CN115466272A - Pyrimido-heterocyclic compound, pharmaceutical composition containing pyrimido-heterocyclic compound and application of pyrimido-heterocyclic compound - Google Patents

Abstract

The invention relates to a pyrimido heterocyclic compound, a pharmaceutical composition containing the same and application thereof. The compound is a compound shown as a formula I or pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, metabolite and prodrug thereof, wherein R is ₁ ～R ₄ And X, Y, Y ₁ The Z and L groups are as defined in the specification. The compound can be used for preparing a medicament for treating and/or preventing cancers.

Description

Pyrimido-heterocyclic compound, pharmaceutical composition containing pyrimido-heterocyclic compound and application of pyrimido-heterocyclic compound

Technical Field

The invention belongs to the technical field of biological medicines, and relates to a pyrimido-heterocyclic compound, a pharmaceutical composition containing the pyrimido-heterocyclic compound and application of the pyrimido-heterocyclic compound.

Background

The Ras gene is an important protooncogene, and is named after the finding in rat sarcoma virus. The ras gene family has three characteristic genes associated with human tumors, namely H-ras, K-ras and N-ras, which are located on chromosomes 11, 12 and 1, respectively, the former two are transforming genes of rat sarcoma virus isolated from human neuroblastoma.

The Ras protein encoded by the Ras gene has a relative molecular mass of 2.1KDa, is positioned on the inner side of a cell membrane and consists of 188 or 189 amino acids. Ras proteins include two conformations: the active GTP binding conformation and the inactive GDP binding conformation can be mutually transformed, and the Ras protein regulates and controls a plurality of signal paths including RAF-MEK-ERK, PI3K/Akt/mTOR and the like by switching between two active states, thereby regulating and controlling functions of cells such as growth, survival, migration, differentiation and the like.

RAS point mutations occur at codons 12, 13 and 61. Following RAS gene mutation, RAS exchanges with GDP/GTP at an increased frequency, RAS binds to GDP for a long period of time, resulting in RAS signaling in a sustained activation state, and uncontrolled cell proliferation, so overactivated RAS signaling can ultimately lead to cancer. RAS gene mutations are found in about one third of human malignancies. The most common oncogenic mutation in the Ras family is the KRAS mutation (85%), whereas oncogenic mutations in NRAS (12%) and HRAS (3%) family members are less common.

KRAS mutations are prevalent in a variety of cancers: including pancreatic cancer (95%), colorectal cancer (45%), and lung cancer (25%).

KRAS mutations include G12C, G12D, G12V and the like, G12D mutations are in pancreatic cancer (25%) colorectal cancer (13.3%), non-small cell lung cancer (4.1%) and small cell lung cancer (1.7%), at present, KRAS G12C mutation drug research has made better progress, a plurality of KRAS G12C inhibitors including AMG-510, MRTX-849 and the like enter clinical tests, and better treatment effect and safety are shown clinically, but KRAS G12D mutation tumors have no effective treatment means, and have larger clinical requirements. Therefore, the development of the high-activity inhibitor aiming at the KRAS G12D mutation has the potential of treating various cancers and has wide market prospect.

Disclosure of Invention

The invention aims to solve the technical problem of providing a compound with a novel structure, a pharmaceutical composition thereof and application thereof. The compound provided by the invention has KRAS G12D inhibitory activity, and provides a new commercial choice for KRAS G12D inhibitors.

The invention solves the technical problem through the following technical scheme.

According to a first aspect of the present invention, there is provided a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, metabolite, prodrug thereof:

wherein, the first and the second end of the pipe are connected with each other,

x is selected from N or CR ₅ ；

Z is selected from N or CR ₅ ；

Y is selected from a single bond, C ₁ -C ₃ Alkyl, oxygen, sulfur, -CO-or NR ₅ (ii) a Each of said alkyl groups being optionally substituted with at least 1R ₅ Substitution;

Y ₁ selected from single bond, C ₁ -C ₃ Alkyl, oxygen, sulfur, -CO-or NR ₅ Each of said alkyl groups being optionally substituted with at least 1R ₅ Substitution;

l is selected from a single bond or C ₁ -C ₅ Alkyl, each of said alkyl being optionally substituted with at least 1R ₇ Substitution;

n is selected from 0, 1,2, 3 or 4;

the R is ₁ Selected from H, halogen, cyano, hydroxy, -CO ₂ R ₅ 、-CON(R ₅ ) ₂ 、C ₁ -C ₃ Alkyl radical, C ₅ -C ₆ Heteroaryl, and wherein said alkyl and heteroaryl are each optionally substituted with at least 1R ₆ Substitution;

said R is ₂ Is selected from C ₁ -C ₁₂ Alkyl radical, C ₁ -C ₁₂ Heteroalkyl group, C ₃ -C ₈ Cycloalkyl, C ₃ -C ₈ Heterocycloalkyl radical, C ₆ -C ₁₂ Bridged heterocycloalkyl radical, C ₆ -C ₁₂ Spiroheterocycloalkyl or C ₆ -C ₁₂ And heterocycloalkyl, and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, spiroheterocycloalkyl, and spiroheterocycloalkyl are each optionally substituted with at least 1R ₇ Substitution;

the R is ₃ Selected from aryl or heteroaryl, wherein said aryl and heterocyclyl are each optionally substituted with at least 1R ₇ Substitution;

the R is ₄ Selected from H, halogen, C ₁ -C ₃ Alkyl radical, C ₃ -C ₈ Cycloalkyl radical, C ₁ -C ₃ Alkoxy or C ₁ -C ₃ A haloalkoxy group;

the R is ₅ Independently selected from hydrogen, OH, CN, NH ₂ Halogen, C ₁ -C ₃ Alkyl radical, C ₃ -C ₈ Cycloalkyl radical, C ₁ -C ₃ Alkoxy or C ₁ -C ₃ A haloalkoxy group;

the R is ₆ Independently selected from hydrogen, OH, CN, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Cycloalkyl or C ₁ -C ₆ An alkoxy group;

the R is ₇ Independently selected from hydrogen, halogen, OH, CN, NH ₂ 、C ₆ -C ₁₀ Aryl radical, C ₅ -C ₁₀ Heteroaryl group, C ₁ -C ₈ Alkyl radical, C ₁ -C ₈ Heteroalkyl group, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, C ₃ -C ₈ Cycloalkyl radical, C ₃ -C ₈ Heterocycloalkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ Alkynyl, -S-C ₁ -C ₈ Alkyl, -O-C ₁ -C ₈ Alkyl, -S-C ₁ -C ₃ Haloalkoxy, -O-C ₁ -C ₃ Haloalkoxy, -N (R) ₅ ) ₂ or-CH ₂ C(＝O)N(R ₅ ) ₂ And wherein each of said aryl, heteroaryl, alkyl, heteroalkyl, cycloalkyl or heterocycloalkylOptionally substituted by at least 1R ₈ Substitution;

said R is ₈ Independently selected from hydrogen, OH, CN, NH ₂ Halogen, C ₁ -C ₃ Alkyl radical, C ₃ -C ₈ Cycloalkyl radical, C ₁ -C ₃ Alkoxy or C ₁ -C ₃ A haloalkoxy group.

The "hetero" represents a heteroatom or a heteroatom group, and the "hetero" of the above-mentioned mesoheteroalkyl group, heterocycloalkyl group, bridged heterocycloalkyl group, spiroheterocycloalkyl group, fused heterocycloalkyl group, heteroaryl group are each independently selected from the group consisting of N, -O-, -S-, -C (= O) N (R) ₅ )-、-N(R ₅ )-、-NH-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O) ₂ -and-N (R) ₅ )C(＝O)N(R ₅ )-。

Preferably, it is a compound as shown in any one of the formulas II, III, IV or V,

in a second aspect, the invention provides the following specific compounds:

in a third aspect, the present invention provides the following specific compounds or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, solvates, metabolites, prodrugs thereof,

in a fourth aspect of the present invention, the groups and substituents thereof described in the general formula of the compounds can be selected by those skilled in the art to provide stable compounds or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, solvates, metabolites, prodrugs thereof, including but not limited to the compounds described in the examples of the present invention.

In a fifth aspect, the present invention provides the above compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, metabolite, prodrug, or pharmaceutical composition thereof, which can be used for preparing KRAS G12D inhibitor for treating diseases caused by KRAS G12D mutation.

In a sixth aspect, the present invention provides a use of the above compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, metabolite, prodrug, or pharmaceutical composition thereof in the preparation of a medicament for treating and/or preventing cancer, wherein the cancer that can be treated and/or prevented includes, but is not limited to, pancreatic cancer, colorectal cancer, and lung cancer, by using the compound of the present invention.

Still other embodiments of the present invention are derived from any combination of the above variables.

The technical effects are as follows:

the compound can be used for preparing medicaments of KRAS G12D inhibitors, can be used for preventing and/or treating KRAS G12D mutant diseases and can be used for preparing medicaments for treating and/or preventing cancers, wherein the cancers to be treated and/or prevented comprise but are not limited to pancreatic cancer, colorectal cancer and lung cancer.

Terms and definitions

Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

"alkyl" refers to a saturated aliphatic hydrocarbon group including straight and branched chain groups of 1 to 20 carbon atoms, such as straight and branched chain groups of 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In this context "alkyl" may be a monovalent, divalent or trivalent radical. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, and various branched chain isomers thereof, and the like. Non-limiting examples also include methylene, methine, ethylene, ethylidene, propylidene, butylidene, and various branched chain isomers thereof. Alkyl groups may be optionally substituted or unsubstituted.

"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 12 ring atoms, which may be, for example, 3 to 12, 3 to 10, or 3 to 6 ring atoms, or may be a3, 4, 5, 6 membered ring. Non-limiting examples of monocyclic radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like. The cyclic group may be optionally substituted or unsubstituted.

"heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, which may be, for example, 3 to 16, 3 to 12, 3 to 10, or 3 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O) _m (wherein m is 0, 1, or 2) but does not include a cyclic moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms of which 1-4 are heteroatoms, more preferably a heterocycloalkyl ring comprising 3 to 10 ring atoms, most preferably a 5-or 6-membered ring of which 1-4 are heteroatoms, more preferably 1-3 are heteroatoms, most preferably 1-2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused, or bridged heterocyclic groups.

"Spiroheterocyclyl" means 5 to 18 membered, two orTwo or more cyclic structures with single rings sharing one atom with each other, containing 1 or more double bonds within the ring, but with none of the rings having a completely co-extensive electron system, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) _P (wherein p is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. Spiro heterocyclic groups are classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiro heterocyclic group or a double spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred is a 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic group. Wherein "a-membered/b-membered monocyclic spiroheterocyclyl" refers to a spiroheterocyclyl in which an a-membered monocyclic ring and a b-membered monocyclic ring share one atom with each other. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: diazaspiro [3.3]Heptane.

"Heterocyclyl" means a5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, in which one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen or S (O) z, (where z is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include diazabicyclo [3.1.1] heptane.

"bridged heterocyclyl" refers to a5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen or S (O) z, (where z is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include 6-azabicyclo [3.1.1] heptane.

The heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic, and bridged heterocyclic) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring to which the parent structure is attached is a heterocyclyl, non-limiting examples of which include: 2,3-dihydrobenzofuran.

"haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more of the same or different halogen atoms, and examples of preferred alkyl or alkoxy groups include, but are not limited to: trifluoromethyl, trifluoroethyl, trifluoromethoxy.

"aryl" means monocyclic, bicyclic, and tricyclic carbon ring systems containing 6 to 14 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms in the ring and one or more attachment points to the rest of the molecule. Examples include, but are not limited to: phenyl, naphthyl, anthracene, and the like. Preferably, the aryl group is a carbocyclic ring system of 6 to 10 or 6 to 7 ring atoms.

"heteroaryl" means monocyclic, bicyclic, and tricyclic ring systems containing 5 to 14 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". Examples include, but are not limited to: furyl, imidazolyl, 2-pyridyl, 3-pyridyl, thiazolyl, purinyl and quinolyl. Preferably, the heteroaryl group is a ring system of 5 to 10 ring atoms.

"halogen" means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example: "heterocyclic group optionally substituted with alkyl" means that alkyl may, but need not, be present, and this description includes the case where the heterocyclic group is substituted with alkyl and the heterocyclic group is not substituted with alkyl.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts with inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like; also included are Salts of amino acids such as arginine, etc., and Salts of organic acids such as glucuronic acid (see Berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Science 66 (1977). Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt. Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents.

"pharmaceutical composition" means a mixture comprising one or more compounds of formula I, as described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, metabolite, prodrug thereof, and other chemical components, as well as other components, such as pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and exert biological activity.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains an acid or base, by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.

In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention in an in vivo environment by chemical or biochemical means.

Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -and (L) -enantiomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.

Unless otherwise indicated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" results from the inability of a double bond or a single bond to rotate freely within a ring-forming carbon atom.

Unless otherwise indicated, the term "diastereomer" refers to a stereoisomer in which the molecules have two or more chiral centers and a non-mirror image relationship between the molecules.

Unless otherwise indicated, "(D)" or "(+)" means dextrorotation, "(L)" or "(-) -means levorotation," (DL) "or" (±) "means racemization.

Using solid wedge keys, unless otherwise indicated

And wedge dotted bond

Representing the absolute configuration of a solid center by means of a straight solid-line bond () and a straight imaginary-line bond

Showing the relative configuration of the centres of solids, by wavy lines

Representing solid-line keys of wedge shape

Or wedge dotted bond

Or by wavy lines

Indicating straight solid-line keys

And straight dotted bond

The compounds of the invention may be present specifically. Unless otherwise indicated, the term "tautomer" or "tautomeric form" means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be rapidly interconverted. If tautomers are possible (e.g., in solution), then the chemical equilibrium of the tautomers can be reached. For example, proton tautomers (proto-tautomers), also known as proton transfer tautomers (prototropic-tautomers), include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence-isomers (valency-tautomer) include interconversion by recombination of some of the bonding electrons. A specific example of where keto-enol tautomerism is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

Unless otherwise indicated, the terms "enriched in one isomer", "isomer enriched", "enantiomer enriched" or "enantiomeric enrichment" refer to a content of one isomer or enantiomer of less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

Unless otherwise indicated, the term "isomeric excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or enantiomers. For example, where one isomer or enantiomer is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomer excess (ee value) is 80%.

Optically active (R) -and (S) -isomers and (D) -and (L) -isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to get the present inventionOne enantiomer of a compound may be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines). The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioactive isotopes, such as tritium (tritium) (III) ³ H) Iodine-125 ( ¹²⁵ 1) Or C-14 ( ¹⁴ C) In that respect For another example, deuterium can be used to replace hydrogen to form a deuterated drug, the bond formed by deuterium and carbon is stronger than the bond formed by common hydrogen and carbon, and compared with an undeuterized drug, the deuterated drug has the advantages of reducing toxic and side effects, increasing the drug stability, enhancing the curative effect, prolonging the biological half-life period of the drug and the like. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.

Detailed Description

The preparation of the compounds of the present invention, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, solvates, metabolites and prodrugs thereof, can be accomplished by the following exemplary procedures as well as the relevant publications used by those skilled in the art, which are not intended to limit the scope of the present invention.

The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS)And (4) determining. NMR was measured using a Bruker AVANCE-400 or Varian Oxford-300 nuclear magnetic instrument in deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDC 1) ₃ ) Deuterated methanol (CD) ₃ OD) internal standard is Tetramethylsilane (TMS) chemical shift is 10 ^-6 (ppm) is given as a unit.

MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: agilent, model: 6110) or Shimadzu SQD (ESI) mass spectrometer (manufacturer: shimadzu, model: 2020).

HPLC measurements were carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfirc C18, 150X4.6mm,5wn, column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18, 150X4.6mm,5ym column).

The thin layer chromatography silica gel plate is Qingdao sea GF254 silica gel plate, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15mm-0.2mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5 mm.

Column chromatography is carried out by using Qingdao sea silica gel of 200-300 meshes as carrier.

Known starting materials of the present invention can be synthesized using or following methods known in the art, companies such as Shaoyuan chemical technology (Accela ChemBio Inc), beijing coupled chemicals, and the like.

In the examples, the reaction was carried out under an argon atmosphere or a nitrogen atmosphere unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L. The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

In the examples, the reaction temperature was room temperature and the temperature range was 20 ℃ to 30 ℃ unless otherwise specified.

The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a system of developing reagents, A: dichloromethane and methanol systems; b: petroleum ether and ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound.

In the examples, unless otherwise specified, the preparative HPLC (formic acid) method used means that the compound is isolated by chromatography under a formic acid system (A phase: H2O +0.225% formic acid, B phase: acetonitrile).

The system of eluents for column chromatography and the system of developing agents for thin layer chromatography used for purifying compounds include a: dichloromethane and methanol systems; b: the volume ratio of the solvent is adjusted according to different polarities of the compounds, and a small amount of triethylamine and acidic or basic reagents can be added for adjustment.

The present invention is described in detail below by way of examples, but is not meant to be limited to any of the disadvantages of the present invention. The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made in the specific embodiments of the invention without departing from the spirit and scope of the invention. The following synthetic schemes describe the steps for preparing the compounds disclosed herein. Unless otherwise indicated, each substituent has the definition as described herein.

Scheme A:

and (3) performing high-temperature ring closure on the compound A1 and urea to obtain A2, and then reacting with phosphorus oxychloride to obtain A3. The compound A3 and corresponding piperazine derivative react under alkaline condition to obtain A4. The compound A4 and corresponding alcohol, thiol or amine are substituted by a suitable strong base, such as sodium tert-butoxide, to give A5. The compound A5 and a proper boric acid ester, boric acid or tin reagent are subjected to coupling reaction to obtain A6. And carrying out deprotection reaction on the compound A6 under an acidic condition to obtain a compound formula II derivative.

Scheme B:

the compound B1 can be obtained by using methods such as urea high-temperature ring closure or sodium cyanate alkaline reaction and the like to obtain B2, and then the compound B1 is reacted with phosphorus oxychloride to obtain B3. The compound B3 and corresponding piperazine derivative react under alkaline condition to obtain B4. The compound B4 and corresponding alcohol, thiol or amine are subjected to substitution reaction under the action of a suitable strong base, such as sodium tert-butoxide, to obtain B5. The compound B5 and a proper boric acid ester, boric acid or tin reagent generate coupling reaction to obtain B6. And carrying out deprotection reaction on the compound A6 under an acidic condition to obtain a compound of a formula III derivative.

Scheme C:

reacting the compound C1 with thionyl chloride to obtain a compound C2, and then reacting with S-methylisothiourea sulfate hydrogen under an alkaline condition to obtain a compound C3, wherein the used alkali can be sodium hydrogen, sodium hydroxide, potassium hydroxide or the like. And (3) carrying out intramolecular ring closure on the compound C3 under an alkaline condition, such as sodium hydrogen and cesium carbonate, to obtain a compound C4, and then reacting with phosphorus oxychloride to obtain C5. The compound C5 and corresponding piperazine derivative react under alkaline condition to obtain C6. The compound C6 and an oxidant, such as m-chloroperoxybenzoic acid, hydrogen peroxide and the like, are subjected to oxidation reaction to obtain a compound C7, and then, a substitution reaction is carried out under an alkaline condition, such as sodium tert-butoxide, to obtain C8. The compound C8 and a proper boric acid ester, boric acid or tin reagent are subjected to coupling reaction to obtain C9. And carrying out deprotection reaction on the compound C9 under an acidic condition to obtain a compound formula IV derivative.

Scheme D:

the compound D1 uses phosphorus pentachloride and phosphorus oxychloride conditions to obtain a compound D2, and then reacts with S-methyl isothiourea sulfate hydrogen under an alkaline condition to obtain a compound D3, wherein the used alkali can be sodium hydrogen, sodium hydroxide or potassium hydroxide and the like. And (3) under the alkaline condition, such as sodium hydrogen and cesium carbonate, intramolecular ring closure is carried out on the compound D3 to obtain a compound D4, and then the compound D4 reacts with phosphorus oxychloride to obtain D5. The compound D5 and the corresponding piperazine derivative react under alkaline conditions to obtain D6. The compound D6 and an oxidant, such as m-chloroperoxybenzoic acid, hydrogen peroxide and the like, are subjected to oxidation reaction to obtain a compound D7, and then, a substitution reaction is carried out under an alkaline condition, such as sodium tert-butoxide, to obtain D8. The compound C8 and a proper boric acid ester, boric acid or tin reagent are subjected to coupling reaction to obtain D9. And carrying out deprotection reaction on the compound D9 under an acidic condition to obtain the compound shown in the formula V.

Example 1: preparation of Compound I-1

The synthesis route is as follows:

the preparation method comprises the following steps:

the first step is as follows: synthesis of Compound 1B

Compound 1A (25g, 119.06mmol) was added to SOCl ₂ To the solution (75 mL) was added DMF (3 drops), and the reaction mixture was brought to 85 ℃ for 1 hour. After TLC showed that the reaction was complete, the reaction solution was spin dried and directly put on to the next step without further purification.

MS(ESI):m/z 228[M+1] ⁺ 。

The second step is that: synthesis of Compound 1C

Sodium hydroxide (21g, 525mmol) was dissolved in water (460 mL), then cooled to 0 ℃, S-methylisothiourea hydrogensulfate (60g, 390.64mmol) was added slowly in portions, the mixture was stirred at 0 ℃ for 30 minutes after the addition was completed, then Compound 1B (27.2g, 119.06mmol) obtained in the previous step was dissolved in methyl t-butyl ether (348 mL), and this solution was added dropwise slowly to the reaction mixture at 0-5 ℃, after the addition was completed, the temperature was slowly raised to room temperature for reaction 1h, after TLC showed that the reaction was completed. The organic layer was separated, the aqueous layer was further extracted with ethyl acetate (100 mL. Times.3), the organic layers were combined, washed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and spin-dried to give product 1C. (33.13 g, light yellow solid, yield: 98.62%).

MS(ESI):m/z 282[M+1] ⁺ 。

The third step: synthesis of Compound 1D

Compound 1C (33g, 116.97mmol) was dissolved in DMF (330 mL) and cesium carbonate (38.28g, 117.44mmol) was added, after which the reaction was warmed to 90 ℃ and stirred for 3h. TLC showed the reaction was completed, the reaction solution was added to water (1.5L), the aqueous phase was extracted with ethyl acetate (500 mL × 3), the aqueous phase was separated, the obtained aqueous phase was adjusted to pH =6 with 6N hydrochloric acid, a large amount of solid was precipitated, and the obtained solid was filtered, washed with water again, and then dried in vacuo to obtain compound 1D (8 g, yellow solid, yield: 27.84%).

MS(ESI):m/z 246[M+1] ⁺ 。

The fourth step: synthesis of Compound 1E

Phosphorus oxychloride (30 mL) was added to compound 1D (3 g, 12.21mmol), the reaction was warmed to 100 ℃ and after TLC showed completion, the reaction was dried and the residue was slowly added to saturated NaHCO ₃ After the aqueous phase was extracted with (50 mL × 3) the organic phases were combined, dried over anhydrous sodium sulfate, dried by spinning, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate =5/1 (volume ratio)) to obtain compound 1E (3.1 g, yellow solid, yield: 96.12%).

MS(ESI):m/z 264[M+1] ⁺ 。

The fifth step: synthesis of Compound 1F

Compound 1E (9g, 34.4 mmol) was added to acetonitrile (100 ml) at room temperature, followed by addition of (S) -4-N-tert-butoxycarbonyl-2-methylpiperazine (9.6 g, 52mmol) and DIEA (6.7g, 52mmol), followed by reflux reaction for 3 hours, TLC showed the reaction to be complete, the reaction solution was concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate =10/1 (V: V vol ratio)) to give compound 1F (9 g, pale yellow solid), yield: and (3) 63.3%.

MS m/z(ESI):428[M+1] ⁺ .

And a sixth step: synthesis of Compound 1H

Compound 1F (1.2g, 2.80mmol) and 1G (0.78g, 3.1mmol) were dissolved in dioxane (20 mL) and water (4 mL), pd (dppf) was added ₂ Cl ₂ DCM (0.11g, 0.14mmol) and potassium carbonate (0.78g, 5.6mmol), and then the reaction solution was reacted at 100 ℃ for 12 hours. TLC showed the reaction was complete, the reaction was added to water (100 mL), the aqueous phase was extracted with ethyl acetate (100 mL × 3), the organic phases were combined and washed with saturated sodium chloride (100 mL × 3), the organic phase was separated, dried over anhydrous sodium sulfate, spun dry, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate =3:1 (vol.%)) to give compound 1H (1.2 g, tan solid, 82% yield).

MS(ESI):m/z 520[M+1] ⁺ 。

The seventh step: synthesis of Compound 1I

Compound 1H (0.12g, 0.23mmol) and sodium tert-butoxide (44mg, 0.46mmol) were dissolved in ethyl acetate (5 mL), and m-CPBA (0.2g, 0.92mmol) was added in portions under ice-bath and reacted at 0 ℃ for 1H. TLC showed the reaction was complete, the reaction was poured into saturated aqueous sodium thiosulfate (25 mL), extracted with ethyl acetate (15 mL × 3), the organic phases were combined, organic and washed with saturated sodium chloride (10 mL × 2), the organic phase was dried over anhydrous sodium sulfate, spun dry, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate =1:1 (vol.)) to give compound 1I (0.1 g, tan oil, 78% yield).

MS(ESI):m/z 552[M+1] ⁺ 。

The eighth step: synthesis of Compound 1K

Compound 1I (0.1g, 0.18mmol) and 1J (29mg, 0.18mmol) were added to toluene (3 mL), and sodium t-butoxide (35mg, 0.36mmol) was added in portions under ice-bath, followed by reaction for 1h under ice-bath. TLC showed the reaction was complete, the reaction was added to saturated aqueous sodium chloride (30 mL), the aqueous phase was extracted with ethyl acetate (15 mL × 3), the organic phases were combined, organic and washed with saturated sodium chloride (10 mL × 2), the organic phase was dried over anhydrous sodium sulfate, spun dry, and the residue was purified by prep-TLC (EA: meOH = 8:1) to give compound 1K (70 mg, yellow solid, 61% yield).

MS(ESI):m/z 631[M+1] ⁺ 。

The ninth step: synthesis of Compound I-1

Compound 1K (70mg, 2.4 mmol) was added to acetonitrile (2 mL), followed by 8% ethyl acetate hydrochloride (1 mL), and the reaction solution was reacted at room temperature for 1h. After TLC showed the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by slurrying with ethyl acetate to give Compound I-1 (50 mg, yellow solid, yield 75%).

MS(ESI):m/z 531[M+1] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ11.90(s,1H),10.13(d,J＝12Hz,1H),9.77–9.60(m,1H),8.55(d,J＝8Hz,1H),8.17-8.09(m,2H),7.78-7.72(m,3H),7.63-7.55(m,2H),5.69-5.45(m,1H),5.08-5.06(m,1H),4.79-4.66(m,2H),4.46(d,J＝16Hz,1H),3.81-3.69(m,3H),3.38-3.29(m,6H),2.70-2.53(m,2H),2.37-2.08(m,4H),1.61(d,J＝8Hz,3H).

Example 2: preparation of Compound I-2

The synthesis route is as follows:

the preparation method comprises the following steps:

the first step is as follows: synthesis of Compound 2C

Compound 2A (3.1g, 11.74mmol) was added to DCM (31 mL), compound 2B (2.49g, 11.74mmol) was added, the mixture was then brought to 0 ℃ and DIEA (3.05g, 23.66mmol, 2.0eq) was added dropwise, the reaction was allowed to warm to room temperature naturally for 1 hour, TLC showed that after the reaction was complete, spin-dried, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate =5/1 (volume ratio)) to give compound 2C (3.76 g of yellow solid, yield: 72.81%).

MS(ESI):m/z 440[M+1] ⁺ 。

The second step is that: synthesis of Compound 2E

Compound 2C (2g, 4.55mmol) and compound 2D (1.15g, 4.55mmol) were added to dioxane (20 mL), potassium carbonate (1.26g, 9.13mmol) was added, followed by Pd (dppf) ₂ Cl ₂ DCM (372mg, 0.45mmol) was added, the reaction solution was replaced with nitrogen three times, and the reaction solution was brought to 100 ℃ for reaction. TLC showed that after the reaction was completed, the reaction solution was added to a saturated aqueous solution of sodium chloride (100 mL) and the aqueous phase was extracted with ethyl acetate (50 mL. Times.3), the organic layers were combined and dried over anhydrous sodium sulfate, then the organic layer was spin-dried, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate =5/1 (volume ratio)) to give compound 2E (1.91 g, brown solid, yield: 79.03%)

MS(ESI):m/z 532[M+1] ⁺ 。

The third step: synthesis of Compound 2F

Compound 2E (600mg, 1.13mmol) was dissolved in DCM (6 mL), and m-CPBA (390mg, 2.259mmolq) was added thereto, followed by bringing the reaction to 0 ℃ for reaction. TLC showed the reaction was complete, saturated aqueous sodium thiosulfate (30 mL) was added, the aqueous phase was extracted with dichloromethane (15 mL × 3), the organic phases were combined and washed with saturated NaCl solution (15 mL × 3), the organic layer was dried with anhydrous sodium sulfate, dried by spin drying, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate =1/1 (volume ratio)) to give compound 2F (210 mg, pale white powder, yield: 33.01%).

MS(ESI):m/z 564[M+1] ⁺ 。

The fourth step: synthesis of Compound 2H

Compound 2F (210mg, 372.57mmol) and 2G (118.63mg, 745.15mmol) were dissolved together in toluene (2mL, 10V) at 0 ℃ and then sodium t-butoxide (35.84mg, 373mmol, 1eq) was added, and the reaction mixture was left to react at 0 ℃ for 5min. After TLC showed the reaction was completed, the reaction solution was added to a saturated aqueous solution of sodium chloride (20 mL), the aqueous phase was extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined and washed with a saturated NaCl solution (10 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate and spun dry, and the resulting residue was purified by pre-TLC (developer: EA/MeOH = 10/1) to obtain Compound 2H (53 mg, yellow solid, yield: 22.13%).

MS(ESI):m/z 645[M+1] ⁺ 。

The fifth step: synthesis of Compound I-2

Compound 2H (53mg, 82.46mmol, 1eq) was dissolved in MeCN (2 mL), 8% ethyl acetate hydrochloride solution (1 mL) was added, the reaction was allowed to warm to room temperature naturally and allowed to react for half an hour, TLC showed the completion of the reaction, the reaction was spin-dried, EA was added, slurried with EA, and filtered to give compound I-2 (27 mg, yellow solid, 60.34%).

MS(ESI):m/z 545[M+1] ⁺

¹ H NMR(400MHz,DMSO-d6)δ11.78(s,1H),10.13(d,J＝10.0Hz,1H),9.80(d,J＝9.6Hz,1H),8.61(d,J＝9.8Hz,1H),8.18(n,J＝7.7Hz,1H),8.10(n,J＝8.1Hz,1H),7.98–7.51(n,5H),5.60(d,J＝52.4Hz,1H),4.69(t,J＝11.2Hz,3H),4.19(s,2H),4.07(d,J＝13.8Hz,2H),3.85(s,4H),3.27(d,J＝12.3Hz,1H),2.69–2.53(n,1H),2.37–1.92(n,7H).

Example 3: preparation of Compound I-3

The synthetic route is as follows:

the preparation method comprises the following steps:

the first step is as follows: synthesis of Compound 3B

Compound 3A (2g, 12.3mmol) was dissolved in THF (30 mL), DMAP (0.15g, 1.23mmol) was added, boc2O (5.36g, 24.5mmol) was added dropwise with stirring at room temperature, stirring was carried out at 70 ℃ for 0.5 hour, boc2O (5.36g, 24.5mmol) was added dropwise, and then the reaction mixture was stirred at 70 ℃ for 1 hour. TLC showed the reaction was complete, the reaction was dried by spinning, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate =20 (volume ratio)) to give compound 3B (4.2 g, white solid, yield 94%).

1H NMR(400MHz,CDCl3)δ7.12(s,2H),1.51(s,18H).

The second step is that: synthesis of Compound 3C

Compound 3B (4.5g, 12.4mmol) was dissolved in THF (60 mL), LDA (2M, 21.7mL, 43.4mmol) was added at-60 ℃ and reacted at-60 ℃ for 0.5h. TLC showed the reaction was complete and the reaction was quenched by pouring saturated aqueous ammonium chloride (250 mL), the organic layer was separated, the aqueous phase was extracted with ethyl acetate (3 × 150 mL), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, spun dry, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate =10 (vol)) to give compound 3C (4 g, yellow solid, 89% yield).

1H NMR(400MHz,CDCl3)δ8.99(s,1H),8.27(s,1H),1.58(s,9H)1.02(s,9H)。

The third step: synthesis of Compound 3D

Compound 3C (4 g,11.0 mmol) was added to ethyl acetate (25 mL), and reacted at 35 ℃ for 48 hours with 8% ethyl acetate hydrochloride (25 mL) under ice bath. TLC showed the reaction was complete, spin dried, residue purified by trituration with MTBE, filtered to give a solid, and dried in vacuo to give compound 3D (2.6 g, white solid, 90% yield).

MS(ESI):m/z 263[M+1] ⁺ 。

The fourth step: synthesis of Compound 3F

Compound 3D (2.5g, 9.5mmol) was added to THF (30 mL), and 3E (2.7g, 14.3mmol) was added dropwise under ice-cooling, followed by reaction at room temperature for 1h. TLC showed the reaction was complete, spun dry, the residue purified by slurrying with petroleum ether, filtered to give a solid, and dried in vacuo to give compound 3F (4 g, white solid, 93% yield).

MS(ESI):m/z 450[M+1] ⁺ 。

The fifth step: synthesis of Compound 3G

Compound 3F (4.5g, 10mmol) was dissolved in MeOH (40 mL), and 7M NH was added dropwise under ice bath ₃ Was reacted at room temperature for 2 hours with a methanol solution (5 mL). TLC showed the reaction was complete, spin dried, the residue was purified by slurrying with MTBE,filtration afforded a solid, which was dried in vacuo to afford compound 3G (2.2G, white solid, 95% yield).

MS(ESI):m/z 232[M+1] ⁺ 。

And a sixth step: synthesis of Compound 3H

Compound 3G (1g, 4.3 mmol) was dissolved in MeOH (12 mL), added in portions with a mass fraction of 60% sodium hydrogen (0.69g, 17.2 mmol) under ice bath, and after the addition was completed, the reaction was carried out at room temperature for half an hour, TLC showed a large amount of starting material, and then heated to 70 ℃ for 12 hours. TLC showed the reaction was complete, methanol was spun off, the residue was quenched into ice water, pH was adjusted to 6 with 2M hydrochloric acid in ice bath, white solid precipitated, and the solid obtained by filtration was washed several times with ice methanol and then dried in vacuo to give compound 3H (0.9 g, white solid, 92% yield).

MS(ESI):m/z 228[M+1] ⁺ 。

The seventh step: synthesis of Compound 3I

Compound 3H (500mg, 2.20mmol) was added to POCl ₃ DIEA (568mg, 4.39mmol) was added dropwise to the mixture in an ice bath (6 mL), the mixture was replaced with nitrogen three times, and the reaction mixture was reacted at 110 ℃ for 2 hours. TLC showed the reaction was complete, and the POCl was spin-dried ₃ To the residue was added 30mL of ice water, the pH was adjusted to 7 with saturated aqueous sodium bicarbonate, and the aqueous phase was extracted with ethyl acetate (3X 15 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate, the organic phase was dried by spinning, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate =5:1 (vol.)) to give compound 3I (520 mg, pale yellow solid, yield 89%).

MS(ESI):m/z 264[M+1] ⁺ 。

Eighth step: synthesis of Compound 3K

Compound 3I (1.00g, 3.78mmol) was added to DCM (20 mL) followed by 3J (803mg, 3.78mmol), DIEA (977mg, 7.56mmol) was added dropwise at minus 40 ℃ and reacted for 0.5h. TLC showed the reaction was complete, water and ethyl acetate were added for extraction, washed with brine, the organic phase was dried over anhydrous sodium sulfate and the spin-dried residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate =3:1 (vol.)) to give compound 3K (1 g, light yellow oil, 60% yield).

MS(ESI):m/z 440[M+1] ⁺ 。

The ninth step: synthesis of Compound 3M

Compound 3K (600mg, 1.36mmol) was added to tetrahydrofuran (10 mL), followed by 3L (433mg, 2.73mmol), and sodium tert-butoxide (262mg, 2.73mmol) was added portionwise at-40 ℃ and reacted for 0.5h. TLC showed the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol =20 (volume ratio)) to obtain compound 3M (430 mg, light yellow oil, yield 56%).

MS(ESI):m/z 563[M+1] ⁺ 。

The tenth step: synthesis of Compound 3O

Compound 3M (0.25g, 0.44mmol) and 3M (0.22g, 0.44mmol) were dissolved in dioxane (6 mL) and water (2 mL), pd (dppf) was added ₂ Cl ₂ DCM (36mg, 0.04mmol) and cesium carbonate (0.29g, 0.89mmol) were purged with nitrogen three times, and then the reaction liquid was reacted at 102 ℃ for 18 hours. TLC showed the reaction was complete, water was added and extracted with ethyl acetate, washed with brine, the organic phase was dried over anhydrous sodium sulfate, spun dry and the residue was purified by prep-TLC (ethyl acetate/methanol/ammonia =20, 0.001 v/v) to give compound 3O (50 mg, brown oil, 13% yield).

MS(ESI):m/z 895[M+1] ⁺ 。

The eleventh step: synthesis of Compound I-3

Compound 3O (50mg, 0.06mmol) was added to DMF (1.0 mL), cesium fluoride (42mg, 0.28mmol) was added, and the reaction solution was allowed to warm and react for 1h. Water was added and extracted with ethyl acetate, washed with brine, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to give a brown oil. The brown oil was dissolved in acetonitrile (2 mL), and then 8% ethyl acetate hydrochloride (1 mL) was added under ice-cooling, and the reaction solution was reacted at room temperature for 1h. TLC showed the reaction was complete, the reaction was concentrated under reduced pressure, and the residue was purified by prep-HPLC to give Compound I-3 (10 mg, pale yellow solid, 30% yield).

MS(ESI):m/z 581[M+1] ⁺ 。

1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.21(s,1H),7.87(d,J＝7.8Hz,1H),7.54(d,J＝6.4Hz,1H),7.44(t,J＝8.0Hz,1H),7.33(d,J＝2.5Hz,1H),7.12(d,J＝2.4Hz,1H),6.11(s,1H),5.35-5.20(m,1H),4.15-4.01(m,2H),3.98-3.85(m,2H),3.82(s,1H),3.49-3.45(m,2H),3.27-3.19(m,2H),3.07(t,J＝9.8Hz,2H),3.01(s,1H),2.83-8-2.76(m,1H),2.1-4-2.08(m,1H),2.05-1.94(m,3H),1.87-1.70(m,4H),1.65-1.55(s,2H).

Example 4: preparation of Compound I-4

The synthetic route is as follows:

the preparation method comprises the following steps:

the first step is as follows: synthesis of Compound 4B

Compound 4A (25g, 193mmol) was dissolved in concentrated sulfuric acid (50 mL), and a mixed solution of concentrated sulfuric acid (45.4 g, 463.17mmol) and concentrated nitric acid (24.3 g, 386mmol) was added while cooling on ice, followed by reaction for 1h while cooling on ice, warming to room temperature, and reaction for 1.5h. TLC showed the reaction was complete, the reaction was slowly added to ice water (500 mL) and the pH was adjusted to 7-8 with 15% aqueous naoh, the phases were extracted with ethyl acetate (3 × 150 mL), the organic phases were combined, the organic phase was dried with anhydrous sodium sulfate, spun dry, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate =3:1 (vol.%)) to give compound 4B (6.0 g, yellow oil, 17% yield).

¹ H-NMR(400MHz,CDCl3)δ10.53(s,1H),8.14(d,J＝5.5Hz，1H)，7.88(d,J＝5.5Hz，1H).

The second step is that: synthesis of Compound 4C

Compound 4B (6.0g, 34.38mmol) was dissolved in CH ₃ CN (53 mL) and MeOH (7 mL) in a mixed solvent, and a solution of trimethylsilylated diazomethane in n-hexane (2M, 34.4mL,68.8 mmol) was added dropwise under ice-cooling, followed by reaction at 0 ℃ for 0.5h. TLC showed the reaction was complete, and saturated aqueous ammonium chloride (250 mL) was poured) The reaction was quenched, the aqueous phase was extracted with ethyl acetate (3 × 150 mL), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, spun dry, and the residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate =5:1 (vol.%) gave compound 4C (3.2 g, yellow oil, 49% yield).

MS(ESI):m/z 189[M+1] ⁺ 。

The third step: synthesis of Compound 4D

Compound 4C (3.2g, 16.97mmol) was added to AcOH (32 mL), and iron powder (4.74g, 84.85mmol) was added thereto with stirring at room temperature, followed by reaction at 40 ℃ for 1 hour. TLC showed the reaction was complete, spin dried, the residue was diluted with ethyl acetate (150 mL), added to saturated aqueous sodium bicarbonate (500 mL), adjusted to pH 7-8, the organic phase was extracted with ethyl acetate again (3 × 150 mL), the organic phases were combined and the organic phase was dried over anhydrous sodium sulfate, spin dried, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate =3:1 (vol.%) to give compound 4D (2.0 g, yellow oil, 74% yield).

MS(ESI):m/z 159[M+1] ⁺ 。

The fourth step: synthesis of Compound 4E

Compound 4D (2.0 g, 12.53mmol) was added to MeCN (20 mL), and NIS (4.23g, 18.80mmol) and p-toluenesulfonic acid monohydrate (240mg, 1.25mmol) were added in portions under ice bath, followed by heating to 70 ℃ for 16h. TLC showed the reaction was complete, spin dried, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate =3:1 (vol.)) to give compound 4E (3.2 g, yellow solid, 89% yield).

MS(ESI):m/z 285[M+1] ⁺ 。

The fifth step: synthesis of Compound 4F

Compound 4E (3.0g, 10.55mmol) was added to MeOH (30 mL), TEA (2.13g, 21.1mmol) was added dropwise, and Pd (dppf) was added ₂ Cl ₂ DCM (396mg, 0.53mmol) was reacted under an atmosphere of carbon monoxide (15 psi) at 70 ℃ for 16h. TLC showed the reaction was complete, the reaction was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate =3:1 (vol.)) to give compound 4F (1.8 g,yellow solid, 78% yield).

MS(ESI):m/z 217[M+1] ⁺ 。

And a sixth step: synthesis of Compound 4G

Compound 4F (1.8g, 8.31mmol) was dissolved in THF (20 mL), and trichloroacetyl isocyanate (2.35g, 12.46mmol) was added dropwise under ice-cooling, followed by reaction at room temperature for 0.5h. After TLC shows that the reaction is finished, the reaction liquid is dried by spinning, and is pulped by PE, the obtained white solid is added into MeOH (15 mL), 40% by mass of methylamine alcohol solution (10 mL) is added dropwise in an ice bath, the reaction is carried out for 1h at the temperature of 0 ℃, a large amount of white solid is separated out, after TLC shows that the reaction liquid is finished, the obtained solid is pulped by EA. The solid was filtered and dried in vacuo to give compound 4G (1.5G, white solid, 80% yield).

MS(ESI):m/z 228[M+1] ⁺ 。

The seventh step: synthesis of Compound 4H

The compound 4G (1.5g, 6.6 mmol) was added to phosphorus oxychloride (20 mL), DIEA (1.7g, 13.2mmol) was added dropwise in ice bath, and the reaction was carried out at 110 ℃ for 3 hours. TLC showed the reaction was complete, spin dried, the residue was diluted with ethyl acetate (50 mL), added to saturated aqueous sodium bicarbonate (200 mL), adjusted to pH 7-8, after separation of the organic phase, the aqueous phase was extracted with ethyl acetate (3 × 50 mL), the organic phases were combined and dried over anhydrous sodium sulfate, spin dried, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate =5:1 (vol.)) to give compound 4H (920 mg, yellow solid, 52% yield).

MS(ESI):m/z 264[M+1] ⁺ 。

Eighth step: synthesis of Compound 4J

Compound 4H (1g, 3.78mmol, WO2020146613) was dissolved in DCM (15 mL), 4I (802mg, 3.78mmol) was added, DIEA (977 mg, 7.56mmol) was added dropwise under ice bath, and the reaction mixture was allowed to warm up for 0.5H. TLC showed the reaction was complete, the reaction was added to 50mL of saturated aqueous sodium chloride solution, the organic phase was separated, water was extracted with additional dichloromethane (3 × 15 mL), the organic phases were combined and the organic phase was dried over anhydrous sodium sulfate, spun dry, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate =3:1 (vol.%)) to give compound 4J (1.2 g, white solid, 72% yield).

MS(ESI):m/z 440[M+1]+。

The ninth step: synthesis of Compound 4L

Compound 4J (400mg, 0.91mmol) was dissolved in THF (6 mL), 4K (144.62mg, 0.91mmol) was added, sodium tert-butoxide (174mg, 1.82mmol) was added in portions at 0 deg.C, and the reaction was warmed to room temperature for 30mins. TLC showed the reaction was complete and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol =20 (vol.)) to give compound 4L (320 mg, light yellow solid, 62% yield).

MS(ESI):m/z 563[M+1] ⁺ 。

The tenth step: synthesis of Compound 4N

Compound 4L (0.25g, 0.44mmol) and 4M (0.22g, 0.44mmol) were dissolved in dioxane (6 mL) and water (2 mL), pd (dppf) was added ₂ Cl ₂ DCM (36mg, 0.04mmol) and cesium carbonate (0.29g, 0.89mmol) were purged with nitrogen three times, and then the reaction liquid was reacted at 102 ℃ for 18 hours. TLC showed the reaction was complete, water was added and extracted with ethyl acetate, washed with brine, the organic phase was dried over anhydrous sodium sulfate, spun dry and the residue was purified by prep-TLC (ethyl acetate/methanol/ammonia =20, 0.001 v/v) to give compound 4N (50 mg, brown oil, 13% yield).

MS(ESI):m/z 851[M+1] ⁺ 。

The eleventh step: synthesis of Compound I-4

Compound 4N (51mg, 0.06mmol) was added to DMF (1.0 mL), cesium fluoride (42mg, 0.28mmol) was added, and the reaction solution was allowed to warm and react for 1h. Water was added and extracted with ethyl acetate, washed with brine, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to give a brown oil. The brown oil was dissolved in acetonitrile (2 mL), and then 8% ethyl acetate hydrochloride (1 mL) was added under ice-cooling, and the reaction solution was reacted at room temperature for 1h. TLC showed the reaction was complete, the reaction was concentrated under reduced pressure, and the residue was purified by prep-HPLC to give Compound I-4 (13 mg, pale yellow solid, yield 33%).

MS(ESI):m/z 595[M+1] ⁺ 。

¹ H-NMR(400MHz,DMSO-d6)δ11.22(s,1H),10.12(s,1H),9.47(d,J＝8.9Hz,1H),9.23(s,1H),9.02(s,1H),7.86(dd,J＝7.6,1.9Hz,1H),7.46–7.36(m,2H),9.29(d,J＝4.0Hz,1H),7.04–7.01(m,1H),5.57(d,J＝52.2Hz,1H),4.76–4.53(m,3H),4.50-4.45(m,1H),4.23-4.21(m,2H),3.93–3.83(m,3H),3.82(s,3H),3.7-3.75(m,1H),3.49(s,1H),3.35-3.24(m,2H),2.58-2.53(m,2H),2.34-2.28(m,1H),2.26–2.12(m,2H),2.21-1.85(m,5H).

Example 5: preparation of Compound I-5

The synthesis route is as follows:

the first step is as follows: synthesis of Compound 5A

Compound 2C (2g, 4.55mmol, 1.0eq) and compound 3N (2.2g, 4.55mmol, 1.0eq) were added to dioxane (20mL, 10V), potassium carbonate (1.26g, 9.13mmol, 2.0eq) was further added, and Pd (dppf) was then added ₂ Cl ₂ DCM (372mg, 455.88mmol, 0.1eq) was added, the reaction mixture was then replaced with nitrogen three times, and the reaction mixture was brought to 100 ℃ for reaction. TLC showed that after the completion of the reaction, extraction was performed with water and ethyl acetate, the organic layer was spin-dried, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate =5/1 (volume ratio)) to obtain Compound 5A (1.88 g, brown solid, yield: 49.5%)

MS(ESI):m/z 772[M+1] ⁺ 。

The second step is that: synthesis of Compound 5B

Compound 5A (872mg, 1.13mmol) was dissolved in DCM (6 mL), and m-CPBA (390mg, 2.26mmol) was added, followed by bringing the reaction to 0 ℃. TLC showed the reaction was complete, quenched by addition of saturated aqueous sodium thiosulfate (20 mL), extracted with DCM (3 × 10 mL), and after combining the organic phases, the organic phase was washed with saturated NaCl solution (15 mL), the organic layer was separated, dried over anhydrous sodium sulfate, spun dried, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate =1/1 (volume ratio)) to give compound 5B (330 mg, pale white powder, yield: 36.3%).

MS(ESI):m/z 804[M+1] ⁺ 。

The third step: synthesis of Compound 5C

Compound 5B (300mg, 0.37mmol) and 2G (118.63mg, 0.74mmol) were added to toluene (2 mL), cooled to 0 ℃ in an ice bath, followed by addition of sodium t-butoxide (35.84mg, 0.37mmol) and then reacted at 0 ℃ for 5min. TLC showed the reaction was complete, extracted with water and ethyl acetate, the organic phase was spun dry and the resulting residue was purified by prep-HPLC (developing solvent: EA/MeOH =10/1, vol) to give compound 5C (62 mg, yellow solid, yield: 19%).

MS(ESI):m/z 883[M+1] ⁺ 。

The fourth step: synthesis of Compound I-5

Compound 5C (53mg, 0.06mmol) was added to DMF (1.0 mL), cesium fluoride (42mg, 0.28mmol) was added, and the reaction solution was allowed to warm and react for 1h. Water was added and extracted with ethyl acetate, washed with brine, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to give a brown oil. The brown oil was dissolved in acetonitrile (2 mL), and then 8% ethyl acetate hydrochloride (1 mL) was added under ice-cooling, and the reaction solution was reacted at room temperature for 1h. TLC showed the completion of the reaction, and the reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC to give Compound I-5 (27 mg, yellow solid, 77.2%).

MS(ESI):m/z 583[M+1] ⁺

¹ H-NMR(400MHz,DMSO)δ9.41(d,J＝10.1Hz,1H),9.14(s,1H),8.27(d,J＝9.4Hz,1H),7.93(d,J＝6.9Hz,1H),7.46(n,2H),7.39(d,J＝2.4Hz,1H),7.12(d,J＝2.5Hz,1H),5.58(d,J＝53.0Hz,1H),4.65–4.55(m,2H),4.52(d,J＝13.0Hz,1H),4.38(d,J＝9.1Hz,1H),4.20(s,2H),3.90(d,J＝14.0Hz,1H),3.80(d,J＝13.8Hz,3H),3.65(s,1H),3.33(s,2H),2.31(d,J＝15.4Hz,2H),2.17(n,2H),2.01(d,J＝26.4Hz,5H).

Example 6: preparation of Compound I-6

The synthetic route is as follows:

the first step is as follows: synthesis of Compound 6B

Compound 6A (600mg, 2.03mmol) was dissolved in DMF (6 mL), compound 2B (473mg, 2.23mmol) was added, DIEA (557mg, 4.06mmol) was added dropwise while cooling on ice, and the mixture was reacted at 0 ℃ for 30mins. TLC showed that after the reaction was completed, the reaction solution was diluted with 30mL of water, the aqueous phase was extracted with ethyl acetate (3X 15 mL), the organic phases were combined, the organic phase was washed with saturated sodium chloride (3X 15 mL), then the organic phase was dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: PE: EA =3:1 (volume ratio)) to obtain compound 6B (920 mg, pale yellow solid, yield 95%).

MS(ESI):m/z 471[M+1] ⁺ 。

The second step is that: synthesis of Compound 6C

Compound 6B (300mg, 0.64mmol) was dissolved in DMF (3 ml), 2G (101mg, 0.64mmol) was added, sodium tert-butoxide (122mg, 1.27mmol) was added in portions on ice and reacted at 0 ℃ for 20mins. TLC showed the reaction was completed, and the reaction solution was diluted by adding 30mL of water, the aqueous phase was extracted with ethyl acetate (3 × 15 mL), the organic phases were combined, the organic phase was washed with saturated sodium chloride (3 × 15 mL), the organic phase was dried with anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: EA: MEOH =20 (volume ratio)) to obtain compound 6C (330 mg, pale yellow solid, yield 87%).

MS(ESI):m/z 594[M+1] ⁺ 。

The third step: synthesis of Compound 6D

Compound 6C (150mg, 0.25mmol) and compound 3N (120mg, 0.25mmol) were dissolved in dioxane (4 mL) and water (1 mL), pd (dppf) was added ₂ Cl ₂ DCM (20mg, 0.025mmol) and potassium carbonate (102mg, 0.76mmol) were purged with nitrogen three times, and then the reaction liquid was reacted at 90 ℃ for 16 hours. TLC showed the reaction was complete, 30mL of water was added to dilute the reaction, and the aqueous phase was diluted with ethyl acetateThe esters (3 × 15 mL) were extracted, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, spun dry, and the residue was purified by prep-TLC (ethyl acetate/methanol/ammonia =20, volume ratio, 1) to give compound 6D (40 mg, brown oil, 18% yield).

MS(ESI):m/z 882[M+1] ⁺ 。

The fourth step: synthesis of Compound 6E

Compound 6D (40mg, 0.05mmol) was dissolved in DMF (2 mL), csF (34mg, 0.23mmol) was added, and the reaction mixture was reacted at room temperature for 2 hours. TLC showed the reaction was complete, the reaction was diluted with 30mL water, the aqueous phase was extracted with ethyl acetate (3 × 15 mL), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate and spun dry to give compound 6E (30 mg, brown oil, 91% yield) which was used in the next step without further purification.

MS(ESI):m/z 726[M+1] ⁺ 。

The fifth step: synthesis of Compound I-6

Compound 6E (30mg, 0.04mmol) was added to acetonitrile (1 mL), followed by 8% ethyl acetate hydrochloride (0.5 mL), and the reaction solution was reacted at room temperature for 1h. TLC showed the reaction was complete, the reaction was concentrated under reduced pressure, and the residue was purified by prep-HPLC to give Compound I-6 (10 mg, pale yellow solid, 41% yield).

MS(ESI):m/z 582[M+1] ⁺ 。

1H NMR(400MHz,DMSO-d6)δ8.27(s,1H),7.91-7.79(m,2H),7.72-7.65(m,1H),7.56-7.42(m,3H),7.25-7.18(m,1H),5.30-5.15(m,1H),4.29(d,J＝12.2Hz,2H),4.15(s,1H),4.10(d,J＝10.3Hz,1H),4.01(d,J＝10.2Hz,1H),3.64(s,1H),3.55-3.50(m,2H),3.43-3.38(m,1H),3.10-3.04(m,3H),2.87-2.76(m,1H),2.19-2.10(m,1H),2.09-1.86(m,3H),1.87-1.74(m,3H),1.72-1.52(m,3H).

Effect example 1: determination of Phospho-ERK inhibitory Activity in tumor cells

Experimental materials:

AGS cells were purchased from tokyo kobai; 1640 media from Biological Industries; fetal bovine serum was purchased from Biosera; advanced Phospho-ERK1/2 (THR 202/TYR 204) KIT was purchased from Cisbio.

The control compound BI-2852 (cas: 2375482-51-0) was purchased from Haoyuan medicine, inc., shanghai.

The experimental method comprises the following steps:

AGS cells are planted in a transparent 96-hole cell culture plate, each hole contains 10000 AGS cells in 80 mu L cell suspension, the cell plate is placed in a carbon dioxide incubator and incubated at 37 ℃ overnight;

after overnight cell culture, the cell culture medium was removed and serum-starved overnight with the addition of serum-free medium.

The test compound was diluted to 2mM with 100% DMSO as a first concentration, and then diluted 5-fold with a pipette to the 8 th concentration, i.e., from 2mM to 0.026. Mu.M. Adding 2 mu L of compound into 78 mu L of cell starvation culture medium, mixing uniformly, adding 20 mu L of compound solution into a hole of a corresponding cell plate, putting the cell plate back into a carbon dioxide incubator, and continuing incubation for 1 hour, wherein the concentration of the compound is 10 mu M-0.128nM, and the concentration of DMSO is 0.5%;

after the incubation is finished, removing cell supernatant, adding 50 mu L of cell lysate into each hole, and incubating for 30 minutes at room temperature by shaking;

diluting Eu-labeled ERK1/2 phosphorylation antibody and d 2-labeled ERK1/2 phosphorylation antibody by 20 times by using detection solution; taking 16 mu L of cell lysate supernatant, putting each well into a new 384 white microplate, adding 2 mu L of Eu-labeled ERK1/2 phosphorylated antibody diluent and 2 mu L d-labeled ERK1/2 phosphorylated antibody diluent, and incubating for 4 hours at normal temperature;

after the incubation was completed, the HTRF excitation was read at 320nm, emission at 615nm,665nm using a multi-label analyzer.

And (3) data analysis:

the original data were converted to inhibition using the equation (Sample-Min)/(Max-Min) 100%, and the IC50 values were obtained by curve fitting with four parameters (log (inhibitor) vs. response — Variable slope mode in GraphPad Prism). Table 1 provides the inhibition of p-ERK by the compounds of the present invention. Wherein A represents the activity data less than 1uM, B represents the activity data between 1uM and 10uM, and C represents the activity data more than 10uM, and the specific experimental results are shown in Table 1.

Table 1: IC50 data of the compounds of formula I of the present invention on phosphorylated ERK (Phospho-ERK) in AGS cell

Compound numbering	IC50(nM)
		Control Compound BI-2852	B
I-1	A
		I-2	A
I-3	A
		I-4	50nM
I-5	A
		I-6	A

And (4) conclusion: as can be seen from Table 1, the compound has obvious inhibition effect on human gastric adenocarcinoma cell phosphorylation highly expressed by KRAS G12D, and can be used as a medicament of KRAS G12D inhibitor.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

Although embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are exemplary and not to be construed as limiting the present invention, and that those skilled in the art may make variations, modifications, substitutions and alterations within the scope of the present invention without departing from the spirit and scope of the present invention. It should be noted that the above embodiments belong to the same inventive concept, and the description of each embodiment has a different emphasis, and reference may be made to the description in other embodiments where the description in individual embodiments is not detailed. The invention is not to be considered as limited to the particular embodiments shown, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (8)

1. A compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, metabolite, prodrug thereof:

wherein the content of the first and second substances,

x is selected from N or CR ₅ ；

Z is selected from N or CR ₅ ；

Y is selected from a single bond, C ₁ -C ₃ Alkyl, oxygen, sulfur, -CO-or NR ₅ (ii) a Each of said alkyl groups being optionally substituted with at least 1R ₅ Substitution;

Y ₁ selected from single bond, C ₁ -C ₃ Alkyl, oxygen, sulfur, -CO-or NR, each of said alkyl being optionally substituted with at least 1R ₅ Substitution;

l is selected from a single bond or C ₁ -C ₅ Alkyl, each of said alkyl being optionally substituted with at least 1R ₇ Substitution;

n is selected from 0, 1,2, 3 or 4;

the R is ₁ Selected from H, halogen, cyano, hydroxy, -CO ₂ R ₅ 、-CON(R ₅ ) ₂ 、C ₁ -C ₃ Alkyl radical, C ₅ -C ₆ Heteroaryl, and wherein said alkyl and heteroaryl are each optionally substituted with at least 1R ₆ Substitution;

the R is ₂ Is selected from C ₁ -C ₁₂ Alkyl radical, C ₁ -C ₁₂ Heteroalkyl group, C ₃ -C ₈ Cycloalkyl, C ₃ -C ₈ Heterocycloalkyl, C ₆ -C ₁₂ Bridged heterocycloalkyl radical, C ₆ -C ₁₂ Spiroheterocycloalkyl or C ₆ -C ₁₂ And heterocycloalkyl, and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, bridged heterocycloalkyl, spiroheterocycloalkyl, and spiroheterocycloalkyl are each optionally substituted with at least 1R ₇ Substitution;

the R is ₃ Selected from aryl or heteroaryl, wherein said aryl and heterocyclyl are each optionally substituted with at least 1R ₇ Substitution;

the R is ₄ Selected from H, halogen, C ₁ -C ₃ Alkyl radical, C ₃ -C ₈ Cycloalkyl radical, C ₁ -C ₃ Alkoxy or C ₁ -C ₃ A haloalkoxy group;

the R is ₅ Independently selected from hydrogen, OH, CN, NH ₂ Halogen, C ₁ -C ₃ Alkyl radical, C ₃ -C ₈ Cycloalkyl radical, C ₁ -C ₃ Alkoxy or C ₁ -C ₃ A haloalkoxy group;

the R is ₆ Independently selected from hydrogen, OH, CN, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Cycloalkyl or C ₁ -C ₆ An alkoxy group;

said R is ₇ Independently selected from hydrogen, halogen, OH, CN, NH ₂ 、C ₆ -C ₁₀ Aryl radical, C ₅ -C ₁₀ Heteroaryl group, C ₁ -C ₈ Alkyl radical, C ₁ -C ₈ Heteroalkyl group, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, C ₃ -C ₈ Cycloalkyl radical, C ₃ -C ₈ Heterocycloalkyl, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ Alkynyl, -S-C ₁ -C ₈ Alkyl, -O-C ₁ -C ₈ Alkyl, -S-C ₁ -C ₃ Haloalkoxy, -O-C ₁ -C ₃ Haloalkoxy, -N (R) ₅ ) ₂ or-CH ₂ C(＝O)N(R ₅ ) ₂ And wherein said aryl, heteroaryl, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl are each optionally substituted with at least 1R ₈ Substitution;

the R is ₈ Independently selected from hydrogen, OH, CN, NH ₂ Halogen, C ₁ -C ₃ Alkyl radical, C ₃ -C ₈ Cycloalkyl radical, C ₁ -C ₃ Alkoxy or C ₁ -C ₃ A haloalkoxy group.

2. The compound, pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, metabolite, prodrug of claim 1 wherein the compound of formula I is selected from the group consisting of

Wherein R is ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、L、Y ₁ And Y is as defined in claim 1, n is 0, 1,2, 3 or 4.

3. The following compounds, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, solvates, metabolites, prodrugs thereof,

4. the following compounds, or pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, solvates, metabolites, prodrugs thereof,

5. a pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, metabolite, prodrug thereof, and at least one pharmaceutically acceptable excipient.

6. Use of a compound of any one of claims 1-4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, metabolite, prodrug, or pharmaceutical composition of claim 5 thereof, for the manufacture of a medicament for the treatment of a disease caused by a KRAS G12D mutation.

7. Use of a compound of any one of claims 1-4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, metabolite, prodrug, or pharmaceutical composition of claim 5 thereof, in the manufacture of a medicament for a KRAS G12D inhibitor.

8. Use of a compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, metabolite, prodrug, or pharmaceutical composition of claim 5 thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of cancer.