A fused ring compound, a pharmaceutical composition thereof, an intermediate, a preparation method and application thereof

Abstract

The application discloses a fused ring compound and a pharmaceutical composition, an intermediate, a preparation method and application thereof. Specifically relates to a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof. The fused ring compound has good KRAS mutant inhibitory activity.

Description

[0001] This application claims priority to Chinese patent application 2025104181413, filed on 2025 / 04 / 03. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to a fused-ring compound, its pharmaceutical composition, intermediates, preparation methods, and applications. Background Technology

[0003] The RAS gene family mainly includes three genes: KRAS, NRAS, and HRAS. RAS genes are proto-oncogenes; once activated, they become oncogenes with oncogenic activity. RAS encodes a group of monomeric globular proteins (21 kDa) composed of 188-189 amino acids, known as p21 proteins or RAS proteins. RAS proteins are GDP / GTP binding proteins, cycling between an inactive GDP-binding state and an active GTP-binding state, acting as a "molecular switch." The GDP / GTP cycle of RAS is activated by guanine nucleotide exchange factors (e.g., SOS or RASGRP) and inactivated by GTPase initiation proteins (GAPs, such as p120GAP or neurofibromatosis protein). The interaction between GAPs and RAS can greatly accelerate the conversion of GTP to GDP, while shutting down the switch inactivates RAS. Any mutation affecting the interaction between RAS and GAPs or the ability to convert GTP back to GDP will result in persistent RAS activation, thus generating a prolongation signaling effect on the cell. Since RAS can regulate cell proliferation, differentiation and senescence through a variety of important signaling pathways, prolonged activation of downstream signaling pathways (such as PI3K-AKT-mTOR, RAF-MEK-ERK, RALGDS-RAL) can ultimately lead to cancer.

[0004] The RAS gene can be kept in a persistently activated state through point mutations, overexpression, gene insertion, and translocation. Point mutations are the most common, present in approximately 30% of human malignancies. The most frequent type of point mutation is KRAS, with common mutation sites at codons 12, 13, and 61, with codon 12 mutations being the most prevalent. These activating mutations increase the amount of GTP-bound RAS protein by inactivating endogenous GTPase activity and inducing resistance to GTPase activation proteins.

[0005] Aberrant expression of KRAS accounts for 20% of all malignancies, with G12C mutation being one of the most common mutations, found in approximately 13% of malignancies. Specifically, the incidence of G12C mutation is approximately 11% in non-small cell lung cancer, and approximately 1%-4% in colorectal cancer, pancreatic cancer, and endometrial cancer.

[0006] A growing body of research has demonstrated the crucial role of KRAS mutants in malignant tumors, making KRAS an important target for the pharmaceutical industry. Developing novel KRAS mutant inhibitors, including KRAS G12C, is of significant clinical importance. Summary of the Invention

[0007] This invention provides a novel fused-ring compound and its pharmaceutical composition, intermediate, preparation method and application, which has good KRAS mutant inhibitory activity.

[0008] This invention discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0009]

[0010] in,

[0011] X is CH or N;

[0012] Y is C(CN) or N;

[0013] R1, R2, and R3 are each independently hydrogen, deuterium, halogen, cyano, or C. 1-6 Alkyl, C 1-6 Alkoxy or C substituted with one or more halogens 1-6 alkyl;

[0014] R4 represents hydrogen, hydroxyl group, and C. 1-6 Alkyl, C 1-6 alkoxy group; wherein, the C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally surrounded by one or more R groups. 4-a replace;

[0015] Each R 4-a Each is independently a deuterium, halogen, hydroxyl group, or C. 1-6 Alkyl or -N(R) a )2;

[0016] Each R5 is independently for halogen, C 1-6 Alkyl, C 1-6 alkoxy or -N(R) a )2;

[0017] m is 0, 1, or 2;

[0018] R6 is -CH=N2, C 2-6 alkenyl or C 2-6 alkynyl group; the C 2-6 alkenyl and C 2-6 Each alkynyl group is independently and optionally surrounded by one or more R groups.6-a replace;

[0019] Each R 6-a Each is independently a deuterium, halogen, cyano, or C group. 1-6 Alkyl, C 1-6 Alkyl group, -ON(R) a 2. C 3-6 cycloalkyl, C 5-10 Aryl, 5-10-membered heteroaryl, or 3-10-membered heterocycloalkyl; wherein, the C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally surrounded by one or more elements selected from halogens, hydroxyl groups, and C. 1-6 Alkoxy, -N(R) a 2. C 5-10 Aryl, C 3-6 Substitution of cycloalkyl, 5-10-membered heteroaryl and 3-10-membered heterocycloalkyl groups;

[0020] Each R7 is independently deuterium, halogen, hydroxyl group, oxo group (=O), C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or C 1-6 Alkylene; wherein, the C 1-6 Alkyl groups are optionally surrounded by one or more elements selected from halogens, hydroxyl groups, and C. 1-6 Alkoxy and -N(R) a Substituents of )2; the C 1-6 Alkoxy and C 1-6 Each alkylene group is independently and optionally substituted with one or more deuterium or halogen substituents;

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

[0022] R8 is hydrogen, C 1-6 Alkyl, C 1-6 alkoxy or -N(R) a )2;

[0023] Each R9 group is independently composed of halogen, cyano, hydroxyl, amino, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C atoms substituted with one or more halogens 1-6 Alkoxy;

[0024] q is 0, 1, or 2;

[0025] Each R a Each is independently hydrogen, cyano, C 1-6Alkyl groups or C groups substituted with one or more deuterium groups 1-6 alkyl.

[0026] In some embodiments, certain groups in the compound of formula (I) or its pharmaceutically acceptable salt are defined as follows, and the definitions of groups not mentioned are as described in any embodiment of the invention (hereinafter referred to as "in some embodiments"):

[0027] In some implementations, X is CH.

[0028] In some implementations, Y is C(CN).

[0029] In some implementations, R1 is a halogen, such as F.

[0030] In some implementations, R2 is a halogen or a C substituted with one or more halogens. 1-6 Alkyl groups, such as F, Cl, or -CF3.

[0031] In some implementations, R3 is hydrogen or a halogen, such as H or F.

[0032] In some implementations, R4 is hydrogen or C 1-6 Alkyl; the C 1-6 Alkyl groups are optionally surrounded by one or more R 4-a replace.

[0033] In some implementation schemes, R 4-a It is deuterium.

[0034] In some implementations, R4 is H, -CH3, or -CD3.

[0035] In some implementations, R5 is a halogen or C 1-6 Alkyl groups, such as F or -CH3.

[0036] In some implementations, m is 0 or 1.

[0037] In some implementations, R6 is -CH=N2 or C 2-6 alkenyl; the C 2-6 Alkenyl groups are optionally separated by one or more R groups 6-a replace.

[0038] In some implementations, each R 6-a Each is independently a deuterium, halogen, cyano, or C group. 1-6 Alkyl, C 1-6 Alkyl group, -ON(R) a 2. C 3-6 cycloalkyl, C 5-10 Aryl, 5-10-membered heteroaryl, or 3-10-membered heterocycloalkyl; wherein, the C1-6 Alkyl groups are optionally surrounded by one or more elements selected from halogens, hydroxyl groups, and C. 1-6 Alkoxy, -N(R) a 2. C 5-10 Aryl, C 3-6 Substitution of cycloalkyl, 5-10-membered heteroaryl and 3-10-membered heterocycloalkyl groups; the C 1-6 The alkoxy group is optionally substituted with one or more halogens; each R a Each is independently hydrogen, cyano, C 1-6 Alkyl groups or C groups substituted with one or more deuterium groups 1-6 alkyl.

[0039] In some implementations, R6 is -CH=N2 or Among them, R 6-1 It is hydrogen, deuterium, or halogen; R 6-2 and R 6-3 Each is independently hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkyl group, -ON(R) a 2. C 3-6 cycloalkyl, C 5-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl; wherein, the C 1-6 Alkyl and C 1-6 Each alkoxy group is optionally surrounded by one or more elements selected from halogens, hydroxyl groups, and C. 1-6 Alkoxy, -N(R) a 2. C 5-10 Aryl, C 3-6 Substitution of cycloalkyl, 5-10-membered heteroaryl and 3-10-membered heterocycloalkyl groups; each R a Each is independently hydrogen, cyano, and C. 1-6 Alkyl groups, or one or more deuterated C groups 1-6 Alkyl; L is a single bond or C 1-4 Alkylene.

[0040] In some implementations, R6 is -CH=N2 or Among them, R 6-1 It is hydrogen, deuterium, or halogen; R 6-2 and R 6-3 Each is independently hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkyl group, -ON(R) a 2. C 3-6 cycloalkyl, C 5-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl; wherein, the C 1-6 Alkyl groups are optionally surrounded by one or more elements selected from halogens, hydroxyl groups, and C.1-6 Alkoxy, -N(R) a 2. C 5-10 Aryl, C 3-6 Substitution of cycloalkyl, 5-10-membered heteroaryl and 3-10-membered heterocycloalkyl groups; the C 1-6 The alkoxy group is optionally substituted with one or more halogens; each R a Each is independently hydrogen, cyano, and C. 1-6 Alkyl groups, or one or more deuterated C groups 1-6 Alkyl; L is a single bond or C 1-4 Alkylene.

[0041] In some implementations, L is a single bond or C. 1-4 Alkylene, for example, a single bond or -CH2-.

[0042] In some implementations, R6 is Among them, R 6-1 R 6-2 R 6-3 Each can be independently hydrogen, deuterium, or halogen, for example, R6 is... or .

[0043] In some implementations, R6 is Where L is C 1-4 Alkylene; R 6-1 R 6-2 Each can be independently hydrogen, deuterium, or halogen, R 6-3 -ON(R) a )2, each R a Each is independently hydrogen, cyano, and C. 1-6 Alkyl groups, or one or more deuterated C groups 1-6 Alkyl groups, such as R6, are -CH=CH-CH2-O-NH-CH3.

[0044] In some implementations, R7 is deuterium, halogen, hydroxyl, or C. 1-6 Alkyl, C 1-6 Alkyl groups; for example, F, Cl, -OH, -CH3 or -OCH3.

[0045] In some implementations, n is 0 or 1, for example, n is 1.

[0046] In some implementations, R8 is -N(R a )2; where each R a Each is independently hydrogen, cyano, C 1-6 Alkyl groups, or one or more deuterated C groups 1-6Alkyl; for example, R8 is -NHCH3, -N(CH3)2, -NHCH(CH3)2, -N(CH3)CH(CH3)2 or -N(CN)CH3.

[0047] In some implementations, R9 is a halogen, cyano, hydroxyl, or C group. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C atoms substituted with one or more halogens 1-6 Alkyl groups; for example, F, Cl, -CN, -OH, -CH3, -OCH3, -CF3, -CHF2, -OCF3, -OCHF2, or .

[0048] In some implementations, q is 0 or 1.

[0049] In some implementation schemes, for , or Preferred , , , , , , , , , , or .

[0050] In some implementation schemes, for .

[0051] In some implementation schemes, for Preferred , , , , , , , , or More preferably , , , , , , , , , or .

[0052] In some implementation schemes, for , , or .

[0053] In some implementation schemes, for The 'a' bond indicates resistance to rotation, which can be represented as: and .

[0054] In some implementation schemes, R1, R2, R3, R 4-a R5, R 6-a R 6-1 R 6-2 R 6-3 In R7 and R9, the halogen is independently F, Cl, Br or I, for example F or Cl.

[0055] In some implementation schemes, R1, R2, R3, R4, R5, R 6-a R 6-2 R 6-3 R7, R8, R9, R a In the middle, the "C" mentioned 1-6 Alkyl group, C substituted with one or more halogens 1-6 "alkyl" or "C substituted with one or more deuteriums" 1-6 The C in "alkyl" 1-6 Each alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, such as methyl.

[0056] In some implementation schemes, R1, R2, R3, R4, R 4-a R5, R 6-a R 6-2 R 6-3 In R7, R8, and R9, the "C" 1-6 "alkoxy" or "C substituted with one or more halogens" 1-6 The C in "alkoxy" 1-6 Each alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy, such as methoxy.

[0057] In some implementations, in R6, the C 2-6 The alkenyl group is vinyl, propenyl, butenyl, butadienyl, pentadienyl, or hexadienyl, for example, vinyl or propenyl.

[0058] In some implementations, in R6, the C 2-6 The alkynyl group can be ethynyl, propynyl, butynyl, or 3-methylbutynyl.

[0059] In some implementation schemes, R 6-a R 6-2 R 6-3 In R7 and R9, the C 3-6 Each cycloalkyl group is independently a monocyclic or bicyclic cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0060] In some implementation schemes, R 6-a R 6-2 R 6-3 In this context, the 3-10 membered heterocyclic alkyl group is a 3-8 membered monocyclic heterocyclic alkyl group or a 5-10 membered bicyclic heterocyclic alkyl group having one, two or three heteroatoms or heteroatom groups selected from N, NH, S and O.

[0061] In some implementation schemes, R 6-a R 6-2 R 6-3 In this context, the 5-10 member heteroaryl group is a 5-6 member monocyclic heteroaryl group or a 7-10 member bicyclic heteroaryl group having one, two, or three heteroatoms or heteroatom groups selected from N, NH, S, and O.

[0062] In some implementation schemes, R 6-a R 6-2 R 6-3 In, the C 5-10 The aryl group is either phenyl or naphthyl.

[0063] In some embodiments, in R7, the 3-6 membered heterocyclic alkyl group is a 3-6 membered heterocyclic alkyl group having one, two or three heteroatoms or heteroatom groups selected from N, NH, S and O, preferably a monocyclic alkyl group.

[0064] In some implementations, in R7, the C 1-6 The alkylene group is methylene (=CH2), ethylene (=CHCH3), n-propylene, or 2-isopropylene (=CH(CH3)2).

[0065] In some implementations, in L, the C 1-4 The alkylene group is -CH2-, -CH2CH2-, -CH(CH3)- or -CH(CH3)CH2-, for example -CH2-.

[0066] In some implementations, the number of the one or more is 1, 2, 3, 4, 5, 6, 7, 8 or 9, for example, 1, 2 or 3.

[0067] In some embodiments, the compound represented by formula (I) may be the compound represented by formula (I-1), the compound represented by formula (I-2), the compound represented by formula (I-3), the compound represented by formula (I-4), the compound represented by formula (I-5), the compound represented by formula (I-6), or the compound represented by formula (I-7).

[0068]

[0069]

[0070] Among them, X, Y, R1, R2, R3, R4, R5, R6, R 6-1 R 6-2 R 6-3 The definitions of R7, R8, R9, L, m, n and q are as described above.

[0071] In some embodiments, the compound of formula (I) has any of the following structures:

[0072] , , , , , ,

[0073] , , ,

[0074] , , ,

[0075] , , ,

[0076] , , or ;

[0077] Preferred

[0078] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Or a pharmaceutically acceptable salt.

[0079] In some embodiments, the compound of formula (I) is a transisomer of the compound of formula (I).

[0080]

[0081] The modified isomer is a compound with a short retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, from 40% to 90% for 2 minutes, and mobile phase B held at 90% for 6 minutes, with a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with the short retention time is approximately 6.096 minutes.

[0082] In some embodiments, the compound of formula (I) is a transisomer of the compound of formula (I).

[0083]

[0084] The modified isomer is a compound with a long retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a long retention time is approximately 6.191 minutes.

[0085] In some embodiments, the compound of formula (I) is a transisomer of the compound of formula (I).

[0086]

[0087] The modified isomer is a compound with a short retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, from 40% to 90% for 2 minutes, and mobile phase B held at 90% for 6 minutes, with a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with the short retention time is approximately 6.597 minutes.

[0088] In some embodiments, the compound of formula (I) is a transisomer of the compound of formula (I).

[0089]

[0090] The modified isomer is a compound with a long retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a long retention time is approximately 6.621 minutes.

[0091] In some embodiments, the compound of formula (I) is a transisomer of the compound of formula (I).

[0092]

[0093] The modified isomer is a compound with a short retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with the short retention time is approximately 6.208 minutes.

[0094] In some embodiments, the compound of formula (I) is a transisomer of the compound of formula (I).

[0095]

[0096] The modified isomer is a compound with a long retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under the above conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a long retention time is approximately 6.272 minutes.

[0097] In some embodiments, the compound of formula (I) is a transisomer of the compound of formula (I).

[0098]

[0099] The modified isomer is a compound with a short retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with the short retention time is approximately 5.355 minutes.

[0100] In some embodiments, the compound of formula (I) is a transisomer of the compound of formula (I).

[0101]

[0102] The modified isomer is a compound with a long retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a long retention time is approximately 5.358 minutes.

[0103] In some embodiments, the compound of formula (I) is a transisomer of the compound of formula (I).

[0104]

[0105] The modified isomer is a compound with a short retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with the short retention time is approximately 5.373 minutes.

[0106] In some embodiments, the compound of formula (I) is a transisomer of the compound of formula (I).

[0107]

[0108] The modified isomer is a compound with a long retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a long retention time is approximately 5.399 minutes.

[0109] In some embodiments, the compound of formula (I) is a transisomer of the compound of formula (I).

[0110]

[0111] The modified isomer is a compound with a short retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with the short retention time is approximately 6.659 minutes.

[0112] In some embodiments, the compound of formula (I) is a transisomer of the compound of formula (I).

[0113]

[0114] The modified isomer is a compound with a long retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, from 40% to 90% for 2 minutes, and mobile phase B held at 90% for 6 minutes, with a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a long retention time is approximately 6.718 minutes.

[0115] In some embodiments, the compound of formula (I) is a transisomer of the compound of formula (I).

[0116]

[0117] The modified isomer is a compound with a short retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, from 40% to 90% for 2 minutes, and mobile phase B held at 90% for 6 minutes, with a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a longer retention time is approximately 6.655 minutes.

[0118] In some embodiments, the compound of formula (I) is a transisomer of the compound of formula (I).

[0119]

[0120] The modified isomer is a compound with a long retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, from 40% to 90% for 2 minutes, and mobile phase B held at 90% for 6 minutes, with a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a long retention time is approximately 6.679 minutes.

[0121] In some embodiments, the compound of formula (I) is a transisomer of the compound of formula (I).

[0122]

[0123] The modified isomer is a compound with a short retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a longer retention time is approximately 5.966 minutes.

[0124] In some embodiments, the compound of formula (I) is a transisomer of the compound of formula (I).

[0125]

[0126] The modified isomer is a compound with a long retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a long retention time is approximately 6.158 minutes.

[0127] The present invention also provides a pharmaceutical composition comprising:

[0128] (1) The compound shown in formula (I) above, or a pharmaceutically acceptable salt thereof, and

[0129] (2) Pharmaceutically acceptable excipients.

[0130] The present invention also provides the use of the compound shown in formula (I) above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the preparation of a KRAS mutant inhibitor, preferably, the KRAS mutant inhibitor being a KRAS G12C mutant inhibitor.

[0131] The present invention also provides the use of the compound of formula (I) above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for treating and / or preventing diseases associated with KRAS mutations.

[0132] The present invention also provides a method for treating and / or preventing diseases associated with KRAS mutations, comprising administering to a patient a therapeutically or preventively effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof.

[0133] In some implementations, the disease associated with KRAS mutations is KRAS mutation-associated cancer.

[0134] In some implementations, the disease associated with the KRAS mutation is selected from lung cancer, colorectal cancer, pancreatic cancer, or endometrial cancer.

[0135] In some implementations, the KRAS mutation is selected from the KRAS G12C mutation.

[0136] The present invention also provides a method for preparing the compound shown in formula (I), which is any of the following methods:

[0137] Method 1: In a solvent, the compound shown in formula (IA) reacts with X-1 or X-2 under basic conditions to give the compound shown in formula (I).

[0138]

[0139] Method 1

[0140] Where R6 is C 2-6 alkenyl or C 2-6 alkynyl group; the C 2-6 alkenyl and C 2-6 Each of the alkynyl groups is optionally surrounded by one or more R groups. 6-a Replacement; X, Y, R1, R2, R3, R4, R5, R 6-a The definitions of R7, R8, R9, m, n, and q are as described above. In Method 1, the solvent is preferably tetrahydrofuran; the base is preferably triethylamine or N,N-diisopropylethylamine; the reaction temperature is preferably 0~35℃; and the reaction time is preferably 0.5~6 hours.

[0141] Method 2: In a solvent, the compound shown in formula (IA) and X-3 undergo a condensation reaction to yield the compound shown in formula (I).

[0142]

[0143] Method 2

[0144] Where R6 is C 2-6 alkenyl or C 2-6 alkynyl group; the C 2-6 alkenyl and C 2-6 Each of the alkynyl groups is optionally surrounded by one or more R groups. 6-a Replacement; X, Y, R1, R2, R3, R4, R5, R 6-a The definitions of R7, R8, R9, m, n, and q are as described above. In Method 2, the solvent is preferably N,N-dimethylformamide; the condensing agent is preferably HATU; the base is preferably triethylamine or N,N-diisopropylethylamine; the reaction temperature is preferably 0~35℃; and the reaction time is preferably 0.5~6 hours.

[0145] In some embodiments, in method 1 or method 2, if R6 has an amino group, the amino group may be protected with a tert-butoxycarbonyl protecting group. If the above-mentioned amino protecting group is present, a further deprotection step is required to obtain the compound shown in formula (I). The subsequent deprotection reaction is preferably carried out in a dichloromethane / trifluoroacetic acid system.

[0146] The present invention also provides a compound as shown in formula (IA),

[0147]

[0148] The definitions of X, Y, R1, R2, R3, R4, R5, R7, R8, R9, m, n, and q are as described above.

[0149] The present invention also provides any of the following compounds,

[0150] , , or .

[0151] definition

[0152] Unless otherwise stated, the terms used in this invention have the following definitions, and the definitions of terms not referred to below are as commonly understood by those skilled in the art.

[0153] In this invention, the term "pharmaceutically acceptable salt" refers to a salt prepared from a compound with a relatively non-toxic, pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When a compound of this invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. When a compound contains both relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt.

[0154] In this invention, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0155] In this invention, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having a specified number of carbon atoms. In some embodiments, the alkyl group is C64-C ... 1-6 Alkyl groups (C1, C2, C3, C4, C5, C6), for example, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl groups, etc. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl and similar alkyl groups.

[0156] In this invention, the term "alkylene" refers to the alkyl group defined above, which is a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon; including but not limited to methylene (-CH2- or =CH2), ethylene (including -CH2CH2-, -CH(CH3)-, =CHCH3), propylene (including -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2- or =CH(CH3)2), etc.

[0157] In this invention, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic cyclic hydrocarbon group, including, for example, monocyclic cycloalkyl, spirocyclic alkyl, fused cycloalkyl, and bridged cycloalkyl. For example, the term "C 3-6 "Cycloalkyl" refers to cycloalkyl groups having 3 to 6 ring carbon atoms, including monocyclic cycloalkyl, spirocyclic cycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0158] In this invention, the term "heterocyclic alkyl" refers to a stable, saturated or partially unsaturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more bridging rings, fused rings, or spirocyclic systems) non-aromatic cyclic group consisting of a carbon atom and 1, 2, 3, 4, 5 or 6 heteroatoms or groups selected from N, NH, O and S.

[0159] In this invention, the term "aryl" refers to an aromatic group consisting of carbon atoms in a conjugated hydrocarbon ring system that satisfies the 4n+2 rule, where each ring is aromatic. Examples of aryl groups include, but are not limited to, phenyl or naphthyl groups.

[0160] In this invention, the term "heteroaryl" refers to an aromatic group formed by replacing carbon atoms on at least one ring with heteroatoms selected from nitrogen, oxygen, or sulfur.

[0161] In this invention, the term "alkoxy group" refers to the -OR group. X , where R X It is an alkyl group as defined above.

[0162] In this invention, the term "amino" refers to -NH2.

[0163] In this invention, the term "oxo-group" refers to the =O group, such as the =O portion in carbonyl (-CO-), nitrosyl (-N=O), sulfinyl (-SO-), or sulfonyl (-SO2-).

[0164] In this invention, the term "cyano" refers to -CN.

[0165] In this invention, the term "hydroxyl group" refers to -OH.

[0166] In this invention, the term "optionally replaced by..." means either "replaced by..." or "not replaced".

[0167] In this invention, the "" in the structural segment This means that the structural segment is connected to the rest of the molecule through this bond. For example, It refers to cyclopropyl.

[0168] In this invention, the "-" at the end of a group indicates that the group is connected to the rest of the molecule through that site.

[0169] In this invention, unless otherwise specified, wedge-shaped solid line keys ( ) and wedge-shaped dashed key ( ) represents the absolute configuration of the center of a solid. It is represented by a straight solid line key ( ) and straight dashed key ( ) indicates the relative configuration of the center of the solid.

[0170] In this invention, the term "pharmaceuticalally acceptable excipients" refers to excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions; these are all substances contained in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0171] In this invention, the term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or induces the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0172] In this invention, the term "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.

[0173] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0174] The reagents and raw materials used in this invention are all commercially available.

[0175] The positive and progressive effects of this invention are as follows: the compounds of this invention have one or more of the following advantages:

[0176] (1) It has good KRAS mutant inhibitory activity;

[0177] (2) It has better selectivity than wild-type KRAS. Detailed Implementation

[0178] The structures of all compounds in this invention can be determined by nuclear magnetic resonance (NMR). 1 Identification by 1H NMR and / or mass spectrometry (MS).

[0179] 1 10 H NMR chemical shifts (δ) recorded in PPM (10 -6 NMR was performed using a Bruker AVANCE-400 spectrometer. Suitable solvents were deuterated chloroform (CDCl3), deuterated methanol (CD3OD), deuterated dimethyl sulfoxide (DMSO-d6), and tetramethylsilane as an internal standard (TMS).

[0180] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 HPLC / 6120 mass spectrometer with an Ultimate C18 column (3.0 × 50 mm, 3 μm) at 40 °C; or a Thermo UltiMate 3000 HPLC / MSQ PLUS mass spectrometer with an XBridge C18 column (3.0 × 50 mm, 3.5 μm) at 30 °C. Agilent gradient elution conditions: 95-5% solvent A1 and 5-95% solvent B1 (0-2.0 min), then 95% solvent B1 and 5% solvent A1 (hold for 1.1 min). Percentages represent the volume percentage of a specific solvent in the total solvent volume. Solvent A1: 0.01% aqueous solution of trifluoroacetic acid (TFA); Solvent B1: 0.01% acetonitrile solution of trifluoroacetic acid; percentages represent the volume percentage of the solute in the solution. Thermo gradient elution condition 2: 95-5% solvent A2 and 5-95% solvent B2 (0-2 minutes), then 95% solvent B2 and 5% solvent A2 (hold for 1.8 minutes), where the percentage is the volume percentage of a particular solvent in the total solvent volume. Solvent A2: 10 mM ammonium bicarbonate aqueous solution; Solvent B2: acetonitrile.

[0181] All compounds of this invention can be separated by preparative high-performance liquid chromatography or rapid column chromatography.

[0182] Preparative high-performance liquid chromatography (prep-HPLC) was performed using a Shimadzu LC-20 preparative HPLC system. The chromatographic columns were either a Welch Ultimate C18 (21.2 × 250 mm, 10 μm) or a Welch Ultimate XB-C18 (30 × 250 mm, 10 μm). Under alkaline conditions: mobile phase A: ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile. Under acidic conditions: mobile phase A: trifluoroacetic acid aqueous solution; mobile phase B: acetonitrile. Detection wavelengths: 214 nm & 254 nm; flow rate: 15.0 mL / min.

[0183] The fast column chromatography (Flash system / Cheetah™) used was an Agera Technologies MP200, with the accompanying normal phase separation column being a Flash column Silica-CS (25g, 40g, 80g, 120g or 330g) manufactured by Tianjin Bona Agera, and the elution system being ethyl acetate / petroleum ether or dichloromethane / methanol; the reversed phase separation column was a C18 reversed phase column (12g, 20g or 40g) manufactured by Changzhou Sante Technology, and the elution system being acetonitrile / trifluoroacetic acid aqueous solution or acetonitrile / ammonium bicarbonate aqueous solution.

[0184] The thin-layer silicone sheet (prep-TLC) is either Yantai Huanghai HSGF254 or Qingdao GF254 silicone sheet.

[0185] All compounds of this invention can be analyzed using ultra-high performance liquid chromatography.

[0186] The ultra-high performance liquid chromatography (UPLC) system used was Waters ACQUITY Hclass; the column was a Waters ACQUITY UPLC BEH Shield RP18 2.1*100mm, 1.7μm; mobile phase A: 5mM potassium dihydrogen phosphate buffer, adjusted to pH 2.5 with phosphoric acid; mobile phase B: acetonitrile. Gradient elution was performed from 10% to 40% mobile phase B for 5 minutes, then from 40% to 90% mobile phase B for 2 minutes, followed by holding at 90% mobile phase B for 6 minutes. Detection wavelength: 214nm; column temperature: 40℃. o C. Flow rate: 0.4 mL / min.

[0187] The microwave reaction described in this embodiment of the invention uses a Biotage® Initiator+Microwave System EU(356006) microwave reactor.

[0188] Unless otherwise specified, all reactions in the present invention can be carried out under a nitrogen or argon atmosphere; in the post-processing of all reactions in the present invention, the extracted organic phase can be dried using anhydrous sodium sulfate or anhydrous magnesium sulfate.

[0189] A hydrogen atmosphere can be achieved in the following ways: 1) Connect a hydrogen balloon with a volume of about 1L to the reaction system; 2) Continuously introduce hydrogen directly into the reaction system at atmospheric pressure; 3) Replace the hydrogen with a sealing tube and then seal it.

[0190] Synthesis of intermediates:

[0191] Synthesis of Intermediate 1: 4-Methoxy-N,N-Dimethylpyrrolidine-3-amine (trans)

[0192]

[0193] Step 1: To a methanol (5 mL) solution of tert-butyl 3-amino-4-methoxypyrrolidine-1-carboxylate (trans) (500 mg, 2.31 mmol), formaldehyde solution (37%, 0.94 g, 11.6 mmol) and acetic acid (28 mg, 0.46 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (580 mg, 9.23 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The solution was diluted with ethyl acetate, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (dichloromethane / methanol = 20 / 1) to give tert-butyl 3-(dimethylamino)-4-methoxypyrrolidine-1-carboxylate (trans) (499 mg) as a colorless oil. m / z: [M+H] + 245.2.

[0194] Step 2: A solution of tert-butyl 3-(dimethylamino)-4-methoxypyrrolidine-1-carboxylate (trans) (499 mg, 2.1 mmol) in 1,4-dioxane-hydrochloride (4 M, 5 mL) was stirred at room temperature for 3 hours, concentrated under reduced pressure, and the residue was concentrated under reduced pressure with dichloromethane solution to obtain intermediate 1 (400 g, hydrochloride) as an off-white solid. m / z: [M+H] + 145.2.

[0195] Intermediate 2: Synthesis of (3R,4R)-4-(dimethylamino)pyrrolidine-3-ol

[0196]

[0197] Using the synthetic method of intermediate 1, intermediate 2 (hydrochloride) was obtained by reacting (3R,4R)-3-amino-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester.

[0198] Intermediate 3: Synthesis of (3R,4S)-3-fluoro-4-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0199]

[0200] Step 1: Benzyl chloroformate (1 g, 5.9 mmol) was added to a solution of (3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (950 mg, 4.65 mmol) and N,N-diisopropylethylamine (1.2 g, 9.3 mmol) in dichloromethane (15 mL). The reaction mixture was stirred at 20 °C for 16 hours. The reaction was quenched with a 10% potassium carbonate aqueous solution (15 mL). The aqueous phase was extracted with dichloromethane, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (tetrahydrofuran / petroleum ether = 1 / 50–1 / 10) to give (3S,4R)-3-(((benzyloxy)carbonyl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (1.3 g) as a colorless gel. m / z: [M+Na] + 361.0.

[0201] Step 2: A mixture of (3S,4R)-3-(((benzyloxy)carbonyl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (1.24 g, 3.7 mmol), iodomethane (1.5 g, 10.6 mmol), and cesium carbonate (3.6 g, 11 mmol) in N,N-dimethylformamide (12 mL) was stirred at 30 °C for 20 hours. The reaction was quenched with water (50 mL). The aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether = 1 / 20-4 / 1) to give (3S,4R)-3-(((benzyloxy)carbonyl)(methyl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (1.24 g) as a colorless gel. m / z: [M+Na] + 375.2.

[0202] Step 3: Add palladium hydroxide / carbon (10%, 0.5 g) to a methanol (15 mL) solution of (3S,4R)-3-(((benzyloxy)carbonyl)(methyl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (1.24 g, 3.5 mmol). After purging the reaction system with nitrogen, stir at room temperature for 16 hours under a hydrogen atmosphere, filter, and concentrate the filtrate under reduced pressure to obtain intermediate 3 (660 mg) as a light brown gel. m / z: [M+H] + 219.2.

[0203] Intermediate 4: Synthesis of (3R,4S)-4-fluoro-N,N-dimethylpyrrolidine-3-amine

[0204]

[0205] Step 1: A mixture of (3R,4S)-3-amino-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (250 mg, 1.22 mmol), formaldehyde aqueous solution (37%, 325 mg, 4 mmol), palladium on carbon (10%, 50 mg), and methanol (5 mL) was purged with nitrogen and stirred at room temperature for 3 hours under a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain (3R,4S)-3-(dimethylamino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (280 mg) as a light brown gel. m / z: [M+H] + 233.2.

[0206] Step 2: A 4M, 5mL solution of (3R,4S)-3-(dimethylamino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (280 mg, 1.21 mmol) in hydrochloric acid and methanol was stirred at 60 °C for 2 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure to give intermediate 4 (150 mg, hydrochloride) as a light brown gel. m / z: [M+H] + 133.2.

[0207] Intermediate 5: Synthesis of (3S,4R)-3-fluoro-4-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0208]

[0209] Intermediate 5 was obtained by reacting (3R,4S)-3-amino-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester using the same method as intermediate 3. m / z: [M+H] + 219.2.

[0210] Intermediate 6: Synthesis of tert-butyl (3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzo[b]thiophene-2-yl)carbamate

[0211]

[0212] Step 1: Under ice bath conditions and nitrogen protection, sodium hydroxide (0.55 g, 60%) was added to a solution of 2-(2,6-dibromophenyl)acetonitrile (3.8 g, 13.8 mmol) in N,N-dimethylformamide (10 mL). The reaction system was stirred at 0 °C for 10 minutes, and then ethyl isothiocyanate (2.1 g, 16 mmol) was added. The reaction system was stirred at 95 °C for 4 hours, concentrated under reduced pressure, and then slurried with water and ethyl acetate. The mixture was filtered, and the filter cake was dried under vacuum to obtain ethyl (4-bromo-3-cyanobenzo[b]thiophene-2-yl)carbamate (1.7 g) as an orange solid.

[0213] Step 2: Sodium hydroxide (1.66 g, 41.6 mmol) was added to a solution of ethyl (4-bromo-3-cyanobenzo[b]thiophene-2-yl)carbamate (1.7 g, 5.2 mmol) in dimethyl sulfoxide (170 mL). The reaction mixture was stirred at 120 °C for 16 hours. After cooling the reaction solution to room temperature, it was poured directly into ice water, filtered, and the filter cake was dried under vacuum to obtain 0.79 g of 2-amino-4-bromobenzo[b]thiophene-3-onitrile as a yellow solid. m / z: [M+H] + 254.9.

[0214] Step 3: To a mixed solution of 2-amino-4-bromobenzo[b]thiophene-3-onitrile (0.77 g, 3.04 mmol) in N,N-dimethylformamide (10 mL) and tetrahydrofuran (2 mL), ditert-butyl dicarbonate (1 g, 4.6 mmol), 4-dimethylaminopyridine (75 mg, 0.61 mmol), and N,N-diisopropylethylamine (0.79 g, 6.1 mmol) were added sequentially. The reaction system was stirred at room temperature for 8 hours under nitrogen protection. The reaction solution was diluted with ethyl acetate and washed with water. The organic phase was separated and concentrated under reduced pressure to obtain (4-bromo-3-cyanobenzo[b]thiophene-2-yl)carbamate tert-butyl ester (700 mg) as a pale yellow solid.

[0215] Step 4: A solution of anhydrous 1,4-dioxane (46 mL) of (4-bromo-3-cyanobenzo[b]thiophene-2-yl)carbamate (2.5 g, 7.08 mmol), tris(dibenzylacetone)dipalladium (320 mg, 0.35 mmol), potassium acetate (2.08 g, 21.2 mmol), tricyclohexylphosphine (200 mg, 0.71 mmol), and pinacol diboronate (5.39 g, 21.2 mmol) was purged with nitrogen and stirred at 95 °C for 3 hours. After cooling to room temperature, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give intermediate 6 (2.5 g) as a pale yellow solid. m / z: [M+Na] + 423.0.

[0216] Intermediate 7: Synthesis of tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzo[b]thiophene-2-yl)carbamate

[0217]

[0218] Intermediate 7 was obtained by reacting 2-(6-bromo-2,3-difluorophenyl)acetonitrile using the same method as intermediate 6. m / z: [M+Na] + 441.2.

[0219] Intermediate 8: Synthesis of tert-butyl (4-bromo-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate

[0220]

[0221] Phosphorus tribromooxyphosphate (7.43 g, 25.9 mmol) was added to a suspension of 2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine-5-oxide (800 mg, 2.59 mmol) in 1,2-dichloromethane (50 mL). The reaction mixture was stirred at 50 °C for 3 hours, and the reaction was quenched with ice. The aqueous phase was extracted with dichloromethane, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (C18, eluent: 0%–90% acetonitrile in 0.05% trifluoroacetic acid aqueous solution) to give intermediate 8 (500 mg) as a pink solid. m / z: [M+H] + 372.0. 1 H NMR (400 MHz, DMSO-d6): δ 12.23(br.s, 1H), 8.36 (s, 1H), 1.56 (s, 9H).

[0222] Intermediate 9: Synthesis of 7-bromo-6-chloro-2,8-difluoro-4-(methylthio)quinazoline

[0223]

[0224] Step 1: Under ice bath conditions, an aqueous solution of sodium methanethiol (20%, 2.54 g, 7.26 mmol) was added to a tetrahydrofuran (20 mL) solution of 7-bromo-2,4,6-trichloro-8-fluoroquinoline (1.6 g, 4.84 mmol). The reaction mixture was stirred at 0 °C for 5 hours, water was added to precipitate the solid, which was filtered and the filter cake was dried under vacuum to obtain 7-bromo-2,6-dichloro-8-fluoro-4-(methylthio)quinazoline (1.66 g) as a white solid. m / z: [M+H] + 341.0.

[0225] Step 2: A solution of 7-bromo-2,6-dichloro-8-fluoro-4-(methylthio)quinazoline (600 mg, 1.75 mmol), triethylenediamine (12 mg, 0.1 mmol), methanesulfonic acid (10 mg, 0.1 mmol), and potassium fluoride (339 mg, 5.84 mmol) in dimethyl sulfoxide (6 mL) was stirred at 65 °C for 13 hours. The reaction solution was poured into ice water, filtered, and the filter cake was slurried with a small amount of ethyl acetate, filtered, and vacuum dried to obtain intermediate 9 (400 mg) as a yellow solid. m / z: [M+H] + 325.0.

[0226] Intermediate 10: Synthesis of 7-bromo-2,6-dichloro-5,8-difluoroquinazoline-4-ol

[0227]

[0228] Step 1: N-chlorosuccinimide (9.2 g, 68.9 mmol) was added to a solution of 2-amino-4-bromo-3,6-difluorobenzoic acid (8.7 g, 34.5 mmol) in concentrated sulfuric acid (85 mL). The reaction mixture was stirred at 80 °C for 16 hours, cooled to room temperature, and the reaction solution was slowly added to ice water. The mixture was filtered, and the filter cake was dried under vacuum to obtain 2-amino-4-bromo-5-chloro-3,6-difluorobenzoic acid (9 g) as a gray solid. m / z: [M+H] + 285.9.

[0229] Step 2: N,N'-carbonyldiimidazole (10 g, 61.7 mmol) was added to a tetrahydrofuran (100 mL) solution of 2-amino-4-bromo-5-chloro-3,6-difluorobenzoic acid (9 g, 31.4 mmol). The reaction mixture was stirred at 50 °C for 2 hours, cooled to room temperature, and concentrated ammonia (200 mL) was slowly added. The resulting mixture was stirred for another 16 hours at room temperature. The reaction was quenched with water, and the aqueous phase was extracted with ethyl acetate (450 mL). The organic phase was separated and concentrated under reduced pressure to obtain 2-amino-4-bromo-5-chloro-3,6-difluorobenzoamide (10 g) as a gray solid. m / z: [M+H] + 285.0.

[0230] Step 3: Triphosgene (3.5 g, 11.8 mmol) was added to a tetrahydrofuran (100 mL) solution of 2-amino-4-bromo-5-chloro-3,6-difluorobenzamide (4.2 g, 14.7 mmol). The reaction mixture was stirred at 70 °C for 2 hours, cooled to room temperature, and quenched with water. The aqueous phase was extracted with ethyl acetate, and the organic phase was separated and concentrated under reduced pressure to give 7-bromo-6-chloro-5,8-difluoroquinazoline-2,4(1H,3H)-dione (3.3 g) as a gray solid. m / z: [M+H] + 310.8.

[0231] Step 4: N,N-diisopropylethylamine (4 mL) was added to a phosphorus oxychloride (17 mL) solution of 1.7 g (5.46 mmol) of 7-bromo-6-chloro-5,8-difluoroquinazoline-2,4(1H,3H)-dione. The reaction mixture was stirred at 110 °C for 2 hours, concentrated under reduced pressure, and the residue was diluted with dichloromethane and then washed with saturated sodium bicarbonate aqueous solution and saturated brine, respectively. The organic phase was separated and concentrated under reduced pressure to give 1.9 g (7-bromo-2,4,6-trichloro-5,8-difluoroquinazoline) as a black solid. m / z: [M+H] + 346.8.

[0232] Step 5: Under ice bath conditions, sodium bicarbonate aqueous solution (1M, 11mL) was added to a tetrahydrofuran (40mL) solution of 7-bromo-2,4,6-trichloro-5,8-difluoroquinazoline (1.9g, 5.45mmol). The reaction mixture was stirred at room temperature for 3 hours. The pH was adjusted to 6-7 with hydrochloric acid (1.0M). The aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane / methanol = 10 / 1) to give intermediate 10 (1.33g) as a gray solid. m / z: [M+H] + 330.8.

[0233] Intermediate 11: Synthesis of (E)-4-(((tert-butoxycarbonyl)(methyl)amino)oxy)but-2-enoic acid

[0234]

[0235] Step 1: Under ice bath conditions, sodium hydroxide (60%, 610 mg, 15.3 mmol) was added to a tetrahydrofuran (20 mL) solution of tert-butyl hydroxycarbamate (750 mg, 5.1 mmol), and the reaction system was stirred at 0 °C for 1 hour. Ethyl (E)-4-bromobut-2-enoate (1.1 g, 5.7 mmol) was added to the above reaction solution, and stirring was continued for 1.5 hours. The reaction was quenched with saturated ammonium chloride aqueous solution, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give ethyl (E)-4-(((tert-butyloxycarbonyl)(methyl)amino)oxy)but-2-enoate (930 mg) as a colorless oil.

[0236] Step 2: Add 2M sodium hydroxide aqueous solution (5 mL) to an ethanol (20 mL) solution of (E)-4-(((tert-Butoxycarbonyl)(methyl)amino)oxy)but-2-enoic acid ethyl ester (800 mg, 3.1 mmol). Stir the reaction mixture at room temperature for 3 hours. Concentrate under reduced pressure to remove most of the ethanol, and extract the residue with methyl tert-butyl ether. Adjust the pH of the aqueous phase to 2-3 with hydrochloric acid (2 M), and then extract the aqueous phase with ethyl acetate. Concentrate the organic phase under reduced pressure to obtain intermediate 11 (600 mg) as a colorless oil.

[0237] Compound synthesis:

[0238] Example 1: Synthesis of 4-((7R)-4-(((R)-1-acryloylpyrrolidine-3-yl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-4-methoxypyrrolidine-1-yl)-8-fluoroquinazoline-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-onitrile (trans) and 4-((7S)-4-(((R)-1-acryloylpyrrolidine-3-yl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-4-methoxypyrrolidine-1-yl)-8-fluoroquinazoline-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-onitrile (trans)

[0239]

[0240]

[0241] Step 1: A mixture of 7-bromo-2,6-dichloro-8-fluoroquinazoline-4-ol (1.09 g, 3.49 mmol), intermediate 7 (2.92 g, 6.98 mmol), potassium phosphate (2.22 g, 10.5 mmol), and 1,1'-bis(di-tert-butylphosphine)ferrocene dichloropalladium (230 mg, 0.35 mmol) in 1,4-dioxane (25 mL) was purged three times with nitrogen. The reaction system was stirred at 90 °C for 2 hours under nitrogen protection. After cooling the reaction solution to room temperature, the reaction was quenched in water. The aqueous phase was extracted with ethyl acetate, the combined organic layers were washed with saturated brine, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (C18, eluent: 0%–75% acetonitrile in 0.1% trifluoroacetic acid aqueous solution) to give compound 1A (650 mg, yield: 36%) as a pale yellow solid. m / z: [M+H] + 523.0.

[0242] Step 2: N,N-diisopropylethylamine (248 mg, 1.92 mmol) and intermediate 1 (125 mg, 0.58 mmol) were added to a solution of compound 1A (250 mg, 0.48 mmol) in N,N-dimethylacetamide (10 mL). The reaction system was microwaved at 80 °C for 1 hour. After cooling to room temperature, the system was purified directly by Flash column chromatography (C18, eluent: 0%–85% acetonitrile in 10 mM ammonium bicarbonate aqueous solution) to obtain compound 1B (223 mg, yield: 74%) as a pale yellow solid. m / z: [M+H] + 631.0.

[0243] Step 3: To a solution of compound 1B (300 mg, 0.48 mmol), (R)-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (190 mg, 0.96 mmol), and N,N-diisopropylethylamine (310 mg, 2.4 mmol) in dimethyl sulfoxide (4 mL), 1H-benzotriazol-1-yloxytripyrrolyl hexafluorophosphate (PyBOP) (420 mg, 0.82 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were purified by silica gel column chromatography (methanol / dichloromethane = 9 / 1) to give compound 1C (390 mg, yield: 100%) as a yellow viscous solid. m / z: [M+H] + 813.1.

[0244] Step 4: A solution of compound 1C (390 mg, 0.48 mmol) in 1,4-dioxane hydrochloride (5 mL, 4 M) was stirred at room temperature for 2 hours. The reaction solution was then concentrated under reduced pressure to give compound 1D (crude product) as a yellow solid. m / z: [M+H] + 613.2.

[0245] Step 5: Under ice bath conditions, acrylic anhydride (9 mg, 0.07 mmol) was added to an anhydrous tetrahydrofuran (2 mL) solution of compound 1D (60 mg, 0.1 mmol) and N,N-diisopropylethylamine (63 mg, 0.49 mmol). The reaction mixture was stirred at 0 °C for 1 hour, and the reaction was quenched with a saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by prep-HPLC (40%–85% acetonitrile in 0.08% ammonium bicarbonate aqueous solution, elution time 10 min) to give compounds 1-1-1 (5.15 mg, yield: 8%) and 1-1-2 (4.37 mg, yield: 7%), both pale yellow solids.

[0246] Compound 1-1-1: Short UPLC retention time, 6.096 min; m / z: [M+H] + 667.2; 1 H NMR(400 MHz, DMSO-d6): δ 8.09 (s, 2H), 7.82 (s, 1H), 7.27 – 7.20 (m, 1H), 7.18 –7.11 (m, 1H), 6.71 – 6.58 (m, 1H), 6.17 (dd, J = 16.8, 2.4Hz, 1H), 5.70 (dd,J = 14.4, 6.4Hz, 1H), 4.96 (dt, J = 30.6, 7.8Hz, 1H), 4.01 – 3.85 (m, 2H), 3.78 – 3.63 (m, 2H), 3.61 – 3.47 (m, 2H), 3.47 – 3.37 (m, 2H), 3.31 (d, J =2.4Hz, 3H), 3.25 (d, J = 7.4Hz, 3H), 2.91 (s, 1H), 2.37 – 2.25 (m, 2H), 2.23(s, 6H), 2.00 (dd, J = 14.6, 7.2Hz, 1H).

[0247] Compound 1-1-2: UPLC retention time is relatively long, 6.191 minutes; m / z: [M+H] + 667.2; 1 H NMR(400 MHz, DMSO-d6): δ 8.10 (s, 2H), 7.82 (s, 1H), 7.23 (s, 1H), 7.14 (t, J =8.8Hz, 1H), 6.65 (dd, J = 16.4, 9.6Hz, 1H), 6.17 (d, J = 14.4Hz, 1H), 5.69(t, J = 11.4Hz, 1H), 5.07 – 4.86 (m, 1H), 4.03 – 3.86 (m, 2H), 3.69 (d, J =18.8Hz, 2H), 3.60 (d, J = 8.8Hz, 2H), 3.54 – 3.39 (m, 2H), 3.31 (d, J =1.4Hz, 3H), 3.25 (d, J = 5.6Hz, 3H), 2.91 (s, 1H), 2.43 – 2.27 (m, 2H), 2.23 (s, 6H), 2.05 – 1.93 (m, 1H).

[0248] Example 2: Synthesis of 4-((7R)-4-(((3S,4R)-1-acryloyl-4-fluoropyrrolidine-3-yl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-4-methoxypyrrolidine-1-yl)-8-fluoroquinazoline-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-onitrile (trans) and 4-((7S)-4-(((3S,4R)-1-acryloyl-4-fluoropyrrolidine-3-yl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-4-methoxypyrrolidine-1-yl)-8-fluoroquinazoline-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-onitrile (trans)

[0249]

[0250] Using the synthesis method of Example 1, (R)-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester in step 3 was replaced with intermediate 3 to obtain compounds 1-2-1 and 1-2-2, both of which are white solids.

[0251] Compound 1-2-1: Short UPLC retention time, 6.597 min; m / z: [M+H] + 685.2; 1 H NMR(400 MHz, CD3OD): δ 7.88 (s, 1H), 7.22 (dd, J = 8.4, 5.0Hz, 1H), 7.10 – 6.98(m, 1H), 6.80 – 6.59 (m, 1H), 6.36 (d, J = 16.8Hz, 1H), 5.83 (d, J = 10.4Hz, 1H), 4.64 (s, 1H), 4.43 (dd, J = 35.0, 10.4Hz, 1H), 4.16 – 3.87 (m, 5H), 3.84– 3.57 (m, 3H), 3.50 (s, 3H), 3.42 (d, J = 1.8Hz, 3H), 3.02 (s, 1H), 2.37 (d,J = 2.4Hz, 6H).

[0252] Compound 1-2-2: UPLC retention time is relatively long, 6.621 minutes; m / z: [M+H] + 685.2; 1H NMR(400 MHz, DMSO-d6): δ 8.11 (s, 1H), 7.84 (d, J = 8.6Hz, 1H), 7.19 (dt, J =17.8, 5.8Hz, 2H), 6.76 – 6.59 (m, 1H), 6.21 (ddd, J = 16.8, 5.0, 2.2Hz, 1H),5.88 – 5.66 (m, 2H), 4.98 – 4.72 (m, 1H), 4.43 – 4.14 (m, 1H), 4.04 (d, J =28.7Hz, 2H), 3.93 – 3.47 (m, 6H), 3.40 (s, 3H), 3.32 (s, 3H), 2.23 (s, 6H).

[0253] Example 3: Synthesis of 4-(4-(((3S,4R)-1-acryloyl-4-fluoropyrrolidine-3-yl)(methyl)amino)-6-chloro-2-((3R,4R)-3-(dimethylamino)-4-hydroxypyrrolidine-1-yl)-8-fluoroquinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-onitrile

[0254]

[0255] Using the synthetic method of Example 1, intermediate 1 in step 2 was replaced with intermediate 2, and (R)-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester in step 3 was replaced with intermediate 3. The resulting compounds 1-3 were off-white solids. The UPLC retention time was 6.176 minutes; m / z: [M+H] + 671.2; 1H NMR (400 MHz, DMSO-d6): δ 8.11 (s,2H), 7.86 – 7.79 (m, 1H), 7.29 – 7.21 (m, 1H), 7.14 (t, J = 8.8Hz, 1H), 6.69– 6.59 (m, 1H), 6.22 (dd, J = 16.8, 2.0Hz, 1H), 5.88 – 5.66 (m, 2H), 5.21 (s,1H), 4.78 (d, J = 30.0Hz, 1H), 4.36 – 4.15 (m, 2H), 4.02 (dd, J = 25.0,11.6Hz, 1H), 3.85 (dd, J = 23.6, 12.0Hz, 4H), 3.66 – 3.47 (m, 2H), 3.36 –3.33 (m, 3H), 2.71 (t, J = 11.8Hz, 1H), 2.25 (s, 6H).

[0256] Example 4: Synthesis of 4-((R)-4-(((3R,4S)-1-acryloyl-4-fluoropyrrolidine-3-yl)(methyl)amino)-6-chloro-2-((3R,4R)-3-(dimethylamino)-4-hydroxypyrrolidine-1-yl)-8-fluoroquinazoline-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-onitrile and 4-((S)-4-(((3R,4S)-1-acryloyl-4-fluoropyrrolidine-3-yl)(methyl)amino)-6-chloro-2-((3R,4R)-3-(dimethylamino)-4-hydroxypyrrolidine-1-yl)-8-fluoroquinazoline-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-onitrile

[0257]

[0258] Using the synthesis method of Example 1, intermediate 1 in step 2 was replaced with intermediate 2, and (R)-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester in step 3 was replaced with intermediate 5 to obtain compounds 1-4-1 and 1-4-2, both of which are white solids.

[0259] Compound 1-4-1: Short UPLC retention time, 6.208 min; m / z: [M+H] + 671.2; 1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 2H), 7.80 (s, 1H), 7.27 – 7.18 (m, 1H), 7.13 (d, J = 9.2Hz, 1H), 6.73 – 6.54 (m, 1H), 6.21 (s, 1H), 5.71 (s, 2H), 5.27 (d,J = 25.6Hz, 1H), 4.80 (s, 1H), 4.31 – 4.10 (m, 2H), 3.86 (s, 2H), 3.82 (s,2H), 3.66 – 3.42 (m, 2H), 3.37 (s, 3H), 2.71 (d, J = 44.0Hz, 1H), 2.27 (s,6H), 2.13 – 1.81 (m, 1H).

[0260] Compound 1-4-2: UPLC retention time was relatively long, 6.272 minutes; m / z [M+H] + 671.2; 1 H NMR (400MHz, DMSO-d6): δ 8.09 (s, 2H), 7.81 (d, J = 7.6Hz, 1H), 7.25 – 7.18 (m, 1H), 7.12 (t, J = 8.8Hz, 1H), 6.72 – 6.57 (m, 1H), 6.19 (d, J = 15.6Hz, 1H), 5.88– 5.61 (m, 2H), 5.30 (s, 1H), 4.84 (d, J = 30.8Hz, 1H), 4.20 (dd, J = 36.0,24.2Hz, 2H), 4.06 – 3.86 (m, 2H), 3.84 – 3.70 (m, 2H), 3.56 (d, J = 46.2Hz,2H), 3.37 (s, 3H), 2.65 (s, 1H), 2.31 (s, 6H), 2.05 – 1.89 (m, 1H).

[0261] Example 5: Synthesis of 4-((S)-4-(((3S,4R)-1-acryloyl-4-fluoropyrrolidine-3-yl)(methyl)amino)-6-chloro-2-((3R,4R)-3-(dimethylamino)-4-hydroxypyrrolidine-1-yl)-8-fluoroquinazoline-7-yl)-2-amino-7-fluorothiopheno[3,2-c]pyridine-3-onitrile and 4-((R)-4-(((3S,4R)-1-acryloyl-4-fluoropyrrolidine-3-yl)(methyl)amino)-6-chloro-2-((3R,4R)-3-(dimethylamino)-4-hydroxypyrrolidine-1-yl)-8-fluoroquinazoline-7-yl)-2-amino-7-fluorothiopheno[3,2-c]pyridine-3-onitrile

[0262]

[0263] Step 1: At -70°C, an anhydrous tetrahydrofuran solution of intermediate 9 (456 mg, 1.4 mmol) in 15 mL of isopropyl magnesium chloride-lithium chloride in 2-methyltetrahydrofuran (1.3 M, 1.86 mL) was added. The reaction mixture was stirred at this temperature for 30 minutes, followed by the addition of a zinc chloride solution in 2-methyltetrahydrofuran (1.9 M, 941 mg). The reaction mixture was gradually brought to room temperature and stirred for 1 hour, then intermediate 8 (750 mg, 2 mmol) and tetra(triphenylphosphine)palladium (870 mg, 0.75 mmol) were added. The reaction system was purged with nitrogen three times, stirred at 85°C for 1.5 hours under a nitrogen atmosphere, cooled to room temperature, and quenched with dilute hydrochloric acid (1 M). The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether = 1 / 8) to give compound 5A (240 mg, yield: 32%) as a yellow solid.

[0264] Step 2: Under ice bath conditions, N,N-diisopropylethylamine (480 mg, 3.7 mmol) was added to a solution of compound 5A (400 mg, 0.74 mmol) and intermediate 2 (250 mg) in N,N-dimethylformamide (3 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into saturated brine, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (methanol / dichloromethane = 1 / 20) to give compound 5B (400 mg, yield: 81%) as a yellow solid. m / z: [M+H] + 648.2.

[0265] Step 3: Lithium hydroxide monohydrate (130 mg, 3.1 mmol) was added to a mixed solution of compound 5B (400 mg, 0.6 mmol) in methanol (16 mL), tetrahydrofuran (8 mL), and water (4 mL). The reaction mixture was stirred at 60 °C for 24 hours, and the pH was adjusted to 6 with dilute hydrochloric acid (2 M). The aqueous phase was extracted with dichloromethane, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (methanol / dichloromethane = 1 / 10) to give compound 5C (320 mg, yield: 84%) as an off-white solid. m / z: [M+H] + 618.1.

[0266] Step 4: PyBOP (260 mg, 0.5 mmol) was added to a solution of compound 5C (140 mg, 0.23 mmol), intermediate 3 (110 mg, 0.5 mmol), and N,N-diisopropylethylamine (100 mg, 0.77 mmol) in dimethyl sulfoxide (2.5 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were purified by silica gel column chromatography (methanol / dichloromethane = 10 / 1) to give compound 5D (155 mg, yield: 82%) as a pale yellow solid. m / z: [M+H] + 818.2.

[0267] Step 5: A solution of compound 5D (155 mg, 0.19 mmol) and trifluoroacetic acid (1 mL) in dichloromethane (2 mL) was stirred at room temperature for 1 hour. The reaction solution was then concentrated under reduced pressure to give compound 5E (crude product) as a yellow solid. m / z: [M+H] + 618.2.

[0268] Step 6: Under ice bath conditions, acrylic anhydride (21.6 mg, 0.17 mmol) was added to a tetrahydrofuran (3 mL) solution of compound 5E (115 mg, 0.19 mmol) and triethylamine (96 mg, 0.95 mmol). The reaction mixture was stirred at 0 °C for 1 hour, and the reaction was quenched with a saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by prep-HPLC (elution of 35%–80% acetonitrile in 0.08% ammonium bicarbonate aqueous solution for 10 minutes) to give compounds 1-5-1 (2.49 mg, yield: 2%) and 1-5-2 (1.81 mg, yield: 1%), both of which were off-white solids.

[0269] Compound 1-5-1: Short UPLC retention time, 5.355 min; m / z [M+H] + 672.2; 1H NMR (400MHz, CD3OD): δ 8.29 (s, 1H), 7.87 (d, J = 6.4Hz, 1H), 6.75 – 6.57 (m, 1H), 6.33 (d, J = 16.8Hz, 1H), 5.88 – 5.64 (m, 2H), 4.82 (dd, J = 20.0, 8.4Hz, 1H), 4.38 (dd, J = 12.2, 6.4Hz, 2H), 4.13 – 3.77(m, 5H), 3.63 – 3.53 (m, 1H), 3.48 (d, J = 11.2Hz, 4H), 2.94 – 2.81 (m, 1H), 2.39 (d, J = 2.2Hz, 6H).

[0270] Compound 1-5-2: UPLC retention time was relatively long, 5.358 minutes; m / z [M+H] + 672.2; 1 H NMR (400MHz, CD3OD): δ 8.29 (s, 1H), 7.89 (d, J = 1.6Hz, 1H), 6.69 (d, J = 10.6Hz, 1H), 6.34 (dd, J = 16.8, 1.6Hz, 1H), 5.80 (d, J = 10.4Hz, 2H), 4.84 (dd, J =21.6, 9.8Hz, 1H), 4.47 – 4.29 (m, 2H), 4.10 – 3.73 (m, 5H), 3.59 (d, J =11.8Hz, 1H), 3.54 – 3.42 (m, 4H), 2.93 – 2.80 (m, 1H), 2.39 (d, J = 2.4Hz, 6H).

[0271] Example 6: Synthesis of 4-((S)-4-(((3R,4S)-1-acryloyl-4-fluoropyrrolidine-3-yl)(methyl)amino)-6-chloro-2-((3R,4R)-3-(dimethylamino)-4-hydroxypyrrolidine-1-yl)-8-fluoroquinazoline-7-yl)-2-amino-7-fluorothieno[3,2-c]pyridine-3-onitrile and 4-((R)-4-(((3R,4S)-1-acryloyl-4-fluoropyrrolidine-3-yl)(methyl)amino)-6-chloro-2-((3R,4R)-3-(dimethylamino)-4-hydroxypyrrolidine-1-yl)-8-fluoroquinazoline-7-yl)-2-amino-7-fluorothieno[3,2-c]pyridine-3-onitrile

[0272]

[0273] Using the synthesis method of Example 5, intermediate 3 in step 4 was replaced with intermediate 5 to obtain compounds 1-6-1 and 1-6-2, both of which are white solids.

[0274] Compound 1-6-1: Short UPLC retention time, 5.373 min; m / z [M+H] + 672.2; 1 H NMR (400MHz, CD3OD): δ 8.29 (s, 1H), 7.87 (d, J = 5.2Hz, 1H), 6.66(s, 1H), 6.33(d, J= 16.8Hz,1H), 5.88 – 5.61 (m, 2H), 4.81 (d, J = 8.8Hz, 1H), 4.38 (d, J =6.2Hz, 2H), 3.99 (ddd, J = 96.4, 49.2, 39.4Hz, 5H), 3.58 (d, J = 5.6Hz, 1H), 3.47 (s, 4H), 2.86 (s, 1H), 2.38 (s, 6H).

[0275] Compound 1-6-2: UPLC retention time was relatively long, 5.399 minutes; m / z [M+H] + 672.2; 1 H NMR (400MHz, CD3OD): δ 8.29 (s, 1H), 7.89 (d, J = 1.6Hz, 1H), 6.69 (d, J = 10.6 Hz, 1H), 6.34 (dd, J= 16.8, 1.6Hz, 1H), 5.80 (d, J = 10.4Hz, 2H), 4.84 (dd, J =21.6, 9.8Hz, 1H), 4.47 – 4.29 (m, 2H), 4.10 – 3.73 (m, 5H), 3.59 (d, J =11.8Hz, 1H), 3.54 – 3.42 (m, 4H), 2.93 – 2.80 (m, 1H), 2.39 (d, J = 2.4Hz, 6H).

[0276] Example 7: Synthesis of 4-((R)-4-(((3S,4R)-1-acryloyl-4-fluoropyrrolidine-3-yl)(methyl)amino)-6-chloro-2-((3R,4S)-3-(dimethylamino)-4-fluoropyrrolidine-1-yl)-8-fluoroquinazoline-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-onitrile and 4-((S)-4-(((3S,4R)-1-acryloyl-4-fluoropyrrolidine-3-yl)(methyl)amino)-6-chloro-2-((3R,4R)-3-(dimethylamino)-4-fluoropyrrolidine-1-yl)-8-fluoroquinazoline-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-onitrile

[0277]

[0278] Using the synthesis method of Example 1, intermediate 1 in step 2 was replaced with intermediate 4, and (R)-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester in step 3 was replaced with intermediate 3 to obtain compounds 1-7-1 and 1-7-2, both of which are white solids.

[0279] Compound 1-7-1: Short UPLC retention time, 6.659 min; m / z: [M+H] + 673.2; 1 H NMR (400 MHz, CD3OD): δ 7.87 (d, J = 1.6Hz, 1H), 7.21 (s, 1H), 7.02 (dd, J = 9.4,8.6Hz, 1H), 6.67 (ddd, J = 31.4, 16.8, 10.4Hz, 1H), 6.34 (dd, J = 16.8, 1.6Hz, 1H), 5.88 – 5.64 (m, 2H), 5.42 – 5.20 (m, 1H), 4.85 – 3.70 (m, 8H), 3.48(d, J = 2.4Hz, 4H), 2.84 (dt, J = 18.6, 8.0Hz, 1H), 2.40 (s, 6H).

[0280] Compound 1-7-2: UPLC retention time is relatively long, 6.718 minutes; m / z: [M+H] + 673.2; 1H NMR (400 MHz, CD3OD): δ 7.88 (s, 1H), 7.20 (dd, J = 8.4, 5.2Hz, 1H), 7.02 (t, J =8.8Hz, 1H), 6.67 (ddd, J = 37.6, 16.8, 10.4Hz, 1H), 6.34 (dd, J = 16.8,1.8Hz, 1H), 5.88 – 5.62 (m, 2H), 5.32 (d, J = 53.4Hz, 1H), 4.68 – 3.72 (m,8H), 3.58 – 3.42 (m, 4H), 2.84 (dt, J = 18.4, 8.2Hz, 1H), 2.40 (d, J = 1.8Hz, 6H).

[0281] Example 8: Synthesis of 4-(4-(((3R,4S)-1-acryloyl-4-fluoropyrrolidine-3-yl)(methyl)amino)-6-chloro-2-((3R,4S)-3-(dimethylamino)-4-fluoropyrrolidine-1-yl)-8-fluoroquinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-onitrile

[0282]

[0283] Using the synthetic method of Example 1, intermediate 1 in step 2 was replaced with intermediate 4, and (R)-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester in step 3 was replaced with intermediate 5 to obtain compounds 1-8 as white solids. The UPLC retention time was 6.657 min; m / z [M+H] + 673.2; 1 H NMR (400 MHz, CD3OD): δ 7.87 (d, J =8.8Hz, 1H), 7.24 – 7.15 (m, 1H), 7.07 – 6.97 (m, 1H), 6.75 – 6.54 (m, 1H), 6.34 (dd, J = 16.8, 1.8Hz, 1H), 5.82 (s, 1H), 5.78 – 5.61 (m, 1H), 5.32 (d, J= 53.6Hz, 1H), 4.70 – 3.63 (m, 8H), 3.50 (d, J = 18.6Hz, 4H), 2.85 (d, J =29.0Hz, 1H), 2.40 (d, J = 2.8Hz, 6H).

[0284] Example 9: Synthesis of 4-((R)-4-(((3S,4R)-1-acryloyl-4-fluoropyrrolidine-3-yl)(methyl)amino)-6-chloro-2-((3R,4S)-3-(dimethylamino)-4-fluoropyrrolidine-1-yl)-5,8-difluoroquinazolin-7-yl)-2-aminobenzo[b]thiophene-3-onitrile and 4-((S)-4-(((3S,4R)-1-acryloyl-4-fluoropyrrolidine-3-yl)(methyl)amino)-6-chloro-2-((3R,4S)-3-(dimethylamino)-4-fluoropyrrolidine-1-yl)-5,8-difluoroquinazolin-7-yl)-2-aminobenzo[b]thiophene-3-onitrile

[0285]

[0286] Using the synthesis method of Example 1, intermediates 6 and 10 were used as starting materials. Intermediate 1 in step 2 was replaced with intermediate 4, and (R)-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester in step 3 was replaced with intermediate 3 to obtain compounds 1-9-1 and 1-9-2, both of which are white solids.

[0287] Compound 1-9-1: UPLC retention time 6.655 min; m / z [M+H] + 673.2; 1 H NMR (400 MHz, CD3OD): δ 7.67 (d, J = 8.6Hz, 1H), 7.25 (dd, J = 15.8, 8.4Hz, 2H), 6.67 (ddd,J = 33.8, 16.8, 10.5 Hz, 1H), 6.33 (d, J = 16.8Hz, 1H), 5.75 (dd, J = 51.2,11.1Hz, 2H), 5.40 – 5.22 (m, 1H), 4.83 – 3.44 (m, 9H), 3.26 (d, J = 6.0Hz,3H), 2.85 (d, J = 28.6Hz, 1H), 2.40 (d, J = 2.4Hz, 6H).

[0288] Compound 1-9-2: UPLC retention time 6.679 min; m / z [M+H] + 673.2; 1H NMR (400 MHz, CD3OD): δ 7.67 (d, J = 7.8Hz, 1H), 7.33 – 7.15 (m, 2H), 6.67 (ddd, J = 43.6,16.8, 10.4Hz, 1H), 6.34 (d, J = 16.4Hz, 1H), 5.73 (dd, J = 59.8, 13.0Hz, 2H), 5.43 – 5.23 (m, 1H), 4.78 – 3.67 (m, 8H), 3.53 (t, J = 10.6Hz, 1H), 3.25 (d,J = 6.4Hz, 3H), 2.87 (d, J = 28.6Hz, 1H), 2.41 (s, 6H).

[0289] Example 10: 2-Amino-4-((R)-6-chloro-2-((3R,4S)-3-(dimethylamino)-4-fluoropyrrolidine-1-yl)-8-fluoro-4-(((3S,4R)-4-fluoro-1-((E)-4-((methylamino)oxy)but-2-enoyl)pyrrolidine-3-yl)(methyl)amino)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-onitrile and 2-amino-4-((S)-6-chloro-2-((3R,4S)-3-(dimethylamino)-4-fluoropyrrolidine-1-yl)-8-fluoro-4-(((3S, Synthesis of 4R)-4-fluoro-1-((E)-4-((methylamino)oxy)but-2-enoyl)pyrrolidine-3-yl)(methyl)amino)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-onitrile

[0290]

[0291]

[0292] Step 1: To a solution of compound 7C (300 mg, 0.48 mmol) and intermediate 11 (250 mg, 1.08 mmol) in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (0.98 g, 7.6 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (0.5 g, 1.3 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (methanol / dichloromethane = 1 / 100~1 / 10) to give compound 10A (200 mg, yield: 50%) as a pale yellow solid. m / z [M+H] + 832.2.

[0293] Step 2: A solution of compound 10A (200 mg, 0.24 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (2 mL) was stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure, and triethylamine was added to the residue to adjust the pH to neutral. The mixture was purified by prep-HPLC (30%–75% acetonitrile in 10 mM ammonium bicarbonate aqueous solution, elution time 13 min) to obtain 1-10-1 (16 mg, yield: 9%) and 1-10-2 (12 mg, yield: 7%), both of which were off-white solids.

[0294] Compound 1-10-1: UPLC retention time 5.966 min; m / z [M+H] + 732.2; 1 H NMR (400MHz, CD3OD): δ 7.95 – 7.78 (m, 1H), 7.25 (s, 1H), 7.08 – 6.85 (m, 2H), 6.50 (dd, J = 30.2, 15.4 Hz, 1H), 5.74 (dd, J = 54.4, 17.9 Hz, 1H), 5.31 (d, J =54.2 Hz, 1H), 4.47 – 3.74 (m, 9H), 3.47 (s, 4H), 2.83 (dt, J = 18.5, 10.5 Hz,1H), 2.67 (d, J = 7.6 Hz, 3H), 2.40 (s, 6H).

[0295] Compound 1-10-2: UPLC retention time 6.158 min; m / z [M+H] + 732.2; 1 H NMR (400 MHz, CD3OD): δ 7.88 (s, 1H), 7.24 – 7.15 (m, 1H), 7.06 – 6.86 (m, 2H), 6.50 (dd, J= 33.8, 15.4 Hz, 1H), 5.76 (dd, J = 53.8, 21.2 Hz, 1H), 5.46 – 5.14 (m, 1H), 4.45 – 3.71 (m, 9H), 3.54 – 3.39 (m, 4H), 2.82 (dd, J = 23.4, 13.8 Hz, 1H), 2.66 (t, J = 6.2 Hz, 3H), 2.40 (s, 6H).

[0296] Example 11: Synthesis of 2-amino-4-(6-chloro-2-((3R,4S)-3-(dimethylamino)-4-fluoropyrrolidine-1-yl)-5,8-difluoro-4-(((3S,4R)-4-fluoro-1-(2-fluoroacryloyl)pyrrolidine-3-yl)(methyl)amino)quinazolin-7-yl)benzo[b]thiophene-3-onitrile

[0297]

[0298] Under ice bath conditions, N,N-diisopropylethylamine (0.5 mL) and HATU (160 mg, 0.42 mmol) were added to a solution of compound 9D (130 mg, 0.21 mmol) and 2-fluoroacrylic acid (30 mg, 0.33 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 0 °C for 30 min. After the reaction was complete, compound 1-11 (15 mg, yield: 10%) was purified directly by prep-HPLC (elution time 13 min in 10 mM ammonium bicarbonate aqueous solution with 35%–80% acetonitrile) to obtain compound 1-11 (15 mg, yield: 10%) as an off-white solid. UPLC retention time was 6.867 min; m / z [M+H] + 691.2; 1 H NMR (400 MHz, CD3OD): δ 7.67 (dd, J =7.8, 1.0Hz, 1H), 7.23 (ddd, J = 21.4, 10.7, 6.8Hz, 2H), 5.72 (d, J = 53.7Hz,1H), 5.63 – 5.21 (m, 3H), 4.64 (s, 2H), 4.19 – 3.85 (m, 5H), 3.51 (dd, J =20.7, 9.8Hz, 1H), 3.25 (t, J = 6.1Hz, 3H), 3.01 (d, J = 14.2Hz, 1H), 2.92 –2.75 (m, 1H), 2.40 (s, 6H).

[0299] Biological Example:

[0300] Example 1: Cell proliferation inhibition experiment

[0301] On day one, the density of suspensions of KRAS G12C-mutated human pancreatic cancer cells MIA PaCa-2 (Nanjing Kebai), KRAS wild-type human melanoma cells A375 (ATCC), or KRAS G12C-mutated human non-small cell lung cancer cells H358 (ATCC) was adjusted to 3.2 × 10⁻⁶. 4Cells / mL were seeded at 95 μL / well in a 96-well plate, resulting in 3000 cells per well. The cell culture plates were incubated overnight at 37°C with 5% CO2. The next day, the test compound was serially diluted with 100% DMSO, and then further diluted with complete culture medium (DMDM + 10% FBS + 1% P / S) to prepare the working solution. 5 μL / well of the working solution was added to the 96-well cell culture plate, with a concentration range of 0.15 nM to 10 μM. The plates were incubated at 37°C with 5% CO2 for 72 hours. Cell Titer-Glo (Cell Titer-glo, Promega) assay reagent was added to each well, and the plates were incubated in the dark for 5 minutes. After standing, Luminescence was detected using a Microplate reader (Tecan, Infinite M1000 Pro). The data were analyzed using Graphpad software, and a four-parameter equation was used to fit the curve and calculate the IC50 of the inhibitor. 50 Values. Where A is ≤10nM, B is >10nM and ≤100nM, C is >100nM and ≤1μM, and D is >1μM. The results are shown in Table 1 below:

[0302] Table 1

[0303] Compound numbering MIA PaCa-2IC50 (nM) H358IC50 (nM) A375IC50 (nM) 1-1-1 A 1-3 A 1-4-1 A 1-5-1 B 1-6-1 B 1-7-1 A D 1-9-1 A 1-10-1 B

[0304] The compounds of this invention exhibit good inhibitory activity against KRAS G12C mutant cell lines and good selectivity against KRAS wild-type cell lines.

[0305] Example 2: pERK cell level assay

[0306] This experiment used the PHOSPHO-ERK1 / 2 (THR202 / TYR 204) (Cisibo, 64ERKPEH) kit to detect the phosphorylation level of ERK1 / 2 in human pancreatic cancer cells MIA PaCa-2, human non-small cell lung cancer H358, or KRAS wild-type human melanoma cells A375, and investigated the inhibitory effect of compounds on KRAS by measuring the phosphorylation level of ERK1 / 2.

[0307] The experiment was conducted according to the manufacturer's protocol. On day one, the density of the MIA PaCa-2 cell, H358 cell, or A375 cell suspension was adjusted to 3.2 × 10⁻⁶. 5 Cells / mL, seeded at 95 μL / well in a 96-well plate, resulting in 3 × 10⁶ cells per well. 4Cell culture plates were incubated overnight at 37°C with 5% CO2. The next day, the compound was serially diluted with 100% DMSO and further diluted with complete culture medium (DMDM + 10% FBS + 1% P / S) to prepare the working solution. 5 μL / well was added to a 96-well cell culture plate, with the target compound concentration ranging from 0.15 nM to 10 μM. The plate was incubated at 37°C with 5% CO2 for 4 hours. After incubation, the culture medium was discarded, and 50 μL / well of 1x lysis buffer was added. The plate was shaken at room temperature for 30 minutes. 16 μL of lysis buffer was added to a white, shallow-well 384-well plate, followed by 4 μL of pre-prepared antibody mixture. The plate was sealed with sealing film and incubated overnight at room temperature. On the third day, the compound was detected using HTRF settings on a TECAN M1000 Pro plate reader, and the IC50 was calculated. 50 Values. Where A is ≤10nM, B is >10nM and ≤100nM, C is >100nM and ≤1μM, and D is >1μM. The results are shown in Table 2 below:

[0308] Table 2

[0309] Compound numbering <![CDATA[MIA PaCa-2pERK IC 50 (nM)]]> 1-7-1 A

[0310] The compounds of this invention exhibit a good inhibitory effect on ERK phosphorylation in KRAS G12C mutant tumor cells.

[0311] Example 3: Pharmacokinetic Experiment

[0312] The test compound was administered orally and intravenously to male SD rats or male ICR mice. Blood samples were collected via the tail vein or submandibular vein, approximately 0.10 mL per sample, anticoagulated with EDTA-K2. Blood collection time points were as follows: Intravenous administration group: before administration, 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h after administration. Oral administration group: before administration, 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h after administration. After collection, blood samples were placed on wet ice and centrifuged to separate plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8°C). Collected plasma was stored at -80°C before analysis. Plasma samples were analyzed using LC-MS / MS (API5500). Based on the drug concentration data, various pharmacokinetic parameters were calculated using the WinNonlin 5.2 non-compartmental model pharmacokinetic calculation software.

[0313] The compounds of this invention have good pharmacokinetic characteristics.

[0314] Example 4: In vivo efficacy experiment

[0315] Cell culture: Human pancreatic cancer cells MIA PaCa-2 or human non-small cell lung cancer cells H358 were cultured in RPMI 1640 medium containing 10% fetal bovine serum at 37°C. o The tumor cells were cultured in a monolayer in an incubator containing 5% CO2. The cells were passaged twice weekly. Cells in the exponential growth phase were harvested and counted for seeding.

[0316] Experimental animals: BALB / c nude mice, 6-8 weeks old, 18-22g, purchased from Jiangsu Jicui Yaokang Biomedical Technology Co., Ltd.

[0317] Experimental method: Cell lines (5.0 × 10⁻⁶) 6 ~1.0×10 7 (0.1 mL / mouse) was injected subcutaneously into the right back of each experimental mouse. The tumor growth was observed regularly until it grew to approximately 100 mm. 3 Mice were randomly grouped according to tumor size and body weight, and administered medication according to the dosing schedule. Throughout the experiment, mouse body weight and tumor size were measured twice a week.

[0318] Formula for calculating tumor size: Tumor volume (mm) 3 = 0.5 × (tumor long diameter × tumor short diameter) 2 ).

[0319] The compounds of this invention have good pharmacological effects.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, X is CH or N; Y is C (CN) or N; R1, R2, and R3 are each independently hydrogen, deuterium, halogen, cyano, or C. 1-6 Alkyl, C 1-6 Alkoxy or C substituted with one or more halogens 1-6 alkyl; R4 represents hydrogen, hydroxyl group, and C. 1-6 Alkyl, C 1-6 alkoxy; wherein, the C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally surrounded by one or more R groups. 4-a replace; Each R 4-a Each is independently a deuterium, halogen, hydroxyl group, or C. 1-6 alkoxy or -N(R) a )2; Each R5 is independently for halogen, C 1-6 Alkyl, C 1-6 alkoxy or -N(R) a )2; m is 0, 1, or 2; R6 is -CH=N2, C 2-6 alkenyl or C 2-6 alkynyl group; the C 2-6 alkenyl and C 2-6 Each alkynyl group is independently and optionally surrounded by one or more R groups. 6-a replace; Each R 6-a Each is independently a deuterium, halogen, cyano, or C group. 1-6 Alkyl, C 1-6 Alkyl group, -ON(R) a 2. C 3-6 cycloalkyl, C 5-10 Aryl, 5-10-membered heteroaryl, or 3-10-membered heterocycloalkyl; wherein, the C 1-6 Alkyl and C 1-6 Each alkoxy group is independently and optionally surrounded by one or more elements selected from halogens, hydroxyl groups, and C. 1-6 Alkoxy, -N(R) a 2. C 5-10 Aryl, C 3-6 Substitution of cycloalkyl, 5-10-membered heteroaryl and 3-10-membered heterocycloalkyl groups; Each R7 is independently deuterium, halogen, hydroxyl group, oxo group (=O), C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or C 1-6 Alkylene; wherein, the C 1-6 Alkyl groups are optionally surrounded by one or more elements selected from halogens, hydroxyl groups, and C. 1-6 Alkoxy and -N(R) a Substituents of )2; the C 1-6 Alkoxy and C 1-6 Each alkylene group is independently and optionally substituted with one or more deuterium or halogen substituents; n is 0, 1, 2, 3 or 4; R8 is hydrogen, C 1-6 Alkyl, C 1-6 alkoxy or -N(R) a )2; Each R9 group is independently halogenated, cyano, hydroxyl, amino, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C atoms substituted with one or more halogens 1-6 Alkoxy; q is 0, 1, or 2; Each R a Each is independently hydrogen, cyano, C 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) X is CH; (2) Y is C(CN); (3) R1 is a halogen, for example, F; (4) R2 is a halogen or a C substituted with one or more halogens. 1-6 Alkyl groups, such as F, Cl, or -CF3; (5) R3 is hydrogen or a halogen, for example, H or F; (6) R 4-a It is deuterium; (7) R4 is hydrogen or C 1-6 Alkyl; the C 1-6 Alkyl groups are optionally surrounded by one or more R 4-a Substitution; for example, R4 can be H, -CH3, or -CD3; (8) R5 is halogen or C 1-6 Alkyl groups, such as F or -CH3; (9) m is 0 or 1; (10) Each R 6-a Each is independently a deuterium, halogen, cyano, or C group. 1-6 Alkyl, C 1-6 Alkyl group, -ON(R) a 2. C 3-6 cycloalkyl, C 5-10 Aryl, 5-10-membered heteroaryl, or 3-10-membered heterocycloalkyl; wherein, the C 1-6 Alkyl groups are optionally surrounded by one or more elements selected from halogens, hydroxyl groups, and C. 1-6 Alkoxy, -N(R) a 2. C 5-10 Aryl, C 3-6 Substitution of cycloalkyl, 5-10-membered heteroaryl and 3-10-membered heterocycloalkyl groups; the C 1-6 The alkoxy group is optionally substituted with one or more halogens; each R a Each is independently hydrogen, cyano, C 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl; (11) R6 is -CH=N2 or C 2-6 alkenyl; the C 2-6 Alkenyl groups are optionally separated by one or more R groups 6-a replace; (12) R7 is deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl groups; for example, F, Cl, -OH, -CH3, or -OCH3; (13) n is 0 or 1, for example, n is 1; (14) R8 is -N(R a )2; where each R a Each is independently hydrogen, cyano, C 1-6 Alkyl groups, or one or more deuterated C groups 1-6 Alkyl; for example, R8 is -NHCH3, -N(CH3)2, -NHCH(CH3)2, -N(CH3)CH(CH3)2 or -N(CN)CH3; (15) R9 is a halogen, cyano, hydroxyl, or C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C atoms substituted with one or more halogens 1-6 Alkyl groups; for example, F, Cl, -CN, -OH, -CH3, -OCH3, -CF3, -CHF2, -OCF3, -OCHF2, or ; (16) q is 0 or 1.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) R6 is -CH=N2 or Among them, R 6-1 It is hydrogen, deuterium, or halogen; R 6-2 and R 6-3 Each is independently hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkyl group, -ON(R) a 2. C 3-6 cycloalkyl, C 5-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl; wherein, the C 1-6 Alkyl and C 1-6 Each alkoxy group is optionally surrounded by one or more elements selected from halogens, hydroxyl groups, and C. 1-6 Alkoxy, -N(R) a 2. C 5-10 Aryl, C 3-6 Substitution of cycloalkyl, 5-10-membered heteroaryl and 3-10-membered heterocycloalkyl groups; each R a Each is independently hydrogen, cyano, and C. 1-6 Alkyl groups, or one or more deuterated C groups 1-6 Alkyl; L is a single bond or C 1-4 Alkyl groups, for example, L is a single bond or -CH2-; (2) R6 is Among them, R 6-1 R 6-2 R 6-3 Each can be independently hydrogen, deuterium, or halogen, for example, R6 is... or ; (3) R6 is Where L is C 1-4 Alkylene; R 6-1 R 6-2 Each can be independently hydrogen, deuterium, or halogen, R 6-3 For -ON(R) a )2, each R a Each is independently hydrogen, cyano, and C. 1-6 Alkyl groups, or one or more deuterated C groups 1-6 Alkyl groups, such as R6, are -CH=CH-CH2-O-NH-CH3; (4) for , or Preferred , , , , , , , , , , or ; (5) for Preferred , , , , , , , , or More preferably , , , , , , , , , or ; (6) for , , or .

4. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 3, characterized in that, It meets one or more of the following conditions: (1) R1, R2, R3, R 4-a R5, R 6-a R 6-1 R 6-2 R 6-3 In R7 and R9, the halogen is independently F, Cl, Br or I, for example F or Cl; (2) R1, R2, R3, R4, R5, R 6-a R 6-2 R 6-3 R7, R8, R9, R a In the middle, the "C" 1-6 Alkyl group, C substituted with one or more halogens 1-6 "alkyl" or "C substituted with one or more deuteriums" 1-6 The C in "alkyl" 1-6 Each alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, for example, methyl; (3) R1, R2, R3, R4, R 4-a R5, R 6-a R 6-2 R 6-3 In R7, R8, and R9, the "C" 1-6 "alkoxy" or "C substituted with one or more halogens" 1-6 The C in "alkoxy" 1-6 Each alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy, such as methoxy; (4) In R6, the C 2-6 The alkenyl group is vinyl, propenyl, butenyl, butadienyl, pentadienyl, or hexadienyl, for example, vinyl or propenyl; (5) In R6, the C 2-6 The alkynyl group is ethynyl, propynyl, butynyl, and 3-methylbutynyl; (6) R 6-a R 6-2 R 6-3 In R7 and R9, the C 3-6 Each cycloalkyl group is independently a monocyclic or bicyclic cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (7) R 6-a R 6-2 R 6-3 In this context, the 3-10 membered heterocyclic alkyl group is a 3-8 membered monocyclic heterocyclic alkyl group or a 5-10 membered bicyclic heterocyclic alkyl group having one, two or three heteroatoms or heteroatom groups selected from N, NH, S and O; (8) R 6-a R 6-2 R 6-3 In this context, the 5-10 membered heteroaryl group is a 5-6 membered monocyclic heteroaryl group or a 7-10 membered bicyclic heteroaryl group having one, two, or three heteroatoms or heteroatom groups selected from N, NH, S, and O; (9) R 6-a R 6-2 R 6-3 In, the C 5-10 The aryl group is phenyl or naphthyl; (10) In R7, the 3-6 membered heterocyclic alkyl group is a 3-6 membered heterocyclic alkyl group having one, two or three heteroatoms or heteroatom groups selected from N, NH, S and O, preferably a monocyclic alkyl group; (11) In R7, the C 1-6 The alkylene groups are methylene (=CH2), ethylene (=CHCH3), n-propylene, and 2-isopropylene (=CH(CH3)2); (12) In L, the C 1-4 The alkylene group is -CH2-, -CH2CH2-, -CH(CH3)- or -CH(CH3)CH2-, for example -CH2-; (13) The number of the one or more is 1, 2, 3, 4, 5, 6, 7, 8 or 9, for example, 1, 2 or 3.

5. The compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4, characterized in that, The compound represented by formula (I) is one of the following compounds: (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), or (I-7). Among them, X, Y, R1, R2, R3, R4, R5, R6, R 6-1 R 6-2 R 6-3 The definitions of R7, R8, R9, L, m, n, and q are as described in any one of claims 1-4.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (I) is selected from any of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , or Preferred , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

7. The compound of formula (I) as claimed in claim 1, characterized in that, The compound represented by formula (I) is any one of the following compounds: (1) The transisomers of the following compounds, The modified isomer is a compound with a short retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with the short retention time is approximately 6.096 minutes; (2) The transisomers of the following compounds, The modified isomer is a compound with a long retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a long retention time is approximately 6.191 minutes; (3) The transisomers of the following compounds, The modified isomer is a compound with a short retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with the short retention time is approximately 6.597 minutes; (4) The transisomers of the following compounds, The modified isomer is a compound with a long retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a long retention time is approximately 6.621 minutes; (5) The transisomers of the following compounds, The modified isomer is a compound with a short retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with the short retention time is approximately 6.208 minutes; (6) The transisomers of the following compounds, The modified isomer is a compound with a long retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a long retention time is approximately 6.272 minutes; (7) The transisomers of the following compounds, The modified isomer is a compound with a short retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with the short retention time is approximately 5.355 minutes; (8) The transisomers of the following compounds, The modified isomer is a compound with a long retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, from 40% to 90% for 2 minutes, and mobile phase B held at 90% for 6 minutes, at a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a long retention time is approximately 5.358 minutes; (9) The transisomers of the following compounds, The modified isomer is a compound with a short retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, from 40% to 90% for 2 minutes, and mobile phase B held at 90% for 6 minutes, at a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with the short retention time is approximately 5.373 minutes; (10) The transisomers of the following compounds, The modified isomer is a compound with a long retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a long retention time is approximately 5.399 minutes; (11) The transisomers of the following compounds, The modified isomer is a compound with a short retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with the short retention time is approximately 6.659 minutes; (12) The transisomers of the following compounds, The modified isomer is a compound with a long retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a long retention time is approximately 6.718 minutes; (13) The transisomers of the following compounds, The modified isomer is a compound with a short retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a longer retention time is approximately 6.655 minutes; (14) The transisomers of the following compounds, The modified isomer is a compound with a long retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a long retention time is approximately 6.679 minutes; (15) The transisomers of the following compounds, The modified isomer is a compound with a short retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under these conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, and mobile phase B held at 90% for 6 minutes, with a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a longer retention time is approximately 5.966 minutes; or, (16) The transisomers of the following compounds, The modified isomer is a compound with a long retention time under the following analytical conditions: the analytical column is a Waters ACQUITY UPLC BEH Shield RP18; mobile phase A is 5 mM potassium dihydrogen phosphate buffer (pH=2.5), and mobile phase B is acetonitrile; gradient elution is performed, with mobile phase B from 10% to 90% for 10-15 minutes; preferably, under the above conditions, the analytical column is a Waters ACQUITY UPLC BEH Shield RP18 2.1*100 mm, 1.7 μm, with gradient elution of mobile phase B from 10% to 40% for 5 minutes, mobile phase B from 40% to 90% for 2 minutes, mobile phase B held at 90% for 6 minutes, and a flow rate of 0.4 mL / min; more preferably, the retention time of the compound with a long retention time is approximately 6.158 minutes.

8. A pharmaceutical composition comprising: (1) The compound of formula (I) as described in any one of claims 1-7, and a pharmaceutically acceptable salt thereof, and (2) Pharmaceutically acceptable excipients.

9. The use of a compound of formula (I) as described in any one of claims 1-7 or a pharmaceutically acceptable salt thereof, or the use of a pharmaceutical composition as described in claim 8, in the preparation of a KRAS mutant inhibitor, preferably, the KRAS mutant inhibitor being a KRAS G12C mutant inhibitor.

10. The use of a compound of formula (I) as described in any one of claims 1-7 or a pharmaceutically acceptable salt thereof, or the use of a pharmaceutical composition as described in claim 8 in the preparation of a medicament for treating diseases associated with KRAS mutations; Preferably, the disease associated with KRAS mutation is a cancer associated with KRAS mutation; more preferably, the disease associated with KRAS mutation is selected from lung cancer, colorectal cancer, pancreatic cancer, or endometrial cancer. The preferred KRAS mutation is the KRAS G12C mutation.

11. A method for preparing a compound as shown in formula (I), wherein the method comprises any of the following: (1) Method 1: In a solvent, the compound shown in formula (IA) reacts with X-1 or X-2 under alkaline conditions to give the compound shown in formula (I). Method 1 in, R6 is C 2-6 alkenyl or C 2-6 alkynyl group; the C 2-6 alkenyl and C 2-6 Each of the alkynyl groups is optionally surrounded by one or more R groups. 6-a Replacement; X, Y, R1, R2, R3, R4, R5, R 6-a The definitions of R7, R8, R9, m, n, and q are as described in any one of claims 1-7; Preferably, in method 1, the solvent is tetrahydrofuran; the base is preferably triethylamine or N,N-diisopropylethylamine; the reaction temperature is preferably 0~35℃; and the reaction time is preferably 0.5~6 hours. (2) Method 2: In a solvent, the compound shown in formula (IA) and X-3 undergo a condensation reaction to obtain the compound shown in formula (I). Method 2 Where R6 is C 2-6 alkenyl or C 2-6 alkynyl group; the C 2-6 alkenyl and C 2-6 Each of the alkynyl groups is optionally surrounded by one or more R groups. 6-a Replacement; X, Y, R1, R2, R3, R4, R5, R 6-a The definitions of R7, R8, R9, m, n, and q are as described in any one of claims 1-7; Preferably, in method 2, the solvent is N,N-dimethylformamide; the condensing agent is HATU; the base is triethylamine or N,N-diisopropylethylamine; the reaction temperature is preferably 0~35℃; and the reaction time is preferably 0.5~6 hours. Alternatively, in method 1 or method 2, if R6 has an amino group, the amino group can be protected by a tert-butoxycarbonyl protecting group. If the above-mentioned amino protecting group is present, a further deprotection step is required to obtain the compound shown in formula (I). Preferably, the deprotection reaction is carried out in a dichloromethane / trifluoroacetic acid system.

12. A compound of formula (IA) or a pharmaceutically acceptable salt thereof, in, The definitions of X, Y, R1, R2, R3, R4, R5, R7, R8, R9, m, n, and q are as described in any one of claims 1-7; Preferably, the compound represented by formula (IA) is: , , or .

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