CN114524810A

CN114524810A - Pyrimidine heterocyclic compound, preparation method and application

Info

Publication number: CN114524810A
Application number: CN202111387596.1A
Authority: CN
Inventors: 万惠新; 王亚周; 马金贵; 王亚辉; 查传涛
Original assignee: Shanghai Lingda Biomedical Co ltd
Current assignee: Shanghai Lingda Biomedical Co ltd
Priority date: 2020-11-21
Filing date: 2021-11-22
Publication date: 2022-05-24
Anticipated expiration: 2041-11-22
Also published as: CN114524810B; WO2022105921A1

Abstract

The invention discloses a pyrimido heterocyclic compound, a preparation method and application thereof, in particular to a pyrimido fused ring compound shown as a general formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, a preparation method and application thereof in pharmacy, wherein the definition of each group is described in the specification.

Description

Pyrimidine heterocyclic compound, preparation method and application

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a pyrimido-heterocyclic compound which has better SOS1 inhibitory activity and can be used for preparing a therapeutic and preventive medicine for treating diseases related to Ras activity or expression or mutation.

Background

Ras protein is a key regulator in normal cell growth and malignant transformation processes, including cell proliferation, survival and invasion, tumor angiogenesis and metastasis. In most human tumors, Ras proteins are aberrantly activated due to mutations in the Ras gene itself or upstream or downstream Ras pathway components, or other changes in Ras signaling. Such mutations reduce the ability of RAS family gtpases to hydrolyze GTP, leaving the molecular switch to remain in an active GTP-bound form at all times, which drives unchecked oncogenic downstream signaling. One strategy to reduce the level of active RAS is against 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 KRAS with GTP, resulting in anti-proliferative 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 at present, and new therapeutic and prophylactic strategies are urgently needed for such cancers. The discovery of Ras-selective targeted drugs by the global academic and industrial communities has been ongoing for many years, but has not been approved to the market to date. In recent two years, targeted drugs directed to Ras drive have entered clinical trials in succession and showed good primary efficacy with encouraging results.

Therefore, more specific, efficient and low-toxic therapeutic drugs with unique mechanisms are urgently needed for Ras-driven tumors to enter the clinic, and the discovery and search of efficient, low-toxic and structurally novel Ras-targeted drugs are still a hot spot in the industry.

Disclosure of Invention

One of the technical problems to be solved by the invention is to provide a novel SOS1 inhibitor for preparing a tumor treatment medicament.

The scheme for solving the technical problems is as follows:

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

in the formula:

R¹independently selected from C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or 5-12 membered heteroaryl, carbocycle or heteroatom containing spiro/bridged ring/fused ring, wherein said C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or 5-12 membered heteroaryl, carbocyclic or heteroatom containing spiro/bridged ring/fused ring, optionally substituted with 1-3RⁿSubstitution; or the two RⁿA 3-12 membered saturated or partially unsaturated, or aromatic ring system may be formed by a carbon chain or heteroatom; said RⁿSelected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, amide, sulfonamide, hydroxy, amino, ureido, phosphoryl, alkylphosphoxy, alkylsilyl, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, haloalkyl, haloalkoxy, C₁-C₆Monoalkylamino group, C₁-C₆Dialkylamino, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl, C₁-C₆alkyl-S-, C₁-C₆alkyl-SO-, C₁-C₆alkyl-SO_2-Etc.;

R^2aand R^2bEach independently selected from hydrogen, deuterium, halogen, C₁-C₆Alkyl, 3-8 membered cycloalkyl or heterocycloalkyl; and R is^2aAnd R^2bOr R^2aWith substituents R on Ar^mA 3-6 membered saturated or partially unsaturated or unsaturated ring system may be formed by a carbon chain or heteroatom;

R³is H, deuterium, halogen, hydroxy, amino, cyano,C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylamino, 3-8 membered cycloalkyl or heterocycloalkyl, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, 5-10 membered aromatic ring or aromatic heterocyclic group;

m is independently selected from N or CR⁴，R⁴Selected from hydrogen, deuterium, halogen, cyano, C₁-C₆Alkyl, 3-8 membered cycloalkyl or heterocycloalkyl;

Ar¹and Ar²Each independently selected from 5-12 membered, monocyclic or bicyclic aryl or heteroaryl groups which may be substituted by one or more (e.g. 1,2,3,4, 5) groups R selected from^mAnd (3) substitution: hydrogen, deuterium, halogen, cyano, nitro, substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, hydroxy, amino, ureido, phosphoryl, alkylphosphoxy, alkylsilyl, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₁-C₁₀Alkoxyalkyl group, C₁-C₁₀Haloalkyl, C₁-C₁₀Haloalkoxy, C1-C₁₀Haloalkoxyalkyl, C₁-C₁₀Monoalkylamino group, C₁-C₁₀Dialkylamino, C₁-C₁₀Monoalkylaminoalkyl radical, C₁-C₁₀Bisalkylaminoalkyl radical, C₁-C₁₀Alkenyl radical, C₁-C₁₀Alkynyl, 3-12 membered cycloalkyl or heterocycloalkyl, C₁-C₁₀alkyl-S-, C₁-C₁₀alkyl-SO-, C₁-C₁₀alkyl-SO₂-, substituted or unsubstituted 5-to 12-membered aryl or heteroaryl, etc., or the two R' s^mA 3-12 membered saturated or partially unsaturated, or aromatic ring system may be formed by a carbon chain or heteroatom; .

One or more (e.g., 1,2,3,4, 5) hydrogen atoms on any of the above groups may be substituted with a substituent selected from the group consisting of:including but not limited to deuterium, halogen, hydroxy, amino, C₁-C₃Monoalkylamino group, C₁-C₃Dialkylamino, C₁-C₃Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl alkyl; wherein said heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, the heterocycloalkyl group containing 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said ring system including spiro, bridged, fused, etc. saturated or partially unsaturated ring systems.

In some preferred embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsioner, solvate, polymorph or prodrug thereof, is preferably a compound of formula (II),

wherein R is³Preferably selected from H, Me, cyclopropyl, chloro; m is preferably N or C-H or C-F or C-CN or C-Me; the ranges for the other groups are as defined above.

In some preferred embodiments, when R^2aAnd R^2bWhen not the same, R^2aAnd R^2bThe carbon atoms commonly attached are in the R configuration.

In some preferred embodiments, R is^2aAnd R^2bThe carbon atoms commonly bonded are carbon atoms of R configuration.

In some preferred embodiments, R^2aAnd R^2bEach independently is hydrogen, C₁-C₆Alkyl, preferably hydrogen, methyl.

In some preferred embodiments, R³Is C₁-C₃Alkyl, preferably methyl.

In some preferred embodiments, M is C-H.

In some preferred embodiments, R¹Is selected from C₁-C₆Alkyl radical, C₃-C₁₂Cycloalkyl, -C₄-C₁₂Cycloalkenyl, 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 invention.

In some preferred embodiments, R¹Is selected from C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 3-8 membered heterocycloalkyl, which may be optionally substituted with 1-3 Rn, as described in the first aspect of the invention.

In some preferred embodiments, R¹Is selected from C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, 5-to 8-membered heterocycloalkyl, - (C1-C6 alkylene) -C₃-C₆Cycloalkyl, - (C1-C6 alkylene) -5-8 membered heterocycloalkyl, which may be optionally substituted with 1-3 Rn, said Rn being halogen, C1-C3 alkyl.

In some preferred embodiments, R¹Selected from the group consisting of 5-6 membered heterocycloalkyl, - (C1-C3 alkylene) -5-6 membered heterocycloalkyl.

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

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

In some preferred embodiments, the compound having the general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsiomer, solvate, polymorph, or prodrug thereof, is characterized by: r¹Preferred are the following groups:

wherein one or more (e.g. 1,2, 3) R^cEach independently selected from hydrogen, deuterium, halogen, -C₁-C₆Alkyl, -OC₁-C₆Alkyl, cyano, hydroxy, amino, -SC₁-C₆Alkyl, -SOC₁-C₆Alkyl, -SO₂C₁-C₆Alkyl, -COC₁-C₆Alkyl, -COOC₁-C₆Alkyl, -CONHC₁-C₆Alkyl, -CON (C)₁-C₆Alkyl) (C₁-C₆Alkyl), 3-6 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl, -C₁-C₆Haloalkyl, -C₁-C₆Haloalkoxy, -C₁-C₆Deuterated alkyl-C₁-C₆Deuterated alkoxy, -O-3-6-membered cycloalkyl or heterocycloalkyl, -C₁-C₆Alkyl OC₁-C₆Alkyl, -C₁-C₆Alkyl NHC₁-C₆Alkyl, -C₁-C₆Alkyl OH, -C₁-C₆Alkyl radical N (C)₁-C₆Alkyl) (C₁-C₆Alkyl), and any two Rc can form a 3-10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring through a carbon chain or a heteroatom; r^dIndependently selected from hydrogen, -C₁-C₆Alkyl, -C₁-C₆Alkyl OC₁-C₆Alkyl, -C₁-C₆Alkyl group SC₁-C₆Alkyl, -C₁-C₆Alkyl SOC₁-C₆Alkyl, -C₁-C₆Alkyl SO₂C₁-C₆Alkyl, -COC₁-C₆Alkyl, -COOC₁-C₆Alkyl, -CONHC₁-C₆Alkyl, -CON (C)₁-C₆Alkyl) (C₁-C₆Alkyl), 3-6 membered cycloalkyl or heterocycloalkyl, 5-10 memberedAryl or heteroaryl, -C₁-C₆Haloalkyl, -C₁-C₆Haloalkoxy, -C₁-C₆Deuterated alkyl, -C₁-C₆Deuterated alkoxy-C₁-C₆Alkyl, -C₁-C₆Alkyl O-3-6 membered cycloalkyl or heterocycloalkyl, -C₁-C₆AlkylNHC₁-C₆Alkyl, -C₁-C₆Alkyl OH, -C₁-C₆Alkyl radical N (C)₁-C₆Alkyl) (C₁-C₆Alkyl), and the like.

In some preferred embodiments, R¹Selected from the group consisting of:

wherein R is^c、R^dAs described in the first aspect of the invention.

In some preferred embodiments, R¹Selected from the group consisting of:

wherein R is^c、R^dAs described in the first aspect of the invention.

In some preferred embodiments, R^cIndependently preferably selected from hydrogen, halogen, -C₁-C₃Alkyl, -C₁-C₃Haloalkyl, 3-6 membered cycloalkyl or heterocycloalkyl; r^dIndependently selected from hydrogen, -C₁-C₃An alkyl group.

In some preferred embodiments, Rn is selected from hydrogen, halogen, C₁-C₃Alkyl, 3-8 membered cycloalkyl or heterocycloalkyl.

In other preferred embodiments, Ar¹And Ar²Each independently 6-10 membered aryl, furyl, thienyl, pyridyl, pyrazolyl.

In other preferred embodimentsIn embodiments, the compound having the general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph, or prodrug thereof, is preferably a compound of the general formula (III):

the ranges for the other groups are as defined above.

In other preferred embodiments, R^mSelected from hydrogen, halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkenyl radical, C₁-C₆Alkynyl, hydroxy, amino, C₁-C₈Monoalkylamino radical, C₁-C₈A dialkylamino group, a C1-C8 acylamino group, a C1-C8 sulfonamido group, a 3-8 membered cycloalkyl group, a 3-8 membered heterocycloalkyl group, a 3-8 membered cycloalkylalkyl group, a 3-8 membered heterocycloalkyl group, a C₁-C₆alkyl-S-, C₁-C₆alkyl-SO-, C₁-C₆alkyl-SO₂-, or the two R' s^mForming a 3-to 8-membered saturated or partially unsaturated, or aromatic ring system via a carbon chain or heteroatom, wherein R is^mMay be further selected from amino, C₁-C₃Monoalkylamino group, C₁-C₃Dialkylamino, C₁-C₃Alkyl, hydroxyl, 3-6 membered heterocycloalkyl alkyl.

In other preferred embodiments, R^mSelected from hydrogen, halogen, C₁-C₆Alkyl radical, C₁-C₄Alkoxy radical, C₁-C₄Alkenyl radical, C₁-C₄Alkynyl, hydroxy, amino, C₁-C₆Monoalkylamino group, C₁-C₆Dialkylamino, C₁-C₆Amide group, C₁-C₆Sulfonamide, 3-to 6-membered heterocycloalkyl- (C1-C3 alkyl)Base) -, 5-10 membered aryl, 5-10 membered heteroaryl, C₁-C₃alkyl-SO₂-, or the two R' s^mA 5-6 membered saturated or partially unsaturated, or aromatic ring system via a carbon chain or heteroatom, wherein R is^mCan be further selected from amino, C₁-C₃Monoalkylamino group, C₁-C₃Dialkylamino, C₁-C₃Alkyl, hydroxyl, 3-6 membered heterocycloalkyl alkyl.

In other preferred embodiments, R^mSelected from hydrogen, halogen, C₁-C₄Monoalkylamino group, C₁-C₄A bisalkylamino group, a 3-6 membered heterocycloalkyl group- (C1-C3 alkyl) -, or two of the above R^mThe saturated ring with 5-6 members is formed by carbon chain or hetero atom.

In some preferred embodiments, R¹、R^2a、R^2b、R³、Ar¹、Ar²And M are each independently the corresponding group in compounds 1-86 prepared in the 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 a second aspect of the invention, a pyrimido fused ring compound shown in formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereomer, a tautomer, a torsional isomer, a solvate, a polymorph or a prodrug thereof is provided,

in the formula:

R¹is independently selected from C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₁₂Cycloalkyl, C₄-C₁₂Cycloalkenyl radical,3-12 membered heterocycloalkyl, 5-12 membered aryl or 5-12 membered heteroaryl, wherein said C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or 5-12 membered heteroaryl can be optionally substituted with 1-3 Rn; or the two Rn can form a 3-12 membered saturated or partially unsaturated, or aromatic ring system through a carbon chain or a heteroatom; rn is selected from hydrogen, deuterium, halogen, cyano, nitro, amide, sulfonamide, hydroxyl, amino, ureido, phosphoryl, alkyl phosphorus oxy, alkyl silicon base, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, haloalkyl, haloalkoxy, C₁-C₆Monoalkylamino group, C₁-C₆Dialkylamino, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl, C₁-C₆alkyl-S-, C₁-C₆alkyl-SO-, C₁-C₆alkyl-SO_2-Etc.;

R^2aand R^2bEach independently selected from hydrogen, deuterium, halogen, C₁-C₆Alkyl, 3-8 membered cycloalkyl or heterocycloalkyl; and R is^2aAnd R^2bA 3-6 membered saturated or partially unsaturated or unsaturated ring system may be formed by a carbon chain or heteroatom;

R³is H, deuterium, halogen, hydroxy, amino, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C6 alkylamino, 3-8 membered cycloalkyl or heterocycloalkyl, C₂-C₄Alkenyl radical, C₂-C₄An alkynyl group;

Ar¹and Ar²Each independently selected from 5-12 membered monocyclic or bicyclic aryl or heteroaryl groups, which aryl or heteroaryl groups may be substituted by one or more groups selected fromGeneration: hydrogen, deuterium, halogen, cyano, nitro, substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, hydroxy, amino, ureido, phosphoryl, alkylphosphoxy, alkylsilyl, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₁-C₁₀Alkoxyalkyl group, C₁-C₁₀Haloalkyl, C₁-C₁₀Haloalkoxy, C1-C₁₀Haloalkoxyalkyl, C₁-C₁₀Monoalkylamino group, C₁-C₁₀Dialkylamino, C₁-C₁₀Monoalkylaminoalkyl radical, C₁-C₁₀Bisalkylaminoalkyl radical, C₁-C₁₀Alkenyl radical, C₁-C₁₀Alkynyl, 3-12 membered cycloalkyl or heterocycloalkyl, C₁-C₁₀alkyl-S-, C₁-C₁₀alkyl-SO-, C₁-C₁₀alkyl-SO₂-and the like; and Ar mentioned above¹And Ar²Any two adjacent substituents on (a) may form a 3-8 membered saturated or partially unsaturated or unsaturated ring system via a carbon chain or heteroatom.

One or more hydrogen atoms on any of the above groups may be substituted with a substituent selected from the group consisting of: including but not limited to deuterium, halogen, C₁-C₃Alkyl, 3-6 membered cycloalkyl or heterocycloalkyl; wherein said heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, the heterocycloalkyl group containing 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said ring system including spiro, bridged, fused, etc. saturated or partially unsaturated ring systems.

In some preferred embodiments, the compound is a compound of formula (II), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomer, solvate, polymorph or prodrug thereof:

wherein R is³Preferably a group of compounds selected from the group consisting of H,me; m is preferably N or C-H or C-F or C-CN or C-Me; the ranges for the other groups are as defined above.

In some preferred embodiments, the compound is a compound of formula (III), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomer, solvate, polymorph or prodrug thereof:

wherein R is¹、M、Ar²Ranges of (d) are as defined above.

In a third aspect of the invention, there is provided a process for the preparation of a compound of formula I, said process comprising steps a-d:

a) carrying out substitution reaction on a compound of a general formula (A) and a compound of a general formula (B) under the catalysis of alkali to generate an intermediate compound (C); and

b) hydrolyzing the intermediate compound of formula (C) to produce an intermediate compound of formula (D);

c) reacting the intermediate (D) compound with R¹NH₂Carrying out condensation reaction in the presence of a condensing agent to generate an intermediate (E);

d) and (3) carrying out a ring closing reaction on the intermediate (E) under the catalysis of acid to generate the general formula (I).

R is alkyl, such as methyl, ethyl, tert-butyl, benzyl, etc.; the ranges for the other groups are as described above;

preferably, said steps a), b), c), d) are each carried out in a solvent and said solvent is selected from the group consisting of: water, methanol, ethanol, isopropanol, butanol, ethylene glycol methyl ether, N-methyl pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, 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 tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or combinations 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 condensing agent 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 (Cartesian condensing agent), PyBOP (1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate), HATU (2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate), TBTU (benzotriazol tetramethyltetrafluoroborate), and the like, 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.

The invention provides a class of preferred compounds of formula (I) including, but not limited to, the following structures:

the invention also aims to provide a medicament for treating or preventing tumors and a composition thereof. The technical scheme for realizing the purpose is as follows:

a pharmaceutical composition for treating tumors, which comprises the pyrimido-heterocyclic compound shown in the general formula (I) or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof and pharmaceutically acceptable carrier.

Another object of the present invention is to provide a use of the above compound. The technical scheme for realizing the purpose is as follows:

the pyrimido heterocyclic compound shown in the general formula (I) or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof is used for preparing medicaments for treating diseases related to Ras mutation, activity or expression quantity, particularly medicaments for treating tumors. The tumor is independently selected from non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostatic cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia, lymph cancer, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.

The invention relates to a compound with the structural characteristics of a general formula (I), which can inhibit a plurality of tumor cells, particularly can efficiently kill tumors related to Ras protein signal channel abnormity, and is a treatment drug with a brand-new action mechanism.

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

Detailed Description

Through long-term and intensive research, the inventor prepares a pyrimido-heterocyclic compound with a novel structure shown in formula I, and finds that the pyrimido-heterocyclic compound has better inhibitory activity for inhibiting SOS1 protein, and the compound has specific inhibitory action on SOS1 protein at very low concentration (which can be as low as less than 100nM), and has quite excellent inhibitory activity on cell proliferation related to Ras pathway, so that the pyrimido-heterocyclic compound can be used for treating related diseases such as tumors caused by Ras mutation or abnormal activity or expression. Based on the above findings, the inventors have completed the present invention.

Term(s) for

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

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

Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods. Unless a specific definition is set forth, the terms used herein in the pertinent description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the instructions of the kit from the manufacturer, or according to the methods known in the art or the instructions of the present invention. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.

When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, -CH₂O-is equivalent to-OCH₂-。

The section headings used herein are for organizational purposes only and are not to 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, operating manuals, and treatises, are hereby incorporated by reference in their entirety.

Certain chemical groups defined herein are preceded by a shorthand notation 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 shorthand notation excludes carbons that may be present in a substituent of the group.

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

In the present application, the term "halogen" means fluorine, chlorine, bromine or iodine; "hydroxy" means an-OH group; "hydroxyalkyl" refers to an alkyl group as defined below substituted with a hydroxyl (-OH) group; "carbonyl" refers to a-C (═ O) -group; "nitro" means-NO₂(ii) a "cyano" means-CN; "amino" means-NH₂(ii) a "substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, e.g., monoalkylamino, dialkylamino, alkylamido, aralkylamino, heteroaralkylamino; "carboxyl" means-COOH.

In this application, the term "alkyl", as a group or as part of another group (e.g. as used in groups such as halogen-substituted alkyl), means a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing no unsaturated bonds, having, for example, from 1 to 12 (preferably from 1 to 8, more preferably from 1 to 6) carbon atoms, and being attached to the rest of the molecule by single bonds. 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-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl, and the like.

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

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

In the present application, the term "cycloalkyl" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting of only carbon atoms and hydrogen atoms, which may include fused, bridged or spiro ring systems, having 3 to 15 carbon atoms, preferably having 3 to 10 carbon atoms, more preferably having 3 to 8 carbon atoms, and which is saturated or unsaturated and may be attached to the rest of the molecule by a single bond via any suitable carbon atom. Unless otherwise specifically indicated in the specification, carbon atoms in cycloalkyl groups may be optionally oxidized. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2, 3-indanyl, 1,2,3, 4-tetrahydro-naphthyl, 5,6,7, 8-tetrahydro-naphthyl, 8, 9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1] heptyl, 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, octahydro-4, 7-methylene-1H-indenyl, octahydro-2, 5-methylene-pentalenyl and the like.

In this application, the terms "heterocyclyl" and "heterocycloalkyl" are used interchangeably as a group or as part of another group and mean a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless otherwise specifically indicated in the specification, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic, or higher ring system, which may include fused, bridged, or spiro ring systems; wherein the nitrogen, carbon or sulfur atom of the heterocyclyl may be optionally oxidized (e.g. S-may be oxidized to-SO-or-SO)₂-, -C-can be oxidized to-CO-); the nitrogen atoms may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be attached to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclic groups 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, heterocyclyl is preferably a stable 4-to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro ring group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-to 8-membered (e.g. 4,5,6,7, 8-membered) non-aromatic monocyclic, bicyclic, bridged or spiro ring group containing 1 to 3 (e.g. 1,2, 3) heteroatoms selected from nitrogen, oxygen and sulfur, wherein the nitrogen, carbon or sulfur atoms in the heterocyclyl 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 ]]Nonan-7-yl, 2-oxa-6-aza-spiro [3.3]Heptane-6-yl, 2, 5-diaza-bicyclo [2.2.1]Heptane-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimididinylAnd the like.

In the present application, the terms "heterocyclylalkyl", are used interchangeably to refer to an alkyl group as defined above substituted with an alkyl group as defined above, or an alkyl group as defined above substituted with an alkyl group as defined above.

In this application, the term "aryl" as a group or as part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present invention, an aryl group may be a monocyclic, bicyclic, tricyclic or higher polycyclic ring system and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is attached to the remainder of the molecule by a single bond via an atom on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2, 3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, and the like.

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

In this application, the term "heteroaryl" as a group or part of another group means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or higher ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the heteroaryl group is attached to the rest of the molecule by a single bond via an atom on the aromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atoms may optionally be quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5-to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5-to 10-membered aromatic group containing 1 to 4 heteroatoms selected from 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, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindolyl, purinyl, quinolyl, isoquinolyl, diazonaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, orthophenanthrolidinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthopyridyl, pyridinyl, and the like, [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-b ] pyridazine, imidazo [1,2-a ] pyrazine and the like.

In the present 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-CONH as defined above₂or-CONH-alkyl as defined above or-CON (alkyl as defined above)₂Wherein the alkyl group is preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group. In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes 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. Chemical moieties are generally considered to be chemical entities that are embedded in or attached to a molecule.

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

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

"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 invention are also intended to be included within the scope of the invention.

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

Conventional techniques for preparing/separating the individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography.

In the present application, the term "pharmaceutically acceptable salts" 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 which 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, and the like; organic acid salts include, but are not limited to, formates, acetates, 2-dichloroacetates, trifluoroacetates, propionates, caproates, caprylates, caprates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartates, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbates, salicylates, 4-aminosalicylates, napadisylates, and the like. These salts can be prepared by methods known in the art.

"pharmaceutically acceptable base addition salts" refers to salts with inorganic or organic bases which maintain the biological effectiveness of the free acid without other side 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 naturally occurring 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, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. 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 different solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the present invention may exist in more than one crystalline form and the present invention is intended to include the various crystalline forms and mixtures thereof.

Typically, crystallization will result in solvates of the compounds of the invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of the 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. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrate, hemihydrate, sesquihydrates, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may form true solvates, but in some cases it is also possible to retain only adventitious water or a mixture of water plus a portion of adventitious solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.

The invention also includes prodrugs of the above compounds. In the present application, the term "prodrug" denotes a compound that can be converted under physiological conditions or by solvolysis to the biologically active compound of the invention. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. Prodrugs may not be active when administered to a subject in need thereof, but are converted in vivo to the active compounds of the invention. Prodrugs are generally rapidly converted in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. Prodrug compounds generally provide solubility, histocompatibility, or sustained release advantages in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups.

In the present application, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of active ingredients and exert biological activity.

The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.

As used herein, a "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that is approved by the relevant governmental regulatory agency for human or livestock use.

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

The terms "preventing," "prevention," and "prevention" as used herein include reducing the likelihood of occurrence or worsening 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 occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease or condition, but has not been diagnosed as having the disease or condition;

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

(iii) alleviating the disease or condition, i.e., causing regression of the state of the disease or condition; or

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

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

The terms "administering," "administration," "administering," and the like, as used herein, refer to a method of delivering a compound or composition to a desired site for a biological effect. These methods include, but are not limited to, oral routes, via 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.

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

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

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

The invention will be further illustrated with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally according to conventional conditions, or according to conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

Examples general preparation method

The first step is as follows: dissolving the 6-chloropyrimidine intermediate (1eq.) in a proper solvent, sequentially adding an organic base (3eq.) and an amine intermediate (1eq.), sealing a tube, heating to 100 ℃, and stirring overnight. And monitoring the reaction completion by LC-MS, cooling to room temperature, adding water into the reaction solution, extracting the water phase with dichloromethane for three times, drying the extract with anhydrous sodium sulfate, concentrating under reduced pressure, separating and purifying the residue to obtain a target product, and confirming the structure by adopting nuclear magnetism and mass spectrometry.

The second step is that: the product of the first step (1eq.) is dissolved in a suitable solvent, added with an inorganic base and stirred at room temperature for several hours. TLC, filtered and concentrated under reduced pressure, dried in vacuo to give crude target product, and confirmed structure by nuclear magnetic and mass spectrometry.

The third step: dissolving the second step product (1eq.) in a suitable solvent, and adding a condensing agent (1.1 eq.), a base (1.2 eq.), and R in that order¹NH₂(1eq.) and reacted at room temperature under nitrogen for overnight hours. TLC monitoring reaction is complete, decompression concentration is carried out, the remainder is separated and purified by silica gel column chromatography to obtain a target product, and nuclear magnetism and mass spectrum are adopted to confirm the structure.

The fourth step: the product of the third step (1eq.) was dissolved in isopropanol, and 5N aqueous HCl (10eq.) was added and stirred at 80 ℃ for 6 hours. TLC monitoring reaction is complete, decompression concentration is carried out, the remainder is separated and purified by silica gel column chromatography to obtain the target compound, and nuclear magnetism and mass spectrum are adopted to confirm the structure.

Preparation of intermediates

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

The method comprises the following steps: tetraethyl titanate (11.3g,49.56mmol) was added to 3-bromo-acetophenone (5.40g,27.26mmol), (R) - (+) tert-butylsulfinamide (3.0g,24.78mmol) in tetrahydrofuran (42mL) under nitrogen. The reaction mixture was heated to 70 ℃ and reacted at this temperature for 16 hours. The reaction mixture was heated to 70 ℃ and reacted at this temperature for 16 hours. The reaction was cooled to room temperature, 70mL of brine was added, stirring was continued for 10min, and 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 give the intermediate compound (6.05g) as a colorless oil. LCMS (ESI) M/z 301.9[ M + H ]]⁺。¹H 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 two: diisobutylaluminum hydride (39.9mL,39.86mmol) was added to the above intermediate (6.0g,19.93mmol) in tetrahydrofuran (200mL) at-78 ℃. The reaction was slowly warmed to room temperature and allowed to react at this temperature for 16 hours. The reaction was quenched by addition of dilute sodium hydroxide solution with ice-cooling. 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 give the compound as a colorless oily compound (5.25 g). LCMS (ESI) M/z 303.1[ M + H ]]⁺。¹H 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 three: tetrakis-triphenylphosphine palladium (1.52g,1.32mmol) was added to a solution of the compound intermediate (4.0g,13.20mmol), 2- (N, N-dimethylaminomethyl) phenylboronic acid (3.07g,17.16mmol), potassium carbonate (3.64g,26.40mmol) and water (10mL) in 1, 4-dioxane (50mL) under nitrogen. The reaction mixture was heated to 100 ℃ and reacted at this temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (200mL) and washed with water (100 mL). The separated organic phase was concentrated under reduced pressure, and the crude product was purified by a reverse phase column to give a brown oily compound (3.46 g). LCMS (ESI) M/z 359.2[ M + H ]]⁺。¹H 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 four: a solution of hydrochloric acid in methanol (4M,15mL,45mmol) was added to a solution of the above intermediate compound (3.46g,9.66mmol) in methanol (15 mL). The reaction mixture was reacted at 20 ℃ for 2 hours. The reaction was checked by LC-MS to be substantially complete, and after removal of the solvent by concentration under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane/methanol ═ 9: 1) to give a pale yellow solid compound (2.5 g). LCMS (ESI) M/z 255.2[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.82-7.69(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＝6.2Hz,3H)。

The preparation conditions are as follows: separation column (SunAire Prep C18 OBD^TM10um, 19 x 250 mm); gradient (5% -95% acetonitrile/0.1% formic acid/water, 16min, flow 20 mL/min).

Analysis conditions were as follows: analytical column (Waters SunFire C18, 4.6 x 50mm, 5 um); gradient (5% -95% acetonitrile/0.1% formic acid/water, 3.0min, flow rate 2.0mL/min, 2.6 min); column temperature: 40 ℃; detection wavelength: 254 nM.

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

The method comprises the following steps: tetraethyl titanate (30.1g,132mmol) was added to 1- (5-bromothien-2-yl) ethyl-1-one (14.89g,72.61mmol), (R) - (+) tert-butylsulfinamide (8g,66mmol) in tetrahydrofuran (100mL) under nitrogen, and the reaction mixture was heated to 70 ℃ and reacted at this temperature for 16 hours. After the reaction mixture was cooled to room temperature, 100ml of brine was added thereto, and stirring was continued for 10 minutes. The reaction mixture was filtered through celite, and the filtrate was extracted 2 times with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether ═ 4:1) to give the intermediate compound (15g, crude) as a brown solid. LCMS (ESI) M/z 307.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d6)δ7.64(d,J＝4.1Hz,1H),7.35(d,J＝4.1Hz,1H),2.64(s,3H),1.18(s,9H)。

Step two: DIBAL-H (61mL,61mmol) was slowly added dropwise to the above intermediate compound (9.3g,30.17mmol) in tetrahydrofuran (200mL) under nitrogen at-78 deg.C, the reaction mixture was slowly warmed to room temperature and allowed to react at this temperature for 16 hours, LCMS detected no starting material and most of it was converted to the desired product. Quench with methanol (50ml), concentrate under reduced pressure to remove the solvent, slurry the crude product with methanol (200ml) and filter through celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether ═ 4:1) to give a brown oily liquid compound (15g, crude product). LCMS (ESI) M/z 309.9[ M + H ]]⁺。¹H 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 three: tetratriphenylphosphine palladium (1.12g,0.965mmol) was added to a solution of the above intermediate compound (3g,9.65mmol), 2-carboxaldehyde phenylboronic acid (1.88g,12.55mmol), potassium carbonate (2.67g,19.3mmol), and water (12mL) in 1, 4-dioxane (60mL) under nitrogen. The reaction mixture was heated to 100 ℃ and reacted at this temperature for 16 hours. The reaction was diluted with ethyl acetate (200mL) and washed with water (100 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was prepared by HPLCPurification gave the intermediate compound (2.6g) as a brown oil. LCMS (ESI) M/z 336.0[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ10.21(d,J＝0.6Hz,1H),8.00(dd,J＝7.8,1.1Hz,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 four: to the above intermediate compound (2.6g,7.75mmol) and pyrrolidine (662mg,9.3mmol) in methanol (30mL) was added 1 drop of glacial acetic acid at room temperature, and the reaction mixture was reacted at 20 ℃ for 2 hours. Sodium cyanoborohydride (1.46g,23.25mmol) was then added to the reaction and the reaction was continued for 12 hours, predominantly by LCMS. The crude product obtained by removing the solvent by concentration under reduced pressure was purified by silica gel column chromatography (eluent: dichloromethane/methanol ═ 9: 1) to give the compound as a pale yellow solid intermediate compound (2.1 g). LCMS (ESI) M/z 391.1[ M + H ]]⁺。

Step five: hydrogen chloride in methanol HCl (g)/MeOH (15mL,45mmol) was added to the above intermediate compound (2.1g,5.38mmol) in methanol (15 mL). The reaction mixture was reacted at 20 ℃ for 2 hours. LCMS check reaction complete. The reaction solution was concentrated under reduced pressure to remove the solvent, and the resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol 9: 1) to give the title compound (1.2g) as a pale yellow solid. LCMS (ESI) M/z 287.1[ M + H]⁺。¹H NMR(400MHz,CD₃OD)δ7.79-7.75(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＝6.9Hz,3H)。

The following intermediates 2 and 4 to 12 were synthesized with reference to the preparation and isolation procedures for the preparation of (R) -1- (2 '- ((dimethylamino) methyl) - [1, 1' -biphenyl ] -3-yl) ethyl-1-amine hydrochloride and (R) -1- (5- (2- (pyrrol-1-ylmethyl) phenyl) thiophen-2-yl) ethyl-1-amine hydrochloride:

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) pyridine [4,3-d ] pyrimidin-7 (6H) -one

The method comprises the following steps: methyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate (360mg,1.32mmol), (R) -1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethan-1-amine (347mg,1.32mmol) and N, N-diisopropylethylamine (515mg,3.96mmol) were added to dimethyl sulfoxide (7mL) and the reaction was blocked at 100 ℃ overnight. The reaction was monitored by LC-MS for completion and cooled to room temperature. Water (30mL) was added to the reaction mixture, extraction was carried out three times with methylene chloride, the extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to reverse phase column chromatography to give 160mg of a solid product. LC-MS (ESI) m/z: 497.1[ M + H]⁺。¹H-NMR(400MHz，DMSO-d6)：δ7.39-7.30(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＝6.8Hz,3H)。

Step two: to a tetrahydrofuran solution (4mL) of the above solid (228mg,0.46mmol) was added an aqueous solution (1mL) of lithium hydroxide (88mg,3.676mmol), and the reaction mixture was stirred at room temperature for 3 hours. TLC detection of the disappearance of the starting material and removal of the solvent under reduced pressure gave 220mg of a crude pale yellow solid which was directly fed to the next reaction. LC-MS (ESI) M/z 483.1[ M + H ]]⁺。

Step three: 2- (7-Azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (514mg,1.35mmol) was added to a solution of the solid (220mg,0.451mmol) from the previous step, 1,1, 1-trifluoropropan-2-amine (102mg,0.901mmol) and N, N-diisopropylethylamine (233mg,1.803mmol) in tetrahydrofuran (20 mL). The reaction was stirred at room temperature overnight. Concentrating under reduced pressure to remove solvent to obtain residuePurification by silica gel column chromatography (ethyl acetate/methanol vol: 20:1) gave 200mg of a brown oil. LC-MS (ESI) M/z 578.1[ M + H ]]⁺。

Step four: to a solution of the above oil (200mg, 0.346mmol) in isopropanol (8mL) was added 5N aqueous hydrochloric acid (1.5mL,7.5 mmol). The reaction mixture was reacted at 80 ℃ for 2 hours. And detecting the complete reaction of the raw materials by LC-MS. The reaction mixture was diluted with dichloromethane (100mL) and washed twice with brine (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Preparative HPLC purification of the residue afforded compound 1-1(Rt ═ 5.15min, 3.6mg, light yellow solid) and compound 1-2(Rt ═ 7.55min, 4.1mg, light yellow solid).

Compound 1-1: LC-MS (Rt ═ 1.207Min) (ESI) M/z 516.1[ M + H]⁺。¹H-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)。

Compounds 1-2: LC-MS (Rt ═ 1.230Min) (ESI) M/z 516.1[ M + H: (M + H)]⁺。¹H-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 procedure of example 1, starting from (R) or (S) -1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethan-1-amine and different commercially available amine reagents, instead of 1,1, 1-trifluoropropan-2-amine, examples 2-18 were obtained:

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

The method comprises the following steps: methyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate (3.0g,11.03mmol), (R) -1- (3-bromobenzene) ethyl-1-amino hydrochloride (2.85g,12.13mmol) and N, N-diisopropylethylamine (4.28g,33.08mmol) were added to dimethyl sulfoxide (15mL) and the mixture was quenched overnight at 100 ℃. The reaction was monitored by LC-MS for completion and cooled to room temperature. Water (50mL) was added to the reaction mixture, extraction was carried out three times with methylene chloride, the extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to reverse phase column chromatography to give 2.04g of a pale yellow solid product. LCMS (ESI) M/z 437.9[ M + H ]]^+.1H NMR(400MHz,DMSO-d6)δ7.57(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 two: to a solution of the above solid (2.0g,4.60mmol) in tetrahydrofuran (20mL) was added hydrogen and oxygenAn aqueous solution (5mL) of lithium (883mg,36.77mmol) was stirred at room temperature for 5 hours. TLC detection of the disappearance of the starting material gave, after removal of the solvent under reduced pressure, a crude product (1.96g) as a pale yellow solid which was directly taken to the next reaction. LC-MS (ESI) M/z 423.9[ M + H ]]⁺。

Step three: the intermediate compound (1.96g,4.60mmol) was dissolved in tetrahydrofuran (200mL) at room temperature, and (tetrahydro-2H-pyran-4-yl) -methylamine (1.59g,13.8mmol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (7.0g,18.4mmol), N, N-diisopropylethylamine (2.38g,18.4mmol) and the reaction mixture were added in this order and reacted at 70 ℃ for 2 hours. The reaction product was mainly detected by LCMS, and ethyl acetate (100mL) diluted the reaction solution and the organic phase was separated, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (ethyl acetate: methanol ═ 20:1) to give 2.1g of a pale yellow solid product. LC-MS (ESI) M/z 519.1[ M + H ]]^+.1H NMR(400MHz,CDCl₃)δ8.34(d,J＝7.5Hz,1H),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 four: aqueous HCl (5N,7.0mL) was added to the above compound (1.35g,2.605mmol) in tetrahydrofuran (32mL) at room temperature and the reaction mixture was allowed to react at 80 ℃ for 2 hours. The reaction was complete by LCMS, and the reaction was diluted with dichloromethane (200mL) and washed with brine. The organic phase was separated, dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether ═ 4:1 to 2:1) to give 1.35g of a pale yellow solid. LCMS (ESI) M/z 457.1[ M + H ]]⁺.¹H NMR(400MHz,CDCl₃)δ9.02(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 five: tetratriphenylphosphine palladium (40mg,0.035mmol) was added to the above compound (0.16g,0.351mmol), 4- ((2- (dimethylamino) ethyl) carbonoyl) phenyl) boronic acid (124 m) under nitrogen blanketg,0.456mmol), potassium carbonate (97mg,0.702mmol), water (2mL) in 1, 4-dioxane (12 mL). The reaction mixture was heated to 100 ℃ and reacted at this temperature for 16 hours. After the reaction solution was diluted with ethyl acetate (200mL), 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 crude product was purified by HPLC prep. to give 10.60mg of a pale yellow solid. LCMS (Rt ═ 0.879min) (ESI) M/z 469.4[ M + H: (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＝4.9Hz,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).

Referring to the procedures of examples 1 and 19, a synthesis procedure substituting (tetrahydro-2H-pyran-4-yl) -methylamine with commercially available different amines as starting material and substituting 4- ((2- (dimethylamino) ethyl) carbonyl) phenyl) boronic acid with different boronic acids as starting material gave examples 20-22:

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

The method comprises the following steps: 2- (6-chloro-5- (1, 3-)Dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetic acid methyl ester (500mg,1.84mmol), (R) -1- (5-bromothienylphen-2-yl) ethyl-1-amino hydrochloride (480mg,2.2mmol) and N, N-diisopropylethylamine (951mg,7.36mmol) were added to DMSO (5mL) and the reaction was blocked overnight at 100 ℃. The reaction was diluted with water (100mL), extracted three times with ethyl acetate (100mL), and the combined organic phases were concentrated under reduced pressure and purified by HPLC to give a white intermediate compound (250 mg). LCMS (ESI) M/z 443.8[ M + H ]]⁺。¹H 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 two: an aqueous solution (1mL) of lithium hydroxide (190mg,4.52mmol) was added dropwise to a solution of the above intermediate compound (250mg,0.56mmol) in tetrahydrofuran (4mL) and reacted at room temperature for 2 hours, whereupon the starting material disappeared by TLC detection. The solvent was removed under reduced pressure to give a crude intermediate (220mg) as a pale yellow solid. LCMS (ESI) M/z 429.8[ M + H ]]⁺.

Step three: HATU (665mg,1.75mmol) was added to a solution of the above intermediate compound (220mg,0.58mmol), 4-aminomethyltetrahydropyran (200mg,1.75mmol) and N, N-diisopropylethylamine (300mg,2.3mmol) in tetrahydrofuran, and reacted at 70 ℃ for 12 hours. The solvent was removed by concentration under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate/methanol 10:1) to give a yellow solid intermediate compound (180 mg). LCMS (ESI) M/z 526.9[ M + H ]]⁺。¹H 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 four: aqueous hydrochloric acid (5M,1.5mL,7.5mmol) was added to a solution of the above intermediate compound (170mg, 0.32mmol) in isopropanol (8 mL). The reaction mixture was reacted at 80 ℃ for 1 hour. LCMS detected complete reaction of starting material. The reaction mixture was diluted with methylene chloride (100mL) and washed with brine. The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude productThe product was purified by silica gel column chromatography (eluent: dichloromethane/methanol ═ 10:1) to give the intermediate compound (150mg) as a pale yellow solid. LCMS (ESI) M/z 463.1[ M + H ]]⁺。

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

Step six: a drop of glacial acetic acid was added to the above intermediate compound (50mg,0.1mmol) and tetrahydropyrrole (21mg,0.3mmol) in methanol (5mL) at room temperature, and the reaction mixture was reacted at 20 ℃ for 2 hours. Sodium cyanoborohydride (19mg,0.3mmol) was added to the reaction and the reaction was continued for 12 hours, LCMS showed no starting material and most was converted to the desired product. The reaction mixture was diluted with ethyl acetate (50mL), washed with brine (30mL), the separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting crude product was prepared by HPLC as a pale yellow solid, the compound of example 32 (4.82 mg). LC-MS (Rt 1.955 min); (ESI) M/z 580.2[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d6)δ9.06(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

The method comprises the following steps: liquid bromine (6.72g,42.0mmol) and aluminum trichloride (11.2g, 84.0mmol) were added to chloroform (50mL) of 1- (4-chlorothien-2-yl) ethyl-1-one (4.5g,28.016mmol) at room temperature, and the reaction mixture was reacted at 60 ℃ for 1 hour. LCMS detection no starting material, most was converted to the desired product. The reaction was diluted with ethyl acetate (100mL), the organic phase washed with sodium chloride solution, the organic phase separated, dried over anhydrous sodium sulfate, concentrated, and purified to give the intermediate compound (5.0g) as a white solid. LCMS (ESI) M/z 240.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO)δ8.05(s,1H),2.53(s,3H)。

Step two: tetraethyl titanate (8.57g,37.58mmol), (R) - (+) tert-butylsulfinamide (2.28g,18.8mmol) was added to the above intermediate compound (5.0g,20.88mmol) in tetrahydrofuran (80mL) at room temperature. The reaction mixture was reacted at 70 ℃ for 16 hours. The LC-MS detection reaction is complete. Water (150mL) was added, extracted three times with ethyl acetate (80mL), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 4:1) to give a pale yellow solid intermediate compound (3.7 g). LCMS (ESI) M/z 343.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d6)δ7.87(s,1H),2.65(s,3H),1.19(s,9H)。

Step three: to the above intermediate compound (3.7g,10.8mmol) in tetrahydrofuran (80mL) was added diisobutylaluminum hydride (33mL) at-60 ℃ or below. The reaction mixture was gradually warmed to room temperature and reacted at this temperature for 16 hours. LCMS detection no starting material, most was converted to the desired product. Methanol (10mL) was added to the reaction solution, and then the reaction solution was diluted with ethyl acetate (100mL), filtered through celite, and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 4:1) to give a pale yellow solid intermediate compound (3.1 g). LCMS (ESI) M/z 345.9[ M + H ]]⁺。¹H 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 four: methanol of HCl (g) at room temperatureThe solution (30mL) was added to methanol (30mL) of the above intermediate compound (3.1g, 8.99mmol), and the reaction mixture was reacted at room temperature for 3 hours. The LCMS reaction was complete and the reaction was directly spun dry and the crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol 10:1) to afford the intermediate compound (2.2g) as a white solid.¹H 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 five: potassium fluoride (854mg,14.7mmol) was added to methyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate (400mg,1.47mmol) and the above intermediate compound (530mg,2.21mmol) in dimethylsulfoxide (10 mL). The reaction mixture was reacted at 100 ℃ for 16 hours with tube sealing. After the reaction solution was diluted with ethyl acetate (50mL), the organic phase was washed with water (20mL), and the separated organic phase was dried over anhydrous sodium sulfate. After concentration of the filtrate under reduced pressure, the crude product was purified by HPLC prep. to give the intermediate compound (350mg) as a white solid. LCMS (ESI) M/z 477.8[ M + H ]]⁺。¹H 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＝6.9Hz,3H)。

Step six, at room temperature, an aqueous solution (2mL) of lithium hydroxide (350mg,0.73mmol) was added to the above intermediate compound (350mg,0.73mmol) in tetrahydrofuran (3mL), and the reaction mixture was reacted at this temperature for 2 hours and checked for completion by LCMS. Concentration under reduced pressure removed the solvent to give the crude intermediate compound (350mg) as a pale yellow solid.

Step seven, the above intermediate compound (350mg,0.73mmol) was dissolved in tetrahydrofuran (80mL) at room temperature, followed by addition of (tetrahydropyran-4-yl) methylamino (254mg,2.20mmol), HATU (837mg,2.20mmol), N, N-diisopropylethylamine (380mg,2.94mmol), and reaction mixture at 70 ℃ for 2 hours. Upon completion of the reaction by LCMS, the reaction solution was diluted with ethyl acetate (150mL), washed twice with water (50mL), the separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by HPLC to give a pale yellow solid intermediate compound (110 mg). LCMS (ESI) M/z 560.9[ M + H ]]⁺。

Step (ii) ofEighthly: 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 ℃ for 2 hours. Reaction completion was detected by LCMS and the reaction was diluted with dichloromethane (100 mL). The reaction solution was washed with brine (80mL), the separated organic phase was separated, dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by HPLC to give an intermediate compound (85mg) as a white solid. LCMS (ESI) M/z 499.1[ M + H ]]⁺。

Step nine: tetratriphenylphosphine palladium (19mg,0.0161mmol) was added to 1, 4-dioxane (16mL) of 2- (pyrrol-1-ylmethyl) phenylboronic acid (43mg,0.21mmol), the above intermediate compound (80mg,0.1607mmol), potassium carbonate (45mg,0.32mmol), and water (3mL) at room temperature. The reaction mixture was reacted at 100 ℃ for 2 hours. LCMS detected complete reaction of starting material. The reaction solution was diluted with ethyl acetate (80mL), filtered through celite, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol ═ 10:1) to give the compound of example 33 (20.2mg) as a white solid. LC-MS (Rt ═ 0.996 min); (ESI) M/z 578.3[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d6)δ9.05(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＝6.8Hz,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

The method comprises the following steps: n-bromosuccinimide NBS (12.69g,71.3mmol) was added to 1- (4-methylthiophen-2-yl) ethyl-1-one (2g,14.3mmol) in ethanol (30mL) at room temperature, and the reaction mixture was reacted at 20 ℃ for 2 hours. LCMS check reaction complete. The reaction was diluted with ethyl acetate (100mL) and the organic phase was washed with sodium chloride solution (50mL)And (4) phase(s). The separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 20:1) to give a white solid intermediate compound (2.5 g). LCMS (ESI) M/z 220.8[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d6)δ7.78(s,1H),2.48(s,3H),2.19(s,3H)。

Step two: tetraethyl titanate (4.5g,19.7mmol), (R) - (+) tert-butylsulfinamide (1.19g,9.86mmol) was added to the above intermediate compound (2.4g,10.9mmol) in tetrahydrofuran (20mL) at room temperature. The reaction mixture was reacted at 70 ℃ for 16 hours. LCMS check reaction was essentially complete and brine (80mL) was added. After the reaction solution was diluted with ethyl acetate (100mL), the separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 4:1) to obtain a pale yellow solid intermediate compound (2.5 g). LCMS (ESI) M/z 323.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d6)δ7.63(s,1H),2.62(s,3H),2.16(s,3H),1.18(s,9H)。

Step three: DIBAL-H (24mL) was added slowly to a solution of the above intermediate compound (2.5g,7.74mmol) in tetrahydrofuran (50mL) at-60 ℃ below zero. The reaction mixture was gradually warmed to room temperature and reacted at this temperature for 16 hours. LCMS detected substantial reaction completion. Methanol (10mL) was added to the reaction mixture, and the mixture was diluted with ethyl acetate (100mL), filtered through celite, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 4:1) to give a pale yellow solid intermediate compound (2.0 g). LCMS (ESI) M/z 325.9[ M + H ]]⁺。

Step four: a methanol solution (20mL) of HCl (g) was added to methanol (20mL) of the above intermediate compound (2.0g, 7.71mmol) at room temperature, and the reaction mixture was reacted at room temperature for 3 hours. LCMS detection reaction was substantially complete. The solvent was removed by concentration under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol ═ 10:1) to give a white solid intermediate compound (1.4 g).¹H 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 five: n is a radical ofN-diisopropylethylamine (750mg,12.3mmol) was added to methyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate (900mg,4.09mmol) in dimethyl sulfoxide (6mL) as the above intermediate compound (500mg,4.09 mmol). The reaction mixture was reacted at 100 ℃ for 16 hours with tube sealing. LCMS detected disappearance of starting material. The reaction solution was diluted with ethyl acetate (100mL), washed twice with brine (50mL), the combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the crude product was prepared by HPLC to give the intermediate compound (240mg) as a white solid. LCMS (ESI) M/z 458.3[ M + H ]]⁺。

Step six: an aqueous solution (2mL) of lithium hydroxide (176mg,4.20mmol) was added to the above intermediate compound (240mg,0.53mmol) in tetrahydrofuran (3mL) at room temperature, the reaction mixture was reacted for 2 hours at this temperature, and all conversion of the starting material to the product was detected by LCMS. The solvents tetrahydrofuran and water were distilled off under reduced pressure to give a white solid compound (240 mg). LCMS (ESI) M/z 444.0[ M + H ]]⁺。

Step seven: the above intermediate compound (240mg,0.53mmol) was dissolved in tetrahydrofuran (50mL) at room temperature, followed by addition of (tetrahydropyran-4-yl) methylamino (182mg,1.575mmol), HATU (599mg,1.58mmol), N, N-diisopropylethylamine (272mg,2.1mmol), and reaction mixture at 70 ℃ for 2 hours. Reaction product was predominantly detected by LCMS. The reaction mixture was diluted with ethyl acetate (100mL), washed twice with brine (50mL), the separated organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by HPLC to give a pale yellow solid compound (160 mg). LCMS (ESI) M/z 541.1[ M + H ]]⁺。

Step eight: aqueous hydrochloric acid (5M,1.5mL) was added to the above intermediate compound (160mg,0.3mmol) in isopropanol (8mL) at room temperature, and the reaction mixture was reacted at 80 ℃ for 2 hours. LCMS detected the reaction was substantially complete. The reaction mixture was diluted with methylene chloride (100mL) 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 resulting crude product was purified by HPLC to give a white solid intermediate compound (85 mg). LCMS (ESI) M/z 479.0[ M + H ]]⁺。

Step nine: tetratriphenylphosphine palladium (20mg, 0.017) at room temperaturemmol) was added to 1, 4-dioxane (5mL) of 2-formaldehyde phenylboronic acid (33mg,0.22mmol), the above intermediate compound (80mg,0.17mmol), potassium carbonate (46mg,0.34mmol), and water (1 mL). The reaction mixture was reacted at 100 ℃ for 2 hours. Ethyl acetate (30mL) was diluted, filtered through celite, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol ═ 10:1) to give a white solid intermediate compound (80 mg). LCMS (ESI) M/z 503.2[ M + H ]]⁺。

Step ten: tetrahydropyrrole (106mg,1.4921mmol) was added to the above intermediate compound (75mg,0.15mmol) in methanol (3mL) at room temperature, and after 1 hour of reaction at 20 ℃, sodium cyanoborohydride (33mg,0.52mmol) was added, and the reaction mixture was reacted at 20 ℃ for 1 hour. LCMS check reaction complete. The reaction was diluted with ethyl acetate (100mL) and the organic phase was washed twice with aqueous sodium chloride (30 mL). The separated organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by HPLC to give the compound of example 34 (5.3mg) as a white solid. LC-MS (Rt ═ 1.067 min); (ESI) M/z 558.3[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d6)δ9.08(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

The method comprises the following steps: 1-Ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (13.85g,72.3mmol) was added to a solution of 3-fluorothiophene-2-carboxylic acid (4.8g,32.85mmol) and N, O-dimethylhydroxylamine hydrochloride (7.05g,72.3mmol) in pyridine (30mL) at room temperature, and the reaction mixture was stirred at room temperatureThe reaction was carried out for 16 hours. The solvent of the reaction solution was removed by concentration under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 4:1) to give a yellow solid intermediate compound (6.1 g). LCMS (ESI) M/z 190.0[ M + H ]]⁺。

Step two: n-bromosuccinimide (17.5g,98.31mmol) was added to N, N-dimethylformamide (100mL) of the above intermediate compound (6.1g,32.8mmol) under nitrogen, and the reaction mixture was heated to 60 ℃ and reacted at this temperature for 16 hours. After diluting with ethyl acetate (500mL), the mixture was washed three times with saturated brine (100mL), 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 give an intermediate compound (3.5g) as a brown solid. LCMS (ESI) M/z 269.8[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d6)δ7.42(s,1H),3.74(s,3H),3.22(s,3H)。

Step three: methylmagnesium bromide (30mL,31.7mmol) was added to the above intermediate compound (3.4g,12.7mmol) in tetrahydrofuran (50mL) at 0 deg.C under nitrogen and the reaction was allowed to continue at 0 deg.C for 1 hour. After the reaction was complete by LCMS detection, the reaction was quenched by addition of ammonium chloride solution (200 mL). The reaction solution was extracted twice with ethyl acetate (150ml), the combined organic phases were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give the crude product as a brown oily intermediate compound (2.2g) by HPLC. LCMS (ESI) M/z 224.8[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d6)δ8.23(s,1H),2.54(s,3H)。

Step four: tetraethyl titanate (3.94g,17.2mmol) was added to the above compound (2.2g,9.5mmol), (R) - (+) tert-butylsulfinamide (1.05g,8.64mmol) in tetrahydrofuran (30mL) under nitrogen, and the reaction mixture was heated to 70 ℃ and reacted at this temperature for 16 h. After the reaction mixture was cooled to room temperature, brine (50ml) was added thereto, stirring was continued for 10 minutes, the reaction mixture was filtered through celite, the filtrate was extracted twice with ethyl acetate (100ml), the combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether 4:1) to give a brown solid intermediateCompound (1.8 g). LCMS (ESI) M/z 326.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d6)δ7.47(s,1H),2.65(d,J＝2.4Hz,3H),1.18(s,9H)。

Step five: DIBAL-H (15mL,14.1mmol) was added to the above intermediate compound (1.8g,5.5mmol) in tetrahydrofuran (30mL) with cooling at-78 deg.C, the reaction mixture was slowly warmed to room temperature and allowed to react at this temperature for 16 hours, and the reaction was essentially complete by LCMS. The reaction was quenched by addition of methanol (20ml), and after most of the solvent was removed by concentration under reduced pressure, the residue was diluted with methanol (200ml), filtered through celite, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether ═ 4:1) to give a brown solid compound (1.4 g). LC-MS (ESI) M/z 329.9[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d6)δ7.19(s,1H),5.89(d,J＝6.6Hz,1H),4.66(m,1H),1.45(d,J＝6.8Hz,3H),1.10(s,9H)。

Step six: a solution of HCl (g) in methanol (10mL,30mmol) was added to the above intermediate compound (1.8g,5.48mmol) in methanol (10 mL). The reaction was allowed to react at room temperature for 2 hours. LCMS reaction was substantially complete. The solvent was removed by concentration under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol ═ 10:1) to give a brown solid intermediate compound (1.4 g). LC-MS (ESI) M/z 206.9[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d6)δ8.76(s,3H),7.33(s,1H),4.70(d,J＝6.6Hz,1H),1.56(d,J＝6.8Hz,3H).

Step seven: methyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate (500mg,1.84mmol), the above intermediate compound (494mg,2.2mmol) and potassium fluoride (1.06g,18.3mmol) were dissolved in dimethyl sulfoxide (5mL), and the reaction was heated to 100 ℃ overnight in a sealed tube. The reaction was checked by LCMS to be essentially complete and the reaction was diluted with ethyl acetate (100mL), washed three times with water (50mL), the combined organic phases were dried over anhydrous sodium sulphate, the filtrate was concentrated under reduced pressure and the crude product was purified by HPLC to give the intermediate compound as a white solid (500 mg). LC-MS (ESI) M/z 462.1[ M + H ]]⁺。¹H 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 eight: an aqueous solution (2mL) of lithium hydroxide (365mg,8.69mmol) was added dropwise to a solution of the above intermediate compound (500mg,1.08mmol) in tetrahydrofuran (10mL) and reacted at room temperature for 2 hours. And detecting the complete reaction of the raw materials by LC-MS. Concentration under reduced pressure removed the solvent to give the crude intermediate product as a pale yellow solid (450 mg). LC-MS (ESI) M/z 447.8[ M + H ]]⁺。

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

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

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

Step (ii) ofTwelve: to the intermediate compound (180mg,0.37mmol) and pyrrolidine (81mg,1.13mmol) in methanol (5mL) was added a drop of glacial acetic acid at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (71mg,1.13mmol) was added to the above reaction solution, and the reaction was continued for 12 hours, and LC-MS checked that the reaction was substantially complete. The reaction mixture was diluted with ethyl acetate (50mL), washed twice with brine (20mL), and the separated organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the resulting crude product was prepared by HPLC to give the compound of example 35 (11.2mg) as a pale yellow solid. LC-MS (Rt 1.962 min); (ESI) M/z 562.2[ M + H ]]⁺。¹H 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)。

Referring to the procedures of examples 1 and 19, a synthesis procedure substituting (tetrahydro-2H-pyran-4-yl) -methylamine with commercially available different amines as starting material and substituting 4- ((2- (dimethylamino) ethyl) carbonyl) phenyl) boronic acid with different boronic acids gave examples 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

The method comprises the following steps: potassium fluoride (4.26g,73.51mmol) was added to 2- (6-chloro-5- (1, 3-dioxolane) at room temperature-2-yl) -2-methylpyrimidin-4-yl) acetic acid methyl ester (2.0g,7.351mmol), (R) -1- (4-bromobenzene) ethyl-1-amine hydrochloride (2.073g,8.822mmol) in dimethyl sulfoxide (40 mL). The reaction mixture was sealed at 100 ℃ for 16 hours. LCMS detection reaction was substantially complete. The reaction was diluted with ethyl acetate (200mL), washed twice with brine (50mL), the combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the crude product was purified by HPLC to afford the intermediate compound (2.4g) as a pale yellow solid. LCMS (ESI) M/z 438.1[ M + H ]]⁺。

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

Step three: the above intermediate compound (2.41g,5.64mmol) was dissolved in tetrahydrofuran (100mL) at room temperature, followed by addition of (tetrahydropyran-4-yl) methylamino (1.95g,16.9mmol), HATU (8.58g,22.6mmol), N, N-diisopropylethylamine (2.92g,22.6mmol), and heating of the reaction mixture to 70 ℃ for 2 hours. LCMS detection reaction was essentially complete. After most of the solvent was removed by concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate (200mL) 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 crude product was subjected to silica gel column chromatography (eluent: ethyl acetate/methanol 20:1) to give a pale yellow solid intermediate compound (2.08 g). LCMS (ESI) M/z 521.2[ M + H ]]⁺。

Step four: aqueous hydrochloric acid (5M,7.0mL) was added to the above intermediate compound (2.08g,4.01mmol) in tetrahydrofuran (32mL) at room temperature, and the reaction mixture was reacted at 80 ℃ for 2 hours. LCMS detection reaction was substantially complete. The reaction was diluted with dichloromethane (200mL), washed twice with brine (50mL), and the combined organic phases were dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol ═ 10:1) to give a pale yellow solid intermediate compound (1.6 g). LCMS (ESI) M/z 459.1[ M + H ]]⁺。¹H 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 four: tetratriphenylphosphine palladium (33mg,0.03mmol) was added to a solution of the above intermediate compound (130mg,0.285mmol), (2- (dimethylformyl) phenyl) boronic acid (72mg,0.37mmol), potassium carbonate (79mg,0.57mmol), and water (2mL) in 1, 4-dioxane (12mL) under nitrogen. The reaction mixture was heated to 100 ℃ and reacted at this temperature for 2 hours. The reaction was diluted with ethyl acetate (200mL), washed twice with brine (50mL), the combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the crude product was purified by HPLC to give the compound of example 42 (20.2mg) as a pale yellow solid. LC-MS (Rt ═ 1.493 min); (ESI) M/z 526.3[ M + H ]]⁺.¹H NMR(400MHz,DMSO-d6)δ9.13(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)。

By reference to the procedure of example 42, a commercially available synthesis method using different amines as starting materials instead of (tetrahydropyran-4-yl) methylamino and different boronic acids as starting materials instead of (2- (dimethylformyl) phenyl) boronic acid gave examples 43 to 47:

referring to the procedures of examples 1 and 19, a synthesis procedure substituting (tetrahydro-2H-pyran-4-yl) -methylamine with commercially available different amines as starting material and substituting 4- ((2- (dimethylamino) ethyl) carbonyl) phenyl) boronic acid with different boronic acids as starting material gave examples 48-50:

by reference to the procedure of example 35, a commercially available synthesis method using different amines as starting materials instead of (tetrahydropyran-4-yl) methylamino and different boric acids as starting materials instead of 2-formylphenylboronic acid gave examples 52-56;

by reference to the procedure of example 35, a commercially available synthesis method using different amines as starting materials instead of (tetrahydropyran-4-yl) methylamino and different boronic acids as starting materials instead of 2-formylphenylboronic acid gave examples 71-80;

by reference to the procedure of example 42, a commercially available synthesis method using a different amine as a starting material instead of (tetrahydropyran-4-yl) methylamino and a different boronic acid as a starting material instead of (2- (dimethylformyl) phenyl) boronic acid gave examples 81-86;

test example 1 inhibitory Activity test of enzyme

KRAS Using CisBio^G12CSOS1 kit for testing compound inhibition SOS1 and KRAS by using Binding assay method^G12CThe efficacy of protein-protein interactions between, the results are in IC₅₀The values are represented.

The test method comprises the following steps: (1) test compounds were tested at 1000nM concentration, compounds were diluted 3-fold in a 384-well plate in 100% DMSO at 200-fold final concentration, 10 concentrations. A50 nL 200-fold final concentration of compound was transferred to the 384well plates of interest using the knockout Echo 550. Respectively adding 50nL of 100% DMSO into the negative control well and the positive control well; (2) preparing a Tag1 SOS1 solution with 4 times of final concentration by using a Diluent buffer; (3) add 2.5. mu.L of 4-fold final concentration of Tag1 SOS1 solution to 384-well plates; (4) 4-fold final concentration of Tag2 KRAS was made up using Diluent buffer^G12CA solution; (5) add 2.5. mu.L of Tag2 KRAS at 4-fold final concentration to the compound wells and positive control wells, respectively^G12CA solution; add 2.5. mu.L of differential buffer to the negative control wells; (6) centrifuging the 384-pore plate at 1000rpm for 30 seconds, shaking and uniformly mixing, and incubating at room temperature for 15 min; (7) preparing a solution of Anti Tag1 TB3+ with the final concentration of 1 time and a solution of Anti Tag2 XL665 with the final concentration of 1 time by using Detection buffer, mixing the two solutions uniformly, and adding 5 mu L of mixed solution into each hole; (8) centrifuging a 384-well plate at 1000rpm for 30 seconds, shaking and uniformly mixing, and incubating for 120 minutes at room temperature; (9) reading Em665/620 by an Envision microplate reader; (10) data analysis, calculation formula

Wherein Min signal negative control well mean; max signal positive control well mean; compound well mean. The fitted dose-effect curve was fitted with the log value of the concentration as the X-axis and the percent inhibition as the Y-axis, using the analysis software GraphPad Prism 5 log (inhibitor) vs. again Variable slope, to obtain the IC of each compound for the enzyme activity₅₀The value is obtained. The fitting formula is: y ═ Bottom + (Top Bottom)/(1+10^ ((LogIC)₅₀X)*Hill Slope))。

As a result: compound Pair KRAS of most examples of the invention^G12Cthe/SOS 1 enzyme shows higher inhibitory activity, IC₅₀Less than 100 nM. (specific IC)₅₀The values are expressed as follows: a. the<50nM；50nM≤B<200nM；C≥200nM).

Test example 2: EXAMPLES Effect of Compounds on MiaPaca-2 cell proliferation

Test method one (2D) MiaPaca-2 cells (pancreatic cancer) cells (100. mu.L/well, 20000 cells/mL) were seeded in 96-well culture plates and supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin sulfate. Cells were treated with a starting 10. mu.M solution of test compound diluted three times in eight gradients using 0.5% dimethylsulfoxide as a blank and 5% CO₂Incubate in the incubator for a certain period of time (5 days). At the end of the incubation, 10. mu.L of MTT stock solution (5mg/mL) was added to each well. The plates were incubated at 37 ℃ for 4 hours and then the medium was removed. Dimethylsulfoxide (100 μ L) was added to each well, followed by sufficient shaking. The absorbance of the formazan product was measured at 570nm on a Thermo Scientific Varioskan Flash multimodal reader. IC was obtained by fitting dose-response data to a three-parameter nonlinear regression model using GraphPad Prism 6.0 software₅₀The value is obtained.

As a result, the compounds of the examples provided herein have proliferation inhibitory activity, IC, on MiaPaca-2 cells₅₀The values are all less than 15 uM; some of the example compounds such as examples 2, 6, 9,10, 15 on MiaPaca-2 cell proliferation inhibitory Activity, IC₅₀Values less than 5uM show excellent in vitro anti-tumor effects. As shown in table (two). Data listing of the proliferation inhibitory activity of compounds of the examples of the invention on MiaPaca-2 cells.

Example numbering	IC₅₀/uM	Example numbering	IC₅₀/uM
				Comparative Compound BI3406	7.85	2	4.42
5	7.4	6	1.67
				7	11.6	9	2.51
10	1.67	15	1.98
				16	6.12

Test example 3: ADMET testing of the example Compounds

(1) Metabolic stability test: carrying out metabolic stability incubation by using 150 mu L liver microsome (final concentration is 0.5mg/mL), wherein the system contains NADPH (final concentration is 1mM), 1 mu M of test compound and positive control midazolam or negative control atenolol, respectively terminating the reaction by using acetonitrile containing tinidazole at 0min, 5min, 10min, 20min and 30min, vortexing for 10min, centrifuging for 10min at 15000rmp, and sampling 50 mu L supernatant in a 96-well plate. The metabolic stability of the compounds was calculated by determining the relative decrease of the bulk drug.

As a result: the compounds of some embodiments of the invention have good stability to liver microsomes of various species (rats, mice, dogs and humans), and show high metabolic activity.

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

Claims

1. A pyrimido-heterocyclic compound shown as general formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof,

in the formula:

R¹independently selected from C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or 5-12 membered heteroaryl, carbocycle or heteroatom containing spiro/bridged ring/fused ring, wherein said C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₁₂Cycloalkyl radical, C₄-C₁₂Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or 5-12 membered heteroaryl, carbocyclic or heteroatom containing spiro/bridged ring/fused ring, optionally substituted with 1-3 Rn; or the two Rn can form a 3-12 membered saturated or partially unsaturated, or aromatic ring system through a carbon chain or a heteroatom; rn is selected from hydrogen, deuterium, halogen, cyano, nitro, amide, sulfonamide, hydroxyl, amino, ureido, phosphoryl, alkyl phosphorus oxy, alkyl silicon base, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, haloalkyl, haloalkoxy, C₁-C₆Monoalkylamino radical, C₁-C₆Dialkylamino, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl, C₁-C₆alkyl-S-, C₁-C₆alkyl-SO-, C₁-C₆alkyl-SO_2-Etc.;

R³is H, deuterium, halogen, hydroxy, amino, cyano, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylamino, 3-8 membered cycloalkyl or heterocycloalkyl, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, 5-10 membered aromatic ring or aromatic heterocyclic group;

Ar¹and Ar²Each independently selected from 5-12 membered monocyclic or bicyclic aryl or heteroaryl groups which may be substituted by one or more groups R^mAnd (3) substitution: hydrogen, deuterium, halogen, cyano, nitro, substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, hydroxy, amino, ureido, phosphoryl, alkylphosphoxy, alkylsilyl, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₁-C₁₀Alkoxyalkyl group, C₁-C₁₀Haloalkyl, C₁-C₁₀Haloalkoxy, C1-C₁₀Haloalkoxyalkyl, C₁-C₁₀Monoalkylamino group, C₁-C₁₀Dialkylamino, C₁-C₁₀Monoalkylaminoalkyl radical, C₁-C₁₀Bisalkylaminoalkyl radical, C₁-C₁₀Alkenyl radical, C₁-C₁₀Alkynyl, 3-12 membered cycloalkyl or heterocycloalkyl, C₁-C₁₀alkyl-S-, C₁-C₁₀alkyl-SO-, C₁-C₁₀alkyl-SO₂-, substituted or unsubstituted 5-12 membered aryl or heteroarylAryl, etc., or two of the above R^mA 3-12 membered saturated or partially unsaturated, or aromatic ring system may be formed by a carbon chain or heteroatom;

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomer, solvate, polymorph, or prodrug thereof, wherein when R2a is not the same as R2b, the carbon atom to which R2a and R2b are both attached is in the R configuration.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsiomer, solvate, polymorph, or prodrug thereof, wherein the compound is of formula (II):

wherein R is³Preferably selected from H, Me, cyclopropyl, chloro; m is preferably N or C-H or C-F or C-CN or C-Me; r¹、R^2a、R^2b、Ar¹、Ar²As defined in claim 1.

4. The compound of any one of claims 1,3, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsiomer, solvate, polymorph, or prodrug thereof, characterized in thatWherein the compound is represented by the general formula (III):

wherein R is¹、M、Ar²As defined in any one of claims 1, 3.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, atropisomer, solvate, polymorph, or prodrug thereof, wherein R is R¹Is selected from C₁-C₆Alkyl radical, C₃-C₁₂Cycloalkyl, -C₄-C₁₂Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or 5-12 membered heteroaryl, optionally substituted with 1-3 Rn, as defined in claim 1.

6. The compound of any one of claims 1,3, 4, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsiomer, solvate, polymorph, or prodrug thereof, wherein R is¹Selected from the group consisting of:

wherein one or more R^cEach independently selected from hydrogen, deuterium, halogen, -C₁-C₆Alkyl, -OC₁-C₆Alkyl, cyano, hydroxy, amino, -SC₁-C₆Alkyl, -SOC₁-C₆Alkyl, -SO₂C₁-C₆Alkyl, -COC₁-C₆Alkyl, -COOC₁-C₆Alkyl, -CONHC₁-C₆Alkyl, -CON (C)₁-C₆Alkyl) (C)₁-C₆Alkyl), 3-6 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl, -C₁-C₆Haloalkyl, -C₁-C₆Haloalkoxy, -C₁-C₆Deuterated alkyl, -C₁-C₆Deuterated alkoxy, -O-3-6 membered cycloalkyl or heterocycloalkyl, -C₁-C₆Alkyl OC₁-C₆Alkyl, -C₁-C₆Alkyl NHC₁-C₆Alkyl, -C₁-C₆Alkyl OH, -C₁-C₆Alkyl radical N (C)₁-C₆Alkyl) (C₁-C₆Alkyl), and any two R^cThe carbon chain or heteroatom can be used for realizing 3-10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring; r^dIs independently selected from-C₁-C₆Alkyl, -C₁-C₆Alkyl OC₁-C₆Alkyl, -C₁-C₆Alkyl group SC₁-C₆Alkyl, -C₁-C₆Alkyl SOC₁-C₆Alkyl, -C₁-C₆Alkyl SO₂C₁-C₆Alkyl, -COC₁-C₆Alkyl, -COOC₁-C₆Alkyl, -CONHC₁-C₆Alkyl, -CON (C)₁-C₆Alkyl) (C₁-C₆Alkyl), 3-6 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl, -C₁-C₆Haloalkyl, -C₁-C₆Haloalkoxy, -C₁-C₆Deuterated alkyl, -C₁-C₆Deuterated alkoxy-C₁-C₆Alkyl, -C₁-C₆Alkyl O-3-6 membered cycloalkyl or heterocycloalkyl, -C₁-C₆Alkyl NHC₁-C₆Alkyl, -C₁-C₆Alkyl OH, -C₁-C₆Alkyl radical N (C)₁-C₆Alkyl) (C₁-C₆Alkyl groups).

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsionmer, solvate, polymorph, or prodrug thereof, wherein R is¹Selected from the group consisting of:

wherein R is^c、R^dAs defined in claim 6.

8. The compound of any one of claims 1,3, 4, 6, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsionade, solvate, polymorph, or prodrug thereof, wherein the compound has the structure:

9. use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsomer, solvate, polymorph or prodrug thereof, for the preparation of a medicament for the treatment of a disease associated with Ras protein activity or expression or mutation, in particular a tumor independently selected from lung cancer, pancreatic cancer, liver cancer, colorectal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, melanoma, thyroid cancer, nasopharyngeal cancer, etc.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsiomer, solvate, polymorph or prodrug thereof, 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.