CN115960105A - KRAS G12D inhibitor and its application in medicine - Google Patents

Abstract

The present invention relates to the compound represented by general formula (I), its tautomer, deuterated substance or pharmaceutically acceptable salt, which has KRAS G12D regulating activity. The invention also relates to processes for the preparation of these compounds and pharmaceutical compositions containing them.

Description

KRAS G12D inhibitors and their medical applications

Technical Field

The present invention relates to compounds represented by general formula (I), their tautomers, deuterated compounds or pharmaceutically acceptable salts, which have KRAS inhibitory activity, in particular KRAS G12D inhibitory activity. The present invention also relates to methods for preparing these compounds and pharmaceutical compositions containing them.

Background Art

Clinical data show that RAS is the gene with the highest mutation rate in human tumors. About 20-30% of all tumors have RAS mutations, and about 98% of pancreatic cancers, 52% of colon cancers, 43% of multiple myeloma, and 32% of lung adenocarcinomas have RAS gene mutations. The most common mutation of RAS is point mutation, which often occurs at codons 12, 13, and 61, and the most common mutation is at codon 12, such as G12C, G12D, or G12V.

Currently, drug development targeting KRAS mutations is one of the current hot spots in new drug research. KRAS G12C inhibitors AMG510 (WO2018217651A1) and MRTX849 (WO2019099524A1) have entered the late clinical stage; and MIRATI is leading in the development of G12D inhibitors (WO2021041671A1).

Based on the importance of abnormal KRAS activation in cancer progression and the prevalence of KRAS gene mutations in human cancers, KRAS has always been a target of interest for drug developers. Despite progress in this field, there is still a need for improved KRAS G12D mutant protein inhibitors in the art.

Summary of the invention

The technical problem to be solved by the present invention is to overcome the problem of lack of KRAS G12D mutant protein inhibitors in the prior art, and provide a compound represented by general formula (I) and its application. The compound represented by general formula (I) provided by the present invention has a good inhibitory effect on KRAS G12D mutant protein.

The present invention provides a compound represented by general formula (I), its tautomer, deuterated substance or pharmaceutically acceptable salt:

in,

X ₁ is selected from CR ₆ or N; R ₆ is selected from H, amino, substituted amino, cyano, C _1-6 alkyl, substituted C _1-6 alkyl, halogen, C _2-6 alkenyl, substituted C _2-6 alkenyl, C _3-6 cycloalkyl or substituted C _3-6 cycloalkyl;

X ₂ is selected from CR ₇ or N; R ₇ is selected from H, halogen, cyano or C _1-6 alkyl;

X ₃ is selected from CR ₈ or N; R ₈ is selected from H, halogen, cyano or C _1-6 alkyl;

L is selected from a bond, O, NR ₉ or C _1-4 alkylene, the C _1-4 alkylene being optionally substituted by one or more R ₉ ; R ₉ is selected from H, halogen, cyano or C _1-6 alkyl, or two R ₉ on the same carbon atom together with the atom to which they are attached form a 3-6 membered cycloalkyl;

R ₁ is absent, or R ₁ , R ₇ together with the atoms to which they are connected form a substituted or unsubstituted 3-10 membered cyclic group; the 3-10 membered cyclic group is selected from cycloalkyl or heterocyclic group; the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from H, halogen, cyano, C _1-6 alkyl or oxo;

R ₂ is absent, or R ₂ , R ₈ together with the atoms to which they are attached form a substituted or unsubstituted 3-10 membered cyclic group; the 3-10 membered cyclic group is selected from cycloalkyl or heterocyclic group; the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from H, halogen, cyano, C _1-6 alkyl or oxo;

_R3 is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more _R10 ;

R ₄ is selected from H, halogen, C _1-6 alkyl or -OR ₁₁ , wherein R ₁₁ is selected from C _1-6 alkyl or C _3-8 cycloalkyl, and R ₁₁ is optionally substituted by one or more substituents selected from hydroxy, halogen, C _1-3 alkyl, C _1-3 alkoxy or cyclopropyl;

R ₅ is selected from aryl or heteroaryl, which is optionally further substituted with one or more R ₁₀ ;

C_2-6烯基、C_2-6炔基、-C_0-6亚烷基-C_3-14环烷基、-C_0-6亚烷基-(3-14元杂环基)、-C_0-6亚烷基-C_6-14芳基或-C_0-6亚烷基-(5-14元杂芳基)，所述C_1-6烷基、C_2-6烯基、C_2-6炔基、-C_0-6亚烷基-C_3-14环烷基、-C_0-6亚烷基-(3-14元杂环基)、-C_0-6亚烷基-C_6-14芳基或-C_0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个R_a所取代；R ₁₀ is selected from H, cyano, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -C _0-6 alkylene-OR _a , -C _0-6 alkylene-OC(O)N(R _a ) ₂ , -C _0-6 alkylene-N(R _a ) ₂ , -C _0-6 alkylene-NR _a C(O)R _a , -C _0-6 alkylene-NR _a C(O)N(R _a ) ₂ , -C _0-6 alkylene-NR _a S(O)R _a , -C _0-6 alkylene-NR _a S(O) ₂ R _a , -C _0-6 alkylene-S(═O)R _a , -C _0-6 alkylene-S(═O) ₂ R _a , -C _0-6 alkylene-SR _a , -C _0-6 alkylene-S(R _a ) ₅ , -C _{-C 0-6} alkylene-C(=O)R _a , -C _0-6 alkylene-C(=O)OR _a , -C _0-6 alkylene-C(=O)N(R _a ) ₂ ,

C _2-6 alkenyl, C _2-6 alkynyl, -C _0-6 alkylene-C _3-14 cycloalkyl, -C _0-6 alkylene-(3-14 membered heterocyclyl), -C _0-6 alkylene-C _6-14 aryl, or -C _0-6 alkylene-(5-14 membered heteroaryl), wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C _0-6 alkylene-C 3-14 cycloalkyl, -C _0-6 alkylene-( _3-14 membered heterocyclyl), -C _0-6 alkylene-C _6-14 aryl, or -C _0-6 alkylene-(5-14 membered heteroaryl) may be further substituted by one or more _Ra ;

each _Ra is independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxyl, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C1-6 heteroalkyl, _C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-14 aryl or _5-14 membered heteroaryl;

The compound of general formula (I) is not

In some embodiments of the present invention, the compound represented by formula (I), its tautomer, deuterated substance or pharmaceutically acceptable salt is selected from the following compounds of formula (IA) or (IB):

Preferably

Wherein, the substituents R ₃ , R ₄ , R ₅ , R ₆ and R ₁₀ are as defined in the general formula (I).

In some embodiments of the present invention, the R ₅ is selected from

In some embodiments of the present invention, L is a bond, R ₃ is a cycloalkyl group, and the cycloalkyl group is further substituted by one or more R ₁₀ ; the R ₁₀ is selected from -C _0-6 alkylene-(3-14 membered heterocyclyl), -C _0-6 alkylene-C _6-14 aryl, -C _0-6 alkylene-N(R _a ) ₂ , -C _0-6 alkylene-NR _a C(O)R _a , -C _0-6 alkylene-NR _a C(O)N(R _a ) ₂ , or -C _0-6 alkylene-(5-14 membered heteroaryl), the -C _0-6 alkylene-(3-14 membered heterocyclyl), -C _0-6 alkylene-C _6-14 aryl or -C _0-6 alkylene-(5-14 membered heteroaryl) may be optionally substituted by one or more R _a ; the R _a are each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy.

In some embodiments of the present invention, L is selected from a bond or a C _1-4 alkylene, R ₃ is selected from a heterocyclyl or a heteroaryl, and the heterocyclyl or heteroaryl is optionally further substituted by one or more R ₁₀ ; the R ₁₀ is selected from H, cyano, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -C _0-6 alkylene-OR _a , -C _0-6 alkylene-OC(O)N(R _a ) ₂ , -C _0-6 alkylene-N(R _a ) ₂ , -C _0-6 alkylene-NR _a C(O)R _a , or -C _0-6 alkylene-NR _a C(O)N(R _a ), and the R _a is each independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl or C _1-6 haloalkyl.

In some embodiments of the present invention, R ₁ and R ₇ together with the atoms to which they are connected form a substituted or unsubstituted 3-10 membered cyclic group; the 3-10 membered cyclic group is selected from cycloalkyl or heterocyclic group; the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from H, halogen, cyano, C _1-6 alkyl or oxo.

In some embodiments of the present invention, said R ₁ is absent.

In some embodiments of the present invention, R ₂ and R ₈ together with the atoms to which they are connected form a substituted or unsubstituted 3-10 membered cyclic group; the 3-10 membered cyclic group is selected from cycloalkyl or heterocyclic group; the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from H, halogen, cyano, C _1-6 alkyl or oxo.

In some embodiments of the present invention, said R ₂ is absent.

In some embodiments of the present invention, R ₄ is halogen, preferably F.

In some embodiments of the present invention, the compound of formula (I) is selected from:

The present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the compound represented by formula (I), its tautomer, deuterated substance or pharmaceutically acceptable salt, and optionally further comprises a pharmaceutically acceptable excipient.

The present invention provides the use of a compound represented by formula (I), its tautomer, deuterated substance or pharmaceutically acceptable salt, or a pharmaceutical composition thereof in preparing a drug.

The present invention further provides a preferred technical solution for the application:

Preferably, the application is application in the preparation of drugs for treating and/or preventing cancer.

Preferably, the use is for preparing a drug for treating and/or preventing a disease mediated by KRAS G12D.

Preferably, the KRAS G12D-mediated disease is cancer.

Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatobiliary carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.

The present invention also provides a method for treating and/or preventing a disease, comprising administering to a subject a therapeutically effective amount of at least one compound represented by structural formula (I) or a pharmaceutical composition containing the compound.

The present invention also provides a method for treating and/or preventing a disease mediated by KRAS G12D, comprising administering to a subject a therapeutically effective amount of at least one compound represented by structural formula (I), its tautomer, deuterated substance or pharmaceutically acceptable salt, or a pharmaceutical composition containing the same.

The present invention also provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of at least one compound represented by structural formula (I), its tautomer, deuterated product or pharmaceutically acceptable salt, or a pharmaceutical composition containing the same.

Preferably, in the above method, the KRAS G12D-mediated disease is cancer.

Preferably, in the above method, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.

Unless otherwise indicated, general chemical terms used in the structural formulae have their usual meanings.

For example, the term "halogen," as used herein, refers to fluorine, chlorine, bromine, or iodine, unless otherwise indicated.

In the present invention, unless otherwise specified, "alkyl" includes a linear or branched monovalent saturated hydrocarbon group. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, " _1-6 " in " _C1-6 alkyl" refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched form.

The term "alkylene" refers to a divalent alkyl linking group. Alkylene formally refers to an alkane with two CH bonds replaced as the point of attachment of the alkylene to the rest of the compound. Similarly, the "C _1-6 " in C _1-6 alkylene refers to an alkylene containing 1, 2, 3, 4, 5, or 6 carbon atoms, including but not limited to methylene, 1,2-ethylene, 1,3-propylene, or 1,2-isopropylene.

"Alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl groups, ie, -O-alkyl.

The term "aryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted 6-14 membered monocyclic or condensed aromatic group. Preferably, the aryl group is a 6-10 membered monocyclic or bicyclic aromatic ring group. Preferably, it is phenyl or naphthyl. Most preferably, it is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl group, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples include but are not limited to benzocyclopentyl.

The term "heterocyclic radical", in the present invention, unless otherwise indicated, refers to a stable ring system consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S, which is a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which includes 3 to 14 carbon atoms, wherein nitrogen or sulfur heteroatoms can be selectively oxidized, and nitrogen heteroatoms can be selectively quaternized. The heterocyclic radical can be connected to any heteroatom or carbon atom to form a stable structure. The examples of these heterocyclic radicals include but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydrooxadiazolyl. The heterocyclyl group may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclyl group.

The term "heteroaryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable 5-membered or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9-membered to 14-membered benzo-fused heteroaromatic ring system or a polycyclic heteroaromatic ring system, which consists of carbon atoms and 1-4 heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatom may be selectively oxidized, and the nitrogen heteroatom may be selectively quaternized. The heteroaryl group may be attached to any heteroatom or carbon atom to form a stable structure. Examples of heteroaryl include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adenine, quinolyl or isoquinolyl. The heteroaryl may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.

The term "cycloalkyl" refers to a cyclic saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent having 3 to 14 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The cycloalkyl may be fused to an aryl, heterocyclyl or heteroaryl ring, wherein the ring connected to the parent structure is a cycloalkyl.

C_2-6烯基、C_2-6炔基、-C_0-6亚烷基-C_3-14环烷基、-C_0-6亚烷基-(3-14元杂环基)、-C_0-6亚烷基-C_6-14芳基或-C_0-6亚烷基-(5-14元杂芳基)，所述C_1-6烷基、C_2-6烯基、C_2-6炔基、-C_0-6亚烷基-C_3-14环烷基、-C_0-6亚烷基-(3-14元杂环基)、-C_0-6亚烷基-C_6-14芳基或-C_0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个R^b所取代。每个R^b各自独立地选自H、卤素、羟基、氨基、氧代基、硝基、氰基、羧基、C_1-6烷基、C_1-6羟基烷基、C_1-6氨基烷基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6卤代烷氧基、C_1-6杂烷基、C_3-8环烷基、3-8元杂环基、C_6-14芳基或5-14元杂芳基。在一些实施例中，取代基独立地选自包含-F、-Cl、-Br、-I、-OH、三氟甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、-SCH₃、-SC₂H₅、甲醛基、-C(OCH₃)、氰基、硝基、-CF₃、-OCF₃、氨基、二甲基氨基、甲硫基、磺酰基和乙酰基的基团。The term "substituted" means that one or more hydrogen atoms in the group are replaced by the same or different substituents, respectively. Typical substituents include, but are not limited to, H, cyano, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -C _0-6 alkylene-OR ^b , -C _0-6 alkylene-OC(O)N(R ^b ) ₂ , -C _0-6 alkylene-N(R ^b ) ₂ , -C _0-6 alkylene-NR ^b C(O)R ^b , -C _0-6 alkylene-NR ^b C(O)N(R ^b ) ₂ , -C _0-6 alkylene-NR ^b S(O)R ^b , -C _0-6 alkylene-NR ^b S(O) ₂ R ^b , -C _0-6 alkylene-S( _═O ⁾ R ^b , -C _0-6 alkylene-S(═O)R b , -C _0-6 alkylene-SR ^b , -C _0-6 alkylene-S(R ^b ) ₅ , -C _{-C 0-6} alkylene-C(=O)R ^b , -C _0-6 alkylene-C(=O)OR ^b , -C _0-6 alkylene-C(=O)N(R ^b ) ₂ ,

C _2-6 alkenyl, C _2-6 alkynyl, -C _0-6 alkylene-C _3-14 cycloalkyl, -C _0-6 alkylene-(3-14 membered heterocyclyl), -C _0-6 alkylene-C _6-14 aryl, or -C _0-6 alkylene-(5-14 membered heteroaryl); the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -C _0-6 alkylene-C _3-14 cycloalkyl, -C _0-6 alkylene-(3-14 membered heterocyclyl), -C _0-6 alkylene-C _6-14 aryl, or -C _0-6 alkylene-(5-14 membered heteroaryl) may be optionally substituted by one or more R ^b . Each ^Rb is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, _C1-6 alkyl, _C1-6 hydroxyalkyl, _C1-6 aminoalkyl, _C1-6 haloalkyl, C1-6 alkoxy, _C1-6 haloalkoxy, _C1-6 heteroalkyl, _C3-8 cycloalkyl, _3-8 membered heterocyclyl, C6-14 aryl, or _5-14 membered heteroaryl. In some embodiments, the substituents are independently selected from groups comprising -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert- _butoxy , _-SCH3 , _-SC2H5 , formaldehyde, -C( _OCH3 ), cyano, nitro, _-CF3 , _-OCF3 , amino, dimethylamino, methylthio, sulfonyl, and acetyl.

When the number of a linking group is 0, such as -(CH ₂ ) ₀ -, it means that the linking group is a bond.

When the compound provided by the invention is an acid, its corresponding salt can be conveniently obtained from pharmaceutically acceptable nontoxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc and the like. Particularly preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Nontoxic organic bases that can be derived into pharmaceutically acceptable salts include primary amines, secondary amines and tertiary amines, also include cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N', N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

When compound provided by the invention is alkali, can be from pharmaceutically acceptable nontoxic acid, including inorganic acid and organic acid, conveniently make its corresponding salt.Such acid includes, as, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, bashing acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid etc.Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid.More preferably, formic acid and hydrochloric acid.

Prodrugs of the compounds of the present invention are included within the scope of the present invention. Generally, the prodrug refers to a functional derivative that is easily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of the compounds of the present application, which can directly or indirectly provide the compounds of the present application or their pharmaceutically active metabolites or residues after administration to a receptor.

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

When the compound represented by formula (I) exists in tautomerism, unless otherwise stated, the present invention includes any possible tautomerism and pharmaceutically acceptable salts thereof, and mixtures thereof.

When the compounds of formula (I) are substituted with heavier isotopes such as deuterium, they may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Therefore, for example, a mixture comprising "a" pharmaceutically acceptable excipient composition can be interpreted as indicating that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

The pharmaceutical composition of the present invention can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

Typical routes of administration of the compounds of the invention or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

The term "treat" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partial or complete stabilization or cure of a disease and/or side effects resulting from a disease. As used herein, "treat" encompasses any treatment of a patient's disease that: (a) inhibits the symptoms of a disease, i.e., arrests its development; or (b) alleviates the symptoms of a disease, i.e., causes regression of the disease or symptoms.

The term "effective amount" means an amount of the compound of the present application that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of the compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

Synthesis scheme:

Step A: Compound I-1 is reacted with benzyl alcohol under alkaline conditions such as Cs ₂ CO ₃ to obtain compound I-2, where Bn is a protecting group;

经过Suzuki偶联反应引入R₅基团；Step B: Compound I-2 is reacted with compound

The R ₅ group was introduced through Suzuki coupling reaction;

Step C: Compound I-3 is treated with palladium carbon hydrogenation to remove the Bn protecting group to obtain compound I-4;

Step D: Compound I-4 is reacted with trifluoromethanesulfonic anhydride under alkaline conditions such as triethylamine to introduce a Tf protecting group to obtain the target product I-5.

经过Sonogashira偶联反应引入炔烃；Step E: Compound I-5 is reacted with a compound in the presence of a Pd catalyst such as Pd(PPh ₃ ) ₂ Cl ₂ and a copper catalyst such as CuI.

Alkynes were introduced via Sonogashira coupling reaction;

Step F: Compound I-6 is subjected to acidic conditions such as the action of TFA to remove the TG protecting group to obtain the target compound I.

DETAILED DESCRIPTION

In order to make the above content clearer and more specific, the present invention will further illustrate the technical scheme of the present invention with the following examples. The following examples are only used to illustrate the specific embodiments of the present invention so that those skilled in the art can understand the present invention, but are not used to limit the scope of protection of the present invention. In the specific embodiments of the present invention, the technical means or methods not specifically described are conventional technical means or methods in the art.

Unless otherwise stated, all temperatures are in degrees Celsius.

The following abbreviations are used in the examples:

DABCO: triethylenediamine;

DIEA: N,N-diisopropylethylamine;

DCM: dichloromethane;

Dioxane: dioxane;

ESI-MS: electrospray ionization mass spectrometry;

Tf2O: trifluoromethanesulfonic anhydride;

EtOH: ethanol;

HOAc: glacial acetic acid;

MeOH: methanol;

POCl3: phosphorus oxychloride;

THF: tetrahydrofuran;

TFA: trifluoroacetic acid;

TEA: triethylamine;

LiAlH4: lithium aluminum hydride;

TBAF: tetrabutylammonium fluoride;

SphosPdG2: chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II);

Pre-HPLC: Preparative High Performance Liquid Phase;

Pre-TLC: Preparing thin layer plates.

Synthesis of intermediate M1:

Step 1: Synthesis of compound M1-2

Iron powder (27 g) was added portionwise to a mixture of compound M1-1 (40 g), HOAc (77 g), EtOH (400 mL) and H ₂ O (160 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then neutralized with NaOH (5N) solution. The mixture was then extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give the desired crude product (34 g, 98% yield) as a brown oil, i.e., compound M1-2. ESI-MS m/z: 190 [M+H] ⁺ .

Step 2: Synthesis of Compound M1-3

2,2,2-Trichloroethane-1,1-diol (66.4 g) and Na ₂ SO ₄ (503.4 g) were dissolved in water (560 mL) and then heated to 55° C. Water (240 mL) and 35% HCl (72 mL) containing compound M1-2 (34 g) were added, and an aqueous solution (100 mL) of hydroxylamine hydrochloride (81.4 g) was added. The resulting mixture was stirred at 90° C. for 3 hours and a yellow precipitate was formed. The mixture was cooled to room temperature. The solid was collected by filtration, rinsed with water, and air-dried to obtain a tan solid product (47 g, 99% yield), i.e., compound M1-3. ESI-MS m/z: 261[M+H] ⁺ .

Step 3: Synthesis of Compound M1-4

At 60°C, compound M1-3 (47 g) was added to concentrated sulfuric acid (300 mL), the temperature was raised to 90°C and maintained for 3 hours, the reaction was complete, the reaction mixture was cooled to room temperature and poured into ice water. The yellow precipitate was collected by filtration and dried to obtain a black solid product (43 g, 99% yield), i.e., compound M1-4.

Step 4: Synthesis of Compound M1-5

At 0°C, H ₂ O ₂ solution (30%, 80 mL) was added to a solution of compound M1-4 (43 g) in NaOH (2N), and the resulting mixture was stirred at 0°C for 30 minutes. The mixture was stirred at room temperature for 2 hours. When the reaction was complete, the mixture was poured into ice water and acidified with concentrated HCl solution. The precipitate was collected by filtration and air-dried to obtain a white solid product (20 g, 49% yield), namely compound M1-5. ESI-MS m/z: 233 [M+H] ⁺ .

Step 6: Synthesis of Compound M1-6

At room temperature, di(imidazole-1-yl)methanone (2.70 g) was added to THF (20 mL) of crude compound M1-5 (4.0 g), and N-ethyl-N-isopropylpropan-2-amine (1.4 g) was added thereto. The mixture was moved to 50° C. for reaction for 2 hours. Compound M1-6 was basically completely converted into an intermediate product. Then the mixture was added dropwise to ice ammonia water (35 mL). The reaction was completed after stirring for 5 min. The mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate=70:30) to obtain the desired target product compound M1-6 (1.6 g) as a brown solid.

Step 7: Synthesis of Compound M1-7

The mixture of compound M1-6 and urea was stirred at 200° C. for 3 hours. The mixture was cooled to room temperature, the solid was washed with ethyl acetate, and the solid was dried to obtain the desired crude solid product M1-7 (209 mg, 78% yield).

Step 8: Synthesis of Compound M1-8

DIPEA was added to a solution of M1-7 in POCl ₃ at room temperature and refluxed at 110° C. for 16 hours. The mixture was cooled to room temperature, concentrated in vacuo to remove POCl ₃ , and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:1 to 50:1) to obtain the desired product M1-8 (209 mg, 78% yield) as a brown solid.

Step 9: Synthesis of Compound M1

At room temperature, M1-8 (3.0 g) was dissolved in 1,4-dioxane (20 ml), tert-butyl (1R, 5S)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (1.6 g) and DIPEA (2.8 g) were added to the solution, and the resulting mixture was stirred at room temperature for 10 minutes. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=75:25 to 65:35) to give the desired product M1 (2.5 g, 57% yield) as a yellow solid. ESI-MS m/z: 471 [M+H] ⁺ .

Synthesis of intermediate M2:

Step 1: Synthesis of compound M2-1

At room temperature, 2-chloro-3-fluoro-pyridine-4-carboxylic acid (54.00 g), toluene (390.00 mL), tert-butyl alcohol (390.00 mL), triethylamine (128.27 mL), powdered 4A molecular sieve (90.00 mL) (pre-activated) were added in sequence, and the mixture was kept at reflux for half an hour (internal temperature 87° C.) under nitrogen protection. The mixture was then naturally cooled to room temperature, and then DPPA (99.44 mL) was added, the temperature was raised to reflux, and the mixture was kept at reflux for 5 hours. The reaction mixture was cooled to below 40°C, and then EA 500mL was added to dilute; the mixture was further cooled to room temperature, and the added molecular sieve was filtered off with diatomaceous earth as the filter aid; the filter residue was rinsed with EA 1500mL for several times and then dried; the filtrate was collected, and washed and separated with water 700mL and saturated brine 700mL in turn; the organic phase was dried over anhydrous sodium sulfate; the mixture was filtered, the desiccant was removed, and the concentrate was concentrated. The concentrate was separated and purified by column chromatography (PE/EA=30:1-20:1), and the eluent was concentrated to finally obtain the target product M2-1 (68.2g, yield 89.88%) as a white solid. ESI-MS m/z: 247.1[M+H] ⁺ .

Step 2: Synthesis of compound M2-2

At room temperature, compound M2-1 (65.00 g) was dissolved in CH ₃ CN (82.00 mL), cooled in a water bath, and hydrochloric acid (4M in dioxane) (38.43 g) was slowly added. The reaction was stirred at room temperature for about 16 hours, and a white solid was precipitated in a suspended state. The reaction mixture was filtered, and the filter cake was rinsed with a small amount of acetonitrile, dried, and the filtrate was discarded. The filter cake was collected and added to a mixture of 700 mL of saturated sodium bicarbonate aqueous solution and 700 mL of ethyl acetate, alkalized, extracted, and separated; the aqueous phase was extracted with 350 mL of ethyl acetate again, and separated; the ethyl acetate phases were combined, and 300 mL of saturated sodium chloride aqueous solution was added for washing and separation; the organic phase was dried over anhydrous sodium sulfate, filtered, the desiccant was removed, and concentrated to obtain the target product M2-2 (36.3 g, yield 94.0%) as a slightly yellow solid powder. ESI-MS m/z: 147.1 [M+H] ⁺ .

Step 3: Synthesis of Compound M2-3

At room temperature, compound M2-2 (36.00 g) was dissolved in acetonitrile (180.00 mL), NIS (66.32 g) and p-toluenesulfonic acid (2.12 g) were added thereto, and the mixture was heated to 70°C under nitrogen protection for reaction. The reaction solution was cooled to 50°C, 900 mL of water was added, and a white solid powder was precipitated. The mixture was slurried for half an hour; filtered, and the filter cake was rinsed with water and dried. The filter cake was collected, 1200 mL of ethyl acetate was added to dissolve it completely, and then washed twice with 350 mL of saturated sodium sulfite aqueous solution, and then washed and separated with 350 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target product M2-3 (63.2 g, yield 94.43%) of light yellow solid particles. ESI-MS m/z: 272.9 [M+H] ⁺ .

Step 4: Synthesis of Compound M2-4

分子筛(20.00mL)加入其中，在氮气氛围中，加热保温100℃反应约7小时。撤去油浴，自然冷却至室温，等待后处理。硅藻土助滤，将反应混合物过滤，抽干；收集滤液，60～70℃浓缩，得到淡黄色固体粗品。滤渣用乙酸乙酯500mL漂洗抽干；收集漂洗液，合并到粗品中，再次浓缩至无液体被蒸馏出；加入乙酸乙酯700mL溶解浓缩所得到固体粗品，然后用每次用饱和氯化钠250mL，洗涤3次，分液。无水硫酸钠干燥有机相，过滤，浓缩得到淡黄色固体，加入PE/EA＝3/1混合物160mL，打浆半小时，过滤、抽干。收集滤饼，45℃水浴，浓缩，再高真空油泵抽拉至恒重；最终得到浅黄色固体粉末状目标产物M2-4(36.1g，产率99.7％)。ESI-MS m/z:172.0[M+H]⁺。At room temperature, compound M2-3 (57.50 g) was dissolved in DMF (22.00 mL), zinc cyanide (32.22 g), tetrakistriphenylphosphine palladium (12.19 g) and powdered

Molecular sieves (20.00 mL) were added, and the mixture was heated and kept at 100 °C in a nitrogen atmosphere for about 7 hours. The oil bath was removed, and the mixture was naturally cooled to room temperature and waited for post-treatment. The reaction mixture was filtered with diatomaceous earth as the filter aid, and then dried; the filtrate was collected and concentrated at 60-70 °C to obtain a pale yellow solid crude product. The filter residue was rinsed with 500 mL of ethyl acetate and dried; the rinse liquid was collected, combined with the crude product, and concentrated again until no liquid was distilled out; 700 mL of ethyl acetate was added to dissolve and concentrate the obtained solid crude product, and then 250 mL of saturated sodium chloride was used each time, washed 3 times, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a pale yellow solid. 160 mL of PE/EA＝3/1 mixture was added, slurried for half an hour, filtered, and dried. The filter cake was collected, concentrated in a 45 °C water bath, and then pumped to constant weight with a high vacuum oil pump; finally, the target product M2-4 (36.1 g, yield 99.7%) was obtained as a pale yellow solid powder. ESI-MS m/z: 172.0 [M+H] ⁺ .

Step 5: Synthesis of Compound M2-5

At room temperature, add concentrated sulfuric acid (61.37 mL) to a 500 mL single-mouth flask, cool to below 10 ° C in an ice-water bath, add compound M2-4 (39.30 g) in batches, stir for 10 minutes, keep warm at 60 ° C in an oil bath in a nitrogen atmosphere, and react for about 1 hour. The reaction solution is cooled to room temperature, then carefully added to 1100 mL of ice-water mixture, diluted and quenched, and a small amount of yellow solid precipitates. After stirring for 10 minutes, filter; collect the filter cake, use 50 mL of saturated sodium bicarbonate aqueous solution, beat for 20 minutes, filter again, collect the two filtrates, and combine; then slowly add sodium carbonate solid, adjust the pH to about 7, and a white solid powder precipitates. Stir for half an hour, filter, and drain; rinse the filter cake with 100 mL of water each time, drain, and rinse twice. The filter cake was collected, placed in a vacuum oven, and dried at 55° C. to constant weight to obtain the target product M2-5 (33.6 g, yield 77.37%) as a beige solid powder. ESI-MS m/z: 190.0 [M+H] ⁺ .

Step 6: Synthesis of Compound M2-6

At room temperature, tetrahydrofuran (470.00 mL) was added. After nitrogen replacement, sodium hydride (10.00 g) was added under the protection of a slight nitrogen flow, and heated in an oil bath, kept at 40-45°C, and stirred for 15 minutes; then compound M2-5 (18.95 g) was added in batches, and after addition, the mixture was kept at 40-45°C for mechanical stirring for 20 minutes, and then CDI (24.31 g) was carefully added in batches, and after addition, the mixture was stirred for 15 minutes, and the mixture was heated in an oil bath for reflux reaction. The reaction solution was cooled to below 10°C with an ice-water bath, and then 500 mL of saturated aqueous ammonium chloride solution was added. A light yellow solid precipitated, and 1000 mL of water was added; then the mixture was transferred to a 5L beaker, and 3000 mL of water was added; the mixture was stirred for 1 hour, filtered, and dried; the filter cake was collected, placed in a vacuum oven, and dried at 50-55°C to constant weight to obtain the target product M2-6 (18.3 g, yield 84.93%) as a light yellow solid powder. ESI-MS m/z: 216.0 [M+H] ⁺ .

Step 7: Synthesis of Compound M2-7

At room temperature, compound M2-6 (18.00 g) and DIEA (36.00 mL) were dissolved in POCl ₃ (180.00 mL), and heated to 100°C for about 2.5 hours under a nitrogen atmosphere. The phosphorus oxychloride was removed by concentration under reduced pressure, and the residue was washed twice with 100 mL of DCM; the residue was dissolved with 400 mL of dichloromethane, and then added dropwise to 500 mL of saturated sodium bicarbonate aqueous solution, and cooled with ice water; after stirring for 15 minutes, the liquid was separated; the aqueous phase was extracted with 300 mL of dichloromethane and separated; the dichloromethane phases were combined, washed with 300 mL of saturated sodium chloride aqueous solution, and separated; dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column (PE/EA=90/10-75/25) to obtain the target product M2-7 (10.95 g, yield 51.94%) as an off-white solid powder. ESI-MS m/z: 251.9 [M+H] ⁺ .

Step 8: Synthesis of Compound M2-8

At room temperature, compound M2-7 (10.50 g) and DIEA (17.18 mL) were dissolved in DCM (120.00 mL), cooled in a water bath, tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.27 g) was added in batches, and then stirred at room temperature for about 10 minutes. 120 mL of dichloromethane was added, and the mixture was washed and separated with 100 mL of water and 100 mL of saturated sodium chloride aqueous solution in sequence, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column (PE/EA=90/10-75/25) and slurrying (40 mL EA+160 mL PE) to obtain the target compound M2-8 (15.9 g, yield 89.26%) as a white solid powder.

Step 9: Synthesis of Compound M2-9

At room temperature, THF (80.00 mL) and benzyl alcohol (1.60 g) were added to the reaction bottle, cooled to 0°C, NaH (0.59 g) was added, and the reaction was resumed to room temperature for 0.4 h, cooled to 0°C, compound M2-8 (5.30 g) was added, and the reaction was resumed to room temperature for 1 h. Water was added to the reaction solution to quench the reaction, extracted with EA, and the organic phase was dried and concentrated. The concentrate was purified by silica gel column (PE~PE:EA=1:1) to obtain the yellow oily target product M2-9 (5.60 g, yield 90.51%). ESI-MS m/z: 500[M+H] ⁺ .

Step 10: Synthesis of Compound M2-10

At room temperature, compound M2-9 (1.90 g), 2-[6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)naphthalen-1-yl]ethynyltripropane-2-ylsilane (2.82 g), SphosPdG2 (0.27 g), K ₃ PO ₄ (2.42 g) were dissolved in a mixed solution of 1,4-dioxane (30.00 mL) and water (5.00 mL) in a reaction bottle, and the mixture was purged with nitrogen and reacted at 95° C. for 10 h under nitrogen protection. EA and water were added to the reaction mixture for extraction, and the organic phase was dried and concentrated. The concentrate was purified by silica gel column (PE～PE:EA＝3:1) to obtain the target product M2-10 (1.80 g, yield 39.85%) as a yellow oil. ESI-MS m/z:902[M+H] ⁺ .

Step 11: Synthesis of Compound M2-11

At room temperature, M2-10 (1.80 g), methanol (25.00 mL) and Pd/C (0.92 g) were added to the reaction flask, and the mixture was reacted at room temperature for 12 h under hydrogen protection after hydrogen replacement. The reaction mixture was filtered, the residue was washed with methanol, the filtrate was concentrated and purified by column to obtain the target compound M2-11 (0.60 g, 37.38%) as a yellow solid. ESI-MS m/z: 812 [M+H] ⁺ .

Step 12: Synthesis of Compound M2

At room temperature, M2-11 (600.00 mg), dry DCM (8.00 mL) and DIEA (0.40 mL) were added to the reaction bottle, the reaction mixture was cooled to -10°C, Tf ₂ O (0.16 mL) was dissolved in DCM and then slowly added to the reaction solution, and the reaction was restored to room temperature for 2 hours. The reaction solution was directly concentrated, and the concentrate was purified by silica gel column (PE~PE:EA＝8:1) to obtain the target intermediate (480.00 mg, 67.91%) as a yellow solid. ESI-MS m/z:944[M+H] ⁺ .

Example 1: Synthesis of Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)ethynyl)-8-fluoroquinazolin-7-yl)naphthalen-2-ol

Step 1: Synthesis of compound 1-1

At room temperature, the compound 1-methoxycarbonylcyclopropane-1-carboxylic acid (5.00 g) was dissolved in DCM (80.00 mL), and DMF (0.27 mL) was added under ice bath, and then oxalyl chloride (8.81 mL) was added dropwise, and stirred at 35° C. for 3 h. Finally, the reaction mixture was directly concentrated to obtain the crude product of the target compound 1-1, which was directly used in the next step reaction.

Step 2: Synthesis of compound 1-2

At room temperature, the crude product 1-1 (5.64 g) was dissolved in DCM (80.00 mL), and TEA (24.11 mL) and dimethylamine hydrochloride (5.66 g) were added in an ice bath. After the addition, the mixture was stirred at room temperature for 1 h. Water was added to the reaction mixture for extraction, and the organic phase was dried and concentrated. The concentrate was purified by silica gel column to obtain the target compound 1-2 (5.4 g, yield 91%).

Step 3: Synthesis of Compound 1-3

At room temperature, compound 1-2 (5.4 g) was dissolved in THF (120 mL), cooled to -20°C, and LiAlH ₄ (4.0 g) was added in batches. After the addition was complete, the temperature was slowly restored to room temperature and stirred for 3 h. After the reaction was completed, 4.0 g of water, 4.0 g of 15% NaOH aqueous solution, and 12.0 g of water were slowly added in sequence under ice bath conditions, and stirring was continued for 1 h. The mixture was filtered and the filtrate was concentrated. The concentrate was purified by silica gel column (MeOH:DCM=0-30%) to obtain the target compound 1-3 (2.5 g, 61%). ESI-MS m/z: 130 [M+H] ⁺ .

Step 4: Synthesis of Compound 1-4

At room temperature, DMSO (2.34 g) was dissolved in DCM (30 mL), and oxalyl chloride (1.9 g) was added dropwise at -78 °C, and stirred for 30 min. Compound 1-3 (1.3 g) in DCM (10 mL) was added dropwise at -78 °C, and stirred for 1 h. Triethylamine (3.1 g) was added dropwise at -78 °C, and the temperature was slowly restored to room temperature after the addition was completed. Water was added to the reaction solution, and the mixture was extracted and separated to remove the aqueous phase. The organic phase was concentrated to obtain a crude product of the target compound 1-4.

Step 5: Synthesis of Compound 1-5

At room temperature, the crude product of the above compound 1-4 and potassium carbonate (2.8 g) were dissolved in methanol (10 mL) and stirred at room temperature for 15 min. Dimethyl (1-diazo-2-oxopropyl)phosphonate (2.5 g) was added dropwise and stirred at room temperature overnight. Toluene and water were added to the reaction solution for extraction, and the organic phase was washed once with a saturated potassium carbonate solution and dried over anhydrous sodium sulfate to obtain a crude product of the target compound 1-5.

Step 6: Synthesis of Compound 1-6

At room temperature, intermediate M1 (1.4 g), benzyl alcohol (0.65 g), cesium carbonate (3.9 g), and DABCO (50 mg) were dissolved in a mixed solution of DMF (10 mL) and THF (10 mL), and stirred overnight at room temperature. Water and EA were added to the reaction mixture, extracted, separated, and the organic phase was dried and concentrated. The concentrate was purified by silica gel column (EA:PE = 0-30%) to obtain the target compound 1-6 (1.9 g, 115%). ESI-MS m/z: 543, 545 [M+H] ⁺ .

Step 7: Synthesis of Compound 1-7

At room temperature, compound 1-6 (1.8 g), (3-((tert-butyldimethylsilyl)oxy)naphthalene-1-yl)boronic acid pinacol ester (2.5 g), SphosPdG2 (0.24 g), potassium phosphate (2.1 g) were dissolved in a mixed solution of 1,4-dioxane (18 mL) and water (2 mL), and stirred at 100°C for 1 h. After the reaction was completed, water and EA were added to the reaction solution, extracted, separated, and the organic phase was dried and concentrated. The concentrate was purified by silica gel column (MeOH: DCM = 0-10%) to obtain the target compound 1-7 (1.9 g, yield 80%).

Step 8: Synthesis of Compound 1-8

At room temperature, compound 1-7 (1.9 g) was dissolved in methanol (40 mL), 10% wet palladium carbon (0.2 g) was added under nitrogen protection, and then replaced with hydrogen, and stirred at room temperature for 12 h. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to obtain the crude product of the target compound 1-8 (1.5 g, yield 88%).

Step 9: Synthesis of Compound 1-9

At room temperature, the crude product of compound 1-8 (1.4 g) was dissolved in DCM (15 mL), triethylamine (1.0 mL) was added under ice bath conditions, trifluoromethanesulfonic anhydride (0.5 mL) was slowly added dropwise, and stirred at 0°C for 1 h after the addition. The reaction solution was directly concentrated, and the concentrate was purified by silica gel column (EA: PE = 0-50%) to obtain the target compound 1-9 (1.37 g, yield 81%). ESI-MSm/z: 763 [M+H] ⁺ .

Step 10: Synthesis of Compound 1-10

At room temperature, compound 1-9 (80 mg), Pd(PPh ₃ ) ₂ Cl ₂ (11 mg), CuI (6 mg), and triethylamine (40 mg) were dissolved in a toluene solution of compound 1-5 and stirred at 50°C for 2 h. Water and EA were added to the reaction solution for extraction and separation. The organic phase was dried and concentrated, and the concentrate was purified by column chromatography (EA:PE=20-50%) to obtain the target compound 1-10 (5 mg). ESI-MS m/z: 737[M+H] ⁺ .

Step 11: Synthesis of Compound 1-11

At room temperature, compound 1-10 (5 mg) was dissolved in THF (5 mL), triethylamine trihydrofluoride (0.1 mL) was added dropwise, and stirred at room temperature for 30 min. The reaction solution was concentrated to obtain a crude product of the target compound 1-11.

Step 12: Synthesis of Compound 1

At room temperature, the crude product of compound 1-11 was dissolved in DCM (5 mL), trifluoroacetic acid (3 mL) was added dropwise thereto, and stirred at room temperature for 30 min. The reaction solution was concentrated to obtain a crude product of compound 1. The crude product of compound 1 was purified by reverse phase preparative column (ACN:H ₂ O=5-50%, plus 0.1% TFA) to obtain the target compound 1 (2.1 mg). ESI-MS m/z: 522 [M+H] ⁺ . ¹ H NMR (500 MHz, MeOD) δ7.97 (d, J=8.7 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.64-7.59 (m, 1H), 7.46-7.41 (m, 2H), 7.27 (d, J=2.0 Hz, 1H), 7.23 (t, J=7.6 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 4 .71(t,J＝15.2Hz,2H),4.24(s,2H),3.88-3.81(m,2H),3.07(s,6H),2.10-1.98(m,2H),1.69-1.57(m,2H),1.45(q,J＝4.7Hz,2H),1.25(d,J＝2.0Hz,2 H),0.90(t,J=6.8Hz,2H).

Example 2: Synthesis of Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(isoindol-2-ylmethyl)cyclopropyl)ethynyl)quinazolin-7-yl)naphthalen-2-ol

The detailed synthesis steps of Compound 2-1 to Compound 2-4 refer to Example 1.

Step 5: Synthesis of Compound 2-5

At room temperature, the crude product of compound 2-4 (2.0 g) and potassium carbonate (2.75 g) were dissolved in methanol (20 mL) and stirred at room temperature for 15 min. Dimethyl (1-diazo-2-oxopropyl)phosphonate (2.49 g) was added dropwise thereto and stirred at room temperature for 2 h. EA and water were added to the reaction solution, extracted, separated, the organic phase was dried and concentrated, and the concentrate was purified by column chromatography (MeOH:DCM=0-20%) to obtain the target compound 2-5 (1.4 g, yield 70%). ESI-MS m/z: 198 [M+H] ⁺ .

Step 6: Synthesis of Compound 2-6

At room temperature, compound 1-9 (200 mg), Pd(PPh ₃ ) ₂ Cl ₂ (37 mg), CuI (15 mg), triethylamine (80 mg), and compound 2-5 (207 mg) were dissolved in DMF (10 mL) and stirred at 40°C for 1 h. Water and EA were added to the reaction solution, extracted, separated, and the organic phase was concentrated. The concentrate was purified by column chromatography (EA:PE=20-50%) to obtain the target compound 2-6 (100 mg, yield 47%). ESI-MS m/z: 811[M+H] ⁺ .

The detailed synthesis steps of compound 2-7 and target compound 2 refer to Example 1. Compound 2 ESI-MS m/z: 596 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO) δ7.98(d,J＝8.7Hz,1H),7.82(d,J＝8.2Hz,1H),7.60-7.53(m,1H),7.45(dd,J＝14.2,6.3Hz,3H),7.38(dd,J＝8.4,5.6Hz,3H),7.29(s,1H),7.2 8-7.22(m,1H),7.11(d,J＝2.1Hz,1H),4.96(s,2H),4.76(s,2H),4.47(t,J＝14.8Hz,2H),4.21(s,2H),3.73(dd,J＝25.2,11.9Hz,4H),2.00(d,J＝10.6Hz ,4H),1.33(s,4H).

Example 3: Synthesis of Compound 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)ethynyl)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol

The detailed synthesis steps of Compound 3-1 to Compound 3-6 refer to Example 1. Compound 3-6 ESI-MS m/z: 886 [M+H] ⁺ .

Step 7: Synthesis of compound 3-7

At room temperature, compound 3-6 (110 mg) was dissolved in THF (5 mL), TBAF (1 M/THF, 0.12 mL) was added dropwise, and stirred at room temperature for 30 min. The reaction solution was concentrated, and the concentrate was purified by column chromatography (MeOH:DCM=0-200%) to obtain the target compound 3-7 (80 mg, yield 90%). ESI-MS m/z: 730 [M+H] ⁺ .

Step 8 The synthesis steps of target compound 3 refer to Example 1. ESI-MS m/z: 585 [M+H] ⁺ .

Example 4: Synthesis of Compound 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)ethynyl)quinazolin-7-yl)naphthalen-2-ol

Step 1: Synthesis of compound 4-1

At room temperature, 1-methoxycarbonylcyclopropane-1-carboxylic acid (5000.00 mg) was dissolved in DCM (50.00 mL), oxalyl chloride (11.74 mL) was added, DMF (0.03 mL) was added, the temperature was raised to 35°C, and the reaction was continued for 1 hour. After concentration, DCM (50.00 mL) was added, the temperature was lowered to 0°C, TEA (24.11 mL) was added, and 3-fluoropyrrolidine (3091.46 mg) was added, and the reaction was continued for 2 hours. The reaction mixture was directly mixed and purified by silica gel column (EA: PE = 1: 1) to obtain the target compound 4-1 (6000.00 mg, yield 80.36%) as a yellow oil.

Step 2: Synthesis of compound 4-2

At room temperature, compound 4-1 (6.20 g) was added to the reaction bottle, THF (70.00 mL) was cooled to -5 °C, LAH (2.5 M/THF) (1.64 g) was added in batches, and after 10 minutes of addition, the reaction was restored to room temperature for 2 hours. The reaction mixture was moved to low temperature and 1.6 mL of water was added to quench the reaction, 1.6 mL of 15% sodium hydroxide aqueous solution was added, and then 4.8 mL of water was added. After stirring for 10 minutes, anhydrous magnesium sulfate was added, and after stirring for 10 minutes, it was filtered, and the filter cake was washed twice with DCM, and the mother liquor was concentrated and purified by silica gel column (DCM~DCM:EA＝3:1) to obtain the target compound 4-2 (4.02 g, yield 80.56%) as a light yellow oil.

Step 3: Synthesis of compound 4-3

At room temperature, anhydrous DCM (15.00 mL) and dry DMSO (2.46 mL) were added to a dry reaction bottle. After adding, the temperature was lowered to -78 ° C under nitrogen protection. 2M oxalyl chloride (1.47 mL) was slowly added. After adding, the reaction was continued at this temperature for 0.5 h. Compound 4-2 (2.00 g) was dissolved in DCM (15.00 mL) and then slowly added to the reaction solution. After adding, the reaction was continued at this temperature for 1 h. Finally, TEA (4.81 mL) was added. After adding, the mixture was stirred at this temperature for 0.3 h and then returned to room temperature. Water and DCM were added to extract the mixture. The organic phase was dried and concentrated to obtain a colorless liquid crude compound 4-3 (1.94 g, yield 98.14%).

Step 4: Synthesis of compound 4-4

At room temperature, the crude product 4-3 (1.90 g), MeOH (20.00 mL) and K ₂ CO ₃ (3.07 g) were added to the reaction bottle, and dimethyl (1-diazo-2-oxypropyl)phosphonate (2.17 mL) was slowly added under stirring at 0°C. After addition, the mixture was returned to room temperature and reacted for 12 h. EA and water were added for extraction, and the organic phase was dried and concentrated. The concentrate was purified by silica gel column (PE～PE:EA＝2:1) to obtain the target product 4-4 (1.25 g, yield 67.36%) as a light yellow liquid.

Step 5: Synthesis of compound 4-5

At room temperature, compound 4-4 (65.77 mg), compound 1-9 (100.00 mg), CuI (7.48 mg), PdCl ₂ (PPh ₃ ) ₂ (18.39 mg), TEA (0.05 mL) and DMF (1.00 mL) were added to the reaction bottle, and the mixture was replaced with nitrogen and reacted at 40°C for 0.5 h under nitrogen protection. Water and EA were added to the reaction mixture for extraction, drying and concentration. The concentrate was purified by (DCM:MeOH=12:1) to obtain the target compound 4-5 (23.00 mg, yield 22.49%) as a yellow solid. ESI-MS m/z: 780 [M+H] ⁺ .

Step 6: Synthesis of Compound 4-6

At room temperature, the above compound 4-5 (23.00 mg), THF (1.00 mL) and triethylamine trihydrofluoride (0.05 mL) were added to the reaction bottle and reacted at room temperature for 0.3 h. The reactants were directly concentrated to obtain a crude yellow oily target compound 4-6, which was directly used in the next step. ESI-MS m/z: 666 [M+H] ⁺ .

Step 7: Synthesis of compound 4

At room temperature, add the above crude product 4-6 (20.00 mg), DCM (1.00 mL) and TFA (1.00 mL) to the reaction bottle and react at room temperature for 0.3 h. First, spin dry the solvent, add DCM to dissolve, adjust pH to 8 with sodium bicarbonate aqueous solution under ice bath, extract with DCM and MeOH, dry the organic phase and concentrate. The concentrate was separated and purified by Pre-TLC (DCM: MeOH: ammonia water = 10: 1: 0.1) to obtain the target product 4 (10.00 mg, yield 58.93%) as a yellow solid. ESI-MS m/z: 566 [M + H] ⁺ . ¹ H NMR(500MHz,MeOD)δ7.84(dd,J＝15.5,7.5Hz,1H),7.73(dd,J＝8.1,4.2Hz,1H),7.48-7.36(m,3H),7.26-7.16(m,2H),7.11(d,J＝2.1Hz,1H),5.19(dd,J＝55.7,5 .1Hz,1H),4.58-4.41(m,2H),3.73-3.55(m,4H),3.22-3.08(m,1H) ,3.07-2.92(m,2H),2.70(dd,J＝12.0,6.5Hz,2H),2.61(t,J＝11.7Hz,1H),2.19(dtd,J＝27.6,13.8,6.7Hz,1H),2.02(ddd,J＝21.0,13.2,6.6Hz,1H),1.8 9(d,J=22.9Hz,4H), 1.20(d,J=3.6Hz,2H), 0.94(dd,J=14.2,11.7Hz,2H).

The following examples were synthesized by the above method or by similar methods using corresponding intermediates.

Pharmacological experiments

Example 1: Cell p-ERK detection test

CRL-1739^TM)或Panc 04.03(

CRL-2555^TM)按5×10⁴/孔的细胞密度铺于96孔板中，置于细胞培养箱隔夜培养。待细胞贴壁后，将待测化合物按照终浓度10000nM、3333nM、1111nM、370.4nM、123.4nM、41.15nM、13.72nM、4.57nM、1.52nM、0.51nM、0.1％DMSO加入96孔板中，培养3h后，利用MSD(MesoScale Discovery)电化学发光免疫检测试剂盒中的lysis buffer(50μL)提取96孔板中各处理细胞样品的蛋白裂解液，利用BCA方法对蛋白裂解液进行定量，并利用lysis buffer将蛋白样品浓度稀释为0.1μg/μL。向MSD检测96孔板中加入25ul/孔的蛋白稀释液，室温孵育3h后加入25μL detection antibody solution，继续室温孵育1h，洗板后加入150μL1×read buffer T。在SECTOR Imager上进行孔板读值，采集原始数据。Two KRas-G12D mutant tumor cells AGS (

CRL-1739 ^TM ) or Panc 04.03 (

CRL-2555 ^TM ) were plated in a 96-well plate at a cell density of 5×10 ⁴ /well and cultured in a cell culture incubator overnight. After the cells adhered, the test compounds were added to the 96-well plate at final concentrations of 10000nM, 3333nM, 1111nM, 370.4nM, 123.4nM, 41.15nM, 13.72nM, 4.57nM, 1.52nM, 0.51nM, and 0.1% DMSO. After culturing for 3 hours, the protein lysate of each treated cell sample in the 96-well plate was extracted using the lysis buffer (50μL) in the MSD (MesoScale Discovery) electrochemiluminescence immunoassay kit, the protein lysate was quantified using the BCA method, and the protein sample concentration was diluted to 0.1μg/μL using the lysis buffer. Add 25ul/well of protein diluent to the MSD detection 96-well plate, incubate at room temperature for 3h, then add 25μL detection antibody solution, continue incubation at room temperature for 1h, wash the plate, and add 150μL 1× read buffer T. Read the plate on the SECTOR Imager and collect raw data.

p-ERK% value = ((2×phosphorylation signal value)/(phosphorylation signal value + total signal value))×100

The p-ERK inhibition percentage was calculated according to the following formula:

Inhibition percentage = (maximum value - measured value) / (maximum value - Blank) × 100

("Maximum" is from 0.1% DMSO control wells, "Blank" is from blank control wells, and "Measured" is from compound-treated wells).

GraphPad Prism software was used for curve fitting and _IC50 values were obtained.

Table 1

Example 2: Cell proliferation assay (AGS)

CRL-1739^TM)按1×10³/孔的细胞密度铺于低吸附96孔板中，置于细胞培养箱隔夜培养。待细胞贴壁后，将待测化合物按照终浓度20000、6666.67、2222.22、740.74、246.91、82.30、27.43、9.14、3.05、0nM(DMSO终浓度均为0.5％)加入96孔板中，37℃培养96h后向各孔加入50μL Cell-titer GLO工作液，震荡混匀后室温孵育10min，在多功能酶标仪读取Luminescence发光值，将发光值数据计算转换为抑制百分数。并根据以下公式，计算细胞增殖抑制百分数：KRas-G12D mutant tumor cells AGS (

CRL-1739 ^TM ) was plated in a low-adsorption 96-well plate at a cell density of 1×10 ³ /well and cultured in a cell culture incubator overnight. After the cells adhered to the wall, the test compound was added to the 96-well plate at a final concentration of 20000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05, 0nM (DMSO final concentration was 0.5%), and 50μL Cell-titer GLO working solution was added to each well after culturing at 37°C for 96h. After oscillation and mixing, the mixture was incubated at room temperature for 10min, and the luminescence value was read on a multifunctional microplate reader. The luminescence value data was converted into inhibition percentage. The cell proliferation inhibition percentage was calculated according to the following formula:

Inhibition percentage = (maximum value - measured value) / (maximum value - Blank) × 100

("Maximum" is from 0.1% DMSO control wells, "Blank" is from blank control wells, and "Measured" is from compound-treated wells).

GraphPad Prism software was used for curve fitting and _IC50 values were obtained.

Table 2

Claims (15)

1. A compound of formula (I), a tautomer, a deuteron, or a pharmaceutically acceptable salt thereof:

wherein,

X ₁ selected from the group consisting of CR ₆ Or N; r is ₆ Selected from H, amino, substituted amino, cyano, C _1-6 Alkyl, substituted C _1-6 Alkyl, haloElement, C _2-6 Alkenyl, substituted C _2-6 Alkenyl radical, C _3-6 Cycloalkyl or substituted C _3-6 A cycloalkyl group;

X ₂ selected from the group consisting of CR ₇ Or N; r is ₇ Selected from H, halogen, cyano or C _1-6 An alkyl group;

X ₃ selected from the group consisting of CR ₈ Or N; r ₈ Selected from H, halogen, cyano or C _1-6 An alkyl group;

l is selected from the group consisting of a bond, O, NR ₉ Or C _1-4 Alkylene of the said C _1-4 Alkylene is optionally substituted by one or more R ₉ Substitution; r ₉ Selected from H, halogen, cyano or C _1-6 Alkyl, or two R on the same carbon atom ₉ Together with the atoms to which they are attached form a 3-6 membered cycloalkyl group;

R ₁ selected from the group consisting of absent, or R ₁ 、R ₇ Together with the atoms to which they are attached form a substituted or unsubstituted 3-10 membered cyclic group; the 3-10 membered cyclic group is selected from cycloalkyl or heterocyclyl; said cycloalkyl or heterocyclyl being optionally substituted by one or more groups selected from H, halogen, cyano, C _1-6 Alkyl or oxo;

R ₂ selected from absent, or R ₂ 、R ₈ Together with the atoms to which they are attached form a substituted or unsubstituted 3-10 membered cyclic group; the 3-10 membered cyclic group is selected from cycloalkyl or heterocyclyl; said cycloalkyl or heterocyclyl being optionally substituted by one or more groups selected from H, halogen, cyano, C _1-6 Alkyl or oxo;

R ₃ selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally further substituted by one or more R ₁₀ Substitution;

R ₄ selected from H, halogen, C _1-6 Alkyl OR-OR ₁₁ Said R is ₁₁ Is selected from C _1-6 Alkyl or C _3-8 Cycloalkyl radical, R ₁₁ Optionally substituted by one or more groups selected from hydroxy, halogen, C _1-3 Alkyl radical, C _1-3 Alkoxy or cyclopropyl;

R ₅ selected from aryl or heteroaryl, said aryl or heteroaryl being optionally further substituted by one or more R ₁₀ Substitution;

R ₁₀ selected from H, cyano, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, -C _0-6 alkylene-OR _a 、-C _0-6 alkylene-OC (O) N (R) _a ) ₂ 、-C _0-6 alkylene-N (R) _a ) ₂ 、-C _0-6 alkylene-NR _a C(O)R _a 、-C _0-6 alkylene-NR _a C(O)N(R _a ) ₂ 、-C _0-6 alkylene-NR _a S(O)R _a 、-C _0-6 alkylene-NR _a S(O) ₂ R _a 、-C _0-6 alkylene-S (= O) R _a 、-C _0-6 alkylene-S (= O) ₂ R _a 、-C _0-6 alkylene-SR _a 、-C _0-6 alkylene-S (R) _a ) ₅ 、-C _0-6 alkylene-C (= O) R _a 、-C _0-6 alkylene-C (= O) OR _a 、-C _0-6 alkylene-C (= O) N (R) _a ) ₂ 、

C _2-6 Alkenyl radical, C _2-6 Alkynyl, -C _0-6 alkylene-C _3-14 Cycloalkyl, -C _0-6 Alkylene- (3-to 14-membered heterocyclic group), -C _0-6 alkylene-C _6-14 Aryl or-C _0-6 Alkylene- (5-to 14-membered heteroaryl), said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, -C _0-6 alkylene-C _3-14 Cycloalkyl, -C _0-6 Alkylene- (3-to 14-membered heterocyclyl), -C _0-6 alkylene-C _6-14 Aryl or-C _0-6 Alkylene- (5-to 14-membered heteroaryl) optionally may be further substituted by 1 or more R _a Substituted;

each R _a Each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxy, C _1-6 Alkyl radical, C _1-6 Hydroxyalkyl radical, C _1-6 Aminoalkyl radical, C _1-6 Alkyl halidesBase, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Heteroalkyl group, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl;

and the compound of the formula (I) is not

2. A compound of formula (I), a tautomer, a deuteron, or a pharmaceutically acceptable salt thereof, selected from compounds of the formula:

preferably, it is

Wherein the substituents are as defined in claim 1.

3. The compound, tautomer, deuteron or pharmaceutically acceptable salt thereof of claim 1 wherein R is ₅ Is selected from

4. A compound, tautomer, deuteron or pharmaceutically acceptable salt thereof according to one of claims 1-3, wherein L is a bond and R is ₃ Is cycloalkyl, said cycloalkyl being further substituted by one or more R ₁₀ Substitution; the R is ₁₀ Is selected from-C _0-6 Alkylene- (3-to 14-membered heterocyclyl), -C _0-6 alkylene-C _6-14 Aryl radical, -C _0-6 alkylene-N (R) _a ) ₂ 、-C _0-6 alkylene-NR _a C(O)R _a 、-C _0-6 alkylene-NR _a C(O)N(R _a ) ₂ or-C _0-6 Alkylene- (5-to 14-membered heteroaryl), said-C _0-6 Alkylene- (3-to 14-membered heterocyclyl), -C _0-6 alkylene-C _6-14 Aryl or-C _0-6 Alkylene- (5-to 14-membered heteroaryl) optionally may be further substituted by 1 or more R _a Substituted; said R is _a Each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxy, C _1-6 Alkyl radical, C _1-6 Hydroxyalkyl radical, C _1-6 Aminoalkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _1-6 A haloalkoxy group.

5. A compound, tautomer, deuteron or pharmaceutically acceptable salt thereof according to any one of claims 1-3 wherein L is selected from the group consisting of a bond and C _1-4 Alkylene of the R ₃ Selected from heterocyclyl or heteroaryl, said heterocyclyl or heteroaryl being optionally further substituted by one or more R ₁₀ Substitution; the R is ₁₀ Selected from H, cyano, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, -C _0-6 alkylene-OR _a 、-C _0-6 alkylene-OC (O) N (R) _a ) ₂ 、-C _0-6 alkylene-N (R) _a ) ₂ 、-C _0-6 alkylene-NR _a C(O)R _a or-C _0-6 alkylene-NR _a C(O)N(R _a ) Said R is _a Each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxy, C _1-6 Alkyl radical, C _1-6 Hydroxyalkyl radical, C _1-6 Aminoalkyl or C _1-6 A haloalkyl group.

6. The compound, tautomer, deuteron or pharmaceutically acceptable salt thereof, of any one of claims 1-5 wherein R ₁ 、R ₇ Together with the atoms to which they are attached form a substituent or notA substituted 3-10 membered cyclic group; the 3-10 membered cyclic group is selected from cycloalkyl or heterocyclyl; said cycloalkyl or heterocyclyl being optionally substituted by one or more groups selected from H, halogen, cyano, C _1-6 Alkyl or oxo.

7. The compound, tautomer, deuteron or pharmaceutically acceptable salt thereof, of any one of claims 1-5 wherein R ₁ Is absent.

8. The compound, tautomer, deuteron or pharmaceutically acceptable salt thereof, of any one of claims 1-5 wherein R ₂ 、R ₈ Together with the atoms to which they are attached form a substituted or unsubstituted 3-10 membered cyclic group; the 3-10 membered cyclic group is selected from cycloalkyl or heterocyclyl; said cycloalkyl or heterocyclyl being optionally substituted by one or more groups selected from H, halogen, cyano, C _1-6 Alkyl or oxo.

9. The compound, tautomer, deuteron or pharmaceutically acceptable salt thereof of any one of claims 1-5, wherein R is ₂ Is absent.

10. The compound, tautomer, deuteron or pharmaceutically acceptable salt thereof of any one of claims 1-9, wherein R is ₄ Is halogen, preferably F.

11. A compound, tautomer, deuteron or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

12. a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-10, or a stereoisomer, tautomer, deuteron, or pharmaceutically acceptable salt thereof.

13. Use of a compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12 for the manufacture of a medicament.

14. The use according to claim 13, wherein the manufacture of a medicament is for the manufacture of a medicament for the treatment and/or prevention of a disease mediated by KRAS G12D.

15. The use of claim 14, wherein the KRAS G12D mediated disease is a cancer selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatobiliary cell carcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, schwannoma, lung squamous cell carcinoma, lichenification, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.