WO2023125627A1

WO2023125627A1 - Nitrogen-containing heterocyclic compound and application thereof

Info

Publication number: WO2023125627A1
Application number: PCT/CN2022/142684
Authority: WO
Inventors: Zhaokui WAN; Xiaodong Li; Michael Lawrence Vazquez; Jingyu Wu
Original assignee: Lynk Pharmaceuticals Co., Ltd.
Priority date: 2021-12-28
Filing date: 2022-12-28
Publication date: 2023-07-06

Abstract

Relates a nitrogen-containing heterocyclic compound and an application thereof. Relates a nitrogen-containing heterocyclic compound represented by formula (I) or (II), a pharmaceutically acceptable salt thereof or a solvate thereof. The nitrogen-containing heterocyclic compound has better inhibitory activity to KRAS-G12D.

Description

Nitrogen-Containing Heterocyclic Compound and Application thereof

The present invention claims the priority of the PCT/CN2021/141878 filed on December 28, 2021, the contents of which are incorporated herein by its entirety.

Field of invention

The present invention relates to a nitrogen-containing heterocyclic compound and an application thereof.

Prior arts

Mutations in the RAS oncogene are the most common activating mutation in human cancer, occurring in 30%of human tumors (Nat. Rev. Drug Discovery 2014, 13, 828-851) . Although the RAS gene family comprise three isoforms (KRAS, HRAS, and NRAS) , 85%of RAS-driven cancers are caused by mutations in the KRAS isoform (J. Cell Sci. 2016, 129, 1287-1292) , with mutations occurring most frequently in solid tumors such as lung adenocarcinoma, pancreatic ductal carcinoma, and colorectal carcinoma. Among KRAS mutant tumors, 80%of all oncogenic mutations occur within codon 12, with the most common mutations being p. G12D (41%) , p. G12V (28%) , and p. G12C (14%) (Cancer Res. 2012, 72, 2457-2467) . Consequently, inhibition of the activated RAS function has been shown to lead not only to reversal of the transformed phenotypes but also to cell death and tumor regression.

Compounds that inhibit RAS are still highly desirable and under deep investigation. Recently a lot of progress has been made in this area, such as SOS inhibitors, as well as the covalent G12C inhibitors. However, G12V and G12D inhibitors are attracting more and more attention.

Content of the present invention

The present invention relates to a nitrogen-containing heterocyclic compound and an application thereof. The nitrogen-containing heterocyclic compound of the present invention has better inhibitory activity to KRAS-G12D.

The present invention provides a nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof or a solvate thereof;

wherein,

X ¹ is C-R ^X1 or N; R ^X1 is hydrogen or halogen;

X ³ is C-H;

R ¹ is C ₆-C ₁₄ aryl, 5 to 14 membered heteroaryl, C ₆-C ₁₄ aryl substituted with one or more R ^1-1 or 5 to 14 membered heteroaryl substituted with one or more R ^1-2; in the 5 to 14 membered heteroaryl (the “5 to 14 membered heteroaryl” means the “5 to 14 membered heteroaryl” or the corresponding part in “5 to 14 membered heteroaryl substituted with one or more R ^1-2” , the other parts of the invention are similar to this) , the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^1-1 and R ^1-2 is independently halogen, cyano, hydroxy, C ₁-C ₄ alkyl, -S-C ₁-C ₃ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₁-C ₃ haloalkyl, -O-C ₁-C ₃ haloalkyl, C ₁-C ₃ alkoxy, -N (R ^N1) ₂ or C ₃-C ₆ cycloalkyl, wherein the C ₃-C ₆ cycloalkyl is optionally substituted with halogen or C ₁-C ₃ alkyl;

R ² is hydrogen, halogen or C ₁-C ₃ alkyl;

L ¹ is single bond, C ₁-C ₄ alkylene, -O-or -N (R ^N1) -;

R ³ is 3 to 12 membered heterocycloalkyl, 3 to 12 membered heterocycloalkyl substituted with one or more R ^3-1-1, or -L ²-R ^3-1;

L ² is -O-, -N (methyl) -, C ₁-C ₄ alkylene or C ₁-C ₄ alkylene substituted with one or more R ^L2; each of R ^L2 is independently hydroxy or C ₁-C ₄ hydroxyalkyl;

R ^3-1 is C ₃-C ₁₂ cycloalkyl, 3 to 12 membered heterocycloalkyl, C ₆-C ₁₄ aryl, 5 to 14 membered heteroaryl, -N (R ^N1) ₂, C ₃-C ₁₂ cycloalkyl substituted with one or more R ^3-1-1, 3 to 12 membered heterocycloalkyl substituted with one or more R ^3-1-2, C ₆-C ₁₄ aryl substituted with one or more R ^3-1-3 or 5 to 14 membered heteroaryl substituted with one or more R ^3-1-4; in the 3 to 12 membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 5 to 14 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; n is independently 0, 1, 2, 3 or 4;

each of R ^3-1-1, R ^3-1-2, R ^3-1-3 and R ^3-1-4 is halogen, cyano, oxo, C ₁-C ₄ alkyl or -N (R ^N1) ₂;

R ⁶ is -CN;

R ⁴ is C ₃-C ₇ cycloalkyl, C ₃-C ₇ cycloalkenyl, 3 to 12 membered nitrogen-containing heterocycloalkyl, 3 to 12 membered nitrogen-containing heterocycloalkenyl, C ₃-C ₆ cycloalkyl substituted with one or more R ^4-1, C ₃-C ₇ cycloalkenyl substituted with one or more R ^4-2, 3 to 12 membered nitrogen-containing heterocycloalkyl substituted with one or more R ^4-3 or 3 to 12 membered nitrogen-containing heterocycloalkenyl substituted with one or more R ^4-4; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^4-1, R ^4-2, R ^4-3 and R ^4-4 is independently oxo, hydroxy, cyano, halogen, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, C ₁-C ₃ cyanoalkyl, C ₃-C ₆ cycloalkyl, C ₁-C ₃ alkoxy or -N (R ^N1) ₂;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl.

In certain embodiments, the nitrogen-containing heterocyclic compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof having the following definition (hereinafter referred to as In certain embodiments) :

R ¹ is C ₆-C ₁₄ aryl, 5 to 14 membered heteroaryl, C ₆-C ₁₄ aryl substituted with one or more R ^1-1 or 5 to 14 membered heteroaryl substituted with one or more R ^1-2; in the 5 to 14 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^1-1 and R ^1-2 is independently halogen, hydroxy, cyano, C ₂-C ₄ alkynyl or C ₁-C ₃ alkoxy.

In certain embodiments, R ¹ is C ₆-C ₁₄ aryl, 5 to 14 membered heteroaryl, C ₆-C ₁₄ aryl substituted with one or more R ^1-1 or 5 to 14 membered heteroaryl substituted with one or more R ^1-2; in the 5 to 14 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^1-1 and R ^1-2 is independently halogen, cyano, hydroxy, C ₁-C ₄ alkyl, C ₂-C ₄ alkynyl, C ₁-C ₃ haloalkyl or C ₃-C ₆ cycloalkyl.

In certain embodiments, R ² is hydrogen or halogen.

In certain embodiments, R ² is halogen.

In certain embodiments, L ¹ is C ₁-C ₄ alkylene, -N (methyl) -or -O-.

In certain embodiments, L ¹ is C ₁-C ₄ alkylene or -O-.

In certain embodiments, L ¹ is -O-.

In certain embodiments, R ³ is 3 to 12 membered heterocycloalkyl, 3 to 12 membered heterocycloalkyl substituted with one or more R ^3-1-1, or -L ²-R ^3-1;

each of R ^3-1-1, R ^3-1-2, R ^3-1-3 and R ^3-1-4 is halogen, cyano, C ₁-C ₄ alkyl or -N (R ^N1) ₂.

L ² is C ₁-C ₄ alkylene or C ₁-C ₄ alkylene substituted with one or more R ^L2; each of R ^L2 is independently hydroxy or C ₁-C ₄ hydroxyalkyl;

each of R ^3-1-1, R ^3-1-2, R ^3-1-3 and R ^3-1-4 is halogen, cyano, oxo, C ₁-C ₄ alkyl or -N (R ^N1) ₂.

In certain embodiments, R ³ is -L ²-R ^3-1;

L ² is -O-, -N (methyl) -or C ₁-C ₄ alkylene;

R ^3-1 is C ₃-C ₁₂ cycloalkyl, 3 to 12 membered heterocycloalkyl, C ₃-C ₁₂ cycloalkyl substituted with one or more R ^3-1-1 or 3 to 12 membered heterocycloalkyl substituted with one or more R ^3-1-2; in the 3 to 12 membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^3-1-1 and R ^3-1-2 is independently halogen or oxo.

In certain embodiments, R ³ is -L ²-R ^3-1;

L ² is -O-, -N (methyl) -or C ₁-C ₄ alkylene;

each of R ^3-1-1 and R ^3-1-2 is independently halogen.

In certain embodiments, R ³ is -L ²-R ^3-1;

L ² is C ₁-C ₄ alkylene;

each of R ^3-1-1 and R ^3-1-2 is independently halogen or oxo.

In certain embodiments, R ³ is -L ²-R ^3-1;

L ² is C ₁-C ₄ alkylene;

each of R ^3-1-1 and R ^3-1-2 is independently halogen.

In certain embodiments, R ⁴ is 3 to 12 membered nitrogen-containing heterocycloalkyl, 3 to 12 membered nitrogen-containing heterocycloalkyl substituted with one or more R ^4-3; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^4-3 is independently C ₁-C ₃ cyanoalkyl or -N (R ^N1) ₂;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl.

In certain embodiments, R ⁴ is C ₄-C ₇ cycloalkyl substituted with one R ^4-1; R ^4-1 is -N (R ^N1) ₂; each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl.

In certain embodiments, in R ⁴, C ₃-C ₇ cycloalkyl, C ₃-C ₇ cycloalkenyl, 3 to 12 membered nitrogen-containing heterocycloalkyl and 3 to 12 membered nitrogen-containing heterocycloalkenyl are bridged rings.

In certain embodiments, R ⁴ meets the following conditions:

wherein, Z ¹ is independently CH, C or N;

e is independently 0, 1, 2, 3 or 4;

R ^Z1 is independently oxo, hydroxy, halogen, cyano, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, C ₁-C ₃ cyanoalkyl, C ₁-C ₃ hydroxyalkyl, C ₃-C ₆ cycloalkyl, -N (R ^N1) ₂, -CO ₂R ^N1, -CO ₂N (R ^N1) ₂ or a 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments, “NH” on ring is not connected with R ^Z1.

In certain embodiments, R ⁴ is

wherein, Z ¹ is independently CH, C or N;

ring A is 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

ring B is C ₃-C ₇ cycloalkyl, C ₃-C ₇ cycloalkenyl, 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

e is independently 0, 1, 2, 3 or 4;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments, R ⁴ is connected to

by a carbon atom or a nitrogen atom;

R ⁴ is 3 to 12 membered nitrogen-containing heterocycloalkyl, 3 to 12 membered nitrogen-containing heterocycloalkenyl; 3 to 12 membered nitrogen-containing heterocycloalkyl substituted with one or more R ^4-3 or 3 to 12 membered nitrogen-containing heterocycloalkenyl substituted with one or more R ^4-4;

in R ⁴, 3 to 12 membered nitrogen-containing heterocycloalkyl has “NH” , the “NH” is not connected with R ^4-3;

in R ⁴, 3 to 12 membered nitrogen-containing heterocycloalkenyl has “NH” , the “NH” is not connected with R ^4-4.

In certain embodiments, R ⁴ is connected to

by a carbon atom or a nitrogen atom;

R ⁴ is C ₃-C ₆ cycloalkyl substituted with one or more R ^4-1, C ₃-C ₇ cycloalkenyl substituted with one or more R ^4-2, 3 to 12 membered nitrogen-containing heterocycloalkyl substituted with one or more R ^4-3 or 3 to 12 membered nitrogen-containing heterocycloalkenyl substituted with one or more R ^4-4;

one of R ^4-1 is NH ₂ or N (methyl) ; one of R ^4-2 is NH ₂ or N (methyl) ; one of R ^4-3 is NH ₂ or N (methyl) ; one of R ^4-3 is NH ₂ or N (methyl) .

In certain embodiments:

X ¹ is C-R ^X1 or N; R ^X1 is hydrogen or halogen;

X ³ is C-H;

each of R ^1-1 and R ^1-2 is independently halogen, cyano, hydroxy, C ₂-C ₄ alkynyl or C ₁-C ₃ alkoxy;

R ² is halogen;

L ¹ is C ₁-C ₄ alkylene, -N (methyl) -or -O-;

R ³ is -L ²-R ^3-1;

L ² is -O-, -N (methyl) -or C ₁-C ₄ alkylene;

each of R ^3-1-1 and R ^3-1-2 is independently halogen or oxo;

R ⁶ is -CN;

R ⁴ is 3 to 12 membered nitrogen-containing heterocycloalkyl, 3 to 12 membered nitrogen-containing heterocycloalkyl substituted with one or more R ^4-3; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^4-3 is independently C ₁-C ₃ cyanoalkyl or -N (R ^N1) ₂;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl.

In certain embodiments:

X ¹ is C-H;

X ³ is C-H;

each of R ^1-1 and R ^1-2 is independently halogen, cyano, hydroxy, C ₁-C ₄ alkyl, C ₂-C ₄ alkynyl, C ₁-C ₃ haloalkyl or C ₃-C ₆ cycloalkyl;

R ² is halogen;

L ¹ is -O-;

R ³ is -L ²-R ^3-1;

L ² is C ₁-C ₄ alkylene;

R ^3-1 is 3 to 12 membered heterocycloalkyl or 3 to 12 membered heterocycloalkyl substituted with one or more R ^3-1-2; in the 3 to 12 membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^3-1-2 is independently halogen or C ₁-C ₄ alkyl;

R ⁶ is -CN;

R ⁴ is 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkyl substituted with one or more R ^4-3; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^4-3 is independently C ₁-C ₃ alkyl or -N (R ^N1) ₂;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl.

In certain embodiments, R ² is hydrogen or halogen;

R ⁴ is connected to

by a carbon atom or a nitrogen atom.

In certain embodiments:

is

wherein, n is 1, 2, 3 or 4, each of R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C ₄ alkyl;

R ⁴ is connected to

by a carbon atom or a nitrogen atom.

In certain embodiments:

is

wherein, m is 1, 2, 3 or 4, each of R ^3-1-2 is independently oxo, halogen or cyano;

each of R ^4-1, R ^4-2, R ^4-3 and R ^4-4 is independently oxo, halogen or cyano;

R ⁴ is connected to

by a carbon atom or a nitrogen atom.

In certain embodiments:

is

wherein, R ⁴ is connected to

by a carbon atom or a nitrogen atom.

In certain embodiments:

is

wherein, R ⁴ is connected to

by a carbon atom or a nitrogen atom.

In certain embodiments:

is

wherein, p is 0, 1, 2 or 3, q is 0, 1, 2 or 3;

R ⁴ is connected to

by a carbon atom or a nitrogen atom.

In certain embodiments:

is

wherein,

R ⁴ is C ₄-C ₇ cycloalkyl substituted with one R ^4-1; R ^4-1 is -N (R ^N1) ₂; each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ⁴ is connected to

by a carbon atom or a nitrogen atom.

In certain embodiments:

is

wherein, Z ¹ is independently CH, C or N;

e is independently 0, 1, 2, 3 or 4;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments:

is

wherein, Z ¹ is independently CH, C or N;

e is independently 0, 1, 2, 3 or 4;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments:

is

Z ¹ is independently CH, C or N;

e is independently 0, 1, 2, 3 or 4;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments:

is

Z ¹ is independently CH, C or N;

e is independently 0, 1, 2, 3 or 4;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments, in R ^X1, the halogen is F, Cl, Br or I.

In certain embodiments, in R ^X1, the halogen is F.

In certain embodiments, in R ¹, the C ₆-C ₁₄ aryl is C ₆-C ₁₀.

In certain embodiments, in R ¹, the C ₆-C ₁₄ aryl is monocyclic ring or bicyclic ring.

In certain embodiments, in R ¹, each ring of C ₆-C ₁₄ aryl is aromatic.

In certain embodiments, in R ¹, the C ₆-C ₁₄ aryl is phenyl, 1-naphthyl, 2-naphthyl or

In certain embodiments, in R ¹, the 5 to 14 membered heteroaryl is 9 to 10 membered heteroaryl.

In certain embodiments, in R ¹, the 5 to 14 membered heteroaryl is monocyclic ring or bicyclic ring.

In certain embodiments, in R ¹, each ring of 5 to 14 membered heteroaryl is aromatic.

In certain embodiments, in R ¹, the number of heteroatoms in 5 to 14 membered heteroaryl is 1 or 2.

In certain embodiments, in R ¹, the heteroatoms in 5 to 14 membered heteroaryl is N.

In certain embodiments, in R ¹, the 5 to 14 membered heteroaryl is pyridyl, indolyl, quinolyl, isoquinolinyl, benzothienyl or benzothiazolyl.

In certain embodiments, in R ¹, the 5 to 14 membered heteroaryl is

In certain embodiments, in R ^1-1 and R ^1-2, the halogen is F, Cl, Br or I.

In certain embodiments, in R ^1-1 and R ^1-2, the halogen is F or Cl.

In certain embodiments, in R ^1-1 and R ^1-2, the halogen is F.

In certain embodiments, in R ^1-1 and R ^1-2, the C ₁-C ₄ alkyl is methyl, ethyl, propyl or isopropyl.

In certain embodiments, in R ^1-1 and R ^1-2, the C ₁-C ₄ alkyl is methyl or ethyl.

In certain embodiments, in R ^1-1 and R ^1-2, the C ₁-C ₄ alkyl is methyl.

In certain embodiments, in R ^1-1 and R ^1-2, the -S-C ₁-C ₃ alkyl is -S-methyl, -S-ethyl, -S-propyl or -S-isopropyl.

In certain embodiments, in R ^1-1 and R ^1-2, the -S-C ₁-C ₃ alkyl is -S-methyl.

In certain embodiments, in R ^1-1 and R ^1-2, the C ₂-C ₄ alkynyl is ethynyl.

In certain embodiments, in R ^1-1 and R ^1-2, the C ₁-C ₃ haloalkyl is -CF ₃.

In certain embodiments, in R ^1-1 and R ^1-2, the -O-C ₁-C ₃ haloalkyl is -O-CF ₃.

In certain embodiments, in R ^1-1 and R ^1-2, the C ₁-C ₃ alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy.

In certain embodiments, in R ^1-1 and R ^1-2, the C ₁-C ₃ alkoxy is methoxy.

In certain embodiments, in R ^1-1 and R ^1-2, the C ₃-C ₆ cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl.

In certain embodiments, in R ^1-1 and R ^1-2, the C ₃-C ₆ cycloalkyl is cyclopropyl.

In certain embodiments, R ¹ is

In certain embodiments, R ¹ is

In certain embodiments, in R ², the halogen is F, Cl, Br or I.

In certain embodiments, in R ², the halogen is F.

In certain embodiments, in R ², the C ₁-C ₃ alkyl is methyl, ethyl, propyl or isopropyl.

In certain embodiments, in L ¹, the C ₁-C ₄ alkylene is methylene, ethylene, propylene or butylene.

In certain embodiments, in R ³, the 3 to 12 membered heterocycloalkyl is 3 to 6 membered heterocycloalkyl.

In certain embodiments, in R ³, the 3 to 12 membered heterocycloalkyl is 4 membered heterocycloalkyl.

In certain embodiments, in R ³, the 3 to 12 membered heterocycloalkyl is monocyclic ring or bicyclic ring.

In certain embodiments, in R ³, the 3 to 12 membered heterocycloalkyl is monocyclic ring, spirocyclic ring or bridged ring.

In certain embodiments, in R ³, the number of heteroatoms in 3 to 12 membered heterocycloalkyl is 1 or 2.

In certain embodiments, in R ³, the heteroatoms in 3 to 12 membered heterocycloalkyl is N.

In certain embodiments, in R ³, the 3 to 12 membered heterocycloalkyl is azetidinyl.

In certain embodiments, in R ³, the 3 to 12 membered heterocycloalkyl is 1-azetidinyl.

In certain embodiments, in L ², the C ₁-C ₄ alkylene is methylene, ethylene, propylene or butylene.

In certain embodiments, R ^3-1 is connected to L ² by a carbon atom or a nitrogen atom.

In certain embodiments, in R ^3-1, the C ₃-C ₁₂ cycloalkyl is C ₃-C ₈ cycloalkyl.

In certain embodiments, in R ^3-1, the C ₃-C ₁₂ cycloalkyl is C ₅-C ₈ cycloalkyl.

In certain embodiments, in R ^3-1, the C ₃-C ₁₂ cycloalkyl is monocyclic ring or bicyclic ring.

In certain embodiments, in R ^3-1, the C ₃-C ₁₂ cycloalkyl is monocyclic ring, spirocyclic ring or bridged ring.

In certain embodiments, in R ^3-1, the C ₃-C ₁₂ cycloalkyl is cyclopentyl or octahydropentalen.

In certain embodiments, in R ^3-1, the 3 to 12 membered heterocycloalkyl is 5 to 10 membered heterocycloalkyl.

In certain embodiments, in R ^3-1, the 3 to 12 membered heterocycloalkyl is 5 to 8 membered heterocycloalkyl.

In certain embodiments, in R ^3-1, the 3 to 12 membered heterocycloalkyl is monocyclic ring or bicyclic ring.

In certain embodiments, in R ^3-1, the 3 to 12 membered heterocycloalkyl is monocyclic ring, spirocyclic ring or bridged ring.

In certain embodiments, in R ^3-1, the number of heteroatoms in 3 to 12 membered heterocycloalkyl is 1 or 2.

In certain embodiments, in R ^3-1, the heteroatoms in 3 to 12 membered heterocycloalkyl is N.

In certain embodiments, in R ^3-1, the 3 to 12 membered heterocycloalkyl is 5 to 6 membered monocyclic heterocycloalkyl.

In certain embodiments, in R ^3-1, the 3 to 12 membered heterocycloalkyl heterocycloalkyl is 7 to 10 membered bridged heterocycloalkyl.

In certain embodiments, in R ^3-1, the 3 to 12 membered heterocycloalkyl is tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl or tetrahydro-1H-pyrrolizin-7a (5H) -yl) .

In certain embodiments, in R ^3-1, the 3 to 12 membered heterocycloalkyl is tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl or

In certain embodiments, in R ^3-1, the 5 to 14 membered heteroaryl is 5 to 6 membered heteroaryl.

In certain embodiments, in R ^3-1, the 5 to 14 membered heteroaryl is monocyclic ring or bicyclic ring.

In certain embodiments, in R ^3-1, the number of heteroatoms in 5 to 14 membered heteroaryl is 1 or 2.

In certain embodiments, in R ^3-1, the heteroatoms in 5 to 14 membered heteroaryl is N.

In certain embodiments, in R ^3-1, the 5 to 14 membered heteroaryl is pyrazolyl.

In certain embodiments, in R ^3-1-1, R ^3-1-2, R ^3-1-3 and R ^3-1-4, the halogen is F, Cl, Br or I.

In certain embodiments, in R ^3-1-1, R ^3-1-2, R ^3-1-3 and R ^3-1-4, the halogen is F.

In certain embodiments, in R ^3-1-1, R ^3-1-2, R ^3-1-3 and R ^3-1-4, the C ₁-C ₄ alkyl is methyl, ethyl, propyl or isopropyl.

In certain embodiments, in R ^3-1-1, R ^3-1-2, R ^3-1-3 and R ^3-1-4, the C ₁-C ₄ alkyl is methyl.

In certain embodiments, -L ¹-R ³ is

In certain embodiments, -L ¹-R ³ is

In certain embodiments, R ⁴ is connected to

by a carbon atom or a nitrogen atom.

In certain embodiments, in R ⁴, the C ₃-C ₇ cycloalkyl is monocyclic ring or bicyclic ring.

In certain embodiments, in R ⁴, the C ₃-C ₇ cycloalkyl is monocyclic ring, spirocyclic ring or bridged ring.

In certain embodiments, in R ⁴, the C ₃-C ₇ cycloalkyl is

cyclopropyl, cyclopentyl or cyclohexyl.

In certain embodiments, in R ⁴, the C ₃-C ₇ cycloalkyl is cyclopentyl.

In certain embodiments, in R ⁴, the C ₃-C ₇ cycloalkyl substituted with one or more R ^4-1 is

In certain embodiments, in R ⁴, the C ₃-C ₇ cycloalkenyl is monocyclic ring or bicyclic ring.

In certain embodiments, in R ⁴, the C ₃-C ₇ cycloalkenyl is monocyclic ring, spirocyclic ring or bridged ring.

In certain embodiments, in R ⁴, the C ₃-C ₇ cycloalkenyl is cyclopropenyl, cyclopentenyl or cyclohexenyl.

In certain embodiments, in R ⁴, the C ₃-C ₇ cycloalkenyl is cyclopentenyl.

In certain embodiments, in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkyl is 5 to 9 membered nitrogen-containing heterocycloalkyl.

In certain embodiments, in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkyl is 5 to 8 membered nitrogen-containing heterocycloalkyl.

In certain embodiments, in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkyl is monocyclic ring or bicyclic ring.

In certain embodiments, in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkyl is monocyclic ring, spirocyclic ring or bridged ring.

In certain embodiments, in R ⁴, the number of heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkyl is 1 or 2.

In certain embodiments, in R ⁴, the heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkyl is N.

In certain embodiments, in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkyl is 5 to 7 membered nitrogen-containing monocyclic heterocycloalkyl.

In certain embodiments, in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkyl is 6 to 8 membered nitrogen-containing bridged heterocycloalkyl.

In certain embodiments, in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkyl is 7 to 9 membered nitrogen-containing spirocyclic heterocycloalkyl.

In certain embodiments, in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkyl is tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,

In certain embodiments, in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is 5 to 9 membered nitrogen-containing heterocycloalkenyl.

In certain embodiments, in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is 5 to 6 membered nitrogen-containing heterocycloalkenyl.

In certain embodiments, in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is monocyclic ring or bicyclic ring.

In certain embodiments, in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is monocyclic ring, spirocyclic ring or bridged ring.

In certain embodiments, in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is monocyclic ring.

In certain embodiments, in R ⁴, the number of heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkenyl is 1 or 2.

In certain embodiments, in R ⁴, the number of heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkenyl is 1.

In certain embodiments, in R ⁴, the heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkenyl is N.

In certain embodiments, in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is 5 to 7 membered nitrogen-containing monocyclic heterocycloalkenyl.

In certain embodiments, in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is 6 to 8 membered nitrogen-containing bridged heterocycloalkenyl.

In certain embodiments, in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is 7 to 9 membered nitrogen-containing spirocyclic heterocycloalkenyl.

In certain embodiments, in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is

In certain embodiments, in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the halogen is F, Cl, Br or I.

In certain embodiments, in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the halogen is F.

In certain embodiments, in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₁-C ₃ alkyl is methyl, ethyl, propyl or isopropyl.

In certain embodiments, in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₁-C ₃ alkyl is methyl.

In certain embodiments, in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₁-C ₃ cyanoalkyl is cyano methyl.

In certain embodimts, in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₃-C ₆ cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl.

In certain embodimts, in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₃-C ₆ cycloalkyl is cyclopropyl.

In certain embodiments, in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₁-C ₃ alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy.

In certain embodiments, in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₁-C ₃ alkoxy is methoxy.

In certain embodiments, in R ^N1, the C ₁-C ₃ alkyl is methyl, ethyl, propyl or isopropyl.

In certain embodiments, in R ^N1, the C ₁-C ₃ alkyl is methyl.

In certain embodiments, “NH” on ring A is not connected with R ^Z1.

In certain embodiments, in ring B, the C ₃-C ₇ cycloalkyl is monocyclic ring or bicyclic ring.

In certain embodiments, in ring B, the C ₃-C ₇ cycloalkyl is monocyclic ring, spirocyclic ring or bridged ring.

In certain embodiments, in ring B, the C ₃-C ₇ cycloalkyl is

cyclopropyl, cyclopentyl or cyclohexyl.

In certain embodiments, in ring B, the C ₃-C ₇ cycloalkyl is cyclopentyl.

In certain embodiments, in ring B, the C ₃-C ₇ cycloalkenyl is monocyclic ring or bicyclic ring.

In certain embodiments, in ring B, the C ₃-C ₇ cycloalkenyl is monocyclic ring, spirocyclic ring or bridged ring.

In certain embodiments, in ring B, the C ₃-C ₇ cycloalkenyl is cyclopropenyl, cyclopentenyl or cyclohexenyl.

In certain embodiments, in ring B, the C ₃-C ₇ cycloalkenyl is cyclopentenyl.

In certain embodiments, in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkyl is 5 to 9 membered nitrogen-containing heterocycloalkyl.

In certain embodiments, in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkyl is 5 to 8 membered nitrogen-containing heterocycloalkyl.

In certain embodiments, in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkyl is monocyclic ring or bicyclic ring.

In certain embodiments, in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkyl is monocyclic ring, spirocyclic ring or bridged ring.

In certain embodiments, in ring A and ring B, the number of heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkyl is 1 or 2.

In certain embodiments, in ring A and ring B, the heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkyl is N.

In certain embodiments, in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkyl is 5 to 7 membered nitrogen-containing monocyclic heterocycloalkyl.

In certain embodiments, in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkyl is 6 to 8 membered nitrogen-containing bridged heterocycloalkyl.

In certain embodiments, in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkyl is 7 to 9 membered nitrogen-containing spirocyclic heterocycloalkyl.

In certain embodiments, in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkyl is tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,

In certain embodiments, in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is 5 to 9 membered nitrogen-containing heterocycloalkenyl.

In certain embodiments, in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is 5 to 6 membered nitrogen-containing heterocycloalkenyl.

In certain embodiments, in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is monocyclic ring or bicyclic ring.

In certain embodiments, in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is monocyclic ring, spirocyclic ring or bridged ring.

In certain embodiments, in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is monocyclic ring.

In certain embodiments, in ring A and ring B, the number of heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkenyl is 1 or 2.

In certain embodiments, in ring A and ring B, the number of heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkenyl is 1.

In certain embodiments, in ring A and ring B, the heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkenyl is N.

In certain embodiments, in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is 5 to 7 membered nitrogen-containing monocyclic heterocycloalkenyl.

In certain embodiments, in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is 6 to 8 membered nitrogen-containing bridged heterocycloalkenyl.

In certain embodiments, in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is 7 to 9 membered nitrogen-containing spirocyclic heterocycloalkenyl.

In certain embodiments, in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is

In certain embodiments, in R ^Z1, the halogen is F, Cl, Br or I.

In certain embodiments, in R ^Z1, the halogen is F.

In certain embodiments, in R ^Z1, the C ₁-C ₃ alkyl is methyl, ethyl, propyl or isopropyl.

In certain embodiments, in R ^Z1, the C ₁-C ₃ alkyl is methyl.

In certain embodiments, in R ^Z1, the C ₁-C ₃ cyanoalkyl is cyano methyl.

In certain embodimts, in R ^Z1, the C ₃-C ₆ cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl.

In certain embodimts, in R ^Z1, the C ₃-C ₆ cycloalkyl is cyclopropyl.

In certain embodiments, in R ^Z1, the C ₁-C ₃ alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy.

In certain embodiments, in R ^Z1, the C ₁-C ₃ alkoxy is methoxy.

In certain embodiments, in R ^N1, the C ₁-C ₃ alkyl is methyl.

In certain embodiments, R ⁴ is

In certain embodiments, R ⁴ is

In certain embodiments, “more” in the above definitions is independently 2, 3, 4 or 5.

In certain embodiments, the nitrogen-containing heterocyclic compound represented by formula I is selected from the group consisting of:

The present invention also provides a pharmaceutical composition, comprising substance X and pharmaceutically acceptable excipient, the substance X is the nitrogen-containing heterocyclic compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof.

The present invention also provides a use of substance X in the manufacture of KRAS-G12D inhibitors;

the substance X is the nitrogen-containing heterocyclic compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof.

In certain embodiments, the KRAS-G12D inhibitors is used in vitro or in vivo.

The present invention also provides a use of substance X in the manufacture of a medicament;

the substance X is the nitrogen-containing heterocyclic compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof;

the medicament is used to treat or prevent KRAS-G12D associated disease or disorder.

In certain embodiments, the KRAS-G12D associated disease or disorder is cancer.

the medicament is used to treat or prevent cancer.

The present invention also provides a method for preventing and/or treating KRAS-G12D associated disease or disorder, which comprises administering to a subject in need thereof a therapeutically effective amount of substance X;

In certain embodiments, the KRAS-G12D associated disease or disorder is cancer.

The present invention also provides a method for preventing and/or treating cancer, which comprises administering to a subject in need thereof a therapeutically effective amount of substance X;

The present invention provides a nitrogen-containing heterocyclic compound represented by formula II, a pharmaceutically acceptable salt thereof or a solvate thereof;

wherein,

X ³ is CH-R ^X3, NH, C-R ^X3 or N; R ^X3 is independently hydrogen or halogen;

is single bond or double bond;

R ⁵ is hydrogen, halogen or C ₁-C ₃ alkyl;

L ¹ is single bond, C ₁-C ₄ alkylene, -O-or -N (R ^N1) -;

X ² is C-R ^X2 or N; R ^X2 is hydrogen, cyano or halogen;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl.

In certain embodiments, the nitrogen-containing heterocyclic compound represented by formula II, the pharmaceutically acceptable salt thereof or the solvate thereof having the following definition (hereinafter referred to as In certain embodiments) :

In certain embodiments, X ³ is CH ₂.

In certain embodiments,

is single bond.

In certain embodiments, R ⁵ is methyl or ethyl.

In certain embodiments, R ⁵ is hydrogen.

each of R ^1-1 and R ^1-2 is independently halogen, cyano, hydroxy, C ₂-C ₄ alkynyl or C ₁-C ₃ alkoxy.

In certain embodiments, L ¹ is C ₁-C ₄ alkylene, -N (methyl) -or -O-.

In certain embodiments, L ¹ is C ₁-C ₄ alkylene or -O-.

In certain embodiments, L ¹ is -O-.

In certain embodiments, R ³ is -L ²-R ^3-1;

L ² is -O-, -N (methyl) -or C ₁-C ₄ alkylene;

each of R ^3-1-1 and R ^3-1-2is independently halogen or oxo.

In certain embodiments, R ³ is -L ²-R ^3-1;

L ² is -O-, -N (methyl) -or C ₁-C ₄ alkylene;

each of R ^3-1-1 and R ^3-1-2is independently halogen.

In certain embodiments, R ³ is -L ²-R ^3-1;

L ² is C ₁-C ₄ alkylene;

each of R ^3-1-1 and R ^3-1-2is independently halogen or oxo.

In certain embodiments, R ³ is -L ²-R ^3-1;

L ² is C ₁-C ₄ alkylene;

each of R ^3-1-1 and R ^3-1-2is independently halogen.

In certain embodiments, X ² is N.

each of R ^4-3 is independently C ₁-C ₃ cyanoalkyl or -N (R ^N1) ₂;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl.

In certain embodiments, R ⁴ meets the following conditions:

wherein, Z ¹ is independently CH, C or N;

e is independently 0, 1, 2, 3 or 4;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments, “NH” on ring is not connected with R ^Z1.

In certain embodiments, R ⁴ is

wherein, Z ¹ is independently CH, C or N;

e is independently 0, 1, 2, 3 or 4;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments, R ⁴ is connected to

by a carbon atom or a nitrogen atom;

In certain embodiments, R ⁴ is connected to

by a carbon atom or a nitrogen atom;

In certain embodiments, R ⁴ is connected to

by a carbon atom or a nitrogen atom.

In certain embodiments:

X ³ is CH ₂;

is single bond;

R ⁵ is hydrogen;

L ¹ is C ₁-C ₄ alkylene, -N (methyl) -or -O-;

R ³ is -L ²-R ^3-1;

L ² is -O-, -N (methyl) -or C ₁-C ₄ alkylene;

each of R ^3-1-1 and R ^3-1-2is independently halogen or oxo;

X ² is N;

each of R ^4-3 is independently C ₁-C ₃ cyanoalkyl or -N (R ^N1) ₂;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl.

In certain embodiments:

X ³ is CH-R ^X3; R ^X3 is halogen;

is single bond;

R ⁵ is hydrogen;

each of R ^1-1 and R ^1-2 is independently halogen, cyano, hydroxy, C ₁-C ₄ alkyl, C ₂-C ₄ alkynyl, C ₁-C ₃ haloalkyl, C ₁-C ₃ alkoxy or C ₃-C ₆ cycloalkyl;

L ¹ is -O-;

R ³ is -L ²-R ^3-1;

L ² is C ₁-C ₄ alkylene;

R ^3-1 is 3 to 12 membered heterocycloalkyl substituted with one or more R ^3-1-2, C ₆-C ₁₄ aryl substituted with one or more R ^3-1-3 or 5 to 14 membered heteroaryl substituted with one or more R ^3-1-4; in the 3 to 12 membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 5 to 14 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; n is independently 0, 1, 2, 3 or 4;

each of R ^3-1-2 and R ^3-1-4 is halogen or C ₁-C ₄ alkyl;

X ² is N;

each of R ^4-3 is independently hydroxy, C ₁-C ₃ alkyl or C ₁-C ₃ cyanoalkyl.

In certain embodiments:

is

R ⁴ is connected to

by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl.

In certain embodiments:

is

R ⁴ is connected to

by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl.

In certain embodiments:

is

R ⁴ is connected to

by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl.

In certain embodiments:

is

R ⁴ is connected to

by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl.

In certain embodiments:

is

R ⁴ is connected to

by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl.

In certain embodiments:

is

R ⁴ is connected to

by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl.

In certain embodiments:

is

R ⁴ is connected to

by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl.

In certain embodiments:

is

R ⁴ is connected to

by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl.

In certain embodiments:

is

R ⁴ is connected to

by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl.

In certain embodiments:

is

R ⁴ is connected to

by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl.

In certain embodiments:

is

wherein, R ⁴ is connected to

by a carbon atom or a nitrogen atom.

In certain embodiments:

is

wherein, p is 0, 1, 2 or 3, q is 0, 1, 2 or 3;

R ⁴ is connected to

by a carbon atom or a nitrogen atom.

In certain embodiments:

is

wherein,

R ⁴ is connected to

by a carbon atom or a nitrogen atom.

In certain embodiments:

is

wherein, p is 0, 1, 2 or 3, q is 0, 1, 2 or 3;

R ⁴ is connected to

by a carbon atom or a nitrogen atom.

In certain embodiments:

is

wherein,

R ⁴ is connected to

by a carbon atom or a nitrogen atom.

In certain embodiments:

is

wherein, Z ¹ is independently CH, C or N;

e is independently 0, 1, 2, 3 or 4;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments:

is

wherein, Z ¹ is independently CH, C or N;

e is independently 0, 1, 2, 3 or 4;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments:

is

wherein,

is single bond;

n is 1, 2, 3 or 4, each of R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C ₄ alkyl;

Z ¹ is independently CH, C or N;

e is independently 0, 1, 2, 3 or 4;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments:

is

Z ¹ is independently CH, C or N;

e is independently 0, 1, 2, 3 or 4;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments, in R ^X3, the halogen is F, Cl, Br or I.

In certain embodiments, in R ^X3, the halogen is F.

In certain embodiments, in R ⁵, the halogen is F, Cl, Br or I.

In certain embodiments, in R ⁵, the halogen is F.

In certain embodiments, in R ⁵, the C ₁-C ₃ alkyl is methyl, ethyl, propyl or isopropyl.

In certain embodiments, in R ⁵, the C ₁-C ₃ alkyl is methyl or ethyl.

In certain embodiments, in R ⁵, the C ₁-C ₃ alkyl is methyl.

In certain embodiments, in R ¹, the C ₆-C ₁₄ aryl is C ₆-C ₁₀.

In certain embodiments, in R ¹, each ring of C ₆-C ₁₄ aryl is aromatic.

In certain embodiments, in R ¹, the 5 to 14 membered heteroaryl is

In certain embodiments, in R ^1-1 and R ^1-2, the halogen is F, Cl, Br or I.

In certain embodiments, in R ^1-1 and R ^1-2, the halogen is F or Cl.

In certain embodiments, in R ^1-1 and R ^1-2, the halogen is F.

In certain embodiments, in R ^1-1 and R ^1-2, the C ₁-C ₄ alkyl is methyl.

In certain embodiments, R ¹ is

In certain embodiments, R ¹ is

In certain embodiments, -L ¹-R ³ is

In certain embodiments, -L ¹-R ³ is

In certain embodiments, in R ^X2, the halogen is F, Cl, Br or I.

In certain embodiments, in R ^X2, the halogen is F.

In certain embodiments, R ⁴ is connected to

by a carbon atom or a nitrogen atom.

In certain embodiments, in R ⁴, the C ₃-C ₇ cycloalkyl is

cyclopropyl, cyclopentyl or cyclohexyl.

In certain embodiments, in R ⁴, the C ₃-C ₇ cycloalkyl is cyclopentyl.

In certain embodiments, in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the halogen is F.

In certain embodiments, in R ^N1, the C ₁-C ₃ alkyl is methyl.

In certain embodiments, “NH” on ring A is not connected with R ^Z1.

In certain embodiments, in ring B, the C ₃-C ₇ cycloalkyl is

cyclopropyl, cyclopentyl or cyclohexyl.

In certain embodiments, in ring B, the C ₃-C ₇ cycloalkyl is cyclopentyl.

In certain embodiments, in R ^Z1, the halogen is F, Cl, Br or I.

In certain embodiments, in R ^Z1, the halogen is F.

In certain embodiments, in R ^Z1, the C ₁-C ₃ alkyl is methyl.

In certain embodiments, in R ^Z1, the C ₁-C ₃ cyanoalkyl is cyano methyl.

In certain embodimts, in R ^Z1, the C ₃-C ₆ cycloalkyl is cyclopropyl.

In certain embodiments, in R ^Z1, the C ₁-C ₃ alkoxy is methoxy.

In certain embodiments, in R ^N1, the C ₁-C ₃ alkyl is methyl.

In certain embodiments, R ⁴ is

In certain embodiments, R ⁴ is

In certain embodiments, the nitrogen-containing heterocyclic compound represented by formula II is selected from the group consisting of:

The present invention also provides a pharmaceutical composition, comprising substance Y and pharmaceutically acceptable excipient, the substance Y is the nitrogen-containing heterocyclic compound represented by formula II, the pharmaceutically acceptable salt thereof or the solvate thereof.

The present invention also provides a use of substance Y in the manufacture of KRAS-G12D inhibitors;

the substance Y is the nitrogen-containing heterocyclic compound represented by formula II, the pharmaceutically acceptable salt thereof or the solvate thereof.

In certain embodiments, the KRAS-G12D inhibitors is used in vitro or in vivo.

The present invention also provides a use of substance Y in the manufacture of a medicament;

the substance Y is the nitrogen-containing heterocyclic compound represented by formula II, the pharmaceutically acceptable salt thereof or the solvate thereof;

In certain embodiments, the KRAS-G12D associated disease or disorder is cancer.

the medicament is used to treat or prevent cancer.

The present invention also provides a method for preventing and/or treating KRAS-G12D associated disease or disorder, which comprises administering to a subject in need thereof a therapeutically effective amount of substance Y;

In certain embodiments, the KRAS-G12D associated disease or disorder is cancer.

The present invention also provides a method for preventing and/or treating cancer, which comprises administering to a subject in need thereof a therapeutically effective amount of substance Y;

The following terms used herein are intended to have the following meanings. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

The term "pharmaceutically acceptable salt" refers to salts or zwitterionic forms of Compound. Salts of Compound can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with a suitable acid. The pharmaceutically acceptable salts of Compound can be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Non-limiting examples of salts of compound include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzene sulfonate, and p-toluenesulfonate salts. In addition, available amino groups present in the compound can be quatemized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.

The term "solvate" refers to a combination, physical association and/or solvation of a compound of the present invention with a solvent molecule, e.g., a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present invention is about 2: 1, about 1: 1 or about 1: 2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, “solvate” encompasses both solution-phase and isolatable solvates. Compounds can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, ethanol, and the like. In some embodiment, the solvate is a hydrate. A “hydrate” relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. A typical, non-limiting, process of preparing a solvate would involve dissolving a compound in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20℃ to about 25℃, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in a crystal of the solvate.

The use of the terms "a" , "an" , "the" , and similar referents in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated.

The terms "C ₁-C ₆ alkyl" , “C ₁-C ₄ alkyl” and “C ₁-C ₃ alkyl” refer to straight and branched chain aliphatic groups having from 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, respectively. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

The terms “C ₁-C ₃ haloalkyl” and “C ₁-C ₄ haloalkyl” refer to a C ₁-C ₃ alkyl chain or C ₁-C ₄ alkyl chain, respectively, as defined herein in which one or more hydrogen has been replaced by a halogen. Examples include trifluoromethyl, difluoromethyl and fluoromethyl.

The term "C ₁-C ₄ alkylene" refers to a C ₁-C ₄ alkyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Exemplary alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.

The terms “C ₁-C ₃ alkoxy” and “C ₁-C ₄ alkoxy” refer to-OC ₁-C ₃ alkyl and -OC ₁-C ₄ alkyl, respectively, wherein the alkyl portion is as defined herein above.

The terms “C ₁-C ₃ hydroxyalkyl” and “C ₁-C ₄ hydroxyalkyl” refer to-C ₁-C ₃ alkylene-OH and -C ₁-C ₄ alkylene-OH, respectively.

The term “C ₂-C ₄ hydroxyalkynyl” refers to -C ₂-C ₄ alkynylene-OH.

The term "cycloalkyl" refers to saturated cyclic hydrocarbon groups having 3 to 12 carbons, for example 3 to 8 carbons, and as a further example 3 to 6 carbons. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term “cycloalkyl” may be a monocyclic, a bicyclic, a spirocyclic or a bridged ring system, such as bicyclo [1.1.1] pentanyl.

The term "cycloalkenyl" refers to partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, for example 3 to 8 carbons, and as a further example 3 to 6 carbons. The term “cycloalkenyl” does not comprise aromatic rings. The term “cycloalkenyl” may be a monocyclic, a bicyclic, a spirocyclic or a bridged ring system.

The term "heterocycloalkyl" is a ring structure having from 3 to 12 atoms, for example 4 to 8 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S, the remainder of the ring atoms being carbon. The heterocycloalkyl may be a monocyclic, a bicyclic, a spirocyclic or a bridged ring system. The heterocycloalkyl is saturated. Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl.

The term "heterocycloalkenyl" group is a ring structure having from 3 to 12 atoms, for example 4 to 8 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S, the remainder of the ring atoms being carbon. The heterocycloalkenyl may be a monocyclic, a bicyclic, a spirocyclic or a bridged ring system. The heterocycloalkenyl is partially unsaturated, and does not comprise aromatic rings..

The term "aryl" group is a C ₆-C ₁₄ aromatic moiety comprising one to three aromatic rings. As one embodiment, the aryl group is a C ₆-C ₁₀ aryl group. Examples of aryl groups include, without limitation, phenyl, naphthyl, anthracenyl and fluorenyl. “Aryl” also refers to bicyclic or tricyclic ring systems in which one or two rings, respectively, of said aryl ring system may be saturated or partially saturated.

The term "heteroaryl" refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 n electrons shared in a cyclic array; and having, in addition to carbon atoms, one to four heteroatoms selected from the group consisting of N, O, and S. Examples of heteroaryl groups include benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl. “Heteroaryl” also refers to bicyclic ring systems or tricyclic ring systems in which one or two rings, respectively, of said aryl ring system may be saturated or partially saturated.

The term “KRAS-G12D inhibitor” refers to capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRAS-G12D.

The term “KRAS-G12D associated disease or disorder” refers to diseases or disorders associated with or mediated by or having a KRAS-G12D. A non-limiting example of a KRAS-G12D associated disease or disorder is a KRAS-G12D associated cancer.

The term "prevent" refers to a method of preventing the onset of a disease or condition and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, "prevent" also includes delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease. The terms "preventing" may include "prophylactic treatment, " which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition

The term "treat" refers to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a compound to a subject in need of such treatment. The treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.

The term “subject” refers to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates or humans. The preferred subjects are humans.

The term "therapeutically effective amount" of a substance refers to an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease or disorder and its complications. The amount that is effective for a particular therapeutic purpose will depend on the severity of the disease or injury as well as on the weight and general state of the subject. It will be understood that determination of an appropriate dosage may be achieved, using routine experimentation, by constructing a matrix of values and testing different points in the matrix, all of which is within the ordinary skills of a trained physician or clinical scientist.

Each of the above preferred conditions can be combined in any way to obtain a better Embodiment of the invention without violating the common knowledge in the art.

The positive progressive effect of the present disclosure is that the nitrogen-containing heterocyclic compounds of the present invention has better inhibitory activity to KRAS.

Detailed description of the preferred embodiment

The following examples further illustrate the present invention, but the present invention is not limited thereto.

Abbreviations

Certain abbreviations are listed below.

Methanol: MeOH

Tetrahedronfuran: THF

Dichloromethane: DCM

Petroleum ether: PE

Ethyl acetate: EtOAc (EA)

Acetonitrile: ACN

Isopropanol: IPA

Triethylamine: TEA

Trifluoroacetic acid: TFA

Sodium hydroxide: NaOH

Nitrogen: N ₂

Thin-Layer Chromatography: TLC

High Performance Liquid Chromatography: HPLC

N,N-Diisopropylethylamine: DIPEA

N,N-Dimethylformamide: DMF

4-Methylbenzene-1-sulfonyl chloride: TsCl

1,1'-Bis (diphenylphosphino) ferrocene: dppf

Triisopropylsilyl: TIPS

Pinacolborate: BPin

Room temperature: RT

Hours: hrs

Representative methods of prep-HPLC: (flow rate and gradient may change)

Exemplary methods for prep-HPLC are provided below.

Method A: NH ₄HCO ₃:

(Column: Gilson2-Xbrige C18 19*150mm, 5μm; mobile phase: CH ₃CN in water (0.1%NH ₄HCO ₃) from 20%to 60%, flow rate: 15ml/min) .

Method B: TFA:

(Column: waters-Xbrige C1810*190mm, 5μm; mobile phase: CH ₃CN in water (0.1%TFA) from 15%to 40%, flow rate: 15ml/min)

Method C: HCOOH:

(Column: waters-Xbrige C1810*190mm, 5μm; mobile phase: CH ₃CN in water (0.1%formic acid) from 15%to 40%, flow rate: 15ml/min)

Method D: NH ₄HCO ₃:

(Column: Waters-Xbrige C18 19*150mm, 5μm; mobile phase: CH ₃CN in water (0.1%NH ₄HCO ₃) from 40%to 60%, flow rate: 20ml/min) .

Method E: NH ₄HCO ₃:

(Column: Waters-Xbrige C18 19*150mm, 5μm; mobile phase: CH ₃CN in water (0.1%NH ₄HCO ₃) from 20%to 45%, flow rate: 20ml/min) .

Method F: HCOOH:

(Column: waters-SunFire C18 19*150mm, 5μm; mobile phase: CH ₃CN in water (0.1%formic acid) from 20%to 60%, flow rate: 20ml/min) .

Representative methods of analytical-HPLC

Method 1: Analysis was performed on an Agilent 1200series HPLC-6120MS. UHPLC Long Gradient Equivalent 5%to 95%acetonitrile (containing 0.02%NH ₄OAc) in water run time of 6.5 minutes with a flow rate of 1.5 mL/min. A Waters Xbridged C18 column (18.5 micron, 4.6*50 mm) was used at a temperature of 40 ℃.

Method 2: Analysis was performed on an Agilent 1200series HPLC-6120MS. UHPLC Long Gradient Equivalent 5%to 95%acetonitrile (containing0.1%trifluoroacetic acid) in water run time of 6.5 minutes with a flow rate of 1.5 mL/min. A Waters Xbridged C18 column (18.5 micron, 4.6*50 mm) was used at a temperature of 40 ℃.

Method 3: Analysis was performed on an Agilent 1260series HPLC-6120MS. UHPLC Long Gradient Equivalent 5%to 95%acetonitrile (containing 0.02%NH4OAc) in water run time of 6.5 minutes with a flow rate of 2 mL/min. A diamonsil Plus C18 column (18.5 micron, 4.6*30 mm) was used at a temperature of 40 ℃.

Method 4: Analysis was performed on an Agilent 1260 series HPLC-6125MS. HPLC Long Gradient Equivalent 5%to 95%acetonitrile in water (0.1%formic acid) run time of 6.0 minutes with a flow rate of 0.9 mL/min. Agilent InfinityLab Poroshell 120 SB-C18 column (2.7 micron, 3.0*100 mm) was used at a temperature of 30 ℃.

Method 5: Analysis was performed on an Agilent 1260 series HPLC-6125MS. HPLC Long Gradient Equivalent 50%to 100%acetonitrile in water (0.1%formic acid) run time of 8.0 minutes with a flow rate of 0.9 mL/min. Agilent InfinityLab Poroshell 120 SB-C18 column (2.7 micron, 3.0*100 mm) was used at a temperature of 30 ℃.

Example 1

Step 1. 7-Bromo-8-fluoro-1H-benzo [d] [1, 3] oxazine-2, 4-dione (1b)

To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (10 g, 42.73 mmol) in THF (80 mL) was added bis (trichloromethyl) carbonate (14 g, 47.18 mmol) at RT. The reaction was stirred at 75 ℃ for 4 hours. After cooling to RT, the reaction mixture was filtered and filtered cake was dried to give compound 1b (9.5 g, 86%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ 12.16 (s, 1H) , 7.72 -7.69 (m, 1H) , 7.57 -7.52 (m, 1H) .

Step 2. 7-Bromo-8-fluoro-2, 4-dihydroxyquinoline-3-carbonitrile (1c)

A solution of 1b (10 g, 38.5 mmol) , TEA (15.6 g, 153.8 mmol) and ethyl 2-cyanoacetate (6.54 g, 57.8 mmol) in DMF (80 mL) was stirred at 90 ℃ for 16 hours. After cooling to RT, the reaction mixture was diluted with H ₂O (30 mL) and acidified with 1N HCl to adjust pH = 2. The formed solid was filtered and the filtered cake was dried to give compound 1c (10.9 g, yield given) as a white solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.12 (s, 1H) , 7.69 -7.66 (m, 1H) , 7.39 -7.34 (m, 1H) .

Step 3. 7-Bromo-2, 4-dichloro-8-fluoroquinoline-3-carbonitrile (1d)

A mixture of 1c (2.5 g, 8.83 mmol) in POCl ₃ (48 mL) and ACN (8 mL) was stirred at 90 ℃ for 3 hours. The reaction mixture was cooled and concentrated. The residue was poured into DCM/Et ₃N (40 mL/4 mL) . The solution was washed with ice water (30mL) and extracted with EtOAc (20 mL *2) . The separated organic layer was dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography (PE/EA = 10/1) to give 1d (770 mg, 27%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.17 (dd, J = 6.0, 8.8 Hz, 1H) , 8.08 (dd, J = 1.2, 8.8 Hz, 1H) .

Step 4. Tert-butyl 3- (7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carbo xylate (1e)

A mixture of 1d (500 mg, 1.56 mmol) , tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (398 mg, 1.88 mmol) and TEA (316 mg, 3.13 mmol) in DCM (10 mL) was stirred at RT for 3 hours. The suspension was filtered and the filtered cake was dried to afford compound 1e (440 mg, 57%yield) as a white solid. LCMS (Method 3) : t _R = 1.83 min, m/z (M+H) ⁺= 495.2.

Step 5. Tert-butyl 3- (7-bromo-3-cyano-8-fluoro-2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1f)

A mixture of 1e (150 mg, 0.30 mmol) , ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methanol (96 mg, 0.60 mmol) and anhydrous K ₂CO ₃ (83 mg, 0.60 mmol) in DMF (1 mL) was stirred at 80 ℃ for 5 hours. After cooling to RT, the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL*2) . The combined organic phases were concentrated to dryness to afford compound 1f (78 mg, 0.12 mmol) as a yellow solid. LCMS (Method 3) : t _R = 1.88 min, m/z (M+H) ⁺= 618.7.

Step 6. Tert-butyl 3- (3-cyano-8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carbo xylate (1g)

A mixture of 1f (78 mg, 0.13 mmol) , 1i (36 mg, 0.13 mmol) , K ₂CO ₃ (35 mg, 0.25 mmol) and Pd (dppf) Cl ₂ (18.6 mg, 0.025 mmol) in 1, 4-Dioxane/H ₂O (1 mL/0.2 mL) was stirred at 100 ℃ for 4 hours under N ₂ atmosphere. The reaction mixture was cooled and concentrated. The residue was purified by column chromatography on silica gel (DCM/MeOH = 10/1) to give 1g (42 mg, 48%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ 10.23 (s, 1H) , 8.02 (d, J = 8.8 Hz, 1H) , 7.66 (d, J = 8.0 Hz, 1H) , 7.57 -7.54 (m, 1H) , 7.49 -7.46 (m, 1H) , 7.41 -7.39 (m, 1H) , 7.33 (t, J = 2.0 Hz, 1H) , 7.03 -6.96 (m, 1H) , 5.37-5.24 (m, 1H) , 4.28-4.22 (m, 3H) , 4.15 -4.13 (m, 1H) , 3.85 -3.65 (m, 2H) , 3.49 -3.46 (m, 2H) , 3.19 -3.02 (m, 3H) , 2.84 -2.82 (m, 1H) , 2.33 -2.20 (m, 3H) , 2.11 -1.98 (m, 3H) , 1.46 (s, 9H) , 1.23 -1.17 (m, 4H) .

Step 7.5-Fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-2-ol (1i)

A mixture of 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (764 mg, 3.01 mmol) , 4-bromo-5-fluoro-naphthalen-2-ol (290 mg, 1.20 mmol, WO2021/41671, Paragraph 01040) , KOAc (230 mg, 2.35 mmol) and Pd (dppf) Cl _2. DCM (88 mg, 0.11 mmol) in dry dioxane (2 mL) was stirred at 90 ℃ for 2 hours under N ₂ atmosphere. The reaction mixture was cooled and concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE/EA = 1/5) to give compound 1i (210 mg, 61%yield) as yellow oil. LCMS (Method 3) : t _R = 1.67min, m/z (M-H) ^-=287.2.

Step 8. 4- (3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinoline-3-carbonitrile (1)

A mixture of 1g (40 mg, 0.057 mmol) in TFA/DCM (0.1mL/0.3 mL) was stirred at RT for 2 hours. The reaction mixture was concentrated and the residue was purified by prep-HPLC (Method C) to give compound 1 (10 mg, 27%yield) as a white solid. LCMS (Method 2) : t _R =2.77 min, m/z (M+H) ⁺=600.3. ¹H NMR (400 MHz, DMSO-d ₆) : δ 10.28 (brs, 1H) , 7.96 (d, J =8.0 Hz, 1H) , 7.66 (d, J = 8.0 Hz, 1H) , 7.42-7.37 (m, 1H) , 7.45-7.43 (m, 1H) , 7.34-7.33 (m, 1H) , 7.03-7.02 (m, 1H) , 6.98-6.96 (m, 1H) , 5.37-5.24 (m, 1H) , 4.24-4.22 (m, 1H) , 4.16-4.14 (m, 1H) , 3.85-3.80 (m, 4H) , 3.60-3.56 (m, 2H) , 3.37-3.20 (m, 3H) , 3.10-3.01 (m, 1H) , 2.24-2.22 (m, 2H) , 2.10-1.80 (m, 8H) .

Example 2

Step 1. (S) -tert-butyl (1- (7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl) pyrrolidin-3-yl) carbamate (2a)

Compound 2a (248 mg, 67%yield) was synthesized by utilizing similar preparative procedure of compound 1 with 1d (250 mg, 0.78 mmol) and (S) -tert-butyl pyrrolidin-3-ylcarbamate (175 mg, 0.94 mmol) as starting materials. ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.05 (d, J = 8.8 Hz, 1H) , 7.72 -7.68 (m, 1H) , 7.29 (s, 1H) , 4.31 -4.27 (m, 1H) , 4.23 -4.41 (m, 3H) , 3.79 -3.77 (m, 1H) , 2.16 -2.12 (m, 1H) , 1.99 -1.97 (m, 1H) , 1.45 (s, 9H) .

Step 2. Tert-butyl ( (S) -1- (7-bromo-3-cyano-8-fluoro-2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl)methoxy) quinolin-4-yl) pyrrolidin-3-yl) carbamate_ (2b)

To a solution of tert-butyl compound 2a (75 mg, 0.16mmol) and ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methanol (51 mg, 0.32mmol) in THF (1 mL) was added LiHMDS (0.64 mL, 0.64 mmol, 1 M in THF) at 0 ℃. The mixture was stirred at 50 ℃ for 2 days and 70 ℃ for 4 hours. The reaction mixture was concentrated and the residue was purified by prep-TLC (PE/EA=2/1) to give compound 2b (15 mg, 16%yield) as a yellow solid. LCMS (Method 3) : t _R = 1.78 min, m/z (M+H) ⁺= 592.3.

Step 3. Tert-butyl ( (S) -1- (3-cyano-8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinolin-4yl) pyrrolidin-3-yl) carbamate (2c)

Compound 2c (10 mg crude) was synthesized by utilizing similar preparative procedure of compound 1 with 2b (15 mg, 0.025 mmol) and 1i (8 mg, 0.025 mmol) as starting materials. LCMS (Method 3) : t _R = 1.52 min, m/z (M+H) ⁺= 674.3.

Step 4. 4- ( (S) -3-aminopyrrolidin-1-yl) -8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7a S) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinoline-3-carbonitrile (2)

Compound 2 (3.2 mg, 40%yield) was synthesized by utilizing similar preparative procedure of compound 1 with 2c (10 mg, 0.015 mmol) as starting material. LCMS (Method 2) : t _R = 3.35 min, m/z (M+H) ⁺= 574.3. ¹H NMR (400 MHz, CD ₃OD) : δ 8.15 (d, J = 8.8 Hz, 1H) , 7.60 (d, J = 8.8 Hz, 1H) , 7.43-7.37 (m, 2H) , 7.29 (d, J = 2.0 Hz, 1H) , 7.03 (d, J = 2.0 Hz, 1H) , 6.93-6.87 (m, 1H) , 5.58-5.45 (m, 1H) , 4.67-4.42 (m, 5H) , 4.35-4.30 (m, 1H) , 4.13-4.10 (m, 1H) , 4.00-3.85 (m, 1H) , 3.75-3.68 (m, 3H) , 2.53-2.45 (m, 2H) , 2.36-2.11 (m, 6H) .

Example 3

Step 1. Tert-butyl 4- (7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl) piperazine-1-carboxylate (3a)

Compound 3a (275 mg, 75%yield) was synthesized by utilizing similar preparative procedure of compound 1 with 1d (250 mg, 0.78 mmol) and tert-butyl piperazine-1-carboxylate (186 mg, 1.0 mmol) as starting materials. ¹H NMR (400 MHz, DMSO-d ₆) : δ 7.52 -7.44 (m, 2H) , 3.72 -3.69 (m, 4H) , 3.67 -3.60 (m, 4H) , 1.44 (s, 9H) .

Step 2. Tert-butyl 4- (7-bromo-3-cyano-8-fluoro-2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinolin-4-yl) piperazine-1-carboxylate (3b)

Compound 3b (68 mg, 45%yield) was synthesized by utilizing similar preparative procedure of compound 1 with 3a (120 mg, 0.25 mmol) and ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methanol (61 mg, 0.38 mmol) as starting materials. LCMS (Method 3) : t _R = 1.53 min, m/z (M+H) ⁺= 592.2.

Step 3. Tert-butyl 4- (3-cyano-8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorohexahyd ro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinolin-4-yl) piperazine-1-carboxylate (3c)

Compound 3c (73 mg crude) was synthesized by utilizing similar preparative procedure of compound 1 with 3b (65 mg, 0.11 mmol) and 1i (32 mg, 0.11 mmol) as starting materials. LCMS (Method 3) : t _R = 1.83 min, m/z (M+H) ⁺= 674.4.

Step 4. 8-Fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (piperazin-1-yl) quinoline-3-carbonitrile (3)

Compound 3 (15.7 mg, 25%yield) was synthesized by utilizing similar preparative procedure of compound 1 with 3c (73 mg crude, 0.11 mmol) as starting material. LCMS (Method 2) : t _R = 2.53 min, m/z (M+H) ⁺= 574.2. ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.19 (s, 1H) , 7.83 (d, J = 8.4 Hz, 1H) , 7.66 (d, J = 8.0 Hz, 1H) , 7.48 -7.40 (m, 2H) , 7.33 (d, J = 2.0 Hz, 1H) , 7.02 (d, J = 2.0 Hz, 1H) , 6.99-6.96 (m, 1H) , 5.38 (s, 0.5H) , 5.24 (s, 0.5H) , 4.23 (d, J = 2.4 Hz, 1H) , 4.21 (d, J = 2.4 Hz, 1H) , 3.68 -3.66 (m, 4H) , 3.24 -3.20 (m, 1H) , 3.10 -3.05 (m, 7H) , 2.85 -2.83 (m, 1H) , 2.11 -2.01 (m, 3H) , 1.85 -1.82 (m, 3H) .

Example 4

Step 1. (S) -tert-butyl (5- (7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl) -5-azaspirocyclic [2.4] heptan-7-yl) carbamate (4a)

Compound 4a (116 mg, 42%yield) was synthesized by utilizing similar preparative procedure of compound 1 with 1d (177 mg, 0.55 mmol) and (S) -tert-butyl 5-azaspirocyclic [2.4] heptan-7-ylcarbamate (123 mg, 0.56 mmol) as starting materials. ¹LCMS (Method 3) : t _R = 1.42 min, m/z (M+H) ⁺= 495.2.

Step 2. Tert-butyl ( (S) -5- (7-bromo-3-cyano-8-fluoro-2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinolin-4-yl) -5-azaspirocyclic [2.4] heptan-7-yl) carbamate (4b)

To a mixture of 4a (120 mg, 0.24mmol) and ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methanol (58 mg, 0.36 mmol) in DMF (1 mL) was added NaH (19 mg, 0.48mmol, 60%in mineral oil) at 0 ℃ for 30 mins. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL *3) . The combined organic phases were dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM/MeOH = 10/1) to give the compound 4b (25 mg, 17%yield) as a white solid. LCMS (Method 3) : t _R = 1.50 min, m/z (M+H) ⁺= 618.9.

Step 3. Tert-butyl ( (S) -5- (3-cyano-8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinolin-4-yl) -5-azaspirocyclic [2.4] heptan-7-yl) carbamate (4c)

Compound 4c (10 mg crude) was synthesized by utilizing similar preparative procedure of compound 1 with 4b (25 mg, 0.04 mmol) and 1i (13 mg, 0.04 mmol) as starting materials. LCMS (Method 3) : t _R = 0.29 min, m/z (M+H) ⁺= 700.7.

Step 4. 4- ( (S) -7-amino-5-azaspirocyclic [2.4] heptan-5-yl) -8-fluoro-7- (8-fluoro-3-hydroxynaphthale n-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinoline-3-carbonitrile (4)

Compound 4 (6.0 mg, 70%yield) was synthesized by utilizing similar preparative procedure of compound 1 with 4c (10 mg, 0.014 mmol) as starting material. LCMS (Method 2) : t _R = 3.44 min, m/z (M+H) ⁺= 600.3. ¹H NMR (400 MHz, CD ₃OD) : δ 8.45 (br s, 1H) , 8.13 (d, J = 8.8 Hz, 1H) , 7.56 (d, J = 8.0 Hz, 1H) , 7.41 -7.35 (m, 2H) , 7.27 (d, J = 2.0 Hz, 1H) , 7.00 (d, J = 2.0 Hz, 1H) , 6.86 (dd, J = 8.0, 13.2 Hz, 1H) , 5.58 (s, 0.5H) , 5.45 (s, 0.5H) , 4.84 -4.25 (m, 3H) , 4.23 (d, J = 11.6 Hz, 1H) , 3.93 -3.72 (m, 4H) , 3.65 -3.60 (m, 1H) , 3.36-3.30 (m, 1H) , 2.56 -2.46 (m, 2H) , 2.38 -2.11 (m, 4H) , 1.37 -1.36 (m, 1H) , 1.14 -1.11 (m, 1H) , 0.96 -0.88 (m, 3H) .

Example 5

Step 1. (S) -tert-butyl (5- (7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl) -5-azaspirocyclic [2.4] heptan-7-yl) carbamate (5a)

Compound 5a (116 mg, 42%yield) was synthesized by utilizing similar preparative procedure of compound 1 with 1d (177 mg, 0.55 mmol) and (S) -tert-butyl 5-azaspirocyclic [2.4] heptan-7-ylcarbamate (123 mg, 0.56 mmol) as starting materials. ¹LCMS (Method 3) : t _R = 1.42 min, m/z (M+H) ⁺= 495.2.

Step 2. Tert-butyl ( (R) -5- (7-bromo-3-cyano-8-fluoro-2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinolin-4-yl) -5-azaspirocyclic [2.4] heptan-7-yl) carbamate (5b)

Compound 5b (60 mg, 65%yield) was synthesized by utilizing similar preparative procedure to the second step of compound 4 with 5a (75 mg, 0.15 mmol) and ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methanol (36 mg, 0.23 mmol) as starting materials. LCMS (Method 3) : t _R = 0.50 min, m/z (M+H) ⁺= 618.7.

Step 3. Tert-butyl ( (R) -5- (3-cyano-8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorohexa hydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinolin-4-yl) -5-azaspirocyclic [2.4] heptan-7-yl) carbamate (5c)

Compound 5c (25 mg crude) was synthesized by utilizing similar preparative procedure of compound 1 with 5b (50 mg, 0.08 mmol) and 1i (23 mg, 0.08 mmol) as starting materials. LCMS (Method 3) : t _R = 0.82 min, m/z (M+H) ⁺= 700.7.

Step 4. 4- ( (R) -7-amino-5-azaspirocyclic [2.4] heptan-5-yl) -8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinoline-3-carbonitrile (5)

Compound 5 (7.3 mg, 34%yield) was synthesized by utilizing similar preparative procedure of compound 1 with 5c (25 mg, 0.036 mmol) as starting materials. LCMS (Method 2) : t _R = 3.67 min, m/z (M+H) ⁺= 600.3. ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.15 (s, 1H) , 8.10 (dd, J = 4.4, 8.8 Hz, 1H) , 7.65 (d, J = 8.0 Hz, 1H) , 7.43 -7.41 (m, 1H) , 7.33 -7.32 (m, 2H) , 7.01 (d, J = 2.0 Hz, 1H) , 7.00 -6.96 (m, 1H) , 5.38 (s, 0.5H) , 5.24 (s, 0.5H) , 4.62 -4.53 (m, 2H) , 4.19 -4.12 (m, 2H) , 4.04 -4.01 (m, 1H) , 3.89 -3.83 (m, 1H) , 3.26 -3.23 (m, 1H) , 3.16 -3.03 (m, 3H) , 2.51 -2.49 (m, 1H) , 2.49 -1.96 (m, 3H) , 1.90 -1.83 (m, 3H) , 1.00 -0.98 (m, 1H) , 0.82 -0.78 (m, 3H) .

Example 6

Step 1. Tert-butyl 4- (3-cyano-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinolin-4-yl) piperazine-1-carboxylate (6b)

Compound 6b (160 mg, crude) was synthesized by utilizing similar preparative procedure to the sixth step of compound 1 with 3b (120 mg, 0.20 mmol) and ( (2-fluoro-6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (114 mg, 0.22 mmol) as starting materials. LCMS (Method 3) : t _R = 1.24 min, m/z (M+H) ⁺= 898.

Step 2. 7- (8-Ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (piperazin-1-yl) quinoline-3-carbonitrile (6c)

To a solution of 6b (140 mg, crude) in dioxane (1 mL) was added HCl/dioxane (1 mL, 6M) at 0 ℃. After stirring at RT for 1 hour, the reaction mixture was filtered and the filter cake was purified by reverse chromatography to afford compound 6c (75 mg crude) . LCMS (Method 3) : t _R = 1.17 min, m/z (M+H) ⁺= 754.7.

Step 3. 7- (8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (piperazin-1-yl) quinoline-3-carbonitrile (6)

A mixture of 6c (75 mg crude) in DMF (1 mL) was added CsF (79 mg, 0.52 mmol) at 0 ℃. After stirring for 5 hours at RT, the reaction mixture was concentrated and the residue was purified by prep-HPLC (method C) to give compound 6 (13 mg, 22%yield) as a green solid. LCMS (Method 1) : t _R = 3.49 min, m/z (M+H) ⁺= 598.2. ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.23 (s, 2H) , 7.97 (dd, J = 8.8, 1.2 Hz, 1H) , 7.78 -7.76 (m, 1H) , 7.49 -7.43 (m, 1H) , 7.37 (s, 2H) , 7.09 (s, 1H) , 5.39 (s, 0.5H) , 5.25 (s, 0.5H) , 4.24 -4.20 (m, 1H) , 4.15 -4.13 (m, 1H) , 3.84 -3.83 (m, 1H) , 3.74 -3.55 (m, 4H) , 3.24 -3.12 (m, 7H) , 2.86 -2.84 (m, 1H) , 2.20 -2.02 (m, 3H) , 1.85 -1.79 (m, 3H) .

Example 7

Step 1. Tert-butyl 2, 4-dichloro-8-oxo-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate (7b)

To a stirred mixture of NaIO ₄ (10.00 g, 46.31 mmol) in H ₂O (85 mL) and ethyl acetate (85 mL) was added tert-butyl 2, 4-dichloro-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate 7a (5.00 g, 16.44 mmol) . After 5 mins, RuCl ₃ (0.51 g, 2.46 mmol) was added and the final reaction mixture was capped loosely stirring at room temperature for 5 hrs. Then the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (30 mL *2) . The combined organic layers were washed with brine (40 mL) , dried over anhydrous Na ₂SO ₄ and filtered. The filtrate was concentrated under vacuum to give the residue, which was purified by silica gel column (PE/EA from 20: 1 to 6: 1) to give the title compound 7b (3.42 g, 65%yield) as light yellow solid. LC-MS (Method 4) : t _R = 3.62 min, m/z (M-Boc+H) ⁺= 218.0.

Step 2. Tert-butyl 4- (4- ( (benzyloxy) carbonyl) piperazin-1-yl) -2-chloro-8-oxo-5, 8-dihydropyrido [3, 4-d] pyrimi dine-7 (6H) -carboxylate (7c)

To a solution of tert-butyl 2, 4-dichloro-8-oxo-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate 7b (1.00 g, 3.14 mmol) and benzyl piperazine-1-carboxylate (0.70 g, 3.18 mmol) in DCM (10 mL) was added DIPEA (0.8 mL, 4.59 mmol) , and the resulting reaction solution was stirred at room temperature for 1hr. Then the reaction solution was washed with water (10 mL) and brine (10 mL) . The organic layer was separated and concentrated under vacuum to give a residue, which was recrystallized from ethyl acetate to give pure product 7c (1.12 g, 71%yield) as a white solid. LC-MS (Method 4) : t _R = 4.55 min, m/z (M+H) ⁺= 502.3.

Step 3. Benzyl 4- (2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate (7d)

To a stirred solution of ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (250 mg, 1.57 mmol) in THF (11 mL) was added NaH (56 mg, 1.4 mmol, 60%in mineral oil) at room temperature, after stirred for 0.5 hr, tert-butyl 4- (4- ( (benzyloxy) carbonyl) piperazin-1-yl) -2-chloro-8-oxo-5, 8-dihydropyrido [3, 4-d] pyrimidine -7(6H) -carboxylate 7c (245 mg, 0.49 mmol) was added. The resulting mixture was stirred at room temperature for 1hr. Then the reaction solution was quenched with MeOH and filtered. The filtrate was concentrated under vacuum to give a residue, which was purified by prep-HPLC (Method D) to afford 7d (56 mg, 21%yield) as a white solid. LC-MS (Method 4) : t _R = 3.04 min, m/z (M+H) ⁺= 525.3.

Step 4. Benzyl 4- (2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (2-methoxyphenyl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate (7e)

To a stirred solution of benzyl 4- (2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate 7d (56 mg, 0.107 mmol) and 1-iodo-2-methoxybenzene (28 mg, 0.120 mmol) in dioxane (5 mL) was added K ₃PO ₄ (62 mg, 0.292 mmol) , CuI (28 mg, 0.147 mmol) and N ¹, N ²-dimethylethane-1, 2-diamine (13.3 mg 0.151 mmol) sequentially. This resulting mixture was stirred at 110 ℃ under N ₂ for 16 hrs. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated under vacuum to give a residue and it was purified by prep-TLC (DCM/MeOH/NH ₄OH=10/1/0.05) to give 7e (32 mg, 47%yield) as a light yellow solid. LC-MS (Method 4) : t _R = 3.71 min, m/z (M+H) ⁺= 631.4.

Step 5. 2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (2-methoxyphenyl) -4- (piperazin-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one (7)

Benzyl

4- (2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (2-methoxyphenyl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate 7e (32mg, 0.051 mmol) was dissolved in aqueous HCl solution (6N, 1 mL) . The resulting mixture was stirred at 90 ℃ for 1 hr. After cooling to room temperature, the reaction solution was concentrated under vacuum to give a residue, which was purified by prep-HPLC (Method E) to afford the final product 7 (9 mg, 36%yield) as a white solid. LC-MS (Method 4) : t _R = 0.66 min, m/z (M+H) ⁺= 497.4. ¹H NMR (400 MHz, CD ₃OD) : δ 7.41 (t, J = 8.6 Hz, 1H) , 7.33 (dd, J = 8.0 Hz, 2.0 Hz, 1H) , 7.18 (dd, J = 8.4 Hz, 1.2 Hz, 1H) , 7.08 -7.04 (m, 1H) , 5.50 -5.35 (m, 1H) , 4.47 (q, J = 12.4 Hz, 2H) , 3.89 (s, 3H) , 3.81 -3.72 (m, 6H) , 3.69 -3.51 (m, 4H) , 3.31 -3.23 (m, 2H) , 3.16 (t, J = 5.2 Hz, 4H) , 3.11 -3.08 (m, 2H) , 2.49 -2.40 (m, 2H) , 2.24 -2.16 (m, 2H) .

Example 8

Step 1. Tert-butyl 4- (8- ( (benzyloxy) carbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2-chloro-8-oxo-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate (8a)

To a solution of tert-butyl 2, 4-dichloro-8-oxo-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate 7b (645 mg, 2.03 mmol) and benzyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (500 mg, 2.03 mmol) in DCM (3 mL) was added DIPEA (0.2 mL, 1.15 mmol) . And the resulting reaction solution was stirred at room temperature for 1hr. Then the reaction solution was washed with water (3 mL) and brine (3 mL) . The organic layer was separated and concentrated under vacuum to give a residue which was further purified over silica gel column (PE/EA from 20: 1 to 5: 1) to give the title compound 8a (789 mg, 74%yield) as a white solid. LC-MS (Method 4) : t _R = 4.66 min, m/z (M+H) ⁺= 528.3.

Step 2. Benzyl 3- (2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (8b)

Tert-butyl

4- (8- ( (benzyloxy) carbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2-chloro-8-oxo-5, 8-dihydropyri do [3, 4-d] pyrimidine-7 (6H) -carboxylate 8a (20 mg, 0.038 mmol) and ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (12 mg, 0.075 mmol) were dissolved in dioxane (1 mL) followed by the addition of t-BuONa (7.6 mg, 0.079 mmol) in one portion. The resulting mixture was irradiated under microwave at 140 ℃ for 3 hrs. Then the reaction solution was centrifuged to remove the solid. The clear solution was separated and concentrated under reduced pressure to give a residue which was purified by prep-HPLC (Method D) to give 8b (3 mg, 14%yield) as a white solid. LC-MS (Method 4) : t _R = 3.10 min, m/z (M+H) ⁺=551.4.

Step 3. Benzyl 3- (2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (8c)

To a stirred solution of benzyl 3- (2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate 8b (40 mg, 0.073 mmol) , and 1-bromo-8-chloronaphthalene (36 mg, 0.149 mmol) in dioxane (2 mL) was added K ₃PO ₄ (39 mg, 0.184 mmol) , CuI (16 mg, 0.084 mmol) and N ¹, N ²-dimethylethane-1, 2-diamine (12.6 mg 0.143 mmol) sequentially. This resulting mixture was stirred at 110 ℃ under N ₂ for 16 hrs. Then the reaction mixture was cooled down to room temperature and filtered. The filtrate was concentrated under vacuum and the residue was purified by prep-HPLC (Method F) to give 8c (7 mg, 14%yield) as light yellow solid. LC-MS (Method 4) : t _R = 4.38 min, m/z (M+H) ⁺=711.4.

Step 4. 4- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-chloronaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one (8)

Benzyl

3- (2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate 8c (7 mg, 0.010 mmol) was dissolved in aqueous HCl solution (6N, 1 mL) , and the resulting solution was stirred at 90 ℃ for 1 hr. Then the reaction solution was evaporated under vacuum to give a residue, which was purified by prep-HPLC (Method E) to afford the final product 8 (2.5 mg, 44%yield) as a white solid. LC-MS (Method 4) : t _R = 2.47 min, m/z (M+H) ⁺=577.4. ¹H NMR (400 MHz, CD ₃OD) : δ 8.03 (dd, J = 7.6 Hz, 2.0 Hz, 1H) , 7.95 (dd, J = 8.4 Hz, 1.2 Hz, 1H) , 7.66 -7.60 (m, 3H) , 7.46 (t, J = 8.0 Hz, 1H) , 5.32 (d, J = 53.6 Hz, 1H) , 4.36 -4.26 (m, 2H) , 4.20 (d, J = 13.2 Hz, 1H) , 4.09 -3.89 (m, 3H) , 3.72 (s, 2H) , 3.53 -3.35 (m, 4H) , 3.25 -3.08 (m, 4H) , 2.43 -2.28 (m, 2H) , 2.21 -2.15 (m, 1H) , 2.11 -2.04 (m, 2H) , 1.98 -1.85 (m, 5H) .

Example 9

Step 1. Tert-butyl (S) -4- (4- (tert-butoxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2-chloro-8-oxo-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate (9a)

To a solution of tert-butyl 2, 4-dichloro-8-oxo-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate 7b (500 mg, 1.571 mmol) and tert-butyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (397 mg, 1.762 mmol) in DCM (10 mL) was added DIPEA (0.3 mL, 1.72 mmol) , and the resulting reaction solution was stirred at room temperature for 1hr. Then the reaction solution was washed with water (10 mL) and brine (10 mL) . The organic layer was separated and concentrated under vacuum to give a residue which was recrystallized from ethyl acetate to give a pure product 9a (677 mg, 85%yield) as a white solid. LC-MS (Method 4) : t _R = 4.02 min, m/z (M+H) ⁺=507.3.

Step 2. Tert-butyl (S) -2- (cyanomethyl) -4- (2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate (9b)

A mixture of tert-butyl (S) -4- (4- (tert-butoxycarbonyl) -3- (cyanomethyl) piperazin-1-yl) -2-chloro-8-oxo-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate 9a (20 mg, 0.038 mmol) and t-BuONa (8.0 mg, 0.083 mmol) in dioxane (1 mL) was added ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (12.6 mg, 0.079 mmol) , and the resulting mixture was irradiated by microwave at 140 ℃ for 3 hrs. Then the reaction solution was centrifuged to remove the solid, and the clear solution was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Method D) to give 9b (2.5 mg, 12%yield) as a white solid. LC-MS (Method 4) : t _R = 2.61 min, m/z (M+H) ⁺=530.3.

Step 3. Tert-butyl (S) -4- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -2 - (cyanomethyl) piperazine-1-carboxylate (9c)

To a stirred solution of tert-butyl (S) -2- (cyanomethyl) -4- (2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) piperazine-1-carboxylate 9b (25 mg, 0.047 mmol) and 1-bromo-8-chloro-3- (methoxymethoxy) naphthalene (20 mg, 0.066 mmol) in dioxane (2 mL) was added K ₃PO ₄ (25 mg, 0.118 mmol) , CuI (10 mg, 0.052 mmol) and N ¹,N ²-dimethylethane-1, 2-diamine (8.2 mg 0.093 mmol) sequentially. This resulting mixture was stirred at 110 ℃ under N ₂ for 16 hrs. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a residue, which was purified by prep-HPLC (Method F) to give 9c (7 mg, 20%yield) as a light yellow solid. LC-MS (Method 4) : t _R = 3.99 min, m/z (M+H) ⁺=750.3.

Step 4. 2- (4- (7- (8-chloro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrroliz in-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (9)

To a solution of tert-butyl (S) -4- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate 9c (7 mg, 0.009 mmol) in MeOH (1 mL) was added aqueous HCl solution (1N, 0.1 mL) , and the resulting solution was stirred at 65 ℃ for 16 hrs. Then the reaction solution was evaporated under vacuum to give a residue which was purified by prep-HPLC (Method E) to afford the final product 9 (3 mg, 53%yield) as a white solid. LC-MS (Method 4) : t _R = 2.13 min, m/z (M+H) ⁺=606.3. ¹H NMR (400 MHz, CD ₃OD) : δ 7.47 (t, J = 8.8 Hz, 2H) , 7.15-7.21 (m, 4H) , 7.11 (d, J = 2.4 Hz, 1H) , 7.07 (d, J = 2.8 Hz, 1H) , 6.95 (bs, 1H) , 6.87 (bs, 1H) , 5.32 &5.28 (d, J = 54 Hz, 2H) , 4.38 (t, J = 10.8 Hz, 2H) , 4.12 &4.06 (d, J = 11.2 Hz, 2H) , 4.02 (d, J = 12.8 Hz, 1H) , 3.82 (dd, J = 11.6 Hz, 22 Hz, 4H) , 3.60-3.68 (m, 4H) , 3.36-3.42 (m, 4H) , 3.13-3.22 (m, 4H) , 2.86-3.01 (m, 13H) , 2.60-2.75 (m, 6H) , 2.49 (dd, J = 6 Hz, 16.8 Hz, 2H) , 2.39 (dd, J = 6.8 Hz, 16.8 Hz, 2H) , 2.24-2.29 (m, 2H) , 2.07-2.20 (m, 4H) , 1.93-1.97 (m, 4H) .

Example 10

Step 1. Benzyl 3- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (10a)

To a stirred solution of benzyl 3- (2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydr opyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate 8b (31 mg, 0.056 mmol) and 1-bromo-8-chloro-3- (methoxymethoxy) naphthalene (46 mg, 0.152 mmol) in dioxane (2 mL) was added K ₃PO ₄ (33 mg, 0.155 mmol) , CuI (11 mg, 0.058 mmol) and N ¹, N ²-dimethylethane-1, 2-diamine (8.2 mg 0.093 mmol) sequentially. This resulting mixture was stirred at 110 ℃ under N ₂ for 16 hrs. Then the reaction mixture was cooled down to room temperature and filtered. The filtrate was concentrated to dryness under vacuum. The residue was purified by prep-HPLC (Method E) to give 10a (6.4 mg, 15%yield) as a light yellow solid. LC-MS (Method 4) : t _R = 4.27 min, m/z (M+H) ⁺=771.3.

Step 2. 4- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-chloro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8(5H) -one (10)

Benzyl

3- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate 10a (6.4 mg, 0.008 mmol) was dissolved in aqueous HCl solution (4N, 1 mL) . The mixture was stirred at 90 ℃ for 0.5 hr. Then the reaction solution was evaporated under vacuum to give a residue which was purified by prep-HPLC (Method F) to afford the final product 10 (4.2 mg, 85%yield) as a reddish solid. LC-MS (Method 4) : t _R =2.06 min, m/z (M+H) ⁺=593.2. ¹H NMR (400 MHz, CD ₃OD) : δ 8.38 (brs, 1H) , 7.71 (d, J = 7.6 Hz, 1H) , 7.35 -7.18 (m, 4H) , 5.47 (d, J = 51.6 Hz, 1H) , 4.65 (s, 2H) , 4.47 (d, J = 12.8 Hz, 2H) , 4.34 (d, J = 13.6 Hz, 2H) , 4.21 (s, 2H) , 4.08 -3.61 (m, 7H) , 3.35 (m, 2H) , 2.37 -2.01 (m, 10H) .

Example 11

Step 1. Tert-butyl 3- (2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (11b)

To a solution of 2, 4, 7-trichloro-8-fluoropyrido [4, 3-d] pyrimidine (607 mg, 2.40 mmol WO2021/41671, Paragraph 0277) and DIPEA (2.05 g, 15.86 mmol) in DCM (10 mL) was added tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (510 mg, 2.40 mmol) at -40 ℃. After stirring at this temperature for 0.5 hour, the reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL*2) . The combined organic layers were washed with brine (30 mL) , dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE/EA = 3: 1) to give compound 11b (370 mg, 36%yield) as a yellow solid. LCMS (Method 3) : t _R = 1.74 min, m/z (M+H) ⁺= 428.1.

Step 2. Tert-butyl 3- (7-chloro-8-fluoro-2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (11c)

A mixture of compound 11b (300 mg, 0.70 mmol) , ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methanol (223 mg, 1.40 mmol) and DIPEA (271 mg, 2.10 mmol) in dioxane (1 mL) was stirred at 80 ℃ for 6 hrs. The reaction mixture was cooled and concentrated under vacuum. The residue was purified by reverse chromatography with (0-50%ACN/H ₂O with 0.1%TFA) to give compound 11c (240 mg, 62%yield) as a yellow solid. LCMS (Method 3) : t _R = 1.55 min, m/z (M+H) ⁺= 551.2.

Step 3. Tert-butyl 3- (8-fluoro-2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7-phenylpyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (11d)

Compound 11d (32 mg crude) was synthesized by utilizing similar preparative procedure to the sixth step of compound 1 with 11c (30 mg, 0.05 mmol) and phenylboronic acid (13 mg, 0.1 mmol) as starting materials. LCMS (Method 3) : t _R = 1.60 min, m/z (M+H) ⁺= 593.3.

Step 4. 4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H -pyrrolizin-7a (5H) -yl) methoxy) -7-phenylpyrido [4, 3-d] pyrimidine (11)

Compound 11 (18.5 mg, 68%yield) was synthesized by utilizing similar preparative procedure of compound 1 with 11d (32 mg crude) as starting material. The compound 11 was purification by prep-HPLC (method C) . LCMS (Method 2) : t _R = 2.69 min, m/z (M+H) ⁺= 493.2. ¹H NMR (400 MHz, DMSO-d ₆) : δ 9.17 (s, 1H) , 8.03 (d, J = 7.6 Hz, 2H) , 7.59 -7.52 (m, 3H) , 5.38 (s, 0.5H) , 5.24 (s, 0.5H) , 4.58 (d, J = 12.8 Hz, 2H) , 4.20 -4.17 (m, 1H) , 4.11 -4.05 (m, 4H) , 3.85 -3.75 (m, 3H) , 3.19 -3.07 (m, 3H) , 2.87 -2.85 (m, 1H) , 2.16 -2.03 (m, 3H) , 1.85 -1.80 (m, 6H) .

Example 12

Step 1. Tert-butyl (1R, 5S) -3- (6-fluoro-7- (8-fluoro-3- ( (2- (trimethylsilyl) ethoxy) methoxy) naphthalen-1-yl) -2- ( ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [2, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (12a)

Compound 12a (21 mg, 32%yield) was synthesized by utilizing similar preparative procedure of compound 1 with 11c (45 mg, 0.08 mmol) and (2- ( ( (5-fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-2-yl) oxy) methoxy) et hyl) trimethylsilane (41 mg, 0.098 mmol, WO2021/41671, Paragraph 01283) as starting materials. LCMS (Method 3) : t _R = 2.32 min, m/z (M+H) ⁺= 808.0.

Step 2. 4- (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -6-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [2, 3-d] pyrimidin-7-yl) -5-fluoronaphthalen-2-ol (12)

Compound 12 (4.5 mg, 28%yield) was synthesized by utilizing similar preparative procedure of the final step of compound 1 with 12a (21 mg, 0.02 mmol) as starting material. The compound 12 was purification by prep-HPLC (method C) . LCMS (Method 3) : t _R = 2.38 min, m/z (M+H) ⁺= 577.3. ¹H NMR (400 MHz, DMSO-d ₆) : δ 10.16 (br s, 1H) , 8.26 (d, J =10.8 Hz, 1H) , 7.63 (d, J = 8.4 Hz, 1H) , 7.42 -7.37 (m, 1H) , 7.29 (s, 1H) , 7.14 (d, J = 2.0 Hz, 1H) , 6.95 (dd, J = 12.4, 7.6 Hz, 1H) , 5.37 (s, 0.5H) , 5.29 (s, 0.5H) , 4.33 (d, J = 13.2 Hz, 2H) , 4.28 (d, J = 10.8 Hz, 1H) , 4.23 (d, J = 10.4 Hz, 1H) , 3.96 (s, 2H) , 3.67 (d, J = 13.6 Hz, 2H) , 3.17 -3.01 (m, 3H) , 2.88 -2.83 (m, 1H) , 2.18 -2.00 (m, 3H) , 1.84 -1.77 (m, 7H) .

Example 13

Step 1. Benzyl (1R, 2R, 4S) -7-azabicyclo [2.2.1] heptan-2-ylcarbamate hydrochloride (13b)

(1R, 2R, 4S) -tert-butyl

2- ( ( (benzyloxy) carbonyl) amino) -7-azabicyclo [2.2.1] heptane-7-carboxylate (160 mg, 0.46 mmol, WO2004/74292, Page 7) was dissolved in HCl/EtOAc (2 mL, 2M) and the resulting mixture was stirred at RT for 2 hours. The mixture was concentrated to dryness to give compound 13b (130 mg, yield given) . LCMS (Method 3) : t _R = 1.15 min, m/z (M+H) ⁺= 247.0.

Step 2. Benzyl ( (1R, 2R, 4S) -7- (7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl) -7-azabicyclo [2.2.1] hepta n-2-yl) carbamate (13c)

To a solution of compound 1d (260 mg, 0.81 mmol) , DIPEA (420 mg, 3.25 mmol) in DCM (5 mL) was added a solution of compound 13b (230 mg, 0.81 mmol) in DCM (5 mL) at 0 ℃. The mixture was stirred at RT for 10 hours. The mixture was diluted with DCM (20 mL) and washed with H ₂O (10 mL) . The separated organic layer was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (PE/EA = 3/1) to give compound 13c (235 mg, 55%yield) as a yellow solid. LCMS (Method 3) : t _R = 1.89 min, m/z (M+H) ⁺= 529.8.

Step 3. Benzyl ( (1R, 2R, 4S) -7- (7-bromo-3-cyano-8-fluoro-2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinolin-4-yl) -7-azabicyclo [2.2.1] heptan-2-yl) carbamate (13d)

Compound 13d (220 mg, 74%yield) was synthesized by utilizing similar preparative procedure to the second step of compound 4 with 13c (240 mg, 0.45 mmol) and ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methanol (87 mg, 0.55 mmol) as starting materials. LCMS (Method 3) : t _R = 0.95 min, m/z (M+H) ⁺= 652.7.

Step 4. Benzyl ( (1R, 2R, 4S) -7- (3-cyano-8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinolin-4-yl) -7-azabicyclo [2.2.1] heptan -2-yl) carbamate (13e)

Compound 13e (35 mg, 92%yield) was synthesized by utilizing similar preparative procedure to the sixth step of compound 1 with 13d (50 mg, 0.077 mmol) and 1i (15 mg, 0.052 mmol) as starting materials. LCMS (Method 3) : t _R = 1.01 min, m/z (M+H) ⁺= 734.7.

Step 5. 4- ( (1R, 2R, 4S) -2-amino-7-azabicyclo [2.2.1] heptan-7-yl) -8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a-yl) methoxy) quinoline-3-carbonitrile (13)

To a solution of 13e (35 mg, 0.048 mmol) in CHCl ₃ (2 mL) was added iodotrimethylsilane (19 mg, 0.095 mmol) . After stirring for 3 hrs at RT, the reaction was quenched with 1 N HCl (0.5 mL) and extracted with EA (5 mL*2) . The combined organic layer was concentrated and purified by column chromatography (DCM/MeOH = 10/1) to afford crude product. The crude product was repurified by prep-TLC (DCM/MeOH = 10/1) to give compound 13 (3 mg, 10% yield) as white solid. LCMS (Method 3) : t _R = 0.65 min, m/z (M+H) ⁺= 600.7. ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.24 -8.22 (m, 2 H) , 7.67 (d, J = 8.0 Hz, 1H) , 7.49 -7.43 (m, 2H) , 7.34 (s, 1H) , 7.03 -6.97 (m, 2H) , 5.69 (s, 0.5H) , 5.54 (s, 0.5H) , 5.07 (s, 1H) , 5.00 (s, 1H) , 3.97 -3.77 (m, 3H) , 3.17 -3.10 (m, 2H) , 2.89 -2.80 (m, 2H) , 2.09 -1.97 (m, 5H) , 1.86 -1.83 (m, 5H) , 1.69 -1.65 (m, 1H) , 1.44 (dd, J = 12.8, 4.8 Hz, 1H) .

Example 14

Step 1. 2, 4-Dichloro-6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one (14a)

To a solution of 7b (5 g, 15.72 mmol) in dioxane (25 mL) was added 4 N HCl/dioxane (25 mL) . The reaction mixture was stirred at room temperature for 4 h. Then the reaction solution was concentrated under vacuum to give a crude product 14a (3.5 g, yield given) as an off-white solid, which was used directly in next step without further purification. LC-MS (Method 4) t _R =2.35 min, m/z (M+H) ⁺ = 218.0.

Step 2. Tert-butyl 3- (2-chloro-8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (14b)

To a solution of 14a (3.5 g, 15.72 mmol) and tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (4.0 g, 18.87 mmol) in DMSO (20 mL) was added DIEA (6.1 g, 47.16 mmol) . And the resulting reaction solution was stirred at 60 ℃ for 1 h. Water (50 mL) was added into and the mixture was extracted with EA (35 mL*3) . The combined organic layer was washed with water (50 mL) and brine (50 mL) and concentrated under vacuum to give a residue which was further purified over flash chromatography on silica gel (DCM/MeOH from 100/1 to 20/1) to give the title compound 14b (4.5 g, 73%yield over two steps) as a brown solid.

Step 3. Tert-butyl 3- (2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (14c)

To a solution of 14b (4.5 g, 11.45 mmol) , ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (5.4 g, 34.35 mmol) and

molecular sieves (4.5 g) in DMSO (50 mL) was added DIEA (4.43 g, 34.35 mmol) in one portion. The resulting mixture was stirred at 140 ℃ for 48 h in a sealed tube. The mixture was filtered and diluted with water (100 mL) . The mixture was extracted with EA (50 mL*3) . The combined organic layer was washed with water (75 mL) and brine (75 mL) and concentrated under vacuum to give a residue which was further purified over flash chromatography on silica gel (DCM/EtOH from 20/1 to 5/1) to give the title compound 14c (4.0 g, 67%yield) as a brown solid. LC-MS (Method 4) t _R = 2.91 min, m/z (M+H) ⁺ = 517.3.

Step 4. 1-Bromo-3-chloro-2-cyclopropyl-5- (methoxymethoxy) benzene (14e)

To a stirred solution of 14d (150 mg, 0.606 mmol) and DIEA (235 mg, 1.82 mmol) in DCM (5 mL) was added bromo (methoxy) methane (151 mg, 1.21 mmol) . This resulting mixture was stirred at 20 ℃ for 16 h. Then the reaction solution was washed with water (3 mL) and brine (3 mL) . The organic layer was separated and concentrated under vacuum to give a residue which was further purified over flash chromatography on silica gel (PE/EA from 1/0 to 50/1) to give the title compound 14e (110 mg, 62%yield) as a yellow liquid.

Step 5. (3-Chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) boronic acid (14f)

To a solution of 14e (100 mg, 0.34 mmol) and triisopropyl borate (96.8 mg, 0.514 mmol, 0.12 mL) in THF (2 mL) was added n-butyllithium (2.4 M, 0.16 mL) at -78 ℃. The resulting solution was stirred at -78 ℃ for 2 h. The reaction solution was quenched with 1 N HCl aq. (1 mL) at -78 ℃, then stirred at 20 ℃ for 1 h. The mixture was extracted with EA (2 mL*3) . The combined organic layer was washed with water (3 mL) and brine (3 mL) , separated and concentrated under vacuum to give a residue which was further purified over Prep-TLC (PE/EA = 2/1) to give the title compound 14f (38 mg, 43%yield) as a yellow solid.

Step 6. Tert-butyl 3- (7- (3-chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro -1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (14g)

A solution of 14c (20 mg, 0.039 mmol) , 14f (20 mg, 0.078 mmol) and Cu ₂ (TMEDA) ₂ (OH) ₂Cl ₂ (9.0 mg, 0.019 mmol) in DCM (1 mL) was stirred at 20 ℃ for 18 h. The reaction solution was concentrated under vacuum to give a residue which was further purified over Prep-TLC (PE/EA = 2/1) to give the title compound 14g (6 mg, 21%yield) as a yellow solid. LC-MS (Method 4) t _R = 4.32 min, m/z (M+H) ⁺ = 727.5.

Step 7. 4- (3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-2-cyclopropyl-5-hydroxyphenyl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one (14)

A solution of 14g (6 mg, 0.008 mmol) in 4 N HCl/dioxane (0.5 mL) was stirred at 20 ℃for 2 h. Then the reaction solution was evaporated under vacuum to give a residue which was purified by Prep-HPLC (Method E) to afford the compound 14 (2.5 mg, 44%yield) as a white solid. LC-MS (Method 4) t _R = 2.79 min, m/z (M+H) ⁺ = 583.3. ¹H NMR (400 MHz, CD ₃OD) δ 6.86 (s, 1H) , 6.67 (s, 1H) , 5.58-5.44 (m, 1H) , 4.54-4.44 (m, 2H) , 4.22 (s, 2H) , 3.92-3.65 (m, 8H) , 3.48-3.36 (m, 1H) , 3.24-3.14 (m, 2H) , 2.74-2.52 (m, 2H) , 2.48-2.26 (m, 3H) , 2.23-2.00 (m, 6H) , 1.72-1.54 (m, 2H) , 1.02-0.85 (m, 2H) , 0.59-0.42 (m, 2H) .

Example 15

Step 1. (3- (Methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) boronicacid (15a)

To a solution of triisopropyl ( (6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) silane (2.0 g, 4.04 mmol) in CHCl ₃/MeOH (1/1, 50 mL) was added 2- (2-hydroxyethylamino) ethanol (4.68 g, 44.49 mmol) at r. t. . Then the mixture was stirred at 70 ℃ for 48 h. The mixture was diluted with H ₂O (100 mL) , extracted with DCM (50 mL*3) , washed with brine (50 mL) , dried over Na ₂SO ₄, concentrated and purified by flash chromatography (PE/EA from 20/1 to 3/1) to get the compound 15a (1.45 g, 87%yield) as an off-white solid. LCMS (Method 5) t _R = 5.79 min, m/z (M+H) ⁺ = 413.2. ¹H NMR (400 MHz, CDCl ₃) δ 7.73 (d, J = 8.4 Hz, 1H) , 7.67 (d, J = 7.2 Hz, 1H) , 7.41-7.37 (m, 3H) , 5.29 (s, 2H) , 4.52 (s, 2H) , 3.51 (s, 3H) , 1.26-1.18 (m, 21H) .

Step 2. Tert-butyl 3- (2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane -8-carboxylate (15b)

A mixture of 14c (20 mg, 0.039 mmol) , 15a (32 mg, 0.078 mmol) , Cu ₂ (TMEDA) ₂ (OH) ₂Cl ₂ (9 mg, 0.019 mmol) in DCM (1 mL) was stirred at 25 ℃ for 72 h under O ₂. The mixture was diluted with H ₂O (10 mL) , extracted with DCM (10 mL*3) , washed with brine (15 mL) , dried over Na ₂SO ₄, concentrated to get the crude compound 15b (15 mg, 44%yield) as a yellow solid. LCMS (Method 5) t _R = 5.03 min, m/z (M+H) ⁺ = 883.7.

Step 3. Tert-butyl 3- (7- (8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H -pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (15c)

To a solution of 15b (15 mg, 0.017 mmol) in THF (0.5 mL) was added TBAF (0.017 mL, 0.017 mmol, 1 M in THF) at r. t. . Then the mixture was stirred at r. t. for 30 min. The mixture was diluted with H ₂O (10 mL) , extracted with EtOAc (10 mL*3) , washed with brine (10 mL) , dried over Na ₂SO ₄, concentrated and purified by Prep-HPLC (Method F) to get the compound 15c (6 mg, 49%yield) as a yellow solid. LCMS (Method 4) t _R = 4.16 min, m/z (M+H) ⁺ =727.5.

Step 4. 4- (3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8(5H) -one (15A and 15B)

To a solution of 15c (4 mg, 0.005 mmol) in ACN (0.5 mL) was added HCl/dioxane (4 M, 0.5 mL) at 0 ℃, then the mixture was stirred at 10 ℃ for 1 h. The mixture was concentrated under vacuum. The residue was diluted with DMF (1 mL) and the pH was adjusted to 8 with saturated NaHCO ₃ aqueous solution. The mixture was filtered and concentrated. The residue was purified by Prep-HPLC (Method F) to get the compound 15A (0.3 mg, 9 %yield) and 15B (1.2 mg, 37%yield) both as an off-white solid.

15A: ¹H NMR (400 MHz, CD ₃OD) δ 7.78 (d, J = 8.4 Hz, 1H) , 7.55 (d, J = 6.8 Hz, 1H) , 7.38 (t, J = 7.2 Hz, 1H) , 7.26 (d, J = 2.4 Hz, 1H) , 7.21 (d, J = 2.4 Hz, 1H) , 5.46-5.33 (m, 1H) , 4.55-4.52 (m, 2H) , 4.47-4.43 (m, 1H) , 4.38-4.34 (m, 1H) , 4.23-4.17 (m, 1H) , 4.09-4.03 (m, 1H) , 3.96-3.93 (m, 3H) , 3.79-3.76 (m, 1H) , 3.73-3.59 (m, 3H) , 3.56 (s, 1H) , 3.53-3.51 (m, 1H) , 3.36-3.32 (1 H) , 3.22-3.19 (m, 1H) , 2.48-2.31 (m, 3H) , 2.25-2.17 (m, 3H) , 2.08-1.95 (m, 4H) . LCMS (Method 4) t _R = 2.67 min, m/z (M+H) ⁺ = 583.4.

According to k-Ras-G12D cocrystal with similar compound (PDB: 7RPZ) in J. Med. Chem. 2022, 65, 3123-3133, the active isomer was identified to 15A.

15B: ¹H NMR (400 MHz, CD ₃OD) δ 7.79 (d, J = 8.4 Hz, 1H) , 7.56 (d, J = 6.8 Hz, 1H) , 7.39 (t, J = 7.2 Hz, 1H) , 7.26 (d, J = 2.4 Hz, 1H) , 7.21 (d, J = 2.4 Hz, 1H) , 5.44-5.30 (m, 1H) , 4.49-4.42 (m, 2H) , 4.39-4.36 (m, 1H) , 4.21-4.17 (m, 1H) , 4.12-4.09 (m, 1H) , 3.97-3.92 (m, 4H) , 3.80-3.68 (m, 2H) , 3.61 (s, 1H) , 3.59-3.55 (m, 3H) , 3.42-3.39 (1 H) , 3.25-3.24 (m, 1H) , 2.48-2.40 (m, 1H) , 2.21-2.17 (m, 4H) , 2.06-1.97 (m, 5H) . LCMS (Method 4) t _R = 2.71 min, m/z (M+H) ⁺ = 583.4.

Example 16

Step 1. 2- (4, 5-Dibromonaphthalen-2-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (16b)

A mixture of 16a (2.0 g, 6.99 mmol) , (1, 5-cyclooctadiene) (methoxy) iridium (I) dimer (229 mg, 0.35 mmol) , 4, 4'-di-tert-butyl-2, 2'-bipyridine (113 mg, 0.42 mmol) and 4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (2.69 g, 20.98 mmol) in THF (30 mL) was stirred at 60 ℃ for 16 h under N ₂. The mixture was concentrated under vacuum to get the crude product 16b (3.0 g, 7.28 mmol, yield given) as a brown oil.

Step 2. 4, 5-Dibromonaphthalen-2-ol (16c)

To a solution of 16b (2.88 g, 6.99 mmol) in H ₂O (30 mL) and THF (30 mL) was added AcOH (30 mL) and hydrogen peroxide (4.76 g, 139.83 mmol, 4.32 mL) at 10 ℃. Then the mixture was stirred at 10 ℃ for 1 h. The mixture was quenched with saturated NaHSO ₃ solution (40 mL) and extracted with EtOAc (40 mL) , washed with brine (40 mL) , dried over Na ₂SO ₄, concentrated and purified by flash chromatography (PE/EA from 10/1 to 3/1) to get compound 16c (800 mg, 38%yield) as an off-white solid. LCMS (Method 4) t _R = 2.44 min, m/z (M-H) ^-= 298.8.

Step 3. 1, 8-Dibromo-3- (methoxymethoxy) naphthalene (16d)

To a solution of 16c (800 mg, 2.65 mmol) in DCM (10 mL) was added DIEA (1.03 g, 7.95 mmol) and bromo (methoxy) methane (497 mg, 3.97 mmol) at 0 ℃. Then the mixture was stirred at 10 ℃ for 30 min. The mixture was diluted with H ₂O (30 mL) , extracted with DCM (30 mL*3) , washed with brine (30 mL) and concentrated to get the crude product 16d (800 mg, 87%yield) as a pale-yellow solid.

Step 4. 8-Bromo-6- (methoxymethoxy) -1-naphthonitrile (16e)

To a solution of 16d (200 mg, 0.57 mmol) in DMF (7 mL) was added CuCN (52 mg, 0.57 mmol) . The mixture was stirred at 100 ℃ under M. W. for 30 min. The mixture was filtrated and purified by Prep-HPLC (Method E) to get the compound 16e (50 mg, 30%yield) and 8-bromo-3- (methoxymethoxy) naphthalene-1-carbonitrile (55 mg, 33%yield) as a white solid. ¹HNMR (400 MHz, CDCl ₃) δ 7.96-7.91 (m, 2H) , 7.69 (d, J = 2.4 Hz, 1H) , 7.47 (t, J = 7.2 Hz, 1H) , 7.42 (d, J = 2.4 Hz, 1H) , 5.28 (s, 2H) , 3.50 (s, 3H) . LCMS (Method 4) t _R = 4.41 min, m/z (M+H) ⁺ = 292.0.

Step 5. Tert-butyl 3- (7- (8-cyano-3- (methoxymethoxy) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (16f)

A mixture of 14c (20 mg, 0.039 mmol) , 16e (23 mg, 0.04 mmol) , Cs ₂CO ₃ (32 mg, 0.09 mmol) and XantPhos Pd G3 (7 mg, 0.008 mmol) in dioxane (0.5 mL) was stirred at 110 ℃under N ₂ for 24 h. The mixture was diluted with H ₂O (10 mL) , extracted with EA (10 mL*3) , washed with brine (15 mL) , dried over Na ₂SO ₄ and concentrated to get the crude compound 16f (18 mg, 64%yield) as a yellow solid. LCMS (Method 4) t _R = 3.95 min, m/z (M+H) ⁺ =728.5.

Step 6. 8- (4- (3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 8-dihydropyrido [3, 4-d] pyrimidin-7 (6H) -yl) -6-hydroxy-1-naphthonitrile (16)

To a solution of 16f (15 mg, 0.021 mmol) in ACN (0.5 mL) was added HCl/dioxane (4 M, 0.5 mL) , then the mixture was stirred at r.t. for 2 h. The mixture was concentrated and purified by Prep-HPLC (Method F) to get the compound 16 (4.0 mg, 33%yield) as a pale-yellow solid. ¹HNMR (400 MHz, CD ₃OD) δ 8.08 (d, J = 8.4 Hz, 1H) , 7.83 (d, J = 6.8 Hz, 1H) , 7.54 (t, J =6.8 Hz, 1H) , 7.34-7.32 (m, 2H) , 5.45-5.33 (m, 1H) , 4.56-4.52 (m, 1H) , 4.47-4.43 (m, 1H) , 4.29-4.25 (m, 1H) , 4.13-4.03 (m, 2H) , 4.00-3.99 (m, 1H) , 3.95-3.71 (m, 2H) , 3.70-3.39 (m, 6H) , 3.28-3.24 (m, 1H) , 3.13-3.09 (m, 1H) , 2.47-2.41 (m, 2 H) , 2.36-2.33 (m, 1H) , 2.24-2.15 (m, 3 H) , 2.02-1.99 (m, 4H) . LCMS (Method 4) t _R = 2.44 min, m/z (M+H) ⁺ = 584.4.

Example 17

Step 1. Tert-butyl 3- (7- (5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (17b)

A mixture of 14c (20 mg, 0.039 mmol) , 17a (26 mg, 0.077 mmol) , Cs ₂CO ₃ (25 mg, 0.077 mmol) and XantPhos Pd G3 (4 mg, 0.004 mmol) in dioxane (1 mL) was stirred overnight at 110 ℃. The mixture was filtered by a pad of celite and purified by Prep-TLC (DCM/MeOH =15/1) to get the compound 17b (30 mg, yield given) as a light yellow solid. LC-MS (Method 4) t _R = 4.09 min, m/z (M+H) ⁺ = 765.5.

Step 2. 4- (3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (5-chloro-6-methyl-1H-indazol-4-yl) -2- ( ( (2R, 7aS) -2 -fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one formic acid (17A and 17B)

To a solution of 17b (30 mg, 0.039 mmol) in ACN (0.5 mL) was added HCl (0.5 mL, 4 M in dioxane) at an ice-bath, then the mixture was stirred at r. t. for 2 h. The mixture was concentrated and purified by Prep-HPLC (Method F) to get the compound 17A (5.6 mg, 25%yield) and 17B (6.0 mg, 26%) both as a pale-yellow solid.

17A: LC-MS (Method 4) t _R = 2.54 min, m/z (M+H) ⁺ = 581.4. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.07 (s, 1H) , 7.59 (s, 1H) , 5.36-5.22 (m, 1H) , 4.07-3.94 (m, 5H) , 3.83-3.81 (m, 2H) , 3.75-3.71 (m, 2H) , 3.37-3.32 (m, 2H) , 3.14-3.03 (m, 6H) , 2.88-2.84 (m, 1H) , 2.14-2.06 (m, 2H) , 2.00-1.78 (m, 9H) .

17B: LC-MS (Method 4) t _R = 2.57 min, m/z (M+H) ⁺ = 581.4. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.07 (s, 1H) , 7.59 (s, 1H) , 5.35-5.21 (m, 1H) , 4.04-3.96 (m, 5H) , 3.82-3.80 (m, 2H) , 3.76-3.70 (m, 2H) , 3.376-3.32 (m, 2H) , 3.15-3.03 (m, 6H) , 2.84-2.82 (m, 1H) , 2.13-2.05 (m, 2H) , 2.04-1.98 (m, 1H) , 1.86-1.74 (m, 8H) .

Example 18

Step 1. 2- (3-Bromo-5-chloro-4- (trifluoromethyl) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (18b)

To a solution of 18a (5.00 g, 19.3 mmol) , 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolane (4.93 g, 38.5 mmol) in THF (60 mL) were added dtbbpy (621 mg, 2.31 mmol) and [Ir (OMe) (cod) ] ₂ (1.28 g, 1.93 mmol) under N ₂, the mixture was stirred at 60 ℃ for 2 h. The mixture was concentrated to give the compound 18b (12.2 g, crude) which was used in next step without further purification. LC-MS (Method 4) t _R = 3.52 min, m/z (M+H) ⁺ = 385.0.

Step 2. 3-Bromo-5-chloro-4- (trifluoromethyl) phenol (18c)

To a solution of 18b (12.0 g, 31.1 mmol) in THF (100 mL) and H ₂O (50 mL) was added AcOH (74.8 g, 1250 mmol ) and H ₂O ₂ (70.6 g, 623 mmol, 30%purity in H ₂O) at 10 ℃. The mixture was stirred at 10 ℃ for 2 h. To the mixture was added water (200 mL) and EtOAc (200 mL) . The organic layer was separated, washed with saturated Na ₂S ₂O ₃ solution (200 mL*2) and then brine (100 mL) , dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash chromatograghy on silica gel (PE/EA from 10/1 to 1/4) to give the compound 18c (5.10 g, 82%yield over two steps) . LC-MS (Method 4) t _R = 2.86 min, m/z (M+H) ⁺ = 275.0.

Step 3. 1-Bromo-3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) benzene (18d)

To a solution of 18c (500 mg, 1.83 mmol) in DCM (10 mL) was added TEA (369 mg, 3.66 mmol) and bromo (methoxy) methane (226 mg, 1.83 mmol) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 2 h, concentrated and purified by flash chromatograghy on silica gel (PE/EA from 10/1 to 1/3) to give the compoound 18d (400 mg, 68%yield) as a yellow solid. LC-MS (Method 4) t _R = 4.45 min, m/z (M+H) ⁺ = 319.0.

Step 4. Tert-butyl 3- (7- (3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) phenyl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin -4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (18e)

To a solution of 18d (60 mg, 0.18 mmol) and 14c (49 mg, 0.09 mmol) in dioxane (1 mL) was added Xantphos Pd G3 (8 mg, 0.009 mmol) and Cs ₂CO ₃ (58.0 mg, 0.18 mmol) at 25 ℃. The reaction mixture was stirred at 100 ℃ for 15 h under N ₂ atmosphere. The mixture was diluted with H ₂O (10 mL) , extracted with EA (20 mL*3) , washed with brine (20 mL) , dried over Na ₂SO ₄, concentrated and purified by flash chromatography on silica gel (DCM/MeOH from 100/1 to 10/1) to get the compound 18e (21 mg, 16%yield) as a yellow solid. LC-MS (Method 4) t _R = 3.54 min, m/z (M+H) ⁺ = 755.3.

Step 5. 4- (3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2-( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one (18)

A solution of 18e (21 mg, 0.28 mmol) in HCl/dioxane (2 mL, 4 M) was stirred at 25 ℃for 2 h. The reaction mixture was concentrated and purified by Prep-HPLC (Method E) to give compound 18 (2.5 mg, 15%yield) as an off-white solid. LC-MS (Method 4) t _R = 2.83 min, m/z (M+H) ⁺ = 611.3. ¹H NMR (400 MHz, CD ₃OD) δ 7.10 (s, 1H) , 6.87 (s, 1H) , 5.69-5.51 (m, 1H) , 4.85-4.41 (m, 4H) , 4.28-4.18 (m, 2H) , 4.07-3.70 (m, 8H) , 3.46-3.37 (m, 1H) , 3.29-3.19 (m, 1H) , 2.81-2.20 (m, 10H) .

Example 19

Step 1. 4-Bromo-5-chloro-1, 1-difluoronaphthalen-2 (1H) -one (19b)

A solution of 19a (508 mg, 1.97 mmol) and selectflour (1.388 g, 3.92 mmol) in MeCN (8 mL) was stirred at r. t. for 2 h. The reaction was quenched with water (10 mL) and extracted with EA (15 mL*3) . The combined organic layer was washed with brine (15 mL) , dried over anhydrous Na ₂SO ₄ and concentrated under vacuum to give the crude product 19b (438 mg, 76%yield) as a brown oil. LC-MS (Method 4) t _R = 3.69 min, m/z (M+H) ⁺ = 292.9.

Step 2. 4-Bromo-5-chloro-1-fluoronaphthalen-2-ol (19c)

A solution of 19b (438 mg, 1.49 mmol) in toluene (2.5 mL) was added dropwise to a solution of Na ₂S ₂O ₄ (859 mg, 4.93 mmol) in H ₂O (4 mL) and i-PrOH (4 mL) at r.t. under nitrogen atmosphere. The resulting reaction mixture was stirred at r.t. overnight. Then the reaction solution was concentrated under vacuum to give a residue, which was purified by flash chromatography on silica gel (PE/EA = 5/1) to afford the compound 19c (276 mg, 67%yield) as a red solid. LC-MS (Method 4) t _R = 5.41 min, m/z (M+H) ⁺ = 274.9.

Step 3. 4-Bromo-5-chloro-1-fluoro-2- (methoxymethoxy) naphthalene (19d)

To a stirred mixture of 19c (276 mg, 1.00 mmol) and DIEA (0.25 mL, 1.43 mmol) in DCM (8 mL) was added bromo (methoxy) methane (112 mg, 0.89 mmol) , and the resulting solution was stirred at r.t. for 2 h. Then the solvent was removed under vacuum, and the residue was purified by flash chromatography on silica gel (PE/EA = 5/1) to afford compound 19d (233 mg, 73%yield) as a red solid. ¹H NMR (400 MHz, CDCl ₃) δ 8.05-8.01 (m, 1H) , 7.87 (d, J = 8.0 Hz, 1H) , 7.60-7.57 (m, 1H) , 7.42-7.36 (m, 1H) , 5.29 (s, 2H) , 3.56 (s, 3H) .

Step 4. Tert-butyl 3- (7- (8-chloro-4-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (19e)

To a stirred solution of 19d (20 mg, 0.064 mmol) and 14c (20 mg, 0.039 mmol) in anhydrous 1, 4-dioxane (1 mL) was added XantPhos Pd G3 (4 mg, 0.004 mmol) and Cs ₂CO ₃ (25 mg, 0.077 mmol) . The resulting mixture was stirred at 110 ℃ under nitrogen atmosphere for 16 h. After cooling down to r. t., the mixture was filtered and the filtrate was concentrated under vacuum to give a crude product 19e (10 mg, 34%yield) as a brown oil. LC-MS (Method 4) t _R = 3.87 min, m/z (M+H) ⁺ = 755.4.

Step 5. 4- (3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-chloro-4-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one (19)

A solution of 19e (10 mg, 0.013 mmol) in MeOH (1 mL) and conc. HCl (0.05 mL) was stirred at 65 ℃ for 16 h. After cooling down to r. t., the reaction solution was concentrated and the residue was purified by Prep-HPLC (Method E) to afford the compound 19 (4.6 mg, 57%yield) as a white solid. LC-MS (Method 4) t _R = 3.56 min, m/z (M+H) ⁺ = 611.3. ¹H NMR (400 MHz, CD ₃OD) δ 8.52 (s, 1H) , 7.98 (s, 1H) , 7.44 (d, J = 4.8 Hz, 2H) , 7.34 (s, 1H) , 5.43-5.30 (m, 1H) , 4.44 -4.34 (m, 2H) , 4.26 -4.23 (m, 1H) , 4.06 -4.02 (m, 2H) , 3.91 (s, 3H) , 3.56 -3.45 (m, 4H) , 3.23 -3.17 (m, 2H) , 2.44 -2.35 (m, 2H) , 2.23 -2.14 (m, 4H) , 1.99 -1.96 (m, 6H) .

Example 20

Step1. Tert-butyl

4- (8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -2-chloro-8-oxo-5, 8-dihydropyrido [3, 4-d] pyrimidine-7 (6H) -carboxylate (20a)

To a solution of 7b (500 mg, 1.57 mmol) in DCM (10 mL) was added tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (334 mg, 1.57 mmol) and DIEA (405 mg, 3.14 mmol) . The reaction mixture was stirred at r. t. for 2 h, concentrated and purified by flash chromatography on silica gel (PE/EA from 10/1 to 1/1) to give compound 20a (500 mg, 65%yield) as a yellow solid. LC-MS (Method 4) t _R = 4.15 min, m/z (M+H) ⁺ = 494.3.

Step 2. Tert-butyl 3- (2- ( (1- (tert-butoxycarbonyl) -4-methylpiperidin-4-yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (20b)

To a solution of 20a (205 mg, 0.41 mmol) and tert-butyl 4- (hydroxymethyl) -4-methylpiperidine-1-carboxylate (124 mg, 0.54 mmol) in anhydrous 1, 4-dioxane (20 mL) was added t-BuONa (80 mg, 0.83 mmol) , and the resulting reaction mixture was stirred at 140 ℃ for 3 h. After cooling down to r. t., the solid was filtered, and the filtrate was concentrated to give a residue which was purified by Prep-HPLC (C18 column, MeCN/H ₂O (0.5%NH ₄HCO ₃) , 5%-35%, 30 min) to afford compound 20a (43 mg, 18%yield) as a white solid. LC-MS (Method 4) t _R = 4.04 min, m/z (M+H) ⁺ = 587.5.

Step 3. Tert-butyl 3- (7- (8-bromo-3- (methoxymethoxy) naphthalen-1-yl) -2- ( (1- (tert-butoxycarbonyl) -4-methyl piperidin-4-yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (20c)

To a stirred solution of 20b (43 mg, 0.073 mmol) and 16d (51 mg, 0.15 mmol) in anhydrous 1, 4-dioxane (2 mL) was added XantPhos Pd G3 (6.5 mg, 0.0068 mmol) and Cs ₂CO ₃ (48 mg, 0.15 mmol) . The resulting mixture was stirred at 110 ℃ under nitrogen atmosphere for 16 h. After cooling down to r. t., the mixture was filtered and the filtrate was concentrated under vacuum to give compound 20c (30 mg, 48%yield) as a brown solid. LC-MS (Method 5) t _R =6.50 min, m/z (M+H) ⁺ = 851.5.

Step 4. 4- (3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-bromo-3-hydroxynaphthalen-1-yl) -2- ( (4-methyl piperidin-4-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one (20d)

A solution of 20c (30 mg, 0.035 mmol) in MeOH (1 mL) and conc. HCl (0.05 mL) was stirred at 65 ℃ for 16 h. After cooling down to r. t., the reaction solution was concentrated and the residue was purified by Prep-HPLC (Method E) to afford compound 20d (6.5 mg, 31%yield) as a white solid. LC-MS (Method 4) t _R = 2.29 min, m/z (M+H) ⁺ = 607.3.

Step 5. 4- (3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (3-hydroxy-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( (4-methylpiperidin-4-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one (20e)

To a solution of 20d (6.5 mg, 0.01 mmol) and ethynyltriisopropylsilane (39.0 mg, 0.21 mmol) in anhydrous DMA (1 mL) was added CuI (1.0 mg, 0.052 mmol) , Pd (PPh ₃) ₂Cl ₂ (1.2 mg, 0.0017 mmol) and DIEA (0.018 mL, 0.10 mmol) . The resulting mixture was stirred at 100 ℃under nitrogen atmosphere for 5 h. Then the mixture was allowed to cool down to r.t. and filtered. The filtrate was purified by Prep-HPLC (Method E) to give compound 20e (3.5 mg, 46%yield) as a white solid. LC-MS (Method 4) t _R = 3.23 min, m/z (M+H) ⁺ = 709.5.

Step 6. 4- (3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-3-hydroxynaphthalen-1-yl) -2- ( (4-methy lpiperidin-4-yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one (20)

To a solution of 20e (3.5 mg, 0.005 mmol) in THF (1 mL) was added TBAF (0.02 mL, 0.02 mmol, 1 M in THF) at 0 ℃, and the resulting reaction solution was stirred at 0 ℃ for 1 h. Then the solvent was removed and the residue was purified by Prep-HPLC (Method E) to afford compound 20 (2.1 mg, 79%yield) as a white solid. LC-MS (Method 4) t _R = 1.55 min, m/z (M+H) ⁺ = 553.4. ¹H NMR (400 MHz, CD ₃OD) δ 7.78 (d, J = 8.0 Hz, 1H) , 7.55 (d, J = 7.2 Hz, 1H) , 7.39 (t, J = 7.2 Hz, 1H) , 7.26 (d, J = 2.4 Hz, 1H) , 7.22 (d, J = 2.4 Hz, 1H) , 4.31-4.15 (m, 4H) , 4.40-3.86 (m, 5H) , 3.56 (s, 1H) , 3.53-3.48 (m, 1H) , 3.38-3.32 (m, 3H) , 3.22-3.16 (m, 3H) , 2.14-1.93 (m, 6H) , 1.66-1.63 (m, 2H) , 1.18 (s, 3H) .

Example 21

Step 1. 7-Bromo-2-chloro-4- ( (3S, 5S) -3, 5-dimethylpiperazin-1-yl) -8-fluoroquinoline-3-carbonitrile (21a)

To a mixture of 1d (200 mg, 0.63 mmol) and DIEA (404 mg, 3.13 mmol) in DCM (2 mL) was added (2S, 6S) -2, 6-dimethylpiperazine (140 mg, 0.75 mmol) at 0 ℃. The reaction was stirred at r.t. for 3 h. The formed solid was filtered, washed with DCM (5 mL) and dried in vacuum to afford 21a (184 mg, 74%yield) as a yellow solid. LC-MS (Method 3) t _R = 1.11 min, m/z (M+H) ⁺ = 397.1.

Step 2. 7-Bromo-4- ( (3S, 5S) -3, 5-dimethylpiperazin-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinoline-3-carbonitrile (21b)

To a solution of 21a (184 mg, 0.46 mmol) and ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (110 mg, 0.69 mmol) in anhydrous THF (1 mL) was added LiHMDS (5.55 mL, 5.55 mmol, 1 M in THF) at 0 ℃. The reaction was stirred at 30 ℃ for 64 h. After cooling to r.t., the reaction mixture was diluted with ice-water (5 mL) and extracted with DCM (10 mL*2) . The combined organic layer was concentrated and purified by flash chromatography on silica gel (DCM/MeOH = 20/1) to afford 21b (90 mg, 37%yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d ₆) δ 7.73 (d, J =9.2 Hz, 1H) , 7.65 (dd, J = 9.2, 6.4 Hz, 1H) , 5.31 (m, 0.5 H) , 4.24 -4.09 (m, 2H) , 3.75 (m, 2H) , 3.40 -3.36 (m, 2H) , 3.18 -3.09 (m, 4H) , 3.07 -3.02 (m, 1H) , 2.84 -2.83 (m, 1H) , 2.19 -1.98 (m, 4H) , 1.86 -1.79 (m, 3H) , 1.07 (d, J = 6.4 Hz, 6H) .

Step 3. 4- ( (3S, 5S) -3, 5-dimethylpiperazin-1-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinoline-3-carbonitrile (21c)

A solution of 21b (50 mg, 0.096 mmol) , ( (2-fluoro-6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (59 mg, 0.16 mmol) , cataCXium (R) APd G3 (14 mg, 0.019 mmol) and K ₃PO ₄ (41 mg, 0.19 mmol) in THF (0.5 mL) and H ₂O (0.1 mL) was stirred at 60 ℃ for 20 h in a sealed tube under N ₂ atmosphere. The reaction mixture was cooled, concentrated and purified by flash chromatography on silica gel (DCM/MeOH = 20/1) to afford 21c (60 mg, 76%yield) as a brown solid. LC-MS (Method 3) t _R = 0.77 min, m/z (M+H) ⁺ = 826.8.

Step 4. 4- ( (3S, 5S) -3, 5-dimethylpiperazin-1-yl) -8-fluoro-7- (7-fluoro-3-hydroxy-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinoline-3-carbonitrile hydrochloride (21d)

A solution of 21c (60 mg, 0.072 mmol) in HCl/EtOAc (1.5 mL, 2 M) was stirred at r.t. for 0.5 h. The reaction mixture was concentrated to afford 21d (58 mg, yield given) as an off-white solid. LC-MS (Method 3) t _R = 0.67 min, m/z (M+H) ⁺ = 782.1.

Step 5. 4- ( (3S, 5S) -3, 5-dimethylpiperazin-1-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8 -fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinoline-3-carbonitrile (21)

A solution of 21d (58 mg, 0.074 mmol) and CsF (135mg, 0.89 mmol) in DMF (1 mL) was stirred at 40 ℃ for 4 h. The reaction mixture was filtered and the filtrate was purifited by Prep-HPLC (Method A) to afford 21 (25 mg, 54%yield) as a yellow solid. LC-MS (Method 1) t _R = 3.44 min, m/z (M+H) ⁺ = 626.1. ¹H NMR (400 MHz, DMSO-d ₆) δ 10.12 (s, 1H) , 7.96 (dd, J = 8.8, 5.6 Hz, 1H) , 7.83 -7.78 (m, 1H) , 7.48 -7.43 (m, 1H) , 7.39 -7.34 (m, 2H) , 7.09 -7.07 (m, 1H) , 5.37 (s, 0.5 H) , 5.24 (s, 0.5 H) , 4.23 -4.07 (m, 2H) , 3.88 -3.76 (m, 3H) , 3.43 -3.40 (m, 2H) , 3.27 -2.98 (m, 6H) , 2.86 -2.80 (m, 1H) , 2.24 -2.00 (m, 3H) , 1.85 -1.79 (m, 3H) , 1.14 -1.11 (m, 6H) .

Example 22

Step 1. Tert-butyl (R) -4- (7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl) -3-methylpiperazine-1-carboxylate (22a)

To a solution of 1d (150 mg, 0.47 mmol) in DCM (2 mL) was added DIEA (182 mg, 1.41 mmol) and tert-butyl (R) -3-methylpiperazine-1-carboxylate (113 mg, 0.56 mmol) at 0 ℃. After stirring at 30 ℃ for 12 h, the reaction mixture was concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 3/1) to afford 22a (350 mg, 89%yield) as a yellow solid. LC-MS (Method 3) t _R = 1.79 min, m/z (M+H) ⁺ = 483.0.

Step 2. Tert-butyl (R) -4- (7-bromo-3-cyano-8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinolin-4-yl) -3-methylpiperazine-1-carboxylate (22b)

To a solution of 22a (100 mg, 0.21 mmol) and ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (50 mg, 0.32 mmol) in anhydrous THF (1 mL) was added LiHMDS (1.2 mL, 1.2 mmol, 1 M in THF) at 0 ℃. After stirring at 30 ℃ overnight, the reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (PE/EA = 2/1) to afford 22b (115 mg, 91%yield) as a yellow oil. LC-MS (Method 3) t _R = 2.00 min, m/z (M+H) ⁺ = 606.2.

Step 3. (R) -tert-butyl 4- (3-cyano-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a-yl) methoxy) quinolin-4-yl) -3-methylpiperazine-1-carboxylate (22c)

To a solution of 22b (50 mg, 0.82 mmol) , cataCXium (R) APd G3 (12 mg, 0.016 mmol) and K ₃PO ₄ (53 mg, 0.25 mmol) in THF/H ₂O (5/1, 0.6 mL) was added ( (2-fluoro-6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (63 mg, 0.12 mmol) under N ₂ atmosphere. After stirring at 60 ℃for 3 h under N ₂ atmosphere, the reaction was concentrated and the residue was purified by flash chromatography on silica gel (PE/EA = 2/1) to afford 22c (60 mg, 80%yield) as a yellow oil. LC-MS (Method 3) t _R = 1.20 min, m/z (M+H) ⁺ = 912.8.

Step 4. 8-Fluoro-7- (7-fluoro-3-hydroxy-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a-yl) methoxy) -4- ( (R) -2-methylpiperazin-1-yl) quinoline-3-carbonitrile hydrochloride (22d)

To a solution of 22c (60 mg, 0.07 mmol) in EtOAc (1 mL) was added HCl/EtOAc (1 mL, 2 M) at 0 ℃. The mixture was stirred at r. t. for 1 h. The solid was filtered and dried to afford 22d (45 mg, 85%yield) as a yellow solid. LC-MS (Method 3) t _R = 1.21 min, m/z (M+H) ⁺ =768.3.

Step 5. 7- (8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- ( (R) -2-methylpiperazin-1-yl) quinoline-3-carbonitrile (22)

A mixture of 22d (45 mg, 0.056 mmol) and CsF (58 mg, 0.88 mmol) in DMF (0.5 mL) was stirred at 40 ℃ for 3 h. The reaction mixture was filtered and the filtrate was purified by Prep-HPLC (Method A) to afford 22 (18 mg, 53%yield) as a yellow solid. LC-MS (Method 2) t _R = 2.89 min, 3.12 min, m/z (M+H) ⁺ = 612.3. ¹H NMR (400 MHz, DMSO-d ₆) δ 10.12 (s, 1H) , 7.97 (dd, J = 9.2, 6.0 Hz, 1H) , 7.90 -7.86 (m, 1H) , 7.48 -7.44 (m, 1H) , 7.42 -7.37 (m, 2H) , 7.09 (dd, J = 8.4, 2.4 Hz, 1H) , 5.38 (s, 0.5H) , 5.26 (s, 0.5H) , 4.21 -4.17 (m, 2H) , 4.08 -4.06 (m, 1H) , 3.82 -3.75 (m, 2H) , 3.11 -3.10 (m, 5H) , 2.92 -2.73 (m, 4H) , 2.21 -2.12 (m, 1H) , 2.08 -2.02 (m, 3H) , 1.84 (s, 3H) , 1.24 -1.16 (m, 3H) .

Example 23

Step 1. Tert-butyl (S) -4- (7- (8-bromo-3- (methoxymethoxy) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -2 - (cyanomethyl) piperazine-1-carboxylate (23a)

To a stirred solution of 9b (23 mg, 0.043 mmol) and 16d (33 mg, 0.095 mmol) in anhydrous 1, 4-dioxane (1 mL) was added XantPhos Pd G3 (6.5 mg, 0.0068 mmol) and Cs ₂CO ₃ (30 mg, 0.092 mmol) . The resulting mixture was stirred at 110 ℃ under nitrogen atmosphere for 16 h. After cooling down to r. t., the mixture was filtered and the filtrate was concentrated under vacuum to give a residue which was purified by Prep-HPLC (Method E) to afford compound 23a (7 mg, 21%yield) as a white solid. LC-MS (Method 4) t _R = 4.17 min, m/z (M+H) ⁺ = 794.3.

Step 2. 2- ( (S) -4- (7- (8-bromo-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (23b)

A solution of 23a (7 mg, 0.009 mmol) in MeOH (1 mL) and conc. HCl (0.05 mL) was stirred at 65 ℃ for 16 h. After cooling down to r. t., the reaction solution was concentrated and the residue was purified by Prep-HPLC (Method E) to afford compound 23b (4 mg, 70%yield) as a white solid. LC-MS (Method 4) t _R = 1.14 min, m/z (M+H) ⁺ = 650.2.

Step 3. 2- ( (S) -4- (2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (3-hydroxy -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (23c)

To a solution of 23b (2.4 mg, 0.004 mmol) and ethynyltriisopropylsilane (6.7 mg, 0.037 mmol) in anhydrous DMA (1 mL) was added CuI (1.0 mg, 0.0052 mmol) , Pd (PPh ₃) ₂Cl ₂ (1.2 mg, 0.0017 mmol) and DIEA (0.007 mL, 0.04 mmol) . The resulting mixture was stirred at 100 ℃ under nitrogen atmosphere for 5 h. Then the mixture was allowed to cool down to r.t. and filtered. The filtrate was concentrated and the residue was purified by Prep-HPLC (Method E) to give the mixture compound 23c (2 mg, 72%yield) as a white solid. LC-MS (Method 4) t _R = 3.50 min, m/z (M+H) ⁺ = 752.5.

Step 4. 2- ( (S) -4- (7- (8-ethynyl-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyr rolizin-7a (5H) -yl) methoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (23)

To a solution of 23c (2.0 mg, 0.0026 mmol) in THF (1 mL) was added TBAF (0.004 mL, 1 M in THF, 0.004 mmol) at 0 ℃, and the resulting reaction solution was stirred at 0 ℃ for 1 h. Then the solvent was removed and the residue was purified by Prep-HPLC (Method F) to afford the compound 23 (1.3 mg, 82%yield) as a white solid. LC-MS (Method 4) t _R = 2.11 min, m/z (M+H) ⁺ = 596.3. ¹H NMR (400 MHz, CDCl ₃) δ 7.65 (d, J = 8.0 Hz, 1H) , 7.39 (d, J = 7.2 Hz, 1H) , 7.28 (t, J = 7.2 Hz, 1H) , 7.19 (d, J = 2.4 Hz, 1H) , 7.07 (d, J = 2.4 Hz, 1H) , 5.35-5.22 (m, 1H) , 4.43-4.36 (m, 1H) , 4.14-4.01 (m, 1H) , 3.88-3.79 (m, 2H) , 3.71-3.61 (m, 3H) , 3.43-3.33 (m, 2H) , 3.29-3.13 (m, 3H) , 3.02-2.83 (m, 4H) , 2.76-2.62 (m, 2H) , 2.53-2.28 (m, 3H) , 2.21-2.07 (m, 2H) , 2.03-1.86 (m, 3H) .

Example 24

Step 1. (8-Fluoro-3- (methoxymethoxy) naphthalen-1-yl) boronic acid (24b)

To a solution of 24a (150 mg, 4.52 mmol) in acetone (1.5 mL) was added HCOONH ₄ (114 mg, 1.81 mmol) in H ₂O (1.5 mL) followed by NaIO ₄ (390 mg, 1.81 mmol) . After stirring at r.t. for 16 h, the reaction mixture was diluted with water (3 mL) and extracted with EtOAc (5 mL*3) . The combined organic layer was concentrated and the residue was purified by flash chromatography on silica gel (PE/EA = 2/1) to afford 24b (62 mg, 55%yield) as a yellow solid. LC-MS (Method 3) t _R = 1.06 min, m/z (M+H) ⁺ = 251.2.

Step 2. Tert-butyl 2-chloro-4- (3-hydroxy-3-methylpiperidin-1-yl) -8-oxo-5, 8-dihydropyrido [3, 4-d] pyrimidine -7 (6H) -carboxylate (24c)

A mixture of 3-methylpiperidin-3-ol hydrochloride (500 mg, 3.30 mmol) , 7b (1.00 g, 3.14 mmol) and TEA (1.27 g, 12.57 mmol) in DCM (0.5 mL) was stirred at 20 ℃ for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (PE/EA = 10/1) to afford 24c (850 mg, 68%yield) as a yellow solid. LC-MS (Method 3) t _R = 1.06 min, m/z (M+H) ⁺ = 397.0.

Step 3. 2-Chloro-4- (3-hydroxy-3-methylpiperidin-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one 2, 2, 2-trifluoroacetate (24d)

A solution of 24c (550 mg, 1.39 mmol) in TFA/DCM (5 mL, v/v = 3/1) was stirred at 25 ℃ for 4 h. The solvent was removed by pumping N ₂ and the residue was lyophilized with water (10 mL) to afford 24d (450 mg, 79%yield) as a yellow solid. LC-MS (Method 3) t _R =0.97 min, m/z (M+H) ⁺ = 297.2.

Step 4. 2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a-yl) methoxy) -4- (3-hydroxy-3-methylpiperidin-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one (24e)

A solution of 24d (400 mg, 1.35 mmol) and [ (2R, 8S) -2-fluoro-1, 2, 3, 5, 6, 7-hexahydropyrrolizin-8-yl] methanol (429 mg, 2.70 mmol) in LiHMDS (4 mL, 1 M in THF ) was stirred at 70 ℃ overnight. After cooling to r.t., the reaction mixture was quenched with water (1 mL) and concentrated. The residue was purified by Prep-HPLC (Method A) to afford 24e (96 mg, 17%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.18 (s, 1H) , 5.30 (s, 0.5H) , 5.19 (s, 0.5H) , 4.34 (s, 1H) , 3.97 (d, J = 10.0 Hz, 1H) , 3.87 (d, J = 10.0 Hz, 1H) , 3.65 -3.62 (m, 1H) , 3.25 -2.89 (m, 7H) , 2.76 -2.69 (m, 2H) , 2.57 -2.50 (m, 1H) , 2.15 -1.68 (m, 8H) , 1.63 -1.44 (m, 3H) , 1.08 (s, 3H) .

Step 5. 7- (8-Fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a-yl) methoxy) -4- (3-hydroxy-3-methylpiperidin-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one (24f)

A mixture of 24e (85 mg, 0.20 mmol) , 24b (56 mg, 0.22 mmol) and Cu ₂ (TMEDA) (OH) ₂Cl ₂ (47 mg, 0.10 mmol) in DCM (0.5 mL) was stirred at r.t. overnight under O ₂ atmosphere. The mixture was diluted with DCM (6 mL) , washed with water (4 mL) and brine (4 mL) . The separated organic layer was concentrated and the residue was purified by Prep-TLC (DCM/MeOH = 10/1) to afford 24f (17 mg, 13%yield) as a yellow solid. LC-MS (Method 3) t _R = 1.58 min, m/z (M+H) ⁺ = 624.4.

Step 6. 7- (8-Fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a -yl) methoxy) -4- (3-hydroxy-3-methylpiperidin-1-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one (24)

To a solution of 24f (15 mg, 0.024 mmol) in EtOAc (1 mL) was added HCl/EtOAc (3 mL, 2 M) at 0 ℃. After stirring at r.t. for 2 h, the reaction mixture was concentrated. The residue was purified by Prep-HPLC (Method A) to afford compound 24 (4.7 mg, 34%yield) as a white solid. LC-MS (Method 1) t _R = 2.76 min, m/z (M+H) ⁺ = 580.3. ¹H NMR (400 MHz, DMSO-d ₆) δ 10.23 (s, 1H) , 7.62 (d, J = 8.0 Hz, 1H) , 7.42 -7.37 (m, 1H) , 7.24 (d, J = 2.0 Hz, 1H) , 7.13 (d, J = 2.0 Hz, 1H) , 7.05 -6.99 (m, 1H) , 5.33 (s, 0.5H) , 5.20 (s, 0.5H) , 4.56 -4.49 (m, 1H) , 4.01 (d, J = 10.0 Hz, 1H) , 3.91 (d, J = 10.4 Hz, 1H) , 3.72 -3.66 (m, 4H) , 3.25 -2.79 (m, 8H) , 2.16 -1.95 (m, 4H) , 1.93 -1.71 (m, 3H) , 1.63 -1.44 (m, 3H) , 1.12 (d, J = 4.8 Hz, 3H) .

Example 25

Step 1. 6- (8- (Tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -5- (2- ( (tert-butoxycarbonyl) amino) ethyl) -2- (2- (1-methyl-1H-imidazol-2-yl) ethoxy) pyrimidine-4-carboxylic acid (25a)

To a solution of 20a (500 mg, 1.01 mmol) in dioxane (9 mL) were added 2- (1-methyl-1H-imidazol-2-yl) ethan-1-ol (192 mg, 2.02 mmol) and t-BuONa (144 mg, 1.5 mmol) at 25 ℃. The mixture was stirred at 90 ℃ for 3 h. The mixture was diluted with H ₂O (5 mL) , extracted with EA (20 mL*3) , washed with brine (20 mL) , dried over Na ₂SO ₄, concentrated and purified by flash chromatography on silica gel (DCM/MeOH from 100/1 to 10/1) to get compound 25a (200 mg, 33%yield) as a white solid. LC-MS (Method 4) t _R = 1.89 min, m/z (M+H) ⁺ = 602.4.

Step 2. 5- (2-Aminoethyl) -6- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- (2- (1-methyl-1H-imidazol-2-yl) ethoxy) pyrimidine-4-carboxylic acid (25b)

To a solution of 25a (200 mg, 0.33 mmol) in CH ₃CN (2 mL) was added HCl/dioaxne (2 ml, 4 M) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 6 h, concentrated and adjusted to pH > 7 with aq Na ₂CO ₃ solution. Then the organic layer was concentrated and purified by flash chromatography on sillca gel (DCM/MeOH from 100/1 to 7/1) to give compound 25b (110 mg, 83%yield) as a yellow solid. LC-MS (Method 4) t _R = 1.58 min, m/z (M+H) ⁺ = 402.3.

Step 3. 4- (3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- (2- (1-methyl-1H-imidazol-2-yl) ethoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one (25c)

To a solution of 25b (110 mg, 0.27 mmol) in DMF (1 mL) was added HATU (154 mg, 0.40 mmol) and DIEA (103 mg, 0.8 mmol) at 25 ℃. The reaction mixture was stirred at 25 ℃for 4 h, diluted with H ₂O (5 mL) , extracted with EA (20 mL*3) , washed with brine (20 mL) , dried over Na ₂SO ₄, concentrated and purified by flash chromatography on silica gel (DCM/MeOH from 100/1 to 10/1) to get compound 25c (50 mg, 48%yield) as a yellow solid. LC-MS (Method 4) t _R = 2.81 min, m/z (M+H) ⁺ = 384.3.

Step 4. Tert-butyl 3- (2- (2- (1-methyl-1H-imidazol-2-yl) ethoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (25d)

To a solution of 25c (50 mg, 0.13 mmol) in THF (1mL) was added Boc ₂O (56 mg, 0.26 mmol) and DIEA (26 mg, 0.26 mmol) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 4 h, diluted with H ₂O (5 mL) , extracted with EA (20 mL*3) , washed with brine (20 mL) , dried over Na ₂SO ₄, concentrated and purified by flash chromatography on silica gel (DCM/MeOH from 100/1 to 15/1) to get compound 25d (60 mg, 95%yield) as a yellow solid. LC-MS (Method 4) t _R = 3.81 min, m/z (M+H) ⁺ = 484.3.

Step 5. Tert-butyl 3- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -2- (2- (1-methyl-1H-imidazol-2-yl) ethoxy) -8-oxo-5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8 -carboxylate (25e)

To a solution of 25d (60 mg, 0.12 mmol) , 1-bromo-8-chloro-3- (methoxymethoxy) naphthalene (56 mg, 0.18mmol) in dioxane (2 mL) was added XantPhos Pd G3 (11 mg, 0.012 mmol) and Cs ₂CO ₃ (78 mg, 0.24 mmol) at 25 ℃. The reaction mixture was stirred at 100 ℃ for 15 h under N ₂ atmosphere, diluted with H ₂O (5 mL) , extracted with EA (20 mL*3) , washed with brine (20 mL) , dried over Na ₂SO ₄, concentrated and purified by flash chromatography on silica gel (DCM/MeOH from 100/1 to 10/1) to get compound 25e (25 mg, 30%yield) as a yellow solid.

LC-MS (Method 4) t _R = 3.36 min, m/z (M+H) ⁺ = 704.3.

Step 6. 4- (3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-chloro-3-hydroxynaphthalen-1-yl) -2- (2- (1-methyl-1H-imidazol-2-yl) ethoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one (25)

To a solution of 25e (25 mg, 0.035 mmol) in CH ₃CN (1 mL) was added HCl/dioxane (1 mL, 4 M) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 5 h, concentrated and purified by Prep-HPLC (Method E) to give compound 25 (3.3 mg, 17%yield) as an off-white solid. LC-MS (Method 4) t _R = 1.05 min, m/z (M+H) ⁺ = 560.3.

1H NMR (400 MHz, CD ₃OD) δ 8.50 (s, 1H) , 7.72 -7.65 (m, 1H) , 7.32 (s, 1H) , 7.31 (d, J = 4.8 Hz, 1H) , 7.24 (d, J = 4.8 Hz, 1H) , 7.17 (d, J = 4.8Hz, 1H) , 6.98 (s, 1H) , 6.87 (s, 1H) , 4.68 (t, J = 7.6Hz, 3H) , 4.17 (d, J = 8.4Hz, 1H) , 4.05 -3.90 (m, 4H) , 3.90 -3.80 (m, 1H) , 3.69 (s, 3H) , 3.46 (d, J = 8.4Hz, 1H) , 3.35 (d, J = 8.4Hz, 1H) , 3.22 -3.06 (m, 5H) , 2.10 -2.01 (m, 2H) .

Example 26

Step 1. 2-Amino-7-bromo-8-fluoro-4-hydroxyquinoline-3-carbonitrile (26a)

To a solution of malononitrile (1.40 g, 21.15 mmol) in anhydrous DMF (30 mL) was added NaH (810 mg, 21.15 mmol, 60%purity in mineral oil) at r. t. . After stirring for 30 min at r.t., to the solution was added 1b (5 g, 19.23 mmol) . The mixture was stirred at 60 ℃ for 30 min. After cooling to r.t., the reaction mixture was diluted with H ₂O (150 mL) and acidified with conc. HCl to pH = 1. The resultant mixture was stirred for 1 h and filtered. The filtrate was concentrated under reduced pressure to afford 26a (4 g, 74%yield) as a white solid. LC-MS (Method 3) t _R = 0.34 min, m/z (M+H) ⁺ = 281.7.

Step 2. 2-Amino-7-bromo-4-chloro-8-fluoroquinoline-3-carbonitrile (26b)

A solution of 26a (5 g, 17.73 mmol) in POCl ₃ (8 mL) was stirred at 110 ℃ for 4 h. The reaction mixture was cooled down to r.t. and the solid was collected by filtering and dried to afford 26b (3.8 g, 71%yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d ₆) δ 9.33 (brs, 2H) , 7.72-7.67 (m, 1H) , 7.51-7.47 (m, 1H) .

Step 3. Tert-butyl 3- (2-amino-7-bromo-3-cyano-8-fluoroquinolin-4-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylate (26c)

To a solution of 26b (2.4 g, 7.99 mmol) , tert-butyl 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydropyrrole-1-carboxylate (2.12 g, 7.19 mmol) and Na ₂CO ₃ (3.39 g, 31.95 mmol) in 1, 4-dioxane/H ₂O/NMP (35 mL, v/v/v = 5/1/1) was added Pd (dppf) Cl ₂ (1.16 g, 1.60 mmol) at r. t. . The reaction was degassed with N ₂ for three times and stirred at 40 ℃ overnight. The suspension was filtered and the filtrate was diluted with EtOAc (50 mL) , washed with water (15 mL) and brine (15 mL) . The separated organic layer was concentrated and the residue was purified by flash chromatography on silica gel (DCM/EA = 15/1) to afford compound 26c (1.69 g, 49%yield) as a red solid. LC-MS (Method 3) t _R = 1.80 min, m/z (M+H) ⁺ = 433.1.

Step 4. Tert-butyl 3- (7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylate (26d)

To a solution of 26c (1.4 g, 3.23 mmol) in ACN (20 mL) was added tert-butyl nitrite (666 mg, 6.46 mmol) . After stirring at r.t. for 10 min, to the reaction was added CuCl (640 mg, 6.46 mmol) . The reaction was stirred at r.t. overnight and diluted with water (10 mL) and NH ₃ ^. H ₂O (4 mL) . The mixture was extracted with EtOAc (15 mL*3) and the combined organic layer was concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 4/1) to afford compound 26d (645 mg, 44%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d ₆) δ8.03-8.01 (m, 1H) , 7.95 (d, J = 9.2 Hz, 1H) , 6.41-6.35 (m, 1H) , 4.47-4.45 (m, 2H) , 4.39 (s, 2H) , 1.47-1.42 (m, 9H) .

Step 5. 7-Bromo-8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (1H-pyrrol-3-yl) quinoline-3-carbonitrile (26e)

To a solution of 26d (93 mg, 0.21 mmol) and ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (49 mg, 0.31 mmol) in anhydrous THF (1.5 mL) was added LiHMDS (0.82 mL, 0.82 mmol, 1 M in THF) at 0 ℃. Then the mixture was stirred at r.t. overnight and quenched with H ₂O (3 mL) . The resultant mixture was extracted with EtOAc (5 mL*2) . The combined organic layer was concentrated and the residue was purified by flash chromatography on silica gel (PE/EA = 2/1) to afford compound 26e (25 mg, 26%yield) as a yellow solid. LC-MS (Method 3) t _R = 1.85 min, m/z (M+H) ⁺ = 473.1.

Step 6. 8-Fluoro-7- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (1H-pyrrol-3-yl) quinoline-3-carbonitrile (26f)

A mixture of 26e (25 mg, 0.053 mmol) , 24a (23 mg, 0.069 mmol) , K ₂CO ₃ (15 mg, 0.11 mmol) and Pd (dppf) Cl ₂ (8 mg, 0.010 mmol) in DMSO/1, 4-dioxane/H ₂O (0.5 mL/0.5 mL/0.1 mL) was stirred at 100 ℃ for 2 h under N ₂ atmosphere. The reaction mixture was diluted with EtOAc (8 mL) , washed with water (3 mL) . The organic layer was concentrated and the residue was purified by flash chromatography on silica gel (DCM/MeOH = 20/1) to afford compound 26f (18 mg, 57%yield) as a yellow oil. LC-MS (Method 3) t _R = 1.63 min, m/z (M+H) ⁺ = 599.5.

Step 7. 8-Fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -4- (1H-pyrrol-3-yl) quinoline-3-carbonitrile (26)

To a solution of 26f (18 mg, 0.030 mmol) in EtOAc (0.5 mL) was added HCl/EtOAc (1 mL, 2 M) . After stirring at r.t. for 30 min, the reaction mixture was concentrated and the residue was purified by Prep-HPLC (Method A) to give compound 26 (4.4 mg, 26%yield) as a white solid. LC-MS (Method 2) t _R = 3.34 min, m/z (M+H) ⁺= 555.0. ¹H NMR (400 MHz, DMSO-d ₆) δ 11.66 (s, 1H) , 8.01 (d, J = 8.4 Hz, 1H) , 7.66 (d, J = 8.4 Hz, 1H) , 7.54 (t, J = 8.0 Hz, 1H) , 7.40 (m, 2H) , 7.09 (s, 1H) , 7.05 (d, J = 2.0 Hz, 1H) , 6.99 (m, 2H) , 6.58 (s, 1H) , 5.40-5.24 (m, 1H) , 4.30-4.21 (m, 2H) , 3.26-3.04 (m, 3H) , 2.87-2.81 (m, 1H) , 2.23-2.01 (m, 3H) , 1.92-1.83 (m, 3H) .

Example 27

Step 1. Tert-butyl 3- (2-amino-7-bromo-3-cyano-8-fluoroquinolin-4-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (27a)

A mixture of 26b (1.37 g, 4.56 mmol) , tert-butyl 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (1.13 g, 3.65 mmol) , Na ₂CO ₃ (3.38 g, 31.91 mmol) and Pd (dppf) Cl ₂ (662 mg, 0.91 mmol) in 1, 4-dioxane (15 mL) , H ₂O (3 mL) and NMP (3 mL) was stirred at 35 ℃ for 18 h under N ₂ atmosphere. After cooling to r. t., the mixture was diluted with H ₂O (10 mL) and extracted with EtOAc (25 mL*2) . The combined organic layer was concentrated. The residue was purified by flash chromatography on silica gel (DCM/EtOAc = 30/1) to afford compound 27a (980 mg, 48%yield) as a yellow solid. LC-MS (Method 3) t _R = 1.66 min, m/z (M+H) ⁺ = 447.1.

Step 2. Tert-butyl 3- (7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (27b)

To a mixture of 27a (1.02 g, 2.28 mmol) and tert-butyl nitrite (353 mg, 3.42 mmol) in ACN (25 mL) was added CuCl (452 mg, 4.56 mmol) . After stirring at r.t. for 18 h, the mixture was diluted with H ₂O (15 mL) and sat. NH ₃. H ₂O (5 mL) and extracted with EtOAc (30 mL*2) . The combined organic layer was concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 10/1) to afford compound 27b (482 mg, 45%yield) as a yellow solid. LC-MS (Method 3) t _R = 1.88 min, m/z (M-56+H) ⁺ = 410.0.

Step 3. Tert-butyl (S) -5- (7-bromo-3-cyano-8-fluoro-2- ( (1-methylpyrrolidin-2-yl) methoxy) quinolin-4-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (27c)

To a solution of 27b (150 mg, 0.32 mmol) and (S) - (1-methylpyrrolidin-2-yl) methanol (74 mg, 0.64 mmol) in THF (4 mL) was added LiHMDS (0.96 mL, 0.96 mmol, 1.0 M in THF) at 0 ℃. The mixture was stirred at r. t. for 2 h and poured into H ₂O (5 mL) . The mixture was extracted with EtOAc (15 mL*2) and the combined organic layer was concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 2/1) to afford compound 27c (146 mg, 83%yield) as a yellow solid. LC-MS (Method 3) t _R = 1.85 min, m/z (M+H) ⁺ =545.3.

Step 4. Tert-butyl (S) -5- (3-cyano-8-fluoro-7- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( (1-methylpyrrolidin-2-yl) methoxy) quinolin-4-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (27d)

A solution of 27c (135 mg, 0.25 mmol) , 24a (99 mg, 0.30 mmol) , K ₂CO ₃ (102 mg, 0.74 mmol) and Pd (dppf) Cl ₂ (18 mg, 0.025 mmol) in 1, 4-dioxane (3 mL) and H ₂O (1 mL) was stirred at 80 ℃ for 2 h under N ₂ atmosphere. The mixture was concentrated and the residue was purified by flash chromatography on silica gel (DCM/MeOH = 20/1) to afford compound 27d (105 mg, 63%yield) as a yellow soild. LC-MS (Method 3) t _R = 2.12 min, m/z (M+H) ⁺ =671.5.

Step 5. (S) -8-Fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (1-methylpyrrolidin-2-yl) methoxy) -4- (1, 2, 5, 6-tetrahydropyridin-3-yl) quinoline-3-carbonitrile (27)

A solution of 27d (25 mg, 0.037 mmol) in HCl/EtOAc (1 mL, 2.0 M) and EtOAc (0.5 mL) was stirred at r.t. for 1 h. The mixture was concentrated and the residue was purified by Prep-HPLC (Method A) to afford compound 27 (5 mg, 25%yield) as a yellow solid. LC-MS (Method 2) t _R = 3.21 min, m/z (M+H) ⁺ = 527.0. ¹H NMR (400 MHz, DMSO-d ₆) δ 10.27 (brs, 1H) , 7.86 (d, J = 8.4 Hz, 1H) , 7.67 (d, J = 8.4 Hz, 1H) , 7.64-7.58 (m, 1H) , 7.46-7.40 (m, 1H) , 7.35-7.06 (m, 2H) , 7.02-6.97 (m, 1H) , 6.14-6.12 (m, 1H) , 4.53-4.40 (m, 2H) , 3.53-3.48 (m, 2H) , 3.23-2.90 (m, 3H) , 2.72-2.67 (m, 1H) , 2.43-2.41 (m, 3H) , 2.33-2.18 (m, 4H) , 2.02-1.95 (m, 1H) , 1.77-1.67 (m, 3H) .

Example 28

Step 1. Tert-butyl 3- (7-bromo-3-cyano-8-fluoro-2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a-yl) methoxy) quinolin-4-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylate (28a)

To a solution of ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (74 mg, 0.46 mmol) in THF (1.5 mL) was added LiHMDS (0.46 mL, 0.46 mmol, 1 M in THF) at 0 ℃. After stirring at r.t. for 30 min, the reaction mixture was cooled to 0 ℃ and to the reaction mixture was added 26d (140 mg, 0.31 mmol) . The reaction was stirred at r.t. for 4 h and quenched with ice water (5 mL) . The resultant mixture was extracted with EtOAc (8 mL*2) and the combined organic layer was concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 2/1) to afford compound 28a (130 mg, 73%yield) as a yellow solid. LC-MS (Method 3) t _R = 0.99 min, m/z (M+H) ⁺ = 575.1.

Step 2. Tert-butyl 3- (3-cyano-8-fluoro-7- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a-yl) methoxy) quinolin-4-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylate (28b)

A solution of 28a (110 mg, 0.19 mmol) , 24a (70 mg, 0.21 mmol) , K ₂CO ₃ (53 mg, 0.38 mmol) and Pd (dppf) Cl ₂ (28 mg, 0.038 mmol) in 1, 4-dioxane/H ₂O (1 mL/0.2 mL) was stirred at 60 ℃ for 4 h under N ₂. Then the mixture was diluted with EtOAc (10 mL) and washed with H ₂O (5 mL) . The organic layer was concentrated and the residue was purified by flash chromatography on silica gel (DCM/MeOH = 20/1) to afford compound 28b (91 mg, 68%yield) as a yellow oil. LC-MS (Method 3) t _R = 1.06 min, m/z (M+H) ⁺ = 701.3.

Step 3. Tert-butyl 3- (3-cyano-8-fluoro-7- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a-yl) methoxy) quinolin-4-yl) pyrrolidine-1-carboxylate (28c)

A mixture of 28b (91 mg, 0.13 mmol) , Pd/C (80 mg, 10%wt wet in 50%water) and Pd (OH) ₂ (80 mg) in EtOH (2 mL) was stirred at r. t. overnight under 50 Psi H ₂. Then the mixture was filtered and washed with EtOH (6 mL) . The filtrate was concentrated to afford 28c (70 mg, 77%yield) as yellow oil. LC-MS (Method 3) t _R = 1.13 min, m/z (M+H) ⁺ = 703.2.

Step 4. 8-Fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a-yl) methoxy) -4- (pyrrolidin-3-yl) quinoline-3-carbonitrile hydrochloride (28)

To a solution of 28c (17 mg, 0.024 mmol) in EtOAc (1 mL) was added HCl/EtOAc (0.5 mL, 2 M) at 0 ℃. After stirring at r.t. for 2 h, the formed solid was filtered and triturated with ether (2 mL) . The solid was filtered and dried to afford compound 28 (8.0 mg, 52%yield) as a yellow solid. LC-MS (Method 2) t _R = 3.38 min, m/z (M+H) ⁺ = 559.1. ¹H NMR (400 MHz, DMSO-d ₆) δ 11.78 (s, 1H) , 10.38 (s, 1H) , 9.81 (s, 1H) , 9.63 (s, 1H) , 8.27 (d, J = 9.2 Hz, 1H) , 7.69 (m, 2H) , 7.43 (m, 1H) , 7.37 (t, J = 2.0 Hz, 1H) , 7.11 (t, J = 2.0 Hz, 1H) , 7.01 -6.97 (m, 1H) , 5.69 (s, 0.5H) , 5.56 (s, 0.5H) , 4.81 -4.67 (m, 2H) , 4.57 -4.52 (m, 1H) , 3.94 -3.75 (m, 4H) , 3.72 -3.59 (m, 2H) , 3.54 -3.43 (m, 1H) , 2.73 -2.50 (m, 4H) , 2.27 -2.20 (m, 2H) , 2.13 -1.91 (m, 3H) .

Example 29

Step 1. 2-Chloro-4- (3, 5-dimethyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one (29a)

A solution of 14a (300 mg, 1.38 mmol) , 3, 5-dimethyl-1- (tetrahydro-2H-pyran-2-yl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H -pyrazole (421 mg, 1.38 mmol) , Pd (PPh ₃) ₄ (159 mg, 0.138 mmol) , Na ₂CO ₃ (438 mg, 4.13 mmol) in dioxane (5 mL) and H ₂O (1 mL) was stirred at 85 ℃ for 4 h. The mixture was concentrated and the residue was purified by flash chromatography on silica gel (DCM/MeOH from 100/1 to 20/1) to get compound 29a (100 mg, 20%yield) as a yellow solid. LC-MS (Method 4) t _R = 2.41 min, m/z (M+H) ⁺ = 362.2.

Step 2. 4- (3, 5-Dimethyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one (29b)

To a solution of 29a (80 mg, 0.22 mmol) , ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (106 mg, 0.66 mmol) in dioxane (1 mL) was added

molecular sieve (80 mg) and DIEA (86 mg, 0.66 mmol) . Then the mixture was stirred at 110 ℃ for 48 h. The mixture was concentrated and the residue was purified by flash chromatography on silica gel (DCM/MeOH from 50/1 to 5/1) to get the compound 29b as a yellow solid. LC-MS (Method 4) t _R = 3.16 min, m/z (M+H) ⁺ = 485.4.

Step 3. 7- (8-Chloro-3- (methoxymethoxy) naphthalen-1-yl) -4- (3, 5-dimethyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one (29c)

A solution of 29b (30 mg, 0.062 mmol) , 1-bromo-8-chloro-3- (methoxymethoxy) naphthalene (37 mg, 0.12 mmol) , XantPhos Pd G3 (10 mg, 0.012 mmol, Cs ₂CO ₃ (50 mg, 0.155 mmol) in dioxane (1 mL) was stirred at 110 ℃ for 24 h. The mixture was concentrated and the residue was purified by flash chromatography on silica gel (DCM/MeOH from 50/1 to 15/1) to get the compound 29c (10 mg, 23%yield) as a yellow solid. LC-MS (Method 4) t _R = 2.65 min, m/z (M+H) ⁺ = 705.4.

Step 4. 7- (8-Chloro-3-hydroxynaphthalen-1-yl) -4- (3, 5-dimethyl-1H-pyrazol-4-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 7-dihydropyrido [3, 4-d] pyrimidin-8 (5H) -one formic acid (29)

To a solution of 29c (10 mg, 0.014 mmol) in ACN (0.5 mL) was added HCl (0.5 mL, 4 M in dioxane) at an ice-bath, then the mixture was stirred at r.t. for 2 h. The mixture was concentrated and the residue was purified by Prep-HPLC (Method F) to get the compound 29 (5.6 mg, 68%yield) as a pale yellow solid. LC-MS (Method 4) t _R = 3.08 min, m/z (M+H) ⁺ =577.4. ¹H NMR (400 MHz, DMSO-d ₆) δ 7.82-7.78 (m, 1H) , 7.39-7.37 (m, 2H) , 7.30-7.28 (m, 2H) , 5.35-5.21 (s, 1H) , 4.11-4.07 (m, 1H) , 4.04-4.01 (m, 1H) , 3.92-3.88 (m, 2H) , 3.11-3.08 (m, 3H) , 3.02-2.97 (m, 2H) , 2.89-2.80 (m, 1H) , 2.20 (s, 6H) , 2.17-2.13 (m, 1H) , 2.08-1.99 (m, 3H) , 1.87-1.73 (m, 2H) .

KRAS-G12D Surface Plasmon Resonnance (SPR) Binding Assay

This example illustrates that exemplary compounds of the present invention bind to KRAS-G12D protein that was measured with Surface plasmon Resonance (SPR) assay in the presence of GTP analogue, GppNHp or not.

For GppNHp loading, 20 μL 8.7 μLM Biotin-KRAS (G12D) (0.2 mg/ml) and 2 μL 80 mM GppNHp (mole ratio～1: 1000) were mixed and diluted to 200 ul (final volume) with incubation buffer (50 mM Hepes pH 7.4, 150 mM NaCl, 5 mM MgCl ₂, 10 mM EDTA and 0.01%Triton X-100) and incubated under 30 ℃ for 1 h. 20 mM of MgCl ₂ (final concentration) was added to stop the GppNHp release.

Prior to test, Biacore 8K (GE) instrument was primed with 1X Running buffer (HBS-P+/10 mM MgCl ₂ /+0.5 mM TCEP 2%DMSO, flow rate: 100 μL/mL) before docking a GE Streptavidin (SA) chip and then primed two additional times prior to beginning the immobilization step. All immobilized protein mixtures were prepared with 20 μg/mL Biotinylated KRAS-G12D protein immobilization settings as below:

The sensor surface was conditioned with three consecutive 1-minute injections of 1 M NaCl in 50 mM NaOH before immobilization. After that, 20 μg/ml Biotin-KRAS (G12D) /Biotin-KRAS (G12D) -GppNHp was injected at 10 μL/min for 320 seconds. A wash using 50%isopropanol in 1 M NaCl and 50 mM NaOH was performed. All compounds were prepared to 10mM DMSO stock prior to being serially diluted by 3-fold to test their affinity to KRAS-G12D protein. Assay setting as below:

Running Buffer plus with 10 mM MgCl ₂, 0.5 mM TCEP and 2%DMSO was used as running buffer for the binding measurement and the experiment was performed under 25 ℃. The compound was diluted with the running buffer to 6-8 concentrations with 1: 2 serial dilution. The compound solutions with sequential concentrations were injected into channels at 100 μL/min, respectively. The binding and dissociation time were 40 and 120 seconds. Solvent correction was performed twice to correct the signals caused by DMSO and blank solution was injected twice to eliminate the reference’s signal. At the end of each cycle, 50%DMOS was injected to wash the system.

Data was analyzed by BIAcore Insight Evaluation Software. After reference and zero concentrations’ signals being subtracted from that of samples, binding kinetic parameters were curve-fitted by 1: 1 binding model and steady state affinity model

The result for exemplary compounds is shown in Table 2. ND=not determined.

KRAS-G12D/RAF1 Binding Assay

This example illustrates that exemplary compounds of present invention bind to KRAS-G12D protein and could block the interaction between KRAS-G12D and RAF1 protein.

The ability of compound to bind to KRAS-G12D protein and block the interaction between KRAS-G12D and RAF1 protein was measured with a Homogeneous Time-resolved Fluorescence (HTRF) assay kit (Cisbio, 63ADK000CB21PEG) . The compound blocking KRAS-G12D/RAF1 interaction will cause a reduction in HTRF signal.

All compounds were prepared to 10 mM DMSO stock prior to being serially diluted by 3-fold to test their activity in KRAS-G12D: RAF1 interaction blocking. Incubate diluted compound with GppNHp loaded Tag2-KRAS-G12D and Tag1-RAF1 for 15 min at Room Temperature. And then add dye labelled anti-Tag2 antibody and Europium conjugated anti-Tag1 antibody mixturex. After 2 hrs incubation at 4 ℃, read plate on Molecular Device (Spectra MAX i3X) plate reader with HTRF module. Data analysis was performed by GraphPad Prism 9 and IC50 was generated with four parameter fit method of dose response curve.

The result for exemplary compounds is shown in Table 2. ND=not determined.

Table 2 SPR and RAS-RAF1 Binding Values of Exemplary Compounds

Example	SPR_Kd, nM (GppNHp)	SPR_Kd, nM	RAS-RAF Binding (IC50, nM) (GppNHp)
1	30700	31500	12065.35
2	294000	195000	2008.41
3	13400	11900	1698.93
4	663000	209000	>20000
5	34500	27600	12174.7
6	1000	1030	453.34
7	ND	ND	>20000
8	3340	3560	21095.41
9	3430	3210	1343.3
10	6080	6010	368.77
11	39300	34300	>20000
12	6200	5340	>20000
13	ND	ND	2152.3
14	ND	ND	207.66
15A	ND	ND	79.5
15B	ND	ND	2451.15
16	ND	ND	225.3
17A	ND	ND	16269.9
18	ND	ND	376.2
19	ND	ND	4429.21
20	ND	ND	2347.77
21	ND	ND	968.35
22	ND	ND	570.15
24	ND	ND	4701.25
25	ND	ND	7243.77

It is to be understood that the foregoing description of preferred embodiments is intended to be purely illustrative of the principles of the invention, rather than exhaustive thereof, and that changes and variations will be apparent to those skilled in the art, and that the present invention is not intended to be limited other than expressly set forth in the following claims.

Claims

A nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof or a solvate thereof;

wherein,

X ¹ is C-R ^X1 or N; R ^X1 is hydrogen or halogen;

X ³ is C-H;

R ¹ is C ₆-C ₁₄ aryl, 5 to 14 membered heteroaryl, C ₆-C ₁₄ aryl substituted with one or more R ^1-1 or 5 to 14 membered heteroaryl substituted with one or more R ^1-2; in the 5 to 14 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^1-1 and R ^1-2 is independently halogen, cyano, hydroxy, C ₁-C ₄ alkyl, -S-C ₁-C ₃ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₁-C ₃ haloalkyl, -O-C ₁-C ₃ haloalkyl, C ₁-C ₃ alkoxy, -N (R ^N1) ₂ or C ₃-C ₆ cycloalkyl, wherein the C ₃-C ₆ cycloalkyl is optionally substituted with halogen or C ₁-C ₃ alkyl;

R ² is hydrogen, halogen or C ₁-C ₃ alkyl;

L ¹ is single bond, C ₁-C ₄ alkylene, -O-or -N (R ^N1) -;

R ³ is 3 to 12 membered heterocycloalkyl, 3 to 12 membered heterocycloalkyl substituted with one or more R ^3-1-1, or -L ²-R ^3-1;

L ² is -O-, -N (methyl) -, C ₁-C ₄ alkylene or C ₁-C ₄ alkylene substituted with one or more R ^L2; each of R ^L2 is independently hydroxy or C ₁-C ₄ hydroxyalkyl;

R ^3-1 is C ₃-C ₁₂ cycloalkyl, 3 to 12 membered heterocycloalkyl, C ₆-C ₁₄ aryl, 5 to 14 membered heteroaryl, -N (R ^N1) ₂, C ₃-C ₁₂ cycloalkyl substituted with one or more R ^3-1-1, 3 to 12 membered heterocycloalkyl substituted with one or more R ^3-1-2, C ₆-C ₁₄ aryl substituted with one or more R ^3-1-3 or 5 to 14 membered heteroaryl substituted with one or more R ^3-1-4; in the 3 to 12 membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 5 to 14 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; n is independently 0, 1, 2, 3 or 4;

each of R ^3-1-1, R ^3-1-2, R ^3-1-3 and R ^3-1-4 is halogen, cyano, oxo, C ₁-C ₄ alkyl or -N (R ^N1) ₂;

R ⁶ is -CN;

R ⁴ is C ₃-C ₇ cycloalkyl, C ₃-C ₇ cycloalkenyl, 3 to 12 membered nitrogen-containing heterocycloalkyl, 3 to 12 membered nitrogen-containing heterocycloalkenyl, C ₃-C ₆ cycloalkyl substituted with one or more R ^4-1, C ₃-C ₇ cycloalkenyl substituted with one or more R ^4-2, 3 to 12 membered nitrogen-containing heterocycloalkyl substituted with one or more R ^4-3 or 3 to 12 membered nitrogen-containing heterocycloalkenyl substituted with one or more R ^4-4; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^4-1, R ^4-2, R ^4-3 and R ^4-4 is independently oxo, hydroxy, cyano, halogen, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, C ₁-C ₃ cyanoalkyl, C ₃-C ₆ cycloalkyl, C ₁-C ₃ alkoxy or -N (R ^N1) ₂;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl.
The nitrogen-containing heterocyclic compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claim 1, wherein, the nitrogen-containing heterocyclic compound represented by formula I meets one or more of the following conditions:

1) R ² is hydrogen or halogen;

2) L ¹ is C ₁-C ₄ alkylene, -N (methyl) -or -O-;

3) in R ⁴, C ₃-C ₇ cycloalkyl, C ₃-C ₇ cycloalkenyl, 3 to 12 membered nitrogen-containing heterocycloalkyl and 3 to 12 membered nitrogen-containing heterocycloalkenyl are bridged ring;

4) R ⁴ meets the following conditions:
wherein, Z ¹ is independently CH, C or N; e is independently 0, 1, 2, 3 or 4; R ^Z1 is independently oxo, hydroxy, halogen, cyano, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, C ₁-C ₃ cyanoalkyl, C ₁-C ₃ hydroxyalkyl, C ₃-C ₆ cycloalkyl, -N (R ^N1) ₂, -CO ₂R ^N1, -CO ₂N (R ^N1) ₂ or a 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl; R ^Z2 is hydrogen or methyl;

5) R ⁴ is
wherein, Z ¹ is independently CH, C or N; ring A is 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; ring B is C ₃-C ₇ cycloalkyl, C ₃-C ₇ cycloalkenyl, 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; e is independently 0, 1, 2, 3 or 4; R ^Z1 is independently oxo, hydroxy, halogen, cyano, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, C ₁-C ₃ cyanoalkyl, C ₁-C ₃ hydroxyalkyl, C ₃-C ₆ cycloalkyl, -N (R ^N1) ₂, -CO ₂R ^N1, -CO ₂N (R ^N1) ₂ or a 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl; R ^Z2 is hydrogen or methyl;

6) R ⁴ is connected to
by a carbon atom or a nitrogen atom; R ⁴ is 3 to 12 membered nitrogen-containing heterocycloalkyl, 3 to 12 membered nitrogen-containing heterocycloalkenyl; 3 to 12 membered nitrogen-containing heterocycloalkyl substituted with one or more R ^4-3 or 3 to 12 membered nitrogen-containing heterocycloalkenyl substituted with one or more R ^4-4; in R ⁴, 3 to 12 membered nitrogen-containing heterocycloalkyl has “NH” , the “NH” is not connected with R ^4-3; in R ⁴, 3 to 12 membered nitrogen-containing heterocycloalkenyl has “NH” , the “NH” is not connected with R ^4-4;

7) R ⁴ is connected to
by a carbon atom or a nitrogen atom; R ⁴ is C ₃-C ₆ cycloalkyl substituted with one or more R ^4-1, C ₃-C ₇ cycloalkenyl substituted with one or more R ^4-2, 3 to 12 membered nitrogen-containing heterocycloalkyl substituted with one or more R ^4-3 or 3 to 12 membered nitrogen-containing heterocycloalkenyl substituted with one or more R ^4-4; one of R ^4-1 is NH ₂ or N (methyl) ; one of R ^4-2 is NH ₂ or N (methyl) ; one of R ^4-3 is NH ₂ or N (methyl) ; one of R ^4-3 is NH ₂ or N (methyl) .
The nitrogen-containing heterocyclic compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claim 2, wherein, the nitrogen-containing heterocyclic compound represented by formula I meets one or more of the following conditions:

8) R ¹ is C ₆-C ₁₄ aryl, 5 to 14 membered heteroaryl, C ₆-C ₁₄ aryl substituted with one or more R ^1-1 or 5 to 14 membered heteroaryl substituted with one or more R ^1-2; in the 5 to 14 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; each of R ^1-1 and R ^1-2 is independently halogen, cyano, hydroxy, C ₂-C ₄ alkynyl or C ₁-C ₃ alkoxy;

9) R ² is halogen;

10) R ³ is -L ²-R ^3-1; L ² is -O-, -N (methyl) -, C ₁-C ₄ alkylene; R ^3-1 is C ₃-C ₁₂ cycloalkyl, 3 to 12 membered heterocycloalkyl, C ₃-C ₁₂ cycloalkyl substituted with one or more R ^3-1-1 or 3 to 12 membered heterocycloalkyl substituted with one or more R ^3-1-2; in the 3 to 12 membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; each of R ^3-1-1 and R ^3-1-2is independently halogen or oxo;

11) R ⁴ is 3 to 12 membered nitrogen-containing heterocycloalkyl, 3 to 12 membered nitrogen-containing heterocycloalkyl substituted with one or more R ^4-3; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; each of R ^4-3 is independently C ₁-C ₃ cyanoalkyl or -N (R ^N1) ₂; each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl.
The nitrogen-containing heterocyclic compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claim 1, wherein, the nitrogen-containing heterocyclic compound represented by formula I has the definition described in any of the following schemes:

scheme 1:

X ¹ is C-H;

X ³ is C-H;

R ¹ is C ₆-C ₁₄ aryl, 5 to 14 membered heteroaryl, C ₆-C ₁₄ aryl substituted with one or more R ^1-1 or 5 to 14 membered heteroaryl substituted with one or more R ^1-2; in the 5 to 14 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^1-1 and R ^1-2 is independently halogen, cyano, hydroxy, C ₁-C ₄ alkyl, C ₂-C ₄ alkynyl, C ₁-C ₃ haloalkyl or C ₃-C ₆ cycloalkyl;

R ² is halogen;

L ¹ is -O-;

R ³ is -L ²-R ^3-1;

L ² is C ₁-C ₄ alkylene;

R ^3-1 is 3 to 12 membered heterocycloalkyl or 3 to 12 membered heterocycloalkyl substituted with one or more R ^3-1-2; in the 3 to 12 membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^3-1-2 is independently halogen or C ₁-C ₄ alkyl;

R ⁶ is -CN;

R ⁴ is 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkyl substituted with one or more R ^4-3; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^4-3 is independently C ₁-C ₃ alkyl or -N (R ^N1) ₂;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

scheme 2:

X ¹ is C-R ^X1 or N; R ^X1 is hydrogen or halogen;

X ³ is C-H;

R ¹ is C ₆-C ₁₄ aryl, 5 to 14 membered heteroaryl, C ₆-C ₁₄ aryl substituted with one or more R ^1-1 or 5 to 14 membered heteroaryl substituted with one or more R ^1-2; in the 5 to 14 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^1-1 and R ^1-2 is independently halogen, cyano, hydroxy, C ₂-C ₄ alkynyl or C ₁-C ₃ alkoxy;

R ² is halogen;

L ¹ is C ₁-C ₄ alkylene, -N (methyl) -or -O-;

R ³ is -L ²-R ^3-1;

L ² is -O-, -N (methyl) -or C ₁-C ₄ alkylene;

R ^3-1 is C ₃-C ₁₂ cycloalkyl, 3 to 12 membered heterocycloalkyl, C ₃-C ₁₂ cycloalkyl substituted with one or more R ^3-1-1 or 3 to 12 membered heterocycloalkyl substituted with one or more R ^3-1-2; in the 3 to 12 membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^3-1-1 and R ^3-1-2is independently halogen or oxo;

R ⁶ is -CN;

R ⁴ is 3 to 12 membered nitrogen-containing heterocycloalkyl, 3 to 12 membered nitrogen-containing heterocycloalkyl substituted with one or more R ^4-3; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^4-3 is independently C ₁-C ₃ cyanoalkyl or -N (R ^N1) ₂;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

scheme 3: R ² is hydrogen or halogen;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

scheme 4:

is

wherein, n is 1, 2, 3 or 4, each of R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C ₄ alkyl;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

scheme 5:

is

wherein, m is 1, 2, 3 or 4, each of R ^3-1-2 is independently oxo, halogen or cyano;

each of R ^4-1, R ^4-2, R ^4-3 and R ^4-4 is independently oxo, halogen or cyano;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

scheme 6:

is

wherein, R ⁴ is connected to
by a carbon atom or a nitrogen atom;

scheme 7:

is

wherein, R ⁴ is connected to
by a carbon atom or a nitrogen atom;

scheme 8:

is

wherein, p is 0, 1, 2 or 3, q is 0, 1, 2 or 3;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

scheme 9:

is

wherein,

R ⁴ is C ₄-C ₇ cycloalkyl substituted with one R ^4-1; R ^4-1 is -N (R ^N1) ₂; each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

scheme 10:

is

wherein, Z ¹ is independently CH, C or N;

ring A is 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

ring B is C ₃-C ₇ cycloalkyl, C ₃-C ₇ cycloalkenyl, 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

e is independently 0, 1, 2, 3 or 4;

R ^Z1 is independently oxo, hydroxy, halogen, cyano, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, C ₁-C ₃ cyanoalkyl, C ₁-C ₃ hydroxyalkyl, C ₃-C ₆ cycloalkyl, -N (R ^N1) ₂, -CO ₂R ^N1, -CO ₂N (R ^N1) ₂ or a 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl;

scheme 11:

is

wherein, Z ¹ is independently CH, C or N;

ring A is 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

ring B is C ₃-C ₇ cycloalkyl, C ₃-C ₇ cycloalkenyl, 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

e is independently 0, 1, 2, 3 or 4;

R ^Z1 is independently oxo, hydroxy, halogen, cyano, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, C ₁-C ₃ cyanoalkyl, C ₁-C ₃ hydroxyalkyl, C ₃-C ₆ cycloalkyl, -N (R ^N1) ₂, -CO ₂R ^N1, -CO ₂N (R ^N1) ₂ or a 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl;

scheme 12:

is

wherein, n is 1, 2, 3 or 4, each of R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C ₄ alkyl;

Z ¹ is independently CH, C or N;

ring A is 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

ring B is C ₃-C ₇ cycloalkyl, C ₃-C ₇ cycloalkenyl, 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

e is independently 0, 1, 2, 3 or 4;

R ^Z1 is independently oxo, hydroxy, halogen, cyano, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, C ₁-C ₃ cyanoalkyl, C ₁-C ₃ hydroxyalkyl, C ₃-C ₆ cycloalkyl, -N (R ^N1) ₂, -CO ₂R ^N1, -CO ₂N (R ^N1) ₂ or a 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl;

scheme 13:

is

wherein, n is 1, 2, 3 or 4, each of R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C ₄ alkyl;

Z ¹ is independently CH, C or N;

ring A is 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

ring B is C ₃-C ₇ cycloalkyl, C ₃-C ₇ cycloalkenyl, 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

e is independently 0, 1, 2, 3 or 4;

R ^Z1 is independently oxo, hydroxy, halogen, cyano, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, C ₁-C ₃ cyanoalkyl, C ₁-C ₃ hydroxyalkyl, C ₃-C ₆ cycloalkyl, -N (R ^N1) ₂, -CO ₂R ^N1, -CO ₂N (R ^N1) ₂ or a 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl.
The nitrogen-containing heterocyclic compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claims 1-4, wherein, the nitrogen-containing heterocyclic compound represented by formula I meets one or more of the following conditions:

12) in R ^X1, the halogen is F, Cl, Br or I;

13) in R ¹, the C ₆-C ₁₄ aryl is C ₆-C ₁₀;

14) in R ¹, the C ₆-C ₁₄ aryl is monocyclic ring or bicyclic ring;

15) in R ¹, each ring of C ₆-C ₁₄ aryl is aromatic;

16) in R ¹, the 5 to 14 membered heteroaryl is 9 to 10 membered heteroaryl;

17) in R ¹, the 5 to 14 membered heteroaryl is monocyclic ring or bicyclic ring;

18) in R ¹, each ring of 5 to 14 membered heteroaryl is aromatic;

19) in R ¹, the number of heteroatoms in 5 to 14 membered heteroaryl is 1 or 2;

20) in R ¹, the heteroatoms in 5 to 14 membered heteroaryl is N;

21) in R ^1-1 and R ^1-2, the halogen is F, Cl, Br or I;

22) in R ^1-1 and R ^1-2, the C ₁-C ₄ alkyl is methyl, ethyl, propyl or isopropyl;

23) in R ^1-1 and R ^1-2, the -S-C ₁-C ₃ alkyl is -S-methyl, -S-ethyl, -S-propyl or -S-isopropyl;

24) in R ^1-1 and R ^1-2, the C ₂-C ₄ alkynyl is ethynyl;

25) in R ^1-1 and R ^1-2, the C ₁-C ₃ haloalkyl is -CF ₃;

26) in R ^1-1 and R ^1-2, the -O-C ₁-C ₃ haloalkyl is -O-CF ₃;

27) in R ^1-1 and R ^1-2, the C ₁-C ₃ alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy;

28) in R ^1-1 and R ^1-2, the C ₃-C ₆ cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl;

29) in R ², the halogen is F, Cl, Br or I;

30) in R ², the C ₁-C ₃ alkyl is methyl, ethyl, propyl or isopropyl;

31) in L ¹, the C ₁-C ₄ alkylene is methylene, ethylene, propylene or butylene;

32) in R ³, the 3 to 12 membered heterocycloalkyl is 3 to 6 membered heterocycloalkyl;

33) in R ³, the 3 to 12 membered heterocycloalkyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

34) in R ³, the number of heteroatoms in 3 to 12 membered heterocycloalkyl is 1 or 2;

35) in R ³, the heteroatoms in 3 to 12 membered heterocycloalkyl is N;

36) in L ², the C ₁-C ₄ alkylene is methylene, ethylene, propylene or butylene;

37) R ^3-1 is connected to L ² by a carbon atom or a nitrogen atom;

38) in R ^3-1, the C ₃-C ₁₂ cycloalkyl is C ₃-C ₈ cycloalkyl;

39) in R ^3-1, the C ₃-C ₁₂ cycloalkyl is monocyclic ring or bicyclic ring;

40) in R ^3-1, the 3 to 12 membered heterocycloalkyl is 5 to 10 membered heterocycloalkyl;

41) in R ^3-1, the 3 to 12 membered heterocycloalkyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

42) in R ^3-1, the number of heteroatoms in 3 to 12 membered heterocycloalkyl is 1 or 2;

43) in R ^3-1, the heteroatoms in 3 to 12 membered heterocycloalkyl is N;

44) in R ^3-1, the 5 to 14 membered heteroaryl is 5 to 6 membered heteroaryl;

45) in R ^3-1, the 5 to 14 membered heteroaryl is monocyclic ring or bicyclic ring;

46) in R ^3-1, the number of heteroatoms in 5 to 14 membered heteroaryl is 1 or 2;

47) in R ^3-1, the heteroatoms in 5 to 14 membered heteroaryl is N;

48) in R ^3-1-1, R ^3-1-2, R ^3-1-3 and R ^3-1-4, the halogen is F, Cl, Br or I;

49) in R ^3-1-1, R ^3-1-2, R ^3-1-3 and R ^3-1-4, the C ₁-C ₄ alkyl is methyl, ethyl, propyl or isopropyl;

50) R ⁴ is connected to
by a carbon atom or a nitrogen atom;

51) in R ⁴, the C ₃-C ₇ cycloalkyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

52) in R ⁴, the C ₃-C ₇ cycloalkenyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

53) in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkyl is 5 to 9 membered nitrogen-containing heterocycloalkyl;

54) in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

55) in R ⁴, the number of heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkyl is 1 or 2;

56) in R ⁴, the heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkyl is N;

57) in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is 5 to 9 membered nitrogen-containing heterocycloalkenyl;

58) in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

59) in R ⁴, the number of heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkenyl is 1 or 2;

60) in R ⁴, the heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkenyl is N;

61) in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the halogen is F, Cl, Br or I;

62) in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₁-C ₃ alkyl is methyl, ethyl, propyl or isopropyl;

63) in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₁-C ₃ cyanoalkyl is cyano methyl;

64) in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₃-C ₆ cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl;

65) in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₁-C ₃ alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy;

66) in R ^N1, the C ₁-C ₃ alkyl is methyl, ethyl, propyl or isopropyl;

67) “NH” on ring A is not connected with R ^Z1;

68) in ring B, the C ₃-C ₇ cycloalkyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

69) in ring B, the C ₃-C ₇ cycloalkenyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

70) in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkyl is 5 to 9 membered nitrogen-containing heterocycloalkyl;

71) in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

72) in ring A and ring B, the number of heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkyl is 1 or 2;

73) in ring A and ring B, the heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkyl is N;

74) in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is 5 to 9 membered nitrogen-containing heterocycloalkenyl;

75) in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

76) in ring A and ring B, the number of heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkenyl is 1 or 2;

77) in ring A and ring B, the heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkenyl is N;

78) in R ^Z1, the halogen is F, Cl, Br or I;

79) in R ^Z1, the C ₁-C ₃ alkyl is methyl, ethyl, propyl or isopropyl;

80) in R ^Z1, the C ₁-C ₃ cyanoalkyl is cyano methyl;

81) in R ^Z1, the C ₃-C ₆ cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl;

82) in R ^Z1, the C ₁-C ₃ alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy;

83) in R ^N1, the C ₁-C ₃ alkyl is methyl, ethyl, propyl or isopropyl;

84) “more” in the above definitions is independently 2, 3, 4 or 5.
The nitrogen-containing heterocyclic compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claim 5, wherein, the nitrogen-containing heterocyclic compound represented by formula I meets one or more of the following conditions:

85) in R ^X1, the halogen is F;

86) in R ^X3, the halogen is F;

87) in R ¹, the C ₆-C ₁₄ aryl is phenyl, 1-naphthyl, 2-naphthyl or

88) in R ¹, the 5 to 14 membered heteroaryl is

89) in R ^1-1 and R ^1-2, the halogen is F or Cl;

90) in R ^1-1 and R ^1-2, the C ₁-C ₄ alkyl is methyl;

91) in R ^1-1 and R ^1-2, the -S-C ₁-C ₃ alkyl is -S-methyl;

92) in R ^1-1 and R ^1-2, the C ₁-C ₃ alkoxy is methoxy;

93) in R ^1-1 and R ^1-2, the C ₃-C ₆ cycloalkyl is cyclopropyl;

94) in R ², the halogen is F;

95) in R ², the C ₁-C ₃ alkyl is methyl;

96) in R ³, the 3 to 12 membered heterocycloalkyl is 1-azetidinyl;

97) in L ², the C ₁-C ₄ alkylene;

98) R ^3-1 is connected to L ² by a nitrogen atom;

99) in R ^3-1, the C ₃-C ₁₂ cycloalkyl is C ₅-C ₈ cycloalkyl;

100) in R ^3-1, the C ₃-C ₁₂ cycloalkyl is monocyclic ring, spirocyclic ring or bridged ring; ;

101) in R ^3-1, the 3 to 12 membered heterocycloalkyl heterocycloalkyl is 7 to 10 membered bridged heterocycloalkyl;

102) in R ^3-1, the 5 to 14 membered heteroaryl is pyrazolyl;

103) in R ^3-1-1, R ^3-1-2, R ^3-1-3 and R ^3-1-4, the halogen is F;

104) in R ^3-1-1, R ^3-1-2, R ^3-1-3 and R ^3-1-4, the C ₁-C ₄ alkyl is methyl;

105) in R ⁴, the C ₃-C ₇ cycloalkyl is
cyclopropyl, cyclopentyl or cyclohexyl;

106) in R ⁴, the C ₃-C ₇ cycloalkenyl is cyclopropenyl, cyclopentenyl or cyclohexenyl;

107) in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkyl is tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,

108) in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is the 3 to 12 membered nitrogen-containing heterocycloalkenyl is

109) in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the halogen is F;

110) in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₁-C ₃ alkyl is methyl;

111) in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₃-C ₆ cycloalkyl is cyclopropyl;

112) in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₁-C ₃ alkoxy is methoxy;

113) in ring B, the C ₃-C ₇ cycloalkyl is
cyclopropyl, cyclopentyl or cyclohexyl;

114) in ring B, the C ₃-C ₇ cycloalkenyl is cyclopropenyl, cyclopentenyl or cyclohexenyl;

115) in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkyl is tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,

116) in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is the 3 to 12 membered nitrogen-containing heterocycloalkenyl is

117) in R ^Z1, the halogen is F;

118) in R ^Z1, the C ₁-C ₃ alkyl is methyl;

119) in R ^Z1, the C ₃-C ₆ cycloalkyl is cyclopropyl;

120) in R ^Z1, the C ₁-C ₃ alkoxy is methoxy;

121) in R ^N1, the C ₁-C ₃ alkyl is methyl.
The nitrogen-containing heterocyclic compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claim 6, wherein, the nitrogen-containing heterocyclic compound represented by formula I meets one or more of the following conditions:

122) R ¹ is

123) -L ¹-R ³ is

124) R ⁴ is
The nitrogen-containing heterocyclic compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claim 1, wherein, the nitrogen-containing heterocyclic compound represented by formula I is selected from the group consisting of:
A pharmaceutical composition, comprising substance X and pharmaceutically acceptable excipient, the substance X is the nitrogen-containing heterocyclic compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claims 1-8.
A use of substance X in the manufacture of KRAS-G12D inhibitors; the substance X is the nitrogen-containing heterocyclic compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claims 1-8;

preferably, the KRAS-G12D inhibitors is used in vitro or in vivo.
A use of substance X in the manufacture of a medicament;

the substance X is the nitrogen-containing heterocyclic compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claims 1-8;

the medicament is used to treat or prevent KRAS-G12D associated disease or disorder;

preferably, the KRAS-G12D associated disease or disorder is cancer.
A use of substance X in the manufacture of a medicament;

the substance X is the nitrogen-containing heterocyclic compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claims 1-8;

the medicament is used to treat or prevent cancer.
A method for preventing and/or treating KRAS-G12D associated disease or disorder, which comprises administering to a subject in need thereof a therapeutically effective amount of substance X;

the substance X is the nitrogen-containing heterocyclic compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claims 1-8;

preferably, the KRAS-G12D associated disease or disorder is cancer.
A method for preventing and/or treating cancer, which comprises administering to a subject in need thereof a therapeutically effective amount of substance X;

the substance X is the nitrogen-containing heterocyclic compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claims 1-8.
A nitrogen-containing heterocyclic compound represented by formula II, a pharmaceutically acceptable salt thereof or a solvate thereof;

wherein,

X ³ is CH-R ^X3, NH, C-R ^X3 or N; R ^X3 is independently hydrogen or halogen;

is single bond or double bond;

R ⁵ is hydrogen, halogen or C ₁-C ₃ alkyl;

R ¹ is C ₆-C ₁₄ aryl, 5 to 14 membered heteroaryl, C ₆-C ₁₄ aryl substituted with one or more R ^1-1 or 5 to 14 membered heteroaryl substituted with one or more R ^1-2; in the 5 to 14 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^1-1 and R ^1-2 is independently halogen, cyano, hydroxy, C ₁-C ₄ alkyl, -S-C ₁-C ₃ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₁-C ₃ haloalkyl, -O-C ₁-C ₃ haloalkyl, C ₁-C ₃ alkoxy, -N (R ^N1) ₂ or C ₃-C ₆ cycloalkyl, wherein the C ₃-C ₆ cycloalkyl is optionally substituted with halogen or C ₁-C ₃ alkyl;

L ¹ is single bond, C ₁-C ₄ alkylene, -O-or -N (R ^N1) -;

R ³ is 3 to 12 membered heterocycloalkyl, 3 to 12 membered heterocycloalkyl substituted with one or more R ^3-1-1, or -L ²-R ^3-1;

L ² is -O-, -N (methyl) -, C ₁-C ₄ alkylene or C ₁-C ₄ alkylene substituted with one or more R ^L2; each of R ^L2 is independently hydroxy or C ₁-C ₄ hydroxyalkyl;

R ^3-1 is C ₃-C ₁₂ cycloalkyl, 3 to 12 membered heterocycloalkyl, C ₆-C ₁₄ aryl, 5 to 14 membered heteroaryl, -N (R ^N1) ₂, C ₃-C ₁₂ cycloalkyl substituted with one or more R ^3-1-1, 3 to 12 membered heterocycloalkyl substituted with one or more R ^3-1-2, C ₆-C ₁₄ aryl substituted with one or more R ^3-1-3 or 5 to 14 membered heteroaryl substituted with one or more R ^3-1-4; in the 3 to 12 membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 5 to 14 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; n is independently 0, 1, 2, 3 or 4;

each of R ^3-1-1, R ^3-1-2, R ^3-1-3 and R ^3-1-4 is halogen, cyano, oxo, C ₁-C ₄ alkyl or -N (R ^N1) ₂;

X ² is C-R ^X2 or N; R ^X2 is hydrogen, cyano or halogen;

R ⁴ is C ₃-C ₇ cycloalkyl, C ₃-C ₇ cycloalkenyl, 3 to 12 membered nitrogen-containing heterocycloalkyl, 3 to 12 membered nitrogen-containing heterocycloalkenyl, C ₃-C ₆ cycloalkyl substituted with one or more R ^4-1, C ₃-C ₇ cycloalkenyl substituted with one or more R ^4-2, 3 to 12 membered nitrogen-containing heterocycloalkyl substituted with one or more R ^4-3 or 3 to 12 membered nitrogen-containing heterocycloalkenyl substituted with one or more R ^4-4; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^4-1, R ^4-2, R ^4-3 and R ^4-4 is independently oxo, hydroxy, cyano, halogen, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, C ₁-C ₃ cyanoalkyl, C ₃-C ₆ cycloalkyl, C ₁-C ₃ alkoxy or -N (R ^N1) ₂;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl.
The nitrogen-containing heterocyclic compound represented by formula II, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claim 15, wherein, the nitrogen-containing heterocyclic compound represented by formula II meets one or more of the following conditions:

125) X ³ is CH ₂;

126)
is single bond;

127) R ⁵ is methyl or ethyl;

128) L ¹ is C ₁-C ₄ alkylene, -N (methyl) -or -O-;

129) X ² is N;

130) in R ⁴, C ₃-C ₇ cycloalkyl, C ₃-C ₇ cycloalkenyl, 3 to 12 membered nitrogen-containing heterocycloalkyl and 3 to 12 membered nitrogen-containing heterocycloalkenyl are bridged ring;

131) R ⁴ meets the following conditions:
wherein, Z ¹ is independently CH, C or N; e is independently 0, 1, 2, 3 or 4; R ^Z1 is independently oxo, hydroxy, halogen, cyano, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, C ₁-C ₃ cyanoalkyl, C ₁-C ₃ hydroxyalkyl, C ₃-C ₆ cycloalkyl, -N (R ^N1) ₂, -CO ₂R ^N1, -CO ₂N (R ^N1) ₂ or a 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl; R ^Z2 is hydrogen or methyl;

132) R ⁴ is
wherein, Z ¹ is independently CH, C or N; ring A is 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; ring B is C ₃-C ₇ cycloalkyl, C ₃-C ₇ cycloalkenyl, 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; e is independently 0, 1, 2, 3 or 4; R ^Z1 is independently oxo, hydroxy, halogen, cyano, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, C ₁-C ₃ cyanoalkyl, C ₁-C ₃ hydroxyalkyl, C ₃-C ₆ cycloalkyl, -N (R ^N1) ₂, -CO ₂R ^N1, -CO ₂N (R ^N1) ₂ or a 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl; R ^Z2 is hydrogen or methyl;

133) R ⁴ is connected to
by a carbon atom or a nitrogen atom; R ⁴ is 3 to 12 membered nitrogen-containing heterocycloalkyl, 3 to 12 membered nitrogen-containing heterocycloalkenyl; 3 to 12 membered nitrogen-containing heterocycloalkyl substituted with one or more R ^4-3 or 3 to 12 membered nitrogen-containing heterocycloalkenyl substituted with one or more R ^4-4; in R ⁴, 3 to 12 membered nitrogen-containing heterocycloalkyl has “NH” , the “NH” is not connected with R ^4-3; in R ⁴, 3 to 12 membered nitrogen-containing heterocycloalkenyl has “NH” , the “NH” is not connected with R ^4-4;

134) R ⁴ is connected to
by a carbon atom or a nitrogen atom; R ⁴ is C ₃-C ₆ cycloalkyl substituted with one or more R ^4-1, C ₃-C ₇ cycloalkenyl substituted with one or more R ^4-2, 3 to 12 membered nitrogen-containing heterocycloalkyl substituted with one or more R ^4-3 or 3 to 12 membered nitrogen-containing heterocycloalkenyl substituted with one or more R ^4-4; one of R ^4-1 is NH ₂ or N (methyl) ; one of R ^4-2 is NH ₂ or N (methyl) ; one of R ^4-3 is NH ₂ or N (methyl) ; one of R ^4-3 is NH ₂ or N (methyl) .
The nitrogen-containing heterocyclic compound represented by formula II, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claim 16, wherein, the nitrogen-containing heterocyclic compound represented by formula II meets one or more of the following conditions:

135) R ¹ is C ₆-C ₁₄ aryl, 5 to 14 membered heteroaryl, C ₆-C ₁₄ aryl substituted with one or more R ^1-1 or 5 to 14 membered heteroaryl substituted with one or more R ^1-2; in the 5 to 14 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; each of R ^1-1 and R ^1-2 is independently halogen, cyano, hydroxy, C ₂-C ₄ alkynyl or C ₁-C ₃ alkoxy;

136) R ³ is -L ²-R ^3-1; L ² is -O-, -N (methyl) -, C ₁-C ₄ alkylene; R ^3-1 is C ₃-C ₁₂ cycloalkyl, 3 to 12 membered heterocycloalkyl, C ₃-C ₁₂ cycloalkyl substituted with one or more R ^3-1-1 or 3 to 12 membered heterocycloalkyl substituted with one or more R ^3-1-2; in the 3 to 12 membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; each of R ^3-1-1 and R ^3-1-2is independently halogen or oxo;

137) R ⁴ is 3 to 12 membered nitrogen-containing heterocycloalkyl, 3 to 12 membered nitrogen-containing heterocycloalkyl substituted with one or more R ^4-3; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;each of R ^4-3 is independently C ₁-C ₃ cyanoalkyl or -N (R ^N1) ₂; each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl.
The nitrogen-containing heterocyclic compound represented by formula II, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claim 15, wherein, the nitrogen-containing heterocyclic compound represented by formula II has the definition described in any of the following schemes:

scheme 1:

X ³ is CH-R ^X3; R ^X3 is halogen;

is single bond;

R ⁵ is hydrogen;

R ¹ is C ₆-C ₁₄ aryl, 5 to 14 membered heteroaryl, C ₆-C ₁₄ aryl substituted with one or more R ^1-1 or 5 to 14 membered heteroaryl substituted with one or more R ^1-2; in the 5 to 14 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^1-1 and R ^1-2 is independently halogen, cyano, hydroxy, C ₁-C ₄ alkyl, C ₂-C ₄ alkynyl, C ₁-C ₃ haloalkyl, C ₁-C ₃ alkoxy or C ₃-C ₆ cycloalkyl;

L ¹ is -O-;

R ³ is -L ²-R ^3-1;

L ² is C ₁-C ₄ alkylene;

R ^3-1 is 3 to 12 membered heterocycloalkyl substituted with one or more R ^3-1-2, C ₆-C ₁₄ aryl substituted with one or more R ^3-1-3 or 5 to 14 membered heteroaryl substituted with one or more R ^3-1-4; in the 3 to 12 membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 5 to 14 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; n is independently 0, 1, 2, 3 or 4;

each of R ^3-1-2 and R ^3-1-4 is halogen or C ₁-C ₄ alkyl;

X ² is N;

R ⁴ is 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkyl substituted with one or more R ^4-3; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^4-3 is independently hydroxy, C ₁-C ₃ alkyl or C ₁-C ₃ cyanoalkyl;

scheme 2:

X ³ is CH ₂;

is single bond;

R ⁵ is hydrogen;

R ¹ is C ₆-C ₁₄ aryl, 5 to 14 membered heteroaryl, C ₆-C ₁₄ aryl substituted with one or more R ^1-1 or 5 to 14 membered heteroaryl substituted with one or more R ^1-2; in the 5 to 14 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^1-1 and R ^1-2 is independently halogen, cyano, hydroxy, C ₂-C ₄ alkynyl or C ₁-C ₃ alkoxy;

L ¹ is C ₁-C ₄ alkylene, -N (methyl) -or -O-;

R ³ is -L ²-R ^3-1;

L ² is -O-, -N (methyl) -or C ₁-C ₄ alkylene;

R ^3-1 is C ₃-C ₁₂ cycloalkyl, 3 to 12 membered heterocycloalkyl, C ₃-C ₁₂ cycloalkyl substituted with one or more R ^3-1-1 or 3 to 12 membered heterocycloalkyl substituted with one or more R ^3-1-2; in the 3 to 12 membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^3-1-1 and R ^3-1-2is independently halogen or oxo;

X ² is N;

R ⁴ is 3 to 12 membered nitrogen-containing heterocycloalkyl, 3 to 12 membered nitrogen-containing heterocycloalkyl substituted with one or more R ^4-3; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^4-3 is independently C ₁-C ₃ cyanoalkyl or -N (R ^N1) ₂;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

scheme 4:

is

wherein, n is 1, 2, 3 or 4, each of R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C ₄ alkyl;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl;

scheme 5:

is

wherein, n is 1, 2, 3 or 4, each of R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C ₄ alkyl;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl;

scheme 6:

is

wherein, n is 1, 2, 3 or 4, each of R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C ₄ alkyl;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl;

scheme 7:

is

wherein, n is 1, 2, 3 or 4, each of R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C ₄ alkyl;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl;

scheme 8:

is

wherein, n is 1, 2, 3 or 4, each of R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C ₄ alkyl;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl;

scheme 9:

is

wherein, n is 1, 2, 3 or 4, each of R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C ₄ alkyl;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl;

scheme 10:

is

wherein, n is 1, 2, 3 or 4, each of R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C ₄ alkyl;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl;

scheme 11:

is

wherein, n is 1, 2, 3 or 4, each of R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C ₄ alkyl;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl;

Scheme 12:

is

wherein, n is 1, 2, 3 or 4, each of R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C ₄ alkyl;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl;

scheme 13:

is

wherein, n is 1, 2, 3 or 4, each of R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C ₄ alkyl;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

R ⁵ is halogen or C ₁-C ₃ alkyl;

scheme 14:

wherein, R ⁴ is connected to
by a carbon atom or a nitrogen atom ;

scheme 15:

is

wherein, p is 0, 1, 2 or 3, q is 0, 1, 2 or 3;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

scheme 16:

is

wherein,

R ⁴ is C ₄-C ₇ cycloalkyl substituted with one R ^4-1; R ^4-1 is -N (R ^N1) ₂; each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

scheme 17:

is

wherein, p is 0, 1, 2 or 3, q is 0, 1, 2 or 3;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

scheme 18:

is

wherein,

R ⁴ is C ₄-C ₇ cycloalkyl substituted with one R ^4-1; R ^4-1 is -N (R ^N1) ₂; each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ⁴ is connected to
by a carbon atom or a nitrogen atom;

scheme 19:

is

wherein, Z ¹ is independently CH, C or N;

ring A is 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

ring B is C ₃-C ₇ cycloalkyl, C ₃-C ₇ cycloalkenyl, 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

e is independently 0, 1, 2, 3 or 4;

R ^Z1 is independently oxo, hydroxy, halogen, cyano, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, C ₁-C ₃ cyanoalkyl, C ₁-C ₃ hydroxyalkyl, C ₃-C ₆ cycloalkyl, -N (R ^N1) ₂, -CO ₂R ^N1, -CO ₂N (R ^N1) ₂ or a 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl;

scheme 20:

is

wherein, Z ¹ is independently CH, C or N;

ring A is 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

ring B is C ₃-C ₇ cycloalkyl, C ₃-C ₇ cycloalkenyl, 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

e is independently 0, 1, 2, 3 or 4;

R ^Z1 is independently oxo, hydroxy, halogen, cyano, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, C ₁-C ₃ cyanoalkyl, C ₁-C ₃ hydroxyalkyl, C ₃-C ₆ cycloalkyl, -N (R ^N1) ₂, -CO ₂R ^N1, -CO ₂N (R ^N1) ₂ or a 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl;

scheme 21:

is

wherein,
is single bond;

n is 1, 2, 3 or 4, each of R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C ₄ alkyl;

Z ¹ is independently CH, C or N;

ring A is 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

ring B is C ₃-C ₇ cycloalkyl, C ₃-C ₇ cycloalkenyl, 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

e is independently 0, 1, 2, 3 or 4;

R ^Z1 is independently oxo, hydroxy, halogen, cyano, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, C ₁-C ₃ cyanoalkyl, C ₁-C ₃ hydroxyalkyl, C ₃-C ₆ cycloalkyl, -N (R ^N1) ₂, -CO ₂R ^N1, -CO ₂N (R ^N1) ₂ or a 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl;

scheme 22:

is

wherein, n is 1, 2, 3 or 4, each of R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C ₄ alkyl;

Z ¹ is independently CH, C or N;

ring A is 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

ring B is C ₃-C ₇ cycloalkyl, C ₃-C ₇ cycloalkenyl, 3 to 12 membered nitrogen-containing heterocycloalkyl or 3 to 12 membered nitrogen-containing heterocycloalkenyl; in the 3 to 12 membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N; in the 3 to 12 membered nitrogen-containing heterocycloalkenyl the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

e is independently 0, 1, 2, 3 or 4;

R ^Z1 is independently oxo, hydroxy, halogen, cyano, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, C ₁-C ₃ cyanoalkyl, C ₁-C ₃ hydroxyalkyl, C ₃-C ₆ cycloalkyl, -N (R ^N1) ₂, -CO ₂R ^N1, -CO ₂N (R ^N1) ₂ or a 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, the heteroatoms are, one or more, selected from the group consisting of O, S and N;

each of R ^N1 is independently hydrogen or C ₁-C ₃ alkyl;

R ^Z2 is hydrogen or methyl.
The nitrogen-containing heterocyclic compound represented by formula II, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claims 15-18, wherein, the nitrogen-containing heterocyclic compound represented by formula II meets one or more of the following conditions:

138) in R ^X3, the halogen is F, Cl, Br or I;

139) in R ⁵, the halogen is F, Cl, Br or I;

140) in R ⁵, the C ₁-C ₃ alkyl is methyl, ethyl, propyl or isopropyl;

141) in R ¹, the C ₆-C ₁₄ aryl is C ₆-C ₁₀;

142) in R ¹, the C ₆-C ₁₄ aryl is monocyclic ring or bicyclic ring;

143) in R ¹, each ring of C ₆-C ₁₄ aryl is aromatic;

144) in R ¹, the 5 to 14 membered heteroaryl is 9 to 10 membered heteroaryl;

145) in R ¹, the 5 to 14 membered heteroaryl is monocyclic ring or bicyclic ring;

146) in R ¹, each ring of 5 to 14 membered heteroaryl is aromatic;

147) in R ¹, the number of heteroatoms in 5 to 14 membered heteroaryl is 1 or 2;

148) in R ¹, the heteroatoms in 5 to 14 membered heteroaryl is N;

149) in R ^1-1 and R ^1-2, the halogen is F, Cl, Br or I;

150) in R ^1-1 and R ^1-2, the C ₁-C ₄ alkyl is methyl, ethyl, propyl or isopropyl;

151) in R ^1-1 and R ^1-2, the -S-C ₁-C ₃ alkyl is -S-methyl, -S-ethyl, -S-propyl or -S-isopropyl;

152) in R ^1-1 and R ^1-2, the C ₂-C ₄ alkynyl is ethynyl;

153) in R ^1-1 and R ^1-2, the C ₁-C ₃ haloalkyl is -CF ₃;

154) in R ^1-1 and R ^1-2, the -O-C ₁-C ₃ haloalkyl is -O-CF ₃;

155) in R ^1-1 and R ^1-2, the C ₁-C ₃ alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy;

156) in R ^1-1 and R ^1-2, the C ₃-C ₆ cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl;

157) in L ¹, the C ₁-C ₄ alkylene is methylene, ethylene, propylene or butylene;

158) in R ³, the 3 to 12 membered heterocycloalkyl is 3 to 6 membered heterocycloalkyl;

159) in R ³, the 3 to 12 membered heterocycloalkyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

160) in R ³, the number of heteroatoms in 3 to 12 membered heterocycloalkyl is 1 or 2;

161) in R ³, the heteroatoms in 3 to 12 membered heterocycloalkyl is N;

162) in L ², the C ₁-C ₄ alkylene is methylene, ethylene, propylene or butylene;

163) R ^3-1 is connected to L ² by a carbon atom or a nitrogen atom;

164) in R ^3-1, the C ₃-C ₁₂ cycloalkyl is C ₃-C ₈ cycloalkyl;

165) in R ^3-1, the C ₃-C ₁₂ cycloalkyl is monocyclic ring or bicyclic ring;

166) in R ^3-1, the 3 to 12 membered heterocycloalkyl is 5 to 10 membered heterocycloalkyl;

167) in R ^3-1, the 3 to 12 membered heterocycloalkyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

168) in R ^3-1, the number of heteroatoms in 3 to 12 membered heterocycloalkyl is 1 or 2;

169) in R ^3-1, the heteroatoms in 3 to 12 membered heterocycloalkyl is N;

170) in R ^3-1, the 5 to 14 membered heteroaryl is 5 to 6 membered heteroaryl;

171) in R ^3-1, the 5 to 14 membered heteroaryl is monocyclic ring or bicyclic ring;

172) in R ^3-1, the number of heteroatoms in 5 to 14 membered heteroaryl is 1 or 2;

173) in R ^3-1, the heteroatoms in 5 to 14 membered heteroaryl is N;

174) in R ^3-1-1, R ^3-1-2, R ^3-1-3 and R ^3-1-4, the halogen is F, Cl, Br or I;

175) in R ^3-1-1, R ^3-1-2, R ^3-1-3 and R ^3-1-4, the C ₁-C ₄ alkyl is methyl, ethyl, propyl or isopropyl;

176) in R ^X2, the halogen is F, Cl, Br or I;

177) R ⁴ is connected to
by a carbon atom or a nitrogen atom;

178) in R ⁴, the C ₃-C ₇ cycloalkyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

179) in R ⁴, the C ₃-C ₇ cycloalkenyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

180) in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkyl is 5 to 9 membered nitrogen-containing heterocycloalkyl;

181) in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

182) in R ⁴, the number of heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkyl is 1 or 2;

183) in R ⁴, the heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkyl is N;

184) in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is 5 to 9 membered nitrogen-containing heterocycloalkenyl;

185) in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

186) in R ⁴, the number of heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkenyl is 1 or 2;

187) in R ⁴, the heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkenyl is N;

188) in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the halogen is F, Cl, Br or I;

189) in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₁-C ₃ alkyl is methyl, ethyl, propyl or isopropyl;

190) in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₁-C ₃ cyanoalkyl is cyano methyl;

191) in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₃-C ₆ cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl;

192) in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₁-C ₃ alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy;

193) in R ^N1, the C ₁-C ₃ alkyl is methyl, ethyl, propyl or isopropyl;

194) “NH” on ring A is not connected with R ^Z1;

195) in ring B, the C ₃-C ₇ cycloalkyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

196) in ring B, the C ₃-C ₇ cycloalkenyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

197) in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkyl is 5 to 9 membered nitrogen-containing heterocycloalkyl;

198) in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

199) in ring A and ring B, the number of heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkyl is 1 or 2;

200) in ring A and ring B, the heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkyl is N;

201) in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is 5 to 9 membered nitrogen-containing heterocycloalkenyl;

202) in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is monocyclic ring or bicyclic ring; preferably, monocyclic ring, spirocyclic ring or bridged ring;

203) in ring A and ring B, the number of heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkenyl is 1 or 2;

204) in ring A and ring B, the heteroatoms in 3 to 12 membered nitrogen-containing heterocycloalkenyl is N;

205) in R ^Z1, the halogen is F, Cl, Br or I;

206) in R ^Z1, the C ₁-C ₃ alkyl is methyl, ethyl, propyl or isopropyl;

207) in R ^Z1, the C ₁-C ₃ cyanoalkyl is cyano methyl;

208) in R ^Z1, the C ₃-C ₆ cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl;

209) in R ^Z1, the C ₁-C ₃ alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy;

210) in R ^N1, the C ₁-C ₃ alkyl is methyl, ethyl, propyl or isopropyl;

211) “more” in the above definitions is independently 2, 3, 4 or 5.
The nitrogen-containing heterocyclic compound represented by formula II, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claim 19, wherein, the nitrogen-containing heterocyclic compound represented by formula II meets one or more of the following conditions:

212) in R ^X3, the halogen is F;

213) in R ⁵, the halogen is F;

214) in R ⁵, the C ₁-C ₃ alkyl is methyl;

215) in R ¹, the C ₆-C ₁₄ aryl is phenyl, 1-naphthyl, 2-naphthyl or

216) in R ¹, the 5 to 14 membered heteroaryl is

217) in R ^1-1 and R ^1-2, the halogen is F or Cl;

218) in R ^1-1 and R ^1-2, the C ₁-C ₄ alkyl is methyl;

219) in R ^1-1 and R ^1-2, the -S-C ₁-C ₃ alkyl is -S-methyl;

220) in R ^1-1 and R ^1-2, the C ₁-C ₃ alkoxy is methoxy;

221) in R ^1-1 and R ^1-2, the C ₃-C ₆ cycloalkyl is cyclopropyl;

222) in R ³, the 3 to 12 membered heterocycloalkyl is 1-azetidinyl;

223) in L ², the C ₁-C ₄ alkylene;

224) R ^3-1 is connected to L ² by a nitrogen atom;

225) in R ^3-1, the C ₃-C ₁₂ cycloalkyl is C ₅-C ₈ cycloalkyl;

226) in R ^3-1, the C ₃-C ₁₂ cycloalkyl is monocyclic ring, spirocyclic ring or bridged ring;

227) in R ^3-1, the 3 to 12 membered heterocycloalkyl heterocycloalkyl is 7 to 10 membered bridged heterocycloalkyl;

228) in R ^3-1, the 5 to 14 membered heteroaryl is pyrazolyl;

229) in R ^3-1-1, R ^3-1-2, R ^3-1-3 and R ^3-1-4, the halogen is F;

230) in R ^3-1-1, R ^3-1-2, R ^3-1-3 and R ^3-1-4, the C ₁-C ₄ alkyl is methyl;

231) in R ^X2, the halogen is F;

232) in R ⁴, the C ₃-C ₇ cycloalkyl is
cyclopropyl, cyclopentyl or cyclohexyl;

233) in R ⁴, the C ₃-C ₇ cycloalkenyl is cyclopropenyl, cyclopentenyl or cyclohexenyl;

234) in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkyl is tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,

235) in R ⁴, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is the 3 to 12 membered nitrogen-containing heterocycloalkenyl is

236) in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the halogen is F;

237) in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₁-C ₃ alkyl is methyl;

238) in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₃-C ₆ cycloalkyl is cyclopropyl;

239) in R ^4-1, R ^4-2, R ^4-3 and R ^4-4, the C ₁-C ₃ alkoxy is methoxy;

240) in ring B, the C ₃-C ₇ cycloalkyl is
cyclopropyl, cyclopentyl or cyclohexyl;

241) in ring B, the C ₃-C ₇ cycloalkenyl is cyclopropenyl, cyclopentenyl or cyclohexenyl;

242) in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkyl is tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,

243) in ring A and ring B, the 3 to 12 membered nitrogen-containing heterocycloalkenyl is the 3 to 12 membered nitrogen-containing heterocycloalkenyl is

244) in R ^Z1, the halogen is F;

245) in R ^Z1, the C ₁-C ₃ alkyl is methyl;

246) in R ^Z1, the C ₃-C ₆ cycloalkyl is cyclopropyl;

247) in R ^Z1, the C ₁-C ₃ alkoxy is methoxy;

248) in R ^N1, the C ₁-C ₃ alkyl is methyl.
The nitrogen-containing heterocyclic compound represented by formula II, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claim 20, wherein, the nitrogen-containing heterocyclic compound represented by formula II meets one or more of the following conditions:

249) R ¹ is

250) -L ¹-R ³ is

251) R ⁴ is
The nitrogen-containing heterocyclic compound represented by formula II, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claim 15, wherein, the nitrogen-containing heterocyclic compound represented by formula II is selected from the group consisting of:
A pharmaceutical composition, comprising substance Y and pharmaceutically acceptable excipient, the substance Y is the nitrogen-containing heterocyclic compound represented by formula II, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claims 15-22.
A use of substance Y in the manufacture of KRAS-G12D inhibitors; the substance Y is the nitrogen-containing heterocyclic compound represented by formula II, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claims 15-22;

preferably, the KRAS-G12D inhibitors is used in vitro or in vivo.
A use of substance Y in the manufacture of a medicament;

the substance Y is the nitrogen-containing heterocyclic compound represented by formula II, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claims 15-22;

the medicament is used to treat or prevent KRAS-G12D associated disease or disorder;

preferably, the KRAS-G12D associated disease or disorder is cancer.
A use of substance Y in the manufacture of a medicament;

the substance Y is the nitrogen-containing heterocyclic compound represented by formula II, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claims 15-22;

the medicament is used to treat or prevent cancer.
A method for preventing and/or treating KRAS-G12D associated disease or disorder, which comprises administering to a subject in need thereof a therapeutically effective amount of substance Y;

the substance Y is the nitrogen-containing heterocyclic compound represented by formula II, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claims 15-22;

preferably, the KRAS-G12D associated disease or disorder is cancer.
A method for preventing and/or treating cancer, which comprises administering to a subject in need thereof a therapeutically effective amount of substance Y;

the substance Y is the nitrogen-containing heterocyclic compound represented by formula II, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in claims 15-22.