RU2842251C2 - Heterocyclic compound having anticancer activity, and use thereof - Google Patents

Abstract

FIELD: medical science.

SUBSTANCE: group of inventions relates to the field of medicine, in particular to pharmaceutical chemistry, and includes triheterocyclic compounds of formula (B), (D), individual compounds presented in the claims, optical isomers and pharmaceutical salts of said compounds, a pharmaceutical composition based thereon and intermediate compounds of formulas (V), (VI), (VII). Values of substitutes in formulas (B), (D), (V), (VI), (VII) are as given in the claim.

EFFECT: triheterocyclic compounds exhibiting the properties of SOS1 inhibitors.

21 cl, 125 ex

Description

CROSS-REFERENCE TO RELATED APPLICATION

The present invention claims the priority and benefits of Chinese Patent Application No. 202111561282.9, filed on December 17, 2021, entitled "HETEROCYCLIC COMPOUND HAVING ANTITUMOR ACTIVITY AND USE THEREOF", and the priority and benefits of Chinese Patent Application No. 202210634934.5, filed on June 7, 2022, entitled "HETEROCYCLIC COMPOUND HAVING ANTITUMOR ACTIVITY AND USE THEREOF", the disclosure of which is incorporated herein by reference in its entirety.

AREA OF TECHNOLOGY

The present invention relates to the technical field of medicine and, in particular, relates to a compound as an SOS1 inhibitor, a composition containing it, a method for producing it and its use.

LEVEL OF TECHNOLOGY

Currently, three genes are known in the RAS family: KRAS (Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog), and HRAS (Harvey mouse sarcoma viral oncogene). RAS family proteins are a class of small GTPases, and RAS is also the first oncogene identified in human tumors. RAS family proteins have weak intrinsic GTPase activity and slow nucleotide turnover rates. Binding of GTPase-activating proteins (GAPs), such as NF1, increases the GTPase activity of RAS family proteins.

Mutations in RAS enzymes are associated with tumorigenesis. The types of RAS mutations vary among tumor types. In human tumors, KRAS mutations (eg, amino acids G12, G13, Q61, A146) are the most common, accounting for about 85%, whereas NRAS mutations (eg, amino acids G12, G13, Q61, A146) and HRAS mutations (eg, amino acids G12, G13, Q61) account for 12% and 3%, respectively. Alterations (eg, mutation, overexpression, gene amplification) in RAS family proteins have also been described as a mechanism of resistance to anticancer drugs, such as the EGFR antibodies cetuximab and panitumumab and the EGFR tyrosine kinase inhibitor osimertinib. For oncogenic RAS mutants, GAP activity is attenuated or significantly reduced, resulting in constitutive activation that underlies oncogenic RAS signaling. Direct inhibition of RAS has been shown to be extremely challenging and refractory to drug targeting due to the picomolar affinity of RAS for GTP at the binding site, the absence of other well-defined pockets, and the extensive and flat protein-protein interactions of RAS with GEFs, GAPs, and effectors. Therefore, inhibition of RAS activation by targeting upstream guanine nucleotide exchange factors such as SOS proteins may hold new promise.

There are two isoforms of human SOS, i.e. SOS1 and SOS2, but most studies have focused on SOS1. Human SOS1 contains 1333 amino acids (15 kDa) having a structure containing an N-terminal histone-like domain, a Dbl homology (DH) domain, a pleckstrin homology (PH) domain, a helical linker (HL), a Ras exchange motif (Rem) domain, and a Cdc25 domain, as well as a C-terminal domain. Of these, PH, Rem, and Cdc25 are components of the catalytic core of the SOS ^cat domain.

In recent decades, interactions between RAS family proteins and SOS1 proteins have been increasingly recognized. In addition, studies have recently been conducted to combine rational design and a screening platform to screen and identify small molecule SOS1 inhibitors, i.e., compounds that bind to SOS1 and inhibit protein-protein interactions with RAS family proteins. For example, a variety of fused cyclic SOS1 inhibitors are described in WO2021105960A1.

Although some small molecule SOS1 inhibitors have been identified, no SOS1 inhibitors have been developed or commercialized at present. Therefore, there is still an urgent need to develop new compounds with marketability potential and better pharmacodynamic and pharmacokinetic properties.

BRIEF DESCRIPTION OF THE INVENTION

The present invention aims to provide a new compound as an SOS1 inhibitor, a composition containing it, a method for producing it and its use for treating a disease mediated by SOS1.

According to a first aspect of the present invention, there is provided a compound represented by the following formula (A), or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof,

(A)

Where represents a single bond or a double bond;

Y and Z both represent C or N, where Z is C when Y is N, and Z is N when Y is C;

Y and Z together with the atoms to which they are attached form a ring A, wherein said ring A is a 5- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl;

one, two or three R's are present², each of which, in each instance, independently represents hydrogen, halogen, hydroxyl, cyano, amino, nitro, formyl, oxo, C_1-6alkyl, C_1-6alkoxy, -C_1-6alkyl-NH(C_1-6alkyl), -C_1-6alkyl-N(C_1-6alkyl)₂, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, where the indicated C_1-6alkyl, C_1-6alkoxy, -C_1-6alkyl-NH(C_1-6alkyl), -C_1-6alkyl-N(C_1-6alkyl)₂, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl all optionally substituted with one or more cyano, hydroxyl or halogen;

R³represents hydrogen, halogen, hydroxyl, amino, cyano, C_1-6alkyl, C_1-6alkoxy, C_3-6cycloalkyl or 3-6-membered heterocyclyl, wherein the specified C_1-6alkyl, C_1-6alkoxy, C_3-6cycloalkyl and 3-6-membered heterocyclyl are all optionally substituted with one or more hydroxyls or halogens;

ring B is C_4-12cycloalkyl, C_4-12cycloalkenyl, 4-12-membered heterocyclyl_,C_6-12aryl, 5-12-membered heteroaryl_,C_6-12aryl condensed C_4-12cycloalkyl_,C_6-12aryl-fused 4-12-membered heterocyclyl or C_6-12aryl fused C_4-12cycloalkenyl;

each R⁴, if present, independently represents hydrogen, cyano, halogen, amino, hydroxyl, oxo, nitro, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, -C_0-6alkyl-NH-C_1-6alkyl, -C_0-6alkyl-N(C_1-6alkyl)(C_1-6alkyl), C_3-6cycloalkyl, C_3-6halocycloalkyl or 3-6-membered heterocyclyl, wherein the specified C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, -C_0-6alkyl-NH-C_1-6alkyl, -C_0-6alkyl-N(C_1-6alkyl)(C_1-6alkyl), C_3-6cycloalkyl, C_3-6halocycloalkyl and 3-6 membered heterocyclyl are all optionally substituted with one or more of the following substituents: halogen, hydroxyl, amino, -SO₂-C_1-4alkyl or oxo; w is 0, 1, 2, 3 or 4;

When represents a double bond, X represents C, and R ¹ attached to it represents -OR ^A , -N(R ^D )R ^B , or R ^C ;

when R¹represents -O-R^A, R^Arepresents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the specified C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3-10-membered heterocyclyl and 5-10-membered heteroaryl all optionally substituted with 1-3 identical or different R^a1;

each R^a1if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, -OC_1-6alkyl, -SC_1-6alkyl, -COC_1-6alkyl, -CH₂COC_1-6alkyl, -CH₂CON(C_1-6alkyl)₂, -CH₂CONHC_1-6alkyl, -NHC_1-6alkyl, -N(C_1-6alkyl)₂, C_3-10cycloalkyl, C_6-10aryl, 3-10-membered heterocyclyl or 5-10-membered heteroaryl;

when R¹represents -N(R^D)R^B, R^Brepresents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, where the indicated C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are all optionally substituted with 1-3 identical or different R^b1;

each R^b1, if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, -OC_1-6alkyl, -SC_1-6alkyl, -COC_1-6alkyl, -CH₂COC_1-6alkyl, -CH₂CON(C_1-6alkyl)₂, -CH₂CONHC_1-6alkyl, -NHC_1-6alkyl, -N(C_1-6alkyl)₂, C_3-10cycloalkyl, C_6-10aryl, 3-10-membered heterocyclyl or 5-10-membered heteroaryl;

R ^D is hydrogen, halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OC _1-6 alkyl, -SC _1-6 alkyl, -COC _1-6 alkyl, -CH ₂ COC _1-6 alkyl, -CH ₂ CON(C _1-6 alkyl) ₂ , -CH ₂ CONHC _1-6 alkyl, -NHC _1-6 alkyl or -N(C _1-6 alkyl) ₂ ;

when R¹represents R^C, R^Crepresents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, where the indicated C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, all optionally substituted with 1-4 identical or different R^c1;

each R^c1, if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, methylsulfonyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, -OC_1-6alkyl, -SC_1-6alkyl, -COC_1-6alkyl, -COC_3-6cycloalkyl, -CH₂COC_1-6alkyl, -CH₂CON(C_1-6alkyl)₂, -CH₂CONHC_1-6alkyl, -NHC_1-6alkyl, -N(C_1-6alkyl)₂, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the specified C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, -OC_1-6alkyl, -SC_1-6alkyl, -COC_1-6alkyl, -COC_3-6cycloalkyl, -CH₂COC_1-6alkyl, -CH₂CON(C_1-6alkyl)₂, -CH₂CONHC_1-6alkyl, -NHC_1-6alkyl, -N(C_1-6alkyl)₂, C_3-10cycloalkyl, C_6-10aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl are all optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, C_1-3alkyl, C_1-3 alkoxy or halogen;

When represents a single bond, X represents N, and attached to it R¹represents C_3-10cycloalkyl, C_3-10cycloalkenyl, C_6-10aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, where the indicated C_3-10cycloalkyl, C_3-10cycloalkenyl, C_6-10aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are all optionally substituted by one or more of the same or different R^a4and/or R^b4;

each R^a4, if present, independently represents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the specified C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are all optionally substituted by one or more of the same or different R^b4and/or R^c4;

each R ^b4 , if present, is independently -OR ^c4 , -NR ^c4 R ^c4 , halogen, -CN, -C(O)R ^c4 , -C(O)OR ^c4 , -C(O)NR ^c4 R ^c4 , -OC(O)R ^c4 , -S(O) ₂ R ^c4 , -S(O) ₂ NR ^c4 R ^c4 , -NHC(O)R ^c4 , -N(C _1-4 alkyl)C(O)R ^c4 , -NHC(O)OR ^c4 or a divalent substituent =O or =NH, wherein said =O and =NH may be substituents only on a non-aromatic ring system;

every R^c4, if present, independently represents hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the specified C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are all optionally substituted by one or more of the same or different R^d4and/or R^e4;

every R^d4, if present, independently represents -OR^e4, -NR^e4R^e4, halogen, -CN, -C(O)R^e4, -C(O)OR^e4, -C(O)NR^e4R^e4, -S(O)₂R^e4 _,-S(O)₂NR^e4R^e4, -NHC(O)R^e4, -N(C_1-4alkyl)C(O)R^e4or a divalent substituent =O, where said =O can only be a substituent in a non-aromatic ring system;

each R^e4, if present, independently represents hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the specified C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl all optionally substituted with one or more hydrogen, cyano, hydroxyl or halogen;

where Z and Y are considered to be atoms of ring A and are counted in the number of atoms of ring A.

Unless otherwise specified, each of the heteroatoms in a heteroaryl and heterocyclyl is independently O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.

Preferably, the present invention provides a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof, wherein the compound has a structure represented by formula (A'):

(A'),

the substituents in formula (A') are as defined in formula (A).

The present invention further relates to a compound represented by the following formula (I), or a stereoisomer, optical isomer, pharmaceutical salt, prodrug or solvate:

(I),

Where represents a single bond or a double bond;

Y and Z both represent C or N, where Z is C when Y is N, and Z is N when Y is C;

Y and Z together with the atoms to which they are attached form a ring A, wherein said ring A is a 5- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl;

one, two or three R's are present², each of which, in each case, independently represents hydrogen, halogen, hydroxyl, cyano, amino, nitro, formyl, oxo, C_1-6alkyl, C_1-6alkoxy, -C_1-6alkyl-NH(C_1-6alkyl), -C_1-6alkyl-N(C_1-6alkyl)₂, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, where the indicated C_1-6alkyl, C_1-6alkoxy, -C_1-6alkyl-NH(C_1-6alkyl), -C_1-6alkyl-N(C_1-6alkyl)₂, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl all optionally substituted with one or more cyano, hydroxyl or halogen;

R³represents hydrogen, halogen, hydroxyl, amino, cyano, C_1-6alkyl, C_1-6alkoxy, C_3-6cycloalkyl or 3-6-membered heterocyclyl, wherein the specified C_1-6alkyl, C_1-6alkoxy, C_3-6cycloalkyl and 3-6-membered heterocyclyl are all optionally substituted with one or more hydroxyls or halogens;

ring B is C_4-12cycloalkyl, C_4-12cycloalkenyl, C_4-12heterocyclyl_,C_6-12aryl, C_5-12heteroaryl, C_6-12aryl condensed C_4-12cycloalkyl_,C_6-12aryl condensed C_4-12heterocyclyl or C_6-12aryl fused C_4-12cycloalkenyl;

each R⁴, if present, independently represents hydrogen, cyano, halogen, amino, hydroxyl, oxo, nitro, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, -C_0-6alkyl-NH-C_1-6alkyl, -C_0-6alkyl-N(C_1-6alkyl)(C_1-6alkyl), C_3-6cycloalkyl, C_3-6halocycloalkyl or 3-6-membered heterocyclyl, wherein the specified C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, -C_0-6alkyl-NH-C_1-6alkyl, -C_0-6alkyl-N(C_1-6alkyl)(C_1-6alkyl), C_3-6cycloalkyl, C_3-6halocycloalkyl and 3-6 membered heterocyclyl are all optionally substituted with one or more of the following substituents: halogen, hydroxyl, amino, -SO₂-C_1-4alkyl or oxo; w is 0, 1, 2, 3 or 4;

When represents a double bond, X represents C, and R is attached to it¹represents -O-R^A, -N(R^D)R^B or R^C;

when R¹represents -O-R^A, R^Arepresents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the specified C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3-10-membered heterocyclyl and 5-10-membered heteroaryl all optionally substituted with 1-3 identical or different R^a1;

each R^a1, if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, -OC_1-6alkyl, -SC_1-6alkyl, -COC_1-6alkyl, -CH₂COC_1-6alkyl, -CH₂CON(C_1-6alkyl)₂, -CH₂CONHC_1-6alkyl, -NHC_1-6alkyl, -N(C_1-6alkyl)₂, C_3-10cycloalkyl, C_6-10aryl, 3-10-membered heterocyclyl or 5-10-membered heteroaryl;

when R¹represents -N(R^D)R^B, R^Brepresents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, where the indicated C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, all optionally substituted with 1-3 identical or different R^b1;

each R^b1, if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, -OC_1-6alkyl, -SC_1-6alkyl, -COC_1-6alkyl, -CH₂COC_1-6alkyl, -CH₂CON(C_1-6alkyl)₂, -CH₂CONHC_1-6alkyl, -NHC_1-6alkyl, -N(C_1-6alkyl)₂, C_3-10cycloalkyl, C_6-10aryl, 3-10-membered heterocyclyl or 5-10-membered heteroaryl;

R ^D is hydrogen, halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OC _1-6 alkyl, -SC _1-6 alkyl, -COC _1-6 alkyl, -CH ₂ COC _1-6 alkyl, -CH ₂ CON(C _1-6 alkyl) ₂ , -CH ₂ CONHC _1-6 alkyl, -NHC _1-6 alkyl or -N(C _1-6 alkyl) ₂ ;

when R¹represents R^C, R^Crepresents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, where the indicated C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, all optionally substituted with 1-3 identical or different R^c1;

each R^c1, if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, -OC_1-6alkyl, -SC_1-6alkyl, -COC_1-6alkyl, -CH₂COC_1-6alkyl, -CH₂CON(C_1-6alkyl)₂, -CH₂CONHC_1-6alkyl, -NHC_1-6alkyl, -N(C_1-6alkyl)₂, C_3-10cycloalkyl, C_6-10aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, where the indicated C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, -OC_1-6alkyl, -SC_1-6alkyl, -COC_1-6alkyl, -CH₂COC_1-6alkyl, -CH₂CON(C_1-6alkyl)₂, -CH₂CONHC_1-6alkyl, -NHC_1-6alkyl, -N(C_1-6alkyl)₂, C_3-10cycloalkyl, C_6-10aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are all optionally substituted with one or more substituents selected from hydroxyl, C_1-3alkyl, C_1-3 alkoxy or halogen;

When represents a single bond, X represents N, and attached to it R¹represents C_3-10cycloalkyl, C_3-10cycloalkenyl, C_6-10aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, where the indicated C_3-10cycloalkyl, C_3-10cycloalkenyl, C_6-10aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are all optionally substituted by one or more of the same or different R^a4and/or R^b4;

each R^a4, if present, independently represents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the specified C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are all optionally substituted by one or more of the same or different R^b4and/or R^c4;

each R ^b4 , if present, is independently -OR ^c4 , -NR ^c4 R ^c4 , halogen, -CN, -C(O)R ^c4 , -C(O)OR ^c4 , -C(O)NR ^c4 R ^c4 , -OC(O)R ^c4 , -S(O) ₂ R ^c4 , -S(O) ₂ NR ^c4 R ^c4 , -NHC(O)R ^c4 , -N(C _1-4 alkyl)C(O)R ^c4 , -NHC(O)OR ^c4 or a divalent substituent =O or =NH, wherein said =O and =NH may be substituents only on a non-aromatic ring system;

each R^c4, if present, independently represents hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the specified C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are all optionally substituted by one or more of the same or different R^d4and/or R^e4;

each R ^d4 , if present, is independently -OR ^e4 , -NR ^e4 R ^e4 , halogen, -CN, -C(O)R ^e4 , -C(O)OR ^e4 , -C(O)NR ^e4 R ^e4 , -S(O) ₂ R ^e4 , -S(O) ₂ NR ^e4 R ^e4 , -NHC(O)R ^e4 , -N(C _1-4 alkyl)C(O)R ^e4 or a divalent substituent =O, wherein said =O can only be a substituent on a non-aromatic ring system;

each R^e4, if present, independently represents hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the specified C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl all optionally substituted with one or more hydrogen, cyano, hydroxyl or halogen;

where Z and Y are considered to be atoms of ring A and are counted in the number of atoms of ring A.

Unless otherwise specified, each of the heteroatoms in a heteroaryl and heterocyclyl is independently O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.

Preferably, the present invention provides a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug or solvate thereof, wherein the compound has a structure represented by formula (II):

(II),

the substituents in formula (II) are as defined in formula (I).

Preferably, the present invention provides a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug or solvate thereof, wherein the compounds have a structure represented by formula (III):

(III),

the substituents in formula (III) are as defined in formula (I).

Preferably, the present invention provides a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug or solvate thereof, wherein the compound has a structure represented by formula (IV):

(IV),

the substituents in formula (IV) are as defined in formula (I).

In one preferred embodiment of the present invention,represents a double bond, X represents C, and attached to it R¹represents -O-R^A.

Preferably R^Arepresents C_1-6alkyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the specified C_1-6alkyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, all optionally substituted with 1-3 identical or different R^a1;

each R^a1, if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, -OC_1-6alkyl, -SC_1-6alkyl, -COC_1-6alkyl, -CH₂COC_1-6alkyl, -CH₂CON(C_1-6alkyl)₂, -CH₂CONHC_1-6alkyl, -NHC_1-6alkyl or -N(C_1-6alkyl)₂.

More preferably R^Arepresents C_3-6cycloalkyl, C_6-10aryl, 3-6-membered heterocyclyl or 5-6-membered heteroaryl, wherein the specified C_3-6cycloalkyl, C_6-10aryl, 3- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl, all optionally substituted with 1-3 identical or different R^a1;

each R^a1, if present, independently represents halogen, hydroxyl, cyano, amino, oxo, formyl, C_1-6alkyl, -OC_1-6alkyl, -SC_1-6alkyl or -COC_1-6alkyl.

More preferably, R ^A is 5-6-membered heterocyclyl or 5-6-membered heteroaryl, wherein said 5-6-membered heterocyclyl and 5-6-membered heteroaryl are both optionally substituted with 1-3 identical or different R ^a1 ;

each R^a1, if present, independently represents halogen, hydroxyl, cyano, amino, oxo, formyl, C_1-4alkyl, -OC_1-4alkyl, -SC_1-4alkyl or -COC_1-4alkyl.

More preferably, R^Ais a 5-6-membered heterocyclyl, wherein said 5-6-membered heterocyclyl is optionally substituted with one or two identical or different R^a1;

each R ^a1 , if present, is independently halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

More preferably, R ^A is a 5-6-membered monocyclic heterocyclyl, wherein said 5-6-membered monocyclic heterocyclyl is optionally substituted with one or two identical or different R ^a1 ; each of the heteroatoms in said 5-6-membered monocyclic heterocyclyl is independently O, N or S, and the number of heteroatoms is 1;

each R ^a1 , if present, is independently halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

More preferably, R^Arepresents tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl, wherein said tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl are all optionally substituted with one or two identical or different R^a1;

each R ^a1 , if present, is independently halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

Even more preferably, R ^A represents the following group: , , , , , or .

In one preferred embodiment of the present invention, is a double bond, X is C, and R ¹ attached to it is -N(R ^D )R ^B .

Preferably R^Brepresents C_1-6alkyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the specified C_1-6alkyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, all optionally substituted with 1-3 identical or different R^b1;

every R^b1, if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, C_1-6alkyl, -OC_1-6alkyl, -SC_1-6alkyl or -COC_1-6alkyl.

More preferable R^Brepresents C_1-6alkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein said C_1-6alkyl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, all optionally substituted with 1-3 identical or different R^b1;

each R^b1, if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, C_1-6alkyl, -OC_1-6alkyl, -SC_1-6alkyl or -COC_1-6alkyl.

More preferable R^Brepresents C_1-6alkyl or 5-6-membered monocyclic heterocyclyl, wherein the specified C_1-6alkyl and 5-6-membered monocyclic heterocyclyl, both optionally substituted by one or two identical or different R^b1; each of the heteroatoms in said 5-6-membered monocyclic heterocyclyl is independently O, N or S, and the number of heteroatoms is 1;

each R^b1, if present, independently represents halogen, oxo, formyl, C_1-4alkyl, -OC_1-4alkyl or -COC_1-4alkyl.

More preferable R^Brepresents methyl, ethyl, n-propyl, isopropyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl, wherein said methyl, ethyl, n-propyl, isopropyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl are all optionally substituted with one or two identical or different R^b1;

each R ^b1 , if present, is independently oxo, formyl, acetyl, methyl, ethyl, methoxy or ethoxy.

Even more preferable, R^Brepresents the following group:, or .

Preferably R^Dis hydrogen, C_1-6alkyl or -OC_1-6alkyl; more preferably R^Dis hydrogen or C_1-3alkyl; even more preferably R^Dis hydrogen or methyl; most preferably R^Dis hydrogen.

In one preferred embodiment of the present invention,represents a double bond, X represents C, and R is attached to it¹represents R^C.

Preferably R^Crepresents C_1-6alkyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the specified C_1-6alkyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, all optionally substituted with 1-3 identical or different R^c1;

each R^c1, if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, -OC_1-6alkyl, -SC_1-6alkyl, -COC_1-6alkyl, -CH₂COC_1-6alkyl, -CH₂CON(C_1-6alkyl)₂, -CH₂CONHC_1-6alkyl, -NHC_1-6alkyl, -N(C_1-6alkyl)₂, C_3-10cycloalkyl or 3-10-membered heterocyclyl, wherein the specified C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, -OC_1-6alkyl, -SC_1-6alkyl, -COC_1-6alkyl, -CH₂COC_1-6alkyl, -CH₂CON(C_1-6alkyl)₂, -CH₂CONHC_1-6alkyl, -NHC_1-6alkyl, -N(C_1-6alkyl)₂, C_3-10cycloalkyl and 3- to 10-membered heterocyclyl, all optionally substituted with one or more substituents selected from hydroxyl, C_1-3alkyl, C_1-3 alkoxy or halogen.

More preferable R^Crepresents C_1-6alkyl, C_3-10cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein said C_1-6alkyl, C_3-10cycloalkyl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, all optionally substituted with 1-3 identical or different R^c1;

each R^c1, if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, C_1-4alkyl, -OC_1-4alkyl, -SC_1-4alkyl, -COC_1-4alkyl, -CH₂CON(C_1-4alkyl)₂, -CH₂CONHC_1-4alkyl or 3-6-membered heterocyclyl, wherein the specified C_1-4alkyl, -OC_1-4alkyl, -SC_1-4alkyl, -COC_1-4alkyl, -CH₂CON(C_1-4alkyl)₂, -CH₂CONHC_1-4alkyl and 3-6 membered heterocyclyl are all optionally substituted with one or more substituents selected from hydroxyl, methyl, methoxy or halogen.

More preferable R^Crepresents a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, wherein said 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are both optionally substituted with 1-3 identical or different R^c1;

each R^c1, if present, independently represents halogen, hydroxyl, cyano, amino, oxo, formyl, C_1-4alkyl, -OC_1-4alkyl, -COC_1-4alkyl, -CH₂CON(C_1-4alkyl)₂or 3-6-membered heterocyclyl, where the specified C_1-4alkyl, -OC_1-4alkyl, -COC_1-4alkyl, -CH₂CON(C_1-4alkyl)₂and 3-6 membered heterocyclyl all optionally substituted with one or more substituents selected from hydroxyl, methyl, methoxy or halogen.

More preferable R^Cis a 5- to 6-membered monocyclic heterocyclyl, 6- to 10-membered spiroheterocyclyl, 6- to 8-membered bridged heterocyclyl or 5- to 6-membered monocyclic heteroaryl, wherein said 5- to 6-membered monocyclic heterocyclyl, 6- to 10-membered spiroheterocyclyl, 6- to 8-membered bridged heterocyclyl and 5- to 6-membered monocyclic heteroaryl are all optionally substituted with 1- to 3 identical or different R^c1;

each R ^c1 , if present, is independently halogen, hydroxyl, cyano, amino, oxo, formyl, acetyl, propionyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH ₂ CON(CH ₃ ) ₂ or 6-membered heterocyclyl, wherein said acetyl, propionyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH ₂ CON(CH ₃ ) ₂ and 6-membered heterocyclyl are all optionally substituted with one or more substituents selected from hydroxyl, methyl, methoxy or halogen.

Even more preferable R^Crepresents a 6-membered monocyclic heterocyclyl, a 4-membered/6-membered spiroheterocyclyl, a 4-membered/4-membered spiroheterocyclyl, a 7-membered bridged heterocyclyl or a 6-membered monocyclic heteroaryl, wherein said 6-membered monocyclic heterocyclyl, 4-membered/6-membered spiroheterocyclyl, 4-membered/4-membered spiroheterocyclyl, 7-membered bridged heterocyclyl and 6-membered monocyclic heteroaryl are all optionally substituted with 1 to 3 identical or different R^c1;

each R ^c1 , if present, is independently halogen, hydroxyl, cyano, amino, oxo, formyl, acetyl, -COCH ₂ CH ₃ , -COCH ₂ OH, hydroxymethyl, hydroxyethyl, -CH ₂ OCH ₃ , methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH ₂ CON(CH ₃ ) ₂ or 6-membered heterocyclyl.

More preferable R^Crepresents,,,,,,,,,,, or , where indicated R^Call are not necessarily replaced by one or two identical or different R^c1;

each R ^c1 , if present, is independently F, Cl, Br, hydroxyl, cyano, amino, oxo, acetyl, -COCH ₂ CH ₃ , -COCH ₂ OH, hydroxymethyl, hydroxyethyl, -CH ₂ OCH ₃ , methoxy, methyl, ethyl, isopropyl, -CH ₂ CON(CH ₃ ) ₂ or morpholinyl.

Even more preferable is R^C, not necessarily substituted R^c1, represents the following group:,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, or .

In one preferred embodiment of the present invention, ring A is a 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein each of the heteroatoms in the 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl is independently O or N, and the number of heteroatoms is from 1 to 4.

More preferably, Ring A is a 5-membered monocyclic heterocyclyl, a 6-membered monocyclic heterocyclyl, a 5-membered monocyclic heteroaryl, a 6-membered monocyclic heteroaryl, a 5-membered/5-membered fused heterocyclyl, a 5-membered/4-membered fused heterocyclyl, a 5-membered/6-membered fused heterocyclyl, a 6-membered/5-membered fused heterocyclyl, a 6-membered/4-membered fused heterocyclyl, a 6-membered/6-membered fused heterocyclyl, a 5-membered/3-membered spiroheterocyclyl, a 5-membered/5-membered spiroheterocyclyl, a 5-membered/4-membered spiroheterocyclyl, a 5-membered/6-membered spiroheterocyclyl, a 6-membered/3-membered spiroheterocyclyl, a 5-membered/5-membered spiroheterocyclyl, a 5-membered/6-membered spiroheterocyclyl, 6-membered/5-membered spiroheterocyclyl, 6-membered/4-membered spiroheterocyclyl or 6-membered/6-membered spiroheterocyclyl, wherein each of the heteroatoms in the 5-membered monocyclic heterocyclyl, 6-membered monocyclic heterocyclyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 5-membered/5-membered fused heterocyclyl, 5-membered/4-membered fused heterocyclyl, 5-membered/6-membered fused heterocyclyl, 6-membered/5-membered fused heterocyclyl, 6-membered/4-membered fused heterocyclyl, 6-membered/6-membered fused heterocyclyl, 5-membered/3-membered spiroheterocyclyl, 5-membered/5-membered spiroheterocyclyl, 5-membered/4-membered spiroheterocyclyl, 5-membered/6-membered spiroheterocyclyl, 6-membered/3-membered spiroheterocyclyl, 6-membered/5-membered spiroheterocyclyl, 6-membered/4-membered spiroheterocyclyl and 6-membered/6-membered spiroheterocyclyl are independently N, and the number of heteroatoms is from 1 to 4.

More preferably, ring A is a 5-membered monocyclic heterocyclyl, a 6-membered monocyclic heterocyclyl, a 5-membered monocyclic heteroaryl, a 6-membered monocyclic heteroaryl, a 5-membered/5-membered fused heterocyclyl, a 5-membered/6-membered fused heterocyclyl or a 5-membered/3-membered spiroheterocyclyl, wherein each of the heteroatoms in the 5-membered monocyclic heterocyclyl, the 6-membered monocyclic heterocyclyl, the 5-membered monocyclic heteroaryl, the 6-membered monocyclic heteroaryl, the 5-membered/5-membered fused heterocyclyl, the 5-membered/6-membered fused heterocyclyl and the 5-membered/3-membered spiroheterocyclyl is independently N, and the number of heteroatoms is from 1 to 3.

More preferably, ring A is a 5-membered monocyclic heterocyclyl or a 5-membered monocyclic heteroaryl, wherein the heteroatoms in the 5-membered monocyclic heterocyclyl and 5-membered monocyclic heteroaryl are N and the number of heteroatoms is from 1 to 3.

Even more preferably, ring A is the following group:

Even more preferably, ring A is the following group:

In one preferred embodiment of the present invention, one, two or three R are present.², each of which, in each case, independently represents hydrogen, halogen, hydroxyl, cyano, amino, nitro, formyl, oxo, C_1-3alkyl, C_1-3alkoxy, -C_1-3alkyl-NH(C_1-3alkyl) or -C_1-3alkyl-N(C_1-3alkyl)₂, where indicated C_1-3alkyl, C_1-3alkoxy, -C_1-3alkyl-NH(C_1-3alkyl) and -C_1-3alkyl-N(C_1-3alkyl)₂all optionally substituted with one or more hydroxyls or halogens;

Additionally, one, two or three are preferably present R², each of which in each instance independently represents hydrogen, halogen, hydroxyl, cyano, amino, nitro, formyl, oxo, methoxy, methyl, ethyl, n-propyl or isopropyl;

Additionally, one or two are preferably present R², each of which in each instance independently represents hydrogen, halogen, hydroxyl, cyano, amino, nitro, methoxy or methyl;

Additionally, one or two are preferably present R², each of which in each case independently represents hydrogen or methyl.

In one preferred embodiment of the present invention R³represents hydrogen, halogen, hydroxyl, amino, cyano, C_1-4alkyl, C_1-4alkoxy or C_3-6cycloalkyl, where the specified C_1-4alkyl, C_1-4alkoxy and C_3-6cycloalkyl all optionally substituted with one or more hydroxyls or halogens;

additionally preferred R³represents hydrogen, halogen, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or methoxy;

additionally preferred R³represents hydrogen, halogen, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl or cyclopropyl;

even more preferable R³represents hydrogen, F, Cl, Br, amino, methyl, ethyl or cyclopropyl.

In one preferred embodiment of the present invention, ring B is C_4-12cycloalkenyl, C_4-12heterocyclyl_,C_6-12aryl, C_6-8aryl condensed C_4-6cycloalkyl, C_6-8aryl condensed C_4-6heterocyclyl or C_5-12heteroaryl.

More preferably, ring B is C_6-10aryl or C_5-10heteroaryl.

More preferably, ring B is phenyl or pyridinyl.

In one preferred embodiment of the present invention, each R⁴, if present, independently represents hydrogen, cyano, halogen, amino, nitro, C_1-4alkyl, C_1-4haloalkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, C_3-6halocycloalkyl or 3-6-membered heterocyclyl, wherein the specified C_1-4alkyl, C_1-4haloalkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, C_3-6halocycloalkyl and 3-6 membered heterocyclyl are all optionally substituted with one or more of the following substituents: halogen, hydroxyl, amino, -SO₂-C_1-4alkyl or oxo; w is 0, 1, 2 or 3.

More preferably each R⁴independently represents hydrogen, cyano, halogen, amino, nitro, C_1-4alkyl, C_1-4haloalkyl or C_1-4hydroxyalkyl, wherein the specified C_1-4alkyl, C_1-4haloalkyl and C_1-4hydroxyalkyl all optionally substituted with one or more of the following substituents: halogen, hydroxyl or amino; w is 1, 2 or 3.

More preferably each R⁴independently represents hydrogen, cyano, halogen, amino, nitro, methyl, ethyl, n-propyl or isopropyl, wherein said methyl, ethyl, n-propyl and isopropyl are all optionally substituted with one or more of the following substituents: halogen or hydroxyl; w represents 1, 2 or 3.

More preferably each R⁴independently represents hydrogen, halogen, amino, methyl, ethyl or isopropyl, wherein said methyl, ethyl and isopropyl are all optionally substituted with one or more of the following substituents: halogen or hydroxyl; w represents 1, 2 or 3.

More preferably each R⁴independently represents hydrogen, halogen, amino, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, -CF₂CH₂OH, -C(CH₃)₂OH or -CF₂CH₃; w represents 1, 2, or 3.

The present invention also relates to a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof, wherein the compound has a structure represented by formula (B):

(B),

where R¹represents -O-R^A, -N(R^D)R^B or R^C;

when R¹represents -O-R^A, R^Arepresents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the specified C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3-10-membered heterocyclyl and 5-10-membered heteroaryl all optionally substituted with 1-3 identical or different R^a1;

each R^a1, if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, -OC_1-6alkyl, -SC_1-6alkyl, -COC_1-6alkyl, -CH₂COC_1-6alkyl, -CH₂CON(C_1-6alkyl)₂, -CH₂CONHC_1-6alkyl, -NHC_1-6alkyl, -N(C_1-6alkyl)₂, C_3-10cycloalkyl, C_6-10aryl, 3-10-membered heterocyclyl or 5-10-membered heteroaryl;

when R¹represents -N(R^D)R^B, R^Brepresents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, where the indicated C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, all optionally substituted with 1-3 identical or different R^b1;

each R^b1, if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, -OC_1-6alkyl, -SC_1-6alkyl, -COC_1-6alkyl, -CH₂COC_1-6alkyl, -CH₂CON(C_1-6alkyl)₂, -CH₂CONHC_1-6alkyl, -NHC_1-6alkyl, -N(C_1-6alkyl)₂, C_3-10cycloalkyl, C_6-10aryl, 3-10-membered heterocyclyl or 5-10-membered heteroaryl;

R ^D is hydrogen, halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OC _1-6 alkyl, -SC _1-6 alkyl, -COC _1-6 alkyl, -CH ₂ COC _1-6 alkyl, -CH ₂ CON(C _1-6 alkyl) ₂ , -CH ₂ CONHC _1-6 alkyl, -NHC _1-6 alkyl or -N(C _1-6 alkyl) ₂ ;

when R¹represents R^C, R^Crepresents C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, where the indicated C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, all optionally substituted with 1-4 identical or different R^c1;

each R^c1, if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, methylsulfonyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, -OC_1-6alkyl, -SC_1-6alkyl, -COC_1-6alkyl, -COC_3-6cycloalkyl, -CH₂COC_1-6alkyl, -CH₂CON(C_1-6alkyl)₂, -CH₂CONHC_1-6alkyl, -NHC_1-6alkyl, -N(C_1-6alkyl)₂, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the specified C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, -OC_1-6alkyl, -SC_1-6alkyl, -COC_1-6alkyl, -COC_3-6cycloalkyl, -CH₂COC_1-6alkyl, -CH₂CON(C_1-6alkyl)₂, -CH₂CONHC_1-6alkyl, -NHC_1-6alkyl, -N(C_1-6alkyl)₂, C_3-10cycloalkyl, C_6-10aryl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl are all optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, C_1-3alkyl, C_1-3 alkoxy or halogen;

there is one or two present R², each of which, in each case, independently represents hydrogen, halogen, hydroxyl, cyano, amino, nitro, formyl, oxo, C_1-6alkyl, C_1-6alkoxy, halogenated C_1-6alkyl or halogenated C_1-6alkoxy;

R³represents hydrogen, halogen, hydroxyl, amino, cyano, C_1-6alkyl, C_1-6alkoxy, C_3-6cycloalkyl or 3-6-membered heterocyclyl, wherein the specified C_1-6alkyl, C_1-6alkoxy, C_3-6cycloalkyl and 3-6-membered heterocyclyl are all optionally substituted with one or more hydroxyls or halogens;

ring B is C_4-12cycloalkyl, C_4-12cycloalkenyl, C_4-12heterocyclyl_,C_6-12aryl, C_5-12heteroaryl, C_6-12aryl condensed C_4-12cycloalkyl_,C_6-12aryl condensed C_4-12heterocyclyl or C_6-12aryl fused C_4-12cycloalkenyl;

each R⁴, if present, independently represents hydrogen, cyano, halogen, amino, hydroxyl, oxo, nitro, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, -C_0-6alkyl-NH-C_1-6alkyl, -C_0-6alkyl-N(C_1-6alkyl)(C_1-6alkyl), C_3-6cycloalkyl, C_3-6halocycloalkyl or 3-6-membered heterocyclyl, wherein the specified C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, -C_0-6alkyl-NH-C_1-6alkyl, -C_0-6alkyl-N(C_1-6alkyl)(C_1-6alkyl), C_3-6cycloalkyl, C_3-6halocycloalkyl and 3-6 membered heterocyclyl are all optionally substituted with one or more of the following substituents: halogen, hydroxyl, amino, -SO₂-C_1-4alkyl or oxo; w is 0, 1, 2, 3 or 4;

unless otherwise specified, each of the heteroatoms in the heteroaryl and heterocyclyl is independently O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.

In one preferred embodiment of the present invention R¹represents -O-R^A, R^Arepresents C_1-6alkyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the specified C_1-6alkyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, all optionally substituted with 1-3 identical or different R^a1;

each R^a1, if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, -OC_1-6alkyl, -SC_1-6alkyl, -COC_1-6alkyl, -CH₂COC_1-6alkyl, -CH₂CON(C_1-6alkyl)₂, -CH₂CONHC_1-6alkyl, -NHC_1-6alkyl or -N(C_1-6alkyl)₂.

More preferably R^Arepresents C_3-6cycloalkyl, C_6-10aryl, 3-6-membered heterocyclyl or 5-6-membered heteroaryl, wherein the specified C_3-6cycloalkyl, C_6-10aryl, 3- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl, all optionally substituted with 1-3 identical or different R^a1;

each R^a1, if present, independently represents halogen, hydroxyl, cyano, amino, oxo, formyl, C_1-6alkyl, -OC_1-6alkyl, -SC_1-6alkyl or -COC_1-6alkyl.

More preferably, R ^A is 5-6-membered heterocyclyl or 5-6-membered heteroaryl, wherein said 5-6-membered heterocyclyl and 5-6-membered heteroaryl are both optionally substituted with 1-3 identical or different R ^a1 ;

every R^a1, if present, independently represents halogen, hydroxyl, cyano, amino, oxo, formyl, C_1-4alkyl, -OC_1-4alkyl, -SC_1-4alkyl or -COC_1-4alkyl.

More preferably, R^Ais a 5-6-membered heterocyclyl, wherein said 5-6-membered heterocyclyl is optionally substituted with one or two identical or different R^a1;

each R ^a1 , if present, is independently halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

More preferably, R ^A is a 5-6-membered monocyclic heterocyclyl, wherein said 5-6-membered monocyclic heterocyclyl is optionally substituted with one or two identical or different R ^a1 ; each of the heteroatoms in said 5-6-membered monocyclic heterocyclyl is independently O, N or S, and the number of heteroatoms is 1;

each R ^a1 , if present, is independently halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

More preferably, R^Arepresents tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl, wherein said tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl are all optionally substituted with one or two identical or different R^a1;

each R ^a1 , if present, is independently halogen, oxo, formyl, acetyl, methyl, ethyl, n-propyl, isopropyl or methoxy.

Even more preferably, R ^A represents the following group: , , , , , or .

In one preferred embodiment of the present invention R¹represents -N(R^D)R^B, where R^Brepresents C_1-6alkyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the specified C_1-6alkyl, C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, all optionally substituted with 1-3 identical or different R^b1;

each R^b1, if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, C_1-6alkyl, -OC_1-6alkyl, -SC_1-6alkyl or -COC_1-6alkyl.

More preferable R^Brepresents C_1-6alkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein said C_1-6alkyl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, all optionally substituted with 1-3 identical or different R^b1;

each R^b1, if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, C_1-6alkyl, -OC_1-6alkyl, -SC_1-6alkyl or -COC_1-6alkyl.

More preferable R^Brepresents C_1-6alkyl or 5-6-membered monocyclic heterocyclyl, wherein the specified C_1-6alkyl and 5-6-membered monocyclic heterocyclyl, both optionally substituted by one or two identical or different R^b1; each of the heteroatoms in said 5-6-membered monocyclic heterocyclyl is independently O, N or S, and the number of heteroatoms is 1;

each R^b1, if present, independently represents halogen, oxo, formyl, C_1-4alkyl, -OC_1-4alkyl or -COC_1-4alkyl.

More preferable R^Brepresents methyl, ethyl, n-propyl, isopropyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl, wherein said methyl, ethyl, n-propyl, isopropyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl are all optionally substituted with one or two identical or different R^b1;

each R ^b1 , if present, is independently oxo, formyl, acetyl, methyl, ethyl, methoxy or ethoxy.

Even more preferable, R^Brepresents the following group:, or .

R^Dis hydrogen, C_1-6alkyl or -OC_1-6alkyl; more preferably R^Dis hydrogen or C_1-3alkyl; even more preferably R^Dis hydrogen or methyl; most preferably R^Dis hydrogen.

In one preferred embodiment of the present invention R¹represents R^C, and R^Crepresents C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the specified C_3-10cycloalkyl, C_6-10aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, all optionally substituted with 1-4 identical or different R^c1;

each R^c1, if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, methylsulfonyl, C_1-6alkyl, -OC_1-6alkyl, -SC_1-6alkyl, -COC_1-6alkyl, -COC_3-6cycloalkyl, -CH₂COC_1-6alkyl, -CH₂CON(C_1-6alkyl)₂, -CH₂CONHC_1-6alkyl, -NHC_1-6alkyl, -N(C_1-6alkyl)₂, C_3-10cycloalkyl or 3-10-membered heterocyclyl, wherein the specified C_1-6alkyl, -OC_1-6alkyl, -SC_1-6alkyl, -COC_1-6alkyl, -COC_3-6cycloalkyl, -CH₂COC_1-6alkyl, -CH₂CON(C_1-6alkyl)₂, -CH₂CONHC_1-6alkyl, -NHC_1-6alkyl, -N(C_1-6alkyl)₂, C_3-10cycloalkyl and 3- to 10-membered heterocyclyl are all optionally substituted with one or more substituents selected from deuterium, hydroxyl, C_1-3alkyl, C_1-3 alkoxy or halogen.

More preferable R^Crepresents C_3-10cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein said C_3-10cycloalkyl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, all optionally substituted with 1-4 identical or different R^c1;

each R^c1, if present, independently represents halogen, hydroxyl, cyano, amino, nitro, oxo, formyl, methylsulfonyl, C_1-4alkyl, -OC_1-4alkyl, -SC_1-4alkyl, -COC_1-4alkyl, -COC_3-6cycloalkyl, -CH₂COC_1-4alkyl, -CH₂CON(C_1-4alkyl)₂, -CH₂CONHC_1-4alkyl, C_3-6cycloalkyl or 3-6-membered heterocyclyl, wherein the specified C_1-4alkyl, -OC_1-4alkyl, -SC_1-4alkyl, -COC_1-4alkyl, -COC_3-6cycloalkyl, -CH₂COC_1-4alkyl, -CH₂CON(C_1-4alkyl)₂, -CH₂CONHC_1-4alkyl, C_3-6cycloalkyl and 3-6 membered heterocyclyl are all optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, C_1-3alkyl, C_1-3 alkoxy or halogen.

More preferable R^Crepresents a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, wherein said 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are both optionally substituted with 1-4 identical or different R^c1;

each R^c1, if present, independently represents halogen, hydroxyl, cyano, amino, oxo, formyl, methylsulfonyl, C_1-4alkyl, -OC_1-4alkyl, -COC_1-4alkyl, -COC_3-6cycloalkyl, -CH₂CON(C_1-4alkyl)₂or 3-6-membered heterocyclyl, where the specified C_1-4alkyl, -OC_1-4alkyl, -COC_1-4alkyl, -COC_3-6cycloalkyl, -CH₂CON(C_1-4alkyl)₂and 3-6 membered heterocyclyl all optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, methyl, methoxy or halogen.

More preferable R^Cis a 5- to 6-membered monocyclic heterocyclyl, a 6- to 10-membered spiroheterocyclyl, a 6- to 8-membered bridged heterocyclyl, an 8- to 10-membered fused heterocyclyl or a 5- to 6-membered monocyclic heteroaryl, wherein said 5- to 6-membered monocyclic heterocyclyl, 6- to 10-membered spiroheterocyclyl, 6- to 8-membered bridged heterocyclyl, 8- to 10-membered fused heterocyclyl and 5- to 6-membered monocyclic heteroaryl are all optionally substituted with 1 to 4 identical or different R^c1;

each R ^c1 , if present, is independently halogen, hydroxyl, cyano, amino, oxo, formyl, acetyl, propionyl, methylsulfonyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH ₂ CON(CH ₃ ) ₂ , -CO-cyclopropyl, -CO-cyclobutyl, 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl, wherein said acetyl, propionyl, methylsulfonyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH ₂ CON(CH ₃ ) ₂ , -CO-cyclopropyl, -CO-cyclobutyl, 4-membered heterocyclyl, 5-membered heterocyclyl and 6-membered heterocyclyl are all optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, methyl, methoxy or halogen.

Even more preferable R^Cis a 6-membered monocyclic heterocyclyl, 4-membered/6-membered spiroheterocyclyl, 4-membered/4-membered spiroheterocyclyl, 6-membered/5-membered fused heterocyclyl, 7-membered bridged heterocyclyl or 6-membered monocyclic heteroaryl, wherein said 6-membered monocyclic heterocyclyl, 4-membered/6-membered spiroheterocyclyl, 4-membered/4-membered spiroheterocyclyl, 6-membered/4-membered fused heterocyclyl, 7-membered bridged heterocyclyl and 6-membered monocyclic heteroaryl are all optionally substituted with 1 to 4 of the same or different R^c1;

each R ^c1 , if present, is independently halogen, hydroxyl, cyano, amino, oxo, formyl, acetyl, propionyl, methylsulfonyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH ₂ CON(CH ₃ ) ₂ , -CO-cyclopropyl, 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl, wherein said acetyl, propionyl, methylsulfonyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH ₂ CON(CH ₃ ) ₂ , -CO-cyclopropyl, 4-membered heterocyclyl, 5-membered heterocyclyl and 6-membered heterocyclyl are all optionally substituted with one or more substituents selected from deuterium, hydroxyl, methyl, methoxy or halogen.

More preferable R^Crepresents,,,,,,,,,,,,,,,,,, or , and the indicated R^Call optionally replaced by 1-4 identical or different R^c1;

each R^c1, if present, independently represents F, Cl, Br, hydroxyl, cyano, amino, oxo, methylsulfonyl, acetyl, -COCH₂CH₃, -COCH₂OH, -COCH₂CN, -CH(OH)(CH₃)₂, hydroxymethyl, hydroxyethyl, -CH₂OCH₃, -CH₂CH₂OCH₃, methoxy, methyl, CD₃, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl,,, -CH₂CON(CH₃)₂or morpholinyl.

Even more preferable, R^C, not necessarily substituted R^c1, represents the following group:

In one preferred embodiment of the present invention, one or two R ² are present, each of which, in each occurrence, independently represents hydrogen, halogen, hydroxyl, cyano, amino, nitro, formyl, oxo, methoxy, methyl, ethyl, n-propyl or isopropyl.

More preferably, one or two R ² are present, each of which, in each occurrence, independently represents hydrogen, halogen, hydroxyl, cyano, amino, nitro, methoxy or methyl.

Even more preferably, one or two are present. R², each of which, in each case, independently represents hydrogen or methyl.

Even more preferable R²is hydrogen.

In one preferred embodiment of the present invention R³represents hydrogen, halogen, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or methoxy.

More preferable R³represents hydrogen, halogen, hydroxyl, amino, cyano, methyl, ethyl, n-propyl, isopropyl or cyclopropyl.

Even more preferable R³represents hydrogen, F, Cl, Br, amino, methyl, ethyl or cyclopropyl.

In one preferred embodiment of the present invention, ring B is _C4-12 cycloalkenyl, 4-12 membered heterocyclyl, _C6-12 aryl, _C6-8 aryl-fused _C4-6 cycloalkyl, _C6-8 aryl-fused _C4-6 heterocyclyl, or 5-12 membered heteroaryl.

More preferably, ring B is C _6-10 aryl, 5-10 membered heteroaryl, or C _6-8 aryl-fused 4-6 membered heterocyclyl.

More preferably, ring B is phenyl, pyridinyl or benzodihydrofuranyl.

In one preferred embodiment of the present invention, each R⁴, if present, independently represents hydrogen, cyano, halogen, amino, nitro, C_1-4alkyl, C_1-4haloalkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, C_3-6halocycloalkyl or 3-6-membered heterocyclyl, wherein the specified C_1-4alkyl, C_1-4haloalkyl, C_1-4hydroxyalkyl, C_3-6cycloalkyl, C_3-6halocycloalkyl and 3-6 membered heterocyclyl are all optionally substituted with one or more of the following substituents: halogen, hydroxyl, amino, -SO₂-C_1-4alkyl or oxo; w is 0, 1, 2 or 3.

More preferably each R⁴independently represents hydrogen, cyano, halogen, amino, nitro, C_1-4alkyl, C_1-4haloalkyl or C_1-4hydroxyalkyl, wherein the specified C_1-4alkyl, C_1-4haloalkyl and C_1-4hydroxyalkyl all optionally substituted with one or more of the following substituents: halogen, hydroxyl or amino; w is 1, 2 or 3.

More preferably each R⁴independently represents hydrogen, cyano, halogen, amino, nitro, methyl, ethyl, n-propyl or isopropyl, wherein said methyl, ethyl, n-propyl and isopropyl are all optionally substituted with one or more of the following substituents: halogen or hydroxyl; w represents 1, 2 or 3.

More preferably each R⁴independently represents hydrogen, halogen, amino, cyano, methyl, ethyl or isopropyl, wherein said methyl, ethyl and isopropyl are all optionally substituted with one or more of the following substituents: halogen or hydroxyl; w represents 1, 2 or 3.

More preferably, each R ⁴ is independently hydrogen, fluoro, amino, cyano, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, -CF ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CF ₂ CH ₃ or -CH ₂ CHF ₂ ; w is 1, 2 or 3.

The present invention relates to a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof, wherein the compound has a structure represented by formula (C):

(C),

the substituents in formula (C) are as defined in formula (B).

The present invention also relates to a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof, wherein the compound has a structure represented by formula (D):

(D),

where R¹, R⁴and w are as defined in formula (A), (A'), (I), (II), (III), (IV), (B), or (C).

Preferably each one R⁴, if present, is independently cyano, halogen, amino, C_1-6alkyl or C_1-6haloalkyl, where the specified C_1-6alkyl and C_1-6haloalkyl both optionally substituted with one or more hydroxyls; w is 1 or 2;

R¹represents -O-R^A, -N(R^D)R^B or R^C;

when R¹represents -O-R^A, R^Ais a 3- to 10-membered heterocyclyl, wherein said 3- to 10-membered heterocyclyl is optionally substituted with 1-3 identical or different R^a1;

every R^a1, if present, independently represents C_1-6alkyl or -COC_1-6alkyl;

when R¹represents -N(R^D)R^B, R^Brepresents C_1-6alkyl or 3-10 membered heterocyclyl, wherein the specified C_1-6alkyl and 3-10 membered heterocyclyl both optionally substituted with 1-3 identical or different R^b1;

each R ^b1 , if present, is independently -OC _1-6 alkyl;

R ^D represents hydrogen;

when R¹represents R^C, R^Crepresents a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, wherein said 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are both optionally substituted with 1-4 identical or different R^c1;

each R^c1, if present, is independently halogen, hydroxyl, cyano, amino, methylsulfonyl, C_1-6alkyl, -OC_1-6alkyl, -COC_1-6alkyl, -COC_3-6cycloalkyl, -CH₂CON(C_1-6alkyl)₂or 3-10-membered heterocyclyl, wherein the specified C_1-6alkyl, -OC_1-6alkyl, -COC_1-6alkyl, -COC_3-6cycloalkyl, -CH₂CON(C_1-6alkyl)₂and 3-10 membered heterocyclyl all optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, C_1-3 alkoxy or halogen.

Unless otherwise specified, each of the heteroatoms in a heteroaryl and heterocyclyl is independently O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.

In one preferred embodiment of the present invention R¹represents -O-R^A, R^Ais a 3- to 6-membered heterocyclyl, wherein said 3- to 6-membered heterocyclyl is optionally substituted with 1-3 identical or different R^a1;

each R^a1, if present, independently represents C_1-6alkyl or -COC_1-6alkyl.

More preferably, R^Ais a 5-6-membered heterocyclyl, wherein said 5-6-membered heterocyclyl is optionally substituted with one or two identical or different R^a1;

each R ^a1 , if present, is independently acetyl, methyl, ethyl, n-propyl, or isopropyl.

More preferably, R ^A is a 5-6-membered monocyclic heterocyclyl, wherein said 5-6-membered monocyclic heterocyclyl is optionally substituted with one or two identical or different R ^a1 ; each of the heteroatoms in said 5-6-membered monocyclic heterocyclyl is independently O, N or S, and the number of heteroatoms is 1;

each R ^a1 , if present, is independently acetyl, methyl, or ethyl.

More preferably, R^Arepresents tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl, wherein said tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl are all optionally substituted with one or two identical or different R^a1;

each R ^a1 , if present, is independently acetyl, methyl, or ethyl.

Even more preferably, R ^A represents the following group: , , , , , or .

In one preferred embodiment of the present invention R¹represents -N(R^D)R^B, R^Brepresents C_1-6alkyl or 3-6-membered monocyclic heterocyclyl, wherein the specified C_1-6alkyl and 3- to 6-membered monocyclic heterocyclyl, both optionally substituted with one or two identical or different R^b1; and each of the heteroatoms in said 3-6 membered monocyclic heterocyclyl is independently O, N or S, and the number of heteroatoms is 1;

every R^b1, if present, independently represents -OC_1-4alkyl.

More preferable R^Brepresents methyl, ethyl, n-propyl, isopropyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl, wherein said methyl, ethyl, n-propyl, isopropyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl are all optionally substituted with one or two identical or different R^b1;

each R ^b1 , if present, is independently methoxy or ethoxy.

Even more preferable, R^Brepresents the following group:, or .

In one preferred embodiment of the present invention R¹represents R^C, R^Crepresents a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, wherein said 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are both optionally substituted with 1-4 identical or different R^c1;

each R^c1, if present, is independently halogen, hydroxyl, cyano, amino, methylsulfonyl, C_1-4alkyl, -OC_1-4alkyl, -COC_1-4alkyl, -COC_3-6cycloalkyl, -CH₂CON(C_1-4alkyl)₂or 3-6-membered heterocyclyl, where the specified C_1-4alkyl, -OC_1-4alkyl, -COC_1-4alkyl, -COC_3-6cycloalkyl, -CH₂CON(C_1-4alkyl)₂and 3-6 membered heterocyclyl all optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, methyl, methoxy or halogen.

More preferable R^Cis a 5- to 6-membered monocyclic heterocyclyl, a 6- to 10-membered spiroheterocyclyl, a 6- to 8-membered bridged heterocyclyl, an 8- to 10-membered fused heterocyclyl or a 5- to 6-membered monocyclic heteroaryl, wherein said 5- to 6-membered monocyclic heterocyclyl, 6- to 10-membered spiroheterocyclyl, 6- to 8-membered bridged heterocyclyl, 8- to 10-membered fused heterocyclyl and 5- to 6-membered monocyclic heteroaryl are all optionally substituted with 1 to 4 identical or different R^c1;

each R ^c1 , if present, is independently halogen, hydroxyl, cyano, amino, methylsulfonyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, acetyl, propionyl, -CO-cyclopropyl, -CO-cyclobutyl, -CH ₂ CON(CH ₃ ) ₂ , 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl, wherein said methylsulfonyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, acetyl, propionyl, -CO-cyclopropyl, -CO-cyclobutyl, -CH ₂ CON(CH ₃ ) ₂ , 4-membered heterocyclyl, 5-membered heterocyclyl and 6-membered heterocyclyl are all optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, methoxy or halogen.

Even more preferable R^Cis a 6-membered monocyclic heterocyclyl, 4-membered/6-membered spiroheterocyclyl, 4-membered/4-membered spiroheterocyclyl, 7-membered bridged heterocyclyl, 6-membered/5-membered fused heterocyclyl or 6-membered monocyclic heteroaryl, wherein said 6-membered monocyclic heterocyclyl, 4-membered/6-membered spiroheterocyclyl, 4-membered/4-membered spiroheterocyclyl, 7-membered bridged heterocyclyl, 6-membered/4-membered fused heterocyclyl and 6-membered monocyclic heteroaryl are all optionally substituted with 1 to 4 of the same or different R^c1;

each R ^c1 , if present, is independently halogen, hydroxyl, cyano, amino, methylsulfonyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, acetyl, propionyl, -CO-cyclopropyl, -CH ₂ CON(CH ₃ ) ₂ , 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl, wherein said methylsulfonyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, acetyl, propionyl, -CO-cyclopropyl, 4-membered heterocyclyl, 5-membered heterocyclyl and 6-membered heterocyclyl are all optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, methoxy or halogen.

More preferable R^Crepresents,,,,,,,,,,,,, or , and the indicated R^Call optionally replaced by 1-4 identical or different R^c1;

each R ^c1 , if present, is independently F, Cl, Br, hydroxyl, cyano, amino, methylsulfonyl, methyl, ethyl, isopropyl, CD ₃ , hydroxymethyl, hydroxyethyl (e.g. 2-hydroxyethyl), -CH(OH)(CH ₃ ) ₂ , -CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₃ , monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl (e.g. 2-fluoroethyl), difluoroethyl (e.g. 2,2-difluoroethyl), trifluoroethyl (e.g. 2,2,2-trifluoroethyl), methoxy, acetyl, -COCH ₂ CH ₃ , -COCH ₂ OH, -COCH ₂ CN, , -CH ₂ CON(CH ₃ ) ₂ , oxetanyl (eg, ) or morpholinyl (for example, morpholin-4-yl).

Even more preferable, R^C, not necessarily substituted R^c1, represents the following group:

In one preferred embodiment of the present invention, each R⁴, if present, is independently cyano, halogen, amino, C_1-4alkyl or C_1-4haloalkyl, where the specified C_1-4alkyl and C_1-4haloalkyl both optionally substituted with one or more hydroxyls; w is 1 or 2.

More preferably, each R ⁴ is independently cyano, fluoro, amino, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, -CF ₂ CH ₂ OH, CF ₂ C(CH ₃ ) ₂ OH, -CF ₂ CH ₃ or -CH ₂ CHF ₂ ; w is 1 or 2.

The present invention relates to a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof, wherein the compound has a structure represented by formula (E):

(E),

the substituents in formula (E) are as defined in formula (D).

The present invention also provides a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof, wherein the compound has a structure represented by formula (F) or formula (F'):

(F) (F'),

where R^c1, R⁴and w are as defined in formula (D) or (E); v is 0 or 1, and when v is 1, R^c1preferably bonded to the N atom.

Preferably R ^c1 is methyl, ethyl, isopropyl, CD ₃ , hydroxymethyl, hydroxyethyl (e.g. 2-hydroxyethyl), monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl (e.g. 2-fluoroethyl), difluoroethyl (e.g. 2,2-difluoroethyl), trifluoroethyl (e.g. 2,2,2-trifluoroethyl), -CH ₂ CON(CH ₃ ) ₂ or oxetanyl (e.g. ).

More preferably, represents the following group: , , , , , , or .

The present invention also provides a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof, wherein the compound has a structure represented by formula (G) or formula (G'):

(G) (G'),

where R^c1, R⁴and w are as defined in formula (D) or (E); v is 0 or 1, and when v is 1, R^c1preferably bonded to the N atom.

Preferably R ^c1 is methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl (eg 2-hydroxyethyl), -CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₃ , monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl (eg 2-fluoroethyl), difluoroethyl (eg 2,2-difluoroethyl), trifluoroethyl (eg 2,2,2-trifluoroethyl) or -CH ₂ CON(CH ₃ ) ₂ .

More preferably, represents the following group: , , , , , , or .

Preferably, the present invention also relates to a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof, wherein the compound has one of the following structures:

.

Preferably, the present invention relates to a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof, wherein the compound has one of the following structures:

.

The present invention also aims to provide an intermediate for use in the preparation of a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof according to the present invention, wherein the intermediate is represented by formula (V):

(V),

where R², R³, ring A, X, Y and Z are as defined in formula (A), (I) or (II);

R ⁵ is halogen, hydroxyl, -O-methylsulfonyl, -O-p-toluenesulfonyl or -O-trifluoromethylsulfonyl, preferably chlorine or hydroxyl.

R ⁶ is halogen, preferably bromine or iodine.

The present invention also aims to provide an intermediate for use in the preparation of a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof according to the present invention, wherein the intermediate is represented by formula (VI):

(VI),

where R², R³, R⁴, w, ring A, X, Y and Z are as defined in formula (A) or (I);

R ⁶ is halogen, preferably bromine or iodine.

In addition, the compound or its stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative according to the present invention has a structure represented by formula (VII):

(VII),

where R², R³, R⁴, w, ring A, X, Y and Z are as defined in formula (II);

R ⁶ is halogen, preferably bromine or iodine.

In addition, the compound or its stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative according to the present invention has a structure represented by formula (VIII):

(VIII),

where R², R³, R⁴, w, ring A, Y and Z are as defined in formula (III);

R ⁶ is halogen, preferably bromine or iodine.

In addition, the compound or its stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative according to the present invention has a structure represented by formula (IX):

(IX),

where R², R³, R⁴, w, ring A, Y and Z are as defined in formula (IV);

R ⁶ is halogen, preferably bromine or iodine.

The present invention also relates to a pharmaceutical composition comprising a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof according to the present invention.

The present invention also relates to a pharmaceutical composition comprising a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof according to the present invention and a pharmaceutically acceptable excipient.

The present invention also aims to provide a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof according to the present invention or a pharmaceutical composition according to the present invention for use as a medicine.

The present invention also aims to provide a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof according to the present invention or a pharmaceutical composition according to the present invention for use in the prevention and/or treatment of a disease mediated by SOS1.

The present invention also aims to provide a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof according to the present invention or a pharmaceutical composition according to the present invention for use in the prevention and/or treatment of a disease caused by RAS mutations.

The present invention also aims to provide the use of a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof according to the present invention or a pharmaceutical composition according to the present invention in the manufacture of a medicament for the prevention and/or treatment of a disease mediated by SOS1.

In some examples, the disease mediated by SOS1 is cancer or tumor and related disease.

In some examples, a disease mediated by SOS1 is lung cancer (e.g., non-small cell lung cancer/NSCLC) and related disease.

The present invention also aims to provide the use of a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof according to the present invention or a pharmaceutical composition according to the present invention in the manufacture of a medicament for the prevention and/or treatment of a disease caused by RAS mutations.

In some examples, the disease caused by RAS mutations is cancer or tumor and related disease.

In some examples, a disease caused by RAS mutations is lung cancer (eg, non-small cell lung cancer/NSCLC) and related disease.

The present invention also aims to provide a method for preventing and/or treating a disease mediated by SOS1, comprising administering to a subject a prophylactically and/or therapeutically effective dose of a compound or its stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative according to the present invention or a pharmaceutical composition according to the present invention.

The present invention is also directed to providing a method for preventing and/or treating a disease caused by RAS mutations, comprising administering to a subject a prophylactically and/or therapeutically effective dose of a compound or its stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative according to the present invention or a pharmaceutical composition according to the present invention.

The present invention also aims to provide the use of a compound or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative thereof according to the present invention or a pharmaceutical composition according to the present invention in the non-diagnostic and non-therapeutic in vitro inhibition of the activity of guanine nucleotide exchange factors (GEFs), wherein the guanine nucleotide exchange factor is SOS1.

The present invention is also directed to providing a method for non-diagnostic and non-therapeutic inhibition of the activity of guanine nucleotide exchange factors in vitro, comprising administering to a subject an inhibitory effective dose of a compound or its stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotopic derivative according to the present invention or a pharmaceutical composition according to the present invention, wherein the guanine nucleotide exchange factor is SOS1.

Advantages of the invention

The present invention relates to a class of structurally novel compounds that provide a new direction for the development of SOS1 inhibitor drugs. In vitro enzymatic inhibition studies show that all of these compounds exhibit a strong inhibitory effect on SOS1 and can be used as promising compounds for the prevention and/or treatment of SOS1-mediated diseases. In addition, these compounds additionally exhibit significant inhibitory activity against NCI-H358 cell proliferation. In addition, the present invention pays great attention to a specific synthesis method that is simple to implement, convenient to operate, and conducive to large-scale industrial production and use.

DETAILED DESCRIPTION

Definitions of terms

The term "optional," "alternative," "optionally," or "alternatively" means that the event or state described below may, but need not, occur, and the description includes the case where the event or state occurs and the case where the event or state does not occur.

Unless otherwise specified, the term "alkyl" refers to a monovalent, straight or branched, saturated aliphatic hydrocarbyl group typically containing from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms (i.e. C_1-10alkyl), further preferably from 1 to 8 carbon atoms (i.e. C_1-8alkyl), more preferably from 1 to 6 carbon atoms (i.e. C_1-6 alkyl). For example, "C_1-6"alkyl" means that such group is alkyl and the number of carbon atoms in the carbon chain is from 1 to 6 (particularly 1, 2, 3, 4, 5 or 6). Non-limiting examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl and the like.

Unless otherwise specified, the term "alkenyl" refers to a monovalent, linear or branched, unsaturated aliphatic hydrocarbyl group having at least one double bond, typically containing from 2 to 20 carbon atoms, preferably from 2 to 10 carbon atoms (i.e. C_2-10alkenyl), more preferably from 2 to 8 carbon atoms (i.e. C_2-8alkenyl), more preferably from 2 to 6 carbon atoms (i.e. C_2-6alkenyl). For example, "C_2-6"alkenyl" means that such group is alkenyl and the number of carbon atoms in the carbon chain is from 2 to 6 (particularly 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl and the like.

Unless otherwise specified, the term "alkynyl" refers to a monovalent, straight or branched, unsaturated aliphatic hydrocarbyl group having at least one triple bond, typically containing from 2 to 20 carbon atoms, preferably from 2 to 10 carbon atoms (i.e. C_2-10alkynyl), more preferably from 2 to 8 carbon atoms (i.e. C_2-8alkynyl), more preferably from 2 to 6 carbon atoms (i.e. C_2-6alkynyl). For example, "C_2-6"alkynyl" means that such group is alkynyl and the number of carbon atoms in the carbon chain is from 2 to 6 (particularly 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and the like.

Unless otherwise specified, the term "cycloalkyl" refers to a monovalent, monocyclic or polycyclic (e.g., fused cyclic, bridged cyclic, or spirocyclic) aliphatic hydrocarbyl group having no unsaturation, typically containing from 3 to 12 carbon atoms (i.e., C_3-12cycloalkyl), more preferably from 3 to 10 carbon atoms (i.e. C_3-10cycloalkyl), more preferably from 3 to 6 carbon atoms (i.e. C_3-6cycloalkyl), from 4 to 6 carbon atoms (i.e. C_4-6cycloalkyl) or from 5 to 6 carbon atoms (i.e. C_5-6cycloalkyl). Non-limiting examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethylcyclopentyl, dimethylcyclobutyl, and the like. Non-limiting examples of fused cycloalkyl include, but are not limited to, decahydronaphthyl, octahydroindenyl, octahydropentalenyl, and the like. Non-limiting examples of bridged cycloalkyl include, but are not limited to,

Non-limiting examples of spirocycloalkyl include, but are not limited to,

and the like.

Unless otherwise specified, the term "cycloalkenyl" refers to a monovalent, monocyclic or polycyclic aliphatic hydrocarbyl group having at least one double bond, typically containing from 3 to 12 carbon atoms (i.e., C_3-12cycloalkenyl), more preferably from 4 to 12 carbon atoms (i.e. C_4-12cycloalkenyl) or from 3 to 10 carbon atoms (i.e. C_3-10cycloalkenyl), more preferably from 3 to 6 carbon atoms (i.e. C_3-6cycloalkenyl), from 4 to 6 carbon atoms (i.e. C_4-6cycloalkenyl) or from 5 to 6 carbon atoms (i.e. C_5-6(cycloalkenyl). Non-limiting monocyclic cycloalkenyl includes, but is not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl, cycloheptatrienyl, cyclooctatrienyl, and the like.

Unless otherwise specified, the term "alkoxy" refers to the group "-O-alkyl" wherein alkyl is as previously defined, i.e., containing from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms (particularly 1, 2, 3, 4, 5 or 6). Illustrative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy and the like.

Unless otherwise specified, the term "halogen" or "halogenated" includes F, Cl, Br and I. The term "haloalkyl" means that one, two or more hydrogen atoms, or all of the hydrogen atoms of an alkyl, as previously defined, are replaced by halogen(s). Typical examples of haloalkyl include CCl₃, CF₃, CHCl₂, CH₂Cl, CH₂Br, CH₂I, CH₂CF₃, CF₂CF₃and the like. Haloalkyl can be expressed in different ways, for example, "C_1-6"haloalkyl" can also be expressed as "halogenated C_1-6alkyl". The term "haloalkoxy" means that one, two or more hydrogen atoms, or all of the hydrogen atoms of an alkoxy, as previously defined, are replaced by halogen(s). Typical examples of haloalkoxy include OCCl₃, OCF₃, OCHCl₂, OCH₂Cl, OCH₂Br, OCH₂I, OCH₂CF₃, OCF₂CF₃and the like. Haloalkoxy can also be expressed in different ways, such as "C_1-6"haloalkoxy" can also be expressed as "halogenated C_1-6alkoxy". The term "halocycloalkyl" means that one, two or more hydrogen atoms or all of the hydrogen atoms of a cycloalkyl, as previously defined, are replaced by halogen(s).

Unless otherwise specified, the term "heterocyclyl" refers to a monovalent, saturated or partially unsaturated, monocyclic or polycyclic (e.g., fused cyclic, bridged cyclic or spirocyclic) aliphatic ring system with a non-aromatic structure overall, typically containing from 3 to 20 ring atoms, wherein one, two, three or more ring atoms are N, O or S and the remaining ring atoms are C, preferably containing from 3 to 12 ring atoms, more preferably from 4 to 12 ring atoms, or from 5 to 12 ring atoms, or from 3 to 10 ring atoms, or from 3 to 8 ring atoms, or from 3 to 6 ring atoms, or from 4 to 6 ring atoms, or from 5 to 6 ring atoms. The number of heteroatoms is preferably from 1 to 4, more preferably from 1 to 3 (i.e., 1, 2, or 3). Non-limiting examples of monocyclic heterocyclyl include, but are not limited to, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, 2,5-dihydrofuranyl, and pyridinonyl. Polycyclic heterocyclyl includes spirocyclic, fused cyclic, and bridged cyclic heterocyclyl. Non-limiting examples of fused cyclic heterocyclyl include, but are not limited to, decahydroquinolinyl, octahydroindolyl, and the like. Non-limiting examples of bridged cyclic heterocyclyl include, but are not limited to,

and the like. Non-limiting examples of spirocyclic heterocyclyl include, but are not limited to,

and the like.

Unless otherwise specified, the term "aryl" refers to a monovalent, monocyclic or polycyclic (e.g., fused ring) aromatic ring system typically containing from 6 to 16 carbon atoms, or from 6 to 14 carbon atoms, or from 6 to 12 carbon atoms, preferably from 6 to 10 carbon atoms. The term "aryl" may be used interchangeably with the term "aromatic ring". Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, pyrenyl, and the like.

Unless otherwise specified, the term "heteroaryl" refers to a monovalent, monocyclic or polycyclic (e.g., fused ring) aromatic ring system, typically comprising a 5-12 membered structure, or preferably a 5-10 membered structure, a 5-8 membered structure, more preferably a 5-6 membered structure, wherein one, two, three or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, each of the heteroatoms independently represents O, N or S, and the number of heteroatoms is preferably 1, 2 or 3. The term "heteroaryl" may be used interchangeably with the term "heteroaromatic ring". Non-limiting examples of heteroaryl include, but are not limited to, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxdiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridinyl, imidazolo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazolo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl and the like.

Unless otherwise noted, the term "hydroxyl" refers to the "-OH" group.

Unless otherwise noted, the term "cyano" refers to the "-CN" group.

Unless otherwise noted, the term "amino" refers to the group "-NH₂" In some cases, the term "amino" also refers to a group in which one or two hydrogen atoms are replaced by alkyl (e.g., C_1-6alkyl, preferably C_1-4alkyl).

Unless otherwise noted, the term "nitro" refers to the "-NO ₂ " group.

Unless otherwise noted, the term "formyl" or "aldehyde" refers to the group "-C(=O)H".

Unless otherwise specified, the term "oxo" refers to an "=O" group bonded to a carbon atom, while the term "oxido" refers to an "=O" group bonded to a heteroatom (e.g., a sulfur atom).

Unless otherwise specified, the term "pharmaceutically acceptable salt", "pharmaceutical salt" or "medicinal salt" refers to a salt suitable, within reasonable medical judgment, for use in contact with the tissues of mammals, in particular humans, without causing excessive toxicity, irritation, allergic reaction, etc., and commensurate with a reasonable benefit-risk ratio. The salt may be prepared in situ during the final separation and purification of the compound of the present invention, or prepared separately by reacting the free base or free acid with a suitable reagent. For example, the free base may be reacted with a suitable acid.

Unless otherwise specified, the term "solvate" or "solvated compound" refers to the physical association of a compound of the present invention with one or more solvent molecules, whether organic or inorganic. Physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are located in a lattice of a crystalline solid, the solvate may be separable. The solvent molecules in the solvate may be regularly and/or randomly arranged. The solvate may contain a stoichiometric or non-stoichiometric amount of solvent molecules. "Solvate" encompasses that which is in the solution phase and that which is separable. Exemplary solvates include, but are not limited to, hydrates, ethanol-solvated complexes, methanol-solvated complexes, and isopropanol-solvated complexes. Methods of solvation are well known in the art.

Unless otherwise specified, a compound of the present invention further includes an "isotopic derivative" (such as a deuterate) thereof. The term "isotopic derivative" means that the compound of the present invention may exist at a trace or isotopically enriched level and contain one or more atoms whose atomic mass or mass number differs from that of the most abundant atom found in nature. The isotope may be radioactive or non-radioactive. Isotopes commonly used for isotopic labeling are: hydrogen isotopes: ² H (D) and ³ H (T); carbon isotopes: ¹³ C and ¹⁴ C; chlorine isotopes: ³⁵ Cl and ³⁷ Cl; fluorine isotope: ¹⁸ F; iodine isotopes: ¹²³ I and ¹²⁵ I; nitrogen isotopes: ¹³ N and ¹⁵ N; oxygen isotopes: ¹⁵ O, ¹⁷ O and ¹⁸ O; and sulfur isotope: ³⁵ S. These isotopically labeled compounds can be used to study the tissue distribution of drug molecules. In particular, ³ H and ¹³ C are more widely used because they are convenient for labeling and suitable for detection. Substitutions with certain heavy isotopes, such as heavy hydrogen ( ² H), can enhance the metabolic stability and prolong the half-life of the compound, thereby fulfilling the goal of dose reduction and providing therapeutic benefits. Isotopically labeled compounds are usually synthesized starting from labeled starting materials using known synthetic methods, such as the synthesis of non-isotopically labeled compounds.

Unless otherwise specified, the term "prodrug" refers to a drug that is transformed into the parent drug in vivo. Prodrugs are often useful because they are easier to administer than their parent drugs in some cases. For example, they may be orally bioavailable, whereas the parent drugs may not be. The solubility of prodrugs is also somewhat improved in a pharmaceutical composition compared to the parent drugs.

Unless otherwise specified, the term "optical isomer" refers to substances that have exactly the same molecular structure and similar physical and chemical properties but have different optical activities.

Unless otherwise specified, the term "stereoisomer" refers to compounds that have the same chemical structure but have different spatial arrangements of atoms or groups. A stereoisomer includes an enantiomer, a diastereomer, a conformational isomer (rotational isomer), a geometric (cis/trans) isomer, an atropisomer, etc. Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, or diastereomers, for example, by chromatography and/or fractional crystallization, depending on differences in the physical and chemical properties of the components.

Unless otherwise specified, a structural formula described herein includes all isomeric forms (e.g., enantiomeric, diastereomeric, geometrical (or conformational) isomeric, and the like): for example, isomers with asymmetric centers having R and S configurations, isomers with (Z) and (E) double bonds, and (Z) and (E) conformational isomers. Thus, both an individual stereoisomer of a compound of the present invention and a mixture thereof with its enantiomer, diastereomer, or geometrical isomer (or conformational isomer) are within the scope of the present invention.

Unless otherwise specified, the term “optionally substitutable,” “optionally substituted with…,” or “optionally substituted by…” means that the hydrogen at the substitutable site of the group as described is substituted or unsubstituted by one or more substituents, preferably selected from the group consisting of halogen, hydroxyl, mercapto, cyano, nitro, amino, azido, oxo, carboxyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkyl, C_1-6alkoxy, C_3-10cycloalkyl, 3-10-membered heterocyclyl, C_6-14aryl and 5-10-membered heteroaryl, where the indicated C_2-6alkenyl, C_2-6alkynyl, C_1-6alkyl, C_1-6alkoxy, C_3-10cycloalkyl, 3-10-membered heterocyclyl, C_6-14aryl and 5-10 membered heteroaryl all optionally substituted with one or more substituents selected from halogen, hydroxyl, amino, cyano, C_1-6alkyl or C_1-6alkoxy.

The present invention will be further illustrated with reference to specific examples. It should be understood that these examples are intended to illustrate the present invention only and do not limit the scope of the present invention. Experimental methods for which specific conditions are not indicated in the following examples are generally carried out in accordance with conventional conditions or conditions recommended by manufacturers. Unless otherwise specified, all professional and scientific terms used herein have the same meanings as those familiar to a person skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are intended for illustrative purposes only.

The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS) and/or high-performance liquid chromatography (HPLC). The NMR instrument is a Bruker AVANCE III 600 MHz; the LC-MS instrument is a WATERS ACQUITY UPLC H-Class PLUS and/or SQD2; and the HPLC instrument is a WATERS e2695_2998 and/or Agilent 1100.

The starting materials used in the examples of the present invention are known and commercially available or can be synthesized using methods known in the art.

Preparation example 1. Synthesis of intermediate compound A

Synthesis of intermediate compound A-2

1-(3-nitro-5-(trifluoromethyl)phenyl)ethenone (10.00 g, 43.0 mmol) was dissolved in ethanol (200 mL), and then iron powder (7.22 g, 129.0 mmol) and concentrated hydrochloric acid (50 mL) were added. The system was reacted at 80 °C for 2 h. LC-MS analysis showed that no raw material remained. The system was cooled and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated and purified by column chromatography (dichloromethane:methanol = 50:1-20:1) to give A-2 (8.12 g, 40.0 mmol, 92%). ESI-MS: m/z 204.12 [M+H] ⁺ .

Synthesis of intermediate compound A-3

A-2 (27.02 g, 133.0 mmol) was dissolved in tetrahydrofuran (50 mL), and then (R)-(+)-2-methyl-2-propanesulfinamide (24.24 g, 200.0 mmol) and Ti(OEt) ₄ (91.02 g, 399 mmol) were added. The system was reacted at 80 °C for 2 h. LC-MS analysis showed that no raw material remained. The reaction solution was quenched with ice-water. The residue was dissolved in ethyl acetate and filtered. The filtrate was evaporated under reduced pressure to remove the solvent. The residue was separated and purified by column chromatography (dichloromethane:methanol = 50:1-20:1) to give the product A-3 (34.65 g, 113.1 mmol, 85%). ESI-MS: m/z 307.12 [M+H] ⁺ .

Synthesis of intermediate compound A-4

A-3 (34.65 g, 113.1 mmol) was dissolved in tetrahydrofuran (50 mL), and sodium borohydride (6.42 g, 169.7 mmol) was added at -78 °C. The temperature of the reaction system was slowly raised to room temperature. LC-MS analysis showed that no raw material remained. The reaction solution was quenched with ice-water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane:methanol = 50:1-20:1) to give A-4 (28.43 g, 92.2 mmol, 82%). ESI-MS: m/z 309.10 [M+H] ⁺ .

Synthesis of intermediate compound A

A-4 (28.43 g, 92.2 mmol) was dissolved in hydrochloric acid in dioxane (50 mL). The system was reacted at room temperature for 2 h. LC-MS analysis showed that no raw material remained. The solvent was removed by evaporation under reduced pressure to give intermediate A as a hydrochloride salt, which was used directly in the next step. ESI-MS: m/z 205.22 [M+H] ⁺ .

The following intermediate compounds can be prepared by referring to the synthesis method of intermediate compound A or the corresponding synthesis methods described in CN110167928A. If necessary, the crude products were purified by chromatography.

No. Structure [M+H] ⁺ No. Structure [M+H] ⁺ B 190.02 J 202.09 C 204.09 K 172.06 D 190.08 L 198.20 E 180.29 M 191.15 F 208.15 N 191.17 G 208.24 O 230.21 H 186.17 P 200,13 I 203.97 Q 161.12

Example 1. Synthesis of compound 1

Synthesis of intermediate compound 1-1

2-Amino-6-chloronicotinic acid (5.00 g, 29.0 mmol) was dissolved in 80 ml of methanol. The system was cooled to 0 °C, and then 16 ml of concentrated sulfuric acid was added. The system was reacted at 80 °C for 5 h. LC-MS analysis showed that no raw material remained. 100 ml of water was added to the reaction solution and extracted with ethyl acetate (100 ml × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 ml × 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:1) to give 1-1 (5.03 g, yield: 93%). ESI-MS: m/z 187.02 [M+H] ⁺ .

Synthesis of intermediate compound 1-2

1-1 (5.03 g, 26.9 mmol) was dissolved in acetonitrile (80 mL), and then N-bromosuccinimide (7.17 g, 40.3 mmol) was added. The system was reacted at room temperature for 1.5 h. LC-MS analysis showed that no raw material remained. The reaction solution was quenched with ice-water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:3) to give 1-2 (6.85 g, yield: 96%). ESI-MS: m/z 265.10/267.13 [M+H] ⁺ .

Synthesis of intermediate compound 1-3

1-2 (6.85 g, 25.8 mmol) was dissolved in 80 ml of acetonitrile, and then 15 ml of methanesulfonic acid was added. The system was reacted at 130 °C for 8 h. LC-MS analysis showed that no raw material remained. The reaction solution was quenched with ice-water and extracted with ethyl acetate (100 ml × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 ml × 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:3) to give 1-3 (1.51 g, yield: 21%). ESI-MS: m/z 274.02/275.98 [M+H] ⁺ .

Synthesis of intermediate compound 1-4

1-3 (1.51 g, 5.50 mmol) was dissolved in 50 mL of ethanol, and then hydrazine hydrate (1.76 g, 55.0 mmol) was added. The system was reacted at 80 °C for 2 h. LC-MS analysis showed that no raw material remained. The solvent was removed by evaporation under reduced pressure. The residue was directly used in the next step. ESI-MS: m/z 270.01/272.03 [M+H] ⁺ .

Synthesis of intermediate compound 1-5

1-4 was dissolved in 30 mL of chloroform, and then 10 mL of triethyl orthoformate was added. The system was reacted at 80 °C for 2 h. LC-MS analysis showed that no raw material remained. The reaction solution was quenched with ice-water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:3) to give 1-5 (1.00 g, yield for two steps: 65%). ESI-MS: m/z 280.00/282.02 [M+H] ⁺ .

Synthesis of intermediate compound 1-6

1-5 (1.00 g, 3.60 mmol) was dissolved in 50 mL of toluene, and then diisopropylethylamine (464 mg, 3.60 mmol) and phosphoryl chloride (2.76 g, 18.0 mmol) were added. The system was reacted at 100 °C for 2 h. LC-MS analysis showed that no raw material remained. The reaction solution was quenched with ice-water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:1) to give 1-6 (800 mg, yield: 75%). ESI-MS: m/z 298.03/300.02 [M+H] ⁺ .

Synthesis of intermediate compound 1-7

1-6 (800 mg, 2.68 mmol) was dissolved in 30 mL of N,N-dimethylformamide, and then diisopropylethylamine (697 mg, 5.40 mmol) and intermediate B (612 mg, 3.24 mmol) were added. The system was reacted at 120 °C for 2 h. LC-MS analysis showed that no raw material remained. The reaction solution was quenched with ice-water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2) and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:2) to give 1-7 (798 mg, yield: 66%). ESI-MS: m/z 451.02/453.07 [M+H] ⁺ .

Synthesis of intermediate compound 1-8

1-7 (100 mg, 0.22 mmol) was dissolved in a solution of dioxane (40 ml) and water (10 ml), and then potassium hydroxide (25 mg, 0.44 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (10 mg, 0.02 mmol) were added. The whole system was allowed to react with stirring at 100 °C for 3 h. TLC analysis showed that no raw material remained. To the reaction solution was added 50 ml of water and extracted with ethyl acetate (30 ml × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 ml × 2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane:methanol = 60:1-20:1) to give 1-8 (40 mg, yield: 47%). ESI-MS: m/z 389.15 [M+H] ⁺ .

Synthesis of compound 1

1-8 (40 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (15 ml), and then (R)-tetrahydrofuran-3-yl p-toluenesulfonate (30 mg, 0.12 mmol) and cesium carbonate (65 mg, 0.20 mmol) were added. The whole system was allowed to react with stirring at 80 °C for 3 h. TLC analysis showed that no raw material remained. To the reaction solution, 30 ml of water was added, and it was extracted with ethyl acetate (30 ml × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 ml × 2), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane:methanol = 60:1-20:1) to give compound 1 (30 mg, yield: 65%). ESI-MS: m/z 459.25 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 9.59 (s, 1H), 8.40 (d, J=7.2 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.63-7.58 (m, 2H), 7.46 (s, 1H), 5.71-5.64 (m, 1H), 5.47-5.45 (m, 1H), 4.05-4.03(m, 1H), 3.98-3.94 (m, 2H), 3.88-3.84 (m, 1H), 2.46 (s, 3H), 2.42-2.37 (m, 2H), 1.66 (d, J=7.2 Hz, 3H).

Example 2. Synthesis of compound 2

Synthesis of intermediate compound 2-1

1-7 (100 mg, 0.22 mmol) was dissolved in dioxane (30 ml), and then N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (84 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) and cesium carbonate (143 mg, 0.44 mmol) were added. The whole system was allowed to react with stirring at 100 °C for 3 h. TLC analysis showed that no raw material remained. To the reaction solution was added 50 ml of water and extracted with ethyl acetate (30 ml × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 ml × 2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane:methanol = 60:1-20:1) to give 2-1 (100 mg, yield: 82%). ESI-MS: m/z 554.19 [M+H] ⁺ .

Synthesis of intermediate compound 2-2

2-1 (100 mg, 0.18 mmol) was dissolved in 4M hydrochloric acid in ethyl acetate (10 mL) and stirred at room temperature for 2 h. TLC analysis showed that no raw material remained. The solvent was removed under reduced pressure to give 2-2 as a residue, which was used directly in the next step. ESI-MS: m/z 454.16 [M+H] ⁺ .

Synthesis of compound 2

2-2 was dissolved in dichloromethane (10 mL), and then triethylamine (36 mg, 0.36 mmol) and acetic anhydride (22 mg, 0.22 mmol) were added. The system was allowed to react with stirring at room temperature for 2 h. TLC analysis showed that no raw material remained. The reaction solution was quenched with water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane:methanol = 60:1-15:1) to give compound 2 (50 mg, yield: 56%). ESI-MS: m/z 496.17 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 9.59 (d, J=3.6 Hz, 1H), 8.75 (dd, J=7.8 Hz, J=7.8 Hz, 1H), 8.03(d, J=5.4 Hz, 1H), 7.83(s, 1H), 7.78 (d, J=7.2 Hz, 1H), 7.63-7.58 (m, 2H), 7.49-7.47 (m, 1H), 5.72-5.68 (m, 1H), 4.33-4.26 (m, 2H), 3.77-3.73(m, 2H), 2.87-2.63(m, 2H), 2.48(s, 3H), 2.13-2.08 (m, 3H), 1.66 (d, J=7.2 Hz, 3H).

Example 3. Synthesis of compound 3

1-7 (100 mg, 0.22 mmol) was dissolved in N-methylpyrrolidone (30 ml), and then N-methylpiperazine (27 mg, 0.27 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol) and sodium tert-butoxide (42 mg, 0.44 mmol) were added. The whole system was allowed to react with stirring at 120 °C for 3 h. TLC analysis showed that no raw material remained. To the reaction mixture was added 50 ml of water and extracted with ethyl acetate (30 ml × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 ml × 2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane:methanol = 60:1-20:1) to give Compound 3 (41 mg, yield: 40%). ESI-MS: m/z 471.18 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 9.53(s, 1H), 8.42 (d, J=7.8 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J=7.2Hz, 1H), 7.61-7.57 (m, 2H), 7.10 (s, 1H), 5.68-5.65 (m, 1H), 3.65-3.60 (m, 4H), 2.63-2.59 (m, 4H), 2.43(s, 3H), 2.30 (s, 3H), 1.65 (d, J=7.2 Hz, 3H).

Example 4. Synthesis of compound 4

1-7 (100 mg, 0.22 mmol) was dissolved in N-methylpyrrolidone (30 ml), and then morpholine (24 mg, 0.27 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol) and sodium tert-butoxide (42 mg, 0.44 mmol) were added. The whole system was allowed to react with stirring at 120 °C for 3 h. TLC analysis showed that no raw material remained. To the reaction mixture was added 50 ml of water and extracted with ethyl acetate (30 ml × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 ml × 2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane:methanol = 60:1-20:1) to give compound 4 (50 mg, yield: 50%). ESI-MS: m/z 458.16 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 9.53(s, 1H), 8.43(d, J=7.8 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J=6.6 Hz, 1H), 7.62-7.58 (m, 2H), 7.13(s, 1H), 5.70-5.65 (m, 1H), 3.88-3.87 (m, 4H), 3.61-3.59 (m, 4H), 2.43(s, 3H), 1.65 (d, J=7.2 Hz, 3H).

Example 5. Synthesis of compound 5

Synthesis of intermediate compound 5-1

4,6-Dichloro-2-methylpyrimidine-5-carbaldehyde (2.00 g, 10.47 mmol) was dissolved in tetrahydrofuran (20 mL), and then (carbethoxymethylene)triphenylphosphorane (5.47 g, 15.71 mmol) and triethylamine (2.12 g, 20.94 mmol) were added. The system was reacted at 80 °C for 6 h. LC-MS analysis showed that no raw material remained. The reaction system was directly separated and purified by column chromatography (n-hexane:ethyl acetate = 20:1-10:1) to give 5-1 (1.71 g, 6.54 mmol, yield: 63%). ESI-MS: m/z 260.85 [M+H] ⁺ .

Synthesis of intermediate compound 5-2

5-1 (1.71 g, 6.54 mmol) was dissolved in N,N-dimethylformamide (20 ml), and then tert-butyl (2-aminoethyl)carbamate (1.26 g, 7.85 mmol) and triethylamine (1.32 g, 13.08 mmol) were added. The system was reacted at room temperature for 12 h. LC-MS analysis showed that no raw material remained. Water (30 ml) was added to the reaction solution and extracted with ethyl acetate (30 ml × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 ml × 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by thin layer chromatography (n-hexane:ethyl acetate = 10:1-3:1) to give 5-2 (2.30 g, 5.99 mmol, yield: 92%). ESI-MS: m/z 385.15 [M+H] ⁺ .

Synthesis of intermediate compound 5-3

5-2 (2.30 g, 5.99 mmol) was dissolved in methanol (30 mL), and then sodium methoxide (3.6 mL, 17.97 mmol, 30 wt % in methanol) was added. The system was reacted at room temperature for 12 h. A solid precipitated from the reaction solution. LC-MS analysis showed that no raw material remained. Water (10 mL) was added to the reaction solution and filtered to afford 5-3 as a white solid (1.60 g, 4.79 mmol, yield: 80%). ESI-MS: m/z 335.07 [M+H] ⁺ .

Synthesis of intermediate compound 5-4

5-3 (1.60 g, 4.79 mmol) was dissolved in dichloromethane (30 mL), and then bromine (1.15 g, 7.19 mmol) was added. The system was reacted at room temperature for 12 h. LC-MS analysis showed that no raw material remained. The reaction system was directly separated and purified by column chromatography (n-hexane:ethyl acetate = 5:1-3:1) to give 5-4 (1.80 g, 4.36 mmol, yield: 91%). ESI-MS: m/z 412.98/415.00 [M+H] ⁺ .

Synthesis of intermediate compound 5-5

5-4 (1.80 g, 4.36 mmol) was dissolved in dichloromethane (20 ml), and then 5 ml of trifluoroacetic acid was added. The system was reacted at room temperature for 4 h. LC-MS analysis showed that no raw material remained. The solvent was removed by evaporation under reduced pressure. To the residue, 15 ml of water was added, and the pH of the mixture was adjusted to 8-9 with saturated aqueous sodium carbonate solution. The obtained product was extracted with ethyl acetate (20 ml × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 ml × 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give 5-5 (0.90 g, 2.88 mmol, yield: 66%). ESI-MS: m/z 312.92/314.91 [M+H] ⁺ .

Synthesis of intermediate compound 5-6

5-5 (0.90 g, 2.88 mmol) was dissolved in toluene (20 mL) and then trimethylaluminum (1.9 mL, 3.75 mmol, 2.0 M in toluene) was slowly added. The system was reacted at 120 °C for 5 h. LC-MS analysis showed that no raw material remained. The reaction was quenched with saturated aqueous ammonium chloride solution. Toluene was removed by evaporation under reduced pressure. The residue was added 15 mL of water, extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2) and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give 5-6 (0.59 g, 2.01 mmol, yield: 70%). ESI-MS: m/z 294.87/296.83 [M+H] ⁺ .

Synthesis of intermediate compound 5-7

5-6 (0.59 g, 2.01 mmol) was dissolved in dichloromethane (10 mL). Boron tribromide (2.52 g, 10.05 mmol) was slowly added in an ice bath and after the addition the ice bath was removed. The system was reacted at room temperature for 72 h. LC-MS analysis showed that no raw material remained. Aqueous sodium carbonate solution was slowly added in an ice bath to quench the reaction. The solid precipitated and was filtered to give 5-7 (0.46 g, 1.64 mmol, yield: 82%). ESI-MS: m/z 280.82/282.84 [M+H] ⁺ .

Synthesis of intermediate compound 5-8

5-7 (50 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (15 mL), and then (R)-1-(3-(trifluoromethyl)phenyl)ethylamine hydrochloride (61 mg, 0.27 mmol), tri(dimethylamino)benzotriazol-1-yloxyphosphonium hexafluorophosphate (102 mg, 0.23 mmol) and 1,8-diazabicycloundec-7-ene (82 mg, 0.54 mmol) were added. The system was reacted at room temperature for 8 h. LC-MS analysis showed that no raw material remained. Water (30 mL) was added to the reaction solution and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2) and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by thin layer chromatography (dichloromethane:methanol = 20:1) to give 5-8 (40 mg, 0.089 mmol, yield: 49%). ESI-MS: m/z 451.94/453.94 [M+H] ⁺ .

Synthesis of compound 5

5-8 (40 mg, 0.089 mmol) was dissolved in a solution of dioxane (10 mL) and water (2 mL), and then 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (31 mg, 0.133 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13 mg, 0.018 mmol) and cesium carbonate (58 mg, 0.178 mmol) were added. The system was reacted at 100 °C for 4 h. LC-MS analysis showed that no raw material remained. The solvent was removed by evaporation under reduced pressure. The residue was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 ml × 2) and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by thin layer chromatography (dichloromethane:methanol:triethylamine = 100:2:1) to give compound 5 (17 mg, 0.035 mmol, yield: 40%). ESI-MS: m/z 481.11 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.37 (s, 1H), 8.32 (s, 1H), 7.78-7.73 (m, 3H), 7.60-7.59 (m, 2H), 7.21 (s, 1H), 6.81 (d, J=12.0 Hz, 1H), 5.61-5.59 (m, 1H), 4.12 (t, J=6.0 Hz, 2H), 3.97 (t, J=6.0 Hz, 2H), 3.46 (s, 3H), 2.31 (s, 3H), 1.59 (d, J=6.0 Hz, 3H).

Example 6. Synthesis of compound 6

Synthesis of intermediate 6-1

5-7 (100 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (15 mL), and then (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (110 mg, 0.54 mmol), tri(dimethylamino)benzotriazol-1-yloxyphosphonium hexafluorophosphate (207 mg, 0.47 mmol) and 1,8-diazabicycloundec-7-ene (164 mg, 1.08 mmol) were added. The system was reacted at room temperature for 8 h. LC-MS analysis showed that no raw material remained. Water (30 mL) was added to the reaction solution and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2) and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by thin layer chromatography (dichloromethane:methanol = 20:1) to give 6-1 (60 mg, yield: 36%). ESI-MS: m/z 466.91/469.12 [M+H] ⁺ .

Synthesis of compound 6

6-1 (60 mg, 0.128 mmol) was dissolved in a solution of dioxane (10 mL) and water (2 mL), and then 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (45 mg, 0.191 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19 mg, 0.026 mmol) and cesium carbonate (84 mg, 0.258 mmol) were added. The system was reacted at 100 °C for 4 h. LC-MS analysis showed that no raw material remained. The solvent was removed by evaporation under reduced pressure. The residue was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 ml × 2) and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by thin layer chromatography (dichloromethane:methanol:triethylamine = 50:2:1) to give compound 6 (20 mg, yield: 31%). ESI-MS: m/z 496.08 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.30 (s, 1H), 8.13(d, J=6.0 Hz, 1H), 7.72 (d, J=6.0 Hz, 1H), 7.32 (s, 1H), 6.88 (d, J=6.0 Hz, 1H), 6.84-6.82 (m, 2H), 6.71 (s, 1H), 5.57 (s, 2H), 5.50-5.47 (m, 1H), 4.07-4.05 (m, 2H), 3.98-3.95 (m, 2H), 3.45 (s, 3H), 2.31 (s, 3H), 1.52 (d, J=6.0 Hz, 3H).

Example 7. Synthesis of compound 7

Synthesis of intermediate 7-1

5-7 (100 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (15 mL), and then (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine hydrochloride (121 mg, 0.54 mmol), tri(dimethylamino)benzotriazol-1-yloxyphosphonium hexafluorophosphate (205 mg, 0.47 mmol) and 1,8-diazabicycloundec-7-ene (163 mg, 1.08 mmol) were added. The system was reacted at room temperature for 8 h. LC-MS analysis showed that no raw material remained. Water (30 mL) was added to the reaction solution and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 ml × 2) and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by thin layer chromatography (dichloromethane:methanol = 20:1) to give 7-1 (110 mg, yield: 68%). ESI-MS: m/z 451.93/453.93 [M+H] ⁺ .

Synthesis of compound 7

7-1 (110 mg, 0.243 mmol) was dissolved in a solution of dioxane (10 mL) and water (2 mL), and then 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (86 mg, 0.366 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.049 mmol) and cesium carbonate (159 mg, 0.488 mmol) were added. The system was reacted at 100 °C for 4 h. LC-MS analysis showed that no raw material remained. The solvent was removed by evaporation under reduced pressure. The residue was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 ml × 2) and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by thin layer chromatography (dichloromethane:methanol:triethylamine = 100:2:1) to give compound 7 (50 mg, yield: 43%). ESI-MS: m/z 481.09 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.33(s, 1H), 8.18 (d, J=6.0 Hz, 1H), 7.72 (d, J=6.0 Hz, 1H), 7.66-7.64 (m, 1H), 7.52-7.50 (m, 1H), 7.33-7.32 (m, 2H), 7.24 (t, J=54.0 Hz, 1H), 6.91-6.89 (m, 1H), 5.75-5.70 (m, 1H), 4.02-3.95 (m, 4H), 3.45(s, 3H), 3.25 (s, 3H), 1.58 (d, J=6.0 Hz, 3H).

Example 8. Synthesis of compound 8

Synthesis of intermediate compound 8-1

5-7 (100 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (15 mL), and then intermediate G (112 mg, 0.54 mmol), tri(dimethylamino)benzotriazol-1-yloxyphosphonium hexafluorophosphate (205 mg, 0.47 mmol) and 1,8-diazabicycloundec-7-ene (163 mg, 1.08 mmol) were added. The system was reacted at room temperature for 8 h. LC-MS analysis showed that no raw material remained. Water (30 mL) was added to the reaction solution and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2) and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by thin layer chromatography (dichloromethane:methanol = 20:1) to give 8-1 (127 mg, yield: 75%). ESI-MS: m/z 470.98/472.98 [M+H] ⁺ .

Synthesis of compound 8

8-1 (113 mg, 0.24 mmol) was dissolved in a solution of dioxane (10 mL) and water (2 mL), and then 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (86 mg, 0.366 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.049 mmol) and cesium carbonate (159 mg, 0.488 mmol) were added. The system was reacted at 100 °C for 4 h. LC-MS analysis showed that no raw material remained. The solvent was removed by evaporation under reduced pressure. The residue was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 ml × 2) and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by thin layer chromatography (dichloromethane:methanol:triethylamine = 100:2:1) to give compound 8 (55 mg, yield: 46%). ESI-MS: m/z 499.11 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.95 (s, 1H), 8.80 (s, 1H), 7.87-7.85 (m, 2H), 7.67 (dd, J=6.6 Hz, J=6.6 Hz, 1H), 7.39 (dd, J=7.8 Hz, J=7.8 Hz, 1H), 6.91 (s, 1H), 6.65 (d, J=6.6 Hz, 1H), 5.77-5.71 (m, 1H), 4.41-4.34 (m, 4H), 3.50 (s, 3H), 2.34 (s, 3H), 1.62 (d, J=6.0 Hz, 3H).

Example 9. Synthesis of compound 9

Synthesis of intermediate 9-1

3-Amino-2-chloroisonicotinic acid (5.00 g, 29.0 mmol) was dissolved in methanol (80 mL). The system was cooled to 0 °C, and then concentrated sulfuric acid (16 mL) was added. The system was reacted at 80 °C for 5 h. LC-MS analysis showed that no raw material remained. Water (100 mL) was added to the reaction solution and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:1) to give 9-1 (5.00 g, yield: 92%). ESI-MS: m/z 187.02 [M+H] ⁺ .

Synthesis of intermediate compound 9-2

9-1 (5.00 g, 26.8 mmol) was dissolved in acetonitrile (80 mL), and then N-bromosuccinimide (7.17 g, 40.3 mmol) was added. The system was reacted at room temperature for 1.5 h. LC-MS analysis showed that no raw material remained. The reaction solution was quenched with ice-water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:3) to give 9-2 (6.85 g, yield: 96%). ESI-MS: m/z 265.10 /267.12 [M+H] ⁺ .

Synthesis of intermediate compound 9-3

9-2 (6.85 g, 25.8 mmol) was dissolved in acetonitrile (80 mL), and then methanesulfonic acid (15 mL) was added. The system was reacted at 130 °C for 8 h. LC-MS analysis showed that no raw material remained. The reaction solution was quenched with ice-water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:3) to give 9-3 (1.51 g, yield: 21%). ESI-MS: m/z 274.02/276.11 [M+H] ⁺ .

Synthesis of intermediate compound 9-4

9-3 (1.51 g, 5.50 mmol) was dissolved in ethanol (50 mL) and then hydrazine hydrate (1.76 g, 55.0 mmol) was added. The system was reacted at 80 °C for 2 h. LC-MS analysis showed that no raw material remained. The solvent was removed by evaporation under reduced pressure. The residue was directly used in the next step. ESI-MS: m/z 270.02/271.06 [M+H] ⁺ .

Synthesis of intermediate compound 9-5

9-4 was dissolved in chloroform (30 mL), and then triethyl orthoformate (10 mL) was added. The system was reacted at 80 °C for 2 h. LC-MS analysis showed that no raw material remained. The reaction solution was quenched with ice-water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:3) to give 9-5 (1.00 g, yield: 65%). ESI-MS: m/z 280.02/282.14 [M+H] ⁺ .

Synthesis of intermediate compound 9-6

9-5 (1.00 g, 3.60 mmol) was dissolved in toluene (50 mL), and then diisopropylethylamine (465 mg, 3.60 mmol) and phosphoryl chloride (2.76 g, 18.0 mmol) were added. The system was reacted at 100 °C for 2 h. LC-MS analysis showed that no raw material remained. The reaction solution was quenched with ice-water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:1) to give 9-6 (800 mg, yield: 74%). ESI-MS: m/z 298.02/300.20 [M+H] ⁺ .

Synthesis of intermediate compound 9-7

9-6 (400 mg, 1.34 mmol) was dissolved in N,N-dimethylformamide (30 mL), and then diisopropylethylamine (349 mg, 2.70 mmol) and intermediate D (384 mg, 2.02 mmol) were added. The system was reacted at 120 °C for 2 h. LC-MS analysis showed that no raw material remained. The reaction solution was quenched with ice-water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2) and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:2) to give 9-7 (397 mg, yield: 66%). ESI-MS: m/z 451.02/453.09 [M+H] ⁺ .

Synthesis of compound 9

9-7 (397 mg, 0.88 mmol) was dissolved in dioxane (30 mL), and then 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (249 mg, 1.06 mmol), tetrakis(triphenylphosphine)palladium (104 mg, 0.09 mmol) and cesium carbonate (574 mg, 1.76 mmol) were added. The whole system was allowed to react with stirring at 100 °C for 3 h. TLC analysis showed that no raw material remained. Water (50 mL) was added to the reaction solution, which was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL × 2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane:methanol = 60:1-20:1) to give compound 9 (253 mg, yield: 60%). ESI-MS: m/z 480.11 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 9.34 (s, 1H), 8.58 (d, J=7.2 Hz, 1H), 7.98 (d, J=6.6 Hz, 1H), 7.94 (s, 1H), 7.70 (dd, J=7.2 Hz, J=7.2 Hz, 1H), 7.53(dd, J=6.6 Hz, J=7.2 Hz, 1H), 7.32 (dd, J=7.8 Hz, J=7.8 Hz, 1H), 7.26 (t, J=54.6 Hz, 1H), 6.87 (d, J=1.8 Hz, 1H), 6.66 (dd, J=1.8 Hz, J=2.4 Hz, 1H), 5.81-5.79 (m, 1H), 3.56 (s, 3H), 2.49 (s, 3H), 1.63 (d, J=6.6 Hz, 3H).

Example 10. Synthesis of compound 10

Synthesis of intermediate 10-1

9-6 (400 mg, 1.34 mmol) was dissolved in N,N-dimethylformamide (30 mL), and then diisopropylethylamine (349 mg, 2.70 mmol) and intermediate G (418 mg, 2.02 mmol) were added. The system was reacted at 120 °C for 2 h. LC-MS analysis showed that no raw material remained. The reaction solution was quenched with ice-water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2) and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:2) to give 10-1 (415 mg, yield: 66%). ESI-MS: m/z 469.02/471.09 [M+H] ⁺ .

Synthesis of compound 10

10-1 (415 mg, 0.88 mmol) was dissolved in dioxane (30 mL), and then 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (249 mg, 1.06 mmol), tetrakis(triphenylphosphine)palladium (104 mg, 0.09 mmol) and cesium carbonate (574 mg, 1.76 mmol) were added. The whole system was allowed to react with stirring at 100 °C for 3 h. TLC analysis showed that no raw material remained. Water (50 mL) was added to the reaction solution, which was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL × 2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane:methanol = 60:1-20:1) to give compound 10 (250 mg, yield: 57%). ESI-MS: m/z 498.11 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 9.34 (s, 1H), 8.64 (d, J=6.6 Hz, 1H), 7.98 (d, J=6.6 Hz, 1H), 7.94 (s, 1H), 7.83(dd, J=7.2 Hz, J=7.2 Hz, 1H), 7.67 (dd, J=6.6 Hz, J=7.2 Hz, 1H), 7.38 (dd, J=7.8 Hz, J=7.8 Hz, 1H), 6.87 (d, J=1.8 Hz, 1H), 6.67 (dd, J=1.8 Hz, J=1.8 Hz, 1H), 5.78-5.74 (m, 1H), 3.56 (s, 3H), 2.47 (s, 3H), 1.64 (d, J=6.6 Hz, 3H).

Example 11. Synthesis of compound 11

Synthesis of intermediate 11-1

Intermediate 1-3 (0.68 g, 2.48 mmol) was dissolved in anhydrous ethanol (10 ml). Aminoacetaldehyde diethyl acetal (0.49 g, 3.72 mmol) and N,N-diisopropylethylamine (0.64 g, 4.96 mmol) were added and reacted under reflux for 5 h. LC-MS analysis showed that no raw material remained. The reaction system was cooled, brine was added and extracted with ethyl acetate. The organic phase was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give 11-1 (0.83 g, yield: 90%). ESI-MS: m/z 371.58/373.32 [M+H] ⁺ .

Synthesis of intermediate 11-2

Intermediate 11-1 (0.83 g, 2.24 mmol) was dissolved in concentrated sulfuric acid, heated to 65 °C and reacted for 2 h. The reaction solution was slowly added dropwise to saturated sodium bicarbonate solution to quench the reaction. The resulting product was extracted with ethyl acetate and the organic phase was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give 11-2 (0.40 g, yield: 63%). ESI-MS: m/z 279.10/301.14 [M+H] ⁺ .

Synthesis of intermediate compound 11-3

Intermediate 11-2 (0.26 g, 0.94 mmol) was dissolved in N,N-dimethylformamide (5 ml), and intermediate B (0.27 g, 1.22 mmol) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.74 g, 1.41 mmol) were added and reacted at room temperature for 2 h. LC-MS analysis showed that no raw material remained. Brine was added to the reaction system and extracted with ethyl acetate. The organic phase was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give 11-3 (0.18 g, yield: 43%). ESI-MS: m/z 449.90/451.91 [M+H] ⁺ .

Synthesis of intermediate compound 11-4

11-3 (180 mg, 0.40 mmol) was dissolved in a solution of dioxane (40 ml) and water (10 ml), and then potassium hydroxide (67 mg, 1.2 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (10 mg, 0.02 mmol) were added. The whole system was allowed to react with stirring at 100 °C for 3 h. TLC analysis showed that no raw material remained. To the reaction solution was added 50 ml of water and extracted with ethyl acetate (30 ml × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 ml × 2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane:methanol = 60:1-20:1) to give 11-4 (71 mg, yield: 46%). ESI-MS: m/z 388.07 [M+H] ⁺ .

Synthesis of compound 11

11-4 (71 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (15 ml), and then (R)-tetrahydrofuran-3-yl p-toluenesulfonate (47 mg, 0.19 mmol) and cesium carbonate (104 mg, 0.32 mmol) were added. The whole system was allowed to react with stirring at 80 °C for 3 h. TLC analysis showed that no raw material remained. To the reaction solution, 30 ml of water was added, and it was extracted with ethyl acetate (30 ml × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 ml × 2), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane:methanol = 60:1-20:1) to give compound 11 (48 mg, yield: 66%). ESI-MS: m/z 458.32 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.29 (s, 1H), 7.87 (d, J=4.8 Hz, 1H), 7.82 (d, J=6.3 Hz, 1H), 7.67-7.53(m, 4H), 5.69 (p, J=7.2 Hz, 1H), 5.51 (d, J=6.5 Hz, 1H), 4.05 (dt, J=10.8, 3.6 Hz, 1H), 3.97-3.91 (m, 2H), 3.84 (td, J=8.3, 4.5 Hz, 1H), 2.45 (s, 3H), 1.68 (d, J=7.1 Hz, 3H), 1.23 (m, 2H).

Example 12 - Example 30:

The following compounds of Examples 12 to 30 can be prepared by referring to the synthetic methods of Examples 1 to 11.

Example No. Structure ERI-MS / [M+H] ^{+ 1} H NMR 12 467.23 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 11.75 (s, 1H), 8.68 (s, 1H), 8.11-8.07 (m, 2H), 7.97 (d, J=7.2 Hz, 1H), 7.66-7.64 (m, 1H), 7.52-7.49 (m, 1H), 7.33-7.30 (m, 1H), 7.24 (t, J=54.0 Hz, 1H), 6.48 (d, J=9.6 Hz, 1H), 5.75-5.70 (m, 1H), 4.07-3.94 (m, 4H), 2.24 (s, 3H), 1.57 (d, J=6.6 Hz, 3H). 13 474.09 14 473.38 15 500.29 16 516.17 17 487.24 18 517.27 19 487.17 20 502.09 21 482.36 22 482.19 23 467.26 24 481.07 25 495.20 26 509.31 27 552.19 28 495.27 29 552.27 30 469.34

Example 31. Synthesis of compound 31

Synthesis of compound 31

Intermediate 7-1 (99 mg, 0.22 mmol) from Example 7 was dissolved in dioxane (30 ml), and then 1-acetyl-5,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (68 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) and cesium carbonate (143 mg, 0.44 mmol) were added. The whole system was allowed to react with stirring at 100 °C for 3 h. TLC analysis showed that no raw material remained. To the reaction solution was added 50 ml of water and extracted with ethyl acetate (30 ml × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 ml × 2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane:methanol = 60:1-15:1) to give compound 31 (69 mg, 0.14 mmol, yield: 64%). ESI-MS: m/z 497.24 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.23(s, 1H), 8.00 (s, 1H), 7.64 (dd, J=7.2 Hz, J=7.2 Hz, 1H), 7.50 (dd, J=7.2 Hz, J=7.2 Hz, 1H), 7.32-7.29 (m, 1H), 7.23(t, J=54.0 Hz, 1H), 6.82 (d, J=87.6 Hz, 1H), 5.75-5.70 (m, 1H), 4.22-4.02 (m, 4H), 3.95-3.92 (m, 2H), 3.67-3.62 (m, 2H), 2.50 (s, 3H), 2.26 (s, 3H), 2.06 (d, J=24.6 Hz, 2H), 1.56 (d, J=6.6 Hz, 3H).

Example 32 - Example 92:

The following compounds of Examples 32 to 92 can be prepared by referring to the synthetic methods of Examples 1 to 11.

Example No. Structure ERI-MS / [M+H] ^{+ 1} H NMR 32 456.15 33 472.11 34 476.33 35 488.12 36 483.24 37 473.37 38 487.26 39 501.14 40 489.21 41 496.35 42 486.29 43 515.18 44 529.21 45 517.14 46 524.19 47 472.34 48 500.29 49 459.28 50 471.23 51 499.31 52 471.22 53 542.36 54 447.14 55 445.17 56 473.32 57 471.13 58 499.33 59 458.19 60 467.18 61 501.24 62 482.18 63 495.27 64 507.25 65 481.14 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.85 (s, 1H), 8.02 (d, J=14.2 Hz, 2H), 7.97 (d, J=6.8 Hz, 1H), 7.77 (s, 1H), 7.73(d, J=6.8 Hz, 1H), 7.65-7.52 (m, 2H), 6.53(d, J=9.5 Hz, 1H), 5.62-5.49 (m, 1H), 4.11-3.89 (m, 4H), 3.48 (s, 3H), 2.28 (s, 3H), 1.59 (d, J=7.0 Hz, 3H). 66 463.31 67 496.17 68 499.19 69 495.17 70 477.34 71 493.32 ¹ H NMR (600 MHz, CD ₃ OD): δ 8.29 (s, 1H), 8.01 (s, 1H), 7.92 (d, J=9.6 Hz, 1H), 7.63(s, 1H), 7.55 (d, J=7.2 Hz, 1H), 7.45-7.40 (m, 2H), 6.64 (d, J=9.6 Hz, 1H), 5.64-5.61 (m, 1H), 4.32-4.24 (m, 2H), 4.07 (t, J=9.6 Hz, 2H), 3.89 (t, J=13.2 Hz, 2H), 3.65 (s, 3H), 2.41 (s, 3H), 1.64 (d, J=7.2 Hz, 3H). 72 495.10 73 499.24 74 495.12 75 479.11 76 481.27 77 495.12 78 495.29 79 509.37 80 509.24 81 521,12 82 535.33 83 507.12 84 507.29 85 460.30 86 460.24 87 459.11 88 473.34 89 501.13 90 474.17 91 488.38 92 487.19

Example 93. Synthesis of compound 93

Synthesis of compound 93

Intermediate 5-8 (40 mg, 0.089 mmol) from Example 5 was dissolved in a solution of dioxane (10 mL) and water (2 mL), and then 1-acetyl-5,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (34 mg, 0.133 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13 mg, 0.018 mmol) and cesium carbonate (58 mg, 0.178 mmol) were added. The system was reacted at 100 °C for 4 h. LC-MS analysis showed that no raw material remained. The solvent was removed by evaporation under reduced pressure. The residue was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 ml × 2) and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by thin layer chromatography (dichloromethane:methanol:trimethylamine = 100:2:1) to give compound 93 (29 mg, 0.058 mmol, yield: 65%). ESI-MS: m/z 497.27 [M+H] ⁺ . ^1H NMR (600 MHz, DMSO- _d6 ): δ 7.97 (s, 1H), 7.76 (s, 1H), 7.72-7.71 (m, 2H), 7.62-7.56 (m, 2H), 7.06 (d, J=96.0 Hz, 1H), 5.60-5.55 (m, 1H), 4.16-4.10 (m, 2H), 4.03-3.90 (m, 4H), 3.66-3.62 (m, 2H), 2.51 (s, 3H), 2.27 (s, 3H), 2.08-2.04 (m, 2H), 1.57 (d, J=6.6 Hz, 3H).

Example 94 - Example 108:

The following compounds of Examples 94 to 108 can be prepared by referring to the synthesis method of Example 93.

Example No. Structure ERI-MS / [M+H] ^{+ 1} H NMR 94 451.23 ^1H NMR (600 MHz, DMSO- _d6 ): δ 9.09 (s, 1H), 8.54 (d, J=3.6 Hz, 1H), 8.38 (d, J=8.0 Hz, 1H), 8.17 (s, 1H), 8.00 (d, J=7.6 Hz, 1H), 7.77 (s, 1H), 7.73(d, J=7.0 Hz, 1H), 7.60-7.56 (m, 2H), 7.49-7.40 (m, 1H), 5.60-5.54 (m, 1H), 4.08-3.87 (m, 4H), 2.28 (s, 3H), 1.57 (d, J=7.0 Hz, 3H). 95 476.09 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 9.45 (s, 1H), 8.99 (s, 1H), 8.93 (s, 1H), 8.33 (s, 1H), 8.04 (d, J=7.0 Hz, 1H), 7.78 (s, 1H), 7.74 (d, J=6.9 Hz, 1H), 7.61-7.57 (m, 2H), 5.63-5.54 (m, 1H), 4.08-3.94 (m, 4H), 2.29 (s, 3H), 1.59 (d, J=6.9 Hz, 3H). 96 452.19 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 9.39 (s, 2H), 9.15 (s, 1H), 8.28 (s, 1H), 7.99 (d, J=6.4 Hz, 1H), 7.77 (s, 1H), 7.73(d, J=6.3 Hz, 1H), 7.63-7.57 (m, 2H), 5.61-5.54 (m, 1H), 4.08-3.91 (m, 4H), 2.29 (s, 3H), 1.58 (d, J=6.3 Hz, 3H). 97 511.21 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.92 (s, 1H), 8.05 (dd, J=9.6 Hz, 2.6 Hz, 1H), 8.01 (s, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.77 (s, 1H), 7.73 (d, J=7.2 Hz, 1H), 7.63-7.54 (m, 2H), 6.53(d, J=9.6 Hz, 1H), 5.60-5.57 (m, 1H), 4.92 (t, J=5.3 Hz, 1H), 4.01-3.96 (m, 6H), 3.67-3.64 (m, 2H), 2.28 (s, 3H), 1.59 (d, J=7.2 Hz, 3H). 98 495.21 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.89 (s, 1H), 8.05 (s, 1H), 8.03-.95 (m, 2H), 7.78 (s, 1H), 7.74 (d, J=7.0 Hz, 1H), 7.65-7.53 (m, 2H), 6.52 (d, J=9.5 Hz, 1H), 5.60-5.55 (m, 1H), 4.19-3.76 (m, 6H), 2.27 (s, 3H), 1.59 (d, J=7.1 Hz, 3H), 1.26 (t, J=7.1 Hz, 3H). 99 481.23 ¹ H NMR (600 MHz, CD ₃ OD): δ 8.28 (s, 1H), 7.82-7.80 (m, 2H), 7.74 (s, 1H), 7.70 (d, J=7.4 Hz, 1H), 7.57-7.48 (m, 2H), 6.51 (t, J=6.8 Hz, 1H), 5.65-5.61 (m, 1H), 4.53-4.45 (m, 2H), 4.06 (t, J=10.2 Hz, 2H), 3.67 (s, 3H), 2.44 (s, 3H), 1.64 (d, J=7.1 Hz, 3H). 100 525.26 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.82 (s, 1H), 8.20-7.90 (m, 3H), 7.78 (s, 1H), 7.73(d, J=7.2 Hz, 1H), 7.62-7.56 (m, 2H), 6.55 (d, J=9.6 Hz, 1H), 5.63-5.55 (m, 1H), 4.14-4.04 (m, 4H), 4.00-3.97 (m, 2H), 3.62 (t, J=5.3 Hz, 2H), 3.26 (s, 3H), 2.29 (s, 3H), 1.59 (d, J=7.1 Hz, 3H). 101 531.23 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.90 (s, 1H), 8.30-7.89 (m, 3H), 7.77 (s, 1H), 7.73 (d, J=7.2 Hz, 1H), 7.61-7.57 (m, 2H), 6.62 (d, J=9.6 Hz, 1H), 6.35 (tt, J=55.4 Hz, 3.7 Hz, 1H), 5.67-5.51 (m, 1H), 4.43(td, J=14.8 Hz, 3.4 Hz, 2H), 4.17-3.83(m, 4H), 2.29 (s, 3H), 1.59 (d, J=7.1 Hz, 3H). 102 481.19 ¹ H NMR (600 MHz, CD ₃ OD): δ 8.00 (s, 1H), 7.78-7.65 (m, 2H), 7.61-7.48 (m, 3H), 6.65 (dd, J=9.1, 1.1 Hz, 1H), 6.46 (dd, J=6.8, 1.2 Hz, 1H), 5.61 (q, J=7.0 Hz, 1H), 4.36-4.18 (m, 2H), 4.13-3.92 (m, 2H), 3.52 (s, 3H), 2.40 (s, 3H), 1.62 (d, J=7.1 Hz, 3H). 103 482.24 ^1H NMR (600 MHz, DMSO- _d6 ): δ 9.19 (s, 1H), 8.21 (s, 1H), 8.11-7.89 (m, 2H), 7.85-7.67 (m, 2H), 7.59 (s, 2H), 5.69-5.46 (m, 1H), 4.20-3.75 (m, 4H), 3.51 (s, 3H), 2.28 (s, 3H), 1.56 (d, J=7.2 Hz, 3H). 104 512.28 ¹ H NMR (600 MHz, CD ₃ OD): δ 8.22 (s, 1H), 8.01 (s, 1H), 7.75 (s, 1H), 7.71 (d, J=7.1 Hz, 1H), 7.61-7.48 (m, 2H), 5.63(q, J=7.0 Hz, 1H), 4.45 (t, J=9.5 Hz, 2H), 4.07 (t, J=10.2 Hz, 2H), 3.49 (s, 3H), 3.40 (s, 3H), 2.43(s, 3H), 1.65 (d, J=7.1 Hz, 3H). 105 509.22 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.19-7.90 (m, 4H), 7.77 (s, 1H), 7.73(d, J=7.1 Hz, 1H), 7.64-7.52 (m, 2H), 6.54 (d, J=9.6 Hz, 1H), 5.63-5.55 (m, 1H), 5.14-5.03(m, 1H), 4.15-3.91 (m, 4H), 2.29 (s, 3H), 1.59 (d, J=7.1 Hz, 3H), 1.33(d, J=2.9 Hz, 3H), 1.31 (d, J=2.9 Hz, 3H). 106 495.24 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.63(s, 1H), 8.01 (s, 1H), 7.98 (d, J=5.4 Hz, 1H), 7.85 (s, 1H), 7.78 (s, 1H), 7.74 (d, J=7.1 Hz, 1H), 7.65-7.54 (m, 2H), 5.64-5.51 (m, 1H), 4.16-3.91 (m, 4H), 3.50 (s, 3H), 2.28 (s, 3H), 2.11 (s, 3H), 1.60 (d, J=7.1 Hz, 3H). 107 511.24 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.20 (s, 1H), 8.10 (d, J=7.7 Hz, 1H), 7.75 (s, 1H), 7.71 (d, J=7.2 Hz, 1H), 7.63-7.53 (m, 3H), 7.25 (d, J=1.8 Hz, 1H), 6.83(dd, J=7.2 Hz, 2.0 Hz, 1H), 5.63-5.51 (m, 1H), 4.89 (t, J=5.3 Hz, 1H), 4.10-3.83(m, 6H), 3.63(dd, J=10.9 Hz, 5.5 Hz, 2H), 2.26 (s, 3H), 1.56 (d, J=7.1 Hz, 3H). 108 523.27 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.38 (s, 1H), 8.32 (s, 1H), 7.85 (d, J=7.3 Hz, 1H), 7.78 (s, 1H), 7.73(d, J=7.3 Hz, 1H), 7.66-7.56 (m, 2H), 7.19 (s, 1H), 6.94 (d, J=6.8 Hz, 1H), 5.69-5.49 (m, 2H), 4.91 (t, J=7.4 Hz, 2H), 4.77 (t, J=7.0 Hz, 2H), 4.21- 3.93(m, 4H), 2.31 (s, 3H), 1.59 (d, J=7.1 Hz, 3H).

Example 109. Synthesis of compound 109

Intermediate 5-8 (40 mg, 0.089 mmol) from Example 5 was dissolved in a solution of dioxane (10 mL) and water (2 mL), and then (1-(methyl-d ₃ )-2-oxo-1,2-dihydropyridin-4-yl)boronic acid pinacol ester (32 mg, 0.133 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13 mg, 0.018 mmol) and cesium carbonate (58 mg, 0.178 mmol) were added. The system was reacted at 100 °C for 4 h. LC-MS analysis showed that no raw material remained. The solvent was removed by evaporation under reduced pressure. The residue was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 ml × 2) and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by thin layer chromatography (dichloromethane:methanol:trimethylamine = 100:2:1) to give compound 109 (25 mg, 0.051 mmol, yield: 57%). ESI-MS: m/z 484.24 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.29 (s, 1H), 8.22 (d, J=7.2 Hz, 1H), 7.77 (s, 1H), 7.76-7.68 (m, 2H), 7.65-7.54 (m, 2H), 7.28 (s, 1H), 6.86 (d, J=7.0 Hz, 1H), 5.65-5.53(m, 1H), 4.22-3.87 (m, 4H), 2.29 (s, 3H), 1.59 (d, J=7.0 Hz, 3H).

Example 110 - Example 121:

The following compounds of Examples 110 to 121 can be prepared by referring to the synthesis method of Example 93.

Example No. Structure ERI-MS / [M+H] ^{+ 1} H NMR 110 507.29 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.29 (s, 1H), 8.21 (d, J=6.7 Hz, 1H), 7.72 (dd, J=11.8, 7.6 Hz, 2H), 7.67 (d, J=7.9 Hz, 1H), 7.62-7.53(m, 2H), 7.32 (s, 1H), 6.89 (dd, J=7.2, 1.9 Hz, 1H), 5.38-5.33(m, 1H), 4.15-3.86 (m, 4H), 3.45 (s, 3H), 1.87-1.75 (m, 1H), 1.56 (d, J=7.1 Hz, 3H), 1.07- 0.99 (m, 1H), 0.91-0.85 (m, 1H), 0.81-0.75 (m, 1H), 0.55-0.51 (m, 1H). 111 507.24 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.77 (s, 1H), 8.15 (s, 2H), 8.01 (d, J=9.3 Hz, 1H), 7.72 (s, 1H), 7.69 (d, J=7.2 Hz, 1H), 7.63-7.52 (m, 2H), 6.54 (d, J=9.5 Hz, 1H), 5.42-5.31 (m, 1H), 4.22-3.92 (m, 4H), 3.50 (s, 3H), 1.82 (ddd, J=12.6, 8.2, 4.7 Hz, 1H), 1.57 (d, J=7.1 Hz, 3H), 1.08-0.99 (m, 1H), 0.92-0.83(m, 1H), 0.81-0.73(m, 1H), 0.57-0.47 (m, 1H). 112 562.28 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.56-8.30 (m, 2H), 8.15 (s, 1H), 7.82 (s, 1H), 7.77 (d, J=5.3 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.64-7.50 (m, 3H), 5.69 (d, J=5.0 Hz, 1H), 5.65-5.56 (m, 1H), 4.35-4.14 (m, 2H), 4.09-3.90 (m, 5H), 2.34 (s, 3H), 1.77-1.53 (m, 9H). 113 499.18 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.30 (s, 1H), 8.17 (d, J=7.7 Hz, 1H), 7.84 (d, J=7.4 Hz, 1H), 7.77 (s, 1H), 7.73(d, J=7.2 Hz, 1H), 7.65-7.55 (m, 2H), 7.52 (s, 1H), 6.97 (dd, J=7.4, 1.8 Hz, 1H), 5.96 (d, J=51.3 Hz, 2H), 5.64-5.55 (m, 1H), 4.09-3.91 (m, 4H), 2.28 (s, 3H), 1.59 (d, J=7.1 Hz, 3H). 114 452.23 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.27 (s, 1H), 8.24 (d, J=6.9 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.71 (d, J=7.2 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.40-7.37 (m, 1H), 7.31 (s, 1H), 6.89 (dd, J=7.1, 1.6 Hz, 1H), 5.57 (p, J=6.9 Hz, 1H), 4.15-3.83(m, 4H), 3.45 (s, 3H), 2.68 (s, 3H), 2.26 (s, 3H), 1.51 (d, J=7.0 Hz, 3H). 115 452.26 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.74 (s, 1H), 8.17 (s, 2H), 7.99 (d, J=8.7 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.64 (d, J=7.1 Hz, 1H), 7.40-7.37 (m, 1H), 6.55 (d, J=9.5 Hz, 1H), 5.68-5.53(m, 1H), 4.24-3.85 (m, 4H), 3.50 (s, 3H), 2.68 (s, 3H), 2.28 (s, 3H), 1.52 (d, J=7.0 Hz, 3H). 116 468.27 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.12 (s, 1H), 7.81 (s, 1H), 7.74 (d, J=7.0 Hz, 1H), 7.62 (d, J=6.6 Hz, 1H), 7.38-7.35 (m, 1H), 6.97 (d, J=99.5 Hz, 1H), 5.62-5.49 (m, 1H), 4.36-3.81 (m, 6H), 3.65-3.61 (m, 2H), 2.66 (s, 3H), 2.24 (s, 3H), 2.05 (d, J=26.0 Hz, 2H), 1.49 (d, J=5.9 Hz, 3H). 117 482.18 ¹ H NMR (600 MHz, CD ₃ OD): δ 8.77 (d, J=4.8 Hz, 1H), 8.74 (s, 1H), 7.85 (d, J=7.2 Hz, 1H), 7.80 (s, 1H), 7.59 (d, J=4.8 Hz, 1H), 6.87 (s, 1H), 6.69 (dd, J=7.2 Hz, J=1.8 Hz, 1H), 5.69-5.65 (m, 1H), 4.66-4.63(m, 2H), 4.17-4.13(m, 2H), 3.66 (s, 3H), 2.42 (s, 3H), 1.72 (d, J=7.2 Hz, 3H). 118 493.21 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.65-8.60 (m, 2H), 7.80 (d, J=6.6 Hz, 1H), 7.61 (s, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.47-7.44 (m, 1H), 7.40 (d, J=7.2 Hz, 1H), 7.06 (s, 1H), 6.73(d, J=6.6 Hz, 1H), 5.64-5.59 (m, 1H), 4.30-4.20 (m, 2H), 3.98 (t, J=10.2 Hz, 2H).
3.87-3.82 (m, 2H), 3.47 (s, 3H), 2.36 (s, 3H), 1.59 (d, J=7.2 Hz, 3H). 119 539.24 ^1H NMR (600 MHz, DMSO- _d6 ): δ 8.85 (s, 1H), 8.18-8.07 (m, 3H), 7.62-7.60 (m, 1H), 7.32-7.30 (m, 1H), 7.24-7.22 (m, 1H), 6.53(d, J=9.0 Hz, 1H), 5.77-5.71 (m, 1H), 5.34 (s, 1H), 4.10-3.96 (m, 4H), 3.49 (s, 3H), 2.24 (s, 3H), 1.55 (d, J=7.2 Hz, 3H), 1.24 (s, 3H), 1.18(s,3H). 120 491.20 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.69 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.12-7.10 (m, 1H), 6.55 (d, J=9.0 Hz, 1H), 5.70-5.67 (m, 1H), 4.87 (d, J=16.8 Hz, 2H), 4.20-4.17 (m, 2H), 4.01-3.98 (m, 2H), 3.49(s, 3H), 2.29(s, 3H), 1.56 (d, J=6.6 Hz, 3H). 121 491.23 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.92 (s, 2H), 7.93(d, J=6.6 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.55 (d, J=7.2 Hz, 1H), 7.13-7.10 (m, 1H), 6.71 (s, 1H), 6.48 (d, J=6.6 Hz, 1H), 5.74-5.69 (m, 1H), 4.88 (t, J=16.2 Hz, 2H), 4.60-4.53(m, 2H), 4.03(t, J=10.2 Hz, 2H), 3.51 (s, 3H), 2.42 (s, 3H), 1.59 (d, J=6.6 Hz, 3H).

Example 122. Synthesis of compound 122

Synthesis of intermediate 122-1

7-1 (99 mg, 0.22 mmol) was dissolved in dioxane (30 ml), and then N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (84 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) and cesium carbonate (143 mg, 0.44 mmol) were added. The whole system was allowed to react with stirring at 100 °C for 3 h. TLC analysis showed that no raw material remained. To the reaction solution was added 50 ml of water and extracted with ethyl acetate (30 ml × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 ml × 2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane:methanol = 60:1-20:1) to give 122-1 (100 mg, yield: 82%). ESI-MS: m/z 555.19 [M+H] ⁺ .

Synthesis of intermediate 122-2

122-1 (100 mg, 0.18 mmol) was dissolved in 4 M hydrochloric acid in ethyl acetate (10 mL) and allowed to react with stirring at room temperature for 2 h. TLC analysis showed that no raw material remained. The solvent was removed under reduced pressure to give 122-2 as a residue, which was used directly in the next step. ESI-MS: m/z 455.18 [M+H] ⁺ .

Synthesis of compound 122

122-2 was dissolved in dichloromethane (10 ml), and then triethylamine (36 mg, 0.36 mmol) and methylsulfonyl chloride (25 mg, 0.22 mmol) were added, and the mixture was stirred at room temperature for 2 h. TLC analysis showed that no raw material remained. Water was added to the reaction solution to quench the reaction, and it was extracted with ethyl acetate (30 ml × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 ml × 2), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane:methanol = 60:1-15:1) to give compound 122 (50 mg, yield: 52%). ESI-MS: m/z 533.20 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.00 (s, 1H), 7.80 (s, 1H), 7.64 (dd, J=7.2 Hz, J=7.2 Hz, 1H), 7.50 (dd, J=7.2 Hz, J=7.2 Hz, 1H), 7.32-7.30 (m, 1H), 7.24 (t, J=54.0 Hz, 1H), 7.11 (s, 1H), 5.75-5.70 (m, 1H), 4.00-3.88 (m, 6H), 3.40-3.37 (m, 2H), 2.95 (s, 3H), 2.72-2.63(m, 2H), 2.24 (s, 3H), 1.56 (d, J=6.6 Hz, 3H).

Example 123 and Example 124:

The following compounds of Examples 123 and 124 can be prepared by referring to the synthesis method of Example 93.

Example No. Structure ERI-MS / [M+H] ^{+ 1} H NMR 123 522.22 ¹ H NMR (600 MHz, CD ₃ OD): δ 7.83(s, 1H), 7.57 (dd, J=7.2 Hz, J=7.2 Hz, 1H), 7.49 (dd, J=7.2 Hz, J=7.2 Hz, 1H), 7.27-7.23(m, 1H), 7.01 (t, J=55.2 Hz, 1H), 6.39 (d, J=87.6 Hz, 1H), 5.78-5.74 (m, 1H), 4.26-4.01 (m, 6H), 3.86-3.84 (m, 1H), 3.72-3.70 (m, 1H), 3.29 (s, 2H), 2.68-2.64 (m, 1H), 2.60-2.56 (m, 1H), 2.34 (s, 3H), 1.63(d, J=7.2 Hz, 3H). 124 541.27 ¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.73(s, 1H), 8.53(s, 1H), 7.67 (dd, J=7.2 Hz, J=7.2 Hz, 1H), 7.53(dd, J=7.2 Hz, J=7.2 Hz, 1H), 7.34-7.31 (m, 1H), 7.24 (t, J=54.0 Hz, 1H), 6.29 (s, 1H), 5.79-5.74 (m, 1H), 4.53-4.47 (m, 2H), 4.21-3.89 (m, 6H), 3.50-3.34 (m, 2H), 2.38 (s, 3H), 1.61 (d, J=6.6 Hz, 3H), 1.37-1.31 (m, 2H), 1.27-1.21 (m, 2H).

Example 125. Synthesis of compound 125

Compound 124 (100 mg, 0.18 mmol) was dissolved in dichloromethane/isopropanol (22 mL, V₁/V₂=1/10) and phenylsilane (19.5 mg, 0.18 mmol) and tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese (7.6 mg, 0.01 mmol) were added successively at room temperature. The reaction solution was purged with oxygen atmosphere three times and stirred at room temperature for 16 h under oxygen atmosphere (balloon). LC-MS showed that the raw material was completely consumed. The reaction solution was filtered, and the resulting filtrate was concentrated under reduced pressure to give the crude product. The crude product was separated and purified by column chromatography (dichloromethane:methanol = 60:1-15:1) to give compound 125 (28 mg, yield: 28%). ESI-MS: m/z 559.24 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): δ 8.32 (d, J=16.0 Hz, 1H), 7.57 (t, J=7.2 Hz, 1H), 7.47 (t, J=7.2 Hz, 1H), 7.23(t, J=8.0 Hz, 1H), 6.99 (t, J=54.8 Hz, 1H), 5.82-5.73(m, 1H), 4.56-4.24 (m, 4H), 4.10 (t, J=10.0 Hz, 2H), 3.85-3.45 (m, 2H), 2.39 (s, 3H), 2.10-2.06 (m, 4H), 1.64 (d, J=7.2 Hz, 3H), 1.28-1.24 (m, 4H).

Biological activity tests:

1. K-Ras ^G12D and hSOS1 binding assay

This assay can be used to study the efficacy of compounds in inhibiting the protein-protein interaction between SOS1 and KRAS G12D. Binding of GST-KRas ^G12D conjugated to anti-GSK-europium (FRET donor) to His-tagged hSOS1 conjugated to anti-6His-XL665 (FRET donor) was detected by homogeneous time-resolved fluorescence (HTRF) and the inhibitory effect of compounds on K-Ras ^G12D binding to hSOS1 was determined.

1.1 Reagents

Buffer (5 mM HEPES pH 7.4, 150 mM NaCl, 10 mM EDTA, 1 mM DTT, 0.05% BAS pH 7.0, 0.0025% lgepal and 100 mM KF);

GST-tagged hK-RasG12D (produced in-house);

His-tagged hSOS1 (produced in-house);

Preparation of liquid Ras mixture:

10 nM (final concentration) GST-hK-RasG12D and 2 nM (final concentration) anti-GSK-europium in assay buffer were mixed and left to stand at room temperature.

Preparation of liquid SOS mixture:

20 nM (final concentration) His-tagged hSOS1 and 10 nM (final concentration) anti-6His-XL665 in assay buffer were mixed and left to stand at room temperature.

The test compound was dissolved in DMSO at a concentration 100 times higher than the assay concentration. 50 nL of the compound solution was pipetted using a Hummingbird liquid handler or an Echo acoustic system into a black microassay plate.

1.2 Stages of the experiment

All steps of the experiment were performed at 20°C. In the experiment, 2.5 μl of Ras liquid mix was added to all wells of the assay plate using a Multidrop dispenser. After a pre-incubation of 2 min, 2.5 μl of SOS liquid mix was added to all test wells except the outer wells, and 2.5 μl of the compound solution as a control was added to the outer wells. After incubation for 60 min, the assay plate was passed through the Pheraster module for HTRF (excitation light: 337 nm, emission light 1: 620 nm, emission light 2: 665 nm).

1.3 Data calculation

IC ₅₀ values were calculated and analyzed using a four-parameter logistic regression model.

1.4 Results of inhibitory activity against SOS1

Illustrative compounds from the examples were tested according to the above method. The obtained data on inhibitory activity towards SOS1 are presented in the table below.

Connection example # Activity by IC ₅₀ (nM) Connection example # Activity by IC ₅₀ (nM) 1 B 2 B 3 B 4 B 5 B 6 A 7 A 8 A 9 B 10 B 11 D 12 A 31 B 65 B 71 A 97 A 98 A 99 B 109 B 118 A 122 A 123 A 124 A

In the table, A means _IC50 < 10 nM, B means 10 nM ≤ _IC50 < 50 nM, C means 50 nM ≤ _IC50 < 100 nM, D means 100 nM ≤ _IC50 < 300 nM.

2. Analysis of cell proliferation inhibition in three-dimensional culture

A cell proliferation inhibition assay was used to determine the ability of compounds to inhibit the proliferation and growth of SOS1-mediated tumor cells at the in vitro 3D cell culture level. The CellTiter-Glo® 3D Cell Viability Assay was used.

2.1 Reagents and materials

NCI-H358: KRAS G12C-mutated non-small cell lung cancer (NSCLC);

CellTiter-Glo® 3D Cell Viability Assay, Promega, G9683;

RPMI 1640 medium, Gibco, A10491-01;

FBS, Gibco, 10099141C.

2.2 Stages of the experiment

2.2.1 Cell culture

Day 1: NCI-H358 cells were passaged into a T75 cell culture flask.

Day 3: The medium was removed; the cells were washed once with DPBS and digested at room temperature or at 37°C using 2 ml of TrypLE™ Express enzyme until the cells were detached; 5 ml of fresh medium was added to the resulting solution and centrifuged at 1000 rpm for 5 min; the supernatant was discarded and 5 ml of fresh medium was added to resuspend the cells; the cells were counted and then seeded at 40 µl/well in a 3D cell culture plate (Echo Qualified, 384-well polypropylene microplate 2.0, clear, flat bottom).

2.2.2 Inhibition of cell proliferation in three-dimensional culture

Day 1: The test compound was dissolved in DMSO to obtain a 10 mM stock solution; after 1000-fold dilution with DMSO, the test compound solution was subjected to ten 3-fold serial dilutions starting from a concentration of 10 μM; 200 nL of the compound solution was added to the culture plate.

Day 8: CTG 3D reagent was added at 40 µl/well and signal was detected using Envision.

2.3 Data Analysis

The IC ₅₀ values of the compounds were approximated using the nonlinear regression equation of Graphpad Prism 8.

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

X: logarithm of compound concentration;

Y: percentage of inhibition (% ing).

2.4 Results of NCI-H358 cell proliferation inhibitory activity

The example compounds were tested according to the above-described method. The obtained data on the inhibitory activity against NCI-H358 cell proliferation are presented in the table below.

Connection example # Activity by IC ₅₀ (nM) Connection example # Activity by IC ₅₀ (nM) 2 C 3 C 4 C 5 A 6 A 7 A 12 C 31 A 65 C 71 C 94 C 95 C 97 C 98 C 99 C 100 C 101 C 102 C 103 C 104 C 105 C 106 C 107 C 108 B 109 B 110 C 111 C 112 C 113 C 117 C 118 C 119 B 120 C 121 C 122 B 123 B 124 B 125 B

In the table, A indicates _IC50 < 50 nM, B indicates 50 nM ≤ _IC50 < 100 nM, C indicates 100 nM ≤ _IC50 < 500 nM.

Claims (140)

1. The compound represented by formula (B), or its optical isomer or pharmaceutical salt, (B), where R ¹ is -OR ^A , -N(R ^D )R ^B or R ^C ; when R ¹ is -OR ^A , R ^A is 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl is optionally substituted with 1-3 identical or different R ^a1 ; each R ^a1 , if present, is independently C _1-6 alkyl or -COC _1-6 alkyl; when R ¹ is -N(R ^D )R ^B , R ^B is C _1-6 alkyl or 3-10 membered heterocyclyl, wherein said C _1-6 alkyl is optionally substituted with 1-3 identical or different R ^b1 ; each R ^b1 , if present, is independently -OC _1-6 alkyl; R ^D represents hydrogen; when R ¹ is R ^C , R ^C is 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein said 3-10 membered heterocyclyl and 5-10 membered heteroaryl are both optionally substituted with 1-4 same or different R ^c1 ; each R ^c1 , if present, is independently halogen, hydroxyl, cyano, amino, oxo, methylsulfonyl, C _1-6 alkyl, -OC _1-6 alkyl, -COC _1-6 alkyl, -COC _3-6 cycloalkyl, -CH ₂ CON(C _1-6 alkyl) ₂ or 3-10 membered heterocyclyl, wherein said C _1-6 alkyl, -COC _1-6 alkyl and -COC _3-6 cycloalkyl are all optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, C _1-3 alkoxy or halogen; one or two R ² are present, each of which, in each instance, independently represents hydrogen or C _1-6 alkyl; R ³ is hydrogen, halogen, amino, C _1-6 alkyl or C _3-6 cycloalkyl; ring B is C _6-12 aryl, C _6-8 aryl-fused 4-6-membered heterocyclyl, or 5-12-membered heteroaryl; each R ⁴ , if present, is independently hydrogen, cyano, halogen, amino, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 haloalkyl is optionally substituted with hydroxyl; w is 0, 1, 2, 3 or 4; unless otherwise specified, each of the heteroatoms in a heteroaryl and heterocyclyl is independently O, N, or S and the number of heteroatoms is 1 or 2. 2. A compound or its optical isomer or pharmaceutical salt according to claim 1, where R ¹ is -OR ^A ; R ^A is 5-6 membered heterocyclyl, wherein the 5-6 membered heterocyclyl is optionally substituted with 1-3 identical or different R ^a1 ; each R ^a1 , if present, is independently C _1-4 alkyl or -COC _1-4 alkyl; more preferably R ^A is 5-6 membered heterocyclyl, wherein said 5-6 membered heterocyclyl is optionally substituted with one or two identical or different R ^a1 ; each R ^a1 , if present, is independently acetyl, methyl, ethyl, n-propyl or isopropyl; more preferably R ^A is a 5-6-membered monocyclic heterocyclyl, wherein said 5-6-membered monocyclic heterocyclyl is optionally substituted with one or two identical or different R ^a1 ; each of the heteroatoms in the 5-6-membered monocyclic heterocyclyl independently represents O or N and the number of heteroatoms is 1; each R ^a1 , if present, is independently acetyl, methyl, ethyl, n-propyl or isopropyl; more preferably R ^A is tetrahydrofuranyl, pyrrolidinyl, piperidinyl or tetrahydropyranyl, wherein said tetrahydrofuranyl, pyrrolidinyl, piperidinyl and tetrahydropyranyl are all optionally substituted with one or two of the same or different R ^a1 ; each R ^a1 , if present, is independently acetyl, methyl, ethyl, n-propyl or isopropyl; even more preferably R ^A represents the following group: , , , , , or . 3. A compound or its optical isomer or pharmaceutical salt according to claim 1, where R ¹ is -N( ^RD ) ^RB ; R ^B is C _1-6 alkyl or 5-6 membered monocyclic heterocyclyl, wherein said C _1-6 alkyl is optionally substituted with one or two identical or different R ^b1 ; each of the heteroatoms in said 5-6 membered monocyclic heterocyclyl is independently O and the number of heteroatoms is 1; each R ^b1 , if present, is independently -OC _1-4 alkyl; more preferably R ^B is methyl, ethyl, n-propyl, isopropyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl, wherein said methyl, ethyl, n-propyl and isopropyl are all optionally substituted with one or two identical or different R ^b1 ; each R ^b1 , if present, is independently methoxy or ethoxy; even more preferably R ^B represents the following group: , or ; R ^D represents hydrogen. 4. The compound or its optical isomer or pharmaceutical salt according to claim 1, where R ¹ is R ^C ; R ^C is 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein said 3-10 membered heterocyclyl and 5-10 membered heteroaryl are both optionally substituted with 1-4 identical or different R ^c1 ; each R ^c1 , if present, is independently halogen, hydroxyl, cyano, amino, oxo, methylsulfonyl, C _1-4 alkyl, -OC _1-4 alkyl, -COC _1-4 alkyl, -COC _3-6 cycloalkyl, -CH ₂ CON(C _1-4 alkyl) ₂ or 3-6 membered heterocyclyl, wherein said C _1-4 alkyl, -COC _1-4 alkyl and -COC _3-6 cycloalkyl are all optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, methoxy or halogen; more preferably R ^C is 5-6-membered monocyclic heterocyclyl, 6-10-membered spiroheterocyclyl, 6-8-membered bridged heterocyclyl, 8-10-membered fused heterocyclyl or 5-6-membered monocyclic heteroaryl, wherein said 5-6-membered monocyclic heterocyclyl, 6-10-membered spiroheterocyclyl, 6-8-membered bridged heterocyclyl, 8-10-membered fused heterocyclyl and 5-6-membered monocyclic heteroaryl are all optionally substituted with 1-4 identical or different R ^c1 ; each R ^c1 , if present, is independently halogen, hydroxyl, cyano, amino, oxo, acetyl, propionyl, methylsulfonyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH ₂ CON(CH ₃ ) ₂ , -CO-cyclopropyl, -CO-cyclobutyl, 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl, wherein said acetyl, propionyl, methyl, ethyl, n-propyl, isopropyl, -CO-cyclopropyl and -CO-cyclobutyl are all optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, methoxy or halogen; even more preferably, R ^C is 6-membered monocyclic heterocyclyl, 4-membered/6-membered spiroheterocyclyl, 4-membered/4-membered spiroheterocyclyl, 6-membered/5-membered fused heterocyclyl, 7-membered bridged heterocyclyl or 6-membered monocyclic heteroaryl, wherein said 6-membered monocyclic heterocyclyl, 4-membered/6-membered spiroheterocyclyl, 4-membered/4-membered spiroheterocyclyl, 6-membered/4-membered fused heterocyclyl, 7-membered bridged heterocyclyl and 6-membered monocyclic heteroaryl are all optionally substituted with 1 to 4 of the same or different R ^c1 ; each R ^c1 , if present, is independently halogen, hydroxyl, cyano, amino, oxo, acetyl, propionyl, methylsulfonyl, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, -CH ₂ CON(CH ₃ ) ₂ , -CO-cyclopropyl, 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl, wherein said acetyl, propionyl, methyl, ethyl, n-propyl, isopropyl and -CO-cyclopropyl are all optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, methoxy or halogen; more preferably R ^C is , , , , , , , , , , , , , , , , , , or and said R ^C are all optionally substituted with 1-4 identical or different R ^c1 ; each R ^c1 , if present, is independently F, Cl, Br, hydroxyl, cyano, amino, oxo, methylsulfonyl, acetyl, -COCH ₂ CH ₃ , -COCH ₂ OH, -COCH ₂ CN, -CH(OH)(CH ₃ ) ₂ , hydroxymethyl, hydroxyethyl, -CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₃ , methoxy, methyl, CD ₃ , ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, , , -CH ₂ CON(CH ₃ ) ₂ or morpholinyl; even more preferably R ^C , optionally substituted by R ^c1 , is the following group: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . 5. A compound or its optical isomer or pharmaceutical salt according to any one of claims 1-4, wherein one or two R ² are present, each of which, in each case, independently represents hydrogen, methyl, ethyl, n-propyl, or isopropyl; more preferably one or two R ² are present, each of which, in each case, independently represents hydrogen or methyl; even more preferably R ² is hydrogen. 6. A compound or its optical isomer or pharmaceutical salt according to any one of claims 1-5, wherein R ³ is hydrogen, halogen, amino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; more preferably R ³ is hydrogen, halogen, amino, methyl, ethyl, n-propyl, isopropyl or cyclopropyl; even more preferably R ³ is hydrogen, F, Cl, Br, amino, methyl, ethyl or cyclopropyl. 7. A compound or its optical isomer or pharmaceutical salt according to any one of claims 1-6, wherein ring B is C _6-10 aryl, 5-10 membered heteroaryl, or C _6-8 aryl-fused 4-6 membered heterocyclyl; more preferably, ring B is phenyl, pyridinyl or benzodihydrofuranyl. 8. A compound or its optical isomer or pharmaceutical salt according to any one of claims 1-7, wherein each R ⁴ , if present, is independently hydrogen, cyano, halogen, amino, C _1-4 alkyl or C _1-4 haloalkyl, wherein said C _1-4 haloalkyl is optionally substituted with hydroxyl; w is 0, 1, 2 or 3; more preferably each R ⁴ is independently hydrogen, cyano, halogen, amino, C _1-4 alkyl or C _1-4 haloalkyl, wherein said C _1-4 haloalkyl is optionally substituted with hydroxyl; w is 1, 2 or 3; more preferably, each R ⁴ is independently hydrogen, fluoro, amino, cyano, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, -CF ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CF ₂ CH ₃ or -CH ₂ CHF ₂ ; w is 1, 2 or 3. 9. A compound or its optical isomer or pharmaceutical salt according to any one of claims 1 to 8, wherein the compound has a structure represented by formula (C) (C), the substituents in formula (C) are as defined in formula (B). 10. The compound represented by formula (D) or its optical isomer or pharmaceutical salt, (D), wherein each R ⁴ , if present, is independently cyano, halogen, amino, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 haloalkyl is optionally substituted with hydroxyl; w is 1 or 2; R ¹ is -OR ^A , -N(R ^D )R ^B or R ^C ; when R ¹ is -OR ^A , R ^A is 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl is optionally substituted with 1-3 identical or different R ^a1 ; each R ^a1 , if present, is independently C _1-6 alkyl or -COC _1-6 alkyl; when R ¹ is -N(R ^D )R ^B , R ^B is C _1-6 alkyl or 3-10 membered heterocyclyl, wherein said C _1-6 alkyl is optionally substituted with 1-3 identical or different R ^b1 ; each R ^b1 , if present, is independently -OC _1-6 alkyl; R ^D represents hydrogen; when R ¹ is R ^C , R ^C is 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein said 3-10 membered heterocyclyl and 5-10 membered heteroaryl are both optionally substituted with 1-4 same or different R ^c1 ; each R ^c1 , if present, is independently halogen, hydroxyl, cyano, amino, methylsulfonyl, C _1-6 alkyl, -OC _1-6 alkyl, -COC _1-6 alkyl, -COC _3-6 cycloalkyl, -CH ₂ CON(C _1-6 alkyl) ₂ or 3-10 membered heterocyclyl, wherein said C _1-6 alkyl, -COC _1-6 alkyl and -COC _3-6 cycloalkyl are all optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, C _1-3 alkoxy or halogen; unless otherwise specified, each of the heteroatoms in a heteroaryl and heterocyclyl is independently O, N, or S and the number of heteroatoms is 1 or 2. 11. The compound or its optical isomer or pharmaceutical salt according to claim 10, wherein R ¹ is -OR ^A , R ^A is 5-6 membered heterocyclyl, wherein said 5-6 membered heterocyclyl is optionally substituted with one or two identical or different R ^a1 ; each R ^a1 , if present, is independently acetyl, methyl, ethyl, n-propyl or isopropyl; more preferably R ^A is a 5-6-membered monocyclic heterocyclyl, wherein said 5-6-membered monocyclic heterocyclyl is optionally substituted with one or two identical or different R ^a1 ; each of the heteroatoms in said 5-6-membered monocyclic heterocyclyl is independently O or N and the number of heteroatoms is 1; each R ^a1 , if present, is independently acetyl, methyl or ethyl; more preferably R ^A is tetrahydrofuranyl, pyrrolidinyl, piperidinyl or tetrahydropyranyl, wherein said tetrahydrofuranyl, pyrrolidinyl, piperidinyl and tetrahydropyranyl are all optionally substituted with one or two of the same or different R ^a1 ; each R ^a1 , if present, is independently acetyl, methyl or ethyl; even more preferably R ^A represents the following group: , , , , , or . 12. A compound or its optical isomer or pharmaceutical salt according to claim 10, wherein R ¹ is -N( ^RD ) ^RB , R ^B is C _1-6 alkyl or a 3-6 membered monocyclic heterocyclyl, wherein said C _1-6 alkyl is optionally substituted with one or two identical or different R ^b1 ; each of the heteroatoms in said 3-6 membered monocyclic heterocyclyl is independently O and the number of heteroatoms is 1; each R ^b1 , if present, is independently -OC _1-4 alkyl; more preferably R ^B is methyl, ethyl, n-propyl, isopropyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl or tetrahydropyranyl, wherein said methyl, ethyl, n-propyl and isopropyl are all optionally substituted with one or two identical or different R ^b1 ; each R ^b1 , if present, is independently methoxy or ethoxy; even more preferably R ^B represents the following group: , or ; R ^D represents hydrogen. 13. The compound or its optical isomer or pharmaceutical salt according to claim 10, wherein R ¹ is R ^C , R ^C is 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein said 3-10 membered heterocyclyl and 5-10 membered heteroaryl are both optionally substituted with 1-4 same or different R ^c1 ; each R ^c1 , if present, is independently halogen, hydroxyl, cyano, amino, methylsulfonyl, C _1-4 alkyl, -OC _1-4 alkyl, -COC _1-4 alkyl, -COC _3-6 cycloalkyl, -CH ₂ CON(C _1-4 alkyl) ₂ or 3-6 membered heterocyclyl, wherein said C _1-4 alkyl, -COC _1-4 alkyl and -COC _3-6 cycloalkyl are all optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, methoxy or halogen; more preferably R ^C is 5-6-membered monocyclic heterocyclyl, 6-10-membered spiroheterocyclyl, 6-8-membered bridged heterocyclyl, 8-10-membered fused heterocyclyl or 5-6-membered monocyclic heteroaryl, wherein said 5-6-membered monocyclic heterocyclyl, 6-10-membered spiroheterocyclyl, 6-8-membered bridged heterocyclyl, 8-10-membered fused heterocyclyl and 5-6-membered monocyclic heteroaryl are all optionally substituted with 1-4 identical or different R ^c1 ; each R ^c1 , if present, is independently halogen, hydroxyl, cyano, amino, methylsulfonyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, acetyl, propionyl, -CO-cyclopropyl, -CO-cyclobutyl, -CH ₂ CON(CH ₃ ) ₂ , 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl, wherein said methyl, ethyl, n-propyl, isopropyl, acetyl, propionyl, -CO-cyclopropyl and -CO-cyclobutyl are all optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, methoxy or halogen; even more preferably R ^C is 6-membered monocyclic heterocyclyl, 4-membered/6-membered spiroheterocyclyl, 4-membered/4-membered spiroheterocyclyl, 7-membered bridged heterocyclyl, 6-membered/5-membered fused heterocyclyl or 6-membered monocyclic heteroaryl, wherein said 6-membered monocyclic heterocyclyl, 4-membered/6-membered spiroheterocyclyl, 4-membered/4-membered spiroheterocyclyl, 7-membered bridged heterocyclyl, 6-membered/4-membered fused heterocyclyl and 6-membered monocyclic heteroaryl are all optionally substituted with 1 to 4 identical or different R ^c1 ; each R ^c1 , if present, is independently halogen, hydroxyl, cyano, amino, methylsulfonyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, acetyl, propionyl, -CO-cyclopropyl, -CH ₂ CON(CH ₃ ) ₂ , 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl, wherein said methyl, ethyl, n-propyl, isopropyl, acetyl, propionyl and -CO-cyclopropyl are all optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, methoxy or halogen; more preferably R ^C is , , , , , , , , , , , , , or and said R ^C are all optionally substituted with 1-4 identical or different R ^c1 ; each R ^c1 , if present, is independently F, Cl, Br, hydroxyl, cyano, amino, methylsulfonyl, methyl, ethyl, isopropyl, CD ₃ , hydroxymethyl, hydroxyethyl, -CH(OH)(CH ₃ ) ₂ , -CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₃ , monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, methoxy, acetyl, -COCH ₂ CH ₃ , -COCH ₂ OH, -COCH ₂ CN, , -CH ₂ CON(CH ₃ ) ₂ , oxetanyl or morpholinyl; even more preferably R ^C , optionally substituted by R ^c1 , is the following group: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . 14. A compound or its optical isomer or pharmaceutical salt according to any one of paragraphs 10-13, wherein each R ⁴ , if present, is independently cyano, halogen, amino, C _1-4 alkyl or C _1-4 haloalkyl, wherein said C _1-4 haloalkyl is optionally substituted with hydroxyl; w is 1 or 2; more preferably, each R ⁴ is independently cyano, fluoro, amino, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, -CF ₂ CH ₂ OH, -CF ₂ C(CH ₃ ) ₂ OH, -CF ₂ CH ₃ or -CH ₂ CHF ₂ ; w is 1 or 2. 15. A compound or its optical isomer or pharmaceutical salt according to any one of claims 10 to 14, wherein the compound has a structure represented by formula (E) (E), the substituents in formula (E) are as defined in formula (D). 16. A compound or its optical isomer or pharmaceutical salt, wherein the compound is one of the following compounds: . 17. A compound or its optical isomer or pharmaceutical salt, wherein the compound is one of the following compounds: . 18. A pharmaceutical composition having inhibitory activity against SOS1, containing an effective amount of a compound or its optical isomer or pharmaceutical salt according to any one of claims 1-17, additionally containing a pharmaceutically acceptable excipient. 19. An intermediate compound represented by formula (V), or an optical isomer or pharmaceutical salt thereof, (V), Where represents a double bond; X is C, Y is C and Z is N; Y and Z, together with the atoms to which they are bonded, form a ring A, where ring A is ; one or two R ² are present, each of which, in each instance, independently represents hydrogen or C _1-6 alkyl; R ³ is hydrogen, halogen, amino, C _1-6 alkyl or C _3-6 cycloalkyl; R ⁵ is halogen or hydroxyl; R ⁶ is a halogen. 20. An intermediate compound represented by formula (VI), or its optical isomer or pharmaceutical salt, (VI), Where represents a double bond; X is C, Y is C and Z is N; Y and Z, together with the atoms to which they are bonded, form a ring A, where ring A is ; one or two R ² are present, each of which, in each instance, independently represents hydrogen or C _1-6 alkyl; R ³ is hydrogen, halogen, amino, C _1-6 alkyl or C _3-6 cycloalkyl; ring B is C _6-12 aryl, C _6-8 aryl-fused 4-6-membered heterocyclyl, or 5-12-membered heteroaryl; each R ⁴ , if present, is independently hydrogen, cyano, halogen, amino, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 haloalkyl is optionally substituted with hydroxyl; w is 0, 1, 2, 3 or 4; R ⁶ is a halogen. 21. An intermediate compound represented by formula (VII), or an optical isomer or pharmaceutical salt thereof, (VII), Where represents a double bond; X is C, Y is C and Z is N; Y and Z, together with the atoms to which they are bonded, form a ring A, where ring A is ; one or two R ² are present, each of which, in each instance, independently represents hydrogen or C _1-6 alkyl; R ³ is hydrogen, halogen, amino, C _1-6 alkyl or C _3-6 cycloalkyl; ring B is C _6-12 aryl, C _6-8 aryl-fused 4-6-membered heterocyclyl, or 5-12-membered heteroaryl; each R ⁴ , if present, is independently hydrogen, cyano, halogen, amino, C _1-6 alkyl or C _1-6 haloalkyl, wherein said C _1-6 haloalkyl is optionally substituted with hydroxyl; w is 0, 1, 2, 3 or 4; R ⁶ is a halogen.