CN113666923A

CN113666923A - Alkoxy alkyl substituted heterocyclic inhibitor and preparation method and application thereof

Info

Publication number: CN113666923A
Application number: CN202010414658.2A
Authority: CN
Inventors: 吕彬华; 崔大为; 刘连军; 韩涛
Original assignee: Suzhou Zelgen Biopharmaceutical Co Ltd; Shanghai Zelgen Pharmatech Co Ltd
Current assignee: Suzhou Zelgen Biopharmaceutical Co Ltd; Shanghai Zelgen Pharmatech Co Ltd
Priority date: 2020-05-15
Filing date: 2020-05-15
Publication date: 2021-11-19
Also published as: WO2021228161A1

Abstract

The invention relates to an alkoxy alkyl substituted heterocyclic inhibitor and a preparation method and application thereof. Specifically, the compound has a structure shown in a formula (I), and the invention also discloses a preparation method of the compound and application of the compound as KRAS^G12CUse of inhibitors of KRAS^G12CHas good selective inhibition effect, better pharmacodynamics and pharmacokinetic performance and lower toxic and side effect.

Description

Alkoxy alkyl substituted heterocyclic inhibitor and preparation method and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to an alkoxy alkyl substituted heterocyclic inhibitor, and a preparation method and application thereof.

Background

Lung cancer is one of the leading causes of death in human cancers. Lung cancer can be divided into Small Cell Lung Cancer (SCLC) and non-small cell lung cancer (NSCLC) according to cell type, with NSCLC accounting for 85% of all lung cancer patients. The global NSCLC market was statistically estimated to be $ 209 billion in 2016, with the U.S. market taking up half, followed by Japan, Germany, and China. From the current trend, the market for non-small cell lung cancer is continuing to grow, and the global market is expected to reach $ 540 billion in 2023 (Nature, 2018; 553(7689):446- > 454).

At present, the main therapeutic drugs for NSCLC include chemotherapeutic drugs, molecular targeted drugs, tumor immunotherapy and the like. The chemotherapy drugs mainly comprise gemcitabine, paclitaxel, platinum drugs and the like, but the drugs generally have poor selectivity and high toxicity, so that relatively strong toxic and side effects are caused. In recent years, molecular targeted drugs have become research hotspots due to the obvious advantages of high selectivity, relatively small toxic and side effects, accurate treatment and the like. Existing NSCLC molecular targeted drugs include EGFR inhibitors (e.g., Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), ALK inhibitors (e.g., Ceritinib, aletinib, Brigatinib, loretinib, ocatinib, etc.), and VEGFR inhibitors (Sorafenib, regrafenib, Cabozantinib, Sunitinib, doranib, etc.) (Current Medicinal Chemistry,2019,26, 1-39).

In lung cancer patients, KRAS mutations are often detected, accounting for approximately 32% of all oncogene mutations. Wherein KRAS^G12CMutations account for 44% of all oncogene mutations within NSCLC. To date, the market has not been targeted to KRAS^G12CMutated drugs are approved for marketing.

Due to KRAS^G12CThe target protein is pathologically associated with a variety of diseases, and thereforeThere is also a need for novel KRAS^G12CThe inhibitor is used for clinical treatment. KRAS with high selectivity and high activity^G12CThe inhibitor may be on KRAS^G12CThe mutation-induced diseases such as cancer are more effectively treated, and the off-target effect potential is reduced, so that the clinical requirement is more urgent.

Disclosure of Invention

The invention aims to provide a novel pair of KRAS^G12CCompounds with selective inhibition and/or better pharmacodynamic properties and uses thereof.

In a first aspect of the present invention, there is provided a compound represented by formula (I), a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof:

in the formula:

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

x is selected from: 4-14 membered saturated or unsaturated cycloalkyl or heterocyclyl, C₆-C₁₄Aryl or 5-14 membered heteroaryl, wherein said saturated or unsaturated cycloalkyl or heterocyclyl, aryl or heteroaryl may be optionally substituted with one or more R⁸Substituted;

y is selected from the group consisting of: bond, O, S, NH, NR⁵、CR⁵R⁶、CONH、CONR⁵、SO₂NH、SO₂NR⁵、NHCO、NR⁵CO、NHSO₂、NR⁵SO₂(ii) a Wherein R is⁵And R⁶The same or different, and each is independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C₁-C₁₈Alkyl, deuterated C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl radical, C₃-C₂₀Cycloalkyl radical, C₁-C₁₈Alkoxy, deuterated C₁-C₁₈Alkoxy, halo C₁-C₁₈Alkoxy, amino, hydroxy, 4-20 memberedHeterocyclic group, C₆-C₁₄Aryl, 5-14 membered heteroaryl;

z is selected from the group consisting of: key, C₁-C₁₈Alkylene, deuterated C₁-C₁₈Alkylene, halogeno C₁-C₁₈Alkylene radical, C₃-C₂₀Cycloalkylene, 4-20 membered heterocyclylene, C₁-C₁₈Alkyleneoxy, deuterated C₁-C₁₈Alkyleneoxy, halogeno C₁-C₁₈An alkyleneoxy group;

R¹selected from the group consisting of:

wherein the content of the first and second substances,

represents a double bond

Or three keys

R^AIs absent or is independently selected from: hydrogen, deuterium, fluoro, cyano, or C₁-C₃An alkyl group;

each R^BIndependently selected from: hydrogen, deuterium, cyano, or C₁-C₃An alkyl group;

wherein R is^AAnd R^BWherein said alkyl group may be substituted with one or more substituents selected from the group consisting of: deuterium, halogen, cyano, amino, C₃-C₇Cycloalkyl, 4-7 membered heterocyclyl, NHR¹⁰Or NR¹⁰R¹¹(ii) a Wherein R is¹⁰And R¹¹Each independently is C₁-C₃An alkyl group;

R²selected from the group consisting of: - (CH)₂)_n、-(CH₂)_nO(CH₂)_q、-(CH₂)_nS、-(CH₂)_nCO、-(CH₂)_nC(O)O、-(CH₂)_nS(O)_q、-(CH₂)_nNR⁵、-(CH₂)_nC(O)NR⁵、-(CH₂)_nNR⁵C(O)、-(CH₂)_nNR⁵C(O)NR⁵、-(CH₂)_nS(O)_qNR⁵、-(CH₂)_nNR⁵S(O)_q、-(CH₂)_nNR⁵S(O)_qNR⁵In which CH₂H in (1) may be substituted by R⁸Substitution;

R³independently selected from the group consisting of: hydrogen, deuterium, hydroxy, halogen, cyano, ═ O, C₁-C₃Alkyl radical, C₁-C₃Alkoxy, halo C₁-C₃Alkyl or C₃-C₆A cycloalkyl group;

l is selected from the group consisting of: a bond, -C (O) -, C₁-C₃An alkylene group of (a);

R⁴selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C₁-C₁₈Alkyl, deuterated C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl radical, C₃-C₂₀Cycloalkyl radical, C₁-C₁₈Alkoxy, deuterated C₁-C₁₈Alkoxy, halo C₁-C₁₈Alkoxy, amino, hydroxy, 4-20 membered heterocyclic group, C₆-C₁₄Aryl, 5-14 membered heteroaryl;

ring C is a 4-20 membered heterocyclylene group; wherein said 4-20 membered heterocyclylene may optionally be substituted with one or more R⁸Substitution;

R⁷independently is-R¹²-O-R¹³Wherein R is¹²Is substituted or unsubstituted C₁-C₆Alkylene radical, R¹³Is substituted or unsubstituted C₁-C₆Alkyl radical, C₃-C₈A cycloalkyl group;

R⁸independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C₁-C₁₈Alkyl, deuterated C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl radical, C₃-C₂₀Cycloalkyl radical, C₁-C₁₈Alkoxy, deuterated C₁-C₁₈Alkoxy, halo C₁-C₁₈Alkoxy, amino, hydroxy, C₃-C₂₀Cycloalkylene, 4-20 membered heterocyclylene, 4-20 membered heterocyclyl, C₆-C₁₄Aryl, 5-14 membered heteroaryl;

R⁹independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C₁-C₁₈Alkyl, deuterated C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl radical, C₃-C₂₀Cycloalkyl radical, C₁-C₁₈Alkoxy, deuterated C₁-C₁₈Alkoxy, halo C₁-C₁₈Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido;

wherein, unless otherwise specified, the above substitution means substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C₁-C₁₈Alkyl, deuterated C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl radical, C₃-C₂₀Cycloalkyl radical, C₁-C₁₈Alkoxy, deuterated C₁-C₁₈Alkoxy, halo C₁-C₁₈Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido;

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 embodiment, X is selected from: 4-14 membered saturated or unsaturated cycloalkyl or heterocyclyl, wherein said saturated or unsaturated isThe saturated cycloalkyl or heterocyclyl group may be optionally substituted by one or more C₁-C₁₈Alkyl, preferably substituted or unsubstituted C₁-C₃Alkyl, wherein said substitution is by cyano or halogen.

In another preferred embodiment, the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug has a structure represented by general formula (II-a) or (II-B):

in the formula:

R¹、R²、R³、R⁴、R⁷、R⁹a, B, C, X, Y, Z, L, m, s, t are as defined above.

In another preferred embodiment, the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof is characterized by having the structure shown in formula (III):

R¹、R²、R³、R⁴、R⁷、R⁹c, X, Y, Z, L, m, s, t are as defined above.

In another preferred embodiment, the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug has the structure shown in formula (IV):

in the formula:

R¹、R²、R³、R⁴、R⁷、R⁸、R⁹c, Y, Z, L, m, s, t are as defined above.

In another preferred embodiment, the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug has the structure shown in formula (V):

in the formula:

R¹、R²、R³、R⁴、R⁷、R⁸、R⁹c, Y, Z, m, s, t are as defined above.

In another preferred embodiment, the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug has the structure shown in formula (VI):

in the formula:

R¹、R²、R³、R⁴、R⁷、R⁸、R⁹c, Z, m, s, t are as defined above.

In another preferred embodiment, the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug has the structure shown in formula (VII):

in the formula:

R¹、R²、R³、R⁴、R⁷、R⁸、R⁹c, m, s, t are as defined above.

In another preferred embodiment, the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, R⁴Selected from the group consisting of substituted or unsubstituted: c₆-C₁₄Aryl, 5-14 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: hydrogen, deuterium, C₁-C₁₈Alkyl, deuterated C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl radical, C₃-C₂₀Cycloalkyl radical, C₁-C₁₈Alkoxy, deuterated C₁-C₁₈Alkoxy, halo C₁-C₁₈Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.

In another preferred embodiment, R⁴Selected from substituted or unsubstituted C₆-C₁₀Aryl, preferably substituted or unsubstituted phenyl or naphthyl, wherein substituted means substituted with one or more groups selected from the group consisting of: c₁-C₁₈Alkyl, deuterated C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl radical, C₃-C₂₀Cycloalkyl radical, C₁-C₁₈Alkoxy, deuterated C₁-C₁₈Alkoxy, halo C₁-C₁₈Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.

In another preferred embodiment, R⁴Selected from substituted or unsubstituted 5-10 membered heteroaryl, preferably substituted or unsubstituted pyridine, benzopyrazole, benzimidazole, benzothiazole, benzoxazole, wherein said substitution means substitution by one or more groups selected from the group consisting of: c₁-C₁₈Alkyl, deuterated C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl radical, C₃-C₂₀Cycloalkyl radical, C₁-C₁₈Alkoxy, deuterated C₁-C₁₈Alkoxy, halo C₁-C₁₈Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.

In another preferred embodiment, ring C is a 4-8 membered heterocyclylene group, which may optionally be substituted with one or more R⁸In which R is⁸Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C₁-C₁₈Alkyl, deuterated C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl radical, C₃-C₂₀Cycloalkyl radical, C₁-C₁₈Alkoxy, deuterated C₁-C₁₈Alkoxy, halo C₁-C₁₈Alkoxy, amino, hydroxy, C₃-C₂₀Cycloalkylene, 4-20 membered heterocyclylene, 4-20 membered heterocyclyl, C₆-C₁₄Aryl, 5-14 membered heteroaryl;

the substitution means substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C₁-C₆Alkyl, deuterated C₁-C₆Alkyl, halo C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl radical, C₁-C₆Alkoxy, deuterated C₁-C₆Alkoxy, halo C₁-C₆Alkoxy, halogen, nitro, hydroxyl, cyano, ester group and amine group.

In another preferred embodiment, the compound of formula (I), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein ring C is selected from the group consisting of:

wherein, Y₁And Y₂Each independentlySelected from: o, CO, CS, S, SO₂、PO、NR¹⁴Or CR¹⁵R¹⁶F is 0, 1, 2 or 3; wherein R is¹⁴Selected from: H. substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₆Cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₄Aryl, substituted or unsubstituted 5-14 membered heteroaryl; r¹⁵And R¹⁶Each independently selected from: H. d, halogen, cyano, hydroxy, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₃-C₆Cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₄Aryl, substituted or unsubstituted 5-14 membered heteroaryl; with the proviso that Y₁And Y₂One of them must be chosen from: o, S, SO₂PO, or NR¹⁴；

Wherein said substitution is by one or more groups selected from the group consisting of: hydrogen, deuterium, C₁-C₆Alkyl, deuterated C₁-C₆Alkyl, halo C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl radical, C₁-C₆Alkoxy, deuterated C₁-C₆Alkoxy, halo C₁-C₆Alkoxy, halogen, nitro, hydroxyl, cyano, ester group and amine group.

In another preferred embodiment, R³Independently selected from the group consisting of: hydrogen, deuterium, C₁-C₃Alkyl, halo C₁-C₃Alkyl or C₃-C₆A cycloalkyl group.

In another preferred embodiment, the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, R⁷Independently is-R¹²-O-R¹³Wherein R is¹²Is substituted or unsubstituted C₁-C₆Alkylene radical, R¹³Is substituted or unsubstituted C₁-C₆Alkyl radical, C₃-C₈A cycloalkyl group;

ring C is selected from the group consisting of:

wherein, Y₁And Y₂Each independently selected from: o, NR¹⁴Or CR¹⁵R¹⁶F is 0, 1, 2 or 3; wherein R is¹⁴Selected from: H. substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₆Cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₄Aryl, substituted or unsubstituted 5-14 membered heteroaryl; r¹⁵And R¹⁶Each independently selected from: H. d, halogen, cyano, hydroxy, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₃-C₆Cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₄Aryl, substituted or unsubstituted 5-14 membered heteroaryl; with the proviso that Y₁And Y₂One of them must be chosen from: o or NR¹⁴；

Wherein said substitution is by one or more groups selected from the group consisting of: H. d, halogen, cyano, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₃-C₆A cycloalkyl group.

In another preferred embodiment, the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, R⁹Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C₁-C₁₈Alkyl, deuterated C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl radical, C₃-C₂₀Cycloalkyl radical, C₁-C₁₈Alkoxy, deuterated C₁-C₁₈Alkoxy, halo C₁-C₁₈Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido;

R⁷independently is-R¹²-O-R¹³Wherein R is¹²Is substituted or unsubstituted C₁-C₃Alkylene radical, R¹³Is substituted or unsubstituted C₁-C₃Alkyl radical, C₃-C₆A cycloalkyl group;

ring C is selected from the group consisting of:

wherein, Y₁And Y₂Each independently selected from: NR (nitrogen to noise ratio)¹⁴Or CR¹⁵R¹⁶F is 0, 1, 2 or 3; wherein R is¹⁴Selected from: H. substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₆Cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₄Aryl, substituted or unsubstituted 5-14 membered heteroaryl; r¹⁵And R¹⁶Each independently selected from: H. d, halogen, cyano, hydroxy, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₃-C₆Cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₄Aryl, substituted or unsubstituted 5-14 membered heteroaryl; with the proviso that Y₁And Y₂One of them must be selected from NR¹⁴；

In another preferred embodiment, R⁹Independently H, C₁-C₆An alkyl group.

In another preferred embodiment, R⁸Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C₁-C₃Alkyl, deuterated C₁-C₃Alkyl radical, C₁-C₃Alkoxy, deuterated C₁-C₃Alkoxy, amino, hydroxy; wherein said substitution is by one or more groups selected from the group consisting of: halogen, cyano, amino, hydroxy.

In another preferred embodiment, the compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein R¹、R²、R³、R⁴、R⁷、R⁹A, B, C, X, Y, Z, L, m, s and t are specific groups corresponding to the specific compounds in the examples.

In another preferred embodiment, the compound of formula (I), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, is selected from the group consisting of:

in another preferred embodiment, the compound of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, is selected from the compounds shown in the examples.

In a second aspect of the present invention, there is provided a process for the preparation of a compound of formula (III), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, characterized in that it comprises the steps of:

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

Reacting one of the amino groups with an amino protecting agent to obtain a compound shown in the formula V-2;

(ii) deprotecting a compound of formula V-2 in an inert solvent in the presence of a deprotection agent to give a compound of formula V-3;

(iii) reacting a compound of formula V-3 with a base in an inert solvent in the presence of a base

Coupling, substitution or acylation reaction is carried out to obtain a compound shown as a formula V-4;

(iv) reacting a compound of formula V-4 with an oxidant in an inert solvent to obtain a compound of formula V-5;

(v) reacting a compound of formula V-5 with a base in an inert solvent in the presence of a base

Reacting to generate a compound shown in the formula V-6;

(vi) deprotecting a compound of formula V-6 in an inert solvent in the presence of an acid to give a compound of formula V-7;

(vii) reacting formula V-7 with GR1 in an inert solvent in the presence of a base and a catalyst to give a compound of formula (III);

wherein G is OH, F, Cl, -O-CO-R¹、-O-CO-CH₂CH(CH₃)₂、-OBt、

Etc.;

in the formula (I), the compound is shown in the specification,

q is a leaving group, e.g. halogen, OH, -O-CO-R⁴-O-CO-CH₂CH(CH₃)₂、OMs、OTs、OTf、B(OH)₂、B(OMe)₂Or

Etc.;

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

R¹、R²、R³、R⁴、R⁷、R⁹a, B, C, L, X, Y, Z, m, s, t are as defined above.

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

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

In another preferred embodiment, in step (i), the amino protecting agent is selected from: (Boc)₂O, benzyl chloroformate, di-tert-butyl dicarbonate, phthaloyl chloride, benzyl chloride, triphenylchloromethane, 9-fluorenylmethyl chloroformate and 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 embodiment, 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: and (3) ethyl acetate.

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

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

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

In a third aspect of the present invention, there is provided a pharmaceutical composition comprising one or more compounds of formula (I) according to the first aspect, stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof; and a pharmaceutically acceptable carrier.

In another preferred embodiment, the pharmaceutical composition further comprises a drug selected from the group consisting of:

PD-1 inhibitors (e.g., nivolumab, pembrolizumab, pidilizumab, cemipimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009, or biologically similar drugs thereof), PD-L1 inhibitors (e.g., durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, A167, F520, GR1405, MSB2311, or biologically similar drugs thereof), CD20 antibodies (e.g., rituximab, obizumab, ofatumumab, tositumomab, MSB 131, tositumomab, TSB 90, TSH-55, TSB-35, TSB-102, TSB-35, TSB-52, TSB-35, TSC-35, TSB-35, TSC-35, TSB-55, TSB-D-35, TSB-D2, TSB-D, Alectonib, Brigatinib, Lorlatinib, oxcarinib), PI3K inhibitors (e.g., Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipaliib, Buparlisib, etc.), BTK inhibitors (e.g., Ibrutinib, Tirabutinib, Acalabastib, Zanbutrutinib, Vecabutinib, etc.), EGFR inhibitors (e.g., Afatinib, Gefitinib, Erlottinib, Lapatinib, Dacomitib, Icotinib, Canertinib, Sapinotinib, Naquratinib, Pyrotinib, Rocilitiniib, Osimetiniib, etc.), inhibitors (e.g., Sorafenib, Parraertinib, Lorlatinib 6284, Lipocinib, etc.), inhibitors (e.g., Lipocinib, VEGF-12, Lipocinib, VEGF-III inhibitors, Lipocinib, VEGF-12, Lipocinib, VEGF-III inhibitors, Lipocinib inhibitors (e, Lipocinib inhibitors, etc.), inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, Lipocinib inhibitors, VEGF-12, VEGF-III inhibitors, VEGF-12, VEGF-III inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, etc.), etc. (e, VEGF-III inhibitors, etc.), and so AS inhibitors, VEGF-12, VEGF-inhibitors (e, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, such AS inhibitors, Lipocinib inhibitors, VEGF-12, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, e, VEGF-12, Lipocinib inhibitors, e, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, e, Lipocinib inhibitors, Lip.

In a fourth aspect of the present invention, there is provided a use of a compound of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to the first aspect, or a pharmaceutical composition according to the third aspect, for the preparation of a medicament for the prophylaxis and/or treatment of KRAS^G12COr an expression level of the compound (b).

In another preferred embodiment, the disease is a tumor or a dysregulated disease.

In another preferred embodiment, the disease is selected from the group consisting of: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, leukemia, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, and skin cancer.

In a fifth aspect of the invention, there is provided a non-diagnostic, non-therapeutic inhibition of KRAS^G12CThe method of (1), comprising the steps of: administering to a patient in need thereof an effective amount of said compound of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, or administering a pharmaceutical composition as described above.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Detailed Description

The present inventors have conducted extensive and intensive studies for a long time to unexpectedly prepare a novel class of KRAS^G12CCompounds with selective inhibition and/or better pharmacodynamic properties. On this basis, the inventors have completed the present invention.

Term(s) for

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

The term "alkyl" refers to straight or branched chain or cyclic alkane groups comprising 1 to 20 carbon atoms, such as 1 to 18 carbon atoms, especially 1 to 18 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Typical "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, n-butyl,

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

The term "C1-C18 alkyl" refers to a straight or branched chain or cyclic alkyl group 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, t-butyl, isobutyl (e.g. butyl, isobutyl)

) N-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl. In the present invention, the alkyl group also includes substituted alkyl groups. "substituted alkyl" means an alkyl group which is substituted at one or more positions, especially 1 to 4 substituents, and may be substituted at any position. Typical substitutions includeBut are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g. monohalogen substituents or polyhalo substituents, the latter being trifluoromethyl or containing Cl₃Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, OR_a、SR_a、S(＝O)R_e、S(＝O)₂R_e、P(＝O)₂R_e、S(＝O)₂OR_e,P(＝O)₂OR_e、NR_bR_c、NR_bS(＝O)₂R_e、NR_bP(＝O)₂R_e、S(＝O)₂NR_bR_c、P(＝O)₂NR_bR_c、C(＝O)OR_d、C(＝O)R_a、C(＝O)NR_bR_c、OC(＝O)R_a、OC(＝O)NR_bR_c、NR_bC(＝O)OR_e,NR_dC(＝O)NR_bR_c、NR_dS(＝O)₂NR_bR_c、NR_dP(＝O)₂NR_bR_c、NR_bC(＝O)R_aOr NR_bP(＝O)₂R_eWherein R is present therein_aMay independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, a 5-14 membered heterocycle or a C6-C14 aromatic ring, R_b、R_cAnd R_dMay independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, a 5-14 membered heterocyclic ring or a C6-C14 aromatic ring, or R_bAnd R_cTogether with the N atom may form a heterocyclic ring; r_eCan independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, a 5-14 membered heterocyclic ring or a C6-C14 aromatic ring. The above-mentioned typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring may be optionally substituted.

The term "alkylene" refers to a group formed by removing a hydrogen atom from an "alkyl" group, such as methylene, ethylene, propylene, isopropylene (e.g.

) Butylene (e.g. butyl oxide)

) Pentylene (e.g. ethylene)

) Hexamethylene (e.g. hexamethylene)

) Heptylene (e.g. ethylene)

) And the like.

The term "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene" has the same meaning and refers to cycloalkylalkyl or alkylcycloalkyl groups which have two hydrogen atoms removed, e.g.

And the like.

The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon compound group containing 3,4, 5,6,7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, including 1 to 4 rings, each ring containing 3 to 8 carbon atoms. Preferably C₃-C₂₀Cycloalkyl, more preferably C₃-C₁₈Cycloalkyl, more preferably C₃-C₁₀Cycloalkyl, more preferably C₃-C₆A cycloalkyl group. "substituted cycloalkyl" means that one or more positions in the cycloalkyl group are substituted, especially 1 to 4 substituents, which may be substituted at any position. In the present invention, "cycloalkyl" includes substituted cycloalkyl groups, typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g. monohalogen take)Substituted or polyhalogenated substituents, the latter being, for example, trifluoromethyl or containing Cl₃Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, OR_a、SR_a、S(＝O)R_e、S(＝O)₂R_e、P(＝O)₂R_e、S(＝O)₂OR_e,P(＝O)₂OR_e、NR_bR_c、NR_bS(＝O)₂R_e、NR_bP(＝O)₂R_e、S(＝O)₂NR_bR_c、P(＝O)₂NR_bR_c、C(＝O)OR_d、C(＝O)R_a、C(＝O)NR_bR_c、OC(＝O)R_a、OC(＝O)NR_bR_c、NR_bC(＝O)OR_e,NR_dC(＝O)NR_bR_c、NR_dS(＝O)₂NR_bR_c、NR_dP(＝O)₂NR_bR_c、NR_bC(＝O)R_aOr NR_bP(＝O)₂R_eWherein R is present therein_aMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R_b、R_cAnd R_dMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R_bAnd R_cTogether with the N atom may form a heterocyclic ring; r_eMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents may be optionally substituted. Typical substitutions also include spirocyclic, bridged or fused ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spiroheterocyclic (excluding heteroaromatic rings), bridged cycloalkyl, bridged alkenyl, bridged heterocyclic (excluding heteroaromatic rings), fused cycloalkyl, fused alkenyl, fused heterocyclyl or fused aromatic ring groups, which may be optionally substituted.

The term "C3-C20 cycloalkylene" refers to a cycloalkyl group that has two hydrogen atoms removed, such as:

and the like.

The term "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group containing 3,4, 5,6,7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms (including but not limited to, for example, a 3-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic ring system) in which at least one heteroatom is present in the ring having at least one carbon atom. Each heteroatom-containing heterocyclic ring may carry 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms, wherein the nitrogen or sulfur atoms may be oxidized and the nitrogen atoms may also be quaternized. The heterocyclic group may be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule. Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidyl, tetrahydropyranyl, morphinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1, 3-dioxanyl, and tetrahydro-1, 1-dioxythiophene, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or are further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring; the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate.

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

and the like. Wherein H of NH may be further substituted; when substituted, the substituents are preferably alkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, 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, having 1 to 5 rings, especially monocyclic and bicyclic groups such as phenyl, biphenyl or naphthyl. Where the aromatic ring contains two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be linked by a single bond (e.g., biphenyl), or fused (e.g., naphthalene, anthracene, etc.). "substituted aryl" means that one or more positions in the aryl group are substituted, especially 1 to 3 substituents, which may 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 (e.g. monohalogen substituents or polyhalo substituents, the latter being trifluoromethyl or containing Cl₃Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, OR_a、SR_a、S(＝O)R_e、S(＝O)₂R_e、P(＝O)₂R_e、S(＝O)₂OR_e,P(＝O)₂OR_e、NR_bR_c、NR_bS(＝O)₂R_e、NR_bP(＝O)₂R_e、S(＝O)₂NR_bR_c、P(＝O)₂NR_bR_c、C(＝O)OR_d、C(＝O)R_a、C(＝O)NR_bR_c、OC(＝O)R_a、OC(＝O)NR_bR_c、NR_bC(＝O)OR_e,NR_dC(＝O)NR_bR_c、NR_dS(＝O)₂NR_bR_c、NR_dP(＝O)₂NR_bR_c、NR_bC(＝O)R_aOr NR_bP(＝O)₂R_eWherein R is present therein_aMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R_b、R_cAnd R_dMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R_bAnd R_cTogether with the N atom may form a heterocyclic ring; r_eMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents may be optionally substituted. Typical substitutions also include fused ring substituents, especially fused ring alkyl, fused ring alkenyl, fused ring heterocyclyl or fused ring aromatic ring groups, which cycloalkyl, cycloalkenyl, heterocyclyl and heterocyclylaryl groups may be optionally substituted.

The term "heteroaryl" refers to a heteroaromatic system comprising 1-4 heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. The heteroaryl group is preferably a 5-to 10-membered ring, more preferably a 5-or 6-membered ring, for example, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl and the like. "heteroaryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate.

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

The term "C1-C18 alkyleneoxy" means a group resulting from the removal of one hydrogen atom from a "C1-C18 alkoxy group".

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

The term "halo" means substituted with halogen.

The term "deuterated" refers to a substitution by deuterium.

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

The term "nitro" refers to a group with the structure NO₂A group of (1).

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

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

The term "amine" refers to a group having the structure-NRR ', where R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R and R' may be the same or different in the dialkylamine fragment.

The term "amido" refers to a group with the structure-CONRR ', where R and R' may 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 and R' may be the same or different in the dialkylamine fragment.

The term "sulfonamide" refers to a sulfonamide group having the structure-SO₂Group of NRR', wherein R andr' may 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 and R' may be the same or different in the dialkylamine fragment.

The term "ureido" refers to a group having the structure — NRCONR 'R ", where R, R' and R" may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R, R' and R "may be the same or different in the dialkylamine fragment.

The term "alkylaminoalkyl" refers to a group having the structure-RNHR ', wherein R and R' may 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 and R' may be the same or different.

The term "dialkylaminoalkyl" refers to a group having 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, a heterocycle or a substituted heterocycle, as defined above. R, R' and R "may be the same or different in the dialkylamine fragment.

The term "alkoxyalkyl" refers to a group having the structure-ROR ', where R, R' may independently represent an alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl group.

The term "heterocyclylalkyl" refers to a group having the structure-RR', wherein R may independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl; r' represents a heterocycle or a substituted heterocycle.

In the present invention, the term "substituted" means that one or more hydrogen atoms on a specified group are replaced with a specified substituent. Particular substituents are those described correspondingly in the foregoing, or as appearing in the examples. Unless otherwise specified, a certain substituted group may have one substituent selected from a specific group at any substitutable site of the group, and the substituents may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Such substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 ureido, and the like.

Unless otherwise stated, it is assumed that any heteroatom that is not in a valence state has sufficient hydrogen to replenish its valence state.

When the substituent is a non-terminal substituent, it is a subunit of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl corresponds to heterocyclylene, alkoxy corresponds to alkyleneoxy, and the like.

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

Active ingredient

As used herein, the terms "compound of the invention" or "active ingredient of the invention" are used interchangeably to refer to a compound of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof. The term also includes racemates, optical isomers.

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

R¹、R²、R³、R⁴、R⁷、R⁹a, B, C, X, Y, Z, L, m, s, t are as defined above. Preferably, the compound of formula (I) has a structure represented by the general formula (II-A) or (II-B):

in the formula:

R¹、R²、R³、R⁴、R⁷、R⁹a, B, C, X, Y, Z, L, m, s, t are as defined above. 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):

in the formula:

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

in the formula:

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

in the formula:

R¹、R²、R³、R⁴、R⁷、R⁸、R⁹c, Z, m, s, t are as defined above.

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

in the formula:

R¹、R²、R³、R⁴、R⁷、R⁸、R⁹c, m, s, t are as defined above.

Preferably, in the compounds as described above, R⁴Is substituted or unsubstituted C₆-C₁₄Aryl, 5-14 membered heteroaryl; more preferably C6-C10 aryl (e.g. substituted or unsubstituted phenyl or naphthyl) or 5-10 membered heteroaryl (e.g. substituted or unsubstituted pyridine, benzopyrazole, benzimidazole, benzothiazole, benzoxazole), wherein said substitution means substitution by one or more groups selected from the group consisting of: c₁-C₁₈Alkyl, deuterated C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl radical, C₃-C₂₀Cycloalkyl radical, C₁-C₁₈Alkoxy, deuterated C₁-C₁₈Alkoxy, halo C₁-C₁₈Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.

Preferably, in the compounds described above, ring C is a 4-8 membered heterocyclylene group; preferably ring C is selected from the group consisting of:

wherein, Y₁、Y₂F, is as defined above, preferably Y₁And Y₂Each independently is NR¹⁴Or CR¹⁵R¹⁶Wherein R is¹⁴Selected from: H. substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₆Cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₄Aryl, substituted or unsubstituted 5-14 membered heteroaryl; r¹⁵And R¹⁶Each independently selected from: H. d, halogen, cyano, hydroxy, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₃-C₆Cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₄Aryl, substituted or unsubstituted 5-14 membered heteroaryl; with the proviso that Y₁And Y₂One of them must be selected from NR¹⁴(ii) a Wherein said substitution is by one or more groups selected from the group consisting of: H. d, halogen, cyano, hydroxy, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₃-C₆A cycloalkyl group.

Preferably, in the compounds as described above, R³Independently selected from the group consisting of: hydrogen, deuterium, C₁-C₃Alkyl, halo C₁-C₃Alkyl or C₃-C₆A cycloalkyl group.

Preferably, in the compounds as described above, R⁸Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C₁-C₃Alkyl, deuterated C₁-C₃Alkyl radical, C₁-C₃Alkoxy, deuterated C₁-C₃Alkoxy, amino, hydroxy; wherein said substitution is selected from the group consisting ofSubstituted with one or more groups of (a): halogen, cyano, amino, hydroxy.

Preferably, in the compounds as described above, R⁹Independently H, C₁-C₆An alkyl group. The salts which the compounds of the invention may form are also within the scope of the invention. Unless otherwise indicated, the compounds of the present invention are understood to include salts thereof. The term "salt" as used herein refers to a salt formed from an inorganic or organic acid and a base in either an acidic or basic form. Furthermore, when a compound of the present invention contains a basic moiety, including but not limited to pyridine or imidazole, and an acidic moiety, including but not limited to carboxylic acid, zwitterions ("inner salts") that may form are included within the scope of the term "salt(s)". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps during manufacture. The compounds of the invention may form salts, for example, by reacting compound I with an amount of acid or base, e.g. an equivalent amount, and salting out in a medium, or lyophilizing in an aqueous solution.

The compounds of the invention may contain basic moieties, including but not limited to amine or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids which may form salts include acetates (e.g. with acetic acid or trihaloacetic acid such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, diglycolates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptonates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g. 2-hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g. 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g. 3-phenylpropionates), phosphates, propionates, citrates, and the like, Picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., with sulfuric acid), sulfonates, tartrates, thiocyanates, tosylates, e.g., p-toluenesulfonate, dodecanoate, and the like

Acidic moieties that certain 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 with bases include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts with organic bases (e.g., organic amines) such as benzathine, dicyclohexylamine, hydrabamine (salt with N, N-bis (dehydroabietyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine, and salts with amino acids such as arginine, lysine, and the like. The basic nitrogen-containing groups may be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenyl bromides), and the like.

Prodrugs and solvates of the compounds of the invention are also contemplated. The term "prodrug" as used herein refers to a compound that undergoes chemical conversion by metabolic or chemical processes to yield a compound, salt, or solvate of the present invention when used in the treatment of a related disease. The compounds of the present invention include solvates, such as hydrates.

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

All stereoisomers of the compounds (e.g., those asymmetric carbon atoms that may exist due to various substitutions), including enantiomeric and diastereomeric forms thereof, are contemplated within the invention. The individual stereoisomers of the compounds of the invention may not be present in combination with the other isomers (e.g. as a pure or substantially pure optical isomer having a particular activity), or may be present as a mixture, e.g. as a racemate, or as a mixture with all or a portion of the other stereoisomers. The chiral center of the invention has two S or R configurations, and is defined by the International Union of theory and applied chemistry (IUPAC) proposed in 1974. The racemic forms can be resolved by physical methods such as fractional crystallization, or by separation of the crystals by derivatization into diastereomers, or by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including, but not limited to, conventional methods such as salt formation with an optically active acid followed by crystallization.

The compounds of the present invention, obtained by preparing, isolating and purifying the compound in sequence, have a weight content of 90% or more, for example, 95% or more, 99% or more ("very pure" compounds), as set forth in the text. Such "very pure" compounds of the invention are also part of the invention herein.

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

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

Specific functional groups and definitions of chemical terms are detailed below. For purposes of the present invention, the chemical Elements are compatible with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics,75^thD. as defined in. The definition of a particular functional group is also described herein. In addition, the basic principles of Organic Chemistry, as well as specific functional groups and reactivities are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, which is incorporated by reference in its entirety.

Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomer, (L) isomer, racemic mixtures and other mixtures thereof. Further the asymmetric carbon atom may represent a substituent such as an alkyl group. All isomers, as well as mixtures thereof, are encompassed by the present invention.

According to the present invention, the mixture of isomers may contain a variety of isomer ratios. For example, in a mixture of only two isomers, the following combinations are possible: 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 invention. Similar ratios, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention, as would be readily understood by one of ordinary skill in the art.

The invention also includes isotopically-labeled compounds, equivalent to those disclosed herein as the original compound. In practice, however, it will often occur that one or more atoms are replaced by an atom having a different atomic weight or mass number. Examples of isotopes that can be listed as compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, respectively²H、³H、¹³C、¹¹C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, wherein isotopes or other isotopic atoms containing such compounds are within the scope of the present invention. Certain isotopically-labelled compounds of the invention, e.g.³H and¹⁴among these, the radioactive isotope of C is useful in tissue distribution experiments of drugs and substrates. Tritium, i.e.³H and carbon-14, i.e.¹⁴C, their preparation and detection are relatively easy. Is the first choice among isotopes. In addition, heavier isotopes such as deuterium, i.e.²H, due to its good metabolic stability, may be advantageous in certain therapies, such as increased half-life in vivo or reduced dose, and therefore, may be preferred in certain circumstances. Isotopically labeled compounds can be prepared by conventional methods by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents, using the protocols disclosed in the examplesAnd (4) preparing.

If it is desired to design the synthesis of a particular enantiomer of a compound of the invention, it may be prepared by asymmetric synthesis or by derivatization with chiral auxiliary agents, separation of the resulting diastereomeric mixture and removal of the chiral auxiliary agent to give the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed therewith with an appropriate optically active acid or base, and the isolated enantiomers can be obtained in pure form by conventional means such as fractional crystallization or chromatography.

As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to extend their inclusion range. In general, the term "substituted", whether occurring before or after the term "optional", in the formula of the present invention including substituents, means that the hydrogen radical is replaced with a substituent of the indicated structure. When a plurality of the specified structures are substituted at a position with a plurality of the specified substituents, each position of the substituents may be the same or different. The term "substituted" as used herein includes all permissible substitutions of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any permissible organic compound described hereinabove to supplement its valence state. Furthermore, the present invention is not intended to be limited in any way as to the permissible substitution of organic compounds. The present invention recognizes that the combination of substituents and variable groups is excellent in the treatment of diseases, such as infectious diseases or proliferative diseases, in the form of stable compounds. The term "stable" as used herein refers to compounds that are stable enough to maintain the structural integrity of the compound when tested for a sufficient period of time, and preferably are effective for a sufficient period of time, and are used herein for the purposes described above.

Metabolites of the compounds and pharmaceutically acceptable salts thereof to which this application relates, and prodrugs that can be converted in vivo to the structures of the compounds and pharmaceutically acceptable salts thereof to which this application relates, are also included in the claims of this application.

Preparation method

The following describes more specifically the process for the preparation of the compounds of formula (III) according to the invention, but these particular processes do not constitute any limitation of the invention. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.

Typically, the compounds of the present invention are prepared by the following procedures, wherein the starting materials and reagents used, unless otherwise specified, are commercially available or synthesized according to the reported literature.

Reacting a compound of formula (V-1) with a diamine compound in an inert solvent (e.g. DMSO) in the presence of a base (e.g. TEA or DIPEA)

With one of the amine groups in the reaction mixture, and then with an amino protecting agent (e.g., (Boc)₂O, benzyl chloroformate, di-tert-butyl dicarbonate, phthaloyl chloride, benzyl chloride, triphenylchloromethane, 9-fluorenylmethyl chloroformate and allyl chloroformate) to obtain a compound shown in a formula V-2; deprotection of the V-2 compound in an inert solvent (e.g., DCM) yields intermediate V-3; reacting a compound of formula V-3 with a base in an inert solvent (e.g., dioxane, toluene) in the presence of a base

Coupling, substitution or acylation reaction is carried out to obtain a compound shown as a formula V-4; in an inert solvent (such as ethyl acetate), generating an intermediate V-5 by a V-4 compound under the action of an oxidant (such as mCPBA); in an inert solvent (such as toluene), compound (V-5) generates an intermediate V-6 under the action of a base (such as NaH, LiHNMDS or tBuOK); deprotection of compound (V-6) to intermediate V-7 in an inert solvent such as dichloromethane under acidic conditions such as TFA; then in an inert solvent (such as DMF),in the presence of a base (e.g., TEA, DIPEA) and a catalyst (e.g., HATU), the formula V-7 and G-R¹Reacting to obtain a formula III; wherein G is OH, F, Cl, -O-CO-R¹、-O-CO-CH₂CH(CH₃)₂、-OBt、

Etc.;

wherein the content of the first and second substances,

Etc.;

R¹、R²、R³、R⁴、R⁷、R⁹a, B, C, L, X, Y, Z, m, s, t are as described above; rs and Rs' are amino protecting groups (e.g., Boc, Bn, Cbz or Fmoc).

In the above reaction steps, the reaction solvent, reaction temperature, reaction time, catalyst, and the like may be selected depending on the particular reactants.

Pharmaceutical compositions and methods of administration

The pharmaceutical composition of the invention is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immunological disease, and metabolic disease.

The compounds of general formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the mode of administration and dosage of the original drug may be maintained unchanged while the compound of formula I is administered simultaneously or subsequently. When the compound of formula I is administered simultaneously with one or more other drugs, it may be preferable to use a pharmaceutical composition containing both one or more known drugs and the compound of formula I. The pharmaceutical combination also includes administration of the compound of formula I in an overlapping time period with one or more other known drugs. When a compound of formula I is administered in a pharmaceutical 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 at which they are administered alone.

Drugs or active ingredients that may be used in combination with the compounds of formula (I) include, but are not limited to: PD-1 inhibitors (e.g., nivolumab, pembrolizumab, pidilizumab, cemipimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009, or biologically similar drugs thereof), PD-L1 inhibitors (e.g., durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, A167, F520, GR1405, MSB2311, or biologically similar drugs thereof), CD20 antibodies (e.g., rituximab, obizumab, ofatumumab, tositumomab, MSB 131, tositumomab, TSB 90, TSH-55, TSB-35, TSB-102, TSB-35, TSB-52, TSB-35, TSC-35, TSB-35, TSC-35, TSB-55, TSB-D-35, TSB-D2, TSB-D, Alectonib, Brigatinib, Lorlatinib, oxcarinib), PI3K inhibitors (e.g., Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipaliib, Buparlisib, etc.), BTK inhibitors (e.g., Ibrutinib, Tirabutinib, Acalabastib, Zanbutrutinib, Vecabutinib, etc.), EGFR inhibitors (e.g., Afatinib, Gefitinib, Erlottinib, Lapatinib, Dacomitib, Icotinib, Canertinib, Sapinotinib, Naquratinib, Pyrotinib, Rocilitiniib, Osimetiniib, etc.), inhibitors (e.g., Sorafenib, Parraertinib, Lorlatinib 6284, Lipocinib, etc.), inhibitors (e.g., Lipocinib, VEGF-12, Lipocinib, VEGF-III inhibitors, Lipocinib, VEGF-12, Lipocinib, VEGF-III inhibitors, Lipocinib inhibitors (e, Lipocinib inhibitors, etc.), inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, Lipocinib inhibitors, VEGF-12, VEGF-III inhibitors, VEGF-12, VEGF-III inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-III inhibitors, etc.), etc. (e, VEGF-III inhibitors, etc.), and so AS inhibitors, VEGF-12, VEGF-inhibitors (e, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-12, Lipocinib inhibitors, such AS inhibitors, Lipocinib inhibitors, VEGF-12, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, e, VEGF-12, Lipocinib inhibitors, e, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, Lipocinib inhibitors, VEGF-inhibitors, e, Lipocinib inhibitors, Lip.

Dosage forms of the pharmaceutical compositions of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, pellicle, dripping pill, topical liniment, controlled release type or delayed release type or nanometer preparation.

The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-1000mg of a compound of the invention per dose. Preferably, said "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 be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like

) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration 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 with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form 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 compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.

In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds of the present invention 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 which may be required if necessary.

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

When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 50 to 1000 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.

The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps: mixing a pharmaceutically acceptable carrier with the compound of the general formula (I) or a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof to form the pharmaceutical composition.

The present invention also provides a method of treatment comprising the steps of: administration of a compound of formula (I) as described in the present invention to a subject in need of such treatmentA compound, or a crystalline form, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, or administering a pharmaceutical composition of the invention for selectively inhibiting KRAS^G12C。

The invention has the following main advantages:

(1) the compound is right to KRAS^G12CHas good selective inhibition effect;

(2) the compound has better pharmacodynamics and pharmacokinetic performance and lower toxic and side effects.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, molecular cloning is generally performed according to conventional conditions such as Sambrook et al: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press,1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are by weight.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.

The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) and liquid mass chromatography (LC-MS).

NMR was detected using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the assay solvent contained deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated acetone (CD)₃COCD₃) Deuterated chloroform (CDCl)₃) And deuterated methanol (CD)₃OD), and internal standards are Tetramethylsilane (TMS), chemical shifts are measured in parts per million (ppm).

Liquid chromatography-mass spectrometry (LC-MS) was detected using a Waters SQD2 mass spectrometer. HPLC measurements were performed using an Agilent1100 high pressure chromatograph (Microsorb 5micron C18100 x 3.0.0 mm column).

Thin layer chromatography silica gel plate is blue island GF254 silica gel plate, TLC is 0.15-0.20mm, and preparative thin layer chromatography is 0.4-0.5 mm. 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 known and commercially available or may be used or synthesized according to literature reports in the art.

All reactions of the present invention are carried out under continuous magnetic stirring under the protection of a dry inert gas (e.g., nitrogen or argon) except for the specific indications, and the reaction temperatures are all in degrees centigrade.

Examples

Preparation of intermediate tert-butyl 12- (cyanomethyl) -4- (7- (8-methylnaphthalen-1-yl) -2- (methylsulfonyl) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

The first step is as follows: preparation of 7-benzyl-2- (methylthio) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidine-4-hydroxy

Sodium metal (11.0g, 478.35mmol) was added in portions to methanol (500ml), and after cooling in an ice-water bath with stirring and clearing, ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (25.0g, 95.67mmol) and S-methylisothiouronium sulfate (47.9g, 172.2mmol) were added in succession. The resulting mixture was stirred at room temperature under nitrogen for 16 h. After the reaction was completed, the reaction solution was adjusted to pH 6 with 2M aqueous hydrochloric acid solution. The resulting mixture was concentrated under reduced pressure to remove methanol. Water (100ml) was added to the residue, which was stirred and then filtered. The filter cake was rinsed once with water (50mL) and once with ethyl acetate (50mL) in that order, and then dried under vacuum at 50 ℃ to give the desired product (25.68g, 93% yield).

LC-MS：m/z 288(M+H)⁺。

The second step is that: preparation of 7-benzyl-4-chloro-2- (methylthio) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidine

7-benzyl-2- (methylthio) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-hydroxy (25.68g, 89.36mmol) was added to phosphorus oxychloride (310 mL). The resulting reaction solution was stirred at 80 ℃ for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove most of phosphorus oxychloride, and then ethyl acetate (500mL) was added. The resulting mixture was adjusted to pH 6 with saturated aqueous sodium bicarbonate. The aqueous phase was separated and extracted with ethyl acetate (3 × 100 mL). All 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 objective product (13.3g, yield 49%).

LC-MS：m/z 306(M+H)⁺。

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

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-diisopropylethylamine (22.8mL, 137.34mmol), and DMSO were added to the reaction flask. The reaction was heated to 80 ℃ under nitrogen for 3h, followed by the addition of di-tert-butyl dicarbonate (26.3mL, 114.45 mmol). After the reaction was complete, the reaction was quenched with water and extracted with ethyl acetate (3 × 100 mL). After all 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 give the objective product (8.21g, yield 73%).

LC-MS：m/z 495(M+H)⁺。

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

Tert-butyl (S) -4- (7-benzyl-2- (methylthio) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (8.21g, 16.6mmol) was added to dichloromethane (160mL), followed by dropwise addition of chloro-1-chloroethyl chloroformate (3.58mL, 33.2mmol) at 0 ℃. After the addition was complete, the reaction was stirred at 15 ℃ for 3 h. The resulting mixture was concentrated under reduced pressure to remove the solvent, and then methanol (160mL) was added. The resulting mixture was stirred at 70 ℃ for 1.5h, then cooled to room temperature, followed by addition of saturated sodium bicarbonate solution (300 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL). After all 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 objective product (4.9g, yield 73%).

LC-MS：m/z 405(M+H)⁺。¹HNMR(400M,CDCl₃)4.52(s,1H),3.93(m,2H),3.78(d,J＝12.4Hz,1H),3.34(m,1H),3.24(m,3H),2.73(m,5H),2.42(s,3H),1.43(s,9H)。

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

Tert-butyl (S) -2- (cyanomethyl) -4- (2- (methylthio) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) piperazine-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 a reaction flask, then replaced three times with nitrogen, followed by Ruphos Pd G3(1.24G, 1.48 mmol). The resulting mixture was replaced with nitrogen three times, heated to 72 ℃ and stirred for 16 hours. The resulting mixture was added to water (100mL) and extracted with ethyl acetate (3 × 100 mL). After all 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 give the objective product (1.17g, yield 42%).

LC-MS：m/z 565(M+H)⁺。

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

Tert-butyl (S) -2- (cyanomethyl) -4- (7- (8-chloronaphthalen-1-yl) -2- (methylthio) -5,6,7, 8-tetrahydropyr-idine [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (350mg, 0.62mmol) was dissolved in ethyl acetate (6mL) and then cooled to 0 ℃ with an ice salt bath; a solution of m-chloroperoxybenzoic acid (216mg, 1.25mmol) in ethyl acetate (3mL) was then added dropwise. After the addition was complete, the reaction was stirred at 0 ℃ for 10min and then quenched with sodium hyposulfite solution (50 mL). The resulting mixture was added to water (30mL) and extracted with ethyl acetate (3 × 30 mL). After all 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 give the objective product (180mg, yield 50%).

LC-MS：m/z 581(M+H)⁺。

Preparation of intermediate 2(2S) -4- (7- (8-chloronaphthalen-1-yl) -6-methyl-2- (methylsulfonyl) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester

LC-MS：m/z 595(M+H)⁺。

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

The first step is as follows: preparation of 3- (tert-butyl-dimethyl-silyloxymethyl) -3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester

Tert-butyl 3, 3-bis-hydroxymethyl-azetidine-1-carboxylate (2g, 9.2mmol) was dissolved in dichloromethane (20mL), cooled to 0 deg.C, and imidazole (940mg, 13.8mmol) and tert-butylchlorodimethylsilane (1.45g,9.7mmol) were added. After the reaction was stirred at room temperature for 16 hours, water (20mL) and ethyl acetate (50mL) were added to the resulting reaction mixture. The organic phase was separated, collected, dried and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (PE: EA ═ 10:1) to obtain the objective product (1.4g, yield: 47%).

The second step is that: preparation of 3- (tert-butyl-dimethyl-silyloxymethyl) -3-methoxymethyl-azetidine-1-carboxylic acid tert-butyl ester

3- (tert-butyl-dimethyl-silyloxymethyl) -3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (1.4g, 4.2mmol) was dissolved in tetrahydrofuran (15mL), cooled to 0 deg.C, followed by the addition of sodium hydride (340mg,8.4mmol) and iodomethane (1.8g, 12.7 mmol). The reaction mixture was stirred at room temperature for 16 hours, and after completion of the reaction, water (20mL) and ethyl acetate (50mL) were added to the reaction mixture. The organic phase was separated, collected, dried and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (PE: EA ═ 10:1) to obtain the objective product (1.4g, yield: 96%).

The third step: preparation of 3-hydroxymethyl-3-methoxymethyl-azetidine-1-carboxylic acid tert-butyl ester

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

The fourth step: preparation of (3-methoxymethyl-1-methyl-azetidin-3-yl) -methanol

3-hydroxymethyl-3-methoxymethyl-azetidine-1-carboxylic acid tert-butyl ester (920mg, 4mmol) was added to tetrahydrofuran (10mL), lithium aluminum hydride (750mg,20mmol) was added, and the reaction solution was stirred at elevated temperature under reflux for 16 h. The reaction solution was cooled to 0 ℃, water (0.75mL), a 15% aqueous solution of sodium hydroxide (0.75mL) and water (2.2mL) were added, and the mixture was stirred for 1 hour, then sodium sulfate was added, dried, filtered, and subjected to silica gel column chromatography (DCM: MeOH ═ 10:1) to obtain the objective product (430mg, yield: 75%).

¹H NMR(400MHz,CDCl₃)δ3.78(s,2H),3.57(s,2H),3.37(s,3H),3.14(t,J＝8.0Hz,2H),3.06(t,J＝8.0Hz,2H),2.98(brs,1H),2.34(s,3H).

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

The first step is as follows: preparation of (S) -4- (7- (8-chloronaphthalen-1-yl) -2- ((3- (methoxymethyl) -1-methylcyclobutan-3-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester

Tert-butyl (S) -2- (cyanomethyl) -4- (7- (8-chloronaphthalen-1-yl) -2- (methylsulfonyl) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (74mg, 0.128mmol) was added to a reaction flask followed by toluene (0.8mL), (3-methoxymethyl-1-methyl-azetidin-3-yl) -methanol (37mg, 0.256mmol), and sodium tert-butoxide (37mg, 0.384mmol) in that order. The reaction was stirred for 0.5h in an ice-water bath, followed by addition of water (50mL) and extraction with ethyl acetate (3X 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 resulting residue was purified using preparative plate (eluent: DCM/MeOH-20/1) to give the objective product (42mg, 50% yield).

LC-MS：m/z 662(M+H)⁺。

The second step is that: preparation of (S) -2- (4- (7- (8-chloronaphthalen-1-yl) -2- ((3- (methoxymethyl) -1-methylcyclobutan-3-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

Tert-butyl (S) -4- (7- (8-chloronaphthalen-1-yl) -2- ((3- (methoxymethyl) -1-methylcyclobutan-3-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (39mg, 0.059mmol) was dissolved in dichloromethane (1mL), followed by trifluoroacetic acid (0.5 mL). The reaction solution is stirred for 0.5h at room temperature, and then is decompressed and concentrated to be dry to obtain a target product, and the target product is directly used for the next reaction without purification.

LC-MS：m/z 562(M+H)⁺。

Preparation of (S) -2- (4- (7- (8-chloronaphthalen-1-yl) -2- ((3- (methoxymethyl) -1-methylcyclobutan-3-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) -1- (2-fluoropropy-loyl) piperazin-2-yl) acetonitrile

(S) -2- (4- (7- (8-chloronaphthalen-1-yl) -2- ((3- (methoxymethyl) -1-methylcyclobutan-3-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile obtained in the above step was added to DMF (0.5mL), followed by the addition of DIPEA (71mg, 0.51mmol) and 2-fluoroacrylic acid (31mg, 0.35mmol) under nitrogen protection and finally HATU (114mg, 0.3 mmol). The obtained reaction solution is stirred for 0.5h under the protection of nitrogen. After completion of the reaction, water (5mL) was added to the reaction mixture, which was extracted with ethyl acetate (3X 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 give the objective product (11mg, yield 30%).

LCMS:m/z 634(M+H)⁺.1H NMR(400MHz，CDCl₃)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).

Examples 2-7 were synthesized according to the procedure of example 1, starting from different starting materials:

example 2(S) -2- (4- (7- (8-chloro-7-fluoronaphthalen-1-yl) -2- ((3- (methoxymethyl) -1-methylcyclobutan-3-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) -1- (2-fluoropropy-loyl) piperazin-2-yl) acetonitrile

LCMS:m/z 652(M+H)⁺.

Example 3(S) -2- (1- (butan-2-carboxaldehyde) -4- (7- (7- (8-chloronaphthalen-1-yl) -2- ((3- (methoxymethyl) -1-methylcyclobutan-3-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile

LCMS:m/z 628(M+H)⁺.

Example 4(S) -1- (4- (7- (8-chloronaphthalen-1-yl) -2- ((3- (methoxymethyl) -1-methylcyclobutan-3-yl) methoxy) -5,6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) -3-methylpiperazin-1-yl) prop-2-en-1-one

LCMS:m/z 591(M+H)⁺.

Example 51- (6- (7- (8-chloronaphthalen-1-yl) -2- ((3- (methoxymethyl) -1-methylcyclobutan-3-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) -2, 6-diazaspiro [3.4] octan-2-yl) prop-2-en-1-one

LCMS:m/z 603(M+H)⁺.

Example 61- (7- (7- (8-chloronaphthalen-1-yl) -2- ((3- (methoxymethyl) -1-methylcyclobutan-3-yl) methoxy) -5,6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) -4, 7-diazaspiro [2.5] octan-4-yl) prop-2-en-1-one

LCMS:m/z 603(M+H)⁺.

Example 72- ((2S) -4- (7- (8-chloronaphthalen-1-yl) -2- ((3- (methoxymethyl) -1-methylcyclobutan-3-yl) methoxy) -6-methyl-5, 6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile

LCMS:m/z 648(M+H)⁺.

Two isomers were obtained by chiral preparative separation: 2- ((2S) -4- ((S) -7- (8-chloronaphthalen-1-yl) -2- ((3- (methoxymethyl) -1-methylcyclobutan-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-chloronaphthalen-1-yl) -2- ((3- (methoxymethyl) -1-methylcyclobutan-3-yl) methoxy) -6-methyl-5, 6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-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 illustrate the present invention, but these examples are not meant to limit the scope of the present invention.

Compound Pair NCI-H358 (KRAS)^G12CMutant) cells and a549 (KRAS)^G12SMutation) cell experiment of antiproliferative activity of cells.

Experimental procedure

To the peripheral wells of 384 microwell plates 40. mu.L of phosphate buffer was added, followed by 40. mu.L of the test cell suspension to the other wells, and the microwell plates were then placed in a carbon dioxide incubator overnight.

The test compounds were diluted in a gradient of 10 concentrations (from 50. mu.M to 0.003. mu.M) and 100nL of each was added to the corresponding well of the microplate. After dosing, 40. mu.L of phosphate buffer was added to each well at line A, P and columns 1 and 24, and the plates were incubated for 5 days in a carbon dioxide incubator.

mu.L of Promega CellTiter-Glo reagent was added to each well of the plate, followed by shaking at room temperature for 10min to stabilize the luminescence signal, which was then read using a Pekinelmer Envision multi-label analyzer.

Finally, IC of the compound was calculated using GraphPad Prism software₅₀And (5) obtaining values, and drawing a fitting curve.

Compound couple NCI-H358 (KRAS) as an example of the present invention^G12CMutant) cells and a549 (KRAS)^G12SMutant) cell antiproliferative activity is shown in table 1.

TABLE 1 antiproliferative activity of the compounds of the examples of the invention

IC₅₀	NCI-H358(μM)	A549(μM)
			Example 1	<0.1uM	>1uM
Example 2	<0.1uM	>1uM
			Example 3	<0.1uM	>1uM
Example 4	0.1-1uM	>1uM
			Example 5	>1uM	>1uM
Example 6	>1uM	>1uM
			Example 7A	0.1-1uM	>1uM
Example 7B	<0.1uM	>1uM

As can be seen from table 1:

example Compounds of the invention for KRAS^G12CThe mutant NCI-H358 cells showed very good cell antiproliferative activity and also for KRAS^G12SThe mutant A549 cells have weak antiproliferative activity and show high selectivity.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A compound represented by formula (I), a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof:

in the formula:

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

y is selected from the group consisting of: bond, O, S, NH, NR⁵、CR⁵R⁶、CONH、CONR⁵、SO₂NH、SO₂NR⁵、NHCO、NR⁵CO、NHSO₂、NR⁵SO₂(ii) a Wherein R is⁵And R⁶The same or different, and each is independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C₁-C₁₈Alkyl, deuterated C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl radical, C₃-C₂₀Cycloalkyl radical, C₁-C₁₈Alkoxy, deuterated C₁-C₁₈Alkoxy, halo C₁-C₁₈Alkoxy, amino, hydroxy, 4-20 membered heterocyclic group, C₆-C₁₄Aryl, 5-14 membered heteroaryl;

R¹selected from the group consisting of:

wherein the content of the first and second substances,

represents a double bond

Or three keys

each R^BIndependently selected from: hydrogen, deuterium, cyano, or C₁-C₃Alkyl radical；

wherein, unless otherwise specified, the above substitution means substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C₁-C₁₈Alkyl, deuterated C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl radical, C₃-C₂₀Cycloalkyl radical, C₁-C₁₈Alkoxy, deuterated C₁-C₁₈Alkoxy, halo C₁-C₁₈Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea;

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.

2. A compound of formula (I), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs according to claim 1, having the structure according to formula (II-a) or (II-B):

in the formula:

R¹、R²、R³、R⁴、R⁷、R⁹a, B, C, X, Y, Z, L, m, s, t are as defined in claim 1.

3. A compound of formula (I), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs according to claim 1, having the structure shown in formula (IV):

in the formula:

R¹、R²、R³、R⁴、R⁷、R⁸、R⁹c, Y, Z, L, m, s, t are as defined in claim 1.

4. A compound of formula (I), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs according to claim 1, having the structure shown in formula (VII):

in the formula:

R¹、R²、R³、R⁴、R⁷、R⁸、R⁹c, m, s, t are as defined in claim 1.

5. The compound of formula (I), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs according to claim 1, wherein R is⁴Selected from the group consisting of substituted or unsubstituted: c₆-C₁₄Aryl, 5-14 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: hydrogen, deuterium, C₁-C₁₈Alkyl, deuterated C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl radical, C₃-C₂₀Cycloalkyl radical, C₁-C₁₈Alkoxy, deuterated C₁-C₁₈Alkoxy, halo C₁-C₁₈Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or urea.

6. A compound of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to any one of claims 1 to 5, characterized in that ring C is selected from the group consisting of:

wherein, Y₁And Y₂Each independently selected from: o, CO, CS, S, SO₂、PO、NR¹⁴Or CR¹⁵R¹⁶F is 0, 1, 2 or 3; wherein R is¹⁴Selected from: H. substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₆Cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₄Aryl, substituted or unsubstituted 5-14 membered heteroaryl; r¹⁵And R¹⁶Each independently selected from: H. d, halogen, cyano, hydroxy, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₃-C₆Cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₄Aryl, substituted or unsubstituted 5-14 membered heteroaryl; with the proviso that Y₁And Y₂One of them must be chosen from: o, S, SO₂PO, or NR¹⁴；

7. The compound of formula (I), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs according to claim 1, wherein R is⁷Independently is-R¹²-O-R¹³Wherein R is¹²Is substituted or unsubstituted C₁-C₆Alkylene radical, R¹³Is substituted or unsubstituted C₁-C₆Alkyl radical, C₃-C₈A cycloalkyl group;

ring C is selected from the group consisting of:

8. A compound of formula (I), as claimed in any one of claims 1 to 7, wherein R is R, a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof⁹Independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C₁-C₁₈Alkyl, deuterated C₁-C₁₈Alkyl, halo C₁-C₁₈Alkyl radical, C₃-C₂₀Cycloalkyl radical, C₁-C₁₈Alkoxy, deuterated C₁-C₁₈Alkoxy, halo C₁-C₁₈Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amine, amide, sulfonamide, or ureido;

ring C is selected from the group consisting of:

wherein, Y₁And Y₂Each independently selected from: NR (nitrogen to noise ratio)¹⁴Or CR¹⁵R¹⁶F is 0, 1, 2 or 3; wherein R is¹⁴Selected from: H. substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₆Cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₄Aryl, substituted or unsubstituted 5-14 membered heteroaryl; r¹⁵And R¹⁶Each independently selected from: H. d, halogen, cyano, hydroxy, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₃-C₆Cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₄Aryl, substituted or unsubstituted 5-14 membered heteroaryl; with the proviso that Y₁And Y₂In which one is provided withOne must be selected from NR¹⁴；

9. A compound of formula (I), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof according to claim 1, wherein said compound is selected from the group consisting of:

10. there is provided a process for the preparation of a compound of formula (III), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, characterized in that it comprises the steps of:

One amine in (1) is reactedReacting with an amino protecting agent to obtain a compound shown as a formula V-2;

Reacting to generate a compound shown in the formula V-6;

(vii) in an inert solvent in the presence of a base and a catalyst, the formulae V-7 and G-R¹Reacting to obtain a compound shown in a formula (III);

wherein G is OH, F, Cl, -O-CO-R¹、-O-CO-CH₂CH(CH₃)₂、-OBt、

Q is a leaving group selected from: halogen, OH, -O-CO-R⁴-O-CO-CH₂CH(CH₃)₂、OMs、OTs、OTf、B(OH)₂、B(OMe)₂Or

R¹、R²、R³、R⁴、R⁷、R⁹a, B, C, L, X, Y, Z, m, s, t are as defined in claim 1.

11. A pharmaceutical composition comprising one or more compounds of formula (I) according to claim 1, stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof; and a pharmaceutically acceptable carrier.

12. Use of a compound of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, according to claim 1, or of a pharmaceutical composition according to claim 11, for the preparation of a medicament for the prophylaxis and/or treatment of KRAS^G12COr an expression level of the compound (b).