WO2024067575A1

WO2024067575A1 - Nitrogen-containing polycyclic compound, and pharmaceutical composition and use thereof

Info

Publication number: WO2024067575A1
Application number: PCT/CN2023/121507
Authority: WO
Inventors: 许祖盛; 楼杨通; 谢铁刚; 申健; 孙庆瑞; 曾坤; 金鑫
Original assignee: 上海璎黎药业有限公司
Priority date: 2022-09-27
Filing date: 2023-09-26
Publication date: 2024-04-04
Also published as: CN117777164A

Abstract

Disclosed are a nitrogen-containing polycyclic compound, and a pharmaceutical composition and use thereof. The nitrogen-containing polycyclic compound of the present invention is a nitrogen-containing polycyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotope compound thereof. The nitrogen-containing polycyclic compound of the present invention is expected to be used for treating and/or preventing various diseases related to Ras.

Description

A nitrogen-containing polycyclic compound, its pharmaceutical composition and application

This application claims the priority of Chinese patent application No. 202211179107.8, filed on September 27, 2022. This application cites the entire text of the above Chinese patent application.

Technical Field

The invention relates to a nitrogen-containing polycyclic compound, a pharmaceutical composition and application thereof.

Background technique

Ras (Rat sarcoma viral oncogene, murine sarcoma viral oncogene) was first discovered in rat sarcoma. The mammalian ras gene family has three members, namely H-ras (HRAS), K-ras (KRAS), and N-ras (NRAS). The fourth exon of K-ras has two variants, A and B. Ras genes are widely present in various eukaryotic organisms such as mammals, fruit flies, fungi, nematodes and yeast, and their expression levels vary in different tissues. H-Ras is mainly expressed in the skin and skeletal muscle, K-Ras is mainly expressed in the colon and thymus, and N-Ras is highly expressed in the testis. Ras protein acts as a molecular switch in the process of cell signal transduction. It regulates signal transduction by switching with GTP/GDP, thereby regulating life processes such as cell proliferation, differentiation, aging and apoptosis.

RAS mutations are closely related to the occurrence and development of human tumors, and Ras mutations exist in about 30% of human tumors. KRAS mutations are the most common, accounting for about 85%, while NRAS and HRAS account for 12% and 3%, respectively. Among them, KRAS mutations are mostly found in pancreatic cancer, colorectal cancer, and lung cancer, NRAS mutations are more common in melanoma and acute myeloid leukemia, and HRAS mutations are more common in bladder cancer and head and neck cancer. Ras oncogene mutations are mainly carried out through point mutations. More than 150 different Ras point mutations have been found, among which mutations at glycine positions 12 and 13 and glutamine 61 are the most common.

For decades, people have been committed to the development of small molecule inhibitors that directly target RAS. Scientists have always hoped to develop GTP-competitive inhibitors that act directly on RAS proteins. However, due to the extremely strong affinity between GTP and RAS (pmol/L level), the high GTP concentration in cells (0.5mM), and the lack of pockets in the RAS protein structure that are conducive to small molecule binding, they have not been successful. In recent years, people have made some progress in drug development using the allosteric sites of the KRAS ^G12C mutant. In 2013, a research team reported the discovery of KRAS ^G12C small molecule inhibitors (Nature, 2013, 503, 548-551). They identified a new binding pocket located below the molecular switch II region from the KRAS ^G12C mutant. These inhibitors bind to this allosteric pocket and form a covalent bond with the nearby cysteine Cys12, thereby selectively inhibiting the activation of KRAS ^G12C . Other researchers have reported cell-active KRAS ^G12C inhibitors (Science, 2016, 351, 604-608).

As one of the most important cancer-driving genes, the G12C mutation of KRAS provides the possibility for the design of irreversible covalent small molecule drugs. After the breakthrough in related scientific research, the research and development of corresponding drugs immediately became a hot spot for the development of new anti-tumor drugs worldwide. In May 2021, Amgen's KRAS G12C inhibitor Lumakras received accelerated approval from the US FDA, achieving a major breakthrough in the "undruggability" of KRAS.

Although major breakthroughs have been made in the research of KRAS G12C inhibitors, current clinical studies of KRAS G12C inhibitors have shown that they are not effective for a long time and are prone to drug resistance. At the same time, many other mutations, including cancers carrying KRAS G12D, G12V, G13D, G12R, G12S, G12A mutations, and KRAS wild-type amplification, lack effective drugs. Therefore, there is an urgent need for Searching for drugs that target KRAS mutations.

In short, after decades of unremitting efforts, people have gradually deepened their understanding of Ras. To date, drugs targeting the KRAS G12C mutation have been launched on the market. There are no particularly effective treatments for other different mutations. Finding compounds with better inhibitory effects on Ras is still a research hotspot and difficulty in the field of new drug development.

Summary of the invention

The technical problem to be solved by the present invention is the lack of effective drugs in the prior art as Ras inhibitors for clinical treatment. To this end, the present invention provides a nitrogen-containing polycyclic compound, a preparation method and application thereof. The nitrogen-containing polycyclic compound is expected to be used to treat and/or prevent various diseases related to Ras.

The present invention solves the above technical problems through the following technical solutions.

The present invention provides a nitrogen-containing polycyclic compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof:

in, represents a single bond or a double bond;

A is -O-, -S- or -NR-, R is hydrogen or C _1-6 alkyl;

s and p are independently 0, 1 or 2;

q is 0 or 1;

m is 0, 1 or 2;

^R2 is -CN, _C1-6 alkyl, _C2-6 alkenyl, C2-6 alkynyl, _C1-6 alkyl substituted by one or _more ^R2-1 , halogen, ^-OR2a , -C(=O) ^R2b , ^-NR2c1R2c2 , -C(=O) ^OR2d , -C(=O) ^NR2e1R2e2 , ^C3-10 ^cycloalkyl , _C3-10 cycloalkyl substituted by one or more ^R2-2 , " _4-10 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O and N", "4-10 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O and N" substituted by one or more ^R2-3 , C6-20 aryl, _C6-20 aryl substituted by one or more ^R2-4 _6-20 aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", or "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N" substituted by one or more R ^2-5 ; when there are multiple substituents, they may be the same or different;

R ^2-1 , R ^2-2 , R ^2-3 , R ^2-4 and R ^2-5 are independently halogen, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl-O-, -C(═O)R ³¹ , -NR ³² R ³³ , -C(═O)OR ³⁴ , or -C(═O)NR ³⁵ R ³⁶ ;

R ^2a , R ^2b , R ^2c1 , R ^2c2 , R ^2d , R ^2e1 and R ^2e2 are independently hydrogen or C _1-6 alkyl;

R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently hydrogen or C _1-6 alkyl;

n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

R ⁴ is independently halogen, cyano, hydroxy, C 1-6 alkyl, C _1-6 alkyl substituted by one or more R ^4-1 , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl-O-, C _1-6 alkyl-O- substituted _by one or more R ^4-2 , C _1-6 alkyl-S-, C _1-6 alkyl-S- substituted by one or more R ^4-3 _, O=, -C(=O)R ^4a , -NR ^4b1 R ^4b2 , -C(=O)OR ^4c or -C(=O)NR ^4d1 R ^4d2 ; or, when n is 2, 3, 4, 5, 6, 7 or 8, any two R ⁴ , independently together with the atoms in the ring to which they are connected, form a 3-8 membered carbocyclic ring, a 4-8 membered unsaturated carbocyclic ring containing one double bond, or a 4-8 membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N;

R ^4-1 , R ^4-2 and R ^4-3 are independently halogen, cyano, hydroxy, C _1-6 alkyl-O-, -NR ⁴ⁱ R ^4j , -C(=O)OR ^4e or -C(=O)NR ^4f1 R ^4f2 ;

R ^4a , R ^4b1 , R ^4b2 , R ^4c , R ^4d1 , R ^4d2 , R ^4e , R ^4f1 , R ^4f2 , R ⁴ⁱ and R ^4j are independently hydrogen or C _1-6 alkyl;

is phenyl, "a 5-7 membered heterocycloalkenyl group containing 1 to 3 heteroatoms which are selected from O, S and N", "a 5-7 membered heteroaryl group containing 1 to 3 heteroatoms which are independently selected from O, S and N" or a 5-7 membered cycloalkenyl group; wherein ^D1 is C, CH or N; _D2 is wherein Z ₁ and Z ₂ are independently a linker, CH, CH ₂ , O, S, N or NH;

r is 0, 1, 2, 3, or 4;

R ⁵ is independently halogen or C _1-6 alkyl;

^X1 and ^X2 are independently ^CRb or N, and ^X1 and ^X2 are not ^CRb at the same time;

R ¹ is C _6-20 aryl, "5-12 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N", C _6-20 aryl substituted by one or more R ^1-1 , or "5-12 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N" substituted by one or more R ^1-2 ; when there are multiple substituents, they may be the same or different;

R ^b , R ^1-1 and R ^1-2 are independently halogen, -OR ^c , cyano, azido, -C(=O)R ¹¹ , -NR ¹² R ¹³ , -C(=O)OR ¹⁴ , -C(=O)NR ¹⁵ R ¹⁶ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, “5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O and N”, C _6-20 aryl, “5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O and N”, C _1-6 alkyl substituted by one or more R ^1-1-1 , C _1-6 alkyl-O- substituted by one or more R ^1-1-2 , C _3-10 cycloalkyl substituted by one or more R ^1-1-3 , "5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O and N" substituted by one or more R ^1-1-4 , C _6-20 aryl substituted by one or more R ^1-1-5 , or "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O and N" substituted by one or more R ^1-1-6 ; when there are multiple substituents, they are the same or different; or, when there are multiple R ^1-1 or R ^1-2 , any two R ^1-1 or two R ^1-2 are connected to independently form a 3-8 membered cycloolefin together with the atoms in the ring to which they are connected;

R ^c , R ¹² and R ¹³ are independently hydrogen, C _1-6 alkyl, C _1-6 alkyl substituted by one or more -OC _1-6 alkyl, C(═O)R ^c1 , -C(═O)OR ^c2 , -C(═O)NR ^c3 R ^c4 or -SO ₂ R ^c5 ; R ^c1 , R ^c2 , R ^c3 , R ^c4 and R ^c5 are independently hydrogen, C _1-6 alkyl, C _3-10 cycloalkyl, “5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms which are independently selected from O and N”, C _6-20 aryl, “5-7 membered heteroaryl containing 1 or 2 heteroatoms which are independently selected from O and N”, C _1-6 alkyl substituted by one or more R ^4-1-1 , C _3-10 cycloalkyl substituted by one or more R ^4-1-2 , "5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O and N" substituted by one or more R ^4-1-3 , C _6-20 aryl substituted by one or more R ^4-1-4 , or "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O and N" substituted by one or more R ^4-1-5 ; when there are multiple substituents, they may be the same or different same;

R ^1-1-1 , R ^1-1-2 , R ^1-1-3 , R ^1-1-4 , R ^1-1-5 , R ^1-1-6 , R ^4-1-1 , R ^{4-1-2 , R 4-1-3} ^, R ^4-1-4 and R ^4-1-5 are independently cyano, halogen, hydroxyl, C _1-6 alkyl-O-, C _1-6 alkyl, -C(＝O)R ²¹ , -NR ²² R ²³ , -C(＝O)OR ²⁴ , or -C(＝O)NR ²⁵ R ²⁶ ;

R ¹¹ , R ²¹ , R ²² , R ²³ , R ¹⁴ , R ²⁴ , R ¹⁵ , R ²⁵ , R ¹⁶ and R ²⁶ are independently hydrogen or C _1-6 alkyl;

_L1 is a linking bond, _C1-6 alkylene, -C(＝O)-, -O(R ^L-1 ) _n1 -, -S(R ^L-2 ) _n2 - or -NR ^L-3 (R ^L-4 ) _n3 -; R ^L-1 , R ^L-2 and R ^L-4 are independently _C1-6 alkylene; R ^L-3 is hydrogen or _C1-6 alkyl; n1, n2 and n3 are independently 0 or 1;

R ³ is C _3-12 cycloalkyl, C _3-12 cycloalkyl substituted by one or more R ^3-1 , "4-12 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N", "4-12 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N" substituted by one or more R ^3-2 , C _1-6 alkyl, C _1-6 alkyl substituted by one or more R ^3-3 , -OR ^d , -SR ^d1 , -NR ^e1 R ^e2 , or -C(＝O)NR ^e3 R ^e4 ; when there are multiple substituents, they may be the same or different;

R ^3-1 , R ^3-2 and R ^3-3 are independently C _1-6 alkyl, C _1-6 alkyl substituted by one or more R ^3-1-1 , hydroxy, azido, C _1-6 alkyl-O-, halogen, O=, -NR ^e5 R ^e6 , -C(=O)NR ^e7 R ^e8 or

R ^d , R ^d1 , ^Re1 , ^Re2 , ^Re3 and ^Re4 are independently hydrogen, C _1-6 alkyl, C _3-10 cycloalkyl, "4-10 membered heterocycloalkyl containing 1 to 3 heteroatoms which are independently selected from O and N", or C _1-6 alkyl substituted by one or more R ^3-1-2 ;

R ^3-1-1 and R ^3-1-2 are independently deuterium, cyano, halogen, hydroxyl, C _1-6 alkyl-O-, -C(═O)R ^e9 , -NR ^e10 R ^e11 , -C(═O)OR ^e12 , or -C(═O)NR ^e13 R ^e14 ;

^Re5 , ^Re6 , ^Re7 , Re8, ^Re9 , ^Re10 , ^Re11 , ^Re12 , ^Re13 and ^Re14 are independently hydrogen or _C1-6 alkyl; or, ^Re5 and ^Re6 , ^Re7 and ^Re8 , ^Re10 and ^Re11 , ^Re13 and ^Re14 respectively form with the N atom to which they are connected “a 4-12 membered heterocycloalkyl group containing 1 to 3 ^heteroatoms , one of which is N, and the other heteroatoms are independently selected from O, S and N”;

R ^e15 and R ^e16 are independently hydrogen or halogen;

^R6 is hydrogen, _C1-6 alkyl, _C3-10 cycloalkyl, "5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O and N", _C6-20 aryl, "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O and N", _C1-6 alkyl substituted by one or more ^R6-1 , _C3-10 cycloalkyl substituted by one or more ^R6-2 , "5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O and N" substituted by one or more ^R6-3 , _C6-20 aryl substituted by one or more ^R6-4 , or "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O and N" substituted by one or more ^R6-5 ; when there are multiple substituents, they may be the same or different;

Alternatively, ^R2 and ^R6 together with the atoms in the ring to which they are connected form a "4-8 membered heterocyclic ring containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N", or a "4-8 membered heterocyclic ring containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N" substituted by one or more ^R6-6 ;

R ^6-1 , R ^6-2 , R ^6-3 , R ^6-4 , R ^6-5 and R ^6-6 are independently cyano, halogen, hydroxyl, C _1-6 alkyl-O-, C _1-6 alkyl, -C(═O)R ⁶¹ , -NR ⁶² R ⁶³ , -C(═O)OR ⁶⁴ , or -C(═O)NR ⁶⁵ R ⁶⁶ ;

R ⁶¹ , R ⁶² , R ⁶³ , R ⁶⁴ , R ⁶⁵ and R ⁶⁶ are independently hydrogen or C _1-6 alkyl.

In a certain embodiment, the nitrogen-containing polycyclic compound as shown in Formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer In the isomers or isotopic compounds thereof, the nitrogen-containing polycyclic compound as shown in Formula I is defined as Scheme 1, Scheme 2 or Scheme 3:

Option One:

represents a single bond or a double bond;

A is O;

s is 0;

q is 0 or 1;

p is 0 or 1;

m is 0 or 1;

n is 0;

is phenyl, "a 5-7 membered heterocycloalkenyl group containing 1 to 3 heteroatoms selected from O, S and N" or "a 5-7 membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S and N"; wherein ^D1 is C or N; _D2 is Wherein Z ₁ and Z ₂ are independently a linker, CH, CH ₂ or N;

r is 0, 1, or 2;

R ⁵ is independently halogen;

^X1 and ^X2 are independently N;

R ¹ is a C _6-20 aryl group substituted by one or more R ^1-1 , or a 5-12-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S and N substituted by one or more R ^1-2 ; when there are multiple substituents, they may be the same or different;

R ^1-1 and R ^1-2 are independently halogen, -OR ^c , cyano, azido, -NR ¹² R ¹³ , C _1-6 alkyl, C _2-6 alkynyl, or C _1-6 alkyl substituted by one or more R ^1-1-1 ; when there are multiple substituents, they may be the same or different;

R ^c , R ¹² and R ¹³ are independently hydrogen, C _1-6 alkyl substituted by one or more -OC _1-6 alkyl, C(═O)R ^c1 , -C(═O)OR ^c2 or -C(═O)NR ^c3 R ^c4 ; R ^c1 , R ^c2 , R ^c3 and R ^c4 are independently hydrogen or C _1-6 alkyl;

R ^1-1-1 is independently halogen;

_L1 is -O(R ^L-1 ) _n1 -; R ^L-1 is C _1-6 alkylene; n1 is 1;

^R3 is a _C3-12 cycloalkyl substituted by one or more ^R3-1 , or a 4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N substituted by one or more ^R3-2 ; when there are multiple substituents, they may be the same or different;

R ^3-1 and R ^3-2 are independently C _1-6 alkyl, C _1-6 alkyl substituted by one or more R ^3-1-1 , halogen or CH ₂ ＝;

R ^3-1-1 is -NR ^e10 R ^e11 ;

R ^e10 and R ^e11 are independently C _1-6 alkyl; or, R ^e10 and R ^e11 and the N atom to which they are connected form a "4-12 membered heterocycloalkyl group containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N";

^R6 is _C1-6 alkyl;

Alternatively, ^R2 and ^R6 together with the atoms in the ring to which they are connected form a "4-8 membered heterocyclic ring containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N";

Option II:

represents a single bond or a double bond;

A is -O-, -S- or -NR-, R is hydrogen or C _1-6 alkyl;

s and p are independently 0, 1 or 2;

q is 0 or 1;

m is 0, 1 or 2;

n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

r is 0, 1, 2, 3, or 4;

R ⁵ is independently halogen or C _1-6 alkyl;

^R1 is a _C6-20 aryl group, a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S and N, or a C _6-20 aryl substituted by multiple R ^1-1 , or "5-12 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N" substituted by one or more R ^1-2 ; when there are multiple substituents, they may be the same or different;

R ^c , R ¹² and R ¹³ are independently hydrogen, C _1-6 alkyl, C(═O)R ^c1 , —C(═O)OR ^c2 , —C(═O)NR ^c3 R ^c4 or —SO ₂ R ^c5 ; R ^c1 , R ^c2 , R ^c3 , R ^c4 and R ^c5 are independently hydrogen, C _1-6 alkyl, C _3-10 cycloalkyl, “5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O and N”, C _6-20 aryl, “5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O and N”, C _1-6 alkyl substituted by one or more R ^4-1-1 , C _3-10 cycloalkyl substituted by one or more R ^4-1-2 , "5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O and N" substituted by R ^4-1-3 , C _6-20 aryl substituted by one or more R ^4-1-4 , or "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O and N" substituted by one or more R ^4-1-5 ; when there are multiple substituents, they may be the same or different;

R ^3-1 , R ^3-2 and R ^3-3 are independently C _1-6 alkyl, C _1-6 alkyl substituted by one or more R ^3-1-1 , hydroxy, azido, C _1-6 alkyl-O-, halogen, O=, CH ₂ =, -NR ^e5 R ^e6 or -C(=O)NR ^e7 R ^e8 ;

^Re5 , ^Re6 , ^Re7 , Re8, ^Re9 , ^Re10 , ^Re11 , ^Re12 , ^Re13 and ^Re14 are independently hydrogen or _C1-6 alkyl; or, ^Re5 and ^Re6 , ^Re7 and ^Re8 , ^Re10 and ^Re11 , ^Re13 and ^Re14 ^, respectively, with the nitrogen atom to which they are connected, form a "containing 1 to 3 heteroatoms, one of which is a heteroatom" "4- to 12-membered heterocycloalkyl" wherein the alkyl is N, and other heteroatoms are independently selected from O, S and N;

R ⁶¹ , R ⁶² , R ⁶³ , R ⁶⁴ , R ⁶⁵ and R ⁶⁶ are independently hydrogen or C _1-6 alkyl;

third solution:

represents a single bond or a double bond;

A is O;

s is 0;

q is 0 or 1;

p is 0 or 1;

m is 0 or 1;

n is 0;

is phenyl, "a 5-7 membered heterocycloalkenyl group containing 1 to 3 heteroatoms selected from O, S and N", or "a 5-7 membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S and N"; wherein ^D1 is C or N; _D2 is Wherein Z ₁ and Z ₂ are independently a linker, CH, CH ₂ or N;

r is 0, 1, or 2;

R ⁵ is independently halogen;

^X1 and ^X2 are independently N;

R ^c , R ¹² and R ¹³ are independently hydrogen, C(═O)R ^c1 or —C(═O)NR ^c3 R ^c4 ; R ^c1 , R ^c3 and R ^c4 are independently hydrogen or C _1-6 alkyl;

R ^1-1-1 is halogen;

_L1 is -O(R ^L-1 ) _n1 -; R ^L-1 is C _1-6 alkylene; n1 is 1;

R ^3-1-1 is -NR ^e10 R ^e11 ;

^R6 is _C1-6 alkyl;

Alternatively, ^R2 and ^R6 together with the atoms in the ring to which they are connected form a "4-8 membered heterocyclic ring containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N".

In one embodiment, A is -O-.

In one scheme, s is 0;

In one scheme, q is 0 or 1;

In one scheme, p is 0 or 1;

In one embodiment, m is 0 or 1.

In one scheme, n is 0;

In one plan, is phenyl, "a 5-7 membered heterocycloalkenyl group containing 1 to 3 heteroatoms which are selected from O, S and N" or "a 5-7 membered heteroaryl group containing 1 to 3 heteroatoms which are independently selected from O, S and N"; wherein ^D1 is C or N; _D2 is wherein Z ₁ and Z ₂ are independently a linker, CH, CH ₂ or N.

In one embodiment, r is 0, 1 or 2.

In one embodiment, R ⁵ is independently halogen.

In one embodiment, ^X1 and ^X2 are independently N.

In one embodiment, R ¹ is a C _6-20 aryl group substituted by one or more R ^1-1 or a " ^{5-12 membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S and N" substituted by one or more R 1-2} ; when there are multiple substituents, they may be the same or different;

R ^1-1-1 is independently halogen.

In one embodiment, R ¹ is C _6-20 aryl substituted by one or more R ^1-1 ; R ^1-1 is independently halogen, -OR ^c , azido, -NR ¹² R ¹³ , C _1-6 alkyl, C _2-6 alkynyl, or C _1-6 alkyl substituted by one or more R ^1-1-1 ; R ^c , R ¹² and R ¹³ are independently hydrogen, C _1-6 alkyl substituted by one or more -OC _1-6 alkyl, C(═O)R ^c1 or -C(═O)NR ^c3 R ^c4 ; R ^c1 , R ^c3 and R ^c4 are independently hydrogen or C _1-6 alkyl; R ^1-1-1 is independently halogen.

In a certain embodiment, R ¹ is a "5-12 membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S and N" substituted by one or more R ^1-2 ; R ^1-2 is independently halogen, cyano, -NR ¹² R ¹³ , C _1-6 alkyl or C _1-6 alkyl substituted by one or more R ^1-1-1 ; R ¹² and R ¹³ are independently hydrogen or -C(＝O)OR ^c2 ; R ^c2 is C _1-6 alkyl; R ^1-1-1 is independently halogen.

In one embodiment, _L1 is -O(R ^L-1 ) _n1 -; R ^L-1 is C _1-6 alkylene; and n1 is 1.

In one embodiment, R ³ is a C _3-12 cycloalkyl substituted by one or more R ^3-1 , or a "4-12 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N" substituted by one or more R ^3-2 ; when there are multiple substituents, they may be the same or different;

R ^3-1-1 is independently -NR ^e10 R ^e11 or "a 4- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S and N";

R ^e10 and R ^e11 are independently C _1-6 alkyl; or, together with the N atom to which they are connected, form a "4-12 membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S and N";

In one embodiment, R ⁶ is C _1-6 alkyl.

In one embodiment, ^R2 and ^R6 are connected to each other and independently form a "4-8 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N" together with the atoms in the ring to which they are connected.

In one scheme, when D ₂ is When _Z1 and _Z2 are independently a linking bond, CH, _CH2 or N, among _Z1 and _Z2 , _Z1 is a linking bond and _Z2 is CH, _CH2 or N.

In one embodiment, the C _1-6 alkyl group is independently C _1-4 alkyl group at each occurrence, and further is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

In one embodiment, when R ² is a C _2-6 alkenyl group, the C _2-6 alkenyl group is a vinyl group, a propenyl group or an allyl group.

In a certain embodiment, when R ² , R ^1-1 and R ^1-2 are independently C _2-6 alkynyl, the C _2-6 alkynyl is C _2-3 alkynyl, such as ethynyl, propynyl or propargyl.

In one embodiment, when R ² is a C _1-6 alkyl substituted by one or more R ^2-1 , the C _1-6 alkyl is a C _1-4 alkyl, further methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

In one embodiment, when R ² , R ⁴ , R ⁵ , R ^2-1 , R ^2-2 , R ^2-3 , R ^2-4 , R ^2-5 , R ^4-1 , R ^4-2 , R ^4-3 , R ^b , R ^1-1 , R ^1-2 , R ^1-1-1 , R ^1-1-2 , R ^1-1-3 , R ^1-1-4 , R ^1-1-5 , R ^1-1-6 , R ^4-1-1 , R ^4-1-2 , R ^4-1-3 , R ^4-1-4 and R ^4-1-5 , R ^3-1 , R ^3-2 and R ^3-3 , R ^3-1-1 , R ^3-1-2 , R ^6-1 ^{, R 6-2} ^, R ^6-3 When halogen is mentioned in the definitions of R ^6-4 , R ^6-5 , R ^6-6 , ^Re15 and ^Re16 , the halogen is fluorine, chlorine, bromine or iodine.

In a certain embodiment, when R ¹ is a C _6-20 aryl group or a C _6-20 aryl group substituted by one or more R ^1-1 , the C _6-20 aryl group is a phenyl group or a naphthyl group.

In a certain embodiment, when R ¹ is a "5-12-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S and N" substituted by one or more R ^1-2 , the "5-12-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S and N" is a "6-9-membered heteroaryl group containing 1 to 2 heteroatoms independently selected from O, S and N", further being a pyridyl group, a benzothiophene group or benzothiazolyl

In one embodiment, when R ^1-1 and R ^1-2 are independently C _1-6 alkyl or C _1-6 alkyl substituted by one or more R ^1-1-1 , the C _1-6 alkyl is C _1-4 alkyl, further methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

In one embodiment, when ^RL-1 is _C1-6 alkylene, the _C1-6 alkylene is _-CH2- _, -CH2CH2- _, _-CH2CH2CH2- _, _-CH (CH3 ₎ _CH2- _, _{-CH2CH2CH2CH2-} _, _-CH (CH3)CH2CH2- _, _-CH2CH ₍ _CH3 )CH2CH2-, _-CH2CH ( _CH3 ) _CH2- , or -C( _CH3 ) _2CH2- .

In one embodiment, when R ³ is a C _3-12 cycloalkyl substituted by one or more R ^3-1 , the C _3-12 cycloalkyl is _{a C 3-6} _cycloalkyl , such as cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl, and another example is cyclopropyl.

In a certain embodiment, when R ³ is a "4-12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S and N" substituted by one or more R ^3-2 , the "4-12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S and N" is a monocycloalkyl group, a spirocycloalkyl group or a bridged cycloalkyl group; for example,

In a certain embodiment, when ^Re10 and ^Re11 form a "4- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N" with the N atom to which they are connected, the "4- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N" is "an 8- to 10-membered heterocycloalkyl group containing 2 heteroatoms, one of which is N, and the other is O", and is further a bridged cycloalkyl group, for example,

In one scheme, when When it is a "5- to 7-membered heterocycloalkenyl group containing 1 to 3 heteroatoms selected from O, S and N", the "5- to 7-membered heterocycloalkenyl group containing 1 to 3 heteroatoms selected from O, S and N" is a 5- to 7-membered heterocycloalkenyl group containing 1 N atom (for example, ).

In one scheme, when When it is a "5- to 7-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S and N", the "5- to 7-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S and N" is a 5- to 7-membered heteroaryl group containing 1 N atom

In one embodiment, A is -O-, s is 0, q is 0 or 1, and p is 0 or 1.

In one embodiment, R ⁵ is independently chloro or fluoro.

In one embodiment, ^R1 is

In one embodiment, L ₁ is -OCH ₂ -.

In one embodiment, ^R3 is

In one embodiment, R ⁶ is -CH ₃ , or R ² and R ⁶ together with the atoms in the ring to which they are attached form a "5-membered heterocyclic ring containing 1 heteroatom N".

In one plan, for

In a certain embodiment, in the nitrogen-containing polycyclic compound as shown in Formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound, the nitrogen-containing polycyclic compound as shown in Formula I is any of the following compounds:

The present invention also provides a compound, the structure of which is shown below:

The present invention also provides a pharmaceutical composition, which comprises substance A and pharmaceutical excipients; the substance A is a therapeutically effective amount of the above-mentioned nitrogen-containing polycyclic compound as shown in Formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound.

The present invention also provides an application of a substance A in the preparation of a RAS inhibitor, wherein the substance A is the nitrogen-containing polycyclic compound shown in Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof.

In the application of the substance A in the preparation of RAS inhibitors, the RAS is wild-type RAS and mutant RAS; the mutant RAS is, for example, KRAS mutation, HRAS mutation or NRAS mutation, wherein the KRAS mutation may be G12, G13 or Q61 mutation, for example, KRAS G12C, KRAS G12D, KRAS G12S, KRAS G12A, KRAS G12V or KRAS G13D, and for example, KRAS G12C, KRAS G12 D or KRAS G12V; the HRAS mutation may be G12, G13 or Q61 mutation, such as HRAS G12C, HRAS G12D, HRAS G12S, HRAS G12A, HRAS G12V or HRAS G13D; the NRAS mutation may be G12, G13 or Q61 mutation, such as NRAS G12C, NRAS G12D, NRAS G12S, NRAS G12A, NRAS G12V or NRAS G13D.

The present invention also provides an application of a substance A in the preparation of a drug, wherein the drug is used to treat or prevent RAS-related diseases; the substance A is the nitrogen-containing polycyclic compound shown in Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotope compound thereof.

In the use of the substance A in the preparation of drugs, the RAS is a wild-type RAS and a mutant RAS; the mutant RAS is, for example, a KRAS mutation, a HRAS mutation or a NRAS mutation, wherein the KRAS mutation may be a G12, G13 or Q61 mutation, such as KRAS G12C, KRAS G12D, KRAS G12S, KRAS G12A, KRAS G12V or KRAS G13D, and for example, KRAS G12C, KRAS G12D or KRAS G12V; the HRAS mutation may be a G12, G13 or Q61 mutation, such as HRAS G12C, HRAS G12D, HRAS G12S, HRAS G12A, HRAS G12V or HRAS G13D; the NRAS mutation may be a G12, G13 or Q61 mutation, such as NRAS G12C, NRAS G12D, NRAS G12S, NRAS G12A、NRAS G12V or NRAS G13D.

In the application of the substance A in the preparation of medicines, the RAS-related diseases are, for example, cancers. The cancers are, for example, one or more of colon cancer, appendix cancer, pancreatic cancer, MYH-related polyposis, blood cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, gastric cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.

The present invention also provides a use of a substance A in the preparation of a drug, wherein the drug is used to treat or prevent cancer; the substance A is the nitrogen-containing polycyclic compound shown in the above formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound. The cancer is, for example, one or more of colon cancer, appendix cancer, pancreatic cancer, MYH-related polyposis, blood cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, gastric cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.

The present invention also provides a method for inhibiting RAS, which comprises administering an effective amount of substance A to a subject; the substance A is the nitrogen-containing polycyclic compound shown in formula I above, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound.

In the method for inhibiting RAS, the RAS is wild-type RAS and mutant RAS; the mutant RAS is, for example, KRAS mutation, HRAS mutation or NRAS mutation, wherein the KRAS mutation may be G12, G13 or Q61 mutation, such as KRAS G12C, KRAS G12D, KRAS G12S, KRAS G12A, KRAS G12V or KRAS G13D, and also such as KRAS G12C, KRAS G12D or KRAS AS G12V; the HRAS mutation may be G12, G13 or Q61 mutation, such as HRAS G12C, HRAS G12D, HRAS G12S, HRAS G12A, HRAS G12V or HRAS G13D; the NRAS mutation may be G12, G13 or Q61 mutation, such as NRAS G12C, NRAS G12D, NRAS G12S, NRAS G12A, NRAS G12V or NRAS G13D.

The present invention also provides a method for treating or preventing RAS-related diseases, comprising administering an effective amount of substance A to a subject; the substance A is the nitrogen-containing polycyclic compound shown in Formula I above, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof.

In the method for treating or preventing RAS-related diseases, the RAS is wild-type RAS and mutant RAS; the mutant RAS is, for example, KRAS mutation, HRAS mutation or NRAS mutation, wherein the KRAS mutation may be G12, G13 or Q61 mutation, for example, KRAS G12C, KRAS G12D, KRAS G12S, KRAS G12A, KRAS G12V or KRAS G13D, and for example, KRAS G12C, KRAS G12 D or KRAS G12V; the HRAS mutation may be G12, G13 or Q61 mutation, such as HRAS G12C, HRAS G12D, HRAS G12S, HRAS G12A, HRAS G12V or HRAS G13D; the NRAS mutation may be G12, G13 or Q61 mutation, such as NRAS G12C, NRAS G12D, NRAS G12S, NRAS G12A, NRAS G12V or NRAS G13D.

In the method for treating or preventing RAS-related diseases, the RAS-related diseases are, for example, cancers. The cancers are, for example, one or more of colon cancer, appendix cancer, pancreatic cancer, MYH-related polyposis, blood cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, gastric cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.

The term "plurality" refers to 2, 3, 4 or 5.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes an inorganic acid, and the inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acid includes organic acids, including but not limited to acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

The term "stereoisomer" refers to isomers caused by the same order of interconnection of atoms or atomic groups in a molecule but different spatial arrangements, such as cis-trans isomers, optical isomers or atropisomers, etc. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by chiral separation by bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds.

The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in two positions in a molecule. For example, acetone and 1-propene-2-ol can be interconverted by the rapid movement of hydrogen atoms on oxygen and α-carbon.

The term "isotopic compound" refers to a compound in which one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2H, 3H, 13C, 14C, 15N, 18O, 17O, 18F, 35S, and 36Cl). The isotopic compounds of the invention can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent according to the methods described herein.

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

The term "alkyl" refers to a straight or branched chain alkyl group having a specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

The term C _1-6 alkyl is preferably C _1-4 alkyl, further methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

The term "alkylene" refers to a linking group between two other groups, which may be straight or branched. Examples include _, but are not limited to, _-CH2- , _-CH2CH2- _, _-CH2CH2CH2CH ( _CH3 )-, _-CH2CH ₍ _CH2CH3 ) _CH2- _.

The term "alkoxy" refers to a group ^-ORX , wherein ^RX is alkyl as defined above.

The term "cycloalkyl" or "carbocycle" refers to a saturated ring having a specified number of carbon atoms (e.g., C _3-6 ) and consisting only of carbon atoms. Cycloalkyl includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The term "aryl" refers to an aromatic group consisting of carbon atoms, each ring having aromatic properties, such as phenyl or naphthyl.

The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic, and at least one ring is aromatic (in accordance with Huckel's rule). The heteroaryl group is connected to other fragments in the molecule through an aromatic ring or a non-aromatic ring. Heteroaryl includes, but is not limited to, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.

The term "heterocyclyl", "heterocycle" or "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 3 to 8 members), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified heteroatom type (one or more of N, O and S), which is a monocyclic, bridged or spirocyclic ring, and each ring is saturated. Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, etc.

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

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

The term "oxo" refers to a =0 group.

The “C _x1 -C _y1 ” substituents (x1 and y1 are integers) with a defined range of carbon numbers, such as “C _x1 -C _y1 ” alkyl, “C _x1 -C _y1 ” cycloalkyl, “C _x1 -C _y1 ” cycloalkenyl, “C _x1 -C _y1 ” alkoxy, “C _x1 -C _y1 ” alkenyl, “C _{x1 -C y1 ” alkynyl, “C x1} _-C _y1 _” aryl, “C _x1 -C _y1 ” heteroaryl or “C _x1 -C _y1 ” heterocyclyl, all represent the carbon number not including the substituents, for example, C ₁ -C ₆ alkyl represents a C ₁ -C ₆ alkyl not including substituents.

Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

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

The positive progressive effect of the present invention is that the present invention provides a nitrogen-containing polycyclic compound, a preparation method and application thereof, and the nitrogen-containing polycyclic compound has a better inhibitory effect on various disease cells with KRAS mutations, and is expected to treat and/or prevent various diseases related to Ras.

Detailed ways

The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples described. The experimental methods for which specific conditions are not specified in the following examples are carried out according to conventional methods and conditions, or are selected according to the product instructions. The solvents involved in the following examples are all analytically pure or chromatographically pure. When the solvents involved in the following examples are mixed solvents, unless otherwise specified, they are all volume ratios. Room temperature refers to ambient temperature, which is 10°C-35°C. Overnight refers to 8-15 hours. Reflux refers to the reflux temperature of the solvent under normal pressure.

The following is a list of abbreviations used in the examples:
DIPEA Diisopropylethylamine
TFA Trifluoroacetic acid
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DABCO 1,4-diazabicyclo[2.2.2]octane
Pd(dppf)Cl ₂ [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride
cataCXium A Pd G3 methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II)
Pd(PPh ₃ ) ₄ -Tetrakistriphenylphosphine Palladium
Pd ₂ (dba) ₃ -trisdibenzylideneacetone dipalladium
XPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
Xantphos 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene
TIPS Triisopropylsilyl
Tf trifluoromethanesulfonyl
THF Tetrahydrofuran
MeOH Methanol
MOM Methoxymethyl
PE Petroleum Ether
EA Ethyl acetate
DCM Dichloromethane
DMF N,N-Dimethylformamide
DMSO Dimethyl sulfoxide
Cbz benzyloxycarbonyl
NBS N-Bromosuccinimide
HATU 2-(7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate
DMAP 4-dimethylaminopyridine
Boc tert-Butyloxycarbonyl
Cbz benzyloxycarbonyl
SelectFluor II 1-Fluoro-4-methyl-1,4-diazabicyclo[2.2.2]octane tetrafluoroborate

Synthesis route of compound 1

Synthesis of compound 1-o

Add compound 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diphenol (1.10 g, 5.10 mmol), phosphorus oxychloride (11 mL), and N,N-diisopropylethylamine (4.2 mL) to the reaction flask. The mixture was replaced with N ₂ and stirred at 100°C for 1 hour. The reaction solution was cooled to room temperature and evaporated to dryness to obtain compound 1-o, which was directly used in the next step reaction.

Synthesis of compound 1-n

Under nitrogen conditions at room temperature, the compound dimethyl pyrazole-3,5-dicarboxylate (5.0g, 27.15mmoL) was dissolved in THF (100mL), and tert-butyl N-(3-hydroxypropyl)carbamate (5.0g, 28.51mmoL) and triphenylphosphine (14.24g, 54.30mmoL) were added in sequence. The mixture was cooled to 0°C, and diisopropyl azodicarboxylate (10.76mL, 54.30mmoL) was added dropwise. After the addition was completed, the reaction mixture was warmed to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by a rapid separation column (PE/EA=1:1) to obtain compound 1-n (crude product, 15g, yield 99% calculated based on purity 61%). LC-MS (ESI): m/z=342.1 (M+H) ⁺ .

Synthesis of compound 1-m

Compound 1-n (5.0 g, 8.94 mmol, purity 61%) was dissolved in DCM (5 mL) under nitrogen at room temperature, and a methanol solution of hydrogen chloride (30 mL) was added. The reaction mixture was stirred overnight under nitrogen at room temperature. The reaction solution was concentrated under reduced pressure to obtain compound 1-m (crude product, 2.5 g), which was used directly in the next step. LC-MS (ESI): m/z = 242.1 (M+H) ⁺ .

Synthesis of compound 1-1

Compound 1-m (2.5 g, 9.00 mmoL) was dissolved in methanol (50 mL) at room temperature, triethylamine (2.50 mL, 18.00 mmoL) was added, and the reaction mixture was stirred at 85 ° C overnight. The mixture was concentrated under reduced pressure, the crude product was diluted with saturated sodium bicarbonate solution (100 mL), and extracted with DCM (100 mL*5). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was suspended in ethyl acetate (10 mL) and stirred for 1 hour under ice-water bath conditions. The mixture was filtered, the solid was washed with ethyl acetate (5 mL), and the solid was collected. After vacuum drying for 1 hour, compound 1-1 (1.4 g, two-step yield 74%) was obtained. LC-MS (ESI): m/z = 210.1 (M+H) ⁺ .

Synthesis of compound 1-k

Compound 1-1 (1.38 g, 6.60 mmol), dry tetrahydrofuran (60 mL), and 1 M borane tetrahydrofuran solution (25 mL, 25 mmol) were added to the reaction flask, and the mixture was stirred overnight at 65°C under nitrogen. The next day, the reaction solution was cooled to room temperature, 60 mL of methanol was added, and the mixture was stirred at 80°C for 5 hours. The reaction solution was dried to obtain compound 1-k (crude product). LC-MS (ESI): m/z = 196.1 (M+H) ⁺ .

Synthesis of compound 1-j

Compound 1-k (crude product), dichloromethane (50 mL), DIPEA (3.48 mL, 19.98 mmol) were added to the reaction flask, and CbzCl (1.125 mL, 7.99 mmol) was added dropwise under ice bath. After addition, the mixture was stirred overnight under nitrogen at room temperature. The next day, saturated sodium bicarbonate solution was added to quench the reaction, and extracted with dichloromethane (50 mL*3). The organic phase was spin-dried and purified by column (mobile phase: ethyl acetate/petroleum ether 0/100 to 100/0) to obtain compound 1-j (1.5 g, two-step yield 68%). LC-MS (ESI): m/z=330.5 (M+H) ⁺ .

Synthesis of compound 1-i

Compound 1-j (1.5 g, 4.55 mmol), acetonitrile (30 mL), and NBS (1.2 g, 6.83 mmol) were added to the reaction flask, and the mixture was stirred at 60° C. for 1 hour. The reaction solution was spin-dried and purified by column chromatography (mobile phase: ethyl acetate/petroleum ether 0/100 to 100/0) to obtain compound 1-i (1.9 g, 100%).

Synthesis of compound 1-h

Compound 1-i (500 mg, 1.22 mmol), 1,4-dioxane (50 mL), water (5 mL), cesium carbonate (1.2 g, 3.69 mmol), Pd(dppf)Cl ₂ ^. CH ₂ Cl ₂ (100 mg, 0.12 mmol) were added to a three-necked flask. The mixture was replaced with nitrogen three times, and compound 2-ethoxyvinyl-1-boronic acid pinacol ester (485 mg, 2.449 mmol) was added through a syringe. The mixture was stirred at 100°C for 2 hours under nitrogen. The reaction solution was dried by spin drying and purified by column (mobile phase: ethyl acetate/petroleum ether 0/100 to 100/0) to obtain compound 1-h (312 mg, 64%). LC-MS (ESI): m/z=400.6 (M+H) ⁺ .

Synthesis of compound 1-g

Compound 1-h (300 mg, 0.75 mmol), tetrahydrofuran (6 mL), and 4 M hydrochloric acid 1,4-dioxane (1.8 mL, 7.51 mmol) were added to the reaction bottle, and the mixture was stirred at room temperature overnight under nitrogen. The next day, the reaction solution was dried by rotary evaporation, quenched by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate (30 mL*2). The organic phase was dried over anhydrous sodium sulfate and dried by rotary evaporation to obtain compound 1-g (crude product). LC-MS (ESI): m/z=372.1 (M+H) ⁺ .

Synthesis of compound 1-f

Compound 1-g (crude product), methanol (20 mL), methylamine hydrochloride (263 mg, 3.90 mmol), sodium acetate borohydride (662 mg, 3.12 mmol) were added to the reaction flask, and the mixture was stirred at room temperature overnight under nitrogen. The next day, the reaction solution was dried and purified by column (mobile phase: ammonia methanol/dichloromethane 0/100 to 10/90) to obtain compound 1-f (66 mg, two-step yield 23%). LC-MS (ESI): m/z = 387.5 (M+H) ⁺ .

Synthesis of compound 1-e

Compound 1-f (66 mg, 0.17 mmol), methanol (20 mL), and triethylamine (0.12 mL, 0.854 mmol) were added to the reaction flask, and the mixture was stirred at 100 ° C overnight in nitrogen. The next day, the reaction solution was dried and purified by column (mobile phase: methanol/dichloromethane 0/100 to 10/90) to obtain compound 1-e (40 mg, 67%). LC-MS (ESI): m/z = 355.6 (M+H) ⁺ .

Synthesis of compound 1-d

Compound 1-e (40 mg, 0.11 mmol), tetrahydrofuran (20 mL), 10% Pd/C (12 mg) were added to the reaction bottle, replaced with hydrogen three times, and stirred at room temperature overnight. The next day, the reaction solution was filtered and the filtrate was dried to obtain compound 1-d (25 mg, 100%). LC-MS (ESI): m/z = 221.1 (M+H) ⁺ .

Synthesis of compound 1-c

Compound 1-o (100 mg, 0.40 mmol), dichloromethane (20 mL), DIPEA (0.21 mL, 1.188 mmol) were added to the reaction bottle, and compound 1-d (87 mg, 0.39 mmol) was added under a dry ice acetone bath. The mixture was stirred at this temperature for 2 hours, quenched with water, extracted with dichloromethane (30 mL*3), dried over anhydrous sodium sulfate, and spin-dried to obtain compound 1-c (204 mg, 100%). LC-MS (ESI): m/z=436.0 (M+H) ⁺ .

Synthesis of compound 1-b

Compound 1-c (172 mg, 0.39 mmol), toluene (10 mL), dichloromethane (6 mL), (2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a (5H)-yl) methanol (94 mg, 0.59 mmol) were added to the reaction bottle, and sodium tert-butoxide (94 mg, 0.99 mmol) was added under ice bath. The mixture was stirred at room temperature for 2 hours under nitrogen, and the reaction solution was directly purified by column (mobile phase: methanol/dichloromethane 0/100 to 10/90) to obtain compound 1-b (156 mg, 71%). LC-MS (ESI): m/z = 559.6 (M + H) ⁺ .

Synthesis of compound 1-a

Compound 1-b (100 mg, 0.18 mmol), 1,4-dioxane (50 mL), water (5 mL), 2-(8-ethyl-7-fluoro-3-(methoxymethyloxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (97 mg, 0.268 mmol), potassium phosphate (114 mg, 0.54 mmol) and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (13 mg, 0.018 mmol) were added to the reaction bottle, nitrogen was replaced three times, and the mixture was placed in an oil bath preheated to 100°C and stirred for 3 hours. The reaction solution was spin-dried and purified by column (mobile phase: methanol/dichloromethane 0/100 to 10/90) to obtain compound 1-a (60 mg, 44%). LC-MS (ESI): m/z = 757.9 (M+H) ⁺ .

Synthesis of compound 1

Compound 1-a (60 mg, 0.079 mmol) and acetonitrile (10 mL) were added to the reaction bottle, and 4 M 1,4-dioxane hydrochloride (1 mL, 4 mmol) was added under ice bath. The mixture was stirred under ice bath for 1 hour, spin dried, purified by preparative HPLC (ammonium bicarbonate), and freeze dried to obtain compound 1 (30 mg, 53%). LC-MS (ESI): m/z = 713.2 (M+H) ⁺ ; ¹ H NMR (400M, CD ₃ OD): δ9.08 (1H, s), 7.70-7.63 (1H, m), 7.29 (1H, d, J = 2.4 Hz), 7.24 (1H, t, J = 9.6 Hz), 7.03 (1H, d, J = 2.8 Hz), 5.39-5.07 (3H, m), 4.62-4.53 (2H, m), 4.47-4.38 (2H, m), 4.33-4.20 (2H, m), 3.67 (2H, t, J = 6.8 Hz), 3.28-3.15 (3H, m), 3.08 (3H, s), 3.05-2.97 (3H, m), 2.52-1.82 (10H, m), 0.78 (3H, t, J = 7.2 Hz).

Synthesis route of compound 2

Synthesis of compound 2-e

4-Benzyloxy-2-methylsulfonyl-5,8-piperidin[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (840 mg, 2.00 mmol), toluene (30 mL), (2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (383 mg, 2.40 mmol), sodium tert-butoxide (289 mg, 3.00 mmol) were added to the reaction bottle, and the mixture was stirred at 0°C for 1 hour under nitrogen protection, and continued to stir at room temperature for 1 hour. The reaction solution was added to a silica gel column and purified by column chromatography (mobile phase: methanol/dichloromethane 1/30 to 1/10) to obtain compound 2-e (561 mg, 56%). LC-MS (ESI): m/z 499.8 (M+H) ⁺ .

Synthesis of compound 2-d

Add 2-e (560 mg, 1.12 mmol), toluene (6 mL), trifluoroacetic acid (0.86 mL, 11.23 mmol) to the reaction flask and protect with nitrogen. Stir the mixture at room temperature for 2 hours, add sodium hydroxide aqueous solution (2M, about 10 mL) to the reaction flask, and adjust the pH to 9.5-10. Extract with EA (10 mL*3) and concentrate. Purify by reverse phase column under alkaline conditions to obtain compound 2-d (371 mg, 83%). LC-MS (ESI): m/z 399.7 (M+H) ⁺ .

Synthesis of compound 2-c

2-d (600 mg, 1.51 mmol), toluene (60 mL), 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthol trifluoromethanesulfonate 748 mg, 1.96 mmol), cesium carbonate (1472 mg, 4.52 mmol), xantphos (174 mg, 0.30 mmol) were added to the reaction flask. The mixture was stirred at room temperature for 20 minutes under nitrogen protection, Pd ₂ (dba) ₃ (138 mg, 0.15 mmol) was added to the reaction solution, and stirring was continued at 110°C for 3 hours under nitrogen protection. The reaction solution was added to a silica gel column and purified by column chromatography (mobile phase: methanol/dichloromethane 1/30 to 1/10) to obtain compound 2-c (76 mg, 8%). LC-MS (ESI): m/z 631.8 (M+H) ⁺ .

Synthesis of compound 2-b

Add 2-c (86 mg, 0.14 mmol), methanol (10 mL), Pd/C (30 mg, content 10%) to the reaction bottle, replace the mixture with hydrogen (1000 mL), and stir at room temperature for 8 hours. The reaction solution was filtered, washed with methanol (10 mL), and the filtrate was concentrated to obtain compound 2-b (69 mg, 94%). LC-MS (ESI): m/z 541.8 (M+H) ⁺ .

Synthesis of compound 2-a

2-b (53 mg, 0.10 mmol), DMSO (6 mL), DIPEA (38 mg, 0.29 mmol) and N-bis(trifluoromethanesulfonyl)aniline (70 mg, 0.20 mmol) were added to the reaction flask. After the addition, the mixture was stirred at room temperature for 4 hours. 1-d (30 mg, 0.14mmol), after addition, stirring was continued at room temperature for ₁ hour. The reaction solution was concentrated, water (20mL) was added to the residue, and filtered. The solid was purified by reverse phase column ( _NH4HCO3 aqueous solution (content about 0.08%)-MeOH = 5%-95%) to obtain compound 2-a (25.8mg, 35%), LC-MS (ESI): m/z 743.9 (M+H) ⁺ .

Synthesis of compound 2

Add 2-a (26 mg, 0.035 mol) and acetonitrile (5 mL) to the reaction flask and stir for 10 minutes under ice-salt bath. Slowly add 1,4-dioxane hydrochloride (4 M, 0.80 mL, 3.20 mmol) to the reaction solution under nitrogen protection, and continue stirring for 30 minutes after the addition is complete. Add ammonia methanol solution (7 M, 10 mL, 70 mmol) to the reaction solution. The mixture is concentrated and purified by preparative HPLC to obtain compound 2 (2.3 mg, 9%), LC-MS (ESI): m/z 699.2 (M+H) ⁺ .

Synthesis route of compound 3

Synthesis of compound 3-i

Compound 1-i (1.80 g, 4.41 mmol) was added to 1,4-dioxane (100 mL) and water (10 mL) under nitrogen at room temperature, and then palladium acetate (0.99 g, 0.44 mmol), potassium [(tert-butyloxycarbonylamino)methyl] trifluoroborate (3.14 g, 13.23 mmol), X-phos (0.63 g, 1.32 mmol), cesium carbonate (4.31 g, 13.23 mmol) were added in sequence. The reaction mixture was stirred at 105°C for 36 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (petroleum ether/ethyl acetate 1/1, to dichloromethane/methanol 10/1) to obtain compound 3-i (0.41 g, 20%). LC-MS (ESI): m/z = 459.4 (M+H) ⁺ .

Synthesis of compound 3-h

3-i (0.88 g, 1.92 mmol), tetrahydrofuran (10 mL), methanol (10 mL), sodium hydroxide (0.50 g, 12.50 mmol) and water (5 mL) were added to the reaction bottle under nitrogen. After the addition, the mixture was protected with nitrogen and stirred at room temperature for 2 hours. The reaction solution was concentrated, and dilute hydrochloric acid (2 M, 7 mL, 14 mmol) was added to the residue and extracted with ethyl acetate (10 mL*3). The organic phase was concentrated to give compound 3-h (0.56 g, 66%).

Synthesis of compound 3-g

Add 3-h (560 mg, 1.26 mmol) and acetonitrile (4 mL) to the reaction bottle. Stir for 10 minutes under ice-water bath. 1,4-Dioxane hydrochloride solution (4M, 1 mL, 4.00 mmol) was slowly added dropwise to the reaction solution, and stirring was continued at the same temperature for 2 hours after the addition was complete. The reaction solution was concentrated to obtain compound 3-g (440 mg, 101%), which was directly used for the next step reaction.

Synthesis of compound 3-f

Under nitrogen, 3-g (0.55 g, 1.60 mmol), HATU (0.91 g, 2.39 mmol), DIPEA (0.51 g, 3.95 mmol) and DMF (6 mL) were added to the reaction flask. The mixture was protected with nitrogen and stirred at room temperature for 1 hour. Saturated sodium bicarbonate (100 mL) was added to the reaction solution and extracted with dichloromethane (100 mL*3). The organic phase was concentrated to obtain a crude product. Compound 3-f (0.30 g, 57%) was obtained by column chromatography (dichloromethane/methanol = 20/1, 10/1). LC-MS (ESI): m/z 327.2 (M+H) ⁺ .

Synthesis of compound 3-e

Under nitrogen, 3-f (296 mg, 0.91 mmol), sodium hydride (60%, 54 mg, 1.35 mmol) and DMF (20 mL) were added to the reaction bottle and stirred in an ice-water bath for 1 hour. Iodomethane was added to the reaction solution (180 mg, 1.27 mmol) and stirred at room temperature for 1 hour. Saturated ammonium chloride (10 mL) was added to the reaction solution and extracted with dichloromethane (20*3 mL). The organic phase was concentrated and purified by column chromatography (dichloromethane/methanol=30/1) to obtain compound 3-e (136 mg, 44%). LC-MS (ESI): m/z 341.6 (M+H) ⁺ .

Synthesis of compound 3-d

Under nitrogen, add 3-e (136 mg, 0.40 mmol), dry palladium carbon (10%, 90 mg), and tetrahydrofuran (20 mL) to the reaction bottle. The mixture is replaced with hydrogen three times and stirred at room temperature for 13 hours. The reaction solution is heated to 40 ° C and stirred for 10 hours. The reaction solution is filtered and the filtrate is concentrated to obtain compound 3-d (68.1 mg, 83%). LC-MS (ESI): m/z 207.2 (M+H) ⁺ .

Synthesis of compound 3-c

Add 1-o (169 mg, 0.67 mmol), dichloromethane (20 mL), DIPEA (256 mg, 1.98 mmol) to the reaction bottle, add 3-d (68 mg, 0.33 mmol) under dry ice acetone bath, and stir at this temperature for 2 hours. Add water to the reaction solution and extract with dichloromethane (20 mL*2). The organic phase is dried over anhydrous sodium sulfate and spin-dried to obtain compound 3-c (110 mg, 79%). LC-MS (ESI): m/z=422.2 (M+H) ⁺ .

Synthesis of compound 3-b

3-c (110 mg, 0.26 mmol), dichloromethane (25 mL), (2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a (5H)-yl) methanol (83 mg, 0.52 mmol) were added to the reaction bottle under nitrogen, sodium tert-butoxide (50 mg, 0.52 mmol) was added under ice-water bath, and stirred under nitrogen in ice-water bath for 2 hours. The reaction solution was quenched with saturated ammonium chloride (20 mL) and extracted with dichloromethane (20 mL*2). The organic phase was concentrated. Compound 3-b (86 mg, 61%) was obtained by column chromatography (dichloromethane/methanol = 20/1, 10/1). LC-MS (ESI): m/z = 545.7 (M+H) ⁺ .

Synthesis of compound 3-a

3-b (86 mg, 0.16 mmol), 1,4-dioxane (20 mL), water (2 mL), 2-(8-ethyl-7-fluoro-3-(methoxymethyloxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (86 mg, 0.24 mmol), potassium phosphate (33 mg, 0.16 mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (80 mg, 0.095 mmol) were added to the reaction bottle under nitrogen, the atmosphere was replaced with nitrogen three times, and the mixture was placed in an oil bath preheated to 100°C and stirred for 3 hours. The reaction solution was dried by rotary evaporation and purified by column chromatography (mobile phase: methanol/dichloromethane = 0/20; 1/10) to obtain compound 3-a (53 mg, 45%). LC-MS (ESI): m/z = 743.8 (M+H) ⁺ .

Synthesis of compound 3

Add 3-a (53 mg, 0.07 mmol) and acetonitrile (6 mL) to the reaction bottle under nitrogen. Stir for 10 minutes under ice-salt bath. Under the protection of 1,4-dioxane hydrochloride (4M, 1mL, 4.00mmol) was slowly added dropwise to the reaction solution, and after the addition was completed, stirring was continued at the same temperature for 60 minutes. Ammonia methanol solution (7M, 5mL, 35mmol) was added to the reaction solution, concentrated, and purified by preparative HPLC to obtain compound 3 (6.6mg, 13%). LC-MS (ESI): m/z 699.8 (M+H) ⁺ .

Synthesis route of compound 4

Synthesis of compound 4-b

3-Bromo-4-trifluoromethylaniline (7.5 g, 31.25 mmol), 1,4-dioxane (100 mL), biboric acid pinacol ester (11.9 g, 46.87 mmol), potassium acetate (9.2 g, 93.74 mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (2.55 g, 3.125 mmol) were added to the reaction bottle, and the mixture was replaced with nitrogen three times and stirred at 100°C overnight. The next day, the reaction solution was dried and separated and purified by a rapid separation column (PE/EA=10:1) to obtain compound 4-b (6.3 g, 70%). LC-MS (ESI): m/z=287.7 (M+H) ⁺ .

Synthesis of compound 3

Compound 4-b (1.5 g, 5.225 mmol), acetonitrile (80 mL), 1-fluoro-4-methyl-1,4-diazabicyclo[2.2.2]octane tetrafluoroborate (2.51 g, 7.837 mmol) were added to the reaction bottle, and the mixture was stirred at room temperature overnight under nitrogen protection. The next day, the reaction solution was dried and separated and purified by a rapid separation column (PE/EA=10:1) to obtain compound 4-a-1 (115 mg, 7%) and compound 4-a-2 (129 mg, 8%). LC-MS (ESI): m/z=305.8 (M+H) ⁺ ; LC-MS (ESI): m/z=305.9 (M+H) ⁺ .

Synthesis of compound 4

4-a-1 (110 mg, 0.36 mmol), 1,4-dioxane (20 mL), water (2 mL), 1-b (50 mg, 0.089 mmol), cesium carbonate (87 mg, 0.27 mmol) and tetrakistriphenylphosphine palladium (10 mg, 0.009 mmol) were added to the reaction flask. The mixture was replaced with nitrogen three times and stirred at 100 ° C overnight. The next day, the reaction solution was dried and purified by column (mobile phase: methanol/dichloromethane 0/100 to 10/90) to obtain compound 4 (30 mg, 48%). LC-MS (ESI): m/z = 702.1 (M+H) ⁺ ; ¹ H NMR (400M, CDCl ₃ )δ8.98(1H,s),7.41(1H,d,J＝11.2Hz),6.81(1H,d,J＝8.4Hz),5.33(1H,d,J＝54Hz),5.08-4.93(2H,m),4.68-4.57(2H,m),4.44-4.24(4H,m),4.17(2H,s),3.57(2H,t,J＝6.8Hz),3.53-3.41(1H,m),3.37-3.21(1H,m),3.15-2.99(4H,m),2.90(2H,t,J＝6.4Hz),2.38-2.15(5H,m),2.09-1.96(4H,m).

Synthesis route of compound 5

Synthesis of compound 5

In an ice-water bath, methylaminocarbonyl chloride (15 mg, 0.14 mmol) and N, N-diisopropylethylamine (18 mg, 0.14 mmol) were slowly added to a solution of compound 1 (20 mg, 0.028 mmol) in dichloromethane (6 mL) . The mixture was reacted at 0°C for 3 hours. After monitoring the reaction and finding that there was still raw material, N, N-diisopropylethylamine (18 mg, 0.14 mmol) and methylaminocarbonyl chloride (15 mg, 0.14 mmol) were added. After the addition, the temperature of the reaction solution slowly rose to room temperature and stirred overnight. Water was added to the reaction solution and extracted with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by rapid column chromatography (mobile phase: 0-100%, dichloromethane: methanol = 10: 1/dichloromethane) to obtain compound 5 (19.2 mg, 89%). LC-MS(ESI):m/z 770.2(M+H) ⁺ .

Synthesis route of compound 6

Synthesis of compound 6

Isobutyl chloride (9 mg, 0.084 mmol) and N,N-diisopropylethylamine (18 mg, 0.14 mmol) were slowly added to a dichloromethane (6 mL) solution of compound 1 (20 mg, 0.028 mmol) under ice-water bath conditions, and the mixture was reacted at 0°C for 1 hour. Water was added, extracted with dichloromethane (30 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by preparative HPLC to obtain compound 6 (8.8 mg, 40%). LC-MS (ESI): m/z 783.3 (M+H) ⁺ .

Synthesis route of compound 7

Synthesis of compound 7-g

Under nitrogen protection and ice bath conditions, 5-fluoro-2-methoxyaniline (9.99 g, 70.78 mmol) was slowly added to a tetrahydrofuran (80 mL) solution of benzoyl isothiocyanate (11 g, 67.41 mmol), and the internal reaction temperature was maintained below 10 ° C. After the addition, the reaction temperature slowly rose to room temperature, stirred for 30 min, sodium hydroxide solution (5M, 16.2 mL, 80.89 mmol) and water (20 mL, 1106.55 mmol) were added, and stirred under reflux for 3.5 h. The reaction solution was cooled to room temperature, water (50 ml) and isopropyl acetate (80 mL) were added, and concentrated hydrochloric acid aqueous solution was added to adjust the pH value to 9-10. The organic phase was dried over anhydrous sodium sulfate, filtered, and spun dry. Ethyl acetate was added to dissolve, and the reduced pressure concentration was continued. Solids precipitated during the concentration process. Not all of them were concentrated to dryness, and the mixture was placed at -20 ° C overnight. The mixture was brought to room temperature, filtered, and the filter cake was washed with petroleum ether. The filter cake was the product. The filtrate was dried by rotary evaporation and purified by silica gel column chromatography (EA/PE, 0-50%) to obtain the product, which was combined to obtain 7-g (10.6 g, 79%). LC-MS (ESI): m/z 201.0 (M+H) ⁺ .

Synthesis of compound 7-f

Under the protection of ice bath and nitrogen, liquid bromine (2.43mL, 47.38mmol) was slowly added to the chloroform (200mL) solution of 7-g (9.3g, 46.45mmol), and the internal temperature was maintained below 7°C. After the addition, the reaction solution was stirred for 30min under ice bath conditions, then heated to reflux and stirred for 2 hours. After the reaction was complete, it was cooled to room temperature, chloroform was removed by spin drying, and then dichloromethane was added to dissolve and concentrated. Solids precipitated during the concentration process. No more concentration was performed, and the solution was placed in a freezer at -20°C overnight. The solution was taken out of the freezer, and a large amount of solids precipitated. It was filtered and the filter cake was washed with petroleum ether. The filter cake was 7-f (12.86g), and the product was hydrobromide. After alkalization, 8.5g of free solid was obtained. LC-MS (ESI): m/z 199.0 (M+H) ⁺ .

Synthesis of compound 7-e

Under nitrogen protection and dry ice acetone bath conditions, slowly add boron tribromide (1M, dichloromethane solution, 107.2mL, 107.2mmol) to a dichloromethane (200mL) solution of 7-f (8.5g, 42.88mmol), and maintain this temperature during the addition process. After the addition is complete, the temperature slowly rises to room temperature and continues to stir overnight. Slowly pour the reaction solution into ice water, stirring while pouring, solid precipitates, filter, and purify the filter cake and filtrate separately. The filter cake is the hydrobromide of the product, which is dissolved in water, and a saturated sodium bicarbonate aqueous solution is added to adjust the pH value to 7-8. A large amount of solid precipitates, filter, collect the filter cake, and pour out the filtrate this time. Add sodium bicarbonate aqueous solution to the first filtrate, adjust the pH value to 7-8, dry the organic phase with anhydrous sodium sulfate, and spin dry to remove the solvent. Solid precipitates during the spin dry process, and the solvent does not need to be completely spin dried, filter, and collect the filter cake. The two filter cakes are combined together and dried to obtain 7-e (7.4g, 94%). LC-MS (ESI): m/z 185.0 (M+H) ⁺ .

Synthesis of compound 7-d

Under ice bath condition, add Boc ₂ O (26.31 g, 120.53 mmol) and triethylamine (11.73 mL, 84.37 mmol) to a tetrahydrofuran (200 mL) solution of 7-e (7.4 g, 40.18 mmol), and then slowly add DMAP (0.49 g, 4.02 mmol). After the addition, slowly raise the reaction temperature to room temperature and stir overnight. After the reaction is complete, add water to the reaction solution, extract with ethyl acetate (100 ml*3), dry the combined organic phase with anhydrous sodium sulfate, filter, spin dry, dissolve the crude product with methanol, add potassium carbonate (16.66 g, 120.53 mmol), stir at room temperature for 4 hours, monitor and show the desired product, spin dry, add water, stir for 0.5 h, a large amount of solid is insoluble, filter, and dry the filter cake to obtain 7-d (11.26 g, 99%). LC-MS(ESI):m/z 285.0(M+H) ⁺ .

Synthesis of compound 7-c

7-d (2 g, 7.04 mmol), DBU (1.07 g, 7.04 mmol) and dichloromethane (30 mL) were added to a 100 ml eggplant-shaped bottle, and then N-phenylbis(trifluoromethanesulfonyl)imide (3.77 g, 10.55 mmol) and DMAP (0.09 g, 0.7 mmol) were added, and the mixture was stirred overnight. The next day, water was added to the reaction solution, and it was extracted with dichloromethane (50 ml*2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by column chromatography (mobile phase: EA/PE, 0-20%) to obtain 7-c (2.28 g, 78%). LC-MS (ESI): m/z 360.9 (M-56+H) ⁺ , 417.0 (M+H) ⁺ .

Synthesis of compound 7-b

7-c (800 mg, 1.92 mmol), bis-pinacol borate (4.88 g, 19.21 mmol), tetrakistriphenylphosphine palladium (222 mg, 0.19 mmol), potassium acetate (566 mg, 5.76 mmol) and 1,4-dioxane (20 mL) were added to a 100 ml eggplant-shaped bottle. The mixture was replaced with nitrogen several times and stirred at 100 ° C over the weekend. The reaction was monitored and showed that it was complete. It was spin-dried, water was added, and it was extracted with ethyl acetate (50 ml * 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase: EA/PE, 0-50%) to obtain 7-b (0.65 g, 85%). LC-MS (ESI): m/z 313.0 (M+H) ⁺ (shown as the molecular weight of boronic acid).

Synthesis of compound 7-a

1-b (25 mg, 0.045 mmol), 7-b (88 mg, 0.224 mmol), tetrakis(triphenylphosphine)palladium (5 mg, 0.004 mmol), cesium carbonate (73 mg, 0.22 mmol), 1,4-dioxane (5 mL) and water (1 mL) were added to a 50 ml eggplant-shaped bottle. The mixture was replaced with nitrogen several times and heated to 90 ° C for overnight reaction. The reaction solution was dried by spin drying, water was added, and extracted with ethyl acetate (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by flash column chromatography (mobile phase: DCM: MeOH (10: 1) / DCM, 0-100%) to obtain 7-a (30 mg, 85%). LC-MS (ESI): m/z 791.8 (M+H) ⁺ .

Synthesis of compound 7

Trifluoroacetic acid (1 mL) was added to a solution of 7-a (30 mg, 0.038 mmol) in dichloromethane (5 mL), and the mixture was stirred at room temperature overnight. The reaction solution was dried by rotary evaporation, saturated sodium bicarbonate aqueous solution was added, and extracted with dichloromethane (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was purified by preparative HPLC to give 7 (6.5 mg, 25%). LC-MS (ESI): m/z 691.3 (M+H) ⁺ .

Synthesis route of compound 8

2-(8-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (22 mg, 0.080 mmol), 1,4-dioxane (15 mL), water (1.5 mL), 1-b (30 mg, 0.054 mmol), cesium carbonate (52 mg, 0.161 mmol) and Pd(PPh ₃ ) ₄ (6 mg, 0.005 mmol) were added to the reaction flask, the mixture was replaced with nitrogen three times, and stirred at 100° C. overnight. The next day, cesium carbonate (52 mg, 0.161 mmol) and Pd(PPh ₃ ) ₄ (6 mg, 0.005 mmol) were added, the mixture was replaced with nitrogen three times, and stirred at 100° C. overnight. The next day, the reaction solution was dried by spin drying and purified by column chromatography (mobile phase: methanol/dichloromethane 0/100 to 10/90) to obtain compound 8 (25 mg, 70%). LC-MS (ESI): m/z = 669.2 (M+H) ⁺ ; ¹ H NMR (400M, CDCl ₃ ): δ9.05 (1H, s), 8.01 (1H, d, J = 7.6 Hz), 7.75 (1H, d, J = 8.4 Hz), 7.64 (1H, t, J = 7.6 Hz), 7.58 (1H, d, J = 6.8 Hz), 7.49-7.41 (1H, m), 7.15-7.07 (1H, m), 5.49-4.87 (3H, m), 4.72-4.22 (6H, m), 3.69-3.52 (3H, m), 3.42-3.25 (1H, m), 3.16-3.04 (4H, m), 3.02-2.85 (2H, m), 2.45-2.18 (5H, m), 2.13-1.96 (4H, m).

Synthesis route of compound 9

Synthesis of compound 9

8-Ethylnaphthalene-1-boronic acid pinacol ester (30 mg, 0.107 mmol), 1,4-dioxane (15 mL), water (1.5 mL), 1-b (30 mg, 0.054 mmol), cesium carbonate (52 mg, 0.161 mmol) and Pd(PPh ₃ ) ₄ (6 mg, 0.005 mmol) were added to the reaction flask. The mixture was replaced with nitrogen three times and stirred at 100°C overnight. The next day, cesium carbonate (52 mg, 0.161 mmol) and Pd(PPh ₃ ) ₄ (6 mg, 0.005 mmol) were added, replaced with nitrogen three times, and stirred at 100°C overnight. The next day, the reaction solution was dried and purified by column (mobile phase: methanol/dichloromethane 0/100 to 10/90) to obtain compound 9 (17 mg, 47%). LC-MS (ESI): m/z=679.3 (M+H) ⁺ ; ¹ H NMR (400M, CDCl ₃ ): δ9.02 (1H, s), 7.98 (1H, d, J=8 Hz), 7.81 (1H, d, J=8.4 Hz), 7.55-7.43 (2H, m), 7.43-7.35 (2H, m), 5.38 (1H, d, J=51.2 Hz), 5.16-4.98 (2H, m), 4.69-4.58 (2H, m), 4.57-4.43 (1H, m), 4.39-4.27 (2H, m), 3.66-3.53 (3H, m), 3.47-3.28 (1H, m), 3.18-3.06 (4H, m), 2.98 (2H, t, J = 7.2 Hz), 2.49-2.23 (7H, m), 2.18-1.98 (4H, m), 0.96 (3H, t, J = 7.6 Hz), 0.91-0.81 (1H, m).

Synthesis route of compound 10

Synthesis of compound 10-c

7-Bromo-2,4,6-trichloro-8-fluoroquinazoline (200 mg, 0.61 mmol), dichloromethane (40 mL), DIPEA (0.316 mL, 1.816 mmol) were added to the reaction flask, and 1-d (133 mg, 0.60 mmol) was added under a dry ice acetone bath. After the addition, the mixture was stirred at room temperature overnight. The next day, water was added to the reaction solution, the aqueous phase and the organic phase were poured out, and the insoluble matter was purified by column (mobile phase: methanol/dichloromethane 0/100 to 10/90) to obtain compound 10-c (200 mg, 64%). LC-MS (ESI): m/z = 513.0 (M+H) ⁺ .

Synthesis of compound 10-b

10-c (180 mg, 0.35 mmol), DMF (10 mL), tetrahydrofuran (10 mL), (2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a (5H)-yl) methanol (167 mg, 1.05 mmol), cesium carbonate (342 mg, 1.05 mmol), DABCO (78 mg, 0.7 mmol) were added to the reaction flask, and the mixture was stirred at room temperature overnight under nitrogen. DABCO (78 mg, 0.7 mmol) was added to the reaction solution, and stirring continued overnight. Water was added to the reaction solution, and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine (30 mL*3), dried, spin-dried, and purified by column (mobile phase: methanol/dichloromethane 0/100 to 10/90) to obtain compound 10-b (116 mg, 52%). LC-MS (ESI): m/z = 636.5 (M+H) ⁺ .

Synthesis of compound 10-a

10-b (40 mg, 0.063 mmol), 1,4-dioxane (15 mL), water (1.5 mL), 2-(8-ethyl-7-fluoro-3-(methoxymethyloxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (34 mg, 0.094 mmol), cesium carbonate (61 mg, 0.188 mmol) and Pd(PPh ₃ ) ₄ (15 mg, 0.013 mmol) were added to the reaction bottle. The mixture was replaced with nitrogen three times and stirred at 100° C. for 3 hours. The reaction solution was spin-dried and purified by column (mobile phase: methanol/dichloromethane 0/100 to 10/90) to obtain compound 10-a (15 mg, 30%). LC-MS (ESI): m/z=790.5 (M+H) ⁺ .

Synthesis of compound 10

10-a (15 mg, 0.019 mmol), acetonitrile (10 mL), and 4M 1,4-dioxane hydrochloride (1 mL, 4 mmol) were added to the reaction flask. After the addition, the mixture was stirred at room temperature for half an hour. The reaction solution was spin-dried and purified by two preparative HPLC (trifluoroacetic acid first, then ammonium bicarbonate) to obtain compound 10 (1.8 mg, 13%). LC-MS (ESI): m/z = 746.3 (M + H) ⁺ .

Synthesis route of compound 11

Synthesis of compound 11-a

5-Bromo-2-fluoro-4-(trifluoromethyl)aniline (500 mg, 1.94 mmol), bipyraclostrobin (1476 mg, 5.814 mmol), 1,4-dioxane (30 mL), potassium acetate (570 mg, 5.814 mmol), Pd(dppf)Cl ₂ (158 mg, 0.194 mmol) were added to the reaction flask. The mixture was replaced with nitrogen three times and stirred at 100°C overnight. The next day, the reaction solution was dried and purified by column chromatography (mobile phase: ethyl acetate/petroleum ether 0/100 to 10/90) to obtain compound 11-a (400 mg, 68%). LC-MS (ESI): m/z=305.9 (M+H) ⁺ .

Synthesis of compound 11

10-b (30 mg, 0.047 mmol), 1,4-dioxane (15 mL), water (1.5 mL), 11-a (22 mg, 0.071 mmol), cesium carbonate (46 mg, 0.141 mmol) and Pd(PPh ₃ ) ₄ (11 mg, 0.009 mmol) were added to the reaction flask. The mixture was replaced with nitrogen three times and stirred at 100°C overnight. The next day, the reaction solution was dried and purified by column (mobile phase: methanol/dichloromethane 0/100 to 10/90), and then purified by preparative HPLC (ammonium bicarbonate) to obtain compound 11 (7.6 mg, 22%). LC-MS (ESI): m/z=735.3 (M+H) ⁺ .

Synthesis route of compound 12

Synthesis of compound 12-e

2-(6-bromo-2,3-difluorophenyl)acetonitrile (400 mg, 1.72 mmol) was dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature under nitrogen atmosphere. Under protection, potassium tert-butoxide (203 mg, 1.81 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 30 min, and then ethoxycarbonyl isothiocyanate (237 mg, 1.81 mmol) was added thereto dropwise. After the addition, stirring was continued at room temperature for 1 hour, and then heated to 100°C and stirred for 1 hour. The reaction solution was poured into 50 mL of water, stirred for 10 min, and the solid was collected by filtration and dried to obtain 12-e (550 mg, 93%). LC-MS (ESI): m/z 340.8 (MH) ^- ; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ12.10 (1H, s), 7.68 (1H, dd, J＝8.8, 4.8 Hz), 7.21 (1H, t, J＝8.8 Hz), 4.30 (2H, q, J＝7.2 Hz), 1.31 (3H, t, J＝7.2 Hz).

Synthesis of compound 12-d

12-e (300 mg, 0.87 mmol) was dissolved in dimethyl sulfoxide (9 mL), and then 5 M sodium hydroxide aqueous solution (9 mL, 45 mmol) was added. The reaction was heated to 130 ° C and reacted at this temperature for 2 hours. The reaction solution was poured into water, and solids precipitated. Stir at room temperature for 30 minutes and let stand overnight. The next day, filter, collect the solids, and dry to obtain 12-d (220 mg, 93%). LC-MS (ESI): m/z 268.9 (MH) ^- .

Synthesis of compound 12-c

To a solution of 12-d (220 mg, 0.81 mmol) in tetrahydrofuran (20 mL) were added di-tert-butyl dicarbonate (531 mg, 2.43 mmol), N,N-diisopropylethylamine (524 mg, 4.06 mmol), 4-dimethylaminopyridine (10 mg, 0.081 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution and extracted with ethyl acetate (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by column chromatography (mobile phase: EA/PE, 0-20%) to obtain 12-c (232 mg, 77%). LC-MS (ESI): m/z 369.0 (MH) ^- .

Synthesis of compound 12-b

12-c (50 mg, 0.13 mmol), bis-pinacol boronate (171 mg, 0.67 mmol), [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium (10 mg, 0.013 mmol), potassium acetate (66 mg, 0.673 mmol) and 1,4-dioxane (8 mL) were added to a 30 mL microwave tube. The microwave tube was replaced with nitrogen several times, sealed, and heated to 100 ° C under microwave conditions for 2 hours. Water was added to the reaction solution and extracted with ethyl acetate (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by column chromatography (mobile phase: EA/PE, 0-20%) to obtain 12-b (50 mg, 89%). LC-MS (ESI): m/z 417.1 (MH) ^- .

Synthesis of compound 12-a

1-b (25 mg, 0.045 mmol), 12-b (37 mg, 0.088 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (6.5 mg, 0.009 mmol), potassium phosphate (51 mg, 0.22 mmol), 1,4-dioxane (2.5 mL) and water (0.5 mL) were added to a 10 mL microwave tube. The microwave tube was replaced with nitrogen several times, sealed, and heated to 80 ° C for overnight reaction. Water was added to the reaction solution and extracted with ethyl acetate (20 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by flash chromatography (mobile phase: DCM: MeOH = 10: 1/DCM, 0-100%) to obtain 12-a (30 mg, 82%). LC-MS(ESI):m/z 815.7(M+H) ⁺ .

Synthesis of compound 12

Trifluoroacetic acid (0.5 mL) was added to a solution of 12-a (30 mg, 0.037 mmol) in dichloromethane (5 mL). The reaction solution was stirred at room temperature overnight. The reaction solution was dried by rotary evaporation, and a saturated aqueous sodium bicarbonate solution was added to the residue, and extracted with ethyl acetate (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was purified by preparative HPLC to obtain 12 (2 mg, 8%). LC-MS (ESI): m/z 715.3 (M+H) ⁺ .

Synthesis route of compound 13

Synthesis of compound 13-b

Add 1-d (70 mg, 0.32 mmol), dichloromethane (10 mL), tetrahydrofuran (10 mL), DIPEA (0.166 mL, 0.96 mmol) to the reaction bottle, cool to about -40 ° C, add 7-bromo-2,,4-dichloro-6,8-difluoroquinazoline (100 mg, 0.32 mmol). After the addition, the mixture was stirred at room temperature overnight. The next day, the reaction solution was dried, and the residue was washed with a mixed solution of dichloromethane (5 mL) and petroleum ether (5 mL), filtered, and the filter cake was obtained as compound 13-b (130 mg, 82%). LC-MS (ESI): m/z = 497.1 (M + H) ⁺ .

Synthesis of compound 13-a

13-b (130 mg, 0.26 mmol), DMF (15 mL), tetrahydrofuran (15 mL), (2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a (5H)-yl) methanol (125 mg, 0.78 mmol), cesium carbonate (255 mg, 0.78 mmol), DABCO (117 mg, 1.05 mmol) were added to the reaction bottle, and the mixture was stirred at room temperature overnight under nitrogen. Water was added to the reaction solution and extracted with ethyl acetate (50 mL * 3). The organic phase was washed with saturated brine (30 mL * 3), dried over anhydrous sodium sulfate, spin-dried, and purified by column (mobile phase: methanol / dichloromethane 0/100 to 10/90) to obtain compound 13-a (117 mg, 72%). LC-MS (ESI): m / z = 620.6 (M + H) ⁺ .

Synthesis of compound 13

13-a (20 mg, 0.032 mmol), 1,4-dioxane (10 mL), water (1 mL), 8-ethylnaphthalene-1-boronic acid pinacol ester (14 mg, 0.048 mmol), cesium carbonate (32 mg, 0.097 mmol) and Pd(PPh ₃ ) ₄ (4 mg, 0.003 mmol) were added to the reaction flask. The mixture was replaced with nitrogen three times and stirred at 100°C overnight. The next day, the reaction solution was dried and purified by column (mobile phase: methanol/dichloromethane 0/100 to 10/90), and then purified by preparative HPLC (ammonium bicarbonate) to obtain compound 13 (2.4 mg, 11%). LC-MS (ESI): m/z=696.3 (M+H) ⁺ .

Synthetic routes of compounds 14-1 and 14-2

Synthesis of compound 14-e

N,N-diisopropylethylamine (1.17 mL, 6.69 mmol) was added to a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (400 mg, 1.12 mmol) in dichloromethane (20 mL) under ice bath conditions, and trifluoromethanesulfonic anhydride (0.75 mL, 4.46 mmol) was slowly added. The mixture was reacted at 0°C for 2 hours, water was added, and the mixture was extracted with dichloromethane (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by column chromatography (mobile phase: EA/PE, 0-10%) to obtain 14-e (640 mg, 92%). LC-MS (ESI): m/z 640.2 (M+NH ₄ ) ⁺ .

Synthesis of compound 14-d

14-e (440 mg, 0.71 mmol), benzophenone imine (128 mg, 0.71 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (82 mg, 0.14 mmol), tris(dibenzylideneacetone)dipalladium (65 mg, 0.071 mmol), cesium carbonate (691 mg, 2.12 mmol) and toluene (10 mL) were added to a 100 mL eggplant-shaped bottle at room temperature. The mixture was replaced with nitrogen several times, heated to 100 ° C, and reacted overnight. The reaction solution was dried by spin drying, water was added, and extracted with ethyl acetate (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by column chromatography (mobile phase: EA/PE, 0-10%) to obtain 14-d (345 mg, 75%). LC-MS (ESI): m/z 654.4 (M+H) ⁺ .

Synthesis of compound 14-c

To a solution of 14-d (150 mg, 0.23 mmol) in ethyl acetate (10 mL) was added a solution of 1,4-dioxane with hydrogen chloride (4 M, 0.3 mL, 1.2 mmol), and the mixture was reacted at room temperature for 30 min. A saturated aqueous sodium bicarbonate solution was added to the reaction solution for neutralization, and then extracted with ethyl acetate (20 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried to give 14-c (110 mg, 98%). LC-MS (ESI): m/z 490.1 (M+H) ⁺ .

Synthesis of compound 14-b

14-c (110 mg, 0.23 mmol), bipyralidin (571 mg, 2.25 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (17 mg, 0.022 mmol), potassium acetate (110 mg, 1.12 mmol) and 1,4-dioxane (9 mL) were added to a 30 mL microwave tube. The microwave tube was replaced with nitrogen several times, sealed, and heated to 100 ° C under microwave conditions for 2 hours. The reaction solution was spin-dried to dry the solvent, and water was added. Extract with ethyl acetate (50 ml). Dry the organic phase with anhydrous sodium sulfate, filter and spin dry to obtain a crude product. The crude product was purified by column chromatography (mobile phase: EA/PE, 0-50%) to obtain 14-b (70 mg, 67%). LC-MS (ESI): m/z 468.3 (M+H) ⁺ .

Synthesis of compound 14-a

1-b (20 mg, 0.036 mmol), 14-b (17 mg, 0.036 mmol), tetrakis(triphenylphosphine)palladium (4 mg, 0.004 mmol), cesium carbonate (23 mg, 0.072 mmol), 1,4-dioxane (3 mL) and water (0.5 mL) were added to a 10 ml microwave tube. The microwave tube was replaced with nitrogen several times, sealed, and the mixture was heated to 100 ° C and stirred overnight. Water was added to the reaction solution and extracted with ethyl acetate (20 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by column chromatography (mobile phase: DCM: MeOH = 10: 1/DCM, 0-100%) to obtain 14-a (29 mg, 94%). LC-MS (ESI): m/z 865.0 (M+H) ⁺ .

Synthesis of compounds 14-1 and 14-2

Cesium fluoride (51 mg, 0.34 mmol) was added to a solution of 14-a (29 mg, 0.034 mmol) in N,N-dimethylformamide (5 mL), and the mixture was replaced with nitrogen several times and reacted at room temperature overnight. Water was added to the reaction solution and extracted with a mixed solvent of dichloromethane: methanol = 10:1 (30 ml*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by preparative HPLC to obtain 14-1 (1.8 mg) and 14-2 (0.3 mg), with a total yield of 9%. 14-1: LC-MS (ESI): m/z 708.3 (M+H) ⁺ ; 14-2: LC-MS (ESI): m/z 708.3 (M+H) ⁺ .

Synthesis route of compound 15

Synthesis of compound 15-b

Add 2-methylene-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (800 mg, 3.82 mmol) and THF (10 mL) to the reaction bottle at room temperature. Nitrogen replacement protection, lithium aluminum tetrahydride tetrahydrofuran solution (1M, 11.5 mL) was added dropwise at room temperature. After addition, the mixture was heated to 80°C and refluxed for 3 hours. The reaction solution was naturally cooled to room temperature, and 100 mL of methanol and 10 g of sodium sulfate decahydrate were added to quench. The mixture was stirred at room temperature for 2 hours, filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrates were combined, concentrated, and purified by reverse phase column (mobile phase: water (5% TFA)/acetonitrile 10/0 to 10/1) to obtain compound 15-b (400 mg, 68%). LC-MS (ESI): m/z 154.0 (M+H) ⁺ .

Synthesis of compound 15-a

1-c (crude product, 300 mg, about 0.50 mmol) and DCM (30 mL) were added to the reaction bottle at room temperature. Nitrogen was replaced and the temperature was lowered to 0°C, and 15-b (400 mg, 2.61 mmol) and sodium tert-butoxide (480 mg, 4.99 mmol) were added. The mixture was stirred at 0°C for 3 hours, and the reaction solution was directly purified by column (mobile phase: DCM/MeOH 10/0 to 10/1) to obtain compound 15-a (250 mg, 90%). LC-MS (ESI): m/z 553.8 (M+H) ⁺ .

Synthesis of compound 15

15-a (50 mg, 0.09 mmol) and 8-ethylnaphthalene-1-boronic acid pinacol ester (33 mg, 0.12 mmol) were added to the reaction bottle at room temperature. Tetrakis(triphenylphosphine)palladium (11 mg, 0.01 mmol), cesium carbonate (74 mg, 0.23 mmol), 1,4-dioxane (5 mL), water (1 mL). The mixture was replaced with N ₂ for protection and heated to 90°C for overnight reaction. The reaction solution was concentrated and purified by preparative HPLC to obtain compound 15 (3 mg, 5%). LC-MS (ESI): m/z 673.9 (M+H) ⁺ .

Synthesis route of compound 16

Synthesis of compound 16-b

To a solution of 1-c (196 mg, 0.45 mmol) in dichloromethane (15 mL) were added {1-[(dimethylamino)methyl]cyclopropyl}methanol (87 mg, 0.67 mmol) and sodium tert-butoxide (129 mg, 1.35 mmol) in an ice-water bath. The mixture was slowly heated to room temperature and reacted overnight at room temperature. Water was added to the reaction solution and extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by column chromatography (mobile phase: methanol/dichloromethane, 0-100%) to give 16-b (87 mg, 37%). LC-MS (ESI): m/z 529.4 (M+H) ⁺ .

Synthesis of compound 16-a

16-b (87 mg, 0.16 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (71 mg, 0.20 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (12 mg, 0.016 mmol), potassium phosphate (105 mg, 0.49 mmol), tetrahydrofuran (5 mL) and water (1 mL) were added to a 30 mL microwave tube. The microwave tube was replaced with nitrogen several times, sealed, heated to 65°C, and stirred overnight. Water was added to the reaction solution and extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by column chromatography (mobile phase: methanol/dichloromethane, 0-100%) to obtain 16-a (90 mg, 75%). LC-MS (ESI): m/z 727.7 (M+H) ⁺ .

Synthesis of compound 16

To a solution of 16-a (90 mg, 0.12 mmol) in acetonitrile (8 mL) was added a solution of 1,4-dioxane with hydrogen chloride (4 M, 1.5 mL, 6 mmol) under ice-water bath conditions. The mixture was reacted at this temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by preparative HPLC to give 16 (50 mg, 59%). LC-MS (ESI): m/z 683.3 (M+H) ⁺ .

Synthesis route of compound 17

Synthesis of compound 17-a

15-a (50 mg, 0.09 mmol), ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (61 mg, 0.13 mmol), cataCXium A Pd G3 (13 mg, 0.02 mmol), potassium phosphate (58 mg, 0.27 mmol), THF (5 mL), water (1 mL) were added to the reaction bottle at room temperature. The mixture was replaced with _N2 for protection and heated to 65 °C for overnight reaction. The reaction solution was concentrated and purified by column chromatography (mobile phase: DCM/MeOH 10/0 to 10/1) to obtain compound 17-a (10 mg, 13%).

Synthesis of compound 17

17-a (10 mg, 0.012 mmol), DMF (2 mL), and cesium fluoride (15 mg, 0.10 mmol) were added to the reaction bottle at room temperature. The mixture was replaced with nitrogen and reacted at 60°C for 1 hour. The reaction solution was filtered and the filtrate was purified by preparative HPLC to obtain compound 17 (3 mg, 37%). LC-MS (ESI): m/z 687.4 (M+H) ⁺ .

Synthesis route of compound 18

Synthesis of compound 18-g

7-Fluoronaphthalene-1-ol (1000 mg, 6.17 mmol), potassium acetate (1210 mg, 12.33 mmol), isopropylphenylruthenium dichloride (378 mg, 0.62 mmol), 1,4-dioxane (15 mL) were added to the reaction bottle at room temperature. Nitrogen was replaced and protected, and (bromoethynyl)triisopropylsilane (1772 mg, 6.78 mmol) was added. After the addition, the mixture was heated to 110 ° C for 18 hours. The reaction solution was concentrated and purified by column (mobile phase: PE/EA 10/0) to obtain compound 18-g (1900 mg, 90%). LC-MS (ESI): m/z 343.2 (M+H) ⁺ .

Synthesis of compound 18-f

Add 18-g (2000 mg, 5.84 mmol) and DCM (30 mL) to the reaction bottle at room temperature. Replace with nitrogen and cool to 0°C. Add triethylamine (1773 mg, 17.52 mmol) and DMAP (143 mg, 1.17 mmol). Add pivaloyl chloride (2112 mg, 17.52 mmol) dropwise. After the addition is complete, the mixture is naturally warmed to room temperature and reacted for 1 hour. Add water to the reaction solution and extract with DCM. Combine the organic phases, wash with water, and dry. Concentrate and purify by column (mobile phase: PE/EA 10/0 to 10/1) to obtain crude compound 18-f (3000 mg). LC-MS (ESI): m/z 427.3 (M+H) ⁺ .

Synthesis of compound 18-e

Add crude compound 18-f (3000 mg, 5.84 mmol), DMF (7 mL), and cesium fluoride (3000 mg, 19.75 mmol) to the reaction flask at room temperature. Replace with nitrogen for protection and react at room temperature for 2 hours. Add water to the reaction solution and extract with EA. Wash the organic phase with water, dry, and concentrate to obtain crude compound 18-e (1700 mg). LC-MS (ESI): m/z 271.1 (M+H) ⁺ .

Synthesis of compound 18-d

Add crude product 18-e (1700 mg, 5.84 mmol), methanol (20 mL), and 10% palladium carbon (200 mg) to the reaction bottle at room temperature. The mixture was replaced with hydrogen for protection and reacted at room temperature for 3 hours. The reaction solution was filtered and the filtrate was concentrated to obtain crude compound 18-d (1800 mg). LC-MS (ESI): m/z 275.1 (M+H) ⁺ .

Synthesis of compound 18-c

Add crude product 18-d (1800 mg, about 5.84 mmol), methanol (10 mL), and potassium hydroxide (982 mg, 17.50 mmol) to the reaction bottle at room temperature. The mixture was replaced with nitrogen for protection and reacted at room temperature for 3 hours. Water was added to the reaction solution, adjusted to acidity with dilute hydrochloric acid, and extracted with EA. The organic phases were combined, washed with water, dried, concentrated, and purified by column (mobile phase: PE/EA 10/0 to 10/2) to obtain compound 18-c (800 mg, 72%). LC-MS (ESI): m/z 190.9 (M+H) ⁺ .

Synthesis of compound 18-b

Add 18-c (800 mg, 4.21 mmol) and DCM (20 mL) to the reaction flask at room temperature. Replace with nitrogen for protection and cool to 0°C. Add triethylamine (638 mg, 6.30 mmol). Add trifluoromethanesulfonic anhydride (1305 mg, 4.63 mmol) dropwise. React at room temperature for 1 hour. Add the reaction solution into ice water and extract with DCM. Combine the organic phases, wash with water, dry, concentrate, and purify by column (mobile phase: PE/EA 10/0 to 10/1) to obtain compound 18-b (770 mg, 57%). LC-MS (ESI): m/z 323.1 (M+H) ⁺ .

Synthesis of compound 18-a

Add 18-b (770 mg, 2.39 mmol), 1,4-dioxane (20 mL), biboronic acid pinacol ester (1213 mg, 4.78 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (175 mg, 0.24 mmol), potassium acetate (703 mg, 7.16 mmol) to the reaction bottle at room temperature. Replace with nitrogen for protection, heat to 90 ° C for 4 hours. The reaction solution is concentrated and purified by column (mobile phase: PE/EA 10/0 to 10/1) to obtain compound 18-a (300 mg, 42%). LC-MS (ESI): m/z 301.0 (M+H) ⁺ .

Synthesis of compound 18

15-a (100 mg, 0.18 mmol), 18-a (65 mg, 0.22 mmol), cataCXium A Pd G3 (13 mg, 0.02 mmol), potassium phosphate (115 mg, 0.54 mmol), THF (2 mL), and water (0.5 mL) were added to the sealed tube at room temperature. The mixture was replaced with _N2 for protection and heated to 65°C for overnight reaction. The reaction solution was concentrated and purified by preparative HPLC to obtain compound 18 (21 mg, 17%). LC-MS (ESI): m/z 691.3 (M+H) ⁺ .

Synthesis route of compound 19

Synthesis of compound 19

1-b (20 mg, 0.036 mmol), 18-a (13 mg, 0.043 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (5 mg, 0.007 mmol), potassium phosphate (38 mg, 0.18 mmol), tetrahydrofuran (2.5 mL) and water (0.5 mL) were added to a 10 mL microwave tube. The microwave tube was replaced with nitrogen several times, sealed, heated to 65 ° C and stirred overnight. The reaction solution was dried by spin drying, and the crude product was purified by preparative HPLC to obtain 19 (13.5 mg, 54%). LC-MS (ESI): m/z 697.3 (M+H) ⁺ .

Synthesis route of compound 20

Synthesis of compound 20

To a solution of 16 (20 mg, 0.035 mmol) in dichloromethane (8 mL) was slowly added methylaminoformyl chloride (16 mg, 0.18 mmol) and N,N-diisopropylethylamine (45 mg, 0.35 mmol) in an ice-water bath, and the mixture was reacted at 0°C for 2 hours. The reaction was monitored by LCMS to find that there was still raw material, and methylaminoformyl chloride (16 mg, 0.18 mmol) was added, and the reaction was continued at 0°C for 2 hours. Water was added to the reaction solution, extracted with dichloromethane (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by column chromatography (mobile phase: methanol/dichloromethane, 0-100%) and preparative HPLC to obtain 20 (5.2 mg, 20%). LC-MS (ESI): m/z 740.3 (M+H) ⁺ .

Effect Example 1 KRAS G12D/G12C/G12V/WT activity evaluation experiment

The experiment used the Transcreener GDP FI Assay kit according to the instructions. The reaction buffer was prepared. The KRAS G12D reaction buffer contained 50mM Tris pH 7.5, 1mM EDTA, 50mM NaCl, 1mM MgCl ₂ , 1mM DTT, 0.1% BSA and 0.01% Tween-20; the KRAS G12C/KRAS G12V/KRAS WT reaction buffer contained 50mM Tris pH 7.5, 1mM EDTA, 50mM NaCl, 4mM MgCl ₂ , 1mM DTT, 0.1% BSA and 0.01% Tween-20. The compound sample was dissolved in DMSO, and after a certain starting concentration, such as 10μM, a 3-fold gradient dilution was performed, and 75nL was transferred to a 384-well reaction plate. At the same time, a DMSO control (positive control) and a control without protein (negative control) were set up. Use reaction buffer to prepare the optimal concentration of KRAS G12D/KRAS G12C/KRAS G12V/KRAS WT protein and GTP. The reaction system includes: 1X reaction buffer, GTP (10μM), protein KRAS G12D (150nM), KRAS G12C (150nM), KRAS G12V (50nM) or KRAS WT (150nM). Add detection Reagent (10 μL), use the microplate reader SpectraMax Paradigm to continuously read the fluorescence signal value (excitation wavelength 580nM/emission wavelength 620nm) within 2 hours (read once every 5 minutes). Copy the value from the plate reader and calculate the slope value, where the maximum value refers to the reading value of the positive control and the minimum value refers to the reading value of the negative control. Inhibition rate (%) = (maximum value-sample value)/(maximum value-minimum value) × 100%. Use the formula Y = Bottom + (Top-Bottom)/(1 + (IC50/X)^HillSlope) to fit the curve and obtain the IC ₅₀ value, where Y is the inhibition rate and X is the compound concentration.

The activity results of representative compounds are shown in Table 1. Among them, "IC ₅₀ >10μM" is indicated by "*", "10μM≥IC ₅₀ >1μM" is indicated by "**", "1μM≥IC ₅₀ >100nM" is indicated by "***", and "IC ₅₀ ≤100nM" is indicated by "****".

Table 1 Activity data of representative compounds of the present invention

Effect Example 2 CTG method to detect the proliferation inhibition of compounds on RAS cell lines

NCI-H358 is a human non-small cell lung cancer cell with KRAS G12C mutation, AGS is a gastric cancer cell with KRAS G12D mutation, SW480 is a colon cancer cell with KRAS G12V mutation, and A375 is a KRAS wild-type malignant melanoma cell. The inhibitory effect of the compound on different KRAS cells was evaluated by detecting the proliferation inhibitory activity of the compound on these cell lines.

The relevant experiments were carried out on 384-well plates or 96-well plates. The specific process is as follows:

Add the cell suspension to be tested to a 384-well or 96-well plate (except the outer wells) (384-well plate: 40 μL; 96-well plate: 100 μL). Place the culture plate in a carbon dioxide incubator overnight. Add the prepared compound to each well (10 compounds with a concentration gradient are obtained by 3-fold dilution). Incubate the cell plate in a carbon dioxide incubator for 120 hours. Add CellTiter Glo reagent to a 384-well or 96-well plate (384-well plate: 25 μL; 96-well plate: 100 μL), shake for 10 minutes in the dark, and incubate for 10 minutes. Place the culture plate in an EnVision reader, use XLFit to draw the efficacy inhibition rate curve and calculate the IC ₅₀ value. The activity results of representative compounds are shown in Table 2 below. Among them, “IC ₅₀ >10μM” is indicated by “*”, “10μM≥IC ₅₀ >1μM” is indicated by “**”, “1μM≥IC ₅₀ >100nM” is indicated by “***”, and “IC ₅₀ ≤100nM” is indicated by “****”.

Table 2 Proliferation inhibition activity of representative compounds of the present invention on RAS-related cells

Although specific embodiments of the present invention are described above, those skilled in the art should understand that these are only examples. Without departing from the principle and essence of the present invention, various changes or modifications may be made to these embodiments. Therefore, the protection scope of the present invention is limited by the appended claims.

Claims

A nitrogen-containing polycyclic compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotopic compound thereof:

in, represents a single bond or a double bond;

A is -O-, -S- or -NR-, R is hydrogen or C 1-6 alkyl;

s and p are independently 0, 1 or 2;

q is 0 or 1;

m is 0, 1 or 2;

R2 is -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl substituted by one or more R2-1 , halogen, -OR2a , -C(=O) R2b , -NR2c1R2c2 , -C(=O) OR2d , -C(=O) NR2e1R2e2 , C3-10 cycloalkyl , C3-10 cycloalkyl substituted by one or more R2-2 , " 4-10 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O and N", "4-10 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O and N" substituted by one or more R2-3 , C6-20 aryl, C6-20 aryl substituted by one or more R2-4 6-20 aryl, "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", or "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N" substituted by one or more R 2-5 ; when there are multiple substituents, they may be the same or different;

R 2-1 , R 2-2 , R 2-3 , R 2-4 and R 2-5 are independently halogen, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-O-, -C(═O)R 31 , -NR 32 R 33 , -C(═O)OR 34 , or -C(═O)NR 35 R 36 ;

R 2a , R 2b , R 2c1 , R 2c2 , R 2d , R 2e1 and R 2e2 are independently hydrogen or C 1-6 alkyl;

R 31 , R 32 , R 33 , R 34 , R 35 and R 36 are independently hydrogen or C 1-6 alkyl;

n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

R 4 is independently halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 4-1 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-O-, C 1-6 alkyl-O- substituted by one or more R 4-2 , C 1-6 alkyl-S-, C 1-6 alkyl-S- substituted by one or more R 4-3 , O=, -C(=O)R 4a , -NR 4b1 R 4b2 , -C(=O)OR 4c or -C(=O)NR 4d1 R 4d2 ; or, when n is 2, 3, 4, 5, 6, 7 or 8, any two R 4 , independently together with the atoms in the ring to which they are connected, form a 3-8 membered carbocyclic ring, a 4-8 membered unsaturated carbocyclic ring containing one double bond, or a 4-8 membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N;

R 4-1 , R 4-2 and R 4-3 are independently halogen, cyano, hydroxy, C 1-6 alkyl-O-, -NR 4i R 4j , -C(=O)OR 4e or -C(=O)NR 4f1 R 4f2 ;

R 4a , R 4b1 , R 4b2 , R 4c , R 4d1 , R 4d2 , R 4e , R 4f1 , R 4f2 , R 4i and R 4j are independently hydrogen or C 1-6 alkyl;

phenyl, "a 5-7 membered heterocycloalkenyl containing 1-3 heteroatoms selected from O, S and N", "a 1-3 heteroatoms, wherein the heteroatoms are independently selected from O, S and N, a 5- to 7-membered heteroaryl group or a 5- to 7-membered cycloalkenyl group; wherein D1 is C, CH or N; D2 is wherein Z 1 and Z 2 are independently a linker, CH, CH 2 , O, S, N or NH;

r is 0, 1, 2, 3, or 4;

R 5 is independently halogen or C 1-6 alkyl;

X1 and X2 are independently CRb or N, and X1 and X2 are not CRb at the same time;

R 1 is C 6-20 aryl, "5-12 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N", C 6-20 aryl substituted by one or more R 1-1 , or "5-12 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N" substituted by one or more R 1-2 ; when there are multiple substituents, they may be the same or different;

R b , R 1-1 and R 1-2 are independently halogen, -OR c , cyano, azido, -C(=O)R 11 , -NR 12 R 13 , -C(=O)OR 14 , -C(=O)NR 15 R 16 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, “5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O and N”, C 6-20 aryl, “5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O and N”, C 1-6 alkyl substituted by one or more R 1-1-1 , C 1-6 alkyl-O- substituted by one or more R 1-1-2 , C 3-10 cycloalkyl substituted by one or more R 1-1-3 , "5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O and N" substituted by one or more R 1-1-4 , C 6-20 aryl substituted by one or more R 1-1-5 , or "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O and N" substituted by one or more R 1-1-6 ; when there are multiple substituents, they are the same or different; or, when there are multiple R 1-1 or R 1-2 , any two R 1-1 or two R 1-2 are connected to independently form a 3-8 membered cycloolefin together with the atoms in the ring to which they are connected;

R c , R 12 and R 13 are independently hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted by one or more -OC 1-6 alkyl, C(═O)R c1 , -C(═O)OR c2 , -C(═O)NR c3 R c4 or -SO 2 R c5 ; R c1 , R c2 , R c3 , R c4 and R c5 are independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, “5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms which are independently selected from O and N”, C 6-20 aryl, “5-7 membered heteroaryl containing 1 or 2 heteroatoms which are independently selected from O and N”, C 1-6 alkyl substituted by one or more R 4-1-1 , C 3-10 cycloalkyl substituted by one or more R 4-1-2 , "5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O and N" substituted by R 4-1-3 , C 6-20 aryl substituted by one or more R 4-1-4 , or "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O and N" substituted by one or more R 4-1-5 ; when there are multiple substituents, they may be the same or different;

R 1-1-1 , R 1-1-2 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-6 , R 4-1-1 , R 4-1-2 , R 4-1-3 , R 4-1-4 and R 4-1-5 are independently cyano, halogen, hydroxyl, C 1-6 alkyl-O-, C 1-6 alkyl, -C(＝O)R 21 , -NR 22 R 23 , -C(＝O)OR 24 , or -C(＝O)NR 25 R 26 ;

R 11 , R 21 , R 22 , R 23 , R 14 , R 24 , R 15 , R 25 , R 16 and R 26 are independently hydrogen or C 1-6 alkyl;

L1 is a linking bond, C1-6 alkylene, -C(＝O)-, -O(R L-1 ) n1 -, -S(R L-2 ) n2 - or -NR L-3 (R L-4 ) n3 -; R L-1 , R L-2 and R L-4 are independently C1-6 alkylene; R L-3 is hydrogen or C1-6 alkyl; n1, n2 and n3 are independently 0 or 1;

R 3 is C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 3-1 , "4-12 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N", "4-12 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N" substituted by one or more R 3-2 , C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 3-3 , -OR d , -SR d1 , -NR e1 R e2 , or -C(＝O)NR e3 R e4 ; when there are multiple substituents, they may be the same or different;

R 3-1 , R 3-2 and R 3-3 are independently C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 3-1-1 , hydroxy, azido, C 1-6 alkyl-O-, halogen, O=, -NR e5 R e6 , -C(=O)NR e7 R e8 or

R d , R d1 , Re1 , Re2 , Re3 and Re4 are independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, "4-10 membered heterocycloalkyl containing 1 to 3 heteroatoms which are independently selected from O and N", or C 1-6 alkyl substituted by one or more R 3-1-2 ;

R 3-1-1 and R 3-1-2 are independently deuterium, cyano, halogen, hydroxyl, C 1-6 alkyl-O-, -C(═O)R e9 , -NR e10 R e11 , -C(═O)OR e12 , or -C(═O)NR e13 R e14 ;

Re5 , Re6 , Re7 , Re8, Re9 , Re10 , Re11 , Re12 , Re13 and Re14 are independently hydrogen or C1-6 alkyl; or, Re5 and Re6 , Re7 and Re8 , Re10 and Re11 , Re13 and Re14 respectively form with the N atom to which they are connected “a 4-12 membered heterocycloalkyl group containing 1 to 3 heteroatoms , one of which is N, and the other heteroatoms are independently selected from O, S and N”;

R e15 and R e16 are independently hydrogen or halogen;

R6 is hydrogen, C1-6 alkyl, C3-10 cycloalkyl, "5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O and N", C6-20 aryl, "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O and N", C1-6 alkyl substituted by one or more R6-1 , C3-10 cycloalkyl substituted by one or more R6-2 , "5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O and N" substituted by one or more R6-3 , C6-20 aryl substituted by one or more R6-4 , or "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O and N" substituted by one or more R6-5 ; when there are multiple substituents, they may be the same or different;

Alternatively, R2 and R6 together with the atoms in the ring to which they are connected form a "4-8 membered heterocyclic ring containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N", or a "4-8 membered heterocyclic ring containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N" substituted by one or more R6-6 ;

R 6-1 , R 6-2 , R 6-3 , R 6-4 , R 6-5 and R 6-6 are independently cyano, halogen, hydroxyl, C 1-6 alkyl-O-, C 1-6 alkyl, -C(═O)R 61 , -NR 62 R 63 , -C(═O)OR 64 , or -C(═O)NR 65 R 66 ;

R 61 , R 62 , R 63 , R 64 , R 65 and R 66 are independently hydrogen or C 1-6 alkyl.
The nitrogen-containing polycyclic compound as shown in Formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound as claimed in claim 1, characterized in that:

A is -O-;

and/or, s is 0;

and/or, q is 0 or 1;

and/or, p is 0 or 1;

and/or, m is 0 or 1;

and/or, n is 0;

and / or, is phenyl, "a 5-7 membered heterocycloalkenyl group containing 1 to 3 heteroatoms selected from O, S and N" or "a 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and the 5- to 7-membered heteroaryl group is "; wherein D1 is C or N; D2 is Wherein Z 1 and Z 2 are independently a linker, CH, CH 2 or N;

and/or, r is 0, 1 or 2;

and/or, R 5 is independently halogen;

and/or, X1 and X2 are independently N;

and/or, R 1 is a C 6-20 aryl group substituted by one or more R 1-1 or a "5-12 membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S and N" substituted by one or more R 1-2 ; when there are multiple substituents, they may be the same or different;

R 1-1 and R 1-2 are independently halogen, -OR c , cyano, azido, -NR 12 R 13 , C 1-6 alkyl, C 2-6 alkynyl, or C 1-6 alkyl substituted by one or more R 1-1-1 ; when there are multiple substituents, they may be the same or different;

R c , R 12 and R 13 are independently hydrogen, C 1-6 alkyl substituted by one or more -OC 1-6 alkyl, C(═O)R c1 , -C(═O)OR c2 or -C(═O)NR c3 R c4 ; R c1 , R c2 , R c3 and R c4 are independently hydrogen or C 1-6 alkyl;

R 1-1-1 is independently halogen;

and/or, L1 is -O(R L-1 ) n1 -; R L-1 is C 1-6 alkylene; n1 is 1;

and/or, R 3 is a C 3-12 cycloalkyl substituted by one or more R 3-1 , or a "4-12 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N" substituted by one or more R 3-2 ; when there are multiple substituents, they may be the same or different;

and/or, R 3-1 and R 3-2 are independently C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 3-1-1 , halogen or CH 2 ＝;

and/or, R 3-1-1 is independently -NR e10 R e11 or "a 4- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S and N";

and/or, Re10 and Re11 are independently C 1-6 alkyl; or, together with the N atom to which they are connected, form a "4-12 membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S and N";

And/or, R 6 is C 1-6 alkyl, or, R 2 and R 6 are connected to each other and independently form a "4-8 membered heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N" together with the atoms in the ring to which they are connected.
The nitrogen-containing polycyclic compound as shown in Formula I according to claim 1 or 2, its pharmaceutically acceptable salt, its stereoisomer, its tautomer or its isotope compound, characterized in that the nitrogen-containing polycyclic compound as shown in Formula I is defined as Scheme 1, Scheme 2 or Scheme 3:

Option One:

represents a single bond or a double bond;

A is O;

s is 0;

q is 0 or 1;

p is 0 or 1;

m is 0 or 1;

n is 0;

is phenyl, "a 5-7 membered heterocycloalkenyl group containing 1 to 3 heteroatoms selected from O, S and N" or "a 5-7 membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S and N"; wherein D1 is C or N; D2 is Wherein Z 1 and Z 2 are independently a linker, CH, CH 2 or N;

r is 0, 1, or 2;

R 5 is independently halogen;

X1 and X2 are independently N;

R 1 is a C 6-20 aryl group substituted by one or more R 1-1 , or a 5-12-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S and N substituted by one or more R 1-2 ; when there are multiple substituents, they may be the same or different;

R 1-1 and R 1-2 are independently halogen, -OR c , cyano, azido, -NR 12 R 13 , C 1-6 alkyl, C 2-6 alkynyl, or C 1-6 alkyl substituted by one or more R 1-1-1 ; when there are multiple substituents, they may be the same or different;

R c , R 12 and R 13 are independently hydrogen, C 1-6 alkyl substituted by one or more -OC 1-6 alkyl, C(═O)R c1 , -C(═O)OR c2 or -C(═O)NR c3 R c4 ; R c1 , R c2 , R c3 and R c4 are independently hydrogen or C 1-6 alkyl;

R 1-1-1 is independently halogen;

L1 is -O(R L-1 ) n1 -; R L-1 is C 1-6 alkylene; n1 is 1;

R3 is a C3-12 cycloalkyl substituted by one or more R3-1 , or a 4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N substituted by one or more R3-2 ; when there are multiple substituents, they may be the same or different;

R 3-1 and R 3-2 are independently C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 3-1-1 , halogen or CH 2 ＝;

R 3-1-1 is -NR e10 R e11 ;

R e10 and R e11 are independently C 1-6 alkyl; or, R e10 and R e11 and the N atom to which they are connected form a "4-12 membered heterocycloalkyl group containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N";

R6 is C1-6 alkyl;

Alternatively, R2 and R6 together with the atoms in the ring to which they are connected form a "4-8 membered heterocyclic ring containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N";

Option II:

represents a single bond or a double bond;

A is -O-, -S- or -NR-, R is hydrogen or C 1-6 alkyl;

s and p are independently 0, 1 or 2;

q is 0 or 1;

m is 0, 1 or 2;

R 2 is -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl substituted by one or more R 2-1 , halogen, -OR 2a , -C(═O)R 2b , -NR 2c1 R 2c2 , -C(═O)OR 2d , -C(═O)NR 2e1 R 2e2 , C 3-10 cycloalkyl, C 3-10 cycloalkyl substituted by one or more R 2-2 , “ 4-10 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O and N” ... "4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O and N", C 6-20 aryl, C 6-20 aryl substituted by one or more R 2-4 , "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N", or "5-12 membered heteroaryl containing 1-4 heteroatoms independently selected from O, S and N" substituted by one or more R 2-5 ; when there are multiple substituents, they may be the same or different;

R 2-1 , R 2-2 , R 2-3 , R 2-4 and R 2-5 are independently halogen, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-O-, -C(═O)R 31 , -NR 32 R 33 , -C(═O)OR 34 , or -C(═O)NR 35 R 36 ;

R 2a , R 2b , R 2c1 , R 2c2 , R 2d , R 2e1 and R 2e2 are independently hydrogen or C 1-6 alkyl;

R 31 , R 32 , R 33 , R 34 , R 35 and R 36 are independently hydrogen or C 1-6 alkyl;

n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

R 4 is independently halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 4-1 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-O-, C 1-6 alkyl-O- substituted by one or more R 4-2 , C 1-6 alkyl-S-, C 1-6 alkyl-S- substituted by one or more R 4-3 , O=, -C(=O)R 4a , -NR 4b1 R 4b2 , -C(=O)OR 4c or -C(=O)NR 4d1 R 4d2 ; or, when n is 2, 3, 4, 5, 6, 7 or 8, any two R 4 , independently together with the atoms in the ring to which they are connected, form a 3-8 membered carbocyclic ring, a 4-8 membered unsaturated carbocyclic ring containing one double bond, or a 4-8 membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N;

R 4-1 , R 4-2 and R 4-3 are independently halogen, cyano, hydroxy, C 1-6 alkyl-O-, -NR 4i R 4j , -C(=O)OR 4e or -C(=O)NR 4f1 R 4f2 ;

R 4a , R 4b1 , R 4b2 , R 4c , R 4d1 , R 4d2 , R 4e , R 4f1 , R 4f2 , R 4i and R 4j are independently hydrogen or C 1-6 alkyl;

is phenyl, "a 5-7 membered heterocycloalkenyl group containing 1 to 3 heteroatoms which are selected from O, S and N", "a 5-7 membered heteroaryl group containing 1 to 3 heteroatoms which are independently selected from O, S and N" or a 5-7 membered cycloalkenyl group; wherein D1 is C, CH or N; D2 is wherein Z 1 and Z 2 are independently a linker, CH, CH 2 , O, S, N or NH;

r is 0, 1, 2, 3, or 4;

R 5 is independently halogen or C 1-6 alkyl;

X1 and X2 are independently CRb or N, and X1 and X2 are not CRb at the same time;

R 1 is C 6-20 aryl, "5-12 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N", C 6-20 aryl substituted by one or more R 1-1 , or "5-12 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N" substituted by one or more R 1-2 ; when there are multiple substituents, they may be the same or different;

R b , R 1-1 and R 1-2 are independently halogen, -OR c , cyano, azido, -C(=O)R 11 , -NR 12 R 13 , -C(=O)OR 14 , -C(=O)NR 15 R 16 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, “5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O and N”, C 6-20 aryl, “5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O and N”, C 1-6 alkyl substituted by one or more R 1-1-1 , C 1-6 alkyl-O- substituted by one or more R 1-1-2 , C 3-10 cycloalkyl substituted by one or more R 1-1-3 , substituted by one or more R 1-1-4 , a 5- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from O and N, a C 6-20 aryl group substituted by one or more R 1-1-5 , or a 5- to 7-membered heteroaryl group containing 1 or 2 heteroatoms independently selected from O and N, substituted by one or more R 1-1-6 ; when there are multiple substituents, the same or different; or, when R 1-1 or R 1-2 is plural, any two R 1-1 or two R 1-2 are connected to independently form a 3-8 membered cycloolefin together with the atoms in the ring to which they are connected;

R c , R 12 and R 13 are independently hydrogen, C 1-6 alkyl, C(═O)R c1 , —C(═O)OR c2 , —C(═O)NR c3 R c4 or —SO 2 R c5 ; R c1 , R c2 , R c3 , R c4 and R c5 are independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, “5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O and N”, C 6-20 aryl, “5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O and N”, C 1-6 alkyl substituted by one or more R 4-1-1 , C 3-10 cycloalkyl substituted by one or more R 4-1-2 , "5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O and N" substituted by R 4-1-3 , C 6-20 aryl substituted by one or more R 4-1-4 , or "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O and N" substituted by one or more R 4-1-5 ; when there are multiple substituents, they may be the same or different;

R 1-1-1 , R 1-1-2 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-6 , R 4-1-1 , R 4-1-2 , R 4-1-3 , R 4-1-4 and R 4-1-5 are independently cyano, halogen, hydroxyl, C 1-6 alkyl-O-, C 1-6 alkyl, -C(＝O)R 21 , -NR 22 R 23 , -C(＝O)OR 24 , or -C(＝O)NR 25 R 26 ;

R 11 , R 21 , R 22 , R 23 , R 14 , R 24 , R 15 , R 25 , R 16 and R 26 are independently hydrogen or C 1-6 alkyl;

L1 is a linking bond, C1-6 alkylene, -C(＝O)-, -O(R L-1 ) n1 -, -S(R L-2 ) n2 - or -NR L-3 (R L-4 ) n3 -; R L-1 , R L-2 and R L-4 are independently C1-6 alkylene; R L-3 is hydrogen or C1-6 alkyl; n1, n2 and n3 are independently 0 or 1;

R 3 is C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 3-1 , "4-12 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N", "4-12 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N" substituted by one or more R 3-2 , C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 3-3 , -OR d , -SR d1 , -NR e1 R e2 , or -C(＝O)NR e3 R e4 ; when there are multiple substituents, they may be the same or different;

R 3-1 , R 3-2 and R 3-3 are independently C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 3-1-1 , hydroxy, azido, C 1-6 alkyl-O-, halogen, O=, CH 2 =, -NR e5 R e6 or -C(=O)NR e7 R e8 ;

R d , R d1 , Re1 , Re2 , Re3 and Re4 are independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, "4-10 membered heterocycloalkyl containing 1 to 3 heteroatoms which are independently selected from O and N", or C 1-6 alkyl substituted by one or more R 3-1-2 ;

R 3-1-1 and R 3-1-2 are independently deuterium, cyano, halogen, hydroxyl, C 1-6 alkyl-O-, -C(═O)R e9 , -NR e10 R e11 , -C(═O)OR e12 , or -C(═O)NR e13 R e14 ;

Re5 , Re6 , Re7 , Re8, Re9 , Re10 , Re11 , Re12 , Re13 and Re14 are independently hydrogen or C1-6 alkyl; or, Re5 and Re6 , Re7 and Re8 , Re10 and Re11 , Re13 and Re14 respectively form with the N atom to which they are connected “a 4-12 membered heterocycloalkyl group containing 1 to 3 heteroatoms , one of which is N, and the other heteroatoms are independently selected from O, S and N”;

R6 is hydrogen, C1-6 alkyl, C3-10 cycloalkyl, "5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O and N", C6-20 aryl, "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O and N", C1-6 alkyl substituted by one or more R6-1 , C3-10 cycloalkyl substituted by one or more R6-2 , "5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from O and N" substituted by one or more R6-3 , C6-20 aryl substituted by one or more R6-4 , or "5-7 membered heteroaryl containing 1 or 2 heteroatoms independently selected from O and N" substituted by one or more R6-5 ; when there are multiple substituents, they may be the same or different;

Alternatively, R2 and R6 together with the atoms in the ring to which they are connected form a "4-8 membered heterocyclic ring containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N", or, a " 4-8 membered heterocyclic ring containing 1 to 3 heteroatoms, wherein One heteroatom is N, and the other heteroatoms are independently selected from O, S and N in a 4- to 8-membered heterocyclic ring";

R 6-1 , R 6-2 , R 6-3 , R 6-4 , R 6-5 and R 6-6 are independently cyano, halogen, hydroxyl, C 1-6 alkyl-O-, C 1-6 alkyl, -C(═O)R 61 , -NR 62 R 63 , -C(═O)OR 64 , or -C(═O)NR 65 R 66 ;

R 61 , R 62 , R 63 , R 64 , R 65 and R 66 are independently hydrogen or C 1-6 alkyl;

third solution:

represents a single bond or a double bond;

A is O;

s is 0;

q is 0 or 1;

p is 0 or 1;

m is 0 or 1;

n is 0;

is phenyl, "a 5-7 membered heterocycloalkenyl group containing 1 to 3 heteroatoms selected from O, S and N", or "a 5-7 membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S and N"; wherein D1 is C or N; D2 is Wherein Z 1 and Z 2 are independently a linker, CH, CH 2 or N;

r is 0, 1, or 2;

R 5 is independently halogen;

X1 and X2 are independently N;

R 1 is a C 6-20 aryl group substituted by one or more R 1-1 , or a 5-12-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S and N substituted by one or more R 1-2 ; when there are multiple substituents, they may be the same or different;

R 1-1 and R 1-2 are independently halogen, -OR c , cyano, azido, -NR 12 R 13 , C 1-6 alkyl, C 2-6 alkynyl, or C 1-6 alkyl substituted by one or more R 1-1-1 ; when there are multiple substituents, they may be the same or different;

R c , R 12 and R 13 are independently hydrogen, C(═O)R c1 or —C(═O)NR c3 R c4 ; R c1 , R c3 and R c4 are independently hydrogen or C 1-6 alkyl;

R 1-1-1 is halogen;

L1 is -O(R L-1 ) n1 -; R L-1 is C 1-6 alkylene; n1 is 1;

R3 is a C3-12 cycloalkyl substituted by one or more R3-1 , or a 4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N substituted by one or more R3-2 ; when there are multiple substituents, they may be the same or different;

R 3-1 and R 3-2 are independently C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 3-1-1 , halogen or CH 2 ＝;

R 3-1-1 is -NR e10 R e11 ;

R e10 and R e11 are independently C 1-6 alkyl; or, R e10 and R e11 and the N atom to which they are connected form a "4-12 membered heterocycloalkyl group containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N";

R6 is C1-6 alkyl;

Alternatively, R2 and R6 together with the atoms in the ring to which they are connected form a "4-8 membered heterocyclic ring containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N".
The nitrogen-containing polycyclic compound as shown in formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof according to any one of claims 1 to 3, characterized in that:

The C 1-6 alkyl group is independently C 1-4 alkyl group at each occurrence, further methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;

and/or, when R 2 is C 2-6 alkenyl, the C 2-6 alkenyl is vinyl, propenyl or allyl;

and/or, when R 2 , R 1-1 and R 1-2 are independently C 2-6 alkynyl, the C 2-6 alkynyl is C 2-3 alkynyl, such as ethynyl, propynyl or propargyl;

and/or, when R 2 is a C 1-6 alkyl group substituted by one or more R 2-1 , the C 1-6 alkyl group is a C 1-4 alkyl group, further being methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;

and/or, when R 2 , R 4 , R 5 , R 2-1 , R 2-2 , R 2-3 , R 2-4, R 2-5 , R 4-1 , R 4-2 , R 4-3 , R b , R 1-1 , R 1-2 , R 1-1-1 , R 1-1-2 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-6 , R 4-1-1 , R 4-1-2 , R 4-1-3 , R 4-1-4 and R 4-1-5 , R 3-1 , R 3-2 and R 3-3 , R 3-1-1 , R 3-1-2 , R 6-1 , R 6-2 , R 6-3 When halogen is mentioned in the definitions of R 6-4 , R 6-5 , R 6-6 , Re15 and Re16 , the halogen is fluorine, chlorine, bromine or iodine;

and/or, when R 1 is a C 6-20 aryl group or a C 6-20 aryl group substituted by one or more R 1-1 , the C 6-20 aryl group is a phenyl group or a naphthyl group;

and/or, when R 1 is a "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S and N" substituted by one or more R 1-2 , the "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S and N" is a "6- to 9-membered heteroaryl group containing 1 to 2 heteroatoms independently selected from O, S and N", and further is pyridyl, thienyl or benzothiazolyl;

and/or, when RL-1 is C1-6 alkylene, the C1-6 alkylene is -CH2- , -CH2CH2- , -CH2CH2CH2- , -CH ( CH3) CH2- , -CH2CH2CH2CH2- , -CH(CH3 ) CH2CH2- , -CH2CH ( CH3 ) CH2CH2- , -CH2CH( CH3 ) CH2CH2- , or -C( CH3 ) 2CH2- ;

and/or, when R 3 is a C 3-12 cycloalkyl substituted by one or more R 3-1 , the C 3-12 cycloalkyl is a C 3 - 6 cycloalkyl, such as cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

and/or, when R 3 is a "4- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S and N" substituted by one or more R 3-2 , the "4- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S and N" is a monocycloalkyl group, a spirocycloalkyl group or a bridged cycloalkyl group;

And/or, when Re10 and Re11 form a "4- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N" with the N atom to which they are connected, the "4- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, S and N" is "an 8- to 10-membered heterocycloalkyl group containing 2 heteroatoms, one of which is N, and the other is O", and is further a bridged cycloalkyl group;

And/or, when D2 is When Z 1 and Z 2 are independently a linker, CH, CH 2 or N, among Z 1 and Z 2 , Z 1 is a linker, and Z 2 is CH, CH 2 or N;

and/or, R 1 is C 6-20 aryl substituted by one or more R 1-1 ; R 1-1 is independently halogen, -OR c , azido, -NR 12 R 13 , C 1-6 alkyl, C 2-6 alkynyl, or C 1-6 alkyl substituted by one or more R 1-1-1 ; R c , R 12 and R 13 are independently hydrogen, C 1-6 alkyl substituted by one or more -OC 1-6 alkyl, C(＝O)R c1 or -C(＝O)NR c3 R c4 ; R c1 , R c3 and R c4 are independently hydrogen or C 1-6 alkyl; R 1-1-1 is independently halogen;

and/or when When it is a “5- to 7-membered heterocycloalkenyl group containing 1 to 3 heteroatoms selected from O, S and N”, the “5- to 7-membered heterocycloalkenyl group containing 1 to 3 heteroatoms selected from O, S and N” is a 5- to 7-membered heterocycloalkenyl group containing 1 N atom;

and/or when When it is a “5- to 7-membered heteroaryl group containing 1 to 3 heteroatoms which are independently selected from O, S and N”, the “5- to 7-membered heteroaryl group containing 1 to 3 heteroatoms which are independently selected from O, S and N” is a 5- to 7-membered heteroaryl group containing 1 N atom.
The nitrogen-containing polycyclic compound as shown in formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof according to any one of claims 1 to 3, characterized in that:

R1 is

and/or, L 1 is -OCH 2 -;

and/or, R3 is

and/or, R 6 is -CH 3 , or, R 2 and R 6 together with the atoms in the ring to which they are connected form a "5-membered heterocyclic ring containing 1 heteroatom N";

and / or, for
The nitrogen-containing polycyclic compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof as described in any one of claims 1 to 3, characterized in that the nitrogen-containing polycyclic compound as shown in Formula I is any of the following compounds:
A compound whose structure is shown below:
A pharmaceutical composition comprising substance A and pharmaceutical excipients; the substance A is a therapeutically effective amount of a nitrogen-containing polycyclic compound as shown in formula I as described in any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof.
A use of a substance A in the preparation of a RAS inhibitor, wherein the substance A is a nitrogen-containing polycyclic compound as shown in formula I as described in any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof.
A use of a substance A in the preparation of a drug, wherein the drug is used to treat or prevent RAS-related diseases; the substance A is a nitrogen-containing polycyclic compound as shown in formula I as described in any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotope compound thereof.
The use according to claim 8 or 9, characterized in that the RAS is wild-type RAS and mutant RAS; the mutant RAS is KRAS mutation, HRAS mutation or NRAS mutation.
A use of a substance A in the preparation of a drug, wherein the drug is used to treat or prevent cancer; the substance A is a nitrogen-containing polycyclic compound as shown in formula I as described in any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or an isotope compound thereof.
The use according to claim 9 or 11 is characterized in that the cancer is one or more of colon cancer, appendix cancer, pancreatic cancer, MYH-related polyposis, blood cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, gastric cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.