN, -OR₈-methylene-OR₈-ethylene-OR₈-propylene-OR₈-isopropylidene-OR₈-O-methylene- (halogen)_1-3-O-ethylene- (halogen)_1-3-O-propylene- (halogen)_1-3-O-isopropylidene- (halogen)_1-3、-NR₈R₉-methylene-NR₈R₉-ethylene-NR₈R₉-propylene-NR₈R₉-isopropylidene-NR₈R₉-O-methylene-NR₈R₉-O-ethylene-NR₈R₉-O-propylene-NR₈R₉-O-isopropylidene-NR₈R₉、-C(＝O)R₈-methylene-C (═ O) R₈-ethylene-C (═ O) R₈-propylene-C (═ O) R₈-isopropylidene-C (═ O) R₈、-C(＝O)OR₈-methylene-C (═ O) OR₈-ethylene-C (═ O) OR₈-propylene-C (═ O) OR₈-isopropylidene-C (═ O) OR₈、-OC(＝O)R₈-methylene-OC (═ O) R₈-ethylene-OC (═ O) R₈-propylene-OC (═ O) R₈-isopropylidene-OC (═ O) R₈、-C(＝O)NR₈R₉-methylene-C (═ O) NR₈R₉-ethylene-C (═ O) NR₈R₉-propylene-C (═ O) NR₈R₉-isopropylidene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈-methylene-NR₈C(＝O)R₈-ethylene-NR₈C(＝O)R₈-propylene-NR₈C(＝O)R₈-isopropylidene-NR₈C(＝O)R₈、-SO₂R₈-methylene-SO₂R₈-ethylene-SO₂R₈-propylene-SO₂R₈-isopropylidene-SO ₂R₈、-S(＝O)₂NR₈R₉-methylene-S (═ O)₂NR₈R₉-ethylene-S (═ O)₂NR₈R₉-propylene-S (═ O)₂NR₈R₉-isopropylidene-S (═ O)₂NR₈R₉、-PO(R₈)₂-methylene-PO (R)₈)₂-ethylene-PO (R)₈)₂-propylene-PO (R)₈)₂-isopropylidene-PO (R)₈)₂3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl; each heterocyclyl independently at each occurrence contains 1 or 2 heteroatoms selected from N or O; each R₃Independently optionally substituted with 1, 2, 3, 4, 5 OR 6 substituents selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

R₃in (R)₈Or R₉) Independently at each occurrence is selected from hydrogen, methyl, ethyl, propyl or isopropyl.

46. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-45, wherein:

each R₃₁Independently at each occurrence is selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, methyl, ethyl, propyl, isopropyl, butyl, or a, Ethynyl, propynyl, -CH₂F、-CHF₂、-CF₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃、-CH(CH₃)(CF₃)、-CH₂OCH₃、-CH₂CH₂OCH₃、-CN、-CH₂CN、-CH₂CH₂CN、-CH₂CH₂CH₂CN、-OH、-OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)₂、-CH₂OH、-CH₂CH₂OH、-CH₂CH₂CH₂OH、-CH₂CH₂CH₂OCH₃、-OCF₃、-OCH₂CF₃、-OCH₂CH₂CF₃、-NH₂、-NHCH₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-N(CH₃)₂、-N(CH₃)CH₂CH₃、-N(CH₃)CH₂CH₂CH₃、-N(CH₃)CH(CH₃)₂、-CH₂NH₂、-CH₂CH₂NH₂、-CH₂CH₂CH₂NH₂、-CH₂N(CH₃)₂、-CH₂CH₂N(CH₃)₂、-CH₂CH₂CH₂N(CH₃)₂、-OCH₂NH₂、-OCH₂CH₂NH₂、-OCH₂CH₂CH₂NH₂、-C(＝O)CH₃、-CH₂C(＝O)CH₃、-CH₂CH₂C(＝O)CH₃、-CH₂CH₂CH₂C(＝O)CH₃、-C(＝O)OCH₃、-CH₂C(＝O)OCH₃、-CH₂CH₂C(＝O)OCH₃、-CH₂CH₂CH₂C(＝O)OCH₃、-OC(＝O)CH₃、-CH₂OC(＝O)CH₃、-CH₂CH₂OC(＝O)CH₃、-CH₂CH₂CH₂OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-CH₂C(＝O)N(CH₃)₂、-CH₂CH₂C(＝O)N(CH₃)₂、-CH₂CH₂CH₂C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-CH₂NHC(＝O)CH₃、-CH₂CH₂NHC(＝O)CH₃、-CH₂CH₂CH₂NHC(＝O)CH₃、-SO₂CH₃、-CH₂SO₂CH₃、-CH₂CH₂SO₂CH₃、-CH₂CH₂CH₂SO₂CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃)、-S(＝O)₂N(CH₃)₂、-CH₂S(＝O)₂N(CH₃)₂、-CH₂CH₂S(＝O)₂N(CH₃)₂、-CH₂CH₂CH₂S(＝O)₂N(CH₃)₂、-PO(CH₃)₂、-CH₂PO(CH₃)₂、-CH₂CH₂PO(CH₃)₂、-CH₂CH₂CH₂PO(CH₃)₂、

Each one of which isR₃₁Independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH₂、-N(CH₃)₂、-CN、-C(＝O)CH₃、-C(＝O)OCH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃) or-S (═ O)₂N(CH₃)₂Substituted or unsubstituted.

47. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-46, wherein:

each R₃₁Independently at each occurrence is selected from-Cl, -CH₃、-CH₂CH₃、-CH(CH₃)₂、-CN、-OCH₂CH₂NH₂、-SO₂CH₃、-PO(CH₃)₂、

48. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-47, wherein:

each one of which isR₃₁Independently at each occurrence is selected from-Cl, -CH ₃、-CH₂CH₃、-CH(CH₃)₂、-CN、-OCH₂CH₂NH₂、-8O₂CH₃、-PO(CH₃)₂、

49. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-48, wherein:

each R₃₁Independently at each occurrence is selected from-CH₃、-CH(CH₃)₂Or

50. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-43, wherein:

each R₃₁Independently at each occurrence, is selected from halogen, -C_1-6Alkyl, -CN, -OH, -O-C_1-6Alkyl, -NH₂、-NH(C_1-6Alkyl), -N (C)_1-6Alkyl radical)₂or-C_3-6A carbocyclic group.

51. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-51, wherein:

each R₃₁Independently at each occurrence is selected from-F, -Cl,-Br、-C_1-3Alkyl, -CN, -OH, -O-C_1-3Alkyl, -NH₂、-NH(C_1-3Alkyl), -N (C) _1-3Alkyl radical)₂or-C_3-6A carbocyclic group.

52. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 50 or 51, wherein:

each R₃₁Independently at each occurrence is selected from the group consisting of-F, -Cl, methyl, ethyl, propyl, isopropyl, -CN, -OH, methoxy, ethoxy, propoxy, isopropoxy, -NH₂、-NHCH₃、-NHCH₂CH₃、-NH(CH₂CH₂CH₃)、-NH(CH(CH₃)₂)、-N(CH₃)₂、-N(CH₂CH₃)₂、-N(CH₃)(CH₂CH₃) 3-membered, 4-membered, 5-membered or 6-membered carbocyclyl.

53. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 50-52, wherein:

each R₃₁Independently at each occurrence is selected from methyl or isopropyl.

54. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-53, wherein:

R₃Selected from:

55. a compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-53, wherein:

each R₃Independently at each occurrence is selected from:

56. a compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-55, wherein:

R₃is selected from

57. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-56, wherein:

L₄selected from the group consisting of absence, (CR)₅R₆)_mOr NR₅；

L₄m in (1) is selected from 1, 2 or 3.

58. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-57, wherein:

L₄Selected from absent or NH.

59. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-56, wherein:

L₄independently selected from absent, O or NH or N (C)_1-6Alkyl groups).

60. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 58 or 59, wherein:

L₄independently selected from absent, O, NH, N (CH)₃)、N(CH₂CH₃) Or N (CH)₂CH₂CH₃)。

61. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 58-60, wherein:

L₄independently selected from absent or NH.

62. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 58-61, wherein:

L₄Independently selected from absent.

63. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-62, wherein:

R₄is selected from

Each one of which is

64. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-63, wherein:

R₄is selected from

65. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-64, wherein:

each G₁And G₂Independently at each occurrence is selected from N or CR ₅；

66. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-65, wherein:

each G₁Independently at each occurrence, selected from N or CH, and each G₂Independently at each occurrence is selected from N or CH.

67. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-66, wherein:

each n1, n2, n3, n4, n5 is independently selected at each occurrence from 0, 1, 2, or 3, provided that n1 and n2 are not simultaneously 0 and n3 and n4 are not simultaneously 0.

68. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-67, wherein:

n1 is selected from 1, 2 or 3;

n2 is selected from 1, 2 or 3.

69. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-68, wherein:

n1 is selected from 1 or 2;

n2 is selected from 1 or 2.

70. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-69, wherein:

R₄is selected from

Each one of which is

71. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-70, wherein:

R₄is selected from

Said

72. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-71, wherein:

R₄is selected from

Said

73. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-72, wherein:

each R₄₁Independently at each occurrence is selected from

74. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to claims 1-73, wherein: each R₄₁Independently at each occurrence is selected from

75. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-74, wherein:

When in use

Is that

When R is_4a、R_4bOr R_4cIndependently at each occurrence, is selected from hydrogen, -F, -Cl, -Br, -C_1-3Alkyl, -C_1-3Alkylene- (halogen)_1-3Hetero atom C_2-3Alkyl, -CN, -OR₈、-C_1-3Alkylene- (OR)₈)_1-3、-NR₈R₉、-C_1-3alkylene-NR₈R₉、-NR₈-C_1-6alkylene-OR₈、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-C_1-3alkylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈、-C_1-3alkylene-NR₈C(＝O)R₈、-C_1-3alkylene-O-C_1-6Aryl, -S (═ O)₂NR₈R₉、-C_3-6Carbocyclyl, 3-6 membered heterocyclyl, -C_1-3Alkylene- (3-6 membered heterocyclyl), each R_4a、R_4bOr R_4cIndependently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, -Br, -C_1-3Alkyl, -C_1-3Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Is gotSubstituted or unsubstituted; or R_4bAnd R_4cTogether with the carbon atoms to which they are both attached form C_3-6A carbocyclic ring or a 3-6 membered heterocyclic ring; or R_4aAnd R_4cTogether with the carbon atoms to which they are respectively attached form C_3-6A carbocyclic ring or a 3-6 membered heterocyclic ring; each heterocycle contains at each occurrence 1, 2 or 3 substituents selected from N, O, S or S (═ O)₂Each carbocyclic or heterocyclic ring being optionally substituted by 1, 2, 3, 4, 5 or 6 heteroatoms selected from-F, -Cl, -Br, -C_1-3Alkyl, -C_1-3Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

when in use

Is that

When each R is_4aIs absent, and R_4bAnd R_4cOne of which is absent, R_4bAnd R_4cOne of the others is selected from hydrogen, -F, -Cl, -Br, oxo, -C_1-3Alkyl, -C _1-3Alkylene- (halogen)_1-3Hetero atom C_1-3Alkyl, -CN, -OR₈、-C_1-3Alkylene- (OR)₈)_1-3、-NR₈R₉、-C_1-3alkylene-NR₈R₉、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-C_1-3alkylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈、-C_1-3alkylene-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉or-C_3-6A carbocyclic group; each R_4bOr R4C is independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, -Br, -C_1-3Alkyl and substituted benzeneC_1-3Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

each R_4dIndependently at each occurrence is selected from-F, -Cl or-Br.

76. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-75, wherein:

when in use

Is selected from

When R is_4a、R_4bOr R_4cIndependently at each occurrence, is selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -methylene- (halogen)_1-3-ethylene- (halogen)_1-3-propylene- (halogen)_1-3Hetero-ethyl, hetero-propyl, -CN, -OR₈-methylene- (OR)₈)_1-3-ethylene- (OR)₈)_1-3-propylene- (OR)₈)_1-3、-NR₈R₉-methylene-NR₈R₉-ethylene-NR₈R₉-propylene-NR₈R₉、-NR₈-methylene-OR₈、-NR₈-ethylene-OR₈、-NR₈-propylene-OR ₈、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉-methylene-C (═ O) NR₈R₉-ethylene-C (═ O) NR₈R₉-propylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈-methylene-NR₈C(＝O)R₈-ethylene-NR₈C(＝O)R₈-propylene-NR₈C(＝O)R₈-methylene-O-phenyl, -ethylene-O-phenyl, -propylene-O-phenyl, -S (═ O)₂NR₈R₉3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, -methylene- (3-6 heterocyclyl), -ethylene- (3-6 heterocyclyl) or-propylene- (3-6 heterocyclyl); each R_4a、R_4bOr R_4cIndependently optionally substituted with 1, 2, 3, 4, 5 OR 6 substituents selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted; or R_4bAnd R_4cTaken together with the carbon atoms to which they are both attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring; or R_4aAnd R_4cTogether with the carbon atom to which they are each attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring; each heterocycle or heterocyclyl contains at each occurrence 1 or 2 substituents selected from N, O or S (═ O) ₂And each carbocyclic, heterocyclic OR heterocyclic group is optionally substituted with 1, 2, 3, 4, 5 OR 6 heteroatoms selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyl, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted with one substituent;

when in use

Is selected from

When each R is_4aIs absent, and R_4bAnd R_4cOne of which is absent, R_4bAnd R_4cIs selected from hydrogen, -F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -methylene- (halogen)_1-3-ethylene- (halogen)_1-3-propylene- (halogen)_1-3Hetero-ethyl, hetero-propyl, -CN, -OR₈-methylene- (OR)₈)_1-3-ethylene- (OR)₈)_1-3-propylene- (OR)₈)_1-3、-NR₈R₉-methylene-NR₈R₉-ethylene-NR₈R₉-propylene-NR₈R₉、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉-methylene-C (═ O) NR₈R₉-ethylene-C (═ O) NR₈R₉-propylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈-methylene-NR₈C(＝O)R₈-ethylene-NR₈C(＝O)R₈-propylene-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉3-, 4-, 5-or 6-membered carbocyclyl; each R_4bOr R_4cIndependently optionally substituted with 1, 2, 3, 4, 5 OR 6 substituents selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

each R_4dIndependently at each occurrence is selected from-Cl or-Br.

77. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-76, wherein:

when in use

Is that

Each R_4a、R_4bOr R_4cIndependently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH₂、-NHCH₃、-N(CH₃)₂、-CN、-C(＝O)CH₃、-C(＝O)OCH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃) or-S (═ O)₂N(CH₃)₂Substituted or unsubstituted; or R_4bAnd R_4cTogether with the carbon atom to which they are both attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring; or R_4aAnd R_4cTogether with the carbon atom to which they are each attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring; each heterocycle or heterocyclyl contains at each occurrence 1 or 2 substituents selected from N, O or S (═ O) ₂And each carbocyclic, heterocyclic or heterocyclic group is optionally substituted with 1, 2, 3, 4, 5 or 6 heteroatoms selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH₂、-NHCH₃、-N(CH₃)₂、-CN、-C(＝O)CH₃、-C(＝O)OCH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃) or-S (═ O)₂N(CH₃)₂Substituted with the substituent(s); or

When in use

Is that

each R_4dIndependently at each occurrence is selected from-Br.

78. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-77, wherein:

R_4a、R_4bOr R_4cIndependently at each occurrence, is selected from hydrogen, -F, -Cl, -CH₃、-CH₂CH₃、-CF₃、-CH₂CHF₂、-CH₂CH₂OCH₃、-CN、-CH₂OH、-N(CH₃)₂、-CH₂N(CH₃)₂、-CH₂NHCH₃、-CH₂CH₂NH₂、-NHCH₂CH₂OH、-COOH、-NHCOCH₃、

Each R_4dIndependently at each occurrence is selected from-Br.

79. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-73, wherein:

R₄₁is selected from

80. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 79, wherein:

R_4a、R_4b、R_4cor R_4eIndependently selected from hydrogen, -F, -Cl, -Br, -C_1-3Alkyl or-C_1-3alkylene-N (C)_1-3Alkyl radical)₂。

81. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 79 or 80, wherein:

R_4a、R_4b、R_4cOr R_4eIndependently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH₂-N(CH₃)₂、-CH₂-N(CH₂CH₃)₂or-CH₂-N(CH₃)(CH₂CH₃)。

82. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 79-81, wherein:

R_4a、R_4b、R_4cor R_4eIndependently selected from hydrogen, -F, methyl or-CH₂-N(CH₃)₂。

83. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 79-82, wherein:

R_4aselected from hydrogen or-F;

R_4bis hydrogen;

R_4cselected from hydrogen or-CH₂-N(CH₃)₂；

R_4eIs methyl.

84. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-83, wherein:

each R₄₁Independently at each occurrence is selected from

85. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-84, wherein:

Each R₄₁Independently at each occurrence is selected from:

86. a compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-85, wherein:

each R₄₁Independently at each occurrence is selected from

87. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-85, wherein:

R₄is independently selected from

Each one of which is

88. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-87, wherein:

each R₄₂Selected from-F, -Cl, -Br, oxo, -C_1-3Alkyl, -C_1-3Alkylene- (halogen) _1-3Hetero atom C_2-3Alkyl, -C_2-5Alkenyl, -C_2-5Alkynyl, -OR₈、-C_1-3Alkylene- (OR)₈)_1-3、-NR₈R₉、-C_1-3alkylene-NR₈R₉、-CN、-C_1-3alkylene-CN, -C (═ O) R₈、-C_1-3alkylene-C (═ O) R₈、-C(＝O)OR₈、-C_1-3alkylene-C (═ O) OR₈、-OC(＝O)R₈、-C_1-3alkylene-OC (═ O) R₈、-C(＝O)NR₈R₉、-C_1-3alkylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈、-C_1-3alkylene-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉、-C_1-3alkylene-S (═ O)₂NR₈R₉、-SO₂R₈、-C_1-3alkylene-SO₂R₈、-NR₈SO₂R₈or-C_1-3alkylene-NR₈SO₂R₈(ii) a Each R₄₂Independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, -Br,-C_1-3Alkyl, -C_1-3Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted; or

89. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-88, wherein:

Each R₄₂Selected from-F, -Cl, -Br, oxo, -C_1-3Alkyl, -C_1-3Alkylene- (halogen)_1-3Hetero atom C_2-3Alkyl, -C_2-5Alkenyl, -C_2-5Alkynyl, -OR₈、-C_1-3Alkylene- (OR)₈)_1-3、-NR₈R₉、-C_1-3alkylene-NR₈R₉、-CN、-C_1-3alkylene-CN, -C (═ O) R₈、-C_1-3alkylene-C (═ O) R₈、-C(＝O)OR₈、-C_1-3alkylene-C (═ O)OR₈、-OC(＝O)R₈、-C_1-3alkylene-OC (═ O) R₈、-C(＝O)NR₈R₉、-C_1-3alkylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈、-C_1-3alkylene-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉、-C_1-3alkylene-S (═ O)₂NR₈R₉、-SO₂R₈、-C_1-3alkylene-SO₂R₈、-NR₈SO₂R₈or-C_1-3alkylene-NR₈SO₂R₈(ii) a Each R₄₂Independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, -Br, -C_1-3Alkyl, -C_1-3Alkoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted; or

90. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-89, wherein:

Each R₄₂Selected from-F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -methylene- (halogen)_1-3-ethylene- (halogen)_1-3-propylene- (halogen)_1-3Heteroethyl, heteropropyl, ethenyl, propenyl, butenyl, pentenyl, ethynyl, propynyl, butynyl, pentynyl, -OR₈-methylene- (OR)₈)_1-3-ethylene- (OR)₈)_1-3-propylene- (OR)₈)_1-3、-NR₈R₉-methylene-NR₈R₉-ethylene-NR₈R₉-propylene-NR₈R₉-CN, -methylene-CN, -ethylene-CN, -propylene-CN, -C (═ O) R₈-methylene-C (═ O) R₈-ethylene-C (═ O) R₈-propylene-C (═ O) R₈、-C(＝O)OR₈-methylene-C (═ O) OR₈-ethylene-C (═ O) OR₈-propylene-C (═ O) OR₈、-OC(＝O)R₈-methylene-OC (═ O) R₈-ethylene-OC (═ O) R₈-propylene-OC (═ O) R₈、-C(＝O)NR₈R₉-methylene-C (═ O) NR₈R₉-ethylene-C (═ O) NR₈R₉-propylene-C (═ O) NR₈R₉、-NR₈C(＝O)R₈-methylene-NR₈C(＝O)R₈-ethylene-NR₈C(＝O)R₈-propylene-NR₈C(＝O)R₈、-S(＝O)₂NR₈R₉-methylene-S (═ O)₂NR₈R₉-ethylene-S (═ O)₂NR₈R₉-propylene-S (═ O)₂NR₈R₉、-SO₂CH₃-methylene-SO₂CH₃-ethylene-SO₂CH₃-propylene-SO₂CH₃、-NHSO₂CH₃、-N(CH₃)SO₂CH₃-methylene-NHSO₂CH₃-ethylene-NHSO₂CH₃or-propylene-NHSO₂CH₃(ii) a Each R₄₂Independently optionally substituted with 1, 2, 3, 4, 5 OR 6 substituents selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR ₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted; or

Two R₄₂Together with the atoms to which they are commonly OR separately attached form a 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 3-membered heterocyclic ring, 4-membered heterocyclic ring, 5-membered heterocyclic ring, OR 6-membered heterocyclic ring, each heterocyclic ring independently containing 1 OR 2 heteroatoms selected from N OR O, each carbocyclic OR heterocyclic ring optionally substituted with 1, 2, 3, 4, 5, OR 6 heteroatoms selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR₈、-NR₈R₉、-CN、-C(＝O)R₈、-C(＝O)OR₈、-OC(＝O)R₈、-C(＝O)NR₈R₉、-NR₈C(＝O)R₈or-S (═ O)₂NR₈R₉Substituted or unsubstituted;

91. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-90, wherein:

each R4₂Selected from-F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -CH₂F、-CH₂Cl、-CHF₂、-CF₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₂F、-CH₂CH₂CHF₂、-CH₂CH₂CF₃、-CH₂OCH₃、-CH₂CH₂OCH₃、-CH₂CH₂CH₂OCH₃Ethenyl, propenyl, butenyl, pentenyl, ethynyl, propynyl, butynyl, pentynyl, -OH, -OCH ₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)₂、-CH₂OH、-CH₂CH₂OH、-CH₂CH₂CH₂OH、-C(OH)(CH₃)₂、-NH₂、-NHCH₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-N(CH₃)₂、-N(CH₃)CH₂CH₃、-N(CH₃)CH₂CH₂CH₃、-N(CH₃)CH(CH₃)₂、-CH₂NH₂、-CH₂CH₂NH₂、-CH₂CH₂CH₂NH₂、-CH₂N(CH₃)₂、-CH₂CH₂N(CH₃)₂、-CH₂CH₂CH₂N(CH₃)₂、-CN、-CH₂CN、-CH₂CH₂CN、-CH₂CH₂CN、-C(＝O)CH₃、-CH₂C(＝O)CH₃、-CH₂CH₂C(＝O)CH₃、-CH₂CH₂CH₂C(＝O)CH₃、-COOH、-CH₂COOH、-CH₂CH₂COOH、-C(＝O)OCH₃、-CH₂C(＝O)OCH₃、-CH₂CH₂C(＝O)OCH₃、-CH₂CH₂CH₂C(＝O)OCH₃、-C(＝O)OCH₂CH₃、-C(＝O)OCH₂CH₂CH₃、-OC(＝O)CH₃、-CH₂OC(＝O)CH₃、-CH₂CH₂OC(＝O)CH₃、-CH₂CH₂CH₂OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-CH₂C(＝O)N(CH₃)₂、-CH₂CH₂C(＝O)N(CH₃)₂、-CH₂CH₂CH₂C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-CH₂NHC(＝O)CH₃、-CH₂CH₂NHC(＝O)CH₃、-CH₂CH₂CH₂NHC(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃)、-S(＝O)₂N(CH₃)₂、-CH₂S(＝O)₂N(CH₃)₂、-CH₂CH₂S(＝O)₂N(CH₃)₂、-CH₂CH₂CH₂S(＝O)₂N(CH₃)₂、-8O₂CH₃、-CH₂SO₂CH₃、-CH₂CH₂SO₂CH₃、-CH₂CH₂CH₂SO₂CH₃、-NHSO₂CH₃、-CH₂NHSO₂CH₃、-CH₂CH₂NHSO₂CH₃or-CH₂CH₂CH₂NH8O₂CH₃(ii) a Each R₄₂Independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH₂、-NHCH₃、-N(CH₃)₂、-CN、-C(＝O)CH₃、-C(＝O)OCH₃、-OC(＝O)CH₃、-C(＝O)NH₂、-C(＝O)NH(CH₃)、-C(＝O)N(CH₃)₂、-NHC(＝O)CH₃、-N(CH₃)C(＝O)CH₃、-S(＝O)₂NH₂、-S(＝O)₂NH(CH₃) or-S (═ O)₂N(CH₃)₂Substituted or unsubstituted; or

92. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-91, wherein:

each R₄₂Is selected from-F, ═ O and-CH₃、-CH₂CH₃、-CH(CH₃)₂、-CHF₂、-CH₂CI、-CF₃、-CH₂CF₃、

Or

Two R₄₂Together with their co-or separately-bound atoms

93. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-87, wherein:

Each R₄₂Independently at each occurrence is selected from-C_1-6An alkyl group; -C_1-6alkylene-CN or by halogen, -NH₂-CN or-OH substituted-C_1-6An alkyl group.

94. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 93, wherein:

each R₄₂Independently at each occurrence is selected from-C_1-3An alkyl group; -C_1-3alkylene-CN or-C substituted by-F or-Cl_1-3An alkyl group.

95. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claim 94, wherein:

each R₄₂Independently at each occurrence is selected from methyl; an ethyl group; propyl; isopropyl group; -methylene-CN; -ethylene-CN; -propylene-CN; methyl substituted by-F or-C1; ethyl substituted with-F or-C1; propyl substituted with-F or-C1; or isopropyl substituted with-F or-Cl.

96. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 94 or 95, wherein:

Each R₄₂Independently at each occurrence is selected from methyl; an ethyl group; -methylene-CN or methyl substituted by-F.

97. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 94-96, wherein:

each R₄₂Independently at each occurrence is selected from-CH₃、-CH₂CH₃、-CH₂CN、-CHF₂or-CF₃。

98. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-97, wherein:

R₄selected from:

99. a compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-98, wherein:

R₄selected from:

100. a compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-99, wherein:

R₄Selected from:

101. a compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-99, wherein:

R₄-L₄-is selected from:

102. a compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1-101, which is selected from:

103. an intermediate of formula (II), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:

wherein the content of the first and second substances,

R₄' is selected from

Said

PG is a protecting group of N atom; preferably PG is

104. An intermediate of formula (II), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to claim 103, wherein the intermediate is selected from the group consisting of:

105. An intermediate, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, wherein the intermediate is selected from the group consisting of:

106. a process for preparing a compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof according to any one of claims 1 to 102, which comprises step a or step B as follows:

step A:

and B:

in step B, R is₁' selected from the group consisting of 1R₁₁2R₁₁Or 3R₁₁substituted-C_6-10Aryl or by 1R₁₁2R₁₁Or 3R ₁₁Substituted 5-10 membered heteroaryl; preferably, R is₁' is 2R₁₁Substituted phenyl; said R₄' is a beltR with a protecting group for N atom₄Such as N-Boc piperazinyl; in step B1, the intermediate B0 is prepared by reacting R₁' halogenation to obtain intermediate B1, preferably the halogenating agent is NCS or NBS; in step B2, the intermediate B1 is prepared by reacting R₄' deprotection and subsequent acylation of the N atom affords said compound of formula (I).

107. The method of claim 106, wherein R in step A or step B₁' is selected from:

in step B, -L₄-R₄' is selected from:

108. a pharmaceutical composition comprising at least one compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof, as claimed in any one of claims 1 to 102, and at least one pharmaceutically acceptable excipient.

109. The pharmaceutical composition of claim 108, wherein the weight ratio of said compound to said excipient ranges from about 0.0001 to about 10.

110. The pharmaceutical composition of claim 108 or 109, wherein the weight ratio of said compound to said excipient ranges from about 0.01 to about 0.8.

111. The pharmaceutical composition of any one of claims 108-110, wherein the weight ratio of said compound to said excipient ranges from about 0.02 to about 0.2.

112. The pharmaceutical composition of any one of claims 108-111, wherein the weight ratio of said compound to said excipient ranges from about 0.05 to about 0.15.

113. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof of any one of claims 1-102; or any one of claims 108-112 for use in the preparation of a medicament for the treatment of a disease or disorder associated with a KRAS mutein.

114. The use of claim 113, wherein the disease or disorder associated with KRAS mutein is a disease or disorder associated with KRAS G12C mutein.

115. The use of claim 113 or 114, wherein the KRAS mutein-related disease or disorder is KRAS G12C mutein-related cancer.

116. The use according to claim 115, wherein said cancer is selected from the group consisting of hematological cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer and lung cancer.

117. The use according to claim 116, wherein the hematological cancer is selected from acute myelogenous leukemia or acute lymphatic leukemia; the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

118. A method of treating a patient having a disease or disorder associated with KRAS mutein comprising administering to said patient a therapeutically effective amount of at least one compound of formula (I) as described in any one of claims 1-102, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof; or the pharmaceutical composition of any one of claims 108-112.

119. The method of claim 118, wherein the disease or disorder associated with KRAS mutein is a disease or disorder associated with KRAS G12C mutein.

120. The method of claim 118 or 119, wherein the disease or disorder associated with KRAS mutein is a cancer associated with KRAS G12C.

121. The method of claim 119, wherein said cancer is selected from the group consisting of hematological cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, and lung cancer.

122. The method of claim 121, wherein said hematological cancer is selected from acute myelogenous leukemia or acute lymphocytic leukemia; the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

123. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, as claimed in any one of claims 1 to 102, for use as a medicament; or the pharmaceutical composition of any one of claims 108-112.