CN117800976A

CN117800976A - Nitrogen-containing heterocyclic compound, preparation method and application

Info

Publication number: CN117800976A
Application number: CN202311267818.5A
Authority: CN
Inventors: 万惠新; 王亚周; 马金贵
Original assignee: Rudong Ringene Pharmaceuticals Co ltd; Shanghai Lingda Biomedical Co ltd
Current assignee: Rudong Ringene Pharmaceuticals Co ltd; Shanghai Lingda Biomedical Co ltd
Priority date: 2022-09-30
Filing date: 2023-09-28
Publication date: 2024-04-02

Abstract

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

Description

Nitrogen-containing heterocyclic compound, preparation method and application

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a nitrogen-containing heterocyclic compound, a compound for inhibiting activity of Ras mutein, a preparation method and application thereof.

Background

Ras is the first oncogene identified in human tumors, and was first discovered in two murine sarcoma viruses. Ras gene familyThere are three members, HRas, KRas, NRas respectively. In human tumors, KRas mutations are most common, accounting for about 85%. Previous studies have shown that KRas mutations are oncogenic because of missense mutations at codon 12, altering the structure of the KRas protein and allowing it to remain active. Ras plays a major role in signaling pathway in activating kinases that control gene transcription, thereby regulating cell differentiation and proliferation, and is intimately involved in tumor cell survival, proliferation, migration, metastasis, and angiogenesis. It is counted that a high proportion of KRas mutations occur in malignant tumors such as pancreatic cancer, colorectal cancer, ovarian cancer, cholangiocarcinoma and the like. However, targeting drugs for common proto-oncogenes such as EGFR, BCL, etc. have been developed for several generations since the first discovery of KRas oncogenes, but targeting drugs for KRas have not been successfully developed all the time. Targeting drugs against KRas pathway mutant tumors have been mainly focused on farnesyl transferase inhibitors and Raf-MEK pathway inhibitors, but have had little effect. In recent years, inhibitors against KRAS-specific gene mutations have been developed as hot spots, although some inhibitors have gradually moved from preclinical hatching to clinical studies, such as KRAS ^G12C AMG510, MRTX1257, etc., and shows a certain efficacy in early clinical trials. Global first money KRAS ^G12C The first clinical data of the inhibitor AMG510 was formally published by the american clinical oncology institute held at month 6 of 2019, in which the drug AMG510 was installed to be shown to prevent tumor growth in most patients with non-small cell lung and colorectal cancer with KRas mutations.

However, the current KRas inhibitors are also limited to only KRas ^G12C Patients with mutations and a large number of KRAS ^G12C Other than mutation inhibitor drug development has not been broken through, such as highly-developed KRas ^G12D 、KRas ^G12V 、KRas ^G13D And the like. Thus, highly specific and excellent drug-specific KRAS-directed drugs were found and sought ^G12C Targeted drugs of specific mutant genes other than those have become a great hotspot in the industry. Through the long-term efforts of the inventor, a class of KRAS mutation inhibitors with novel structure and action mechanism, especially KRAS, is discovered ^G12D The mutation has better activity and drug-forming property.

Disclosure of Invention

The invention aims to solve the technical problems of KRAS in the prior art ^G12D The problem of lack of inhibitors provides a class of nitrogen-containing heterocyclic compounds, a preparation method and application. The nitrogen-containing heterocyclic compounds provided by the invention are brand new KRAS ^G12D Inhibitors, which exhibit good inhibitory activity; the preparation has good inhibitory activity on tumor cells and good drug-forming property, and has wide drug development prospect.

The invention solves the technical problems by the following technical proposal:

the invention provides a nitrogen-containing heterocyclic compound shown in a general formula (I), or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof,

wherein,

R ¹ selected from substituted or unsubstituted 3-12 membered cycloalkyl or heterocycloalkyl, said substituents being selected from one or more R ¹⁰ ，R ¹⁰ Independently selected from: halogen, cyano, hydroxy, amino, acyl, sulfonyl, - (CO) -NR ¹¹ R ¹² 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkenyl, C ₁ -C ₆ Alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkylcyano, C ₁ -C ₆ Alkyl hydroxy, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-6 membered aryl or heteroaryl, or two R ¹⁰ And together with the carbon atom or heteroatom to which they are attached form a 3-12 membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic ring system including spiro, bridged, fused or fused rings; r is R ¹¹ 、R ¹² Independently selected from hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkyl, 3-8 membered cycloalkyl or heterocycloalkyl, or R ¹¹ 、R ¹² Together with the attached N atom form a 3-8 membered cycloalkyl or heterocycloalkyl group; the heterocyclic alkyl, heteroaryl and heterocyclic ring system contains 1-3 hetero atoms selected from N, O, S, P, si, se;

R ² selected from substituted or unsubstituted C ₁ -C ₆ Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or heteroaryl, C ₁ -C ₆ An alkyl-substituted 3-12 membered cycloalkyl or heterocycloalkyl, a 5-16 membered saturated or partially unsaturated carbocyclic or heterocyclic ring system including spiro, bridged, fused or fused rings; the substituents are one or more R ²¹ ，R ²¹ Independently selected from the following groups: halogen, cyano, hydroxy, amino, (C) ₁ -C ₆ Alkyl) NH- (C ₁ -C ₆ Alkyl group ₂ N-、(C ₁ -C ₆ Alkyl) NH-C ₁ -C ₆ Alkyl-, (C) ₁ -C ₆ Alkyl group ₂ N-C ₁ -C ₆ Alkyl-, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or heteroaryl, 3-12 membered cycloalkyl or heterocycloalkyl substituted C ₁ -C ₆ Alkyl, etc., or two R ²¹ Together with the carbon atom or heteroatom to which they are attached, form a 3-8 membered cycloalkyl or heterocycloalkyl group; the 3-12 membered heterocycloalkyl, 5-12 membered heteroaryl, 3-12 membered heterocycloalkyl substituted C ₁ -C ₆ The heterocycloalkyl group, the 5-16 membered saturated or partially unsaturated heterocyclic ring system or the 5-12 membered heteroaryl group in the alkyl group contains 1 to 3N, O, S, P, si, B, se heteroatoms, which may optionally be in different oxidation states; r is R ²¹ May further optionally be substituted with one or more R ²¹¹ Substituted, R ²¹¹ Independently selected from halogen, cyano, hydroxy, amino, C ₁ -C ₆ Alkyl-imino-, cyano-imino-, 3-6 membered cycloalkyl-imino-, C ₁ -C ₆ Alkyl or haloalkyl, C ₁ -C ₆ Alkoxy, 3-to 10-membered cycloalkyl or heterocycloalkyl, 3-to 10-membered halocycloalkyl or haloheterocycloalkyl substitution; r is R ²¹¹ Wherein said heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, S, P, si, se;

l is selected from carbon-carbon single bond, carbon-carbon double bond, carbon-carbon triple bond, CHR ⁵ 、O、S(O) _t 、NR ^5a R ^5b ；R ⁵ 、R ^5a And R is ^5b Selected from H, C ₁ -C ₆ Alkyl of (a);

L ₁ selected from direct bond, CHR ⁵ 、O、S(O) _t 、NR ^5a R ^5b ；R ⁵ 、R ^5a And R is ^5b Selected from H, C ₁ -C ₆ Alkyl of (a);

R ⁴ a group selected from one or more of the following groups: hydrogen, deuterium, halogen, hydroxy, amino, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkoxy, 3-to 12-membered cycloalkyl or heterocycloalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, -P (O) t- (C) ₁ -C ₆ Alkyl), -S (O) t- (C) ₁ -C ₆ Alkyl), an amide group, a sulfonamide group, a urea group, a 5-to 12-membered aryl or heteroaryl group, or R as defined above ¹ And R is ⁴ Any two substituents between the two groups form a 3-12 membered saturated or partially unsaturated or aromatic ring system or aromatic heterocyclic system through carbon atoms or hetero atoms; the heterocycloalkyl, heteroaryl and aromatic heterocyclic system contains 1-3 hetero atoms selected from N, O, S, P;

t is selected from 0-2;

alternatively, R ¹ And R is ⁴ And the carbon or heteroatom (nitrogen, or oxygen, or sulfur) to which they are attached form a new saturated or unsaturated heterocyclic ring system, said new saturated or unsaturated heterocyclic ring system being a 6-7 membered heterocyclic ring;

ar is selected from a substituted or unsubstituted 5-12 membered aromatic or heteroaromatic ring, and may be substituted with one or more R ³ Substitution; r is R ³ Independently selected from halogen, hydroxy, amino, cyanoRadical, C ₁ -C ₆ Alkyl, 3-6 membered cycloalkyl or heterocycloalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, (C) ₁ -C ₆ Alkyl) NH- (C ₁ -C ₆ Alkyl group ₂ N-; the heterocycloalkyl group and the aromatic heterocycle contain 1 to 3 hetero atoms selected from N, O, S, P;

m is N or CR ⁶ ；R ⁶ Selected from hydrogen, deuterium, halogen, -CN, C ₁ -C ₃ Alkyl, C ₁ -C ₃ A haloalkyl group;

cy is selected from a 5-6 membered saturated or partially unsaturated carbocyclic or heterocyclic ring system, or a 5-6 membered aromatic or heteroaromatic ring system; the heterocyclic ring system or the aromatic heterocyclic ring system contains 1-3 hetero atoms selected from N, O, S, P, B, si.

In certain preferred embodiments of the present invention, certain groups of the nitrogen-containing heterocyclic compounds of formula I, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, torsional isomers, solvates, polymorphs, or prodrugs thereof, are defined as follows, and the non-mentioned groups are as described in any one of the embodiments of the present invention (abbreviated as "in certain embodiments of the present invention").

In certain embodiments of the present invention, the nitrogen-containing heterocyclic compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, stereoisomer, solvate, polymorph or prodrug thereof, wherein,

when R is ² Selected from 3-12 membered heterocycloalkyl, 5-12 membered heteroaryl, C ₁ -C ₆ An alkyl-substituted 3-12 membered heterocycloalkyl, 5-16 membered saturated or partially unsaturated heterocyclic ring system including spiro, bridged, fused or fused rings; the heterocycloalkyl, heteroaryl, and heterocyclic ring systems contain 1 to 3 heteroatoms independently selected from N, O, P, S, si, se;

alternatively, when R ²¹ Independently selected from 3-12 membered heterocycloalkyl, 5-12 membered heteroaryl, 3-12 membered heterocycloalkyl substituted C ₁ -C ₆ Alkyl, etc., orTwo R ²¹ When taken together with the carbon atom or heteroatom to which they are attached form a 3-8 membered heterocycloalkyl; the heterocycloalkyl group and heteroaryl group contain 1-3N, O, S, P, si, B, se heteroatoms, and the heteroatoms can be optionally in different oxidation states.

In certain embodiments of the invention, a nitrogen-containing heterocyclic compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, has a structure as shown in formula (II):

wherein W, W ₁ Each independently selected from N or CR ⁴ ，Ar、R ³ 、R ⁴ 、M、L、L ₁ 、R ¹⁰ 、R ² 、R ¹ The scope of (2) is as described elsewhere herein.

In certain aspects of the invention, C ₂ -C ₆ Alkenyl group is C ₂ -C ₄ Alkenyl, preferably ethenyl or propenyl;

in certain aspects of the invention, C ₂ -C ₆ Alkynyl is C ₂ -C ₄ Alkynyl, preferably

In certain aspects of the invention, C ₁ -C ₆ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl;

in certain aspects of the invention, C ₁ -C ₆ Halogen in the haloalkyl is fluorine, chlorine, bromine or iodine;

in certain embodiments of the invention, the 3-6 membered cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexenyl, or cyclohexyl.

In certain aspects of the invention, R ¹⁰ 、R ²¹ 、R ²¹¹ The number of (2) is 0,1. 2 or 3.

m is N, C-H, C-F, C-CN;

alternatively, cy is selected from the group consisting of:

alternatively, R ⁴ Preferably selected from hydrogen, deuterium, halogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, cyano, amino, C ₃ -C ₆ Cycloalkyl or halocycloalkyl, C ₂ -C ₄ Alkenyl group, C ₂ -C ₄ Alkynyl groups of (a) and the like;

alternatively, R ¹ Selected from a substituted or unsubstituted 5-10 membered cycloalkyl or heterocycloalkyl, preferably from a substituted or unsubstituted piperidine ring, piperazine ring, homopiperazine ring, pyrrolidine ring, homopiperidine ring, morpholine ring, homomorpholine ring, said substituents R ¹⁰ Preferably from halogen, C1-C6 alkyl, hydroxy, amino, =O, 3-to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring systems, or form a substituted or unsubstituted bicyclic ring system with 5-to 6-membered aryl or heteroaryl, or two R ¹⁰ And together with the carbon atom or heteroatom to which they are attached form a 5-6 membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic ring system including spiro, bridged, fused or fused rings;

Alternatively, ar is preferably selected from a benzene ring, a pyridine ring, a naphthalene ring, a benzothiazole ring, a benzothiophene ring, an indazole ring, an indole ring, an azaindole ring, a benzimidazole ring, etc.;

alternatively, R ³ Independently selected from hydrogen, halogen, hydroxy, amino, cyano, and C ₁ -C ₆ Alkyl, 3-6 membered cycloalkyl or heterocycloalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy groups, and the like;

alternatively, L is selected from: CH (CH) ₂ O, NH or S;

alternatively, L ₁ Selected from: direct bond, CH ₂ O, NH or S;

alternatively, R ² Selected from the group consisting ofWherein m and n are each an integer from 0 to 3; preferably 1 or 2; ry is selected from 3-12 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, said heterocycloalkyl or heteroaryl containing 1-3N, O, S, P, si, B, se heteroatoms, which optionally may be in different oxidation states; r is R ^p And R is ^q Selected from hydrogen, halogen, C ₁ -C ₆ Alkyl or alkoxy, 3-6 membered cycloalkyl or heterocycloalkyl, hydroxy, amino, or R ^p And R is ^q Forming a 3-8 membered cycloalkyl or heterocycloalkyl; r is R ^p 、R ^q Ry may optionally be further substituted with one or more R ²¹¹ Substituted, halogen, cyano, C ₁ -C ₆ Alkyl-imino-, cyano-imino-, 3-6 membered cycloalkyl-imino-, C ₁ -C ₆ Alkyl or haloalkyl, 3-12 membered cycloalkyl or heterocycloalkyl, 3-12 membered halocycloalkyl or haloheterocycloalkyl.

In certain embodiments of the present invention, the nitrogen-containing heterocyclic compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, stereoisomer, solvate, polymorph or prodrug thereof, is characterized in that R ¹ Preferably selected from

Alternatively, cy is selected from

Alternatively, R ³ Ar is selected from a substituted or unsubstituted benzene ring, pyridine ring, naphthalene ring, benzothiazole ring, benzothiophene ring; the substituents are independently selected from hydroxy, amino, halogen, cyano, vinyl, ethynyl, C1-C3 alkyl or haloalkyl;

alternatively, L is preferably selected from-O-;

alternatively, L ₁ Preferably from direct bond, CH ₂ ；

Alternatively, R ² Preferably selected fromWherein Ry is selected from substituted 5-12 membered cycloalkyl or 5-12 membered heterocycloalkyl containing 1-3S, or P, or Si, or selenium; r is R ^p And R is ^q Selected from hydrogen, halogen, C ₁ -C ₆ Alkyl or alkoxy, hydroxy, amino, or R ^p And R is ^q Forming a 3-8 membered cycloalkyl or heterocycloalkyl;

alternatively, R ⁴ Selected from hydrogen, deuterium, halogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, cyano, amino, C ₃ -C ₆ Cycloalkyl or halocycloalkyl, C ₂ -C ₄ Alkenyl group, C ₂ -C ₄ Alkynyl groups of (a) and the like;

in some embodiments of the present invention, the nitrogen-containing heterocyclic compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, stereoisomer, solvate, polymorph or prodrug thereof, wherein,

M is preferably N, C-H, C-F, C-CN;

alternatively, cy is preferably selected from

Alternatively, R ¹ Preferably selected from:

r is as described above ¹ Any hydrogen of the radicals being able to be replaced by halogen, hydroxy, C ₁ -C ₆ Alkyl, or = O substitution;

alternatively, R ³ Ar is selected from

Alternatively, L is selected from O;

alternatively, L ₁ Selected from direct bond, CH ₂ ；

Alternatively, R ² Preferably is R ⁶ Selected from hydrogen, deuterium, halogen, cyano, C ₁ -C ₃ Alkyl or C ₁ -C ₃ A haloalkyl group;

alternatively, R ⁴ Selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, cyano, amino, cyclopropyl, vinyl, ethynyl, and the like.

In certain aspects of the invention, when R ¹ And R is ⁴ The compounds of formula (I) may have the structure of formula (III) when a new heterocyclic ring system is constituted by sharing one carbon or heteroatom (nitrogen, or oxygen, or sulfur atom),

wherein r is 0, 1 or 2; p is selected from 1 or 2; w, W ₁ Independently selected from N or CR ⁴ ；

L ₂ Is O, S or NR ⁷ ，R ⁷ Is hydrogen, deuterium, halogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, cyano, amino, C ₃ -C ₆ Cycloalkyl or halocycloalkyl; l (L) ₂ Preferably O;

q is- (CH) ₂ ) _q -L ₃ -(CH ₂ ) _q -or not present; q is selected from 1 or 2;

L ₃ selected from chemical bonds, O, S, NR ⁸ Or is absent, R ⁸ Is hydrogen, deuterium, halogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, cyano, amino, C ₃ -C ₆ Cycloalkyl or halocycloalkyl; q is preferably selected from-CH ₂ CH ₂ -；

R ¹⁰ Independently selected from deuterium, halogen, cyano, hydroxy, amino, C1-C6 acyl, sulfonyl, - (CO) -NR ¹¹ R ¹² 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkylcyano, C ₁ -C ₆ Alkyl hydroxy, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-6 membered aryl or heteroaryl; other groups Ar, R ³ 、R ⁴ 、M、L、L ₁ 、R ² 、R ¹⁰ As described elsewhere herein;

in some aspects of the present invention,preferably +.>

In certain embodiments of the present invention, the 3-12 membered cycloalkyl or heterocycloalkyl substituted alkyl is preferably (3-12 membered cycloalkyl or heterocycloalkyl) -C ₁ -C ₆ Alkyl-; the alkyl-substituted amino group is preferably (C) ₁ -C ₆ Alkyl) NH-or (C) ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Alkyl) N-;

in certain aspects of the invention, R ¹¹ 、R ¹² Independently selected from hydrogen, halogen, methyl;

in certain aspects of the invention, when R ¹¹ 、R ¹² When taken together with the attached N atom form a 5-8 membered heterocycloalkyl, the 3-8 membered heterocycloalkyl is preferably

In certain aspects of the invention, R ^p And R is R ^q Forming a three-membered carbocyclic ring with the attached carbon atom;

in certain aspects of the invention, when R ²¹ In the case of 3-12 membered heterocycloalkyl, the 3-12 membered heterocycloalkyl is 5-10 membered heterocycloalkyl, preferably

In certain aspects of the invention, two R ²¹ When taken together with the carbon atom or heteroatom to which they are attached, form a 3-8 membered cycloalkyl, the 3-8 membered cycloalkyl is a three membered carbocyclic ring;

in certain embodiments of the invention, ry is preferably

In certain aspects of the invention, when R ¹⁰ Is C ₁ -C ₆ When alkyl hydroxy of (C) ₁ -C ₆ Preferably HO-CH ₂ -、HO-CH ₂ -CH ₂ -；

In certain embodiments of the invention, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, has the following structure:

thus, throughout this specification, one skilled in the art may select the groups and substituents thereof in the nitrogen-containing heterocyclic compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, stereoisomer, solvate, polymorph or prodrug thereof, to provide a stable nitrogen-containing heterocyclic compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, stereoisomer, solvate, polymorph or prodrug thereof, including but not limited to the compounds described in the examples of the invention.

The nitrogen-containing heterocyclic compounds of formula I, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, torsional isomers, solvates, polymorphs, or prodrugs thereof, according to the invention, may be synthesized by methods that include methods similar to those known in the chemical arts, the steps and conditions of which may be referred to in the art as procedures and conditions of similar reactions, particularly in light of the description herein. The starting materials are typically from commercial sources, such as Aldrich or can be readily prepared using methods well known to those skilled in the art (available via SciFinder, reaxys on-line databases).

In the invention, the nitrogen-containing heterocyclic compound shown in the formula I or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof can also be prepared into the nitrogen-containing heterocyclic compound shown in the formula I or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, and other nitrogen-containing heterocyclic compounds shown in the formula I or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof can be obtained by peripheral modification by adopting a conventional method in the art.

In general, the compounds of the invention may be prepared by the methods described herein, wherein the substituents are as defined in formula I, unless otherwise indicated. The following reaction schemes and examples are provided to further illustrate the present invention.

The invention also provides a preparation method of the nitrogen-containing heterocyclic biaryl compound shown in the formula I, which comprises the following steps:

a) Combining a compound of formula (A) with R ¹ -H under alkaline conditions, to produce a compound of formula (B);

b) Combining a compound of formula (B) with R ² -L-H is subjected to substitution reaction or metal catalytic coupling reaction under alkaline condition to generate a compound of the general formula (C);

c) The compound of the general formula (C) and arylboric acid or arylborate or arylmetal reagent (Ar-M) are subjected to a transition metal catalytic coupling reaction to generate the general formula (I).

X is halogen, and the definition of each other group is as described above;

preferably, each of said steps a), b), c) is performed in a solvent, and said solvent is selected from the group consisting of: water, methanol, ethanol, isopropanol, butanol, ethylene glycol methyl ether, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 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 t-butoxide, sodium t-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or a combination thereof; the organic base is selected from the group consisting of: pyridine, triethylamine, N, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, or combinations thereof.

Preferably, the transition metal catalyst is selected from the group consisting of: tris (dibenzylideneacetone) dipalladium (Pd) ₂ (dba) ₃ ) Tetrakis (triphenylphosphine) palladium (Pd (PPh) ₃ ) ₄ ) Palladium acetate, palladium chloride, dichloro-bis (triphenylphosphine) palladium, trifluoropalladium acetate, triphenylphosphine palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, bis (triphenylphosphine) palladium dichloride, 1, 2-bis (diphenylphosphino) ethane palladium dichloride, or a combination thereof; the catalyst ligand is selected from the group consisting of: tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-benzylphosphine, tricyclohexylphosphine, tri-o-benzylphosphine, or a combination thereof.

The invention also provides a preparation method of the nitrogen-containing heterocyclic compound shown in the formula I, which comprises the following steps of d-g:

X is halogen, pg is benzyl or Boc protecting group, and the definition of other groups is as described above;

d) The compound of the general formula (D) and the nitrogen-containing spiro ringOr bridged ring compounds R ¹ -H under basic conditions, to produce a compound of formula (N);

e) Reacting a compound of the general formula (E) with an alkyl-substituted hydroxy or amino compound H-L-R under the action of a base ² Generating a compound of a general formula (F) by substitution reaction;

f) Removing protecting groups from the compound of the general formula (F) by an acid catalysis or transition metal catalysis hydrogenation method to generate a compound of the general formula (G);

g) Coupling reaction of the compound of the general formula (G) with substituted aryl halide or aryl boric acid under the catalysis of transition metal to generate the compound of the general formula (I);

preferably, the steps d), e), f), g) are each carried out in a solvent, and the solvent is selected from the group consisting of: water, methanol, ethanol, isopropanol, butanol, ethylene glycol methyl ether, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof.

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

Preferably, the transition metal palladium catalyst is selected from the group consisting of: tris (dibenzylideneacetone) dipalladium (Pd) ₂ (dba) ₃ ) Tetrakis (triphenylphosphine) palladium (Pd (PPh) ₃ ) ₄ ) Palladium acetate, palladium chloride, dichloro-bis (triphenylphosphine) palladium, trifluoroacetate, triphenylphosphine palladium acetate, [1,1' -bis (diphenylphosphino) dicyclopentadieneIron (Fe)]Palladium dichloride, bis (triphenylphosphine) palladium dichloride, 1, 2-bis (diphenylphosphino) ethane palladium dichloride, or a combination thereof; the catalyst ligand is selected from the group consisting of: tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-benzylphosphine, tricyclohexylphosphine, tri-o-benzylphosphine, or a combination thereof.

Preferably, the transition metal copper catalyst is selected from the group consisting of: copper acetate, copper trifluoroacetate, copper sulfate, copper bromide, copper chloride, copper iodide, or a combination thereof.

The necessary starting materials or reagents for preparing the compounds of formula I are commercially available or may be prepared by synthetic methods known in the art. The compounds of the invention may be prepared as free bases or as salts thereof with acids, as described in the experimental section below. The term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein, and has all of the pharmaceutical activity of the parent compound. Pharmaceutically acceptable salts can be prepared by adding the corresponding acid to a suitable organic solvent for the organic base, and processing according to conventional methods.

Examples of salification include: salifying with inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and salts formed with organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, eurynic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid or trimethylacetic acid.

X is halogen, pg is benzyl or Boc protecting group, and the definition of other groups is as described above; the nitrogen-containing heterocyclic compounds of formula I, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, torsional isomers, solvates, polymorphs, or prodrugs thereof, may have one or more chiral carbon atoms, and thus may be isolated as optically pure isomers, e.g., pure enantiomers, or racemates, or mixed isomers. Pure single isomers may be obtained by separation methods in the art, such as chiral crystallization to form salts, or chiral preparative column separation.

The chemicals used in the synthetic routes described in this patent include solvents, reagents, catalysts, and protecting groups, deprotecting groups, including t-butoxycarbonyl (Boc). The above-described methods may additionally include steps prior to or subsequent to the steps specifically described herein, and suitable protecting groups may be added or removed to provide the subject compounds. In addition, the various synthetic steps may be performed alternately or sequentially to obtain the final target product.

It is another object of the present invention to provide a medicament for treating or preventing tumors and a composition thereof. The technical scheme for achieving the purpose is as follows:

the invention provides a pharmaceutical composition comprising an effective amount of a nitrogen-containing heterocyclic compound shown as the formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, and (one or more) pharmaceutically acceptable carrier (pharmaceutical auxiliary materials). For example, such pharmaceutical compositions may comprise one or more additional nitrogen-containing heterocyclic biaryl compounds of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof. In the pharmaceutical composition, the nitrogen-containing heterocyclic biaryl compound shown in the formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof can be used in an amount effective for treatment.

The invention provides a pharmaceutical composition for treating tumors, which consists of a nitrogenous heterocyclic compound shown in the general formula I, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, torsional isomers, solvates, polymorphs or prodrugs thereof and a pharmaceutically acceptable carrier.

It is a further object of the present invention to provide the use of the above compounds. The technical scheme for achieving the purpose is as follows:

the invention also provides an application of the nitrogen-containing heterocyclic compound shown in the formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof in preparing Ras mutant protein inhibitor; in the application, the Ras mutant protein can be KRAS ^G12D The method comprises the steps of carrying out a first treatment on the surface of the The Ras mutein inhibitors are useful in mammalian organisms; it is also useful in vitro, mainly as an experimental use, for example: provides comparison as a standard sample or a control sample, or is prepared into a kit according to a conventional method in the field, and provides rapid detection for the inhibition effect of Ras mutant protein.

The invention also provides an application of the nitrogen-containing heterocyclic compound shown in the formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof in preparing medicines; the medicine can be used for treating diseases related to activity or expression quantity of Ras mutant protein; alternatively, the drug may be a therapeutic drug for tumors. The Ras mutant protein can be KRAS ^G12D . The tumor is independently selected from non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.

Another aspect of the invention relates to a method for preventing and/or treating a disease associated with activity or expression of a Ras mutein, comprising administering to a patient a therapeutically effective amount of the nitrogen-containing heterocyclic compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof.

Another aspect of the present invention relates to a method for preventing and/or treating tumors, which comprises administering to a patient a therapeutically effective amount of the nitrogen-containing heterocyclic compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof.

Another aspect of the invention relates to a medicament for preventing and/or treating a disease or tumor associated with activity or expression of a Ras mutein, which comprises the nitrogen-containing heterocyclic compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof.

The nitrogen-containing heterocyclic compound shown in the general formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof is used for preparing medicaments for treating diseases related to activity or expression quantity of Ras mutant protein, in particular to medicaments for treating tumors. The tumor is independently selected from non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, 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 various tumor cells, in particular can kill KRAS with high efficiency ^G12D The tumor related to abnormal mutein signal pathway is a new therapeutic drug with a novel action mechanism.

The pharmaceutical excipients can be those which are widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

Substances that may be pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum stearate, lecithin, serum proteins, such as human serum proteins, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; a gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol, phosphate buffer, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating materials, sweetening, flavoring and perfuming agents, preserving and antioxidant agents.

The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.

The pharmaceutical dosage forms of the compounds of the present invention may be provided in the form of immediate release, controlled release, sustained release or target drug release systems. For example, common dosage forms include solutions and suspensions, (micro) emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols and freeze-dried formulations. Depending on the route of administration used, special devices may be required to administer or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators, or Special bottles (Special flash). Pharmaceutical dosage forms often consist of a drug, excipients and a container/sealing system. One or more excipients (also known as inactive ingredients) may be added to the compounds of the present invention to improve or promote the manufacture, stability, administration and safety of the drug, and may provide a means to achieve a desired drug release profile. Thus, the type of excipient added to a drug may depend on various factors, such as the physical and chemical characteristics of the drug, the route of administration, and the manufacturing steps. Pharmaceutically acceptable excipients are present in this field and include those listed in the various pharmacopoeias. (see U.S. Pharmacopeia (U.S.Pharmacopeia, USP), japanese Pharmacopeia (Japanese Pharmacopoeia, JP), european Pharmacopeia (European Pharmacopoeia, EP) and British Pharmacopeia (British pharmacopoeia, BP); U.S. food and drug administration (the U.S. food and Drug Administration, www.fda.gov) drug evaluation and research center (Centerfor Drug Evaluation and Research, CEDR) publications, for example, inactive ingredient guide (Inactive Ingredient Guide, 1996); pharmaceutical additives handbook written by Ash and Ash (Hand book of Pharmaceutical Additives,2002, incorporated information resources, inc. (Synapse Information Resources, inc., endiott NY; etc.).

Pharmaceutical dosage forms of the compounds of the present invention may be manufactured by any of the methods well known in the art, for example by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tabletting, suspending, extruding, spray-drying, grinding, emulsifying, (nano/micro) encapsulating, packaging, or lyophilizing processes. As noted above, the compositions of the present invention may include one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecule into a formulation for pharmaceutical use.

The pharmaceutical compositions of the invention may be administered topically or systemically, e.g. for enteral, such as rectal or oral administration, or for parenteral administration to a mammal (especially a human), and comprise a therapeutically effective amount of a compound according to the invention, a stereoisomer or a pharmaceutically acceptable salt thereof as active ingredient, together with a pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier. A therapeutically effective amount of the active ingredient is defined as above and below and depending on the species, weight, age, individual condition, individual pharmacokinetic parameters, disease to be treated and mode of administration of the mammal, for enteral administration, such as oral administration, the compounds of the invention can be formulated in a wide variety of dosage forms.

The pharmaceutical compositions and dosage forms may comprise one or more compounds of the present invention, stereoisomers thereof, or one or more pharmaceutically acceptable salts thereof, as an active ingredient. The pharmaceutically acceptable carrier may be a solid or a liquid. Solid forms of preparation include powders, tablets, pills, troches, capsules, cachets, suppositories, and dispersible granules. The solid carrier may also be one or more substances that act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is usually a finely divided solid, which is a mixture with the finely divided active component. In tablets, the active ingredient is typically mixed with a carrier having the necessary binding capacity in a suitable ratio and compacted in the shape and size desired. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter and the like. Formulations of the active compounds may include an encapsulating material as a carrier providing a capsule in which the active ingredient with or without the carrier is surrounded by a carrier to which it is bound.

Other forms suitable for oral administration include liquid form preparations, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations intended to be converted to liquid form preparations shortly before use. The emulsion may be prepared in solution, for example in an aqueous propylene glycol solution, or may contain an emulsifier such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, fragrances, stabilizers and thickeners. Aqueous suspensions may be prepared by dispersing the finely divided active component in water with binders such as natural or synthetic gums, resins, methylcellulose, carboxymethylcellulose and other commonly used suspending agents. Solid form preparations include solutions, suspensions and emulsions which may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.

Exemplary combinations for rectal administration include suppositories, which may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic glycerides or polyethylene glycols, which are solid at ordinary temperatures, but melt and/or dissolve in the rectal cavity to release the drug.

The compounds of the invention may also be administered parenterally, for example, by inhalation, injection or infusion, such as by intravenous, intra-arterial, intra-osseous, intramuscular, intra-cerebral, extra-cerebral, intra-synovial, intra-sternal, intrathecal, intralesional, intracranial, intratumoral, intradermal, and subcutaneous injection or infusion.

Thus, for parenteral administration, the pharmaceutical compositions of the invention may be in the form of sterile injectable or infusible preparations, e.g., as sterile aqueous or oleaginous suspensions. The suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., tween 80) and suspending agents. The sterile injectable or infusible formulation may also be a sterile injectable or infusible solution or suspension in a non-toxic parenterally acceptable diluent or solvent. For example, the pharmaceutical composition may be a solution in 1, 3-butanediol. Other examples of acceptable vehicles and solvents that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, mannitol, water, ringer's solution, and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil may be employed for this purpose including synthetic mono-or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant. Solutions for parenteral use may also include suitable stabilizers and, if desired, buffer substances. Suitable stabilizers include antioxidants such as sodium bisulfate, sodium sulfite or ascorbic acid, citric acid and salts thereof and sodium EDTA alone or in combination. The parenteral solution may also contain preservatives such as benzalkonium chloride, parahydroxybenzoic acid or propyl parahydroxybenzoate and chlorobutanol.

For inhalation or nasal administration, suitable pharmaceutical formulation chamber particles, aerosols, powders, mists or droplets, for example, have an average size of about 10 microns or less in diameter. For example, compositions for inhalation may be prepared in saline as solutions, using benzyl alcohol or other suitable preservatives, absorption promoters for improving bioavailability, fluorocarbon and/or other solubilizing or dispersing agents known in the art.

The pharmaceutical compositions of the present invention may also be administered topically to the skin or mucosa. For topical application, the pharmaceutical composition may be, for example, a lotion, gel, paste, tincture, transdermal patch, gel for transmucosal delivery.

The pharmaceutical compositions may be formulated in a suitable ointment comprising the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes and water. Alternatively, the pharmaceutical compositions may be formulated as suitable lotions or emulsions comprising the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of the present invention may also be administered topically to the lower intestinal tract in rectal suppository formulations or in suitable enema formulations. Suitable pharmaceutical excipients (e.g. carriers) and methods for preparing pharmaceutical dosage forms are described in standard reference textbooks in the pharmaceutical formulation arts (Remington's Pharmaceutical Sciences, mack Publishing Company)

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. The limited space is not described in any more detail herein.

Terminology

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 hereby 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 inventive subject matter. In this application, the singular is used to include 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" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.

The definition of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY TH ED." vols. A (2000) and B (2001), plenum Press, new York). Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods are employed unless otherwise indicated. Unless specifically defined otherwise, the terms used herein in the description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques may 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 manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present invention. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.

When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH ₂ O-is equivalent to-OCH ₂ -。

The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter. 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 simplified symbol to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl, C _1-6 Alkyl or C _1- C 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 reduced notation does not include carbon that may be present in a substituent of the group.

Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5 or 6 carbon atoms. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.

In this context, a numerical range as defined in substituents, such as 0 to 4, 1-4, 1 to 3, etc., indicates an integer within the range, such as 1-6 is 1, 2, 3, 4, 5, 6.

In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.

In some specific structures, when an alkyl group is explicitly represented as a linking group, then the alkyl group represents a linked alkylene group, e.g., the group "halo-C ₁ -C ₆ C in alkyl' ₁ -C ₆ Alkyl is understood to mean C ₁ -C ₆ Alkylene (e.g., methylene, ethylene, propylene, butylene, pentylene, isopropylene, isobutylene, sec-butylene, tert-butylene, isopentylene, 2-methylbutylene, 1-ethylpropylene, 1, 2-dimethylpropylene, neopentylene or 1, 1-dimethylpropylene, etc.).

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

The term "comprising" is an open-ended expression, i.e. including what is indicated by the invention, but not excluding other aspects.

The term "substituted" refers to any one or more hydrogen atoms on a particular atom being substituted with a substituent, including heavy hydrogen and variants of hydrogen, so long as the valence of the particular atom is normal and the substituted compound is stable.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. Further, when the group is substituted with 1 or more of the substituents, the substituents are independent of each other, that is, the 1 or more substituents may be different from each other or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.

In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C ₁ ～C ₆ Alkyl "or" C _1-6 Alkyl "means in particular methyl, ethyl, C independently disclosed ₃ Alkyl, C ₄ Alkyl, C ₅ Alkyl and C ₆ An alkyl group; "C _1-4 Alkyl "refers specifically to independently disclosed methyl, ethyl, C ₃ Alkyl (i.e. propyl, including n-propyl and isopropyl), C ₄ Alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).

In the present application, the term "halogen" refers to fluorine, chlorine, bromine or iodine; "hydroxy" refers to an-OH group; "hydroxyalkyl" refers to an alkyl group as defined below substituted with a hydroxy (-OH); "carbonyl" refers to a-C (=o) -group; "nitro" means-NO ₂ The method comprises the steps of carrying out a first treatment on the surface of the "cyano" refers to-CN; "amino" means-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the "substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, e.g., mono-, di-, alkylamido, aralkylamino, heteroaralkylamino; "carboxy" means-COOH; "acyl" refers to a-C (=o) H group; "sulfone group" means-S (=O) ₂ -a group; "sulfoxide" refers to the-S (=o) -group; "sulfonyl" means-S (=o) ₂ An H group; "urea" means-NH-C (=o) -NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the "sulfonylurea" means-S (=o) ₂ -NH-C(＝O)-NH ₂ A group; "alkoxy" refers to an alkyl-O-group as defined below.

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

The term "alkylene" as used herein refers to a saturated, branched or straight chain or cyclic hydrocarbon group of the number of carbon atoms (typically 1-6 carbon atoms) and having two monovalent radical centers derived from the removal of two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Typical alkylene groups include, but are not limited to, methylene (-CH) ₂ (-) ethylene { including 1, 2-ethylene (-CH) ₂ CH ₂ (-), 2-dimethylene (-CH (CH) ₃ ) (-) } propylene { including 2-methylpropylene (-CH (CH) ₃ )CH ₂ (-), isopropylidene (-C (CH) ₃ ) ₂ (-), 1, 3-propylene (-CH) ₂ CH ₂ CH ₂ (-) } butylene { including 1, 4-butylene (-CH) ₂ CH ₂ CH ₂ CH ₂ -)}。

In the present application, the term "alkenyl" as part of a group or other group means a straight or branched hydrocarbon chain group consisting of only carbon 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 linked to the rest of the molecule by a single bond, such as, but not limited to, ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1, 4-dienyl, and the like.

In this application, the term "alkynyl" as part of a group or other group means a straight or branched hydrocarbon chain group consisting of only 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 attached to the remainder of the molecule by a single bond, such as, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, and the like.

In this application, as part of a group or other group, the term "cycloalkyl" means a stable, non-aromatic, mono-or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms, which may include fused ring systems, bridged ring systems, or spiro ring systems, having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be attached to the remainder 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 optionally be oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexanyl, 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 [ 2.2.2.2 ] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octenyl, bicyclo [ 2.1.1 ] octadienyl, adamantylene, and the like.

In the present application, the term "heterocyclyl" as part of a group or other group means 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 specifically indicated otherwise in the present specification, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include fused, bridged or spiro ring systems; the nitrogen, carbon or sulfur atoms in the heterocyclyl may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclyl may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclyl 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 remainder of the molecule is a non-aromatic ring atom. For the purposes of the present invention, heterocyclyl groups are preferably stable 4-to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 4-to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. 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] heptan-6-yl, 2, 5-diaza-bicyclo [2.2.1] heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxacyclopentyl, tetrahydroisoquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimidyl, and the like.

In the present application, the term "heterocycloalkyl" means a stable 3-to 20-membered saturated cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur, as part of a group or other groups. Unless otherwise specifically indicated in the present specification, a heterocycloalkyl group may be either a monocyclic ("monocyclic heterocycloalkyl") or a bicyclic, tricyclic or higher ring system, which may include fused, bridged or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocycloalkyl"). The heterocycloalkyl bicyclic ring system may include one or more heteroatoms in one or both rings, and is saturated for purposes of the present invention, a heterocycloalkyl group is preferably a stable 4-to 12-membered saturated monocyclic, bicyclic, bridged or spiro ring group containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-to 7-membered saturated monocyclic, bicyclic, bridged or spiro ring group containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, in particular, the 4-to 7-membered heterocycloalkyl group may contain 3, 4, 5 or 6 carbon atoms and one or two of the heteroatoms or heteroatom-containing groups, provided that the total number of ring atoms is not greater than 7, in particular the heterocycloalkyl group may contain 3, 5 or 6 carbon atoms and the total number of heteroatoms or heteroatom-containing groups ("the total number of heteroatoms may be 3, 5 or 6 heteroatoms").

In this application, the term "aryl" as part of a group or other 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, aryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that the aryl groups are linked to the remainder of the molecule by single bonds via atoms on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, 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, as part of a group or other group, the term "heteroaryl" means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur within the ring. Unless otherwise specifically indicated in the present specification, heteroaryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that heteroaryl groups are attached to the remainder of the molecule via an atom on an aromatic ring by a single bond. The nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. For the purposes of the present invention, heteroaryl groups are preferably stable 5-to 12-membered aromatic groups comprising 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-to 10-membered aromatic groups comprising 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or 5-to 6-membered aromatic groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthyridinyl, [1,2,4] triazolo [4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [1, 4] triazolo [1, 4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [ 2,4] a ] 1, 4-imidazo [ 2, 4-a ] 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.

As used herein, the singular forms "a", "an", and "the" are understood to include plural referents unless the context clearly dictates otherwise. Furthermore, the term "comprising" is an open-ended limitation and does not exclude other aspects, i.e. it includes the content indicated by the invention.

Unless otherwise indicated, the present invention employs conventional methods of mass spectrometry, elemental analysis, and the various steps and conditions are referred to in the art by conventional procedures and conditions.

The present invention employs, unless otherwise indicated, standard nomenclature for analytical chemistry, organic synthetic chemistry and optics, and standard laboratory procedures and techniques. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and light emitting device performance detection.

In addition, unless explicitly indicated otherwise, the description of the invention as "…" independently is to be understood broadly as meaning that each individual described may be independent of the other, and may be the same or different. In more detail, the description "… is independently" may mean that specific options expressed between the same symbols in different groups do not affect each other; it may also be expressed that specific options expressed between the same symbols in the same group do not affect each other.

Those skilled in the art will appreciate that, in accordance with convention used in the art, the present application describes the structural formula of a group as used inMeaning that the corresponding group is linked to other fragments, groups in the compound through this site.

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 aryl groups and unsubstituted aryl groups.

The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a particular fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded or attached to a molecule.

"stereoisomers" refer 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 an olefinic double bond is contained in the compounds of the present invention, 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 invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and thus may be produced in 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, such as crystallization and chiral chromatography.

Conventional techniques for preparing/separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography, see, for example, gerald gabiz and Martin g.schmid (eds.), chiral Separations, methods and Protocols, methods in Molecular Biology, vol.243,2004; m.stalcup, chiral Separations, annu.rev.animal.chem.3:341-63, 2010; fumigs et al (EDs.), VOGEL' S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY.sup.TH ED, longman Scientific and Technical Ltd., essex,1991,809-816; heller, acc.chem.Res.1990,23,128.

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

By "pharmaceutically acceptable acid addition salt" is meant a salt with an inorganic or organic acid that retains 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, formate, acetate, 2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalenedisulfonate, and the like. These salts can be prepared by methods known in the art.

By "pharmaceutically acceptable base addition salt" is meant a salt formed with an inorganic or organic base that is capable of maintaining the bioavailability 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 natural substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, 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.

"polymorphs" refer to the 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 crystal form, and the present invention is intended to include various crystal forms and mixtures thereof.

In general, crystallization will produce solvates of the compounds of the present invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of a compound of the 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 monohydrate, dihydrate, hemihydrate, sesquihydrate, 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 may also retain only adventitious water or a mixture of water plus a portion of the 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 present invention are also included within the scope of the present invention.

The invention also includes prodrugs of the above compounds. In this application, the term "prodrug" means a compound that can be converted into a biologically active compound of the invention under physiological conditions or by solvolysis. 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 an individual in need thereof, but are converted in vivo to the active compounds of the present invention. Prodrugs are typically rapidly converted in vivo to the parent compounds of the present 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. Specific methods of prodrug preparation can be found in saunnier, m.g., et al, biorg. Med. Chem. Lett.1994,4,1985-1990; greenwald, r.b., et al, j.med.chem.2000,43,475.

In this application, "pharmaceutical composition" refers to a formulation of a compound of the invention with a medium commonly 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 promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.

The term "pharmaceutically acceptable" as used herein refers to a material (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 material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.

In this application, "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, stabilizer, isotonizing agent, solvent, or emulsifying agent that is approved by the relevant government regulatory agency as acceptable for human or livestock use.

The "tumor", "cell proliferation abnormality related disease", and the like of the present invention include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, pancreatic cancer, lung squamous carcinoma, 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 "prevent", "preventing" and "preventing" as used herein include reducing the likelihood of a patient from developing or worsening a disease or condition.

The term "treatment" and other similar synonyms as used herein include the following meanings:

(i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder;

(ii) Inhibiting the disease or disorder, i.e., inhibiting its progression;

(iii) Alleviating a disease or condition, i.e., causing the state of the disease or condition to subside; or alternatively

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

The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.

The terms "administering," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Application techniques useful in the compounds and methods described herein are well known to those skilled in the art, for example, at Goodman and Gilman, the Pharmacological Basis of Therapeutics, current ed.; pergamon; and Remington's, pharmaceutical Sciences (current edition), mack Publishing co., easton, pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

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

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

Protecting groups may be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, t.w. and p.g.m. wuts, protective Groups in Organic Synthesis, (1999), 4th Ed. The protecting group may also be a polymeric resin.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

The reagents and materials used in the present invention are commercially available.

The invention has the positive progress effects that: provides a nitrogen-containing heterocyclic compound which can be used as KRAS ^G12D An inhibitor; it can be used for preparing antitumor drugs, and preventing and/or treating tumor.

Detailed Description

The inventor prepares a class of nitrogen-containing heterocyclic compounds with novel structure shown in formula I through long-term and intensive research, and discovers that the nitrogen-containing heterocyclic compounds have better KRAS inhibition effect ^G12D Protein inhibitory Activity and said Compounds are useful in lower concentrations (as low as less than 500 nM), i.e. against KRAS ^G12D The associated cell proliferation and downstream signal pERK inhibitory activity were quite excellent (IC ₅₀ Even less than 100 nM), and thus can be used in therapy with KRAS ^G12D Related diseases such as tumor caused by mutation or abnormal expression. Based on the above findings, the inventors have completed the present invention.

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications. The experimental methods in the following examples, in which specific conditions are not noted, are generally in accordance with conventional conditions, or in accordance with the conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.

Intermediate A1: 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline

Step one: 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (1.5 g,5.62 mmol) and urea (2.7 g,44.9 mmol) were mixed and heated to 200℃for 4 hours. Cooled to room temperature, then water (50 mL) was added, heated to 100 ℃ and stirred for an additional hour, filtered while hot. The solid was slurried with ethyl acetate (50 mL) and the filtered solid dried to give a reddish brown intermediate product (1.3 g). LC-MS [ M-H ]] ^- :m/z 292.9。 ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.50-11.3(dt,2H),7.83(s,1H)。

Step two: the above intermediate compound (413 mg,1.41 mmol) was suspended in POCl ₃ To (20 mL) was added three drops of N, N-dimethylaniline, heated at reflux overnight, dried, the residue was dissolved in DCM (10 mL), and saturated NaHCO was added dropwise ₃ In water and kept at pH 7-8, extracted three times with DCM (30 mL). The combined organic phases were dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure to give intermediate A1 (219 mg) as a yellow solid. LC-MS [ M+H ]] ⁺ :m/z 328.8/330.8。 ¹ HNMR(400MHz,DMSO-d ₆ ):δ8.05(s,1H)。

Referring to the synthetic routes and methods of patents WO2021041671A1 and WO2021118877A1, the following intermediate compounds A2, B1-B3 are prepared;

intermediate C1:1- ((1- (hydroxymethyl) cyclopropyl) methyl) -4-methyl-1, 4-azaphospha-hex-4-oxide

Step one: under nitrogen, methylphosphoryl dichloride (3.97 g,30.1 mmol) was added to a solution of tetrahydrochysene The furan solution (50 mL) was cooled to-78 degrees, then vinylmagnesium bromide (2M, 35mL,70 mmol) was slowly added. After continuing the stirring reaction at this temperature for one hour, ethanol (10 mL) was added, followed by warming and stirring overnight. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/ethanol=30/1) to obtain an intermediate compound (3.1 g) as a white oil. ¹ H NMR(400MHz,DMSO-d ₆ ):δ6.07-6.38(m,6H),1.61(d,J＝7.2Hz,3H)。

Step two: to an ethanol solution (30 mL) of the intermediate compound (0.8 g,6.85 mmol) under nitrogen was added benzylamine (733 mg,6.85 mmol). The reaction mixture was heated to 100 degrees and reacted overnight. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/ethanol=25/1) to give an intermediate compound (750 mg) as a white oil. LC-MS [ M+H ]] ⁺ :m/z 224.1。 ¹ H NMR(400MHz,CDCl3):δ7.26-7.38(m,5H),3.71-3.73(m,2H),2.96-3.01(m,2H),2.63-2.65(m,2H),1.86-1.99(m,4H),1.39(d,J＝7.2Hz,3H)。

Step three: to the above intermediate compound (750 mg,3.36 mmol) in dichloroethane (10 mL) was added 1-chloroethyl chloroformate (578mg, 4.03 mmol) under nitrogen. The reaction mixture was heated to 100 degrees and stirred overnight. The reaction mixture was concentrated under reduced pressure, the crude product was dried and slurried with petroleum ether, and the filtered solid was dried to give 4-methyl-1, 4-azaphospha-hexylene 4-oxide hydrochloride (380 mg). LC-MS [ M+H ] ] ⁺ :m/z 134.1。

Step four: to dichloroethane (50 mL) of cyclohexane-1, 1-dimethanol (5.11 g,50.1 mmol) under nitrogen was added imidazole (7.5 g,110.2 mmol) and tert-butyldiphenylsilicon chloride (13.8 g,50.1 mmol). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was washed twice with saturated brine (30 mL), and the separated organic phase was dried over anhydrous sodium sulfate. The filtered organic phase was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10:1) to give the intermediate product (12.6 g) as a white solid. LC-MS [ M+H ]] ⁺ :m/z 341.2。

Step five: in a solution of the above intermediate (3 g,8.8 mmol) in methylene chloride (30 mL) under nitrogenMethanesulfonyl chloride (1.04 g,9.1 mmol) and triethylamine (1.87 g,18.5 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture was added saturated aqueous sodium bicarbonate (20 mL). The separated organic phase was washed twice with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The filtered organic phase was concentrated under reduced pressure to give the crude oily intermediate product (2.6 g). LC-MS [ M+H ]] ⁺ :m/z 419.2。

Step six: to a solution of the above intermediate (910 mg,2.2 mmol) in N, N-dimethylformamide (10 mL) under nitrogen was added 4-methyl-1, 4-azaphospha-hexylene 4-oxide hydrochloride (380 mg,2.2 mmol) and potassium carbonate (695 mg,5.0 mmol). The reaction mixture was stirred at 50 degrees overnight. After adding water (50 mL) to the reaction solution, extraction was performed twice with ethyl acetate (50 mL). 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=8:1) to give intermediate (150 mg) as a white solid. LC-MS [ M+H ] ] ⁺ :m/z 456.2。

Step seven: to a solution of the above intermediate (150 mg,0.33 mmol) in methanol (10 mL) was added ammonium fluoride (40 mg,1.1 mmol). The reaction mixture was stirred at 60 degrees for 3 hours. TLC detection reaction was complete. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) to give an intermediate (43 mg) as a white solid. LC-MS [ M+H ]] ⁺ :m/z 218.2。 ¹ H NMR(400MHz,DMSO):δ4.40(br.s,1H),3.30(s,2H),2.93-2.83(m,2H),2.59-2.55(m,2H),2.36(s,2H),1.81-1.67(m,4H),1.42-1.38(m,3H),0.43-0.40(m,2H),0.23-0.21(m,2H)。

Intermediate C2:1- ((1- (hydroxymethyl) cyclopropyl) methyl) -4-cyclopropyl-1, 4-azaphospha-hex-4-oxide

Referring to the synthesis method of the intermediate C1, the intermediate C2 is prepared by replacing methyl phosphoryl dichloride with cyclopropyl phosphoryl dichloride. LC-MS [ M+H ]] ⁺ :m/z 218.2。 ¹ H NMR(400MHz,DMSO):δ4.42(br.s,1H),3.32(s,2H),2.93-2.85(m,2H),2.61-2.54(m,2H),2.35(s,2H),1.81-1.67(m,4H),1.39(m,1H)，0.75-0.71(m,2H),0.66-0.59(m,2H),0.43-0.41(m,2H),0.31-0.28(m,2H)。

Intermediate C3:4- ((1- (hydroxymethyl) cyclopropyl) methyl) -1- (methylimino) -1λ ⁶ -thiomorpholine-1-oxide

Step one: to a solution of tert-butyl 1-iminothiomorpholine-4-carboxylate (3.7 g,15.8 mmol) in tetrahydrofuran (50 mL) under nitrogen was added potassium carbonate (4.45 g,32.2 mmol) and methyl iodide (2.27 g,16.0 mmol). The reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain an intermediate compound (3.1 g) as a white solid. LC-MS [ M+H ] ] ⁺ :m/z 249.1。

Step two: to a solution of the above intermediate (3.1 g,12.5 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (2 mL,26.9 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give a crude white solid compound (2.3 g). LC-MS [ M+H ]] ⁺ :m/z 149.0。

Step three: referring to the sixth preparation of intermediate C1, the synthesis of 4-methyl-1, 4-azaphospha-hexylene 4-oxide hydrochloride using the above intermediate replaced a white solid compound (1.6 g). LC-MS [ M+H ]] ⁺ :m/z 471.1。

Step four: referring to the seventh preparation of intermediate C1, removal of the protecting group from the above intermediate gave C3 compound as a white solid (450 mg). LC-MS [ M+H ]] ⁺ :m/z 471.1。 ¹ H NMR(400MHz,DMSO):δ4.43(br.s,1H),3.36(s,2H),2.93-2.83(m,2H),2.65-2.55(m,5H),2.36(s,2H),1.81-1.67(m,4H),0.43-0.40(m,2H),0.23-0.21(m,2H)。

Intermediate C4:4- ((1- (hydroxymethyl) cyclopropyl) methyl) -1- (cyclopropylimino) -1λ ⁶ -thiomorpholine-1-oxide

Referring to the synthesis of intermediate C3, intermediate C4 was prepared by substituting iodocyclopropane for methyl iodide. LC-MS [ M+H ]] ⁺ :m/z 259.1。 ¹ H NMR(400MHz,DMSO):δ4.43(br.s,1H),3.36(s,2H),2.93-2.83(m,2H),2.65-2.55(m,3H),2.36(s,2H),1.81-1.67(m,4H),0.81-0.57(m,4H),0.43-0.40(m,2H),0.23-0.21(m,2H)。

Intermediate C5: n-4- ((1- (hydroxymethyl) cyclopropyl) methyl) -1-oxide-1λ ⁶ -thiomorpholin-1-ylidene) aminonitriles

Step one: to a solution of thiomorpholine-4-carboxylic acid benzyl ester (3.6 g,14.8 mmol), cyanamide (0.59 g,15.5 mmol) and potassium tert-butoxide (1.8 g,16.0 mmol) in ethanol (20 mL) was added N-bromosuccinimide (2.85 g,16.1 mmol). The reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) to obtain a yellow solid intermediate compound (1.1 g). LC-MS [ M+H ] ] ⁺ :m/z 278.1。

Step two: to an ethanol solution (10 mL) of the above intermediate compound (1.1 g,4.0 mmol) were added m-chloroperoxybenzoic acid (1.40 g,8.1 mmol) and potassium carbonate (1.17 g,8.5 mmol). The reaction mixture was stirred at room temperature overnight. After 50mL of water was added to the reaction mixture, the reaction mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were concentrated under reduced pressure and the resulting crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=1:1) to give the compound as a white solid (470 mg). LC-MS [ M+H ]] ⁺ :m/z 294.0。

Step three: to an ethanol solution (5 mL) of the above intermediate compound (470 mg,1.6 mmol) was added 5% palladium on carbon (55 mg,0.5 mmol). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) overnight. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give a white solid compound (120 m)g)。LC-MS[M+H] ⁺ :m/z 160.0。

Step four: referring to the sixth preparation of intermediate C1, the above intermediate was used in place of 4-methyl-1, 4-azaphospha-hexylene 4-oxide hydrochloride to synthesize a white solid compound (150 mg). LC-MS [ M+H ]] ⁺ :m/z 482.2。

Step five: referring to the seventh preparation of intermediate C1, removal of the protecting group from the above intermediate gave C5 compound as a white solid (40 mg). LC-MS [ M+H ]] ⁺ :m/z 244.0。 ¹ H NMR(400MHz,DMSO):δ4.43(br.s,1H),3.37(s,2H),2.93-2.83(m,2H),2.68-2.55(m,2H),2.32(s,2H),1.83-1.65(m,4H),0.45-0.40(m,2H),0.26-0.22(m,2H)。

Intermediate C6: (1- (selenomorphlmethyl) cyclopropyl) methanol

Step one: to an anhydrous ethanol suspension (30 mL) of selenium powder (3.95 g,49.4 mmoL) was slowly added sodium borohydride (1.9 g,50.3 mmoL) at-10℃under nitrogen. After the reaction mixture became clear, sodium hydroxide (2.1 g,52.5 mmol) was added in portions to the reaction solution, and stirring was continued for 30 minutes. A solution of bis (2-chloroethyl) amine (7.08 g,50.2 mmol) in ethanol (5 mL) was slowly added to the reaction mixture, and the mixture was heated under reflux for 6 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered, distilled under reduced pressure, and the low-boiling point solvent was removed to obtain a crude intermediate compound (2.5 g) as a colorless oil. LC-MS [ M+H ]] ⁺ :m/z 151.1。

Step two: to a dichloromethane solution of the above intermediate (2.5 g,16.5 mmol) under nitrogen, 1- (chloroformyl) cyclopropane-1-ethyl carbonate (2.90 g,16.5 mmol) and triethylamine (3.34 g,33.0 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:4) to obtain a colorless oily compound (3.6 g). LC-MS [ M+H ]] ⁺ :m/z 292.0。

Step three: under nitrogen, the intermediate (3.6 g,12.4mAfter the temperature of the tetrahydrofuran solution (50 mL) was lowered to-70℃and lithium aluminum hydride (1.41 g,37.3 mmol) was added thereto in portions. After stirring the reaction mixture at this temperature for 30 minutes, it was slowly warmed to room temperature and stirred overnight. The LC-MS detection reaction was substantially complete. After the reaction solution was cooled to zero, ethyl acetate (20 mL) was added to the reaction solution, and the mixture was slowly warmed to room temperature and stirred for half an hour. Then, water (1.4 g) was slowly added to the reaction solution, sodium hydroxide (0.14 g) and water (4.2 g) were further added, the reaction mixture was stirred for several minutes, then, filtration was carried out, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:2) to give an intermediate C6 compound (2.1 g) as a colorless oil. LC-MS [ M+H ] ] ⁺ :m/z 236.0。 ¹ H NMR(400MHz,DMSO):δ4.43(br.s,1H),3.39(s,2H),2.93-2.85(m,2H),2.68-2.57(m,2H),2.32(s,2H),1.53-1.44(m,4H),0.48-0.43(m,2H),0.28-0.24(m,2H).

Intermediate C7:4- ((1- (hydroxymethyl) cyclopropyl) methyl) selenomorph 1-oxide

Step one: to a methanol solution (5 mL) of intermediate C6 (500 mg,2.1 mmol) was added a 30% hydrogen peroxide solution (5 mL). The reaction mixture was stirred at room temperature for 3 hours. To the reaction solution were added ethyl acetate (30 mL) and water (20 mL). The separated organic phase was washed three times with water and then concentrated under reduced pressure. The resulting crude product was dried to give intermediate C7 compound (340 mg) as a white solid. LC-MS [ M+H ]] ⁺ :m/z 252.0。 ¹ H NMR(400MHz,DMSO):δ4.43(br.s,1H),3.39(s,2H),2.93-2.85(m,2H),2.68-2.57(m,2H),2.32(s,2H),1.93-1.77(m,4H),0.47-0.41(m,2H),0.29-0.23(m,2H).

Intermediate C8: (1- (4, 4-dimethyl-1, 4-azasilan-1-yl) methyl) cyclopropyl) methanol

Referring to the synthetic method of intermediate C6,the intermediate C8 compound was prepared as a colourless oil. LC-MS [ M+H ]] ⁺ :m/z 214.2。 ¹ H NMR(400MHz,DMSO):δ4.43(br.s,1H),3.39(s,2H),2.93-2.85(m,2H),2.68-2.57(m,2H),2.32(s,2H),0.75-0.65(m,4H),0.47-0.41(m,2H),0.29-0.23(m,2H),0.19-0.16(s,6H).

Intermediate C9: (1- (8-aza-5-silaspiro [4.5] sunflower-8-yl) methyl) cyclopropyl) methanol

Referring to the synthesis of intermediate C6, a colorless oily intermediate C9 compound was prepared. LC-MS [ M+H ]] ⁺ :m/z 214.2。 ¹ H NMR(400MHz,DMSO):δ4.43(br.s,1H),3.39(s,2H),2.93-2.85(m,2H),2.68-2.57(m,2H),2.32(s,2H),0.95-0.65(m,8H),0.47-0.41(m,2H),0.29-0.23(m,2H),0.19-0.16(s,4H).

Intermediate A3: 7-bromo-2, 6-dichloro-5, 8-difluoroquinazolin-4-ol

Step one: to a solution of 2-amino-4-bromo-3, 6-difluorobenzoic acid (7.0 g,27.9 mmol) in concentrated sulfuric acid (85 mL) was added N-chlorosuccinimide (7.5 g,55.8 mmol). The reaction mixture was stirred at 80℃for 16 hours. The reaction solution was cooled to room temperature, and the reaction solution was slowly added to ice water. The precipitate formed was filtered and after washing the filter cake with water, dried in vacuo to give a grey solid (5.2 g). LC-MS [ M+H ] ] ⁺ :m/z287.8/285.8。

Step two: to a solution of the above intermediate compound (5.2 g,18.3 mmol) in tetrahydrofuran (300 mL) were added carbonylimidazole (5.9 g,36.6 mmol) and triethylamine (7.5 g,74.1 mmol). The reaction mixture was stirred at 50℃for 2 hours, cooled to room temperature and ammonium chloride (2.1 g,39.2 mmol) was slowly added. The reaction mixture was stirred at room temperature for a further 16 hours. After the water quenching reaction, most of the organic solvent is removed under reduced pressure. The aqueous phase was extracted with ethyl acetate (300 mL), the separated organic phase was concentrated under reduced pressure, and the crude product was chromatographed on a silica gel column (elution)The preparation method comprises the following steps: petroleum ether/ethyl acetate=3:1) to afford intermediate (4.2 g) as a grey solid. LC-MS [ M+H ]] ⁺ :m/z 286.0。

Step three: triphosgene (4.69 g,15.8 mmol) was added to a tetrahydrofuran solution (250 mL) of the above intermediate compound (4.2 g,14.7 mmol), and the reaction mixture was stirred at 70℃for 2 hours. After cooling to room temperature, water is added to quench the reaction, and the organic solvent is removed by decompression concentration. The aqueous phase was extracted with ethyl acetate and the separated organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=1:1) to give compound as a white solid (2.8 g). LC-MS [ M+H ]] ⁺ :m/z 312.8。

Step four: to a solution of the intermediate compound (2.7 g,9.3 mmol) in phosphorus oxychloride (100 mL) was added N, N-diisopropylethylamine (4 mL). The reaction mixture was stirred at ll0℃for 3 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was diluted with methylene chloride (50 mL) and then washed with saturated sodium bicarbonate water. The separated organic phase was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=4:1) to give the compound as a grey solid (2.3 g). LC-MS [ M+H ] ] ⁺ :m/z 350.5。

Step five, to a tetrahydrofuran solution (100 mL) of the above intermediate compound (2.3 g,6.6 mmol) was added an aqueous sodium bicarbonate solution (2M, 5.5mL,11 mmol) with ice-water bath cooling. The reaction mixture was stirred at room temperature for 3 hours. After the LC-MS detection reaction was substantially complete, the pH of the solution was adjusted to approximately 7 with 1M aqueous hydrochloric acid. The aqueous phase was extracted twice with ethyl acetate (200 mL) and the combined organic phases concentrated under reduced pressure. The crude product obtained was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give an off-white solid A3 intermediate compound (1.3 g). LC-MS [ M+H ]] ⁺ :m/z 330.8。

Intermediate A4:2,4,5, 7-tetrachloro-8-fluoropyrido [4,3-d ] pyrimidine

Step one: n, N-dimethyl to 2, 6-dichloropyridin-4-amine (5.1 g,31.3 mmol)To a mixture of formamide (30 mL) and acetic acid (20 mL) was added SelectFuor (13.3 g,37.6 mmol). The reaction mixture was heated to 80 degrees and reacted for half an hour. The LC-MS detection reaction was essentially complete. The reaction mixture was diluted with water (50 mL), and extracted twice with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:5) to give intermediate compound (3.2 g) as a white solid. LC-MS [ M+H ] ] ⁺ :m/z 183.0/181.0。

Step two: to a solution of the above intermediate compound (3.2 g,17.7 mmol) in methylene chloride (30 mL) was added di-tert-butyl dicarbonate (8.2 g,37.4 mmol), 4-dimethylaminopyridine (457 mg,3.74 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:5) to give a white solid compound (4.5 g). LC-MS [ M+H ]] ⁺ :m/z 381.1/383.1。

Step three: lithium diisopropylamide (2M, 11.8mL,23.6 mmol) was slowly added dropwise to a tetrahydrofuran solution (30 mL) of the above intermediate compound (4.5 g,11.8 mmol) at-78 ℃. After 2 hours of reaction at this temperature, the reaction mixture was slowly warmed to room temperature. To the reaction mixture was added water (20 mL) to quench the reaction. The reaction mixture was concentrated under reduced pressure to remove most of the organic solvent, and then extracted twice with ethyl acetate (30 mL). The combined organic phases were concentrated under reduced pressure and the resulting crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:5) to give the intermediate compound (2.7 g) as a yellow solid. LC-MS [ M+H ]] ⁺ :m/z 381.1/383.1。 ¹ H NMR(400MHz,DMSO-d6):δ10.1(s,lH),1.53(s,9H),1.45(s,9H)。

Step four: to a solution of the intermediate compound (2.7 g,7.1 mmol) in methylene chloride (60 mL) was added trifluoroacetic acid (30 mL). The reaction mixture was stirred at room temperature for 16 hours and monitored by LC-MS for completion. The reaction solution was concentrated under reduced pressure to give a yellow solid compound (1.3 g). LC-MS [ M+H ] ] ⁺ :m/z 225.0/227.0。

Step five: to an ethanol solution (50 mL) of the above intermediate compound (1.3 g,5.77 mmol) was added concentrated sulfuric acid (5 mL). The reaction mixture was heated to 8The reaction was carried out overnight at 0 ℃. After the reaction solution was cooled to room temperature, a saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the pH of the solution was adjusted to neutral. The reaction solution was extracted with ethyl acetate, and the separated organic phase was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1:3) to obtain a yellow solid intermediate compound (1.28 g). LC-MS [ M+H ]] ⁺ :m/z 253.0/255.0。

Step six: to a solution of the above intermediate compound (1.28 g,5.06 mmol) in tetrahydrofuran (10 mL) was added trichloroacetyl isocyanate (1.91 g,10.1 mmol), and the reaction mixture was stirred at room temperature for 3 hours. LC-MS monitored reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) to give a white solid compound (1.89 g). LC-MS [ M+H ]] ⁺ :m/z 441.5/443.5。

Step seven: to a methanolic solution (20 mL) of the above intermediate compound (1.89 g,4.28 mmol) was added a methanolic solution (5M, 3mL,15 mmol) of ammonia. The reaction mixture was stirred at room temperature for 4 hours. LC-MS monitored reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give a white solid compound (0.82 g). LC-MS [ M+H ] ] ⁺ :m/z 250.0/252.0。

Step eight: the above intermediate compound (0.82 g,3.28 mmol) was dissolved in phosphorus oxychloride (30 mL). After the addition of N, N-diisopropylethylamine (0.64 g,4.92 mmol) at room temperature, the reaction mixture was heated to 100℃and stirred overnight. LC-MS monitored completion of the reaction, and the reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1:4) to give intermediate compound (0.68 g) as a white solid. LC-MS [ M+H ]] ⁺ :m/z 287.5/285.5。

Intermediate A5:2- (hydroxymethyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

Step one: under the protection of nitrogen, 8- (tertiary butyl) -2-ethyl-4-oxo-3, 8-diazabicyclo [3 ] compound.2.1]To a solution of octane-2, 8-dicarboxylic acid ester (5.0 g,16.7 mmol) in tetrahydrofuran (300 mL) was added borane in dimethyl sulfide complex (2M, 25mL,50 mmol). The reaction mixture was stirred at room temperature for 18 hours. Methanol (50 mL) was added to the reaction mixture, and the mixture was heated to 50℃and stirred overnight. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=2:1) to give compound as a white solid (3.3 g). LC-MS [ M+H ]] ⁺ :m/z 285.2。

Step two: a solution of the intermediate compound (3.3 g,11.6 mmol) in tetrahydrofuran (250 mL) was cooled to-20℃under nitrogen. Lithium aluminum hydride (660 mg,17.4 mmol) was added in portions to the reaction solution at this temperature. The reaction mixture was kept at below zero for 1 hour and then slowly warmed to room temperature. After LC-MS detects the disappearance of the raw materials, the reaction solution is reduced to zero, and 5mL of water is slowly added into the reaction solution for quenching reaction. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:2) to give intermediate A5 compound (1.1 g) as a white solid. LC-MS [ M+H ] ] ⁺ :m/z 243.2。

Example general preparation method 1

The first step: the intermediate compound A (1 eq.) is dissolved in a suitable solvent and an amine or alcohol intermediate R is added ¹ -H (1.05 eq.) and organic base (3.5 eq.). The reaction was slowly warmed to room temperature and stirred overnight. LC-MS monitors the reaction completely, water is added into the reaction solution, the water phase is extracted three times by ethyl acetate, the extract is dried by anhydrous sodium sulfate, the concentration is reduced, the remainder is separated and purified to obtain the target product, and the structure is confirmed by nuclear magnetism and mass spectrum.

And a second step of: by reacting amines or alcohols as intermediates R ² L-H (1 eq.) is dissolved in a suitable solvent, an inorganic base (2 eq.) is added with low temperature cooling, and after stirring for half an hour, the intermediate of the above-mentioned first step product formula (B) is added. The reaction was then stirred at room temperature overnight. TLC monitoring of completion of the reaction, water quenchingAfter the sterilization, the mixture is concentrated under reduced pressure, and the residue is prepared, separated and purified by silica gel column chromatography or HPLC to obtain the target compound, and the structure is confirmed by nuclear magnetism and mass spectrum.

And a third step of: under nitrogen protection, the above general formula product C (1 eq.) and arylboronic acid (ester) or arylmetal reagent (1.2 eq.) are dissolved in a suitable solvent, a transition metal catalyst (0.1 eq.) and an inorganic base (2 eq.) are added, heated to 80-100 degrees for several hours of reaction, cooled to room temperature, the reaction solution is poured into water and extracted with ethyl acetate. The organic phase is washed by saturated saline, and after concentration, the crude product is prepared, separated and purified by silica gel column chromatography or HPLC to obtain the target compound, and the structure is confirmed by nuclear magnetism and/or mass spectrum.

Example general preparation method 2

The first step: the intermediate compound A (1 eq.) is dissolved in a suitable solvent and an amine or alcohol intermediate R is added ¹ -H (1.05 eq.) and organic base (2 eq.). The reaction was slowly warmed to room temperature and stirred overnight. LC-MS monitors the reaction completely, water is added into the reaction solution, the water phase is extracted three times by ethyl acetate, the extract is dried by anhydrous sodium sulfate, the concentration is reduced, the remainder is separated and purified to obtain the target product, and the structure is confirmed by nuclear magnetism and mass spectrum.

And a second step of: intermediate compound B (1 eq.) was dissolved in an appropriate solvent, and an inorganic base (1.5 eq.) and a palladium transition metal catalyst (0.2 eq.) were added, and the phosphine ligand (0.2 eq.) was heated for several hours. The LC-MS detection reaction was substantially complete. The reaction liquid is filtered by diatomite, washed by organic solvent, and after the filtrate is decompressed and concentrated, the crude product is separated and purified to obtain the target product, and the structure is confirmed by nuclear magnetism and mass spectrum.

And a third step of: intermediate compound C (1 eq.) was dissolved in an appropriate solvent and palladium on carbon (0.1 eq.) was stirred at room temperature under hydrogen atmosphere for several hours. After the LC-MS detection reaction was substantially complete, the celite was filtered. Washing with organic solvent, concentrating the combined organic phases under reduced pressure, separating and purifying the obtained crude product to obtain the target product, and confirming the structure by adopting nuclear magnetism and mass spectrum.

Fourth step: intermediate compound D (1 eq.) was dissolved in an appropriate solvent, substituted aryl boronic acid (ester) (1.2 eq.) was added and the ketone acetate (0.5 eq.) was reacted overnight at room temperature. Or the above intermediate compound F (1 eq.) is dissolved in an appropriate solvent, and the substituted aryl halide (1 eq.) and the transition metal Pd complex (0.2 eq.) are added and reacted under nitrogen with heating for several hours. The LC-MS detection reaction was essentially complete. Concentrating the reaction liquid under reduced pressure, separating and purifying the obtained crude product to obtain a target product, and confirming the structure by adopting nuclear magnetism and mass spectrum.

Example general preparation method 3

The first step: intermediate compound a (1 eq.) is dissolved in an appropriate solvent and amine or alcohol intermediate B (1.05 eq.) and inorganic base (2 eq.) are added. The reaction was slowly warmed to room temperature and stirred overnight. LC-MS monitors the reaction to be complete, water is added into the reaction solution, the water phase is extracted three times by ethyl acetate, the extract is dried by anhydrous sodium sulfate, the concentration is reduced, and the remainder is separated and purified to obtain a target product (C), and the structure is confirmed by nuclear magnetism and mass spectrum.

And a second step of: intermediate C (1.0 eq) was dissolved in an appropriate solvent and an appropriate halogenating reagent (3.0 eq) was added. The reaction is heated to 60 to 100 ℃ for reaction for several hours, and after post-treatment. The crude product is prepared and purified to obtain a target product (D), and a structure is confirmed by adopting nuclear magnetism and mass spectrum.

In the third step, the intermediate (D) (1.0 eq) of the previous step was dissolved in an appropriate solvent, and a base (1.2 eq) was added. The reaction mixture was stirred at room temperature overnight. After the LC-MS detection reaction is completed, preparing and purifying a crude product obtained after the post-treatment of the reaction liquid to obtain a target compound (E), and confirming a structure by adopting nuclear magnetism and mass spectrum.

Fourth step: the product of the above step, general formula (E), was dissolved in a suitable solvent, arylboronic acid (ester) or arylmetal reagent (1.2 eq.) was added, and a transition metal catalyst (0.1 eq.) and inorganic base (2 eq.) were added, and the reaction was heated to 80 to 100℃for several hours, and the LC-MS detection was completed. After the post-treatment of the reaction liquid, the obtained crude product is prepared and purified to obtain the target compound (F), and the structure is confirmed by adopting nuclear magnetism and mass spectrum.

Fifth step: by reacting amines or alcohols as intermediates R ² L-H (1 eq.) is dissolved in a suitable solvent, an inorganic base (2 eq.) is added with low temperature cooling, and after stirring for half an hour, the intermediate of formula (F) is added as a product of the previous step. The reaction was then stirred at room temperature overnight. TLC monitoring reaction is complete, water quenching is carried out, decompression concentration is carried out, the residue is prepared and separated and purified by silica gel column chromatography or HPLC to obtain the target compound (G), and nuclear magnetism and mass spectrum are adopted to confirm the structure.

And sixth, dissolving the product of the general formula (G) in a proper solvent, and hydrogenating to remove the protecting group on the amino group under the catalysis of acid or palladium. After the reaction post-treatment, preparing and purifying the crude product to obtain the target compound (I), and confirming the structure by adopting nuclear magnetism and mass spectrum.

Example 1:1- ((1- (((4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -6-chloro-7- (8-ethyne-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoroquinazolin-2-yl) oxy) methyl) cyclopropyl) methyl) -4-methyl-1, 4-azaphospha-hex-4-oxide

The first step: to intermediate A1 (275 mg,0.84 mmol) in dichloromethane DCM (15 mL) was added 3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (178 mg,0.84 mmol) and triethylamine TEA (0.5 mL,4.20 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:1) to give a yellow solid product (213 mg) LC-MS [ M+H)] ⁺ :m/z 505.0/507.0。

And a second step of: to a suspension of sodium hydride NaH (20 mg,0.50 mmol) in tetrahydrofuran (10 mL) at zero degrees was added intermediate C1 (108 mg,0.50 mmol). After the reaction mixture was stirred at this temperature for half an hour, a solution of the intermediate product of the previous step (213 mg,0.42 mmol) in tetrahydrofuran (3 mL) was added. Reaction The mixture was stirred at room temperature for 3 hours. The LC-MS detection reaction was essentially complete. To the reaction solution was added a saturated aqueous ammonium chloride solution (50 mL), followed by extraction three times with ethyl acetate (50 mL). The combined organic phases were dried and concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=30:1) to give the product as a yellow solid (210 mg). LC-MS [ M+H ]] ⁺ :m/z 686.1/688.1。

And a third step of: to a solution of the above intermediate (105 mg,0.15 mmol) in 1, 4-dioxane/water (12 mL/4 mL) was added at room temperature boric acid ester B1 (71 mg,0.15 mmol), tetrakis (triphenylphosphine) palladium (24 mg,0.02 mmol) and sodium carbonate powder (Na ₂ CO ₃ ) (56 mg,0.53 mmol) and the reaction mixture was stirred overnight at 100deg.C under argon. LC-MS detection reaction was complete. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by a silica gel column (eluent: dichloromethane/methanol=10:1) to obtain a yellow solid product (83 mg). LC-MS m/z 946.2[ M+H ]] ⁺ 。

Fourth step: to the intermediate (80 mg,0.08 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the concentrated crude product was dissolved in tetrahydrofuran (5 mL), to which was added cesium fluoride (90 mg,0.6 mmol). The reaction mixture was stirred for a further 3 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to give a yellow solid, example 1 compound (13 mg). LC-MS [ M+H ] ] ⁺ :m/z 692.5。 ¹ HNMR(400MHz,DMSO)δ10.26(s,1H),7.95(m,1H),7.77(s,1H),7.45(m,1H),7.36(s,1H),7.05(s,1H),4.25(m,4H),3.92(s,1H),3.50(m,4H),2.99-2.81(m,2H),2.62(m,2H),2.48-2.39(m,2H),1.86-1.61(m,8H),1.37(m,3H),0.64(m,2H),0.41(m,2H).

The following example compounds were obtained in analogy to example 1 using the general preparation of examples using intermediates A1, B1, C2-C5 and other starting materials commercially available:

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example 6:1- ((1- (((4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethyne-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4,3-d ] pyrimidin-2-) oxy) methyl) cyclopropyl) methyl) -4-methyl-1, 4-azaphospha-hex-ne-4-oxide

The first step: the first step of the synthetic method of reference example 1 was performed using intermediate A2 (251 mg,1.0 mmol) and 3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (213 mg,1.0 mmol) was substituted to give the product as a yellow solid (305 mg). LC-MS [ M+H ]] ⁺ :m/z 428.1。

And a second step of: in the second step of the synthesis method of reference example 1, the above intermediate (305 mg,0.7 mmol) and intermediate C1 (155 mg,0.7 mmol) were subjected to substitution reaction to give a white solid compound (220 mg). LC-MS [ M+H ]] ⁺ :m/z 610.2。

And a third step of: in the third step of the synthetic method of reference example 1, substitution reaction was carried out with the above intermediate (245 mg,0.4 mmol) and boric acid ester intermediate C1 (210 mg,0.4 mmol) to give a white solid compound (110 mg). LC-MS [ M+H ]] ⁺ :m/z 912.2。

Fourth step: in the fourth step of the synthesis of reference example 1, the intermediate (110 mg,0.4 mmol) was deprotected with trifluoroacetic acid and ammonium fluoride to give after HPLC preparation the compound of example 6 (27 mg) as a white solid LC-MS [ M+H ] ⁺ :m/z 659.1。 ¹ H NMR(400MHz,DMSO)δ10.15(s,1H),9.03(s,1H),7.97(m,1H),7.46(m,1H),7.39(m,1H),7.18(m,1H),4.49(m,1H),4.34-4.23(m,3H),3.96(s,1H),3.64(m,1H),3.55(m,3H),2.93(m,2H),2.69-2.52(m,3H),2.47-2.37(m,2H),1.75(m,4H),1.67(m,4H),1.38(m,3H),0.65(m,2H),0.43(m,2H).

Using the general preparation of the examples, starting from intermediates A2, B1, C2-C5 and other starting materials commercially available, the following example compounds were obtained with reference to example 6 in a similar manner:

using the general preparation of the examples, with intermediates A1-A2, B1-B3, C1-C5 and other starting materials commercially available, the following example compounds were obtained in analogy to examples 1 and 2:

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example 31:1- ((1- (4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalene-1-)

Phenyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-2-yl) oxy) methyl) cyclopropyl) -4-methyl-1, 4-azaphospha-hex-4-oxide

The first step: to a methanol solution (20 mL) of boric acid ester B2 (500 mg,1.39 mmol) was added 30% hydrogen peroxide (20 mL) under ice-bath cooling. The reaction mixture was stirred at room temperature for 3 hours. After 50mL of water was added to the reaction mixture, ethyl acetate (30 mL) was extracted twice, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was dissolved in methylene chloride (30 mL) and cooled in an ice bath to give a reaction solutionTo this mixture were added trifluoromethanesulfonic anhydride (290 mg,1.03 mmol) and triethylamine (0.5 mL). After the reaction mixture was stirred at room temperature for 2 hours, it was washed twice with saturated brine (20 mL), and the separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude intermediate naphthol triflate (270 mg). LC-MS m/z 383.0[ M+H ] ] ⁺ .

And a second step of: under the protection of nitrogen, 7-benzyl-2, 4-dichloro-5, 6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidine (2.0 g,6.8 mmol) was dissolved in N, N-dimethylformamide DMF (20 mL) and 3, 8-diazabicyclo [3.2.1 ] was added]Tert-butyl octane-8-carboxylate (2.4 g,6.8 mmol) and N, N-diisopropylethylamine (2.6 g,20.4 mmol) were stirred overnight at room temperature. The LC-MS detection reaction was substantially complete, water (30 mL) was added to the reaction solution, and extraction was performed twice with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. The filtrate was 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 intermediate product (3.5 g) as a white solid. LC-MS [ M+H ]] ⁺ :m/z 470.2。

And a third step of: the above intermediate compound (1.0 g,2.1 mmol) and intermediate C1 (934 mg,4.3 mmol) were dissolved in toluene (30 mL) under nitrogen, cesium carbonate (2.08 g,9.6 mmol) and Pd were added ₂ (dba) ₃ (195 mg,0.21 mmol) and Ruphos (199mg, 0.43 mmol). The reaction was heated to 110℃and stirred overnight. The LC-MS detection reaction was substantially complete, water (30 mL) was added to the reaction solution, and extraction was performed twice with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1:20) to give an intermediate product (650 mg) as a yellow solid. LC-MS [ M+H ] ] ⁺ :m/z 651.4。

And a third step of: to t-butanol (15 mL) of the above intermediate compound (200 mg,0.31 mmol) was added wet palladium on carbon (30 mg) under a hydrogen atmosphere. The reaction was stirred at room temperature for 48 hours. The LC-MS detection reaction is basically complete, and the reaction solution is filtered through kieselguhr and washed by ethanol. The filtrate was concentrated under reduced pressure to give an intermediate product (170 mg) as a pale yellow solid. LC-MS [ M+H ]] ⁺ :m/z 561.3。

Fourth step: under the protection of nitrogenNext, the above intermediate compound (170 mg,0.3 mmol) and trifluoromethanesulfonic acid ester (120 mg,0.35 mmol) of the intermediate naphthol prepared above were dissolved in toluene (30 mL), cesium carbonate (163 mg,0.5 mmol) and Pd were added ₂ (dba) ₃ (34 mg,0.04 mmol) and 2-dicyclohexylphosphine-2 ',6' -diisopropyloxybiphenyl Ruphos (23 mg,0.05 mmol). The reaction was heated to 80℃and stirred overnight. The LC-MS detection reaction was substantially complete, water (30 mL) was added to the reaction solution, and extraction was performed twice with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by HPLC to give a pale yellow solid intermediate product (40 mg). LC-MS [ M+H ]] ⁺ :m/z 749.4。

Fifth step: the intermediate compound (40 mg,0.05 mmol) was dissolved in tetrahydrofuran (10 mL) under nitrogen, and trifluoroacetic acid (1 mL) was added. Stirring for 30 minutes at room temperature. The LC-MS detection reaction was substantially complete, and to the reaction mixture was added saturated aqueous sodium bicarbonate (10 mL) and extracted twice with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by HPLC to give the compound of example 31 (7 mg) as a pale yellow solid. LC-MS [ M+H ] ] ⁺ :m/z 649.3。 ¹ H NMR(400MHz,CD ₃ OD)δ8.01(m,1H),7.58-7.25(m,3H),4.82-4.37(m,6H),3.88-3.65(m,7H),2.47-1.42(m,18H),1.08(m,3H),0.65-0.55(m,2H),0.46-0.36(m,2H)。

Using the general preparation of the examples, starting with intermediates C1-C5 and other starting materials commercially available, the following example compounds were obtained in analogy to example 31:

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the following example compounds were obtained by analogy with reference to examples 1 and 6 using the general preparation of the examples using intermediates A1, A2, B1-B3, C1-C9 and other starting materials commercially available:

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example 71:1- ((1- (((7- (6-amino-4-methyl-3- (trifluoromethyl) pyridin-2-yl) -4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -6-chloro-8-fluoroquinazolin-2-yl) oxy) methyl) cyclopropyl) methyl) -4-methyl-1, 4-azaphospha-hex-4-oxide

The first step: to 3- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1 under nitrogen protection]To a solution of tert-butyl octane-8-carboxylate (2.6 g,5.16 mmol) in N, N-dimethylformamide (30 mL) was added potassium fluoride (8.5 g,114 mmol). The reaction mixture was heated to 120 degrees and reacted overnight. After completion of the LC-MS detection reaction, water (60 mL) was added. The reaction mixture was extracted twice with ethyl acetate (100 mL), and the separated organic phase was dried over anhydrous sulfuric acid and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10:1) to give intermediate compound (900 mg) as a white solid. LC-MS m/z 491.0[ M+H ] ] ⁺ .

And a second step of: to a solution of the above intermediate compound (500 mg,1.02 mmol) and N, N-bis (4-methoxybenzyl) -4-methyl-6- (tri-N-butyltin) pyridin-2-amine (650 mg,1.02 mmol) in 1, 4-dioxane (20 mL) under nitrogen was added tetrakis (triphenylphosphine) palladium (173 mg,0.15 mmol), cuprous iodide (57 mg,0.3 mmol) and lithium chloride (65 mg,1.5 mmol). The reaction mixture was heated to 120℃and reacted overnight. LC-MS detection reaction was complete. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2:1) to give a white solid compound (430 mg). LC-MS m/z 757.3[ M+H ]] ⁺ .

And a third step of: to a solution of the intermediate compound (430 mg,0.57 mmol) in N, N-dimethylformamide (10 mL) was added N-iodosuccinimide (129 mg,0.57 mmol). The reaction mixture was stirred at room temperature for 2 hours. The LC-MS detection reaction was essentially complete. After 50mL of water was added to the reaction mixture, the mixture was extracted twice with ethyl acetate (50 mL). The combined organic phases were concentrated under reduced pressure and the resulting crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=3:1) to give the compound as a white solid (510 mg). LC-MS m/z 883.2[ M+H ]] ⁺ .

Fourth step: to a solution of the intermediate compound (510 mg,0.58 mmol) in N, N-dimethylformamide (10 mL) under nitrogen was added cuprous iodide (385 mg,2.02 mmol), hexamethylphosphoric triamide (1.20 g,6.7 mmol) and fluorosulfonyl difluoromethyl acetate (1.29 g,6.7 mmol). The reaction mixture was heated to 90 degrees and stirred for 3 hours. After completion of the LC-MS detection reaction, 50mL of water was added to the reaction solution, followed by extraction twice with ethyl acetate (50 mL). 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=3:1) to give a white solid compound (220 mg). LC-MS m/z 825.2[ M+H ] ] ⁺ .

Fifth step: the second-step method of reference example 1, the above intermediate compound (110 mg,0.13 mmol) was reacted with intermediate C1 to give a white solid intermediate compound (90 mg). LC-MS m/z 1022.4[ M+H ]] ⁺ .

Sixth step: at room temperature, in the aboveTo intermediate (90 mg,0.08 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the concentrated crude product was prepared by HPLC to give a white solid, the compound of example 71 (20 mg). LC-MS m/z 682.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO)δ7.87(m,1H),6.83(s,2H),6.50(s,1H),4.63-4.32(m,2H),4.27-4.17(m,4H),4.01-3.62(m,3H),3.56-3.37(m,1H),3.17-3.25(m,2H),2.91(m,1H),2.43(m,1H),2.37(s,3H),2.28-2.14(m,2H),2.07-1.51(m,8H),1.38(m,1H),0.92(m,1H),0.77-0.65(m,2H),0.38(m,1H).

Using the general preparation of the examples, starting from intermediates C7-C9 and other commercially available starting materials, the following example compounds were obtained in analogy to example 71:

example 76:6- (3-chloro-1-fluoro-13- ((1- (selenomorphine methyl) cyclopropyl) methoxy) -5a,6,7,8,9, 10-hexahydro-5H-6, 9-methano-azepino [2',1':3,4] [1,4] oxazepino [5,6,7-de ] quinazolin-2-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Step one: sodium hydrogen (60% in mineral oil, 595mg,4.12 mmol) was added to a solution of A5 (1.2 g,4.95 mmol) in tetrahydrofuran (50 mL) at room temperature. After the mixture was stirred at room temperature for 30 minutes, a solution of compound A3 (1.36 g, mmol) in tetrahydrofuran (5 mL) was added. After the reaction mixture was heated to 60 degrees, the reaction was continued for 3 hours. After cooling to room temperature, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (30 mL) and concentrated under reduced pressure to remove most of the organic solvent. To the residue were added ethyl acetate (50 mL) and water (20 mL). The separated aqueous phase was extracted twice with ethyl acetate. The combined organic phases were concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=1:1) to give the compound as a yellow solid (1.02 g). LC-MS m/z:553.0[M+H] ⁺ 。

Step two: to a solution of the above intermediate compound (1.02 g,1.85 mmol) in methylene chloride (30 mL) were added BOP-Cl (1.41 g,5.55 mmol) and diisopropylethylamine (2.39 g,18.5 mmol). The reaction mixture was stirred at room temperature for 4 hours. LC-MS detection of the completion of the basic reaction, concentration of the reaction solution under reduced pressure, and purification of the crude product by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2:1) gave a yellow solid compound (0.75 g). LC-MS m/z 535.0[ M+H ]] ⁺ 。

Step three: the first-step synthesis of reference example 71 was carried out by reacting the above intermediate compound (750 mg,1.40 mmol) with potassium fluoride to obtain a yellow solid compound (540 mg). LC-MS m/z 519.0[ M+H ]] ⁺ 。

Step four: the second-step synthesis of reference example 71 was performed using the above intermediate (540 mg,1.04 mmol) and N, N-bis (4-methoxybenzyl) -4-methyl-6- (tri-N-butyltin) pyridin-2-amine to give a yellow solid (439 mg). LC-MS m/z 785.3[ M+H ]] ⁺ 。

Step five: the third step of the synthesis method of reference example 71 was carried out using the above intermediate (439 mg,0.56 mmol) and iodosuccinimide to give a yellow solid compound (485 mg). LC-MS m/z 911.1[ M+H ]] ⁺ 。

Step six: the fourth synthesis step of reference example 71 was carried out using the above intermediate (481mg, 0.53 mmol) and methyl fluorosulfonyldifluoroacetate to give the compound (143 mg) as a yellow solid. LC-MS m/z 853.2[ M+H ] ] ⁺ 。

Step seven: the fifth step of the synthesis method of reference example 71 was carried out using the above intermediate (70 mg,0.08 mmol) and C6 to give the compound (45 mg) as a yellow solid. LC-MS m/z 1068.3[ M+H ]] ⁺ 。

Step eight: the sixth synthesis step, reference example 71, was carried out using the above intermediate (45 mg,0.04 mmol) and trifluoroacetic acid to give the compound (17 mg) as a yellow solid. LC-MS m/z 728.1[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,CD ₃ OD)δ7.93(s,1H),4.82-4.05(m,4H),3.84-3.45(m,6H),2.89-1.65(m,16H),0.65-0.53(m,2H),0.46-0.35(m,2H).

Using the general preparation of the examples, with intermediate C1 or C7-C9 and other starting materials commercially available, the following example compounds were obtained in analogy to example 76:

example 81: 3-chloro-5- (3-chloro-1-fluoro-13- ((1- (selenomorphine) methyl) cyclopropyl) methoxy) -5a,6,7,8,9, 10-hexahydro-5H-6, 9-methano-azepino [2',1':3,4] [1,4] oxazepino [5,6,7-de ] quinazolin-2-yl) -4- (trifluoromethyl) aniline

Step one: reference example 1, the third reaction step, 2-bromo-3-chloro-1, 13-difluoro-5 a,6,7,8,9, 10-hexahydro-5H-6, 9-bridge iminoazepino [2',1':3,4][1,4]Oxazepino [5,6,7-de ]]Quinazoline-15-formyl tert-butyl ester (250 mg,0.48 mmol) was reacted with (3-chloro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- (trifluoromethyl) -phenyl) carbamoyl tert-butyl ester to give the compound (150 mg) as a white solid. LC-MS m/z 732.1[ M+H ] ] ⁺ 。

Step two: reference example 71A fifth step synthesis was performed using the above intermediate compound (75 mg,0.10 mmol) and intermediate C6 to give a yellow solid compound (43 mg). LC-MS m/z 947.2[ M+H ]] ⁺ 。

Step three: referring to the sixth synthesis of example 71, the intermediate compound (42 mg,0.04 mmol) described above was reacted with trifluoroacetic acid to give the compound of example 81 (16 mg) as a yellow solid. LC-MS m/z 747.1[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,CD ₃ OD)δ6.96(s,1H),6.75(s,1H),4.82-4.05(m,4H),3.84-3.45(m,6H),2.49-1.65(m,13H),0.65-0.53(m,2H),0.46-0.35(m,2H).

Example 82: 3-chloro-5- (3-chloro-1-fluoro-13- ((1- ((4, 4-dimethyl-1, 4-azepin-1-yl) methyl) cyclopropyl) methoxy) -5a,6,7,8,9, 10-hexahydro-5H-6, 9-diimine azepino [2',1':3,4] [1,4] oxazepino [5,6,7-de ] quinazolin-2-yl) -4- (trifluoromethyl) aniline

Referring to the synthesis of example 81, the compound of example 82 was prepared as a white solid using intermediate C8 instead of C6. LC-MS m/z 725.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,CD ₃ OD)δ6.96(s,1H),6.75(s,1H),4.82-4.05(m,4H),3.84-3.45(m,4H),2.49-1.65(m,13H),0.65-0.25(m,6H),0.01(s,6H).

Example 83:6- (4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((1- (selenomorphine methyl) cyclopropyl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Step one: the second step of the Synthesis of reference example 6 was performed with intermediate 3- (2, 7-dichloro-8-fluoropyrido [4, 3-d)]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1 ]Reaction of octane-8-formyl tert-butyl ester (262 mg,0.61 mmol) with intermediate C6 gave the compound (280 mg) as a white solid. LC-MS m/z 627.1[ M+H ]] ⁺ .

Step two: the second reaction step of reference example 71 was carried out using the above intermediate compound (280 mg,0.45 mmol) and N, N-bis (4-methoxybenzyl) -4-methyl-6- (tri-N-butyltin) pyridin-2-amine to give a yellow solid compound (204 mg). LC-MS m/z 939.3[ M+H ]] ⁺ .

Step three: the third reaction step of reference example 71 was carried out using the above intermediate compound (204 mg,0.22 mmol) and N-iodosuccinimide to give a yellow solid compound (160 mg). LC-MS m/z 1065.2[ M+H ]] ⁺ .

Step four: the fourth step of the Synthesis method of reference example 71 was repeated with 160mg (0.15 mmol) of the intermediate compound and fluorosulfonyl group as mentioned aboveMethyl difluoroacetate was reacted to prepare a yellow solid compound (55 mg). LC-MS m/z 1007.0[ M+H ]] ⁺ .

Step five: referring to the sixth synthesis of example 71, the intermediate compound (55 mg,0.05 mmol) described above was reacted with trifluoroacetic acid to give the compound of example 83 (22 mg) as a yellow solid. LC-MS m/z 667.0[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO)δ9.00(s,1H),6.79(s,2H),6.49(s,1H),4.37(m,2H),4.26(m,2H),3.56(m,4H),2.84-2.76(m,4H),2.61-2.36(m,6H),2.36(s,3H),1.62(m,4H),0.64(t,J＝4.9Hz,2H),0.41(t,J＝4.9Hz,2H).

Referring to the preparation of example 83, the following examples 84 and 85 were prepared using the general preparation of examples using different borates and intermediates C8 or C9 and other starting materials commercially available:

Example 86:6- (1-fluoro-12- ((1- (selenomorphine methyl) cyclopropyl) methoxy) -5a,6,7,8,9, 10-hexahydro-5H-4-epoxy-3, 10a,11,13, 14-pentaaza-6, 9-menaquino [1,8-ab ] hept-2-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine

Step one: to a solution of A5 (500 mg,2.06 mmol) in methylene chloride (50 mL) was added imidazole (500 mg,7.3 mmol) and tert-butyldiphenylchlorosilane (2.33 g,8.5 mmol). The reaction mixture was stirred at room temperature overnight. To the reaction solution was added a saturated ammonium chloride solution (20 mL). The separated organic phase was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) to give a white solid compound (780 mg). LC-MS m/z 481.2[ M+H ]] ⁺ .

Step two: to a solution of intermediate A4 (433 mg,1.51 mmol) in dichloromethane (50 mL) were added the above intermediate (780 mg,1.62 mmol) and N, N-diisopropylethylamine (387 mg,3.0 mmol). The reaction mixture was stirred at room temperature for 20 hours. After the reaction solution was washed with water, the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) to give a yellow solid compound (590 mg). LC-MS m/z 730.1[ M+H ]] ⁺ .

Step three: referring to the synthesis of example 1, the second step, intermediate compound (390 mg,0.53 mmol) described above was reacted with intermediate C6 to give yellow solid compound (450 mg). LC-MS m/z 929.2[ M+H ] ] ⁺ .

Step four: to a solution of the above intermediate compound (450 mg,0.48 mmol) in tetrahydrofuran was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 1.5mL,1.5 mmol). The reaction mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2:1) to obtain a yellow solid compound (235 mg). LC-MS m/z 655.1[ M+H ]] ⁺ .

Step five: the second-step synthesis of reference example 71 was performed using the above intermediate (235 mg,0.36 mmol) and N, N-bis (4-methoxybenzyl) -4-methyl-6- (tri-N-butyltin) pyridin-2-amine to give a yellow solid compound (105 mg). LC-MS m/z 967.3[ M+H ]] ⁺ .

Step six: the third step of the synthesis method of reference example 71 was carried out using the above intermediate (105 mg,0.11 mmol) and iodosuccinimide to give a yellow solid compound (89 mg). LC-MS m/z 1093.2[ M+H ]] ⁺ .

Step seven: the fourth synthesis step of reference example 71 was carried out using the above intermediate (89 mg,0.08 mmol) and methyl fluorosulfonyl difluoroacetate to give the compound (35 mg) as a yellow solid. LC-MS m/z 1035.3[ M+H ]] ⁺ .

Step eight: the sixth synthesis step, referenced in example 71, was carried out using the above intermediate (35 mg,0.03 mmol) in reaction with trifluoroacetic acid to provide the compound of example 86 (9 mg) as a yellow solid. LC-MS m/z 695.1 [M+H] ⁺ . ¹ H NMR(400MHz,CD ₃ OD)δ7.95(s,1H),4.82-4.05(m,4H),3.84-3.45(m,6H),2.89-1.65(m,15H),0.65-0.53(m,2H),0.46-0.35(m,2H).

Referring to the preparation of example 86, the following examples were prepared using the general preparation of examples using different borates and intermediates C6-C9 and other starting materials commercially available:

referring to the preparation of example 71, the following examples were prepared using the general preparation of examples using different borates and intermediates C7-C9 and other starting materials commercially available:

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referring to the preparation of example 83, the following examples were prepared using the general preparation of examples using different borates and intermediates C7-C9 and other starting materials commercially available:

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test example 1 pair KRAS of the inventive Compound ^G12D Impact test of mediated ERK phosphorylation Capacity

The testing method comprises the following steps: 1) Expression of KRAS ^G12D AGS cells (ATCC) were cultured in DMEM medium containing 10% fetal bovine serum, 10mM HEPES and penicillin/streptomycin, inoculated in 96-well plates at a density of 40,000 cells/well, and attached for 12-14 hours. 2) After 3 hours, the medium was removed, 150. Mu.L of 4.0% formaldehyde was added, and the plate was incubated at room temperature for 20 minutes. 3) The plates were washed with PBS and infiltrated with 150. Mu.L ice-cold methanol for 10 min. 4) Binding of non-specific antibodies to the plates was blocked with 100 μl of blocking buffer for 1 hour at room temperature. Phosphorylation of ERK was detected using p-ERK specific antibodies, GAPDH as an internal standard. The information and experimental conditions of the antibody are as follows: p-ERK (Cell signaling) was diluted 1:500 in blocking buffer+0.05% tween 20; GAPDH was diluted 1:500 in blocking buffer+0.05% tween 20. The antibody was incubated for 2h at room temperature, PBS+0.05% Tween20, and the plate was washed. The secondary antibodies used to display primary antibodies were added as follows: anti-rabbit-680 was diluted 1:1000 in blocking buffer+0.05% tween20, anti-mouse-800 was diluted 1:1000 in blocking buffer+0.05% tween20 and incubated for 1 hour at room temperature. 5) Plates were washed with PBS +0.05% tween20, 100 μl PBS was added to each well and the plates were read. 6) The phosphorylated ERK (Thr 202/Tyr 204) signal was normalized to GAPDH signal for each well and the percentage of DMSO control value was calculated. Calculation of IC by four-parameter dose-response curve fitting ₅₀ Values.

Results: the invention provides a significant portion of the compounds of the examples which have a significant inhibitory effect on phosphorylated ERK levels in AGS cells, IC of all examples ₅₀ All less than 3000nM, and some examples even less than 100nM. Specific activity results are shown in the table. (C represents 1000 nM.ltoreq.IC ₅₀ <3000nM, B represents 500 nM.ltoreq.IC ₅₀ <1000nM, A represents IC ₅₀ <500nM)

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Test example two, test example Compounds for BaF3-KRAS-G12D cell proliferation inhibition Activity

The test adopts CellTiter-Glo (CTG) kit provided by Promega company, which is a method for detecting cell viability by a homogenization method, and the cell viability of the cultured cells is determined by quantifying ATP.

1. Experimental reagent consumable: RPMI1640 (Hyclone, SH 30809.01), fetal Bovine Serum (FBS, gibco, 10099-141), phosphate Buffered Saline (PBS, solarbio, P1020-500), celltiter Glo assay kit (Promega, G7573), blank 96-cell culture plate (Thermo, 165305).

2. Experimental instrument equipment: CO2 incubator (Thermo Scientific, model 3100 Series), microscope (OLYMPUS, CKX41 SF), multifunctional microplate reader (BMG,plus), biosafety cabinet (Thermo, model 1300 Series A2).

3. Cell proliferation assay: all cell lines were cultured in complete medium at 37℃under 5% CO 2. Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was checked by trypan blue exclusion, ensuring that cell viability was above 90%. The cell density was adjusted using complete medium and then seeded into 96 well cell culture plates with 90 μl total of 3000 cells per well. Cells in 96-well plates were incubated at 37℃under 5% CO 2. A 10-fold drug solution was prepared and then transferred from 10 μl of each serial diluted compound to the corresponding experimental well of a 96-well cell plate, the initial concentration of compound test 10um, 3-fold dilution, 9 concentrations, three multiplex wells were set for each drug concentration. Cells in the dosed 96-well plates were incubated at 37℃under 5% CO2 for a further 72 hours before CTG analysis. The CTG reagent was thawed and the cell plates equilibrated to room temperature for 30 minutes. An equal volume of CTG solution was added to each well. Cells were lysed by shaking on an orbital shaker for 5 minutes. The cell plates were left at room temperature for 20 minutes to stabilize the luminescence signal. Using Luminescence Read Mode, luminescence values (luminescences) were read and data collected.

4. Data analysis: the data were analyzed using GraphPad Prism 7.0 software, and non-linear S-curve regression was used to fit the data to yield the dose-response curve, and IC50 values were calculated therefrom. Cell viability (%) = (Lum) _{Drug to be tested} -Lum _{Culture broth control} )/(Lum _{Cell control} -Lum _{Culture broth control} ) X 100%. (A represents IC ₅₀ Value of<200nM, B represents 200 nM.ltoreq.IC ₅₀ Value of<1000nM, C represents IC ₅₀ ≥1000nM)

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All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims

1. A nitrogen-containing heterocyclic compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, stereoisomer, solvate, polymorph or prodrug thereof,

wherein,

R ¹ selected from substituted or unsubstituted 3-12 membered cycloalkyl or heterocycloalkyl, said substituents being selected from one or more R ¹⁰ ，R ¹⁰ Independently selected from: deuterium, halogen, cyano, hydroxy, amino, C1-C6 acyl, sulfonyl, - (CO) -NR ¹¹ R ¹² 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkylcyano, C ₁ -C ₆ Alkyl hydroxy, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-6 membered aryl or heteroaryl, or two R ¹⁰ And together with the carbon atom or heteroatom to which they are attached form a 3-12 membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic ring system including spiro, bridged, fused or fused rings; r is R ¹¹ 、R ¹² Independently selected from hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkyl, 3-8 membered cycloalkyl or heterocycloalkyl, or R ¹¹ 、R ¹² Together with the attached N atom form a 3-8 membered cycloalkyl or heterocycloalkyl group; the heterocyclic alkyl, heteroaryl and heterocyclic ring system contains 1-3 hetero atoms selected from N, O, S, P;

R ² selected from substituted or unsubstituted C ₁ -C ₆ Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or heteroaryl, C ₁ -C ₆ An alkyl-substituted 3-12 membered cycloalkyl or heterocycloalkyl, a 5-16 membered saturated or partially unsaturated carbocyclic or heterocyclic ring system including spiro, bridged, fused or fused rings; the substituents are one or more R ²¹ ，R ²¹ Independently selected from the following groups: halogen, cyano, hydroxy, amino, (C) ₁ -C ₆ Alkyl) NH- (C ₁ -C ₆ Alkyl group ₂ N-、(C ₁ -C ₆ Alkyl) NH-C ₁ -C ₆ Alkyl-, (C) ₁ -C ₆ Alkyl group ₂ N-C ₁ -C ₆ Alkyl-, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or heteroaryl, 3-12 membered cycloalkyl or heterocycloalkyl substituted C ₁ -C ₆ Alkyl, etc., or two R ²¹ Together with the carbon atom or heteroatom to which they are attached, form a 3-8 membered cycloalkyl or heterocycloalkyl group; the 3-12 membered heterocycloalkyl, 5-12 membered heteroaryl, 3-12 membered heterocycloalkyl substituted C ₁ -C ₆ The heterocycloalkyl, 5-16 membered saturated or partially unsaturated heterocyclic ring system, 5-12 membered heteroaryl or 3-8 membered heterocycloalkyl in the alkyl group contains 1 to 3 heteroatoms independently selected from N, O, S, P, si, B, se, which heteroatoms may optionally be in different oxidation states; r is R ²¹ May further optionally be substituted with one or more R ²¹¹ Substituted, R ²¹¹ Independently selected from halogen, cyano, hydroxy, amino, C ₁ -C ₆ Alkyl-imino-, cyano-imino-, 3-6 membered cycloalkyl-imino-, C ₁ -C ₆ Alkyl, C of (2) ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, 3-to 10-membered cycloalkyl or heterocycloalkyl, 3-to 10-membered halocycloalkyl or haloheterocycloalkyl substitution; r is R ²¹¹ Wherein said heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, S, P, si, se;

l is selected from carbon-carbon single bond, carbon-carbon double bond, carbon-carbon triple bond, CHR ⁵ 、O、S(O) _t Or NR (NR) ^5a R ^5b ；R ⁵ 、R ^5a And R is ^5b Selected from H or C ₁ -C ₆ Alkyl of (a);

R ⁴ is one or more groups independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxy, amino, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkoxy, 3-to 12-membered cycloalkyl or heterocycloalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, -P (O) t- (C) ₁ -C ₆ Alkyl), -S (O) t- (C) ₁ -C ₆ Alkyl), an amide group, a sulfonamide group, a urea group, a 5-to 12-membered aryl or heteroaryl group, or R as defined above ¹ And R is ⁴ Any two substituents between the two groups form a 3-12 membered saturated or partially unsaturated or aromatic ring system or aromatic heterocyclic system through carbon atoms or hetero atoms; the heterocycloalkyl, heteroaryl and aromatic heterocyclic system contains 1-3 hetero atoms selected from N, O, S, P;

t is selected from 0-2;

ar is selected from a substituted or unsubstituted 5-12 membered aromatic or heteroaromatic ring, and may be substituted with one or more R ³ Substitution; r is R ³ Independently selected from halogen, hydroxy, amino, cyano, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, 3-6 membered cycloalkyl or heterocycloalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, (C) ₁ -C ₆ Alkyl) NH- (C ₁ -C ₆ Alkyl group ₂ N-; the heterocycloalkyl group and the aromatic heterocycle contain 1 to 3 hetero atoms selected from N, O, S, P;

M is N or CR ⁶ ；R ⁶ Selected from hydrogen, deuterium, halogen, -CN, C ₁ -C ₃ Alkyl, C ₁ -C ₃ A haloalkyl group; the method comprises the steps of carrying out a first treatment on the surface of the

Cy is selected from a 5-6 membered saturated or partially unsaturated carbocyclic or heterocyclic ring system, or a 5-6 membered aromatic or heteroaromatic ring system; the heterocyclic ring system, the aromatic heterocycle or the aromatic heterocycle system contains 1-3 hetero atoms selected from N, O, S, P.

2. The nitrogen-containing heterocyclic compound of the general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, according to claim 1, which has a structure represented by the formula (II):

wherein W, W ₁ Each independently selected from N or CR ⁴ ；

Ar、R ³ 、R ⁴ 、M、L、L ₁ 、R ¹⁰ 、R ² 、R ¹ The range of (2) is as defined in claim 1.

3. A nitrogen-containing heterocyclic compound of the general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, as claimed in claim 1, wherein one or more of the following conditions are satisfied:

(1)C ₂ -C ₆ alkenyl group is C ₂ -C ₄ Alkenyl, preferably ethenyl or propenyl;

(2)C ₂ -C ₆ alkynyl is C ₂ -C ₄ Alkynyl, preferably

(3)C ₁ -C ₆ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl;

(4)C ₁ -C ₆ Halogen in the haloalkyl is fluorine, chlorine, bromine or iodine;

(5) The 3-6 membered cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexenyl or cyclohexyl.

4. A nitrogen-containing heterocyclic compound of the general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, as claimed in claim 1, wherein:

m is N, C-H, C-F, C-CN;

alternatively, cy is selected from the group consisting of:

alternatively, R ¹ Selected from a substituted or unsubstituted 5-10 membered cycloalkyl or heterocycloalkyl, preferably from a substituted or unsubstituted piperidine ring, piperazine ring, homopiperazine ring, pyrrolidine ring, homopiperidine ring, morpholine ring, homomorpholine ring; said substituent R ¹⁰ Preferably from halogen, C1-C6 alkyl, hydroxy, amino, =O, 3-to 6-membered saturated or partially unsaturated carbocyclic or heterocyclic ring systems, or two R ¹⁰ And together with the carbon atom or heteroatom to which they are attached form a 5-6 membered saturated or partially unsaturated or aromatic carbocyclic or heterocyclic ring system including spiro, bridged, fused or fused rings;

Alternatively, when R ¹ And R is ⁴ The compounds of formula (I) may have the structure of formula (III) when a new heterocyclic ring system is constituted by sharing one carbon or heteroatom (nitrogen, or oxygen, or sulfur atom),

wherein r is 0, 1, 2 or 3; p is selected from 1 or 2; w, W ₁ Independently selected from N or CR ⁴ ；

L ₂ Is O, S or NR ⁷ ，R ⁷ Is hydrogen, deuterium, halogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, cyano, amino, C ₃ -C ₆ Cycloalkyl or halocycloalkyl, C ₂ -C ₄ Alkenyl group, C ₂ -C ₄ Alkynyl of (a); l (L) ₂ Preferably O;

q is- (CH) ₂ )n-L ₃ -(CH ₂ ) n-or absent; l (L) ₃ Selected from O, S, NR ⁸ Or is absent, R ⁸ Is hydrogen, deuterium, halogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, cyano, amino, C ₃ -C ₆ Cycloalkyl or halocycloalkyl, C ₂ -C ₄ Alkenyl group, C ₂ -C ₄ Alkynyl of (a); q is preferably selected from-CH ₂ CH ₂ -；

R ¹⁰ Independently selected from deuterium, halogen, cyano, hydroxy, amino, C1-C6 acyl, sulfonyl, - (CO) -NR ¹¹ R ¹² 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkylcyano, C ₁ -C ₆ Alkyl hydroxy, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-6 membered aryl or heteroaryl; other groups Ar, R ³ 、R ⁴ 、M、L、L ₁ 、R ² As claimed in claim 1;

preferably +.>

Alternatively, R ³ Independently selected from hydrogen, halogen, hydroxy, amino, cyano, and C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, 3-6 membered cycloalkyl or heterocycloalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy groups, and the like;

alternatively, L is selected from: CH (CH) ₂ O, NH or S;

alternatively, L ₁ Selected from: direct bond, CH ₂ O, NH or S;

alternatively, when R ²¹ In the case of 3-12 membered heterocycloalkyl, the 3-12 membered heterocycloalkyl is 5-10 membered heterocycloalkyl, preferably

Alternatively, two R ²¹ When taken together with the carbon atom or heteroatom to which they are attached, form a 3-8 membered cycloalkyl, said 3-8 membered cycloalkyl is cyclopropyl;

alternatively, when R ² In the case of substituted C1-C6 alkyl, the substituted C1-C6 alkyl isWherein m and n are each an integer from 0 to 3; m and n are preferably 1 and 2; ry is selected from 3-12 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, said heterocycloalkyl or heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, S, P, si, B, se, said heteroatoms optionally being in different oxidation states; r is R ^p And R is ^q Selected from hydrogen, halogen, C ₁ -C ₆ Alkyl or alkoxy, 3-6 membered cycloalkyl or heterocycloalkyl, hydroxy, amino, or R ^p And R is ^q Forming a 3-8 membered cycloalkyl or heterocycloalkyl; r is R ^p 、R ^q Ry or R ^p And R is ^q The 3-8 membered cycloalkyl or heterocycloalkyl formed may optionally be further substituted with one or more R ²¹¹ Substituted, R ²¹¹ Independently selected from halogen, cyano, C ₁ -C ₆ Alkyl-imino-, cyano-imino-, 3-6 membered cycloalkyl-imino-, C ₁ -C ₆ Alkyl or haloalkyl, 3-12 membered cycloalkyl or heterocycloalkyl, 3-12 membered halocycloalkyl or haloheterocycloalkyl.

5. The nitrogen-containing heterocyclic compound as described in claim 1, which is represented by the general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof,

R ¹ preferably selected from

Alternatively, cy is selected from

alternatively, L is preferably selected from-O-;

alternatively, L ₁ Preferably from direct bond, CH ₂ ；

Alternatively, R ² In the case of substituted C1-C6 alkyl, the substituted C1-C6 alkyl isWherein Ry is selected from substituted 5-12 membered cycloalkyl or 5-12 membered heterocycloalkyl containing 1-3 heteroatoms selected from S, P, se or Si; r is R ^p And R is ^q Selected from hydrogen, halogen, C ₁ -C ₆ Alkyl or alkane of (2)Oxy, hydroxy, amino, or R ^p And R is ^q Forming a 3-8 membered cycloalkyl or heterocycloalkyl; r is R ^p 、R ^q Ry or R ^p And R is ^q The 3-8 membered cycloalkyl or heterocycloalkyl formed may optionally be further substituted with one or more R ²¹¹ Substituted, R ²¹¹ Independently selected from halogen, cyano, C ₁ -C ₆ Alkyl-imino-, cyano-imino-, 3-6 membered cycloalkyl-imino-, C ₁ -C ₆ An alkyl or haloalkyl group, a 3-12 membered cycloalkyl or heterocycloalkyl group, a 3-12 membered halocycloalkyl or haloheterocycloalkyl group;

alternatively, R ⁴ Selected from hydrogen, deuterium, halogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, cyano, amino, C ₃ -C ₆ Cycloalkyl or halocycloalkyl, C ₂ -C ₄ Alkenyl group, C ₂ -C ₄ Alkynyl groups of (a) and the like.

6. A nitrogen-containing heterocyclic compound of the general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, as claimed in claim 1, wherein:

m is preferably N, C-H, C-F, C-CN;

alternatively, cy is preferably selected from

Alternatively, R ¹ Preferably selected from:

alternatively, R ³ Ar is selected from

alternatively, R ⁴ Selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, trifluoromethyl, cyano, amino, cyclopropyl, vinyl, ethynyl, and the like;

alternatively, R ¹¹ 、R ¹² Independently selected from hydrogen, halogen, methyl;

alternatively, when R ¹¹ 、R ¹² When taken together with the attached N atom form a 3-8 membered heterocycloalkyl, the 3-8 membered heterocycloalkyl is preferably

Alternatively, R ^p And R is R ^q Forming a three-membered carbocyclic ring with the attached carbon atom;

alternatively, ry is preferably

Alternatively, when R ¹⁰ Is C ₁ -C ₆ When alkyl hydroxy of (C) ₁ -C ₆ Preferably HO-CH ₂ -、HO-CH ₂ -CH ₂ -。

7. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, wherein the compound has the structure:

8. a pharmaceutical composition comprising an effective amount of the nitrogen-containing heterocyclic compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, and a pharmaceutically acceptable carrier.

9. Use of a nitrogen-containing heterocyclic compound as described in any one of claims 1-7, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, or a pharmaceutical composition as described in claim 8, for the preparation of a Ras mutein inhibitor or medicament; the Ras mutant protein can be KRAS ^G12D The method comprises the steps of carrying out a first treatment on the surface of the The medicine can be used for treating diseases related to activity or expression quantity of Ras mutant protein; alternatively, the drug may be a therapeutic drug for a tumor; the tumor is independently selected from non-small cell lung cancer, small cellLung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, stomach cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer.