WO2022105921A1

WO2022105921A1 - Pyrimido-heterocyclic compound, preparation method therefor, and use thereof

Info

Publication number: WO2022105921A1
Application number: PCT/CN2021/132190
Authority: WO
Inventors: 万惠新; 王亚周; 马金贵; 王亚辉; 查传涛
Original assignee: 上海凌达生物医药有限公司
Priority date: 2020-11-21
Filing date: 2021-11-22
Publication date: 2022-05-27
Also published as: CN114524810B; CN114524810A

Abstract

The present invention relates to a class of pyrimido-heterocyclic compounds, a preparation method therefor, and a use thereof. The compound is specifically a pyrimido-fused ring compound represented by general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, a tautomer, a twisted isomer, a solvate, a polymorph, or a prodrug thereof, a preparation method therefor, and a pharmaceutical use thereof. The compound can be used as an SOS1 inhibitor in the preparation of a tumor treatment drug.

Description

A class of pyrimido-heterocyclic compounds, preparation method and use

technical field

The invention belongs to the field of medicinal chemistry, and in particular relates to a class of pyrimido-heterocyclic compounds, which have good SOS1 inhibitory activity and can be used to prepare therapeutic and preventive medicines for diseases related to Ras activity or expression or mutation.

Background technique

Ras proteins are key regulators in normal cell growth and malignant transformation, including cell proliferation, survival and invasion, tumor angiogenesis and metastasis. In most human tumors, Ras proteins are abnormally activated due to mutations in the ras gene itself or in upstream or downstream components of the Ras pathway, or other alterations in Ras signaling. Such mutations reduce the ability of RAS family GTPases to hydrolyze GTP, allowing this molecular switch to remain in the active GTP-bound form, which drives unexamined oncogenic downstream signaling. One strategy to reduce levels of active RAS is to target guanine nucleotide exchange factors (GEFs), which allow RAS to cycle from an inactive GDP-bound state to an active GTP-bound form. By preventing the formation of the KRAS-SOS1 complex, SOS1 inhibitors block reloading of KRAS with GTP, resulting in antiproliferative activity. Inhibition of SOS1 may represent a viable approach to targeting RAS-driven tumors.

Ras-driven cancers remain the most clinically intractable class of diseases, for which new therapeutic and preventive strategies are urgently needed. The discovery of drugs that selectively target Ras in academia and industry around the world has been going on for many years, but so far, no drugs have been approved for marketing. In the past two years, targeted drugs driven by Ras have entered the clinical trial stage one after another, and have shown good preliminary efficacy, and the results are encouraging.

Therefore, there is an urgent need for more therapeutic drugs with unique mechanisms, high efficiency and low toxicity to enter the clinic for Ras-driven tumors. The discovery and search for Ras-targeted drugs with high efficiency, low toxicity and novel structure is still a hot field in the industry.

SUMMARY OF THE INVENTION

One of the technical problems to be solved by the present invention is to provide a new type of SOS1 inhibitor for preparing a tumor therapeutic drug.

The solution to the above technical problems is as follows:

In the first aspect of the present invention, there is provided a pyrimido-heterocyclic compound having the general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof , tautomer, torsion isomer, solvate, polymorph or prodrug,

where:

R ¹ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₂ cycloalkyl, C ₄ - C ₁₂ cycloalkenyl, 3-12-membered heterocycloalkyl, 5-12-membered aryl or 5-12-membered heteroaryl, carbocyclic or heteroatom-containing spiro/bridged/fused ring, wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₂ cycloalkyl, C ₄ -C ₁₂ cycloalkenyl, 3-12 membered heterocycloalkane base, 5-12-membered aryl or 5-12-membered heteroaryl, carbocyclic or heteroatom-containing spiro/bridged/fused ring, which may be optionally substituted by 1-3 R ⁿ ; or two of the above Each R ⁿ can form a 3-12-membered saturated or partially unsaturated, or aromatic ring system through a carbon chain or a heteroatom; the R ^{n is} selected from hydrogen, deuterium, halogen, cyano, nitro, amide, sulfone Amide, hydroxyl, amino, ureido, phosphoryl, alkylphosphooxy, alkylsilyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, haloalkyl, haloalkoxy, C ₁ - C ₆ monoalkylamino, C ₁ -C ₆ dialkylamino, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl, C ₁ -C ₆ alkyl-S-, C ₁ - C ₆ alkyl-SO-, C ₁ -C ₆ alkyl-SO _2- , etc.;

R ^2a and R ^2b are each independently selected from hydrogen, deuterium, halogen, C ₁ -C ₆ alkyl, 3-8 membered cycloalkyl or heterocycloalkyl; and R ^2a and R ^2b or R ^2a and Ar The substituent R ^m can form a 3-6 membered saturated or partially unsaturated or unsaturated ring system through a carbon chain or a heteroatom;

R ³ is H, deuterium, halogen, hydroxyl, amino, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylamino, 3-8 membered cycloalkyl or heterocycloalkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, 5-10 membered aromatic ring or aromatic heterocyclyl;

M is independently selected from N or CR ⁴ , and R ⁴ is selected from hydrogen, deuterium, halogen, cyano, C ₁ -C ₆ alkyl, 3-8 membered cycloalkyl or heterocycloalkyl;

Ar ¹ and Ar ² are independently selected from 5-12-membered 5-12-membered monocyclic or bicyclic aryl or heteroaryl groups, and the above aryl or heteroaryl groups may be composed of one or more (eg 1, 2, 3, 4, 5) is substituted with a group R ^m selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, hydroxyl, amino, Urea group, phosphoryl group, alkylphosphoryloxy group, alkylsilyl group, C ₁ -C ₁₀ alkyl group, C ₁ -C ₁₀ alkoxy group, C ₁ -C ₁₀ alkoxy alkyl group, C ₁ -C ₁₀ Haloalkyl, C ₁ -C ₁₀ haloalkoxy, C1-C ₁₀ haloalkoxyalkyl, C ₁ -C ₁₀ monoalkylamino, C ₁ -C ₁₀ dialkylamino, C ₁ -C ₁₀ monoalkyl Aminoalkyl, C ₁ -C ₁₀ dialkylaminoalkyl, C ₁ -C ₁₀ alkenyl, C ₁ -C ₁₀ alkynyl, 3-12-membered cycloalkyl or heterocycloalkyl, 3-12-membered ring Alkyl or heterocycloalkylalkyl, C ₁ -C ₁₀ alkyl-S-, C ₁ -C ₁₀ alkyl-SO-, C ₁ -C ₁₀ alkyl-SO ₂ -, substituted or unsubstituted 5 -12-membered aryl or heteroaryl, etc., or the above two R ^m can form a 3-12-membered saturated or partially unsaturated, or aromatic ring system through carbon chains or heteroatoms;

One or more (such as 1, 2, 3, 4, 5) hydrogen atoms on any of the above-mentioned groups may be substituted by a substituent selected from the group consisting of, but not limited to, deuterium, halogen, hydroxyl, amino, C ₁ -C ₃ monoalkylamino, C ₁ -C ₃ dialkylamino, C ₁ -C ₃ alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl Cycloalkylalkyl; wherein, the heteroaryl group contains 1-3 heteroatoms selected from the following group: N, O, P or S, and the heterocycloalkyl group contains 1-3 heteroatoms selected from the following group: Group of heteroatoms: N, O, P or S, the ring system includes spiro, bridged, condensed, fused and other saturated or partially unsaturated ring systems.

In some preferred embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion, or enantiomer thereof Isomers, solvates, polymorphs or prodrugs, preferably compounds represented by the general formula (II),

wherein ^R3 is preferably selected from H, Me, cyclopropyl, chlorine; M is preferably selected from N or CH or CF or C-CN or C-Me; the scope of other groups is as defined above.

In some preferred embodiments, when R ^2a and R ^2b are not the same, the carbon atom to which the R ^2a and R ^2b are commonly attached is in the R configuration.

In some preferred embodiments, the carbon atom to which the R ^2a and R ^2b are commonly attached is an R-configuration carbon atom.

In some preferred embodiments, R ^2a and R ^2b are each independently hydrogen, C ₁ -C ₆ alkyl, preferably hydrogen, methyl.

In some preferred embodiments, R ³ is C ₁ -C ₃ alkyl, preferably methyl.

In some preferred embodiments, M is C-H.

In some preferred embodiments, R ¹ is selected from C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -C ₄ -C ₁₂ cycloalkenyl, 3-12 membered heterocycloalkyl, 5- 12-membered aryl or 5-12 membered heteroaryl, which may be optionally substituted with 1-3 Rn as described in the first aspect of the present invention.

In some preferred embodiments, R ¹ is selected from C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, which may be optionally substituted with 1-3 Rn , the Rn is as described in the first aspect of the present invention.

In some preferred embodiments, R1 is selected from ^C1 _- _C6 alkyl, C3 _- _C6 cycloalkyl, 5-8 membered heterocycloalkyl, -(C1-C6 alkylene) _-C3 -C6cycloalkyl, -(C1- _C6alkylene )-5-8 membered heterocycloalkyl, which may be optionally substituted by 1-3 Rn, wherein Rn is halogen, C1-C3alkyl .

In some preferred embodiments, R ¹ is selected from 5-6 membered heterocycloalkyl, -(C1-C3 alkylene)-5-6 membered heterocycloalkyl.

In some preferred embodiments, the heterocycloalkyl group is a C5-C6 heterocycloalkyl group comprising 1-3 (eg, 1, 2, 3) heteroatoms selected from O, S, N.

In some preferred embodiments, the heteroatom or carbon atom can be further oxidized, eg -S- can be oxidized to -SO- or _-SO2- , -C- can be oxidized to -CO-.

In some preferred embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion, or enantiomer thereof Isomers, solvates, polymorphs or prodrugs, characterized in that R ¹ is preferably selected from the following groups:

wherein one or more (eg 1, 2, 3) R ^c is independently selected from hydrogen, deuterium, halogen, -C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, cyano, hydroxyl, Amino, -SC ₁ -C ₆ alkyl, -SOC ₁ -C ₆ alkyl, -SO ₂ C ₁ -C ₆ alkyl, -COC ₁ -C ₆ alkyl, -COOC ₁ -C ₆ alkyl, - CONHC ₁ -C ₆ alkyl, -CON(C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), 3-6 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or hetero Aryl, -C ₁ -C ₆ haloalkyl, -C ₁ -C ₆ haloalkoxy, -C ₁ -C ₆ deuterated alkyl, -C ₁ -C ₆ deuterated alkoxy, -O-3- 6-membered cycloalkyl or heterocycloalkyl, -C ₁ -C ₆ alkyl OC ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl NHC ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl OH, -C ₁ -C ₆ alkyl N(C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), and between any two Rc can form 3-10 yuan through carbon chain or heteroatom Saturated or partially unsaturated carbocyclic or heterocycle; R ^d is independently selected from hydrogen, -C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl, OC ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl Alkyl SC ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl SOC ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl SO ₂ C ₁ -C ₆ alkyl, -COC ₁ -C ₆ Alkyl, -COOC ₁ -C ₆ alkyl, -CONHC ₁ -C ₆ alkyl, -CON(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl), 3-6 membered cycloalkyl or Heterocycloalkyl, 5-10 membered aryl or heteroaryl, -C ₁ -C ₆ haloalkyl, -C ₁ -C ₆ haloalkoxy, -C ₁ -C ₆ deuterated alkyl, -C ₁ - C ₆ deuterated alkoxy-C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O-3-6 membered cycloalkyl or heterocycloalkyl, -C ₁ -C ₆ alkyl NHC ₁ - C ₆ alkyl, -C ₁ -C ₆ alkyl OH, -C ₁ -C ₆ alkyl N(C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) and the like.

In some preferred embodiments, R ¹ is selected from the following groups:

wherein R ^c and R ^d are as described in the first aspect of the present invention.

In some preferred embodiments, R ¹ is selected from the following groups:

In some preferred embodiments, R ^c is independently preferably selected from hydrogen, halogen, -C ₁ -C ₃ alkyl, -C ₁ -C ₃ haloalkyl, 3-6 membered cycloalkyl or heterocycloalkyl; R ^d is independently selected from hydrogen, -C ₁ -C ₃ alkyl.

In some preferred embodiments, Rn is selected from hydrogen, halogen, _C1 _- C3 alkyl, 3-8 membered cycloalkyl, or heterocycloalkyl.

In other preferred embodiments, Ar ¹ and Ar ² are each independently 6-10 membered aryl, furyl, thienyl, pyridyl, pyrazolyl.

In other preferred embodiments, the compound having the general formula (I), or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer, tautomer, Torsion isomers, solvates, polymorphs or prodrugs, which are preferably compounds represented by the general formula (III):

The scope of other groups is as defined above.

In other preferred embodiments, R ^m is selected from hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, Hydroxyl, amino, C ₁ -C ₈ monoalkylamino, C ₁ -C ₈ dialkylamino, C1-C8 amido, C1-C8 sulfonamido, 3-8 membered cycloalkyl, 3-8 membered hetero Cycloalkyl, 3-8 membered cycloalkylalkyl, 3-8 membered heterocycloalkylalkyl, C ₁ -C ₆ alkyl-S-, C ₁ -C ₆ alkyl-SO-, C ₁ - C ₆ alkyl-SO ₂ -, or the above two R ^m form a 3-8 membered saturated or partially unsaturated, or aromatic ring system through a carbon chain or heteroatom, wherein the R ^m can be further selected from amino , C ₁ -C ₃ monoalkylamino, C ₁ -C ₃ dialkylamino, C ₁ -C ₃ alkyl, hydroxyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkylalkyl Substituents are substituted.

In other preferred embodiments, R ^m is selected from hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkenyl, C ₁ -C ₄ alkynyl, Hydroxyl, amino, C ₁ -C ₆ monoalkylamino, C ₁ -C ₆ dialkylamino, C ₁ -C ₆ amido, C ₁ -C ₆ sulfonamido, 3-6 membered heterocycloalkyl, 3-6-membered heterocycloalkyl-(C1-C3 alkyl)-, 5-10-membered aryl, 5-10-membered heteroaryl, C ₁ -C ₃ alkyl-SO ₂ -, or the above two R ^m constitutes a 5-6 membered saturated or partially unsaturated, or aromatic ring system through a carbon chain or heteroatom, wherein the R ^m may be further selected from amino, C ₁ -C ₃ monoalkylamino, C ₁ -C Substituent substitution of C ₃ dialkylamino, C ₁ -C ₃ alkyl, hydroxyl, 3-6-membered heterocycloalkyl, and 3-6-membered heterocycloalkylalkyl.

In other preferred embodiments, R ^m is selected from hydrogen, halogen, C ₁ -C ₄ monoalkylamino, C ₁ -C ₄ dialkylamino, 3-6 membered heterocycloalkyl, 3-6 membered Heterocycloalkyl-(C1-C3 alkyl)-, or the above two R ^m form a 5-6 membered saturated ring through a carbon chain or heteroatom.

In some preferred embodiments, R ¹ , R ^2a , R ^2b , R ³ , Ar ¹ , Ar ² , M are each independently the corresponding groups in compounds 1-86 prepared in Examples.

In some preferred embodiments, the compound is any one of Compounds 1-86 prepared in the Examples or a pharmaceutically acceptable salt thereof.

In the second aspect of the present invention, there is provided a pyrimido-fused ring compound represented by general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomers, torsion isomers, solvates, polymorphs or prodrugs,

where:

R ¹ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₂ cycloalkyl, C ₄ - C ₁₂ cycloalkenyl, 3-12-membered heterocycloalkyl, 5-12-membered aryl or 5-12-membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₁₂ cycloalkyl, C ₄ -C ₁₂ cycloalkenyl, 3-12-membered heterocycloalkyl, 5-12-membered aryl or 5-12-membered heteroaryl The base can be optionally substituted by 1-3 Rn; or the above two Rn can form a 3-12-membered saturated or partially unsaturated, or aromatic ring system through a carbon chain or a heteroatom; the Rn is selected from hydrogen , deuterium, halogen, cyano, nitro, amide, sulfonamide, hydroxyl, amino, urea, phosphoryl, alkylphosphooxy, alkylsilyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy, haloalkyl, haloalkoxy, C ₁ -C ₆ monoalkylamino, C ₁ -C ₆ dialkylamino, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl, C ₁ -C ₆ alkyl-S-, C ₁ -C ₆ alkyl-SO-, C ₁ -C ₆ alkyl-SO _2- , etc.;

R ^2a and R ^2b are each independently selected from hydrogen, deuterium, halogen, C ₁ -C ₆ alkyl, 3-8 membered cycloalkyl, or heterocycloalkyl; and R ^2a and R ^2b may pass through a carbon chain or a heteroatom Form 3-6 membered saturated or partially unsaturated or unsaturated ring systems;

R ³ is H, deuterium, halogen, hydroxyl, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C 6 alkylamino, 3-8 membered Cycloalkyl or heterocycloalkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl;

Ar ¹ and Ar ² are independently selected from 5-12-membered monocyclic or bicyclic aryl or heteroaryl groups, which may be substituted by one or more groups selected from the group consisting of: Hydrogen, deuterium, halogen, cyano, nitro, substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, hydroxyl, amino, urea, phosphoryl, alkylphosphooxy, alkylsilyl, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkoxy alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ haloalkoxy, C 1 -C ₁₀ haloalkoxy Alkyl, C ₁ -C ₁₀ monoalkylamino, C ₁ -C ₁₀ dialkylamino, C ₁ -C ₁₀ monoalkylaminoalkyl, C ₁ -C ₁₀ dialkylaminoalkyl, C ₁ - C ₁₀ alkenyl, C ₁ -C ₁₀ alkynyl, 3-12 membered cycloalkyl or heterocycloalkyl, 3-12 membered cycloalkyl or heterocycloalkylalkyl, C ₁ -C ₁₀ alkyl-S -, C ₁ -C ₁₀ alkyl-SO-, C ₁ -C ₁₀ alkyl-SO ₂ -, etc.; and any two adjacent substituents on the above Ar ¹ and Ar ² may pass through carbon chains or heteroatoms 3-8 membered saturated or partially unsaturated or unsaturated ring systems are formed.

One or more hydrogen atoms on any of the above-mentioned groups may be substituted by a substituent selected from the following group: including but not limited to deuterium, halogen, C ₁ -C ₃ alkyl, 3-6 membered cycloalkyl or heterocyclic Cycloalkyl; wherein, the heteroaryl group contains 1-3 heteroatoms selected from the following group: N, O, P or S, and the heterocycloalkyl group contains 1-3 heteroatoms selected from the following group Heteroatom: N, O, P or S, and the ring system includes a saturated or partially unsaturated ring system such as spiro, bridged, condensed, and parallel.

In some preferred embodiments, the compound is a compound represented by the general formula (II), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof isomers, torsion isomers, solvates, polymorphs or prodrugs:

wherein R ³ is preferably selected from H, Me; M is preferably selected from N or CH or CF or C-CN or C-Me; the ranges of other groups are as defined above.

In some preferred embodiments, the compound is a compound represented by the general formula (III), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof isomers, torsion isomers, solvates, polymorphs or prodrugs:

wherein the ranges of R ¹ , M, Ar ² are as defined above.

In a third aspect of the present invention, there is provided a method for preparing a compound of formula I, the method comprising steps a-d:

a) subjecting the compound of general formula (A) and the compound of general formula (B) to a substitution reaction under base catalysis to form an intermediate (C) compound; and

b) hydrolyzing the compound of the intermediate general formula (C) to generate the compound of the intermediate (D);

c) The intermediate (D) compound and R ¹ NH ₂ undergo a condensation reaction under the participation of a condensing agent to generate the intermediate (E);

d) subjecting the intermediate (E) to a ring-closure reaction under acid catalysis to generate the general formula (I).

R is an alkyl group, such as methyl, ethyl, tert-butyl, benzyl, etc.; the scope of other groups is as described above;

Preferably, the steps a), b), c), d) are each carried out in a solvent selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, ethyl alcohol Glycol methyl ether, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N- Dimethylacetamide, dioxane, or a combination thereof.

Preferably, the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, carbonic acid Potassium hydrogen, sodium carbonate, sodium bicarbonate, or a combination thereof; the organic base is selected from the group consisting of pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] Undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, or a combination thereof.

Preferably, the condensation reagent is selected from the group consisting of DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), CDI (carbonyldiimidazole), EDCI (1-ethyl-3 (3-dimethylpropylamine) carbodiimide), HOAt (1-hydroxy-7-azabenzotriazole), HOBt (1-hydroxybenzotriazole), BOP (Carter condensing agent), PyBOP ( 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate), HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyl urea hexafluorophosphate), TBTU (benzotriazole tetramethyltetrafluoroboric acid), etc., or a combination thereof.

Preferably, the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, trifluoromethanesulfonic acid, or combinations thereof.

A class of preferred compounds of general formula (I) provided by the present invention includes but is not limited to the following structures:

Another object of the present invention is to provide a medicament for treating or preventing tumors and a composition thereof. The technical solutions to achieve the above purpose are as follows:

A pharmaceutical composition for treating tumors, which is composed of a pyrimido heterocyclic compound represented by the above general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof , tautomer, torsion isomer, solvate, polymorph or prodrug and a pharmaceutically acceptable carrier.

Another object of the present invention is to provide a use of the above compound. The technical solutions to achieve the above purpose are as follows:

The pyrimido-heterocyclic compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer, tautomer, and torsion isomer Forms, solvates, polymorphs or prodrugs are used to prepare medicines for the treatment of diseases related to Ras mutation, activity or expression level, especially for the treatment of tumors. The tumor is independently selected from the group consisting of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, bowel cancer, bile duct cancer, brain cancer, leukemia, lymphoma Carcinoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.

The present invention relates to a compound with general formula (I) structure, which can inhibit various tumor cells, especially can efficiently kill tumors related to abnormal Ras protein signaling pathway, and is a kind of therapeutic drug with a new mechanism of action.

It should be understood that, within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be repeated here.

Detailed ways

After long-term and in-depth research, the inventor has prepared a class of pyrimidoheterocyclic compounds with a novel structure shown in formula I, and found that it has a good inhibitory activity against SOS1 protein, and the compound has a very low concentration. (can be as low as less than 100nM), that is, it has a specific inhibitory effect on the SOS1 protein, and has an excellent inhibitory activity on cell proliferation related to the Ras pathway, so it can be used for the treatment of RAS mutation or abnormal activity or expression. Diseases such as tumors. Based on the above findings, the inventors have completed the present invention.

the term

Unless otherwise defined, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, publications cited throughout this document are incorporated by reference in their entirety unless otherwise indicated.

It is to be understood that both the foregoing brief description and the following detailed description are exemplary and explanatory only and do not limit the subject matter of the invention in any way. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It must be noted that the singular forms used in this specification and the claims include the plural forms of referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" and "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "including" and other forms such as "comprising", "including" and "comprising" is not intended to be limiting.

Unless otherwise stated, conventional methods within the skill in the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy and pharmacological methods are employed. Unless specific definitions are presented, the terms employed herein in the related descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention. The techniques and methods described above can generally be carried out according to conventional methods well known in the art from the descriptions in the various general and more specific documents cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.

When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, _-CH2O- is equivalent to _-OCH2- .

Section headings used herein are for the purpose of organizing the article only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are hereby incorporated by reference in their entirety.

Certain chemical groups defined herein are preceded by abbreviated symbols to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the simplified notation does not include carbons that may be present in the substituents of the group.

In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings shown below unless specifically indicated otherwise.

In this application, the term "halogen" refers to fluorine, chlorine, bromine or iodine; "hydroxy" refers to the -OH group; "hydroxyalkyl" refers to an alkane as defined below substituted with a hydroxyl group (-OH). "carbonyl" refers to a -C(=O)- group; "nitro" refers to _-NO2 ; "cyano" refers to -CN; "amino" refers to _-NH2 ; "substituted amino" means an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylamido, aralkyl amino, heteroaralkylamino; "carboxy" refers to -COOH.

In this application, the term "alkyl" as a group or part of another group (eg, as used in a halogen-substituted alkyl group, etc.) means consisting only of carbon and hydrogen atoms, free from unsaturation A bond, a straight or branched hydrocarbon chain group having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and connected to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl, etc.

In this application, the term "alkenyl" as a group or part of another group means consisting of carbon and hydrogen atoms only, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) a straight or branched hydrocarbon chain group, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, butan- 1-alkenyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl and the like.

In this application, the term "alkynyl" as a group or part of another group means consisting only of carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having eg A straight or branched hydrocarbon chain group of 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms connected to the rest of the molecule by a single bond, such as, but not limited to, ethynyl , prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, etc.

In this application, the term "cycloalkyl" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, which may include fused Ring systems, bridged ring systems or spiro ring systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and which are saturated or unsaturated and can be The carbon atoms are attached to the rest of the molecule by single bonds. Unless specifically stated otherwise in this specification, carbon atoms in a cycloalkyl group may be optionally oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2] octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octa Hydrogen-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-cyclopentadienyl, etc.

In this application, as a group or part of another group, the terms "heterocyclyl" and "heterocycloalkyl" are used interchangeably to mean from 2 to 14 carbon atoms and from 1 to 6 carbon atoms selected from the group consisting of A stable 3- to 20-membered non-aromatic cyclic group composed of heteroatoms of nitrogen, phosphorus, oxygen and sulfur. Unless otherwise specified in this specification, the heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more ring ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; The nitrogen, carbon, or sulfur atoms of the C can be optionally oxidized (eg, S- can be oxidized to -SO- or -SO ₂ -, -C- can be oxidized to -CO-); nitrogen atoms can be optionally quaternized ; and the heterocyclyl group may be partially or fully saturated. A heterocyclyl group can be attached to the rest of the molecule via a carbon atom or a heteroatom and through a single bond. In heterocyclyl containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclyl group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur groups, more preferably stable 4- to 8-membered (eg 4, 5, 6, 7, 8-membered) containing 1 to 3 (eg 1, 2, 3) heteroatoms selected from nitrogen, oxygen and sulfur A non-aromatic monocyclic, bicyclic, bridged or spirocyclic group wherein the nitrogen, carbon or sulfur atom in the heterocyclic group may be optionally oxidized. Examples of heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonyl Alk-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutanyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indoline, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl , phthalimide, etc.

In this application, the terms "heterocyclylalkyl", "heterocycloalkylalkyl" are used interchangeably and refer to an alkyl group as defined above substituted with a heterocyclyl group as defined above, or Heterocyclyl as defined above substituted with alkyl as defined above.

As used herein, as a group or as part of another group, the term "aryl" means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms. For the purposes of the present invention, an aryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by single bonds. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3(4H)-one-7-yl and the like.

In this application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.

In this application, as a group or part of another group, the term "heteroaryl" means a ring having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 selected from nitrogen 5- to 16-membered conjugated ring system groups of heteroatoms of , oxygen and sulfur. Unless specifically stated otherwise in this specification, a heteroaryl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and can also be fused to a cycloalkyl or heterocyclyl group as defined above, provided that the heterocyclic group The aryl group is attached to the rest of the molecule by a single bond through an atom on the aromatic ring. A nitrogen, carbon or sulfur atom in a heteroaryl group can optionally be oxidized; the nitrogen atom can optionally be quaternized. For the purposes of the present invention, a heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 1 to 4 selected heteroatoms. A stable 5- to 10-membered aromatic group from heteroatoms of nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl , purinyl, quinolinyl, isoquinolinyl, diazanaphthyl, naphthyridinyl, quinoxalinyl, pteridyl, carbazolyl, carboline, phenanthridine, phenanthroline, acridine base, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxtriazolyl, cinnoline, quinazolinyl, phenylthio, indolizine, o-phenanthrenyl, Isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, [1,2,4]triazolo[4 ,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1, 2,4]Triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine Wait.

In this application, the term "heteroarylalkyl" refers to an alkyl group, as defined above, substituted with a heteroaryl group, as defined above.

In the present application, the term "amido" includes -alkyl as defined above-CONH2 or -CONH _- alkyl as defined above or -CON(alkyl as defined above) ₂ , wherein said alkyl is preferably C1- C6 alkyl, more preferably C1-C3 alkyl. In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.

The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a specific fragment or functional group in a molecule. A chemical moiety is usually thought of as a chemical entity embedded or attached to a molecule.

"Stereoisomers" refer to compounds that consist of the same atoms, bonded by the same bonds, but have different three-dimensional structures. The present invention will cover various stereoisomers and mixtures thereof.

When olefinic double bonds are contained in the compounds of the present invention, unless otherwise stated, the compounds of the present invention are intended to include both E- and Z-geometric isomers.

"Tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention are also intended to be included within the scope of the present invention.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may give rise to enantiomeric, diastereomeric, and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as their racemates and optically pure forms. The compounds of the present invention can be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as crystallization and chiral chromatography.

Conventional techniques for preparing/separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives using, for example, chiral high performance liquid chromatography) ).

In this application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"Pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include but are not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include but are not limited to formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, hexamethylene Acid, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-toluenesulfonate , alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, etc. These salts can be prepared by methods known in the art.

"Pharmaceutically acceptable base addition salts" refers to salts with inorganic or organic bases that retain the biological availability of the free acid without other adverse effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperazine pyridine, N-ethylpiperidine, polyamine resin, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

"Polymorph" refers to the distinct solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more distinct molecular arrangements. Certain compounds of the present invention may exist in more than one crystalline form, and the present invention is intended to include each crystalline form and mixtures thereof.

Typically, crystallization results in solvates of the compounds of the present invention. The term "solvate" as used in the present invention refers to an aggregate comprising one or more molecules of a compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Accordingly, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the present invention may form true solvates, but in some cases, only indefinite water or mixtures of water plus some indefinite solvent may remain. The compounds of the present invention may be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.

The present invention also includes prodrugs of the above compounds. In the present application, the term "prodrug" refers to a compound that can be converted into a biologically active compound of the present invention under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the present invention. A prodrug may be inactive when administered to an individual in need thereof, but be converted in vivo to an active compound of the present invention. Prodrugs are typically rapidly transformed in vivo to yield the parent compounds of the invention, eg, by hydrolysis in blood. Prodrug compounds generally provide the advantages of solubility, histocompatibility or sustained release in mammalian organisms. Prodrugs include known amino and carboxyl protecting groups.

As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a medium generally accepted in the art for delivering a biologically active compound to a mammal (eg, a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration of the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

The term "pharmaceutically acceptable" as used herein refers to a substance (eg, a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing adverse biological effects React or interact in an undesirable manner with any component contained in the composition.

In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory authority as acceptable for human or livestock use , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.

The "tumor", "diseases related to abnormal cell proliferation" and the like in the present invention include but are not limited to leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, bowel cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.

As used herein, the terms "prophylactic", "preventing" and "preventing" include reducing the likelihood of the occurrence or exacerbation of a disease or disorder in a patient.

As used herein, the term "treatment" and other similar synonyms include the following meanings:

(i) preventing the emergence of a disease or disorder in mammals, particularly when such mammals are susceptible to, but have not been diagnosed with, the disease or disorder;

(ii) inhibiting the disease or disorder, i.e. arresting its development;

(iii) alleviating the disease or disorder, i.e. causing the state of the disease or disorder to resolve; or

(iv) alleviating symptoms caused by the disease or disorder.

As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of at least one agent or compound sufficient to alleviate, to some extent, one or more symptoms of the disease or disorder being treated upon administration. amount. The result can be a reduction and/or amelioration of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is that amount of a composition comprising a compound disclosed herein required to provide clinically significant relief of a condition. An effective amount appropriate in any individual case can be determined using techniques such as dose escalation assays.

The terms "administering," "administering," "administering," and the like, as used herein, refer to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, the oral route, the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

As used herein, the terms "drug combination", "drug combination", "combination", "administration of other treatments", "administration of other therapeutic agents" and the like refer to drug treatments obtained by admixing or combining more than one active ingredient, It includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or single dosage form. The term "unfixed combination" refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation at variable intervals to a patient as separate entities. These also apply to cocktail therapy, eg the administration of three or more active ingredients.

It will also be understood by those skilled in the art that in the methods described below, intermediate compound functional groups may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, amino, mercapto, and carboxylic acid. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable thiol protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.

Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The protecting group can also be a polymeric resin.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions in the following examples are generally in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise specified.

Example General Preparation Method

Step 1: Dissolve the 6-chloropyrimidine intermediate (1eq.) in an appropriate solvent, add an organic base (3eq.) and an amine intermediate (1eq.) in turn, seal the tube and heat to 100°C and stir overnight. The reaction was completed by LC-MS monitoring, cooled to room temperature, water was added to the reaction solution, the aqueous phase was extracted three times with dichloromethane, the extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified to obtain the target product, which was confirmed by nuclear magnetic resonance and mass spectrometry. structure.

Step 2: Dissolve the product of the first step (1 eq.) in a suitable solvent, add an inorganic base, and stir at room temperature for several hours. The reaction was completed by TLC monitoring, filtered and concentrated under reduced pressure, and the crude target product was obtained by vacuum drying. The structure was confirmed by nuclear magnetic resonance and mass spectrometry.

The third step: Dissolve the product of the second step above (1eq.) in a suitable solvent, add condensing agent (1.1eq), base (1.2eq), and R ¹ NH ₂ (1 eq.) successively, under nitrogen protection at room temperature The reaction was overnight hours. The completion of the reaction was monitored by TLC, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the target product, and the structure was confirmed by nuclear magnetic resonance and mass spectrometry.

Step 4: Dissolve the product of the third step (1eq.) in isopropanol, add 5N HCl aqueous solution (10eq.), and stir at 80 degrees for 6 hours. The completion of the reaction was monitored by TLC, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the target compound, and the structure was confirmed by nuclear magnetic resonance and mass spectrometry.

Intermediate preparation

Intermediate 1: (R)-1-(2'-((dimethylamino)methyl)-[1,1'-biphenyl]-3-yl)ethyl-1-amine hydrochloride

Step 1: Under nitrogen protection, tetraethyl titanate (11.3g, 49.56mmol) was added to 3-bromo-acetophenone (5.40g, 27.26mmol), (R)-(+)tert-butylsulfinamide ( 3.0 g, 24.78 mmol) in tetrahydrofuran (42 mL). The reaction mixture was heated to 70°C and reacted at this temperature for 16 hours. The reaction mixture was heated to 70°C and reacted at this temperature for 16 hours. The reaction solution was cooled to room temperature, 70 mL of brine was added, and stirring was continued for 10 minutes. The reaction mixture was filtered through celite and washed twice with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:4) to obtain a colorless oily intermediate compound (6.05 g). LCMS (ESI) m/z: 301.9 [M+H] ⁺ . ¹ H NMR(400MHz, DMSO-d6)δ8.03(s,1H),7.90(d,J=7.8Hz,1H),7.80-7.73(m,1H),7.47(m,1H),2.72(s , 3H), 1.22(s, 9H).

Step 2: At -78°C, diisobutylaluminum hydride (39.9 mL, 39.86 mmol) was added to the above intermediate (6.0 g, 19.93 mmol) in tetrahydrofuran (200 mL). The reaction slowly warmed to room temperature and was allowed to react at this temperature for 16 hours. Under ice bath cooling, dilute sodium hydroxide solution was added to quench the reaction. The reaction mixture was filtered through celite and washed twice with ethyl acetate (100 mL). The combined organic phases were concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the compound as a colorless oily compound (5.25 g). LCMS (ESI) m/z: 303.1 [M+H] ⁺ . ¹ H NMR(400MHz,DMSO-d6)δ7.63(s,1H),7.45-7.36(m,2H),7.29(m,1H),5.77(d,J=7.7Hz,1H),4.37(m , 1H), 1.38 (d, J=6.8Hz, 3H), 1.12 (s, 9H).

Step 3: under nitrogen protection, tetrakis-triphenylphosphine palladium (1.52g, 1.32mmol) was added to the compound above intermediate compound (4.0g, 13.20mmol), 2-(N,N-dimethylaminomethyl) ) phenylboronic acid (3.07 g, 17.16 mmol), potassium carbonate (3.64 g, 26.40 mmol) and water (10 mL) in 1,4-dioxane (50 mL). The reaction mixture was heated to 100°C and reacted at this temperature for 16 hours. The reaction solution was diluted with ethyl acetate (200 mL) and washed with water (100 mL). The separated organic phase was concentrated under reduced pressure, and the crude product was purified by reverse phase column to give a brown oily compound (3.46 g). LCMS (ESI) m/z: 359.2 [M+H] ⁺ . ¹ H NMR(400MHz, DMSO-d6)δ7.54-7.47(m,1H),7.43(s,1H),7.38(d,J=4.8Hz,2H),7.33(m,2H),7.29-7.22 (m, 2H), 5.69(m, 1H), 4.43(m, 1H), 3.32(s, 2H), 2.08(s, 6H), 1.43(d, J=6.8Hz, 3H), 1.12(s, 9H).

Step 4: A methanol solution of hydrochloric acid (4M, 15 mL, 45 mmol) was added to the above intermediate compound (3.46 g, 9.66 mmol) in methanol (15 mL). The reaction mixture was reacted at 20 degrees for 2 hours. LC-MS detected that the reaction was basically completed. After the solvent was removed by concentration under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane/methanol=9:1) to obtain a pale yellow solid compound (2.5 g). LCMS (ESI) m/z: 255.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ 7.82-7.69 (m, 1H), 7.66-7.53 (m, 4H), 7.50 (s, 1H), 7.41 (d, J=6.1Hz, 2H), 4.59 (m, 1H), 4.42 (s, 2H), 2.67 (s, 6H), 1.70 (d, J=6.2 Hz, 3H).

Preparative conditions: Separation column (SunFire Prep C18 OBD ^™ , 10um, 19*250mm); gradient (5%-95% acetonitrile/0.1% formic acid/water, 16 min, flow rate 20 mL/min). Analytical conditions: analytical column (Waters SunFire C18, 4.6*50mm, 5um); gradient (5%-95% acetonitrile/0.1% formic acid/water, 3.0min, flow rate 2.0mL/min, 2.6min); column temperature: 40°C ; Detection wavelength: 254 nM.

Intermediate 3: (R)-1-(5-(2-(pyrrol-1-ylmethyl)phenyl)thiophen-2-yl)ethyl-1-amine hydrochloride

Step 1: Under nitrogen protection, tetraethyl titanate (30.1g, 132mmol) was added to 1-(5-bromothiophen-2-yl)ethyl-1-one (14.89g, 72.61mmol), (R) -(+)tert-butylsulfinamide (8 g, 66 mmol) in tetrahydrofuran (100 mL), the reaction mixture was heated to 70°C and reacted at this temperature for 16 hours. After the reaction solution was cooled to room temperature, 100 ml of brine was added, and stirring was continued for 10 minutes. The reaction mixture was filtered through celite, and the filtrate was extracted twice with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, and after concentration, the crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=4:1) to obtain a brown solid intermediate compound (15 g, crude product). LCMS (ESI) m/z: 307.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 7.64 (d, J=4.1 Hz, 1H), 7.35 (d, J=4.1 Hz, 1H), 2.64 (s, 3H), 1.18 (s, 9H).

Step 2: Under nitrogen protection, under -78 ℃ of cooling, DIBAL-H (61ml, 61mmol) was slowly added dropwise to the tetrahydrofuran (200mL) of the above-mentioned intermediate compound (9.3g, 30.17mmol), and the reaction mixture was slowly warmed to The reaction was carried out at room temperature for 16 hours, no starting material was detected by LCMS, and most of the reaction was converted to the desired product. Methanol (50ml) was added to quench, and the solvent was removed by concentration under reduced pressure. The crude product was slurried with methanol (200ml) and filtered through celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=4:1) to obtain a brown oily liquid compound (15 g, crude product). LCMS (ESI) m/z: 309.9 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ7.06 (d, J=3.8Hz, 1H), 6.89 (dd, J=3.8, 0.9Hz, 1H), 5.90 (m, 1H), 4.57 (m, 1H) ), 1.47(d, J=6.8Hz, 3H), 1.12(s, 9H).

Step 3: under nitrogen protection, tetrakistriphenylphosphine palladium (1.12g, 0.965mmol) was added to the above-mentioned intermediate compound (3g, 9.65mmol), 2-formaldehyde phenylboronic acid (1.88g, 12.55mmol), potassium carbonate ( 2.67 g, 19.3 mmol) in 1,4-dioxane (60 mL) in water (12 mL). The reaction mixture was heated to 100°C and reacted at this temperature for 16 hours. The reaction solution was diluted with ethyl acetate (200 mL), then washed with water (100 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was preparatively purified by HPLC to give the intermediate compound (2.6 g) as a brown oil. LCMS (ESI) m/z: 336.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.21 (d, J=0.6 Hz, 1H), 8.00 (dd, J=7.8, 1.1 Hz, 1H), 7.61 (m, 1H), 7.55-7.46 (m, 2H), 7.08(d, J＝3.0Hz, 1H), 6.92(d, J＝3.6Hz, 1H), 4.90-4.82(m, 1H), 3.58(d, J＝3.6Hz, 1H), 1.66( d, J=6.6Hz, 3H), 1.26(s, 9H).

Step 4: At room temperature, 1 drop of glacial acetic acid was added to the methanol (30 mL) of the above-mentioned intermediate compound (2.6 g, 7.75 mmol) and tetrahydropyrrole (662 mg, 9.3 mmol), and the reaction mixture was reacted at 20 ° C for 2 Hour. Then sodium cyanoborohydride (1.46 g, 23.25 mmol) was added to the above reaction solution, and the reaction was continued for 12 hours. LCMS detected the main product. The crude product obtained by concentration under reduced pressure to remove the solvent was purified by silica gel column chromatography (eluent: dichloromethane/methanol=9:1) to obtain the compound as a pale yellow solid intermediate compound (2.1 g). LCMS (ESI) m/z: 391.1 [M+H] ⁺ .

Step 5: Hydrogen chloride methanol solution HCl(g)/MeOH (15 mL, 45 mmol) was added to the above intermediate compound (2.1 g, 5.38 mmol) in methanol (15 mL). The reaction mixture was reacted at 20 degrees for 2 hours. The reaction was complete by LCMS. After the reaction solution was concentrated under reduced pressure to remove the solvent, the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=9:1) to obtain the target compound (1.2 g) as a pale yellow solid. LCMS (ESI) m/z: 287.1 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ 7.79-7.75 (m, 1H), 7.60-7.50 (m, 3H), 7.32 (d, J=3.6Hz, 1H), 7.13 (d, J=3.6Hz) ,1H),4.83(m,1H),4.58(s,2H),3.54-3.44(m,2H),3.02(d,J=8.1Hz,2H),2.06-1.94(m,4H),1.77( d, J=6.9 Hz, 3H).

Preparation of (R)-1-(2'-((dimethylamino)methyl)-[1,1'-biphenyl]-3-yl)ethyl-1-amine hydrochloride and (R) - Preparation and isolation of 1-(5-(2-(pyrrol-1-ylmethyl)phenyl)thiophen-2-yl)ethyl-1-amine hydrochloride The following intermediates 2 and 4- 12:

Example 1: 4-(((R)-1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)-ethyl)amino)-2-methyl -6-((S or R)-1,1,1-trifluoropropyl-2-yl)pyridin[4,3-d]pyrimidin-7(6H)-one

Step 1: Methyl 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)acetate (360 mg, 1.32 mmol), (R )-1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethan-1-amine (347 mg, 1.32 mmol) and N,N-diisopropylethyl Amine (515 mg, 3.96 mmol) was added to dimethyl sulfoxide (7 mL), and the tube was sealed at 100°C for reaction overnight. The reaction was complete as monitored by LC-MS and cooled to room temperature. Water (30 mL) was added to the reaction solution, extracted three times with dichloromethane, the extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to reverse column chromatography to obtain 160 mg of solid product. LC-MS (ESI) m/z: 497.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d6): δ 7.39-7.30 (m, 4H), 7.16 (d, J=3.6Hz, 1H), 7.03 (m, 2H), 5.89 (s, 1H), 5.75 -5.58(m, 1H), 4.15-4.00(m, 2H), 3.98-3.81(m, 2H), 3.71-3.60(m, 4H), 3.37(s, 3H), 2.35(s, 3H), 2.11 (s, 6H), 1.61 (d, J=6.8 Hz, 3H).

Step 2: To the tetrahydrofuran solution (4 mL) of the above solid (228 mg, 0.46 mmol) was added an aqueous solution (1 mL) of lithium hydroxide (88 mg, 3.676 mmol), and the reaction solution was stirred at room temperature for 3 hours. TLC detected the disappearance of the reaction raw materials, and the solvent was removed under reduced pressure to obtain 220 mg of a pale yellow solid crude product, which was directly put into the next reaction. LC-MS (ESI) m/z: 483.1 [M+H] ⁺ .

Step 3: Add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (514mg, 1.35mmol) to the solid in the previous step (220 mg, 0.451 mmol), 1,1,1-trifluoropropan-2-amine (102 mg, 0.901 mmol) and N,N-diisopropylethylamine (233 mg, 1.803 mmol) in tetrahydrofuran (20 mL) . The reaction solution was stirred at room temperature overnight. After concentration under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography (ethyl acetate/methanol volume ratio 20:1) to obtain 200 mg of brown oil. LC-MS (ESI) m/z: 578.1 [M+H] ⁺ .

Step 4: To a solution of the above oil (200 mg, 0.346 mmol) in isopropanol (8 mL) was added 5N aqueous hydrochloric acid (1.5 mL, 7.5 mmol). The reaction mixture was reacted at 80 degrees for 2 hours. LC-MS detected that the reaction of the starting materials was complete. The reaction solution was diluted with dichloromethane (100 mL), and the reaction solution was washed twice with brine (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was preparatively purified by HPLC to obtain compound 1-1 (Rt=5.15 min, 3.6 mg, pale yellow solid) and compound 1-2 (Rt=7.55 min, 4.1 mg, pale yellow solid).

Preparative conditions: Separation column (SunFire Prep C18 OBD ^™ , 10um, 19*250mm); gradient (5%-95% acetonitrile/0.1% formic acid/water, 16 min, flow rate 20 mL/min).

Analytical conditions: analytical column (Waters SunFire C18, 4.6*50mm, 5um); gradient (5%-95% acetonitrile/0.1% formic acid/water, 3.0min, flow rate 2.0mL/min, 2.6min); column temperature: 40°C ; Detection wavelength: 254nM.

Compound 1-1: LC-MS (Rt=1.207Min) (ESI) m/z: 516.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d6): δ9.09(m,1H), 9.04(s,1H), 8.21(s,1H), 7.42(m,2H), 7.34-7.29(m,2H) ,7.20(d,J＝3.6Hz,1H),7.11(d,J＝3.3Hz,1H),6.22(s,1H),6.08(m,1H),5.96(m,1H),3.36(s, 2H), 2.33(s, 3H), 2.10(s, 6H), 1.71(d, 7.2Hz, 3H), 1.69(d, J=6.9Hz, 3H).

Compound 1-2: LC-MS (Rt=1.230 Min) (ESI) m/z: 516.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d6): δ9.10(s, 1H), 9.03(s, 1H), 8.22(s, 1H), 7.46-7.41(m, 1H), 7.39(dd, J= 6.6,2.2Hz,1H),7.34-7.28(m,2H),7.20(d,J=3.6Hz,1H),7.12(d,J=3.3Hz,1H),6.22(s,1H),6.13- 6.00(m, 1H), 5.95(d, J=5.1Hz, 1H), 3.37(s, 2H), 2.33(s, 3H), 2.12(s, 6H), 1.72(d, 7.2Hz, 3H), 1.69 (d, J=6.9, 3H).

Referring to the method of Example 1, with (R) or (S)-1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethan-1-amine and different The commercially available amine reagent is the synthetic method of replacing 1,1,1-trifluoropropane-2-amine as the raw material to obtain Example 2-18:

Example 19: (R)-N-(2-(dimethylamino)ethyl)-3'-(1-((2-methyl-7-oxo-6-((tetrahydro-2H-pyridine) Pyran-4-yl)methyl)-6,7-dihydropyridin[4,3-d]pyrimidin-4-yl)amino)ethyl)-[1,1'-diphenyl]-4-carbonic acid Amide

Step 1: Methyl 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)acetate (3.0 g, 11.03 mmol), ( R)-1-(3-bromophenyl)ethyl-1-amino hydrochloride (2.85 g, 12.13 mmol) and N,N-diisopropylethylamine (4.28 g, 33.08 mmol) were added to dimethylidene sulfone (15 mL), seal the tube at 100°C and react overnight. The reaction was complete as monitored by LC-MS and cooled to room temperature. Water (50 mL) was added to the reaction solution, extracted three times with dichloromethane, the extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to reverse column chromatography to obtain 2.04 g of a pale yellow solid product. LCMS (ESI) m/z: 437.9 [M+H] ^+.1 H NMR (400MHz, DMSO-d6) δ 7.57 (m, 1H), 7.46-7.35 (m, 2H), 7.29 (m, 1H) ,6.97(d,J＝7.8Hz,1H),5.92(s,1H),5.34(m,1H),4.15-4.10(m,2H),3.98-3.93(m,2H),3.70(s,2H) ), 3.59(s, 3H), 2.26(s, 3H), 1.47(d, J=7.0Hz, 3H).

Step 2: To the tetrahydrofuran solution (20 mL) of the above solid (2.0 g, 4.60 mmol), an aqueous solution (5 mL) of lithium hydroxide (883 mg, 36.77 mmol) was added, and the reaction solution was stirred at room temperature for 5 hours. TLC detected the disappearance of the reaction raw materials, and the solvent was removed under reduced pressure to obtain a pale yellow solid crude product (1.96 g), which was directly put into the next reaction. LC-MS (ESI) m/z: 423.9 [M+H] ⁺ .

Step 3: At room temperature, the above-mentioned intermediate compound (1.96g, 4.60mmol) was dissolved in tetrahydrofuran (200mL), followed by adding (tetrahydro-2H-pyran-4-yl)-methylamine (1.59g, 13.8mmol) ), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (7.0g, 18.4mmol), N,N-diisopropyl Ethylamine (2.38 g, 18.4 mmol), the reaction mixture was reacted at 70 degrees for 2 hours. The main reaction product was detected by LCMS. The reaction solution was diluted with ethyl acetate (100 mL) and the organic phase was separated. The organic phase was dried with anhydrous sodium sulfate. After the filtrate was concentrated under reduced pressure, the crude product was subjected to silica gel column chromatography (ethyl acetate:methanol= 20:1) Purification yielded 2.1 g of light yellow solid product. LC-MS (ESI) m/z: 519.1 [M+H] ^+.1 H NMR (400 MHz, CDCl ₃ ) δ 8.34 (d, J=7.5 Hz, 1 H), 7.44 (m, 2H), 7.26- 7.17(m, 2H), 7.07(m, 1H), 6.00(s, 1H), 5.39(m, 1H), 4.20-4.08(m, 4H), 3.94(m, 2H), 3.85(s, 2H) ,3.36(m,2H),3.15(t,J=6.4Hz,2H),2.57(s,3H),1.83-1.71(m,1H),1.67-1.54(m,5H),1.33-1.21(m , 2H).

Step 4: Aqueous HCl (5N, 7.0 mL) was added to the above compound (1.35 g, 2.605 mmol) in tetrahydrofuran (32 mL) at room temperature, and the reaction mixture was reacted at 80°C for 2 hours. LCMS detected the completion of the reaction, the reaction solution was diluted with dichloromethane (200 mL), and the reaction solution was washed with brine. The organic phase was separated and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=4:1 to 2:1) to obtain 1.35 g of pale yellow solid. LCMS (ESI) m/z: 457.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.02 (s, 1H), 8.28 (s, 1H), 7.50 (s, 1H), 7.32 ( m, 2H), 7.13(m, 1H), 6.40(s, 1H), 5.69(m, 1H), 3.96(m, 1H), 3.89-3.74(m, 3H), 3.18(m, 2H), 2.42 (s, 3H), 2.11(m, 1H), 1.58(d, J=6.9Hz, 3H), 1.44(m, 2H), 1.22(m, 2H).

Step 5: Under nitrogen protection, tetrakistriphenylphosphine palladium (40mg, 0.035mmol) was added to the above compound (0.16g, 0.351mmol), 4-((2-(dimethylamino)ethyl)carbonyl)benzene yl)boronic acid (124 mg, 0.456 mmol), potassium carbonate (97 mg, 0.702 mmol), water (2 mL) in 1,4-dioxane (12 mL). The reaction mixture was heated to 100°C and reacted at this temperature for 16 hours. After diluting the reaction solution with ethyl acetate (200 mL), the reaction solution was washed with water and brine, respectively. The separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting crude product was preparatively purified by HPLC to yield 10.60 mg of a pale yellow solid. LCMS (Rt=0.879min) (ESI) m/z: 469.4[M+H] ⁺ ^.1H NMR (400MHz, DMSO-d6)δ9.11(s,1H),8.53(d,J=7.8Hz, 1H), 8.42(m, 1H), 7.93(d, J=8.3Hz, 2H), 7.85-7.76(m, 3H), 7.61(d, J=3.6Hz, 1H), 7.47(d, J=4.9 Hz, 2H), 6.09(s, 1H), 5.71-5.64(m, 1H), 4.01-4.81(m, 4H), 3.39-3.34(m, 2H), 3.27-3.21(m, 2H), 2.43- 2.40(m, 2H), 2.25(s, 3H), 2.19(s, 6H), 2.12–2.07(m, 1H), 1.63(d, J=7.0Hz, 3H), 1.53(m, 2H), 1.33 –1.25(m,2H).

With reference to the method for Examples 1 and 19, use commercially available different amines as raw materials to replace (tetrahydro-2H-pyran-4-yl)-methylamine, and different boronic acids as raw materials to replace 4-((2-( The synthetic method of dimethylamino) ethyl) carbonic acid acyl) phenyl) boronic acid, obtains embodiment 20-22:

Referring to the method of Example 1, with (R) or (S)-1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethan-1-amine and different The commercially available amine reagent is the synthetic method of raw material substitution 1,1,1-trifluoropropane-2-amine, obtains embodiment 23-31:

Example 32: (R)-4-((1-(5-(4,5-difluoro-2-(pyrrol-1-ylmethyl)phenyl)thiophen-2-yl)ethyl)amino) -2-Methyl-6-((tetrahydro-2H-pyran-4-yl)methyl)pyrido[4,3-d]pyrimidin-7(6H)-one

Step 1: methyl 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)acetate (500mg, 1.84mmol), (R) -1-(5-Bromothiophen-2-yl)ethyl-1-amino hydrochloride (480 mg, 2.2 mmol) and N,N-diisopropylethylamine (951 mg, 7.36 mmol) were added to DMSO (5 mL) ), the tube was sealed at 100°C for overnight reaction. The reaction solution was diluted with water (100 mL) and extracted three times with ethyl acetate (100 mL). The combined organic phases were concentrated under reduced pressure and purified by HPLC to obtain a white intermediate compound (250 mg). LCMS (ESI) m/z: 443.8 [M+H] ⁺ . ¹ H NMR(400MHz,DMSO-d6)δ7.06(d,J=3.8Hz,1H),7.00(d,J=8.0Hz,1H),6.86(dd,J=3.8,1.0Hz,1H), 5.86(s, 1H), 5.55(t, J=7.2Hz, 1H), 4.07(m, 2H), 3.90(m, 2H), 3.71(s, 2H), 3.59(s, 3H), 2.34(s , 3H), 1.55 (d, J=6.9Hz, 3H).

Step 2: An aqueous solution (1 mL) of lithium hydroxide (190 mg, 4.52 mmol) was added dropwise to a solution of the above intermediate compound (250 mg, 0.56 mmol) in tetrahydrofuran (4 mL), and the reaction was performed at room temperature for 2 hours. TLC detected the disappearance of the raw materials. The solvent was removed under reduced pressure to give the crude intermediate as a pale yellow solid (220 mg). LCMS(ESI) m/z: 429.8[M+H] ⁺ .

Step 3: HATU (665mg, 1.75mmol) was added to the above intermediate compound (220mg, 0.58mmol), 4-aminomethyltetrahydropyran (200mg, 1.75mmol) and N,N-diisopropylethylamine ( 300 mg, 2.3 mmol) in tetrahydrofuran solution, react at 70°C for 12 hours. The solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10:1) to obtain a yellow solid intermediate compound (180 mg). LCMS (ESI) m/z: 526.9 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d6)δ7.94(d,J=5.4Hz,1H),7.06(d,J=3.8Hz,1H),6.85(dd,J=3.8,1.0Hz,1H), 6.80(d, J＝7.9Hz, 1H), 5.91(s, 1H), 5.53(m, 1H), 4.10(m, 2H), 3.91(m, 2H), 3.85-3.80(m, 2H), 3.50 (s,2H),3.22(m,2H),2.94(m,2H),2.69(m,1H),2.33(s,3H),1.68-1.58(m,1H),1.55(m,4H), 1.20-1.07 (m, 2H).

Step 4: Aqueous hydrochloric acid (5M, 1.5 mL, 7.5 mmol) was added to a solution of the above intermediate compound (170 mg, 0.32 mmol) in isopropanol (8 mL). The reaction mixture was reacted at 80 degrees for 1 hour. The reaction of the raw materials was detected by LCMS. The reaction solution was diluted with dichloromethane (100 mL), and the reaction solution was washed with brine. The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to obtain a pale yellow solid intermediate compound (150 mg) . LCMS (ESI) m/z: 463.1 [M+H] ⁺ .

Step 5: Under nitrogen protection, tetrakistriphenylphosphine palladium (13mg, 0.017mmol) was added to the above simplified compound (80mg, 0.173mmol), 4,5-difluoro-2-(pinacol boronate)benzaldehyde (27 mg, 0.207 mmol), potassium carbonate (30 mg, 0.34 mmol), water (1 mL) in 1,4-dioxane (5 mL). The reaction mixture was heated to 100°C and reacted at this temperature for 2 hours. LCMS detected the disappearance of the starting material. The reaction solution was diluted with ethyl acetate (50 mL) and washed with brine (20 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10:1) to obtain a pale yellow solid compound (50 mg). LCMS (ESI) m/z: 525.2 [M+H] ⁺ .

Step 6: At room temperature, a drop of glacial acetic acid was added to the above intermediate compound (50 mg, 0.1 mmol) and tetrahydropyrrole (21 mg, 0.3 mmol) in methanol (5 mL), and the reaction mixture was reacted at 20° C. for 2 hours. Sodium cyanoborohydride (19 mg, 0.3 mmol) was added to the above reaction solution, and the reaction was continued for 12 hours. LCMS detected no starting material, most of which were converted into the desired product. The reaction solution was diluted with ethyl acetate (50 mL) and washed with brine (30 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was prepared by HPLC to obtain a pale yellow solid Example 32 compound (4.82 mg). LC-MS (Rt=1.955 min); (ESI) m/z: 580.2 [M+H] ⁺ ^.1 H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.66 (d, J= 8.0Hz, 1H), 7.51-7.43(m, 2H), 7.19(m, 1H), 7.12-7.10(m, 1H), 6.12(s, 1H), 5.88(t, J=7.1Hz, 1H), 3.95-3.81(m, 4H), 3.52(s, 2H), 3.23(m, 2H), 2.39(s, 4H), 2.31(s, 3H), 2.07(s, 1H), 1.69(d, J= 6.9Hz, 3H), 1.62 (s, 4H), 1.43 (m, 2H), 1.27 (m, 2H).

Example 33: (R)-4-((1-(4-Chloro-5-(2-(pyrrol-1-ylmethyl)phenyl)thiophen-2-yl)ethyl)amino)-2- Methyl-6-((tetrahydro-2H-pyran-4-yl)methyl)pyrido[4,3-d]pyrimidin-7(6H)-one

Step 1: Add liquid bromine (6.72g, 42.0mmol), aluminum trichloride (11.2g, 84.0mmol) to 1-(4-chlorothiophen-2-yl)ethyl-1 ketone (4.5g) at room temperature , 28.016 mmol) in chloroform (50 mL), the reaction mixture was reacted at 60 °C for 1 hour. No starting material was detected by LCMS and most of it was converted to the desired product. The reaction solution was diluted with ethyl acetate (100 mL), the organic phase was washed with sodium chloride solution, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified to obtain a white solid intermediate compound (5.0 g). LCMS (ESI) m/z: 240.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.05 (s, 1H), 2.53 (s, 3H).

Step 2: at room temperature, tetraethyl titanate (8.57g, 37.58mmol), (R)-(+) tert-butylsulfinamide (2.28g, 18.8mmol) were added to the above-mentioned intermediate compound (5.0g, 20.88 mmol) in tetrahydrofuran (80 mL). The reaction mixture was reacted at 70 degrees for 16 hours. The reaction was complete as detected by LC-MS. Water (150 mL) was added and extracted three times with ethyl acetate (80 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate). Ester=4:1) was purified to give the intermediate compound (3.7 g) as a pale yellow solid. LCMS (ESI) m/z: 343.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 2.65 (s, 3H), 1.19 (s, 9H).

Step 3: Add diisobutylaluminum hydride (33 mL) to the above intermediate compound (3.7 g, 10.8 mmol) in tetrahydrofuran (80 mL) at below minus 60°C. The reaction mixture was gradually warmed to room temperature, and the reaction was carried out at this temperature for 16 hours. No starting material was detected by LCMS and most of it was converted to the desired product. Methanol (10 mL) was added to the reaction solution, then the reaction solution was diluted with ethyl acetate (100 mL), filtered through celite, and the reaction solution was concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent: petroleum ether/acetic acid). Ethyl ester = 4:1) was purified to give a pale yellow solid intermediate compound (3.1 g). LCMS (ESI) m/z: 345.9 [M+H] ⁺ . ¹ H NMR(400MHz, DMSO-d6)δ7.08(s,1H),6.01(d,J=7.5Hz,1H),4.60-4.55(m,1H),1.47(d,J=6.8Hz,3H) ), 1.13(s, 9H).

Step 4: The methanol solution (30 mL) of HCl (g) was added to the methanol (30 mL) of the above intermediate compound (3.1 g, 8.99 mmol) at room temperature, and the reaction mixture was reacted at room temperature for 3 hours. The LCMS reaction was completed, the reaction solution was directly spun dry, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to obtain a white solid intermediate compound (2.2 g). ¹ H NMR (400MHz, DMSO-d6) δ8.74(br.s, 2H), 7.35(s, 1H), 4.65(q, J=6.8Hz, 1H), 1.57(d, J=6.8Hz, 3H) ).

Step 5: Potassium fluoride (854 mg, 14.7 mmol) was added to 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)acetic acid Methyl ester (400 mg, 1.47 mmol) and the above intermediate compound (530 mg, 2.21 mmol) in dimethyl sulfoxide (10 mL). The reaction mixture was sealed and reacted at 100°C for 16 hours. After the reaction solution was diluted with ethyl acetate (50 mL), the organic phase was washed with water (20 mL), and the separated organic phase was dried over anhydrous sodium sulfate. After the filtrate was concentrated under reduced pressure, the obtained crude product was purified by preparative HPLC to give the intermediate compound (350 mg) as a white solid. LCMS (ESI) m/z: 477.8 [M+H] ⁺ . ¹ H NMR(400MHz,DMSO-d6)δ7.06-7.03(m,2H),5.87(s,1H),5.53(m,1H),4.09(m,2H),3.91(m,2H),3.72 (s, 2H), 3.59 (s, 3H), 2.35 (s, 3H), 1.56 (d, J=6.9 Hz, 3H).

Step 6: at room temperature, an aqueous solution (2mL) of lithium hydroxide (350mg, 0.73mmol) was added to the tetrahydrofuran (3mL) of the above-mentioned intermediate compound (350mg, 0.73mmol), and the reaction mixture was reacted at this temperature for 2 hours , LCMS detected the reaction was complete. The solvent was removed by concentration under reduced pressure to obtain a pale yellow solid crude intermediate compound (350 mg).

Step seven: at room temperature, the above-mentioned intermediate compound (350mg, 0.73mmol) was dissolved in tetrahydrofuran (80mL), followed by adding (tetrahydropyran-4-yl)methylamino (254mg, 2.20mmol), HATU ( 837mg, 2.20mmol), N,N-diisopropylethylamine (380mg, 2.94mmol), the reaction mixture was reacted at 70 degrees for 2 hours. After the completion of the reaction was detected by LCMS, the reaction solution was diluted with ethyl acetate (150 mL) and washed twice with water (50 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was prepared and purified by HPLC to obtain a light yellow color Solid intermediate compound (110 mg). LCMS (ESI) m/z: 560.9 [M+H] ⁺ .

Step 8: Aqueous hydrochloric acid (5M, 1.5mL) was added to the above intermediate compound (110mg, 0.2mmol) in isopropanol (8mL) at room temperature, and the reaction mixture was reacted at 80 degrees for 2 hours. The reaction was complete as detected by LCMS, and the reaction solution was diluted with dichloromethane (100 mL). The reaction solution was washed with brine (80 mL), the separated organic phase was separated and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by HPLC to obtain a white solid intermediate compound (85 mg). LCMS (ESI) m/z: 499.1 [M+H] ⁺ .

Step 9: At room temperature, tetrakistriphenylphosphine palladium (19mg, 0.0161mmol) was added to 2-(pyrrol-1-ylmethyl)phenylboronic acid (43mg, 0.21mmol), the above-mentioned intermediate compound (80mg, 0.1607mmol) ), potassium carbonate (45 mg, 0.32 mmol), water (3 mL) in 1,4-dioxane (16 mL). The reaction mixture was reacted at 100 degrees for 2 hours. Complete reaction of starting material was detected by LCMS. The reaction solution was diluted with ethyl acetate (80 mL), filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to obtain a white solid Example Example 33 Compound (20.2 mg). LC-MS (Rt=0.996 min); (ESI) m/z: 578.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.05 (br.s, 1H), 8.67 (br. s, 1H), 7.51(d, J=7.5Hz, 1H), 7.40(m, 1H), 7.31(m, 1H), 7.24(d, J=6.7Hz, 1H), 7.13(s, 1H), 6.12(s, 1H), 5.81(m, 1H), 3.92(m, 2H), 3.83(m, 2H), 3.43(s, 2H), 3.23(m, 2H), 2.28(m, 7H), 2.07 (m, 1H), 1.68 (d, J=6.8 Hz, 3H), 1.55 (m, 4H), 1.43 (m, 2H), 1.34-1.21 (m, 2H).

Example 34: (R)-4-((1-(4-Methyl-5-(2-(pyrrol-1-ylmethyl)phenyl)thiophen-2-yl)ethyl)amino)-2 -Methyl-6-((tetrahydro-2H-pyran-4-yl)methyl)pyrido[4,3-d]pyrimidin-7(6H)-one

Step 1: At room temperature, N-bromosuccinimide NBS (12.69g, 71.3mmol) was added to 1-(4-methylthiophen-2-yl)ethyl-1-one (2g, 14.3mmol) In ethanol (30 mL), the reaction mixture was reacted at 20 °C for 2 hours. The reaction was complete by LCMS. The reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was washed with sodium chloride solution (50 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20:1) to obtain a white solid intermediate compound (2.5 g) ). LCMS (ESI) m/z: 220.8 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 2.48 (s, 3H), 2.19 (s, 3H).

Step 2: At room temperature, tetraethyl titanate (4.5g, 19.7mmol), (R)-(+) tert-butylsulfinamide (1.19g, 9.86mmol) were added to the above-mentioned intermediate compound (2.4g, 10.9 mmol) in tetrahydrofuran (20 mL). The reaction mixture was reacted at 70 degrees for 16 hours. The reaction was almost complete by LCMS, and brine (80 mL) was added. After diluting the reaction solution with ethyl acetate (100 mL), the separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate=4:1) Purification gave a pale yellow solid intermediate compound (2.5 g). LCMS (ESI) m/z: 323.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 7.63 (s, 1H), 2.62 (s, 3H), 2.16 (s, 3H), 1.18 (s, 9H).

Step 3: DIBAL-H (24 mL) was slowly added to a solution of the above intermediate compound (2.5 g, 7.74 mmol) in tetrahydrofuran (50 mL) at minus 60°C. The reaction mixture was gradually warmed to room temperature, and the reaction was carried out at this temperature for 16 hours. The reaction was basically complete as detected by LCMS. Methanol (10 mL) was added to the reaction solution, diluted with ethyl acetate (100 mL), filtered through Celite, the filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate= 4:1) Purification to obtain a pale yellow solid intermediate compound (2.0 g). LCMS (ESI) m/z: 325.9 [M+H] ⁺ .

Step 4: At room temperature, the methanol solution (20 mL) of HCl (g) was added to the methanol (20 mL) of the above intermediate compound (2.0 g, 7.71 mmol), and the reaction mixture was reacted at room temperature for 3 hours. The reaction was basically complete as detected by LCMS. The solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to obtain a white solid intermediate compound (1.4 g). ¹ H NMR(400MHz,DMSO-d6)δ8.70(br.s,2H),7.09(s,1H),4.60(s,1H),2.12(s,3H),1.55(d,J=6.6Hz , 3H).

Step 5: N,N-diisopropylethylamine (750mg, 12.3mmol) was added to the above intermediate compound (500mg, 4.09mmol), 2-(6-chloro-5-(1,3-dioxolane) -2-yl)-2-methylpyrimidin-4-yl)acetic acid methyl ester (900 mg, 4.09 mmol) in dimethylsulfoxide (6 mL). The reaction mixture was sealed and reacted at 100°C for 16 hours. LCMS detected the disappearance of the starting material. The reaction solution was diluted with ethyl acetate (100 mL), washed twice with brine (50 mL), the combined organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was prepared by HPLC to obtain a white solid intermediate compound (240 mg ). LCMS (ESI) m/z: 458.3 [M+H] ⁺ .

Step 6: At room temperature, an aqueous solution (2 mL) of lithium hydroxide (176 mg, 4.20 mmol) was added to the tetrahydrofuran (3 mL) of the above-mentioned intermediate compound (240 mg, 0.53 mmol), and the reaction mixture was reacted at this temperature for 2 hours , LCMS detected that all the raw materials were converted into products. The solvent tetrahydrofuran and water were spun off under reduced pressure to give a white solid compound (240 mg). LCMS (ESI) m/z: 444.0 [M+H] ⁺ .

Step 7: At room temperature, the above intermediate compound (240 mg, 0.53 mmol) was dissolved in tetrahydrofuran (50 mL), and (tetrahydropyran-4-yl)methylamino (182 mg, 1.575 mmol), HATU ( 599mg, 1.58mmol), N,N-diisopropylethylamine (272mg, 2.1mmol), the reaction mixture was reacted at 70 degrees for 2 hours. The reaction product was mainly detected by LCMS. The reaction solution was diluted with ethyl acetate (100 mL), washed twice with brine (50 mL), the separated organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by HPLC to obtain a pale yellow solid compound (160 mg) .

LCMS (ESI) m/z: 541.1 [M+H] ⁺ .

Step 8: Aqueous hydrochloric acid (5M, 1.5mL) was added to the isopropanol (8mL) of the above intermediate compound (160mg, 0.3mmol) at room temperature, and the reaction mixture was reacted at 80 degrees for 2 hours. The reaction was substantially complete as detected by LCMS. The reaction solution was diluted with dichloromethane (100 mL) and washed with brine (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by HPLC to give a white solid intermediate compound (85 mg). LCMS (ESI) m/z: 479.0 [M+H] ⁺ .

Step 9: at room temperature, tetrakistriphenylphosphine palladium (20mg, 0.017mmol) was added to 2-formaldehyde phenylboronic acid (33mg, 0.22mmol), the above-mentioned intermediate compound (80mg, 0.17mmol), potassium carbonate (46mg, 0.34 mmol), water (1 mL) in 1,4-dioxane (5 mL). The reaction mixture was reacted at 100 degrees for 2 hours. Diluted with ethyl acetate (30 mL), filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to obtain a white solid intermediate compound ( 80 mg). LCMS (ESI) m/z: 503.2 [M+H] ⁺ .

Step 10: At room temperature, add tetrahydropyrrole (106 mg, 1.4921 mmol) to the above intermediate compound (75 mg, 0.15 mmol) in methanol (3 mL), react at 20 ° C for 1 hour, add sodium cyanoborohydride (33 mg, 0.52 mmol), the reaction mixture was reacted at 20°C for 1 hour. The reaction was complete by LCMS. The reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was washed twice with aqueous sodium chloride solution (30 mL). The separated organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by HPLC to obtain the compound of Example 34 (5.3 mg) as a white solid. LC-MS (Rt=1.067 min); (ESI) m/z: 558.3 [M+H] ⁺ ^.1 H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.64 (s, 1H) ,8.17(s,2H),7.53(d,J＝7.5Hz,1H),7.37(t,J＝7.0Hz,1H),7.27(t,J＝7.0Hz,1H),7.17(d,J＝ 7.4Hz, 1H), 6.94(s, 1H), 6.11(s, 1H), 5.84(d, J=6.8Hz, 1H), 3.97(m, 1H), 3.84(m, 3H), 3.43(s, 2H), 3.23(s, 2H), 2.31(d, J=6.7Hz, 7H), 2.12–2.01(m, 1H), 1.93(s, 3H), 1.66(d, J=6.8Hz, 3H), 1.60(m, 4H), 1.43(d, J=12.2Hz, 2H), 1.27(m, 2H).

Example 35: (R)-4-((1-(3-Fluoro-5-(2-(pyrrol-1-ylmethyl)phenyl)thiophen-2-yl)ethyl)amino)-2- Methyl-6-((tetrahydro-2H-pyran-4-yl)methyl)pyrido[4,3-d]pyrimidin-7(6H)-one

Step 1: At room temperature, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (13.85g, 72.3mmol) was added to 3-fluorothiophene-2-carboxylic acid (4.8g) , 32.85 mmol) and N,O-dimethylhydroxylamine hydrochloride (7.05 g, 72.3 mmol) in pyridine (30 mL), the reaction mixture was reacted at room temperature for 16 hours. The solvent of the reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=4:1) to obtain a yellow solid intermediate compound (6.1 g). LCMS (ESI) m/z: 190.0 [M+H] ⁺ .

Step 2: Under nitrogen protection, N-bromosuccinimide (17.5g, 98.31mmol) was added to the above intermediate compound (6.1g, 32.8mmol) in N,N-dimethylformamide (100mL) , the reaction mixture was heated to 60°C and reacted at this temperature for 16 hours. After adding ethyl acetate (500 mL) to dilute, and then washing with saturated brine (100 mL) three times, the separated organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (detergent: ethyl acetate/petroleum ether=4:1) to obtain a brown solid intermediate compound (3.5 g). LCMS (ESI) m/z: 269.8 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 7.42 (s, 1H), 3.74 (s, 3H), 3.22 (s, 3H).

Step 3: Under nitrogen protection, methylmagnesium bromide (30ml, 31.7mmol) was added to the tetrahydrofuran (50mL) of the above intermediate compound (3.4g, 12.7mmol) at 0°C, and the reactant was continued at 0°C React for 1 hour. After the reaction of the raw materials was detected by LCMS, ammonium chloride solution (200 mL) was added to quench the reaction. The reaction solution was extracted twice with ethyl acetate (150 ml), the combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the crude product obtained was subjected to HPLC to prepare a brown oily intermediate compound (2.2 g). LCMS (ESI) m/z: 224.8 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 2.54 (s, 3H).

Step 4: Under nitrogen protection, tetraethyl titanate (3.94g, 17.2mmol) was added to the above compound (2.2g, 9.5mmol), (R)-(+) tert-butylsulfinamide (1.05g, 8.64 g) mmol) in tetrahydrofuran (30 mL), the reaction mixture was heated to 70°C and reacted at this temperature for 16 hours. After the reaction solution was cooled to room temperature, brine (50 ml) was added, and stirring was continued for 10 minutes. The reaction mixture was filtered through celite, the filtrate was extracted twice with ethyl acetate (100 ml), and the combined organic phases were dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=4:1) to obtain a brown solid intermediate compound (1.8 g). LCMS (ESI) m/z: 326.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 7.47 (s, 1H), 2.65 (d, J=2.4 Hz, 3H), 1.18 (s, 9H).

Step 5: DIBAL-H (15ml, 14.1mmol) was added to the tetrahydrofuran (30mL) of the above-mentioned intermediate compound (1.8g, 5.5mmol) under cooling at -78°C, the reaction mixture was slowly raised to room temperature and left there. The reaction was carried out at the temperature for 16 hours, and the reaction was basically complete as detected by LCMS. Methanol (20 ml) was added to quench the reaction, and after concentration under reduced pressure to remove most of the solvent, the residue was diluted with methanol (200 ml), filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (eluent). : ethyl acetate/petroleum ether=4:1) was purified to obtain a brown solid compound (1.4 g). LC-MS (ESI) m/z: 329.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 7.19 (s, 1H), 5.89 (d, J=6.6 Hz, 1H), 4.66 (m, 1H), 1.45 (d, J=6.8Hz, 3H), 1.10 (s, 9H).

Step 6: A solution of HCl (g) in methanol (10 mL, 30 mmol) was added to the above intermediate compound (1.8 g, 5.48 mmol) in methanol (10 mL). The reactants were reacted at room temperature for 2 hours. The LCMS reaction was essentially complete. The solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to obtain a brown solid intermediate compound (1.4 g). LC-MS (ESI) m/z: 206.9[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ 8.76(s, 3H), 7.33(s, 1H), 4.70(d, J= 6.6Hz, 1H), 1.56(d, J=6.8Hz, 3H).

Step 7: Methyl 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)acetate (500 mg, 1.84 mmol), the above middle The bulk compound (494 mg, 2.2 mmol) and potassium fluoride (1.06 g, 18.3 mmol) were dissolved in dimethyl sulfoxide (5 mL) and the reaction was heated to 100 degrees overnight in a sealed tube. LCMS detected that the reaction was basically complete. The reaction solution was diluted with ethyl acetate (100 mL), washed three times with water (50 mL), the combined organic phases were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained crude product was prepared and purified by HPLC to obtain a white solid intermediate Compound (500 mg). LC-MS (ESI) m/z: 462.1 [M+H] ⁺ . ¹ H NMR(400MHz,DMSO-d6)δ7.18(s,1H),7.08(d,J=7.5Hz,1H),5.88(s,1H),5.55(m,1H),4.09(m,2H ), 3.96-3.91(m, 2H), 3.71(s, 2H), 3.59(s, 3H), 2.56-2.55(m, 1H), 2.33(s, 3H), 1.55(d, J=6.9Hz, 3H).

Step 8: An aqueous solution (2 mL) of lithium hydroxide (365 mg, 8.69 mmol) was added dropwise to a solution of the above intermediate compound (500 mg, 1.08 mmol) in tetrahydrofuran (10 mL), and the reaction was carried out at room temperature for 2 hours. LC-MS detected that the reaction of the starting materials was complete. Concentration under reduced pressure to remove the solvent gave a pale yellow solid crude intermediate product (450 mg). LC-MS (ESI) m/z: 447.8 [M+H] ⁺ .

Step 9: HATU (665mg, 1.75mmol) was added to the above intermediate compound (220mg, 0.58mmol), (tetrahydropyran-4-yl)methylamino (200mg, 1.75mmol) and N,N-diiso In a solution of propylethylamine (300 mg, 2.3 mmol) in tetrahydrofuran, the reaction solution was heated to 70° C. to react for 2 hours. The solvent was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10:1) to obtain a yellow solid intermediate compound (180 mg). LC-MS (ESI) m/z: 545.0 [M+H] ⁺ .

Step ten: Aqueous hydrochloric acid (5M, 1.5 mL, 7.5 mmol) was added to a solution of the above intermediate compound (350 mg, 0.52 mmol) in isopropanol (8 mL). The reaction mixture was reacted at 80 degrees for 1 hour. The reaction of the raw materials was detected by LCMS. The reaction solution was diluted with dichloromethane (100 mL), washed twice with brine (30 mL), the separated organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (eluent: dichloromethane). Methane/methanol=10:1) was purified to give a pale yellow solid compound (180 mg). LC-MS (ESI) m/z: 483.1 [M+H] ⁺ .

Step eleven: under nitrogen protection, tetrakistriphenylphosphine palladium (58mg, 0.05mmol) was added to 2-formaldehyde phenylboronic acid (98mg, 0.65mmol), the above intermediate compound (250mg, 0.5mmol), potassium carbonate ( 138 mg, 0.1 mmol) and water (1 mL) in 1,4-dioxane (5 mL). The reaction mixture was heated to 100°C and reacted at this temperature for 16 hours. The reaction was basically complete as detected by LCMS. The reaction solution was diluted with ethyl acetate (50 mL), washed twice with brine (10 mL), and the separated organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to obtain a pale yellow solid compound (180 mg). LC-MS (ESI) m/z: 507.2 [M+H] ⁺ .

Step 12: At room temperature, a drop of glacial acetic acid was added to the above intermediate compound (180 mg, 0.37 mmol), tetrahydropyrrole (81 mg, 1.13 mmol) in methanol (5 mL), and the reaction mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (71 mg, 1.13 mmol) was added to the above reaction solution, and the reaction was continued for 12 hours. LC-MS detected that the reaction was basically complete. The reaction solution was diluted with ethyl acetate (50 mL), washed twice with brine (20 mL), and the separated organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the obtained crude product was prepared by HPLC to obtain the compound of Example 35 (11.2 mg) as a pale yellow solid. LC-MS (Rt=1.962 min); (ESI) m/z: 562.2 [M+H] ⁺ . ¹ H NMR(400MHz, DMSO-d6)δ9.09(s,1H),8.64(d,J=8.0Hz,1H),7.44-7.40(m,2H),7.35-7.33(m,2H),7.24 (s,1H),6.12(s,1H),5.88-5.85(m,1H),4.00-3.95(m,1H),3.91-3.82(m,3H),3.54(s,2H),3.26-3.21 (m, 2H), 2.38(m, 7H), 2.30(s, 3H), 2.08(m, 1H), 1.68(d, J=6.8Hz, 3H), 1.61(m, 4H), 1.33-1.30( m, 2H), 1.27-1.24 (m, 2H).

With reference to the method for Examples 1 and 19, use commercially available different amines as raw materials to replace (tetrahydro-2H-pyran-4-yl)-methylamine, and different boronic acids as raw materials to replace 4-((2-( The synthetic method of dimethylamino) ethyl) carbonic acid acyl) phenyl) boronic acid, obtains embodiment 36-41:

Example 42: (R)-N,N-Dimethyl-4'-(1-((2-methyl-7-oxo-6-((tetrahydro-2H-pyran-4-yl) Methyl)-6,7-dihydropyridine[4,3-d]pyrimidin-4-yl)amino)ethyl)-[1,1'-diphenyl]-2-carbonic acid amide

Step 1: Potassium fluoride (4.26g, 73.51mmol) was added to 2-(6-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyrimidine-4 at room temperature -yl)methyl acetate (2.0 g, 7.351 mmol), (R)-1-(4-bromophenyl)ethyl-1-amine hydrochloride (2.073 g, 8.822 mmol) in dimethyl sulfoxide (40 mL) )middle. The reaction mixture was sealed and reacted at 100°C for 16 hours. The reaction was basically complete as detected by LCMS. The reaction solution was diluted with ethyl acetate (200 mL), washed twice with brine (50 mL), the combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the crude product obtained was purified by HPLC to obtain a pale yellow solid intermediate compound (2.4g). LCMS (ESI) m/z: 438.1 [M+H] ⁺ .

Step 2: At room temperature, an aqueous solution (8 mL) of lithium hydroxide (1.19 g, 49.6 mmol) was added to the tetrahydrofuran (40 mL) of the above-mentioned intermediate compound (2.7 g, 6.21 mmol), and the reaction mixture was reacted at this temperature for 2 hours . The reaction was basically complete as detected by LCMS. Concentration under reduced pressure to remove the solvent gave a pale yellow solid intermediate product (2.5 g). LCMS (ESI) m/z: 422.1 [M+H-Li] ⁺ .

Step 3: At room temperature, the above intermediate compound (2.41g, 5.64mmol) was dissolved in tetrahydrofuran (100mL), and (tetrahydropyran-4-yl)methylamino (1.95g, 16.9mmol) was added successively, HATU (8.58 g, 22.6 mmol), N,N-diisopropylethylamine (2.92 g, 22.6 mmol), the reaction mixture was heated to 70 degrees and reacted for 2 hours. The reaction was basically complete as detected by LCMS. After concentrating under reduced pressure to remove most of the solvent, the reaction solution was diluted with ethyl acetate (200 mL) and washed twice with water (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (eluent: ethyl acetate/methanol=20:1) to obtain a pale yellow solid intermediate compound (2.08 g) . LCMS (ESI) m/z: 521.2 [M+H] ⁺ .

Step 4: At room temperature, aqueous hydrochloric acid (5M, 7.0 mL) was added to the above intermediate compound (2.08 g, 4.01 mmol) in tetrahydrofuran (32 mL), and the reaction mixture was reacted at 80°C for 2 hours. The reaction was basically complete as detected by LCMS. The reaction solution was diluted with dichloromethane (200 mL), washed twice with brine (50 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to obtain a pale yellow solid intermediate compound (1.6 g). LCMS (ESI) m/z: 459.1 [M+H] ⁺ . ¹ H NMR(400MHz, DMSO-d6)δ9.11(s,1H),8.55(d,J=7.4Hz,1H),7.63-7.45(m,2H),7.38(d,J=8.4Hz,2H) ), 6.10(s, 1H), 5.54(m, 1H), 4.00(m, 1H), 3.92-3.77(m, 3H), 3.23(m, 2H), 3.17(m, 1H), 2.23(s, 3H), 2.10 (m, 1H), 1.54 (d, J=7.0Hz, 3H), 1.44 (m, 2H), 1.34-1.22 (m, 2H).

Step 4: Under nitrogen protection, tetrakistriphenylphosphine palladium (33mg, 0.03mmol) was added to the above intermediate compound (130mg, 0.285mmol), (2-(dimethylformyl)phenyl)boronic acid (72mg, 0.37 mmol), potassium carbonate (79 mg, 0.57 mmol), water (2 mL) in 1,4-dioxane (12 mL). The reaction mixture was heated to 100°C and reacted at this temperature for 2 hours. The reaction solution was diluted with ethyl acetate (200 mL), washed twice with brine (50 mL), the combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by HPLC to obtain a pale yellow solid of Example 42. Compound (20.2 mg). LC-MS (Rt=1.493 min); (ESI) m/z: 526.3 [M+H] ⁺ ^.1 H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.53 (d, J= 7.7Hz, 1H), 7.70(m, 4H), 7.53(d, J=8.2Hz, 2H), 7.48(d, J=8.2Hz, 2H), 6.10(s, 1H), 5.66(m, 1H) ,4.01(m,1H),3.93-3.81(m,3H),3.25(m,2H),2.97(m,6H),2.25(s,3H),2.11(m,1H),1.60(d,J =7.0Hz, 3H), 1.45 (m, 2H), 1.34-1.23 (m, 2H).

With reference to the method of Example 42, commercially available different amines are used as raw materials to replace (tetrahydropyran-4-yl) methylamino, and different boronic acids are used as raw materials to replace (2-(dimethylformyl) phenyl) ) the synthetic method of boronic acid, obtains embodiment 43-47:

With reference to the method for Examples 1 and 19, use commercially available different amines as raw materials to replace (tetrahydro-2H-pyran-4-yl)-methylamine, and different boronic acids as raw materials to replace 4-((2-( The synthetic method of dimethylamino) ethyl) carbonic acid acyl) phenyl) boronic acid, obtains embodiment 48-50:

With reference to the method of Example 35, commercially available different amines are the raw materials to replace (tetrahydropyran-4-yl) methylamino, and different boronic acids are the synthetic methods of raw materials to replace 2-formaldehyde phenylboronic acid, to implement Example 52-56;

With reference to the method for Example 35, take commercially available different amines as raw materials to replace (tetrahydropyran-4-yl) methylamino, and different boronic acids as raw materials to replace the synthetic method of 2-formaldehyde phenylboronic acid, obtain implementation Example 71-80;

With reference to the method of Example 42, use commercially available different amines as raw materials to replace (tetrahydropyran-4-yl) methylamino, and different boronic acids as raw materials to replace (2-(dimethylformyl) phenyl) ) the synthetic method of boronic acid, obtains embodiment 81-86;

Test Example 1 Enzyme Inhibitory Activity Test

CisBio's KRAS ^G12C /SOS1 kit was used to test the efficacy of compounds in inhibiting the protein-protein interaction between SOS1 and KRAS ^G12C by Binding assay, and the results were expressed as IC ₅₀ values.

Test method: (1) The test concentration of the test compound is 1000 nM, and the 100% DMSO solution diluted to 200 times the final concentration in a 384-well plate is diluted 3 times with 10 concentrations. Use a dispenser Echo 550 to transfer 50 nL of 200-fold final concentration of compound to the 384 well plate of interest. Add 50nL of 100% DMSO to negative control wells and positive control wells respectively; (2) Prepare 4 times final concentration of Tag1SOS1 solution with Diluent buffer; (3) Add 2.5 μL of 4 times final concentration of Tag1SOS1 solution to 384-well plate ; (4) Prepare 4 times final concentration of Tag2 KRAS ^G12C solution with Diluent buffer; (5) Add 2.5 μL of 4 times final concentration of Tag2 KRAS ^G12C solution to compound wells and positive control wells respectively; add 2.5 μL to negative control wells μL of diluent buffer; (6) Centrifuge the 384-well plate at 1000rpm for 30 seconds, shake and mix, and incubate at room temperature for 15 minutes; (7) Use Detection buffer to prepare 1x final concentration of Anti Tag1 TB3+ solution and 1x final concentration of Anti Tag2 XL665 After mixing the two solutions, add 5 μL of the mixed solution to each well; (8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, and incubate at room temperature for 120 minutes after shaking and mixing; (9) Use an Envision microplate reader to read Em665/620 ; (10) Data analysis, calculation formula

The mean value of Min signal negative control wells; the mean value of Max signal positive control wells; the mean value of Compound signal compound wells. The fitted dose-response curve takes the log value of the concentration as the X-axis, and the percentage inhibition rate on the Y-axis. The log(inhibitor) vs.response Variable slope of the analysis software GraphPad Prism 5 is used to fit the dose-response curve to obtain the effect of each compound on the enzyme. _IC50 value for activity. The fitting formula is: Y=Bottom+(Top Bottom)/(1+10^((LogIC ₅₀ X)*Hill Slope)).

Results: Most of the compounds in the examples of the present invention showed high inhibitory activity against KRAS ^G12C /SOS1 enzyme, with IC ₅₀ less than 100 nM. (The specific IC ₅₀ values are expressed as follows: A<50nM;50nM≤B<200nM; C≥200nM).

Test Example 2: Effects of Example Compounds on MiaPaca-2 Cell Proliferation

Test method one (2D): MiaPaca-2 cells (pancreatic cancer) cells (100 μL/well, 20,000 cells/mL) were seeded in 96-well culture plates supplemented with 10% fetal bovine serum and 1% penicillin/sulfuric acid Streptomycin. Using 0.5% dimethyl sulfoxide as a blank control, cells were treated with a solution of the test compound at a starting concentration of 10 μM, eight serial three-fold dilutions, and incubated in a 5% CO ₂ incubator for a certain period of time (5 days). At the end of the incubation, 10 μL of MTT stock solution (5 mg/mL) was added to each well. The plates were incubated at 37°C for 4 hours, then the medium was removed. Dimethyl sulfoxide (100 μL) was added to each well and shaken well. The absorbance of the formazan product was measured at 570 nm on a Thermo Scientific Varioskan Flash multimode reader. _IC50 values were obtained by fitting the dose-response data to a three-parameter nonlinear regression model using GraphPad Prism 6.0 software.

Results: The proliferation inhibitory activity of the example compounds provided by the present invention on MiaPaca-2 cells, the IC ₅₀ values were all less than 15uM; some example compounds such as Examples 2, 6, 9, 10, 15 The proliferation inhibition of MiaPaca-2 cells Activity, IC ₅₀ value is less than 5uM, showing excellent in vitro anti-tumor effect. As shown in Table (2). List of data on the inhibitory activity data of the compounds of the examples of the present invention on the proliferation of MiaPaca-2 cells.

实施例编号Example number	IC ₅₀/uM _IC50 /uM	实施例编号Example number	IC ₅₀/uM _IC50 /uM
对比化合物BI3406Comparative compound BI3406	7.857.85	22	4.424.42
55	7.47.4	66	1.671.67
77	11.611.6	99	2.512.51
1010	1.671.67	1515	1.981.98
1616	6.126.12

Test Example 3: ADMET Test of Example Compounds

(1) Metabolic stability test: 150 μL of liver microsomes (final concentration 0.5 mg/mL) were used for metabolic stability incubation, and the system contained NADPH (final concentration 1 mM), 1 μM test compound and positive control midazole The reaction was terminated with acetonitrile containing tinidazole at 0min, 5min, 10min, 20min and 30min, respectively, vortexed for 10min, centrifuged at 15000rmp for 10min, and 50 μL of supernatant was injected into a 96-well plate. Compound metabolic stability was calculated by determining the relative reduction of the original drug.

Results: Some of the compounds in the examples of the present invention had good stability to liver microsomes of various genera (rat, mouse, dog, human), and showed high metabolizability.

Example number

Liver microsomal stability (T _1/2 /min)

	大鼠rat	小鼠mouse	狗dog	猴monkey	人people
1919	49.249.2	11.711.7	108108	42.442.4	403403
6767	343.5343.5	403403	100.7100.7	25.125.1	107.9107.9
7373	32.932.9	403403	223.3223.3	21.121.1	26.326.3
8585	369.1369.1	403403	403403	362.4362.4	99.599.5

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

Claims

A pyrimido heterocyclic compound as shown in general formula I, or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer, tautomer, and torsion isomer , solvates, polymorphs or prodrugs,

where:

R 1 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 12 cycloalkyl, C 4 - C 12 cycloalkenyl, 3-12-membered heterocycloalkyl, 5-12-membered aryl or 5-12-membered heteroaryl, carbocyclic or heteroatom-containing spiro/bridged/fused ring, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkenyl, 3-12 membered heterocycloalkane base, 5-12-membered aryl or 5-12-membered heteroaryl, carbocyclic or heteroatom-containing spiro/bridged/fused ring, optionally substituted with 1-3 Rn; or two of the above Rn can form a 3-12-membered saturated or partially unsaturated, or aromatic ring system through carbon chains or heteroatoms; the Rn is selected from hydrogen, deuterium, halogen, cyano, nitro, amide, sulfonamide, hydroxyl , amino, ureido, phosphoryl, alkyl phosphoroxy, alkylsilyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, haloalkyl, haloalkoxy, C 1 -C 6 mono Alkylamino, C 1 -C 6 dialkylamino, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl, C 1 -C 6 alkyl-S-, C 1 -C 6 alkane base-SO-, C 1 -C 6 alkyl-SO 2- ;

R 2a and R 2b are each independently selected from hydrogen, deuterium, halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl; and R 2a and R 2b or R 2a and Ar The substituent R m can form a 3-6 membered saturated or partially unsaturated or unsaturated ring system through a carbon chain or a heteroatom;

R 3 is H, deuterium, halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylamino, 3-8 membered cycloalkyl or heterocycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, 5-10 membered aromatic ring or aromatic heterocyclyl;

M is independently selected from N or CR 4 , and R 4 is selected from hydrogen, deuterium, halogen, cyano, C 1 -C 6 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl;

Ar 1 and Ar 2 are independently selected from 5-12-membered monocyclic or bicyclic aryl or heteroaryl groups, which may be represented by one or more groups R m selected from the group consisting of Substituted: hydrogen, deuterium, halogen, cyano, nitro, substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, hydroxyl, amino, urea, phosphoryl, alkylphosphooxy, alkylsilyl, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 alkoxy alkyl, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, C 1 -C 10 haloalkane Oxyalkyl, C 1 -C 10 monoalkylamino, C 1 -C 10 dialkylamino, C 1 -C 10 monoalkylaminoalkyl, C 1 -C 10 dialkylaminoalkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, 3-12 membered cycloalkyl or heterocycloalkyl, 3-12 membered cycloalkyl or heterocycloalkyl alkyl, C 1 -C 10 alkyl -S-, C 1 -C 10 alkyl-SO-, C 1 -C 10 alkyl-SO 2 -, substituted or unsubstituted 5-12-membered aryl or heteroaryl, or the above two R m A 3-12-membered saturated or partially unsaturated, or aromatic ring system can be formed through carbon chains or heteroatoms;

One or more hydrogen atoms on any of the above-mentioned groups may be substituted by a substituent selected from the following group: including but not limited to deuterium, halogen, C 1 -C 3 alkyl, 3-6 membered cycloalkyl or heterocyclic Cycloalkyl; wherein, the heteroaryl group contains 1-3 heteroatoms selected from the following group: N, O, P or S, and the heterocycloalkyl group contains 1-3 heteroatoms selected from the following group Heteroatom: N, O, P or S, the ring system includes spiro, bridged, fused, and saturated or partially unsaturated ring systems.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph thereof, or an enantiomer thereof A compound or prodrug, characterized in that, when R 2a and R 2b are different, the carbon atom to which the R 2a and R 2b are connected together is in the R configuration.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph thereof compound or prodrug, characterized in that the compound is a compound represented by the general formula (II):

Wherein R 3 is preferably selected from H, Me, cyclopropyl, chlorine; M is preferably selected from N or CH or CF or C-CN or C-Me; the range of R 1 , R 2a , R 2b , Ar 1 , Ar 2 is as claimed as defined in Requirement 1.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph thereof, or an enantiomer thereof compound or prodrug, characterized in that R 2a and R 2b are each independently hydrogen, C 1 -C 6 alkyl, preferably hydrogen and methyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph thereof, or an enantiomer thereof compound or prodrug, characterized in that R 3 is a C 1 -C 3 alkyl group, preferably a methyl group.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph thereof compound or prodrug, wherein M is C-H.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph thereof, or an enantiomer thereof A compound or prodrug, wherein Ar 1 and Ar 2 are each independently a 6- to 10-membered aryl group, a furanyl group, a thienyl group, a pyridyl group, and a pyrazolyl group.
The compound of any one of claims 1 and 3, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, Solvate, polymorph or prodrug, characterized in that the compound is a compound represented by the general formula (III):

wherein the ranges of R 1 , M and Ar 2 are as defined in any one of claims 1 and 3 .
The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph thereof, or an enantiomer thereof compound or prodrug, characterized in that R m is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, Hydroxyl, amino, C 1 -C 8 monoalkylamino, C 1 -C 8 dialkylamino, C1-C8 amido, C1-C8 sulfonamido, 3-8 membered cycloalkyl, 3-8 membered hetero Cycloalkyl, 3-8 membered cycloalkylalkyl, 3-8 membered heterocycloalkylalkyl, C 1 -C 6 alkyl-S-, C 1 -C 6 alkyl-SO-, C 1 - C 6 alkyl-SO 2 -, or the above two R m form a 3-8 membered saturated or partially unsaturated, or aromatic ring system through a carbon chain or heteroatom, wherein the R m can be further selected from amino , C 1 -C 3 monoalkylamino, C 1 -C 3 dialkylamino, C 1 -C 3 alkyl, hydroxyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkylalkyl Substituents are substituted.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph thereof, or an enantiomer thereof compound or prodrug, characterized in that R m is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, Hydroxyl, amino, C 1 -C 6 monoalkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 amido, C 1 -C 6 sulfonamido, 3-6 membered heterocycloalkyl, 3-6-membered heterocycloalkyl-(C1-C3 alkyl)-, 5-10-membered aryl, 5-10-membered heteroaryl, C 1 -C 3 alkyl-SO 2 -, or the above two R m constitutes a 5-6 membered saturated or partially unsaturated, or aromatic ring system through a carbon chain or heteroatom, wherein the R m may be further selected from amino, C 1 -C 3 monoalkylamino, C 1 -C Substituent substitution of C 3 dialkylamino, C 1 -C 3 alkyl, hydroxyl, 3-6-membered heterocycloalkyl, and 3-6-membered heterocycloalkylalkyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph thereof, or an enantiomer thereof compound or prodrug, characterized in that R m is selected from hydrogen, halogen, C 1 -C 4 monoalkylamino, C 1 -C 4 dialkylamino, 3-6 membered heterocycloalkyl, 3-6 membered Heterocycloalkyl-(C1-C3 alkyl)-, or the above two R m form a 5-6 membered saturated ring through a carbon chain or heteroatom.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph thereof, or an enantiomer thereof compound or prodrug, characterized in that R 1 is selected from C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, -C 4 -C 12 cycloalkenyl, 3-12 membered heterocycloalkyl, 5 -12-membered aryl or 5-12 membered heteroaryl optionally substituted with 1-3 Rn as defined in claim 1.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph thereof, or an enantiomer thereof compound or prodrug, characterized in that R 1 is selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, which can be optionally surrounded by 1-3 Rn Substituted, said Rn is as defined in claim 1 .
The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph thereof, or an enantiomer thereof compound or prodrug, characterized in that R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 5-8 membered heterocycloalkyl, -(C1-C6 alkylene)-C 3 - C6 cycloalkyl, -(C1-C6 alkylene)-5-8 membered heterocycloalkyl, which may be optionally substituted by 1-3 Rn, said Rn being halogen, C1-C3 alkane base.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph thereof, or an enantiomer thereof compound or prodrug, characterized in that R 1 is selected from 5-6-membered heterocycloalkyl, -(C1-C3 alkylene)-5-6-membered heterocycloalkyl.
The compound of any one of claims 1, 3, 8, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer thereof body, solvate, polymorph or prodrug, characterized in that R 1 is selected from the following groups:

wherein one or more R c is independently selected from hydrogen, deuterium, halogen, -C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, cyano, hydroxy, amino, -SC 1 -C 6 alkyl base, -SOC 1 -C 6 alkyl, -SO 2 C 1 -C 6 alkyl, -COC 1 -C 6 alkyl, -COOC 1 -C 6 alkyl, -CONHC 1 -C 6 alkyl, - CON(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), 3-6 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl, -C 1 -C 6 haloalkyl, -C 1 -C 6 haloalkoxy, -C 1 -C 6 deuterated alkyl, -C 1 -C 6 deuterated alkoxy, -O-3-6 membered cycloalkyl or heterocycloalkane base, -C 1 -C 6 alkyl OC 1 -C 6 alkyl, -C 1 -C 6 alkyl NHC 1 -C 6 alkyl, -C 1 -C 6 alkyl OH, -C 1 -C 6 Alkyl N(C 1 -C 6 alkyl) (C 1 -C 6 alkyl), and between any two R c can be through a carbon chain or heteroatomic 3-10-membered saturated or partially unsaturated carbocyclic ring or heterocycle; R d is independently selected from -C 1 -C 6 alkyl, -C 1 -C 6 alkyl OC 1 -C 6 alkyl, -C 1 -C 6 alkyl SC 1 -C 6 alkyl , -C 1 -C 6 alkyl SOC 1 -C 6 alkyl, -C 1 -C 6 alkyl SO 2 C 1 -C 6 alkyl, -COC 1 -C 6 alkyl, -COOC 1 -C 6 Alkyl, -CONHC 1 -C 6 alkyl, -CON(C 1 -C 6 alkyl) (C 1 -C 6 alkyl), 3-6 membered cycloalkyl or heterocycloalkyl, 5-10 membered Aryl or heteroaryl, -C 1 -C 6 haloalkyl, -C 1 -C 6 haloalkoxy, -C 1 -C 6 deuterated alkyl, -C 1 -C 6 deuterated alkoxy -C 1 -C 6 alkyl, -C 1 -C 6 alkyl O-3-6 membered cycloalkyl or heterocycloalkyl, -C 1 -C 6 alkyl NHC 1 -C 6 alkyl, -C 1 - C 6 alkyl OH, -C 1 -C 6 alkyl N(C 1 -C 6 alkyl) (C 1 -C 6 alkyl).
The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph thereof, or an enantiomer thereof substance or prodrug, characterized in that R 1 is selected from the following groups:

wherein R c , R d are as defined in claim 16 .
The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph thereof, or an enantiomer thereof substance or prodrug, characterized in that R 1 is selected from the following groups:
wherein R c , R d are as defined in claim 16 .
The compound of claim 16, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph thereof compound or prodrug, wherein R c is independently selected from hydrogen, halogen, -C 1 -C 3 alkyl, -C 1 -C 3 haloalkyl, 3-6 membered cycloalkyl or heterocycloalkyl; R d is independently selected from hydrogen, -C 1 -C 3 alkyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph thereof, or an enantiomer thereof compound or prodrug, characterized in that R 1 , R 2a , R 2b , R 3 , Ar 1 , Ar 2 , and M are each independently the corresponding groups in the compounds 1-86 prepared in the examples.
The compound of any one of claims 1, 3, 8, 16, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion thereof Isomers, solvates, polymorphs or prodrugs, characterized in that the compound has the following structure:
The compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvent thereof Use of compound, polymorph or prodrug, characterized in that it is used to prepare a drug for the treatment of diseases related to Ras protein activity or expression or mutation, especially a drug for the treatment of tumors, the tumor is independently selected from lung cancer , pancreatic cancer, liver cancer, colorectal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, melanoma, thyroid cancer, nasopharyngeal cancer.
Comprising a compound according to any one of claims 1-21 or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, A pharmaceutical composition composed of a solvate, a polymorph or a prodrug, wherein the pharmaceutical composition comprises:

(i) an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof ;and

(ii) A pharmaceutically acceptable carrier.