WO2025223536A1 - Fused bicyclic compound and use thereof - Google Patents

Abstract

The present application relates to the field of pharmaceutical chemistry, and relates to a fused bicyclic compound and a use thereof, and in particular to a fused bicyclic compound, a preparation method for the compound, a pharmaceutical composition containing the compound, and a use of the compound in the treatment of diseases. The structure of the fused bicyclic compound is represented by formula (I).

Description

Fused bicyclic compounds and their uses

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority and benefit to Chinese patent application No. 202410517289.8 filed with the China National Intellectual Property Administration on April 26, 2024, and Chinese patent application No. 202510502592.5 filed with the China National Intellectual Property Administration on April 21, 2025, the contents of which are incorporated herein by reference in their entirety.

Technical Field

This application belongs to the field of medicinal chemistry and relates to fused bicyclic compounds and their uses, specifically fused bicyclic compounds, their preparation methods, pharmaceutical compositions containing the compounds, and their uses in treating diseases.

Background Technology

Wolframin (WFS1) is a polymeric endoplasmic reticulum transmembrane protein that regulates endoplasmic reticulum stress by influencing intracellular Ca2 ⁺ homeostasis and the unfolded protein response (UPR). Previous research on WFS1 has primarily focused on Wolfram syndrome, diabetes, and Alzheimer's disease; however, recent findings indicate that WFS1 is widely expressed in solid tumors, making it a highly promising target for anti-tumor therapy.

Invention Details

On the one hand, this application relates to compounds of formula (I) or pharmaceutically acceptable salts thereof.

in,

It can be independently selected from either a single bond or a double bond;

^X1 , ^X2 , ^X5 , and ^X6 are each independently selected from N or ^CR1 ;

^X3 and ^X4 are each independently selected from N, C or ^CR1 ;

Each ^R1 is independently selected _from hydrogen, deuterium, oxo, halogen, -OH, _-NH2 , -CN, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylthio, _C1-6 alkylamino, _diC1-6 alkylamino, _haloC1-6 alkyl, haloC1-6 alkoxy, _haloC1-6 alkylthio, _haloC1-6 alkylamino, or _halodiC1-6 alkylamino;

Ring A is selected from the following groups optionally substituted with one or more ^RA groups: 3-12-membered heterocyclic groups, 6-10-membered aryl groups, or 5-10-membered heteroaryl groups;

Each ^RA is independently selected from oxo, deuterium, halogen, -OH, _-NH2 , -CN, -C(O)NR ^{a1Ra2 , -NR a1C(O)Ra2, -OC(O)Ra2, -C(O)OR a2 , -S ( O} ) ^Ra2 , -S(O ⁾ _2Ra2 , -NR ^a1S (O) ^2Ra2 , -S(O) _2NR ^a1Ra2 , or optionally substituted with one or more ^{Ra3 groups} , including _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylthio, _C1-6 alkylamino, _diC1-6 alkylamino, 3-12 membered cycloalkyl, _3-12 membered heterocycloalkyl, 3-12 membered _{cycloalkylC1-6} alkylene, or 3-12 membered _{heterocycloalkylC1-6} alkylene;

^Ra1 is independently selected from hydrogen, deuterium, or _C1-6 alkyl groups optionally substituted with one or more ^Ra3 ;

^Ra2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more ^Ra3 groups of the following: _C1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered cycloalkyl _C1-6 alkylene, or 3-12 membered heterocycloalkyl _C1-6 alkylene;

Each ^Ra3 is independently _{selected from} oxo, deuterium, halogen, -OH, _-NH2 , -CN, _C1-4 alkyl, _C1-4 alkoxy, _C1-4 alkylthio, _C1-4 alkylamino, diC1-4 alkylamino, _haloC1-4 alkyl, _haloC1-4 alkoxy, haloC1-4 alkylthio, _haloC1-4 alkylamino, or _halodiC1-4 alkylamino;

The ring B is selected from the following groups optionally substituted with one or more R ^B : 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl;

Each ^Rb is independently selected from oxo, deuterium, halogen, -CN, ^-ORb2 , ^-SRb2 , ^-NRb1Rb2 , -C(O) ^NRb1Rb2 , -C( ^O )NRb1ORb2, ^-NRb1C ( ^{O)Rb2 , -NRb1C} (O ^{)NRb1Rb2 ,} -OC(O) ^Rb2 , -C( ^O ) ^ORb2 , -C(O) ^Rb2 , -S( _O ) ^Rb2 , -S(O) ^2Rb2 , -C( ^Rb1 ) _2S (O) ^{2Rb2 , -NRb1S} (O) ^2Rb2 , _-S (O) _2NRb1Rb2 , or optionally substituted with one or _more ^Rb3 groups ^, including the following ^groups : C _1-6 alkyl, 3-12 cycloalkyl, 3-12 heterocycloalkyl, 3-12 heterocycloalkenyl, 5-10 heteroaryl, 3-12 cycloalkyl C _1-6 alkylene, or 3-12 heterocycloalkyl C _1-6 alkylene;

^Rb1 is independently selected from hydrogen, deuterium, or _C1-6 alkyl groups optionally substituted with one or more ^Rb3 ;

^Rb2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more of the following groups: _C1-6 alkyl, 3-12 cycloalkyl, 3-12 heterocycloalkyl, 3-12 heterocycloalkenyl, 5-10 heteroaryl, _3-12 cycloalkyl C1-6 alkylene, or 3-12 heterocycloalkyl _C1-6 ^alkylene ;

Each ^Rb3 is independently _{selected from} oxo, deuterium, halogen, -OH, _-NH2 , -CN, _C1-4 alkyl, _C1-4 alkoxy, _C1-4 alkylthio, _C1-4 alkylamino, _diC1-4 alkylamino, C1-4 alkylcarbonyl, _haloC1-4 alkyl, _haloC1-4 alkoxy, _haloC1-4 alkylthio, _haloC1-4 alkylamino, or halodiC1-4 alkylamino;

Each ^R2 is independently _{selected from} oxo, deuterium, halogen, -OH, _-NH2 , -CN, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylthio, _C1-6 alkylamino, diC1-6 alkylamino, _haloC1-6 alkyl, _haloC1-6 alkoxy, haloC1-6 alkylthio, _haloC1-6 alkylamino, or _halodiC1-6 alkylamino;

Alternatively, two R2 ^atoms located on the same ring atom together with the ring atom form a group optionally substituted by one or more ^R2a , namely a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl.

Each R ^2a is independently selected from oxo, deuterium, halogen, -OH, -NH ₂ , -CN, C _{1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, diC 1-4 alkylamino, haloC 1-4 alkyl, haloC 1-4 alkoxy , haloC 1-4 alkylthio ,} haloC _1-4 alkylamino, or halodiC _1-4 alkylamino;

m is selected from 0, 1, 2, 3, 4, 5, or 6.

In some implementations, the component is selected from single bonds. In some implementations, structural fragments... Selected from In some implementations, structural fragments Selected from

In some implementations, the component is selected from double bonds. In some implementations, the structural segment... Selected from In some implementations, structural fragments Selected from

In some implementations, structural fragments The ring C and structural fragments The N-connection. In some implementations, structural fragments Ring A and structural fragments N-connection.

In some implementations, structural fragments ^X1 , ^X2 , ^X5 , or ^X6 and structural fragments N-connection.

In some implementations, structural fragments Selected from In some implementations, structural fragments Selected from

In some implementations, ^X1 , ^X2 , ^X5 , or ^X6 are not all selected from N.

In some implementations, ^X2 is N and ^X6 is N.

In some implementations, ^X2 is N and ^X6 is ^CR1 . In some implementations, ^X2 is N and ^X6 is CH.

In some implementations, ^X2 is ^CR1 and ^X6 is ^CR1 .

In some implementations, ^X2 is ^CR1 and ^X6 is N. In some implementations, ^X2 is CH and ^X6 is N.

In some implementations, ^X1 and ^X5 are selected from ^CR1 .

In some implementations, ^X3 and ^X4 are selected from C.

In some implementations, ^X3 and ^X4 are not both selected from N.

In some implementations, ^X3 is N, and ^X4 is C or ^CR1 . In some implementations, ^X3 is N, and ^X4 is C or CH.

In some implementations, ^X3 is C or ^CR1 , and ^X4 is N. In some implementations, ^X3 is C or CH, and ^X4 is N.

In some implementations, ^X3 is C or ^CR1 , and ^X4 is C or ^CR1 . In some implementations, ^X3 is C or CH, and ^X4 is C or CH.

In some implementations, structural fragments Selected from Wherein, the substitution position of ^R1 is on ring C; n is selected from 0, 1, 2, 3 or 4.

In some implementations, structural fragments Selected from Wherein, the substitution position of ^R1 is on ring C; n is selected from 0, 1, or 2.

In some embodiments, each ^R1 is independently selected from hydrogen, deuterium, oxo, halogen, -OH, _-NH2 , -CN, _C1-4 alkyl, _C1-4 alkoxy, _C1-4 alkylthio, _C1-4 alkylamino, _diC1-4 alkylamino, _haloC1-4 alkyl, _haloC1-4 alkoxy, _haloC1-4 alkylthio, _haloC1-4 alkylamino, or _halodiC1-4 alkylamino.

In some embodiments, each ^R1 is independently selected from hydrogen, deuterium, oxo, halogen, -OH, _-NH2 , -CN, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 alkylthio, _C1-3 alkylamino, _diC1-3 alkylamino, _haloC1-3 alkyl, _haloC1-3 alkoxy, _haloC1-3 alkylthio, _haloC1-3 alkylamino, or _halodiC1-3 alkylamino.

In some embodiments, each ^R1 is independently selected from hydrogen, deuterium, oxo, -F, -Cl, -Br, -OH, _-NH2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, halomethyl, or halomethoxy.

In some implementations, each ^R1 is independently selected from hydrogen, deuterium, oxo, -F, -Cl, -Br, -OH, _-NH2 , -CN, methyl, ethyl, methoxy, methylamino, dimethylamino, _-CF3 , or _-OCF3 .

In some embodiments, ring A is selected from the following groups optionally substituted with one or more ^RA groups: 3-10 membered heterocyclic groups, 6-10 membered aryl groups, or 5-10 membered heteroaryl groups.

In some embodiments, ring A is selected from the following groups optionally substituted with one or more ^RA groups: 3-8 membered heterocyclic groups, 6-8 membered aryl groups, or 5-8 membered heteroaryl groups.

In some embodiments, ring A is selected from the following groups optionally substituted with one or more ^RA groups: 5-6 membered heterocyclic group, phenyl group, or 5-6 membered heteroaryl group.

In some embodiments, ring A is selected from the following groups optionally substituted with one or more ^RA groups: phenyl, pyrrolyl, dihydropyrrolyl, pyrrolyl, pyrazolyl, dihydropyrazolyl, pyrazolyl, tetrahydrofuranyl, dihydrofuranyl, furanyl, imidazoalkyl, dihydroimidazoyl, imidazoyl, thiophenyl, dihydrothiophenyl, thiophenyl, tetrahydropyranyl, dihydropyranyl, pyranyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, pyridinyl, tetrahydropyrimidinyl, dihydropyrimidinyl The group is pyrimidinyl, piperazinyl, tetrahydropyrazinyl, dihydropyrazinyl, pyrazinyl, tetrahydropyridazinyl, dihydropyridazinyl, pyridazinyl, thiazolyl, dihydrothiazolyl, thiazolyl, isothiazolyl, dihydroisothiazolyl, isothiazolyl, oxazolyl, dihydrooxazolyl, oxazolyl, isoxazolyl, dihydroisooxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, or tetrazolyl.

In some embodiments, ring A is selected from the following groups optionally substituted with one or more ^RA groups: phenyl, dihydropyrrolyl, pyrrolyl, pyrazolyl, dihydrofuranyl, furanyl, imidazolyl, dihydrothiophenyl, thiophenyl, tetrahydropyridyl, pyridyl, thiazolyl, 1,2,3-triazolyl, or 1,2,4-triazolyl.

In some embodiments, ring A is selected from the following groups optionally substituted with one or more ^RNA groups: In this context, atoms marked with "*" represent X ³ , and atoms marked with "#" represent X ⁴ .

In some embodiments, ring A is selected from the following groups optionally substituted with one or more ^RNA groups: In this context, atoms marked with "*" represent X ³ , and atoms marked with "#" represent X ⁴ .

In some embodiments, each ^RA is independently selected from oxo, deuterium, halogen, -OH, _-NH2 , -CN, -C(O)NR ^a1Ra2 , -NR ^a1C (O) ^Ra2 , ^{-OC(O)Ra2 ,} -C ₍ O)OR ^a2 , -S(O) ^Ra2 , -S(O) _2Ra2 , -NR ^a1S (O ^{)2Ra2 ,} -S(O) _2NR ^a1Ra2 , or optionally substituted with one or more ^{Ra3 groups} , including _C1-4 alkyl, _C1-4 alkoxy, _C1-4 alkylthio, _C1-4 alkylamino, _diC1-4 alkylamino, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, 3-10 membered _{cycloalkylC1-4} alkylene, or 4-10 membered _{heterocycloalkylC1-4} alkylene.

In some embodiments, each ^RA is independently selected from oxo, deuterium, halogen, -OH, _-NH2 , -CN, -C(O)NR ^{a1 Ra2} , -NR ^a1 C(O) ^Ra2 , -OC(O) ^Ra2 , -C(O)OR ^a2 , -S(O) ^Ra2 , ^-S (O) _2Ra2 ^{, -NR a1 S(O)2Ra2 ,} _-S (O) _2NR ^{a1 Ra2} , or optionally substituted with one or more ^Ra3 groups, including _C1-3 alkyl, _C1-3 alkoxy, _C1-3 alkylthio, _C1-3 alkylamino, _diC1-3 alkylamino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkyl _C1-3 alkylene, or 4-6 membered heterocycloalkyl _C1-3 alkylene.

In some embodiments, each ^RA is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, _-NH2 , -CN, -C(O)NR ^{a1 Ra2} , -C(O)OR ^a2 , -S(O) ^Ra2 , -S(O) _2Ra2 ^, or optionally substituted with one or more ^Ra3 groups, namely: _C1-3 alkyl, _C1-3 alkoxy, C1-3 alkylamino, _diC1-3 alkylamino, 3-6 membered cycloalkyl, _4-6 membered heterocycloalkyl, 3-6 membered cycloalkyl _C1-3 alkylene, or 4-6 membered heterocycloalkyl _C1-3 alkylene.

In some embodiments, each ^Ra is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, _-NH₂ , -CN, -C(O)NR ^{a1 Ra₂} , -C(O)OR ^a₂ , -S(O) ^Ra₂ , -S(O) _₂Ra₂ , or optionally substituted with one or more ^Ra₃ groups, including: methyl, ethyl, ⁿ -propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, methylethylamino, cyclopropane, cyclobutane, cyclopentane, cyclohexane _, aziridine, tetrahydrofuranyl, pyrrolyl, thiazolyl, piperidinyl, piperazine, morpholinyl _, cyclopropane C1-3 alkylene, cyclobutane C1-3 alkylene, cyclopentane _C1-3 alkylene, cyclohexane C1-3 alkylene, aziridine _C1-3 alkylene, _{tetrahydrofuranyl} C1-3 alkylene _1-3 alkylene, pyrrolidinyl C _1-3 alkylene, thiazolyl C _1-3 alkylene, piperidinyl C _1-3 alkylene, piperazinyl C _1-3 alkylene, morpholinyl C _1-3 alkylene.

In some implementations, each ^RA is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, _-NH₂ , -CN, Methyl, methoxy, _-CF3 .

In some embodiments, ^Ra1 is independently selected from hydrogen, deuterium, or _C1-4 alkyl groups optionally substituted with one or more ^Ra3 .

In some embodiments, ^Ra1 is independently selected from hydrogen, deuterium, or optionally substituted with one or more ^Ra3 groups, such as methyl, ethyl, n-propyl, and isopropyl.

In some implementations, ^Ra1 is independently selected from hydrogen.

In some embodiments, ^Ra2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more ^Ra3 groups, namely: _C1-4 alkyl, 3-10 cycloalkyl, 3-10 heterocycloalkyl, 3-10 cycloalkyl _C1-4 alkylene, or 3-10 heterocycloalkyl _C1-4 alkylene.

In some embodiments, ^Ra2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more ^Ra3 groups, namely: _C1-3 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkyl _C1-3 alkylene, or 4-6 membered heterocycloalkyl _C1-3 alkylene.

In some embodiments, ^Ra2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more ^Ra3 groups, including: methyl, ethyl, n-propyl, isopropyl, cyclopropane, _cyclobutane , aziridine, pyrrolidine, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, cyclopropane _C1-3 alkylene, cyclobutane _C1-3 alkylene, aziridine _C1-3 alkylene, pyrrolidine _C1-3 alkylene, tetrahydrofuranyl C1-3 alkylene, piperidinyl _C1-3 alkylene, piperazinyl _C1-3 alkylene, and morpholinyl _C1-3 alkylene.

In some embodiments, ^Ra2 is independently selected from groups optionally substituted with one or more ^Ra3 , namely methyl, ethyl, n-propyl, or isopropyl.

In some implementations, ^Ra2 is independently selected from ethyl groups.

In some embodiments, each ^Ra3 is independently selected from oxo, deuterium, halogen, -OH, _-NH2 , -CN, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 alkylthio, _C1-3 alkylamino, diC1-3 alkylamino, _haloC1-3 alkyl, _haloC1-3 alkoxy, _haloC1-3 alkylthio, _{haloC1-3 alkylamino} , or _halodiC1-3 alkylamino.

In some embodiments, each ^Ra3 is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, _-NH2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, halomethyl, or halomethoxy.

In some implementations, each ^Ra3 is independently selected from -F or -Cl.

In some implementations, ring A is selected from... In this context, atoms marked with "*" represent X ³ , and atoms marked with "#" represent X ⁴ .

In some implementations, structural fragments Selected from Where n is selected from 0, 1, 2, 3, or 4; p is selected from 0, 1, 2, 3, or 4.

In some implementations, structural fragments Selected from Where n is selected from 0, 1, or 2; p is selected from 0, 1, 2, or 3.

In some implementations, structural fragments Selected from

In some implementations, structural fragments Selected from

In some implementations, structural fragments Selected from

In some embodiments, ring B is selected from the following groups optionally substituted with one or more ^RBs : 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl.

In some embodiments, ring B is selected from the following groups optionally substituted with one or more ^RBs : 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, or 5-9 membered heteroaryl.

In some embodiments, ring B is selected from the following groups optionally substituted with one or more ^RBs : 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 6-8 membered aryl, or 5-8 membered heteroaryl.

In some embodiments, ring B is selected from the following groups optionally substituted with one or more ^RBs : 3-6 membered cycloalkyl, 4-6 membered heterocyclic, phenyl, naphthyl, or 5-6 membered heteroaryl.

In some embodiments, ring B is selected from the following groups optionally substituted with one or more ^RBs : 6-10 aryl or 5-10 heteroaryl.

In some embodiments, cycloB is selected from the following groups optionally substituted with one or more R ^B groups: cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, thiophenyl, thiazoyl, isothiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperazine, morpholinyl, dihydropyrrolyl, dihydropyrazolyl, dihydrofuranyl, dihydroimidazoyl, dihydrothiophenyl, dihydropyranyl, tetrahydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, dihydropyrazineyl Tetrahydropyrazinyl, dihydropyridazinyl, tetrahydropyridazinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, furanyl, imidazolyl, thiophenyl, pyranyl, pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrroloimidazolyl, pyrrolopyrazolyl, imidazopyrazolyl, pyrazololopyrazolyl, benzopyrroleyl, benzimidazolyl, pyridinolopyrroleyl, pyridinoloimidazolyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, or pyrrolopyridazinyl.

In some embodiments, ring B is selected from phenyl, naphthyl, pyridine, or pyridinium imidazolyl groups optionally substituted with one or more ^RBs . In some embodiments, ring B is selected from phenyl groups optionally substituted with one or more ^RBs . In some embodiments, ring B is selected from naphthyl groups optionally substituted with one or more ^RBs . In some embodiments, ring B is selected from pyridine groups optionally substituted with one or more ^RBs . In some embodiments, ring B is selected from pyridinium imidazolyl groups optionally substituted ^{with one or more RBs .}

In some implementation schemes, ring B is selected from... In some implementation schemes, ring B is selected from...

In some implementation schemes, ring B is selected from...

In some implementation schemes, ring B is selected from... In some implementation schemes, ring B is selected from...

In some embodiments, each ^Rb is independently selected from oxo, deuterium, ^halogen , ^-CN , ^-ORb2 , ^-SRb2 , ^-NRb1Rb2 , -C(O) ^NRb1Rb2 , -C(O)NRb1ORb2, ^-NRb1C (O) ^Rb2 , ^-NRb1C (O) ^NRb1Rb2 , ^-OC (O) ^Rb2 , ^-C (O) ^ORb2 , -C(O) ^Rb2 , -S(O) ^Rb2 , _-S (O) ^2Rb2 , -C( ^Rb1 ) _2S ( _O ) ^2Rb2 _, ^-NRb1S ₍ O) ^2Rb2 , -S(O) ^2NRb1Rb2 , or optionally substituted with one or more ^{Rb3 groups} , including ^the following groups: C _1-4 alkyl, 3-10 cycloalkyl, 4-10 heterocycloalkyl, 4-10 heterocycloalkenyl, 5-10 heteroaryl, 3-10 cycloalkyl C _1-4 alkylene, or 4-10 heterocycloalkyl C _1-4 alkylene.

In some embodiments, each ^Rb is independently selected from oxo, deuterium, halogen, ^-CN , ^-ORb2 , ^-NRb1Rb2 , ^-C (O) ^NRb1Rb2 , -C(O) ^NRb1ORb2 , -NRb1C(O) ^Rb2 , ^-NRb1C (O ^{)NRb1Rb2 ,} -OC(O ^{) Rb2} , -C( _O ) ^ORb2 , -C(O) ^Rb2 , -S(O) ^Rb2 , -S( _O ^{)2Rb2 ,} -C( ^Rb1 ) _2S (O) ^2Rb2 , ^-NRb1S (O) _2Rb2 , -S(O) ^2NRb1Rb2 , or optionally substituted with _one or more ^{Rb3 groups} , including ^the following groups: C _1-3 alkyl, 3-6 cycloalkyl, 4-9 heterocycloalkyl, 4-9 heterocycloalkenyl, 5-6 heteroaryl, 3-6 cycloalkyl C _1-3 alkylene, or 4-6 heterocycloalkyl C _1-3 alkylene.

In some implementations, each ^RB is independently selected from oxo, deuterium, -F, -Cl, -Br, -CN, -OR ^b2 , -NR ^b1 R ^b2 , -C(O)NR ^b1 R ^b2 , -C(O)NR ^b1 OR ^b2 , -C(O)OR ^b2 , -NR ^b1 C(O)R ^b2 , -NR ^b1 C(O)NR ^b1 R ^b2 , -C(O)R ^b2 , -S(O)R ^b2 , -S(O) ₂ R ^b2 , -C(R ^b1 ) ₂ S(O) ₂ R ^b2 , -NR ^b1 S(O) ₂ R ^b2 , or optionally by one or more R The following groups are substituted with ^b3 : methyl, ethyl, n-propyl, isopropyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, tetrahydrofuranyl, pyrrolyl, pyrazolyl, imidazolyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperazinyl, morpholinyl. Dihydropyrrolyl, dihydropyrazolyl, dihydrofuranyl, dihydroimidazolyl, dihydrothiophenyl, dihydropyranyl, tetrahydropyranyl, dihydropyridyl, tetrahydropyridyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, dihydropyrazinyl, tetrahydropyrazinyl, dihydropyridazinyl, tetrahydropyridazinyl, pyrrolyl, pyrazolyl, furanyl, imidazolyl, thiophenyl, pyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, _isothiazolyl , _oxazolyl , isoxazolyl, triazolyl, tetrazolyl, cyclopropane C1-3 alkylene, cyclobutane C1-3 alkylene, cyclopentane C1-3 alkylene, cyclohexane _C1-3 alkylene, azacyclobutane _C1-3 alkylene, tetrahydrofuranyl _C1-3 alkylene, pyrrolyl _C1-3 alkylene, thiazolyl C1-3 _{alkylene 1-3} alkylene, piperidinyl C _1-3 alkylene, piperazine C _1-3 alkylene, or morpholinyl C _1-3 alkylene.

In some embodiments, each ^Rb is independently selected from deuterium, halogen, ^-CN , ^-ORb2 , ^-NRb1Rb2 , -C(O) ^NRb1Rb2 , -C(O) ^NRb1ORb2 , -NRb1C( ^{O)Rb2 , -NRb1C (} _O ) ^NRb1Rb2 , -C(O) ^Rb2 , -S(O) ^Rb2 , _-S (O) ^2Rb2 , -C ^{( Rb1} ) _2S ( _O ) ^2Rb2 , ^-NRb1S (O) ^2Rb2 , -S(O) ^2NRb1Rb2 , or optionally substituted with _one or more ^Rb3 groups, including 4-9-membered ^{heterocyclic alkyl} , 4-9-membered heterocyclic alkenyl, or 5-6-membered heteroaryl.

In some embodiments, each ^Rb is independently ^selected from deuterium, -F, -Cl, ^-Br , -CN, ^-ORb2 , ^-NRb1Rb2 , -C(O) ^NRb1Rb2 , -C(O) ^NRb1ORb2 , ^-NRb1C (O ^{) Rb2} , _-NRb1C (O) ^NRb1Rb2 , -C(O) ^Rb2 , ^{-S(O)Rb2, -S(O)2Rb2, -C(Rb1)2S(O)2Rb2 , -NRb1S ( O} ₎ ^{2Rb2 , or} _optionally substituted with one or more ^Rb3 groups, including pyrrolidinyl, isothiazolyl, piperidinyl, _piperazinyl , morpholinyl, etc. Dihydropyrrole, tetrahydropyridyl, or pyrazolyl.

In some embodiments, ^Rb1 is independently selected from hydrogen, deuterium, or _C1-4 alkyl groups optionally substituted with one or more ^Rb3 .

In some embodiments, ^Rb1 is independently selected from hydrogen, deuterium, or optionally substituted with one or more ^Rb3 groups, namely methyl, ethyl, n-propyl, and isopropyl.

In some implementations, ^Rb1 is independently selected from hydrogen or methyl.

In some embodiments, ^Rb2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more ^Rb3 groups of the following: _C1-4 alkyl, 3-10 cycloalkyl, 3-10 heterocycloalkyl, 3-10 heterocycloalkenyl, 5-10 heteroaryl, _3-10 cycloalkyl C1-4 alkylene, or 3-10 heterocycloalkyl _C1-4 alkylene.

In some embodiments, ^Rb2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more ^Rb3 groups, namely: _C1-3 alkyl, 3-6 cycloalkyl, 4-6 heterocycloalkyl, 4-6 heterocycloalkenyl, 5-6 heteroaryl, 3-6 cycloalkyl _C1-3 alkylene, or 4-6 heterocycloalkyl _C1-3 alkylene.

In some embodiments, ^Rb2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more ^Rb3 groups, including: methyl, ethyl, n-propyl, isopropyl, cyclopropane, cyclobutane, aziridine, oxacyclobutane, pyrrolyl, imidazoalkyl, tetrahydrofuranyl, thiophenyl, thiazoalkyl, isothiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperazine, morpholinyl, dihydropyrrolyl, dihydropyrazolyl, dihydrofuranyl, dihydroimidazoyl, and dihydrothiophenyl. Dihydropyranyl, tetrahydropyranyl, dihydropyridyl, tetrahydropyridyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, dihydropyridazinyl, tetrahydropyridazinyl, pyrroleyl, pyrazolyl, furanyl, imidazolyl, thiophenyl, pyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, isothiazolyl, _oxazolyl , isoxazolyl, triazolyl, tetrazolyl, _{cyclopropane C1-3} alkylene, cyclobutane C1-3 alkylene, azirane-butane C1-3 alkylene, oxacyclobutane _C1-3 alkylene, pyrroleyl _C1-3 alkylene, tetrahydrofuranyl _C1-3 alkylene, piperidinyl _C1-3 alkylene, piperazinyl _C1-3 alkylene, morpholinyl _{C1-3 alkylene} .

In some embodiments, ^Rb2 is independently selected from hydrogen or optionally substituted with one or more ^Rb3 groups, namely: methyl, ethyl, n-propyl, isopropyl, cyclopropane, cyclobutane, oxetane, pyrrolyl, pyrazinyl, cyclobutanemethylene, or oxetanemethylene.

In some implementations, ^Rb2 is independently selected from methyl groups.

In some embodiments, each ^Rb3 is independently selected from oxo, deuterium, halogen, -OH, _-NH2 , -CN, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 alkylthio, _C1-3 alkylamino, _diC1-3 alkylamino, _C1-3 alkylcarbonyl, _haloC1-3 alkyl, _haloC1-3 alkoxy, _haloC1-3 alkylthio, _haloC1-3 alkylamino, or _halodiC1-3 alkylamino.

In some embodiments, each ^Rb3 is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, _-NH2 , -CN, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 alkylthio, _C1-3 alkylamino, _diC1-3 alkylamino, C1-3 alkylcarbonyl, _haloC1-3 alkyl, _haloC1-3 alkoxy, _haloC1-3 alkylthio, _haloC1-3 alkylamino, or _{halodiC1-3 alkylamino} .

In some embodiments, each ^Rb3 is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, _-NH2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, methylcarbonyl, halomethyl, or halomethoxy.

In some implementations, each ^Rb3 is independently selected from oxo, deuterium, -F, -Cl, -OH, methyl, methoxy, methyl carbonyl, or _-CF3 .

In some implementations, each ^RB is independently selected from -F, -Cl, _-NH₂ , -OH, _-OCH₃ , _-OCF₃ , -CN,

In some implementation schemes, ring B is selected from...

In some embodiments, each ^R2 is independently selected from oxo, deuterium, halogen, -OH, _-NH2 , -CN, _C1-4 alkyl, _C1-4 alkoxy, _C1-4 alkylthio, _C1-4 alkylamino, diC1-4 alkylamino, _haloC1-4 alkyl, _haloC1-4 alkoxy, _haloC1-4 alkylthio, _haloC1-4 alkylamino, or _halodiC1-4 alkylamino; or, two ^R2s located on the same _ring atom together with the ring atom form a group optionally substituted with one or more ^R2a, which is a 3-10 membered cycloalkyl or a 3-10 membered heterocycloalkyl.

In some embodiments, each ^R2 is independently selected from oxo, deuterium, halogen, -OH, _-NH2 , -CN, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 alkylthio, _C1-3 alkylamino, diC1-3 alkylamino, _haloC1-3 alkyl, _haloC1-3 alkoxy, _haloC1-3 alkylthio, _haloC1-3 alkylamino, or _halodiC1-3 alkylamino; or, two ^R2s located on the same _ring atom together with the ring atom form a group optionally substituted by one or more ^R2a, which is a 3-6 membered cycloalkyl or a 4-6 membered heterocycloalkyl.

In some embodiments, each ^R2 is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, _-NH2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, halomethyl, or halomethoxy; or, two ^R2s located on the same ring atom together with the ring atom form a group optionally substituted with one or more ^R2a, namely: cyclopropane, cyclobutane, aziridine, pyrrolidinyl, thiazolyl, isothiazolyl, piperidinyl, piperazine, or morpholinyl.

In some embodiments, each ^R2 is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, _-NH2 , -CN, methyl, ethyl, methoxy, methylamino, dimethylamino, _-CF3 , or _-OCF3 ; or, two ^R2s located on the same ring atom together with the ring atom form a cyclopropane that is optionally substituted with one or more ^R2a .

In some embodiments, each ^R2 is independently selected from -F; or, two ^R2s located on the same ring atom together with the ring atom form a cyclopropane group.

In some embodiments, each R ^2a is independently selected from oxo, deuterium, halogen, -OH, -NH ₂ , -CN, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _{1-3 alkylamino, diC 1-3 alkyl} , haloC _1-3 alkyl, haloC _1-3 alkoxy, haloC _1-3 alkylthio, haloC _1-3 alkylamino, or halodiC _1-3 alkylamino.

In some embodiments, each R ^2a is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH ₂ , -CN, C _1-3 alkyl, C _1-3 alkoxy, C _{1-3 alkylthio, C 1-3 alkylamino} , diC _1-3 alkylamino, haloC _1-3 alkyl, haloC _1-3 alkoxy, haloC _1-3 alkylthio, haloC _1-3 alkylamino, or halodiC _1-3 alkylamino.

In some embodiments, each R ^2a is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH ₂ , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, halomethyl, or halomethoxy.

In some embodiments, each R ^2a is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH ₂ , -CN, methyl, ethyl, methoxy, methylamino, dimethylamino, -CF ₃ , or -OCF ₃ .

In some implementations, n is selected from 0, 1, 2, or 3.

In some implementations, n is selected from 0, 1, or 2.

In some implementations, m is selected from 0, 1, 2, 3, or 4.

In some implementations, n is selected from 0, 1, 2, or 3.

In some implementations, m is selected from 0, 1, or 2.

In some implementations, p is selected from 0, 1, 2, or 3.

In some implementations, p is selected from 0, 1, or 2.

In some embodiments, this application relates to compounds of formula (I-1), formula (II), formula (III), formula (II-1), formula (II-1-a'), formula (II-1-a”), formula (II-2), formula (II-2-a'), and formula (II-2-a”), their stereoisomers, or pharmaceutically acceptable salts thereof.

in, The definitions of ^X1 , ^{X2 , X3} , X4, ^X5 , ^X6 , R1, ^R2 , ^RA , m, p, ring A, and ring ^B are as described in this application.

In some embodiments, the _C1-6 alkyl group is selected from _C1-4 alkyl, _C1-3 alkyl, or _C1-2 alkyl.

In some embodiments, the _C1-6 alkylene is selected from _C1-4 alkylene, _C1-3 alkylene, or _C1-2 alkylene.

In some embodiments, the halogen is selected from -F, -Cl, -Br, or -I.

In some embodiments, the halogenation is selected from fluorination, chlorination, or bromination. In some embodiments, the halogenation is selected from fluorination or chlorination. In some embodiments, the halogenation is selected from fluorination.

In some embodiments, the one or more is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the one or more is selected from 1, 2, 3, 4, or 5. In some embodiments, the one or more is selected from 1, 2, 3, or 4. In some embodiments, the one or more is selected from 1, 2, or 3.

In some embodiments, the 3-12 yuan is selected from 3 yuan, 4 yuan, 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan, 10 yuan, 11 yuan, or 12 yuan, or a range thereof. In some embodiments, the 5-10 yuan is selected from 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan, or 10 yuan, or a range thereof. In some embodiments, the 6-10 yuan is selected from 6 yuan, 7 yuan, 8 yuan, 9 yuan, or 10 yuan, or a range thereof.

In some implementations, the 3-12 yuan is selected from 3-10 yuan, 3-8 yuan, 3-6 yuan, 4-10 yuan, 4-8 yuan, 4-6 yuan, 5-10 yuan, 5-8 yuan, or 5-6 yuan. In some implementations, the 5-10 yuan is selected from 5-9 yuan, 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6-8 yuan, 7-9 yuan, 7-8 yuan, or 6-7 yuan. In some implementations, the 6-10 yuan is selected from 6-9 yuan, 6-8 yuan, 6-7 yuan, 7-10 yuan, 7-9 yuan, 7-8 yuan, or 6-7 yuan.

In some embodiments, the heterocyclic alkyl, heterocyclic alkenyl, heterocyclic or heteroaryl group contains one, two or three heteroatoms selected from N, O or S.

In some embodiments, the heterocyclic alkyl, heterocyclic alkenyl, heterocyclic or heteroaryl groups contain one, two or three nitrogen atoms.

In some embodiments, the heterocyclic alkyl, heterocyclic alkenyl, heterocyclic or heteroaryl groups contain one N atom and one O atom.

In some embodiments, the heterocyclic alkyl, heterocyclic alkenyl, heterocyclic or heteroaryl groups contain one N atom and one S atom.

In some embodiments, the heterocyclic alkyl, heterocyclic alkenyl, heterocyclic group, or heteroaryl group contains one oxygen atom. In some embodiments, the heterocyclic alkyl, heterocyclic alkenyl, heterocyclic group, or heteroaryl group contains one sulfur atom. In some embodiments, the heterocyclic alkyl, heterocyclic alkenyl, heterocyclic group, or heteroaryl group contains one nitrogen atom.

In some embodiments, the heterocyclic group, heterocyclic alkenyl group, or heterocyclic alkyl group includes a monocyclic, spirocyclic, fused, or bridged ring.

This application provides the following compounds or pharmaceutically acceptable salts thereof:

This application also provides the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

On the other hand, this application provides pharmaceutical compositions comprising the above-described compounds of this application, their stereoisomers, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions of this application further include pharmaceutically acceptable excipients.

On the other hand, this application provides a method for treating mammalian diseases, comprising administering to a mammal, preferably a human, a therapeutically effective amount of the above-described compound of this application, its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of this application.

On the other hand, this application provides the use of the above-mentioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof, in the preparation of medicaments for treating diseases.

On the other hand, this application provides the use of the above-mentioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof in the treatment of diseases.

On the other hand, this application provides the above-mentioned compounds of this application, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of this application for the treatment of diseases.

In some implementations, the disease is selected from WFS1-related diseases.

In some implementations, the disease or WFS1-related disease is selected from cancer.

In some implementations, the disease or WFS1-related disease is selected from solid tumors.

In some implementations, the disease or WFS1-related disease is selected from multiple myeloma and lung cancer (e.g., non-small cell lung cancer).

Technical effect

The compounds, their stereoisomers, or pharmaceutically acceptable salts of this application exhibit good WFS1 binding activity and cell proliferation inhibition activity (e.g., NCI-H929 cells) and in vivo tumor suppression activity, while demonstrating good drug-like properties in in vitro and in vivo pharmacokinetic, bioavailability, and/or pharmacodynamic studies.

definition

Unless otherwise stated, the following terms as used in this application shall have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

The terms “optional” or “optionally” mean that the event or condition described below may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, the ethyl group being “optionally” substituted with a _halogen means that the ethyl group may be unsubstituted ( _CH₂CH₃ ), monosubstituted (e.g. _{, CH₂CH₂F} ), _{polysubstituted} (e.g., _CHFCH₂F , _{CH₂CHF₂ ,} etc.), or fully substituted ( _{CF₂CF₃ )} . Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and/or cannot be synthesized is introduced.

The term "substituent" as used herein includes, but is not limited to, the terms "alkyl,""alkoxy,""alkathioyl,""cycloalkoxy,""heteroalkyl,""alkenyl,""alkynyl,""cycloalkenyl,""cycloalkyl,""cycloalkynyl,""heterocycloalkyl,""heterocycloalkenyl,""heterocycloalkyl,""aryl,""heteroaryl,""alkylene," etc., and their corresponding non-limiting or exemplary groups. Some non-limiting examples of the "substituent" include protium, deuterium, tritium, -OH, -SH, halogen, amino, nitro, nitrosyl, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, carboxaldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo- Cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclic, heterocyclicoxy, heterocyclicthio, heterocyclic alkyl, heterocyclic alkoxy, heterocyclic alkylthio, acyl, acyloxy, carbamate group, amide group, ureyl, epoxy group and ester group, etc., wherein said groups are optionally substituted by one or more substituents selected from: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH ₂ , -C(O)NH-alkyl, -C(O)N(alkyl) ₂ , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) ₂ -alkyl, -S(O) ₂ NH ₂ , -S(O) ₂ NH-alkyl, -S(O) ₂ N(alkyl) ₂ , cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, heterocyclic alkyl, heterocyclic alkylalkyl, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, aryl, arylalkyl or aryloxy.

In this article, C _{_mn} means that the part has an integer number of carbon atoms within a given range. For example, "C _{_1-6}" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms.

When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by two Rs, each R has an independent option.

Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is spatially impossible and/or cannot be synthesized.

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

When one of the variables is selected as a covalent bond, it means that the two groups connected to it are directly linked. For example, in A-L-Z, when L represents a covalent bond, it means that the structure is actually A-Z.

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

The term "alkylene" refers to a saturated straight-chain or branched divalent hydrocarbon group of the general formula _CnH2n , typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 _carbon atoms. For example, the term "C1-6 alkylene" refers to an alkylene containing 1 to ₆ carbon atoms. The term "C0-6 alkylene" refers to a single bond or a _C1-6 alkylene. Non-limiting examples of _alkylene include, but are _not limited to, _methylene ( _{-CH2- )} , ethylene ( _-CH2CH2- ), propylene ( _-CH2CH2CH2- or _-CH2CH ( _CH3 )-), _butylene ( _{-CH2CH2CH2CH2-} , -CH2CH( _CH3 ) _CH2- or _-CH2CH2CH ( _CH3 )- ₎ , etc. The alkylene group is optionally substituted by one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.

The term "alkyl" refers to a hydrocarbon group with the general formula C _{_n}H _{_2n+1}, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The alkyl group can be straight-chain or branched. For example, the term "C _{_1-6}alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). The alkyl group is optionally substituted by one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy. Similarly, the alkyl portion (i.e., alkyl group) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above.

The term "alkoxy" refers to an -O-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The alkyl moiety is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

The term "alkylamino" refers to -NH-alkyl, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The alkyl moiety is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

The term "dialkylamino" refers to -N(alkyl) ₂ , typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The alkyl moiety is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

The term "alkylsulfonyl" refers to _-SO₂ -alkyl, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The alkyl moiety is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

The term "alkylthio" refers to -S-alkyl, which typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The alkyl moiety is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc. The alkenyl group may optionally be substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkoxy, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

The term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C- _CH3 ), 2-propynyl (-CH2 _- C≡CH), 1,3-butyrynyl (-C≡CC≡CH), etc. The alkynyl group may optionally be substituted by one or more substituents selected from: oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

The term "cycloalkyl" refers to a fully saturated carbon ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, or 5- to 6-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc. The cycloalkyl group is optionally substituted by one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) _NH₂ , -C(O)NH-alkyl, -C(O)N(alkyl) _₂ , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) _₂ -alkyl, -S(O _{) ₂NH₂} , -S(O _{) ₂NH} -alkyl, -S(O)₂N(alkyl) _₂ , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heteroalkylalkylene, heteroalkyloxy, heteroalkyl, heteroalkylalkylene, heteroalkyloxy, heteroalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbon ring having at least one double bond and which may exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, or 5- to 6-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, and cycloheptadienyl. The cycloalkenyl group is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) _NH₂ , -C(O)NH-alkyl, -C(O)N(alkyl) _₂ , -NHC(O)-alkyl, -C(O ₎ -alkyl, -S(O)-alkyl, -S(O) _₂ -alkyl, -S(O) _₂NH₂ , -S(O) _₂NH -alkyl, -S(O) _₂N (alkyl) _₂ , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heteroalkylalkylene, heteroalkyloxy, heteroalkyl, heteroalkylalkylene, heteroalkyloxy, heteroalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

The term "heterocyclic alkyl" refers to a fully saturated cyclic group that may exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 12-membered, 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, 5- to 6-membered, 3- to 7-membered, or 4- to 6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and/or boron (preferably 1 or 2 heteroatoms). Examples of 3-membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, cyclothioethylene, and cycloazoethylene; non-limiting examples of 4-membered heterocyclic alkyl groups include, but are not limited to, acridine, oxadiazolyl, and thiobutylcycloyl; examples of 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, and tetrahydropyrazolyl; examples of 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxane, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, and 1,4-dithiaalkyl; and examples of 7-membered heterocyclic alkyl groups include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. The heterocyclic alkyl group is optionally substituted by one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) _NH₂⁻ , -C(O)NH₂-alkyl, -C(O)N(alkyl) _₂ , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S ₍ O) _₂ -alkyl, -S(O) _₂NH₂ , -S(O ₎ ₂NH₂-alkyl, -S(O) _₂N (alkyl) _₂ , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heteroalkylalkylene, heteroalkyloxy, heteroalkyl, heteroalkylalkylene, heteroalkyloxy, heteroalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

The term "heterocyclic group" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated) and can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 12-membered, 3- to 10-membered, 3- to 8-membered, 3- to 7-membered, 3- to 6-membered, 4- to 10-membered, 4- to 8-membered, 4- to 6-membered, 5- to 10-membered, 5- to 8-membered, or 5- to 6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, silicon, phosphorus, oxygen, and/or nitrogen, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C=O, NO, and S(O) _p , where p is 1 or 2). Non-limiting examples of heterocyclic groups include, but are not limited to, ethylene oxide, tetrahydrofuranyl, dihydrofuranyl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, pyrrolyl, N-methylpyrrolyl, dihydropyrrolyl, piperidinyl, piperazine, pyrazolyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophene, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.3]heptyl, etc. In some embodiments, the heterocyclic group is selected from monocyclic or fused-ring groups. In some embodiments, the heterocyclic group is fused-ring, such as benzo5-6-membered heterocyclic groups, 5-6-membered heteroaryl- _C5-6 cycloalkyl groups, 5-6-membered heteroaryl-5-6-membered heterocyclic groups, etc., specifically as follows: In this application, the ring connected to the parent structure by the heterocyclic group can be either an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) _NH₂ , -C(O)NH-alkyl, -C(O)N(alkyl) _₂ , -NHC(O)-alkyl, -C(O ₎ -alkyl, -S(O)-alkyl, -S(O) _₂ -alkyl, -S(O) _₂NH₂ , -S(O) _₂NH -alkyl, -S(O) _₂N (alkyl) _₂ , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heteroalkylalkylene, heteroalkyloxy, heteroalkyl, heteroalkylalkylene, heteroalkyloxy, heteroalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

The term "aryl" refers to an aromatic cyclic group consisting of an all-carbon monocyclic or fused polycyclic ring with a conjugated π-electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, 6-12 carbon atoms, or 6-10 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracene. The aryl group is optionally substituted by one or more substituents selected from the following: hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) _NH₂ , -C(O)NH-alkyl, -C(O)N(alkyl) _₂ , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) _₂ - _{alkyl, -S(O)₂NH₂ ,} -S(O) _₂NH -alkyl, -S(O) _₂N (alkyl) _₂ , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heteroalkylalkylene, heteroalkyloxy, heteroalkyl, heteroalkylalkylene, heteroalkyloxy, heteroalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

The term "heteroaryl" refers to an aromatic cyclic group having a conjugated π-electron system, containing at least one ring atom selected from N, O, and S, with the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C=O, NO, and S(O) _p , where p is 1 or 2). The heteroaryl can be a monocyclic, fused bicyclic, or fused tricyclic system, wherein each ring is aromatic. The heteroaryl typically has 5 to 14 ring atoms, 5 to 12 ring atoms, 5 to 10 ring atoms, 5 to 8 ring atoms, 5 to 7 ring atoms, or 5 to 6 membered ring atoms. Preferred heteroaryls are selected from a single 4 to 8-membered ring, especially a 5 to 6-membered ring, or multiple fused rings containing 5 to 14, especially 5 to 10, ring atoms. The heteroaryl can be attached to the rest of the molecule via heteroatoms or carbon atoms. Non-limiting examples of the heteroaryl group include, but are not limited to, pyrrole rings (including N-pyrrole, 2-pyrrole, and 3-pyrrole rings, etc.), pyrazole rings (including 2-pyrrole and 3-pyrrole rings, etc.), imidazole rings (including N-imidazolium, 2-imidazolium, 4-imidazolium, and 5-imidazolium rings, etc.), oxazole rings (including 2-oxazole, 4-oxazole, and 5-oxazole rings, etc.), triazole rings (1H-1,2,3-triazole rings, 2H-1,2,3-triazole rings, 1H-1,2,4-triazole rings, and 4H-1,2,4-triazole rings, etc.), tetrazolium rings, isoxazole rings (3-isooxazole rings, 4-isooxazole rings, and 5-isooxazole rings, etc.), and thiazole rings (including 2-thiazole rings, 4-thiazole rings, etc.). The rings include azole rings and 5-thiazole rings, furan rings (including 2-furan rings and 3-furan rings), thiophene rings (including 2-thiophene rings and 3-thiophene rings), pyridine rings (including 2-pyridine rings, 3-pyridine rings and 4-pyridine rings), pyrazine rings, pyrimidine rings (including 2-pyrimidine rings and 4-pyrimidine rings), benzothiazole rings (including 5-benzothiazole rings), purine rings, benzimidazole rings (including 2-benzimidazole rings), benzoxazole rings, indole rings (including 5-indole rings), isoquinoline rings (including 1-isoquinoline rings and 5-isoquinoline rings), quinoxaline rings (including 2-quinoxaline rings and 5-quinoxaline rings), and quinoline rings (including 3-quinoline rings and 6-quinoline rings). The heteroaryl group is optionally substituted by one or more substituents selected from: hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) _NH₂ , -C(O)NH-alkyl, -C(O)N(alkyl) _₂ , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) _₂ -alkyl, -S(O _{)₂NH₂ ,} -S(O) _₂NH -alkyl, -S(O) _₂N (alkyl) _₂ , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclic, heteroalkylalkylene, heteroalkyloxy, heteroalkyl, heteroalkylalkylene, heteroalkyloxy, heteroalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

The term "treatment" means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

(i) Suppress the disease or disease state, that is, curb its development;

(ii) Relieve the disease or disease state, even if the disease or disease state subsides.

The term “prevention” means administering the compounds or preparations described in this disclosure to prevent a disease or one or more symptoms associated with the disease, including preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

The term "therapeutic effective amount" means the amount of the compound of this application used to treat (i) the specific disease, condition, or disorder described herein, (ii) reduce, improve, or eliminate one or more symptoms of the specific disease, condition, or disorder described herein, or (iii) prevent or delay the onset of one or more symptoms of the specific disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and/or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit/risk ratio.

As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

Unless otherwise specified, singular terms encompass plural terms, and plural terms encompass singular terms. Unless otherwise specified, the words "an" or "a" mean "at least one" or "at least one".

The compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons.

This application also includes compounds of this application that are identical to those described herein, but with one or more atoms labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ^2H , ^3H , ^11C , ^13C , ^14C , 13N, ^15N , ^15O , ^17O , ^18O , ^31P , ^32P , ^35S , ^18F , ^123I , ^125I , and ^{36Cl ,} respectively.

Certain isotopically labeled compounds of this application (e.g., those labeled with ^3H and ^14C ) can be used in the analysis of compound and/or substrate tissue distribution. Tritium (i.e., ^3H ) and carbon-14 (i.e., ^14C ) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emission isotopes, such as ^15O , ^13N , ^11C , and ^18F , can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of this application can generally be prepared by replacing unlabeled reagents with isotopically labeled reagents using a procedure similar to those disclosed in the schemes and/or examples below.

Furthermore, substitution with a heavier isotope (such as deuterium (i.e., ^2H )) can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and is therefore preferred in certain situations, where deuterium substitution can be partial or complete, with partial deuterium substitution referring to at least one hydrogen atom being replaced by at least one deuterium atom. Exemplary deuterated compounds are shown below, but are not limited thereto.

The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key Represents the relative configuration of the center of a solid.

The compounds of this application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized using chiral starting materials or chiral reagents. Non-limiting examples of stereoisomers include, but are not limited to:

The compounds disclosed herein may have one or more blocked isomers, unless otherwise stated, which are photoactive isomers resulting from the restriction of free rotation between single bonds. The chiral axis compounds of this disclosure can be isolated in racemic form. When the energy barrier for free rotation of the single bonds in the chiral axis compounds of this disclosure is sufficiently high, their blocked isomers can be isolated in photoactive pure form.

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

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

The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of this disclosure to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, gels, pastes, suspensions, etc., for oral administration to patients.

Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

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

In all methods of administration of the compounds of general formula I described herein, the daily dose is from 0.01 to 200 mg/kg body weight.

The compounds of this application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this application.

The chemical reactions in the specific embodiments of this application are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required in this application. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

In some embodiments, the compounds disclosed herein can be prepared by those skilled in the art of organic synthesis by referring to the following route, wherein ^X1 , ^X2 , X3, ^X4 , ^X5 , ^X6 , ^R1 , ^R2 , n, ^m , ring A, and ring B are defined as described in this application; ^LG1 and ^LG2 are each independently selected from suitable leaving groups, which may be selected from halogens (e.g., -Cl).

Route 1:

Route 2:

Detailed Implementation

For clarity, the present invention is further illustrated by examples, but these examples are not intended to limit the scope of this application. It will be apparent to those skilled in the art that various changes and modifications can be made to specific embodiments of the invention without departing from the spirit and scope thereof. All reagents used in this application are commercially available and can be used without further purification.

The compounds of this application can be prepared by those skilled in the art of organic synthesis with reference to the routes or methods of the following embodiments. The resulting compounds can be characterized by known instruments or methods, including but not limited to mass spectrometry, nuclear magnetic resonance, etc.

This application uses the following abbreviations:

Bu represents butyl; SFC represents supercritical fluid chromatography; Rt represents retention time; DMSO represents dimethyl sulfoxide; Boc represents tert-butyloxycarbonyl; NMP represents N-methylpyrrolidone; "h" represents hours; "min" represents minutes; THF represents tetrahydrofuran; DMF represents N,N-dimethylformamide; _PdCl₂ ( _PPh₃ ) _₂ represents bis(triphenylphosphine)palladium dichloride; NMP represents N-methylpyrrolidone; _Boc₂O represents ditert-butyl dicarbonate.

Preparation example d-1:

Step a:

Compound d-1a (5 g), chloroformamidine hydrochloride (7.3 g), and dimethyl sulfone (15 mL) were added to a 200 mL flask. Under nitrogen protection, the mixture was stirred at 150 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and 200 mL of ice water was added. The mixture was stirred evenly for 10 min, and then ammonia was added to adjust the pH to alkaline. The mixture was filtered, and the filter cake was collected to give compound d-1b. LC-MS: m/z = 168.08 (M+H) ⁺ .

Step b:

Compound d-1b (2 g) and tetramethylammonium chloride (1.96 g) were dispersed in acetonitrile (25 mL). After uniform mixing, phosphorus oxychloride (18.3 g) was slowly added dropwise under ice bath conditions. The mixture was stirred at low temperature for 10 min, then heated to 80 °C and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature and slowly added dropwise to crushed ice. The mixture was extracted with ethyl acetate (200 mL). The organic layer was adjusted to alkaline pH with saturated sodium carbonate solution, allowed to stand for separation, collected, and concentrated under reduced pressure. The organic phase was purified by column chromatography (dichloromethane:methanol = 100:1–50:1) to obtain compound d-1. LC-MS: m/z = 186.00 (M+H) ⁺ .

Example 1

Step 1:

3-((tributyltinyl)methoxy)prop-1-amine (14.8 g), 2-chloro-4-methanesulfonylbenzaldehyde (8.55 g), and 4A molecular sieve (15 g) were dispersed in acetonitrile (200 mL) under nitrogen protection and reacted at room temperature for 5 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 1a.

Step 2:

Copper(II) trifluoromethanesulfonate (14.15 g) was dispersed in dichloromethane (500 mL) and hexafluoroisopropanol (130 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (4.2 g) was slowly added dropwise, and the reaction was allowed to proceed for 1 h at room temperature. Compound 1a was dispersed in dichloromethane (60 mL) and slowly added to the above reaction system, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the reaction solution was poured into a saturated sodium bicarbonate solution (300 mL) and 10% ammonia solution (200 mL), stirred for 30 min, allowed to stand for separation, extracted with dichloromethane (50 mL * 3), and the organic phases were combined. The organic phases were washed successively with a saturated sodium bicarbonate solution (200 mL) and a saturated sodium chloride solution (200 mL), collected, dried over anhydrous sodium sulfate for 1 h, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dispersed in acetonitrile (300 mL), extracted with n-heptane (50 mL x 5), the acetonitrile phase was collected and concentrated under reduced pressure, and purified by column chromatography (dichloromethane:ethyl acetate = 20:1–10:1–dichloromethane:methanol = 500:1–200:1) to give compound 1b. LC-MS: m/z = 289.98 (M+H) ⁺ .

Step 3:

Compound d-1 (150 mg), compound 1b (280 mg), and potassium iodide (268 mg) were dispersed in N-methylpyrrolidone (20 mL), and the mixture was heated to 160 °C and reacted for 7.5 h. The reaction solution was subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia water (30%-70%/0-45 min gradient elution)) to obtain compound 1 (Rt 22.5 min, LC-MS: m/z = 439.13 (M+H) ⁺ ).

Step 4:

Compound 1 was prepared by SFC (YMC AD-H 10μm 30*250 column; 0.2% diethylamine methanol-CO2 (50%-50%/0-15min isocratic elution)) to obtain compound 1-A (Rt 2.7min) and compound 1-B (Rt 5.2min).

Compound 1-A: LC-MS: m/z = 439.12 (M+H) ⁺ ; ^¹H NMR (500MHz, DMSO-d6 ₎ )δ:8.01(s,1H),7.95(d,J＝5.5Hz,1H),7.83-7.81(m,1H),7.65(d,J＝8.0Hz,1H),7.01(d,J＝5.5Hz,1H),5.99-5.96((m,1H),5.71(s, 2H),4.79-4.76(m,1H),4.32-4.30(m,1H),4.04-3.95(m,2H),3.86-3.81((m,1H),3.63-3.58(m,1H),3.28(s,3H),2.07-1.92(m,2H).

Compound 1-B: LC-MS: m/z = 439.13 (M+H) ⁺ ; ^¹H NMR (500MHz, DMSO-d6 ₎ )δ:8.01(s,1H),7.95(d,J＝5.5Hz,1H),7.83-7.81(m,1H),7.65(d,J＝8.5Hz,1H),7.01(d,J＝5.5Hz,1H),5.99-5.96((m,1H),5.71(s, 2H),4.79-4.76(m,1H),4.32-4.30(m,1H),4.04-3.95(m,2H),3.86-3.81((m,1H),3.63-3.58(m,1H),3.28(s,3H),2.07-1.93(m,2H).

Compound 1-A has a shorter retention time in a chiral column than 1-B, while compound 1-B has a longer retention time in a chiral column than 1-A.

Example 2

Step 1:

Compound 1b (300 mg), 2,4-dichloropyrido[3,2-d]pyrimidine (208 mg), and N,N-diisopropylethylamine (268 mg) were dispersed in tetrahydrofuran (20 mL) and stirred at room temperature for 17 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = pure dichloromethane ~100:1) to give compound 2a. LC-MS: m/z = 453.11 (M+H) ⁺ .

Step 2:

Compound 2a (300 mg) and 2,4-dimethoxybenzylamine (330 mg) were dispersed in N-methylpyrrolidone (10 mL), and the mixture was heated to 180 °C and reacted for 4 h. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 2b. LC-MS: m/z = 584.24 (M+H) ⁺ .

Step 3:

Compound 2b (500 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (TAC18 250*50 mm, 10 μm column; acetonitrile-0.1% ammonia solution (15-45%/0-60 min gradient elution)) to obtain compound 2 (Rt 49 min, LC-MS: m/z = 434.16 (M+H) ⁺ ).

Step 4:

Compound 2 was subjected to preparative liquid chromatography (YMC-Amylose-SA, 10 μm, 30*250 column; ethanol solution of n-hexane-0.1% diethylamine (gradient elution 10%-70%/0-60 min)) to obtain compound 2-A (Rt 28 min) and compound 2-B (Rt 36 min).

Compound 2-A: LC-MS: m/z = 434.25 (M+H) ⁺ , ^1H NMR (500MHz, DMSO-d6 ₎ )δ:8.20-8.12(m,1H),7.99(s,1H),7.80(dd,J＝8.5,2.0Hz,1H),7.66(d ,J＝8.0Hz,1H),7.56(d,J＝7.0Hz,1H),7.42-7.41(m,1H),7.05-6.95(m,1 H),6.22(s,2H),4.26-4.24((m,1H),3.97-3.84(m,3H),3.66-3.61(m,1H ),3.28(s,3H),2.15-2.11(m,1H),1.90-1.89(m,1H),1.35-1.34(m,1H).

Compound 2-B: LC-MS: m/z = 434.19 (M+H) ⁺ , ^1H NMR (500MHz, DMSO-d6 ₎ )δ:8.22-8.10(m,1H),7.99(s,1H),7.80(dd,J=8.0,1.5Hz,1H),7.66(d ,J＝8.0Hz,1H),7.56(d,J＝7.5Hz,1H),7.42-7.41(m,1H),6.98-6.92(m,1 H),6.26(s,2H),4.26-4.24((m,1H),3.96-3.84(m,3H),3.66-3.61(m,1H ),3.28(s,3H),2.15-2.10(m,1H),1.90-1.89(m,1H),1.35-1.34(m,1H).

Compound 2-A has a shorter retention time in chiral columns than 2-B, while compound 2-B has a longer retention time in chiral columns than 2-A.

Example 3

Step 1:

Compound 1b (403 mg), 2,4-dichloropyrido[2,3-d]pyrimidine (232 mg), and N,N-diisopropylethylamine (299 mg) were dispersed in anhydrous tetrahydrofuran (10 mL) and stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = pure dichloromethane ~100:1) to give compound 3a. LC-MS: m/z = 453.10 (M+H) ⁺ .

Step 2:

Compound 3a (498 mg) and 2,4-dimethoxybenzylamine (551 mg) were dispersed in N-methylpyrrolidone (10 mL), and the mixture was heated to 180 °C and reacted for 4 h. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 3b. LC-MS: m/z = 584.23 (M+H) ⁺ .

Step 3:

Compound 3b (980 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 250*50 mm, 10 μm column; acetonitrile-0.1% ammonia solution (15-50%/0-60 min gradient elution)) to obtain compound 3 (Rt 50 min, LC-MS: m/z = 434.21 (M+H) ⁺ ).

Example 4

Compound 1b (100 mg), 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-2-amine (100 mg), and sodium iodide (100 mg) were dispersed in anhydrous N-methylpyrrolidone (NMP) (10 mL). The mixture was heated to 150 °C and stirred for 3 h under nitrogen protection. After the reaction was completed, the reaction solution was subjected to preparative liquid chromatography (YMC TA C18 250*50 mm, 10 μm column; acetonitrile-0.1% ammonia solution (10-80%/0-120 min gradient elution)) to obtain compound 4 (Rt 67 min, LC-MS: m/z = 422.18 (M+H) ⁺ ).

Example 5

Step 1:

Compound 1b (300 mg), 2,4-dichlorofurano[3,2-d]pyrimidine (189 mg), and sodium iodide (300 mg) were dispersed in anhydrous NMP (10 mL), and the mixture was stirred at 150 °C for 4 h under nitrogen protection. After the reaction was complete, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The solution was purified by column chromatography (dichloromethane:methanol = pure dichloromethane ~250:1) to give compound 5a. LC-MS: m/z = 442.03 (M+H) ⁺ .

Step 2:

Compound 5a (300 mg) and 2,4-dimethoxybenzylamine (340 mg) were dispersed in N-methylpyrrolidone (10 mL), and the mixture was heated to 180 °C and reacted for 4 h. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 5b. LC-MS: m/z = 573.14 (M+H) ⁺ .

Step 3:

Compound 5b (500 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18, specification 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient elution: 0-3 min 15% B, 3-5 min 15%-30% B, 5-85 min 30%-70% B) to obtain compound 5 (Rt 30 min, LC-MS: m/z = 423.12 (M+H) ⁺ ).

Example 6

Step 1:

Compound 1b (300 mg), 5,7-dichlorothiazo[5,4-d]pyrimidine (206 mg), and sodium iodide (300 mg) were dispersed in anhydrous NMP (10 mL), and the mixture was stirred at 150 °C for 5 h under nitrogen protection. After the reaction was complete, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The solution was purified by column chromatography (dichloromethane:methanol = pure dichloromethane ~100:1) to give compound 6a. LC-MS: m/z = 458.98 (M+H) ⁺ .

Step 2:

Compound 6a (365 mg) and 2,4-dimethoxybenzylamine (398 mg) were dispersed in N-methylpyrrolidone (10 mL), and the mixture was heated to 180 °C and reacted for 3 h. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 6b. LC-MS: m/z = 590.11 (M+H) ⁺ .

Step 3:

Compound 6b (500 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18, specification 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient elution: 0-3 min 15% B, 3-5 min 15%-30% B, 5-85 min 30%-75% B) to obtain compound 6 (Rt 33 min, LC-MS: m/z = 440.07 (M+H) ⁺ ).

Example 7

Step 1:

Compound 1b (300 mg), 2,4-dichlorothiophene[2,3-d]pyrimidine (205 mg), and sodium iodide (300 mg) were dispersed in anhydrous NMP (10 mL), and the mixture was stirred at 150 °C for 5 h under nitrogen protection. After the reaction was complete, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The solution was purified by column chromatography (dichloromethane:methanol = pure dichloromethane ~100:1) to give compound 7a. LC-MS: m/z = 458.00 (M+H) ⁺ .

Step 2:

Compound 7a (319 mg) and 2,4-dimethoxybenzylamine (350 mg) were dispersed in N-methylpyrrolidone (10 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 7b. LC-MS: m/z = 589.13 (M+H) ⁺ .

Step 3:

Compound 7b (500 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 250*50 mm, 10 μm column; acetonitrile-0.1% ammonia solution (gradient elution 15-80%/0-90 min)) to obtain compound 7 (Rt 65 min, LC-MS: m/z = 439.08 (M+H) ⁺ ).

Example 8

Step 1:

Compound 1b (750 mg), N-Boc-2,4-dichloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine, and N,N-diisopropylethylamine (222 mg) were dispersed in n-butanol (25 mL), and the mixture was stirred at 100 °C for 12 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = pure dichloromethane ~500:1) to give compound 8a. LC-MS: m/z = 543.11 (M+H) ⁺ .

Step 2:

Compound 8a (440 mg) and 2,4-dimethoxybenzylamine (680 mg) were dispersed in N-methylpyrrolidone (40 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into water (400 mL), extracted with ethyl acetate, and the organic phase was collected. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 8b. LC-MS: m/z = 674.22 (M+H) ⁺ .

Step 3:

Compound 8b (1000 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia aqueous solution (10%-60%/0-45 min gradient elution) to obtain compound 8 (Rt 28.0 min, LC-MS: m/z = 424.20 (M+H) ⁺ ).

Example 9

Compound 1b (100 mg), 4-chloroquinazoline-2-amine (200 mg), and sodium iodide (100 mg) were dispersed in anhydrous NMP (10 mL), and the mixture was stirred at 150 °C for 3 h under nitrogen protection. After the reaction was completed, the reaction solution was subjected to preparative liquid chromatography (YMC TA C18 250*50 mm, 10 μm column; acetonitrile-0.1% ammonia solution (20-50%/0-80 min gradient elution) to obtain compound 9 (Rt 62 min, LC-MS: m/z = 433.14 (M+H) ⁺ ).

Example 10

Step 1:

Compound 1b (300 mg), 2,4-dichloro-5,7-dihydrofuranopyrimidine (190 mg), and sodium iodide (300 mg) were dispersed in anhydrous NMP (10 mL), and the mixture was stirred at 150 °C for 5 h under nitrogen protection. After the reaction was complete, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The solution was purified by column chromatography (dichloromethane:methanol = pure dichloromethane ~100:1) to give compound 10a. LC-MS: m/z = 444.06 (M+H) ⁺ .

Step 2:

Compound 10a (308 mg) and 2,4-dimethoxybenzylamine (350 mg) were dispersed in N-methylpyrrolidone (10 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate, and the organic phase was collected. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 10b. LC-MS: m/z = 575.20 (M+H) ⁺ .

Step 3:

Compound 10b (300 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 250*50 mm, 10 μm column; acetonitrile-0.1% ammonia solution (20-50%/0-60 min gradient elution) to obtain compound 10 (Rt 30 min, LC-MS: m/z = 425.18 (M+H) ⁺ ).

Example 11

Step 1:

Compound 1b (300 mg), 2,4-dichloro-6,7-dihydrothiophene[3,2-d]pyrimidine (200 mg), and sodium iodide (300 mg) were dispersed in anhydrous NMP (10 mL). The mixture was heated to 150 °C and stirred for 3 h under nitrogen protection. After the reaction was complete, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The solution was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The solution was purified by column chromatography (dichloromethane:methanol = pure dichloromethane ~100:1) to give compound 11a. LC-MS: m/z = 460.02 (M+H) ⁺ .

Step 2:

Compound 11a (174 mg) and 2,4-dimethoxybenzylamine (189 mg) were dispersed in N-methylpyrrolidone (10 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate, and the organic phase was collected. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 11b. LC-MS: m/z = 591.17 (M+H) ⁺ .

Step 3:

Compound 11b (300 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 250*50 mm, 10 μm column; acetonitrile-0.1% ammonia solution (15-30%/0-55 min gradient elution) to obtain compound 11 (Rt 41 min, LC-MS: m/z = 441.07 (M+H) ⁺ ).

Example 12

Step 1:

Compound 1b (289 mg), 2,4,6-trichlorothiophenepyrimidine (239 mg), and sodium iodide (300 mg) were dispersed in anhydrous NMP (10 mL), and the mixture was stirred at 150 °C for 2 h under nitrogen protection. After the reaction was complete, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The solution was purified by column chromatography (dichloromethane:methanol = pure dichloromethane ~100:1) to give compound 12a. LC-MS: m/z = 491.98 (M+H) ⁺ .

Step 2:

Compound 12a (370 mg) and 2,4-dimethoxybenzylamine (376 mg) were dispersed in N-methylpyrrolidone (10 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate, and the organic phase was collected. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 12b. LC-MS: m/z = 623.19 (M+H) ⁺ .

Step 3:

Compound 12b (300 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 250*50 mm, 10 μm column; acetonitrile-0.1% ammonia solution (10-50%/0-80 min gradient elution) to obtain compound 12 (Rt 75 min, LC-MS: m/z = 473.07 (M+H) ⁺ ).

Example 13

Step 1:

Compound 1b (2.0 g), 6-bromo-2,4-dichlorothiopheno[3,2-d]pyrimidine (1.9 g), and sodium iodide (3.1 g) were dispersed in anhydrous NMP (100 mL) and reacted at 150 °C for 2 h under nitrogen protection. After the reaction was complete, the reaction solution was poured into water (1000 mL), extracted with ethyl acetate (500 mL), and the organic phase was collected. The solution was washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The solution was purified by column chromatography (dichloromethane:methanol = pure dichloromethane ~100:1) to give compound 13a. LC-MS: m/z = 535.94 (M+H) ⁺ .

Step 2:

Compound 13a (1.7 g) and 2,4-dimethoxybenzylamine (1.8 g) were dispersed in N-methylpyrrolidone (100 mL), and the mixture was heated to 180 °C and reacted for 3 h. After the reaction was completed, the reaction solution was poured into water (70 mL), extracted with ethyl acetate, and the organic phase was collected. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 13b. LC-MS: m/z = 667.11 (M+H) ⁺ .

Step 3:

Compound 13b (300 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 250*50 mm, 10 μm column; acetonitrile-0.1% ammonia solution (15-65%/0-80 min gradient elution) to obtain compound 13 (Rt 55 min, LC-MS: m/z = 516.98 (M+H) ⁺ ).

Examples 14 to 45

Referring to routes 1 and 2 of this application and Examples 1-13, the following compounds were prepared:

Example 46

Step 1:

3-((tributyltinyl)methoxy)prop-1-amine (1.8 g), 2-chloro-4-ethanesulfonylbenzaldehyde (1 g), and 4A molecular sieve (10 g) were dispersed in dichloromethane (20 mL) under nitrogen protection and reacted at room temperature for 4 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 46a.

Step 2:

Copper(II) trifluoromethanesulfonate (1.5 g) was dispersed in dichloromethane (20 mL) and hexafluoroisopropanol (20 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.46 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 46a was dispersed in dichloromethane (60 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the reaction solution was poured into a saturated sodium bicarbonate solution (100 mL) and 10% ammonia solution (50 mL), stirred for 30 min, allowed to stand for separation, extracted with dichloromethane (50 mL * 3), and the organic phases were combined. The organic phases were washed successively with saturated sodium bicarbonate solution (100 mL) and saturated sodium chloride solution (100 mL), collected, dried over anhydrous sodium sulfate for 1 h, filtered, and the filtrate was concentrated under reduced pressure. The residue was dispersed in acetonitrile (100 mL), extracted with n-heptane (50 mL * 4), the acetonitrile phase was collected and concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 400:1 ~ 200:1) to give compound 46b. LC-MS: m/z = 304.15 (M + H) ⁺ .

Step 3:

Compound 46b (650 mg), 2,4-dichloropyrido[3,2-d]pyrimidine (428 mg), and N,N-diisopropylethylamine (553 mg) were added to anhydrous tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to give compound 46c. LC-MS: m/z = 467.11 (M+H) ⁺ .

Step 4:

Compound 46c (280 mg) and bis(2,4-dimethoxybenzyl)amine (380 mg) were dispersed in N-methylpyrrolidone (5 mL), and the mixture was heated to 180 °C and reacted for 1.5 h. After the reaction was completed, the reaction solution was poured into water (50 mL), extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 46d. LC-MS: m/z = 748.35 (M+H) ⁺ .

Step 5:

Compound 46d (300 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; acetonitrile-0.1% ammonia aqueous solution (20%-80%/0-45 min gradient elution) to obtain compound 46 (Rt 27.0 min, LC-MS: m/z = 448.17 (M+H) ⁺ ).

Example 47

Step 1:

3-((tributyltinyl)methoxy)prop-1-amine (0.81 g), 4-methanesulfonylnaphthaldehyde (0.5 g), and 4A molecular sieve (0.75 g) were dispersed in dichloromethane (15 mL) under nitrogen protection and reacted at room temperature for 5 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 47a.

Step 2:

Copper(II) trifluoromethanesulfonate (0.78 g) was dispersed in dichloromethane (25 mL) and hexafluoroisopropanol (10 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.23 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 47a was dispersed in dichloromethane (15 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the reaction solution was poured into 10% ammonia water (50 mL), stirred for 30 min, allowed to stand for phase separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dispersed in acetonitrile (50 mL), washed with n-heptane (10 mL * 5), the acetonitrile phase was collected and concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 200:1–150:1) to obtain compound 47b. LC-MS: m/z = 306.12(M+H) ⁺ .

Step 3:

Compound 47b (200 mg), 2,4-dichloropyrido[3,2-d]pyrimidine (155 mg), and N,N-diisopropylethylamine (170 mg) were dispersed in THF (20 mL) and reacted at room temperature for 2.5 h. The reaction solution was concentrated under reduced pressure to give compound 47c. LC-MS: m/z = 469.16 (M+H) ⁺ .

Step 4:

Compound 47c (300 mg) and bis(2,4-dimethoxybenzyl)amine (406 mg) were dispersed in N-methylpyrrolidone (12 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into water (150 mL), extracted with ethyl acetate (150 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 47d. LC-MS: m/z = 750.36 (M+H) ⁺ .

Step 5:

Compound 47d (300 mg) was dispersed in trifluoroacetic acid (15 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; acetonitrile-0.1% ammonia solution (20%-80%/0-45 min gradient elution) to obtain compound 47 (Rt 29 min, LC-MS: m/z = 450.21 (M+H) ⁺ ).

Example 48

Step 1:

3-((tributyltinyl)methoxy)prop-1-amine (4.6 g), methyl 3-chloro-4-carboxybenzoate (2.0 g), and 4A molecular sieve (3.0 g) were dispersed in dichloromethane (30 mL) under nitrogen protection and reacted at room temperature for 16 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 48a.

Step 2:

Copper(II) trifluoromethanesulfonate (4.4 g) was dispersed in dichloromethane (90 mL) and hexafluoroisopropanol (30 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (1.3 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 48a was dispersed in dichloromethane (30 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the reaction solution was poured into 10% ammonia water (90 mL), stirred for 30 min, allowed to stand for phase separation, extracted with dichloromethane (20 mL * 3), and the organic phases were combined. The organic phases were washed successively with sodium bicarbonate solution (100 mL) and sodium chloride solution (100 mL), collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 48b was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1). LC-MS: m/z = 269.93 (M + H) ⁺ .

Step 3:

Compound 48b (350 mg), 2,4-dichloropyrido[3,2-d]pyrimidine (260 mg), and N,N-diisopropylethylamine (504 mg) were dispersed in THF (25 mL) and reacted at room temperature for 16 h. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 300:1 to 5:1) to give compound 48c. LC-MS: m/z = 433.00 (M+H) ⁺ .

Step 4:

Compound 48c (340 mg) and 2,4-dimethoxybenzylamine (270 mg) were dispersed in N-methylpyrrolidone (25 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into water (250 mL), extracted with ethyl acetate (100 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 48d. LC-MS: m/z = 550.07 (M+H) ⁺ .

Step 5:

Compound 48d (100 mg) was dispersed in DMF (4 mL), and N,N-diisopropylethylamine (78 mg) and hydroxylamine hydrochloride (26 mg) were added. The mixture was stirred at room temperature for 0.5 h, and then benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (120 mg) was added. The reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction solution was poured into water (50 mL), extracted with a 10/1 dichloromethane/methanol mixture (22 mL), separated, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 48e. LC-MS: m/z = 565.10 (M+H) ⁺ .

Step 6:

Compound 48e (100 mg) was dispersed in trifluoroacetic acid (1.2 mL) and dichloromethane (3.6 mL) and reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18, specification 50*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 10%-50% B 0-60 min, gradient elution) to obtain compound 48 (Rt 43 min, LC-MS: m/z = 415.05 (M+H) ⁺ ).

Example 49

Step 1:

2-Chloro-4,6-difluorobenzaldehyde (5 g) and sodium methanesulfinate (2.92 g) were dispersed in dimethyl sulfoxide (50 mL), and the mixture was heated to 110 °C and reacted overnight under nitrogen protection. The reaction was then stopped, and the reaction solution was quenched by adding dropwise to ice water (500 mL). The mixture was extracted with ethyl acetate (300 mL), and the organic phase was collected and concentrated under reduced pressure. The resulting product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1–2:1) to give compound 49a.

Step 2:

3-((tributyltinyl)methoxy)prop-1-amine (1.1 g), compound 49a (680 mg), and 4A molecular sieve (5 g) were dispersed in dichloromethane (30 mL) under nitrogen protection and reacted at room temperature for 8 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 49b.

Step 3:

Copper(II) trifluoromethanesulfonate (1.2 g) was dispersed in dichloromethane (45 mL) and hexafluoroisopropanol (15 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.37 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 49b was dispersed in dichloromethane (30 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the reaction solution was poured into 10% ammonia water (100 mL), stirred for 30 min, allowed to stand for phase separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 1000:1 ~ 20:1) to obtain compound 49c.

Step 4:

Compound 49c (126 mg), 2,4-dichloropyrido[3,2-d]pyrimidine (82 mg), and N,N-diisopropylethylamine (106 mg) were dispersed in THF (5 mL) and reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 200:1–100:1) to give compound 49d. LC-MS: m/z = 471.10 (M+H) ⁺ .

Step 5:

Compound 49d (164 mg) and 2,4-dimethoxybenzylamine (116 mg) were dispersed in N-methylpyrrolidone (5 mL), and the mixture was heated to 180 °C and reacted for 4 h. After the reaction was completed, the reaction solution was poured into water (300 mL), extracted with ethyl acetate (150 mL), and the organic phase was collected. The organic phase was washed three times with brine (300 mL), collected, and concentrated under reduced pressure to give compound 49e. LC-MS: m/z = 602.24 (M+H) ⁺ .

Step 6:

Compound 49e (200 mg) was dispersed in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) and stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18, 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 15%-65% B 0-60 min, gradient elution) to obtain compound 49 (Rt 40 min, LC-MS: m/z = 452.16 (M+H) ⁺ ).

Example 50

Following the preparation method of compound 49, compound 50 was prepared by replacing 2-chloro-4,6-difluorobenzaldehyde with 2-chloro-3,4-difluorobenzaldehyde. LC-MS: m/z = 452.13 (M+H) ⁺ .

Example 51

Step 1:

2-Chloro-4-fluorobenzaldehyde (20 g) and sodium sulfide (45.5 g) were dispersed in DMF (100 mL) under nitrogen protection and stirred overnight at room temperature. The reaction was stopped, and the reaction mixture was quenched by adding dropwise to water (800 mL). The mixture was extracted twice with ethyl acetate (400 mL), and the organic phase was discarded. The remaining aqueous phase was pH adjusted to acidity and extracted twice with ethyl acetate (500 mL). The organic phase was collected and concentrated under reduced pressure. The residue was slurried with petroleum ether (200 mL) and ethyl acetate (20 mL), and filtered to give compound 51a ^. LC-MS: m/z = 171.12 (MH)

Step 2:

Copper(II) trifluoromethanesulfonate (3.22 g) was dispersed in dichloromethane (100 mL) and hexafluoroisopropanol (35 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.955 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. 3-((tributyltinyl)methoxy)propyl-1-amine (1.7 g), compound 51a (700 mg), and 4A molecular sieve (7 g) were dispersed in dichloromethane (40 mL) under nitrogen protection and reacted at room temperature for 4 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was dispersed in dichloromethane (40 mL) and slowly added to the above reaction system. The reaction was carried out overnight at room temperature. After the reaction was complete, the reaction solution was poured into saturated sodium bicarbonate solution (200 mL) and 10% ammonia solution (200 mL), stirred for 30 min, allowed to stand for separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, and washed successively with saturated sodium bicarbonate solution (100 mL) and saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate for 1 h, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 1000:1 ~ 5:1) to obtain compound 51b.

Step 3:

Compound 51b (717 mg) and Boc anhydride (1.93 g) were dispersed in methanol (5 mL) and dichloromethane (5 mL) and stirred overnight at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 100:1 to 1:1) to obtain compound 51c.

Step 4:

Compound 51c (400 mg) was dispersed in THF (10 mL). Tris(2-formylethyl)phosphonic acid hydrochloride (404 mg) was slowly added to the reaction system, and water (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected and concentrated under reduced pressure to obtain compound 51d.

Step 5:

Compound 51d (370 mg) was dispersed in anhydrous DMF (15 mL). Under ice bath conditions, NaH (60%, 86 mg) was slowly added to the reaction system. After stirring for 30 min, monofluoroiodomethane (344 mg) was added to the reaction system, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was poured into an ammonium chloride aqueous solution (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 50:1 to 2:1) to obtain compound 51e.

Step 6:

Compound 51e (100 mg) was dispersed in dichloromethane (1 mL), acetonitrile (3 mL), and water (1 mL). Under ice bath conditions, _RuCl3 (11 mg) was slowly added to the reaction system, and the mixture was stirred for 5 min. Then, sodium periodate (85 mg) was added to the reaction system, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (100 mL), and the organic phase was collected and concentrated under reduced pressure to obtain compound 51f.

Step 7:

Compound 51f (104 mg) was dispersed in 2 mL of ethyl acetate solution in 4.0 M hydrochloric acid and stirred at room temperature for 4 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, 100 mL of ethyl acetate was added, and then the pH was adjusted to alkaline with saturated sodium bicarbonate aqueous solution. The organic phase was collected and concentrated under reduced pressure to give compound 51 g. LC-MS: m/z = 308.08 (M+H) ⁺ .

Step 8:

Compound 51 g (43 mg), 2,4-dichloropyrido[3,2-d]pyrimidine (33 mg), and N,N-diisopropylethylamine (36 mg) were dispersed in THF (4 mL) and reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 500:1–100:1) to give compound 51 h. LC-MS: m/z = 471.10 (M+H) ⁺ .

Step 9:

Compound 51i (62 mg) and 2,4-dimethoxybenzylamine (66 mg) were dispersed in N-methylpyrrolidone (3 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into water (300 mL), extracted with ethyl acetate (150 mL), and the organic phase was collected. The organic phase was washed three times with brine (300 mL), collected, and concentrated under reduced pressure to obtain compound 51i. LC-MS: m/z = 602.21 (M+H) ⁺ .

Step 10:

Compound 51i (100 mg) was dispersed in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) and stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18, specification 30*250 mm, 10 μm, mobile phase: A: 0.1% formic acid, B: acetonitrile; gradient: 20%-70% B 0-60 min, gradient elution) to obtain compound 51 (Rt 29 min, LC-MS: m/z = 452.19 (M+H) ⁺ ).

Example 52

Step 1:

Compound 51d (390 mg) was dispersed in anhydrous DMF (10 mL). Under ice bath conditions, NaH (60%, 68 mg) was slowly added to the reaction system. After stirring for 30 min, trifluoroiodomethane (443 mg) was added to the reaction system, and the mixture was stirred overnight at room temperature. After the reaction was completed, the reaction solution was poured into an ammonium chloride aqueous solution (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 50:1 to 2:1) to obtain compound 52a.

Step 2:

Compound 52a (98 mg) was dispersed in dichloromethane (5 mL). Under ice bath conditions, m-chloroperoxybenzoic acid (164 mg) was slowly added to the reaction system, and the mixture was stirred overnight at room temperature. After the reaction was completed, the reaction solution was poured into a 10% sodium thiosulfate aqueous solution (150 mL), extracted with dichloromethane (100 mL), and the organic phase was collected. The organic phase was then washed with a 10% sodium hydroxide aqueous solution (100 mL), collected, and concentrated under reduced pressure to obtain compound 52b.

Step 3:

Compound 52b (56 mg) was dispersed in 2 mL of ethyl acetate solution in 4.0 M hydrochloric acid and stirred at room temperature for 4 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, 100 mL of ethyl acetate was added, and then the pH was adjusted to alkaline with saturated sodium bicarbonate aqueous solution. The organic phase was collected and concentrated under reduced pressure to give compound 52c. LC-MS: m/z = 328.11 (M+H) ⁺ .

Step 4:

Compound 52c (0.13 mmol), 2,4-dichloropyrido[3,2-d]pyrimidine (32 mg), and N,N-diisopropylethylamine (84 mg) were dispersed in THF (4 mL) and reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 500:1–100:1) to give compound 52d. LC-MS: m/z = 491.31 (M+H) ⁺ .

Step 5:

Compound 52d (50 mg) and 2,4-dimethoxybenzylamine (35 mg) were dispersed in N-methylpyrrolidone (5 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into water (300 mL), extracted with ethyl acetate (150 mL), and the organic phase was collected. The organic phase was washed three times with brine (300 mL), collected, and concentrated under reduced pressure to give compound 52e. LC-MS: m/z = 622.20 (M+H) ⁺ .

Step 6:

Compound 52e (60 mg) was dispersed in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) and stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18, specification 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: methanol; gradient: 30%-100% B 0-45 min, gradient elution) to obtain compound 52 (Rt 36 min, LC-MS: m/z = 472.14 (M+H) ⁺ ).

Example 53

Step 1:

1 g of 6-bromo-2,4-dichlorothiopheno[3,2-D]pyrimidine was added to a 100 mL reaction flask. Under nitrogen purging protection, 45 mL of anhydrous tetrahydrofuran was added to the flask and dispersed evenly. 3.5 mL of 1.3 M magnesium chloride tetrahydrofuran solution was slowly added dropwise to the reaction system, and the mixture was stirred for 5 min. 5 mL of anhydrous tetrahydrofuran and 0.64 mL of heavy water were mixed evenly and added dropwise to the reaction system, which was stirred overnight at room temperature. The reaction was stopped, and the reaction solution was quenched by adding dropwise to a saturated ammonium chloride aqueous solution (300 mL). The mixture was extracted with 200 mL of ethyl acetate, and the organic phase was collected and concentrated under reduced pressure. The resulting compound 53a was purified by column chromatography (petroleum ether:ethyl acetate = 100:1–30:1).

Step 2:

Compound 1b (290 mg), compound 53a (206 mg), and potassium iodide (320 mg) were dispersed in anhydrous N-methylpyrrolidone (10 mL) under nitrogen protection and reacted at 180 °C for 4 h. After the reaction was complete, the reaction solution was poured into water (300 mL), extracted with ethyl acetate (150 mL), and the organic phase was collected. The organic phase was washed three times with brine (300 mL), collected, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 500:1–100:1) to obtain compound 53b. LC-MS: m/z = 459.11 (M+H) ⁺ .

Step 3:

Compound 53b (296 mg) and 2,4-dimethoxybenzylamine (323 mg) were dispersed in N-methylpyrrolidone (10 mL), and the mixture was heated to 180 °C and reacted for 4 h. After the reaction was completed, the reaction solution was poured into water (300 mL), extracted with ethyl acetate (150 mL), and the organic phase was collected. The organic phase was washed three times with brine (300 mL), collected, and concentrated under reduced pressure to obtain compound 53c. LC-MS: m/z = 590.21 (M+H) ⁺ .

Step 4:

Compound 53c (300 mg) was dispersed in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) and stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18, 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; 10%-50% B 0-60 min, 50%-80% B 60-90 min, gradient elution) to obtain compound 53 (Rt 85 min, LC-MS: m/z = 440.12 (M+H) ⁺ ).

Example 54

Following the preparation method of compound 53, compound 54 was prepared by replacing 6-bromo-2,4-dichlorothieno[3,2-D]pyrimidine with 7-bromo-2,4-dichlorothieno[3,2-D]pyrimidine. LC-MS: m/z = 440.19 (M+H) ⁺ .

Example 55

Step 1:

Compound 1b (1.2 g), 2,4,6-trichloro-pyrido[3,2-D]pyrimidine (1.0 g), and N,N-diisopropylethylamine (1.1 g) were dispersed in THF (100 mL) and reacted at room temperature for 3 h. The reaction solution was concentrated under reduced pressure to give compound 55a, which was used directly in the next reaction. LC-MS: m/z = 487.06 (M+H) ⁺ .

Step 2:

Compound 55a (2.0 g) and bis(2,4-dimethoxybenzyl)amine (2.7 g) were dispersed in N-methylpyrrolidone (100 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into water (600 mL), extracted with ethyl acetate (400 mL), and the organic phase was collected. The organic phase was washed three times with brine (200 mL), collected, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 20:1) to obtain compound 55b. LC-MS: m/z = 768.27 (M+H) ⁺ .

Step 3:

Compound 55b (150 mg) and 10% palladium on carbon (45 mg) were dispersed in deuterated methanol (5 mL), and the mixture was stirred at room temperature under a deuterium balloon at atmospheric pressure for 12 h. After the reaction was completed, the mixture was filtered, the filtrate was collected and concentrated under reduced pressure to give compound 55c. LC-MS: m/z = 735.34 (M+H) ⁺ .

Step 4:

Compound 55c (100 mg) was dispersed in trifluoroacetic acid (5 mL) and reacted at room temperature for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18, specification 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 10%-50% B 0-60 min, gradient elution) to obtain compound 55 (Rt 45 min, LC-MS: m/z = 435.21 (M+H) ⁺ ).

Example 56

Following the preparation method of compound 55, compound 56 was prepared by replacing 2,4,6-trichloro-pyridano[3,2-D]pyrimidine with 2,4,7-trichloro-pyridano[3,2-D]pyrimidine. LC-MS: m/z = 435.23 (M+H) ⁺ .

Example 57

Step 1:

24.6 g of 3-((tributyltinyl)methoxy)prop-1-amine, 13.6 g of 2-chloro-4-bromobenzaldehyde, and 200 g of 4A molecular sieve were dispersed in 400 mL of dichloromethane under nitrogen protection and reacted at room temperature for 5 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 57a.

Step 2:

Copper(II) trifluoromethanesulfonate (25.0 g) was dispersed in dichloromethane (600 mL) and hexafluoroisopropanol (260 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (7.4 g) was slowly added dropwise, and the reaction was allowed to proceed for 1 h at room temperature. Compound 57a was dispersed in dichloromethane (400 mL) and slowly added to the above reaction system, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the reaction solution was poured into a saturated sodium bicarbonate solution (500 mL) and a 10% ammonia solution (300 mL), stirred for 30 min, allowed to stand for phase separation, and the organic phase was washed successively with a saturated sodium bicarbonate solution (500 mL) and a saturated sodium chloride solution (500 mL). The organic phase was collected, dried over anhydrous sodium sulfate for 1 h, filtered, and the filtrate was concentrated under reduced pressure. Compound 57b was purified by column chromatography (dichloromethane:methanol = 100:1–20:1). LC-MS: m/z = 289.95(M+H) ⁺ .

Step 3:

Compound d-1 (1.35 g), compound 57b (2.11 g), and potassium iodide (2.4 g) were dispersed in N-methylpyrrolidone (50 mL), and the mixture was heated to 160 °C and reacted for 4 h. The reaction solution was cooled to room temperature, and a 10:1 dichloromethane/methanol mixture (300 mL) was added for extraction. The organic phase was collected, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 100:1–10:1) to obtain compound 57c. LC-MS: m/z = 439.09 (M+H) ⁺ .

Step 4:

Compound 57c (100 mg), tributyl(1-ethoxyethylene)tin (360 mg), and _PdCl₂ ( _PPh₃ ) _₂ (30 mg) were dispersed in 1,4-dioxane (10 mL) under nitrogen protection and heated to 80 °C for 6 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 57d. LC-MS: m/z = 431.23 (M+H) ^⁺ .

Step 5:

Compound 57d was dispersed in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) and stirred at room temperature for 1 h. The reaction was stopped, concentrated under reduced pressure, and the solution was purified by preparative liquid chromatography (YMC TA C18, 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 15%-60% B 0-60 min, gradient elution) to obtain compound 57 (Rt 35 min, LC-MS: m/z = 403.23 (M+H) ⁺ ).

Example 58

Step 1:

Compound 57b (1.9 g), 2,4-dichloropyrido[3,2-d]pyrimidine (1.3 g), and N,N-diisopropylethylamine (1.7 g) were added to anhydrous tetrahydrofuran (100 mL), and the mixture was stirred at room temperature for 18 h. The reaction solution was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 50:1 to 1:1) to give compound 58a. LC-MS: m/z = 453.09 (M+H) ⁺ .

Step 2:

Compound 58a (1.9 g) and bis(2,4-dimethoxybenzyl)amine (2.6 g) were dispersed in N-methylpyrrolidone (30 mL), and the mixture was heated to 180 °C and reacted for 1 h. After the reaction was completed, the reaction solution was poured into water (300 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was washed with saturated brine (100 mL * 2), concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 100:1 ~ 20:1) to obtain compound 58b. LC-MS: m/z = 734.18 (M + H) ⁺ .

Step 3:

Compound 58b (200 mg), tributyl(1-ethoxyethylene)tin (360 mg), and _PdCl₂ ( _PPh₃ ) _₂ (30 mg) were dispersed in 1,4-dioxane (2 mL) under nitrogen protection and reacted at 80 °C for 8 h. The reaction mixture was cooled to room temperature and added to water (200 mL). Extraction was performed with ethyl acetate (100 mL), and the organic phase was collected and concentrated under reduced pressure to give compound 58c. LC-MS: m/z = 726.35 (M+H) ^⁺ .

Step 4:

Compound 58c was dispersed in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) and stirred at room temperature for 18 h. The reaction was stopped, concentrated under reduced pressure, and the mixture was subjected to preparative liquid chromatography (YMC TA C18, 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 20%-70% B 0-60 min, gradient elution) to obtain compound 58 (Rt 41 min, LC-MS: m/z = 398.25 (M+H) ⁺ ).

Example 59

Step 1:

Compound 58b (4.1 g) was dispersed in dichloromethane (100 mL) and trifluoroacetic acid (20 mL) and stirred at room temperature for 16 h. The reaction was stopped, and the reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 100:1–10:1) to give compound 59a. LC-MS: m/z = 434.13 (M+H) ⁺ .

Step 2:

Compound 59a (100 mg), 4-pyrazoloboroate pinacol ester (97 mg), chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine(2-amino-1,1'-biphenyl-2-yl)palladium(II) (26 mg) and _K₂CO₃ (69 mg) were dispersed in 1,4- _dioxane (10 mL) under nitrogen protection and heated to 90 °C for 6 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure. The filtrate was then subjected to preparative liquid chromatography (YMC TA C18, 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 15-30% B 0-10 min, 30-75% B 10-80 min; gradient elution) to obtain compound 59 (Rt 40 min, LC-MS: m/z = 422.09 (M+H) ^⁺ ).

Example 60-R

Step 1:

59a (100 mg), (R)-1-methylpyrrolidine-3-amine (100 mg), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (20 mg), and potassium tert-butoxide (50 mg) were dispersed in 1,4-dioxane (10 mL) under nitrogen protection and heated to 60 °C for 12 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure. The filtrate was then subjected to preparative liquid chromatography (YMC TA C18, 30*250 mm, 10 μm, mobile phase: A: 0.1% formic acid, B: acetonitrile; gradient: 10%-60% B-60 min; gradient elution) to obtain compound 60-R (Rt 10 min, LC-MS: m/z = 454.70 (M+H) ⁺ ).

Step 2:

Compound 60-R was separated into compound 60-R-A (Rt 12.09 min) and compound 60-R-B (Rt 17.03 min) by preparative liquid chromatography (YMC SA 10 μm 20*250 column; 0.1% diethylamine ethanol-n-hexane (5%-50%/0-40 min) gradient elution).

Compound 60-R-A has a shorter retention time in chiral columns than 60-R-B, while compound 60-R-B has a longer retention time in chiral columns than 60-R-A.

Example 60-S

Step 1:

Referring to step 1 of Example 60-R, (R)-1-methylpyrrolidine-3-amine was replaced with (S)-1-methylpyrrolidine-3-amine to prepare compound 60-S. LC-MS: m/z = 454.10 (M+H) ⁺ .

Step 2:

Compound 60-S was separated into compound 60-S-A (Rt 12.45 min) and compound 60-S-B (Rt 15.30 min) by preparative liquid chromatography (YMC SA 10 μm 20*250 column; 0.1% diethylamine ethanol-n-hexane (5%-50%/0-40 min) gradient elution).

Compound 60-S-A has a shorter retention time in chiral columns than 60-S-B, while compound 60-S-B has a longer retention time in chiral columns than 60-S-A.

Example 61

Step 1:

Compound 59a (100 mg), acetamide (68 mg), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (36 mg), and potassium tert-butoxide (51 mg) were dispersed in 1,4-dioxane (10 mL) under nitrogen protection and heated to 90 °C for 6 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure. The filtrate was then subjected to preparative liquid chromatography (YMC TA C18, 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 20%-60% B 0-60 min; gradient elution) to obtain compound 61 (Rt 37 min, LC-MS: m/z = 413.26 (M+H) ⁺ ).

Step 2:

Compound 61 was separated by preparative liquid chromatography (YMC Amylose-SA, 30*150mm, 10μm, mobile phase: A: n-hexane, B: 0.2% diethylamine ethanol; gradient: 5%-65% B/0-60min; gradient elution) to obtain compound 61-A (Rt 20min) and compound 61-B (Rt 23min).

Compound 61-A has a shorter retention time in chiral columns than 61-B, while compound 61-B has a longer retention time in chiral columns than 61-A.

Examples 62 to 83

Referring to routes one and two of this application, as well as Examples 60-R, 60-S and 61, the following compounds were prepared:

Example 84

Compound 57c (100 mg), ethylsulfonamide (124 mg), potassium tert-butoxide (51 mg), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (36 mg) were dispersed in anhydrous 1,4-dioxane (10 mL), and the mixture was heated to 75 °C and reacted for 8 h. After the reaction was completed, the reaction solution was filtered, the filtrate was collected and concentrated under reduced pressure, and compound 84 was obtained by preparative liquid chromatography (YMC TA C18, specification 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 10%-50% B 0-60 min gradient elution). The elution was carried out by LC-MS (Rt 33 min, m/z = 468.18 (M+H) ⁺ ).

Example 85-R

Step 1:

Compound 57c (1 g), (R)-1-methylpyrrolidine-3-amine (1.14 g), potassium tert-butoxide (510 mg), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (361 mg) were dispersed in anhydrous 1,4-dioxane (60 mL). The mixture was heated to 75 °C and stirred overnight. After the reaction was completed, the reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 85-R. LC-MS: m/z = 459.09 (M+H) ⁺ .

Step 2:

Compound 85-R was separated into compound 85-R-A (Rt 13.28 min) and compound 85-R-B (Rt 19.34 min) by preparative liquid chromatography (YMC SA 10 μm 30*250 column; 0.1% diethylamine ethanol-n-hexane (10%-70%/0-45 min) gradient elution).

Compound 85-RA: LC-MS: m/z = 459.10 (M+H) ⁺ ; ^1H NMR (500MHz, DMSO-d ₆ ) δ: 8.01 (s, 1H), 7.87 (s, 1H), 7.59-7.57 (d, J = 7Hz, 1H), 6.52 (s, 1H), 5.97 (s, 1H), 5.69-5.67 (d, J = 10.5Hz, 1H), 4.24-4.22 (d, J = 9.5Hz, 2H), 3.98-3.82 (m, 10H), 3.63-3.58 (m, 1H), 3.26 (s, 3H), 2.26 (s, 3H), 1.94-1.78 (m, 2H).

Compound 85-RB: LC-MS: m/z=459.09(M+H) ⁺ ; ¹ H NMR (500MHz, DMSO-d ₆ )δ:7.88-7.87(d,J＝5.5Hz,1H),7.04-7.02(d,J＝8Hz,1H),6.97-6.96(d,J＝5.5Hz,1H),6.60-6.59(d,J＝2Hz ,1H),6.48-6.46(m,1H),5.79(s,1H),4.81(s,1H),4.29(s,1H),4.05-4.01(m,1H),3.82-3.81(m,1H),3.80- 3.79(m,1H),3.72-3.70(d,J＝10.5Hz,2H),3.58-3.47(m,1H),2.37-2.36(m,1H),2.30-2.28(m,1H),2.27(s, 3H),2.23-2.17(m,1H),1.99(s,2H),1.90-1.78(m,1H),1.52-1.51(m,1H),1.35-26(m,2H),1.24-23(m,1H).

Compound 85-R-A has a shorter retention time in chiral columns than 85-R-B, while compound 85-R-B has a longer retention time in chiral columns than 85-R-A.

Example 85-S

Step 1:

Following step 1 of Example 85-R, (R)-1-methylpyrrolidine-3-amine was replaced with (S)-1-methylpyrrolidine-3-amine to prepare compound 85-S. LC-MS: m/z = 459.04 (M+H) ⁺ .

Step 2:

Compound 85-S was separated into compound 85-S-A (Rt 16.32 min) and compound 85-S-B (Rt 19.41 min) by preparative liquid chromatography (YMC SA 10 μm 30*250 column; 0.1% diethylamine ethanol-n-hexane (10%-70%/0-45 min) gradient elution).

Compound 85-S-A has a shorter retention time in chiral columns than 85-S-B, while compound 85-S-B has a longer retention time in chiral columns than 85-S-A.

Examples 86 to 102

Referring to routes one and two of this application, as well as Examples 84, 85-R and 85-S, the following compounds were prepared:

Example 103

Step 1:

Compound 59a (1.0 g), 2,4-dimethoxybenzylamine (0.75 g), potassium tert-butoxide (0.51 g), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.36 g) were dispersed in anhydrous 1,4-dioxane (100 mL), and the mixture was heated to 75 °C and reacted for 5 h. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to give compound 103a. LC-MS: m/z = 521.00 (M+H) ⁺ .

Step 2:

Compound 103a (1.5 g) was dispersed in dichloromethane (100 mL) and trifluoroacetic acid (20 mL) and reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18, specification 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 30%-70% B-60 min, gradient elution) to obtain compound 103 (Rt 42 min, LC-MS: m/z = 370.99 (M+H) ⁺ ).

Step 3:

Compound 103 was separated by preparative liquid chromatography (YMC Amylose-C Neo(AD) coated type, size 20*200mm, 10μm, mobile phase: A: n-hexane, B: 0.2% diethylamine-ethanol; gradient: 20%-70% B 0-30min; gradient elution) to obtain compound 103-A (Rt 17min) and compound 103-B (Rt 19min).

Compound 103-A has a shorter retention time in chiral columns than 103-B, while compound 103-B has a longer retention time in chiral columns than 103-A.

Example 104

Step 1:

Compound 57c (100 mg), 2,4-dimethoxybenzylamine (114 mg), potassium tert-butoxide (51 mg), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (36 mg) were dispersed in anhydrous 1,4-dioxane (10 mL), and the mixture was heated to 75 °C and reacted for 4 h. After the reaction was completed, the reaction mixture was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain compound 104a. LC-MS: m/z = 526.16 (M+H) ⁺ .

Step 2:

Compound 104a was dispersed in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) and stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18, 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 20%-60% B-60 min gradient elution) to obtain compound 104 (Rt 44 min, LC-MS: m/z = 376.19 (M+H) ⁺ ).

Step 3:

Compound 104 was separated by preparative liquid chromatography (YMC-SJ, specification 20*250, 10μm; mobile phase: 0.2% diethylamine ethanol-n-hexane (10%-80%/0-70min gradient elution)) to obtain compound 104-A (Rt 39min) and compound 104-B (Rt 44min).

Compound 104-A has a shorter retention time in chiral columns than 104-B, while compound 104-B has a longer retention time in chiral columns than 104-A.

Example 105-R

Referring to steps 1 and 2 of Example 57, 2-chloro-4-bromobenzaldehyde was replaced with 5-bromo-2-chlorobenzaldehyde, and then compound 105a was prepared referring to steps 1 and 2 of Example 58 and step 1 of Example 59. LC-MS: m/z = 434.10 (M+H) ⁺

Step 1:

Compound 105a (200 mg), (R)-1-methylpyrrolidine-3-amine (230 mg), potassium tert-butoxide (51.6 mg), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (36.5 mg) were dispersed in anhydrous 1,4-dioxane (10 mL) and the mixture was heated to 75 °C and reacted for 8 h. After the reaction was completed, the reaction solution was filtered, the filtrate was collected and concentrated under reduced pressure, and compound 105-R was obtained by preparative liquid chromatography (YMC TA C18, specification 30*250mm, 10μm, mobile phase: A: 0.1% ammonia, B: methanol; gradient: 40%-100% B 0-45min gradient elution) (Rt 37.5min, LC-MS: m/z＝454.08(M+H) ⁺ ).

Step 2:

Compound 105-R was separated by preparative liquid chromatography (CHIRALPAK IG 5μm 20*250 column; 0.1% diethylamine ethanol-n-hexane (10%-70%/0-45min gradient elution)) to obtain compound 105-R-A (Rt 31.41min) and compound 105-R-B (Rt 34.16min).

Compound 105-R-A has a shorter retention time in chiral columns than 105-R-B, while compound 105-R-B has a longer retention time in chiral columns than 105-R-A.

Example 105-S

Step 1:

Following step 1 of Example 105-R, (R)-1-methylpyrrolidine-3-amine was replaced with (S)-1-methylpyrrolidine-3-amine to prepare compound 105-S. LC-MS: m/z = 454.04 (M+H) ⁺ .

Step 2:

Compound 105-S was separated into compound 105-S-A (Rt 25.05 min) and compound 105-S-B (Rt 31.29 min) by preparative liquid chromatography (CHIRALPAK IG, 5 μm, 20*250 column; 0.1% diethylamine ethanol-n-hexane (15%-70%/0-45 min gradient elution)).

Compound 105-S-A has a shorter retention time in chiral columns than 105-S-B, while compound 105-S-B has a longer retention time in chiral columns than 105-S-A.

Example 106

Step 1:

3-((tributyltinyl)methoxy)prop-1-amine (20 g), 2-bromo-5-chloropyridin-4-carboxaldehyde (10 g), and 4A molecular sieve (150 g) were dispersed in dichloromethane (400 mL) under nitrogen protection and reacted at room temperature for 5 h. The reaction was then stopped to give compound 106a, which was used directly in the next reaction.

Step 2:

Copper(II) trifluoromethanesulfonate (25.0 g) was dispersed in dichloromethane (500 mL) and hexafluoroisopropanol (260 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (7.4 g) was slowly added dropwise, and the reaction was allowed to proceed for 1 h at room temperature. Compound 106a was then slowly added to the reaction system, and the reaction proceeded overnight at room temperature. After the reaction was complete, the reaction solution was poured into a saturated sodium bicarbonate solution (500 mL) and a 10% ammonia solution (300 mL), stirred for 30 min, and allowed to stand for phase separation. The organic phase was washed successively with a saturated sodium bicarbonate solution (500 mL) and a saturated sodium chloride solution (500 mL). The organic phase was collected, dried over anhydrous sodium sulfate for 1 h, filtered, and the filtrate was concentrated under reduced pressure. Compound 106b was purified by column chromatography (petroleum ether:ethyl acetate = 100:1–10:1). LC-MS: m/z = 290.81 (M+H) ⁺ .

Step 3:

Compound 106b (3.9 g), 2,4-dichloropyrido[3,2-d]pyrimidine (2.6 g), and N,N-diisopropylethylamine (3.4 g) were added to anhydrous tetrahydrofuran (80 mL), and the mixture was stirred at room temperature for 18 h. The reaction solution was concentrated and purified by column chromatography (dichloromethane:methanol = 100:1–20:1) to give compound 106c. LC-MS: m/z = 453.78 (M+H) ⁺ .

Step 4:

Compound 106c (1.0 g) and 2,4-dimethoxybenzylamine (2.1 g) were added to n-butanol (2 mL), and the reaction was carried out at 120 °C for 18 h. The reaction solution was concentrated and purified by column chromatography (dichloromethane:methanol = 100:1 to 50:1) to obtain compound 106d. LC-MS: m/z = 584.96 (M+H) ⁺ .

Step 5:

Compound 106d (15.0 g) was dispersed in dichloromethane (50 mL) and trifluoroacetic acid (50 mL) and stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 100:1 to 20:1) to obtain compound 106e. LC-MS: m/z = 434.90 (M+H) ⁺ .

Step 6:

Compound 106e (100 mg), (R)-1-methylpyrrolidine-3-amine (115 mg), potassium tert-butoxide (77 mg), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (36.5 mg) were dispersed in anhydrous 1,4-dioxane (10 mL) and the mixture was heated to 75 °C and reacted for 8 h. After the reaction was completed, the reaction solution was filtered, the filtrate was collected and concentrated under reduced pressure, and compound 106 was obtained by preparative liquid chromatography (YMC AQ C18, specification 50*250mm, 10μm, mobile phase: A: 0.5% formic acid-water, B: acetonitrile; gradient: 5%-30% B-60min gradient elution) (Rt 37min, LC-MS: m/z＝455.07(M+H) ⁺ ).

Example 107

Compound 57c (120 mg), 3-methylaminooxetine (118 mg), methanesulfonic acid (2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (22 mg), cesium carbonate (264 mg), and dioxane (15 mL) were added to a reaction flask, and the mixture was heated to 90 °C for 8 h under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Preparative liquid chromatography (YMC TA C18, 30*250mm, 10μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 30%-85%-B 0-60min, wavelength 254nm, v＝25ml/min) was performed to obtain compound 107 (Rt 31min, LC-MS: m/z＝446.22(M+H) ⁺ ).

Example 108

Compound 59a (150 mg), 3-methylaminooxetine (152 mg), methanesulfonic acid (2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (27 mg), cesium carbonate (342 mg), and dioxane (15 mL) were added to a reaction flask, and the mixture was heated to 90 °C for 8 h under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Preparative liquid chromatography (YMC TA C18, 50*250mm, 10μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 20%-60%-B 0-60min, wavelength 254nm, v＝60ml/min) was performed to obtain compound 108 (Rt 50min, LC-MS: m/z＝441.25(M+H) ⁺ ).

Example 109

Step 1:

Compound 59a (80 mg), methanol (50 mg), methanesulfonic acid (2-di-tert-butylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg), cesium carbonate (120 mg), and dioxane (15 mL) were added to a reaction flask. Under nitrogen protection, the mixture was heated to 90 °C and reacted for 2 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Preparative liquid chromatography (LC-MS) was performed (YMC TA C18, 50*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 30%-90%-B 0-60 min, wavelength 254 nm, v = 60 mL/min) to obtain compound 109 (Rt 50 min, LC-MS: m/z = 386.09 (M+H) ⁺ ).

Example 110

Step 1:

Compound 57c (120 mg), 3-oxetine (118 mg), methanesulfonic acid (2-di-tert-butylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (22 mg), cesium carbonate (264 mg), and dioxane (15 mL) were added to a reaction flask, and the mixture was heated to 90 °C for 8 h under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Preparative liquid chromatography (YMC TA C18, 30*250mm, 10μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 30%-90%-B 0-60min, wavelength 254nm, v＝40ml/min) was performed to obtain compound 110 (Rt 27min, LC-MS: m/z＝432.05(M+H) ⁺ ).

Step 2:

Compound 110 was separated by preparative liquid chromatography (SA, size 30*150mm, 10μm, mobile phase: A: n-hexane, B: ethanol; gradient: 10%-70% B0-60min, gradient elution) to obtain compound 110-A (Rt 32min) and compound 110-B (Rt 36min).

Compound 110-A: LC-MS: m/z = 432.05 (M+H) ⁺ ; ^¹H NMR (500MHz, DMSO-d6 ₎ )δ:7.88(d,J＝5.5Hz,1H),7.06(d,1H),6.96(d,J＝5.5Hz,1H),6.65(d,1H) ,6.527(d,1H),6.426-6.404((m,1H),4.825-4.79(m,3H),4.54-4.47(m,1H ),4.38-4.33(m,2H),4.28(m,1H),3.99-3.88((m,1H),3.79-3.67(m,2H),3 .59-3.54(m,1H),1.992-1.972(m,1H),1.821-1.795(m,1H),1.234(m,1H).

Compound 110-B: LC-MS: m/z = 432.06 (M+H) ⁺ ; ^¹H NMR (500MHz, DMSO-d6 ₎ )δ:7.88(d,J＝5.5Hz,1H),7.06(d,1H),6.96(d,J＝5.5Hz,1H),6.65(d,1H) ,6.527(d,1H),6.426-6.404((m,1H),4.825-4.79(m,3H),4.54-4.47(m,1H ),4.38-4.33(m,2H),4.28(m,1H),3.99-3.88((m,1H),3.79-3.67(m,2H),3 .59-3.54(m,1H),1.992-1.972(m,1H),1.821-1.795(m,1H),1.234(m,1H).

Compound 110-A has a shorter retention time in chiral columns than 110-B, while compound 110-B has a longer retention time in chiral columns than 110-A.

Example 111

Step 1:

Compound 59a (120 mg), 3-oxetine (118 mg), methanesulfonic acid (2-di-tert-butylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (22 mg), cesium carbonate (264 mg), and dioxane (15 mL) were added to a reaction flask, and the mixture was heated to 90 °C for 8 h under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then purified by preparative liquid chromatography (YMC TA C18, 30*250mm, 10μm, mobile phase: A: 0.1% ammonia, B: methanol; gradient: 40%-90%-B 0-45min, wavelength 254nm, v＝40ml/min) to obtain compound 111 (Rt 32.2min, LC-MS: m/z＝427.13(M+H) ⁺ ).

Step 2:

Compound 111 was separated by preparative liquid chromatography (SA, size 30*150mm, 10μm, mobile phase: A: n-hexane, B: ethanol; gradient: 10%-70% B0-60min, gradient elution) to obtain compound 111-A (Rt 17min) and compound 111-B (Rt 23min).

Compound 111-A: LC-MS: m/z=427.13(M+H) ⁺ ; ¹ H NMR (500MHz, DMSO-d ₆ )δ:8.23(d,1H),7.55(s,1H),7.41(d,1H),7.16(s,1H),6.57(d,1H),6.50(d,1H),6.38(d,1H),4.82-4.78(q,J＝6Hz,2H),4.5 1-4.67(m,1H),4.38-4.34(q,J=6Hz,2H),4.12(s,1H),3.83(m,2H),3.66-3.63(m,2H),2.00(m,1H),1.82(m,1H),1.23(m,2H).

Compound 111-B: LC-MS: m/z=427.11(M+H) ⁺ ; ¹ H NMR (500MHz, DMSO-d ₆ )δ:8.23(d,1H),7.55(s,1H),7.41(d,1H),7.16(s,1H),6.57(d,1H),6.50(d,1H),6.38(d,1H),4.82-4.78(q,J＝6Hz,2H),4.5 1-4.67(m,1H),4.38-4.34(q,J=6Hz,2H),4.12(s,1H),3.83(m,2H),3.66-3.63(m,2H),2.00(m,1H),1.82(m,1H),1.23(m,2H).

Compound 111-A has a shorter retention time in chiral columns than 111-B, while compound 111-B has a longer retention time in chiral columns than 111-A.

Example 112

Step 1:

3-((tributyltinyl)methoxy)prop-1-amine (3.4 g), 3-chloro-4-carboxybenzonitrile (1.0 g), and 4A molecular sieve (5 g) were dispersed in dichloromethane (15 mL) under nitrogen protection and reacted at room temperature for 5 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 112a.

Step 2:

Copper(II) trifluoromethanesulfonate (2.2 g) was dispersed in dichloromethane (25 mL) and hexafluoroisopropanol (20 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.64 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 112a was dispersed in dichloromethane (25 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the reaction solution was poured into 10% ammonia water (50 mL), stirred for 30 min, allowed to stand for phase separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dispersed in acetonitrile (50 mL), washed with n-heptane (10 mL * 5), the acetonitrile phase was collected and concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 200:1–150:1) to obtain compound 112b. LC-MS: m/z = 237.11(M+H) ⁺ .

Step 3:

Compound 112b (250 mg), 2,4-dichloropyrido[3,2-d]pyrimidine (216 mg), and N,N-diisopropylethylamine (271 mg) were dispersed in THF (10 mL) and reacted at room temperature for 2.5 h. The reaction solution was concentrated under reduced pressure to give compound 112c. LC-MS: m/z = 400.18 (M+H) ⁺ .

Step 4:

Compound 112c (210 mg) and bis(2,4-dimethoxybenzyl)amine (285 mg) were dispersed in N-methylpyrrolidone (5 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into water (150 mL), extracted with ethyl acetate (150 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 112d. LC-MS: m/z = 681.30 (M+H) ⁺ .

Step 5:

Compound 112d (200 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by preparative liquid chromatography (YMC TA C18, specification 50*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 10%-80%-B 0-90 min, wavelength 254 nm, v = 60 mL/min) to obtain compound 112 (Rt 71 min, LC-MS: m/z = 381.25 (M+H) ⁺ ).

Example 113

Step 1:

Compound 112b (250 mg), 2,4-dichlorothiopheno[3,2-D]pyrimidine (216 mg), and N,N-diisopropylethylamine (271 mg) were dispersed in N-methylpyrrolidone (10 mL) and reacted at 170 °C for 5 h. After the reaction was completed, 50 mL of purified water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 113a. LC-MS: m/z = 405.13 (M + H) ⁺ .

Step 2:

Compound 113a (450 mg) and bis(2,4-dimethoxybenzyl)amine (705 mg) were dispersed in N-methylpyrrolidone (20 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into water (150 mL), extracted with ethyl acetate (150 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 113b. LC-MS: m/z = 686.29 (M+H) ⁺ .

Step 3:

Compound 113b (450 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by preparative liquid chromatography (YMC TA C18, specification 50*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 20%-60%-B0-60 min, wavelength 254 nm, v = 60 mL/min) to obtain compound 113 (Rt 50 min, LC-MS: m/z = 386.18 (M+H) ⁺ ).

Example 114

Step 1:

3-((tributyltinyl)methoxy)prop-1-amine (4 g), 2-chloro-4-methoxybenzaldehyde (1.2 g), and 4A molecular sieve (5 g) were dispersed in dichloromethane (15 mL) under nitrogen protection and reacted at room temperature for 5 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 114a.

Step 2:

Copper(II) trifluoromethanesulfonate (2.5 g) was dispersed in dichloromethane (25 mL) and hexafluoroisopropanol (20 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.75 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 114a was dispersed in dichloromethane (25 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the reaction solution was poured into 10% ammonia water (50 mL), stirred for 30 min, allowed to stand for phase separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dispersed in acetonitrile (50 mL), washed with n-heptane (10 mL * 5), the acetonitrile phase was collected and concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 200:1–150:1) to obtain compound 114b. LC-MS: m/z = 242.10(M+H) ⁺ .

Step 3:

Compound 114b (170 mg), 2,4-dichlorothiopheno[3,2-D]pyrimidine (144 mg), and N,N-diisopropylethylamine (181 mg) were dispersed in NMP (5 mL) and reacted at 170 °C for 5 h. After the reaction was completed, 50 mL of purified water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 114c. LC-MS: m/z = 410.18 (M + H) ⁺ .

Step 4:

Compound 114c (300 mg) and bis(2,4-dimethoxybenzyl)amine (245 mg) were dispersed in N-methylpyrrolidone (5 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into water (150 mL), extracted with ethyl acetate (150 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 114d. LC-MS: m/z = 691.27 (M+H) ⁺ .

Step 5:

Compound 114d (380 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by preparative liquid chromatography (YMC TA C18, specification 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 50%-90%-B0-45 min, wavelength 254 nm, v = 40 mL/min) to obtain compound 114 (Rt 28 min, LC-MS: m/z = 391.19 (M+H) ⁺ ).

Example 115

Step 1:

3-((tributyltinyl)methoxy)prop-1-amine (4 g), 2-chloro-4-isopropylthiobenzaldehyde (1.2 g), and 4A molecular sieve (5 g) were dispersed in dichloromethane (15 mL) under nitrogen protection and reacted at room temperature for 5 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 115a.

Step 2:

Copper(II) trifluoromethanesulfonate (2.5 g) was dispersed in dichloromethane (25 mL) and hexafluoroisopropanol (20 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.75 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 115a was dispersed in dichloromethane (25 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the reaction solution was poured into 10% ammonia water (50 mL), stirred for 30 min, allowed to stand for phase separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dispersed in acetonitrile (50 mL), washed with n-heptane (10 mL * 5), the acetonitrile phase was collected and concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 200:1–150:1) to obtain compound 115b. LC-MS: m/z = 286.13(M+H) ⁺ .

Step 3:

Compound 115b (570 mg), di-tert-butyl dicarbonate (870 mg), and tetrahydrofuran (15 mL) were added to a reaction flask and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 20:1 to 10:1) to obtain compound 115c.

Step 4:

Compound 115c (560 mg), acetonitrile (30 mL), and dichloromethane (10 mL) were added to a reaction flask. The mixture was stirred, cooled in an ice-water bath, and then purified water (10 mL) and ruthenium trichloride (60 mg) were added. Sodium periodate (465 mg) was added in portions, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was added to purified water (100 mL), and then extracted with ethyl acetate (100 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 115d.

Step 5:

Compound 115d (690 mg) and dichloromethane (5 mL) were added to a reaction flask and stirred. Then, 5 mL of 4N hydrogen chloride ethyl acetate solution was added, and the mixture was stirred at room temperature for 30 min. After the reaction was complete, 10 mL of saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to weakly alkaline. The solution was then extracted with ethyl acetate (100 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 115e.

Step 6:

Compound 115e (250 mg), 2,4-dichloropyrido[3,2-d]pyrimidine (173 mg), and N,N-diisopropylethylamine (204 mg) were dispersed in tetrahydrofuran (5 mL) and reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to give compound 115f. LC-MS: m/z = 481.16 (M+H) ⁺ .

Step 7:

Compound 115f (342 mg) and 2,4-dimethoxybenzylamine (238 mg) were dispersed in N-methylpyrrolidone (10 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into water (150 mL), extracted with ethyl acetate (150 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 115 g of compound. LC-MS: m/z = 612.13 (M+H) ⁺ .

Step 8:

Compound 115 g (490 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by liquid chromatography (YMC TA C18, specification 30*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 20%-35%-B 0-10 min, 35%-70%-B 10-80 min; wavelength 254 nm, v = 30 mL/min) to obtain compound 115 (Rt 39 min, LC-MS: m/z = 462.01 (M+H) ⁺ ).

Example 116

Step 1:

3-((tributyltinyl)methoxy)prop-1-amine (3.4 g), 2-chloro-4-fluorobenzaldehyde (1.0 g), and 4A molecular sieve (5 g) were dispersed in dichloromethane (15 mL) under nitrogen protection and reacted at room temperature for 5 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 116a.

Step 2:

Copper(II) trifluoromethanesulfonate (2.2 g) was dispersed in dichloromethane (25 mL) and hexafluoroisopropanol (20 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.64 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 116a was dispersed in dichloromethane (25 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the reaction solution was poured into 10% ammonia water (50 mL), stirred for 30 min, allowed to stand for phase separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dispersed in acetonitrile (50 mL), washed with n-heptane (10 mL * 5), the acetonitrile phase was collected and concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 200:1–150:1) to obtain compound 116b. LC-MS: m/z = 229.95(M+H) ⁺ .

Step 3:

Compound 116b (250 mg), 2,4-dichloropyrido[3,2-d]pyrimidine (216 mg), and N,N-diisopropylethylamine (271 mg) were dispersed in THF (10 mL) and reacted at room temperature for 2.5 h. The reaction solution was concentrated under reduced pressure to give compound 116c. LC-MS: m/z = 393.02 (M+H) ⁺ .

Step 4:

Compound 116c (210 mg) and 2,4-dimethoxybenzylamine (285 mg) were dispersed in N-methylpyrrolidone (5 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into water (150 mL), extracted with ethyl acetate (150 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 116d. LC-MS: m/z = 524.09 (M+H) ⁺ .

Step 5:

Compound 116d (200 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by preparative liquid chromatography (YMC TA C18, specification 50*250 mm, 10 μm, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 30%-90%-B0-60 min, wavelength 254 nm, v = 60 mL/min) to obtain compound 116 (Rt 45 min, LC-MS: m/z = 374.08 (M+H) ⁺ ).

Example 117

Referring to Example 116, 2-chloro-4-fluorobenzaldehyde was replaced with 2-chloro-5-fluorobenzaldehyde to prepare compound 117. LC-MS: m/z = 374.08 (M+H) ⁺ .

Example 118

Referring to the preparation method of compound 47c in Example 47, in step 1, 4-bromo-1-naphthoaldehyde was replaced with 4-methanesulfonylnaphthoaldehyde to prepare compound 118a.

Step 1:

Compound 118a (1 g) and 2,4-dimethoxybenzylamine (1.78 g) were dispersed in N-methylpyrrolidone (50 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into water (500 mL), extracted with ethyl acetate (250 mL), the organic phase was collected, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 118b.

Step 2:

Compound 118b (1.2 g) and trifluoroacetic acid (10 mL) were dispersed in dichloromethane (10 mL) and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was diluted with dichloromethane (100 mL) and slowly added dropwise to a saturated potassium carbonate solution to adjust the pH to alkaline. The organic phase was separated and concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 200:1 to 6:1) to obtain compound 118c.

Step 3:

Compound 118c (20 mg), acetamide (13 mg), potassium tert-butoxide (10 mg), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (8 mg) were dispersed in 1,4-dioxane (2 mL). The mixture was heated to 90 °C and stirred for 3 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% formic acid solution (20%-70%/0-60 min gradient elution) to obtain compound 118. LC-MS: m/z = 429.13 (M+H) ⁺ .

Example 119

Compound 57c (100 mg), compound 119a (58 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (26 mg), potassium phosphate (97 mg), and water (1 mL) were dispersed in 1,4-dioxane (5 mL). The mixture was heated to 90 °C and stirred for 2 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (30%-100%/0-45 min gradient elution) to obtain compound 119. LC-MS: m/z = 428.03 (M+H) ⁺ .

Example 120

Following the preparation method of compound 119, compound 120 was prepared by replacing compound 119a with 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-2,5-dihydro-1H-pyrrole. LC-MS: m/z = 442.03 (M+H) ⁺ .

Example 121

Following the preparation method of compound 119, compound 121a was prepared by replacing compound 119a with 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine. LC-MS: m/z = 542.07 (M+H) ⁺ .

Step 1:

Compound 121a (3g), 10% Pd/C (3g), and 10% Pd(OH) _₂ /C (3g) were dispersed in methanol (150mL). The mixture was purged with nitrogen three times and then with hydrogen three times. The mixture was then heated to 50°C under hydrogen atmosphere and stirred overnight. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 500:1 to 20:1) to obtain compound 121b. LC-MS: m/z = 544.11 (M+H) ^⁺ .

Step 2:

Compound 121b (380 mg) and trifluoroacetic acid (5 mL) were dispersed in dichloromethane (5 mL) and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (10%-90%/0-60 min gradient elution) to obtain compound 121. LC-MS: m/z = 444.01 (M+H) ⁺ .

Example 122

Step 1:

3-((tributyltinyl)methoxy)prop-1-amine (2.04 g), 2-chloro-5-nitrobenzaldehyde (1.0 g), and 4A molecular sieve (6 g) were dispersed in dichloromethane (27 mL) under nitrogen protection and reacted at room temperature for 4 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 122a, which was used directly in the next step.

Step 2:

Copper(II) trifluoromethanesulfonate (2.1 g) was dispersed in hexafluoroisopropanol (14 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.67 g) was slowly added dropwise, and the reaction was carried out at room temperature for 0.5 h. Compound 122a was dispersed in dichloromethane (56 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the reaction solution was poured into 10% ammonia water (28 mL) and saturated sodium bicarbonate solution (14 mL), stirred for 15 min, allowed to stand for separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dispersed in acetonitrile (50 mL), washed with n-heptane (10 mL * 5), the acetonitrile phase was collected and concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 200:1–150:1) to give compound 122b. LC-MS: m/z = 257.07 (M + H) ⁺ .

Step 3:

Compound 122b (500 mg), 2,4-dichloropyrido[3,2-d]pyrimidine (467 mg), and N,N-diisopropylethylamine (755 mg) were dispersed in tetrahydrofuran (20 mL) and reacted at room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure to give compound 122c. LC-MS: m/z = 420.08 (M+H) ⁺

Step 4:

Compound 122c (800 mg) and bis(2,4-dimethoxybenzyl)amine (1.2 g) were dispersed in N-methylpyrrolidone (20 mL), and the mixture was heated to 180 °C and reacted for 4 h. After the reaction was completed, the reaction solution was poured into water (150 mL), extracted with ethyl acetate (150 mL), and the organic phase was collected. The mixture was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 122d. LC-MS: m/z = 701.31 (M+H) ⁺

Step 5:

Compound 122d (500 mg) was dispersed in trifluoroacetic acid (15 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 122e. LC-MS: m/z = 401.10 (M+H) ⁺ .

Step 6:

Compound 122e (280 mg) was dispersed in ethanol (5 mL) and purified water (2.5 mL), and reduced iron powder (80 mg) and ammonium chloride (75 mg) were added. The mixture was heated to 70 °C and reacted for 1 h. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure. Compound 122e was obtained by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; acetonitrile-0.1% ammonia solution (20%-80%/0-45 min gradient elution). LC-MS: m/z = 371.25 (M+H) ⁺ .

Step 7:

Compound 122 was separated by preparative liquid chromatography (Daicel IG 5μm 10*250 column; 0.1% diethylamine ethanol-n-hexane (15%-60%/0-45min gradient elution)) to obtain compound 122-A (Rt 24.23min) and compound 122-B (Rt 27.58min).

Compound 122-A has a shorter retention time in chiral columns than 122-B, while compound 122-B has a longer retention time in chiral columns than 122-A.

Example 123

Step 1:

Compound 122 (100 mg), acetyl chloride (32 mg), and N,N-diisopropylethylamine (105 mg) were dispersed in tetrahydrofuran (5 mL) and reacted at room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; acetonitrile-0.1% ammonia solution (20%-80%/0-45 min gradient elution) to obtain compound 123. LC-MS: m/z = 413.26 (M+H) ⁺ .

Step 2:

Compound 123 was separated by preparative liquid chromatography (YMC TA C18 10μm 30*250 column; acetonitrile-0.1% ammonia-water (30%-70%/0-60min gradient elution)) to obtain compound 123-A (Rt 23.2min) and compound 123-B (Rt 30.3min).

Compound 123-A has a shorter retention time in chiral columns than 123-B, while compound 123-B has a longer retention time in chiral columns than 123-A.

Example 124

Compound 122 (100 mg), trifluoroacetic acid (47 mg), and N,N-diisopropylethylamine (105 mg) were dispersed in DMF (5 mL). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (206 mg) was added under ice bath conditions, and the reaction was brought to room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; acetonitrile-0.1% ammonia solution (20%-80%/0-45 min gradient elution) to obtain compound 124. LC-MS: m/z = 467.18 (M+H) ⁺ .

Example 125

Step 1:

3-((tributyltinyl)methoxy)prop-1-amine (1.72 g), 2-chloro-5-bromobenzaldehyde (1.0 g), and 4A molecular sieve (6 g) were dispersed in dichloromethane (23 mL) under nitrogen protection and reacted at room temperature for 4 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 125a, which was used directly in the next step.

Step 2:

Copper(II) trifluoromethanesulfonate (1.8 g) was dispersed in hexafluoroisopropanol (10 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.57 g) was slowly added dropwise, and the reaction was carried out at room temperature for 0.5 h. Compound 125a was dispersed in dichloromethane (40 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the reaction solution was poured into 10% ammonia water (20 mL) and saturated sodium bicarbonate solution (10 mL), stirred for 15 min, allowed to stand for separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dispersed in acetonitrile (50 mL), washed with n-heptane (10 mL * 5), the acetonitrile phase was collected and concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 200:1–150:1) to give compound 125b. LC-MS: m/z = 289.98 (M + H) ⁺ .

Step 3:

Compound 125b (300 mg), 2,4-dichloropyrido[3,2-d]pyrimidine (248 mg), and N,N-diisopropylethylamine (400 mg) were dispersed in THF (15 mL) and reacted at room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure to give compound 125c. LC-MS: m/z = 452.98 (M+H) ⁺ .

Step 4:

Compound 125c (400 mg) and bis(2,4-dimethoxybenzyl)amine (559 mg) were dispersed in N-methylpyrrolidone (10 mL), and the mixture was heated to 180 °C and reacted for 4 h. After the reaction was completed, the reaction solution was poured into water (150 mL), extracted with ethyl acetate (150 mL), and the organic phase was collected. The mixture was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 125d. LC-MS: m/z = 734.21 (M+H) ⁺ .

Step 5:

Compound 125d (500 mg) was dispersed in trifluoroacetic acid (15 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 125e. LC-MS: m/z = 434.11 (M+H) ⁺ .

Step 6:

Compound 125e (100 mg) was dispersed in 1,4-dioxane, and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (36.5 mg), potassium tert-butoxide (52 mg), and methylamine hydrochloride (31 mg) were added. Nitrogen gas was purged, and the mixture was heated to 75 °C for 3 h. After the reaction was complete, the reaction solution was filtered and concentrated under reduced pressure. Compound 125e was obtained by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; acetonitrile-0.1% ammonia solution (20%-80%/0-45 min gradient elution). LC-MS: m/z = 385.11 (M+H) ⁺ .

Example 126

Compound 125e (100 mg) was dispersed in 1,4-dioxane, and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (36.5 mg) and potassium hydroxide (52 mg) were added. Nitrogen gas was purged, and the mixture was heated to 75 °C and reacted for 3 h. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure. Compound 126 was obtained by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; acetonitrile-0.1% ammonia solution (20%-80%/0-45 min gradient elution). LC-MS: m/z = 372.09 (M+H) ⁺ .

Example 127

Compound 125e (100 mg) was dispersed in 1,4-dioxane, and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (36.5 mg), potassium tert-butoxide (52 mg), and formamide (21 mg) were added. Nitrogen gas was purged, and the mixture was heated to 75 °C and reacted for 3 h. After the reaction was complete, the reaction solution was filtered and concentrated under reduced pressure. Compound 127 was obtained by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; acetonitrile-0.1% ammonia solution (20%-80%/0-45 min gradient elution). LC-MS: m/z = 399.07 (M+H) ⁺ .

Example 128

Compound 125e (100 mg) was dispersed in 1,4-dioxane, and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (36.5 mg), potassium tert-butoxide (52 mg), and trifluoroethylamine (46 mg) were added. Nitrogen gas was purged, and the mixture was heated to 50 °C and reacted for 1 h. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure. Compound 128 (Rt 29 min, LC-MS: m/z = 453.09 (M+H) ⁺ ) was obtained by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; acetonitrile-0.1% ammonia solution (20%-80%/0-45 min gradient elution)).

Example 129

Compound d-1 (61 mg), compound 47b (100 mg), and sodium iodide (98 mg) were dispersed in N-methylpyrrolidone (8 mL), and the mixture was heated to 160 °C and reacted for 4.5 h. The reaction solution was subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia water (10%-50%/0-60 min gradient elution)) to obtain compound 129 (Rt 42 min, LC-MS: m/z = 455.15 (M+H) ⁺ ).

Example 130

Step 1:

3-((tributyltinyl)methoxy)prop-1-amine (2.4 g), 2-chloro-4-((methanesulfonyl)methyl)benzaldehyde (1.0 g), and 4A molecular sieve (1.5 g) were dispersed in dichloromethane (30 mL) under nitrogen protection and reacted at room temperature for 5 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 130a.

Step 2:

Copper(II) trifluoromethanesulfonate (1.54 g) was dispersed in dichloromethane (30 mL) and hexafluoroisopropanol (19 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.46 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 130a was dispersed in dichloromethane (46 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the reaction solution was poured into 10% ammonia water (50 mL), stirred for 30 min, allowed to stand for phase separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dispersed in acetonitrile (50 mL), washed with n-heptane (10 mL * 5), the acetonitrile phase was collected and concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 100:1–50:1) to obtain compound 130b. LC-MS: m/z = 304.09(M+H) ⁺ .

Step 3:

Compound 130b (200 mg), 2,4-dichloropyrido[3,2-d]pyrimidine (155 mg), and N,N-diisopropylethylamine (170 mg) were dispersed in THF (5 mL) and reacted at room temperature for 4 h. The reaction solution was concentrated under reduced pressure to give compound 130c. LC-MS: m/z = 467.13 (M+H) ⁺ .

Step 4:

Compound 130c and bis(2,4-dimethoxybenzyl)amine (400 mg) were dispersed in N-methylpyrrolidone (12 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (100 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 130d. LC-MS: m/z = 748.36 (M+H) ⁺ .

Step 5:

Compound 130d (300 mg) was dispersed in trifluoroacetic acid (15 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (20%-90%/0-45 min gradient elution) to obtain compound 130 (Rt 22.5 min, LC-MS: m/z = 448.20 (M+H) ⁺ ).

Example 131

Compound d-1 (48 mg), compound 130b (80 mg), and sodium iodide (79 mg) were dispersed in N-methylpyrrolidone (8 mL), and the mixture was heated to 160 °C and reacted for 4.5 h. Compound 131 (Rt 36 min, LC-MS: m/z = 453.15 (M+H) ⁺ ) was obtained by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia water (10%-50%/0-60 min gradient elution)).

Example 132

Compound 105a (70 mg), 3-hydroxypyrrolidine (42 mg), tris(dibenzylacetone)palladium (14 mg), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (10 mg), and cesium carbonate (105 mg) were dispersed in dioxane (8 mL) and reacted at 100 °C for 3 h. Compound 132 was obtained by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (20%-70%/0-60 min gradient elution)). The reaction time was 42 min, LC-MS: m/z = 441.23 (M+H) ⁺ .

Example 133

Compound 105a (80 mg), 3-oxetanediamine (80 mg), tris(dibenzylacetone)palladium (17 mg), 2-(dicyclohexylphosphine)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (10 mg), and sodium tert-butoxide (53 mg) were dispersed in dioxane (10 mL), and the mixture was heated to 90 °C and reacted for 3 h. The reaction mixture was then subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (10%-50%/0-60 min gradient elution)) to obtain compound 133 (Rt 44 min, LC-MS: m/z = 427.26 (M+H) ⁺ ).

Example 134

Following the preparation method of compound 57c in Example 57, 2-chloro-4-bromobenzaldehyde was replaced with 5-bromo-2-chlorobenzaldehyde to prepare compound 134a. LC-MS: m/z = 438.97 (M+H) ⁺

Step 1:

Compound 134a (50 mg), 3-hydroxypyrrolidine (32 mg), tris(2-benzylacetone)palladium (10 mg), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (7 mg), and cesium carbonate (110 mg) were dispersed in dioxane (5 mL) and reacted at 100 °C for 3 h. Compound 134 was obtained by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (20%-70%/0-60 min gradient elution)). The reaction time was 49 min, and the reaction volume was LC-MS: m/z = 446.19 (M+H) ⁺ .

Example 135

Compound 134a (100 mg), 3-oxetanediamine (84 mg), tris(dibenzylacetone)palladium (21 mg), 2-(dicyclohexylphosphine)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (12 mg), and sodium tert-butoxide (66 mg) were dispersed in dioxane (10 mL), and the mixture was heated to 90 °C and reacted for 8 h. The reaction mixture was then subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (10%-50%/0-60 min gradient elution)) to obtain compound 135 (Rt 24 min, LC-MS: m/z = 432.03 (M+H) ⁺ ).

Example 136

Step 1:

3-((tributyltinyl)methoxy)prop-1-amine (3.2 g), 6-chloroimidazole[1,2-a]pyridine-7-carboxaldehyde (1.0 g), and 4A molecular sieve (2 g) were dispersed in dichloromethane (30 mL) under nitrogen protection and reacted at room temperature for 5 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 136a.

Step 2:

Copper(II) trifluoromethanesulfonate (2 g) was dispersed in dichloromethane (30 mL) and hexafluoroisopropanol (19 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.6 g) was slowly added dropwise, and the reaction was allowed to proceed for 1 h at room temperature. Compound 136a was dispersed in dichloromethane (46 mL) and slowly added to the above reaction system. The reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the reaction solution was poured into an ammonia-methanol solution (50 mL), stirred for 10 min, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 100:1–20:1) to obtain compound 136b. LC-MS: m/z = 252.09 (M+H) ⁺ .

Step 3:

Compound 136b (300 mg), 2,4-dichloropyrido[3,2-d]pyrimidine (240 mg), and N,N-diisopropylethylamine (310 mg) were dispersed in THF (20 mL) and reacted at room temperature for 4 h. The reaction solution was concentrated under reduced pressure to give compound 136c. LC-MS: m/z = 415.2 (M+H) ⁺ .

Step 4:

Compound 136c (300 mg) and bis(2,4-dimethoxybenzyl)amine (690 mg) were dispersed in N-methylpyrrolidone (5 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into ethyl acetate (200 mL), washed three times with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 136d. LC-MS: m/z = 696.26 (M+H) ⁺ .

Step 5:

Compound 136d (300 mg) was dispersed in trifluoroacetic acid (15 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (20%-55%/0-70 min gradient elution) to obtain compound 136 (Rt 48 min, LC-MS: m/z = 396.11 (M+H) ⁺ ).

Example 137

Step 1:

3-((tributyltinyl)methoxy)propyl-1-amine (8.3 g), ethyl 3-trifluoromethoxy-4-carboxybenzoate (4.4 g), and 4A molecular sieve (9 g) were dispersed in dichloromethane (130 mL) under nitrogen protection and reacted at room temperature for 4 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 137a.

Step 2:

Copper(II) trifluoromethanesulfonate (6.1 g) was dispersed in dichloromethane (300 mL) and hexafluoroisopropanol (85 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (1.8 g) was slowly added dropwise, and the reaction was allowed to proceed overnight at room temperature. Compound 137a was dispersed in dichloromethane (40 mL) and slowly added to the above reaction system, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the reaction solution was poured into 10% ammonia water (150 mL), stirred for 30 min, allowed to stand for phase separation, extracted with dichloromethane (150 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (200 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dispersed in acetonitrile (150 mL), washed with n-heptane (30 mL * 5), the acetonitrile phase was collected and concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 400:1 ~ 200:1) to give compound 137b. LC-MS: m/z = 334.16 (M + H) ⁺ .

Step 3:

Compound 137b (1.3 g) and _Boc₂O (1.3 g) were dissolved in THF (20 mL) and reacted at room temperature for 4 h. The reaction solution was concentrated under reduced pressure and subjected to column chromatography (PE:EA = 15:1) to give compound 137c. LC-MS: m/z = 434.16 (M+H) ^⁺ .

Step 4:

Compound 137c (1.5 g) and calcium chloride (1.7 g) were dispersed in ethanol (40 mL), and sodium borohydride (0.98 g) was added. The mixture was reacted overnight at room temperature. The reaction solution was quenched with saturated ammonium chloride solution (200 mL), extracted with ethyl acetate (300 mL), washed with saturated brine (100 mL), dried, and concentrated to give compound 137d. LC-MS: m/z = 392.16 (M+H) ⁺ .

Step 5:

Compound 137d (1.3 g) and triphenylphosphine (1.0 g) were dissolved in dichloromethane (25 mL), and N-bromosuccinimide (0.88 g) was added. The mixture was reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure and subjected to column chromatography (PE:EA = 20:1) to give compound 137e. LC-MS: m/z = 454.15 (M+H) ⁺ .

Step 6:

Compound 137e (1.3 g) and sodium methanethiol (0.4 g) were dissolved in methanol (20 mL) and reacted at room temperature for 4 h. Water (50 mL) and ethyl acetate (100 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography (PE:EA = 20:1) to give compound 137f. LC-MS: m/z = 422.11 (M+H) ⁺ .

Step 7:

Compound 137f (1.1 g) was dissolved in dichloromethane (20 mL), and m-chloroperoxybenzoic acid (1.0 g) was added. The reaction was carried out at room temperature for 4 h. The reaction was quenched with saturated sodium carbonate solution (50 mL) and saturated sodium sulfite solution (50 mL), and extracted with dichloromethane (150 mL). The mixture was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography (PE:EA = 15:1) to give compound 137 g. LC-MS: m/z = 454.20 (M+H) ⁺ .

Step 8:

Compound 137 g (0.6 g) was dissolved in ethyl acetate (10 mL), and a solution of 4N hydrogen chloride in ethyl acetate (0.55 mL) was added. The reaction was carried out at room temperature for 0.5 h. A saturated sodium carbonate solution (50 mL) and ethyl acetate (100 mL) were added. The mixture was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography (dichloromethane:methanol = 100:1) to give compound 137 h. LC-MS: m/z = 354.20 (M+H) ⁺ .

Step 9:

Compound 137i (150 mg), 2,4-dichloropyrido[3,2-d]pyrimidine (90 mg), and N,N-diisopropylethylamine (110 mg) were dispersed in THF (10 mL) and reacted at room temperature for 3 h. The reaction solution was concentrated under reduced pressure to give compound 137i. LC-MS: m/z = 517.09 (M+H) ⁺ .

Step 10:

Compound 137i (240 mg) and bis(2,4-dimethoxybenzyl)amine (440 mg) were dispersed in N-methylpyrrolidone (5 mL), and the mixture was heated to 180 °C and reacted for 2 h. After the reaction was completed, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (100 mL), and the organic phase was collected. The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 137j. LC-MS: m/z = 798.25 (M+H) ⁺ .

Step 11:

Compound 137j (300 mg) was dispersed in trifluoroacetic acid (15 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (15%-65%/0-60 min gradient elution) to obtain compound 137 (Rt 29 min, LC-MS: m/z = 498.03 (M+H) ⁺ ).

Example 138

Compound 137h (180 mg), compound d-1 (93 mg), and sodium iodide (150 mg) were dispersed in N-methylpyrrolidone (5 mL), and the mixture was heated to 180 °C and reacted for 4 h. The reaction mixture was then subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (15%-65%/0-60 min gradient elution)) to obtain compound 138 (Rt 32 min, LC-MS: m/z = 502.99 (M+H) ⁺ ).

Example 139

Step 1:

Compound 58b (200 mg), 1-(2,4-dimethoxybenzyl)urea (287 mg), [(2-di-tert-butylphosphine-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (23 mg), and potassium tert-butoxide (33 mg) were dispersed in dioxane (6 mL), and the mixture was heated to 60 °C and reacted for 3 h. After the reaction was completed, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (100 mL), the organic phase was collected, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 139a. LC-MS: m/z = 864.35 (M+H) ⁺ .

Step 2:

Compound 139a (300 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (20%-70%/0-60 min gradient elution) to obtain compound 139 (Rt 27 min, LC-MS: m/z = 414.25 (M+H) ⁺ ).

Step 3:

Compound 139 was separated by preparative liquid chromatography (YMC-Amylose-SA, 10 μm, 30*250 column; hexane-0.2% diethylamine in ethanol solution (10%-90%/0-40 min gradient elution)) to obtain compound 139-A (Rt 17 min) and compound 139-B (Rt 25 min).

Compound 139-A: LC-MS: m/z=414.10(M+H) ⁺ ; ¹ H NMR (500MHz, CDCl ₃ )δ:8.67(s,1H),8.45-8.00(br,1H),7.73(d,1H),7.54(s,1H),7.41(d,J＝4.0Hz,1H),7.26(d,J＝4.0Hz,1H) ,7.06(dd,1H),6.26(brs,2H),5.90(s,2H),4.18(m,1H),3.92-3.58(m,4H),1.76-2.12(m,2H),1.23(m,2H).

Compound 139-B: LC-MS: m/z=414.10(M+H) ⁺ ; ¹ H NMR (500MHz, CDCl ₃ )δ:8.70(s,1H),8.45-8.05(br,1H),7.73(d,1H),7.54(s,1H),7.41(d,J＝4.0Hz,1H),7.26(d,J＝4.0Hz,1H) ,7.07(dd,1H),6.25(brs,2H),5.91(s,2H),4.18(m,1H),3.95-3.56(m,4H),1.76-2.14(m,2H),1.23(m,2H).

Compound 139-A has a shorter retention time in chiral columns than 139-B, while compound 139-B has a longer retention time in chiral columns than 139-A.

Example 140

Step 1:

Compound 57c (150 mg), 1-(2,4-dimethoxybenzyl)urea (360 mg), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (54 mg), and potassium tert-butoxide (77 mg) were dispersed in dioxane (8 mL), and the mixture was heated to 60 °C and reacted for 3 h. After the reaction was completed, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (100 mL), and the organic phase was collected. The mixture was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 140a. LC-MS: m/z = 569.20 (M+H) ⁺ .

Step 2:

Compound 140a (200 mg) was dispersed in trifluoroacetic acid (6 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (10%-60%/0-60 min gradient elution) to obtain compound 140 (Rt 37 min, LC-MS: m/z = 419.08 (M+H) ⁺ ).

Example 141

Step 1:

Compound 125d (300 mg), 1-(2,4-dimethoxybenzyl)urea (424 mg), [(2-di-tert-butylphosphine-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (64 mg), and potassium tert-butoxide (92 mg) were dispersed in dioxane (12 mL), and the mixture was heated to 60 °C and reacted for 3 h. After the reaction was completed, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (100 mL), the organic phase was collected, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 141a. LC-MS: m/z = 864.35 (M+H) ⁺ .

Step 2:

Compound 141a (400 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (20%-60%/0-60 min gradient elution) to obtain compound 141 (Rt 39 min, LC-MS: m/z = 414.10 (M+H) ⁺ ).

Example 142

Step 1:

3-((tributyltinyl)methoxy)prop-1-amine (7.8 g), 2-bromo-5-chloropyridin-4-carboxaldehyde (3.0 g), and 4A molecular sieve (6 g) were dispersed in dichloromethane (60 mL) under nitrogen protection and reacted at room temperature for 5 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 142a.

Step 2:

Copper(II) trifluoromethanesulfonate (5.0 g) was dispersed in dichloromethane (25 mL) and hexafluoroisopropanol (60 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (1.5 g) was slowly added dropwise, and the reaction was allowed to proceed for 0.5 h at room temperature. Compound 142a was dispersed in dichloromethane (90 mL) and slowly added to the above reaction system. The reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the reaction solution was poured into 10% ammonia water (50 mL), stirred for 30 min, allowed to stand for phase separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 200:1 ~ 100:1) to obtain compound 142b. LC-MS: m/z = 290.83 (M + H) ⁺ .

Step 3:

Compound 142b (500 mg), 2,4-dichloropyrido[3,2-d]pyrimidine (380 mg), and N,N-diisopropylethylamine (445 mg) were dispersed in THF (20 mL) and reacted at room temperature for 2.5 h. The reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 200:1–100:1) to give compound 142c. LC-MS: m/z = 453.87 (M+H) ⁺ .

Step 4:

Compound 142c (600 mg), 2,4-dimethoxybenzylamine (1100 mg), tris(dibenzylacetone)dipalladium (119 mg), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (81 mg), and cesium carbonate (850 mg) were dispersed in dioxane (12 mL), and the mixture was heated to 90 °C and reacted for 3 h. After the reaction was completed, the reaction solution was poured into water (150 mL), extracted with ethyl acetate (150 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 142d. LC-MS: m/z = 672.16 (M+H) ⁺ .

Step 5:

Compound 142d (600 mg) was dispersed in trifluoroacetic acid (15 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (15%-80%/0-60 min gradient elution) to obtain compound 142 (Rt 29 min, LC-MS: m/z = 372.05 (M+H) ⁺ ).

Step 6:

Compound 142 was subjected to preparative liquid chromatography (Daicel IC, 10 μm, 30*250 column; hexane-0.2% diethylamine in ethanol solution (20%-80%/0-40 min gradient elution)) to obtain compound 142-A (Rt 18 min) and compound 142-B (Rt 25 min).

Compound 142-A: LC-MS: m/z=372.06(M+H) ⁺ ; ¹ H NMR (500MHz, DMSO-d ₆ )δ:8.38-8.37(m,1H),8.32(s,1H),7.99-7.97(m,1H),7.77-7.74(m,1H),7.25(s,1H),5.84-5.81(m ,1H),5.08-5.04(m,1H),4.33-4.27(m,1H),4.05-3.96(m,3H),3.71-3.68(m,1H),2.18-1.97(m,6H).

Compound 142-B: LC-MS: m/z=372.06 (M+H) ⁺ ; ¹ H NMR (500MHz, DMSO-d ₆ )δ:8.08(s,1H),7.89-7.87(d,J＝10Hz,1H),7.56(s,1H),7.40(s,1H),6.83(s,1H),6.47(s,1H),5.11(s,1 H),4.27-4.25(d,J=9Hz,1H),4.05-3.93(m,1H),3.80-3.61(m,3H),2.07-1.84(m,4H),1.19-1.16(m,2H).

Compound 142-A has a shorter retention time in chiral columns than 142-B, while compound 142-B has a longer retention time in chiral columns than 142-A.

Example 143

Step 1:

3-((tributyltinyl)methoxy)prop-1-amine (4.0 g), 2-chlorobenzaldehyde (1.0 g), and 4A molecular sieve (6 g) were dispersed in dichloromethane (60 mL) under nitrogen protection and reacted at room temperature for 5 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 143a.

Step 2:

Copper(II) trifluoromethanesulfonate (2.57 g) was dispersed in dichloromethane (150 mL) and hexafluoroisopropanol (39 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.76 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 143a was dispersed in dichloromethane (60 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the reaction solution was poured into a saturated sodium bicarbonate solution (300 mL) and 10% ammonia solution (200 mL), stirred for 30 min, allowed to stand for separation, extracted with dichloromethane (50 mL * 3), and the organic phases were combined. The organic phases were washed successively with saturated sodium bicarbonate solution (200 mL) and saturated sodium chloride solution (200 mL), collected, dried over anhydrous sodium sulfate for 1 h, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dispersed in acetonitrile (300 mL), extracted with n-heptane (50 mL x 5), the acetonitrile phase was collected and concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 20:1 to 10:1 -- dichloromethane: methanol = 500:1 to 200:1) to give compound 143b. LC-MS: m/z = 212.15 (M + H) ⁺ .

Step 3:

Compound 143b (212 mg), 2,4-dichlorothiophene[2,3-d]pyrimidine (205 mg), and sodium iodide (300 mg) were dispersed in anhydrous N-methylpyrrolidone (10 mL). The mixture was heated to 150 °C and stirred for 5 h under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The solution was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 500:1 to 200:1) to obtain compound 143c. LC-MS: m/z = 380.16 (M+H) ⁺ .

Step 4:

Compound 143c (190 mg) and 2,4-dimethoxybenzylamine (314 mg) were dispersed in N-methylpyrrolidone (10 mL), and the mixture was heated to 180 °C and reacted for 4 h. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 143d. LC-MS: m/z = 511.20 (M+H) ⁺ .

Step 5:

Compound 143d (170 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure and poured into a 10% sodium carbonate aqueous solution (200 mL). Extraction was performed with dichloromethane (200 mL), and the organic phase was collected. The mixture was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 50:1–10:1) to obtain compound 143. LC-MS: m/z = 361.20 (M+H) ⁺ .

Example 144

Step 1:

Compound 143b (106 mg), 2,4-dichloropyrido[3,2-d]pyrimidine (100 mg), and N,N-diisopropylethylamine (193 mg) were dispersed in tetrahydrofuran (20 mL) and reacted with stirring at room temperature for 17 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = pure dichloromethane ~100:1) to give compound 144a. LC-MS: m/z = 375.20 (M+H) ⁺ .

Step 2:

Compound 144a (217 mg) and 2,4-dimethoxybenzylamine (393 mg) were dispersed in N-methylpyrrolidone (10 mL), and the mixture was heated to 180 °C and reacted for 4 h. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 144b. LC-MS: m/z = 506.25 (M+H) ⁺ .

Step 3:

Compound 144b (101 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted overnight at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure and poured into a 10% sodium carbonate aqueous solution (200 mL). Extraction was performed with dichloromethane (200 mL), and the organic phase was collected. The mixture was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification was performed by column chromatography (dichloromethane:methanol = 50:1–10:1) to obtain compound 144. LC-MS: m/z = 356.24 (M+H) ⁺ .

Example 145

Step 1:

10.2 g of 3-((tributyltinyl)methoxy)prop-1-amine, 3.0 g of 6-bromo-4-chloronicotinaldehyde, and 6 g of 4A molecular sieve were dispersed in 60 mL of dichloromethane under nitrogen protection and reacted at room temperature for 5 h. The reaction was stopped, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 145a.

Step 2:

Copper(II) trifluoromethanesulfonate (4.91 g) was dispersed in dichloromethane (150 mL) and hexafluoroisopropanol (39 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (1.45 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 145a was dispersed in dichloromethane (60 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the reaction solution was poured into a saturated sodium bicarbonate solution (300 mL) and 10% ammonia solution (200 mL), stirred for 30 min, allowed to stand for separation, extracted with dichloromethane (50 mL * 3), and the organic phases were combined. The organic phases were washed successively with saturated sodium bicarbonate solution (200 mL) and saturated sodium chloride solution (200 mL), collected, dried over anhydrous sodium sulfate for 1 h, filtered, and the filtrate was concentrated under reduced pressure. The residue was dispersed in acetonitrile (300 mL), extracted with n-heptane (50 mL * 5), the acetonitrile phase was collected and concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 500:1 ~ 200:1) to obtain compound 145b.

Step 3:

Compound 145b (2.9 g), 2,4-dichloropyrido[3,2-d]pyrimidine (2.0 mg), and N,N-diisopropylethylamine (3.87 g) were dispersed in tetrahydrofuran (200 mL) and stirred at room temperature for 17 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = pure dichloromethane ~100:1) to obtain compound 145c.

Step 4:

Compound 145c (2.28 g) and 2,4-dimethoxybenzylamine (4.2 g) were dispersed in N-methylpyrrolidone (10 mL), and the mixture was heated to 180 °C and reacted for 4 h. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), the organic phase was collected, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 145d.

Step 5:

Compound 145d (101 mg) was dispersed in trifluoroacetic acid (10 mL) and reacted overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure, poured into a 10% sodium carbonate aqueous solution (200 mL), extracted with dichloromethane (200 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 50:1 to 10:1) to obtain compound 145e.

Step 6:

Compound 145e (436 mg), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (8 mg), ammonium chloride (204 mg), and potassium tert-butoxide (672 mg) were dispersed in anhydrous 1,4-dioxane (20 mL). The mixture was stirred at 75 °C for 4 h under nitrogen protection. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 10:1 to 3:1) to obtain compound 145e. LC-MS: m/z = 372.03 (M+H) ⁺ .

Step 7:

Compound 145 was subjected to preparative liquid chromatography (Daicel ID 10μm 20*250 column; 0.1% diethylamine ethanol-n-hexane (20%-80%/0-40min gradient elution)) to obtain compound 145-A (Rt 15.0min) and compound 145-B (Rt 22.5min).

Compound 145-A: LC-MS: m/z = 372.06 (M+H) ⁺ ; ^¹H NMR (500MHz, DMSO-d ₆ ) δ: 8.46-8.45 (m, 2H), 7.85-7.74 (m, 1H), 7.37-7.32 (m, 1H), 6.85-6.82 (m, 1H), 5.90-5.76 (m, 2H), 5.01-4.98 (m, 1H), 4.22-4.05 (m, 3H), 3.98-3.89 (m, 2H), 3.87-3.72 (m, 1H), 2.12-1.90 (m, 2H), 1.29-1.24 (m, 1H), 0.87-0.85 (m, 1H).

Compound 145-A has a shorter retention time in chiral columns than 145-B, while compound 145-B has a longer retention time in chiral columns than 145-A.

Example 146

Compound 145e (436 mg), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (8 mg), (R)-1-methylpyrrolidine-3-amine (400 mg), and potassium tert-butoxide (224 mg) were dispersed in anhydrous 1,4-dioxane (20 mL). The mixture was stirred at 75 °C for 4 h under nitrogen protection. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 10:1 to 3:1) to obtain compound 146. LC-MS: m/z = 455.10 (M+H) ⁺ .

Example 147

Referring to the preparation process of compound 1b in Example 1, in step 1, 2-chloro-4-methanesulfonylbenzaldehyde was replaced with tert-butyl 5-chloro-2-fluoro-4-carboxyphenylcarbamate to prepare compound 147a. LC-MS: m/z = 345.13 (M+H) ⁺ .

Step 1:

Compound 147a (200 mg), 2,4-dichloropyrido[3,2-d]pyrimidine (174.5 mg), and N,N-diisopropylethylamine (375 mg) were dispersed in tetrahydrofuran (15 mL) and reacted with the mixture at room temperature for 17 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 100:1 to 60:1) to obtain compound 147b. LC-MS: m/z = 508.12 (M+H) ⁺ .

Step 2:

Compound 147b (240 mg) and 2,4-dimethoxybenzylamine (315 mg) were dispersed in N-methylpyrrolidone (10 mL), and the mixture was heated to 180 °C and reacted for 4 h. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 147c. LC-MS: m/z = 639.13 (M+H) ⁺ .

Step 3:

Compound 147c (240 mg) was dispersed in trifluoroacetic acid (2 mL) and dichloromethane (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (TAC18 250*50 mm, 10 μm column; acetonitrile-0.1% ammonia solution (15-45%/0-60 min gradient elution)) to obtain compound 147. LC-MS: m/z = 389.09 (M+H) ⁺ .

Example 148

Compound 57c (180 mg), compound 148a (123 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (47 mg), potassium phosphate (260 mg), and water (1.2 mL) were dispersed in 1,4-dioxane (6 mL). The mixture was heated to 85 °C and stirred for 3 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (30%-100%/0-45 min gradient elution) to obtain compound 148. LC-MS: m/z = 483.98 (M+H) ⁺ .

Example 149

Following the preparation method of compound 148, compound 149 was prepared by replacing compound 148a with 1-acetyl-5,6-dihydro-2H-pyridine-4-boronic acid pinacol ester. LC-MS: m/z = 484.02 (M+H) ⁺ .

Example 150

Compound 57c (480 mg), N,O-dimethylhydroxylamine hydrochloride (300 mg), 4-dimethylaminopyridine (232 mg), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (82.4 mg), palladium acetate (16 mg), potassium phosphate (1.21 g), and hexacarbonyltungsten (100 mg) were dispersed in 1,4-dioxane (10 mL), and the mixture was microwaved to 120 °C for 90 min. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The solution was then subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (30%-100%/0-45 min gradient elution) to obtain compound 150. LC-MS: m/z = 418.06 (M+H) ⁺ .

Example 151

Compound 59a (430 mg), N,O-dimethylhydroxylamine hydrochloride (300 mg), 4-dimethylaminopyridine (232 mg), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (82.4 mg), palladium acetate (16 mg), potassium phosphate (1.21 g), and hexacarbonyltungsten (100 mg) were dispersed in 1,4-dioxane (10 mL), and the mixture was microwaved to 120 °C for 90 min. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Compound 151 was obtained by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (30%-100%/0-45 min gradient elution). LC-MS: m/z = 413.24 (M+H) ⁺ .

Example 152

Compound 112 (100 mg), 30% _H₂O₂ (5 mL), and potassium carbonate (109 mg) were dispersed in dimethyl sulfoxide (5 mL) and reacted at room temperature for 12 _h . After the reaction was completed, the reaction solution was subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (30%-100%/0-45 min gradient elution) to obtain compound 152. LC-MS: m/z = 399.25 (M+H) ^⁺ .

Example 153

Following the preparation procedure of compound 148, compound 153 was prepared by replacing compound 148a with 1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester. LC-MS: m/z = 442.21 (M+H) ⁺ .

Step 1:

Compound 153 was subjected to preparative liquid chromatography (YMC-Amylose-SA, 10 μm, 30*250 column; 0.2% diethylamine ethanol-n-hexane (20%-80%/0-60 min gradient elution)) to obtain compound 153-A (Rt 22 min) and compound 153-B (Rt 25 min).

Compound 153-A: LC-MS: m/z = 442.21 (M+H) ⁺ ; ^1H NMR (500MHz, DMSO-d ₆ ) δ: 7.90 (d, J = 5.5Hz, 1H), 7.46 (s, 1H), 7.34-7.29 (m, 2H), 6.96 (d, J = 5.5Hz, 1H), 6.25 (s, 1H), 5.90-5.74 (m, 3H), 4.82-4.81 (m, 1H), 4.34 (s, 1H), 3.95-3.87 (m, 2H), 3.79-3.55 (m, 3H), 2.90-2.87 (m, 2H), 2.29 (s, 2H), 2.01-1.85 (m, 2H), 1.35-1.22 (m, 2H).

Compound 153-B: LC-MS: m/z = 442.21 (M+H) ⁺ ; ^¹H NMR (500MHz, DMSO-d6 ₎ δ: 7.90 (d, J = 5.5 Hz, 1H), 7.46 (s, 1H), 7.34-7.29 (m, 2H), 6.96 (d, J = 5.5 Hz, 1H), 6.25 (s, 1H), 5.90-5.74 (m, 3H), 4.82-4.81 (m, 1H), 4.34 (s, 1H), 3.95-3.87 (m, 2H), 3.79-3.55 (m, 3H), 2.90-2.87 (m, 2H), 2.29 (s, 2H), 2.01-1.85 (m, 2H), 1.34-1.22 (m, 2H). Compound 153-A has a shorter retention time than 153-B in chiral columns, while compound 153-B has a longer retention time than 153-A in chiral columns.

Example 154

Compound 57c (775 mg), hexahydro-1H-furano[3,4-C]pyrrole (100 mg), methanesulfonic acid (2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (140 mg), and cesium carbonate (860 mg) were dispersed in N,N-dimethylformamide (10 mL). The mixture was heated to 85 °C and stirred for 5 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (30%-100%/0-45 min gradient elution) to obtain compound 154. LC-MS: m/z = 472.20 (M+H) ⁺ .

Example 155

Compound 59a (700 mg), hexahydro-1H-furano[3,4-C]pyrrole (100 mg), methanesulfonic acid (2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (140 mg), and cesium carbonate (860 mg) were dispersed in N,N-dimethylformamide (10 mL). The mixture was heated to 85 °C and stirred for 5 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% ammonia solution (30%-100%/0-45 min gradient elution) to obtain compound 155. LC-MS: m/z = 467.27 (M+H) ⁺ .

Example 156

Following the preparation process of compound 1b in Example 1, in step 1, 2-chloro-4-methanesulfonylbenzaldehyde was replaced with 2,5-dimethoxybenzaldehyde to prepare compound 156a. LC-MS: m/z = 238.14 (M+H) ⁺ .

Step 1:

Compound 156a (150 mg) and 2,4-dichlorothiophene[3,2-d]pyrimidine (157 mg) were dispersed in N-methylpyrrolidone (3 mL). The mixture was heated to 180 °C and reacted for 3 h. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 156b. LC-MS: m/z = 406.09 (M+H) ⁺ .

Step 2:

Compound 156b (255 mg) and 2,4-dimethoxybenzylamine (316 mg) were dispersed in N-methylpyrrolidone (3 mL), and the mixture was heated to 180 °C and reacted for 6 h. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 156c. LC-MS: m/z = 537.21 (M+H) ⁺ .

Step 3:

Compound 156c (100 mg) was dispersed in trifluoroacetic acid (2 mL) and dichloromethane (5 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (TAC18 250*50 mm, 10 μm column; acetonitrile-0.1% ammonia solution (15-45%/0-60 min gradient elution)) to obtain compound 156. LC-MS: m/z = 387.26 (M+H) ⁺ .

Example 157

Step 1:

Compound 156a (90 mg), 2,4-dichloropyrido[3,2-d]pyrimidine (90 mg), and N,N-diisopropylethylamine (147 mg) were dispersed in tetrahydrofuran (3 mL) and stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 100:1 to 60:1) to obtain compound 157a. LC-MS: m/z = 401.13 (M+H) ⁺ .

Step 2:

Compound 157a (380 mg) and 2,4-dimethoxybenzylamine (475 mg) were dispersed in N-methylpyrrolidone (5 mL), and the mixture was heated to 180 °C and reacted for 3 h. After the reaction was completed, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 157b. LC-MS: m/z = 532.25 (M+H) ⁺ .

Step 3:

Compound 157b (100 mg) was dispersed in trifluoroacetic acid (2 mL) and dichloromethane (10 mL) and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and subjected to preparative liquid chromatography (TAC18 250*50 mm, 10 μm column; acetonitrile-0.1% ammonia solution (15-45%/0-60 min gradient elution)) to obtain compound 157. LC-MS: m/z = 382.30 (M+H) ⁺ .

Experimental Example 1: In vitro cell proliferation inhibitory activity

1.1 Assay of NCI-H929 cell proliferation inhibition activity

Collect healthy NCI-H929 cells into centrifuge tubes, adjust the cell density to 5 × ^10⁴ cells/mL, and seed them into 96-well plates (100 μL/well). Incubate overnight in a cell culture incubator. Add compounds using a nanoparticle pipette to a final concentration of 10 μM-4.6 nM, with two replicates. Include a control. After culturing for another 96 hours, add the assay reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL/well). Incubate for 2 hours, and then measure the absorbance at 450 nm using an Envision microplate reader. Perform four-parameter analysis, fit a dose-response curve, and calculate the _IC50 .

The determination results of some compounds are shown in Table 1.

Table 1



Note: A indicates IC ₅₀ ≤ 500nM.

1.2: In vitro liver microsomal stability

Liver microsomal incubation samples (species: human and mouse) were prepared as follows: mixed PBS buffer (pH 7.4), liver microsomal solution (0.5 mg/mL), test compound, and NADPH + _MgCl2 solution were incubated at 37°C and 300 rpm for 1 hour. Samples at 0 hours were prepared as follows: mixed PBS buffer (pH 7.4), liver microsomal solution (0.5 mg/mL), and test compound. After adding acetonitrile solution containing internal standard, protein precipitation was performed to prepare the supernatant, which was then diluted for LC/MS/MS analysis. The results are shown in Table 2.

Table 2

1.3 Huh7 Cell Level Protein Content Measurement (JESS)

Huh7 cells in good growth condition were collected into centrifuge tubes, and the cell density was adjusted to 2.5 × ^10⁵ cells/mL. The cells were then seeded into 6-well plates (2 mL/well) and cultured overnight in a cell culture incubator. The compound was manually diluted and added to a final concentration of 1 μM. A control was also set up. After further culturing for 2 h, 6 h, and 24 h, cells were collected, lysed, and proteins were extracted and quantified. Subsequent protein sample preparation and primary antibody preparation (XBP1s (manufacturer: Abcam); GAPDH (manufacturer: CST)) were performed according to the Protein Simple experimental instructions. The secondary antibody was directly used from the kit. The sample plate was taken from the rabbit secondary antibody detection kit (manufacturer: Protein Simple) of the protein quantification analyzer, and the prepared sample and reagents were added sequentially to the plate. The protein quantification analyzer was run according to the instrument's operating procedures, and the protein content was analyzed based on the grayscale scanning of the bands.

Claims (15)

Compound of formula (I) or a pharmaceutically acceptable salt thereof,
in, It can be independently selected from either a single bond or a double bond; X1 , X2 , X5 , and X6 are each independently selected from N or CR1 ; X3 and X4 are each independently selected from N, C or CR1 ; Each R1 is independently selected from hydrogen, deuterium, oxo, halogen, -OH, -NH2 , -CN, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, haloC1-6 alkyl, haloC1-6 alkoxy, haloC1-6 alkylthio, haloC1-6 alkylamino, or halodiC1-6 alkylamino; Ring A is selected from the following groups optionally substituted with one or more RA groups: 3-12-membered heterocyclic groups, 6-10-membered aryl groups, or 5-10-membered heteroaryl groups; Each RA is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -C(O)NR a1Ra2 , -NR a1C(O)Ra2, -OC(O)Ra2, -C(O)OR a2 , -S ( O ) Ra2 , -S(O ) 2Ra2 , -NR a1S (O) 2Ra2 , -S(O) 2NR a1Ra2 , or optionally substituted with one or more Ra3 groups , including C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered cycloalkylC1-6 alkylene, or 3-12 membered heterocycloalkylC1-6 alkylene; Ra1 is independently selected from hydrogen, deuterium, or C1-6 alkyl groups optionally substituted with one or more Ra3 ; Ra2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more Ra3 groups of the following: C1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered cycloalkyl C1-6 alkylene, or 3-12 membered heterocycloalkyl C1-6 alkylene; Each Ra3 is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino, haloC1-4 alkyl, haloC1-4 alkoxy, haloC1-4 alkylthio, haloC1-4 alkylamino, or halodiC1-4 alkylamino; The ring B is selected from the following groups that are optionally substituted with one or more R B : 3-12-membered cycloalkyl, 3-12-membered heterocyclic, 6-10-membered aryl, or 5-10-membered heteroaryl; Each Rb is independently selected from oxo, deuterium, halogen, -CN, -ORb2 , -SRb2 , -NRb1Rb2 , -C(O) NRb1Rb2 , -C( O )NRb1ORb2, -NRb1C ( O)Rb2 , -NRb1C (O )NRb1Rb2 , -OC(O) Rb2 , -C( O ) ORb2 , -C(O) Rb2 , -S( O ) Rb2 , -S(O) 2Rb2 , -C( Rb1 ) 2S (O) 2Rb2 , -NRb1S (O) 2Rb2 , -S (O) 2NRb1Rb2 , or optionally substituted with one or more Rb3 groups , including the following groups : C 1-6 alkyl, 3-12 cycloalkyl, 3-12 heterocycloalkyl, 3-12 heterocycloalkenyl, 5-10 heteroaryl, 3-12 cycloalkyl C 1-6 alkylene, or 3-12 heterocycloalkyl C 1-6 alkylene; Rb1 is independently selected from hydrogen, deuterium, or C1-6 alkyl groups optionally substituted with one or more Rb3 ; Rb2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more of the following groups: C1-6 alkyl, 3-12 cycloalkyl, 3-12 heterocycloalkyl, 3-12 heterocycloalkenyl, 5-10 heteroaryl, 3-12 cycloalkyl C1-6 alkylene, or 3-12 heterocycloalkyl C1-6 alkylene ; Each Rb3 is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino, C1-4 alkylcarbonyl, haloC1-4 alkyl, haloC1-4 alkoxy, haloC1-4 alkylthio, haloC1-4 alkylamino, or halodiC1-4 alkylamino; Each R2 is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, haloC1-6 alkyl, haloC1-6 alkoxy, haloC1-6 alkylthio, haloC1-6 alkylamino, or halodiC1-6 alkylamino; Alternatively, two R2 atoms located on the same ring atom together with the ring atom form a group optionally substituted by one or more R2a , namely a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl. Each R 2a is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, diC 1-4 alkylamino, haloC 1-4 alkyl, haloC 1-4 alkoxy , haloC 1-4 alkylthio , haloC 1-4 alkylamino, or halodiC 1-4 alkylamino; m is selected from 0, 1, 2, 3, 4, 5, or 6. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, is characterized in that X1 and X5 are selected from CR1 . The compound of formula (I) as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that X2 is N and X6 is N; Alternatively, X2 is N, and X6 is CR1 ; Alternatively, X2 is CR1 , and X6 is CR1 ; Alternatively, X2 can be CR1 , and X6 can be N. The compound of formula (I) as described in any one of claims 1-3, or a pharmaceutically acceptable salt thereof, is characterized in that X3 and X4 are selected from C; Alternatively, X3 is N, and X4 is C or CR1 ; Alternatively, X3 and X4 can be N; Alternatively, X3 can be C or CR1 , and X4 can be N; Alternatively, X3 can be C or CR1 , and X4 can be C or CR1 . The compound of formula (I) as claimed in any one of claims 1-4, or a pharmaceutically acceptable salt thereof, is characterized in that each R1 is independently selected from hydrogen, deuterium, oxo, halogen, -OH, -NH2 , -CN, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio , C1-4 alkylamino, diC1-4 alkylamino, haloC1-4 alkyl, haloC1-4 alkoxy, haloC1-4 alkylthio, haloC1-4 alkylamino, or halodiC1-4 alkylamino; Alternatively, each R1 may be independently selected from hydrogen, deuterium, oxo, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, halomethyl, or halomethoxy. Alternatively, each R1 may be independently selected from hydrogen, deuterium, oxo, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, ethyl, methoxy, methylamino, dimethylamino, -CF3 , or -OCF3 . The compound of formula (I) as claimed in any one of claims 1-5, or a pharmaceutically acceptable salt thereof, is characterized in that ring A is selected from the following groups optionally substituted with one or more RA groups: 3-10-membered heterocyclic group, 6-10-membered aryl group, or 5-10-membered heteroaryl group; Alternatively, ring A is selected from the following groups optionally substituted with one or more RA groups: 5-6 membered heterocyclic group, phenyl group, or 5-6 membered heteroaryl group; Alternatively, ring A is selected from the following groups optionally substituted with one or more RA groups: phenyl, pyrrolyl, dihydropyrrolyl, pyrrolyl, pyrazolyl, dihydropyrazolyl, pyrazolyl, tetrahydrofuranyl, dihydrofuranyl, furanyl, imidazoalkyl, dihydroimidazoyl, imidazoyl, thienyl, dihydrothienyl, thienyl, tetrahydropyranyl, dihydropyranyl, pyranyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, pyridinyl, tetrahydropyrimidinyl, dihydropyrimidinyl alkyl, pyrimidinyl, piperazinyl, tetrahydropyrazinyl, dihydropyrazinyl, pyrazinyl, tetrahydropyridazinyl, dihydropyridazinyl, pyridazinyl, thiazolyl, dihydrothiazolyl, thiazolyl, isothiazolyl, dihydroisothiazolyl, isothiazolyl, oxazolyl, dihydrooxazolyl, oxazolyl, isoxazolyl, dihydroisooxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, or tetrazolyl; Alternatively, ring A is selected from the following groups optionally substituted with one or more RA groups: phenyl, dihydropyrrolyl, pyrrolyl, pyrazolyl, dihydrofuranyl, furanyl, imidazolyl, dihydrothiophenyl, thiophenyl, tetrahydropyridyl, pyridyl, thiazolyl, 1,2,3-triazolyl, or 1,2,4-triazolyl. Alternatively, ring A may be selected from the following groups optionally substituted with one or more RNA groups: Among them, atoms marked with "*" represent X3 , and atoms marked with "#" represent X4 ; Alternatively, ring A is selected from In this context, atoms marked with "*" represent X 3 , and atoms marked with "#" represent X 4 . The compound of formula (I) as claimed in any one of claims 1-6, or a pharmaceutically acceptable salt thereof, is characterized in that each Ra is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -C(O)NR a1 Ra2 , -NR a1 C(O) Ra2 , -OC(O) Ra2 , -C(O)OR a2 , -S(O) Ra2 , -S(O)2Ra2 , -NR a1 S(O) 2Ra2 , -S(O) 2NR a1 Ra2 , or optionally substituted with one or more Ra3 groups, including: C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino , 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, 3-10 membered cycloalkyl C1-4 alkylene, or 4-10 membered heterocycloalkyl C 1-4 alkylene groups; Alternatively, each RA may be independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, -C(O)NR a1 Ra2 , -C(O)OR a2 , -S(O) Ra2 , -S(O) 2 Ra2 , or optionally substituted with one or more Ra3 groups, namely: C1-3 alkyl, C1-3 alkoxy, C1-3 alkylamino, diC1-3 alkylamino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkyl C1-3 alkylene, or 4-6 membered heterocycloalkyl C1-3 alkylene; Alternatively, each Ra is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH₂ , -CN, -C(O)NR a1 Ra₂ , -C(O)OR a₂ , -S(O) Ra₂ , -S(O) ₂Ra₂ , or optionally substituted with one or more Ra₃ groups , including: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, methylethylamino, cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, tetrahydrofuranyl, pyrrolyl, thiazolyl, piperidinyl, piperazine, morpholinyl, cyclopropane C1-3 alkylene, cyclobutane C1-3 alkylene, cyclopentane C1-3 alkylene, cyclohexane C1-3 alkylene, aziridine C1-3 alkylene, tetrahydrofuranyl C1-3 alkylene, cyclopropane C1-3 alkylene, cyclobutane C1-3 alkylene, tetrahydrofuranyl C1-3 alkylene, cyclopropane C1-3 alkylene, cyclobutane C1-3 alkylene, cyclohex ... aziridine C1-3 alkylene, tetrahydrofuranyl C1-3 alkylene, cyclopropane C1-3 alkylene, cyclobutane C1-3 alkylene, cyclopropane C1-3 alkylene, cyclobutane C1-3 alkylene, tetrahydrofuranyl C1-3 alkylene, cyclopropane C1-3 alkylene, cyclobutane C1-3 alkylene, 1-3 alkylene, pyrrolidinyl C 1-3 alkylene, thiazolyl C 1-3 alkylene, piperidinyl C 1-3 alkylene, piperazinyl C 1-3 alkylene, morpholinyl C 1-3 alkylene; Alternatively, each RA can be independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH₂ , -CN, Methyl, methoxy, -CF3 . The compound of formula (I) as described in any one of claims 1-7, or a pharmaceutically acceptable salt thereof, is characterized by a structural fragment Selected from Wherein, the substitution position of R1 is on ring C; n is selected from 0, 1, 2, 3 or 4; Or, structural fragments Selected from Where n is selected from 0, 1, 2, 3, or 4; p is selected from 0, 1, 2, 3, or 4; Or, structural fragments Selected from The compound of formula (I) as claimed in any one of claims 1-8 or a pharmaceutically acceptable salt thereof is characterized in that ring B is selected from the following groups optionally substituted with one or more RBs : 3-10-membered cycloalkyl, 3-10-membered heterocyclic, 6-10-membered aryl, or 5-10-membered heteroaryl. Alternatively, ring B is selected from the following groups optionally substituted with one or more R B groups: cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, thiophenyl, thiazoyl, isothiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperazinyl, morpholinyl, dihydropyrrolyl, dihydropyrazolyl, dihydrofuranyl, dihydroimidazoyl, dihydrothiophenyl, dihydropyranyl, tetrahydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, dihydropyrazinyl Tetrahydropyrazinyl, dihydropyridazinyl, tetrahydropyridazinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, furanyl, imidazolyl, thiophenyl, pyranyl, pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrroloimidazolyl, pyrrolopyrazolyl, imidazopyrazolyl, pyrazololopyrazolyl, benzopyrryl, benzimidazolyl, pyridinolopyrryl, pyridinoloimidazolyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, or pyrrolopyridazinyl; Alternatively, ring B is selected from phenyl, naphthyl, pyridyl, or pyridinium imidazolyl groups optionally substituted with one or more RB groups . The compound of formula (I) as claimed in any one of claims 1-9, or a pharmaceutically acceptable salt thereof, is characterized in that each Rb is independently selected from oxo, deuterium, halogen, -CN, -ORb2 , -SRb2 , -NRb1Rb2 , -C ( O)NRb1Rb2, -C(O)NRb1ORb2 , -NRb1C ( O ) Rb2 , -NRb1C (O) NRb1Rb2, -OC(O)Rb2 , -C(O) ORb2 , -C(O) Rb2 , -S(O) Rb2 , -S(O)2Rb2, -C(Rb1)2S(O)2Rb2, -NRb1S(O)2Rb2 , -S ( O ) 2NRb1Rb2 , or optionally substituted with one or more Rb3 groups: C 1-4 alkyl, 3-10 cycloalkyl, 4-10 heterocycloalkyl, 4-10 heterocycloalkenyl, 5-10 heteroaryl, 3-10 cycloalkyl C 1-4 alkylene, or 4-10 heterocycloalkyl C 1-4 alkylene; Alternatively, each RB is independently selected from oxo, deuterium, -F, -Cl, -Br, -CN, -OR b2 , -NRb1Rb2 , -C(O)NR b1  Rb2 , -C(O)NR b1 OR b2 , -NR b1 C(O)R b2 , -NR b1 C(O)NR b1 Rb2 , -C(O)Rb2 , -S(O)Rb2 , -S(O) 2  Rb2, -C(R b1 ) 2 S(O)2R b2 , -NR b1 S(O) 2  R b2 , or optionally by one or more R b2  The following groups are substituted with b3 : methyl, ethyl, n-propyl, isopropyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, tetrahydrofuranyl, pyrrolyl, pyrazolyl, imidazolyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperazinyl, morpholinyl. Dihydropyrrolyl, dihydropyrazolyl, dihydrofuranyl, dihydroimidazolyl, dihydrothiophenyl, dihydropyranyl, tetrahydropyranyl, dihydropyridyl, tetrahydropyridyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, dihydropyrazinyl, tetrahydropyrazinyl, dihydropyridazinyl, tetrahydropyridazinyl, pyrrolyl, pyrazolyl, furanyl, imidazolyl, thiophenyl, pyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, isothiazolyl , oxazolyl , isoxazolyl, triazolyl, tetrazolyl, cyclopropane C1-3 alkylene, cyclobutane C1-3 alkylene, cyclopentane C1-3 alkylene, cyclohexane C1-3 alkylene, azacyclobutane C1-3 alkylene, tetrahydrofuranyl C1-3 alkylene, pyrrolyl C1-3 alkylene, thiazolyl C1-3 alkylene 1-3 alkylene, piperidinyl C1-3 alkylene, piperazinyl C1-3 alkylene, or morpholinyl C1-3 alkylene; Alternatively, each R B is independently selected from deuterium, halogen, -CN, -OR b2 , -NR b1 R b2 , -C(O)NR b1 R b2 , -C(O)NR b1 OR b2 , -NR b1 C(O)R b2 , -NR b1 C(O)NR b1 R b2 , -C(O)R b2 , -S(O)R b2 , -S(O) 2 R b2 , -C(R b1 ) 2 S(O) 2 R b2 , -NR b1 S(O) 2 R b2 , -S(O) 2 NR b1 R b2 , or optionally substituted with one or more R b3 groups, including 4-9-membered heterocyclic alkyl, 4-9-membered heterocyclic alkenyl, or 5-6-membered heteroaryl groups; Alternatively, each Rb may be independently selected from deuterium, -F, -Cl , -Br, -CN , -ORb2 , -NRb1Rb2 , -C(O) NRb1Rb2 , -C ( O)NRb1ORb2, -NRb1C (O) Rb2 , -NRb1C (O) NRb1Rb2 , -C( O)Rb2, -S(O)Rb2, -S(O)2Rb2, -C(Rb1)2S(O)2Rb2 , -NRb1S ( O ) 2Rb2 , or optionally substituted with one or more Rb3 groups, including pyrrolidinyl, isothiazolyl, piperidinyl, piperazinyl , morpholinyl , etc. Dihydropyrrole, tetrahydropyridyl, or pyrazolyl; Alternatively, Rb1 is independently selected from hydrogen, deuterium, or optionally substituted by one or more Rb3 groups, namely: methyl, ethyl, n-propyl, isopropyl; Alternatively, Rb2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more of the following groups: methyl, ethyl, n-propyl, isopropyl, cyclopropane, cyclobutane, aziridine, oxaziridine, pyrrolyl, imidazoalkyl, tetrahydrofuranyl, thiophenyl, thiazoalkyl, isothiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperazine, morpholinyl, dihydropyrrolyl, dihydropyrazolyl, dihydrofuranyl, dihydroimidazoyl, dihydrothiophenyl. Dihydropyranyl, tetrahydropyranyl, dihydropyridyl, tetrahydropyridyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, dihydropyridazinyl, tetrahydropyridazinyl, pyrroleyl, pyrazolyl, furanyl, imidazolyl, thiophenyl, pyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, isothiazolyl , oxazolyl, isoxazolyl, triazolyl, tetrazolyl, cyclopropane C1-3 alkylene, cyclobutane C1-3 alkylene, azacyclobutane C1-3 alkylene, oxacyclobutane C1-3 alkylene, pyrroleyl C1-3 alkylene, tetrahydrofuranyl C1-3 alkylene, piperidinyl C1-3 alkylene, piperazinyl C1-3 alkylene, morpholinyl C1-3 alkylene ; Alternatively, each Rb3 may be independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, methylcarbonyl, halomethyl, or halomethoxy. Alternatively, each RB can be independently selected from -F, -Cl, -NH₂ , -OH, -OCH₃ , -OCF₃ , -CN, The compound of formula (I) as claimed in any one of claims 1-10, or a pharmaceutically acceptable salt thereof , is characterized in that each R2 is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino, haloC1-4 alkyl, haloC1-4 alkoxy, haloC1-4 alkylthio, haloC1-4 alkylamino, or halodiC1-4 alkylamino; or, two R2s located on the same ring atom together with the ring atom form a group optionally substituted by one or more R2a , which is a 3-10 membered cycloalkyl or a 3-10 membered heterocycloalkyl. Alternatively, each R2 may be independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, halomethyl, or halomethoxy; or, two R2s located on the same ring atom together with the ring atom may form a group optionally substituted with one or more R2a, namely: cyclopropane, cyclobutane, aziridine, pyrrolidinyl, thiazolyl, isothiazolyl, piperidinyl, piperazine, or morpholinyl; Alternatively, each R2 may be independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, ethyl, methoxy, methylamino, dimethylamino, -CF3 , or -OCF3 ; or, two R2s located on the same ring atom together with the ring atom may form a cyclopropane that may be optionally substituted with one or more R2a . Alternatively, each R2 may be independently selected from -F; or, two R2s located on the same ring atom may form a cyclopropane group together with the ring atom. The compound of formula (I) as claimed in any one of claims 1-11, or a pharmaceutically acceptable salt thereof, is characterized in that it is selected from compounds of formula (I-1), formula (II), formula (III), formula (II-1), formula (II-1-a'), formula (II-1-a”), formula (II-2), formula (II-2-a'), formula (II-2-a”), their stereoisomers, or pharmaceutically acceptable salts thereof.

in, The definitions of ^X1 , ^X2 , ^X3 , X4, ^X5 , ^X6 , ^R1 , ^R2 , ^RA , m, p, ring A, and ring B are as described in any one of claims ^1-11 . The compound of formula (I) as described in any one of claims 1-12, or a pharmaceutically acceptable salt thereof, is selected from the following compounds or pharmaceutically acceptable salts thereof:





Alternatively, selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:










A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1-13 or a pharmaceutically acceptable salt thereof; further comprising a pharmaceutically acceptable excipient. The use of the compound of formula (I) according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition according to claim 14 in the preparation of a medicament for treating a disease; optionally, the disease is selected from WFS1-related diseases; or the disease is selected from cancer; or the disease is selected from solid tumors; or the disease is selected from multiple myeloma and lung cancer; or the disease is selected from non-small cell lung cancer.