WO2025149082A1 - Substituted bridge ring inhibitor, and preparation method therefor and use thereof - Google Patents

Abstract

A substituted bridge ring compound having a structure represented by formula (A0), and a preparation method therefor and the use thereof. The compound has a good selective inhibitory effect on KRAS G12D, and has better pharmacodynamic and pharmacokinetic properties and lower toxic side effects.

Description

Substituted bridge ring inhibitors and preparation method and application thereof Technical Field

The invention belongs to the field of medicines, and specifically relates to a substituted bridge ring inhibitor and a preparation method and application thereof.

Background Art

About a quarter of all human tumors are caused by RAS mutations, and nearly one million people lose their lives each year. In the RAS family, KRAS mutations account for 85% of all RAS mutations. KRAS mutations are found in nearly 90% of pancreatic cancers, 30-40% of colon cancers, and 15-20% of lung cancers (mainly non-small cell lung cancer). The most important mutations in KRAS mutations are G12C and G12D mutations, of which G12C mutations mainly occur in HSCLC, while G12D mutations mainly occur in pancreatic cancer. So far, there are still no drugs approved for the KRAS ^G12D mutation on the market.

At present, conventional treatments for pancreatic cancer in clinical practice include gemcitabine monotherapy, gemcitabine combined with albumin-paclitaxel, and FOLFIRINOX regimen (oxaliplatin + irinotecan + 5-FU/LV). Among them, liposomal irinotecan is suitable for the treatment of patients with advanced pancreatic cancer who have not responded well to gemcitabine chemotherapy (second-line therapy) in combination with fluorouracil and folinic acid. But in general, there are currently limited effective treatments for pancreatic cancer, and the overall survival time of patients does not exceed 1 year. Although drug exploration for patients with advanced pancreatic cancer is ongoing, research progress has been relatively slow so far.

Since the KRAS ^G12D target protein is pathologically associated with a variety of diseases, especially pancreatic cancer, new KRAS ^G12D inhibitors are currently needed for clinical treatment. Highly selective and highly active KRAS ^G12D inhibitors can more effectively treat diseases such as cancer caused by KRAS ^G12D mutations, and have the potential to reduce off-target effects, so they have more urgent clinical needs.

Summary of the invention

The object of the present invention is to provide a novel class of compounds having selective inhibitory effects on KRAS ^G12D and/or better pharmacodynamic properties and uses thereof.

In a first aspect, the present invention provides a compound of formula (A0), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs:

Ring C is selected from the following group:

Y is a bond or O;

for

Z is selected from a bond or a substituted or unsubstituted C ₁ -C ₆ alkylene group; wherein the substitution refers to substitution by one or more R;

W is selected from substituted or unsubstituted C ₃ -C ₁₄ cycloalkyl, or substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclic group; wherein the substitution refers to substitution by one or more R;

R ¹ is selected from hydrogen or deuterium; n is 0, 1, 2, 3, 4, 5 or 6;

R ¹¹ is selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-6 membered heterocyclyl;

m is 0, 1, 2, 3, 4, 5 or 6;

^R10 is selected from the following group:

_V1 , _V2 , _V3 , _V5 are each independently selected from: N or _CRv ; _Rv are the same or different and are each independently selected from the following groups: substituted or unsubstituted: H, _C1 - _C3 alkyl, C3- _C6 cycloalkyl, _4-6 membered heterocyclyl, _C1 - _C3 alkoxy, _C3 - _C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated _C1 - _C3 alkyl, halogenated _C3 - _C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO)-C3- _C6 cycloalkyl, ( _NH2 ) _-C1 - _C3 alkyl, ( _NH2 ) _{-C3 -C6 cycloalkyl} , halogen, CN, -C≡CH, -C≡C- _CH3 , -C≡C-( _C3 -C ₆ cycloalkyl), -C≡C-(4-6 membered heterocyclyl), OH, NH ₂ , CONH ₂ , NHCO(C ₁ -C ₆ alkyl), NHCO(C ₃ -C ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), wherein the substitution refers to substitution by one or more R;

Or _V1 and _V2 are cyclized to form a substituted or unsubstituted group: phenyl or 5-6 membered heteroaryl; wherein the substitution refers to substitution by one or more R;

X is selected from: S, or O;

Each R is the same or different and is independently selected from the group consisting of deuterium, C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halogenated C ₁ -C ₁₈ alkyl, (C ₃ -C ₁₈ cycloalkyl)C ₁ -C ₁₈ alkyl, (4-20 membered heterocyclyl)C ₁ -C ₁₈ alkyl, (C ₁ -C ₁₈ alkoxy)C ₁ -C ₁₈ alkyl, (C ₃ -C ₁₈ cycloalkyloxy)C ₁ -C ₁₈ alkyl, (4-20 membered heterocyclyloxy)C ₁ -C ₁₈ alkyl, vinyl, ethynyl, (C ₁ -C ₆ alkyl)vinyl, deuterated (C ₁ -C ₆ alkyl)vinyl, halogenated (C ₁ -C ₆ alkyl)vinyl, (C ₁ -C ₆ alkyl)ethynyl, deuterated (C ₁ -C ₆ alkyl)ethynyl, halogenated (C _{1 -C} 6 alkyl) -C ₆ alkyl)ethynyl, (C ₃ -C ₁₄ cycloalkyl)ethynyl, (4-14 membered heterocyclyl)ethynyl, C ₁ -C ₁₈ alkoxy, deuterated C ₁ -C ₁₈ alkoxy, halogenated C ₁ -C ₁₈ alkoxy, 4-20 membered heterocyclyl C(O), C ₃ -C ₂₀ cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfonamide, sulfone or urea.

In another preferred embodiment, the compound is a compound of formula I0,

wherein R _x is selected from hydrogen, or CH ₃ ;

R _p is selected from hydrogen, or C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, or 4-6 membered heterocyclyl;

R ¹⁰ , Z, W, R ¹ , n and m are as defined above.

In another preferred embodiment, R ¹⁰ is wherein _V1 , _V2 , _V3 and _V5 are each independently selected from: N, or _CRv ; _{Rv are} the same or different and are each independently selected from: H, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclyl, _C1 - _C3 alkoxy, C3- _C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated _C1 - _{C3 alkyl} , halogenated _C3 - _C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl, ( _NH2 )-C1- _C3 alkyl, ( _NH2 ) _{-C3 -C6 cycloalkyl} , halogen, CN, -C≡CH, -C≡C- _CH3 , -C≡C-( _C3 -C ₆ cycloalkyl), -C≡C-(4-6 membered heterocyclyl), OH, NH ₂ , CONH ₂ , NHCO(C ₁ -C ₆ alkyl), NHCO(C ₃ -C ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl).

In another preferred embodiment, R ¹⁰ is wherein R _y2 is NH ₂ , and R _y1 , R _y3 , R _y4 and R _y5 are each independently selected from the group consisting of H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated C ₁ -C ₃ alkyl, halogenated C ₃ -C ₆ cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO)-C ₁ -C ₃ alkyl, (HO)-C _{3 -C 6} cycloalkyl, (NH ₂ )-C ₁ -C ₃ alkyl, (NH ₂ )-C ₃ -C ₆ cycloalkyl, halogen, CN, -C≡CH, -C≡C-CH ₃ , -C≡C-(C ₃ -C ₆ cycloalkyl), -C≡C-(4-6 membered heterocyclyl), OH, NH ₂ , CONH ₂ , NHCO(C ₁ -C ₆ alkyl), NHCO(C ₃ -C ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl).

In another preferred embodiment, Ry ₅ is selected from: halogenated C ₁ -C ₃ alkyl (such as CF ₃ , CF ₂ CF ₃ ), C ₃ -C ₆ cycloalkyl, or 4-6 membered heterocyclic group.

In another preferred embodiment, Ry ₁ is selected from: H or halogen.

In another preferred embodiment, R _y3 is selected from: H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, -C≡CH, -C≡C-CH ₃ , -C≡C-(C ₃ -C ₆ cycloalkyl), -C≡C-(4-6 membered heterocyclyl), or halogen.

In another preferred embodiment, Ry ₄ is selected from: C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, -C≡CH, -C≡C-CH ₃ , -C≡C-(C ₃ -C ₆ cycloalkyl), -C≡C-(4-6 membered heterocyclyl), or halogen.

In another preferred embodiment, R ¹⁰ is

U is selected from: N, CH, CD, CF;

R ⁴ is selected from the group consisting of substituted or unsubstituted halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl;

R ⁵ , R ⁶ , R ⁷ , and R ⁹ are the same or different, and are independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R;

^R8 is _NH2 .

In another preferred embodiment, U, R ⁶ , R ⁷ , R ⁹ and R ⁸ are as defined above;

R ⁵ is selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R;

^R4 is selected from the following groups _{which are substituted or unsubstituted: H, C1-C3 alkyl, C3-C6 cycloalkyl , 4-6 membered} heterocyclyl, C1- _C3 alkoxy, _C3 - _C6 cycloalkyloxy, _4-6 membered heterocyclyloxy, halogenated _C1 - _C3 alkyl, halogenated _C3 -C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl, ( _NH2 )-C1- _C3 alkyl, ( _NH2 ) _{-C3 -C6 cycloalkyl} , halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), _{NHCO(C3-C6 cycloalkyl), SO2NH2 , NHSO2 ( C1 - C6} alkyl), _NHSO2 ( _C3 -C ₆ cycloalkyl); wherein the substitution refers to substitution by one or more R.

In another preferred embodiment, R ⁴ and R ⁵ are as defined above, U is CH, R ⁶ , R ⁷ and R ⁹ are independently H or deuterium, and R ₈ is NH ₂ .

In another preferred embodiment, R ¹⁰ is

U' is selected from: O, or S;

U" is selected from: N, or C(CN);

R ^7' , R ^8' , R ^9' are the same or different, and are independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R;

R ^5' is NH ₂ .

In another preferred embodiment, the compound has a structure represented by formula (IA) or formula (IB):

R ¹⁰ , Z, W, R ¹ and n are as defined above.

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

wherein V ₁ , V ₂ , V ₃ , V ₅ , R _v , Z, W, R ¹ and n are as defined above.

In another preferred embodiment, the compound has a structure represented by formula (II-A), or formula (II-B), or formula (II-C), or formula (II-D), or formula (II-E), or formula (II-F):

R ¹² are the same or different and are each independently selected from hydrogen or deuterium;

R ⁴ is selected from the group consisting of substituted or unsubstituted halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl; wherein the substitution refers to substitution by one or more R;

R ⁵ is selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R;

o is 0, 1, or 2;

wherein V ₁ , V ₂ , V ₃ , V ₅ , and R are as defined above.

In another preferred embodiment, The substituted or unsubstituted group is selected from the following groups: aniline, naphthylamine, 5-6-membered monocyclic heteroaryl (such as pyridyl) amine, 9-10-membered bicyclic heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran, quinoline, quinazoline) amine, wherein the substitution is substituted by one or more groups selected from the following group: halogen, hydroxyl, cyano, _NH2 , _C1 - _C6 alkyl, halogenated _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogenated _C1 - _C6 alkoxy, _C3 - _C6 cycloalkyl, 4-6-membered heterocyclyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl; preferably, Selected from:

In another preferred embodiment, Selected from the following substituted or unsubstituted groups: 9-10 membered bicyclic heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran, pyridothiazole, pyridothiphene, pyridotfuran) amine, wherein the substitution is substituted by one or more groups selected from the following group: halogen, hydroxyl, cyano, _NH2 , _C1 - _C6 alkyl, halogenated _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogenated _C1 -C6 alkoxy, _C3 - _C6 cycloalkyl, _4-6 membered heterocyclyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl; preferably, Selected from:

In another preferred embodiment, W is selected from: substituted or unsubstituted 4-7 membered monocyclic heterocyclyl, substituted or unsubstituted C ₃ -C ₇ monocyclic cycloalkyl, substituted or unsubstituted 6-10 membered bicyclic heterocyclyl, substituted or unsubstituted C 6 -C 10 bicyclic cycloalkyl, substituted or unsubstituted 7-12 membered tricyclic heterocyclyl, substituted or unsubstituted C ₇ -C ₁₂ tricyclic cycloalkyl, preferably, W is a substituted or unsubstituted 8-12 membered N-containing heterocyclyl, wherein the substitution refers to substitution by one or more R, and R is defined as described in claim 1;

Preferably, ring W is selected from:

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

Or choose from the following groups:

Or choose from the following groups:

Or choose from the following groups:

Or choose from the following groups:

In another preferred embodiment, ring C, Y, A, Z, W, R ¹ , R ¹⁰ , R ¹¹ and m are independently selected from the corresponding groups in the above specific compounds.

In another preferred embodiment, the compound is preferably the compound prepared in the examples.

In a second aspect, the present invention provides a method for preparing a compound of formula (A0), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, comprising the steps (taking formula I0 as an example):

(i) reacting a compound of formula V-1 with a compound of formula V-2 in an inert solvent in the presence of a base, with or without a Pd catalyst, with or without a condensing agent to obtain a compound of formula V-3;

(ii) reacting a compound of formula V-3 with a compound of formula V-4 in an inert solvent in the presence of a base with or without a Pd catalyst to obtain a compound of formula V-5;

(iii) removing the protecting groups PG1, PG2 and/or PG3 from the compound of formula V-5 under the action of an acid (such as TFA, HCl, etc.) or under Pd-catalyzed hydrogenation conditions to obtain a compound of formula (I0);

In the formula,

X ₁ , X ₂ and X ₃ are each independently selected from: OH, halogen, OTf, OTs or OMs;

PG1 and PG2 are each independently selected from: Boc, Cbz, Bn or PMB;

PG3 is selected from: None, Boc, Cbz, Bn or PMB;

V ₁ , V ₂ , V ₃ , V ₅ , R ¹ , R ^x , Z, W and n are as defined above.

The third aspect of the present invention provides a pharmaceutical composition comprising one or more compounds described in the first aspect, their stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs; 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 (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or the above drugs, biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzu mab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipali sib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tuc idinostat, vorinostat, fimepinostat, droxinostat, entinostat, dacinostat, quisinostat, tacedinaline, etc.), CDK inhibitors (such as palbociclib, ribociclib, abemaciclib, milciclib, trilaciclib, lerociclib, etc.), MEK inhibitors (such as selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or a combination thereof.

In a fourth aspect, the present invention provides a use of the compound described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition described in the third aspect, for preparing a drug for preventing and/or treating a disease related to the activity or expression of KRAS ^G12D .

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

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

In a fourth aspect, the present invention provides a non-diagnostic, non-therapeutic method for inhibiting KRAS ^G12D , comprising the steps of administering to a subject in need thereof an effective amount of the compound as described in the first aspect, its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administering the pharmaceutical composition as described above.

In another preferred embodiment, the subject is a mammal, preferably a human.

In a fifth aspect, the present invention provides a method for inhibiting KRAS ^G12D activity in vitro, comprising the steps of contacting the compound as described in the first aspect, its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition as described above with proteins or cells, thereby inhibiting the activity of KRAS ^G12D .

In another preferred embodiment, the cells are selected from the group consisting of macrophages, intestinal cells (including intestinal stem cells, intestinal epithelial cells), or a combination thereof.

In another preferred embodiment, the cells are from rodents (such as mice and rats) or primates (such as humans).

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

DETAILED DESCRIPTION

After long-term and in-depth research, the inventor unexpectedly prepared a new type of compound with selective KRAS ^G12D inhibition and/or better pharmacodynamic properties. On this basis, the inventor completed the present invention.

the term

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

The term "alkyl" by itself or as part of another group refers to a straight or branched alkane group, which may contain 1-20 carbon atoms, such as 1-18 carbon atoms, especially 1-18 carbon atoms, preferably 1-10 carbon atoms (C1-C10), and more preferably 1-6 carbon atoms (C1-C6 or C1-C3). Typical "alkyl" includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, The term "alkyl" refers to alkyl radicals such as pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc. In the present invention, alkyl radicals also include substituted alkyl radicals. "Substituted alkyl radicals" refer to alkyl radicals that are substituted at one or more positions, especially 1 to 4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl ₃ ), cyano, nitro, oxygen (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic, _ORa , _SRa , S(=O) _Re , S(=O) _2Re , P(=O) _2Re , _S (=O) _2ORe , _P (=O) _2ORe , _{NRbRc , NRbS} ( ₌ O) _2Re , _NRbP (=O) _2Re , _S (=O) _2NRbRc , _{P (} =O _{) 2NRbRc} , _C (=O) _{ORd ,} C(=O _{) Ra} , C(=O _{) NRbRc} , OC(=O) _Ra , OC(＝O)NR _b R _c , NR _b C(＝O)OR _e , NR _d C(＝O)NR _b R _c , NR _d S(＝O) ₂ NR _b R _c , NR _d P(＝O) ₂ NR _b R _c , NR _b C(＝O)R _a , or NR _b P(＝O) ₂ R _e , wherein _Ra appearing herein may 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 _c and R _d may independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, a 5-14 membered heterocycle or a C6-C14 aromatic ring, or R _b and R _c together with the N atom may form a heterocycle; R _e can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, 5-14 membered heterocyclic ring or C6-C14 aromatic ring. The above typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or aromatic ring can be optionally substituted.

The term "alkylene" refers to a group formed by removing a hydrogen atom from an alkyl or substituted alkyl group, such as methylene, ethylene, propylene, isopropylene (such as ), butylene (such as ), pentylene (such as ), hexamethylene (such as ), heptylene (such as ), In addition, the term also includes a methylene group of an alkylene group (such as C1-C18 alkylene group) replaced by a cycloalkylene group (such as C3-C20 cycloalkylene group), for example, "C1-C18 alkylene group C3-C20 cycloalkylene group" or "C3-C20 cycloalkylene group C1-C18 alkylene group", and the alkylene group is preferably or C1-C3 alkylene group.

The term "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene" has the same meaning and refers to a group formed by removing two hydrogen atoms from a cycloalkylalkyl or alkylcycloalkyl group, such as wait.

In the present invention, the term "alkenyl" refers to a straight or branched hydrocarbon group containing one or more double bonds and generally having a length of 2 to 20 carbon atoms. Alkenyl is preferably C2-C6 alkenyl, more preferably C2-C4 alkenyl. Alkenyl includes, but is not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-butene-1-yl, etc. In the present invention, alkenyl includes substituted alkenyl.

The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds and generally having a length of 2 to 20 carbon atoms. Alkynyl is preferably C2-C6 alkynyl, more preferably C2-C4 alkynyl. Alkynyl includes, but is not limited to, ethynyl, propynyl or similar groups. In the present invention, alkynyl also includes substituted alkynyl, and the substituent may be halo, hydroxyl, cyano, nitro, etc.

In the present invention, the term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon compound group, including 1-4 rings, each ring containing 3-8 carbon atoms. The term " _C3 - _C20 " refers to a cycloalkyl containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, _{16, 17, 18, 19 or 20 carbon atoms. The cycloalkyl is preferably a C3-C14 cycloalkyl , more} preferably a _C3 - _C10 cycloalkyl, more preferably a C3-C6 monocyclic cycloalkyl, a _C7 - _C10 bicyclic or tricyclic cycloalkyl. "Substituted cycloalkyl" refers to a cycloalkyl in which one or more positions are substituted, especially 1-4 substituents, which can be substituted at any position. In the present invention, "cycloalkyl" includes substituted cycloalkyl, typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, a monohalogen substituent or a polyhalogen substituent, the latter such as trifluoromethyl or an alkyl containing Cl ₃ ), cyano, nitro, oxygen (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, _alkenyl , cycloalkenyl, alkynyl, heterocycle, aromatic _ring , ORa, _SRa , S(=O) _Re , S(=O) _2Re , _P (=O) _2Re , S(=O) _2ORe , _P (=O _{) 2ORe , NRbRc , NRbS} ( ₌ O) _2Re , _{NRbP (} =O) _2Re , S(=O) _2NRbRc , P(=O) _2NRbRc , _C (=O) _ORd , C(= _{O ) Ra} , C(=O _{) NRbRc} , OC(＝O) _Ra , OC(＝O) _NRbRc , _NRbC (＝O) _ORe , _NRdC (＝O) _NRbRc , _NRdS (＝O _{) 2NRbRc} , _NRdP (＝O) _2NRbRc , _NRbC (＝O) _{Ra ,} or _NRbP (＝O) _2Re , wherein _Ra appearing herein can independently represent hydrogen, _{deuterium, alkyl ,} cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or _aromatic ring, _Rb , _Rc and _Rd can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic ring or aromatic ring, or _Rb and _Rc together with the N _atom can form a heterocyclic ring; _Re can independently represent hydrogen, deuterium, _alkyl , cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or aromatic ring. The above typical substituents can be optionally substituted. Typical substitutions also include spirocyclic, bridged or fused ring substituents, especially spirocyclic alkyl, spirocyclic alkenyl, spirocyclic heterocyclic (excluding heteroaromatic rings), bridged cycloalkyl, bridged cycloalkenyl, bridged heterocyclic (excluding heteroaromatic rings), fused cycloalkyl, fused cycloalkenyl, fused heterocyclic or fused aromatic rings, and the above cycloalkyl, cycloalkenyl, heterocyclic and heterocyclic aromatic groups can be optionally substituted. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, etc.

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

wait.

In the present invention, the term "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to 3-7 membered monocyclic, 4-7 membered monocyclic, 6-11 membered bicyclic or 8-16 membered tricyclic or polycyclic system), wherein at least one heteroatom is present in the ring having at least one carbon atom. The term "4-20 membered heterocyclyl" refers to a heterocyclyl containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms. "Heterocyclyl" has the same meaning as "saturated or unsaturated heterocyclyl". "Heterocyclyl" is preferably a 4-14 membered heterocyclyl (including but not limited to a 4-6 membered monocyclic, 7-10 membered bicyclic or 8-14 membered tricyclic or polycyclic system), more preferably a 4-12 membered heterocyclyl, more preferably a 4-10 membered heterocyclyl, such as a 4-6 membered monocyclic heterocyclyl, a 7-10 membered bicyclic or tricyclic heterocyclyl, more preferably a 4-8 membered heterocyclyl, more preferably a 4-6 membered heterocyclyl. Each heterocyclic ring containing heteroatoms may carry 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms, wherein the nitrogen atoms or sulfur atoms may be oxidized and the nitrogen atoms may be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom residue of the ring or ring system molecule, preferably to N or C atoms on 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-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxanyl and tetrahydro-1,1-dioxythiophene, and the like. The polycyclic heterocyclic group includes spirocyclic, condensed and bridged heterocyclic groups; wherein the spirocyclic, condensed and bridged heterocyclic groups involved are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring; the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, thiol, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate.

The term "C4-C20 heterocyclylene" refers to a group formed by removing two hydrogen atoms from a heterocyclyl group, such as: wait.

In the present invention, the term "aryl" refers to an aromatic cyclic hydrocarbon group having 1-5 rings, especially monocyclic and bicyclic groups. Among them, " _C6 - _C14 aryl" refers to an aromatic cyclic hydrocarbon compound group containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring carbon atoms. Aryl includes phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be connected by a single bond (such as biphenyl) or fused (such as naphthalene, anthracene, etc.). "Substituted aryl" means that one or more positions in the aryl are substituted, especially 1-3 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl ₃ ), cyano, nitro, oxo (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, _ORa , _SRa , S(=O) _Re , S(=O) _2Re , _P (=O) _2Re , _S (=O) _{2ORe , P(=O)2ORe, NRbRc , NRbS ( = O} ) _2Re , _NRbP (=O) _2Re , _S (= _O ) _2NRbRc , P(=O) _2NRbRc , _{C (} =O) _ORd , C(=O) _Ra , _C (=O _{) NRbRc} , OC(=O) _Ra , OC(＝O)NR _b R _c , NR _b C(＝O)OR _e , NR _d C(＝O)NR _b R _c , NR _d S(＝O) ₂ NR _b R _c , NR _d P(＝O) ₂ NR _b R _c , NR _b C(＝O)R _a , or NR _b P(＝O) ₂ R _e , wherein _Ra appearing herein can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or aromatic ring, R _b , R _c and R _d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic ring or aromatic ring, or R _b and R _c together with the N atom can form a heterocyclic ring; _Re can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or aromatic ring. The above typical substituents can be optionally substituted. Typical substitutions also include fused ring substituents, especially fused cycloalkyl, fused cycloalkenyl, fused heterocyclic or fused aromatic ring groups, wherein the cycloalkyl, cycloalkenyl, heterocyclic and heterocyclic aromatic groups may be optionally substituted.

The term "heteroaryl" refers to an aromatic cyclic hydrocarbon group containing 1 to 4 heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. Among them, "5-14 membered heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms. The heteroaryl is preferably 5 to 10 rings, more preferably 5 or 6, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazoxinyl, triazolyl and tetrazolyl. "Heteroaryl" may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following 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.

In the present invention, the term "alkoxy" refers to a straight chain or branched alkoxy group, including alkyl-O-, alkyl-O-alkyl, wherein "C ₁ -C ₁₈ alkoxy" refers to a straight chain or branched alkoxy group having 1 to 18 carbon atoms, including C ₁ -C ₁₈ alkyl-O-, -C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably, it is C ₁ -C ₈ alkoxy, more preferably C1 -C ₆ alkoxy.

In the present invention, the term "cycloalkyloxy" refers to cycloalkyl-O-, wherein "C ₃ -C ₂₀ cycloalkyloxy" refers to C ₃ -C ₂₀ cycloalkyl-O-, wherein C ₃ -C ₂₀ cycloalkyl is as defined above.

In the present invention, the term "heterocyclyloxy" refers to heterocyclyl-O-, wherein "4-20 membered heterocyclyloxy" refers to 4-20 membered heterocyclyl-O-, wherein the 4-20 membered heterocyclyl is as defined above.

In the present invention, the term "C ₁ -C ₁₈ alkyleneoxy group" refers to a group obtained by removing a hydrogen atom from a "C ₁ -C ₁₈ alkoxy group".

In the present invention, the term "halogen" or "halo" refers to chlorine, bromine, fluorine, and iodine.

In the present invention, the term "halogenated" means substituted with halogen.

In the present invention, the term "deuterated" means substituted with deuterium.

In the present invention, the term "hydroxyl" refers to a group having the structure OH.

In the present invention, the term "nitro" refers to a group having the structure NO ₂ .

In the present invention, the term "cyano group" refers to a group having the structure CN.

In the present invention, 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, heterocycle or substituted heterocycle. The ester group is preferably -COO C ₁ -C ₆ alkyl.

The term "amine group" refers to a group with the structure -NRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine fragment. The amine group is preferably _NH2 , NH _C1 - _C6 alkyl, N( _C1 - _C6 alkyl) ₂ .

The term "amido" refers to a group with the structure -CONRR' or -NRCOR', wherein R and R' can each 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. The amide group is preferably _CONH2 , NHCO( _C1 - _C6 alkyl), NHCO( _C3 - _C6 cycloalkyl).

The term "sulfonamido" refers to a group with the structure _-S2ONRR ' or _-NRSO2R ', wherein R and R' can each 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. The sulfonamido _is preferably _SO2NH2 , _NHSO2 ( _C1 - _C6 alkyl), _NHSO2 ( _C3 - _C6 cycloalkyl).

The term "sulfone" refers to a group having the structure _-SO2R , wherein 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.

The term "urea group" refers to a group having the structure -NRCONR'R", wherein R, R' and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" can be the same or different in the dialkylamine fragment.

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

The term "dialkylaminoalkyl" refers to a group having the structure -RNHR'R", wherein R, R' and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" can be the same or different in the dialkylamine moiety.

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

In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is the substituent described above, or the substituent appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is those stable or chemically feasible combinations. The substituents include, 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 heterocyclic group, aryl, heteroaryl, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amine group, C1-C6 alkoxy group, C1-C10 sulfonyl group, and C1-C6 urea group, etc.

Unless otherwise stated, any heteroatom with unsatisfied valence is assumed to have sufficient hydrogen atoms to complete its valence.

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

In the present invention, a plurality refers to 2, 3, 4, or 5.

Active ingredients

As used herein, "compounds of the present invention" refers to compounds represented by Formula I, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of the compounds of Formula I.

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

The compounds of the present invention contain basic fragments, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor salt, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide [0013] The invention also includes but is not limited to the following: esters, isothioates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonates, dodecanoates, and the like.

Some compounds of the present invention may contain acidic fragments, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed with organic bases (such as organic amines), such as benzathine, dicyclohexylamine, hepamine (salt formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate), long chain halides (such as chlorides, bromides and iodides of decyl, dodecyl, tetradecyl and tetradecyl), aralkyl halides (such as benzyl and phenyl bromides), etc.

Prodrugs and solvates of the compounds of the present invention are also within the scope of the invention. The term "prodrug" herein refers to a compound that undergoes chemical transformation by metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when treating a related disease. The compounds of the present invention include solvates, such as hydrates.

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

All stereoisomers of the compounds (e.g., those due to asymmetric carbon atoms that may exist for various substitutions), including enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist simultaneously with other isomers (e.g., as a pure or substantially pure optical isomer having a particular activity), or may be mixtures, such as racemates, or mixtures with all other stereoisomers or portions thereof. The chiral centers of the present invention have two configurations, S or R, as defined by the 1974 recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods, such as fractional crystallization, or by crystallization of diastereoisomers derived therefrom, or by separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods, such as recrystallization after salt formation with an optically active acid.

The compounds of the present invention are prepared, separated and purified to obtain compounds with a weight content of equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), which are listed in the text description. Such "very pure" compounds of the present invention are also considered part of the present invention.

All configurational isomers of the compounds of the present invention are within the scope of the invention, whether in mixture, pure or very pure form. The definition of the compounds of the present invention includes 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 chemical term definitions are described in detail below. For purposes of the present invention, chemical elements are as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, ^75th Ed. Definitions of specific functional groups are also described therein. In addition, the basic principles of organic chemistry as well as specific functional groups and reactivity are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 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 their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures and other mixtures. In addition, asymmetric carbon atoms may represent substituents, such as alkyl. All isomers and their mixtures are included in the present invention.

According to the present invention, the ratio of isomers contained in the mixture of isomers can be various. For example, in the mixture of only two isomers, there can be the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of isomers are within the scope of the present invention. Similar ratios that are easily understood by ordinary technicians in this profession, and ratios for more complex mixtures of isomers are also within the scope of the present invention.

The present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number from the original atoms. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as ^2H , ^3H , ^13C , ^11C , ^14C , ^15N , ^18O , ^17O , ^31P , ^32P , ^35S , ^18F and ^36Cl , respectively. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as radioactive isotopes of ^3H and ^14C , are also included, which are useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. ^3H and carbon-14, i.e. ^14C , are relatively easy to prepare and detect. is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e., ² H, may be preferred in some cases due to their good metabolic stability, which has advantages in certain therapies, such as increasing half-life in vivo or reducing dosage. Isotope-labeled compounds can be prepared by general methods by replacing readily available isotope-labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

If a synthesis of a specific enantiomer of the compound of the present invention is to be designed, it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting diastereomeric mixture can be separated, and the chiral auxiliary can be removed to obtain the pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a diastereomeric salt can be formed with a suitable optically active acid or base, and then separated by conventional means such as fractional crystallization or chromatography, and then the pure enantiomer can be obtained.

As described herein, the compounds of the present invention can be replaced with any number of substituents or functional groups to expand its scope. Generally, the term "substituted" appears before or after the term "optional", and the general formula including substituents in the formulation of the present invention refers to the use of a specified structural substituent to replace the hydrogen free radical. When multiple positions in a specific structure are substituted by multiple specific substituents, the substituents can be the same or different at each position. The term "substituted" used herein includes all allowed organic compound substitutions. In a broad sense, allowed substituents include non-cyclic, cyclic, branched non-branched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, heteroatom nitrogen can have hydrogen substituents or any allowed organic compounds described above to supplement its valence. In addition, the present invention is not intended to limit the allowed substitution of organic compounds in any way. The present invention believes that the combination of substituents and variable groups is very good in the treatment of diseases in the form of stable compounds, such as infectious diseases or proliferative diseases. As used herein, the term "stable" refers to compounds that are stable and that maintain the structural integrity of the compound over a period of time sufficient to be detected, and preferably over a period of time sufficient to be effective, as used herein for the purposes described above.

The metabolites of the compounds and pharmaceutically acceptable salts thereof involved in the present application, as well as prodrugs that can be converted into the structures of the compounds and pharmaceutically acceptable salts involved in the present application in vivo, are also included in the claims of the present application. In the present invention, the term "prodrug" refers to a compound that is inactive or less active in vitro after the drug is modified by chemical structure to introduce an easy leaving group, but releases active drugs in vivo through conversion with the participation of enzymes (such as hydrolases, oxidases, etc.) or non-enzymes (such as pH, light, radiation, etc.) to exert its pharmacological effect. The prodrugs include (but are not limited to): carboxylates, phosphates, carbamates, carbonates, etc. The structure of the easy leaving group is (but is not limited to):

Preparation method

The preparation method of the compound of formula (A0) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combination can be easily carried out by a technician in the field to which the present invention belongs.

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

Preferably, the compound of the present invention is prepared by the following method (taking formula (I0) as an example):

(i) reacting a compound of formula V-1 with a compound of formula V-2 in an inert solvent in the presence of a base, with or without a Pd catalyst, with or without a condensing agent to obtain a compound of formula V-3;

(ii) reacting a compound of formula V-3 with a compound of formula V-4 in an inert solvent in the presence of a base with or without a Pd catalyst to obtain a compound of formula V-5;

(iii) removing the protecting groups PG1, PG2 and/or PG3 from the compound of formula V-5 under the action of an acid (such as TFA, HCl, etc.) or under Pd-catalyzed hydrogenation conditions to obtain a compound of formula (I0);

In the formula,

X ₁ , X ₂ and X ₃ are each independently selected from: OH, halogen, OTf, OTs or OMs;

PG1 and PG2 are each independently selected from: Boc, Cbz, Bn or PMB;

PG3 is selected from: None, Boc, Cbz, Bn or PMB;

V ₁ , V ₂ , V ₃ , V ₅ , R ¹ , R ^x , Z, W and n are as defined above.

Pharmaceutical compositions and methods of administration

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

The compound of general formula (I0) can be used in combination with other drugs known to treat or improve similar symptoms. When administered in combination, the administration method and dosage of the original drug can remain unchanged, and the compound of formula I can be taken simultaneously or subsequently. When the compound of formula (I0) is taken simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used. Drug combination also includes taking the compound of formula (I0) and one or more other known drugs in overlapping time periods. When the compound of formula (I0) is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of them taken alone.

The drugs or active ingredients that can be used in combination with the compound of formula (I0) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, L ZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, o binutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Om ipalisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Visusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or a combination thereof. The dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, film, pill, external ointment, controlled release or sustained release or nano preparation.

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

"Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations 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, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl 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 the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into 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 compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

Besides such inert diluents, the composition may also include 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 such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may include 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 non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds of the 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 that may be required.

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

When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I0) of the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, thereby forming a pharmaceutical composition.

The present invention also provides a treatment method, which comprises the steps of administering the compound of general formula (A0) of the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, or administering the pharmaceutical composition of the present invention to a subject in need of treatment, for selectively inhibiting KRAS ^G12D .

Compared with the prior art, the present invention has the following main advantages:

(1) The compound has a good selective inhibitory effect on KRAS ^G12D ;

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

The present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally carried out according to conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

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

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

NMR was measured using a Bruker AVANCE-400 NMR spectrometer. The measurement solvents included deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated acetone (CD ₃ COCD ₃ ), deuterated chloroform (CDCl ₃ ) and deuterated methanol (CD ₃ OD). Tetramethylsilane (TMS) was used as the internal standard. Chemical shifts were measured in parts per million (ppm).

Liquid chromatography-mass spectrometry (LC-MS) was performed using a Waters SQD2 mass spectrometer. HPLC was performed using an Agilent 1100 high pressure chromatograph (Microsorb 5micron C18 100x 3.0mm column).

The thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, TLC uses 0.15-0.20 mm, and preparative thin layer chromatography uses 0.4 mm-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 all known and commercially available, or can be synthesized using or according to literature data reported in the art.

Unless otherwise specified, all reactions of the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) with continuous magnetic stirring, and the reaction temperatures are all degrees Celsius.

Example CA-1: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

Step 1: Preparation of (1R,5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-5-chloro-2-fluoro-6-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol (78 mg, 0.81 mmol) was dissolved in tetrahydrofuran (2 mL), followed by the addition of sodium tert-butoxide (78 mg, 0.81 mmol). The mixture was stirred at room temperature for 1 min, and then a solution of (1R,5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-5-chloro-2-fluoro-6-(trifluoromethyl)phenyl)-2-(methylsulfinyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (230 mg, 0.27 mmol) in tetrahydrofuran (1 mL) was added. The resulting mixture was stirred at room temperature for 1 h, then quenched with water and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (150 mg).

Step 2: Preparation of (1R,5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-(prop-1-yn-1-yl)-6-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

Under argon protection, (1R,5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-5-chloro-2-fluoro-6-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4 ,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (150 mg, 0.15 mmol) was dissolved in toluene (3 mL), followed by the addition of tributyl(1-propynyl)tin (198 mg, 0.60 mmol) and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (32 mg, 0.045 mmol). The resulting mixture was stirred at 110 °C for 2 h under an argon atmosphere, then quenched with water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (110 mg).

Step 3: Preparation of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

(1R,5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-(prop-1-yn-1-yl)-6-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (110 mg, 0.11 mmol) was dissolved in trifluoroacetic acid (4 mL). The resulting mixture was stirred at 40°C for 2 h and then concentrated under reduced pressure. The residue was separated by preparative liquid phase to obtain the target product (40 mg).

LC-MS: m/z 663(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ7.93(s,1H),6.90(d,J＝8.4Hz,1H),6.07(s,2H),5.10–5.00(m,1H),4.84–4.72(m,1H),4.65–4.56(m,1H),4.09–3.93( m,3H),3.90–3.80(m,2H),3.59–3.42(m,3H),3.14–2.95(m,4H),2.86–2.78(m,1H),2.77–2.66(m,1H),2.12–1.40(m,16H).

Example CA-1 was subjected to chiral separation to obtain two isomers, Example CA-1A and Example CA-1B: 3-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(propan-1 3-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

Example C1A

LC-MS: m/z 663 (M+H) ⁺ .

Example C1B

LC-MS: m/z 663 (M+H) ⁺ .

The following compounds were synthesized using the same method as in Example C1 with different starting materials:

Example CA-2 3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-4-(1-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

LC-MS: m/z 677 (M+H) ⁺ .

Example CA-2 was subjected to chiral separation to obtain two isomers, Example CA-2A, Example CA-2B, Example CA-2C and Example CA-2D: 3-((S)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-7,8-dihydro-5H-pyran[4 ,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline, 3-((R)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2 -fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline, 3-((S)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline, 3-((R)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

Example CA-2A

LC-MS: m/z 677 (M+H) ⁺ .

Example CA-2B

LC-MS: m/z 677 (M+H) ⁺ .

Example CA-2C

LC-MS: m/z 677 (M+H) ⁺ .

Example CA-2D

LC-MS: m/z 677 (M+H) ⁺ .

Example CA-3 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-ethynyl-4-(trifluoromethyl)aniline

LC-MS: m/z 649 (M+H) ⁺ .

Example CA-3 was subjected to chiral separation to obtain two isomers, Example CA-3A and Example CA-3B: 3-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2- Fluoro-5-ethynyl-4-(trifluoromethyl)aniline and 3-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-ethynyl-4-(trifluoromethyl)aniline

Example CA-3A

LC-MS: m/z 649 (M+H) ⁺ .

Example CA-3B

LC-MS: m/z 649 (M+H) ⁺ .

Example CB-1 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-chloro-2-fluoro-4-(trifluoromethyl)aniline

Step 1: Dissolve (1R,5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-5-chloro-2-fluoro-6-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (50 mg, 0.05 mmol) in trifluoroacetic acid (2 mL). The resulting mixture was stirred at 40°C for 2 h and then concentrated under reduced pressure. The residue was separated by preparative liquid phase to obtain the target product (15 mg, 45.6%).

LC-MS: m/z 659 (M+H) ⁺ .

Example CB-1 was subjected to chiral separation to give two isomers, Example CB-1A and Example CB-1B: 3-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)- 5-Chloro-2-fluoro-4-(trifluoromethyl)aniline and 3-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-chloro-2-fluoro-4-(trifluoromethyl)aniline

Example CB-1A

LC-MS: m/z 659 (M+H) ⁺ .

Example CB-1B

LC-MS: m/z 659 (M+H) ⁺ .

The following compounds were synthesized using different starting materials in the same manner as in Example CB-1:

Example CB-2 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-methyl-4-(trifluoromethyl)aniline

LC-MS: m/z 639 (M+H) ⁺ .

Example CB-2 was subjected to chiral separation to give two isomers, Example CB-2A and Example CB-2B: 3-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2 3-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-methyl-4-(trifluoromethyl)aniline

Example CB-2A

LC-MS: m/z 639 (M+H) ⁺ .

Example CB-2B

LC-MS: m/z 639 (M+H) ⁺ .

Example CB-3 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-3-methyl-4-(trifluoromethyl)aniline

LC-MS: m/z 639 (M+H) ⁺ .

Example CB-3 was subjected to chiral separation to give two isomers, Example CB-3A and Example CB-3B: 5-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2 -fluoro-3-methyl-4-(trifluoromethyl)aniline and 5-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-3-methyl-4-(trifluoromethyl)aniline

Example CB-3A

LC-MS: m/z 639 (M+H) ⁺ .

Example CB-3B

LC-MS: m/z 639 (M+H) ⁺ .

Example CB-4 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline

LC-MS: m/z 641 (M+H) ⁺ .

Example CB-4 was subjected to chiral separation to obtain two isomers, Example CB-4A and Example CB-4B: 3-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-7 3-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline

Example CB-4A

LC-MS: m/z 641 (M+H) ⁺ .

Example CB-4B

LC-MS: m/z 641 (M+H) ⁺ .

Examples CC-1A and CC-1B 4-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine and 4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine

Example CC-1A

LC-MS: m/z 631(M+H)+.

Example CC-1B

LC-MS: m/z 631(M+H)+.

Examples CC-2A and CC-2B 4-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-amine and 4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-amine

Example CC-2A

LC-MS: m/z 635(M+H)+.

Example CC-2B

LC-MS: m/z 635(M+H)+.

Biological test cases

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

KRAS ^Gl2D binding inhibition assay

Experimental procedures

TR-FRET technology was used to detect the binding ability of the compounds to KRAS ^G12D protein. Biotin-labeled GDP-loaded KRAS ^G12D recombinant human protein was co-incubated with Cy5-labeled tracer, europium-labeled streptavidin, and compound (2% DMSO final concentration) in buffer (HEPES (pH 7.5), MgCl ₂ , Tween-20 and DTT). After incubation at 22°C for 60 minutes, the reaction activity was detected by EnVision multi-function microplate reader dual wavelength technology, and the protein binding capacity (POC) was calculated using ratiometric emission factor.

100POC means no compound; 0POC means that the control compound completely inhibits the binding of the tracer to KRAS ^G12D at this concentration. The POC value is fitted by a four-parameter logistic model curve, and _IC50 represents the 50POC concentration value.

The results showed that the compounds of the present invention showed good inhibitory activity against KRAS ^G12D .

ERK phosphorylation inhibition assay

Experimental procedures

KRAS ^G12D mutant cells (such as GP2D, AGS, etc.) were seeded in a 384-well plate and cultured overnight in a 37° C., 5% CO 2 incubator.

Add 200 nL of the diluted compound using Echo 500, with a final DMSO concentration of 0.5%, and incubate in a 37°C, 5% CO2 incubator for 1 hour. Add hEGF and let it act for 10 minutes.

Remove the culture medium, add cell fixative, and fix the cells.

Wash once with PBS and incubate in cold 100% methanol.

Remove the methanol and add PBS to wash once.

Remove PBS, add Li-Cor blocking buffer to each well, and block for 1 hr at room temperature.

Remove the blocking solution, add primary antibody mixture to each well, and incubate at 4°C overnight.

Remove the primary antibody mixture and add PBST to wash three times.

Add the secondary antibody mixture and incubate at room temperature in the dark for 45 min.

Remove the secondary antibody mixture, add PBST and wash 3 times, finally aspirate PBST, invert and centrifuge at 1000 rpm for 1 min.

Odyssey CLx readings.

The results showed that the compounds of the present invention showed good inhibitory activity on ERK phosphorylation in KRAS ^G12D mutant cells.

Inhibitory effect of compounds on proliferation of KRAS G12D mutant cells

Experimental steps: 1. Cell culture

(a) Resuscitate cells in T75 cell culture flasks:

(b) When the cell confluence reached 80-90%, the cells were passaged.

2. Cell Proliferation Assay

Experimental procedures

Use a nanoliter pipetting system to add the diluted test compound to a 384-well cell culture plate and set up duplicate wells. Add an equal volume of culture medium to the positive control group; add an equal volume of DMSO to the negative control group, and centrifuge at 1000 rpm for 1 minute at room temperature.

The cells were inoculated into a) 384 culture plate, and the negative control group was added with an equal volume of cells, and the positive control group was added with an equal volume of culture medium only. Centrifuged at 1000 rpm for 1 min at room temperature, and the final DMSO concentration of the compound was 0.5%, and incubated in a 37°C, 5% CO2 constant temperature incubator for 7 days.

Add 20 μL/well 3D to b) in a 384-well cell culture plate, shake at 320 rpm for 20 min in the dark, and incubate at room temperature for 2 hrs in the dark.

The luminescence value was read using Envision multi-function microplate reader.

3. Data Analysis

The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1-(RLU compound-RLU blank control)/(RLU solvent control-RLU blank control))*100%. The inhibition rates of different concentrations of the compound were calculated in Excel, and then the inhibition curves were plotted and related parameters were calculated using GraphPad Prism software, including the minimum inhibition rate, maximum inhibition rate, and _IC50 .

The structure of the reference compound MRTX1133 is as follows:

Table 1 Cell proliferation inhibition activity of the compounds in the examples of the present invention

The results showed that the compounds of the present invention showed good inhibitory activity against the proliferation of KRAS ^G12D mutant cells.

Pharmacokinetic testing evaluation

Male ICR mice, weighing 22-24 g, were fasted overnight and orally administered with a 30 mg/kg solution of the compound of the present invention or a control compound [10% DMSO + 60% PEG400 + 30% aqueous solution]. Blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0 and 24 h after administration of the compound of the present invention, and the concentration of the compound of the present invention or the control compound in plasma was determined by LC/MS/MS.

It can be seen from the test results that the compound of the present invention has good oral pharmacokinetic properties.

Pharmacokinetic testing evaluation

Male SD rats, weighing about 220 g, were fasted overnight and orally administered with a 30 mg/kg solution of the compound of the present invention or a control compound [10% DMSO + 60% PEG400 + 30% aqueous solution]. Blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0 and 24 h after administration of the compound of the present invention, and the concentration of the compound of the present invention or the control compound in plasma was determined by LC/MS/MS.

It can be seen from the test results that the compound of the present invention has good pharmacokinetic properties.

Anti-tumor activity pharmacodynamics test evaluation (AsPC-1CDX tumor model)

100uL of 5x10 ⁶ AsPC-1 tumor cell suspension was subcutaneously inoculated into the right posterior abdomen of nude mice. The health of mice was monitored daily, and measurements were started when the tumor grew to a palpable size. The tumor volume was calculated using the formula: 0.5xLxW ² , where L and W represent the length and width of the tumor, respectively. When the tumor grew to ～200mm ³ , the mice were randomly divided into groups. The mice were intraperitoneally injected or orally with the corresponding dose of compound every day, and their general condition was monitored at the same time. The tumor was measured 3 times a week, and the body weight was measured twice a week.

It can be seen from the test results that the compound of the present invention has a good anti-tumor effect.

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

Claims (15)

The compound of formula (A0), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug:
Ring C is selected from the following group: Y is a bond or O; for Z is selected from a bond or a substituted or unsubstituted C ₁ -C ₆ alkylene group; wherein the substitution refers to substitution by one or more R; W is selected from substituted or unsubstituted C ₃ -C ₁₄ cycloalkyl, or substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclic group; wherein the substitution refers to substitution by one or more R; R ¹ is selected from hydrogen or deuterium; n is 0, 1, 2, 3, 4, 5 or 6; R ¹¹ is selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 4-6 membered heterocyclyl; m is 0, 1, 2, 3, 4, 5 or 6; ^R10 is selected from the following group: _V1 , _V2 , _V3 , _V5 are each independently selected from: N or _CRv ; _Rv are the same or different and are each independently selected from the following groups: substituted or unsubstituted: H, _C1 - _C3 alkyl, C3- _C6 cycloalkyl, _4-6 membered heterocyclyl, _C1 - _C3 alkoxy, _C3 - _C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated _C1 - _C3 alkyl, halogenated _C3 - _C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO)-C3- _C6 cycloalkyl, ( _NH2 ) _-C1 - _C3 alkyl, ( _NH2 ) _{-C3 -C6 cycloalkyl} , halogen, CN, -C≡CH, -C≡C- _CH3 , -C≡C-( _C3 -C ₆ cycloalkyl), -C≡C-(4-6 membered heterocyclyl), OH, NH ₂ , CONH ₂ , NHCO(C ₁ -C ₆ alkyl), NHCO(C ₃ -C ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl), wherein the substitution refers to substitution by one or more R; Or _V1 and _V2 are cyclized to form the following substituted or unsubstituted groups: phenyl or 5-6 membered heteroaryl; wherein the substitution refers to substitution by one or more R; X is selected from: S, or O; Each R is the same or different and is independently selected from the group consisting of deuterium, C ₁ -C ₁₈ alkyl, deuterated C ₁ -C ₁₈ alkyl, halogenated C ₁ -C ₁₈ alkyl, (C ₃ -C ₁₈ cycloalkyl)C ₁ -C ₁₈ alkyl, (4-20 membered heterocyclyl)C ₁ -C ₁₈ alkyl, (C ₁ -C ₁₈ alkoxy)C ₁ -C ₁₈ alkyl, (C ₃ -C ₁₈ cycloalkyloxy)C ₁ -C ₁₈ alkyl, (4-20 membered heterocyclyloxy)C ₁ -C ₁₈ alkyl, vinyl, ethynyl, (C ₁ -C ₆ alkyl)vinyl, deuterated (C ₁ -C ₆ alkyl)vinyl, halogenated (C ₁ -C ₆ alkyl)vinyl, (C ₁ -C ₆ alkyl)ethynyl, deuterated (C ₁ -C ₆ alkyl)ethynyl, halogenated (C _{1 -C} 6 alkyl) -C ₆ alkyl)ethynyl, (C ₃ -C ₁₄ cycloalkyl)ethynyl, (4-14 membered heterocyclyl)ethynyl, C ₁ -C ₁₈ alkoxy, deuterated C ₁ -C ₁₈ alkoxy, halogenated C ₁ -C ₁₈ alkoxy, 4-20 membered heterocyclyl C(O), C ₃ -C ₂₀ cycloalkyl, 4-20 membered heterocyclyl, C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfonamide, sulfone or urea. The compound according to claim 1, its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that the compound is a compound of formula (I0),
wherein R _x is selected from hydrogen, or CH ₃ ; R _p is selected from hydrogen, or C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, or 4-6 membered heterocyclyl; R ¹⁰ , Z, W, R ¹ , n and m are as defined in claim 1 . The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that R ¹⁰ is wherein _V1 , _V2 , _V3 and _V5 are each independently selected from: N, or _CRv ; _{Rv are} the same or different and are each independently selected from: H, _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, 4-6 membered heterocyclyl, _C1 - _C3 alkoxy, C3- _C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated _C1 - _{C3 alkyl} , halogenated _C3 - _C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl, ( _NH2 )-C1- _C3 alkyl, ( _NH2 ) _{-C3 -C6 cycloalkyl} , halogen, CN, -C≡CH, -C≡C- _CH3 , -C≡C-( _C3 -C ₆ cycloalkyl), -C≡C-(4-6 membered heterocyclyl), OH, NH ₂ , CONH ₂ , NHCO(C ₁ -C ₆ alkyl), NHCO(C ₃ -C ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl). The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that R ¹⁰ is wherein R _y2 is NH ₂ , and R _y1 , R _y3 , R _y4 and R _y5 are each independently selected from the group consisting of H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated C ₁ -C ₃ alkyl, halogenated C ₃ -C ₆ cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO)-C ₁ -C ₃ alkyl, (HO)-C _{3 -C 6} cycloalkyl, (NH ₂ )-C ₁ -C ₃ alkyl, (NH ₂ )-C ₃ -C ₆ cycloalkyl, halogen, CN, -C≡CH, -C≡C-CH ₃ , -C≡C-(C ₃ -C ₆ cycloalkyl), -C≡C-(4-6 membered heterocyclyl), OH, NH ₂ , CONH ₂ , NHCO(C ₁ -C ₆ alkyl), NHCO(C ₃ -C ₆ cycloalkyl), SO ₂ NH ₂ , NHSO ₂ (C ₁ -C ₆ alkyl), NHSO ₂ (C ₃ -C ₆ cycloalkyl). In another preferred embodiment, Ry ₅ is selected from: halogenated C ₁ -C ₃ alkyl (such as CF ₃ , CF ₂ CF ₃ ), C ₃ -C ₆ cycloalkyl, or 4-6 membered heterocyclic group. In another preferred embodiment, Ry ₁ is selected from: H or halogen. In another preferred embodiment, R _y3 is selected from: H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, -C≡CH, -C≡C-CH ₃ , -C≡C-(C ₃ -C ₆ cycloalkyl), -C≡C-(4-6 membered heterocyclyl), or halogen. In another preferred embodiment, Ry ₄ is selected from: C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, -C≡CH, -C≡C-CH ₃ , -C≡C-(C ₃ -C ₆ cycloalkyl), -C≡C-(4-6 membered heterocyclyl), or halogen. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that R ¹⁰ is U is selected from: N, CH, CD, CF; R ⁴ is selected from the group consisting of substituted or unsubstituted halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl; R ⁵ , R ⁶ , R ⁷ , and R ⁹ are the same or different, and are independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R; ^R8 is _NH2 . In another preferred embodiment, U, R ⁶ , R ⁷ , R ⁹ and R ⁸ are as defined above; R ⁵ is selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R; ^R4 is selected from the following groups _{which are substituted or unsubstituted: H, C1-C3 alkyl, C3-C6 cycloalkyl , 4-6 membered} heterocyclyl, C1- _C3 alkoxy, _C3 - _C6 cycloalkyloxy, _4-6 membered heterocyclyloxy, halogenated _C1 - _C3 alkyl, halogenated _C3 -C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO) _-C1 - _C3 alkyl, (HO) _-C3 - _C6 cycloalkyl, ( _NH2 )-C1- _C3 alkyl, ( _NH2 ) _{-C3 -C6 cycloalkyl} , halogen, CN, -C≡CH, OH, _NH2 , _CONH2 , NHCO( _C1 - _C6 alkyl), _{NHCO(C3-C6 cycloalkyl), SO2NH2 , NHSO2 ( C1 - C6} alkyl), _NHSO2 ( _C3 -C ₆ cycloalkyl); wherein the substitution refers to substitution by one or more R. In another preferred embodiment, R ⁴ and R ⁵ are as defined above, U is CH, R ⁶ , R ⁷ and R ⁹ are independently H or deuterium, and R ₈ is NH ₂ . The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that R ¹⁰ is U' is selected from: O, or S; U" is selected from: N, or C(CN); R ^7' , R ^8' , R ^9' are the same or different, and are independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R; R ^5' is NH ₂ . The compound according to claim 1, its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has a structure represented by formula (IA) or formula (IB):
R ¹⁰ , Z, W, R ¹ and n are as defined in claim 1 . The compound according to claim 1, its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that the compound is selected from the group consisting of:
Wherein, V ₁ , V ₂ , V ₃ , V ₅ , R _v , Z, W, R ¹ and n are as defined in claim 1. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has a structure represented by formula (II-A), or formula (II-B), or formula (II-C), or formula (II-D), or formula (II-E) or formula (II-F):
R ¹² are the same or different and are each independently selected from hydrogen or deuterium; R ⁴ is selected from the group consisting of substituted or unsubstituted halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl; wherein the substitution refers to substitution by one or more R; R ⁵ is selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy; wherein the substitution refers to substitution by one or more R; o is 0, 1, or 2; Wherein, V ₁ , V ₂ , V ₃ , V ₅ , and R are as defined in claim 1. The compound according to claim 1, its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that: The substituted or unsubstituted group is selected from the following groups: aniline, naphthylamine, 5-6-membered monocyclic heteroaryl (such as pyridyl) amine, 9-10-membered bicyclic heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran, quinoline, quinazoline) amine, wherein the substitution is substituted by one or more groups selected from the following group: halogen, hydroxyl, cyano, _NH2 , _C1 - _C6 alkyl, halogenated _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogenated _C1 - _C6 alkoxy, _C3 - _C6 cycloalkyl, 4-6-membered heterocyclyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl; preferably, Selected from:
The compound according to claim 1, its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that: Selected from the following substituted or unsubstituted groups: 9-10 membered bicyclic heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran, pyridothiazole, pyridothiphene, pyridotfuran) amine, wherein the substitution is substituted by one or more groups selected from the following group: halogen, hydroxyl, cyano, _NH2 , _C1 - _C6 alkyl, halogenated _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogenated _C1 -C6 alkoxy, _C3 - _C6 cycloalkyl, _4-6 membered heterocyclyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl; preferably, Selected from: The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1 to 8, characterized in that W is selected from: substituted or unsubstituted 4-7 membered monocyclic heterocyclyl, substituted or unsubstituted C ₃ -C ₇ monocyclic cycloalkyl, substituted or unsubstituted 6-10 membered bicyclic heterocyclyl, substituted or unsubstituted C 6 -C 10 bicyclic cycloalkyl, substituted or unsubstituted 7-12 membered tricyclic heterocyclyl, substituted or unsubstituted C ₇ -C ₁₂ tricyclic cycloalkyl, preferably, W is a substituted or unsubstituted 8-12 membered N-containing heterocyclyl, wherein the substitution refers to substitution by one or more R, and R is defined as described in claim 1; Preferably, ring W is selected from: The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof according to any one of claims 1 to 12, characterized in that the compound is selected from the group consisting of:

Or choose from the following groups:
Or choose from the following groups:

Or choose from the following groups:
Or choose from the following groups:
A pharmaceutical composition, characterized in that it comprises one or more compounds according to any one of claims 1 to 13, their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs; and a pharmaceutically acceptable carrier. A use of a compound according to any one of claims 1 to 13, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or the pharmaceutical composition according to claim 14, characterized in that it is used to prepare a drug for preventing and/or treating a disease related to the activity or expression of KRAS ^G12D .