CN118510785A

CN118510785A - Nitrogen-containing heterocyclic compound and application thereof

Info

Publication number: CN118510785A
Application number: CN202280086987.6A
Authority: CN
Inventors: 万昭奎; 李晓东; 迈克尔·劳伦斯·巴斯克斯; 吴景雨
Original assignee: Lingke Pharmaceutical Hangzhou Co ltd
Current assignee: Lingke Pharmaceutical Hangzhou Co ltd
Priority date: 2021-12-28
Filing date: 2022-12-28
Publication date: 2024-08-16
Also published as: WO2023125627A1

Abstract

The invention discloses a nitrogen-containing heterocyclic compound and application thereof. The invention specifically discloses a nitrogen-containing heterocyclic compound shown as a formula I or a formula II and pharmaceutically acceptable salts or solvates thereof. The nitrogen-containing heterocyclic compound provided by the invention has better inhibition activity on KRAS-G12D.

Description

Nitrogen-containing heterocyclic compound and application thereof

The present invention claims priority to PCT/CN2021/141878 filed at 28 of 12 of 2021, the contents of which are incorporated herein in their entirety.

Technical Field

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

Background

RAS oncogene mutation is the most common activating mutation in human cancers, occurring in 30% of human tumors (Nat. Rev. Drug Discovery 2014, 13828-851). Although the RAS gene family includes three subtypes (KRAS, HRAS and NRAS), 85% of RAS-driven cancers are caused by mutations in the KRAS subtype (j.cell sci.20166121287-1292), which are most common in solid tumors such as lung adenocarcinoma, pancreatic ductal carcinoma and colorectal carcinoma. In KRAS mutant tumors, 80% of oncogenic mutations occur within codon 12, with the most common mutations being p.g12d (41%), p.g12v (28%) and p.g12c (14%) (cancer research, 2012, 722457-2467). Thus, inhibition of activated RAS function has been shown to result not only in reversal of the transformed phenotype, but also in cell death and tumor regression.

Compounds that inhibit RAS are still highly desirable and are under intense research. In recent years, many advances have been made in this field, such as SOS inhibitors, and covalent G12C inhibitors. However, G12V and G12D inhibitors are of increasing interest.

Disclosure of Invention

The invention relates to a nitrogen-containing heterocyclic compound and application thereof. The nitrogen-containing heterocyclic compound provided by the invention has better inhibition activity on KRAS-G12D.

The invention provides a nitrogen-containing heterocyclic compound shown in a formula I, and pharmaceutically acceptable salt or 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-C₁₄ aryl, 5 to 14 membered heteroaryl, C ₆-C₁₄ aryl substituted with one or more R ^1-1, or 5 to 14 membered heteroaryl substituted with one or more R ^1-2; in a 5-to 14-membered heteroaryl group ("5-to 14-membered heteroaryl" refers to the corresponding moiety in a "5-to 14-membered heteroaryl" or "5-to 14-membered heteroaryl substituted with one or more R ^1-2", as in the other moieties of the invention), the number of heteroatoms is 1,2,3 or 4, one or more of which are selected from the group consisting of O, S and N;

R ^1-1 and R ^1-2 are each independently halogen, cyano, hydroxy, C ₁-C₄ alkyl, -S-C ₁-C₃ alkyl, C ₂-C₄ alkenyl, C ₂-C₄ alkynyl, C ₁-C₃ haloalkyl, -O-C ₁-C₃ haloalkyl, C ₁-C₃ alkoxy, -N (R ^N1)₂ or C ₃-C₆ cycloalkyl, wherein C ₃-C₆ cycloalkyl is optionally substituted by halogen or C ₁-C₃ alkyl;

R ² is hydrogen, halogen or C ₁-C₃ alkyl;

L ¹ is a single bond, C ₁-C₄ alkylene, -O-or-N (R ^N1) -;

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

L ² is-O-, -N (methyl) -, C ₁-C₄ alkylene or C ₁-C₄ alkylene substituted by one or more R ^L2; each R ^L2 is independently hydroxy or C ₁-C₄ hydroxyalkyl;

R ^3-1 is C ₃-C₁₂ cycloalkyl, 3 to 12 membered heterocycloalkyl, C ₆-C₁₄ aryl, 5 to 14 membered heteroaryl, -N (R ^N1)₂, C ₃-C₁₂ cycloalkyl substituted with one or more R ^3-1-1, C ₆-C₁₄ aryl substituted with one or more R ^3-1-2, C ₆-C₁₄ 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, wherein the 3 to 12 membered heterocycloalkyl has a number of 1, 2, 3, or 4, wherein one or more of the heteroatoms is selected from O, S and N, wherein the number of heteroatoms is 1, 2, 3, or 4, wherein one or more of the heteroatoms is selected from the group consisting of O, S and N, and wherein N is independently 0, 1, 2, 3, or 4;

R ^3-1-1、R^3-1-2、R^3-1-3 and R ^3-1-4 are each halogen, cyano, oxo, C ₁-C₄ alkyl or-N (R ^N1)₂;

r ⁶ is-CN;

R ⁴ is C ₃-C₇ cycloalkyl, C ₃-C₇ cycloalkenyl, 3-to 12-membered nitrogen containing heterocycloalkyl, 3-to 12-membered nitrogen containing heterocycloalkenyl, C ₃-C₆ cycloalkyl substituted with one or more R ^4-1, C ₃-C₇ 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, and one or more of the heteroatoms is selected from O, S and N; in the 3-to 12-membered nitrogen-containing heterocycloalkenyl group, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are one or more selected from O, S and N;

R ^4-1、R^4-2、R^4-3 and R ^4-4 are each independently oxo, hydroxy, cyano, halogen, C ₁-C₃ alkyl, C ₁-C₃ alkoxy, C ₁-C₃ cyanoalkyl, C ₃-C₆ cycloalkyl, C ₁-C₃ alkoxy or-N (R ^N1)₂;

Each R ^N1 is independently hydrogen or C ₁-C₃ alkyl.

In certain embodiments, the nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, or a solvate thereof has the following definition (hereinafter "in certain embodiments"):

R ¹ is C ₆-C₁₄ aryl, 5 to 14 membered heteroaryl, C ₆-C₁₄ aryl substituted with one or more R ^1-1, or 5 to 14 membered heteroaryl substituted with one or more R ^1-2; in a 5-to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, one or more of said heteroatoms being selected from the group consisting of O, S and N;

R ^1-1 and R ^1-2 are each independently halogen, cyano, hydroxy, C ₂-C₄ alkynyl or C ₁-C₃ alkoxy.

In certain embodiments, R ¹ is C ₆-C₁₄ aryl, 5 to 14 membered heteroaryl, C ₆-C₁₄ aryl substituted with one or more R ^1-1, or 5 to 14 membered heteroaryl substituted with one or more R ^1-2; in a 5-to 14-membered heteroaryl, the number of heteroatoms is 1,2, 3 or 4, one or more of said heteroatoms being selected from the group consisting of O, S and N;

r ^1-1 and R ^1-2 are each independently halogen, cyano, hydroxy, C ₁-C₄ alkyl, C ₂-C₄ alkynyl, C ₁-C₃ haloalkyl or C ₃-C₆ 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-C₄ alkylene, -N (methyl) -or-O-.

In certain embodiments, L ¹ is C ₁-C₄ alkylene or-O-.

In certain embodiments, R 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;

R ^3-1 is C ₃-C₁₂ cycloalkyl, 3 to 12 membered heterocycloalkyl, C ₆-C₁₄ aryl, 5 to 14 membered heteroaryl, -N (R ^N1)₂, C ₃-C₁₂ cycloalkyl substituted with one or more R ^3-1-1, 3-12 membered heterocycloalkyl substituted with one or more R ^3-1-2, C ₆-C₁₄ 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, wherein the 3 to 12 membered heterocycloalkyl has a1, 2,3, or 4 heteroatom number, one or more of the heteroatoms is selected from O, S and N, 5 to 14 membered heteroaryl has a1, 2,3, or 4 heteroatom number, one or more of the heteroatoms is selected from the group consisting of O, S and N, and N is independently 0,1, 2,3, or 4;

R ^3-1-1、R^3-1-2、R^3-1-3 and R ^3-1-4 are each halogen, cyano, C ₁-C₄ alkyl or-N (R ^N1)₂).

L ² is C ₁-C₄ alkylene or C ₁-C₄ alkylene substituted with one or more R ^L2; each R ^L2 is independently hydroxy or C ₁-C₄ hydroxyalkyl;

R ^3-1 is C ₃-C₁₂ cycloalkyl, 3 to 12 membered heterocycloalkyl, C ₆-C₁₄ aryl, 5 to 14 membered heteroaryl, -N (R ^N1)₂, C ₃-C₁₂ 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-C₁₄ 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, wherein the 3 to 12 membered heterocycloalkyl has a1, 2,3, or 4 heteroatom number, one or more of the heteroatoms is selected from O, S and N, 5 to 14 membered heteroaryl has a1, 2,3, or 4 heteroatom number, one or more of the heteroatoms is selected from the group consisting of O, S and N, and N is independently 0,1, 2,3, or 4;

R ^3-1-1、R^3-1-2、R^3-1-3 and R ^3-1-4 are each halogen, cyano, oxo, C ₁-C₄ 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-C₄ alkylene;

R ^3-1 is C ₃-C₁₂ cycloalkyl, 3 to 12 membered heterocycloalkyl, C ₃-C₁₂ cycloalkyl substituted by one or more R ^3-1-1 or 3 to 12 membered heterocycloalkyl substituted by one or more R ^3-1-2; in the 3-to 12-membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and one or more of the heteroatoms is selected from O, S and N;

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

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

L ² is-O-, -N (methyl) -or C ₁-C₄ alkylene;

R ^3-1-1 and R ^3-1-2 are each independently halogen.

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

L ² is C ₁-C₄ alkylene;

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

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

L ² is C ₁-C₄ alkylene;

R ^3-1-1 and R ^3-1-2 are each independently halogen.

In certain embodiments, 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, and one or more of the heteroatoms is selected from O, S and N;

each R ^4-3 is independently C ₁-C₃ cyanoalkyl or-N (R ^N1)₂;

Each R ^N1 is independently hydrogen or C ₁-C₃ alkyl.

In certain embodiments, R ⁴ is C ₄-C₇ cycloalkyl substituted with 1R ^4-1; r ^4-1 is-N (R ^N1)₂; each R ^N1 is independently hydrogen or C ₁-C₃ alkyl).

In certain embodiments, in R ⁴, C ₃-C₇ cycloalkyl, C ₃-C₇ cycloalkenyl, 3 to 12 membered nitrogen containing heterocycloalkyl, and 3 to 12 membered nitrogen containing heterocycloalkenyl are bridged rings.

In certain embodiments, R ⁴ satisfies 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, halo, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C ₃-C₆ cycloalkyl, -N (RN 1) 2, -CO2RN1, -CO2N (RN 1) 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 being selected from one or more of O, S and N;

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments, "NH" on the ring is not attached to R ^Z1.

In certain embodiments, R ⁴ is

Wherein Z ¹ is independently CH, C or N;

Ring a is a3 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, and the heteroatoms are one or more selected from O, S and N; in the 3-to 12-membered nitrogen-containing heterocycloalkenyl group, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are one or more selected from O, S and N;

Ring B is C ₃-C₇ cycloalkyl, C ₃-C₇ 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, and the heteroatoms are one or more selected from O, S and N; in the 3-to 12-membered nitrogen-containing heterocycloalkenyl group, the number of heteroatoms is 1,2,3 or 4, and the heteroatoms are one or more selected from O, S and N;

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

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments, R ⁴ is attached through a carbon atom or a nitrogen atom

R ⁴ is a 3-to 12-membered nitrogen-containing heterocycloalkyl, a 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, the 3-to 12-membered nitrogen-containing heterocycloalkyl has "NH" which is not attached to R ^4-3;

In R ⁴, the 3-to 12-membered nitrogen-containing heterocycloalkyl has "NH" which is not attached to R ^4-4.

R ⁴ is C ₃-C₆ cycloalkyl substituted with one or more R ^4-1, C ₃-C₇ 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;

r ^1-1 and R ^1-2 are each independently halogen, cyano, hydroxy, C ₂-C₄ alkynyl or C ₁-C₃ alkoxy;

r ² is halogen;

L ¹ is C ₁-C₄ alkylene, -N (methyl) -or-O-;

r ³ is-L ²-R^3-1;

L ² is-O-, -N (methyl) -or C ₁-C₄ alkylene;

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

r ⁶ is-CN;

R ⁴ is a 3-to 12-membered nitrogen containing heterocycloalkyl or a 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, and one or more of the heteroatoms is selected from O, S and N;

each R ^4-3 is independently C ₁-C₃ cyanoalkyl or-N (R ^N1)₂;

Each R ^N1 is independently hydrogen or C ₁-C₃ alkyl.

In certain embodiments:

X ¹ is C-H;

X ³ is C-H;

r ^1-1 and R ^1-2 are each independently halogen, cyano, hydroxy, C ₁-C₄ alkyl, C ₂-C₄ alkynyl, C ₁-C₃ haloalkyl or C ₃-C₆ cycloalkyl;

r ² is halogen;

l ¹ is-O-;

r ³ is-L ²-R^3-1;

L ² is C ₁-C₄ alkylene;

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

Each R ^3-1-2 is independently halogen or C ₁-C₄ alkyl;

r ⁶ is-CN;

Each R ^4-3 is independently C ₁-C₃ alkyl or-N (R ^N1)₂;

Each R ^N1 is independently hydrogen or C ₁-C₃ alkyl.

In certain embodiments, R ² is hydrogen or halogen;

R ⁴ is bound by carbon or nitrogen atoms

In certain embodiments:

Is that

Wherein n is 1,2,3 or 4, each R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C₄ alkyl;

R ⁴ is bound by carbon or nitrogen atoms

In certain embodiments:

Is that

Wherein m is 1, 2, 3 or 4, and r ^3-1-2 are each independently oxo, halogen or cyano;

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

R ⁴ is bound by carbon or nitrogen atoms

In certain embodiments:

Is that

Wherein R ⁴ is bound by a carbon or nitrogen atom

In certain embodiments:

Is that

Wherein R ⁴ is bound by a carbon or nitrogen atom

In certain embodiments:

Is that

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

R ⁴ is bound by carbon or nitrogen atoms

In certain embodiments:

Is that

Wherein,

R ⁴ is C ₄-C₇ cycloalkyl substituted with 1R ^4-1; r ^4-1 is-N (R ^N1)₂; each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ⁴ is bound by carbon or nitrogen atoms

In certain embodiments:

Is that

Wherein Z ¹ is independently CH, C or N;

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

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments:

Is that

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-C₃ alkyl, C ₁-C₃ alkoxy, C ₁-C₃ cyanoalkyl, C ₁-C₃ hydroxyalkyl, C ₃-C₆ cycloalkyl, -N (R ^N1)₂、-CO₂R^N1、-CO₂N(R^N1)₂ or 5 to 6 membered heteroaryl, wherein the number of heteroatoms in the 5 to 6 membered heteroaryl is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments:

Is that

Z ¹ is independently CH, C or N;

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

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments:

Is that

Z ¹ is independently CH, C or N;

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

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments, in R ^X1, halogen is F, cl, br, or I.

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

In certain embodiments, in R ¹, the C ₆-C₁₄ aryl is C ₆-C₁₀ aryl.

In certain embodiments, in R ¹, the C ₆-C₁₄ aryl is monocyclic or bicyclic.

In certain embodiments, in R ¹, each ring of the C ₆-C₁₄ aryl is aromatic.

In certain embodiments, in R ¹, the C ₆-C₁₄ aryl is phenyl, 1-naphthyl, 2-naphthyl, or

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

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

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

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

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

In certain embodiments, in R ¹ -to 14-membered heteroaryl is pyridinyl, indolyl, quinolinyl, isoquinolinyl, benzothienyl, or benzothiazolyl.

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

In certain embodiments, in R ^1-1 and R ^1-2, halogen is F, cl, br, or I.

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

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

In certain embodiments, in R ^1-1 and R ^1-2, the C ₁-C₄ alkyl is methyl, ethyl, propyl, or isopropyl.

In certain embodiments, in R ^1-1 and R ^1-2, the C ₁-C₄ alkyl is methyl or ethyl.

In certain embodiments, in R ^1-1 and R ^1-2, the C ₁-C₄ alkyl is methyl.

In certain embodiments, in R ^1-1 and R ^1-2, -S-C ₁-C₃ alkyl is-S-methyl, -S-ethyl, -S-propyl, or-S-isopropyl.

In certain embodiments, in R ^1-1 and R ^1-2, -S-C ₁-C₃ alkyl is-S-methyl.

In certain embodiments, in R ^1-1 and R ^1-2, the C ₂-C₄ alkynyl is ethynyl.

In certain embodiments, in R ^1-1 and R ^1-2, the C ₁-C₃ haloalkyl is-CF ₃.

In certain embodiments, in R ^1-1 and R ^1-2, -O-C ₁-C₃ haloalkyl is-O-CF ₃.

In certain embodiments, in R ^1-1 and R ^1-2, the C ₁-C₃ alkoxy group is methoxy, ethoxy, n-propoxy, or isopropoxy.

In certain embodiments, in R ^1-1 and R ^1-2, the C ₁-C₃ alkoxy group is methoxy.

In certain embodiments, in R ^1-1 and R ^1-2, the C ₃-C₆ cycloalkyl is cyclopropyl, cyclopentyl, or cyclohexyl.

In certain embodiments, in R ^1-1 and R ^1-2, the C ₃-C₆ cycloalkyl is cyclopropyl.

In certain embodiments, R ¹ is

In certain embodiments, in R ², halogen is F, cl, br, or I.

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

In certain embodiments, in R ², C ₁-C₃ alkyl is methyl, ethyl, propyl, or isopropyl.

In certain embodiments, in L ¹, C ₁-C₄ alkylene is methylene, ethylene, propylene, or butylene.

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

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

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

In certain embodiments, in R ³, the heteroatom in the 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, C ₁-C₄ alkylene is methylene, ethylene, propylene, or butylene.

In certain embodiments, R ^3-1 is attached to L2 through a carbon atom or a nitrogen atom.

In certain embodiments, in R ^3-1, C ₃-C₁₂ cycloalkyl is C ₃-C₈ cycloalkyl.

In certain embodiments, in R ^3-1, C ₃-C₁₂ cycloalkyl is C ₅-C₈ cycloalkyl.

In certain embodiments, in R ^3-1, C ₃-C₁₂ cycloalkyl is monocyclic or bicyclic.

In certain embodiments, in R ^3-1, C ₃-C₁₂ cycloalkyl is monocyclic, spiro, or bridged.

In certain embodiments, in R ^3-1, C ₃-C₁₂ cycloalkyl is cyclopentyl or octahydropentalene.

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

In certain embodiments, in R ^3-1, 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 a monocyclic or bicyclic ring.

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

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

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

In certain embodiments, in R ^3-1, 3 to 12 membered heterocycloalkyl is a5 to 6 membered monocyclic heterocycloalkyl.

In certain embodiments, in R ^3-1, the 3-to 12-membered heterocycloalkyl is a 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-pyrrolazin-7 a (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, 5 to 14 membered heteroaryl is 5 to 6 membered heteroaryl.

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

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

In certain embodiments, in R ^3-1, the heteroatom in the 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, 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, 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-C₄ 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-C₄ alkyl is methyl.

In certain embodiments, -L ¹-R³ is

In certain embodiments, in R ⁴, C ₃-C₇ cycloalkyl is monocyclic or bicyclic.

In certain embodiments, in R ⁴, C ₃-C₇ cycloalkyl is monocyclic, spiro, or bridged.

In certain embodiments, in R ⁴, C ₃-C₇ cycloalkyl isCyclopropyl, cyclopentyl, or cyclohexyl.

In certain embodiments, in R ⁴, C ₃-C₇ cycloalkyl is cyclopentyl.

In certain embodiments, in R ⁴, C ₃-C₇ cycloalkyl substituted with one or more R ^4-1 is

In certain embodiments, in R ⁴, the C ₃-C₇ cycloalkenyl is mono-or bi-cyclic.

In certain embodiments, in R ⁴, C ₃-C₇ cycloalkenyl is monocyclic, spiro, or bridged.

In certain embodiments, in R ⁴, C ₃-C₇ cycloalkenyl is cyclopropenyl, cyclopentenyl or cyclohexenyl.

In certain embodiments, in R ⁴, C ₃-C₇ cycloalkenyl is cyclopentenyl.

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

In certain embodiments, in R ⁴, 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 a monocyclic or bicyclic ring.

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

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

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

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

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

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

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, 3 to 12 membered nitrogen containing heterocyclenyl is 5 to 9 membered nitrogen containing heterocyclenyl.

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

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

In certain embodiments, in R ⁴, the 3-to 12-membered nitrogen-containing heterocyclenyl is a single ring, a spiro ring, or a bridged ring.

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

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

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

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

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

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

In certain embodiments, in R ⁴, the 3-to 12-membered nitrogen-containing heterocycloalkenyl is a 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, halogen is F, cl, br, or I.

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

In certain embodiments, in R ^4-1、R^4-2、R^4-3 and R ^4-4, the C ₁-C₃ 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-C₃ alkyl is methyl.

In certain embodiments, in R ^4-1、R^4-2、R^4-3 and R ^4-4, the C ₁-C₃ cyanoalkyl group is cyanomethyl.

In certain embodiments, in R ^4-1、R^4-2、R^4-3 and R ^4-4, the C ₃-C₆ cycloalkyl is cyclopropyl, cyclopentyl, or cyclohexyl.

In certain embodiments, in R ^4-1、R^4-2、R^4-3 and R ^4-4, the C ₃-C₆ cycloalkyl is cyclopropyl.

In certain embodiments, in R ^4-1、R^4-2、R^4-3 and R ^4-4, the C ₁-C₃ alkoxy group 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-C₃ alkyl is methoxy.

In certain embodiments, in R ^N1, C ₁-C₃ alkyl is methyl, ethyl, propyl, or isopropyl.

In certain embodiments, in R ^N1, the C ₁-C₃ alkyl is methyl.

In certain embodiments, "NH" on ring a is not attached to R ^Z1.

In certain embodiments, in ring B, C ₃-C₇ cycloalkyl is monocyclic or bicyclic.

In certain embodiments, in ring B, C ₃-C₇ cycloalkyl is a monocyclic, spiro, or bridged ring.

In certain embodiments, in ring B, C ₃-C₇ cycloalkyl isCyclopropyl, cyclopentyl, or cyclohexyl.

In certain embodiments, in ring B, C ₃-C₇ cycloalkyl is cyclopentyl.

In certain embodiments, in ring B, the C ₃-C₇ cycloalkenyl is monocyclic or bicyclic.

In certain embodiments, in ring B, C ₃-C₇ cycloalkenyl is a monocyclic, spiro, or bridged ring.

In certain embodiments, in ring B, C ₃-C₇ cycloalkenyl is cyclopropenyl, cyclopentenyl or cyclohexenyl.

In certain embodiments, in R ⁴, C ₃-C₇ cycloalkenyl is cyclopentenyl.

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

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

In certain embodiments, in the a and B rings, the 3-to 12-membered nitrogen containing heterocycloalkyl is a single ring or a double ring.

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

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

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

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

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

In certain embodiments, in the a and B rings, the 3-to 12-membered nitrogen-containing heterocycloalkyl is a 7-to 9-membered nitrogen-containing spirocycloalkyl.

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

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

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

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

In certain embodiments, in ring a and ring B, the 3-to 12-membered nitrogen-containing heterocycloalkenyl is a single ring, a spiro ring, or a bridged ring.

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

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

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

In certain embodiments, in the a and B rings, the 3-to 12-membered nitrogen-containing heterocyclenyl is a 5-to 7-membered nitrogen-containing monocyclic heterocyclenyl.

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

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

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

In certain embodiments, in R ^Z1, halogen is F, cl, br, or I.

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

In certain embodiments, in R ^Z1, C ₁-C₃ alkyl is methyl, ethyl, propyl, or isopropyl.

In certain embodiments, in R ^Z1, the C ₁-C₃ alkyl is methyl.

In certain embodiments, in R ^Z1, C ₁-C₃ cyanoalkyl is cyanomethyl.

In certain embodiments, in R ^Z1, C ₃-C₆ cycloalkyl is cyclopropyl, cyclopentyl, or cyclohexyl.

In certain embodiments, in R ^Z1, C ₃-C₆ cycloalkyl is cyclopropyl.

In certain embodiments, in R ^Z1, C ₁-C₃ alkoxy is methoxy, ethoxy, n-propoxy, or isopropoxy.

In certain embodiments, in R ^Z1, the C ₁-C₃ alkoxy group is methoxy.

In certain embodiments, in R ^N1, the C ₁-C₃ alkyl is methyl.

In certain embodiments, R ⁴ is

In certain embodiments, "plurality" in the above definition 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 invention also provides a pharmaceutical composition, which comprises a substance X and a pharmaceutically acceptable excipient, wherein the substance X is a nitrogenous heterocyclic compound shown in a formula I, and pharmaceutically acceptable salt or solvate thereof.

The invention also provides the use of substance X in the preparation of KRAS-G12D inhibitors;

the substance X is a nitrogen-containing heterocyclic compound shown in a formula I, a pharmaceutically acceptable salt thereof or a solvate thereof.

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

The invention also provides the application of the substance X in preparing medicines;

The substance X is a nitrogen-containing heterocyclic compound shown in a formula I, a pharmaceutically acceptable salt or a solvate thereof;

the medicament is used for treating or preventing KRAS-G12D related diseases or symptoms.

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

the medicine can be used for treating or preventing cancer.

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

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

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

The invention provides a nitrogen-containing heterocyclic compound shown in a formula II, and pharmaceutically acceptable salt or solvate thereof;

wherein,

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

is a single bond or a double bond;

r ⁵ is hydrogen, halogen or C ₁-C₃ alkyl;

L ¹ is a single bond, C ₁-C₄ alkylene, -O-or-N (R ^N1) -;

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

Each R ^N1 is independently hydrogen or C ₁-C₃ alkyl.

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

In certain embodiments, X ³ is CH ₂.

In some embodiments of the present invention, in some embodiments,Is a single bond.

In certain embodiments, R ⁵ is methyl or ethyl.

In certain embodiments, R ⁵ is hydrogen.

In certain embodiments, L ¹ is C ₁-C₄ alkylene, -N (methyl) -or-O-.

In certain embodiments, L ¹ is C ₁-C₄ alkylene or-O-.

In certain embodiments, R ¹ is-O-.

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

L ² is-O-, -N (methyl) -or C ₁-C₄ alkylene;

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

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

L ² is-O-, -N (methyl) -or C ₁-C₄ alkylene;

R ^3-1-1 and R ^3-1-2 are each independently halogen.

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

L ² is C ₁-C₄ alkylene;

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

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

L ² is C ₁-C₄ alkylene;

R ^3-1-1 and R ^3-1-2 are each independently halogen.

In certain embodiments, X ² is N.

each R ^4-3 is independently C ₁-C₃ cyanoalkyl or-N (R ^N1)₂;

Each R ^N1 is independently hydrogen or C ₁-C₃ alkyl.

In certain embodiments, R ⁴ satisfies the following conditions:

Wherein Z ¹ is independently CH, C or N;

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

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments, "NH" on the ring is not attached to 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 R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments:

X ³ is CH ₂;

Is a single bond;

R ⁵ is hydrogen;

L ¹ is C ₁-C₄ alkylene, -N (methyl) -or-O-;

r ³ is-L ²-R^3-1;

L ² is-O-, -N (methyl) -or C ₁-C₄ alkylene;

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

X ² is N;

each R ^4-3 is independently C ₁-C₃ cyanoalkyl or-N (R ^N1)₂;

Each R ^N1 is independently hydrogen or C ₁-C₃ alkyl.

In certain embodiments:

x ³ is CH-R ^X3;R^X3 is halogen;

Is a single bond;

R ⁵ is hydrogen;

R ^1-1 and R ^1-2 are each independently halogen, cyano, hydroxy, C ₁-C₄ alkyl, C ₂-C₄ alkynyl, C ₁-C₃ haloalkyl, C ₁-C₃ alkoxy or C ₃-C₆ cycloalkyl;

l ¹ is-O-;

r ³ is-L ²-R^3-1;

L ² is C ₁-C₄ alkylene;

R ^3-1 is 3-to 12-membered heterocycloalkyl substituted by one or more R ^3-1-2, C ₆-C₁₄ aryl substituted by one or more R ^3-1-3, or 5-to 14-membered heteroaryl substituted by one or more R ^3-1-4; in the 3-to 12-membered heterocycloalkyl, the number of heteroatoms is 1,2, 3 or 4, and one or more of the heteroatoms is selected from O, S and N; in a 5-to 14-membered heteroaryl, the number of heteroatoms is 1,2, 3 or 4, one or more of said heteroatoms being selected from the group consisting of O, S and N; n is independently 0,1, 2, 3 or 4;

R ^3-1-2 and R ^3-1-4 are each halogen or C ₁-C₄ alkyl;

X ² is N;

R ^4-3 is each independently hydroxy, C ₁-C₃ alkyl or C ₁-C₃ cyanoalkyl.

In certain embodiments:

Is that

R ⁴ is bound by carbon or nitrogen atoms

R ⁵ is halogen or C ₁-C₃ alkyl.

In certain embodiments:

Is that

R ⁴ is bound by carbon or nitrogen atoms

R ⁵ is halogen or C ₁-C₃ alkyl.

In certain embodiments:

Is that

R ⁴ is bound by carbon or nitrogen atoms

R ⁵ is halogen or C ₁-C₃ alkyl.

In certain embodiments:

Is that

R ⁴ is bound by carbon or nitrogen atoms

R ⁵ is halogen or C ₁-C₃ alkyl.

In certain embodiments:

Is that

R ⁴ is bound by carbon or nitrogen atoms

R ⁵ is halogen or C ₁-C₃ alkyl.

In certain embodiments:

Is that

R ⁴ is bound by carbon or nitrogen atoms

R ⁵ is halogen or C ₁-C₃ alkyl.

In certain embodiments:

Is that

R ⁴ is bound by carbon or nitrogen atoms

R ⁵ is halogen or C ₁-C₃ alkyl.

In certain embodiments:

Is that

R ⁴ is bound by carbon or nitrogen atoms

R ⁵ is halogen or C ₁-C₃ alkyl.

In certain embodiments:

Is that

R ⁴ is bound by carbon or nitrogen atoms

R ⁵ is halogen or C ₁-C₃ alkyl.

In certain embodiments:

Is that

R ⁴ is bound by carbon or nitrogen atoms

R ⁵ is halogen or C ₁-C₃ alkyl.

In certain embodiments:

Is that

Wherein R ⁴ is bound by a carbon or nitrogen atom

In certain embodiments:

Is that

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

R ⁴ is bound by carbon or nitrogen atoms

In certain embodiments:

Is that

Wherein,

R ⁴ is bound by carbon or nitrogen atoms

In certain embodiments:

Is that

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

R ⁴ is bound by carbon or nitrogen atoms

In certain embodiments:

Is that

Wherein,

R ⁴ is bound by carbon or nitrogen atoms

In certain embodiments:

Is that

Wherein Z ¹ is independently CH, C or N;

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

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments:

Is that

Wherein Z ¹ is independently CH, C or N;

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

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments:

Is that

Wherein,Is a single bond;

n is 1, 2, 3 or 4, each R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C₄ alkyl;

Z ¹ is independently CH, C or N;

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

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments:

Is that

Z ¹ is independently CH, C or N;

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

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl.

In certain embodiments, in R ^X3, halogen is F, cl, br, or I.

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

In certain embodiments, in R ⁵, halogen is F, cl, br, or I.

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

In certain embodiments, in R ⁵, C ₁-C₃ alkyl is methyl, ethyl, propyl, or isopropyl.

In certain embodiments, in R ⁵, C ₁-C₃ alkyl is methyl or ethyl.

In certain embodiments, in R ⁵, the C ₁-C₃ alkyl is methyl.

In certain embodiments, in R ¹, the C ₆-C₁₄ aryl is C ₆-C₁₀ aryl.

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

In certain embodiments, in R ^1-1 and R ^1-2, halogen is F, cl, br, or I.

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

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

In certain embodiments, in R ^1-1 and R ^1-2, the C ₁-C₄ alkyl is methyl.

In certain embodiments, in R ^1-1 and R ^1-2, -S-C ₁-C₃ alkyl is-S-methyl.

In certain embodiments, R ¹ is

In certain embodiments, -L ¹-R³ is

In certain embodiments, in R ^X2, halogen is F, cl, br, or I.

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

In certain embodiments, R ⁴ is attached through a carbon atom or a nitrogen atomIn certain embodiments, in R ⁴, C ₃-C₇ cycloalkyl is monocyclic or bicyclic.

In certain embodiments, in R ⁴, C ₃-C₇ cycloalkyl is cyclopentyl.

In certain embodiments, in R4, the C ₃-C₇ cycloalkenyl is monocyclic or bicyclic.

In certain embodiments, in R ⁴, C ₃-C₇ cycloalkenyl is cyclopentenyl.

In certain embodiments, in R ⁴, 3 to 12 membered nitrogen containing heterocycloalkyl is a 5 to 7 membered nitrogen containing monocyclic 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 ^4-1、R^4-2、R^4-3 and R ^4-4, halogen is F.

In certain embodiments, in R ^N1, the C ₁-C₃ alkyl is methyl.

In certain embodiments, "NH" on ring a is not attached to R ^Z1.

In certain embodiments, in ring B, C ₃-C₇ cycloalkyl is cyclopentyl.

In certain embodiments, in ring B, C ₃-C₇ cycloalkenyl is cyclopentenyl.

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

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

In certain embodiments, in R ^Z1, halogen is F, cl, br, or I.

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

In certain embodiments, in R ^Z1, the C ₁-C₃ alkyl is methyl.

In certain embodiments, in R ^Z1, C ₁-C₃ cyanoalkyl is cyanomethyl.

In certain embodiments, in R ^Z1, C ₃-C₆ cycloalkyl is cyclopropyl.

In certain embodiments, in R ^Z1, the C ₁-C₃ alkoxy group is methoxy.

In certain embodiments, in R ^N1, the C ₁-C₃ alkyl is methyl.

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 invention also provides a pharmaceutical composition, which comprises a substance Y and a pharmaceutically acceptable excipient, wherein the substance Y is a nitrogenous heterocyclic compound shown in a formula II, and pharmaceutically acceptable salt or solvate thereof.

The invention also provides the use of the Y substance in the preparation of KRAS-G12D inhibitors;

Substance Y is a nitrogen-containing heterocyclic compound shown in formula II, a pharmaceutically acceptable salt thereof or a solvate thereof.

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

The invention also provides the application of the substance Y in preparing medicines;

the substance Y is a nitrogen-containing heterocyclic compound shown in a formula II, a pharmaceutically acceptable salt or a solvate thereof;

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

the medicine can be used for treating or preventing cancer.

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

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

The present invention also provides a method of preventing and/or treating cancer, the method comprising 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 commonly understood by one of ordinary skill in the art to which this invention belongs.

The term "pharmaceutically acceptable salt" refers to the salt or zwitterionic form of a compound. Salts of the compounds may be prepared during the final isolation and purification of the compounds, or by reacting the compounds separately with a suitable acid. The pharmaceutically acceptable salt of the compound may be an acid addition salt formed with a pharmaceutically acceptable acid. Examples of acids that can be used to form pharmaceutically acceptable salts include inorganic acids (e.g., nitric acid, boric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid) and organic acids (e.g., oxalic acid, maleic acid, succinic acid, and citric acid). Non-limiting examples of salts of the compounds include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphoronate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylene sulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzenesulfonate, and p-toluenesulfonate. Furthermore, the available amino groups present in the compounds may be replaced by the chlorides, bromides and iodides of methyl, ethyl, propyl, butyl groups; dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate; decyl, lauryl, myristyl and steryl chlorides, bromides and iodides; benzyl bromide and phenethyl bromide were quaternized.

The term "solvate" refers to a combination, physical association and/or solvation of a compound of the invention with a solvent molecule, such as a di-, mono-, or hemi-solvate, wherein the ratio of solvent molecule to compound of the invention is about 2:1, about 1:1, or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonds, including hydrogen bonding. In some cases, the solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. Thus, "solvate" encompasses both solution phases and separable solvates. The compounds may be present as solvates with pharmaceutically acceptable solvents (e.g., water, methanol, ethanol, etc.). In some embodiments, the solvate is a hydrate. "hydrate" is a specific subset of solvates whose solvent molecules are water. Solvates may generally act as pharmacological equivalents. The preparation of solvates is well known in the art. A typical, non-limiting method of preparing the solvate is to dissolve the compound in the desired solvent (organic solvent, water or mixtures thereof) at a temperature of from 20 ℃ to above about 25 ℃ and then cool the solution at a rate sufficient to form crystals and isolate the crystals by known methods such as filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of solvent in the solvate crystals.

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

The terms "C ₁-C₆ alkyl", "C ₁-C₄ alkyl" and "C ₁-C₃ alkyl" refer to straight and branched chain aliphatic groups having 1 to 6 carbon atoms, 1 to 4 carbon atoms or 1 to 3 carbon atoms, respectively. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

The terms "C ₁-C₃ haloalkyl" and "C ₁-C₄ haloalkyl" refer to the product of substitution of one or more hydrogens in a C ₁-C₃ alkyl chain or a C ₁-C₄ alkyl chain, respectively, as defined herein with halogens. Examples thereof include trifluoromethyl, difluoromethyl and fluoromethyl.

The term "C ₁-C₄ alkylene" refers to a C ₁-C₄ alkyl group as defined above, which is located between and used to link two other chemical groups. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

The terms "C ₁-C₃ alkoxy" and "C ₁-C₄ alkoxy" refer to-OC ₁-C₃ alkyl and-OC ₁-C₄ alkyl, respectively, wherein the alkyl moieties are as defined above.

The terms "C ₁-C₃ hydroxyalkyl" and "C ₁-C₄ hydroxyalkyl" refer to-C ₁-C₃ alkylene-OH and-C ₁-C₄ alkylene-OH, respectively.

The term "C ₂-C₄ hydroxyalkynyl" refers to-C ₂-C₄ 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, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term "cycloalkyl" may be a monocyclic, bicyclic, spiro, or bridged ring system, such as bicyclo [1.1.1] pentyl.

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

The term "heterocycloalkyl" is a cyclic structure having 3 to 12 atoms (e.g., 4 to 8 atoms) wherein one or more atoms are selected from the group consisting of N, O and S and the remaining ring atoms are carbon. Heterocycloalkyl groups may be monocyclic, bicyclic, helical, or bridged ring systems. Heterocycloalkyl groups are saturated. Examples of heterocyclic groups include, but are not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl.

The term "heterocycloalkenyl" group is a cyclic structure having 3 to 12 atoms (e.g., 4 to 8 atoms) where one or more atoms are selected from the group consisting of N, O and S and the remaining ring atoms are carbon. Heterocycloalkenyl groups can be monocyclic, bicyclic, spiro, or bridged ring systems. Heterocycloalkenyl groups are partially unsaturated and contain no aromatic ring.

The term "aryl" is a C ₆-C₁₄ aromatic group containing 1 to 3 aromatic rings. As an example, the aryl group may be a C ₆-C₁₀ aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl. "aryl" also refers to a bi-or tri-cyclic ring system wherein one or both rings of the aromatic ring system may be saturated or partially saturated, respectively.

The term "heteroaryl" refers to a group having 5 to 14 ring atoms (preferably 5,6, 9 or 10 ring atoms); 6, 10 or 14n shared electrons are annularly arranged; examples of heteroaryl groups, which have one to four heteroatoms selected from the group consisting of N, O and S in addition to carbon atoms, include benzimidazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl. "heteroaryl" also refers to bicyclic or tricyclic ring systems, wherein one or two rings in the aromatic ring system may be saturated or partially saturated, respectively.

The term "KRAS-G12D inhibitor" refers to an agent capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRAS-G12D.

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

The term "preventing" refers to a method of preventing a disease or disorder and/or its concomitant occurrence or preventing a subject from suffering from a disease. As used herein, "preventing" also includes delaying the onset of a disease and/or its attendant symptoms, and reducing the risk of a subject suffering from a disease. The term "preventing" may include "prophylactic treatment" which refers to reducing the likelihood of recurrence of a disease or disorder not suffering from, but at risk of contracting, or susceptible to, a disease or disorder again in a subject, or a previously controlled disease or disorder.

The term "treating" refers to eliminating, reducing or ameliorating a disease or disorder and/or symptoms associated therewith. Although the treatment of a disease or condition does not require complete elimination of the disease, condition or symptoms associated therewith, this is not precluded. The term "treatment" and synonyms refer to the administration of a therapeutically effective amount of a compound to a subject in need of such treatment. Treatment may be directed to symptoms, such as suppression of symptoms. It can be effective in the short term, can be performed in the medium term, or can be a long term treatment, such as maintenance treatment.

The term "subject" refers to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, or humans. The preferred subject is a human.

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

The above-described preferred conditions may be combined in any manner to obtain a preferred embodiment of the invention without departing from the common general knowledge in the art.

The positive progress effect of the invention is that the nitrogenous heterocyclic compound has better inhibition activity on KRAS.

Detailed Description

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

Abbreviations (abbreviations)

Some abbreviations are listed below.

Methanol MeOH

Tetrahydrofuran THF

Dichloromethane DCM

Petroleum ether: PE (polyethylene)

Ethyl acetate: etOAc (EA)

Acetonitrile ACN

Isopropyl alcohol: IPA (isopropyl alcohol)

Triethylamine: TEA (TEA)

Trifluoroacetic acid: TFA (TFA)

Sodium hydroxide: naOH

Nitrogen gas: n ₂

Thin layer chromatography: TLC of

High performance liquid chromatography: HPLC (high Performance liquid chromatography)

N, N-diisopropylethylamine: DIPEA (DIPEA)

N, N-dimethylformamide: DMF (dimethyl formamide)

Para-toluenesulfonyl chloride TsCl

1,1' -Bis (diphenylphosphine) ferrocene dppf

Triisopropylsilyl (Triisopropylsilyl) TIPS

Pinacol borate: BPin A

Normal temperature RT

Hours: hrs

Representative method of preparative high performance liquid chromatography: (flow and gradient may change)

Exemplary methods for preparative HPLC are provided below.

Method A, NH ₄HCO₃:

( Chromatographic column Gilson2-Xbrige C, 19 x 150mm,5 μm; mobile phase: acetonitrile in water (0.1% nh ₄HCO₃) ratio from 20% to 60%, flow rate: 15ml/min ).

Method B TFA:

( Chromatographic column: waters-Xbrige C, 10 x 190mm,5 μm; mobile phase: acetonitrile in water (0.1% tfa) ratio from 15% to 40%, flow rate: 15ml/min )

HCOOH:

( Chromatographic column: waters-Xbrige C, 10 x 190mm,5 μm; mobile phase: acetonitrile in water (0.1% formic acid) ratio from 15% to 40%, flow rate: 15ml/min )

Method D, NH ₄HCO₃:

( Column chromatography, waters-Xbrige C, 19 x 150mm,5 μm; mobile phase: acetonitrile in water (0.1% nh ₄HCO₃) ratio from 40% to 60%, flow rate: 20ml/min ).

Method E: NH ₄HCO₃:

( Column chromatography, waters-Xbrige C, 19 x 150mm,5 μm; mobile phase: acetonitrile in water (0.1% nh ₄HCO₃) ratio from 20% to 45%, flow rate: 20ml/min ).

Method F: HCOOH:

( Chromatographic column: waters-SunFire C18 x 150mm,5 μm; mobile phase: acetonitrile in water (0.1% formic acid) ratio from 20% to 60%, flow rate: 20ml/min ).

Representative method of analytical HPLC

Method 1: analysis was performed on an Agilent 1200series HPLC-6120 MS. UHPLC long gradient: acetonitrile in water (0.02% NH ₄ OAc) at a ratio of 5% to 95%, run time 6.5 minutes, flow rate 1.5mL/min. Waters Xbridged C18 column (18.5 microns, 4.6 x 50 mm) was used at 40 ℃.

Method 2: analysis was performed on an Agilent 1200series HPLC-6120 MS. UHPLC long gradient: acetonitrile in water (0.1% trifluoroacetic acid) ratio from 5% to 95%, run time 6.5 minutes, flow rate 1.5mL/min. Waters Xbridged C18 column (18.5 microns, 4.6 x 50 mm) was used at 40 ℃.

Method 3: analysis was performed on an Agilent 1260series HPLC-6120 MS. UHPLC long gradient: acetonitrile in water (0.02% NH ₄ OAc) at a ratio of 5% to 95%, run time 6.5 minutes, flow rate 2mL/min. Diamonsil Plus C18 columns (18.5 microns, 4.6 x 30 mm) were used at a temperature of 40 ℃.

Method 4: analysis was performed on an Agilent 1260series HPLC-6125 MS. HPLC long gradient: acetonitrile in water (0.1% formic acid) ratio from 5% to 95%, run time 6.0 minutes, flow rate 0.9mL/min. Agilent InfinityLab Poroshell 120SB-C18 columns (2.7 microns, 3.0 x 100 mm) were used at a temperature of 30deg.C.

Method 5: analysis was performed on an Agilent 1260series HPLC-6125 MS. HPLC long gradient: acetonitrile in water (0.1% formic acid) ratio from 50% to 100%, run time of 8.0 minutes, flow rate of 0.9mL/min. Agilent InfinityLab Poroshell 120SB-C18 columns (2.7 microns, 3.0 x 100 mm) were used at a temperature of 30deg.C.

Example 1

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

A solution (14 g,47.18 mmol) of 2-amino-4-bromo-3-fluorobenzoic acid (10 g,42.73 mmol) was added to THF (80 mL) and stirred at 75℃for 4 hours at room temperature. After cooling to RT-the reaction mixture was filtered and the filter cake was dried to give compound 1b (9.5 g, 86% yield) as a white solid. ¹H NMR(400MHz,DMSO-d₆ ) Delta 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 (1 c)

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) was added to DMF (80 mL) and stirred at 90℃for 16 h. After cooling to RT, the reaction mixture was diluted with HO ₂ (30 mL), acidified with 1N HCl, and ph=2. The solid formed was filtered and the cake after filtration was dried to give compound 1c (10.9 g, yield given) as a white solid. ¹H NMR(400MHz,DMSO-d₆ ) Delta 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 (1 d)

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 concentrated by cooling. The residue was poured into DCM/Et ₃ N (40 mL/4 mL). Washed with ice water (30 mL) and extracted with ethyl acetate (20 mL x 2). The separated organic layer was dried over NaS ₂ O and concentrated by filtration ₄. The residue was purified by column chromatography (PE/ea=10/1) to give 1d (770 mg, yield 27%) as a yellow solid. ¹H NMR(400MHz,DMSO-d₆ ) δ8.17 (dd, j=6.0, 8.8hz,1 h), 8.08 (dd, j=1.2, 8.8hz,1 h).

Step 4 tert-butyl 3- (7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1 e)

A mixture of 1d (500 mg,1.56 mmol), tert-butyl 3, 8-diazonium bicyclo [3.2.1] octane-8-carboxylate (390 mg,1.88 mmol) and TEA (316 mg,3.13 mmol) was RT-stirred in DCM (10 mL) for 3 h. The suspension was filtered and the filter cake after filtration was dried to give compound 1e (440 mg, 57% yield) as a white solid. LCMS (method 3): t= _R1.83min,m/z(m+H)＝⁺ 495.2.

Step 5 3- (7-bromo-3-cyano-8-fluoro-2- ((2R, 7 aS) -2-fluoro hexahydro-1H-pyrrolin-7 a (5H) -yl) methoxyquinolin-4-yl) -3, 8-diazobicyclooctane-8-carboxylate (1 f)

A mixture of 1e (150 mg,0.30 mmol), (2R, 7 aS) -2-fluorohexahydro-1H-pyri-rolizin-7 a (5H) -yl) methanol (96 mg,0.60 mmol) and anhydrous KCO (83 ₂mg₃, 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 ethyl acetate (5 mL x 2). The combined organic phases were concentrated to dryness to give compound 1f (78 mg,0.12 mmol) as a yellow solid. LCMS (method three): t=1.88 _R min,m/z(m+H)＝618.⁺ 7.

Step 6 3- (3-cyano-8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolin-7 a (5H) -yl) methoxyquinolin-4-yl) -3, 8-diazabicyclooctane-8-carboxylate (1 g)

1F (78 mg,0.13 mmol), 1i (36 mg,0.13 mmol), K ₂CO₃ (35 mg,0.25 mmol) and Pd (dppf) Cl ₂ (18.6 mg,0.025 mmol) were mixed in 1, 4-dioxane/HO ₂ (1 mL/0.2 mL) and stirred for 4 hours at 100deg.C without atmosphere ₂. The reaction mixture was concentrated by cooling. The residue was purified by column chromatography on silica gel (DCM/meoh=10/1) to give 1g (42 mg, yield 48%) of a yellow solid ¹H NMR(400MHz,DMSO-d₆):δ10.23(s,1H),8.02(d,J＝8.8Hz,1H),7.66(d,J＝8.0Hz,1H),7.57-7.54(m,1H),7.49-7.46(m,1H),7.41-7.39(m,1H),7.33(t,J＝2.0Hz,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,3H),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, 5-tetramethyl-13-dioxaborane-2-yl) naphthalen-2-ol

4, 5-Tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (764 mg,3.01 mmol), 4-bromo-5-fluoronaphthalen-2-ol (290 mg,1.20mmol, WO2021/41671, paragraph 01040), KOAc (230 mg,2.35 mmol) and Pd (dppf) Cl _2. DCM (88 mg,0.11 mmol) were mixed in dry dioxane (2 mL) and stirred at 90℃for ₂ hours in the absence of atmosphere. The reaction mixture was concentrated by cooling under vacuum. Purification by silica gel column chromatography (PE/ea=1/5) gave compound 1i (210 mg, yield 61%) as butter. LCMS (method 3) t _R＝1.67min,m/z(m-h)^- = 287.2.

Step 8 4- (3, 8-diazo [3.2.1] oct-3-yl) -8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) quinoline-3-carbonitrile (1)

A mixture of 1g (40 mg,0.057 mmol) TFA/DCM (0.1 mL/0.3 mL) was stirred at RT for 2 hours. The reaction mixture was concentrated, and the residue was purified by pretreated high performance liquid chromatography (MethodC) to give compound 1 (10 mg, yield 27%) as a white solid. LCMS (method two ):t_R＝2.77min,m/z(m+H)⁺＝600.3.¹H NMR(400MHz,DMSO-d₆):δ10.28(brs,1H)、7.96(d,J＝8.0Hz,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 (2 a)

Compound 2a (248 mg, yield) was synthesized using a preparation procedure similar to that of compound 1 starting from 1d (250 mg,0.78 mmol) and (S) -tert-butylpyrrolidine-3-carbamate (175 mg,0.94 mmol) 67％).¹H NMR(400MHz,DMSO-d₆):δ8.05(d,J＝8.8Hz,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, 7 aS) -2-fluorohexahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) quinolin-4-yl) pyrrolidin-3-yl) carbon (2 b)

To THF (1 mL) was added a solution of LiHMDS (0.64 mL,0.64mmol,1M in THF) tert-butyl compound 2a (75 mg,0.16 mmol) and ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (51 mg,0.32 mmol) (0deg.C). The mixture was stirred at 50℃for 2 days and at 70℃for 4 hours. The reaction mixture was concentrated and the residue was purified by pre-tlc (PE/ea=2/1) to give compound 2b (15 mg, 16% yield) as a yellow solid. LCMS (method 3) t=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, 7 aS) -2-fluorohexahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) quinolin-4-yl) pyrrolin-3-yl) carbamate (2 c)

Starting from 2b (15 mg,0.025 mmol) and 1i (8 mg,0.025 mmol), compound 2c (10 mg crude) was synthesized using a similar procedure to that described for compound 1. LCMS (method 3) t _R＝1.52min,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, 7 aS) -2-fluorohexahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) quinoline-3-carbonitrile (2)

Compound 2 (3.2 mg, 40% yield) was synthesized using a similar preparation procedure as compound 1 starting from 2c (10 mg,0.015 mmol). LCMS (method two) ):t_R＝3.35min,m/z(m+H)⁺＝574.3.¹H NMR(400MHz,CD₃OD):δ8.15(d,J＝8.8Hz,1H),7.60(d,J＝8.8Hz,1H),7.43-7.37(m,2H),7.29(d,J＝2.0Hz,1H),7.03(d,J＝2.0Hz,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 (3 a)

Starting from 1d (250 mg,0.78 mmol) and tert-butylpiperazine-1-carboxylate (186 mg,1.0 mmol), compound 3a (275 mg, yield) was synthesized using a similar preparation process as compound 1 75％).¹H NMR(400MHz,DMSO-d₆):δ7.52-7.44(m,2H),3.72-3.69(m,4H),3.67-3.60(m,4H),1.44(s,9H).

Step 2 4- (7-bromo-3-cyano-8-fluoro-2- ((2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolin-7 a (5H) -yl) methoxy quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl (3 b)

Compound 3b (68 mg, yield 45%) was synthesized using a similar preparation procedure as compound 1 starting from 3a (120 mg,0.25 mmol) and (2 r,7 as) -2-fluoro hexahydro-1H-pyrrolizine-7 a (5H) -acyl) methanol (61 mg,0.38 mmol). LCMS (method three): t=1.53 _Rmin,m/z(m+H)＝592.2⁺.

Step 3 tert-butyl 4- (3-cyano-8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolin-7 a (5H) -yl) methoxyquinolin-4-yl) piperazine-1-carboxylic acid ester (3 c)

Starting from 3b (65 mg,0.11 mmol) and 1i (32 mg,0.11 mmol), compound 3c (73 mg crude) was synthesized using a similar preparation method to compound 1. LCMS (method 3) t _R＝1.83min,m/z(m+H)⁺ = 674.4.

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

Compound 3 (15.7 mg, 25% yield) was synthesized using a similar procedure to that of compound 1 starting from 3c (73 mg crude, 0.11 mmol). LCMS (method two) ):t_R＝2.53min,m/z(m+H)⁺＝574.2.¹H NMR(400MHz,DMSO-d₆):δ8.19(s,1H),7.83(d,J＝8.4Hz,1H),7.66(d,J＝8.0Hz,1H),7.48-7.40(m,2H),7.33(d,J＝2.0Hz,1H),7.02(d,J＝2.0Hz,1H),6.99-6.96(m,1H),5.38(s,0.5H),5.24(s,0.5H),4.23(d,J＝2.4Hz,1H),4.21(d,J＝2.4Hz,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

First step (S) - (5- (7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl) -5-azaspiro [2.4] hept-7-yl) carbamic acid tert-butyl ester (4 a)

Compound 4a (116 mg, yield 42%) was synthesized using a similar preparation method as compound 1 starting from 1d (177 mg,0.55 mmol) and (S) -tert-butyl 5-azaspiro [2.4] hept-7-ylcarbamate (123 mg,0.56 mmol). ¹LCMS(Method3):t_R＝1.42min,m/z(M+H)⁺ = 495.2.

Second step tert-butyl ((S) -5- (7-bromo-3-cyano-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinolin-4-yl) -5-azaspiro [2.4] hept-7-yl) carbamate (4 b)

To a mixture of 4a (120 mg,0.24 mmol) and ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolidin-7 a (5H) -yl) methanol (58 mg,0.36 mmol) in DMF (1 mL) was added NaH (19 mg,0.48mmol,60% dispersed in mineral oil) and stirred at 0deg.C for 30 min. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic phases were dried over anhydrous Na ₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/meoh=10/1) to give compound 4b (25 mg,17% yield) as a white solid. LCMS (Method 3): t _R＝1.50min,m/z(M+H)⁺ = 618.9.

Tertiary butyl ((S) -5- (3-cyano-8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinolin-4-yl) -5-azaspiro [2.4] hept-7-yl) carbamate (4 c)

Compound 4c (10 mg crude) was synthesized using a similar preparation as compound 1 starting from 4b (25 mg,0.04 mmol) and 1i (13 mg,0.04 mmol). LCMS (Method 3): t _R＝0.29min,m/z(M+H)⁺ = 700.7.

Fourth step 4- ((S) -7-amino-5-azaspiro [2.4] hept-5-yl) -8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinoline-3-carbonitrile (4)

Compound 4 (6.0 mg,70% yield) was synthesized using a similar preparation method as compound 1 starting from 4c (10 mg,0.014 mmol) ).LCMS(Method 2):t_R＝3.44min,m/z(M+H)⁺＝600.3.¹H NMR(400MHz,CD₃OD):δ8.45(br s,1H),8.13(d,J＝8.8Hz,1H),7.56(d,J＝8.0Hz,1H),7.41-7.35(m,2H),7.27(d,J＝2.0Hz,1H),7.00(d,J＝2.0Hz,1H),6.86(dd,J＝8.0,13.2Hz,1H),5.58(s,0.5H),5.45(s,0.5H),4.84-4.25(m,3H),4.23(d,J＝11.6Hz,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-azacyclo [2.4] heptan-7-yl) carbamate (5 a)

Starting from 1d (177 mg,0.55 mmol) and (S) -tert-butyl 5-aza-bicyclo [2.4] hept-7-carbamate (123 mg,0.56 mmol), compound 5a (116 mg, 42% yield) was synthesized using a similar procedure to that of compound 1. LC ¹ MS (method 3): t=1. _R 42min,m/z(m+H)＝49⁺ 5.2.2.

Step 2 tert-butyl ((R) -5- (7-bromo-3-cyano-8-fluoro-2- ((2R, 7 aS) -2-fluoro hexahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) quinolin-4-yl) -5-azacyclo [2.4] heptan-7-yl) carbamate (5 b)

Compound 5b (60 mg,65% yield) was synthesized using a similar preparation procedure as compound 4 starting from 5a (75 mg,0.15 mmol) and (2 r,7 as) -2-fluoro hexahydro-1H-pyrrolin-7 a (5H) -yl) methanol (36 mg,0.23 mmol). LCMS (method 3) t=0.50 _R min,m/z(m+H)＝618.⁺.

Step 3 tert-butyl ((R) -5- (3-cyano-8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) quinolin-4-yl) -5-azacyclo [2.4] heptan-7-yl) carbamate (5 c)

Compound 5c (25 mg crude) was synthesized using a similar preparation procedure as compound 1 starting from 5b (50 mg,0.08 mmol) and 1i (23 mg,0.08 mmol). LCMS (method three): t _R＝0.82min,m/z(m+H)⁺ = 700.7.

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

Compound 5 (7.3 mg, 34% yield) was synthesized using a similar preparation procedure as compound 1 starting from 5c (25 mg,0.036 mmol). LCMS (method) 2):t_R＝3.67min,m/z(m+H)⁺＝600.3,¹H NMR(400MHz,dm₆sod):δ8.15(s,1H),8.10(dd,J＝4.4,8.8Hz,1H),7.65(d,J＝8.0Hz,1H),7.43-7.41(m,1H),7.33-7.32(m,2H),7.00-6.96(m,1H),5.38(s,0.5H),5.04-4.01(m,1H),4.62-4.53(m,2H),4.19-4.12(m,2H),3.26-3.03(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

First step tert-butyl 4- (3-cyano-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinolin-4-yl) piperazine-1-carboxylate (6 b)

Compound 6b (160 mg, crude) was synthesized by using a procedure similar to the sixth step of the preparation method of compound 1, starting with 3b (120 mg,0.20 mmol) and ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (114 mg,0.22 mmol). LCMS (Method 3): t _R＝1.24min,m/z(M+H)⁺ = 898.4

Second step 7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (piperazin-1-yl) quinoline-3-carbonitrile (6 c)

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

Third step 7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (piperazin-1-yl) quinoline-3-carbonitrile (6)

To a solution of 6c (75 mg crude) in DMF (1 ml) was added CsF (79 mg,0.52 mmol) at 0deg.C. After stirring at room temperature for 5 hours, the reaction was concentrated and the residue was purified by preparative HPLC (method C) to give compound 6 (13 mg,22% yield ).LCMS(Method 1):t_R＝3.49min,m/z(M+H)⁺＝598.2.¹H NMR(400MHz,DMSO-d₆):δ8.23(s,2H),7.97(dd,J＝8.8,1.2Hz,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) as a green solid

Step1 tert-butyl 2, 4-dichloro-8-oxo-5, 8-dihydropyridine [3,4-d ] pyrimidine-7 (6H) -carboxylate (7 b)

After NaIO ₄ (10.00 g,46.31 mmol) was stirred in HO ₂ (85 mL) and ethyl acetate (85 mL), 2, 4-dichloro-5, 8-dihydropyridine [3,4-d ] pyrimidine-7 (6H) -carboxylic acid 7a tert-butyl (5.00 g,16.44 mmol) was added. After 5 minutes RuCl (0.51 g,2.46 ₃ mmol) was added and the final reaction mixture was capped and stirred loosely at room temperature for 5 hours. The organic layer was then separated and the aqueous layer was extracted with ethyl acetate (30 ml x 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous NaSO and filtered ₂.₄ and the filtrate concentrated in vacuo to give the residue which was purified by column chromatography on silica gel (PE/EA 20:1-6:1) to give the title compound 7b (3.42 g, 65% yield) as a pale yellow solid. LC-MS (method four) t=3.62 min, m/z (m-boc _R+H)⁺ = 218.0.

Step 2 tert-butyl 4- (4- (phenoxy) carbonyl) piperazin-1-yl) -2-chloro-8-oxo-5, 8-dihydropyridine [3,4-d ] pyrimidine-7 (6H) -carboxylate (7 c)

DIPEA (0.8 mL,4.59 mmol) was added to a solution of 2, 4-dichloro-8-oxo-5, 8-dihydropyridine [3,4-d ] tert-butylpyrimidine-7 (6H) -carboxylic acid 7b (1.00 g,3.14 mmol) and benzylpiperazine-1-carboxylic acid (0.70 g,3.18 mmol) in DCM (10 mL) and stirred at room temperature for 1hr. The reaction solution was then washed with water (10 mL) and brine (10 mL). The organic layer was separated and concentrated in vacuo 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 four): t= _R 4.55min,m/z(m+H)＝⁺ 502.3.

Step 3 4- (2- ((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy-8-oxo-5, 6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid ester (7 d)

After stirring (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (250 mg,1.57 mmol) in THF (11 mL), naH (56 mg,1.4mmol,60% mineral oil) was added at room temperature and stirring for 0.5hr, tert-butyl 4- (4- (phenoxy) carbonyl) piperazin-1-yl) -2-chloro-8-oxo-5, 8-dihydropyridine [3,4-d ] -7 (6H) -carboxylic acid 7c (245 mg,0.49 mmol) was added. The resulting mixture was stirred at room temperature for 1hr. The reaction solution was then quenched with MeOH and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by pre-high performance liquid chromatography (method D) to give 7D (56 mg,21% yield) as a white solid. LC-MS (method four): t=3.04 min, m/z (m ⁺ _R +h) = 525.3.

Step 4 4- (2- ((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy-7- (2-methoxy) -8-oxo-5, 6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid ester (7 e)

To dioxane (5 mL) was added a stirred solution of KPO (62 ₄ ₃ mg,0.292 mmol), cuI (28 mg,0.147 mmol) and N, N-dimethylethane-1, ² -diamine (13.3 mg,0.151 mmol) in sequence of 4- (2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrroline-7 a (5H) -acyl) -8-oxo-5, 6,7, 8-tetrahydropyridin-4-acyl) -piperazine-1-carboxylic acid 7d (56 mg,0.107 mmol) and 1-iodo-2-methyl ¹ oxybenzene (28 mg,0.120 mmol). The resulting mixture was stirred at 110℃under N for 16 hours. ₂ After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give a residue which was purified by prep. chromatography (DCM/MeOH/NH ₄ oh=10/1/0.05) to give 7e (32 mg, 47% yield) as a pale yellow solid. LC-MS (method four): t=3.71 min, m/z (m+h) ⁺ _R = 631.4.

Step 5 2- ((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -7- (2-methoxyphenyl) -4- (piperazin-1-yl) -6, 7-dihydropyridine [3,4-d ] pyrimidine-8 (5H) -1 (7)

4- (2- ((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy-7- (2-methoxyphenyl) -8-oxo-5, 6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid 7e (32 mg,0.051 mmol) was dissolved in aqueous solution (6N, 1 mL). The resulting mixture was stirred at 90℃for 1 hour. After cooling to room temperature, the reaction mixture was concentrated in vacuo to give a residue, which was purified by pre-high performance liquid chromatography (E method) to give final product 7 (9 mg, yield 36%) as a white solid .¹H NMR(400MHz,CD₃OD):δ7.⁺41(t_R,J＝8.6Hz,1H),7.33(¹dd,J＝8.0Hz,2.0Hz,1H),7.18(dd,J＝8.4Hz,1.2Hz,1H),7.08-7.04(m,1H),5.50-5.35(m,1H),4.47(q,J＝12.4Hz,2H),3.89(s,3H),3.81-3.72(m,6H),3.31-3.23(m,2H),3.16(t,J＝5.2Hz,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] oct-3-yl) -2-chloro-8-oxo-5, 8-dihydropyridine [3,4-d ] pyrimidine-7 (6H) -carboxylate (8 a)

DIPEA (0.2 mL,1.15 mmol) was added to DCM (3 mL) to give a solution of 2, 4-dichloro-8-oxo-5, 8-dihydropyridine [3,4-d ] pyrimidine-7 (6H) -carboxylate 7b tert-butyl (640 mg,2.03 mmol) and 3, 8-diazonium-ratio-cyclo [3.2.1] octane-8-carboxylate (500 mg,2.03 mmol). And the resulting reaction solution was stirred at room temperature for 1hr. The reaction solution was then 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 on a silica gel column (PE/EA from 20:1 to 5:1) to give the title compound 8a (789 mg, yield 74%) as a white solid. LC-MS (method four): t= _R 4.66min,m/z(m+H)＝⁺ 528.3.

Step 2 3- (2- ((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy-8-oxo-5, 6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) -3, 8-diazobicyclo [3.2.1] octane-8-carboxylate (8 b)

Tert-butyl 4- (8- (phenoxy) carbonyl) -3, 8-diazo [3.2.1] oct-3-yl) -2-chloro-8-oxo-5, 8-dihydropyridine [3,4-d ] pyrimidine-7 (6H) -carboxylic acid 8a (20 mg,0.038 mmol) and ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (12 mg,0.075 mmol) were dissolved in dioxane (1 mL) and then t-Buona (7.6 mg,0.079 mmol) was added in one portion. The resulting mixture was irradiated with microwaves at 140℃for 3 hours. The reaction solution was then centrifuged to remove solids. The clear solution was concentrated under reduced pressure to give a residue, which was purified by pre-high performance liquid chromatography (method D) to give 8b (3 mg, yield 14%) as a white solid. LC-MS (method four): t=3.10 min ⁺ _R, m/z (m+h) = 551.4.

Step 3 3- (2- ((2R, 7 aS) -2-Fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy-8-oxo-5, 6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) -3, 8-diazobicyclo [3.2.1] octane-8-carboxylate (8 c)

To dioxane (2 mL) was added KPO (39 ₄ ₃ mg,0.184 mmol), cuI (16 mg,0.084 mmol) and N, N-dimethylethane-1, ² -diamine (12.6 mg0.143 mmol) in sequence to form a stirred solution of 3- (2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy-8-oxo-5, 6,7, 8-tetrahydropyridin-3, 4-d pyrimidin-4-yl) -3, 8-diazobicyclo [3.2.1] octane- ¹ -carboxylic acid 8b (40 mg,0.073 mmol) and 1-bromo-8-chloronaphthalene (36 mg,0.149 mmol). The resulting mixture was stirred at 110℃under N for 16 hours. ₂ The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by pre-high performance liquid chromatography (F) to give 8c (7 mg, yield 14%) as a pale yellow solid. LC-MS (method four): t=4.38 min, m/z (m+h _R ⁺) = 711.4.

Step 44- (3, 8-diazo [3.2.1] oct-3-yl) -7- (8-chloronaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -6, 7-dihydropyridine [3,4-d ] pyrimidin-8 (5H) -1 (8)

3- (2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy-8-oxo-5, 6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) -3, 8-diazobicyclo [3.2.1] octane-8-carboxylic acid 8c (7 mg, 0.010mmol) was dissolved in aqueous solution (6N, 1 mL) and stirred at 90℃for 1H. The reaction solution was evaporated in vacuo to give a residue, which was purified by pre-high performance liquid chromatography (Method E) to give final product 8 (2.5 mg, yield 44%) as a white solid. LC-MS (method 4) t=2.47 min, m _R/z (m+H) = 577.4H core ⁺ magnetic resonance (400MHz ¹,CD₃OD):δ8.03(dd,J＝7.6Hz,2.0Hz,1H),7.95(dd,J＝8.4Hz,1H),7.66-7.60(m,3H),7.46(t,J＝8.0Hz,1H),5.32(d,J＝53.6Hz,1H),4.36-4.26(m,2H),4.20(d,J＝13.2Hz,1H),4.09-3.89(m,3H),3.72(s,2H),3.53-3.35(m,4H),3.25-3.08(m,2H),2.43-2.28(m,2H),2.21-2.04(m,2H),1.98-1.85(m,5H).

Example 9

Step 1 tert-butyl (S) -4- (4- (tert-butylcarbonyl) -3- (cyanoethyl) piperazin-1-yl) -2-chloro-8-oxo-5, 8-dihydropyridine [3,4-d ] pyrimidine-7 (6H) -carboxylate (9 a)

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

Step2 tert-butyl (S) -2- (cyanoethyl) -4- (2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy-8-oxo-5, 6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate (9 b)

A mixture of tert-butyl (S) -4- (4- (tert-butoxycarbonyl) -3- (cyanoethyl) piperazin-1-yl) -2-chloro-8-oxo-5, 8-dihydropyridine [3,4-d ] -7 (6H) -carboxylic acid 9a (20 mg,0.038 mmol) and t-Buona (8.0 mg,0.083 mmol) was added to (2R, 7 aS) -2-fluorotetrahydro-1H-pyrroline-7 a (5H) -yl) methanol (12.6 mg,0.079 mmol) in dioxane (1 mL) and microwaved at 140℃for 3 hours. The reaction solution was centrifuged to remove solids, and the supernatant was concentrated under reduced pressure to give a residue, which was purified by pre-high performance liquid chromatography (Method D) to give 9b (2.5 mg, yield 12%) as a white solid. LC-MS (method four): t=2.61 min, m/z (m+h) =530.3. _R ⁺ A

Step 3 tert-butyl (S) -4- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy-8-oxo-5, 6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) -2- (cyanoethyl) piperazine-1-carboxylate (9 c)

To a stirred solution of KPO (25 mg,0.118 mmol), cuI (10 mg,0.052 mmol) and N, N-dimethylethane-1-2-diamine (8.2 mg,0.093 mmol) in (S) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrroline-7 a (5H) -acyl) methoxy-8-oxo-5, 6,7, 8-tetrahydropyridin-4-acyl) piperazine-1-carboxylic acid 9b (25 ₃mg₄, 0.047 mmol) and 1- ¹ bromo-8-chloro-3- (methoxy ² methoxy) naphthalene (20 mg,0.066 mmol) were added sequentially to dioxane (2 mL). The resulting mixture was stirred at 110℃under N for 16 hours. ₂ After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by pre-high performance liquid chromatography (method F) to give 9c (7 mg, yield 20%) as a pale yellow solid. LC-MS (method four): t=3.99 min, m/z (m+h ⁺ _R) = 750.3.

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

(S) -4- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -8-oxo-5, 6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) -2- (cyanoethyl) piperazine-1-carboxylic acid 9c (7 mg,0.009 mmol) was added to MeOH (1 mL) in water (1N, 0.1 mL) and stirred at 65℃for 16H. The reaction solution was then evaporated under vacuum to give a residue which was purified by pre-high performance liquid chromatography (E) to give the final product 9 (3 mg, yield 53%) as a white solid. LC-MS (methods 4):t＝2.13min,m/z(_R m+H)＝606.3H NMR(400⁺MHz,CD₃OD¹):δ7.47(t,J＝8.8Hz,2H),7.15-7.21(m,4H),7.11(d,J＝2.4Hz,1H),7.07(d,J＝2.8Hz,1H),6.95(bs,1H),6.87(bs,1H),5.32 and 5.28 (d, J=54 Hz, 2H), 4.38 (t, J=10.8 Hz, 2H), 4.12 and 4.06(d,J＝11.2Hz,2H),4.02(d,J＝12.8Hz,2H),3.82(dd,J＝11.6Hz,22Hz,4H),3.60-3.68(m,4H),3.36-3.42(m,4H),2.86-3.01(m,13H),2.60-2.75(dd,J＝6Hz,16.8Hz,2H),2.39(dd,J＝6.8Hz,16.8Hz,2H),2.24-2.29(m,2H),2.07-2.20(m,4H),1.93-1.97(m,4h).

Example 10

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

KPO (33 ₃ mg,0.155 mmol), cuI (11 mg,0.058 mmol) and N, N-dimethylethane-1-2-diamine (8.2 mg,0.093 mmol) were added sequentially to dioxane (2 mL) to form a stirred solution of 3- (2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrroline-7 a (5H) -acyl) methoxybenzene-8-oxo-5, 6,7, 8-tetrahydropyridine [3,4-d ] azo ² pyridin-4-yl) -3, 8-diazobicyclo [3.2.1] octane-8-carboxylic acid 8b (31 mg ₄, 0.056 mmol) and 3-bromo-8-chloro-3- (methyl ¹ oxymethoxy) naphthalene (46 mg,0.152 mmol). The resulting mixture was stirred at 110℃under N for 16 hours. ₂ The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated to dryness in vacuo. The residue was purified by pre-high performance liquid chromatography (E method) to give 10a (6.4 mg,15% yield) as a pale yellow solid. LC-MS (method four): t=4.27 min, m/z (m+ _R ⁺ H) = 771.3.

Step 2 4- (3, 8-diazo [3.2.1] oct-3-yl) -7- (8-chloro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -6, 7-dihydropyridine [3,4-d ] pyrimidine-8 (5H) -1 (10)

3- (7- (8-Chloro-3- (methoxymethoxy) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy-8-oxo-5, 6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) -3, 8-diazobicyclo [3.2.1] octane-8-carboxylic acid 10a (6.4 mg,0.008 mmol) was dissolved in aqueous solution (4N, 1 mL). The mixture was stirred at 90℃for 0.5 h. The reaction solution was then evaporated under vacuum to give a residue which was purified by pre-high performance liquid chromatography (method F) to give the final product 10 (4.2 mg, 85% yield) as a red solid .LC-MS(Method 4):t_R＝2.06min,m/z(m+H)＝593.2.¹H NMR(400MHz¹,CD₃OD):δ8.38(brs,1H),7.71(d,J＝7.6Hz,1H),7.35-7.18(m,4H),5.47(d,J＝51.6Hz,1H),4.65(s,2H),4.47(d,J＝12.8Hz,2H),4.34(d,J＝13.6Hz,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-fluoropyridine [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (11 b)

2,4, 7-Trichloro-8-fluoropyridine [4,3-d ] pyrimidine (607mg,2.40mmol WO2021/41671, paragraph 0277) and DIPEA (2.05 g,15.86 mmol) were added to a solution of DCM (10 mL) at-40℃and tert-butyl 3, 8-diazo-bicyclo [3.2.1] octane-8-carboxylate (510 mg,2.40 mmol) was added. After stirring at this temperature for 0.5 h, the reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over NaS ₂ O, and concentrated by filtration ₄. The residue was purified by column chromatography on silica gel (PE/ea=3:1) to give compound 11b (370 mg, yield 36%) as a yellow solid. LCMS (method 3): t=1.74 _R min,m/z(m+H)＝428.⁺ 1.

Step 2 3- (7-chloro-8-fluoro-2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidin-4-yl) -3, 8-diazobicyclo [3.2.1] octane-8-carboxylate (11 c)

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

Step 3 3- (8-fluoro-2- ((2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolin-7 a (5H) -yl) methoxy-7-phenylpyridine [4,3-d ] pyrimidin-4-yl) -3, 8-diazobicyclo [3.2.1] octane-8-carboxylate (11 d) tert-butyl

Compound 11d (32 mg crude) was synthesized using a preparation process similar to that of the sixth step of compound 1 starting with 11c (30 mg,0.05 mmol) and phenylboronic acid (13 mg,0.1 mmol). LCMS (method 3) t _R＝1.60min,m/z(m+H)⁺ = 593.3.

Step 4 4- ((1R, 5S) -3, 8-diazo [3.2.1] oct-3-yl) -8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -7-phenylpyridine [4,3-d ] pyrimidine (11)

Compound 11 (18.5 mg, 68% yield) was synthesized using a similar procedure to compound 1 starting from 11d (32 mg crude). Compound 11 was purified by pre-high performance liquid chromatography (C method), LCMS (method 2):t_R＝2.69min,m/z(m+H)⁺＝493.2.¹HNMR(400MHz,DMSO-d₆):δ9.17(s,1H),8.03(d,J＝7.6Hz,2H),7.59-7.52(m,3H),5.38(s,0.5H),5.24(s,0.5H),4.58(d,J＝12.8Hz,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) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) yl) methoxy) pyridin [2,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (12 a)

Compound 12a (21 mg, 32% yield) was prepared using compounds 1 and 11c (45 mg, 0.08 mmol) and (2- (((5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxapolan-2-yl) naphthalen-2-yl) oxy) methoxy) ethyl) trimethylsilane (41 mg, 0.098 mmol, WO2021/41671, paragraph 01083) as starting materials. LCMS (method three): t _R＝2.32min,m/z(m+H)⁺ = 808.0.

Step 2 4- (4- ((1R, 5S) -3, 8-diazo [3.2.1] oct-3-yl) -6-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridin [2,3-d ] pyrimidin-7-yl) -5-fluoronaphthalen-2-ol (12)

Compound 12 (4.5 mg, 28% yield) was synthesized using a method similar to that of 12a (21 mg, 0) in the last step of compound 1. 02 mmol) as starting material .LCMS(method 3):t_R＝2.38min,m/z(m+H)⁺＝577.3.¹H NMR(400MHz,DMSO-d₆):δ10.16(br s,1H),8.26(d,J＝10.8Hz,1H),7.63(d,J＝8.4Hz,1H),7.42-7.37(m,1H),7.29(d,J＝2.0Hz,1H),6.95(dd,J＝12.4,7.6Hz,1H),5.37(s,0.5H),5.29(s,0.5H),4.33(d,J＝13.2Hz,2H),4.28(d,J＝10.8Hz,1H),4.23(d,J＝10.4Hz,2H),3.96(s,2H),3.67(d,J＝13.6Hz,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] heptane-2-carbamate hydrochloride (13 b)

(1R, 2R, 4S) -tert-butyl 2- ((phenoxy) carbonyl) amino-7-aza- [2.2.1] heptane-7-carboxylic acid ester (160 mg,0.46mmol, WO2004/74292, page 7) was dissolved in hydrochloric acid/ethyl acetate (2 ml, 2M) and stirred for 2 hours at RT. The mixture was concentrated to dryness to give compound 13b (130 mg, giving yield). LCMS (method 3): t=1.15 _R 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-azacyclo [2.2.1] heptan-2-yl) carbamate (13 c)

To a solution of compound 1d (260 mg,0.81 mmol) in 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 0deg.C. The RT was stirred for 10 hours. Dilute with DCM (20 mL) and wash with HO ₂ (10 mL). The separated organic layer was dried over NaS ₂ O and ₄ filtered. The filtrate was concentrated to dryness. Purification by silica gel column chromatography (PE/ea=3/1) gave compound 13c (235 mg, 55% yield) as a yellow solid. LCMS (method three): t=1.89 _R min,m/z(m+H)＝529.⁺ 8.

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

Compound 13d (220 mg, yield 74%) was synthesized using a similar preparation procedure as compound 4 of the second step starting from 13c (240 mg,0.45 mmol) and (2 r,7 as) -2-fluoro hexahydro-1H-pyrrolin-7 a (5H) -yl) methanol (87 mg,0.55 mmol). LCMS (method 3) t=0.95 _R 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, 7 aS) -2-fluorohexahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) quinolin-4-yl) -7-azacyclo [2.2.1] heptan-2-yl) carbamate (13 e)

Compound 13e (35 mg, 92% yield) was synthesized using a similar preparation procedure as the sixth step of compound 1 starting from 13d (50 mg,0.077 mmol) and 1i (15 mg,0.052 mmol). LCMS (method 3) t _R＝1.01min,m/z(m+H)⁺ = 734.7.

Step 5 4- ((1R, 2R, 4S) -2-amino-7-azacyclo [2.2.1] heptan-7-yl) -8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1 h-pyrrolin-7-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 at RT for 3h, the reaction was quenched with 1 hydrochloric acid (0.5 mL) and extracted with EA (5 mL x 2). The combined organic layers were concentrated and purified by column chromatography (DCM/meoh=10/1) to give the crude product. The crude product was repurified by prep. chromatography (DCM/meoh=10/1) to give compound 13 (3 mg, 10% yield) as a white solid. LCMS (method) 3):t_R＝0.65min,m/z(m+H)⁺＝60 ¹0.7H NMR(400MHz,DMSO-d₆):δ8.24-8.22(m,2H),7.67(d,J＝8.0Hz,1H),7.49-7.43(m,2H),7.34(s,1H),7.03-6.97(m,2H),5.69(s,1H),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＝12.8,4.8Hz,1H).

Example 14

Step 12, 4-dichloro-6, 7-dihydropyrido [3,4-d ] pyrimidin-8 (5H) -one (14 a)

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

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

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

Step 3 tert-butyl 3- (2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy-8-oxo-5, 6,7, 8-tetrahydropyridine [3,4-d ] pyrimidin-4-yl) -3, 8-diazobicyclo [3.2.1] octane-8-carboxylate (14 c)

In a solution of 14b (4.5 g,11.45 mmol), (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methanol (5.4 g,34.35 mmol) and 4Molecular sieves (4.5 g) to DMSO (50 mL) was added DIEA (4.43 g,34.35 mmol). The resulting mixture was stirred in a sealed tube at 140℃for 48h. The mixture was filtered and diluted with water (100 mL). EA extraction (50 ml x 3). The combined organic layers were washed with water (75 mL) and brine (75 mL), concentrated in vacuo to give a residue which was further purified by flash chromatography on silica gel (DCM/EtOH from 20/1 to 5/1) to give title compound 14c (4.0 g, 67% yield) as a brown solid. LC-MS (method four) t=2.91 _R min,m/z(m+H)＝517.⁺ 3.

Step4 1-bromo-3-chloro-2-cyclopropyl-5- (methoxymethoxy) benzene (14 e)

A solution of bromo (methoxy) methane (151 mg,1.21 mmol) and 14d (150 mg,0.606 mmol) and DIEA (235 mg,1.82 mmol) was stirred in DCM (5 mL). The resulting mixture was stirred at 20℃for 16 hours. The reaction solution was then washed with water (3 mL) and brine (3 mL). The organic layer was separated and concentrated in vacuo to give a residue which was further purified by 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 (14 f)

A solution of 14e (100 mg,0.34 mmol) and triisopropyl borate (96.8 mg,0.514mmol,0.12 mL) in THF (2 mL) was added N-butyllithium (2.4M, 0.16 mL) at-78deg.C, stirred at-78deg.C for 2h, the reaction solution quenched with 1N HCl aq (1 mL) at-78deg.C, then stirred at 20deg.C for 1h, and the mixture extracted with EA (2 mL. Times.3). The combined organic layers were washed with water (3 ml) and brine (3 ml), separated and concentrated under vacuum to give a residue which was further purified on 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, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) yl) methoxy-8-oxo-5, 6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) -3, 8-diazobicyclo [3.2.1] octane-8-carboxylate (14 g)

A solution of 14c (20 mg,0.039 mmol), 14f (20 mg,0.078 mmol) and Cu ₂(TMEDA)₂(OH)₂Cl₂ (9.0 mg,0.019 mmol) in DCM (1 mL) was stirred at 20deg.C for 18h, the reaction solution was concentrated in vacuo to give a residue, and further purified on Prep-TLC (PE/EA=2/1) to give title compound 14g (6 mg,21% yield) as a yellow solid. LC-MS (method four) t _R＝4.32min,m/z(m+H)⁺ = 727.5.

Step 7 4- (3, 8-diazo [3.2.1] oct-3-yl) -7- (3-chloro-2-cyclopropyl-5-hydroxyphenyl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -6, 7-dihydropyridine [3,4-d ] pyrimidine-8 (5H) -1 (14)

14G (6 mg,0.008 mmol) of a solution of 4N HCl/dioxane (0.5 mL) was taken and stirred at 20℃for 2 hours, then the reaction solution was evaporated in vacuo to give a residue which was purified by Prep-HPLC (method E) to give compound 14 (2.5 mg, yield 44%) as a white solid. LC-MS (method four) )t_R＝2.79min,m/z(m+H)⁺＝583.3.¹H NMR(400MHz,CD₃OD)δ6.86(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

First step (3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) boronic acid (15 a)

To a solution of triisopropyl ((6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) naphthalen-1-yl) ethynyl) silane (2.0 g,4.04 mmol) in CHCl ₃/MeOH (1/1, 50 ml) at room temperature was added 2- (2-hydroxyethylamino) ethanol (4.68 g,44.49 mmol). The reaction solution was then stirred at 70℃for 48 hours. The reaction was diluted with water (100 mL), extracted with DCM (50 ml×3), washed with brine (50 mL), dried over Na ₂SO₄, concentrated and purified by flash chromatography (PE/EA from 20/1 to 3/1) to give compound 15a (1.45 g, yield 87%) as an off-white solid .LCMS(Method 5)t_R＝5.79min,m/z(M+H)⁺＝413.2.¹H NMR(400MHz,CDCl₃)δ7.73(d,J＝8.4Hz,1H),7.67(d,J＝7.2Hz,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).

Second step tert-butyl 3- (2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (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 (15 b)

A mixture of 14c(20mg,0.039mmol)、15a(32mg,0.078mmol)、Cu₂(TMEDA)₂(OH)₂Cl₂(9mg,0.019mmol) in DCM (1 mL) was stirred at 25℃under an oxygen atmosphere for 72 hours. The reaction was diluted with H ₂ O (10 mL), extracted with DCM (10 ml×3), washed with brine (15 mL), dried over Na ₂SO₄, and concentrated to give crude compound 15b (15 mg,44% yield) as a yellow solid. LCMS (Method 5) t _R＝5.03min,m/z(M+H)⁺ = 883.7.

Tertiary butyl 3- (7- (8-ethynyl-3- (methoxymethoxy) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (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 (15 c)

To a solution of 15b (15 mg,0.017 mmol) in THF (0.5 mL) was added TBAF (0.017 mL,0.017mmol,1M in THF) at room temperature. The reaction was then stirred at room temperature for 30 minutes. The reaction was diluted with water (10 mL), extracted with EtOAc (10 ml×3), washed with brine (10 mL), dried over Na ₂SO₄, concentrated and purified by preparative HPLC (method F) to give compound 15c (6 mg,49% yield) as a yellow solid. LCMS (Method 4) t _R＝4.16min,m/z(M+H)⁺ = 727.5.

Fourth step 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (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 (4M, 0.5 mL) at 0deg.C, and the reaction was stirred at 10deg.C for 1 hour. The reaction was concentrated in vacuo. The residue was diluted with DMF (1 mL) and the pH was adjusted to 8 with saturated aqueous NaHCO ₃. The reaction solution was filtered and concentrated. The residue was purified by preparative HPLC (method F) to give compound 15A (0.3 mg,9% yield) and 15B (1.2 mg,37% yield) as off-white solids.

15A:¹H NMR(400MHz,CD₃OD)δ7.78(d,J＝8.4Hz,1H),7.55(d,J＝6.8Hz,1H),7.38(t,J＝7.2Hz,1H),7.26(d,J＝2.4Hz,1H),7.21(d,J＝2.4Hz,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(1H),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＝2.67min,m/z(M+H)⁺＝583.4.

Co-crystals of k-Ras-G12D with similar compounds (PDB: 7 RPZ) were described in J.Med. Chem.2022,65, 3123-3133. The active isomer was identified as 15A.

15B:¹H NMR(400MHz,CD₃OD)δ7.79(d,J＝8.4Hz,1H),7.56(d,J＝6.8Hz,1H),7.39(t,J＝7.2Hz,1H),7.26(d,J＝2.4Hz,1H),7.21(d,J＝2.4Hz,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(1H),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＝2.71min,m/z(M+H)⁺＝583.4.

Example 16

First step 2- (4, 5-dibromonaphthalen-2-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (16 b)

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

Second step 4, 5-dibromonaphthalen-2-ol (16 c)

To a solution of 16b (2.88 g,6.99 mmol) in water (30 mL) and THF (30 mL) at 10deg.C was added AcOH (30 mL) and hydrogen peroxide (4.76 g,139.83mmol,4.32 mL). The reaction solution was then stirred at 10℃for 1 hour. The reaction was quenched with saturated NaHSO ₃ solution (40 mL) and extracted with EtOAc (40 mL), washed with brine (40 mL), dried over Na ₂SO₄, concentrated and purified by flash chromatography (PE/EA from 10/1 to 3/1) to give compound 16c (800 mg, 38% yield) as an off-white solid. LCMS (Method 4) t _R＝2.44min,m/z(M-H)^- = 298.8.

Third step 1, 8-dibromo-3- (methoxymethoxy) naphthalene (16 d)

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 0deg.C. The reaction solution was then stirred at10℃for 30 minutes. The reaction was diluted with water (30 mL), extracted with DCM (30 mL x 3), washed with brine (30 mL) and concentrated to give crude 16d (800 mg,87% yield) as a pale yellow solid.

Fourth step 8-bromo-6- (methoxymethoxy) -1-naphthalonitrile (16 e)

To a solution of 16d (200 mg,0.57 mmol) in DMF (7 mL) was added CuCN (52 mg,0.57 mmol). The reaction solution was stirred at 100℃for 30 minutes under microwaves. The reaction solution was filtered and purified by preparative HPLC (method E) to give compound 16E (50 mg, 30% yield) and 8-bromo-3- (methoxymethoxy) naphthalene-1-carbonitrile (55 mg,33% yield) as a white solid ).¹HNMR(400MHz,CDCl₃)δ7.96-7.91(m,2H),7.69(d,J＝2.4Hz,1H),7.47(t,J＝7.2Hz,1H),7.42(d,J＝2.4Hz,1H),5.28(s,2H),3.50(s,3H).LCMS(Method 4)t_R＝4.41min,m/z(M+H)⁺＝292.0.

Fifth step tert-butyl 3- (7- (8-cyano-3- (methoxymethoxy) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (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 (16 f)

A mixture of 14c (20 mg,0.039 mmol), 16e (23 mg,0.04 mmol), cs ₂CO₃ (32 mg,0.09 mmol) and XantPhos Pd G3 (7 mg,0.008 mmol) in dioxane ((0.5 mL) was stirred at 110 ℃ C. Under nitrogen for 24 hours. The reaction was diluted with water (10 mL), extracted with EA (10 mL. Times.3), washed with brine (15 mL), dried over Na ₂SO₄ and concentrated to give crude compound 16f (18 mg,64% yield) as a yellow solid, LCMS (Method 4) t _R＝3.95min,m/z(M+H)⁺ = 728.5.

Sixth step 8- (4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-oxo-5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) -6-hydroxy-1-naphthyridine (16)

To a solution of 16f (15 mg,0.021 mmol) in ACN (0.5 mL) was added HCl/dioxane (4M, 0.5 mL) and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated and purified by preparative HPLC (method F) to give compound 16 (4.0 mg,33% yield) as a pale yellow solid ).¹HNMR(400MHz,CD₃OD)δ8.08(d,J＝8.4Hz,1H),7.83(d,J＝6.8Hz,1H),7.54(t,J＝6.8Hz,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,2H),2.36-2.33(m,1H),2.24-2.15(m,3H),2.02-1.99(m,4H).LCMS(Method 4)t_R＝2.44min,m/z(M+H)⁺＝584.4.

Example 17

Step 1 tert-butyl 3- (7- (5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1-indenazol-4-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy-8-oxo-5, 6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) -3, 8-diazobicyclo [3.2.1] octane-8-carboxylate (17 b))

14C (20 mg,0.039 mmol), 17a (26 mg,0.077 mmol), cs ₂CO₃ (25 mg,0.077 mmol) and XantPhos Pd G3 (4 mg, 0.004mmol) in dioxane (1 mL) were stirred overnight at 110 ℃. The mixture was filtered through a pad of azure stone and purified by Prep-TLC (DCM/meoh=15/1) to give compound 17b (30 mg, yield given) as a pale yellow solid. LC-MS (method four) t=4.09 _R min,m/z(m+H)＝765.5⁺.

Step 2 4- (3, 8-diazo [3.2.1] oct-3-yl) -7- (5-chloro-6-methyl-1H-inden-4-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyridin-7A (5H) -yl) methoxy) -6, 7-dihydropyridine [3,4-d ] pyrimidine-8 (5H) -monocarboxylic acid (17A and 17B)

A solution of 17b (30 mg,0.039 mmol) ACN (0.5 mL) was added to hydrochloric acid (0.5 mL,4M dioxane) in an ice bath, followed by stirring at room temperature for 2 hours. The mixture was concentrated and purified by preparative high performance liquid chromatography (method F) to give compound 17A (5.6 mg,25% yield) and 17B (6.0 mg, 26%) as pale yellow solids.

17A LC-MS (method four) )t_R＝2.54min,m/z(m+H)⁺＝581.4.¹H NMR(400MHz,DMSO-d₆)δ8.07(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 four) )t_R＝2.57min,m/z(m+H)⁺＝581.4.¹H NMR(400MHz,DMSO-d₆)δ8.07(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

First step 2- (3-bromo-5-chloro-4- (trifluoromethyl) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (18 b)

To a solution of 18a (5.00 g,19.3 mmol), 4, 5-tetramethyl-1, 3, 2-dioxaborolan (4.93 g,38.5 mmol) in THF (60 mL) were added dtbbpy (6271 mg,2.31 mmol) and [ Ir (OMe) (cod) ] ₂ (1.28 g,1.93 mmol) under nitrogen atmosphere, and the reaction was stirred at 60℃for 2 hours. The reaction solution was concentrated to give compound 18b (12.2 g, crude), which was used in the next step without further purification. LC-MS (Method 4) t _R＝3.52min,m/z(M+H)⁺ =385.0.

Second step 3-bromo-5-chloro-4- (trifluoromethyl) phenol (18 c)

To a solution of 18b (12.0 g,31.1 mmol) in THF (100 mL) and water (50 mL) at 10deg.C were added AcOH (74.8 g, 660 mmol) and H ₂O₂ (70.6 g, 627 mmol,30% purity in water). The reaction solution was stirred at 10℃for 2 hours. To the reaction solution were added water (200 mL) and EtOAc (200 mL). The organic layer was separated, washed with saturated Na ₂S₂O₃ solution (200 ml×2), then brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash chromatography on silica gel (PE/EA from 10/1 to 1/4) to give compound 18c (5.10 g, 82% yield in two steps). LC-MS (Method 4) t _R＝2.86min,m/z(M+H)⁺ =275.0.

Third step 1-bromo-3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) benzene (18 d)

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 was stirred at 25 ℃ for 2 hours, concentrated and purified by flash chromatography on silica gel (PE/EA from 10/1 to 1/3) to give compound 18d (400 mg,68% yield) as a yellow solid. LC-MS (Method 4) t _R＝4.45min,m/z(M+H)⁺ = 319.0.

Fourth step tert-butyl 3- (7- (3-chloro-5- (methoxymethoxy) -2- (trifluoromethyl) phenyl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (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 (18 e)

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,0.09 mmol) and Cs ₂CO₃ (58.0 mg,0.18 mmol) at 25 ℃. The reaction solution was stirred at 100℃under nitrogen for 15 hours. The reaction was diluted with water (10 mL), extracted with EA (20 ml×3), washed with brine (20 mL), dried over Na ₂SO₄, concentrated and purified by flash chromatography on silica gel (DCM/MeOH from 100/1 to 10/1) to give compound 18e (21 mg,16% yield) as a yellow solid. LC-MS (Method 4) t _R＝3.54min,m/z(M+H)⁺ =755.3.

Fifth step 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (3-chloro-5-hydroxy-2- (trifluoromethyl) phenyl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (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, 4M) was stirred at 25℃for 2h. The reaction was concentrated and purified by preparative HPLC (method E) to give compound 18 as an off-white solid (2.5 mg,15% yield ).LC-MS(Method4)t_R＝2.83min,m/z(M+H)⁺＝611.3.¹H NMR(400MHz,CD₃OD)δ7.10(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 (1 h) -19 days (b)

19A (508 mg,1.97 mmol) and selected flour (1.3838 g,3.92 mmol) were added to MeCN (8 mL) and stirred at room temperature for 2 hours, the reaction quenched with water (10 mL) and extracted with EA (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous NaS ₂ O, and ₄ concentrated in vacuo to give crude 19b (438 mg, 76% yield) as a brown oil. LC-MS (method 4) t=3.69 _Rmin,m/z(m+H)＝292.9⁺.

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

A solution of 19b (438 mg,1.49 mmol) in toluene (2.5 mL) was added dropwise to a solution of HO ₂ (4 mL) and i-PrOH (4 mL) containing NaS ₂O₂(₄ mg,4.93 mmol) under a nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature overnight. The reaction was concentrated in vacuo to give a residue which was purified by flash chromatography on silica gel (PE/ea=5/1) to give compound 19c (276 mg, 67% yield) as a red solid. LC-MS (method 4) t=5. _R 41min,m/z(m+H)＝27⁺ 4.9.

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

19C (276 mg,1.00 mmol) and DIEA (0.25 mL,1.43 mmol) were mixed in DCM (8 mL), bromomethyl (112 mg,0.89 mmol) was added, stirred at room temperature for 2h, then the solvent was removed in vacuo and the residue flash chromatographed on silica gel (PE/EA=5/1) to give compound 19d (233 mg,73% yield) as a red solid ¹.h NMR(400MHz,CDCl₃)δ8.05-8.01(m,1H),7.87(d,J＝8.0Hz,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, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) yl) methoxy-8-oxo-5, 6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (19 e)

XantPhos Pd G3 (4 mg, 0.04 mmol) and CsCO ₂(25₃ mg,0.077 mmol) were added and 19d (20 mg,0.064 mmol) and 14c (20 mg,0.039 mmol) were stirred in anhydrous 1, 4-dioxane (1 mL). The resulting mixture was stirred under nitrogen at 110 ℃ for 16h, cooled to rt, and the mixture was filtered and the filtrate concentrated in vacuo to give crude product 19e (10 mg, 34% yield) as brown oil. LC-MS (method 4) t=3. _R 87min,m/z(m+H)＝75⁺ 5.4.4.

Step 5 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-chloro-4-fluoro-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -6, 7-dihydropyridine [3,4-d ] pyrimidine-8 (5H) -1 (19)

19E (10 mg,0.013 mmol) in MeOH (1 ml) and cont. Hydrochloric acid (0.05 mL) was stirred at 65deg.C for 16h. After cooling to room temperature, the reaction solution was concentrated, and the residue was purified by preparative high performance liquid chromatography (E method) to give compound 19 (4.6 mg, yield 57%) as a white solid. LC-MS (method) 4)t_R＝3.56min,m/z(m+H)⁺＝611.3.¹H NMR(400MHz,CD₃OD)δ8.52(s,1H)、7.98(s,1H)、7.44(d,J＝4.8Hz,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

Step 1 tert-butyl 4- (8- (tert-butylcarbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2-chloro-8-oxo-5, 8-dihydropyridine [3,4-d ] pyrimidine-7 (6H) -carboxylate (20 a)

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

Step 2 tert-butyl 3- (2- (1- (tert-butylcarbonyl) -4-methylpiperidin-4-yl) methoxy-8-oxo-5, 6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) -3, 8-diazo [3.2.1] octane-8-carboxylate (20 b)

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 reaction mixture was stirred at 140℃for 3h. After cooling to rt, the solid was filtered and the filtrate was concentrated to give a residue which was purified by preparative high performance liquid chromatography (C18 column, meCN/HO (0.5% ₂NH₄HCO₃),_5％-35％, 30 min) to give compound 20a (43 mg, yield 18%) as a white solid LC-MS (method four) t=4.04 min, m ⁺ _R/z (m+h) = 587.5.

Step 3 tert-butyl 3- (7- (8-bromo-3- (methoxymethoxy) naphthalen-1-yl) -2- ((1- (tert-butoxy) -4-methylpiperidin-4-yl) methoxy-8-oxo-5, 6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) -3, 8-diazobicyclo [3.2.1] octane-8-carboxylate (20 c)

XantPhos Pd G3 (6.5 mg,0.0068 mmol) and CsCO ₂(48₃ mg,0.15 mmol) were added as stirred solutions of 20b (43 mg,0.073 mmol) and 16d (51 mg,0.15 mmol), respectively, of anhydrous 1, 4-dioxane (2 mL). The resulting mixture was stirred under nitrogen at 110 ℃ for 16h, cooled to rt, the mixture was filtered and the filtrate concentrated in vacuo to afford compound 20c (30 mg, 48% yield) as a brown solid. LC-MS (method five) t=6.50 min ⁺ _R, m/z (m+h) =851.5.

Step 4 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-bromo-3-hydroxynaphthalen-1-yl) -2- ((4-methylpiperidin-4-yl) methoxy) -6, 7-dihydropyridine [3,4-d ] pyrimidine-8 (5H) -1 (20 d)

20C (30 mg,0.035 mmol) in MeOH (1 ml) and conc. Hydrochloric acid (0.05 mL) was stirred at 65deg.C for 16h. After cooling to room temperature, the reaction solution was concentrated, and the residue was purified by preparative high performance liquid chromatography (E method) to give compound 20d (6.5 mg, yield 31%) as a white solid. LC-MS (method four) t _R＝2.29min,m/z(m+H)⁺ = 607.3.

Step 5 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (3-hydroxy-8- (triisopropylsilyl) ethyl) naphthalen-1-yl) -2- ((4-methylpiperidin-4-yl) methoxy) -6, 7-dihydropyridine [3,4-d ] pyrimidin-8 (5H) -1 (20 e)

To anhydrous DMA (1 mL) was added 20d (6.5 mg,0.01 mmol) and ethyltriisopropylsilane (39.0 mg,0.21 mmol) in CuI (1.0 mg,0.052 mmol), pd (PPh ₃)₂Cl₂ (1.2 mg,0.0017 mmol) and DIEA (0.018 mL,0.10 mmol), respectively, the resulting mixture was stirred under a nitrogen atmosphere at 100deg.C for 5h and then cooled to room temperature and filtered.

Step 6 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethyl-3-hydroxynaphthalen-1-yl) -2- ((4-methylpiperidin-4-yl) methoxy) -6, 7-dihydropyridine [3,4-d ] pyrimidine-8 (5H) -1 (20)

TBAF (0.02mL,0.02mmol,1M in THF) was added to a solution of 20E (3.5 mg,0.005 mmol) in THF (1 mL) at 0deg.C, reacted at 0deg.C with stirring for 1h, the solvent was removed, and purified by preparative high performance liquid chromatography (E) to give compound 20 (2.1 mg,79% yield) as a white solid. LC-MS (method four) )t_R＝1.55min,m/z(m+H)⁺＝553.4.¹H NMR(400MHz,CD₃OD)δ7.78(d,J＝8.0Hz,1H),7.55(d,J＝7.2Hz,1H),7.26(d,J＝2.4Hz,1H),7.22(d,J＝2.4Hz,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

Steps 1 7-Bromo-2-chloro-4- ((3 s,5 s) 3, 5-dimethylpiperazin-1-yl) 8-fluoroquinoline-3-carbonitrile (21)

To a mixture of (2S, 6S) -2, 6-dimethylpiperazine (140 mg,0.75 mmol) to 1d (200 mg,0.63 mmol) and DIEA (404 mg,3.13 mmol) was added in DCM (2 mL) at 0deg.C. The reaction was stirred at room temperature for 3 hours. The solid formed was filtered, washed with DCM (5 mL) and dried in vacuo to give 21a (184 mg, yield 74%) as a yellow solid. LC-MS (method 3) t=1.11 _Rmin,m/z(m+H)＝397.1⁺.

Step 2 7-bromo-4- ((3 s,5 s) -3, 5-dimethylpiperazin-1-yl) -8-fluoro-2- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxyquinoline-3-carbonitrile (21 b)

LiHMDS (5.55mL,5.55mmol,1M in THF) was added to a solution of 21a (184 mg,0.46 mmol) and ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (110 mg,0.69 mmol) in dry THF (1 mL) at 0deg.C. The reaction was stirred at 30 ℃ for 64h, cooled to room temperature, and the reaction mixture was diluted with ice water (5 mL) and extracted with DCM (10 mL x 2). The combined organic layers were concentrated on silica gel (DCM/meoh=20/1) and purified by flash chromatography to give 21b (90 mg, 37% yield) as a brown solid .HNMR(¹400MHz,DMSO-d₆)δ7.73(d,J＝9.2Hz,1H),7.65(dd,J＝9.2,6.4Hz,1H),5.31(m,0.5H),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＝6.4Hz,6H).

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

21B (50 mg,0.096 mmol), (2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethyl) triisopropylsilane (59 mg,0.16 mmol), cataCXium (R) APd G3 (14 mg,0.019 mmol) and K ₃PO₄ (41 mg,0.19 mmol) in THF (0.5 mL) and HO ₂ (0.1 mL) were stirred in a closed tube at 60℃for 20h without gas ₂. The reaction mixture was cooled, concentrated, and purified by flash chromatography on silica gel (DCM/meoh=20/1) to give 21c (60 mg, 76% yield) as a brown solid. LC-MS (method 3) t=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) ethyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) yl) methoxy) quinoline-3-carbonitrile hydrochloride (21 d)

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

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

A solution of 21d (58 mg,0.074 mmol) and CsF (135 mg,0.89 mmol) was added to DMF (1 mL) and stirred at 40℃for 4 hours. The reaction mixture was filtered and the filtrate was purified with prepre-hplc (method a) to give 21 (25 mg,54% yield) as a yellow solid. LC-MS (method) 1)t_R＝3.44min,m/z(m+H)⁺＝626.¹1H NMR(400MHz,DMSO-d₆)δ10.12(s,1H),7.96(dd,J＝8.8,5.6Hz,1H),7.83-7.78(m,1H),7.48-7.43(m,2H),7.09-7.07(m,1H),5.37(s,0.5H),5.24(s,0.5H),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,3H),2.24-2.00(m,3H),1.85-1.79(m,3H),1.14-1.11(m,6H).

Example 22

First step (R) -4- (7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (22 a)

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 0deg.C. After stirring at 30℃for 12 hours, the reaction solution was concentrated. The residue was purified by flash chromatography on silica gel (PE/ea=3/1) to give 22a (350 mg,89% yield) as a yellow solid. LC-MS (Method 3) t _R＝1.79min,m/z(M+H)⁺ =483.0.

Second step tert-butyl (R) -4- (7-bromo-3-cyano-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinolin-4-yl) -3-methylpiperazine-1-carboxylate (22 b)

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

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

To a solution of 22b (50 mg,0.82 mmol), cataCXium (R) APd G3 (12 mg,0.016 mmol) and K ₃PO₄ (53 mg,0.25 mmol) in THF/water (5/1, 0.6 mL) under nitrogen was added ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (63 mg,0.12 mmol). After stirring at 60 ℃ under nitrogen for 3 hours, the reaction was concentrated and the residue was purified by flash chromatography on silica gel (PE/ea=2/1) to give 22c (60 mg,80% yield) as a yellow oil. LC-MS (Method 3) t _R＝1.20min,m/z(M+H)⁺ = 912.8.

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

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

Fifth step 7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (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 3h. The reaction solution was filtered and the filtrate was purified by preparative HPLC (method a) to give 22 (18 mg,53% yield) as a yellow solid ).LC-MS(Method 2)t_R＝2.89min,3.12min,m/z(M+H)⁺＝612.3.¹H NMR(400MHz,DMSO-d₆)δ10.12(s,1H),7.97(dd,J＝9.2,6.0Hz,1H),7.90-7.86(m,1H),7.48-7.44(m,1H),7.42-7.37(m,2H),7.09(dd,J＝8.4,2.4Hz,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, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy-8-oxo-5, 6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) -2- (cyanoethyl) piperazine-1-carboxylate (23 a)

XantPhos Pd G3 (6.5 mg,0.0068 mmol) and CsCO ₂(30₃ mg,0.092 mmol) were added and 9b (23 mg,0.043 mmol) and 16d (33 mg,0.095 mmol) were stirred in anhydrous 1, 4-dioxane (1 mL). The resulting mixture was stirred under nitrogen at 110℃for 16 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by prepre-hplc (method E) to give compound 23a (7 mg, 21% yield) as a white solid. LC-MS (method four) t=4.17 min, m _R ⁺/z (m+h) = 794.3.

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

23A (7 mg,0.009 mmol) in MeOH (1 ml) and conc. HCl (0.05 mL) was stirred at 65deg.C for 16h. After cooling to room temperature, the reaction solution was concentrated, and the residue was purified by preparative high performance liquid chromatography (E method) to give compound 23b (4 mg, yield 70%) as a white solid. LC-MS (method 4) t _R＝1.14min,m/z(m+H)⁺ = 650.2.

Steps 3 (2) - (4- (2- (((2 r, 7) 2-fluorotetrahydro-1h-pyrrolizin-7a (5 h) -yl) methoxy) 7- (3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) 8-oxo-5,6 days, 7 days, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (23 c)

To anhydrous DMA (1 mL) was added 23b (2.4 mg, 0.04 mmol) and a solution of acetylene triisopropylsilane (6.7 mg,0.037 mmol) in CuI (1.0 mg,0.0052 mmol), pd (PPh ₃)₂Cl₂ (1.2 mg,0.0017 mmol) and DIEA (0.0070 mL,0.04 mmol), respectively, and the resulting mixture was stirred under a nitrogen atmosphere at 100deg.C for 5h, then cooled to room temperature and filtered, the filtrate was concentrated, and the residue was purified by High Performance Liquid Chromatography (HPLC) to give compound 23c (2 mg, yield 72%) as a white solid.

Step 4 2- ((S) -4- (7- (8-ethyl-3-hydroxynaphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -8-oxo-5, 6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (23)

TBAF (0.004mL,1M in THF,0.004mmol) was added to a solution of 23c (2.0 mg,0.0026 mmol) in THF (1 mL) at 0deg.C, reacted at 0deg.C with stirring for 1h, then the solvent was removed and purified by preparative high performance liquid chromatography (method F) to give compound 23 (1.3 mg,82% yield) as a white solid .NMR(400MHz,CDCl₃)_Rδ7.65(d,J＝8.0Hz,1H)⁺、7.39(d,J＝7.2Hz,1H)、7.28(t,J＝7.2Hz,1H)、7.19(d,J＝2.4Hz,1H)、7.07(d,J＝2.4Hz,1H)、5.35-5.22(m,1H)、4.43-4.36(m,1H)、4.14-4.01(m,1H)、3.¹88-3.79(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 (24 b)

HCOONH ₄ (114 mg,1.81 mmol) was added to a solution of 24a (150 mg,4.52 mmol) in acetone (1.5 mL) in HO ₂ (1.5 mL), followed by NaIO (₄ 390mg,1.81 mmol). After isothermal stirring for 16h, the reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL x 3). After concentration of the combined organic layers, the residue was purified by flash chromatography on PE/ea=2/1 silica gel to give 24b (62 mg, 55% yield) as a yellow solid. LC-MS (method 3) t=1. _R 06min,m/z(m+H)＝25⁺ 1.2.1.

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

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

Step 3 2-chloro-4- (3-hydroxy-3-methylpiperidin-1-yl) -6, 7-dihydropyridine [3,4-d ] pyrimidine-8 (5H) -1, 2-trifluoroacetate (24 d)

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

Step 4 2- ((2R, 7 aS) -2-Fluorohexahydro-1H-pyrrolin-7 a-yl) methoxy-4- (3-hydroxy-3-methylpiperidin-1-yl) -6, 7-dihydropyridine [3,4-d ] pyrimidine-8 (5H) -1 (24 e)

A solution of 24d (400 mg,1.35 mmol) and [ (2R, 8S) -2-fluoro-1, 2,3,5,6, 7-hexahydropyri rolizin-8-yl ] methanol (428 mg,2.70 mmol) in LiHMDS (4 mL,1M in THF) was stirred at 70℃overnight. After cooling to room temperature, it was quenched with 1mL of water. Purification by preparative high performance liquid chromatography (Method A) gave 24e (96 mg, 17% yield) as a yellow solid .¹H NMR(400MHz,DMSO-d₆)δ8.18(s,1H)、5.30(s,0.5H)、5.19(s,0.5H)、4.34(s,1H)、3.97(d,J＝10.0Hz,1H)、3.87(d,J＝10.0Hz,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, 7 aS) -2-fluorohexahydro-1H-pyrrolin-7 a-yl) methoxy) -4- (3-hydroxy-3-methylpiperidin-1-yl) -6, 7-dihydropyridine [3,4-d ] pyrimidine-8 (5H) -1 (24 f)

24E (85 mg,0.20 mmol), 24b (56 mg,0.22 mmol) and Cu ₂(TMEDA)(OH)₂Cl₂ (47 mg,0.10 mmol) were mixed in DCM (0.5 mL) and stirred overnight at ₂ room temperature under an atmosphere of 0. 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 give 24f (17 mg, 13% yield) as a yellow solid. LC-MS (method 3) t _R＝1.58min,m/z(m+H)⁺ = 624.4.

Step 6 7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolin-7 a-yl) methoxy) -4- (3-hydroxy-3-methylpiperidin-1-yl) -6, 7-dihydropyridine [3,4-d ] pyrimidine-8 (5H) -1 (24)

Hydrochloric acid/EtOAc (3 mL, 2M) was added to a solution of 24f (15 mg,0.024 mmol) in EtOAc (1 mL) at 0deg.C. After stirring at room temperature for 2h, the reaction mixture was concentrated. Purification by preparative high performance liquid chromatography (Method a) gave compound 24 (4.7 mg, 34% yield) as a white solid. LC-MS (method) 1)t_R＝2.76min,m/z(m+H)⁺＝5 ¹83.H NMR(400MHz,dm₆sod)δ10.23(s,1H),7.62(d,J＝8.0Hz,1H),7.42-7.37(m,1H),7.24(d,J＝2.0Hz,1H),7.13(d,J＝2.0Hz,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＝10.0Hz,1H),3.91(d,J＝10.4Hz,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＝4.8Hz,3H).

Example 25

Step 1 6- (8- (tert-butylcarbonyl) -3, 8-diazo [3.2.1] oct-3-yl) -5- (2- (tert-butylcarbonyl) amino) ethyl) -2- (2- (1-methyl-1 h-imidazol-2-yl) ethoxy) pyrimidine-4-carboxylic acid (25 a)

To a solution of dioxane (9 mL) was added 2- (1-methyl-1 h-imidazol-2-yl) ethylene glycol (192 mg,2.02 mmol) and t-Buona (144 mg,1.5 mmol) in 20a (500 mg,1.01 mmol) mass. Stirring at 90 ℃ for 3h, ho dilution (₂ mL), EA extraction (20 mL x 3), brine wash (20 mL), naSO ₂ drying, concentration ₄ purification on silica gel (DCM/MeOH from 100/1 to 10/1) afforded compound 25a (200 mg, 33% yield) as a white solid. LC-MS (method four) t=1.89 min, m/z (m+h) ⁺ =602.4.

Step 2 5- (2-aminoethyl) -6- (3, 8-diazo [3.2.1] oct-3-yl) -2- (2- (1-methyl-1 h-imidazol-2-yl) ethoxy) pyrimidine-4-carboxylic acid (25 b)

To a solution of CH ₃ CN (2 ml) was added hydrochloric acid/dioxin (2 ml, 4M) at a concentration of 25a (200 mg,0.33 mmol) at a temperature of 0 ℃. The reaction mixture was stirred at 0 ℃ for 6h, concentrated with aq NaC ₂Os₃ olution to pH >7. The organic layer was then concentrated and flash chromatographed on silica gel (DCM/MeOH from 100/1 to 7/1) to give compound 25b (110 mg, 83% yield) as a yellow solid. LC-MS (method four) t=1.58 _R min,m/z(m+H)＝402.3⁺.

Step 3 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (2- (1-methyl-1H-imidazol-2-yl) ethoxy) -6, 7-dihydropyridine [3,4-d ] pyrimidine-8 (5H) -1 (25 c)

To a solution of 25b (110 mg,0.27 mmol) HATU (154 mg,0.40 mmol) and DIEA (103 mg,0.8 mmol) in DMF (1 mL) was added at 25 ℃. The reaction mixture was stirred at 25 ℃ for 4h, diluted with HO ₂ (5 mL), extracted with EA (20 mL x 3), washed with brine (20 mL), dried over NaS ₂ O, and ₄ concentrated and purified on silica gel (DCM/MeOH from 100/1 to 10/1) to give compound 25c (50 mg, yield 48%) as a yellow solid. LC-MS (method four) t=2. _R81min,m/z(m+H)＝38⁺ 4.3.

Step 4 3- (2- (2- (1-methyl-1 h-imidazol-2-yl) ethoxy) -8-oxo-5, 6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (25 d)

To a solution of BocO ₂ (56 mg,0.26 mmol) and DIEA (26 mg,0.26 mmol) in THF (1 mL) was added 25c (50 mg,0.13 mmol) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 4h, diluted with HO ₂ (5 mL), extracted with EA (20 mL x 3), washed with brine (20 mL), dried over NaS ₂ O, and ₄ concentrated and purified on silica gel (DCM/MeOH from 100/1 to 15/1) to give compound 25d (60 mg, 95% yield) as a yellow solid. LC-MS (method four) t=3. _R81min,m/z(m+H)＝48⁺ 4.3.

Step 5 3- (7- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -2- (2- (1-methyl-1 h-imidazol-2-yl) ethoxy) -8-oxo-5, 6,7, 8-tetrahydropyridin [3,4-d ] pyrimidin-4-yl) -3, 8-diazobicyclo [3.2.1] octane-8-carboxylate (25 e)

1-Bromo-8-chloro-3- (methoxymethoxy) naphthalene (56 mg,0.18 mmol) in dioxane (2 mL) was added XantPhos Pd G3 (11 mg,0.012 mmol) and CsCO ₂(78₃ mg,0.24 mmol) at 25℃and solution 25d (60 mg,0.12 mmol). The reaction mixture was stirred at Natmosphere ₂ ℃ for 15h, diluted with ho (5 mL), EA extracted ₂ (20 mL x 3), washed with brine (20 mL), dried over NaSO, concentrated on silica gel (DCM/MeOH from 100/1 to 10/1) and purified ₄ by flash chromatography of ₂ to give compound 25e (25 mg,30% yield) as a yellow solid.

LC-MS (method four) t _R＝3.36min,m/z(m+H)⁺ = 704.3.

Step 6 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-chloro-3-hydroxynaphthalen-1-yl) -2- (2- (1-methyl-1H-imidazol-2-yl) ethoxy) -6, 7-dihydropyridine [3,4-d ] pyrimidin-8 (5H) -1 (25)

Hydrochloric acid/dioxane (1 mL ) was added to a solution of 25e (25 mg,0.035 mmol) in CH ₃ CN (1 mL) at 0deg.C. The reaction mixture was stirred at 0deg.C for 5h, and concentrated for purification by preparative high performance liquid chromatography (Method E) to give compound 25 (3.3 mg, 17% yield) as an off-white solid. LC-MS (method 4) t _R＝1.05min,m/z(m+H)⁺ =560.3.

1H NMR(400MHz,CD₃OD)δ8.50(s,1H)、7.72-7.65(m,1H)、7.32(s,1H)、7.31(d,J＝4.8Hz,1H)、7.24(d,J＝4.8Hz,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(d,J＝8.4Hz,1H)、3.46(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 (26)

To anhydrous DMF (30 mL) was added a solution of malononitrile (1.40 g,21.15 mmol) (810 mg,21.15mmol, 60% purity of mineral oil). After stirring at r.t for 30 minutes, 1b (5 g,19.23 mmol) was added to the solution. After stirring at 60℃for 30min, cooling to room temperature, the reaction mixture was diluted with HO ₂ (150 mL) and acidified with conc. HCl to ph=1. The resulting mixture was stirred for 1h and filtered. The filtrate was concentrated under reduced pressure to give 26a (4 g, yield 74%) as a white solid. LC-MS (method 3) t=0. _R 34min,m/z(m+H)＝28⁺ 1.7.1.

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

A solution of 26a (5 g,17.73 mmol) in POCl ₃ (8 mL) was stirred at 110℃for 4h, the reaction mixture was cooled to room temperature, the solid was collected by filtration and dried to give 26b (3.8 g,71% yield) as an off-white solid. ¹h NMR(400MHz,DMSO-d₆ ) Delta 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-1 h-pyrrole-1-carboxylate (26 c)

Pd (dppf) Cl ₂ (1.16 g,1.60 mmol) was added to 1, 4-dioxane/HO ₂/NMP (35 mL, v/v/v=5/1/1) to give 26b (2.4 g,7.99 mmol) of tert-butyl 3- (₃, 4, 5-tetramethyl-1, 3, 2-dioxaboronate-2-yl) -2, 5-dihydropyrrole-1-carboxylate (2.12 g,7.19 mmol) and NaC ₂ O (3.39 g,31.95 mmol) in solution. The reaction was degassed 3 times ₂ with N and stirred overnight at 40 ℃. The suspension was filtered, and the filtrate was diluted with ethyl acetate (50 mL), washed with water (15 mL) and brine (15 mL). The separated organic layer was concentrated and the residue purified by flash chromatography on silica gel (DCM/ea=15/1) to give compound 26c (1.69 g, yield 49%) as a red solid. LC-MS (method 3) t=1. _R80min,m/z(m+H)＝43⁺ 3.1.1.

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

To a solution of 26c (1.4 g,3.23 mmol) of ACN (20 mL) was added tert-butyl nitrite (666 mg,6.46 mmol). After stirring at room temperature for 10 minutes, cuCl (640 mg,6.46 mmol) was added. The reaction was stirred at room temperature overnight and diluted with water (10 mL) and NHHO ₃·(₂ mL). The mixture was extracted with ethyl acetate (15 ml x 3) and the combined organic layers were concentrated. Flash chromatography on silica gel (PE/ea=4/1) afforded compound 26d (645 mg, 44% yield) as a white solid .H NMR¹(400MHz,DMSO-d₆)δ8.03-8.01(m,1H),7.95(d,J＝9.2Hz,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, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -4- (1H-pyrrol-3-yl) quinoline-3-carbonitrile (26 e)

LiHMDS (0.82mL,0.82mmol,1M in THF) was added to a solution of 26d (93 mg,0.21 mmol) and ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (49 mg,0.31 mmol) in anhydrous THF (1.5 mL) at 0deg.C. The mixture was then stirred at room temperature overnight and quenched with HO (3 ml ₂). The resulting mixture was extracted with ethyl acetate (5 ml x 2). After concentrating the combined organic layers, the residue was purified by flash chromatography on silica gel (PE/ea=2/1) to give compound 26e (25 mg, 26% yield) as a yellow solid. LC-MS (method 3) t=1.85 min ⁺ _R, m/z (m+h) = 473.1.

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

26E (25 mg,0.053 mmol), 24a (23 mg,0.069 mmol), K ₂CO₃ (15 mg,0.11 mmol) and Pd (dppf) Cl ₂ (8 mg, 0.010mmol) were mixed in DMSO/1, 4-dioxane/HO ₂ (0.5 mL/0.5mL/0.1 mL) and stirred for 2h under an N atmosphere ₂ at 100deg.C. The reaction mixture was diluted with ethyl acetate (8 mL) and washed with water (3 mL). The organic layer was concentrated and the residue purified by flash chromatography on silica gel (DCM/meoh=20/1) to give compound 26f (18 mg, 57% yield) as yellow oil. LC-MS (method 3) t=1.63 min, m/z (m+h) ⁺ = 599.5.

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

A solution of 26f (18 mg,0.030 mmol) in EtOAc (0.5 mL) was added HCl/EtOAc (1 mL, 2M), left to stand and stir for 30min, and the reaction mixture concentrated and purified by preparative high performance liquid chromatography (method a) to give compound 26 (4.4 mg, 26% yield) as a white solid. LC-MS (method two) )t_R＝3.34min,m/z(m+H)⁺＝555.0.¹H NMR(400MHz,DMSO-d₆)δ11.66(s,1H)、8.01(d,J＝8.4Hz,1H)、7.66(d,J＝8.4Hz,1H)、7.54(t,J＝8.0Hz,1H)、7.40(m,2H)、7.09(s,1H)、7.05(d,J＝2.0Hz,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 (27 a)

26B (1.37 g,4.56 mmol), tert-butyl 3- (4, 5-tetramethyl-1, 3, 2-di oxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (1.13 g,3.65 mmol), naC ₂O(₃ 3.38.38 g,31.91 mmol) and Pd (dppf) Cl ₂ (662 mg,0.91 mmol) were mixed in 1, 4-dioxane (15 mL), HO ₂ (3 mL) and NMP (3 mL) and stirred for 18H at 35℃under N atmosphere ₂. After cooling to room temperature, diluted with HO (10 mL), ₂ was extracted with EtOAc (25 mL x 2). The combined organic layers were concentrated. Purification by flash chromatography on silica gel (DCM/etoac=30/1) afforded compound 27a (980 mg, yield 48%) as a yellow solid. LC-MS (method 3) t=1.66 min, m ⁺ _R/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 (27 b)

To ACN (25 mL) was added a mixture of 27a (1.02 g,2.28 mmol) and tert-butyl nitrite (353 mg,3.42 mmol) CuCl (452 mg,4.56 mmol). After stirring for 18h, dilute with HO ₂ (15 mL) and stand for NH. ₃H₂ O (5 mL), extracted with EtOAc (30 mL x 2). The combined organic layers were concentrated. Purification by flash chromatography on PE/ea=10/1 on silica gel gave compound 27b (482 mg, 45% yield) as a yellow solid. LC-MS (method 3) t=1. _R 88min,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 (27 c)

LiHMDS (0.96mL,0.96mmol,1.0M in THF) was added to a solution of 27b (150 mg,0.32 mmol) and (S) - (1-methylpyridin rolidin-2-yl) methanol (74 mg,0.64 mmol) (4 mL) in THF (0deg.C). The mixture was stirred at room temperature for 2 hours and poured into HO ₂ (5 mL). The mixture was extracted with EtOAc (15 ml x 2) and the combined organic layers were concentrated. Flash chromatography on silica gel (PE/ea=2/1) afforded compound 27c (146 mg, 83% yield) as a yellow solid. LC-MS (method 3) t=1.85 _Rmin,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) -carboxylic acid ester (27 d)

A solution of 27c (135 mg,0.25 mmol), 24a (99 mg,0.30 mmol), K ₂CO₃ (102 mg,0.74 mmol) and Pd (dppf) Cl ₂ (18 mg,0.025 mmol) was taken and stirred in 1, 4-dioxane (3 mL) and HO ₂ (1 mL) for 2h at 80℃under an N atmosphere ₂. The mixture was concentrated and the residue purified by flash chromatography on silica gel (DCM/meoh=20/1) to give compound 27d (105 mg, 63% yield) as a yellow solid. LC-MS (method 3) t=2.12 min, m/z (m+ _R ⁺ 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) quinone-3-carbonitrile (27)

A solution of 27d (25 mg,0.037 mmol) HCl/EtOAc (1 mL, 2.0M) and EtOAc (0.5 mL) was taken and stirred at room temperature for 1h. The mixture was concentrated, and the residue was purified by preparative high performance liquid chromatography (method a) to give compound 27 (5 mg, yield 25%) as a yellow solid .¹H NMR(400MHz,DMSO-d₆)_Rδ10.27(brs,1H)⁺,7.86(d,J＝¹ 8.4Hz,1H),7.67(d,J＝8.4Hz,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- ((2 r,7 as) -2-fluoro hexahydro-1 h-pyrrolin-7 a-yl) methoxy) quinolin-4-yl) -2, 5-dihydro-1 h-pyrrole-1-carboxylate (28 a)

To a solution of (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (74 mg,0.46 mmol) in THF (1.5 mL) was added LiHMDS (0.46mL,0.46mmol,1M in THF) at 0deg.C. After stirring at room temperature for 30min, the reaction mixture was cooled to 0 ℃ and 26d (140 mg,0.31 mmol) was added to the reaction mixture. The reaction was stirred at room temperature for 4 hours and quenched with 5mL ice water. The resulting mixture was extracted with EtOAc (8 ml x 2) and the combined organic layers were concentrated. Flash chromatography purification of the residue on silica gel (PE/ea=2/1) afforded compound 28a (130 mg, 73% yield) as a yellow solid. LC-MS (method 3) t=0.99 _R min,m/z(m+H)＝575.1⁺.

Step 2 3- (3-cyano-8-fluoro-7- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1 h-pyrrolin-7-yl) methoxyquinolin-4-yl) -2, 5-dihydro-1 h-pyrrole-1-carboxylic acid ester (28 b)

A solution of 28a (110 mg,0.19 mmol), 24a (70 mg,0.21 mmol), K ₂CO₃ (53 mg,0.38 mmol) and Pd (dppf) Cl ₂ (28 mg,0.038 mmol) in 1, 4-dioxane/HO ₂ (1 mL/0.2 mL) was stirred at 60℃for 4h at n ₂, then diluted with EtOAc (10 mL) and washed with HO ₂ (5 mL). The organic layer was concentrated and the residue purified by flash chromatography on silica gel (DCM/meoh=20/1) to give compound 28b (91 mg, 68% yield) as butter. LC-MS (method 3) t=1. _R 06min,m/z(m+H)＝70⁺ 1.3.1.

Step 3 tert-butyl 3- (3-cyano-8-fluoro-7- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1 h-pyrrolin-7-yl) methoxyquinolin-4-yl) pyrrolidine-1-carboxylate (28 c)

A mixture of 28b (91 mg,0.13 mmol), pd/C (80mg,10%wt wet in 50%water) and Pd (OH) ₂ (80 mg) in EtOH (2 mL) was stirred overnight at 50Psi h ₂, then the mixture was filtered and washed with EtOH (6 mL). The filtrate was concentrated to give 28c (70 mg, 77% yield) butter. LC-MS (method 3) t=1. _R 13min,m/z(m+H)＝70⁺ 3.2.2.

Step 4 8-fluoro-7- (8-fluoro-3-hydroxynaphthalen-1-yl) -2- ((2R, 7 aS) -2-fluorohexahydro-1 h-pyrrolin-7-yl) methoxy) -4- (pyrrolidin-3-yl) quinoline-3-carbonitrile hydrochloride (28)

HCl/EtOAc (0.5 mL, 2M) was added to a solution of 28c (17 mg,0.024 mmol) in EtOAc (1 mL) at 0 ℃. After stirring at room temperature for 2h, the solid formed was filtered and triturated with diethyl ether (2 ml). The solid was filtered and dried to give compound 28 (8.0 mg,52% yield) as a yellow solid .¹H NMR(400MHz,DMSO-d₆)_Rδ11.78(s,1H)⁺,10.38(s,1H),9.¹81(s,1H),9.63(s,1H),8.27(d,J＝9.2Hz,1H),7.69(m,2H),7.43(m,1H),7.37(t,J＝2.0Hz,1H),7.11(t,J＝2.0Hz,1H),7.01-6.97(m,1H),5.69(s,0.5H),5.56(s,0.5H),4.81-4.67(m,2H),4.57-4.59(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

Step1 2-chloro-4- (3, 5-dimethyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) -6, 7-dihydropyran [3,4-d ] pyrimidine-8 (5H) -1 (29 a)

A solution of 14a (300 mg,1.38 mmol), 3, 5-dimethyl-1- (tetrahydro-2 h-pyran-2-yl) -4- (4, 5-tetramethyl-1, 3, 2-di oxaborolan-2-yl) -1 h-pyrazole (426 mg,1.38 mmol), pd (PPh ₃)(159mg₄,0.138mmol)、NaCO(438₂mg₃, 4.13 mmol) dioxane (5 mL) and HO (1 mL) ₂ was stirred at 85℃for 4h, the mixture was concentrated and the residue purified by flash chromatography on silica gel (DCM/MeOH from 100/1 to 20/1) to give compound 29a (100 mg, 20% yield) as a yellow solid. LC-MS (method four) t=2.41 min _R ⁺, m/z (m+h) = 362.2.

Step 2 4- (3, 5-dimethyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -6, 7-dihydropyridine [3,4-d ] pyrimidin-8 (5H) -1 (29 b)

To a solution of 29a (80 mg,0.22 mmol) ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol (106 mg,0.66 mmol) in dioxane (1 mL) was added 4 timesMolecular sieves (80 mg) and DIEA (86 mg,0.66 mmol). The mixture was then concentrated at 110℃with stirring for 48h, and the residue was purified by flash chromatography on silica gel (DCM/MeOH from 50/1 to 5/1) to give compound 29b as a yellow solid. LC-MS (method four) t=3.16 min, m/z (m+h) = ⁺ _R 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, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -6, 7-dihydropyridine [3,4-d ] pyrimidine-8 (5H) -1 (29 c)

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), csCO ₂(50₃ mg,0.155 mmol) in dioxane (1 mL) was stirred at 110℃for 24h, the mixture was concentrated and the residue purified by flash chromatography on silica gel (DCM/MeOH: 50/1-15/1) to give compound 29c (10 mg, 23% yield) as a yellow solid. LC-MS (method four) t=2. _R65min,m/z(m+H)＝70⁺ 5.4.4.

Step 4 7- (8-chloro-3-hydroxynaphthalen-1-yl) -4- (3, 5-dimethyl-1H-pyrazol-4-yl) -2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -6, 7-dihydropyridine [3,4-d ] pyrimidine-8 (5H) -1 carboxylic acid (29)

HCl (0.5 mL,4M dioxane) was added to a solution of ACN (0.5 mL), 29c (10 mg,0.014 mmol) was added to an ice bath, and then stirred at room temperature for 2h. The mixture was concentrated and the residue was purified by preparative high performance liquid chromatography (method F) to give compound 29 (5.6 mg,68% yield) as a pale yellow solid. LC-MS (method four )t_R＝3.08min,m/z(m+H)⁺＝577.4.¹H NMR(400MHz,DMSO-d₆)δ7.82--7.78(m,1H),7.39--7.37(m,2H),7.30--7.28(m,2H),5.35--5.21( years ,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(, 6H), 2.17-2.13 (m, 1H), 2.08-1.99 (m, 3H), 1.87-1.73 (m, 2H).

TABLE 1

KRAS-G12D Surface Plasmon Resonance (SPR) binding assay

This example illustrates the binding of exemplary compounds of the invention to KRAS-G12D protein in incubation buffer (50 mM

Hepes pH 7.4, 150mM NaCl, 5mM MgCl ₂, 10mM EDTA and 0.01% Triton X-100)), 20mM MgCl ₂ (final concentration) was added after incubation at 30℃for 1 hour to terminate GppNHp release, as determined by Surface Plasmon Resonance (SPR).

Prior to testing, prior to docking the GE Streptavidin (SA) chip, the Biacore 8K (GE) instrument was perfused with 1X Running buffer (HBS-p+/10 mM MgCl ₂/+ 0.5mM TCEP 2%DMSO, flow rate: 100 μl/mL), and after docking, was perfused twice before starting the immobilization step. All the immobilized protein mixtures were prepared on a 20. Mu.g/mL scale. The biotinylated KRAS-G12D protein was immobilized as follows:

The sensor surface was conditioned by 3 consecutive 1 minute injections of 1M NaCl in 50mM NaOH prior to immobilization. Thereafter, 20. Mu.g/ml of Biotin-KRAS (G12D)/Biotin-KRAS (G12D) -GppNHp was injected at a rate of 10. Mu.L/min for 320 seconds. Washing was performed using 1M NaCl with 50% isopropanol and 50mM NaOH. All compounds were prepared as 10mM DMSO stock solution and then serially diluted 3-fold to test their affinity for KRAS-G12D protein. The measurement steps are as follows:

Running Buffer plus containing 10mM MgCl ₂, 0.5mM TCEP and 2% DMSO was used as a Running buffer for binding measurements, and the experiment was performed at 25 ℃. Compounds were diluted to 6-8 concentrations using Running buffer at 1:2 serial dilutions. Compound solutions having continuous concentrations were injected into the channels at a rate of 100 μl/min, respectively. The binding and dissociation times were 40 seconds and 120 seconds, respectively. Two solvent corrections were performed to correct DMSO-induced signals, and two blank solutions were injected to eliminate the reference signal. At the end of each cycle, 50% dmos was injected to clean the system.

The data were analyzed by BIAcore Insight Evaluation Software. After subtracting the reference and zero concentration signals from the sample signal, curve fitting of the binding kinetics parameters was performed by a 1:1 binding model and a steady state affinity model

The results of the exemplary compounds are shown in table 2. Nd=not measured.

KRAS-G12D/RAF1 binding experiments

This example illustrates that exemplary compounds of the invention bind to KRAS-G12D protein and can block interactions between KRAS-G12D and RAF1 proteins.

The ability of compounds to bind to KRAS-G12D protein and block interactions between KRAS-G12D and RAF1 protein was measured using a Homogeneous Time Resolved Fluorescence (HTRF) detection kit (Cisbio, 63ADK000CB21 PEG). Compounds that block KRAS-G12D/RAF1 interactions will result in a decrease in HTRF signal.

All compounds were prepared as 10mM DMSO stock solution and then serially diluted 3-fold to test their activity in KRAS-G12D: RAF1 interaction block. The diluted compound was incubated with GppNHp-loaded Tag2-KRAS-G12D and Tag1-RAF1 for 15 min at room temperature. A dye-labeled anti-Tag 2 antibody and europium-conjugated anti-Tag 1 antibody mixture was then added. After incubation for 2 hours at 4 ℃, the plates were read on a Molecular Device (Spectra MAX i 3X) reader with HTRF module. Data analysis was performed by GRAPHPAD PRISM and IC50 was obtained by a four-parameter fitting method of dose response curves.

The results of the exemplary compounds are shown in table 2. Nd=not measured.

Table 2 shows SPR and RAS-RAF1 binding values for exemplary Compounds

It should be understood that the foregoing description of the preferred embodiments is intended to be purely illustrative of the principles of the invention and is not exhaustive, and that modifications and variations will be apparent to those skilled in the art, the invention not being intended to be limited except as explicitly defined in the following claims.

Claims

1. 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 ² is hydrogen, halogen or C ₁-C₃ alkyl;

L ¹ is a single bond, C ₁-C₄ alkylene, -O-or-N (R ^N1) -;

r ⁶ is-CN;

R ⁴ is C ₃-C₇ cycloalkyl, C ₃-C₇ cycloalkenyl, 3-to 12-membered nitrogen containing heterocycloalkyl, 3-to 12-membered nitrogen containing heterocycloalkenyl, C ₃-C₆ cycloalkyl substituted with one or more R ^4-1, C ₃-C₇ 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, and one or more of the heteroatoms is selected from O, S and N; in the 3-to 12-membered nitrogen-containing heterocycloalkenyl group, the number of heteroatoms is 1,2,3 or 4, and the heteroatoms are one or more selected from O, S and N;

Each R ^N1 is independently hydrogen or C ₁-C₃ alkyl.

2. The nitrogen-containing heterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 1, wherein the nitrogen-containing heterocyclic compound of formula I satisfies one or more of the following conditions:

1) R ² is hydrogen or halogen;

2) L ¹ is C ₁-C₄ alkylene, -N (methyl) -or-O-;

3) In R ⁴, C ₃-C₇ cycloalkyl, C ₃-C₇ cycloalkenyl, 3 to 12 membered nitrogen containing heterocycloalkyl, and 3 to 12 membered nitrogen containing heterocycloalkenyl are bridged rings;

4) R ⁴ satisfies the following conditions: Or alternatively 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-C₃ alkyl, C ₁-C₃ alkoxy, C ₁-C₃ cyanoalkyl, C ₁-C₃ hydroxyalkyl, C ₃-C₆ cycloalkyl, -N (R ^N1)₂、-CO₂R^N1、-CO₂N(R^N1)₂ or 5 to 6 membered heteroaryl, wherein the number of heteroatoms is 1,2,3 or 4, one or more of the heteroatoms is selected from O, S and N, each R ^N1 is independently hydrogen or C ₁-C₃ alkyl, R ^Z2 is hydrogen or methyl;

5) R ⁴ is Wherein Z ¹ is independently CH, C, or N; ring a is a 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, and one or more of the heteroatoms is selected from O, S and N; in the 3-to 12-membered nitrogen-containing heterocycloalkenyl group, the number of heteroatoms is 1, 2,3 or 4, and the heteroatoms are one or more selected from O, S and N; ring B is C ₃-C₇ cycloalkyl, C ₃-C₇ 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, and one or more of the heteroatoms is selected from O, S and N; in the 3-to 12-membered nitrogen-containing heterocycloalkenyl group, the number of heteroatoms is 1, 2,3 or 4, and the heteroatoms are one or more selected from O, S and N; e is independently 0,1, 2,3 or 4; r ^Z1 is independently oxo, hydroxy, halogen, cyano, C ₁-C₃ alkyl, C ₁-C₃ alkoxy, C ₁-C₃ cyanoalkyl, C ₁-C₃ hydroxyalkyl, C ₃-C₆ cycloalkyl, -N (R ^N1)₂、-CO₂R^N1、-CO₂N(R^N1)₂ or 5 to 6 membered heteroaryl, wherein the number of heteroatoms is 1, 2,3 or 4, one or more of the heteroatoms is selected from O, S and N, each R ^N1 is independently hydrogen or C ₁-C₃ alkyl, R ^Z2 is hydrogen or methyl;

6) R ⁴ is bound by carbon or nitrogen atoms R ⁴ is a 3-to 12-membered nitrogen-containing heterocycloalkyl, a 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, the 3-to 12-membered nitrogen-containing heterocycloalkyl has "NH" which is not attached to R ^4-3; in R ⁴, the 3-to 12-membered nitrogen-containing heterocycloalkenyl has "NH" that is not linked to R ^4-4;

7) R ⁴ is bound by carbon or nitrogen atoms R ⁴ is C ₃-C₆ cycloalkyl substituted with one or more R ^4-1, C ₃-C₇ 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 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).

3. The nitrogen-containing heterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 2, wherein the nitrogen-containing heterocyclic compound of formula I satisfies one or more of the following conditions:

8) R ¹ is C ₆-C₁₄ aryl, 5 to 14 membered heteroaryl, C ₆-C₁₄ aryl substituted with one or more R ^1-1, or 5 to 14 membered heteroaryl substituted with one or more R ^1-2; in a 5-to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, one or more of said heteroatoms being selected from the group consisting of O, S and N; r ^1-1 and R ^1-2 are each independently halogen, cyano, hydroxy, C ₂-C₄ alkynyl or C ₁-C₃ alkoxy;

9) R ² is halogen;

10 R ³ is-L ²-R^3-1;L² is-O-, -N (methyl) -, C ₁-C₄ alkylene; r ^3-1 is C ₃-C₁₂ cycloalkyl, 3 to 12 membered heterocycloalkyl, C ₃-C₁₂ cycloalkyl substituted by one or more R ^3-1-1 or 3 to 12 membered heterocycloalkyl substituted by one or more R ^3-1-2; in the 3-to 12-membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and one or more of the heteroatoms is selected from O, S and N; r ^3-1-1 and R ^3-1-2 are each independently halogen or oxo;

11 R ⁴ is a 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, and one or more of the heteroatoms is selected from O, S and N; each R ^4-3 is independently C ₁-C₃ cyanoalkyl or-N (R ^N1)₂; each R ^N1 is independently hydrogen or C ₁-C₃ alkyl).

4. The nitrogen-containing heterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 1, wherein the nitrogen-containing heterocyclic compound of formula I has the definition set forth in any one of the following schemes:

scheme one:

X ¹ is C-H;

X ³ is C-H;

r ² is halogen;

l ¹ is-O-;

r ³ is-L ²-R^3-1;

L ² is C ₁-C₄ alkylene;

Each R ^3-1-2 is independently halogen or C ₁-C₄ alkyl;

r ⁶ is-CN;

Each R ^4-3 is independently C ₁-C₃ alkyl or-N (R ^N1)₂;

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

Scheme 2:

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

X ³ is C-H;

r ² is halogen;

L ¹ is C ₁-C₄ alkylene, -N (methyl) -or-O-;

r ³ is-L ²-R^3-1;

L ² is-O-, -N (methyl) -or C ₁-C₄ alkylene;

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

r ⁶ is-CN;

R ⁴ is a 3-to 12-membered nitrogen containing heterocycloalkyl or a 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, and one or more of the heteroatoms is selected from O, S and N; each R ^4-3 is independently C ₁-C₃ cyanoalkyl or-N (R ^N1)₂;

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

Scheme 3: r ² is hydrogen or halogen;

R ⁴ is bound by carbon or nitrogen atoms

Scheme 4:

Is that Wherein n is 1,2,3 or 4, each R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C₄ alkyl;

R ⁴ is bound by carbon or nitrogen atoms

Scheme 5:

Is that Wherein m is 1, 2, 3 or 4, and r ^3-1-2 are each independently oxo, halogen or cyano;

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

R ⁴ is bound by carbon or nitrogen atoms

Scheme 6:

Is that

Wherein R ⁴ is bound by a carbon or nitrogen atom

Scheme 7:

Is that

Wherein R ⁴ is bound by a carbon or nitrogen atom

Scheme 8:

Is that Wherein p is 0, 1,2 or 3, q is 0, 1,2 or 3;

R ⁴ is bound by carbon or nitrogen atoms

Scheme 9:

Is that

Wherein,

R ⁴ is bound by carbon or nitrogen atoms

Scheme 10:

Is that

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-C₃ alkyl, C ₁-C₃ alkoxy, C ₁-C₃ cyanoalkyl, C ₁-C₃ hydroxyalkyl, C ₃-C₆ cycloalkyl, -N (R ^N1)₂、-CO₂R^N1、-CO₂N(R^N1)₂ or 5 to 6 membered heteroaryl, wherein the number of heteroatoms in the 5 to 6 membered heteroaryl is 1, 2, 3 or 4, and one or more of the heteroatoms is selected from O, S and N;

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl;

Scheme 11:

Is that

Wherein Z ¹ is independently CH, C or N;

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

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl;

Scheme 12:

Is that

Z ¹ is independently CH, C or N;

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

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl;

Scheme 13:

Is that

Z ¹ is independently CH, C or N;

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

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl.

5. The nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, or a solvate thereof according to claims 1 to 4, wherein the nitrogen-containing heterocyclic compound represented by formula I satisfies one or more of the following conditions:

12 R ^X1, the halogen is F, cl, br or I;

13 R ¹, the C ₆-C₁₄ aryl is C ₆-C₁₀ aryl;

14 R ¹, the C ₆-C₁₄ aryl is monocyclic or bicyclic;

15 R ¹, each ring of the C ₆-C₁₄ aryl is aromatic;

16 R ¹, the 5-to 14-membered heteroaryl is a 9-to 10-membered heteroaryl;

17 R ¹, the 5-to 14-membered heteroaryl is monocyclic or bicyclic;

18 R ¹, each ring of the 5-to 14-membered heteroaryl is aromatic;

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

20 R ¹, the heteroatom in the 5-to 14-membered heteroaryl is N;

21 R ^1-1 and R ^1-2, said halogen being F, cl, br or I;

22 R ^1-1 and R ^1-2, said C ₁-C₄ alkyl is methyl, ethyl, propyl or isopropyl;

23 R ^1-1 and R ^1-2, said-S-C ₁-C₃ alkyl is-S-methyl, -S-ethyl, -S-propyl or-S-isopropyl;

24 R ^1-1 and R ^1-2, said C ₂-C₄ alkynyl is ethynyl;

25 R ^1-1 and R ^1-2, said C ₁-C₃ haloalkyl is-CF ₃;

26 R ^1-1 and R ^1-2, said-O-C ₁-C₃ haloalkyl is-O-CF ₃;

27 R ^1-1 and R ^1-2, said C ₁-C₃ alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy;

28 R ^1-1 and R ^1-2, said C ₃-C₆ cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl;

29 R ², the halogen is F, cl, br or I;

30 R ², the C ₁-C₃ alkyl is methyl, ethyl, propyl or isopropyl;

31 L ¹, the C ₁-C₄ alkylene is methylene, ethylene, propylene or butylene;

32 R ³, the 3-to 12-membered heterocycloalkyl is a 3-to 6-membered heterocycloalkyl;

33 R ³, the 3-to 12-membered heterocycloalkyl is a single ring or a double ring; preferably, a single ring, spiro ring or bridged ring;

34 R ³, the 3-to 12-membered heterocycloalkyl having 1 or 2 heteroatoms;

35 R ³, the heteroatom in the 3-to 12-membered heterocycloalkyl is N;

36 L ², the C ₁-C₄ alkylene is methylene, ethylene, propylene or butylene;

37 R ^3-1 is linked to L ² via a carbon or nitrogen atom;

38 R ^3-1, the C ₃-C₁₂ cycloalkyl is C ₃-C₈ cycloalkyl;

39 R ^3-1, the C ₃-C₁₂ cycloalkyl is monocyclic or bicyclic;

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

41 R ^3-1, the 3-to 12-membered heterocycloalkyl is a single ring or a double ring; preferably, a single ring, spiro ring or bridged ring;

42 R ^3-1, the 3-to 12-membered heterocycloalkyl having 1 or 2 heteroatoms;

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

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

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

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

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

48 R ^3-1-1、R^3-1-2、R^3-1-3 and R ^3-1-4, said halogen being F, cl, br or I;

49 R ^3-1-1、R^3-1-2、R^3-1-3 and R ^3-1-4, said C ₁-C₄ alkyl is methyl, ethyl, propyl or isopropyl;

50 R ⁴ is bound via a carbon atom or a nitrogen atom

51 R ⁴, the C ₃-C₇ cycloalkyl is monocyclic or bicyclic; preferably, a single ring, spiro ring or bridged ring;

52 R ⁴, the C ₃-C₇ cycloalkenyl is mono-or bi-cyclic; preferably, a single ring, spiro ring or bridged ring;

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

54 R ⁴, the 3-to 12-membered nitrogen-containing heterocycloalkyl is a single ring or a double ring; preferably, a single ring, spiro ring or bridged ring;

55 R ⁴, the 3-to 12-membered nitrogen-containing heterocycloalkyl having 1 or 2 heteroatoms;

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

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

58 R ⁴, the 3-to 12-membered nitrogen-containing heterocycloalkenyl is monocyclic or bicyclic; preferably, a single ring, spiro ring or bridged ring;

59 R ⁴, the 3-to 12-membered nitrogen-containing heterocycloalkenyl has 1 or 2 heteroatoms;

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

61 R ^4-1、R^4-2、R^4-3 and R ^4-4, said halogen being F, cl, br or I;

62 R4 ^-1、R^4-2、R^4-3 and R ^4-4, said C ₁-C₃ alkyl is methyl, ethyl, propyl or isopropyl;

63 R ^4-1、R^4-2、R^4-3 and R ^4-4, said C ₁-C₃ cyanoalkyl group is cyanomethyl;

64 R ^4-1、R^4-2、R^4-3 and R ^4-4, said C ₃-C₆ cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl;

65 R ^4-1、R^4-2、R^4-3 and R ^4-4, said C ₁-C₃ alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy;

66 R ^N1, the C ₁-C₃ alkyl is methyl, ethyl, propyl or isopropyl;

67 "NH" on ring A is not attached to R ^Z1;

68 In ring B), the C ₃-C₇ cycloalkyl is monocyclic or bicyclic; preferably, a single ring, spiro ring or bridged ring;

69 In the B ring, the C ₃-C₇ cycloalkenyl is a single ring or a double ring; preferably, a single ring, spiro ring or bridged ring;

70 In ring a and ring B, the 3-to 12-membered nitrogen-containing heterocycloalkyl group is a 5-to 9-membered nitrogen-containing heterocycloalkyl group;

71 Ring a and ring B, the 3-to 12-membered nitrogen-containing heterocycloalkyl being a single ring or a double ring; preferably, a single ring, spiro ring or bridged ring;

72 Ring a and ring B, the 3-to 12-membered nitrogen-containing heterocycloalkyl having 1 or 2 heteroatoms;

73 Ring a and ring B, the heteroatom in the 3-to 12-membered nitrogen-containing heterocycloalkyl being N;

74 Ring a and ring B, the 3-to 12-membered nitrogen-containing heterocycloalkenyl group is a 5-to 9-membered nitrogen-containing heterocycloalkenyl group;

75 Ring a and ring B, the 3-to 12-membered nitrogen-containing heterocycloalkenyl is monocyclic or bicyclic; preferably, a single ring, spiro ring or bridged ring;

76 Ring a and ring B, the 3-to 12-membered nitrogen-containing heterocycloalkenyl having 1 or 2 in number of heteroatoms;

77 Ring a and ring B, the heteroatom in the 3-to 12-membered nitrogen-containing heterocycloalkenyl being N;

78 R ^Z1, halogen is F, cl, br or I;

79 R ^Z1, the C ₁-C₃ alkyl is methyl, ethyl, propyl or isopropyl;

80 R ^Z1, the C ₁-C₃ cyanoalkyl group is cyanomethyl;

81 R ^Z1, the C ₃-C₆ cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl;

82 R ^Z1, the C ₁-C₃ alkoxy group is methoxy, ethoxy, n-propoxy or isopropoxy;

83 R ^N1, the C ₁-C₃ alkyl is methyl, ethyl, propyl or isopropyl;

84 "plurality" in the above definition is independently 2, 3, 4 or 5.

6. The nitrogen-containing heterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 5, wherein the nitrogen-containing heterocyclic compound of formula I satisfies one or more of the following conditions:

85 In R ^X1, halogen is F;

86 In R ^X3, halogen is F;

87 R ¹, C ₆-C₁₄ aryl is phenyl, 1-naphthyl, 2-naphthyl or

88 In R ¹, 5 to 14 membered heteroaryl is

89 R ^1-1 and R ^1-2, halogen is F or Cl;

90 R ^1-1 and R ^1-2, C ₁-C₄ alkyl is methyl;

91 R ^1-1 and R ^1-2, -S-C ₁-C₃ alkyl is-S-methyl;

92 R ^1-1 and R ^1-2, C ₁-C₃ alkoxy is methoxy;

93 R ^1-1 and R ^1-2, C ₃-C₆ cycloalkyl is cyclopropyl;

94 In R ², halogen is F;

95 In R ², C ₁-C₃ alkyl is methyl;

96 R ³, 3-to 12-membered heterocycloalkyl is 1-azetidinyl;

97 In L ², C ₁-C₄ alkylene;

98 R ^3-1 is linked to L ² via a nitrogen atom;

99 In R ^3-1, C ₃-C₁₂ cycloalkyl is C ₅-C₈ cycloalkyl;

100 In R ^3-1, C ₃-C₁₂ cycloalkyl is a monocyclic ring, a spiro ring or a bridged ring;

101 In R ^3-1, 3-to 12-membered heterocycloalkyl is 7-to 10-membered bridged heterocycloalkyl;

102 In R ^3-1, 5 to 14 membered heteroaryl is pyrazolyl;

103 R ^3-1-1、R^3-1-2、R^3-1-3 and R ^3-1-4, halogen is F;

104 R ^3-1-1、R^3-1-2、R^3-1-3 and R ^3-1-4C₁-C₄ alkyl are methyl;

105 In R ⁴, C ₃-C₇ cycloalkyl is Cyclopropyl, cyclopentyl or cyclohexyl;

106 In R ⁴, C ₃-C₇ cycloalkenyl is cyclopropenyl, cyclopentenyl or cyclohexenyl;

107 In R ⁴, 3-to 12-membered nitrogen-containing heterocycloalkyl is tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl

108 R ⁴, wherein 3 to 12 membered nitrogen-containing heterocycloalkenyl is 3 to 12 membered nitrogen-containing heterocycloalkenyl

109 R ^4-1、R^4-2、R^4-3 and R ^4-4, halogen is F;

110 R ^4-1、R^4-2、R^4-3 and R ^4-4, C ₁-C₃ alkyl is methyl;

111 R ^4-1、R^4-2、R^4-3 and R ^4-4, C ₃-C₆ cycloalkyl is cyclopropyl;

112 R ^4-1、R^4-2、R^4-3 and R ^4-4, C1-C3 alkoxy is methoxy;

113 In ring B, C ₃-C₇ cycloalkyl is Cyclopropyl, cyclopentyl or cyclohexyl;

114 In ring B, C ₃-C₇ 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, 3-to 12-membered nitrogen-containing heterocycloalkenyl is 3-to 12-membered nitrogen-containing heterocycloalkenyl

117 In R ^Z1, halogen is F;

118 In R ^Z1, C ₁-C₃ alkyl is methyl;

119 In R ^Z1, C ₃-C₆ cycloalkyl is cyclopropyl;

120 In R ^Z1, C ₁-C₃ alkoxy is methoxy;

121 In R ^N1, C ₁-C₃ alkyl is methyl.

7. The nitrogen-containing heterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 6, wherein the nitrogen-containing heterocyclic compound of formula I satisfies one or more of the following conditions:

122 R1 is

123 -L ¹-R³ is

124 R ⁴ is

8. The nitrogen-containing heterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 1, wherein the nitrogen-containing heterocyclic compound of formula I is selected from the group consisting of:

9. A pharmaceutical composition comprising a substance X which is a nitrogen-containing heterocyclic compound of formula I as defined in claims 1-8, a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutically acceptable excipient.

10. Use of substance X in the preparation of KRAS-G12D inhibitors; the substance X is a nitrogen-containing heterocyclic compound shown in a formula I, a pharmaceutically acceptable salt or a solution thereof as defined in claims 1-8;

preferably, the KRAS-G12D inhibitor is used in vitro or in vivo.

11. Use of substance X in the preparation of a medicament;

Substance X is a nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, or a solvate thereof as defined in claims 1 to 8;

The medicament is used for treating or preventing KRAS-G12D related diseases or conditions;

Preferably, the KRAS-G12D related disease or disorder is cancer.

12. Use of substance X in the preparation of a medicament;

the medicine can be used for treating or preventing cancer.

13. A method for preventing and/or treating a KRAS-G12D-related disease or disorder comprising administering to a subject in need thereof a therapeutically effective amount of substance X;

Preferably, the KRAS-G12D related disease or disorder is cancer.

14. A method for preventing and/or treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of substance X;

Substance X is a nitrogen-containing heterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, or a solvate thereof as defined in claims 1-8.

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

wherein,

is a single bond or a double bond;

r ⁵ is hydrogen, halogen or C ₁-C₃ alkyl;

L ¹ is a single bond, C ₁-C₄ alkylene, -O-or-N (R ^N1) -;

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

Each R ^N1 is independently hydrogen or C ₁-C₃ alkyl.

16. The nitrogen-containing heterocyclic compound of formula II, a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 15, wherein the nitrogen-containing heterocyclic compound of formula II satisfies one or more of the following conditions:

125 X ³ is CH ₂;

126) Is a single bond;

127 R ⁵ is methyl or ethyl;

128 L ¹ is C ₁-C₄ alkylene, -N (methyl) -or-O-;

129 X ² is N;

130 In R ⁴, C ₃-C₇ cycloalkyl, C ₃-C₇ cycloalkenyl, 3-to 12-membered nitrogen-containing heterocycloalkyl, and 3-to 12-membered nitrogen-containing heterocycloalkenyl are bridged rings;

131 R ⁴ satisfies the following condition: Or alternatively 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-C₃ alkyl, C ₁-C₃ alkoxy, C ₁-C₃ cyanoalkyl, C ₁-C₃ hydroxyalkyl, C ₃-C₆ cycloalkyl, -N (R ^N1)₂、-CO₂R^N1、-CO₂N(R^N1)₂ or 5 to 6 membered heteroaryl, wherein the number of heteroatoms is 1,2,3 or 4, one or more of the heteroatoms is selected from O, S and N, each R ^N1 is independently hydrogen or C ₁-C₃ alkyl, R ^Z2 is hydrogen or methyl;

132 R ⁴ is Wherein Z ¹ is independently CH, C, or N; ring a is a 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, and one or more of the heteroatoms is selected from O, S and N; in the 3-to 12-membered nitrogen-containing heterocycloalkenyl group, the number of heteroatoms is 1, 2,3 or 4, and the heteroatoms are one or more selected from O, S and N; ring B is C ₃-C₇ cycloalkyl, C ₃-C₇ 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, and one or more of the heteroatoms is selected from O, S and N; in the 3-to 12-membered nitrogen-containing heterocycloalkenyl group, the number of heteroatoms is 1, 2,3 or 4, and the heteroatoms are one or more selected from O, S and N; e is independently 0,1, 2,3 or 4; r ^Z1 is independently oxo, hydroxy, halogen, cyano, C ₁-C₃ alkyl, C ₁-C₃ alkoxy, C ₁-C₃ cyanoalkyl, C ₁-C₃ hydroxyalkyl, C ₃-C₆ cycloalkyl, -N (R ^N1)₂、-CO₂R^N1、-CO₂N(R^N1)₂ or 5 to 6 membered heteroaryl, wherein the number of heteroatoms is 1, 2,3 or 4, one or more of the heteroatoms is selected from O, S and N, each R ^N1 is independently hydrogen or C ₁-C₃ alkyl, R ^Z2 is hydrogen or methyl;

133 R ⁴ is bound via a carbon atom or a nitrogen atom R ⁴ is a 3-to 12-membered nitrogen-containing heterocycloalkyl, a 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, the 3-to 12-membered nitrogen-containing heterocycloalkyl has "NH" which is not attached to R ^4-3; in R ⁴, the 3-to 12-membered nitrogen-containing heterocycloalkenyl has "NH" that is not linked to R ^4-4;

134 R ⁴ is bound via a carbon atom or a nitrogen atom R ⁴ is C ₃-C₆ cycloalkyl substituted with one or more R ^4-1, C ₃-C₇ 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 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).

17. The nitrogen-containing heterocyclic compound of formula II, a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 16, wherein the nitrogen-containing heterocyclic compound of formula II satisfies one or more of the following conditions:

135 R ¹ is C ₆-C₁₄ aryl, 5 to 14 membered heteroaryl, C ₆-C₁₄ aryl substituted with one or more R ^1-1, or 5 to 14 membered heteroaryl substituted with one or more R ^1-2; in a 5-to 14-membered heteroaryl, the number of heteroatoms is 1,2, 3 or 4, one or more of said heteroatoms being selected from the group consisting of O, S and N; r ^1-1 and R ^1-2 are each independently halogen, cyano, hydroxy, C ₂-C₄ alkynyl or C ₁-C₃ alkoxy;

136 R ³ is-L ²-R^3-1;L² is-O-, -N (methyl) -, C ₁-C₄ alkylene; r ^3-1 is C ₃-C₁₂ cycloalkyl, 3 to 12 membered heterocycloalkyl, C ₃-C₁₂ cycloalkyl substituted by one or more R ^3-1-1 or 3 to 12 membered heterocycloalkyl substituted by one or more R ^3-1-2; in the 3-to 12-membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and one or more of the heteroatoms is selected from O, S and N; r ^3-1-1 and R ^3-1-2 are each independently halogen or oxo;

137 R ⁴ is a 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, and one or more of the heteroatoms is selected from O, S and N; each R ^4-3 is independently C ₁-C₃ cyanoalkyl or-N (R ^N1)₂; each R ^N1 is independently hydrogen or C ₁-C₃ alkyl).

18. The nitrogen-containing heterocyclic compound of formula II, a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 15, wherein the nitrogen-containing heterocyclic compound of formula II has the definition described in any one of the following schemes:

Scheme 1:

x ³ is CH-R ^X3;R^X3 is halogen;

Is a single bond;

R ⁵ is hydrogen;

l ¹ is-O-;

r ³ is-L ²-R^3-1;

L ² is C ₁-C₄ alkylene;

R ^3-1-2 and R ^3-1-4 are each halogen or C ₁-C₄ alkyl;

X ² is N;

Each R ^4-3 is independently hydroxy, C ₁-C₃ alkyl or C ₁-C₃ cyanoalkyl;

Scheme 2:

X ³ is CH ₂;

Is a single bond;

R ⁵ is hydrogen;

L ¹ is C ₁-C₄ alkylene, -N (methyl) -or-O-;

r ³ is-L ²-R^3-1;

L ² is-O-, -N (methyl) -or C ₁-C₄ alkylene;

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

X ² is N;

each R ^4-3 is independently C ₁-C₃ cyanoalkyl or-N (R ^N1)₂;

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

Scheme 4:

R ⁴ is bound by carbon or nitrogen atoms

R ⁵ is halogen or C ₁-C₃ alkyl;

scheme 5:

Is that

Wherein n is 1, 2, 3 or 4, each R ^1-1 is independently halogen, cyano, ethynyl or C ₁-C₄ alkyl; r ⁴ is bound by carbon or nitrogen atoms

R ⁵ is halogen or C ₁-C₃ alkyl;

scheme 6:

Is that

R ⁵ is halogen or C ₁-C₃ alkyl;

scheme 7:

Is that

R ⁵ is halogen or C ₁-C₃ alkyl;

scheme 8:

Is that

R ⁵ is halogen or C ₁-C₃ alkyl;

Scheme 9:

Is that

R ⁵ is halogen or C ₁-C₃ alkyl;

Scheme 10:

Is that

R ⁵ is halogen or C ₁-C₃ alkyl;

Scheme 11:

Is that

R ⁵ is halogen or C ₁-C₃ alkyl;

Scheme 12:

Is that

R ⁵ is halogen or C ₁-C₃ alkyl;

Scheme 13:

Is that

R ⁵ is halogen or C ₁-C₃ alkyl;

Scheme 14:

Is that

Wherein R ⁴ is bound by a carbon or nitrogen atom

Scheme 15:

Is that

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

R ⁴ is bound by carbon or nitrogen atoms

Scheme 16:

Is that

Wherein,

R ⁴ is C ₄-C₇ cycloalkyl substituted with 1R ^4-1; r ^4-1 is-N (R ^N1)₂; each R ^N1 is independently hydrogen or C ₁-C₃ alkyl; R ⁴ is linked by a carbon or nitrogen atom

Scheme 17:

Is that

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

R ⁴ is bound by carbon or nitrogen atoms

Scheme 18:

Is that

Wherein,

Scheme 19:

Is that

Wherein Z ¹ is independently CH, C or N;

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

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl;

scheme 20:

Is that

Wherein Z ¹ is independently CH, C or N;

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

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl;

scheme 21:

Is that

Wherein,Is a single bond;

Z ¹ is independently CH, C or N;

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

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl;

Scheme 22:

Is that

Z ¹ is independently CH, C or N;

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

each R ^N1 is independently hydrogen or C ₁-C₃ alkyl;

R ^Z2 is hydrogen or methyl.

19. The nitrogen-containing heterocyclic compound of formula II, a pharmaceutically acceptable salt thereof, or a solvate thereof according to claims 15-18, wherein the nitrogen-containing heterocyclic compound of formula II satisfies one or more of the following conditions:

138 R ^X3, the halogen is F, cl, br or I;

139 R ⁵, the halogen is F, cl, br or I;

140 R ⁵, the C ₁-C₃ alkyl is methyl, ethyl, propyl or isopropyl;

141 R ¹, the C ₆-C₁₄ aryl is C ₆-C₁₀ aryl;

142 R ¹, the C ₆-C₁₄ aryl is monocyclic or bicyclic;

143 R ¹, each ring of the C ₆-C₁₄ aryl is aromatic;

144 R ¹, the 5-to 14-membered heteroaryl is a 9-to 10-membered heteroaryl;

145 R ¹, the 5-to 14-membered heteroaryl is monocyclic or bicyclic;

146 R ¹, each ring of the 5-to 14-membered heteroaryl is aromatic;

147 R ¹, the number of heteroatoms of the 5-to 14-membered heteroaryl is 1 or 2;

148 R ¹, the heteroatom in the 5-to 14-membered heteroaryl is N;

149 R ^1-1 and R ^1-2, said halogen being F, cl, br or I;

150 R ^1-1 and R ^1-2, said C ₁-C₄ alkyl is methyl, ethyl, propyl or isopropyl;

151 R ^1-1 and R ^1-2, said-S-C ₁-C₃ alkyl is-S-methyl, -S-ethyl, -S-propyl or-S-isopropyl;

152 R ^1-1 and R ^1-2, said C ₂-C₄ alkynyl is ethynyl;

153 R ^1-1 and R ^1-2, said C ₁-C₃ haloalkyl is-CF ₃;

154 R ^1-1 and R ^1-2, said-O-C ₁-C₃ haloalkyl is-O-CF ₃;

155 R ^1-1 and R ^1-2, said C ₁-C₃ alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy;

156 R ^1-1 and R ^1-2, said C ₃-C₆ cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl;

157 L ¹, the C ₁-C₄ alkylene is methylene, ethylene, propylene or butylene;

158 R ³, the 3-to 12-membered heterocycloalkyl is a 3-to 6-membered heterocycloalkyl;

159 R ³, the 3-to 12-membered heterocycloalkyl is a single ring or a double ring; preferably, a single ring, spiro ring or bridged ring;

160 R ³, the 3-to 12-membered heterocycloalkyl having 1 or 2 heteroatoms;

161 R ³, the heteroatom in the 3-to 12-membered heterocycloalkyl is N;

162 L ², the C ₁-C₄ alkylene is methylene, ethylene, propylene or butylene;

163 R ^3-1 is linked to L ² via a carbon or nitrogen atom;

164 R ^3-1, the C ₃-C₁₂ cycloalkyl is C ₃-C₈ cycloalkyl;

165 R ^3-1, the C ₃-C₁₂ cycloalkyl is monocyclic or bicyclic;

166 R ^3-1, the 3-to 12-membered heterocycloalkyl is a 5-to 10-membered heterocycloalkyl;

167 R ^3-1, the 3-to 12-membered heterocycloalkyl is a single ring or a double ring; preferably, a single ring, spiro ring or bridged ring;

168 R ^3-1, the 3-to 12-membered heterocycloalkyl having 1 or 2 heteroatoms;

169 R ^3-1, the heteroatom in the 3-to 12-membered heterocycloalkyl is N;

170 R ^3-1, the 5-to 14-membered heteroaryl is a 5-to 6-membered heteroaryl;

171 R ^3-1, the 5-to 14-membered heteroaryl is monocyclic or bicyclic;

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

173 R ^3-1, the heteroatom in the 5-to 14-membered heteroaryl is N;

174 R ^3-1-1、R^3-1-2、R^3-1-3 and R ^3-1-4, halogen is F, cl, br or I;

175 R ^3-1-1、R^3-1-2、R^3-1-3 and R ^3-1-4, C ₁-C₄ alkyl is methyl, ethyl, propyl or isopropyl;

176 R ^X2, halogen is F, cl, br or I;

177 R ⁴ is bound via a carbon atom or a nitrogen atom

178 R ⁴, the C ₃-C₇ cycloalkyl is monocyclic or bicyclic; preferably, a single ring, spiro ring or bridged ring;

179 R ⁴, the C ₃-C₇ cycloalkenyl is mono-or bi-cyclic; preferably, a single ring, spiro ring or bridged ring;

180 R ⁴, the 3-to 12-membered nitrogen-containing heterocycloalkyl is a 5-to 9-membered nitrogen-containing heterocycloalkyl;

181 R ⁴, the 3-to 12-membered nitrogen-containing heterocycloalkyl is a single ring or a double ring; preferably, a single ring, spiro ring or bridged ring;

182 R ⁴, the 3-to 12-membered nitrogen-containing heterocycloalkyl having 1 or 2 heteroatoms;

183 In R ⁴, the heteroatom in the 3-to 12-membered nitrogen-containing heterocycloalkyl is N;

184 R ⁴, the 3-to 12-membered nitrogen-containing heterocycloalkenyl is a 5-to 9-membered nitrogen-containing heterocycloalkenyl;

185 R ⁴, the 3-to 12-membered nitrogen-containing heterocycloalkenyl is monocyclic or bicyclic; preferably, a single ring, spiro ring or bridged ring;

186 R ⁴, the 3-to 12-membered nitrogen-containing heterocycloalkenyl has 1 or 2 heteroatoms;

187 R ⁴, the heteroatom in the 3-to 12-membered nitrogen-containing heterocycloalkenyl is N;

188 R ^4-1、R^4-2、R^4-3 and R ^4-4, said halogen being F, cl, br or I;

189 R4 ^-1、R^4-2、R^4-3 and R ^4-4, said C ₁-C₃ alkyl is methyl, ethyl, propyl or isopropyl;

190 R ^4-1、R^4-2、R^4-3 and R ^4-4, said C ₁-C₃ cyanoalkyl group is cyanomethyl;

191 R ^4-1、R^4-2、R^4-3 and R ^4-4, said C ₃-C₆ cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl;

192 R ^4-1、R^4-2、R^4-3 and R ^4-4, said C ₁-C₃ alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy;

193 R ^N1, the C ₁-C₃ alkyl is methyl, ethyl, propyl or isopropyl;

194 "NH" on ring A is not attached to R ^Z1;

195 In ring B), the C ₃-C₇ cycloalkyl is monocyclic or bicyclic; preferably, a single ring, spiro ring or bridged ring;

196 In the B ring, the C ₃-C₇ cycloalkenyl is a single ring or a double ring; preferably, a single ring, spiro ring or bridged ring;

197 In ring a and ring B, the 3-to 12-membered nitrogen-containing heterocycloalkyl is a 5-to 9-membered nitrogen-containing heterocycloalkyl;

198 Ring a and ring B, the 3-to 12-membered nitrogen-containing heterocycloalkyl being a single ring or a double ring; preferably, a single ring, spiro ring or bridged ring;

199 Ring a and ring B, the 3-to 12-membered nitrogen-containing heterocycloalkyl having 1 or 2 heteroatoms;

200 Ring a and ring B, the heteroatom in the 3-to 12-membered nitrogen-containing heterocycloalkyl being N;

201 Ring a and ring B, the 3-to 12-membered nitrogen-containing heterocycloalkenyl group is a 5-to 9-membered nitrogen-containing heterocycloalkenyl group;

202 Ring a and ring B, 3 to 12 membered nitrogen containing heterocycloalkenyl is monocyclic or bicyclic; preferably, a single ring, spiro ring or bridged ring;

203 Ring a and ring B, the 3-to 12-membered nitrogen-containing heterocycloalkenyl having 1 or 2 in number of heteroatoms;

204 Ring a and ring B, the heteroatom in the 3-to 12-membered nitrogen-containing heterocycloalkenyl is N;

205 R ^Z1, the halogen is F, cl, br or I;

206 R ^Z1, the C ₁-C₃ alkyl is methyl, ethyl, propyl or isopropyl;

207 R ^Z1, the C ₁-C₃ cyanoalkyl group is cyanomethyl;

208 R ^Z1, the C ₃-C₆ cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl;

209 R ^Z1, the C ₁-C₃ alkoxy group is methoxy, ethoxy, n-propoxy or isopropoxy;

210 R ^N1, the C ₁-C₃ alkyl is methyl, ethyl, propyl or isopropyl;

211 "plurality" in the above definition is independently 2,3,4 or 5.

20. The nitrogen-containing heterocyclic compound of formula II, a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 19, wherein the nitrogen-containing heterocyclic compound of formula II satisfies one or more of the following conditions:

212 In R ^X3, halogen is F;

213 In R ⁵, halogen is F;

214 In R ⁵, C ₁-C₃ alkyl is methyl;

215 R ¹, C ₆-C₁₄ aryl is phenyl, 1-naphthyl, 2-naphthyl or

216 In R ¹, 5 to 14 membered heteroaryl is

217 R ^1-1 and R ^1-2, halogen is F or Cl;

218 R ^1-1 and R ^1-2, C ₁-C₄ alkyl is methyl;

219 R ^1-1 and R ^1-2, -S-C ₁-C₃ alkyl is-S-methyl;

220 R ^1-1 and R ^1-2, C ₁-C₃ alkoxy is methoxy;

221 R ^1-1 and R ^1-2, C ₃-C₆ cycloalkyl is cyclopropyl;

222 R ³, 3-to 12-membered heterocycloalkyl is 1-azetidinyl;

223 In L ², C ₁-C₄ alkylene;

224 R ^3-1 is linked to L ² via a nitrogen atom;

225 In R ^3-1, C ₃-C₁₂ cycloalkyl is C ₅-C₈ cycloalkyl;

226 In R ^3-1, C ₃-C₁₂ cycloalkyl is a monocyclic ring, a spiro ring or a bridged ring;

227 In R ^3-1, 3-to 12-membered heterocycloalkyl is 7-to 10-membered bridged heterocycloalkyl;

228 In R ^3-1, 5 to 14 membered heteroaryl is pyrazolyl;

229 R ^3-1-1、R^3-1-2、R^3-1-3 and R ^3-1-4, halogen is F;

230 R ^3-1-1、R^3-1-2、R^3-1-3 and R ^3-1-4C₁-C₄ alkyl are methyl;

231 In R ^X2, halogen is F;

232 In R ⁴, C ₃-C₇ cycloalkyl is Cyclopropyl, cyclopentyl or cyclohexyl;

233 In R ⁴, C ₃-C₇ cycloalkenyl is cyclopropenyl, cyclopentenyl or cyclohexenyl;

234 In R ⁴, 3-to 12-membered nitrogen-containing heterocycloalkyl is tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl

235 R ⁴, wherein 3 to 12 membered nitrogen-containing heterocycloalkenyl is 3 to 12 membered nitrogen-containing heterocycloalkenyl

236 R ^4-1、R^4-2、R^4-3 and R ^4-4, halogen is F;

237 R ^4-1、R^4-2、R^4-3 and R ^4-4, C ₁-C₃ alkyl is methyl;

238 R ^4-1、R^4-2、R^4-3 and R ^4-4C₃-C₆ cycloalkyl are cyclopropyl;

239 R ^4-1、R^4-2、R^4-3 and R ^4-4, C1-C3 alkoxy is methoxy;

240 In ring B, C ₃-C₇ cycloalkyl is Cyclopropyl, cyclopentyl or cyclohexyl;

241 In ring B, C ₃-C₇ 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, 3-to 12-membered nitrogen-containing heterocycloalkenyl is 3-to 12-membered nitrogen-containing heterocycloalkenyl

244 In R ^Z1, halogen is F;

245 In R ^Z1, C ₁-C₃ alkyl is methyl;

246 In R ^Z1, C ₃-C₆ cycloalkyl is cyclopropyl;

247 In R ^Z1, C ₁-C₃ alkoxy is methoxy;

248 In R ^N1, C ₁-C₃ alkyl is methyl.

21. The nitrogen-containing heterocyclic compound of formula II, a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 20, wherein the nitrogen-containing heterocyclic compound of formula II satisfies one or more of the following conditions:

249 R1 is

250 -L ¹-R³ is

251 R ⁴ is

22. The nitrogen-containing heterocyclic compound of formula II, a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 15, wherein the nitrogen-containing heterocyclic compound of formula II is selected from the group consisting of:

23. A pharmaceutical composition comprising a substance Y which is a nitrogen-containing heterocyclic compound of formula II as described in claims 15-22, a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutically acceptable excipient.

24. Use of substance Y in the preparation of KRAS-G12D inhibitors; the substance Y is a nitrogen-containing heterocyclic compound shown in the formula II, a pharmaceutically acceptable salt or a solvate thereof, which are shown in the claims 15-22;

preferably, the KRAS-G12D inhibitor is used in vitro or in vivo.

25. Use of a substance Y in the preparation of a medicament;

The substance Y is a nitrogen-containing heterocyclic compound shown in the formula II, a pharmaceutically acceptable salt or a solvate thereof, which are shown in the claims 15-22;

Preferably, the KRAS-G12D related disease or disorder is cancer.

26. Use of a substance Y in the preparation of a medicament;

the medicine can be used for treating or preventing cancer.

27. A method for preventing and/or treating a KRAS-G12D-related disease or disorder comprising administering to a subject in need thereof a therapeutically effective amount of substance Y;

Preferably, the KRAS-G12D related disease or disorder is cancer.

28. A method for preventing and/or treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of substance Y;

substance Y is a nitrogen-containing heterocyclic compound represented by formula II, a pharmaceutically acceptable salt thereof, or a solvate thereof as claimed in claims 15 to 22.