WO2021228161A1

WO2021228161A1 - Alkoxlyalkyl-substituted heterocyclic inhibitor, preparation method therefor, and use thereof

Info

Publication number: WO2021228161A1
Application number: PCT/CN2021/093444
Authority: WO
Inventors: 吕彬华; 崔大为; 刘连军; 韩涛
Original assignee: 苏州泽璟生物制药股份有限公司; 上海泽璟医药技术有限公司
Priority date: 2020-05-15
Filing date: 2021-05-12
Publication date: 2021-11-18
Also published as: CN113666923A

Abstract

The present invention relates to an alkoxlyalkyl-substituted heterocyclic inhibitor, preparation method therefor, and use thereof. Specifically, the compound of the present invention has a structure represented by formula (I). Further disclosed in the present invention are a preparation method for the compound, and a use of the compound as a KRASG12C inhibitor. The compound has an excellent ability to selectively inhibit KRASG12C, better pharmacodynamic and pharmacokinetic performance, and reduced toxic side effects.

Description

Alkoxyalkyl substituted heterocyclic group inhibitor and preparation method and application thereof

Technical field

The invention belongs to the field of medicine, and specifically relates to an alkoxyalkyl substituted heterocyclic group inhibitor and a preparation method and application thereof.

Background technique

Lung cancer is one of the important causes of human cancer deaths. According to the cell type, lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Among them, NSCLC accounts for 85% of all lung cancer patients. According to statistics, the global NSCLC market was approximately US$20.9 billion in 2016, of which the US market accounted for half, followed by Japan, Germany and China. Judging from current trends, the non-small cell lung cancer market has maintained continuous growth, and the global market is expected to reach 54 billion U.S. dollars in 2023 (Nature, 2018; 553(7689):446-454).

At present, the main therapeutic drugs for NSCLC are divided into chemotherapy drugs, molecular targeted drugs, and tumor immunotherapy. Among them, chemotherapeutic drugs mainly include gemcitabine, paclitaxel and platinum drugs, but these drugs generally have poor selectivity and high toxicity, which leads to relatively strong side effects. In recent years, molecular targeted drugs have gradually become research hotspots due to their high selectivity, relatively small side effects, and their obvious advantages such as precise treatment. Existing NSCLC molecular targeted drugs include EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocartinib, etc.) (Nil, etc.), and VEGFR inhibitors (Sorafenib, Regorafenib, Cabozantinib, Sunitinib, Donafenib, etc.) (Current Medicinal Chemistry, 2019, 26, 1-39).

In lung cancer patients, KRAS mutations are frequently detected, accounting for about 32% of all oncogene mutations. Among them, KRAS ^G12C mutation accounts for 44% of all oncogene mutations in NSCLC. So far, no ^{drugs targeting KRAS G12C} mutations have been approved on the market.

Since the KRAS ^G12C target protein is pathologically related to a variety of diseases, there is a need for new KRAS ^G12C inhibitors for clinical treatment. Highly selective and active KRAS ^G12C inhibitors can ^{more effectively treat cancers and other diseases caused by KRAS G12C} mutations, and reduce the potential for off-target effects, so they have more urgent clinical needs.

Summary of the invention

The purpose of the present invention is to provide a new class of ^compounds with selective inhibitory effect on KRAS G12C and/or better pharmacodynamic properties and uses thereof.

The first aspect of the present invention provides a compound represented by formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug:

Where:

A and B are the same or different, independently selected from CH or N;

X is selected from: a 4-14 membered saturated or unsaturated cycloalkyl or heterocyclic group, a C ₆ -C ₁₄ aryl group or a 5-14 membered heteroaryl group, wherein the saturated or unsaturated cycloalkyl group Or a heterocyclic group, an aryl group or a heteroaryl group may be optionally substituted ^{by one or more R 8;}

Y is selected from the following group: bond, O, S, NH, NR ⁵ , CR ⁵ R ⁶ , CONH, CONR ⁵ , SO ₂ NH, SO ₂ NR ⁵ , NHCO, NR ⁵ CO, NHSO ₂ , NR ⁵ SO ₂ ; Wherein, R ⁵ and R ^{6 are the} same or different, and are each independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halogen Substituted C ₁ -C ₁₈ alkyl, C ₃ -C ₂₀ cycloalkyl, C ₁ -C ₁₈ alkoxy, deuterated C ₁ -C ₁₈ alkoxy, halogenated C ₁ -C ₁₈ alkoxy, amino , Hydroxyl, 4-20 membered heterocyclic group, C ₆ -C ₁₄ aryl group, 5-14 membered heteroaryl group;

Z is selected from the following group: bond, C ₁ -C ₁₈ alkylene, deuterated C ₁ -C ₁₈ alkylene, halogenated C ₁ -C ₁₈ alkylene, C ₃ -C ₂₀ cycloalkylene, 4 -20-membered heterocyclylene, C ₁ -C ₁₈ alkyleneoxy, deuterated C ₁ -C ₁₈ alkyleneoxy, halogenated C ₁ -C ₁₈ alkyleneoxy;

R ^{1 is} selected from the following group:

in,

Represents double bond "=" or triple bond "≡";

R ^A is absent, or independently selected from: hydrogen, deuterium, fluoro, cyano or C ₁ -C ₃ alkyl;

Each R ^{B is} independently selected from: hydrogen, deuterium, cyano or C ₁ -C ₃ alkyl;

Wherein, ^{the alkyl group in R A} and R ^B may be substituted by one or more substituents selected from the following group: deuterium, halogen, cyano, amino, C ₃ -C ₇ cycloalkyl, 4-7 member Heterocyclic group, NHR ¹⁰ or NR ¹⁰ R ¹¹ ; wherein R ¹⁰ and R ¹¹ are each independently a C ₁ -C ₃ alkyl group;

R ^{2 is} selected from the following group: -(CH ₂ ) _n , -(CH ₂ ) _n O(CH ₂ ) _q , -(CH ₂ ) _n S, -(CH ₂ ) _n CO, -(CH ₂ ) _n C (O)O, -(CH ₂ ) _n S(O) _q , -(CH ₂ ) _n NR ⁵ , -(CH ₂ ) _n C(O)NR ⁵ , -(CH ₂ ) _n NR ⁵ C(O ), -(CH ₂ ) _n NR ⁵ C(O)NR ⁵ , -(CH ₂ ) _n S(O) _q NR ⁵ , -(CH ₂ ) _n NR ⁵ S(O) _q , -(CH ₂ ) _n NR ⁵ S(O) _q NR ⁵ , where H in _{CH 2} can be replaced ^{by R 8;}

R ^{3 is} independently selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, cyano, =0, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogenated C ₁ -C ₃ alkyl or C ₃ -C ₆ cycloalkyl;

L is selected from the following group: bond, -C(O)-, C ₁ -C ₃ alkylene;

R ^{4 is} selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halogenated C ₁ -C ₁₈ alkyl, C ₃ -C ₂₀ cycloalkyl, C ₁ -C ₁₈ alkoxy, deuterated C ₁ -C ₁₈ alkoxy, halogenated C ₁ -C ₁₈ alkoxy, amino, hydroxyl, 4-20 membered heterocyclic group, C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl;

Ring C is a 4-20 membered heterocyclylene; wherein, the 4-20 membered heterocyclylene may be optionally substituted ^{by one or more R 8;}

R ^{7 is} independently -R ¹² -OR ¹³ , wherein R ¹² is a substituted or unsubstituted C ₁ -C ₆ alkylene group, and R ¹³ is a substituted or unsubstituted C ₁ -C ₆ alkyl group, C _3- C ₈ cycloalkyl;

R ^{8 is} independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halo C ₁ -C ₁₈ alkyl, C ₃ -C ₂₀ cycloalkyl, C ₁ -C ₁₈ alkoxy, deuterated C ₁ -C ₁₈ alkoxy, halogenated C ₁ -C ₁₈ alkoxy, amino, hydroxyl, C ₃ -C ₂₀ cycloalkane Group, 4-20 membered heterocyclylene, 4-20 membered heterocyclic group, C ₆ -C ₁₄ aryl group, 5-14 membered heteroaryl group;

R ^{9 is} independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halo C ₁ -C ₁₈ alkyl, C ₃ -C ₂₀ cycloalkyl, C ₁ -C ₁₈ alkoxy, deuterated C ₁ -C ₁₈ alkoxy, halogenated C ₁ -C ₁₈ alkoxy, C ₆ -C ₁₄ aryl, 5-14 member Heteroaryl, 4-20 membered heterocyclic group, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or ureido group;

Wherein, unless otherwise specified, the above substitution refers to substitution by one or more groups selected from the following group: hydrogen, deuterium, C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halogenated C ₁ -C ₁₈ alkyl, C ₃ -C ₂₀ cycloalkyl, C ₁ -C ₁₈ alkoxy, deuterated C ₁ -C ₁₈ alkoxy, halogenated C ₁ -C ₁₈ alkoxy, C _6- C ₁₄ aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea group;

m is an integer of 0, 1, 2 or 3;

n is an integer of 0, 1, 2, 3, 4 or 5;

p is an integer of 1 or 2;

q is an integer of 0, 1, 2, 3, 4 or 5;

s is an integer of 1, 2 or 3;

t is an integer of 0, 1, 2 or 3.

In another preferred example, X is selected from: 4-14 membered saturated or unsaturated cycloalkyl or heterocyclic group, wherein the saturated or unsaturated cycloalkyl or heterocyclic group can be optionally One or more substituted or unsubstituted C ₁ -C ₁₈ alkyl groups, preferably substituted or unsubstituted C ₁ -C ₃ alkyl groups, wherein the substitution refers to substitution by cyano or halogen.

In another preferred embodiment, the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have Structure shown in general formula (II-A) or (II-B):

Where:

The definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁹ , A, B, C, X, Y, Z, L, m, s, and t are as described above.

In another preferred embodiment, the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs are characterized by Is that it has the structure shown in formula (III):

The definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁹ , C, X, Y, Z, L, m, s, and t are as described above.

In another preferred embodiment, the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have The structure shown in formula (IV):

Where:

The definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , C, Y, Z, L, m, s, and t are as described above.

In another preferred embodiment, the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have The structure shown in formula (V):

Where:

The definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , C, Y, Z, m, s, and t are as described above.

In another preferred embodiment, the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have The structure shown in formula (VI):

Where:

The definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , C, Z, m, s, and t are as described above.

In another preferred embodiment, the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have The structure shown in formula (VII):

Where:

The definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , C, m, s, and t are as described above.

In another preferred embodiment, the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, R ⁴ Selected from substituted or unsubstituted groups from the following group: C ₆ -C ₁₄ aryl groups, 5-14 membered heteroaryl groups; wherein, the substitution refers to substitution by one or more groups selected from the following group: hydrogen , Deuterium, C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halo C ₁ -C ₁₈ alkyl, C ₃ -C ₂₀ cycloalkyl, C ₁ -C ₁₈ alkoxy, deuterium Substituted C ₁ -C ₁₈ alkoxy, halogenated C ₁ -C ₁₈ alkoxy, C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic group, halogen, nitro, Hydroxyl group, cyano group, ester group, amine group, amide group, sulfonamide group or urea group.

In another preferred embodiment, R ^{4 is} selected from substituted or unsubstituted C ₆ -C ₁₀ aryl groups, preferably substituted or unsubstituted phenyl or naphthyl, wherein the substitution means being selected from the following group Substitution of one or more groups: C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halo C ₁ -C ₁₈ alkyl, C ₃ -C ₂₀ cycloalkyl, C ₁ -C ₁₈ alkoxy, deuterated C ₁ -C ₁₈ alkoxy, halogenated C ₁ -C ₁₈ alkoxy, C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic group , Halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea group.

In another preferred embodiment, R ^{4 is} selected from substituted or unsubstituted 5-10 membered heteroaryl groups, preferably substituted or unsubstituted pyridine, benzopyrazole, benzimidazole, benzothiazole, benzoxazole Azoles, wherein the substitution refers to substitution by one or more groups selected from the following group: C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halogenated C ₁ -C ₁₈ alkyl , C ₃ -C ₂₀ cycloalkyl, C ₁ -C ₁₈ alkoxy, deuterated C ₁ -C ₁₈ alkoxy, halogenated C ₁ -C ₁₈ alkoxy, C ₆ -C ₁₄ aryl, 5 -14 membered heteroaryl group, 4-20 membered heterocyclic group, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or ureido group.

In another preferred embodiment, ring C is a 4-8 membered heterocyclylene, which may be optionally substituted with one or more R ⁸ , wherein R ^{8 is} independently selected from the following group of substituted or unsubstituted groups : Hydrogen, deuterium, C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halo C ₁ -C ₁₈ alkyl, C ₃ -C ₂₀ cycloalkyl, C ₁ -C ₁₈ alkoxy , Deuterated C ₁ -C ₁₈ alkoxy, halogenated C ₁ -C ₁₈ alkoxy, amino, hydroxyl, C ₃ -C ₂₀ cycloalkylene, 4-20 membered heterocyclylene, 4-20 membered Heterocyclic group, C ₆ -C ₁₄ aryl group, 5-14 membered heteroaryl group;

The substitution refers to substitution by one or more groups selected from the group consisting of hydrogen, deuterium, C ₁ -C ₆ alkyl, deuterated C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl , C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkoxy, deuterated C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkoxy, halogen, nitro, hydroxyl, cyano , Ester group, amino group.

In another preferred example, ring C is selected from the following group:

Wherein, Y ₁ and Y ₂ are each independently selected from: O, CO, CS, S, SO, SO ₂ , PO, NR ¹⁴ or CR ¹⁵ R ¹⁶ , f is 0, 1, 2 or 3; wherein, R ¹⁴ Selected from: H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, substituted or unsubstituted 5-14 membered heteroaryl; R ¹⁵ and R ¹⁶ are each independently selected from: H, D, halogen, cyano, hydroxyl, substituted or unsubstituted C _1- C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted Or unsubstituted C ₆ -C ₁₄ aryl, substituted or unsubstituted 5-14 membered heteroaryl; the restriction is that one of Y ₁ and Y ₂ must be selected from: O, S, SO, SO ₂ , PO , Or NR ¹⁴ ;

Wherein, the substitution refers to substitution by one or more groups selected from the following group: hydrogen, deuterium, C ₁ -C ₆ alkyl, deuterated C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ Alkyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkoxy, deuterated C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkoxy, halogen, nitro, hydroxyl, Cyano groups, ester groups, amine groups. In another preferred embodiment, R ^{3 is} independently selected from the group consisting of hydrogen, deuterium, C ₁ -C ₃ alkyl, halogenated C ₁ -C ₃ alkyl, or C ₃ -C ₆ cycloalkyl.

In another preferred embodiment, R ^{3 is} independently selected from the following group: deuterium, C ₁ -C ₃ alkyl, halogenated C ₁ -C ₃ alkyl, or C ₃ -C ₆ cycloalkyl.

In another preferred embodiment, R ^{7 is} independently -R ¹² -OR ¹³ , wherein R ¹² is a substituted or unsubstituted C ₁ -C ₆ alkylene group, and R ¹³ is a substituted or unsubstituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl;

Ring C is selected from the following group:

Wherein, Y ₁ and Y ₂ are each independently selected from: O, NR ¹⁴ or CR ¹⁵ R ¹⁶ , and f is 0, 1, 2 or 3; wherein, R ^{14 is} selected from: H, substituted or unsubstituted C _1- C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, substituted or unsubstituted R ¹⁵ and R ¹⁶ are each independently selected from: H, D, halogen, cyano, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C _1- C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, substituted Or unsubstituted 5-14 membered heteroaryl; the restriction is that one of Y ₁ and Y ₂ must be selected from: O or NR ¹⁴ ;

Wherein, the substitution refers to substitution by one or more groups selected from the following group: H, D, halogen, cyano, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl.

In another preferred embodiment, R ^{9 is} independently selected from the following substituted or unsubstituted groups: hydrogen, deuterium, C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halo C _1- C ₁₈ alkyl, C ₃ -C ₂₀ cycloalkyl, C ₁ -C ₁₈ alkoxy, deuterated C ₁ -C ₁₈ alkoxy, halogenated C ₁ -C ₁₈ alkoxy, C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or ureido group;

R ^{7 is} independently -R ¹² -OR ¹³ , wherein R ¹² is a substituted or unsubstituted C ₁ -C ₃ alkylene group, and R ¹³ is a substituted or unsubstituted C ₁ -C ₃ alkyl group, C _3- C ₆ cycloalkyl;

Ring C is selected from the following group:

Wherein, Y ₁ and Y ₂ are each independently selected from: NR ¹⁴ or CR ¹⁵ R ¹⁶ , and f is 0, 1, 2 or 3; wherein, R ^{14 is} selected from: H, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, substituted or unsubstituted 5 -14 membered heteroaryl; R ¹⁵ and R ¹⁶ are each independently selected from: H, D, halogen, cyano, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C _1- C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, substituted or unsubstituted Substituted 5-14 membered heteroaryl; the restriction is that one of Y ₁ and Y ₂ must be selected from NR ¹⁴ ;

In another preferred embodiment, R ^{9 is} independently H, C ₁ -C ₆ alkyl.

In another preferred embodiment, R ^{8 is} independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C ₁ -C ₃ alkyl, deuterated C ₁ -C ₃ alkyl, C ₁ -C ₃ Alkoxy, deuterated C ₁ -C ₃ alkoxy, amino, and hydroxy; wherein, the substitution refers to substitution by one or more groups selected from the following group: halogen, cyano, amino, and hydroxy.

In another preferred example, f is 1.

In another preferred embodiment, ring C is selected from:

In another preferred embodiment, ring C is

Wherein, Y ₁ is NR ¹⁴ , Y ₂ is CR ¹⁵ R ¹⁶ , and f is 0, 1 or 2; wherein, R ^{14 is} selected from: H, substituted or unsubstituted C ₁ -C ₆ alkyl; R ¹⁵ and R ¹⁶ are each independently selected from: H, D, halogen, cyano, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy.

In another preferred example, X is a 6-11 membered bicyclic heterocyclic group, wherein the heterocyclic group may be ^{substituted by R 8} ; R ^{8 is} independently selected from the following group of substituted or unsubstituted groups: hydrogen, Deuterium, C ₁ -C ₃ alkyl, deuterated C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, deuterated C ₁ -C ₃ alkoxy; wherein the substitution refers to being selected from One or more of the following groups are substituted: halogen, cyano, amino, and hydroxyl.

In another preferred embodiment, R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁹ , A, B, C, X, Y, Z, L, m, s, and t are each in the embodiment. Specific groups corresponding to specific compounds.

In another preferred embodiment, the compound is selected from the following group:

In another preferred example, the compound is selected from the compounds shown in the examples.

The second aspect of the present invention provides a method for preparing a compound of formula (III), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs , Which is characterized in that it includes the steps:

(i) In the presence of a base in an inert solvent, the compound of formula V-1 and diamine-based compounds

One of the amine groups in is reacted and then reacted with the amino protecting agent to obtain the compound of formula V-2;

(ii) In an inert solvent, in the presence of a deprotecting agent, the compound of formula V-2 is deprotected to obtain a compound of formula V-3;

(iii) In an inert solvent, in the presence of a base, the compound of formula V-3 and

Coupling, substitution or acylation reaction occurs to obtain a compound of formula V-4;

(iv) In an inert solvent, the compound of formula V-4 is reacted with an oxidizing agent to obtain a compound of formula V-5;

(v) In an inert solvent, in the presence of a base, the compound of formula V-5 and

The reaction produces a compound of formula V-6;

(vi) In an inert solvent, in the presence of an acid, the compound of formula V-6 is deprotected to obtain the compound of formula V-7;

(vii) In an inert solvent, in the presence of a base and a catalyst, the formula V-7 is reacted with GR ¹ to obtain the compound of formula (III);

Among them, G is OH, F, Cl, -O-CO-R ¹ , -O-CO-CH ₂ CH(CH ₃ ) ₂ , -OBt,

Wait;

Where

Q is a leaving group, such as halogen, OH, -O-CO-R ⁴ -O-CO-CH ₂ CH(CH ₃ ) ₂ , OMs, OTs, OTf, B(OH) ₂ , B(OMe) ₂ or

Wait;

Rs and Rs' are protecting groups for amino, and the protecting groups are selected from: Boc, Bn, Cbz or Fmoc;

R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁹ , A, B, C, L, X, Y, Z, m, s, and t are as defined above.

In another preferred example, in the step (i), the base is TEA or DIPEA.

In another preferred embodiment, in the step (i), the inert solvent is selected from: DMSO.

In another preferred embodiment, in the step (i), the amino protecting agent is selected from: (Boc) ₂ O, benzyl chloroformate, di-tert-butyl dicarbonate, phthaloyl chloride, benzyl chloride, triphenyl Methyl chloromethane, 9-fluorenyl methyl chloroformate, allyl chloroformate.

In another preferred embodiment, in the step (ii), the deprotection agent is 1-chloroethyl chloroformate.

In another preferred embodiment, in the step (ii), the inert solvent is selected from dichloromethane.

In another preferred example, in the step (iii), the inert solvent is selected from: dioxane.

In another preferred embodiment, in the step (iii), the base is cesium carbonate.

In another preferred embodiment, in the step (iv), the oxidizing agent is mCPBA.

In another preferred embodiment, in the step (iv), the inert solvent is selected from ethyl acetate.

In another preferred example, in the step (v), the base is sodium alkoxide, potassium alkoxide, NaH or LiHNMDS, preferably sodium tert-butoxide or potassium tert-butoxide.

In another preferred embodiment, in the step (v), the inert solvent is selected from toluene.

In another preferred embodiment, in the step (vi), the acid is TFA.

In another preferred embodiment, in the step (vi), the inert solvent is selected from dichloromethane.

In another preferred embodiment, in the step (vii), the inert solvent is selected from: DMF.

In another preferred example, in the step (vii), the base is TEA or DIPEA.

In another preferred example, in the step (vii), the condensing agent is HATU.

The third aspect of the present invention provides a pharmaceutical composition comprising one or more of the compounds described in the first aspect, their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrated Substances, solvates or prodrugs; and pharmaceutically acceptable carriers.

In another preferred embodiment, the pharmaceutical composition further comprises a drug selected from the following group: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemipilimab, JS-001, SHR-120, BGB-A317, IBI- 308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biological analogues of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I- tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI -1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, okatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.) ), BTK inhibitors (e.g. Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (e.g. Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Naquotinib, etc.) VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib, S unitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Milciclib, Trilaciclib, etc.) Etc.), MEK inhibitors (e.g. Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (e.g. Vistusertib, etc.), SHP2 inhibitors (Such as RMC-4630, JAB-3068, TNO155, etc.) or a combination thereof.

The fourth aspect of the present invention provides a compound of the first aspect, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or The use of the pharmaceutical composition described in the third aspect is to prepare a pharmaceutical composition for preventing and/or treating diseases related to the activity or expression of ^{KRAS G12C.}

In another preferred example, the disease is a tumor or a disordered disease.

In another preferred embodiment, the disease is selected from the following group: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, gastric cancer, liver cancer, colorectal cancer, melanoma, lymphoma, blood cancer , Brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.

The fifth aspect of the present invention provides a non-diagnostic and non-therapeutic method for inhibiting KRAS ^G12C , which comprises the steps of: administering an effective amount of the compound, its stereoisomers, and tautomers to the patient in need Constructs, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administration of the above-mentioned pharmaceutical composition.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as the embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, I will not repeat them one by one here.

Detailed ways

After long-term and in-depth research, the inventors unexpectedly prepared a new type of KRAS ^{G12C compound} with selective inhibition and/or better pharmacodynamic properties. On this basis, the inventor completed the present invention.

the term

In the present invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

The term "alkyl" refers to a straight or branched chain or cyclic alkane group containing 1-20 carbon atoms, such as 1-18 carbon atoms, especially 1-18 carbon atoms, preferably 1-10 carbon atoms The carbon atom, more preferably contains 1-6 carbon atoms. Typical "alkyl" includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl,

Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and many more.

The term "C1-C18 alkyl" refers to straight or branched chain or cyclic alkyl, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17 or 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl

N-butyl, tert-butyl, isobutyl (e.g.

), n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl. In the present invention, the alkyl group also includes a substituted alkyl group. "Substituted alkyl" means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, single halogen substituent or polyhalogen substituent, the latter such as trifluoromethyl or _{alkyl containing Cl 3} ), Nitrile, nitro, oxygen (such as =0), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR _a , SR _a , S(=O)R _e , S(=O) ₂ R _e , P(=O) ₂ R _e , S(=O) ₂ OR _e , P(=O) ₂ OR _e , NR _b R _c , NR _b S(=O) ₂ R _e , NR _b P(=O) ₂ R _e , S(=O) ₂ NR _b R _c , P(=O) ₂ NR _b R _c , C(=O)OR _d , C(=O)R _a , C(=O)NR _b R _c , OC(=O)R _a , OC(=O)NR _b R _c , NR _b C(=O)OR _e ,NR _d C (=O)NR _b R _c , NR _d S(=O) ₂ NR _b R _c , NR _d P(=O) ₂ NR _b R _c , NR _b C(=O)R _a , or NR _b P( =O) ₂ R _e , where R _a appearing here can independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 Alkynyl, 5-14 membered heterocycle or C6-C14 aromatic ring, R _b , R _c and _Rd can independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, 5-14 membered heterocycle Or C6-C14 aromatic ring, or R _b and R _c together with N atom can form a heterocyclic ring; R _e can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3 -C6 cycloalkenyl, C2-C6 alkynyl, 5-14 membered heterocyclic ring or C6-C14 aromatic ring. The above-mentioned typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring may be optionally substituted.

The term "alkylene" refers to a group formed by the removal of a hydrogen atom from the "alkyl" group, such as methylene, ethylene, propylene, isopropylene (such as

), butylene (e.g.

), pentylene (e.g.

), hexyl (e.g.

), Heptyl (e.g.

)Wait.

The term "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene" has the same meaning and refers to the removal of cycloalkylalkyl or alkylcycloalkyl A group formed by two hydrogen atoms, such as

Wait.

The term "cycloalkyl" refers to complete saturation containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms The cyclic hydrocarbon group includes 1-4 rings, each of which contains 3-8 carbon atoms. Preferably it is a C ₃ -C ₂₀ cycloalkyl group, more preferably a C ₃ -C ₁₈ cycloalkyl group, more preferably a C ₃ -C ₁₀ cycloalkyl group, more preferably a C ₃ -C ₆ cycloalkyl group . "Substituted cycloalkyl" means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which can be substituted at any position. In the present invention, "cycloalkyl" includes substituted cycloalkyl. Typical substitutions include but are not limited to one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., single halogen substituent or polyhalogen substituent, later Such as trifluoromethyl or _{alkyl containing Cl 3} ), nitrile, nitro, oxygen (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, Alkynyl, heterocycle, aromatic ring, OR _a , SR _a , S(=O)R _e , S(=O) ₂ R _e , P(=O) ₂ R _e , S(=O) ₂ OR _e , P(=O) ₂ OR _e , NR _b R _c , NR _b S(=O) ₂ R _e , NR _b P(=O) ₂ R _e , S(=O) ₂ NR _b R _c , P(= O) ₂ NR _b R _c , C(=O)OR _d , C(=O)R _a , C(=O)NR _b R _c , OC(=O)R _a , OC(=O)NR _b R _c , NR _b C(=O)OR _e , NR _d C(=O)NR _b R _c , NR _d S(=O) ₂ NR _b R _c , NR _d P(=O) ₂ NR _b R _c , _{NR b C (= O) R} a, or _{_{NR b P (= O) 2}} R e, wherein R _a occurring here can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, Alkynyl, heterocyclic or aromatic ring, R _b , R _c and _Rd can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R _b and R _c together with N atom can form Heterocycle; R _e can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aromatic ring. The above-mentioned typical substituents may be optionally substituted. Typical substitutions also include spirocyclic, bridged or fused ring substituents, especially spirocyclic alkyl, spirocycloalkenyl, spirocyclic heterocycle (excluding heteroaromatic rings), bridged cycloalkyl, bridged cycloalkenyl, Bridged heterocyclic ring (excluding heteroaromatic ring), fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aromatic The group can be optionally substituted.

The term "C3-C20 cycloalkylene" refers to a group formed by removing two hydrogen atoms from a cycloalkyl group, such as:

Wait.

The term "heterocyclyl" refers to complete saturation containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms Or partially unsaturated cyclic groups (including but not limited to such as 3-7 membered monocyclic ring, 6-11 membered bicyclic ring, or 8-16 membered tricyclic ring system), in which at least one heteroatom is present in at least A ring of carbon atoms. Each heterocyclic ring containing heteroatoms can have 1, 2, 3 or 4 heteroatoms. These heteroatoms are selected from nitrogen atoms, oxygen atoms or sulfur atoms. The nitrogen atom or sulfur atom can be oxidized, and the nitrogen atom can also be Is quaternized. The heterocyclic group can be attached to any heteroatom or carbon atom residue of the ring or ring system molecule. Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidine Group, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepine Inyl group, 4-piperidinone group, tetrahydropyranyl group, morpholino group, thiomorpholino group, thiomorpholine sulfoxide group, thiomorpholine sulfone group, 1,3-dioxanyl group and Tetrahydro-1,1-dioxythiophene, etc. Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected to other groups through a single bond, or through a ring Any two or more of the above atoms are further connected to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups; the heterocyclic group may be substituted or unsubstituted. When substituted, The substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxy, and carboxylate.

The term "4-20 membered heterocyclylene" refers to a group formed by removing two or more hydrogen atoms from a heterocyclic group, such as:

Wait. Among them, the H of NH may be further substituted; when substituted, the substituent is preferably alkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl Group, alkoxyalkyl, hydroxyalkyl, aminoalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl.

The term "aryl" refers to an aromatic cyclic hydrocarbon compound group containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring carbon atoms, with 1-5 rings, especially monocyclic And bicyclic groups such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic ring of the aryl group can be connected by a single bond (such as biphenyl) or condensed (such as naphthalene, anthracene, etc.). "Substituted aryl" means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, single halogen substituent or polyhalogen substituent, the latter such as trifluoromethyl or _{alkyl containing Cl 3} ), Nitrile, nitro, oxygen (such as =0), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR _a , SR _a , S(=O)R _e , S(=O) ₂ R _e , P(=O) ₂ R _e , S(=O) ₂ OR _e , P(=O) ₂ OR _e , NR _b R _c , NR _b S(=O) ₂ R _e , NR _b P(=O) ₂ R _e , S(=O) ₂ NR _b R _c , P(=O) ₂ NR _b R _c , C(=O)OR _d , C(=O)R _a , C(=O)NR _b R _c , OC(=O)R _a , OC(=O)NR _b R _c , NR _b C(=O)OR _e ,NR _d C (=O)NR _b R _c , NR _d S(=O) ₂ NR _b R _c , NR _d P(=O) ₂ NR _b R _c , NR _b C(=O)R _a , or NR _b P( = O) ₂ R _e, wherein R _a occurring here can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R _b, R _c, and R _d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R _b and R _c together with the N atom can form a heterocyclic ring; R _e can independently represent hydrogen, deuterium, alkyl, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring. The above-mentioned typical substituents may be optionally substituted. Typical substitutions also include fused ring substituents, especially fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aromatic The group can be optionally substituted.

The term "heteroaryl" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms, where the heteroatoms are selected from oxygen, nitrogen and sulfur. The heteroaryl group is preferably a 5- to 10-membered ring, more preferably 5-membered or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , Furyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazole and tetrazolyl, etc. "Heteroaryl" may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, and alkoxy , Haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkane Sulfur group, oxo group, carboxyl group and carboxylate group.

The term "C1-C18 alkoxy" refers to a linear or branched or cyclic alkoxy group having 1 to 18 carbon atoms, including C1-C18 alkyl-O-, -C1-C6 alkyl-O- The C1-C6 alkyl group includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. It is preferably a C1-C8 alkoxy group, and more preferably a C1-C6 alkoxy group.

The term "C1-C18 alkoxy" refers to a group obtained by removing one hydrogen atom from the "C1-C18 alkoxy".

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

The term "halo" refers to substitution by halogen.

The term "deuterated" refers to substitution by deuterium.

The term "hydroxyl" refers to a group with the structure OH.

The term "nitro" refers to a group _{bearing the structure NO 2.}

The term "cyano" refers to a group with the structure CN.

The term "ester group" refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aromatic Group or substituted aryl, heterocycle or substituted heterocycle.

The term "amino" refers to a group with the structure -NRR', where R and R'can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R and R'may be the same or different in the dialkylamine segment.

The term "amido" refers to a group with the structure -CONRR', where R and R'can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R and R'may be the same or different in the dialkylamine segment.

The term "sulfonamido" refers to a group with the structure -SO ₂ NRR', where R and R'can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, ring Alkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R and R'may be the same or different in the dialkylamine segment.

The term "ureido" refers to a group with the structure -NRCONR'R", where R, R'and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl , Cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R'and R" may be the same or different in the dialkylamine segment.

The term "alkylaminoalkyl" refers to a group with the structure -RNHR', where R and R'can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, Cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R and R'can be the same or different.

The term "dialkylaminoalkyl" refers to a group with the structure -RNHR'R", where R, R'and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted Cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R, R'and R" may be the same or different in the dialkylamine segment.

The term "alkoxyalkyl" refers to a group with the structure -ROR', where R and R'can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl Or substituted cycloalkenyl, aryl or substituted aryl.

The term "heterocyclylalkyl" refers to a group with the structure -RR', where R can independently represent an alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted Cycloalkenyl, aryl or substituted aryl; R'represents heterocycle or substituted heterocycle.

In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position. Those skilled in the art should understand that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. The substituents such as (but not limited to): halogen, hydroxyl, cyano, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, and C1-C6 ureido and so on.

Unless otherwise stated, it is assumed that any heteroatom with a dissatisfaction valence state has enough hydrogen atoms to supplement its valence state.

When a substituent is a non-terminal substituent, it is a subunit of the corresponding group, for example, an alkyl group corresponds to an alkylene group, a cycloalkyl group corresponds to a cycloalkylene group, a heterocyclic group corresponds to a heterocyclylene group, and an alkoxy group corresponds to Alkyleneoxy and so on.

In the present invention, the term "plurality" means 2, 3, 4, 5 independently.

Active ingredient

As used herein, the terms "compounds of the present invention" or "active ingredients of the present invention" are used interchangeably and refer to compounds of formula (I), their stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable The salt, hydrate, solvate or prodrug of. The term also includes racemates and optical isomers.

The compound of formula (I) has the following structure:

Preferably, the compound of formula (I) has a structure represented by general formula (II-A) or (II-B):

Where:

Preferably, the compound of formula (I) has the structure shown in formula (III):

Preferably, the compound of formula (I) has the structure shown in formula (IV):

Where:

Preferably, the compound of formula (I) has the structure shown in formula (V):

Where:

Preferably, the compound of formula (I) has the structure shown in formula (VI):

Where:

Preferably, the compound of formula (I) has the structure shown in formula (VII):

Where:

Preferably, in the compound as described above, R ⁴ is a substituted or unsubstituted C ₆ -C ₁₄ aryl group, a 5-14 membered heteroaryl group; more preferably a C6-C10 aryl group (such as substituted or unsubstituted Phenyl or naphthyl) or 5-10 membered heteroaryl (such as substituted or unsubstituted pyridine, benzopyrazole, benzimidazole, benzothiazole, benzoxazole), wherein the substitution refers to One or more group substitutions selected from the following group: C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halogenated C ₁ -C ₁₈ alkyl, C ₃ -C ₂₀ cycloalkyl, C ₁ -C ₁₈ alkoxy, deuterated C ₁ -C ₁₈ alkoxy, halogenated C ₁ -C ₁₈ alkoxy, C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 4-20 Member heterocyclic group, halogen, nitro group, hydroxyl group, cyano group, ester group, amine group, amide group, sulfonamide group or urea group.

Preferably, in the compound as described above, ring C is a 4-8 membered heterocyclylene; preferably ring C is selected from the following group:

Wherein, Y ₁ , Y ₂ , and f are as defined above, preferably Y ₁ and Y ₂ are each independently NR ¹⁴ or CR ¹⁵ R ¹⁶ , wherein R ^{14 is} selected from: H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, substituted or Unsubstituted 5-14 membered heteroaryl; R ¹⁵ and R ¹⁶ are each independently selected from: H, D, halogen, cyano, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₄ aryl , Substituted or unsubstituted 5-14 membered heteroaryl; the restriction is that one of Y ₁ and Y ₂ must be selected from NR ¹⁴ ; wherein, the substitution refers to one or more groups selected from the following group Substitution: H, D, halogen, cyano, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl.

Preferably, in the compound as described above, R ^{3 is} independently selected from the group consisting of hydrogen, deuterium, C ₁ -C ₃ alkyl, halo C ₁ -C ₃ alkyl or C ₃ -C ₆ cycloalkyl.

Preferably, in the compound as described above, R ^{8 is} independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C ₁ -C ₃ alkyl, deuterated C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, deuterated C ₁ -C ₃ alkoxy, amino, hydroxy; wherein, the substitution refers to substitution by one or more groups selected from the following group: halogen, cyano, amino, Hydroxy.

Preferably, in the compound as described above, R ^{9 is} independently H, C ₁ -C ₆ alkyl.

Preferably, in formula (VII), R ^{4 is} selected from the following group of substituted or unsubstituted groups: phenyl, naphthyl,

R ^{3 is} independently selected from the group consisting of hydrogen, deuterium, C ₁ -C ₃ alkyl, halo C ₁ -C ₃ alkyl, or C ₃ -C ₆ cycloalkyl;

m is 0 or 1;

Ring C is

Wherein, Y ₁ is NR ¹⁴ , Y ₂ is CR ¹⁵ R ¹⁶ , and f is 0, 1 or 2; wherein, R ^{14 is} selected from: H, substituted or unsubstituted C ₁ -C ₆ alkyl; R ¹⁵ and R ¹⁶ are each independently selected from: H, D, halogen, cyano, hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy;

R ^{8 is} independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C ₁ -C ₃ alkyl, deuterated C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, deuterated C ₁ -C ₃ alkoxy; wherein, the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, amino, and hydroxy;

t is 0;

Unless otherwise specified, the above substitution refers to substitution by one or more groups selected from the following group: D, halogen, cyano, hydroxyl, C ₁ -C ₆ alkyl.

Preferably, in the present invention, X is selected from: 6-11 membered bicyclic heterocyclic group, wherein the heterocyclic group may be ^{substituted by R 8} ; R ^{8 is} independently selected from the following groups of substituted or unsubstituted: Hydrogen, deuterium, C ₁ -C ₃ alkyl, deuterated C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, deuterated C ₁ -C ₃ alkoxy; wherein, the substitution refers to One or more group substitutions selected from the following group: halogen, cyano, amino, and hydroxyl.

Salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise specified, the compounds in the present invention are understood to include their salts. The term "salt" as used herein refers to a salt formed into an acid or basic form with an inorganic or organic acid and a base. In addition, when the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and when it contains an acidic fragment, including but not limited to carboxylic acid, the zwitterion ("internal salt") that may be formed is contained in Within the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, they can be used in separation or purification steps in the preparation process. The compound of the present invention may form a salt. For example, the compound I can be obtained by reacting with a certain amount of acid or base, such as an equivalent amount, to salt out in the medium, or freeze-drying in an aqueous solution.

The basic fragments contained in the compounds of the present invention, including but not limited to amines or pyridine or imidazole rings, may form salts with organic or inorganic acids. Typical acids that can form salts include acetate (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, and benzoate. , Benzene sulfonate, hydrogen sulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate, Ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, isethionate (E.g. 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g. 2-naphthalenesulfonate), nicotinate, nitrate, oxalic acid Salt, pectinate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfate (such as formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as p-toluenesulfonate, dodecanoate, etc.

The acidic fragments that some compounds of the present invention may contain, including but not limited to carboxylic acids, may form salts with various organic or inorganic bases. Typical salts formed by bases include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed by organic bases (such as organic amines), such as benzathine and bicyclohexyl Amine, Hypamine (a salt formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butyl Base amines, and salts with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecular alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (E.g., dimethyl sulfate, diethyl, dibutyl and dipentyl sulfate), long-chain halides (such as chlorides and bromides of decyl, dodecyl, tetradecyl and tetradecyl) And iodide), aralkyl halide (such as benzyl and phenyl bromide) and so on.

The prodrugs and solvates of the compounds of the present invention are also covered. The term "prodrug" herein refers to a compound that undergoes metabolism or chemical transformation through a chemical process to produce the compound, salt, or solvate of the present invention when treating related diseases. The compounds of the present invention include solvates such as hydrates.

The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imine ethers). All these tautomers are part of the invention.

All stereoisomers of compounds (for example, those asymmetric carbon atoms that may exist due to various substitutions), including their enantiomeric and diastereomeric forms, fall within the scope of the present invention. The independent stereoisomers of the compound in the present invention may not coexist with other isomers (for example, as a pure or substantially pure optical isomer with special activity), or may be a mixture, such as Racemates, or mixtures with all other stereoisomers or part of them. The chiral center of the present invention has two configurations, S or R, defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. The racemic form can be resolved by physical methods, such as fractional crystallization, or separation of crystallization by derivatization into diastereomers, or separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to traditional methods, such as salt formation with an optically active acid and recrystallization.

In the compound of the present invention, the weight content of the compound obtained by successive preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), as described in the text Listed. Here, such "very pure" compounds of the invention are also part of the invention.

All configuration isomers of the compounds of the present invention are within the scope of coverage, whether in mixture, pure or very pure form. The definition of the compound of the present invention includes two olefin isomers, cis (Z) and trans (E), as well as cis and trans isomers of carbocyclic and heterocyclic rings.

Throughout the specification, groups and substituents can be selected to provide stable fragments and compounds.

Specific functional groups and chemical term definitions are described in detail below. For purposes of the present invention, the chemical elements with the Periodic Table of the Elements, CAS version , of Chemistry and Physics, 75 th Ed same as defined in Handbook.. The definition of specific functional groups is also described therein. In addition, the basic principles of organic chemistry and specific functional groups and reactivity are also explained in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and the entire contents are included in the list of references.

Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, and exogenous Spin mixtures and other mixtures. In addition, the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and their mixtures are included in the present invention.

According to the present invention, the ratio of the mixture of isomers containing the isomers can be varied. For example, a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2,99:1, or 100:0, all ratios of isomers are within the scope of the present invention. Similar ratios that are easily understood by those skilled in the art, and ratios that are mixtures of more complex isomers are also within the scope of the present invention.

The present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. In practice, however, it usually occurs when one or more atoms are replaced by atoms whose atomic weight or mass number is different. Examples of isotopes that can be classified as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, and ¹⁸ O, respectively. , ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention. Certain isotope-labeled compounds of the present invention, such as ^{radioisotopes of 3} H and ¹⁴ C, are also among them, which are useful in tissue distribution experiments of drugs and substrates. Tritium, which is ³ H and carbon-14, which is ¹⁴ C, is relatively easy to prepare and detect. It is the first choice among isotopes. In addition, heavier isotopic substitutions such as deuterium, ie ² H, have advantages in certain therapies due to its good metabolic stability, such as increasing the half-life or reducing the dosage in the body, so it can be given priority in some cases. Isotopically-labeled compounds can be prepared by general methods, by replacing readily available isotope-labeled reagents with non-isotopic reagents, using the protocol disclosed in the example.

If you want to design the synthesis of a specific enantiomer of the compound of the present invention, it can be prepared by asymmetric synthesis, or derivatized with a chiral adjuvant, and the resulting diastereomeric mixture is separated, and then the chiral adjuvant is removed. Pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation crystallization or chromatography, etc. After separation by conventional means, the pure enantiomer is obtained.

As described herein, the compounds of the present invention can be combined with any number of substituents or functional groups to expand their scope of inclusion. Generally, whether the term "substituted" appears before or after the term "optional", the general formula including substituents in the formula of the present invention refers to the replacement of hydrogen radicals with designated structural substituents. When a plurality of positions in a specific structure are substituted by a plurality of specific substituents, each position of the substituents may be the same or different. The term "substitution" as used herein includes all permissible substitution of organic compounds. Broadly speaking, the permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any permitted organic compound as described above to supplement its valence. In addition, the present invention is not intended to limit the permitted substitution of organic compounds in any way. The present invention believes that the combination of substituents and variable groups is good in the treatment of diseases in the form of stable compounds, such as infectious diseases or proliferative diseases. Here, the term "stable" refers to a compound that is stable and can be tested for a long enough time to maintain the structural integrity of the compound, preferably for a long enough time to be effective, and is used herein for the above purpose.

The metabolites of the compounds and their pharmaceutically acceptable salts involved in this application, as well as the prodrugs that can be transformed into the structure of the compounds and their pharmaceutically acceptable salts involved in this application, are also included in the claims of this application. middle.

Preparation

The preparation methods of the compound of formula (III) of the present invention are described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.

Typically, the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used, unless otherwise specified, can be purchased through commercial channels or synthesized according to reported literature.

In an inert solvent (such as DMSO), the compound of formula (V-1) reacts with diamine-based compounds under the action of a base (such as TEA or DIPEA)

One of the amino groups in it reacts with an amino protecting agent (such as (Boc) ₂ O, benzyl chloroformate, di-tert-butyl dicarbonate, phthaloyl chloride, benzyl chloride, triphenylchloromethane, chloroformic acid- 9-fluorenyl methyl ester and allyl chloroformate) to obtain the compound of formula V-2; in an inert solvent (such as DCM), the V-2 compound is deprotected to generate intermediate V-3; in an inert solvent (such as two Oxane, toluene), in the presence of a base, the compound of formula V-3 and

Coupling, substitution or acylation reaction takes place to obtain the compound of formula V-4; in an inert solvent (such as ethyl acetate), the compound of V-4 generates intermediate V-5 under the action of an oxidizing agent (such as mCPBA); in an inert solvent (Such as toluene), compound (V-5) can generate intermediate V-6 under the action of alkali (such as NaH, LiHNMDS or tBuOK); in an inert solvent (such as dichloromethane), under acid (such as TFA) conditions , Compound (V-6) is deprotected to produce intermediate V-7; then in an inert solvent (such as DMF), in the presence of a base (such as TEA, DIPEA) and a catalyst (such as HATU), formula V-7 and GR ¹ Reaction to obtain formula III; where G is OH, F, Cl, -O-CO-R ¹ , -O-CO-CH ₂ CH(CH ₃ ) ₂ , -OBt,

Wait;

in,

Wait;

R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁹ , A, B, C, L, X, Y, Z, m, s, t are as described above; Rs and Rs' are protection of amino groups Base (such as Boc, Bn, Cbz, or Fmoc).

In the above reaction steps, the reaction solvent, reaction temperature, reaction time, catalyst, etc. can be selected according to the specific reactants.

Pharmaceutical composition and method of administration

The pharmaceutical composition of the present invention is used to prevent and/or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.

The compound of general formula (I) can be used in combination with other drugs known to treat or improve similar conditions. In the case of combined administration, the mode of administration and dosage of the original drug can be kept unchanged, while the compound of formula I is administered at the same time or subsequently. When the compound of formula I and one or more other drugs are taken at the same time, a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used. The combination of drugs also includes taking the compound of formula I and one or several other known drugs at overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dose of the compound of formula I or the known drug may be lower than the dose of the compound used alone.

Drugs or active ingredients that can be used in combination with the compound of general formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemipilimab, JS-001, SHR-120, BGB- A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, etc.) CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biological analogues of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, etc.) tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan, etc., CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX -148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, okatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Caboza ntinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Tribociclib, Miliclib , Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 Inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or a combination thereof.

The dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, dripping pill, external liniment, controlled release or sustained release or nano preparation.

The pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. The "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/agent, more preferably, 10-1000 mg of the compound of the present invention/agent. Preferably, the "one dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid). , Magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween)

), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration .

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such compositions may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.

In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

The composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

The dosage forms of the compound of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.

The treatment method of the present invention can be administered alone or in combination with other treatment means or therapeutic drugs.

When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) in need of treatment, wherein the dosage is the pharmaceutically effective dosage considered to be administered, and for a 60kg body weight, a day The administered dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.

The present invention also provides a method for preparing a pharmaceutical composition, which comprises the steps of: combining a pharmaceutically acceptable carrier with the compound of general formula (I) of the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form a pharmaceutical composition.

The present invention also provides a treatment method, which comprises the steps of: administering the compound of the general formula (I) of the present invention, or a crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, to a subject in need of treatment , Or administer the pharmaceutical composition of the present invention for selectively inhibiting KRAS ^G12C .

The present invention has the following main advantages:

(1) The compound has a very good selective inhibitory effect ^{on KRAS G12C;}

(2) The compound has better pharmacodynamics, pharmacokinetic properties and lower toxic and side effects.

The present invention will be further explained below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions in the following examples are usually in accordance with the conventional conditions such as Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions described in the manufacturer The suggested conditions. Unless otherwise stated, percentages and parts are calculated by weight.

Unless otherwise defined, all professional and scientific terms used in the text have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar or equivalent to the content described can be applied to the method of the present invention. The preferred implementation methods and materials described in this article are for demonstration purposes only.

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and liquid mass spectrometry (LC-MS).

NMR was detected by Bruker AVANCE-400 nuclear magnetic instrument. The solvent for measurement includes deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated acetone (CD ₃ COCD ₃ ), deuterated chloroform (CDCl ₃ ) and deuterated methanol ( CD ₃ OD), etc. The internal standard uses tetramethylsilane (TMS), and the chemical shift is measured in units of parts per million (ppm).

Liquid mass spectrometry (LC-MS) is detected by Waters SQD2 mass spectrometer. HPLC measurement uses Agilent1100 high pressure chromatograph (Microsorb 5 micron C18 100 x 3.0mm chromatographic column).

The thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, the TLC uses 0.15-0.20mm, and the preparative thin layer chromatography uses 0.4mm-0.5mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.

The starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by using or according to literature reported in the field.

Except for special instructions, all reactions in the present invention are carried out by continuous magnetic stirring under the protection of dry inert gas (such as nitrogen or argon), and the reaction temperature is all degrees Celsius.

Example

Intermediate 1 2-(cyanomethyl)-4-(7-(8-methylnaphthalene-1-yl)-2-(methylsulfoxide)-5,6,7,8-tetrahydropyridine [3 ,4-d)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

Step 1: Preparation of 7-benzyl-2-(methylthio)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidine-4-hydroxyl

Sodium metal (11.0g, 478.35mmol) was added to methanol (500ml) in batches, cooled in an ice-water bath and stirred to dissolve, and then 1-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester (25.0g , 95.67 mmol) and S-methylisothiourea sulfate (47.9 g, 172.2 mmol). The resulting mixture was stirred at room temperature for 16 h under the protection of nitrogen. After the reaction, the pH of the reaction solution was adjusted to 6 with a 2M aqueous hydrochloric acid solution. The resulting mixture was concentrated under reduced pressure to remove methanol. Water (100ml) was added to the residue, stirred and filtered. The filter cake was washed successively with water (50 mL) and ethyl acetate (50 mL) once, and then dried under vacuum at 50° C. to obtain the target product (25.68 g, yield 93%).

LC-MS: m/z 288(M+H) ⁺ .

Step 2: Preparation of 7-benzyl-4-chloro-2-(methylthio)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidine

Add 7-benzyl-2-(methylthio)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidine-4-hydroxy (25.68g, 89.36mmol) to phosphorus oxychloride (310mL). The resulting reaction solution was stirred at 80°C for 3h. After the reaction, the reaction solution was concentrated under reduced pressure to remove most of the phosphorus oxychloride, and then ethyl acetate (500 mL) was added. The resulting mixture was adjusted to pH 6 with saturated aqueous sodium bicarbonate solution. After the aqueous phase was separated, it was extracted with ethyl acetate (3 x 100 mL). After all the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the target product (13.3 g, yield 49%).

LC-MS: m/z 306(M+H) ⁺ .

The third step: (S)-4-(7-benzyl-2-(methylthio)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)-2 -(Cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

The 7-benzyl-4-chloro-2-(methylthio)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidine (7.0g, 22.89mmol), (S)-2 -(Piperazin-2-yl)acetonitrile dihydrochloride (5.44g, 27.47mmol), N,N-diisopropylethylamine (22.8mL, 137.34mmol) and DMSO were added to the reaction flask. Under the protection of nitrogen, the reaction solution was heated to 80° C. and stirred for 3 h, and then di-tert-butyl dicarbonate (26.3 mL, 114.45 mmol) was added. After the reaction was completed, the reaction solution was quenched with water, and then extracted with ethyl acetate (3 x 100 mL). After all the organic phases were combined, washed once with saturated sodium chloride, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the target product (8.21 g, yield 73%).

LC-MS: m/z 495(M+H) ⁺ .

The fourth step: (S)-2-(cyanomethyl)-4-(2-(methylthio)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidine-4- Yl) piperazine-1-carboxylic acid tert-butyl ester

Add (S)-4-(7-benzyl-2-(methylthio)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)-2-(cyano Tert-butyl methyl)piperazine-1-carboxylate (8.21g, 16.6mmol) was added to dichloromethane (160mL), and then at 0°C, 1-chloroethyl chloroformate (3.58mL, 33.2mmol). After the addition, the reaction solution was stirred at 15°C for 3h. The resulting mixture was concentrated under reduced pressure to remove the solvent, and then methanol (160 mL) was added. The resulting mixture was stirred at 70°C for 1.5 h, then cooled to room temperature, and then saturated sodium bicarbonate solution (300 mL) was added. The resulting mixture was extracted with ethyl acetate (3x 100 mL). After all the organic phases were combined, washed once with saturated sodium chloride, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: DCM/MeOH=100/1 to 30/1) to obtain the target product (4.9 g, yield 73%).

LC-MS: m/z 405(M+H) ⁺ . ¹ HNMR (400M, CDCl ₃ ) 4.52 (s, 1H), 3.93 (m, 2H), 3.78 (d, J = 12.4 Hz, 1H), 3.34 (m, 1H), 3.24 (m, 3H), 2.73 ( m, 5H), 2.42 (s, 3H), 1.43 (s, 9H).

The fifth step: (S)-2-(cyanomethyl)-4-(7-(8-chloronaphthalene-1-yl)-2-(methylthio)-5,6,7,8-tetra Preparation of tert-butyl hydropyridine [3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

(S)-2-(cyanomethyl)-4-(2-(methylthio)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)piper Tert-Butylazine-1-carboxylate (2g, 4.94mmol), 1-bromo-8-chloronaphthalene (2.96g, 12.35mmol), cesium carbonate (4.83g, 14.82mmol) and dioxane (80mL) were added to the reaction The bottle was then replaced with nitrogen three times, and then Ruphos Pd G3 (1.24g, 1.48mmol) was added. The resulting mixture was replaced with nitrogen three times and then heated to 72°C and stirred for 16 h. The resulting mixture was added with water (100 mL), and then extracted with ethyl acetate (3 x 100 mL). After all the organic phases were combined, washed once with saturated sodium chloride, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE/EA=1/0 to 5/1) to obtain the target product (1.17 g, yield 42%).

LC-MS: m/z 565(M+H) ⁺ .

The sixth step: (S)-2-(cyanomethyl)-4-(7-(8-chloronaphthalene-1-yl)-2-(methylsulfoxide)-5,6,7,8 -The preparation of tert-butyl tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Add (S)-2-(cyanomethyl)-4-(7-(8-chloronaphthalene-1-yl)-2-(methylthio)-5,6,7,8-tetrahydropyridine [ 3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (350mg, 0.62mmol) was dissolved in ethyl acetate (6mL), then cooled to 0℃ with an ice salt bath; then added dropwise A solution of m-chloroperoxybenzoic acid (216 mg, 1.25 mmol) in ethyl acetate (3 mL). After the addition, the reaction solution was stirred at 0°C for 10 min, and then quenched with sodium hyposulfite solution (50 mL). The resulting mixture was added with water (30 mL), and then extracted with ethyl acetate (3 x 30 mL). After all the organic phases were combined, washed once with saturated sodium chloride, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (PE:EA=1:0 to 0:1) to obtain the target product (180 mg, yield 50%).

LC-MS: m/z 581(M+H) ⁺ .

Intermediate 2(2S)-4-(7-(8-chloronaphthalene-1-yl)-6-methyl-2-(methylsulfoxide)-5,6,7,8-tetrahydropyridine[ Preparation of tert-butyl 3,4-d)pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

LC-MS: m/z 595(M+H) ⁺ .

Preparation of intermediate 3 (3-methoxymethyl-1-methyl-azetidin-3-yl)-methanol

The first step: the preparation of 3-(tert-butyl-dimethyl-silyloxymethyl)-3-hydroxymethyl-azetidine-1-carboxylate tert-butyl ester

Dissolve 3,3-bis-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (2g, 9.2mmol) in dichloromethane (20mL), cool to 0°C, and then add imidazole (940mg, 13.8mmol) and tert-butylchlorodimethylsilane (1.45g, 9.7mmol). After the reaction was stirred at room temperature for 16 hours, water (20 mL) and ethyl acetate (50 mL) were added to the resulting reaction solution. The organic phase was separated and collected, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (PE:EA=10:1) to obtain the target product (1.4g, yield: 47%).

Step 2: Preparation of 3-(tert-butyl-dimethyl-silyloxymethyl)-3-methoxymethyl-azetidine-1-carboxylic acid tert-butyl ester

Dissolve 3-(tert-butyl-dimethyl-silyloxymethyl)-3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (1.4g, 4.2mmol) in tetrahydrofuran (15mL ), cooled to 0°C, and then sodium hydrogen (340 mg, 8.4 mmol) and methyl iodide (1.8 g, 12.7 mmol) were added. The reaction solution was stirred and reacted at room temperature for 16 hours. After the reaction was completed, water (20 mL) and ethyl acetate (50 mL) were added to the reaction solution. The organic phase was separated and collected, dried and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (PE:EA=10:1) to obtain the target product (1.4g, yield: 96%).

The third step: Preparation of tert-butyl 3-hydroxymethyl-3-methoxymethyl-azetidine-1-carboxylate

Add tert-butyl 3-(tert-butyl-dimethyl-silyloxymethyl)-3-methoxymethyl-azetidine-1-carboxylate (1.4g, 4mmol) to methanol (10mL), p-toluenesulfonic acid monohydrate (77mg, 0.4mmol) was added, and then the reaction solution was stirred at room temperature for 16h. The reaction solution was concentrated to remove methanol, and silica gel column chromatography (PE:EA=1:1) was used to obtain the target product (920 mg, yield: 98%).

Fourth step: Preparation of (3-methoxymethyl-1-methyl-azetidin-3-yl)-methanol

Add tert-butyl 3-hydroxymethyl-3-methoxymethyl-azetidine-1-carboxylate (920 mg, 4 mmol) to tetrahydrofuran (10 mL), and add lithium aluminum hydride (750 mg, 20 mmol) , And then the reaction solution was heated and stirred for 16 hours under reflux. The reaction solution was cooled to 0°C, water (0.75mL), 15% sodium hydroxide aqueous solution (0.75mL) and water (2.2mL) were added, after the addition was stirred for 1h, then sodium sulfate was added to dry, filtered, and silica gel column chromatography ( DCM:MeOH=10:1) to obtain the target product (430mg, yield: 75%).

¹ H NMR (400MHz, CDCl ₃ ) δ 3.78 (s, 2H), 3.57 (s, 2H), 3.37 (s, 3H), 3.14 (t, J = 8.0 Hz, 2H), 3.06 (t, J = 8.0Hz, 2H), 2.98 (brs, 1H), 2.34 (s, 3H).

Example 1 (S)-2-(4-(7-(8-chloronaphthalene-1-yl)-2-((3-(methoxymethyl)-1-methylcyclobutylamine-3- Yl)methoxy)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile preparation

The first step: (S)-4-(7-(8-chloronaphthalene-1-yl)-2-((3-(methoxymethyl)-1-methylcyclobutylamine-3-yl) (Methoxy)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester

Add (S)-2-(cyanomethyl)-4-(7-(8-chloronaphthalene-1-yl)-2-(methylsulfoxide)-5,6,7,8-tetrahydro Pyridine[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (74mg, 0.128mmol) was added to the reaction flask, followed by toluene (0.8mL), (3-methoxy Methyl-1-methyl-azetidin-3-yl)-methanol (37 mg, 0.256 mmol) and sodium tert-butoxide (37 mg, 0.384 mmol). The reaction solution was stirred for 0.5 h in an ice-water bath, then water (50 mL) was added, and then extracted with ethyl acetate (3 x 30 mL). All organic phases were combined, washed once with saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified with a preparation plate (eluent: DCM/MeOH=20/1) to obtain the target product (42 mg, yield 50%).

LC-MS: m/z 662(M+H) ⁺ .

The second step: (S)-2-(4-(7-(8-chloronaphthalene-1-yl)-2-((3-(methoxymethyl)-1-methylcyclobutylamine-3 -Yl)methoxy)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

Add (S)-4-(7-(8-chloronaphthalene-1-yl)-2-((3-(methoxymethyl)-1-methylcyclobutylamino-3-yl)methoxy )-5,6,7,8-Tetrahydropyridine[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (39mg, 0.059mmol) Dissolve in dichloromethane (1 mL), then add trifluoroacetic acid (0.5 mL). The reaction solution was stirred at room temperature for 0.5 h, and then concentrated to dryness under reduced pressure to obtain the target product, which was directly used in the next reaction without purification.

LC-MS: m/z 562(M+H) ⁺ .

The third step: (S)-2-(4-(7-(8-chloronaphthalene-1-yl)-2-((3-(methoxymethyl)-1-methylcyclobutylamine-3 -Yl)methoxy)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile Preparation

The (S)-2-(4-(7-(8-chloronaphthalene-1-yl)-2-((3-(methoxymethyl)-1-methylcyclobutylamine- 3-yl)methoxy)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile was added to DMF (0.5mL), Then DIPEA (71 mg, 0.51 mmol) and 2-fluoroacrylic acid (31 mg, 0.35 mmol) were added under the protection of nitrogen, and finally HATU (114 mg, 0.3 mmol) was added. The resulting reaction solution was stirred for 0.5h under nitrogen protection. After the reaction was completed, water (5 mL) was added to the reaction solution and extracted with ethyl acetate (3 x 3 mL). The organic phases were combined and washed 4 times with saturated sodium chloride solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative chromatography to obtain the target product (11 mg, yield 30%).

LCMS: m / z 634 (M + H) + .1H NMR (400MHz, CDCl 3) δ7.68 (d, J = 8Hz, 1H), 7.56-7.53 (m, 1H), 7.45-7.44 (m, 2H ),7.40-7.36(m,1H),7.19-7.14(m,1H),5.30(d,J=16Hz,1H), 5.18(d,J=13.6Hz,1H), 4.80(brs,1H), 4.48-4.31(m,3H),3.82-3.74(m,5H),3.56-3.50(m,5H),3.35(s,3H),3.20-3.05(m,4H),2.95-2.75(m,2H) ), 2.57-2.51 (m, 4H), 1.25-1.18 (m, 2H).

According to the method of Example 1, Examples 2-7 were synthesized with different starting materials:

Example 2 (S)-2-(4-(7-(8-chloro-7-fluoronaphthalene-1-yl)-2-((3-(methoxymethyl)-1-methylcyclobutane Amino-3-yl)methoxy)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazine-2- Base) acetonitrile

LCMS: m/z 652(M+H) ⁺ .

Example 3 (S)-2-(1-(But-2-aldehyde)-4-(7-(7-(8-chloronaphthalene-1-yl)-2-((3-(methoxy (Methyl)-1-methylcyclobutylamino-3-yl)methoxy)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazine-2- Base) acetonitrile

LCMS: m/z 628(M+H) ⁺ .

Example 4 (S)-1-(4-(7-(8-chloronaphthalene-1-yl)-2-((3-(methoxymethyl)-1-methylcyclobutylamine-3- Yl)methoxy)-5,6,7,8-tetrahydropyridine(3,4-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-ene-1 -ketone

LCMS: m/z 591(M+H) ⁺ .

Example 5 1-(6-(7-(8-chloronaphthalene-1-yl)-2-((3-(methoxymethyl)-1-methylcyclobutylamine-3-yl)methoxy Yl)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)-2,6-diazaspiro[3.4]octane-2-yl)propan-2- En-1-one

LCMS: m/z 603(M+H) ⁺ .

Example 6 1-(7-(7-(8-chloronaphthalene-1-yl)-2-((3-(methoxymethyl)-1-methylcyclobutylamine-3-yl)methoxy Yl)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-yl)prop-2- En-1-one

LCMS: m/z 603(M+H) ⁺ .

Example 7 2-((2S)-4-(7-(8-chloronaphthalene-1-yl)-2-((3-(methoxymethyl)-1-methylcyclobutylamine-3- Yl)methoxy)-6-methyl-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazine-2 -Based) acetonitrile

LCMS: m/z 648(M+H) ⁺ .

After chiral preparation and separation, two isomers were obtained: 2-((2S)-4-((S)-7-(8-chloronaphthalene-1-yl)-2-((3-(methoxymethyl) )-1-Methylcyclobutylamine-3-yl)methoxy)-6-methyl-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)-1 -(2-Fluoroacryloyl)piperazin-2-yl)acetonitrile and 2-((2S)-4-((R)-7-(8-chloronaphthalene-1-yl)-2-((3- (Methoxymethyl)-1-methylcyclobutylamino-3-yl)methoxy)-6-methyl-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidine- 4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

Isomer 7A

LCMS: m/z 648(M+H) ⁺ .

Isomer 7B

LCMS: m/z 648(M+H) ⁺ .

Biological test evaluation

The following biological test examples further describe and explain the present invention, but these examples are not meant to limit the scope of the present invention.

Cellular experiment of the anti-proliferative activity of the compound on NCI-H358 (KRAS ^G12C mutation) cells and A549 (KRAS ^{G12S mutation) cells.}

Experimental steps

Add 40 μL of phosphate buffer to the outer wells of the 384 microwell plate, and then add 40 μL of the cell suspension to be tested to other wells, and then place the microwell plate in a carbon dioxide incubator overnight.

The compound to be tested was diluted in a gradient, each compound was diluted in 10 concentration gradients (diluted from 50 μM to 0.003 μM) and 100 nL was added to the corresponding wells of the microplate. After adding the drug, add 40 μL of phosphate buffer to each well in rows A, P and columns 1, 24, and then place the microtiter plate in a carbon dioxide incubator for 5 days.

Add 20 μL of Promega CellTiter-Glo reagent to each well of the microtiter plate, then shake at room temperature for 10 minutes to stabilize the luminescence signal, and then use the PekinElmer Envision multi-label analyzer to read.

Finally, GraphPad Prism software was used to calculate the IC ₅₀ value of the compound and draw a fitting curve.

The anti-proliferative activities of the example compounds of the present invention on NCI-H358 (KRAS ^G12C mutation) cells and A549 (KRAS ^G12S mutation) cells are shown in Table 1.

Table 1 Anti-proliferative activity of the example compounds of the present invention

It can be seen from Table 1:

The compounds of the examples of the present invention ^{show good cell anti-proliferation activity against KRAS G12C} mutant NCI-H358 cells, and at the same time have ^{weak anti-proliferative activity against KRAS G12S} mutant A549 cells, showing high selectivity.

All documents mentioned in the present invention are cited as references in this application, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

The compound represented by formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs:

Where:

A and B are the same or different, independently selected from CH or N;

X is selected from: a 4-14 membered saturated or unsaturated cycloalkyl or heterocyclic group, a C 6 -C 14 aryl group or a 5-14 membered heteroaryl group, wherein the saturated or unsaturated cycloalkyl group Or a heterocyclic group, an aryl group or a heteroaryl group may be optionally substituted by one or more R 8;

Y is selected from the following group: bond, O, S, NH, NR 5 , CR 5 R 6 , CONH, CONR 5 , SO 2 NH, SO 2 NR 5 , NHCO, NR 5 CO, NHSO 2 , NR 5 SO 2 ; Wherein, R 5 and R 6 are the same or different, and are each independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogen Substituted C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, amino , Hydroxyl, 4-20 membered heterocyclic group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group;

Z is selected from the following group: bond, C 1 -C 18 alkylene, deuterated C 1 -C 18 alkylene, halogenated C 1 -C 18 alkylene, C 3 -C 20 cycloalkylene, 4 -20-membered heterocyclylene, C 1 -C 18 alkyleneoxy, deuterated C 1 -C 18 alkyleneoxy, halogenated C 1 -C 18 alkyleneoxy;

R 1 is selected from the following group:
in,
Represents a double bond
Or three keys

R A is absent, or independently selected from: hydrogen, deuterium, fluoro, cyano or C 1 -C 3 alkyl;

Each R B is independently selected from: hydrogen, deuterium, cyano or C 1 -C 3 alkyl;

Wherein, the alkyl group in R A and R B may be substituted by one or more substituents selected from the following group: deuterium, halogen, cyano, amino, C 3 -C 7 cycloalkyl, 4-7 member Heterocyclic group, NHR 10 or NR 10 R 11 ; wherein R 10 and R 11 are each independently a C 1 -C 3 alkyl group;

R 2 is selected from the following group: -(CH 2 ) n -, -(CH 2 ) n O(CH 2 ) q -, -(CH 2 ) n S-, -(CH 2 ) n CO-, -(CH 2 ) n C(O)O-, -(CH 2 ) n S(O) q -, -(CH 2 ) n NR 5 -, -(CH 2 ) n C(O)NR 5 -, -(CH 2 ) n NR 5 C(O)-, -(CH 2 ) n NR 5 C(O)NR 5 -,-(CH 2 ) n S(O) q NR 5 -,-(CH 2 ) n NR 5 S(O) q -, -(CH 2 ) n NR 5 S(O) q NR 5 -, wherein the H in CH 2 can be replaced by R 8;

R 3 is independently selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, cyano, =0, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl;

L is selected from the following group: bond, -C(O)-, C 1 -C 3 alkylene;

R 4 is selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, amino, hydroxyl, 4-20 membered heterocyclic group, C 6 -C 14 aryl, 5-14 membered heteroaryl;

Ring C is a 4-20 membered heterocyclylene; wherein, the 4-20 membered heterocyclylene may be optionally substituted by one or more R 8;

R 7 is independently -R 12 -OR 13 , wherein R 12 is a substituted or unsubstituted C 1 -C 6 alkylene group, and R 13 is a substituted or unsubstituted C 1 -C 6 alkyl group, C 3- C 8 cycloalkyl;

R 8 is independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, amino, hydroxyl, C 3 -C 20 cycloalkane Group, 4-20 membered heterocyclylene, 4-20 membered heterocyclic group, C 6 -C 14 aryl group, 5-14 membered heteroaryl group;

R 9 is independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14 member Heteroaryl, 4-20 membered heterocyclic group, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or ureido group;

Wherein, unless otherwise specified, the above substitution refers to substitution by one or more groups selected from the following group: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 6- C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea group;

m is an integer of 0, 1, 2 or 3;

n is an integer of 0, 1, 2, 3, 4 or 5;

p is an integer of 1 or 2;

q is an integer of 0, 1, 2, 3, 4 or 5;

s is an integer of 1, 2 or 3;

t is an integer of 0, 1, 2 or 3.
The compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs according to claim 1, characterized in that it It has the structure shown in general formula (II-A) or (II-B):

Where:

The definitions of R 1 , R 2 , R 3 , R 4 , R 7 , R 9 , A, B, C, X, Y, Z, L, m, s, and t are as described in claim 1.
The compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs according to claim 1, characterized in that it It has the structure shown in formula (IV):

Where:

The definitions of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , C, Y, Z, L, m, s, and t are as described in claim 1.
The compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs according to claim 1, characterized in that it It has the structure shown in formula (VII):

Where:

The definitions of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , C, m, s, and t are as described in claim 1.
The compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs according to claim 1, wherein R 4 is selected from the following group of substituted or unsubstituted groups: C 6 -C 14 aryl, 5-14 membered heteroaryl; wherein, the substitution refers to substitution by one or more groups selected from the following group: Hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, Deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic group, halogen, nitro , Hydroxy, cyano, ester, amine, amide, sulfonamide or urea group.
The compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to any one of claims 1 to 5, characterized in that: Ring C is selected from the following group:

Wherein, Y 1 and Y 2 are each independently selected from: O, CO, CS, S, SO, SO 2 , PO, NR 14 or CR 15 R 16 , f is 0, 1, 2 or 3; wherein, R 14 Selected from: H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 14 aryl, substituted or unsubstituted 5-14 membered heteroaryl; R 15 and R 16 are each independently selected from: H, D, halogen, cyano, hydroxyl, substituted or unsubstituted C 1- C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted Or unsubstituted C 6 -C 14 aryl, substituted or unsubstituted 5-14 membered heteroaryl; the restriction is that one of Y 1 and Y 2 must be selected from: O, S, SO, SO 2 , PO , Or NR 14 ;

Wherein, the substitution refers to substitution by one or more groups selected from the following group: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 Alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, halogen, nitro, hydroxyl, Cyano groups, ester groups, amine groups.
The compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs according to claim 1, wherein R 7 is independently -R 12 -OR 13 , wherein R 12 is a substituted or unsubstituted C 1 -C 6 alkylene group, and R 13 is a substituted or unsubstituted C 1 -C 6 alkyl group, C 3 -C 8 cycloalkyl;

Ring C is selected from the following group:

Wherein, Y 1 and Y 2 are each independently selected from: O, NR 14 or CR 15 R 16 , and f is 0, 1, 2 or 3; wherein, R 14 is selected from: H, substituted or unsubstituted C 1- C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 14 aryl, substituted or unsubstituted R 15 and R 16 are each independently selected from: H, D, halogen, cyano, hydroxyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1- C 6 alkoxy, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 14 aryl, substituted Or unsubstituted 5-14 membered heteroaryl; the restriction is that one of Y 1 and Y 2 must be selected from: O or NR 14 ;

Wherein, the substitution refers to substitution by one or more groups selected from the following group: H, D, halogen, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl.
The compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to any one of claims 1-7, characterized in that: R 9 is independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14 member Heteroaryl, 4-20 membered heterocyclic group, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or ureido group;

R 7 is independently -R 12 -OR 13 , wherein R 12 is a substituted or unsubstituted C 1 -C 3 alkylene group, and R 13 is a substituted or unsubstituted C 1 -C 3 alkyl group, C 3- C 6 cycloalkyl;

Ring C is selected from the following group:

Wherein, Y 1 and Y 2 are each independently selected from: NR 14 or CR 15 R 16 , and f is 0, 1, 2 or 3; wherein, R 14 is selected from: H, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 14 aryl, substituted or unsubstituted 5 -14 membered heteroaryl; R 15 and R 16 are each independently selected from: H, D, halogen, cyano, hydroxyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1- C 6 alkoxy, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 14 aryl, substituted or unsubstituted Substituted 5-14 membered heteroaryl; the restriction is that one of Y 1 and Y 2 must be selected from NR 14 ;

Wherein, the substitution refers to substitution by one or more groups selected from the following group: H, D, halogen, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl.
The compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to any one of claims 6-8, characterized in , F is 1.
The compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1, wherein the compound is selected from The next group:
Provided is a method for preparing a compound of formula (III), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, which is characterized in that it comprises step:

(i) In the presence of a base in an inert solvent, the compound of formula V-1 and diamine-based compounds
One of the amine groups in is reacted and then reacted with the amino protecting agent to obtain the compound of formula V-2;

(ii) In an inert solvent, in the presence of a deprotecting agent, the compound of formula V-2 is deprotected to obtain a compound of formula V-3;

(iii) In an inert solvent, in the presence of a base, the compound of formula V-3 and
Coupling, substitution or acylation reaction occurs to obtain a compound of formula V-4;

(iv) In an inert solvent, the compound of formula V-4 is reacted with an oxidizing agent to obtain a compound of formula V-5;

(v) In an inert solvent, in the presence of a base, the compound of formula V-5 and
The reaction produces a compound of formula V-6;

(vi) In an inert solvent, in the presence of an acid, the compound of formula V-6 is deprotected to obtain the compound of formula V-7;

(vii) In an inert solvent, in the presence of a base and a catalyst, the formula V-7 is reacted with GR 1 to obtain the compound of formula (III);

Among them, G is OH, F, Cl, -O-CO-R 1 , -O-CO-CH 2 CH(CH 3 ) 2 , -OBt,

Q is a leaving group, and the leaving group is selected from: halogen, OH, -O-CO-R 4 -O-CO-CH 2 CH(CH 3 ) 2 , OMs, OTs, OTf, B(OH ) 2 , B(OMe) 2 or

Rs and Rs' are protecting groups for amino, and the protecting groups are selected from: Boc, Bn, Cbz or Fmoc;

R 1 , R 2 , R 3 , R 4 , R 7 , R 9 , A, B, C, L, X, Y, Z, m, s, t are defined as described in claim 1.
A pharmaceutical composition, characterized in that it contains one or more of the compounds described in any one of claims 1-10, their stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable Salts, hydrates, solvates or prodrugs; and pharmaceutically acceptable carriers.
A compound according to any one of claims 1-10, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs or claims The use of the pharmaceutical composition described in 12 is characterized in that it is used to prepare a pharmaceutical composition for preventing and/or treating diseases related to the activity or expression of KRAS G12C.