CN118043330A

CN118043330A - KRAS G12D inhibitor compounds and preparation methods and applications thereof

Info

Publication number: CN118043330A
Application number: CN202280065933.1A
Authority: CN
Inventors: 邹昊; 祝东星; 祝伟; 李正涛
Original assignee: Hainan Xiansheng Zaiming Pharmaceutical Co ltd
Current assignee: Hainan Xiansheng Zaiming Pharmaceutical Co ltd
Priority date: 2021-09-29
Filing date: 2022-09-28
Publication date: 2024-05-14
Also published as: WO2023051586A1

Abstract

公开了作为KRAS G12D抑制剂的化合物或其立体异构体或其可药用盐，所述化合物具有式(I)所示的结构。还公开了所述式(I)化合物或其立体异构体或其可药用盐的制备方法、含有所述化合物或其立体异构体或其可药用盐的药物组合物、以及所述化合物或其立体异构体或其可药用盐在预防或治疗与KRAS G12D突变相关的疾病或病症中的用途。 Disclosed are compounds or stereoisomers or pharmaceutically acceptable salts thereof as KRAS G12D inhibitors, wherein the compounds have a structure as shown in formula (I). Also disclosed are methods for preparing the compounds of formula (I) or stereoisomers or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the compounds or stereoisomers or pharmaceutically acceptable salts thereof, and uses of the compounds or stereoisomers or pharmaceutically acceptable salts thereof in preventing or treating diseases or conditions associated with KRAS G12D mutations.

Description

KRAS G12D inhibitor compound, and preparation method and application thereof

The invention claims priority from the prior application with the name of KRAS G12D inhibitor compound, preparation method and application, which is submitted to China national intellectual property agency on 9 months of 2021 and 29 days, and has the patent application number of 202111151279. X. The entire contents of the above-mentioned prior application are incorporated by reference into the present invention.

Technical Field

The present invention relates to compounds which are KRAS G12D inhibitor compounds or stereoisomers thereof or pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing the compounds or stereoisomers thereof or pharmaceutically acceptable salts thereof, and the use of the compounds or stereoisomers thereof or pharmaceutically acceptable salts thereof in the prevention or treatment of diseases or disorders associated with KRAS G12D mutations.

Background

RAS is a GTP binding protein involved in regulating cell proliferation, cell differentiation, cell adhesion, apoptosis, and cell migration. Mutation of the RAS gene will result in permanently activated RAS proteins, even in the absence of an incoming signal, will result in intracellular overactive signaling and ultimately may lead to cancer. Three RAS genes in humans (HRAS, KRAS and NRAS) are the most common oncogenes in human cancers, with activated RAS gene mutations in about 20% of human tumors (TARGETING RAS SIGNALLING PATHWAYS IN CANCER therapy. Downward, j. Nat Rev cancer.2003,3 (1), 11-22). Two-line treatment of non-small cell lung cancer, in which a particular RAS gene mutation (KRAS G12C) has been demonstrated to be useful in the treatment of cancer, such as Sotorasib has been approved by the FDA as a KRAS G12C mutation, but there is currently a lack of sufficiently safe and/or effective drugs for KRAS G12D mutation, and thus, there is a need to further develop new KRAS G12D inhibitors.

Disclosure of Invention

The present invention relates to compounds of formula (I) or stereoisomers or pharmaceutically acceptable salts thereof,

Wherein,

Ring B is selected from an 8-10 membered nitrogen containing heterocyclyl optionally substituted with R ¹, said nitrogen containing heterocyclyl being in bridged ring form;

R ¹ is selected from halogen, OH, =o, CN, C ₁-C ₆ alkyl, C ₁-C ₆ alkoxy, HC (=o) -, -CO ₂R ^1a、-CON(R ^1a) ₂, and 5-6 membered heteroaryl, wherein the C ₁-C ₆ alkyl, C ₁-C ₆ alkoxy, or 5-6 membered heteroaryl is optionally substituted with R ^1b;

Ring A is a 5-6 membered heteroaromatic ring, a benzene ring, a 4-7 membered heterocyclic ring, or a C ₃-C ₆ cycloalkenyl ring, the 5-6 membered heteroaromatic ring, the benzene ring, the 4-7 membered heterocyclic ring, or the C ₃-C ₆ cycloalkenyl ring being optionally substituted with R ⁴;

R ⁴ is selected from deuterium, halogen, OH, =o, CN, C ₁-C ₆ alkyl, C ₁-C ₆ alkoxy, C ₃-C ₁₀ cycloalkyl and C ₃-C ₁₀ cycloalkyloxy, said C ₁-C ₆ alkyl, C ₁-C ₆ alkoxy, C ₃-C ₁₀ cycloalkyl or C ₃-C ₁₀ cycloalkyloxy being optionally substituted by R ^4a;

l is selected from O, -C (=o) -and a bond;

R ³ is selected from C ₆-C ₁₄ aryl and 5-14 membered heteroaryl, said C ₆-C ₁₄ aryl or 5-14 membered heteroaryl optionally substituted with R ^3a;

X is selected from CR ⁵ and N;

R ⁵ is selected from H, halogen, OH, CN, NO ₂、NH ₂、NH(C ₁-C ₃ alkyl), N (C ₁-C ₃ alkyl) ₂、C ₁-C ₃ alkyl, C ₁-C ₃ haloalkyl, C ₁-C ₃ alkoxy, C ₁-C ₃ haloalkoxy, C ₂-C ₄ alkynyl, C ₃-C ₁₀ cycloalkyl and C ₃-C ₁₀ cycloalkyloxy;

W is selected from O, NR ⁶ and a bond;

R ² is selected from Said R ² is optionally substituted with R ⁷;

R ⁷ is selected from deuterium, halogen, OH, CN, C ₁-C ₆ alkyl, C ₁-C ₆ alkoxy, C ₃-C ₁₀ cycloalkyl and C ₃-C ₁₀ cycloalkyloxy, said C ₁-C ₆ alkyl, C ₁-C ₆ alkoxy, C ₃-C ₁₀ cycloalkyl or C ₃-C ₁₀ cycloalkyloxy being optionally substituted with R ^7a;

r ^3a is selected from halogen, OH, CN, C ₁-C ₆ alkyl, C ₁-C ₆ alkoxy, C ₁-C ₆ alkylthio, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, -CH ₂C(＝O)N(R ^3b) ₂、-(C ₂-C ₄ alkynylene) -N (R ^3b) ₂、N(R ^3b) ₂、C ₃-C ₁₀ cycloalkyl and 5-6 membered heteroaryl, said C ₁-C ₆ alkyl, C ₁-C ₆ alkoxy, C ₁-C ₆ alkylthio, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₂-C ₄ alkynylene, C ₃-C ₁₀ cycloalkyl or 5-6 membered heteroaryl being optionally substituted with R ^3c;

Or two R ^3a together with the atoms to which each is attached form a C ₄-C ₆ cycloalkenyl or a 5-7 membered heterocyclyl, which C ₄-C ₆ cycloalkenyl or 5-7 membered heterocyclyl is optionally substituted with R ^3d;

R ^1a、R ^3b and R ⁶ are independently selected from H and C ₁-C ₆ alkyl;

R ^1b、R ^3c、R ^3d、R ^4a and R ^7a are independently selected from deuterium, halogen, OH, CN, = O, NH ₂、C ₁-C ₆ alkyl and C ₁-C ₆ alkoxy;

n is selected from 0,1 and 2.

In some embodiments, ring B is selected from an 8-membered nitrogen containing heterocycloalkyl optionally substituted with R ¹, said nitrogen containing heterocycloalkyl being in bridged ring form.

In some embodiments, ring B is selected from the following groups optionally substituted with R ¹:

In some embodiments, R ¹ is selected from halogen, OH, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, HC (=o) -, -CO ₂R ^1a、-CON(R ^1a) ₂, and 5-6 membered heteroaryl, said C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, or 5-6 membered heteroaryl optionally substituted with R ^1b.

In some embodiments, R ^1a is selected from H and C ₁-C ₃ alkyl.

In some embodiments, R ¹ is selected from halogen, OH, C ₁-C ₃ alkyl, and C ₁-C ₃ alkoxy, the C ₁-C ₃ alkyl or C ₁-C ₃ alkoxy being optionally substituted with R ^1b.

In some embodiments, R ^1b is selected from deuterium, halogen, OH, CN, and NH ₂.

In some embodiments, R ^1b is selected from halogen, OH, and CN.

In some embodiments, R ¹ is selected from halogen, OH, methyl, methoxy, CN, CNCH ₂-、CNCH ₂CH ₂ -, and hydroxymethyl.

In some embodiments, ring B is selected from

In some embodiments, ring a is selected from the following groups optionally substituted with R ⁴: 5-6 membered heteroaromatic rings, benzene rings, tetrahydropyridine rings, dihydropyran rings, cyclohexene and cyclohexadiene.

In some embodiments, ring a is selected from the group consisting of a benzene ring, a6 membered heteroaryl ring, a6 membered heterocycle, and a C ₆ cycloalkenyl ring, the benzene ring, 6 membered heteroaryl ring, 6 membered heterocycle, or C ₆ cycloalkenyl ring being optionally substituted with R ⁴.

In some embodiments, ring a is selected from the following groups optionally substituted with R ⁴:

In some embodiments, ring a is selected from optionally substituted with R ⁴

In some embodiments, R ⁴ is selected from halogen, OH, = O, C ₁-C ₆ alkyl, and C ₁-C ₆ alkoxy, the C ₁-C ₆ alkyl or C ₁-C ₆ alkoxy being optionally substituted with R ^4a.

In some embodiments, R ⁴ is selected from halogen, =o, and C ₁-C ₆ alkyl optionally substituted with R ^4a.

In some embodiments, R ^4a is selected from halogen, OH, and CN.

In some embodiments, R ⁴ is selected from F, cl and methyl.

In some embodiments, L is selected from O and a bond.

In some embodiments, L is selected from a bond.

In some embodiments, L is O.

In some embodiments, R ³ is selected from naphthyl, phenyl, and 5-10 membered heteroaryl, optionally substituted with R ^3a.

In some embodiments, R ³ is selected from the group consisting of naphthyl, phenyl, pyridinyl, benzopyrrolyl, benzopyrazolyl, benzothienyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzisothiazolyl, benzimidazolyl, and benzofuranyl, said naphthyl, phenyl, pyridinyl, benzopyrrolyl, benzopyrazolyl, benzothienyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzisothiazolyl, benzimidazolyl, or benzofuranyl optionally substituted with R ^3a.

In some embodiments, R ³ is selected from the group consisting of naphthyl, phenyl, pyridinyl, benzothienyl, and benzopyrazolyl, said naphthyl, phenyl, pyridinyl, benzothienyl, or benzopyrazolyl optionally being substituted with R ^3a.

In some embodiments, R ^3a is selected from halogen, OH, CN, C ₁-C ₆ alkyl, C ₁-C ₆ alkoxy, C ₁-C ₆ alkylthio, C ₂-C ₄ alkynyl, -CH ₂C(＝O)N(R ^3b) ₂、-(C ₂-C ₄ alkynylene) -N (R ^3b) ₂、N(R ^3b) ₂、C ₃-C ₆ cycloalkyl and 5-6 membered heteroaryl, the C ₁-C ₆ alkyl, C ₁-C ₆ alkoxy, C ₁-C ₆ alkylthio, C ₂-C ₄ alkynyl, C ₂-C ₄ alkynylene, C ₃-C ₆ cycloalkyl or 5-6 membered heteroaryl being optionally substituted with R ^3c; or two R ^3a's together with the atoms to which they are each attached form a C ₄-C ₆ cycloalkenyl group or a 5-7 membered heterocyclyl group, which C ₄-C ₆ cycloalkenyl group or 5-7 membered heterocyclyl group is optionally substituted with R ^3d.

In some embodiments, R ^3a is selected from halogen, OH, CN, C ₁-C ₆ alkyl, C ₁-C ₆ alkoxy, C ₁-C ₆ alkylthio, C ₂-C ₄ alkynyl, -CH ₂C(＝O)N(R ^3b) ₂、-(C ₂-C ₄ alkynylene) -N (R ^3b) ₂、N(R ^3b) ₂、C ₃-C ₆ cycloalkyl and 5-6 membered heteroaryl, the C ₁-C ₆ alkyl, C ₁-C ₆ alkoxy, C ₁-C ₆ alkylthio, C ₂-C ₄ alkynyl, C ₂-C ₄ alkynylene, C ₃-C ₆ cycloalkyl or 5-6 membered heteroaryl being optionally substituted with R ^3c.

In some embodiments, R ^3b is selected from H and C ₁-C ₃ alkyl.

In some embodiments, R ^3c is selected from deuterium, halogen, OH, CN, NH ₂, and C ₁-C ₃ alkoxy.

In some embodiments, R ^3c is selected from F.

In some embodiments, R ^3d is selected from halogen, OH, C ₁-C ₃ alkyl, and C ₁-C ₃ alkoxy.

In some embodiments, R ^3a is selected from halogen, OH, CN, CF ₃、CHF ₂, methyl, hydroxymethyl, -CH ₂OCH ₃, ethyl, hydroxyethyl, 2-trifluoroethyl, 2-difluoroethyl, 2-fluoroethyl, n-propyl, isopropyl, 1-hydroxy-1-methylethyl, 1-F-1-methylethyl, 3-fluoropropyl, isobutyl, -C (CH ₃)CH ₂CH ₃, methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, methylthio, trifluoromethylthio 、CNCH ₂CH ₂-、NH ₂、NHCH ₃、N(CH ₃) ₂、NHCH ₂CH ₃、 ethynyl 、-C≡C-CH ₂OH、-C≡C-CH ₂NH ₂、-C≡C-CH ₂D、-CH ₂C≡CH、-C≡C-CH ₃、-C≡C-CH ₂CH ₃、-CH ₂C(＝O)NH ₂、 cyclopropyl, 1-methylcyclopropyl, 2-fluorocyclopropyl, 2-methylcyclopropyl, cyclobutyl and triazolyl, or two R ^3a together with the atoms to which they are each attached form cyclohexenyl, cyclopentenyl orThe cyclohexenyl, cyclopentenyl orOptionally substituted with methyl, OH or halogen.

In some embodiments, R ^3a is selected from F, cl, OH, ethynyl, CF ₃, methyl, ethyl, NH ₂, and CN.

In some embodiments, R ³ is selected from

In some embodiments, R ³ -L is selected from

In some embodiments, R ⁵ is selected from H, OH, CN, C ₂-C ₄ alkynyl, C ₁-C ₃ haloalkyl, and C ₃-C ₆ cycloalkyl.

In some embodiments, R ⁵ is selected from H, CN, C ₂-C ₄ alkynyl, and C ₁-C ₃ haloalkyl.

In some embodiments, R ⁵ is selected from H, CN and-c≡ch.

In some embodiments, W is O or NH.

In some embodiments, W is O.

In some embodiments, n is 1.

In some embodiments, R ² is selected from the following groups optionally substituted with R ⁷:

In some embodiments, R ² is selected from the group consisting of optionally substituted with R ⁷

In some embodiments, R ⁷ is selected from halogen, OH, CN, C ₁-C ₆ alkyl, and C ₁-C ₆ alkoxy, said C ₁-C ₆ alkyl or C ₁-C ₆ alkoxy being optionally substituted with R ^7a.

In some embodiments, R ^7a is selected from deuterium, halogen, OH, CN, and NH ₂.

In some embodiments, R ⁷ is selected from halogen and halogenated C ₁-C ₆ alkyl.

In some embodiments, R ⁷ is selected from F.

In some embodiments, R ² is selected from

In some embodiments, W- (CH ₂) _n-R ²) is selected from

In some embodiments, the compounds of formula (I) of the present invention are selected from compounds of formula (IIa):

Wherein as ring A Optionally also substituted with R ⁴, and the rings B, R ⁴、L、R ³、X、W、R ² and n are as defined in formula (I).

In some embodiments, the compounds of formula (I) of the present invention are selected from compounds of formula (IIb):

Wherein, Represents a single bond or a double bond as ring AOptionally also substituted with R ⁴, and the rings B, R ⁴、L、R ³、X、W、R ² and n are as defined in formula (I).

In some embodiments, the compounds of formula (I) of the present invention are selected from compounds of formula (IIc):

In some embodiments, the compounds of formula (I) of the present invention are selected from the following compounds:

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) of the present invention or a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant.

In another aspect, the invention provides a method of treating a disease or condition associated with a KRAS G12D mutation in a mammal comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In another aspect, the present invention provides a method of treating a neoplasm in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In another aspect, the invention provides the use of a compound of formula (i) or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of a disease associated with a KRAS G12D mutation.

In another aspect, the present invention provides the use of a compound of formula (i) or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of a tumor.

In another aspect, the invention provides the use of a compound of formula (i) or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of a disease associated with a KRAS G12D mutation.

In another aspect, the present invention provides the use of a compound of formula (i) or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of a tumor.

In another aspect, the present invention provides a compound of formula (i) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of a disease associated with a KRAS G12D mutation.

In another aspect, the present invention provides a compound of formula (i) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of a tumor.

In some embodiments, the disease associated with the KRAS G12D mutation is selected from a tumor.

In some embodiments, the tumor is selected from cancer.

In some embodiments, the cancer is selected from gastric cancer.

Definition and description of terms

Unless otherwise indicated, the terms used in the present invention have the following meanings, and the groups and term definitions recited in the present invention, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and combined with each other. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.

Herein, a method of manufacturing a semiconductor deviceRepresenting the ligation site.

Herein, keys depicted by solid lines and dashed linesRepresents a single bond or a double bond.

The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J.chem. Ed.1985, 62:114-120. Unless otherwise indicated, wedge keys and virtual wedge keys are usedRepresenting the absolute configuration of a solid center by using black real and virtual keysRepresenting the relative configuration of a stereocenter (e.g., the cis-trans configuration of a alicyclic compound).

The term "tautomer" refers to a functional group isomer that results from the rapid movement of an atom in a molecule at two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The location of the equilibrium depends on the chemical nature of the molecule. For example, among many aliphatic aldehydes and ketones such as acetaldehyde, the ketone type predominates; whereas, among phenols, the enol form is dominant. The present invention encompasses all tautomeric forms of the compounds.

The term "stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers and diastereomers.

The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present invention may exist in specific geometric or stereoisomeric forms. Particular geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic or other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which fall within the definition of compounds of the invention. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms may be present in the substituents such as alkyl groups, and all such isomers and mixtures thereof are included within the definition of compounds of the invention. The asymmetric atom-containing compounds of the present invention may be isolated in optically pure form or in racemic form, which may be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =o), meaning that two hydrogen atoms are substituted, oxo does not occur on the aromatic group.

The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that ethyl can be unsubstituted (CH ₂CH ₃), monosubstituted (CH ₂CH ₂F、CH ₂CH ₂ Cl, etc.), polysubstituted (CHFCH ₂F、CH ₂CHF ₂、CHFCH ₂Cl、CH ₂CHCl ₂, etc.), or fully substituted (CF ₂CF ₃、CF ₂CCl ₃、CCl ₂CCl ₃, etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.

When any variable (e.g., R ¹、R ⁴) occurs more than once in the composition or structure of a compound, its definition in each case is independent. For example, if one group is substituted with 2R ⁴, then each R ⁴ has an independent option.

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

When one of the variables is selected from chemical bonds or is absent, the two groups representing its attachment are directly linked, e.g., when L in A-L-R ³ represents a bond, it is meant that the structure is actually A-R ³.

The linking group referred to herein is arbitrary in its linking direction unless the linking direction is indicated. For example when building blocksWherein ring A is selected fromAt this time, the structural unitCan be eitherMay also be

C _m-C _n herein refers to an integer number of carbon atoms in the m-n range. For example, "C ₁-C ₆" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

The term "alkyl" refers to a hydrocarbon group of the formula C _nH _2n+1, which may be straight or branched. The term "C ₁-C ₆ alkyl" is understood to mean a straight or branched saturated monovalent hydrocarbon radical having 1,2, 3, 4, 5 or 6 carbon atoms. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, etc. The term "C ₁-C ₃ alkyl" is understood to mean a straight or branched saturated monovalent hydrocarbon radical having from 1 to 3 carbon atoms. The "C ₁-C ₆ alkyl" may comprise "C ₁-C ₃ alkyl".

The term "haloalkyl" refers to a group resulting from substitution of any one or more hydrogen atoms in the alkyl group with halogen atoms. In the case where a plurality of hydrogen atoms are substituted, each halogen atom for substitution is selected independently of one another. "C ₁-C ₃ haloalkyl" refers to a group resulting from substitution of any one or more hydrogen atoms in "C ₁-C ₃ alkyl" with halogen atoms.

The term "alkoxy" refers to a monovalent group generated by the loss of a hydrogen atom on a hydroxyl group of a straight or branched chain alcohol, and is understood to be "alkyloxy" or "alkyl-O-". The term "C ₁-C ₆ alkoxy" may be understood as "C ₁-C ₆ alkyloxy" or "C ₁-C ₆ alkyl-O-"; the term "C ₁-C ₃ alkoxy" is understood to mean "C ₁-C ₃ alkyloxy" or "C ₁-C ₃ alkyl-O-". The "C ₁-C ₆ alkoxy" may further comprise "C ₁-C ₃ alkoxy".

The term "haloalkoxy" refers to a group resulting from substitution of any one or more hydrogen atoms in the alkoxy group with halogen atoms. In the case where a plurality of hydrogen atoms are substituted, each halogen atom for substitution is selected independently of one another. "C ₁-C ₃ haloalkoxy" refers to a group resulting from substitution of any one or more hydrogen atoms in "C ₁-C ₃ alkoxy" with halogen atoms.

The term "alkenyl" refers to a monovalent unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, straight or branched chain, and having at least one double bond. The term "C ₂-C ₄ alkenyl" is understood to mean a straight-chain or branched unsaturated monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3 or 4 carbon atoms, a "C ₂-C ₄ alkenyl" preferably being a C ₂ or C ₃ alkenyl radical. It will be appreciated that where the alkenyl group comprises more than one double bond, the double bonds may be separated or conjugated to each other. Specific examples of the alkenyl group include, but are not limited to, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, isopropenyl, 2-methylpropan-2-enyl, 1-methylpropan-2-enyl, 2-methylpropan-1-enyl, (E) -1-methylpropan-1-enyl, or (Z) -1-methylpropan-1-enyl, and the like.

The term "alkynyl" refers to a straight or branched monovalent unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms having at least one triple bond. The term "C ₂-C ₄ alkynyl" is understood to mean a straight or branched unsaturated monovalent hydrocarbon radical which contains one or more triple bonds and has 2, 3 or 4 carbon atoms. Examples of "C ₂-C ₄ alkynyl" include, but are not limited to, ethynyl (-C.ident.CH), propynyl (-C.ident.CCH _3、-CH ₂ C.ident.CH), but-1-ynyl, but-2-ynyl, or but-3-ynyl. "C ₂-C ₄ alkynyl" may include "C ₂-C ₃ alkynyl" and examples of "C ₂-C ₃ alkynyl" include ethynyl (-C.ident.CH), prop-1-ynyl (-C.ident.CCH ₃), prop-2-ynyl (propargyl).

The term "alkynylene" refers to a divalent group resulting from the removal of one more hydrogen atom from the "alkynyl". "C ₂-C ₄ alkynylene" refers to a divalent group resulting from the removal of one more hydrogen atom from the "C ₂-C ₄ alkynyl" and examples thereof include, but are not limited to, -C.ident.C-CH ₂ -, and the like.

The term "cycloalkyl" refers to a fully saturated carbocycle in the form of a single ring, a parallel ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. The term "C ₃-C ₁₀ cycloalkyl" is understood to mean a saturated monovalent monocyclic, fused, spiro or bridged ring having 3,4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, spiro [4.5] decyl, and the like. The term "C ₃-C ₁₀ cycloalkyl" may include "C ₃-C ₆ cycloalkyl" and the term "C ₃-C ₆ cycloalkyl" is understood to mean a saturated monovalent mono-or bicyclic hydrocarbon ring having 3,4, 5 or 6 carbon atoms, specific examples including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the like.

The term "cycloalkyloxy" is understood as "cycloalkyl-O-". The term "C ₃-C ₁₀ cycloalkoxy" may comprise "C ₃-C ₆ cycloalkyloxy".

The term "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon group containing at least one carbon-carbon double bond. "C ₃-C ₆ cycloalkenyl" refers to non-aromatic cyclic hydrocarbons having 3, 4,5, or 6 carbon atoms as ring atoms and containing at least one carbon-carbon double bond. Specific examples of C ₃-C ₆ cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. The term "C ₃-C ₆ cycloalkenyl" may include "C ₄-C ₆ cycloalkenyl", "C ₄-C ₆ cycloalkenyl" may further include "C ₆ cycloalkenyl".

The term "heterocyclyl" refers to a fully saturated or partially saturated (wholly not aromatic heteroaromatic) monovalent monocyclic, fused, spiro, or bridged ring radical containing 1-5 heteroatoms or groups of heteroatoms (i.e., groups containing heteroatoms) in the ring atoms, including but not limited to nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), S (=o) ₂ -, -S (=o) -and optionally substituted-NH-, -S (=o) (=nh) -, -C (=o) NH-, -C (=nh) -, -S (=o) ₂ NH-, S (=o) NH-, or-NHC (=o) NH-, and the like. The term "4-10 membered heterocyclic group" means a heterocyclic group having 4,5, 6,7,8, 9 or 10 ring atoms and containing 1 to 5 heteroatoms or groups of heteroatoms independently selected from the above. "4-10 membered heterocyclic group" includes "8-10 membered heterocyclic group", "8-10 membered heterocyclic group" further includes "4-7 membered heterocyclic group", "4-7 membered heterocyclic group" further includes "5-7 membered heterocyclic group", "5-7 membered heterocyclic group" further includes 6 membered heterocyclic group ". Specific examples of 4-membered heterocyclyl groups include, but are not limited to, azetidinyl or oxetanyl; specific examples of 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4, 5-dihydro-oxazolyl, or 2, 5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclyl groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, or 4H- [1,3,4] thiadiazinyl; specific examples of 7-membered heterocyclyl groups include, but are not limited to, diazepinyl. The heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5 membered bicyclic groups include, but are not limited to, hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl; specific examples of 5,6 membered bicyclo groups include, but are not limited to, hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl, 5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazinyl, or 5,6,7, 8-tetrahydroimidazo [1,5-a ] pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused ring group of the above 4-7 membered heterocyclic group, specific examples include, but are not limited to, dihydroisoquinolinyl and the like. The "4-7 membered heterocyclic group" may further include the ranges of "4-6 membered heterocyclic group", "5-6 membered heterocyclic group", "4-7 membered heterocycloalkyl group", "4-6 membered heterocycloalkyl group", "5-6 membered heterocycloalkyl group" and the like. In the present invention, although some bicyclic heterocyclic groups contain a benzene ring or a heteroaryl ring in part, the heterocyclic groups as a whole are not aromatic.

The term "nitrogen-containing heterocyclic group" refers to a "heterocyclic group" containing at least one nitrogen atom as a ring atom.

The term "heterocycloalkyl" refers to a monovalent cyclic group that is fully saturated and exists as a single ring, a parallel ring, a bridged ring, or a spiro ring, etc., having 1-5 heteroatoms or groups of heteroatoms (i.e., groups of heteroatoms) in the ring atoms of the ring, including, but not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S (=o) ₂ -, -S (=o) -and optionally substituted-NH-, -S (=o) (=nh) -, -C (=o) NH-, -C (=nh) -, -S (=o) ₂ NH-, S (=o) NH-, or-NHC (=o) NH-, etc. The term "4-10 membered heterocycloalkyl" refers to a heterocycloalkyl group having a number of ring atoms of 4,5, 6, 7, 8, 9 or 10, and containing 1 to 5 heteroatoms or groups of heteroatoms independently selected from those described above. "4-10 membered heterocycloalkyl" includes "8-10 membered heterocycloalkyl".

The term "nitrogen-containing heterocycloalkyloxy" refers to a "heterocycloalkyl" group containing at least one nitrogen atom as a ring atom.

The term "aryl" refers to an all-carbon monocyclic or fused-polycyclic aromatic ring radical having a conjugated pi-electron system. The aryl group may have 6 to 14 carbon atoms or 6 to 10 carbon atoms. The term "C ₆-C ₁₄ aryl" is understood to mean a monovalent aromatic, monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 14 carbon atoms. In particular a ring having 6 carbon atoms ("C ₆ aryl"), such as phenyl; or a ring having 9 carbon atoms ("C ₉ aryl"), such as indenyl; or a ring having 10 carbon atoms ("C ₁₀ aryl"), such as naphthyl; or a ring having 13 carbon atoms ("C ₁₃ aryl"), such as fluorenyl; or a ring having 14 carbon atoms ("C ₁₄ aryl"), such as anthracenyl. The term "C ₆-C ₁₀ aryl" is understood to mean an all-carbon monocyclic or bicyclic radical of monovalent aromaticity or of partial aromaticity having from 6 to 10 carbon atoms. The term "C ₆-C ₁₄ aryl" may include "C ₆-C ₁₀ aryl".

The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring system containing at least one ring atom selected from N, O, S and the remaining ring atoms being aromatic ring groups of C. The term "5-14 membered heteroaryl" is understood to include such monovalent monocyclic or bicyclic aromatic ring systems: it has 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like, and their benzo derivatives, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or the like, and their benzo derivatives, such as quinolinyl, quinazolinyl, or isoquinolinyl, or the like; or an axcinyl group, an indolizinyl group, a purinyl group, etc., and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl, and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms and which contains 1 to 3, preferably 1 to 2 heteroatoms independently selected from N, O and S. The term "5-14 membered heteroaryl" may comprise "5-10 membered heteroaryl", "5-10 membered heteroaryl" may further comprise "5-6 membered heteroaryl", "5-6 membered heteroaryl" may still further comprise "6 membered heteroaryl".

The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" refers to an-OH group.

The term "cyano" refers to a-CN group.

The term "mercapto" refers to a-SH group.

The term "amino" refers to the-NH ₂ group.

The term "nitro" refers to the-NO ₂ group.

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

The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable acids or bases, including salts of compounds with inorganic or organic acids, and salts of compounds with inorganic or organic bases.

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

The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.

The words "comprise" or "include" and variations thereof such as "comprises" or "comprising" are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to.

The invention also includes isotopically-labeled compounds of the invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ²H、 ³H、 ¹¹C、 ¹³C、 ¹⁴C、 ¹³N、 ¹⁵N、 ¹⁵O、 ¹⁷O、 ¹⁸O、 ³¹P、 ³²P、 ³⁵S、 ¹⁸F、 ¹²³I、 ¹²⁵I and ³⁶ Cl, respectively, and the like.

Certain isotopically-labeled compounds of the present invention (e.g., labeled with ³ H and ¹⁴ C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes such as ¹⁵O、 ¹³N、 ¹¹ C and ¹⁸ F are useful in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the schemes and/or examples below by substituting an isotopically-labeled reagent for an non-isotopically-labeled reagent.

The pharmaceutical compositions of the present invention may be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.

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

The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, emulsifying, lyophilizing, and the like.

In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.

The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving a tablet or dragee core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, and the like.

The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

In all methods of administration of the compounds of formula (I) described herein, the dosage administered per day is from 0.01mg/kg to 200mg/kg body weight, preferably from 0.05mg/kg to 50mg/kg body weight, more preferably from 0.1mg/kg to 30mg/kg body weight, either alone or in divided doses.

The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.

The chemical reactions of the embodiments of the present invention are accomplished in a suitable solvent that is compatible with the chemical changes of the present invention and the reagents and materials required therefor. In order to obtain the compounds of the present invention, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the embodiments already present.

In some embodiments, some of the compounds of formula (I) of the present invention may be prepared by one skilled in the art of organic synthesis by either scheme 1 or scheme 2 below:

scheme 1

Scheme 2

Wherein X ₁ is selected from CH, CR ⁴ or N, X ₂ is selected from halogen, ring B, L, R ³、R ⁴、W、R ² and N are as defined in formula (I);

In the synthetic route 1 and the synthetic route 2, the compound shown in the formula (I-1) is subjected to substitution reaction to obtain the compound shown in the formula (I-2); the compound shown in the formula (I-2) is subjected to an insertion carbonyl coupling reaction in the presence of a catalyst under an alkaline condition to obtain a compound shown in the formula (I-3); the compound shown in the formula (I-3) and the compound shown in the formula (I-4) react under tetrahydrofuran, then ammonia water methanol solution is added, and the compound shown in the formula (I-5) is obtained through cyclization reaction; the compound shown in the formula (I-5) is subjected to substitution reaction under the condition of phosphorus oxychloride to obtain a compound shown in the formula (I-6); the compound shown in the formula (I-6) is subjected to substitution reaction under alkaline conditions to obtain a compound shown in the formula (I-7); the compound shown in the formula (I-7) is subjected to substitution reaction under alkaline conditions to obtain a compound shown in the formula (I-8); the compound shown in the formula (I-8) and the compound shown in the formula (I-9) are subjected to C-C coupling reaction in the presence of a catalyst under alkaline conditions to obtain the compound shown in the formula (I).

In some embodiments, some of the compounds of the general formula (I) of the present invention may be prepared by one skilled in the art of organic synthesis by the following scheme 3:

Scheme 3

Wherein R ⁴、L、R ³, ring B, W, R ² and n are as defined in formula (I);

In the synthetic route 3, the compounds shown in the formula (II-1) and the formula (I-9) are subjected to C-C coupling reaction under alkaline conditions in the presence of a catalyst to obtain the compound shown in the formula (II-2); the compound shown in the formula (II-2) and the compound shown in the formula (II-3) are subjected to substitution reaction under alkaline conditions to obtain a compound shown in the formula (II-4); cyclizing a compound shown in the formula (II-4) and a compound shown in the formula (II-5) under alkaline conditions to obtain a compound shown in the formula (II-6); the compound shown in the formula (II-6) can be subjected to substitution reaction under the condition of phosphorus oxychloride according to ① th route to obtain a compound shown in the formula (II-7), and then the compound shown in the formula (II-7) is subjected to substitution reaction under the alkaline condition to obtain a compound shown in the formula (II-8); or the compound shown in the formula (II-6) can be subjected to substitution reaction under the alkaline condition according to the ② th path in the presence of a catalyst to directly obtain the compound shown in the formula (II-8); the compound shown in the formula (II-8) is subjected to oxidation reaction under the oxidation condition to obtain a compound shown in the formula (II-9); the compound shown in the formula (II-9) is subjected to substitution reaction under alkaline conditions to obtain the compound shown in the formula (I).

Detailed Description

The invention is described in detail below by way of examples, which are not meant to limit any disadvantages of the invention. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention. All reagents used in the present invention are commercially available and can be used without further purification.

Unless otherwise indicated, the ratio of the mixed solvent is a volume mixing ratio. Unless otherwise indicated,% refers to wt%.

The compounds being obtained by hand or by handSoftware naming, commercial compounds are referred to by vendor catalog names.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). The unit of NMR shift was 10 ^-6 (ppm). The solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is Tetramethylsilane (TMS); "IC ₅₀" refers to half the inhibitory concentration, and refers to the concentration at which half the maximum inhibitory effect is achieved.

Description of terms or abbreviations:

DIEA: n, N-diisopropylethylamine; boc: t-butoxycarbonyl; TIPS: triisopropylsilyl; TBAF: tetrabutylammonium fluoride; 1,4-dioxane: pd (dppf) Cl ₂: [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride; m: moles/liter.

The eluent below can be a mixed eluent formed by two or more solvents, the ratio of which is the volume ratio of the solvents, for example, 0-10% methanol/dichloromethane represents the volume ratio of methanol to dichloromethane in the mixed eluent in the gradient elution process, which is 0:100-10:100.

Example 1: preparation of 4- (4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((octahydro-2 aH-pyrrolo [2,1,5-cd ] pyrrolizine-2 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (compound 1)

The synthetic route is as follows:

Step1: preparation of octahydro-2 aH-pyrrolo [2,1,5-cd ] pyrrolizine-2 a-carboxylate (1 b)

Octahydro-2 aH-pyrrolo [2,1,5-cd ] pyrrolizine-2 a-carbonitrile (0.30 g,1.9mmol, prepared as described in literature Crystal Growth & Design (2009), 9 (4), 1786-1792) was dissolved in concentrated hydrochloric acid (5 mL, w/w 37%) and reacted at 100℃for 16 hours. The solvent was distilled off under reduced pressure to obtain the title compound 1b (0.35 g) as a solid.

Step 2: preparation of (octahydro-2 aH-pyrrolo [2,1,5-cd ] pyrrolizin-2 a-yl) methanol (1 c)

Compound 1b (0.3 g,1.4 mmol) was added to a 1M solution of borane in tetrahydrofuran (5 mL) at 0deg.C. After stirring at 0℃for 1 hour, methanol (10 mL) was added thereto, and the mixture was reacted at room temperature for 16 hours. Concentrating the reaction solution, and purifying the obtained residue by reverse phase chromatographyC ₁₈ quick silica gel column, 0.1% ammonia: acetonitrile = 20:1 to 1: 1) to give the title compound 1c (0.12 g) as a solid.

LC-MS:m/z(ESI):168[M+H] ⁺。

Step 3: preparation of tert-butyl 3- (7-chloro-8-fluoro-2- ((octahydro-2 aH-pyrrolo [2,1,5-cd ] pyrrolizin-2 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1 e)

Compound 1c (0.05 g,0.3 mmol), compound 1d (0.08 g,0.19mmol, prepared using the method disclosed in WO 2021/04671A 1 as intermediate 5) and DIEA (0.085 g,0.66 mmol) were dissolved in 1, 4-dioxane (2 mL) and heated at 100deg.C for 16 hours. Concentrating the reaction solution, and purifying the obtained residue by reverse phase chromatographyC ₁₈ quick silica gel column, 0.1% ammonia: acetonitrile=5: 1 to 1:20 elution) to give the title compound 1e (0.065 g) as a solid.

MS m/z(ESI):559[M+H] ⁺。

Step 4: preparation of tert-butyl 3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((octahydro-2 aH-pyrrolo [2,1,5-cd ] pyrrolizin-2 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1 g)

A mixture of 1e (0.065 g,0.12 mmol), 1f (0.06 g,0.12mmol, prepared using the method disclosed in WO 2021/04671A 1 as intermediate 15) was heated to react for 16 hours at 100deg.C under nitrogen atmosphere, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.008 g,0.012 mmol), cesium carbonate (0.095 g,0.29 mmol), 1, 4-dioxane (2 mL) and water (0.5 mL). Concentrating the reaction solution, and purifying the obtained residue by reverse phase chromatographyC ₁₈ quick silica gel column, 0.1% ammonia: acetonitrile = 1:1 to 1:20 elution) to give 1g (0.045 g) of the title compound as a solid.

MS m/z(ESI):909[M+H] ⁺。

Step 5: preparation of 4- (4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((octahydro-2 aH-pyrrolo [2,1,5-cd ] pyrrolizine-2 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (compound 1)

1G (0.04 g,0.044 mmol) was dissolved in tetrabutylammonium fluoride in tetrahydrofuran (1 mol/L,2 mL) and reacted at 20℃for 1 hour. The reaction mixture was concentrated, and the residue was purified by reverse phase chromatography (0.1% aqueous ammonia: acetonitrile=4:1 to 1:20), and the resultant was concentrated under reduced pressure, dried, and then added with a1, 4-dioxane solution (1 mol/L,1 mL) of hydrogen chloride at 0℃to react for 3 hours at 0 ℃. Concentrating the reaction solution, and purifying the residue by reversed phase chromatographyC ₁₈ quick silica gel column, 0.1% ammonia: acetonitrile=4: 1 to 1:4 elution) to give the title compound 1 (0.008 g) as a solid.

MS m/z(ESI):609[M+H] ⁺；

¹HNMR(400MHz,DMSO-d ₆):δ10.16(s,1H),9.03(s,1H),7.97(dd,J＝9.1,5.9Hz,1H),7.46(t,J＝9.0Hz,1H),7.39(d,J＝2.5Hz,1H),7.17(d,J＝2.4Hz,1H),4.47(d,J＝11.1Hz,1H),4.31(d,J＝11.9Hz,1H),4.09(s,2H),3.93(s,1H),3.63(d,J＝12.1Hz,1H),3.59–3.50(m,3H),3.40–3.34(m,3H),1.93–1.82(m,2H),1.81–1.72(m,2H),1.71–1.62(m,7H),1.56–1.41(m,4H).

Referring to the synthetic methods of the above examples and the aforementioned general synthetic schemes 1, 2 and 3, the following compounds were synthesized, whose structure and mass spectral data were:

biological Activity and related Property test cases

Test example 1 inhibition of AGS cell proliferation by KRAS G12D inhibitor

1. Experimental instrument and materials

Instrument name	Equipment manufacturer	Model number
Full-automatic cell counter	Beckman	Vi-CELL XR
Oscillator	Boxun	BSD-YX3400
Board reading instrument	PerkinElmer	Envision
Centrifugal machine	Eppendorf	Eppendorf Mixmate
Compound dilution and sample adding instrument	PerkinElmer	Echo
Cell incubator	THERMO	THERMO Heracell VIOS 250i
AGS cells	ATCC	CRL-1739

The cell AGS used in the experiment was a KRAS G12D mutant cell line. Cells were subcultured with Ham's F-12K (Kaighn's) medium plus 10% FBS. Liquid nitrogen freezes cells with low cell algebra. Kit for detection3D Cell Viability Assay) a homogeneous assay for detecting the number of viable cells in a 3D cell micro-tissue by quantifying ATP. The kit produces a luminescent signal proportional to the amount of ATP present, which is directly proportional to the number of cells.

Other reagents and consumables required for the experiment were as follows:

2. Experimental procedure

The AGS cells thus cultured were washed once with PBS, digested with pancreatin, collected and centrifuged, and after counting by re-suspension with a culture solution (Ham's F-12K+10% FBS+1% Penicillin-Streptomycin), the cell concentration was adjusted, and the cell seeds were cultured in 384-well plates (200 cells/20. Mu.l/well), 37℃and 5% CO ₂ cell culture chambers overnight. Test compounds were dissolved in DMSO and stock solutions were stored at a concentration of 10mM. Compound mother liquor was diluted in gradient by the dose-response procedure of an Echo instrument, the dilution procedure was performed to verify 50 μl of the total system, an initial concentration of 50 μl, 3-fold dilution, 10 concentration points, and the total volume of compound and DMSO was 250nL. After the end of the procedure, 30. Mu.L of culture medium was added to each well, and after centrifugation at 1000rpm for 5 minutes in a centrifuge, the culture was continued in a cell incubator for 7 days. After day 7, the cell plates were equilibrated to room temperature and 25 μl of 3D CTG reagent was added to each well, followed by shaking for 10 minutes and then left at room temperature in the dark for 30 minutes. Chemiluminescent signal the Luminescence signal in each well was measured using an Envision reader (emission wavelength 400-700 nm). 100% inhibition was defined as the level of inhibition of proliferation of cells under treatment with 10. Mu.M positive compound. The positive compound was the compound of example 252 prepared as described in example 252 of the specification of patent application WO2021041671 A1.

3. Data analysis

The formula of the inhibition rate of the compound to the cell proliferation is as follows:

Cell proliferation inhibition% = (average_h-Sample)/(average_h-L) x 100%

Wherein:

H＝Ave(Relative Signal_cell only DMSO)；

L＝Ave(Relative Signal_10μM positive compound)；

Sample refers to the signal value read from each well of the dosing group.

Data analysis was performed by XLfit, concentration-effect curves were fitted using a nonlinear four-parameter curve, and IC ₅₀ for the compound was calculated:

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀-X)*HillSlope))

Wherein:

x is Log value of compound concentration value;

Percent inhibition (inhibition%);

Bottom is the minimum percent inhibition;

Top is the maximum percent inhibition;

HillSlope is the slope coefficient of the curve.

The inhibitory activity of the compounds of the present invention on AGS cell proliferation was determined by the above assay, and the IC ₅₀ values measured are shown in table 1.

TABLE 1

Numbering of compounds	IC ₅₀(nM)
1	164

Claims

A compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

in,

Ring B is selected from an 8-10 membered nitrogen-containing heterocyclic group optionally substituted by R ¹ , wherein the nitrogen-containing heterocyclic group is in the form of a bridged ring;

R ¹ is selected from halogen, OH, ＝O, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, HC(＝O)-, -CO ₂ R ^1a , -CON(R ^1a ) ₂ , and 5-6 membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or 5-6 membered heteroaryl is optionally substituted by R ^1b ;

Ring A is a 5-6 membered heteroaryl, phenyl, 4-7 membered heterocyclyl or C ₃ -C ₆ cycloalkenyl group, and the 5-6 membered heteroaryl, phenyl, 4-7 membered heterocyclyl or C ₃ -C ₆ cycloalkenyl group is optionally substituted by R ⁴ ;

R ⁴ is selected from deuterium, halogen, OH, ═O, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl and C ₃ -C ₁₀ cycloalkyloxy, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl or C ₃ -C ₁₀ cycloalkyloxy is optionally substituted with R ^4a ;

L is selected from O, -C(=O)-, and a bond;

R ³ is selected from C ₆ -C ₁₄ aryl and 5-14 membered heteroaryl, wherein the C ₆ -C ₁₄ aryl or 5-14 membered heteroaryl is optionally substituted by R ^3a ;

X is selected from CR ⁵ and N;

R ⁵ is selected from H, halogen, OH, CN, NO ₂ , NH ₂ , NH(C ₁ -C ₃ alkyl), N(C ₁ -C ₃ alkyl) ₂ , C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkoxy, C ₂ -C ₄ alkynyl, C ₃ -C ₁₀ cycloalkyl and C ₃ -C ₁₀ cycloalkyloxy;

W is selected from O, NR ⁶ and a bond;

R ² is selected from Said R ² is optionally substituted by R ⁷ ;

R ⁷ is selected from deuterium, halogen, OH, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl and C ₃ -C ₁₀ cycloalkyloxy, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl or C ₃ -C ₁₀ cycloalkyloxy is optionally substituted with R ^7a ;

R ^3a is selected from halogen, OH, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, -CH ₂ C(═O)N(R ^3b ) ₂ , -(C ₂ -C ₄ alkynylene)-N(R ^3b ) ₂ , N(R ^3b ) ₂ , C ₃ -C ₁₀ cycloalkyl and 5-6 membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₂ -C ₄ alkynylene, C ₃ -C ₁₀ cycloalkyl or 5-6 membered heteroaryl is optionally substituted with R ^3c ;

Alternatively, two R ^3a together with the atoms to which they are attached form a C ₄ -C ₆ cycloalkenyl or a 5-7 membered heterocyclyl, wherein the C ₄ -C ₆ cycloalkenyl or the 5-7 membered heterocyclyl is optionally substituted by R ^3d ;

R ^1a , R ^3b and R ⁶ are independently selected from H and C ₁ -C ₆ alkyl;

R ^1b , R ^3c , R ^3d , R ^4a and R ^7a are independently selected from deuterium, halogen, OH, CN, ═O, NH ₂ , C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy;

n is selected from 0, 1 and 2.

The compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt according to claim 1, wherein ring B is selected from the following groups optionally substituted by R ¹ :

The compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is selected from the following groups optionally substituted by R ⁴ : 5-6 membered heteroaryl, phenyl, tetrahydropyridyl, dihydropyranyl, cyclohexenyl and cyclohexadienyl, preferably selected from the following groups optionally substituted by R ⁴ : More preferably, the following groups optionally substituted by R ⁴ are present: More preferably, it is optionally substituted by R ⁴

The compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt according to claim 1, wherein R ⁴ is selected from halogen, OH, =O, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy, and the C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy is optionally substituted by R ^4a .

The compound of formula (I) according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from O and a bond.

The compound of formula (I) according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from naphthyl, phenyl and 5-10 membered heteroaryl, and the naphthyl, phenyl or 5-10 membered heteroaryl is optionally substituted by R ^3a .

The compound of formula (I) according to claim 1 or 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R ^3a is selected from halogen, OH, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₂ -C ₄ alkynyl, -CH ₂ C(＝O)N(R ^3b ) ₂ , -(C ₂ -C ₄ alkynylene)-N(R ^3b ) ₂ , N(R ^3b ) ₂ , C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl, and the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₂ -C ₄ alkynyl, C ₂ -C ₄ alkynylene, C ₃ -C ₆ cycloalkyl or 5-6 membered heteroaryl is optionally substituted by R ^3c ; or two R ^3a together with the atoms to which they are attached form a C ₄ -C The C ₄ _{-C 6} _cycloalkenyl or 5-7 membered heterocyclyl is optionally substituted by R ^3d .

The compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt according to claim 1, wherein R ⁵ is selected from H, CN, C ₂ -C ₄ alkynyl and C ₁ -C ₃ haloalkyl.

The compound of formula (I) according to claim 1, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein W is O.

The compound of formula (I) according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is selected from the following groups optionally substituted by R ⁷ :

The compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt according to claim 1, wherein the compound of formula (I) is selected from the compound of formula (IIa):

Among them, as ring A is further optionally substituted by R ⁴ , and Ring B, R ⁴ , L, R ³ , X, W, R ² and n are as defined in claim 1 .

The compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt according to claim 1, wherein the compound of formula (I) is selected from the compound of formula (IIb):

in, represents a single bond or a double bond, as ring A is further optionally substituted by R ⁴ , and Ring B, R ⁴ , L, R ³ , X, W, R ² and n are as defined in claim 1 .

The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is selected from the compound of formula (IIc):

The compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt according to claim 1, wherein the compound has a structure selected from one of the following:

A pharmaceutical composition comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Use of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15 for preventing or treating a disease or condition associated with a KRAS G12D mutation, wherein the disease or condition associated with a KRAS G12D mutation is preferably selected from tumors.