CN114616232A - Azepadinopyrimidine derivatives and medical application thereof - Google Patents

Abstract

Relates to an azacycloheptane pyrimidine derivative and medical application thereof, and the specific structure is shown as formula (I). Also relates to a preparation method of the compound, a pharmaceutical composition and application of the compound as a KRas G12C inhibitor in treating cancer.

Description

Azepadinopyrimidine derivatives and medical application thereof

Cross reference to related citations

The present application claims priority from chinese patent application No. 201910843832.2 entitled "azepan-pyrimidine derivatives and pharmaceutical uses thereof", filed 2019, 9, 6/9, the entire contents of which are incorporated herein by reference.

Technical Field

The present application relates to azacycloheptopyrimidine derivatives, processes for their preparation, pharmaceutical compositions containing them, and their use as KRas G12C inhibitors in the treatment of cancer.

Background

The Ras gene is an important protooncogene, named after being found in rat sarcoma virus, and its encoded Ras protein is located inside the cell membrane, can bind to GTP/GDP and can hydrolyze GTP with the aid of Gtpase Activator Protein (GAP). Ras proteins control "on" and "off" in the signaling process of growth factors and cytokines through interconversion between active (GTP-bound) and inactive (GDP-bound) conformations, playing an important role in the life processes of Cell proliferation, differentiation, senescence and apoptosis (Bos J L et al, Cell,2007,129(5): 865-. There are three members of the human Ras gene family: harva rat sarcoma virus oncogene homolog (HRas), neuroblastoma rat sarcoma virus oncogene homolog (NRas), and Krestin rat sarcoma virus oncogene homolog (KRas), wherein KRas is expressed predominantly in intestine, lung, and thymus (Rajalingam K et al, Biochim Biophys Acta,2007,1773(8): 1177-.

Studies have shown that Ras gene mutations occur in more than 30% of human tumors, with KRas mutations accounting for approximately 86% (Riely G J et al, Proc Am Thorac Soc,2009,6(2): 201-. For the KRas mutation, the mutation at glycine position 12 (G12) accounted for approximately 80%, while the G12C mutation (glycine at position 12 mutated to cysteine) accounted for approximately 14% of all the mutations at G12 (Prior I A et al, Cancer Res,2012,72(10): 2457-. The G12 mutation can reduce the catalytic activity of GAP, and finally promote the continuous activation of Ras, so that Ras cannot effectively regulate and control cell signal transduction, thereby promoting the occurrence and development of tumors.

In recent years, some progress has been made in drug development using the allosteric site of the KRas G12C mutant. At present, KRas G12C inhibitors are being developed including ARS-1620, MRTX-1257, AMG-510 and MRTX-849, wherein AMG-510 and MRTX-849 have already entered clinical trial.

Detailed Description

The present application relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

when q is 0, p is 2,

selected from single bonds;

or, when q is 1, p is 1,

selected from single bonds or double bonds;

alternatively, when q is 2, p is 0,

selected from single bonds;

when in use

Selected from the double bonds, R⁴And/or R⁶Is absent;

a moiety selected from

Or

Wherein R is selected from H or C_1-6An alkyl group;

or, A-R²Part is selected from

Is a 4-10 membered heterocycloalkyl group containing at least two N atoms;

is a 4-7 membered heterocycloalkyl group containing at least one N atom;

each R¹Substituted on the ring, independently selected from halogen, oxo, -OH, -NH₂-CN, or optionally substituted by 1,2 or 3R⁰Substituted with the following groups: c_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino, or di-C_1-6An alkylamino group;

each R⁰Independently selected from halogen, -OH, -NH₂、-CN、C _1-4Alkoxy radical, C_1-4Alkylamino, or di-C_1-4An alkylamino group;

m is 0, 1,2,3,4, 5 or 6;

each R²Independently selected from C_1-6Alkylcarbonyl, halo C_1-6Alkylcarbonyl group, C_1-6Alkoxycarbonyl group, C_1-6Alkylsulfonyl, -C (O) C ≡ CR^b、-SO ₂C≡CR ^b、-C(O)C(R ^a)＝C(R ^b) ₂or-SO₂C(R ^a)＝C(R ^b) ₂；

Each R^aIndependently selected from H, halogen, or C_1-4An alkyl group;

each R^bIndependently selected from H or optionally substituted with 1,2 or 3R^cSubstituted with the following groups: c_1-6Alkyl radical, C_1-4Alkoxy radical C_1-3Alkyl radical, C_1-4Alkylamino radical C_1-3Alkyl, di-C_1-4Alkylamino radical C_1-3Alkyl, 3-7 membered cycloalkyl C_1-3Alkyl, or 4-7 membered heterocycloalkyl C_1-3An alkyl group;

each R^cIndependently selected from halogen, -OH, -NH₂、-CN、C _1-6Alkyl radical, C_1-6Alkoxy, or halo C_1-6An alkyl group;

x is selected from a single bond, -S-, -O-, -NH-, or-N (C)_1-3Alkyl) -;

R ³selected from H or optionally substituted by 1,2,3 or 4R^dSubstituted with the following groups: c_1-6Alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, benzo 4-6 membered heterocyclyl, 4-7 membered heterocycloalkyl C_1-3Alkyl, or 5-6 membered heteroaryl C_1-3An alkyl group;

each R^dIndependently selected from halogen, -OH, oxo, -NH₂、-CN、C _1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, di-C_1-4Alkylamino, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 4-7 membered heterocycloalkyl C_1-3Alkyl, wherein, said C_1-4Alkylamino, di-C_1-4Alkylamino is optionally substituted with a substituent selected from 1 or 2 cyano or 5-6 membered heteroaryl;

y is selected from a single bond, -CH₂-, or a carbonyl group;

b is selected from optionally substituted by 1,2,3,4, 5 or 6R^eSubstituted phenyl, naphthyl, 5-6 membered heteroaryl, benzo 5-6 membered cycloalkenyl, benzo 5-6 membered heterocyclyl, or benzo 5-6 membered heteroaryl;

each R^eIndependently selected from halogen, -CN, -OH, -NH₂、C _1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino, di-C_1-6Alkylamino, halogeno C_1-6Alkyl, halo C_1-6Alkoxy, halo C_1-6Alkylthio, halo C_1-6Alkylamino, di (halo C)_1-6Alkyl) amino, or optionally substituted by 1,2 or 3R^e1Substituted with the following groups: 3-7 membered cycloalkyl, 3-7 membered cycloalkyl C_1-3Alkyl, 4-7 membered heterocycloalkyl, or 4-7 membered heterocycloalkyl C_1-3An alkyl group;

each R^e1Independently selected from halogen, -CN, -OH, -NH₂、C _1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino, or di-C_1-4An alkylamino group;

R ⁴、R ⁵independently selected from H, halogen, -OH, -NH₂、-CN、C _1-6Alkyl radical, C_1-6Alkoxy, or halo C_1-6Alkyl, or, R⁴And R⁵Together form a carbonyl group, a 3-6 membered cycloalkyl group or a 4-6 membered heterocycloalkyl group;

R ⁶、R ⁷independently selected from H, halogen, -OH, -NH₂、-CN、C _1-6Alkyl radical, C_1-6Alkoxy, or halo C_1-6Alkyl, or, R⁶And R⁷Together form a carbonyl group, a 3-6 membered cycloalkyl group or a 4-6 membered heterocycloalkyl group.

In some embodiments of the present invention, the substrate is,

is a 4-10 or 4-9 membered heterocycloalkyl containing two N's; in some embodiments of the present invention, the substrate is,

is a 4-7 membered or 4-6 heterocycloalkyl group containing one N; in some embodiments, the heterocycloalkyl is a monocyclic heterocycle or a spiroheterocycle.

In some embodiments, a moiety is selected from

Wherein R is selected from H or C_1-6An alkyl group.

In some embodiments, A-R²Part is selected from

In some embodiments, a moiety is selected from

Wherein R is selected from H or C_1-6An alkyl group. In some embodiments, a moiety is selected from

In some embodiments, A-R²Part is selected from

Wherein R is selected from H or C_1-6An alkyl group.

In some embodiments, R is selected from H. In some embodiments, R is selected from C_1-4An alkyl group. In some embodiments, R is selected from methyl or ethyl.

In some embodiments, R¹Independently selected from halogen, oxo, -OH, -NH₂-CN, or optionally substituted by 1,2 or 3R⁰Substituted as inThe following groups: c_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino, or di-C_1-4An alkylamino group. In some embodiments, R¹Independently selected from the group optionally substituted with 1,2 or 3R⁰Substituted C_1-4An alkyl group.

In some embodiments, R⁰Independently selected from halogen, -OH, -NH₂、-CN、C _1-3Alkoxy radical, C_1-3Alkylamino, or di-C_1-3An alkylamino group. In some embodiments, R⁰Independently selected from-CN, or C_1-3An alkoxy group.

In some embodiments, R¹Independently selected from C_1-4Alkyl, cyano C_1-3Alkyl, or C_1-3Alkoxy radical C_1-3An alkyl group. In some embodiments, R¹Independently selected from methyl, cyanomethyl, or methoxymethyl. In some embodiments, R¹Independently selected from cyanomethyl.

In some embodiments, m is 0, 1,2,3, or 4. In some embodiments, m is 0, 1, or 2.

In some embodiments, A-R²Part is selected from

In some embodiments, A-R²Part is selected from

In some embodiments, A-R²Part is selected from

In some embodiments, A-R²Part is selected from

In some embodiments, A-R²Part is selected from

In some embodiments, A-R²Part is selected from

In some embodiments, R²Independently selected from C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl, or C_1-4An alkylsulfonyl group.

In some embodiments, R²Independently selected from halogeno C_1-4An alkylcarbonyl group. In some embodiments, R²Independently selected from fluoro C_1-4Alkylcarbonyl or chloro C_1-4An alkylcarbonyl group.

In some embodiments, R²Independently selected from-C (O) C ≡ CR^b、-SO ₂C≡CR ^b、-C(O)C(R ^a)＝C(R ^b) ₂or-SO₂C(R ^a)＝C(R ^b) ₂. In some embodiments, R²Independently selected from-C (O) C ≡ CR^b、-C(O)C(R ^a)＝CH(R ^b) or-SO₂CH＝CH(R ^b). In some embodiments, R²Independently selected from-C (O) C (R)^a)＝CH(R ^b)。

In some embodiments, R^aIndependently selected from H, fluoro, chloro, methyl or ethyl. In some embodiments, R^aIndependently selected from H.

In some embodiments, R^bIndependently selected from H or optionally substituted with 1,2 or 3R^cSubstituted with the following groups: c_1-4Alkyl, di-C_1-3Alkylamino radical C_1-2Alkyl, or 4-6 membered heterocycloalkyl C_1-2An alkyl group. In some embodiments, R^bIndependently selected from H or optionally substituted with 1,2 or 3R^cSubstituted with the following groups: methyl, dimethylaminomethyl, morpholinylmethyl, piperidinylmethyl, tetrahydropyrrolylmethyl, or azetidinylmethyl. In some embodiments, R^bIndependently selected from H.

In some embodiments, R^cIndependently selected from fluorine, chlorine, -OH, -NH₂、-CN、C _1-3Alkyl radical, C_1-3Alkoxy, or fluoro C_1-3An alkyl group. In some embodiments, R^cIndependently selected from fluoro, chloro, methyl, ethyl or trifluoromethyl.

In some embodiments, the R is²Selected from the group consisting of:

in some embodiments, the R is²Selected from the group consisting of:

in some embodiments, the R is²Selected from the group consisting of:

in some embodiments, the R is²Selected from the group consisting of:

in some embodiments, X is selected from a single bond, -O-, or-NH-. In some embodiments, X is selected from-O-, or-NH-. In some embodiments, X is selected from-O-.

In some embodiments, R³Selected from H or optionally substituted by 1,2,3 or 4R^dSubstituted with the following groups: c_1-4Alkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, benzo 5-6 membered heterocyclyl, 4-7 membered heterocycloalkyl C_1-3Alkyl, or 5-6 membered heteroaryl C_1-3An alkyl group. In some embodiments, R³Selected from the group optionally substituted by 1,2,3 or 4R^dSubstituted groups as follows: 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl C_1-3Alkyl, or 5-6 membered heteroaryl C_1-3An alkyl group. In thatIn some embodiments, R³Selected from the group consisting of optionally substituted by 1,2,3 or 4R^dSubstituted groups as follows: 4-7 membered heterocycloalkyl C_1-3An alkyl group. In some embodiments, R³Selected from H or optionally substituted by 1,2,3 or 4R^dSubstituted with the following groups: methyl, ethyl, propyl, 1,2,3, 4-tetrahydroisoquinolinyl, azetidinyl, azetidinylethyl, azetidinylpropyl, tetrahydropyrrolylmethyl, tetrahydropyrrolethyl, tetrahydropyrrolylpropyl, morpholinyl, piperazinyl, piperidinyl, piperidinylethyl, piperidinylpropyl, morpholinylpropyl, pyrimidinyl, pyrimidinylmethyl, pyrimidineethyl, pyridinylethyl, and the like,

In some embodiments, R³Selected from H or optionally substituted by 1,2,3 or 4R^dSubstituted with the following groups: tetrahydropyrrolemethyl, tetrahydropyrrolethyl, tetrahydropyrrolpropyl, morpholinyl, piperazinyl, piperidinyl, piperidinylethyl, piperidinopropyl, morpholinopropyl, pyrimidinyl, pyrimidinylmethyl, pyrimidinylethyl,

In some embodiments, R³Selected from H or optionally substituted by 1,2,3 or 4R^dSubstituted with the following groups: tetrahydropyrrolemethyl, tetrahydropyrrolethyl, tetrahydropyrrolpropyl, morpholinylpropyl, tetrahydropyrrolethyl, tetrahydropyrrolylpropyl, tetrahydropyrrolyl, and tetrahydropyrrolyl,

In some embodiments, R³Selected from the group consisting of optionally substituted by 1,2,3 or 4R^dSubstituted tetrahydropyrrolemethyl.

In some embodiments, R^dIndependently selected from halogen, oxo, -OH, -NH₂、C _1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, diC _1-4Alkylamino, 4-7 membered heterocycloalkyl, or 4-7 membered heterocycloalkyl C_1-3Alkyl, wherein, said C_1-4Alkylamino, di-C_1-4Alkylamino is optionally substituted with 1 or 2 substituents selected from cyano or 5-6 membered heteroaryl. In some embodiments, R^dIndependently selected from fluoro, oxo, -OH, -NH₂Methyl, ethyl, isopropyl, tert-butyl, methoxy, dimethylamino, diethylamino, morpholinyl, tetrahydropyranyl, tetrahydropyrrolylmethyl, piperidinylmethyl, and the like,

In some embodiments, R^dIndependently selected from halogen, or C_1-4An alkyl group. In some embodiments, R^dIndependently selected from fluorine, or methyl.

In some embodiments, the R is³Selected from H,

In some embodiments, the R is³Is selected from

In some embodiments, the R is³Is selected from

In some embodiments, Y is selected from a single bond.

In some embodiments, B is selected from optionally substituted with 1,2,3,4, 5, or 6R^eSubstituted with the following groups: phenyl, indenyl, 2, 3-dihydroindenyl, naphthyl, 1,2,3, 4-tetrahydronaphthalene, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrahydroquinolyl, 1,2,3, 4-tetrahydroisoquinolyl, quinoxalyl, tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, benzimidazolyl, benzpyrazolyl, indolyl, isoindolyl, indolinyl, or benzo [ d ] d][1,3]Dioxoles. In some embodiments, B is selected from optionally substituted with 1,2,3,4, 5, or 6R^eSubstituted with the following groups: phenyl, 2, 3-dihydroindenyl, naphthyl, thienyl, thiazolyl, pyridyl, benzopyrazolyl, or benzo [ d][1,3]Dioxoles. In some embodiments, B is selected from optionally substituted with 1,2,3, or 4R^eSubstituted phenyl, naphthyl, benzopyrazolyl, or pyridyl. In some embodiments, B is selected from optionally substituted with 1,2,3, or 4R^eA substituted phenyl group. In some embodiments, B is selected from optionally substituted with 1,2,3, or 4R^eSubstituted naphthyl. In some embodiments, B is selected from optionally substituted with 1,2,3, or 4R^eA substituted pyridyl group.

In some embodiments, R^eIndependently selected from halogen, -CN, -OH, -NH₂、C _1-4Alkyl, halo C_1-4Alkyl, halo C_1-4Alkoxy, halo C_1-4Alkylthio radical, C_1-4Alkoxy radical, C_1-4Alkylamino, di-C_1-4Alkylamino, or optionally substituted by 1,2 or 3R^e1Substituted groups as follows: 3-6 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 4-7 membered heterocycloalkyl C_1-3An alkyl group. In some embodiments, R^eIndependently selected from fluorine, chlorine, bromine, iodine, -CN, -OH, -NH₂Methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl,

Difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, methoxy, ethoxy, methylamino, dimethylamino, or optionally substituted with 1,2 or 3R^e1Substituted with the following groups: cyclopropane, cyclobutane, cyclopentane, cyclohexane, tetrahydropyrrolidine, piperidine, piperazine, tetrahydropyranyl, morpholine, tetrahydropyrrolidine methyl, piperidine methyl, piperazine methyl, tetrahydropyranyl methyl, or morpholine methyl. In some embodiments, R^eIndependently selected from fluorine, chlorine, bromine, iodine, -CN, -OH, -NH₂Methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl,

Trifluoromethoxy, trifluoromethylthio, methoxy, methylamino, dimethylamino, or optionally substituted with 1,2 or 3R^e1Substituted with the following groups: cyclopropane, morpholinyl, piperazinemethyl, or morpholinomethyl.

In some embodiments, R^e1Independently selected from fluorine, chlorine, bromine, iodine, -CN, -OH, -NH₂Methyl, ethyl, trifluoromethyl, methoxy, methylamino, or dimethylamino. In some embodimentsIn, R^e1Independently selected from fluorine, -CN, -OH, -NH₂Methyl, or ethyl.

In some embodiments, B is selected from

In some embodiments, B is selected from

In some embodiments, B is selected from

In some embodiments, B is selected from

In some embodiments, B is selected from

In some embodiments, B is selected from

In some embodiments, B is selected from

In some embodiments, B is selected from

In some embodiments, B is selected from

In some embodiments, B is selected from

In some embodiments, when R³Not optionally substituted by 1,2,3 or 4R^dSubstituted tetrahydropyrrole C_1-3Alkyl, B is selected from

In some embodiments, when R³Not optionally substituted by 1,2,3 or 4R^dSubstituted tetrahydropyrrolemethyl radicals, B being selected from

In some embodiments, R⁴、R ⁵Independently selected from H, halogen, -OH, -NH₂、-CN、C _1-4Alkyl radical, C_1-4Alkoxy, or halo C_1-4An alkyl group. In some embodiments, R⁴、R ⁵Independently selected from H, halogen, -OH, -NH₂-CN, -methyl, ethyl, methoxy, difluoromethyl, or trifluoromethyl. In some embodiments, R⁴、R ⁵Independently selected from H, halogen, or methyl. In some embodiments, R⁴、R ⁵Are both methyl or R⁴、R ⁵Are both fluorine. In some embodiments, R⁴、R ⁵Are all H.

In some embodiments, R⁴And R⁵Together form a carbonyl group. In some embodiments, R⁴And R⁵Together form a 3-6 membered cycloalkyl group. In some embodiments, R⁴And R⁵Together form a cyclopropyl, cyclobutyl, or cyclopentyl group. In some embodiments, R⁴And R⁵Together forming a cyclopropyl group.

In some embodiments, R⁶、R ⁷Independently selected from H, halogen, -OH, -NH₂、-CN、C _1-4Alkyl radical, C_1-4Alkoxy, or halo C_1-4An alkyl group. In some embodiments, R⁶、R ⁷Independently selected from H, halogen, -OH, -NH₂-CN, methyl, ethyl, methoxy, difluoromethyl, or trifluoromethyl. In some embodiments, R⁶、R ⁷Independently selected from H, halogen, or methyl. In some embodiments, R⁶、R ⁷Are all H.

In some embodiments, R⁶And R⁷Together form a carbonyl group. In some embodiments, R⁶And R⁷Together form a 3-6 membered cycloalkyl group. In some embodiments, R⁶And R⁷Together form a cyclopropyl, cyclobutyl, or cyclopentyl group. In some embodiments, R⁶And R⁷Together forming a cyclopropyl group.

In some embodiments, said C_1-6Alkyl is selected from C_1-4An alkyl group. In some embodiments, said C_1-4The alkyl group being selected from C_1-3Alkyl or C_1-2An alkyl group.

In some embodiments, the heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O.

In some embodiments, the heterocycloalkyl group contains 1N atom.

In some embodiments, the heterocycloalkyl group contains 2N atoms.

In some embodiments, the heterocycloalkyl group contains 1O atom.

In some embodiments, the heterocycloalkyl group contains 1N atom and 1O atom.

In some embodiments, the heterocyclyl contains 1 or 2 heteroatoms selected from N or O.

In some embodiments, the heterocyclyl contains 1N atom.

In some embodiments, the heterocyclyl contains 2O atoms.

In some embodiments, the heteroaryl contains 1,2, or 3 heteroatoms selected from S, N or O.

In some embodiments, the heteroaryl contains 1 or 2 heteroatoms selected from S, N.

In some embodiments, the heteroaryl group contains 1 or 2N atoms.

In some embodiments, the heterocycloalkyl group comprises a monocyclic ring, a spiro ring, or a bridged ring. In some embodiments, the heterocycloalkyl group comprises a monocyclic ring or a spiro ring. In some embodiments, the heterocycloalkyl group comprises a single ring or a bridged ring.

In some embodiments, when q is 1, p is 1,

two of the compounds of formula (I) when selected from single or double bonds

Not simultaneously selected from double bonds.

The present application relates to compounds of formula (IIa) or formula (IIb) or formula (IIc) or pharmaceutically acceptable salts thereof,

wherein R is²、R ³、R ⁴、R ⁵、R ⁶、R ⁷X, Y, A, B, p, q and

portions are as defined above.

The present application relates to compounds of formula (Ia) or formula (Ib) or formula (Ic) or formula (Id) or formula (Ie) or formula (If) or a pharmaceutically acceptable salt thereof,

wherein R is¹、R ²、R ³、R ⁴、R ⁵、R ⁶、R ⁷X, m, A and B are as defined above.

The present application relates to compounds of the following formula (III) or formula (IIIa) or formula (IIIb) or formula (IIIc) or formula (IIId) or formula (IIIe) or pharmaceutically acceptable salts thereof:

wherein R is³、R ^a、R ^bX, B, p, q are as defined above.

The present application also relates to the following compounds, or pharmaceutically acceptable salts thereof:

the present application also relates to the following compounds or pharmaceutically acceptable salts thereof:

in another aspect, the present application relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the pharmaceutical compositions of the present application further comprise a pharmaceutically acceptable excipient.

In another aspect, the present application relates to a method of treating KRas G12C-related diseases in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In another aspect, the application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a disease associated with KRas G12C.

In another aspect, the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment of a KRas G12C-related disease.

In another aspect, the application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating a KRas G12C-related disease.

In some embodiments of the present application, the KRas G12C-associated disease is preferably cancer.

In some embodiments of the present application, the cancer comprises lung cancer, pancreatic cancer.

In some embodiments of the present application, the cancer is lung cancer, preferably non-small cell lung cancer.

Definition of

The following terms used in the present application have the following meanings, unless otherwise specified. A particular term should not be considered as ambiguous or unclear without special definition, but rather construed according to ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.

The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., ═ O), meaning that two hydrogen atoms are substituted, oxo does not occur on the aryl.

The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halo means that the ethyl group may be unsubstituted (CH)₂CH ₃) Monosubstituted (e.g. CH)₂CH ₂F) Polysubstituted (e.g. CHFCH)₂F、CH ₂CHF ₂Etc.) or completely substituted (CF)₂CF ₃). It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution pattern which is sterically impossible and/or cannot be synthesized.

Herein C_m-nIt is the moiety that has an integer number of carbon atoms in the given range. E.g. "C_1-6By "is meant that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 2R, then there are separate options for each R.

When the number of one linking group is 0, e.g. - (CH)₂) ₀-, indicates that the linking group is a covalent bond.

When one of the variables is selected from a covalent bond, it means that the two groups to which it is attached are directly linked, for example, where L represents a covalent bond in A-L-Z, it means that the structure is actually A-Z.

When the linking group is listed without indicating its direction of attachment, its direction of attachment is arbitrary, such as in A-L-Z, where the linking group L is-M-W-which indicates that the structure may be A-M-W-Z or A-W-M-Z.

When a substituent's bond is cross-linked to two atoms on a ring, such substituent may be bonded to any atom on the ring. For example, a structural unit

Meaning that it may be substituted at any position on the cyclohexyl or cyclohexadiene.

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

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

The term "cyano" refers to the group — CN.

The term "mercapto" refers to the-SH group.

The term "amino" refers to the group-NH₂A group.

The term "nitro" means-NO₂A group.

The term "alkaneBy "radical" is meant a radical of the formula C_nH _2n+1A hydrocarbon group of (1). The alkyl group may be linear or branched. For example, the term "C_1-6Alkyl "means an alkyl group having 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, and the like). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio groups have the same definitions as above.

The term "alkoxy" refers to-O-alkyl.

The term "alkylamino" refers to-NH-alkyl.

The term "dialkylamino" refers to-N (alkyl)₂。

The term "alkylsulfonyl" refers to-SO₂-an alkyl group.

The term "alkylthio" refers to-S-alkyl.

The term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one double bond, consisting of carbon atoms and hydrogen atoms. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1, 3-butadienyl, and the like.

The term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one triple bond composed of carbon atoms and hydrogen atoms. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C ≡ CH), 1-propynyl (-C ≡ C-CH)₃) 2-propynyl (-CH)₂-C.ident.CH), 1, 3-butadiynyl (-C.ident.C-C.ident.CH), and the like.

The term "cycloalkyl" refers to a carbon ring that is fully saturated and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, and the like.

The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the carbocycle is typically a 5 to 8 membered ring. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.

The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuryl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, and the like.

The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 12 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxiranyl, thietanyl, cycloazenyl, non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thiabutinyl, examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, examples of tetrahydropyrazolyl, 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thialkyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, and examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, thiepanyl.

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi-electron system. For example, the aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3, 4-tetrahydronaphthalene, and the like.

The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 4-to 8-membered ring, especially a 5-to 8-membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.

The term "treating" means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is predisposed to the disease condition but has not yet been diagnosed as having it;

(ii) inhibiting the disease or disease state, i.e., arresting its development;

(iii) alleviating the disease or condition, i.e., causing regression of the disease or condition.

The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art, in view of their own knowledge and this disclosure.

The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As the pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like can be mentioned.

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

The term "pharmaceutically acceptable adjuvants" refers to those adjuvants which do not have a significant irritating effect on 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, for example carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

The words "comprise" or "comprise" and variations thereof such as "comprises" or "comprising," are to be understood in an open, non-exclusive sense, i.e., "including but not limited to.

The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, wherein the proton can migrate between two ring nitrogens. Valence tautomers include interconversion by recombination of some of the bonding electrons.

The application also includesIsotopically-labeled compounds of the present application, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as respectively²H、 ³H、 ¹¹C、 ¹³C、 ¹⁴C、 ¹³N、 ¹⁵N、 ¹⁵O、 ¹⁷O、 ¹⁸O、 ³¹P、 ³²P、 ³⁵S、 ¹⁸F、 ¹²³I、 ¹²⁵I and³⁶cl, and the like.

Certain isotopically-labelled compounds of the present application (e.g. with³H and¹⁴c-labeled ones) can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation)³H) And carbon-14 (i.e.¹⁴C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as¹⁵O、 ¹³N、 ¹¹C and¹⁸f can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

In addition, heavier isotopes are used (such as deuterium (i.e., deuterium)²H) Substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances where deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium.

The compounds of the present application may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms 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 by using chiral starting materials or chiral reagents. Non-limiting examples of stereoisomers include, but are not limited to:

the compounds of the present application may have one or more atropisomers, which, unless otherwise indicated, refers to the optically active isomer resulting from the hindrance of free rotation between single bonds. The compounds of the present application containing a chiral axis can be isolated in racemic form. When the energy barrier for free rotation of a single bond of a compound containing a chiral axis is sufficiently high, its atropisomer can be isolated in an optically active pure form. Non-limiting examples of atropisomers include, but are not limited to:

the pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.

Typical routes of administration of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.

In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These adjuvants enable the compounds of the present application to be formulated as tablets, pills, lozenges, dragees, capsules, gels, slurries, suspensions and the like, for oral administration to a patient.

Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid adjuvants, optionally the mixture obtained is milled, if desired with further suitable adjuvants, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.

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

In all methods of administration of the compounds of formula I described herein, the daily dose administered is from 0.01 to 200mg/kg body weight, and the compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, the examples herein.

The chemical reactions of the embodiments herein are carried out in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.

In some implementationsIn schemes, the compounds of formula (Ia) herein can be prepared by those skilled in the art of organic synthesis via scheme 1, wherein R is²、R ³Parts X, A and B are as defined above.

Route 1

Under proper conditions, the raw material 1a-1 is subjected to substitution reaction to obtain an intermediate 1a-2, intramolecular condensation of the intermediate 1a-2 is carried out to obtain an intermediate 1a-3, then condensation reaction is carried out to obtain an intermediate 1a-4, and the intermediate 1a-4 is subjected to reaction to obtain an intermediate 1 a-5. And carrying out substitution reaction on the intermediate 1a-5 and a corresponding ring A compound to obtain an intermediate 1a-6, protecting the N atom of the ring A to obtain an intermediate 1a-7, carrying out substitution reaction on the intermediate 1a-7 to obtain an intermediate 1a-8, and removing the N atom protecting group on the seven-membered ring to obtain an intermediate 1 a-9. The intermediate 1a-9 and corresponding ring B compound are subjected to coupling reaction to obtain an intermediate 1a-10, deprotection is carried out to obtain an intermediate 1a-11, and finally the intermediate and R compound are subjected to coupling reaction²The corresponding acyl halide compound reacts to obtain the compound of the formula (Ia).

In some embodiments, the compounds of formula (Ib) herein may be prepared by one skilled in the art of organic synthesis via scheme 2, wherein R is²、R ³Parts X, A and B are as defined above.

Route 2

Under proper conditions, the raw material 1b-1 is subjected to condensation reaction to obtain an intermediate 1b-2, then the reaction is carried out to obtain an intermediate 1b-3, the intermediate 1b-3 is subjected to substitution reaction with a corresponding ring A compound to obtain an intermediate 1b-4, then the N atom of the ring A is protected to obtain an intermediate 1b-5, the intermediate 1b-5 is subjected to substitution reaction to obtain an intermediate 1b-6, and then the N atom protecting group on the seven-membered ring is removed to obtain an intermediate 1 b-7. Intermediate 1B-7 and corresponding ring B compound are subjected to coupling reaction to obtain an intermediate 1B-8, deprotection is carried out to obtain an intermediate 1B-9, and finally the intermediate and R are subjected to coupling reaction²The corresponding acyl halide compound reacts to obtain the compound of the formula (Ib).

Each of the products of the reactions in the above routes may be obtained by conventional separation techniques including, but not limited to, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials may be synthesized by themselves or purchased from commercial establishments (such as, but not limited to, Adrich or Sigma). These materials can be characterized using conventional means, such as physical constants and spectral data. The compounds described herein can be synthesized as a single isomer or as a mixture of isomers.

The following abbreviations are used in this application:

aq represents aqueous; SEMCl represents (2- (chloromethoxy) ethyl) trimethylsilane; eq represents equivalent; 1,3-DPPP represents 1, 3-bis (diphenylphosphino) propane; DCM represents dichloromethane; DMSO represents dimethyl sulfoxide; tol represents toluene; PE represents petroleum ether; DMF represents N, N-dimethylformamide; NMP stands for N-methylpyrrolidone; EtOAc for ethyl acetate; i-PrOH represents isopropanol; EtOH stands for ethanol; MeOH is methanol; MeONa is sodium methoxide; THF represents tetrahydrofuran; BPO stands for benzoyl peroxide; boc represents tert-butyloxycarbonyl; bn represents a benzyl group; t is₃P is propyl phosphoric anhydride; HOAc is acetic acid; NaCNBH₃Is sodium cyanoborohydride; LAH is lithium aluminum hydride; 9-BBN is 9-borabicyclononane; MsCl is methanesulfonyl chloride; rt is room temperature; O/N is overnight; boc₂O is di-tert-butyl dicarbonate; TFA is trifluoroacetic acid; TFAA is trifluoroacetic anhydride; TEA is triethylamine; DIEA is N, N-diisopropylethylamine; DIBAL-H is diisobutylaluminum hydride; NBS is bromosuccinimide; DPPF is 1,1' -bis (diphenylphosphino) ferrocene; ph₃P is triphenylphosphine; pd (OAc)₂Is palladium acetate; pd (PPh)₃P) ₂CL ₂Is bis (triphenylphosphine) palladium chloride; pd₂(dba) ₃Is tris (benzylidene acetone) dipalladium; XANTPHOS is 4, 5-bis (diphenylphosphino) -9, 9-dimethylA xanthene group; n-BuLi is n-butyllithium; t-BuOK is potassium tert-butoxide; t-BuONa is sodium tert-butoxide; NaOt-Bu is sodium tert-butoxide; NaO^tBu is sodium tert-butoxide; RuPhos-Pd-G3 is methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II); HATU is 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate; ACE-Cl is 1-chloroethyl chloroformate; DCE is 1, 2-dichloroethane; ACN is acetonitrile; THP is 2-tetrahydropyranyl.

The compound is artificially synthesized or

The software names, and the commercial compounds used the supplier catalog names.

For clarity, the invention is further illustrated by examples, which do not limit the scope of the application. Having described the present application in detail and disclosed specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made to the embodiments of the present application without departing from the spirit and scope of the application.

All reagents used herein were commercially available and used without further purification.

Examples

Example 1

Step 1

Mixing the raw materials1-1(10.0 g) was dissolved in N, N-dimethylformamide (100 ml), and ethyl 5-bromobutyrate (11.9 g) and triethylamine (8.00g) were added in this order. The resulting solution was stirred at 100 ℃ for 16 hours. After the reaction was complete, it was cooled to room temperature, diluted with water (200 ml) and extracted with ethyl acetate (200 ml × 3). The organic phases are combined and concentrated to dryness. The crude product was purified by silica gel column chromatography (acetic acid B)10% -20%) to obtain the invented product1-2(11.4 g).

LC-MS:m/z 322(M+H) ⁺

Step 2

Mixing the raw materials1-2(11.4 g) was dissolved in toluene (50 mL) and tert-butanol (3.70 g), potassium tert-butoxide (5.97 g) were added at 0 deg.C. The resulting mixture was warmed to 100 ℃ and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature. Water (200 ml) was added to dilute and extracted with ethyl acetate (200 ml x 3). The organic phase is combined to give the crude product which is then concentrated to dryness. Purifying the product by silica gel column chromatography (10-20% ethyl acetate/petroleum ether) to obtain the product1-3(6.14 g).

LC-MS:m/z 276(M+H) ⁺

Step 3

Mixing the raw materials1-3(14.3 g) in dry methanol (200 ml) and a solution of sodium methoxide in methanol (30%) (36.0 g), thiourea (15.2 g) was added at 0 ℃. The resulting mixture was warmed to 80 ℃ and stirred for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature. Dilute hydrochloric acid (1 mol/l) was added to adjust the pH to 7. The precipitated solid was collected by filtration and washed with water (50 ml). Drying the solid to obtain the product1-4(13.0 g).

LC-MS:m/z 288(M+H) ⁺

Step 4

Mixing the raw materials1-4(13.0 g) was suspended in phosphorus oxychloride (130 ml) and N, N-dimethylformamide (13.0 ml) was added. The resulting suspension was stirred at 100 ℃ for 5 hours. After the reaction, the reaction solution was concentrated to dryness. The residue was taken up in water (100 ml) and the pH adjusted to 8 with anhydrous sodium carbonate. The mixture was extracted with ethyl acetate (200 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (10% -50% ethyl acetate/petroleum ether) to obtain the product1-5(7.50 g).

LC-MS:m/z 308(M+H) ⁺

Step 5

Mixing the raw materials1-5(7.50 g) was dissolved in isopropanol (100 ml) and 2-cyanomethylpiperazine dihydrochloride (5.29 g), diisopropylethylamine (12.6 g) were added in that order. The resulting mixture was reacted at 80 ℃ for 12 hours. After the reaction was complete, water (200 ml) was added for dilution. And extracted with ethyl acetate (200 ml x 3). The organic phases were combined, washed with saturated brine (200 ml), dried over anhydrous sodium sulfate and concentrated to dryness to give the product1-6(7.00 g).

LC-MS:m/z 397(M+H) ⁺

Step 6

Mixing the raw materials1-6(7.00 g) was dissolved in anhydrous tetrahydrofuran (100 ml), and di-tert-butyl dicarbonate (4.61 g) and diisopropylethylamine (2.72 g, 21.1 mmol) were added in this order. The resulting solution was reacted at room temperature for 3 hours. After completion of the reaction, water (150 ml) was added to dilute and extracted with ethyl acetate (150 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (30% -60% ethyl acetate/petroleum ether) to obtain the product1-7(6.30 g).

LC-MS:m/z 497(M+H) ⁺

Step 7

(S) -prolinol (2.18 g) was dissolved in anhydrous tetrahydrofuran (80 mL) and sodium hydride (60%) (0.760 g) was added at 0 deg.C. After reacting for 30 minutes at 0 ℃, adding the raw materials1-7(6.30 g). The resulting solution was reacted at 70 ℃ for 3 hours. After the reaction, the reaction mixture was cooled to room temperature. Quenched by addition of saturated aqueous ammonium chloride (150 ml) and extracted with ethyl acetate (150 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (methanol/dichloromethane is 5% -20%) to obtain the product1-8(4.20 g).

LC-MS:m/z 576(M+H) ⁺

Step 8

Mixing the raw materials1-8(4.20 g) in anhydrous methanol (1)00 ml) were added successively palladium on carbon (10%) (0.42 g) and a solution of ammonia in methanol (7 mol/l) (10 ml) under nitrogen protection. The resulting reaction solution was replaced with hydrogen gas 3 times, and reacted at 40 ℃ for 16 hours. After the reaction, the palladium-carbon is filtered. Concentrating the filtrate to dryness to obtain the product1-9(2.55 g).

LC-MS:m/z 486(M+H) ⁺

Step 9

Mixing the raw materials1-9(50.0 mg) was dissolved in toluene (2 ml), and 1-bromonaphthalene (25.5 mg), sodium tert-butoxide (49.4 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg) were added in this order. The resulting solution was stirred at 90 ℃ for 3 hours. After completion of the reaction, it was cooled to room temperature, diluted with water (15 ml) and extracted with ethyl acetate (15 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (10% -20% of dichloromethane/methanol) to obtain the product1-10(25.0 mg).

LC-MS:m/z 612(M+H) ⁺

Step 10

To the raw material1-10(25.0 mg) to a solution of hydrogen chloride in 1, 4-dioxane (2 ml) was added. The resulting solution was stirred at room temperature for 10 minutes. After the reaction is finished, concentrating to be dry to obtain the product1-11(15.0 mg). The product is used for the next reaction without purification.

LC-MS:m/z 512(M+H) ⁺

Step 11

Mixing the raw materials1-11(15.0 mg) was dissolved in dichloromethane (2 ml), cooled to-40 ℃ and triethylamine (13.8 mg) and acryloyl chloride (2.47 mg) were added in that order. The resulting solution was reacted at-40 ℃ for 10 minutes. After the reaction was complete, quench with water (5 ml) and concentrate to dryness. The crude product was purified by preparative chromatography (Column: Xbridge Shield RP18 OBD Column,5um, 19X 150 mm; mobile phase A: water (10 mmol/l, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate25 ml/min; gradient is 38-59%; the time is 8 minutes; detector wavelength 254/220 nm) to obtain the product1(10.8 mg).

LC-MS:m/z 566(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.95(d,J＝8.4Hz,1H),7.82(d,J＝9.0Hz,1H),7.56(d,J＝8.1Hz,1H),7.46-7.31(m,3H),7.22(d,J＝7.8Hz,1H),7.00-6.75(m,1H),6.31(dd,J ₁＝1.5Hz,J ₂＝16.5Hz,1H),5.85(dd,J ₁＝1.5Hz,J ₂＝10.5Hz,1H),5.12-4.60(m,1H),4.43-4.30(m,4H),4.21-4.08(m,1H),4.06-3.91(m,2H),3.82-3.63(m,1H),3.58-3.43(m,3H),3.16-2.93(m,6H),2.83-2.67(m,1H),2.50(s,3H),2.40-2.31(m,1H),2.25-2.03(m,3H),1.87-1.65(m,3H).

Example 2

Step 1

Compound (I)2-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 8-chloro-1-bromonaphthalene (49.5 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product2-1(25.0 mg).

LC-MS:m/z 646(M+H) ⁺

Step 2

Compound (I)2-2Synthetic reference compounds of1-11. Raw materials2-1(25.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 2 ml). Obtaining the product2-2(20.0 mg).

LC-MS:m/z 546(M+H) ⁺.

Step 3

Compound (I)2Synthetic reference compounds of1. Starting materials2-2(20.0 mg), triethylamine (17.4 mg), acryloyl chloride (4.6 mg), dichloromethane (5 ml). Obtaining the product2(4.1 mg).

LC-MS:m/z 600(M+H) ⁺

¹H-NMR(DMSO)δ:7.90-7.83(m,1H),7.73-7.63(m,1H),7.55-7.22(m,4H),6.97-6.77(m,1H),6.19(d,J＝15.6Hz,1H),5.77(d,J＝10.5Hz,1H),5.04-4.76(m,1H),4.53-4.10(m,4H),4.08-3.96(m,1H),3.74-3.41(m,5H),3.15-2.85(m,3H),2.83-2.66(m,6H),2.30(s,3H),2.21-2.10(m,1H),2.02-1.76(m,2H),1.69-1.51(m,3H).

Example 3

Step 1

Compound (I)3-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 8-fluoro-1-bromonaphthalene (46.2 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product3-1(25.0 mg).

LC-MS:m/z 630(M+H) ⁺

Step 2

Compound (I)3-2Synthetic reference compounds of1-11. Raw materials3-1(25.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 2 ml). Obtaining the product3-2(20.0 mg).

LC-MS:m/z 530(M+H) ⁺.

Step 3

Compound (I)3Synthetic reference compounds of1. Starting materials3-2(20.0 mg), triethylamine (17.4 mg), acryloyl chloride (4.6 mg), dichloromethane (5 ml). To obtain the product3(4.1 mg).

LC-MS:m/z 584(M+H) ⁺

¹H-NMR(DMSO)δ:7.90-7.83(m,1H),7.73-7.63(m,1H),7.55-7.22(m,4H),6.97-6.77(m,1H),6.19(d,J＝15.6Hz,1H),5.77(d,J＝10.5Hz,1H),5.04-4.76(m,1H),4.53-4.10(m,4H),4.08-3.96(m,1H),3.74-3.41(m,5H),3.15-2.85(m,3H),2.83-2.66(m,6H),2.30(s,3H),2.21-2.10(m,1H),2.02-1.76(m,2H),1.69-1.51(m,3H).

Example 5

Step 1

Compound (I)5-1Synthetic reference compounds of1. Raw materials4-2(20.0 mg), 4-bromocrotonyl chloride (8.34 mg), dichloromethane (5 ml). Obtaining the product5-1(18.3 mg).

LC-MS:m/z 672(M+H) ⁺

Step 2

Mixing the raw materials5-1(18.3 mg) was dissolved in N, N-dimethylformamide (3 ml), and N, N-diisopropylethylamine (7.02 mg) and morpholine (2.86 mg) were added in that order. The resulting solution was reacted at room temperature for 16 hours. After the reaction was complete, quench with water (5 ml) and concentrate to dryness. The crude product was purified by preparative chromatography (Column: Xbridge Shield RP18 OBD Column,5um, 19X 150 mm; mobile phase A: water (10 mmol/l, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 37-63%; time 8 min; detector wavelength 254/220 nm) to give the product5(2.00 mg).

LC-MS:m/z 679(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.72-7.61(m,2H),7.44-7.11(m,4H),6.92-6.67(m,2H),5.17-5.05(m,1H),4.70-4.56(m,1H),4.49-4.28(m,3H),4.25-4.07(m,2H),3.97-3.59(m,7H),3.54-3.39(m,2H),3.27-3.22(m,2H),3.14-2.87(m,6H),2.86-2.70(m,4H),2.60-2.44(m,5H),2.44-2.33(m,1H),2.19-1.94(m,4H),1.88-1.58(m,4H).

Example 6

Compound (I)6Synthetic reference compounds of5. Raw materials5-1(15 mg), N, N-diisopropylethylamine (7.19 mg), 3-flubutadine hydrochloride (2.00 mg) N, N-dimethylformamide (3 ml). Obtaining the product6(0.30 mg).

LC-MS:m/z 667(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.81-7.53(m,2H),7.49-7.11(m,4H),6.89-6.54(m,2H),5.35-5.20(m,1H),5.18-4.99(m,2H),4.67-4.60(m,2H),4.59-4.50(m,1H),4.49-4.29(m,2H),4.26-4.06(m,2H),4.02-3.62(m,5H),3.59-3.35(m,6H),3.30-2.88(m,7H),3.87-2.45(m,5H),2.44-2.16(m,2H),2.13-2.74(m,4H).

Example 10, example 11 and example 12

Step 1

Compound (I)10-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 2-bromo-6-methyl-trifluorotoluene (49.0 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylPhosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product10-1(25.0 mg).

LC-MS:m/z 644(M+H) ⁺

Step 2

Compound (I)10-2Synthetic reference compounds of1-11. Raw materials10-1(25.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product10-2(21.0 mg).

LC-MS:m/z 544(M+H) ⁺.

Step 3

Compound (I)10Synthetic reference compounds of1. Raw materials10-2(21.0 mg), triethylamine (18.3 mg), acryloyl chloride (4.93 mg), dichloromethane (5 ml). Obtaining the product10(13.5 mg).

LC-MS:m/z 598(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.42(t,J＝7.8Hz,1H),7.30(d,J＝8.1Hz,1H),7.11(d,J＝7.5Hz,1H),6.94-6.74(m,1H),6.30(d,J＝16.5Hz,1H),5.84(d,J＝10.5Hz,1H),5.22-5.04(m,1H),4.71-4.47(m,1H),4.42-4.28(m,2H),4.27-4.06(m,3H),3.97-3.78(m,2H),3.57-3.37(m,1H),3.30-3.20(m,2H),3.16-2.93(m,4H),2.93-2.70(m，3H),2.51(s,3H),2.47(q,J＝3.6Hz,3H),2.42-2.31(m,1H),2.17-1.93(m,3H),1.90-1.63(m,3H).

Step 4

Compound (I)10Resolution was prepared by chiral high pressure (column: CHIRAL ART Cellulose-SB2 x 25cm,5 um; mobile phase A: n-hexane (0.1%, diethylamine), mobile phase: isopropanol; flow rate: 20 ml/min; gradient: 30%, time 20 min; detector wavelength 254/220 nm). ) Is a product11And12。

product(s)11: retentionThe time was 2.09 minutes and,

¹H-NMR(CD ₃OD)δ:7.42(t,J＝7.8Hz,1H),7.31(d,J＝8.1Hz,1H),7.11(d,J＝7.5Hz,1H),6.96-6.76(m,1H),6.30(d,J＝16.6Hz,1H),5.85(d,J＝10.6Hz,1H),5.23-5.03(m,1H),4.68-4.58(m,1H),4.40-4.28(m,2H),4.27-4.07(m,3H),3.97-3.80(m,2H),3.72-3.58(m,1H),3.29-3.22(m,2H),3.13-2.75(m,7H),2.51(s,3H),2.47(q,J＝3.6Hz,3H),2.43-2.35(m,1H),2.14-1.96(m,3H),1.88-1.68(m,3H).

compound (I)12: the retention time was 3.20 minutes,

¹H-NMR(CD ₃OD)δ:7.42-7.39(m,1H),7.31(d,J＝8.1Hz,1H),7.12(d,J＝7.5Hz,1H),6.96-6.76(m,1H),6.30(d,J＝16.6Hz,1H),5.87(d,J＝10.6Hz,1H),5.26-5.05(m,1H),4.70-4.59(m,1H),4.40-4.32(m,2H),4.29-4.07(m,3H),3.97-3.81(m,2H),3.70-3.58(m,1H),3.33-3.22(m,3H),3.13-3.07(m,1H),3.06-2.98(m,2H),2.92-2.80(m,3H),2.51(s,3H),2.47-2.40(m,4H),2.15-1.90(m,3H),1.88-1.68(m,3H).

example 13

Step 1

Compound (I)13-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 2-bromo-6-chlorotrifluorotoluene (53.1 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product13-1(28.0 mg).

LC-MS:m/z 664(M+H) ⁺

Step 2

Compound (I)13-2Synthetic reference compounds of1-11. Raw materials13-1(28.0Mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). To obtain the product13-2(24.3 mg).

LC-MS:m/z 564(M+H) ⁺.

Step 3

Compound (I)13Synthetic reference compounds of1. Raw materials13-2(23.3 mg), triethylamine (19.6 mg), acryloyl chloride (5.28 mg), dichloromethane (5 ml). To obtain the product13(8.70 mg).

LC-MS:m/z 618(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.43(t,J＝8.2Hz,1H),7.30-7.22(m,2H),6.94-6.75(m,1H),6.30(d,J＝16.5Hz,1H),5.84(d,J＝10.5Hz,1H),5.19-5.01(m,1H),4.69-4.46(m,1H),4.41-4.20(m,4H),3.99-3.75(m,3H),3.69-3.59(m,1H),3.47-3.36(m,1H),3.29-3.22(m,1H),3.19-2.89(m,4H),2.88-2.73(m,3H),2.53(s,3H),2.45-2.33(m,1H),2.19-1.94(m,3H),1.91-1.67(m,3H).

Example 15

Step 1

Compound (I)15-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 1-bromo-7-methylnaphthalene (34.0 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product15-1(25.0 mg).

LC-MS:m/z 626(M+H) ⁺

Step 2

Compound (I)15-2Synthetic reference compounds of1-11. Raw materials 15-1(25.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product15-2(21.5 mg).

LC-MS:m/z 526(M+H) ⁺.

Step 3

Compound (I)15Synthetic reference compounds of1. Raw materials15-2(21.5 mg), triethylamine (19.4 mg), acryloyl chloride (5.20 mg), dichloromethane (5 ml). To obtain the product15(4.8 mg).

LC-MS:m/z 580(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.78-7.65(m,2H),7.50(d,J＝8.1Hz,1H),7.37-7.24(m,2H),7.17(d,J＝7.4Hz,1H),6.93-6.79(m,1H),6.31(d,J＝16.6Hz,1H),5.85(d,J＝10.7Hz,1H),5.22-5.08(m,1H),4.69-4.53(m,1H),4.49-4.31(m,2H),4.23-4.09(m,1H),4.05-3.88(m,2H),3.80-3.66(m,1H),3.61-3.41(m,3H),3.41-3.38(m,1H),3.22-2.91(m,6H),2.84-2.74(m,1H),2.52(s,3H),2.42-2.37(m,1H),2.35(s,3H),2.25-2.01(m,3H),1.91-1.67(m,3H).

Example 16

Step 1

Compound (I)16-1Synthetic reference compounds of1-10. Starting materials1-9(50.0 mg), 1-bromo-7-chloronaphthalene (49.4 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product16-1(29.0 mg).

LC-MS:m/z 646(M+H) ⁺

Step 2

Compound (I) 16-2Synthetic reference compounds of1-11. Raw materials16-1(29.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product16-2(24.5 mg).

LC-MS:m/z 546(M+H) ⁺.

Step 3

Compound (I)16Synthetic reference compounds of1. Raw materials16-2(24.5 mg), triethylamine (21.3 mg), acryloyl chloride (5.73 mg), dichloromethane (5 ml). Obtaining the product16(5.0 mg).

LC-MS:m/z 600(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.93-7.78(m,2H),7.58(d,J＝8.1Hz,1H),7.51-7.36(m,2H),7.29(d,J＝7.8Hz,1H),6.91-6.78(m,1H),6.31(d,J＝16.5Hz,1H),5.85(d,J＝10.7Hz,1H),5.21-5.07(m,1H)，4.70-4.54(m,1H),4.49-4.35(m,2H),4.28(d,J＝4.2Hz,2H),4.08-3.90(m,2H),3.81-3.65(m,1H),3.61-3.52(m,1H),3.51-3.37(m,2H),3.31-2.81(m,7H),2.55(s,3H),2.47-2.37(m,1H),2.28-2.02(m,3H),1.92-1.72(m,3H).

Example 17

Step 1

Compound (I)17-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 2-bromo-6-methoxytrifluorotoluene (52.3 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product17-1(32.0 mg).

LC-MS:m/z 660(M+H) ⁺

Step 2

Compound (I)17-2Synthetic reference compounds of1-11. Raw materials17-1(32.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). To obtain the product17-2(27.8 mg).

LC-MS:m/z 560(M+H) ⁺.

Step 3

Compound (I)17Synthetic reference compounds of1. Raw materials17-2(27.8 mg), triethylamine (23.6 mg), acryloyl chloride (6.34 mg), dichloromethane (5 ml). Obtaining the product17(9.20 mg).

LC-MS:m/z 614(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.41(t,J＝8.1Hz,1H),6.96-6.71(m,3H),6.30(d,J＝16.8Hz,1H),5.84(d,J＝10.8Hz,1H),5.21-5.05(m,1H),4.76-4.46(m,1H),4.43-4.33(m,2H),4.33-4.17(m,2H),4.16-4.00(m,1H),3.98-3.88(m,1H),3.86(s,3H),3.83-3.74(m,1H),3.71-3.54(m,1H),3.49-3.35(m,2H),3.24-2.77(m,7H),2.56(s,3H),2.49-2.36(m,1H),2.18-1.93(m,3H),1.91-1.68(m,3H).

Example 18

Step 1

Compound (I)18-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 3-bromo-4-trifluoromethylpyridine (46.4 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product18-1(26.0 mg).

LC-MS:m/z 631(M+H) ⁺

Step 2

Compound (I)18-2Synthetic reference compounds of1-11. Raw materials18-1(26.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product18-2(22.5 mg).

LC-MS:m/z 531(M+H) ⁺.

Step 3

Compound (I)18Synthetic reference compounds of1. Raw materials18-2(22.5 mg), triethylamine (20.1 mg), acryloyl chloride (5.40 mg), dichloromethane (5 ml). Obtaining the product18(8.30 mg).

LC-MS:m/z 585(M+H) ⁺

¹H-NMR(CD ₃OD)δ:8.69(s,1H),8.48(d,J＝5.1Hz,1H),7.64(d,J＝5.1Hz,1H),6.94-6.76(m,1H),6.30(d,J＝16.5Hz,1H),5.85(d,J＝10.6Hz,1H),5.21-5.03(m,1H),4.81-4.51(m,1H),4.44-4.25(m,4H),4.21-4.04(m,1H),3.96-3.78(m,2H),3.75-3.59(m,1H),3.56-3.41(m,2H),3.16-2.69(m,7H),2.52(s,3H),2.44-2.32(m,1H),2.19-1.99(m,3H),1.89-1.65(m,3H).

Example 19

Step 1

Compound (I)19-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 2-bromo-6-fluorotrifluorotoluene (49.9 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product19-1(27.0 mg).

LC-MS:m/z 648(M+H) ⁺

Step 2

Compound (I)19-2Synthetic reference compounds of1-11. Raw materials19-1(27.0 mg), 1, 4-dioxane solution of hydrogen chloride (4 mol/l, 5 ml). Obtaining the product19-2(25.6 mg).

LC-MS:m/z 548(M+H) ⁺.

Step 3

Compound (I)19Synthetic reference compounds of1. Raw materials19-2(25.6 mg), triethylamine (22.2 mg), acryloyl chloride (5.96 mg), dichloromethane (5 ml). To obtain the product19(5.9 mg).

LC-MS:m/z 602(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.65-7.57(m,1H),7.45-7.35(m,2H),6.93-4.78(m,1H),6.30(d,J＝16.5Hz,1H),5.85(d,J＝10.6Hz,1H),5.22-5.07(m,1H),4.82-4.48(m,1H),4.40-4.27(m,2H),4.24-4.01(m,2H),4.00-3.79(m,2H),3.75-3.44(m,2H),3.28-3.17(m,2H),3.13-2.70(m,7H),2.50(s,3H),2.42-2.32(m,1H),2.15-1.93(m,3H),1.88-1.67(m,3H).

Example 20

Step 1

Compound (I)20-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 2-fluoro-bromobenzene (35.8 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product20-1(31.0 mg).

LC-MS:m/z 580(M+H) ⁺

Step 2

Compound (I)20-2Synthetic reference compounds of1-11. Raw materials20-1(31.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product20-2(26.6 mg).

LC-MS:m/z 480(M+H) ⁺.

Step 3

Compound (I)20Synthetic reference compounds of1. Raw materials20-2(26.6 mg), triethylamine (26.1 mg), acryloyl chloride (7.02 mg), dichloromethane (5 ml). Obtaining the product20(6.8 mg).

LC-MS:m/z 534(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.06-6.95(m,3H),6.93-6.73(m,5H),6.28(d,J＝16.5Hz,1H),5.83(d,J＝10.5Hz,1H),5.18-5.02(m,1H),4.78-4.50(m,1H),4.47-4.26(m,4H),3.96-3.95(m,2H),3.56(t,J＝6.3Hz,2H),3.29-2.71(m,6H),2.52(s,3H),2.38(q,J＝9.0Hz,1H),2.17-1.99(m,3H),1.90-1.68(m,3H).

Example 21

Step 1

Compound (I)21-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 1-bromo-4-fluoro-2, 3-o-xylene (41.6 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). To obtain the product21-1(32.0 mg).

LC-MS:m/z 608(M+H) ⁺

Step 2

Compound (I)21-2Synthetic reference compounds of1-11. Raw materials21-1(32.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). To obtain the product21-2(27.8 mg).

LC-MS:m/z 508(M+H) ⁺.

Step 3

Compound (I)21Synthetic reference compounds of1. Raw materials21-2(27.8 mg), triethylamine (25.9 mg), acryloyl chloride (6.95 mg), dichloromethane (5 ml). Obtaining the product21(8.8 mg).

LC-MS:m/z 562(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.08-6.98(m,1H),6.94-6.78(m,2H),6.30(d,J＝16.5Hz,1H), 5.85(d,J＝10.5Hz,1H),5.20-5.07(m,1H),4.82-4.47(m,1H),4.44-4.31(m,2H),4.19-3.81(m,5H),3.74-3.54(m,1H),3.29-2.82(m,9H),2.55(s,3H),2.49-2.37(m,1H),2.17(d,J＝2.1Hz,3H),2.15(s,3H),2.13-1.94(m,3H),1.92-1.69(m,3H).

Example 23

Step 1

Compound (I)23-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 1-bromo-2-chloro-3-fluorobenzene (42.8 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product23-1(31.0 mg).

LC-MS:m/z 614(M+H) ⁺

Step 2

Compound (I)23-2Synthetic reference compounds of1-11. Raw materials23-1(31.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product23-2(27.2 mg).

LC-MS:m/z 514(M+H) ⁺.

Step 3

Compound (I)23Synthetic reference compounds of1. Raw materials23-2(27.2 mg), triethylamine (25.0 mg), acryloyl chloride (6.72 mg), dichloromethane (5 ml). Obtaining the product23(6.8 mg).

LC-MS:m/z 568(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.27-7.18(m,1H),7.02-6.95(m,1H),6.93-6.74(m,2H),6.29(d,J＝16.5Hz,1H),5.84(d,J＝10.5Hz,1H),5.19-5.04(m,1H),4.69-4.51(m,1H),4.43-4.29(m,3H),4.14-3.82(m,3H),3.74-3.58(m,1H),3.51-3.38(m,2H),3.30-3.25(m,1H),3.16-2.73(m,7H),2.53(s,3H),2.44-2.34(m,1H),2.22-2.01(m,3H),1.89-1.68(m,3H).

Example 24

Step 1

Compound (I)24-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 2-bromo-6-fluoro-anisole (42.0 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Get the productArticle (A)24-1(26.0 mg).

LC-MS:m/z 610(M+H) ⁺

Step 2

Compound (I)24-2Synthetic reference compounds of1-11. Raw materials24-1(26.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product24-2(22.8 mg).

LC-MS:m/z 510(M+H) ⁺.

Step 3

Compound (I)24Synthetic reference compounds of1. Raw materials24-2(22.8 mg), triethylamine (21.1 mg), acryloyl chloride (5.67 mg), dichloromethane (5 ml). Obtaining the product24(7.2 mg).

LC-MS:m/z 564(M+H) ⁺

¹H-NMR(CD ₃OD)δ:6.96-6.62(m,4H),6.29(d,J＝16.5Hz,1H),5.83(d,J＝10.5Hz,1H),5.20-5.02(m,1H),4.79-4.52(m,1H),4.42-4.35(m,3H),4.13-3.79(m,3H),3.72-3.58(m,1H),3.54(s,3H),3.52-3.42(m,2H),3.30-2.74(m,8H),2.54(s,3H),2.43-2.34(m,1H),2.19-1.98(m,3H),1.91-1.68(m,3H).

Example 25

Step 1

Compound (I)25-1Synthetic reference compounds of1-10. Starting materials1-9(50.0 mg), 2-bromotrifluoromethoxybenzene (49.4 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product25-1(32.0 mg).

LC-MS:m/z 646(M+H) ⁺

Step 2

Compound (I)25-2Synthetic reference compounds of1-11. Raw materials25-1(32.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product25-2(27.9 mg).

LC-MS:m/z 546(M+H) ⁺.

Step 3

Compound (I)25Synthetic reference compounds of1. Raw materials25-2(27.9 mg), triethylamine (24.3 mg), acryloyl chloride (6.52 mg), dichloromethane (5 ml). Obtaining the product25(7.7 mg).

LC-MS:m/z 600(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.29-7.16(m,2H),7.15-7.07(m,1H),7.00-6.73(m,2H),6.29(d,J＝16.5Hz,1H),5.83(d,J＝10.5Hz,1H),5.20-5.01(m,1H),4.80-4.50(m,1H),4.44-4.30(m,3H),4.15-3.75(m,3H),3.71-3.54(m,1H),3.51-3.37(m,2H),3.26-2.74(m,8H),2.53(s,3H),2.43-2.33(m,1H),2.20-2.02(m,3H),1.89-1.68(m,3H).

Example 26

Step 1

Compound (I)26-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 4-bromo-3-trifluoromethyl-pyridine (46.3 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product 26-1(29.0 mg).

LC-MS:m/z 631(M+H) ⁺

Step 2

Compound (I)26-2Synthetic reference compounds of1-11. Raw materials26-1(29.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product26-2(25.5 mg).

LC-MS:m/z 531(M+H) ⁺

Step 3

Compound (I)26Synthetic reference compounds of1. Raw materials26-2(25.5 mg), triethylamine (22.7 mg), acryloyl chloride (6.12 mg), dichloromethane (5 ml). Obtaining the product26(8.9 mg).

LC-MS:m/z 585(M+H) ⁺

¹H-NMR(CD ₃OD)δ:8.39(d,J＝4.2Hz,1H),7.93(d,J＝8.4,1H),7.67-7.58(m,1H),7.96-7.76(m,1H),6.30(d,J＝16.5Hz,1H),5.85(d,J＝10.5Hz,1H),5.22-5.03(m,1H),4.81-4.51(m,1H),4.42-4.20(m,4H),4.14-3.81(m,3H),3.76-3.62(m,1H),3.47-3.39(m,1H),3.30-3.23(m,1H),3.14-2.73(m,7H),2.51(s,3H),2.40-2.32(m,1H),2.15-1.95(m,3H),1.87-1.64(m,3H).

Example 27

Step 1:

compound (I)27-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 2-bromo-4-fluorotrifluorotoluene (49.8 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II)(25.8 mg), toluene (2 ml). Obtaining the product27-1(27.5 mg).

LC-MS:m/z 648(M+H) ⁺

Step 2:

compound (I)27-2Synthetic reference compounds of1-11. Raw materials27-1(27.5 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). To obtain the product27-2(24.3 mg).

LC-MS:m/z 548(M+H) ⁺

Step 3

Compound (I)27Synthetic reference compounds of1. Raw materials27-2(24.3 mg), triethylamine (0.0289 ml), acryloyl chloride (4.50 mg), dichloromethane (5 ml). Obtaining the product27(7.5 mg).

LC-MS:m/z 602(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.74-7.61(m,1H),7.35-7.20(m,1H),7.10-6.98(m,1H),6.97-6.70(m,1H),6.29(d,J＝16.5Hz,1H),5.84(d,J＝10.5Hz,1H),5.19-4.98(m,1H),4.77-4.41(m,3H),4.37-4.10(m,3H),3.98(d,J＝15.0Hz,1H),3.85(d,J＝12.0Hz,1H),3.74-3.43(m,3H),3.19-2.89(m,7H),2.87(s,3H),2.37-2.25(m,1H),2.25-1.67(m,6H).

Example 28

Step 1:

compound (I)28-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 3-bromo-2-methyltrifluorotoluene (49.0 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl) (2-amino-1,1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product28-1(31.4 mg).

LC-MS:m/z 644(M+H) ⁺

Step 2:

compound (I)28-2Synthetic reference compounds of1-11. Starting materials28-1(31.4 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product28-2(27.3 mg).

LC-MS:m/z 544(M+H) ⁺

Step 3

Compound (I)28Synthetic reference compounds of1. Raw materials28-2(27.3 mg), triethylamine (0.0310 ml), acryloyl chloride (4.83 mg), dichloromethane (5 ml). Obtaining the product28(8.2 mg).

LC-MS:m/z 598(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.47-7.25(m,3H),6.91-6.76(m,1H),6.29(d,J＝16.5Hz,1H),5.34(d,J＝10.5Hz,1H),5.19-5.02(m,1H),4.66-4.51(m,1H),4.43-4.23(m,2H),4.21-4.03(m,3H),4.01-3.84(m,2H),3.76-3.60(m,1H),3.46-3.35(m,1H),3.29-3.22(m,1H),3.16-2.88(m,6H),2.83-2.70(m,1H),2.52(s,3H),2.44-2.32(m,1H),2.27(s,3H),2.18-1.98(m,3H),1.89-1.66(m,3H).

Example 29

Step 1:

compound (I)29-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 2-bromo-6-chlorotoluene (46.7 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2', 6)' -diisopropoxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 mL). Obtaining the product29-1(29.3 mg).

LC-MS:m/z 610(M+H) ⁺

Step 2:

compound (I)29-2Synthetic reference compounds of1-11. Raw materials29-1(29.3 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product29-2(25.8 mg).

LC-MS:m/z 510(M+H) ⁺.

Step 3

Compound (I)29Synthetic reference compounds of1. Raw materials29-2(25.8 mg), triethylamine (0.0329 ml), acryloyl chloride (5.16 mg), dichloromethane (5 ml). Obtaining the product29(7.9 mg).

LC-MS:m/z 564(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.20-7.01(m,3H),6.98-6.75(m,1H),6.30(d,J＝16.5Hz,1H),5.84(d,J＝10.5Hz,1H),5.20-5.03(m,1H),4.72-4.48(m,1H),4.43-4.27(m,2H),4.26-4.03(m,3H),4.03-3.81(m,2H),3.78-3.61(m,1H),3.61-3.44(m,1H),3.44-3.35(m,1H),3.30-3.23(m,1H),3.19-2.85(m,5H),2.85-2.72(m,1H),2.52(s,3H),2.46-2.31(m,1H),2.21(s,3H),2.17-1.94(m,3H),1.93-1.65(m,3H).

Example 30

Step 1:

compound (I)30-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 2, 3-difluorobromobenzene (39.6 mg)Sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product30-1(29.1 mg).

LC-MS:m/z 598(M+H) ⁺.

Step 2:

compound (I)30-2Synthetic reference compounds of1-11. Raw materials30-1(29.1 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product30-2(25.1 mg).

LC-MS:m/z 498(M+H) ⁺.

Step 3

Compound (I)30Synthetic reference compounds of1. Raw materials30-2(25.1 mg), triethylamine (0.0327 ml), acryloyl chloride (5.11 mg), dichloromethane (5 ml). To obtain the product30(5.7 mg).

LC-MS:m/z 552(M+H) ⁺

¹H-NMR(CD ₃OD)δ:6.98-6.63(m,4H),6.23(d,J＝16.5Hz,1H),5.83(d,J＝10.5Hz,1H),5.17-5.03(m,1H),4.67-4.57(m,1H),4.51-4.29(m,4H),4.16-4.00(m,1H),3.98-3.85(m,1H),3.79(d,J＝9.6Hz,1H),3.65-3.58(m,2H),3.27-2.74(m,8H),2.54(s,3H),2.46-2.36(m,1H),2.20-1.99(m,3H),1.92-1.68(m,3H).

Example 31

Step 1:

compound (I)31-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 2, 3-Dimethylbromobenzene (37.9 mg)) Sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product31-1(30.1 mg).

LC-MS:m/z 590(M+H) ⁺.

Step 2:

compound (I)31-2Synthetic reference compounds of1-11. Raw materials31-1(30.1 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product31-2(26.1 mg).

LC-MS:m/z 490(M+H) ⁺.

Step 3

Compound (I)31Synthetic reference compounds of1. Raw materials31-2(26.1 mg), triethylamine (0.0345 ml), acryloyl chloride (5.39 mg), dichloromethane (5 ml). Obtaining the product31(7.3 mg).

LC-MS:m/z 544(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.07-6.95(m,2H),6.94-6.76(m,2H),6.29(d,J＝16.5Hz,1H),5.84(d,J＝10.5Hz,1H),5.20-5.04(m,1H),4.70-4.50(m,1H),4.44-4.28(m,2H),4.21-3.80(m,5H),3.76-3.55(m,1H),3.30-3.18(m,3H),3.15-3.07(m,1H),3.06-2.96(m,2H),2.95-2.85(m,2H),2.85-2.74(m,1H),2.53(s,3H),2.44-2.33(m,1H),2.24(s,3H),2.16-2.11(m,1H),2.09(s,3H),2.07-1.92(m,2H),1.90-1.66(m,3H).

Example 32

Step 1:

compound (I)32-1Synthetic reference compounds of1-10. Starting materials1-9(50.0 mg), 3-bromo-2-methylanisole (41.2 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). To obtain the product32-1(31.4 mg).

LC-MS:m/z 606(M+H) ⁺.

Step 2:

compound (I)32-2Synthetic reference compounds of1-11. Raw materials32-1(31.4 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product32-2(27.1 mg).

LC-MS:m/z 506(M+H) ⁺.

Step 3

Compound (I)32Synthetic reference compounds of1. Raw materials32-2(27.1 mg), triethylamine (0.0348 ml), acryloyl chloride (5.42 mg), dichloromethane (5 ml). Obtaining the product32(7.9 mg).

LC-MS:m/z 560(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.10(t,J＝8.4Hz,1H),7.01-6.79(m,1H),6.76(d,J＝8.1Hz,1H),6.66(d,J＝8.1Hz,1H),6.29(d,J＝16.5Hz,1H),5.84(d,J＝10.5Hz,1H),5.20-5.06(m,1H),4.64(m,1H),4.41-4.29(m,2H),4.11(q,J＝17.1Hz,3H),3.99-3.85(m,2H),3.80(s,3H),3.74-3.57(m,1H),3.29-3.18(m,2H),3.13-2.71(m,7H),2.51(s,3H),2.43-2.31(m,1H),2.23-2.02(m,3H),2.00(s,3H),1.91-1.64(m,3H).

Example 33

Step 1:

compound (I) 33-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), m-trifluoromethylbromobenzene (46.1 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product33-1(32.4 mg).

LC-MS:m/z 630(M+H) ⁺.

Step 2:

compound (I)33-2Synthetic reference compounds of1-11. Raw materials33-1(32.4 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product33-2(28.4 mg).

LC-MS:m/z 530(M+H) ⁺.

Step 3

Compound (I)33Synthetic reference compounds of1. Raw materials33-2(28.4 mg), triethylamine (0.0349 ml), acryloyl chloride (5.45 mg), dichloromethane (5 ml). To obtain the product33(8.8 mg).

LC-MS:m/z 584(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.28(t,J＝7.5Hz,1H),7.19-6.97(m,2H),6.95-6.68(m,2H),6.25(d,J＝16.5Hz,1H),5.81(d,J＝10.5Hz,1H),4.71-4.57(m,3H),4.46-4.28(m,2H),4.18-3.49(m,6H),3.25-3.03(m,3H),3.03-2.75(m,5H),2.54(s,3H),2.46-2.31(m,1H),2.28-1.64(m,6H).

Compound 34

Step 1:

compound (I)34-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 2, 3-dichlorobromobenzene (46.4 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). To obtain the product34-1(34.5 mg).

LC-MS:m/z 630(M+H) ⁺.

Step 2:

compound (I)34-2Synthetic reference compounds of1-11. Starting materials34-1(34.5 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product34-2(30.1 mg).

LC-MS:m/z 530(M+H) ⁺.

Step 3

Compound (I)34Synthetic reference compounds of1. Raw materials34-2(30.1 mg), triethylamine (0.0370 ml), acryloyl chloride (5.77 mg), dichloromethane (5 ml). Obtaining the product34(7.3 mg).

LC-MS:m/z 584(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.26-7.10(m,3H),6.95-6.74(m,1H),6.29(d,J＝16.8Hz,1H),5.84(d,J＝10.8Hz,1H),5.19-5.07(m,1H),4.76-4.63(m,1H),4.45-4.18(m,4H),4.15-3.74(m,3H),3.73-3.54(m,1H),3.50-3.36(m,2H),3.30-3.23(m,1H),3.1 4-2.72(m,6H),2.52(s,3H),2.44-2.32(m,1H),2.22-1.98(m,3H),1.90-1.65(m,3H).

Example 35 and example 36

Racemic compound34High chiral propertyResolution into monomers by pressure preparation35And36. Column type: CHIRAL PAK IC 2 × 25cm,5 um; mobile phase A is methyl tert-butyl ether (0.1% diethylamine), and mobile phase is ethanol; the flow rate is 20 ml/min; gradient of 40% for 20 min; detector wavelength 254/220 nm).

Compound (I)35: the retention time was 1.26 minutes,

¹H-NMR(CD ₃OD)δ:7.28-7.08(m,3H),6.93-6.72(m,1H),6.29(d,J＝16.2Hz,1H),5.84(d,J＝10.7Hz,1H),5.19-5.00(m,1H),4.78-4.49(m,1H),4.43-4.32(m,2H),4.30-4.19(m,2H),4.10-3.82(m,2H),3.75-3.37(m,3H),3.29-3.22(m,1H),3.19-2.80(m,7H),2.57(s,3H),2.50-2.38(m,1H),2.25-2.00(m,3H),1.97-1.66(m,3H).

compound (I)36: the retention time was 1.68 minutes,

¹H-NMR(CD ₃OD)δ:7.28-7.08(m,3H),6.93-6.72(m,1H),6.29(d,J＝16.5Hz,1H),5.84(d,J＝10.7Hz,1H),5.19-5.00(m,1H),4.78-4.49(m,1H),4.43-4.32(m,2H),4.30-4.19(m,2H),4.10-3.82(m,2H),3.75-3.37(m,3H),3.29-3.22(d,J＝3.9Hz,1H),3.19-2.80(m,7H),2.57(s,3H),2.50-2.38(m,1H),2.25-2.00(m,3H),1.97-1.66(m,3H).

example 37

Step 1:

compound (I)37-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 3-bromo-6-fluorotrifluorotoluene (49.8 mg), sodium tert-butoxide (98.9 mg), R-methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). To obtain the product37-1(33.7 mg).

LC-MS:m/z 648(M+H) ⁺

Step 2:

compound (I)37-2Synthetic reference compounds of1-11. Raw materials37-1(33.7 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product37-2(29.7 mg).

LC-MS:m/z 548(M+H) ⁺

Step 3

Compound (I)37Synthetic reference compounds of1. Raw materials37-2(29.7 mg), triethylamine (0.0354 ml), acryloyl chloride (5.53 mg), dichloromethane (5 ml). To obtain the product37(9.3 mg).

LC-MS:m/z 602(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.13-6.99(m,3H),6.94-6.66(m,1H),6.26(d,J＝16.2Hz,1H),5.81(d,J＝10.8Hz,1H),5.15-4.99(m,1H),4.69-4.53(m,3H),4.44-4.30(m,2H),4.11-3.54(m,5H),3.24-2.73(m,8H),2.53(s,3H),2.46-2.34(m,1H),2.20-1.66(m,6H).

Example 38

Step 1:

compound (I)38-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 3-bromo-2-chlorotoluene (42.0 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product38-1(32.9 mg).

LC-MS:m/z 610(M+H) ⁺.

Step 2:

compound (I)38-2Synthetic reference compounds of1-11. Starting materials38-1(32.9 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product38-2(29.0 mg).

LC-MS:m/z 510(M+H) ⁺.

Step 3

Compound (I)38Synthetic reference compounds of1. Raw materials38-2(29.0 mg), triethylamine (0.0369 ml), acryloyl chloride (5.75 mg), dichloromethane (5 ml). Obtaining the product38(9.0 mg).

LC-MS:m/z 564(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.18-7.01(m,2H),6.96(d,J＝7.5Hz,1H),6.92-6.72(m,1H),6.29(d,J＝16.8Hz,1H),5.84(d,J＝10.8Hz,1H),5.21-5.08(m,1H),4.73-4.50(m,2H),4.44-4.27(m,2H),4.26-4.18(m,2H),4.01-3.81(m,2H),3.74-3.53(m, 1H),3.52-3.35(m,2H),3.28-3.20(m,1H),3.14-2.74(m,6H),2.53(s,3H),2.46-2.37(m,1H),2.34(s,3H),2.25-1.94(m,3H),1.94-1.64(m,3H).

Example 39

Step 1

Compound (I)39-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 1-bromo-2-fluoro-3-methoxy-benzene (40.0 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product39-1(29.0 mg, g.).

LC-MS:m/z 610(M+H) ⁺

Step 2

Compound (I)39-2Synthetic reference compounds of1-11. Raw materials39-1(29.0 mg), 1, 4-dioxane solution of hydrogen chloride (4 mol/l, 5 ml). Obtaining the product39-2(25.3 mg).

LC-MS:m/z 510(M+H) ⁺.

Step 3

Compound (I)39Synthetic reference compounds of1. Raw materials39-2(25.3 mg), triethylamine (23.4 mg), acryloyl chloride (6.30 mg), dichloromethane (5 ml). Obtaining the product39(7.8 mg).

LC-MS:m/z 564(M+H) ⁺

¹H-NMR(CD ₃OD)δ:6.96-6.71(m,2H),6.65-6.52(m,2H),6.28(d,J＝16.8Hz,1H),5.83(d,J＝10.5Hz,1H),5.18-5.00(m,1H),4.67-4.58(m,1H),4.46-4.31(m,4H),4.07-3.87(m,1H),3.82(s,3H),3.80-3.72(m,1H),3.61-3.49(m,2H),3.28-3.09(m,3H),3.06-2.76(m,6H),2.54(s,3H),2.46-2.32(m,1H),2.17-1.99(m,3H),1.93-1.69(m,3H).

Example 40

Step 1

Compound (I)40-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 1-bromo-3-fluoro-2-difluorotoluene (46.1 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). To obtain the product40-1(32.0 mg).

LC-MS:m/z 630(M+H) ⁺

Step 2

Compound (I)40-2Synthetic reference compounds of1-11. Raw materials40-1(32.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product40-2(28.1 mg).

LC-MS:m/z 530(M+H) ⁺.

Step 3

Compound (I)40Synthetic reference compounds of1. Raw materials40-2(28.1 mg), triethylamine (25.1 mg), acryloyl chloride (6.75 mg), dichloromethane (5 ml). Obtaining the product40(8.8 mg).

LC-MS:m/z 584(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.46(q,J＝7.2Hz,1H),7.10(d,J＝9.0Hz,1H),6.98-6.66(m,3H),6.30(d,J＝16.9Hz,1H),5.85(d,J＝10.5Hz,1H),5.19-5.01(m,1H),4.75-4.48(m,1H),4.42(d,J＝5.7Hz,2H),4.37-4.19(m,2H),4.16-3.82(m,3H),3.74-3.38(m,3H),3.27-2.84(m,7H),2.63(s,3H),2.58-2.48(m,1H),2.21-1.67(m,6H).

EXAMPLE 41

Step 1

Compound (I)41-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 1-bromo-3-difluoromethyl-2-toluene (45.3 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product41-1(35.0 mg).

LC-MS:m/z 626(M+H) ⁺

Step 2

Compound (I)41-2Synthetic reference compounds of1-11. Starting materials41-1(35.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product41-2(30.9 mg).

LC-MS:m/z 526(M+H) ⁺.

Step 3

Compound (I)41Synthetic reference compounds of1. Raw materials41-2(30.9 mg), triethylamine (27.8 mg), acryloyl chloride (7.47 mg), dichloromethane (5 ml). Obtaining the product41(9.8 mg).

LC-MS:m/z 580(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.34-7.20(m,3H),7.07-6.66(m,2H),6.30(d,J＝16.5Hz,1H),5.85(d,J＝10.5Hz,1H),5.24-5.04(m,1H),4.69-4.57(m,1H),4.42-4.30(m,2H),4.21-4.03(m,3H),4.01-3.81(m,2H),3.73-3.45(m,1H),3.42-3.35(m,1H),3.31-3.24(m,1H),3.18-2.74(m,7H),2.53(s,3H),2.45-2.34(m,1H),2.23(t,J＝1.4Hz,3H),2.18-1.98(m,3H),1.93-1.67(m,3H).

Example 42

Step 1:

at room temperature, mixing the raw materials1-7(3.60 g) was dissolved in 1, 2-dichloroethane (100 ml). N, N-diisopropylethylamine (2.81 g) and 1-chloroethyl chloroformate (2.59 g) were successively added. The reaction was carried out at room temperature for 1 hour. After concentration under reduced pressure, methanol (100 ml) was added to dissolve the mixture, and the reaction mixture was refluxed at 70 ℃ for 1 hour. Quench with slow addition of water (100 ml). Extract with ethyl acetate (100 ml x 3). Organic compoundsThe phases were combined and washed with saturated brine (100 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. Purifying the crude product by silica gel column chromatography (methanol/dichloromethane is 5% -15%), and obtaining the product42-1(2.42 g).

LC-MS:m/z 407(M+H) ⁺.

Step 2:

at room temperature, mixing the raw materials42-1(2.42 g) was dissolved in toluene (50 ml), and 8-methyl-1-bromonaphthalene (2.62 g), sodium tert-butoxide (1.99 g), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (0.497 g) were added in this order. The resulting mixture was replaced with nitrogen gas 3 times, and then reacted at 90 ℃ for 3 hours. After the reaction was complete, quench with water (100 ml). Extract with ethyl acetate (100 ml x 3). The organic phases were combined and washed with saturated brine (100 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. Purifying the crude product by silica gel column chromatography (15% -30% petroleum ether/ethyl acetate) to obtain the product42-2(1.75 g).

LC-MS:m/z 547(M+H) ⁺.

And step 3:

n-methyl-4, 4-difluoro-L-prolinol (69.5 mg) was dissolved in tetrahydrofuran (5.0 ml) at room temperature, and sodium hydride (60%) (18.3 mg) was added at 0 ℃. After reacting for 30 minutes at room temperature, the raw materials were added42-2(50.0 mg). The reaction mixture was reacted at 70 ℃ for 2 hours. After the reaction was complete, water (20 ml) was added and quenched. Extract with ethyl acetate (20 ml x 3). The organic phases were combined and washed with saturated brine (20 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. Purifying the crude product by silica gel column chromatography (methanol/dichloromethane is 5% -20%), and obtaining the product42-3(53.9 mg).

LC-MS:m/z 662(M+H) ⁺.

And 4, step 4:

at room temperature, mixing the raw materials42-3(53.9 mg) was dissolved in a1, 4-dioxane solution of hydrogen chloride (4 mol/l, 10 ml). The reaction was carried out at room temperature for 1 hour. After the reaction is finished, decompressing and concentrating to obtain a crude product42-4(44.9 mg). The product is used for the next reaction without purification.

LC-MS:m/z 562(M+H) ⁺.

And 5:

at room temperature, mixing the raw materials42-4(44.9 mg) was suspended in dichloromethane (10 ml), and triethylamine (37.9 mg) and acryloyl chloride (8.1 mg) were added sequentially at-40 ℃. The reaction solution was reacted at-40 ℃ for 1 hour. After the reaction was complete, water (20 ml) was added and quenched. Extract with dichloromethane (20 ml x 3). The organic phases were combined and washed with saturated brine (20 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative reverse phase chromatography (Column: SunAire Prep C18 OBD Column,5um 10nm,19 x 150 mm; mobile phase A: water (0.05%, trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 35-70%; time 8 min; detector wavelength 254/220 nm) to give the product42(24.8 mg).

LC-MS:m/z 616(M+H) ⁺.

¹H-NMR(CD ₃OD)δ:7.69-7.66(m,2H),7.42-7.19(m,4H),7.00-6.80(m,1H),6.32(d,J＝16.8Hz,1H),5.86(d,J＝10.5Hz,1H),5.15(s,1H),4.62-4.41(m,4H),4.17(t,J＝12.6Hz,2H),3.95-3.56(m,3H),3.47-3.39(m,3H),3.04-2.93(m,6H),2.83(s,3H),2.77-2.66(m,1H),2.59-2.50(m,1H),2.45(s,3H),2.22-2.04(m,3H).

Example 43

Step 1:

mixing the raw materials43-3(2 g) was dissolved in a dry tetrahydrofuran (100 ml) solution, bubbled with nitrogen for 2 minutes, and a solution of lithium aluminum hydride in tetrahydrofuran (1 mol per liter, 34.3 ml) was slowly added dropwise at 0 ℃. The reaction solution was reacted at 0 ℃ for 1 hour and then at 70 ℃ for 2 hours. After completion of the reaction, it was cooled to room temperature, quenched by addition of sodium sulfate decahydrate (10 g), and extracted with ethyl acetate (150 ml × 3). Washing the organic phase with saturated brine, and concentrating to obtain the compound43-4(844 mg).

LC-MS m/z 134(M+H) ⁺.

Step 2:

compound (I)43-1Synthetic reference compounds of42-3. Wherein the raw materials42-2(50.0 mg), (2S,4R)43-4(60.8 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 ml). Obtaining the product43-1(47.4 mg).

LC-MS:m/z 644(M+H) ⁺.

And step 3:

compound (I)43-2Synthetic reference compounds of42-4. Wherein the raw materials43-1(47.4 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 10 ml). Obtaining the product43-2(40.7 mg). The product is used for the next reaction without purification.

LC-MS:m/z 544(M+H) ⁺.

And 4, step 4:

compound (I)43Synthetic reference compounds of42. Wherein the raw materials43-2(40.7 mg), triethylamine (35.6 mg), acryloyl chloride (7.6 mg), dichloromethane (10 ml). The reaction product was purified by preparative reverse phase chromatography (Column: Xbridge Shield RP18 OBD Column,5um, 19X 150 mm; mobile phase A: water (1)0 mmol/l, ammonium bicarbonate), mobile phase B acetonitrile; flow rate 25 ml/min; gradient of 43-70%; the time is 8 minutes; wavelength of the detector 254/220 nm) to obtain the product43(24.9 mg).

LC-MS:m/z 598(M+H) ⁺.

¹H-NMR(CD ₃OD)δ:7.74-7.67(m,2H),7.45-7.31(m,3H),7.21(d,J＝4.8Hz,1H),7.00-6.80(m,1H),6.20(d,J＝16.8Hz,1H),5.86(d,J＝10.5Hz,1H),5.08-5.01(m,1H),4.39(t,J＝17.1Hz,2H),4.28-4.23(m,1H),4.17-3.96(m,3H),3.72-3.59(m,3H),3.46-3.39(m,2H),3.31-3.21(m,2H),3.17-3.14(m,1H),3.10-3.05(m,1H),3.01-2.92(m,2H),2.85-2.82(m,2H),2.77(d,J＝6.0Hz,4H),2.34(s,3H),2.12-1.79(m,4H).

Example 44

Step 1:

mixing the raw materials44-3(2 g) was dissolved in a dry solution of tetrahydrofuran (100 ml), bubbled with nitrogen for 2 minutes, and a solution of lithium aluminum hydride in tetrahydrofuran (1 mol per liter, 34.3 ml) was slowly added dropwise at 0 ℃. The reaction solution was reacted at 0 ℃ for 1 hour and then at 70 ℃ for 2 hours. After completion of the reaction, it was cooled to room temperature, quenched by addition of sodium sulfate decahydrate (10 g), and extracted with ethyl acetate (150 ml × 3). Washing the organic phase with saturated brine, and concentrating to obtain the compound44-4(844 mg).

LC-MS m/z 134(M+H) ⁺.

Step 2:

compound (I)44-1Synthetic reference compounds of42-3. Wherein the raw materials42-2(50.00 mg) of,44-4(61.2 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 ml). Obtaining the product44-1(52.3 mg).

LC-MS:m/z 644(M+H) ⁺.

And step 3:

compound (I)44-2Synthetic reference compounds of42-4. Wherein the raw materials44-1(52.3 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 10 ml). Obtaining the product44-2(45.4 mg). The product is used for the next reaction without purification.

LC-MS:m/z 544(M+H) ⁺.

And 4, step 4:

compound (I)44Synthetic reference compounds of42. Wherein the raw materials44-2(45.4 mg), triethylamine (40.5 mg), acryloyl chloride (9.0 mg), dichloromethane (10 ml). Purifying the reacted product with preparative reverse phase chromatographic Column (Column: Xbridge Prep C18 OBD Column,5um,19 x 150 mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 36-64%; time 10 min; detector wavelength 254/220 nm) to obtain product44(26.8 mg).

LC-MS:m/z 598(M+H) ⁺.

¹H-NMR(CD ₃OD)δ:7.68-7.64(m,2H),7.43-7.19(m,4H),7.00-6.80(m,1H),6.31(d,J＝12.6Hz,1H),5.86(d,J＝8.1Hz,1H),5.21-5.05(m,1H),4.61(s,1H),4.47-4.31(m,3H),4.17(t,J＝12.3Hz,2H),3.94-3.57(m,4H),3.51-3.37(m,2H),3.30-3.23(m,2H),3.15-3.00(m,3H),2.95-2.89(m,1H),2.83(s,3H),2.80-2.77(m,1H),2.58-2.51(m,1H),2.47(s,3H),2.21-1.84(m,4H).

Example 45

Step 1:

compound (I)45-1Synthetic reference compounds of42-3. Wherein the raw materials42-2(50.0 mg), N-hydroxyethylpiperidine (58.9 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 ml). Obtaining the product45-1(53.3 mg).

LC-MS:m/z 640(M+H) ⁺.

Step 2:

compound (I)45-2Synthetic reference compounds of42-4. Wherein the raw materials45-1(53.3 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 10 ml). Obtaining the product45-2(45.7 mg). The product is used for the next reaction without purification.

LC-MS:m/z 540(M+H) ⁺.

And step 3:

compound (I)45Synthetic reference compounds of42. Wherein the raw materials45-2(45.7 mg), triethylamine (40.3 mg), acryloyl chloride (8.6 mg), dichloromethane (10 ml). After the reaction, the product was purified by preparative reverse phase chromatography (Column: Xbridge Shield RP18 OBD Column,5um, 19X 150 mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 35-80%; time 8 min; detector wavelength 254/220 nm) to give the product45(24.3 mg).

LC-MS:m/z 594(M+H) ⁺.

¹H-NMR(CD ₃OD)δ:7.69-7.63(m,2H),7.43-7.19(m,4H),7.00-6.80(m,1H),6.31(d,J＝17.1Hz,1H),5.86(d,J＝10.8Hz,1H),5.15(s,1H),4.50-4.39(m,3H),4.16(t,J＝12.6Hz,2H),3.92-3.67(m,3H),3.46-3.36(m,3H),3.30-3.24(m,1H),3.11-2.86(m,5H),2.84(s,3H),2.76(t,J＝2.4Hz,2H),2.55(s,3H),2.03(s,2H),1.64-1.57(m,4H),1.50-1.43(m,2H).

Example 46

Step 1:

at room temperature, mixing the raw materials46-3(1.10 g) was dissolved in acetonitrile (50 ml), and potassium carbonate (965 mg) and bromoethanol (915 mg) were added in this order. The resulting reaction mixture was reacted at 90 ℃ for 12 hours. After the reaction was complete, quench with water (150 ml). Extract with ethyl acetate (150 ml x 3). The organic phases were combined and washed with saturated brine (150 ml). Drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the product46-4(525.0 mg).

LC-MS:m/z 166(M+H) ⁺.

Step 2:

compound (I)46-1Synthetic reference compounds of42-3. Wherein the raw materials42-2(50.0 mg) of a compound,46-4(75.6 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 ml). Obtaining the product46-1(54.0 mg).

LC-MS:m/z 676(M+H) ⁺.

And step 3:

compound (I)46-2Synthetic reference compounds of42-4. Wherein the raw materials46-1(54.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 10 ml). Obtaining the product46-2(45.9 mg). Without the need forAnd (5) purifying and directly using for the next reaction.

LC-MS:m/z 576(M+H) ⁺.

And 4, step 4:

compound (I)46Synthetic reference compounds of42. Wherein the raw materials46-2(45.9 mg), triethylamine (33.8 mg), acryloyl chloride (8.1 mg), dichloromethane (10 ml). After the reaction, the product was purified by preparative reverse phase chromatography (Column: Xbridge Shield RP18 OBD Column,5um, 19X 150 mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 50-75%; time 8 min; detector wavelength 254/220 nm) to give the product46(26.9 mg).

LC-MS:m/z 630(M+H) ⁺.

¹H-NMR(CD ₃OD)δ:7.68-7.64(m,2H),7.43-7.18(m,4H),7.00-6.80(m,1H),6.31(d,J＝16.5Hz,1H),5.86(d,J＝10.5Hz,1H),5.2(s,1H),4.49-4.39(m,3H),4.15(t,J＝12.3Hz,2H),3.92-3.66(m,3H),3.45-3.36(m,2H),3.30-3.25(m,1H),3.15-3.00(m,4H),2.94-2.83(m,6H),2.69(s,4H),2.04-1.91(m,6H).

Example 47

Step 1:

at room temperature, mixing the raw materials47-3(1.10 g) was dissolved in acetonitrile (50 ml), and potassium carbonate (965 mg) and bromoethanol (915 mg) were added in this order. The resulting reaction mixture was reacted at 90 ℃ for 12 hours. After the reaction was complete, quench with water (150 ml). Extract with ethyl acetate (150 ml x 3). The organic phases are combinedThen, the mixture was washed with saturated brine (150 ml). Drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the product47-4(586 mg).

LC-MS:m/z 166(M+H) ⁺.

And 2, step:

compound (I)47-1Synthetic reference compounds of42-3. Wherein the raw materials42-2(50.0 mg) of a compound,47-4(75.6 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 ml). Obtaining the product47-1(53.5 mg).

LC-MS:m/z 676(M+H) ⁺.

And step 3:

compound (I)47-2Synthetic reference compounds of42-4. Wherein the raw materials47-1(53.5 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 10 ml). Obtaining the product47-2(45.8 mg). The product is used for the next reaction without purification.

LC-MS:m/z 576(M+H) ⁺.

And 4, step 4:

compound (I)47Synthetic reference compounds of42. Wherein the raw materials47-2(45.8 mg), triethylamine (33.8 mg), acryloyl chloride (8.1 mg), dichloromethane (10 ml). After the reaction, the product was purified by preparative reverse phase chromatography (Column: Xbridge Shield RP18 OBD Column,5um, 19X 150 mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 55-70%; time 8 min; detector wavelength 254/220 nm) to give product47(26.1 mg).

LC-MS:m/z 630(M+H) ⁺.

¹H-NMR(CD ₃OD)δ:7.69-7.64(m,2H),7.42-7.19(m,4H),7.00-6.80(m,1H),6.32(d,J＝17.1Hz,1H),5.87(d,J＝11.4Hz,1H),5.15-5.05(m,1H),4.50-4.40(m,3H),4.17(t,J＝12.0Hz,2H),3.94-3.67(m,3H),3.47-3.38(m,2H),3.30-3.26(m,1H),3.11-3.00(m,4H),2.95-2.75(m,8H),2.58(s,2H),2.04-1.74(m,6H).

Example 48

Step 1:

at room temperature, mixing the raw materials48-3(1.10 g) was dissolved in acetonitrile (50 ml), and potassium carbonate (3.47 g) and bromopropanol (1.91 g) were added in this order. The resulting reaction mixture was reacted at 90 ℃ for 12 hours. After the reaction was complete, quench with water (150 ml). Extract with ethyl acetate (150 ml x 3). The organic phases were combined and washed with saturated brine (150 ml). Drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the product48-4(1.06 g).

LC-MS:m/z 146(M+H) ⁺.

Step 2:

compound (I)48-1Synthetic reference compounds of42-3. Wherein the raw materials42-2(50.0 mg) of a compound,48-4(66.7 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 ml). Obtaining the product48-1(50.1 mg).

LC-MS:m/z 656(M+H) ⁺.

And step 3:

compound (I)48-2Synthetic reference compounds of42-4. Wherein the raw materials48-1(50.1 mg), 1,4-Dioxane solution (4 mol/l, 10 ml). Obtaining the product48-2(40.5 mg). The product is used for the next reaction without purification.

LC-MS:m/z 556(M+H) ⁺.

And 4, step 4:

compound (I)48Synthetic reference compounds of42. Wherein the raw materials48-2(40.5 mg), triethylamine (34.8 mg), acryloyl chloride (7.4 mg), dichloromethane (10 ml). After the reaction, the product was purified by preparative reverse phase chromatography (Column: Xbridge Shield RP18 OBD Column,5um, 19X 150 mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 55-65%; time 8 min; detector wavelength 254/220 nm) to give product48(22.0 mg).

LC-MS:m/z 610(M+H) ⁺.

¹H-NMR(CD ₃OD)δ:7.69-7.64(m,2H),7.42-7.20(m,4H),7.00-6.80(m,1H),6.32(d,J＝17.1Hz,1H),5.87(d,J＝9.9Hz,1H),4.64(s,1H),4.46-4.37(m,3H),4.16(t,J＝12.6Hz,2H),3.93-3.73(m,3H),3.67(s,5H),3.51-3.38(m,2H),3.29-3.25(m,1H),3.10-3.01(m,3H),2.96-2.92(m,1H),2.84(s,3H),2.55-2.48(m,6H),2.09-1.94(m,4H).

Example 49

Step 1:

at room temperature, mixing the raw materials49-3(1.10 g) was dissolved in acetonitrile (50 ml), and potassium carbonate (3.06 g), bromopropanol (1.68 g) were added in this order. The reaction solution thus obtainedThe reaction was carried out at 90 ℃ for 12 hours. After the reaction was complete, quench with water (150 ml). Extract with ethyl acetate (150 ml x 3). The organic phases were combined and washed with saturated brine (150 ml). Drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the product49-4(841.0 mg).

LC-MS:m/z 158(M+H) ⁺.

Step 2:

compound (I)49-1Synthetic reference compounds of42-3. Wherein the raw materials42-2(50.0 mg) of a compound,49-4(71.9 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 ml). Obtaining the product49-1(49.9 mg).

LC-MS:m/z 668(M+H) ⁺.

And step 3:

compound (I)49-2Synthetic reference compounds of42-4. Wherein the raw materials49-1(49.9 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 10 ml). Obtaining the product49-2(39.4 mg). The product is used for the next reaction without purification.

LC-MS:m/z 568(M+H) ⁺.

And 4, step 4:

compound (I)49Synthetic reference compounds of42. Wherein the raw materials49-2(39.4 mg), triethylamine (33.8 mg), acryloyl chloride (7.2 mg), dichloromethane (10 ml). After the reaction, the product was purified by preparative reverse phase chromatography (Column: Xbridge Shield RP18 OBD Column,5um, 19X 150 mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 40-58%; time 8 min; detector wavelength 254/220 nm) to give the product49(21.0 mg).

LC-MS:m/z 622(M+H) ⁺.

¹H-NMR(CD ₃OD)δ:7.68-7.64(m,2H),7.43-7.19(m,4H),7.00-6.80(m,1H),6.31(d,J＝16.5Hz,1H),5.86(d,J＝10.5Hz,1H),5.15-5.05(m,1H),4.63(s,3H),4.45-4.37(m,4H),4.15(t,J＝12.6Hz,2H),4.00(d,J＝6.30Hz,1H),3.92-3.77(m,2H),3.59-3.58(m,2H),3.46-3.36(m,2H),3.30-3.25(m,1H),3.10-2.99(m,3H),2.94-2.78(m,5H),2.76-2.69(m,1H),2.58(d,J＝6.6Hz,1H),2.10-1.86(m,5H),1.731(d,J＝7.8Hz,1H).

Example 50

Step 1:

at room temperature, mixing the raw materials50-3(1.10 g) was dissolved in acetonitrile (5 ml), and potassium carbonate (3.06 g), bromopropanol (1.68 g) were added in this order. The resulting reaction mixture was reacted at 90 ℃ for 12 hours. After the reaction was complete, quench with water (150 ml). Extract with ethyl acetate (150 ml x 3). The organic phases were combined and washed with saturated brine (150 ml). Drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the product50-4(799.2 mg).

LC-MS:m/z 158(M+H) ⁺.

Step 2:

compound (I)50-1Synthetic reference compounds of42-3. Wherein the raw materials42-2(50.0 mg) of a compound,50-4(71.9 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 ml). Obtaining the product50-1(50.5 mg).

LC-MS:m/z 668(M+H) ⁺.

And step 3:

compound (I)50-2Synthetic reference compounds of42-4. Wherein the raw materials50-1(50.5 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 10 ml). Obtaining the product50-2(41.4 mg). The product is used for the next reaction without purification.

LC-MS:m/z 568(M+H) ⁺.

And 4, step 4:

compound (I)50Synthetic reference compounds of42. Wherein the raw materials50-2(41.4 mg), triethylamine (34.7 mg), acryloyl chloride (7.4 mg), dichloromethane (10 ml). After the reaction, the product was purified by preparative reverse phase chromatography (Column: XBridge Shield RP18 OBD Column,5um,19 x 150 mm; mobile phase a: water (10 mmol/l, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 38-52%; time 8 min; detector wavelength 254/220 nm) to give the product50(22.8 mg).

LC-MS:m/z 622(M+H) ⁺.

¹H-NMR(CD ₃OD)δ:7.68-7.64(m,2H),7.43-7.19(m,4H),7.00-6.80(m,1H),6.31(d,J＝12.3Hz,1H),5.86(d,J＝8.1Hz,1H),5.15-5.05(m,1H),4.82-4.60(m,1H),4.44-4.37(m,4H),4.15(t,J＝12.6Hz,2H),4.00(d,J＝6.60Hz,1H),3.92-3.67(m,3H),3.59-3.57(m,2H),3.45-3.35(m,2H),3.30-3.25(m,1H),3.15-2.97(m,4H),2.93-2.88(m,1H),2.85-2.79(m,4H),2.76-2.69(m,1H),2.57(d,J＝8.1Hz,1H),2.10-1.86(m,5H),1.72(d,J＝7.5Hz,1H).

Example 51

Step 1

Mixing the raw materials1-5(1.50 g) dissolved in isopropanol (30 mm)L), N-Boc-piperazine (1.10 g), diisopropylethylamine (1.26 g) were added in this order. The resulting mixture was reacted at 80 ℃ for 12 hours. After the reaction was complete, water (100 ml) was added for dilution. And extracted with ethyl acetate (100 ml x 3). The organic phases were combined, washed with saturated brine (200 ml), dried over anhydrous sodium sulfate and concentrated to dryness to give the product51-2(1.34 g).

LC-MS:m/z 458(M+H) ⁺

Step 2

(S) -prolinol (0.51 g) was dissolved in anhydrous tetrahydrofuran (15 ml) and sodium hydride (60%) (0.188 g) was added at 0 deg.C. After reacting for 30 minutes at 0 ℃, adding the raw materials51-2(1.34 g). The resulting solution was reacted at 70 ℃ for 3 hours. After the reaction, the reaction mixture was cooled to room temperature. Quenched by addition of saturated aqueous ammonium chloride (50 ml) and extracted with ethyl acetate (80 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (methanol/dichloromethane is 5% -20%) to obtain the product51-3(1.19 g).

LC-MS:m/z 537(M+H) ⁺

Step 3

Mixing the raw materials51-3(1.19 g) was dissolved in dry methanol (30 ml) and palladium on carbon (10%) (0.119 g) was added successively under nitrogen. The resulting reaction solution was replaced with hydrogen gas 3 times, and reacted at room temperature for 16 hours. After the reaction, the palladium-carbon is filtered. Concentrating the filtrate to dryness to obtain the product51-4(0.913 g).

LC-MS:m/z 447(M+H) ⁺

Step 4

Mixing the raw materials51-4(50.0 mg) was dissolved in toluene (2 ml), and 8-methyl-1-bromonaphthalene (37.0 mg), sodium tert-butoxide (108 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (28.1 mg) were added in this order. The resulting solution was stirred at 90 ℃ for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and diluted with water (15 ml)And extracted with ethyl acetate (15 ml x 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (10% -20% of dichloromethane/methanol) to obtain the product51-5(40.0 mg).

LC-MS:m/z 587(M+H) ⁺

Step 5

To the raw material51-5To (40.0 mg) was added a solution of hydrogen chloride in 1, 4-dioxane (5 ml). The resulting solution was stirred at room temperature for 10 minutes. After the reaction is finished, concentrating to be dry to obtain the product51-6(30 mg). The product is used for the next reaction without purification.

LC-MS:m/z 487(M+H) ⁺

Step 6

Mixing the raw materials51-6(30.0 mg) was dissolved in dichloromethane (5 ml), cooled to-40 ℃ and triethylamine (31.4 mg) and acryloyl chloride (8.44 mg) were added in that order. The resulting solution was reacted at-40 ℃ for 10 minutes. After the reaction was complete, quench with water (5 ml) and concentrate to dryness. The crude product was purified by preparative chromatography (Column: Xbridge Shield RP18 OBD Column,5um, 19X 150 mm; mobile phase A: water (10 mmol/l, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 38-59%; time 8 min; detector wavelength 254/220 nm) to give the product51(11.2 mg).

LC-MS:m/z 541(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.69-7.62(m,2H),7.42-7.36(m,2H),7.29(t,J＝7.2Hz,1H),7.19(d,J＝6.9Hz,1H),6.89-6.78(m,1H),6.31-6.22(m,1H),5.84-5.78(m,1H),4.44-4.25(m,3H),4.14(d,J＝15.3Hz,1H),3.92-3.77(m,4H),3.54-3.31(m,6H),3.11-2.99(m,2H),2.94-2.85(m,1H),2.83(s,3H),2.78-2.68(m,1H),2.47(d,J＝2.7Hz,3H),2.41-2.28(m,1H),2.11-1.95(m,3H),1.87-1.65(m,3H).

Example 52

Step 1:

compound (I)52-1Synthetic reference compounds of51-5. Starting materials51-4(raw materials 1(50.0 mg), 8-chloro-1-bromonaphthalene (40.3 mg), sodium tert-butoxide (108 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (28.1 mg) and toluene (2 ml) were added to obtain a product52-1(50.0 mg).

LC-MS:m/z 607(M+H) ⁺.

And 2, step:

compound (I)52-2Synthetic reference compounds of51-6. Raw materials52-1(50.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product52-2(43.0 mg).

LC-MS:m/z 507(M+H) ⁺.

Step 3

Compound (I)52Synthetic reference compounds of51. Raw materials52-2(43.0 mg), triethylamine (40.1 mg), acryloyl chloride (10.8 mg), dichloromethane (5 ml). Obtaining the product52(7.8 mg).

LC-MS:m/z 561(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.79(d,J＝8.4Hz,1H),7.64(d,J＝8.1Hz,1H),7.48(d, J＝7.8Hz,1H),7.45-7.31(m,3H),6.90-6.77(m,1H),6.25(d,J＝16.5Hz,1H),5.80(d,J＝10.5Hz,1H),4.41-4.23(m,4H),3.92-3.72(m,4H),3.60-3.36(m,6H),3.12-2.98(m,2H),2.90-2.99(m,2H),4.48(d,J＝1.2Hz,3H),2.40-2.30(m,1H),2.18-1.65(m,6H).

Example 53

Step 1:

at room temperature, mixing the raw materials1-5(2.00 g) was dissolved in isopropanol (50 ml), and diisopropylethylamine (2.52 g) and (S) -4-N-tert-butoxycarbonyl-2-methylpiperazine (1.43 g) were added in this order. The resulting mixture was reacted at 80 ℃ for 12 hours. After the reaction was complete, water (100 ml) was added for dilution. And extracted with ethyl acetate (100 ml x 3). The organic phases were combined, washed with saturated brine (200 ml), dried over anhydrous sodium sulfate and concentrated to dryness to give the product53-1(1.04 g).

LC-MS:m/z 472(M+H) ⁺.

Step 2:

(S) -prolinol (0.41 g) was dissolved in anhydrous tetrahydrofuran (20 ml) and sodium hydride (60%) (0.14 g) was added at 0 deg.C. After reacting for 30 minutes at 0 ℃, adding the raw materials53-1(1.04 g). The resulting solution was reacted at 70 ℃ for 3 hours. After the reaction, the reaction mixture was cooled to room temperature. Quenched by addition of saturated aqueous ammonium chloride (50 ml) and extracted with ethyl acetate (80 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (methanol/dichloromethane is 5% -20%) to obtain the product53-2(716 mg).

LC-MS:m/z 551(M+H) ⁺.

And 3, step 3:

at room temperature, mixing the raw materials53-2(716 mg) was dissolved in dry methanol (30 ml) and palladium on carbon (10%) (71.6 mg) was added under nitrogen. The resulting reaction solution was replaced with hydrogen gas 3 times, and reacted at room temperature for 2 hours. After the reaction, the palladium-carbon is filtered. Concentrating the filtrate to dryness to obtain the product53-3(540 mg).

LC-MS:m/z 461(M+H) ⁺.

And 4, step 4:

at room temperatureThen, the raw materials are mixed53-3(120 mg) was dissolved in toluene (3 ml), and 1-bromo-8-methylnaphthalene (115 mg), sodium tert-butoxide (250 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (65.3 mg) were added in this order. The resulting solution was stirred at 90 ℃ for 3 hours. After the reaction was complete, it was cooled to room temperature, diluted with water (15 ml) and extracted with ethyl acetate (15 ml × 3), the organic phases combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (10% -20% of dichloromethane/methanol) to obtain the product53-4(92.8 mg).

LC-MS:m/z 601(M+H) ⁺.

And 5:

at room temperature, adding the raw materials53-4(92.8 mg) to a solution of hydrogen chloride in 1, 4-dioxane (10 ml) was added. The resulting solution was stirred at room temperature for 10 minutes. After the reaction is finished, concentrating to be dry to obtain the product53-5(75.9 mg). The product is used for the next reaction without purification.

LC-MS:m/z 501(M+H) ⁺.

Step 6:

mixing the raw materials53-5(75.9 mg) was dissolved in dichloromethane (10 ml), cooled to-40 ℃ and triethylamine (71.7 mg) and acryloyl chloride (15.3 mg) were added in that order. The resulting solution was reacted at-40 ℃ for 10 minutes. After the reaction was complete, quench with water (10 ml), extract with ethyl acetate (15 ml x3), combine the organic phases and concentrate to dryness. The crude product was purified by preparative chromatography (Column: Xbridge Shield RP18 OBD Column,5um, 19X 150 mm; mobile phase A: water (10 mmol/l, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 35-80%; time 12 min; detector wavelength 254/220 nm) to give the product53(57.1 mg).

LC-MS:m/z 555(M+H) ⁺.

¹H-NMR(CD ₃OD)δ:7.69-7.62(m,2H),7.43-7.18(m,4H),6.93-6.77(m,1H),6.29(d,J＝16.2Hz,1H),5.82(d,J＝11.1Hz,1H),4.52-4.27(m,4H),4.19-3.93(m,3H),3.73-3.35(m,5H),3.29-3.15(m,1H),3.10-2.99(m,2H),2.91-2.86(m,1H),2.83(d,J＝5.7Hz,3H),2.80-2.68(m,1H),2.47(d,J＝2.7Hz,3H),2.34(q,J＝9.0Hz,1H),2.13-1.96(m,3H),1.85-1.76(m,2H),1.73-1.62(m,1H),1.31-1.18(m,3H).

Example 54

Step 1:

compound (I)54-1Synthetic reference compounds of53-4. Wherein the raw materials53-3(120 mg), 8-chloro-1-bromonaphthalene (125 mg), sodium tert-butoxide (250.5 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (65.5 mg), toluene (3 ml). Obtaining the product54-1(107 mg).

LC-MS:m/z 621(M+H) ⁺.

Step 2:

compound (I)54-2Synthetic reference compounds of53-5. Wherein the raw materials54-1(107 mg), 1, 4-dioxane solution of hydrogen chloride (4 mol/l, 10 ml). Obtaining the product54-2(90.7 mg).

LC-MS:m/z 521(M+H) ⁺.

And step 3:

compound (I)54Synthetic reference compounds of53. Raw materials54-2(90.7 mg), triethylamine (82.6 mg), acryloyl chloride (17.7 mg), dichloromethane (1 ml). Obtaining the product54(61.7 mg).

LC-MS:m/z 575(M+H) ⁺.

¹H-NMR(CD ₃OD)δ:7.79(d,J＝8.1Hz,1H),7.64(t,J＝7.5Hz,1H),7.50-7.29(m,4H),6.93-6.77(m,1H),6.29(d,J＝16.8Hz,1H),5.81(d,J＝10.8Hz,1H),4.58-4.38(m,1H),4.33-4.27(m,4H),4.13-3.92(m,2H),3.73-3.37(m,5H),3.29-3.16(m,1H),3.11-2.97(m,2H),2.87-2.70(m,2H),2.47(d,J＝1.5Hz,3H),2.35(q,J＝9.0Hz,1H),2.19-2.02(m,2H),1.97-1.90(m,1H),1.86-1.77(m,2H),1.74-1.63(m,1H),1.28-1.16(m,3H).

Example 56

Step 1:

compound (I)56-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 4-bromo-2-chlorophenylmethyl ether (45.3 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product56-1(29.0 mg).

LC-MS:m/z 626(M+H) ⁺.

Step 2:

compound (I)56-2Synthetic reference compounds of1-11. Raw materials56-1(30 mg), 1, 4-dioxane solution of hydrogen chloride (4 mol/l, 5 ml). To obtain the product56-2(25.7 mg).

LC-MS:m/z 526(M+H) ⁺.

Step 3

Compound (I)56Synthetic reference compounds of1. Raw materials56-2(25.7 mg), triethylamine (0.0318 ml), acryloyl chloride (5.16 mg), dichloromethane (5 ml). Obtaining the product56(7.0 mg).

LC-MS:m/z 580(M+H) ⁺

¹H-NMR(CD ₃OD)δ:6.92-6.66(m,4H),6.25(d,J＝16.8Hz,1H),5.81(d,J＝10.5Hz,1H),5.11-5.03(m,1H),4.67-4.59(m,1H),4.57-4.50(m,2H),4.50-4.30(m,2H),4.16-3.96(m,1H),3.95-3.78(m,2H),3.75(s,3H),3.72-3.50(m,2H),3.26-2.73(m,8H),2.53(s,3H),2.46-2.29(m,1H),2.25-1.65(m,6H).

Example 57

Step 1:

compound (I)57-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 3-bromo-5-chloro-4-methylpyridine (42.2 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product57-1(34.4 mg).

LC-MS:m/z 611(M+H) ⁺.

And 2, step:

compound (I)57-2Synthetic reference compounds of1-11. Raw materials57-1(34.4 mg), 1, 4-dioxane solution of hydrogen chloride (4 mol/l, 5 ml). Obtaining the product57-2(30.0 mg).

LC-MS:m/z 511(M+H) ⁺.

Step 3

Compound (I)57Synthetic reference compounds of1. Raw materials57-2(30.0 mg), triethylamine (0.0382 ml), acryloyl chloride (5.96 mg), dichloromethane (5 ml). Obtaining the product57(8.8 mg).

LC-MS:m/z 565(M+H) ⁺

¹H-NMR(CD ₃OD)δ:8.20(d,J＝3.9Hz,2H),6.98-6.72(m,1H),6.29(d,J＝16.8Hz,1H),5.84(d,J＝10.8Hz,1H),5.21-5.02(m,1H),4.68-4.54(m,1H),4.39-4.14(m,4H),4.03-3.82(m,2H),3.79-3.36(m,4H),3.17-2.71(m,7H),2.51(s,3H),2.45-2.31(m,1H),2.26(s,3H),2.21-1.99(m,3H),1.92-1.66(m,3H).

Example 58

Step 1

Mixing the raw materials58-1(10.0 g) was dissolved in dry methanol (150 ml) and a solution of sodium methoxide in methanol (30%) (26.2 g), thiourea (11.0 g) was added at 0 deg.c. The resulting mixture was warmed to 80 ℃ and stirred for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature. Dilute hydrochloric acid (1 mol/l) was added to adjust the pH to 7. The precipitated solid was collected by filtration and washed with water (50 ml). Drying the solid to obtain the product58-2(8.10 g). The product is used for the next reaction without purification.

LC-MS:m/z 288(M+H) ⁺

Step 2

Mixing the raw materials58-2(8.10 g) was suspended in phosphorus oxychloride (100 ml) and N, N-dimethylformamide (10 ml) was added. The resulting suspension was stirred at 100 ℃ for 12 hours. After the reaction, the reaction solution was concentrated to dryness. Water (100 ml) was added to the residue and the pH was adjusted to 8 with anhydrous sodium carbonate solution. The mixture was extracted with ethyl acetate (200 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (10% -50% ethyl acetate/petroleum ether) to obtain the product58-3(6.50 g).

LC-MS:m/z 308(M+H) ⁺

Step 3

Mixing the raw materials58-3(6.50 g) was dissolved in isopropanol (100 ml) and 2-cyanomethylpiperazine dihydrochloride (4.59 g), diisopropylethylamine (10.9 g) were added in this order. The resulting mixture was reacted at 80 ℃ for 24 hours. After the reaction was complete, water (200 ml) was added and quenched. And extracted with ethyl acetate (200 ml x 3). The organic phases were combined, washed with saturated brine (200 ml), dried over anhydrous sodium sulfate and concentrated to dryness to give the product58-4(6.10 g). The product is used for the next reaction without purification.

LC-MS:m/z 397(M+H) ⁺

Step 4

Mixing the raw materials58-4(6.10 g) was dissolved in anhydrous tetrahydrofuran (100 ml), and di-tert-butyl dicarbonate (4.03 g) and diisopropylethylamine (2.38 g) were added in this order. The resulting solution was reacted at reflux for 1 hour. After the reaction, the reaction mixture was cooled to room temperature. Water (150 ml) was added to dilute and extracted with ethyl acetate (150 ml x 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (30% -60% ethyl acetate/petroleum ether) to obtain the product58-5(5.50 g).

LC-MS:m/z 497(M+H) ⁺

Step 5

(S) -prolinol (1.91 g) was dissolved in anhydrous tetrahydrofuran (100 ml) and sodium hydride (60%) (0.665 g) was added at 0 deg.C. After reacting for 30 minutes at 0 ℃, adding the raw materials58-5(5.50 g). The resulting solution was reacted at reflux for 3 hours. After the reaction, the reaction mixture was cooled to room temperature. Quenched by addition of saturated aqueous ammonium chloride (150 ml) and extracted with ethyl acetate (150 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (methanol/dichloromethane is 5% -20%) to obtain the product58-6(4.20 g).

LC-MS:m/z 576(M+H) ⁺

Step 6

Mixing the raw materials58-6(4.20 g) dissolved in anhydrous sodium benzoateTo an alcohol (100 ml), palladium on carbon (10%) (0.42 g) and a methanol solution of ammonia (7 mol/l) (10 ml) were sequentially added under nitrogen protection. The resulting reaction solution was replaced with hydrogen gas 3 times, and reacted at 40 ℃ for 3 hours. After the reaction, the palladium-carbon is filtered. Concentrating the filtrate to dryness to obtain the product58-7(2.50 g).

LC-MS:m/z 486(M+H) ⁺

Step 7

Mixing the raw materials58-7(50.0 mg) was dissolved in toluene (2 ml), and 1-bromonaphthalene (25.5 mg), sodium tert-butoxide (49.4 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (8.6 mg) were added in this order. The resulting solution was stirred at 90 ℃ for 3 hours. After completion of the reaction, it was cooled to room temperature, diluted with water (15 ml) and extracted with ethyl acetate (15 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (10% -20% of dichloromethane/methanol) to obtain the product58-8(25.0 mg).

LC-MS:m/z 612(M+H) ⁺

Step 8

To the raw material58-8(25.0 mg) was added a solution of hydrogen chloride in 1, 4-dioxane (2 ml). The resulting solution was stirred at room temperature for 1 hour. After the reaction is finished, concentrating to be dry to obtain the product58-9(15.0 mg). The product is used for the next reaction without purification.

LC-MS:m/z 512(M+H) ⁺

Step 9

Mixing the raw materials58-9(15.0 mg) was dissolved in dichloromethane (2 ml), cooled to-40 ℃ and triethylamine (13.8 mg) and acryloyl chloride (2.5 mg) were added in that order. The resulting solution was reacted at-40 ℃ for 1 hour. After the reaction was complete, quench with water (5 ml) and concentrate to dryness. The resulting crude product was purified by preparative chromatography (Column: Xbridge Shield RP18 OBD Column,5um, 19X 150 mm; mobile phase A: water (10 mmol/l, ammonium bicarbonate) and mobile phase B: acetonitrile;flow rate: 25 ml/min; a gradient; 42-61%; the time is 8 minutes; detector wavelength 254/220 nm) to obtain the product58(7.8 mg).

LC-MS:m/z 566(M+H) ⁺

¹H-NMR(CD ₃OD)δ:8.37(d,J＝8.1Hz,1H),7.85(d,J＝6.6Hz,1H),7.60-7.46(m,3H),7.40(t,J＝8.1Hz,1H),7.16(d,J＝6.9Hz,1H),6.93-6.75(m,1H),6.29(dd,J ₁＝1.5Hz,J ₂＝16.5Hz,1H),5.84(dd,J ₁＝1.5Hz,J ₂＝10.5Hz,1H),5.12-4.60(m,1H),4.45-4.35(m,2H),4.18-4.03(m,1H),3.93-3.77(m,2H),3.71-3.51(m,2H),3.30-3.23(m,6H),3.22-3.01(m,6H),2.89-2.77(m,1H),2.56(s,3H),2.46-2.38(m,1H),2.18-2.07(m,1H),1.91-1.71(m,3H).

Example 59

Step 1

Compound (I)59-1Synthetic reference compounds of58-8. Raw materials58-7(50.0 mg), 8-methyl-1-bromonaphthalene (45.3 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product59-1(27.0 mg).

LC-MS:m/z 626(M+H) ⁺

Step 2

Compound (I)59-2Synthetic reference compounds of58-9. Raw materials59-1(27.0 mg), 1, 4-dioxane (4 mol/l, 2 ml). Obtaining the product59-2(22.0 mg).

LC-MS:m/z 526(M+H) ⁺

Step 3

Compound (I)59Synthetic reference compounds of58. Raw materials59-2(22.0 mg), triethylamine (19.8 mg), acryloyl chloride (5.3 mg), dichloromethane (5 ml). Obtaining the product59(7.2 mg).

LC-MS:m/z 580(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.70-7.63(m,2H),7.40-7.28(m,4H),6.94-6.70(m,1H),6.29(d,J＝16.5Hz,1H),5.83(d,J＝10.5Hz,1H),5.12-4.66(m,1H),4.46-4.36(m,2H),4.16-3.99(m,1H),3.91-3.74(m,2H),3.55-3.36(m,5H),3.16(d,J＝7.2Hz,3H),3.13-2.82(m,10H),2.54(s,3H),2.47(q,J＝3.6Hz,1H),2.21-2.09(m,1H),1.95-1.72(m,3H).

Example 60

Step 1

Compound (I)60-1Synthetic reference compounds of58-8. Raw materials58-7(50.0 mg), 8-fluoro-1-bromonaphthalene (46.2 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product60-1(24.0 mg).

LC-MS:m/z 630(M+H) ⁺

Step 2

Compound (I)60-2Synthetic reference compounds of58-9. Raw materials60-1(24.0 mg), 1, 4-dioxane (4 mol/l, 2 ml). To obtain the product60-2(20.0 mg).

LC-MS:m/z 530(M+H) ⁺

Step 3

Compound (I)60Synthetic reference compounds of58. Raw materials60-2(20.0 mg), triethylamine (17.8 mg), acryloyl chloride (4.8 mg), dichloromethane (5 ml). Obtaining the product60(8.0 mg).

LC-MS:m/z 584(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.67(d,J＝6.9Hz,1H),7.57(d,J＝8.1Hz,1H),7.46-7.38(m,2H),7.21-7.12(m,2H),6.97-6.74(m,1H),6.28(d,J＝16.5Hz,1H),5.84(d,J＝10.5Hz,1H),5.13-4.65(m,1H),4.40-4.17(m,2H),4.21-4.04(m,1H),3.96-3.83(m,1H),3.81-3.55(m,4H),3.48-3.35(m,1H),3.29-3.18(m,2H),3.16-2.90(m,9H),2.63(s,3H),2.53(q,J＝3.6Hz,1H),2.25-2.10(m,1H),1.96-1.75(m,3H).

Example 61

Step 1

Compound (I)61-1Synthetic reference compounds of58-8. Starting materials58-7(50.0 mg), 8-chloro-1-bromonaphthalene (49.5 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product61-1(25.0 mg).

LC-MS:m/z 646(M+H) ⁺

Step 2

Compound (I)61-2Synthetic reference compounds of58-9. Raw materials61-1(25.0 mg), 1, 4-dioxane (4 mol/l, 2 ml). Obtaining the product61-2(21.0 mg).

LC-MS:m/z 546(M+H) ⁺

Step 3

Compound (I)61Synthetic reference compounds of58. Raw materials61-2(21.0 mg), triethylamine (18.2 mg), acryloyl chloride (4.9 mg), dichloromethane (5 ml). Obtaining the product61(8.5 mg).

LC-MS:m/z 600(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.81(d,J＝7.2Hz,1H),7.66(d,J＝7.8Hz,1H),7.58(d,J＝6.9Hz,1H),7.47-7.31(m,3H),6.94-6.71(m,1H),6.28(d,J＝16.5Hz,1H), 5.84(d,J＝10.5Hz,1H),5.13-4.65(m,1H),4.40-4.13(m,2H),4.18-4.03(m,1H),3.91-3.75(m,2H),3.67-3.50(m,4H),3.31-3.20(m,2H),3.17-3.07(m,2H),3.03-2.79(m,7H),2.55(s,3H),2.41(q,J＝3.6Hz,1H),2.17-2.06(m,1H),1.90-1.68(m,3H).

Example 62

Step 1

Mixing the raw materials58-3(3.00 g) was dissolved in isopropanol (80 ml), and (S) -2-cyanomethylpiperazine dihydrochloride (2.31 g) and diisopropylethylamine (5.04 g) were added in this order. The resulting mixture was reacted at 80 ℃ for 24 hours. After the reaction was complete, water (200 ml) was added for dilution. And extracted with ethyl acetate (200 ml x 3). The organic phases were combined, washed with saturated brine (200 ml), dried over anhydrous sodium sulfate and concentrated to dryness to give the product62-1(2.80 g).

LC-MS:m/z 397(M+H) ⁺

Step 2

Mixing the raw materials62-1(2.80 g) was dissolved in anhydrous tetrahydrofuran (50 ml), and di-tert-butyl dicarbonate (1.85 g) and diisopropylethylamine (1.37 g) were added in this order. The resulting solution was reacted at reflux for 1 hour. After the reaction, the reaction mixture was cooled to room temperature. Water (150 mm) was addedL) and extracted with ethyl acetate (150 ml x 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (30-60% ethyl acetate/petroleum ether) to obtain the product62-2(2.70 g).

LC-MS:m/z 497(M+H) ⁺

Step 3

(S) -prolinol (0.938 g) was dissolved in anhydrous tetrahydrofuran (100 ml) and sodium hydride (60%) (0.326 g) was added at 0 deg.C. After reacting for 30 minutes at 0 ℃, adding the raw materials62-2(2.70 g). The resulting solution was reacted at 70 ℃ for 3 hours. After the reaction, the reaction mixture was cooled to room temperature. Quenched by addition of saturated aqueous ammonium chloride (150 ml) and extracted with ethyl acetate (150 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (methanol/dichloromethane is 5% -20%) to obtain the product62-3(2.20 g).

LC-MS:m/z 576(M+H) ⁺

Step 4

Mixing the raw materials62-3(2.20 g) was dissolved in dry methanol (80 ml) and palladium on carbon (10%) (0.22 g) was added under nitrogen in succession with a solution of ammonia in methanol (7 mol/l) (8 ml). The resulting reaction solution was replaced with hydrogen gas 3 times, and reacted at 40 ℃ for 3 hours. After the reaction, the palladium-carbon is filtered. Concentrating the filtrate to dryness to obtain the product62-4(1.50 g).

LC-MS:m/z 486(M+H) ⁺

Step 5

Mixing the raw materials62-4(50.0 mg) was dissolved in toluene (2 ml), and 8-methyl-1-bromonaphthalene (27.2 mg), sodium tert-butoxide (49.4 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (8.6 mg) were added in this order. The resulting solution was reacted at 90 ℃ for 3 hours. After completion of the reaction, it was cooled to room temperature, diluted with water (15 ml) and extracted with ethyl acetate (15 ml × 3). The organic phases are combined and concentrated to dryness. The crude product was chromatographed on silica gel columnPurifying (10% -20% of dichloromethane/methanol) to obtain the product62-5(24.0 mg).

LC-MS:m/z 626(M+H) ⁺

Step 6

To the raw material62-5(24.0 mg) to a solution of hydrogen chloride in 1, 4-dioxane (2 ml) was added. The resulting solution was stirred at room temperature for 1 hour. After the reaction is finished, concentrating to be dry to obtain the product62-6(15.0 mg). The product is used for the next reaction without purification.

LC-MS:m/z 526(M+H) ⁺

Step 7

Mixing the raw materials62-6(15.0 mg) was dissolved in dichloromethane (2 ml), cooled to-40 ℃ and triethylamine (13.4 mg) and acryloyl chloride (2.4 mg) were added in that order. The resulting solution was reacted at-40 ℃ for 1 hour. After the reaction was complete, quench with water (5 ml) and concentrate to dryness. The crude product was purified by preparative chromatography (Column: Xbridge Shield RP18 OBD Column,5um, 19X 150 mm; mobile phase A: water (10 mmol/l, ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 25 ml/min; gradient: 42-61%, time 8 min; detector wavelength 254/220 nm) to give the product62(7.8 mg).

LC-MS:m/z 580(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.74-7.62(m,2H),7.45-7.28(m,4H),6.95-6.77(m,1H),6.29(dd,J ₁＝1.5Hz,J ₂＝16.5Hz,1H),5.84(dd,J ₁＝1.5Hz,J ₂＝10.5Hz,1H),5.12-4.60(m,1H),4.45-4.35(m,2H),4.18-4.03(m,1H),3.93-3.77(m,2H),3.71-3.51(m,2H),3.50-3.36(m,3H),3.35-3.28(m,2H)，3.19(d,J＝7.2Hz,3H),3.16-3.09(m,4H),3.07-2.82(m,5H),2.72(s,3H),2.30-2.15(m,1H),2.00-1.80(m,3H).

Example 63

Mixing the raw materials62-6(15.5 mg) was dissolved in dichloromethane (2 ml), cooled to-40 ℃ and triethylamine (13.8 mg) and vinylsulfonyl chloride (3.5 mg) were added in that order. The resulting solution was reacted at-40 ℃ for 10 minutes. After completion of the reaction, quench with water (5 ml) and extract with ethyl acetate (10 ml × 3). The organic phases were combined and washed with saturated brine (150 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crude product was purified by preparative chromatography (Column: Xbridge Shield RP18 OBD Column,5um,19 x 150 mm; mobile phase A: water (10 mmol/l, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 40-75%; time 8 min; detector wavelength 254/220 nm) to give the product63(10.8 mg).

LC-MS:m/z 616(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.66(dd,J ₁＝7.2Hz,J ₂＝5.4Hz,2H),7.39-7.27(m,4H),6.78 (dd,J ₁＝9.9Hz,J ₂＝6.6Hz,1H),6.27(d,J＝16.2Hz,1H),6.06(d,J＝9.6Hz,1H),4.54(q,J ₁＝11.7Hz,J ₂＝13.2Hz,2H),4.43-4.39(m,1H),3.88(d,J＝13.8Hz,1H),3.73-3.67(m,2H),3.56-3.37(m,7H),3.15(d,J＝9.6Hz,4H),3.10-2.88(m,8H),2.83(s,3H),2.36-2.21(m,1H),2.10-1.85(m,3H).

Example 64

Mixing the raw materials62-6(15.5 mg) was dissolved in dichloromethane (2 ml), cooled to-40 ℃ and then triethylamine (13.8 mg) and 3- (N, N-dimethylamino) methacryloyl chloride (4.0 mg) were added in that order. The resulting solution was reacted at-40 ℃ for 10 minutes. After the reaction was complete, add water (10 ml) and quench with ethyl acetateEster (10 ml x3) extraction. The organic phases were combined and washed with saturated brine (10 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crude product was purified by preparative chromatography (Column: Xbridge Shield RP18 OBD Column,5um, 19X 150 mm: mobile phase A: water (10 mmol/l, ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 25 ml/min, gradient: 35-72%, time 8 min, detector wavelength 254/220 nm) to give the product64(10.5 mg).

LC-MS:m/z 637(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.72-7-64(m,2H),7.40-7.27(m,4H),6.91-6.63(m,2H),5.09(s,1H),4.46(d,J＝5.4Hz,2H),3.60-3.40(m,4H),3.29-3.22(m,4H),3.16(d,J＝6.3Hz,3H),3.12-2.87(m,8H),2.67(s,3H),2.62-2.54(m,1H),2.33(s,6H),2.26-2.10(m,2H),1.98-1.90(m,3H),1.88-1.75(m,2H),1.61(s,1H).

Example 65

Mixing the raw materials62-6(15.5 mg) was dissolved in dichloromethane (2 ml), cooled to-40 ℃ and then N, N-diisopropylethylamine (7.1 mg), propylphosphoric anhydride (50% ethyl acetate solution) (35.1 mg), 2-butynoic acid (4.6 mg) were added in that order. The resulting solution was reacted at 0 ℃ for 1 hour. After completion of the reaction, quench with water (5 ml) and extract with ethyl acetate (10 ml × 3). The organic phases were combined and washed with saturated brine (150 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crude product was purified by preparative chromatography (Column: Xbridge Shield RP18 OBD Column,5um, 19X 150 mm; mobile phase A: water (10 mmol/l, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 32-70%; time 8 min; detector wavelength 254/220 nm) to give the product65(8.1 mg).

LC-MS:m/z 592(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.66(dd,J ₁＝7.5Hz,J ₂＝5.4Hz,2H),7.39-7.27(m,4H),5.02(s,1H),4.48-4.45(m,2H),3.53-3.40(m,4H),3.29-2.26(m,1H),3.23-3.20(m,1H),3.17-3.08(m,7H),3.05-2.86(m,6H),2.70(d,J＝3.3Hz,3H),2.65-2.60(m,1H),2.25-2.16(m,2H),2.09(d,J＝11.1Hz,3H),2.00-1.80(m,4H).

Example 66

Step 1

Mixing the raw materials58-3(3.00 g) was dissolved in isopropanol (80 ml), and (R) -2-cyanomethylpiperazine dihydrochloride (2.31 g) and diisopropylethylamine (5.04 g) were added in this order. The resulting mixture was reacted at 80 ℃ for 24 hours. After the reaction was complete, water (200 ml) was added for dilution. And extracted with ethyl acetate (200 ml x 3). The organic phases were combined, washed with saturated brine (200 ml), dried over anhydrous sodium sulfate and concentrated to dryness to give the product66-1(2.70 g).

LC-MS:m/z 397(M+H) ⁺

Step 2

Mixing the raw materials66-1(2.70 g) was dissolved in anhydrous tetrahydrofuran (50 ml), and di-tert-butyl dicarbonate (1.78 g) and diisopropylethylamine (1.32 g) were added in this order. The resulting solution was refluxed for 1 hour. After the reaction, the reaction mixture was cooled to room temperature. Water (150 ml) was added to dilute and extracted with ethyl acetate (150 ml x 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (30% -60% ethyl acetate/petroleum ether) to obtain the product66-2(2.70 g).

LC-MS:m/z 497(M+H) ⁺

Step 3

(S) -prolinol (0.938 g) was dissolved in anhydrous tetrahydrofuran (100 ml) at 0 deg.CSodium hydride (60%) (0.326 g) was added. After reacting for 30 minutes at 0 ℃, adding the raw materials66-2(2.70 g). The resulting solution was reacted at 70 ℃ for 3 hours. After the reaction, the reaction mixture was cooled to room temperature. Quenched by addition of saturated aqueous ammonium chloride (150 ml) and extracted with ethyl acetate (150 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (methanol/dichloromethane is 5% -20%) to obtain the product66-3(2.25 g).

LC-MS:m/z 576(M+H) ⁺

Step 4

Mixing the raw materials66-3(2.25 g) was dissolved in dry methanol (80 ml) and palladium on carbon (10%) (0.22 g) was added under nitrogen in succession with a solution of ammonia in methanol (7 mol/l) (8 ml). The resulting reaction solution was replaced with hydrogen gas 3 times, and reacted at 40 ℃ for 3 hours. After the reaction, the palladium-carbon is filtered. Concentrating the filtrate to dryness to obtain the product66-4(1.60 g).

LC-MS:m/z 486(M+H) ⁺

Step 5

Mixing the raw materials66-4(50.0 mg) was dissolved in toluene (2 ml), and 8-methyl-1-bromonaphthalene (27.2 mg), sodium tert-butoxide (49.4 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (8.6 mg) were added in this order. The resulting solution was stirred at 90 ℃ for 3 hours. After completion of the reaction, it was cooled to room temperature, diluted with water (15 ml) and extracted with ethyl acetate (15 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (10% -20% of dichloromethane/methanol) to obtain the product66-5(24.0 mg).

LC-MS:m/z 626(M+H) ⁺

Step 6

To the raw material66-5(24.0 mg) to a solution of hydrogen chloride in 1, 4-dioxane (2 ml) was added. The resulting solution was stirred at room temperature for 1 hour. After the reaction is finished, concentrating to be dry to obtain the product66-6(15.0 mg). The product is used for the next reaction without purification.

LC-MS:m/z 526(M+H) ⁺

Step 7

Mixing the raw materials66-6(15.0 mg) was dissolved in dichloromethane (2 ml), cooled to-40 ℃ and triethylamine (13.4 mg) and acryloyl chloride (2.4 mg) were added in that order. The resulting solution was reacted at-40 ℃ for 1 hour. After the reaction was complete, quench with water (5 ml) and concentrate to dryness. The crude product was purified by preparative chromatography (Column: Xbridge Shield RP18 OBD Column,5um, 19X 150 mm; mobile phase A: water (10 mmol/l, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 42-61%; time 8 min; detector wavelength 254/220 nm) to give the product66(7.8 mg).

LC-MS:m/z 580(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.70-7.63(m,2H),7.39-7.27(m,4H),6.92-6.75(m,1H),6.28(d,J＝16.5Hz,1H),5.83(d,J＝10.5Hz,1H),5.12-4.60(m,1H),4.50-4.22(m,2H),4.18-4.01(m,1H),3.93-3.77(m,2H),3.71-3.62(m,1H),3.55-3.39(m,4H),3.30-3.23(m,2H)，3.19-3.06(m,7H),3.04-2.83(m,5H),2.72(s,3H),2.27-2.17(m,1H),2.01-1.79(m,3H).

Example 67

Step 1:

compound (I)67-1Synthetic reference compounds of66-5. Raw materials66-4(50.0 mg), 1-bromonaphthalene (42.4 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product67-1(30.0 mg).

LC-MS:m/z 612(M+H) ⁺

Step 2:

compound (I)67-2Synthetic reference compounds of66-6. Raw materials67-1(30.0 mg), 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product67-2(26.0 mg).

LC-MS:m/z 512(M+H) ⁺

And step 3:

compound (I)67Synthetic reference compounds of66. Raw materials67-2(26.0 mg), triethylamine (24.0 mg), acryloyl chloride (6.45 mg), dichloromethane (5 ml). Obtaining the product67(3.7 mg).

LC-MS:m/z 566(M+H) ⁺

¹H-NMR(CD ₃OD)δ:8.36(d,J＝8.4Hz,1H),7.89-7.82(m,1H),7.63-7.36(m,4H),7.16(d,J＝7.5Hz,1H),6.94-6.73(m,1H),6.29(d,J＝16.7Hz,1H),5.84(d,J＝10.6Hz,1H),5.17-5.05(m,1H),4.81-4.52(m,1H),4.54-4.43(m,2H),4.17-4.01(m,1H),3.99-3.52(m,4H),3.31-2.88(m,11H),2.69(s,3H),2.67-2.52(m,1H),2.3-2.14(m,1H),2.06-1.71(m,4H).

Example 68

Step 1:

compound (I)68-1Synthetic reference compounds of66-5. Raw materials66-4(50.0 mg), 8-chloro-1-bromonaphthalene (49.4 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). To obtain the product68-1(48.0 mg).

LC-MS:m/z 646(M+H) ⁺

Step 2:

compound (I)68-2Synthetic reference compounds of66-6. Raw materials68-1(48.0 mg), 1, 4-dioxane (4 mol/l, 5 ml). To obtain the product68-2(42.0 mg).

LC-MS:m/z 546(M+H) ⁺

And 3, step 3:

compound (I)68Synthetic reference compounds of66. Starting materials68-2(42.0 mg), triethylamine (36.5 mg), acryloyl chloride (9.81 mg), dichloromethane (5 ml). Obtaining the product68(6.0 mg).

LC-MS:m/z 600(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.82(d,J＝7.7Hz,1H),7.67(d,J＝8.0Hz,1H),7.58(d,J＝7.5Hz,1H),7.49-7.31(m,3H),6.95-6.72(m,1H),6.29(d,J＝16.5Hz,1H),5.83(d,J＝10.6Hz,1H),5.18-5.04(m,1H),4.81-4.55(m,1H),4.34(d,J＝5.7Hz,2H),4.17-3.71(m,4H),3.70-3.48(m,4H),3.33-3.16(m,2H),3.13-2.83(m,7H),2.63(s,3H),2.59-2.45(m,1H),2.25-2.06(m,1H),2.01-1.71(m,3H).

Example 69

Step 1:

compound (I)69-1Synthetic reference compounds of66-5. Starting materials66-4(50.0 mg), 8-ethyl-1-bromonaphthalene (48.2 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). To obtain the product69-1(36.0 mg).

LC-MS:m/z 640(M+H) ⁺

Step 2:

compound (I)69-2Synthetic reference compounds of66-6. Raw materials69-1(36.0 mg), 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product69-2(31.4 mg).

LC-MS:m/z 540(M+H) ⁺

And step 3:

compound (I)69Synthetic reference compounds of66. Raw materials69-2(31.4 mg), triethylamine (27.6 mg), acryloyl chloride (7.4 mg), dichloromethane (5 ml). Obtaining the product69(7.4 mg).

LC-MS:m/z 594(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.72-7.64(m,2H),7.40-7.30(m,4H),6.89-6.72(m,1H),6.28(d,J＝4.8Hz,1H),5.83(d,J＝10.5Hz,1H),5.18-4.97(m,1H),4.79-4.38(m,3H),4.21-3.37(m,12H),3.21-2.90(m,7H),2.89-2.83(m,1H),2.81(s,3H),2.34-2.20(m,1H),2.10-1.81(m,3H),1.28(q,J＝7.5Hz,3H).

Example 70

Step 1

Mixing the raw materials58-3(2.00 g) was dissolved in isopropanol (80 ml), and tert-butyl piperazinecarboxylate (1.45 g) and diisopropylethylamine (1.68 g) were added in this order. The resulting mixture was reacted at 80 ℃ for 24 hours. After the reaction was complete, water (200 ml) was added for dilution. And extracted with ethyl acetate (100 ml x 3). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated to dryness to give the product 70-1(1.30 g).

LC-MS:m/z 458(M+H) ⁺

Step 2

(S) -prolinol (0.528 g) was dissolved in anhydrous tetrahydrofuran (100 ml) and sodium hydride (60%) (0.183 g) was added at 0 deg.C. After reacting for 30 minutes at 0 ℃, adding the raw materials70-1(1.30 g). The resulting solution was reacted at 70 ℃ for 3 hours. After the reaction, the reaction mixture was cooled to room temperature. Quenched by addition of saturated aqueous ammonium chloride (100 ml) and extracted with ethyl acetate (100 ml × 3). The organic phases are combined and concentrated to dryness. The crude product is purified by silica gel column chromatography (methanol/dichloromethane is 5% -20%) to obtain the product70-2(1.10 g).

LC-MS:m/z 537(M+H) ⁺

Step 3

Mixing the raw materials70-2(1.10 g) was dissolved in dry methanol (40 ml) and palladium on carbon (10%) (0.11 g) and ammonia in methanol (7 mol/l) (4 ml) were added successively under nitrogen protection. The resulting reaction solution was replaced with hydrogen gas 3 times, and reacted at 40 ℃ for 3 hours. After the reaction, the palladium-carbon is filtered. Concentrating the filtrate to dryness to obtain the product70-3(0.80 g).

LC-MS:m/z 447(M+H) ⁺

Step 4

Mixing the raw materials70-3(50.0 mg) was dissolved in toluene (2 ml), and 8-methyl-1-bromonaphthalene (49.2 mg), sodium tert-butoxide (53.7 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (9.4 mg) were added in this order. The resulting solution was stirred at 90 ℃ for 3 hours. After completion of the reaction, it was cooled to room temperature, diluted with water (15 ml) and extracted with ethyl acetate (15 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (10% -20% of dichloromethane/methanol) to obtain the product70-4(21.0 mg).

LC-MS:m/z 587(M+H) ⁺

Step 5

To the raw material70-4(21.0 mg) to a solution of hydrogen chloride in 1, 4-dioxane (2 ml) was added. The resulting solution was stirred at room temperature for 1 hour. After the reaction is finished, concentrating to be dry to obtain the product70-5(15.0 mg). The product is used for the next reaction without purification.

LC-MS:m/z 487(M+H) ⁺

Step 6

Mixing the raw materials70-5(15.0 mg) was dissolved in dichloromethane (2 ml), cooled to-40 ℃ and triethylamine (14.5 mg) and acryloyl chloride (2.6 mg) were added in that order. The resulting solution was reacted at-40 ℃ for 1 hour. After the reaction was complete, quench with water (5 ml) and concentrate to dryness. The crude product was purified by preparative chromatography (Column: Xbridge Shield RP18 OBD Column,5um, 19X 150 mm; mobile phase A: water (10 mmol/l, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 30-65%; time 8 min; detector wavelength 254/220 nm) to give the product70(7.8 mg).

LC-MS:m/z 541(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.70-7.63(m,2H),7.39-7.27(m,4H),6.85-6.76(m,1H),6.29(dd,J ₁＝2.1Hz,J ₂＝16.8Hz,1H),5.79(dd,J ₁＝2.1Hz,J ₂＝10.8Hz,1H),4.61-4.45(m,2H),3.84-3.77(m,4H),3.52-3.37(m,9H),3.16(s,3H),3.13-2.95(m,4H),2.90-2.85(m,2H),2.84(s,3H),2.33-2.22(m,1H),2.09-1.88(m,3H).

Example 71

Step 1

Mixing the raw materials58-3(2.00 g) was dissolved in isopropanol (80 ml), and (S) -3-methyl was added sequentiallyTert-butyl piperazinecarboxylate (1.56 g), diisopropylethylamine (1.68 g). The resulting mixture was reacted at 80 ℃ for 24 hours. After the reaction was complete, water (200 ml) was added for dilution. And extracted with ethyl acetate (100 ml x 3). The organic phases are combined, washed with saturated brine (100 ml), dried with anhydrous sodium sulfate and concentrated to dryness to obtain the product71-1(1.00 g).

LC-MS:m/z 472(M+H) ⁺

Step 2

(S) -prolinol (0.365 g) was dissolved in anhydrous tetrahydrofuran (100 ml) and sodium hydride (60%) (0.127 g) was added at 0 deg.C. After reacting for 30 minutes at 0 ℃, adding the raw materials71-1(1.00 g). The resulting solution was reacted at 70 ℃ for 3 hours. After the reaction, the reaction mixture was cooled to room temperature. Quenched by addition of saturated aqueous ammonium chloride (50 ml) and extracted with ethyl acetate (50 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (methanol/dichloromethane is 5% -20%) to obtain the product71-2(0.850 g).

LC-MS:m/z 551(M+H) ⁺

Step 3

Mixing the raw materials71-2(0.850 g) was dissolved in dry methanol (25 ml) and palladium on carbon (10%) (0.085 g), ammonia in methanol (7 mol/l) (2.5 ml) was added successively under nitrogen. The resulting reaction solution was replaced with hydrogen gas 3 times, and reacted at 40 ℃ for 3 hours. After the reaction, the palladium-carbon is filtered. Concentrating the filtrate to dryness to obtain the product71-3(0.550 g).

LC-MS:m/z 461(M+H) ⁺

Step 4

Mixing the raw materials71-3(50.0 mg) was dissolved in toluene (2 ml), and 8-methyl-1-bromonaphthalene (47.7 mg), sodium tert-butoxide (51.8 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (9.0 mg) were added in this order. The resulting solution was stirred at 90 ℃ for 3 hours. After the reaction is finishedAfter cooling to room temperature, it was diluted with water (15 ml) and extracted with ethyl acetate (15 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (10% -20% of dichloromethane/methanol) to obtain the product71-4(23.0 mg).

LC-MS:m/z 601(M+H) ⁺

Step 5

To the raw material71-4(23.0 mg) to a solution of hydrogen chloride in 1, 4-dioxane (2 ml) was added. The resulting solution was stirred at room temperature for 1 hour. After the reaction is finished, concentrating to be dry to obtain the product71-5(15.0 mg). The product is used for the next reaction without purification.

LC-MS:m/z 501(M+H) ⁺

Step 6

Mixing the raw materials71-5(15.0 mg) was dissolved in dichloromethane (2 ml), cooled to-40 ℃ and triethylamine (14.5 mg) and acryloyl chloride (2.5 mg) were added in that order. The resulting solution was reacted at-40 ℃ for 1 hour. After the reaction was complete, quench with water (5 ml) and concentrate to dryness. The crude product was purified by preparative chromatography (Column: Xbridge Shield RP18 OBD Column,5um, 19X 150 mm; mobile phase A: water (10 mmol/l, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 42-62%; time 8 min; detector wavelength 254/220 nm) to give the product71(7.8 mg).

LC-MS:m/z 555(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.70-7.63(m,2H),7.39-7.27(m,4H),6.88-6.73(m,1H),6.27(dd,J ₁＝2.1Hz,J ₂＝16.8Hz,1H),5.80(dd,J ₁＝2.1Hz,J ₂＝10.8Hz,1H),4.56-4.38(m,3H),4.23-4.02(m,3H),3.95-3.82(m,1H),3.69-3.37(m,6H),3.30-3.21(m,2H),3.16(d,J＝4.8Hz,3H),3.12-2.93(m,4H),2.89-2.80(m,1H),2.77(s,3H),2.28-2.18(m,1H),2.02-1.82(m,3H),1.24-1.19(m,3H)

Example 72

Step 1

Compound (I)72-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg), 3- (1, 1-difluoroethyl) -bromobenzene (45.3 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). To obtain the product72-1(32.0 mg).

LC-MS:m/z 626(M+H) ⁺

Step 2

Compound (I)72-2Synthetic reference compounds of1-11. Raw materials72-1(32.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product72-2(28.4 mg).

LC-MS:m/z 526(M+H) ⁺.

Step 3

Compound (I)72Synthetic reference compounds of1. Raw materials72-2(28.4 mg), triethylamine (25.6 mg), acryloyl chloride (6.88 mg), dichloromethane (5 ml). Obtaining the product72(8.9 mg).

LC-MS:m/z 580(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.19(t,J＝8.0Hz,1H),6.97(s,1H),6.90(d,J＝8.7Hz,1H),6.85-6.68(m,J＝7.5Hz,2H),6.26(d,J＝16.7Hz,1H),5.81(d,J＝10.5Hz,1H),4.63(d,J＝2.3Hz,2H),4.46-4.32(m,2H),4.12-3.46(m,6H),3.24-3.06(m,3H),3.02-2.73(m,6H),2.56(s,3H),2.47-2.37(m,1H),2.17-1.75(m,9H).

Example 73

Step 1:

at room temperature, mixing the raw materials73-3(1.00 g) was dissolved in THF (5 mL), and triethylamine (0.734 g) and bromomethyl methyl ether (0.722 g) were added in that order. The resulting reaction solution was left at room temperature to react for 2 hours. After the reaction was complete, water (50 ml) was added and quenched. Extract with ethyl acetate (50 ml x 3). The organic phases were combined and washed with saturated brine (50 ml). Drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the product73-4(1.10 g).

LC-MS:m/z 251(M+H) ⁺

And 2, step:

compound (I)73-1Synthetic reference compounds of1-10. Raw materials1-9(50.0 mg) of a compound,73-4(51.5 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product73-1(35.0 mg).

LC-MS:m/z 656(M+H) ⁺

And step 3:

compound (I)73-2Synthetic reference compounds of1-11. Raw materials73-1(35.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product73-2(28.9 mg).

LC-MS:m/z 512(M+H) ⁺.

And 4, step 4:

compound (I)73Synthetic reference compounds of1. Raw materials73-2(28.9 mg), triethylamine (26.7 mg), acryloyl chloride (5.27 mg), dichloromethane (5 ml). The crude product was purified by preparative chromatography (Column: Xbridge Shield RP18 OBD Column,5um,19 x 150 mm; mobile phase A: water (0.5% formic acid), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 27% -47% for 8 min; detector wavelength 254/220 nm) to give the product73(5.3 mg).

LC-MS:m/z 566(M+H) ⁺

¹H-NMR(CD ₃OD)δ:8.58(s,1H),7.05(t,J＝8.1Hz,1H),6.91-6.74(m,1H),6.70(d,J＝8.3Hz,1H),6.63(d,J＝8.1Hz,1H),6.30(d,J＝16.8Hz,1H),5.85(d,J＝10.5Hz,1H),5.18-5.08(m,1H),4.70-4.48(m,2H),4.26(s,2H),4.17-3.84(m,3H),3.75-3.54(m,3H),3.53-3.35(m,3H),3.30-2.99(m,5H),2.97(s,3H),2.92-2.86(m,1H),2.40-2.28(m,1H),2.19-1.96(m,5H).

Example 74

Step 1:

compound (I)74-1Synthetic reference compounds of1-10. Starting materials1-9(50.0 mg), 3, 4-dichlorobromobenzene (46.1 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (25.8 mg), toluene (2 ml). Obtaining the product74-1(31.9 mg).

LC-MS:m/z 630(M+H) ⁺

Step 2:

compound (I)74-2Synthetic reference compounds of1-10. Raw materials74-1(31.9 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product74-2(28.5 mg).

LC-MS:m/z 530(M+H) ⁺

Step 3

Compound (I)74Synthetic reference compounds of1. Raw materials74-2(28.5 mg), triethylamine (25.4 mg), acryloyl chloride (5.77 mg), dichloromethane (5 ml). Obtaining the product74(7.0 mg).

LC-MS:m/z 584(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.19(d,J＝9.0Hz,1H),6.96(d,J＝3.0Hz,1H),6.91-6.67(m,2H),6.26(d,J＝16.8Hz,1H),5.81(d,J＝10.5Hz,1H),5.15-4.97(m,1H),4.64-4.51(m,2H),4.41(d,J＝5.7Hz,2H),4.13-3.96(m,1H),3.95-3.71(m,3H),3.69-3.44(m,2H),3.27-3.07(m,3H),3.02-2.80(m,5H),2.58(s,3H),2.53-2.41(m,1H),2.24-2.06(m,1H),2.04-1.67(m,5H).

Example 75

Step 1:

compound (I)75-1Synthetic reference compounds of42-2. Wherein the raw materials42-1(1.00 g), 2, 3-dichloro-1-bromobenzene (1.10 g), sodium tert-butoxide (1.18 g), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (0.206 g), toluene (20 ml). Obtaining the product75-1(400 mg).

LC-MS:m/z 551(M+H) ⁺

Step 2:

at room temperature, mixing the raw materials75-1(50.0 mg) and 3-amino-N, N-dimethylpropionamide (21.1 mg) were dissolved in dimethyl sulfoxide (2.0 ml), and N, N-diisopropylethylamine (35.2 mg) was added. The reaction solution was left to react overnight at 120 ℃. After the reaction was complete, water (20 ml) was added and quenched. Extract with ethyl acetate (20 ml x 3). The organic phases were combined and washed with saturated brine (20 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. Purifying the crude product by silica gel column chromatography (methanol/dichloromethane is 5% -20%), and obtaining the product75-2(25.0 mg).

LC-MS:m/z 631(M+H) ⁺

And step 3:

compound (I)75-3Synthetic reference compounds of42-4. Wherein the raw materials75-2(25.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product75-3(22.3 mg). The product is used for the next reaction without purification.

LC-MS:m/z 531(M+H) ⁺

And 4, step 4:

compound (I)75Synthetic reference compounds of42. Wherein the raw materials75-3(22.3 mg), triethylamine (19.9 mg), acryloyl chloride (5.35 mg), dichloromethane (5 ml). Obtaining the product75(4.0 mg).

LC-MS:m/z 585(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.25-7.10(m,3H),6.94-6.78(m,1H),6.29(d,J＝16.8Hz,1H),5.84(d,J＝10.5Hz,1H),5.25-5.11(m,1H),4.22-4.04(m,3H),3.88-3.74(m,2H),3.70-3.58(m,3H),3.50-3.35(m,3H),3.21-3.14(m,1H),3.05(s,3H),3.04-2.95(m,2H),2.93(s,3H),2.81(t,J＝5.2Hz,2H),2.70(t,J＝6.6Hz,2H),2.17-1.95(m,2H).

Example 76

Step 1:

compound (I)76-1Synthetic reference compounds of42-2. Wherein the raw materials42-1(1.00 g), 1-bromo-3-methyl-2-trifluorotoluene (1.17 g), sodium tert-butoxide (1.18 g), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (0.206 g), toluene (20 ml). Obtaining the product76-1(350 mg).

LC-MS:m/z 565(M+H) ⁺

And 2, step:

compound (I)76-2Synthetic reference compounds of42-3. Wherein the raw materials76-1(50.0 mg) and 5-hydroxypyrimidine (12.8 mg), sodium hydride (60%) (5.32 mg), tetrahydrofuran (5.0 ml). Obtaining the product76-2(27.0 mg).

LC-MS:m/z 625(M+H) ⁺

And step 3:

compound (I)76-3Synthetic reference compounds of42-4. Wherein the raw materials76-2(27.0 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product76-3(23.5 mg). The product is used for the next reaction without purification.

LC-MS:m/z 525(M+H) ⁺

And 4, step 4:

compound (I)76Synthetic reference compounds of42. Wherein the raw materials76-3(23.5 mg), triethylamine (21.1 mg), acryloyl chloride (5.66 mg), dichloromethane (5 ml). Obtaining the product76(8.2 mg).

LC-MS:m/z 579(M+H) ⁺

¹H-NMR(CDCl ₃)δ:9.06(s,1H),8.72(s,2H),7.36(d,J＝8.0Hz,1H),7.19(d,J＝8.1Hz,1H),7.06(d,J＝7.8Hz,1H),6.65-6.52(m,1H),6.40(d,J＝16.5Hz,1H),5.84(d,J＝10.2Hz,1H),5.24-4.97(m,1H),4.28-4.04(m,2H),3.91-3.52(m,3H),3.38-3.11(m,3H),3.07-3.65(m,5H),2.49(s,3H),2.19-1.89(m,3H).

Example 77

Step 1:

compound (I)77-1Synthetic reference compounds of42-3. Wherein the raw materials76-1(50.0 mg) and pyrimidine-2-methanol (14.6 mg), sodium hydride (60%) (5.32 mg), tetrahydrofuran (5.0 ml). To obtain the product77-1(27.8 mg).

LC-MS:m/z 639(M+H) ⁺

Step 2:

compound (I)77-2Synthetic reference compounds of42-4. Wherein the raw materials77-1(27.8 mg), hydrogen chloride in 1, 4-dioxane (4 mol/l, 5 ml). Obtaining the product77-2(24.5 mg). The product is used for the next reaction without purification.

LC-MS:m/z 539(M+H) ⁺

And 3, step 3:

compound (I)77Synthetic reference compounds of42. Wherein the raw materials77-2(24.5 mg), triethylamine (21.6 mg), acryloyl chloride (5.80 mg), dichloromethane (5 ml). Obtaining the product77(4.0 mg).

LC-MS:m/z 593(M+H) ⁺

¹H-NMR(CDCl ₃)δ:8.74(d,J＝4.9Hz,2H),7.33(t,J＝7.9Hz,1H),7.22(t,J＝4.9Hz,1H),7.14(d,J＝8.1Hz,1H),7.02(d,J＝7.6Hz,1H),6.67-6.50(m,1H),6.38(d,J＝16.7Hz,1H),5.82(d,J＝10.0Hz,1H),5.56(s,2H),5.23-4.91(m,1H),4.73-4.43(m,1H),4.19(q,J＝17.4Hz,2H),3.91-3.51(m,3H),3.32-3.11(m,3H),3.00-2.65(m,5H),2.48(s,3H),2.09-1.91(m,2H).

Example 78

Step 1

Mixing the raw materials78-1(22.0 g) was dissolved in N, N-dimethylformamide (250 ml), and ethyl 5-bromovalerate (26.3 g) and N, N-diisopropylethylamine (17.9 g) were added in this order. The resulting solution was stirred at 80 ℃ for 24 hours. After completion of the reaction, it was cooled to room temperature, diluted with water (200 ml) and extracted with ethyl acetate (200 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (10% -20% ethyl acetate/petroleum ether) to obtain the product78-2(13.1 g).

LC-MS:m/z 304(M+H) ⁺

Step 2

Mixing the raw materials78-2(13.1 g) was dissolved in N, N-dimethylformamide (150 ml), and N, N-diisopropylethylamine (6.65 g) and oxalyl chloride monoethyl ester (6.42 g) were sequentially added. The resulting solution was stirred at room temperature for 16 hours. After completion of the reaction, water (150 ml) was added to dilute and extracted with ethyl acetate (200 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (10% -20% ethyl acetate/petroleum ether) to obtain the product78-3(8.00 g).

LC-MS:m/z 404(M+H) ⁺

Step 3

Mixing the raw materials78-3(8.00g) was dissolved in N, N-dimethylformamide (100 ml), and hydrogen was addedSodium chloride (1.20 g). The resulting solution was stirred at 110 ℃ for 16 hours. After completion of the reaction, it was cooled to room temperature, diluted with water (100 ml) and extracted with ethyl acetate (200 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (20% -30% ethyl acetate/petroleum ether) to obtain the product78-4(4.00 g).

LC-MS:m/z 358(M+H) ⁺

Step 4

Mixing the raw materials78-4(4.00 g) was dissolved in ethanol (100 ml) and a solution of sodium ethoxide in ethanol (1.20 g) was added in sequence. The resulting solution was stirred at 80 ℃ for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, the pH was adjusted to weak acidity with dilute hydrochloric acid, diluted with water (100 ml), and extracted with ethyl acetate (200 ml. times. 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (20% -30% ethyl acetate/petroleum ether) to obtain the product78-5(400 mg).

LC-MS:m/z 370(M+H) ⁺

Step 5

Mixing the raw materials78-5(400 mg) was suspended in phosphorus oxychloride (100 ml) and N, N-dimethylformamide (1 ml) was added. The resulting solution was stirred at 80 ℃ for 16 hours. After the reaction, the reaction solution was concentrated to dryness. The residue was taken up in water (100 ml) and the pH adjusted to 8 with anhydrous sodium carbonate. Water (100 ml) was added to dilute and extracted with ethyl acetate (100 ml x 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (20% -30% ethyl acetate/petroleum ether) to obtain the product78-6(326 mg).

LC-MS:m/z 390(M+H) ⁺

Step 6

Mixing the raw materials78-6(326 mg) was dissolved in isopropanol (100 ml) and 2-cyanomethylpiperazine dihydrochloride (182 mg), N-diisopropylethylamine (377 mg) were added in this order. The resulting solution was stirred at room temperature for 1 hour. After the reaction is finished, water (100 ml) is added for dilution, andextract with ethyl acetate (100 ml x 3). The organic phases are combined and concentrated to be dry to obtain the product78-7(294 mg).

LC-MS:m/z 479(M+H) ⁺

Step 7

Mixing the raw materials78-7(294 mg) was dissolved in anhydrous tetrahydrofuran (50 ml), and di-tert-butyl dicarbonate (160 mg) and N, N-diisopropylethylamine (119 mg) were added in this order. The resulting solution was reacted at 50 ℃ for 2 hours. After completion of the reaction, water (50 ml) was added to dilute and extracted with ethyl acetate (50 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (30% -60% ethyl acetate/petroleum ether) to obtain the product78-8(254 mg).

LC-MS:m/z 579(M+H) ⁺

Step 8

(S) -prolinol (75.7 mg) was dissolved in anhydrous tetrahydrofuran (50 mL) and sodium hydride (60%) (26.3 mg) was added at 0 deg.C. After reacting for 30 minutes at 0 ℃, adding the raw materials78-8(254 mg). The resulting solution was reacted at 70 ℃ for 3 hours. After the reaction, the reaction mixture was cooled to room temperature. Quenched by addition of saturated aqueous ammonium chloride (50 ml) and extracted with ethyl acetate (50 ml × 3). The organic phases are combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (methanol/dichloromethane is 5% -20%) to obtain the product78-9(98.0 mg).

LC-MS:m/z 658(M+H) ⁺

Step 9

To the raw material78-9(98.0 mg) to a solution of hydrogen chloride in 1, 4-dioxane (5 ml) was added. The resulting solution was stirred at room temperature for 10 minutes. After the reaction is finished, concentrating to be dry to obtain the product78-10(53.0 mg). The product is used for the next reaction without purification.

LC-MS:m/z 558(M+H) ⁺

Step 10

Mixing the raw materials78-10(53.0 mg) was dissolved in dichloromethane (5 ml), cooled to-40 ℃ and triethylamine (28.8 mg) and acryloyl chloride (12.8 mg) were added in that order. The resulting solution was reacted at-40 ℃ for 10 minutes. After the reaction was complete, quench with water (5 ml) and concentrate to dryness. The crude product was purified by preparative chromatography (Column: Xbridge Shield RP18 OBD Column,5um,19 x 150 mm; mobile phase A: water (0.5% formic acid), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 40-70%; time 8 min; detector wavelength 254/220 nm) to give the product78(10.0 mg).

LC-MS:m/z 612(M+H) ⁺

¹H-NMR(CD ₃OD)δ:8.52(s,1H),7.77(d,J＝6.8Hz,1H),7.65-7.45(m,2H),6.84(s,1H),6.32(d,J＝16.0Hz,1H),5.86(d,J＝12.0Hz,1H),5.31-5.06(m,1H),4.43-4.02(m,3H),4.00-3.75(m,2H),3.75-3.50(m,4H),3.22-2.87(m,9H),2.42(s,3H),2.40-2.20(m,3H),2.18-1.89(m,5H).

Example 79

Step 1:

at room temperature, mixing the raw materials1-9(126.4 mg) was dissolved in toluene (3 ml), and 2-bromo-3-fluoroanisole (106.4 mg), sodium tert-butoxide (250 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (65.3 mg) were added in that order. The resulting solution was stirred at 90 ℃ for 3 hours. After the reaction was complete, it was cooled to room temperature, diluted with water (15 ml) and extracted with ethyl acetate (15 ml × 3), the organic phases combined and concentrated to dryness. Purifying the crude product by silica gel column chromatography (10% -20% of dichloromethane/methanol) to obtain the product79-1(96.7 mg).

LC-MS:m/z 610(M+H) ⁺.

Step 2:

at room temperature, adding the raw materials79-1(96.7 mg) to a solution of hydrogen chloride in 1, 4-dioxane (10 ml) was added. The resulting solution was stirred at room temperature for 10 minutes. After the reaction is finished, concentrating to be dry to obtain the product79-2(79.6 mg). The product is used for the next reaction without purification.

LC-MS:m/z 510(M+H) ⁺.

And 3, step 3:

mixing the raw materials79-2(79.6 mg) was dissolved in dichloromethane (10 ml), cooled to-40 ℃ and triethylamine (71.7 mg) and acryloyl chloride (15.3 mg) were added in that order. The resulting solution was reacted at-40 ℃ for 10 minutes. After the reaction was complete, quench with water (10 ml), extract with ethyl acetate (15 ml x3), combine the organic phases and concentrate to dryness. The crude product was purified by preparative chromatography (Column: Xbridge Shield RP18 OBD Column,5um, 19X 150 mm; mobile phase A: water (10 mmol/l, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 35-80%; time 12 min; detector wavelength 254/220 nm) to give the product79(59.6 mg).

LC-MS:m/z 564(M+H) ⁺

¹H-NMR(CD ₃OD)δ:7.05-7.04(m,1H),7.03-6.77(m,2H),6.67-6.66(m,1H),6.30(d,J＝12.3Hz,1H),5.85(dd,J＝7.8Hz,1H),5.12-5.03(m,1H),4.56-4.40(m,2H),4.43-4.40(m,2H),4.39-4.20(m,2H),3.98-3.80(m,2H),3.77(s,3H),3.75-3.62(m,1H),3.52-3.47(m,1H),3.35-3.25(m,3H),3.11-2.97(m,3H),2.95-2.91(m,2H),2.70-2.60(m,4H),2.20-2.10(m,1H),2.05-1.89(m,4H),1.85-1.75(m,1H).

Test example 1 detection of protein covalent addition reaction product

3uM test compound and 2uM GDP-His-KRAS-G12C protein complex were added to reaction buffer (12.5mM HEPES, pH7.5,75mM NaCl,1mM MgCl)₂) Incubate at room temperature for 5 and 30 minutes, respectively, after which the reaction is stopped with formic acid at a final concentration of 5%. The sample was centrifuged at 15,000 rpm for 10 minutes and the supernatant was transferred to a Waters Acquity I ClassInstrumental analysis was performed to determine the relative amounts of His-KRAS-G12C and His-KRAS-G12C complex covalently bound to the compound, respectively.

The binding capacity (POC value, percent of control) of the compound to KRAS-G12C protein after 5 and 30 minutes of incubation was calculated as follows:

POC [% ] x 100 [% ] of the peak of the complex after addition reaction of protein and compound/(peak of the complex after addition reaction of protein and compound + peak of protein ]

The test results of the example compounds are shown in table 1.

Table 1: amount of compound bound to KRAS-G12C protein

Note: + represents that the POC value is more than or equal to 30% and less than 50%;

+ represents POC value of 50% or more and less than 80%;

and +++ represents POC value ≥ 80%.

Experimental example 2 KRAS-G12C inhibitory Activity

ERK protein phosphorylation assay

H358 cells (ATCC, CRL-5807) or MIA PaCa-2(ATCC, CRL-1420) expressing KRAS-G12C protein were seeded 6000 cells per well in polylysine-coated 384-well cell culture plates (Corning, BD356663) with a medium composition of RPMI1640(Gibco, A10491-01), 10% FBS (Gibco, 10099141C) and 1% Pen/Strep (Gibco, 15140-122) in a 5% carbon dioxide cell incubator for 16 hours; the compound diluted in gradient was added to the cell culture medium with Echo550 at a final DMSO concentration of 0.5% and incubation continued for 3 hours; then 40 uL/well of 8% paraformaldehyde (Solambio, P1112) was added and incubated for 20 minutes at room temperature; after PBS washing, 40 uL/hole cold 100% methanol is added, and the mixture is infiltrated for 10 minutes at room temperature; after PBS washing, 20 uL/hole of blocking solution (LI-COR, 927-; then rabbit anti-phospho-p 44/42MAPK (T202/Y204) antibody (CST, 4370S) was diluted 1:1000 with blocking solution, mouse anti-GAPDH (D4C6R) antibody (CST, 97166S) was diluted 1:2000 and added to the cells at 20 uL/well and blocked overnight at 4 degrees; PBST washing 3 times, each time of 2 minutes of incubation, after that with blocking solution according to 1:1000 dilution of goat anti rabbit 800CW antibody (LI-COR, 926 and 32211) and goat anti mouse 680RD antibody (LI-COR, 926 and 68070), according to 20 uL/hole into cells, at room temperature for 45 minutes of incubation; PBST was washed 3 times with 2 min of each incubation, and the cell culture plates were finally inverted and centrifuged at 1000rpm for 1 min before reading the fluorescence signal with the Odyssey CLx.

Data from XLFit 5.0 by 4 parameter formula Y ═ Bottom + (Top-Bottom)/(1+10^ ((Logic50-X) } HillSlope) fitting calculation of IC₅₀The value is obtained.

The test results of the example compounds are shown in table 2.

Table 2: results of compound ERK protein phosphorylation assay

Note: a represents IC₅₀≤50nM；

B represents 50nM < IC₅₀≤150nM；

C represents 150nM < IC₅₀≤500nM；

D represents 500nM < IC₅₀≤999nM；

-representing IC₅₀The value was not detected.

2. Cell proliferation inhibition assay

Gradient diluted compounds were added to low adsorption round bottom 384 well cell culture plates (Corning, CLS3830-50EA) with Echo550, 40uL of a suspension containing 400H 358 or MIA PaCa-2 cells per well, and cultured for 3 days at 37S ℃ in a 5% carbon dioxide cell incubator; 3D CellTiter-Glo reagent (Promega, G9683) was thawed in a 4 ℃ refrigerator one day in advance, equilibrated at room temperature for 30 minutes before use, added to the cell culture plate at 20uL per well, allowed to stand at room temperature for 2 hours at 100rpm after 30 minutes, and the luminescence signal was read using Envision 2104.

Data from XLFit 5.0 by 4 parameter formula Y ═ Bottom + (Top-Bottom)/(1+10^ ((Logic50-X) } HillSlope) fitting calculation of IC₅₀The value is obtained.

The test results of the example compounds are shown in table 3.

Table 3: results of cell proliferation inhibition assay

Note: a represents IC₅₀≤50nM；

B represents 50nM < IC₅₀≤150nM；

C represents 150nM < IC₅₀≤500nM；

D represents 500nM < IC₅₀≤999nM。

Test example 3 pharmacokinetic experiment

1. Liver microsome metabolic stability test

1) The reaction system was prepared as follows

2) The reaction was preincubated in a water bath at 37 ℃ for 10 minutes. To the reaction system was added 40. mu.L of 10mM NADPH solution, the final concentration of NADPH was 1mM each. As a negative control, 40. mu.L of ultrapure water was used in place of the NADPH solution. The negative control serves to exclude the effect of chemical stability of the compound itself.

3) The reaction was initiated by adding 4. mu.L of 200. mu.M test compound to the reaction system, the final concentration of drug being 2. mu.M.

4) At 0, 15, 30, 45 and 60 minutes, 50 μ L of the reaction sample was removed and quenched with 4-fold cold acetonitrile containing internal standards (200nM alprazolam, 200nM labetalol, 2 μ M ketoprofen, 200nM caffeine). The samples were centrifuged at 3,220g for 45 minutes. After the centrifugation is finished, 90 mu L of supernatant and 90 mu L of ultrapure water are uniformly mixed for LC-MS/MS analysis and detection.

The results of the test for the compound of example 66 are shown in table 4.

Table 4: results of Compound liver microsome stability test

2. Plasma stability test

The test results for representative example compounds are shown in table 5.

Table 5: results of compound mouse plasma stability experiment

Claims (11)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

   

   wherein the content of the first and second substances,

   when q is 0, p is 2,

   

   selected from single bonds;

   orWhen q is 1, p is 1,

   

   selected from single bonds or double bonds;

   or, when q is 2, p is 0, and

   

   selected from single bonds;

   when in use

   

   Selected from the double bonds, R⁴And/or R⁶Is absent;

   a moiety selected from

   

   Wherein R is selected from H or C_1-6An alkyl group;

   or, A-R²Part is selected from

   

   

   Is a 4-10 membered heterocycloalkyl group containing at least two N atoms;

   

   is a 4-7 membered heterocycloalkyl group containing at least one N atom;

   each R¹Substituted on the ring, independently selected from halogen, oxo, -OH, -NH₂CN, or optionallyBy 1,2 or 3R⁰Substituted with the following groups: c_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino, or di-C_1-6An alkylamino group;

   each R⁰Independently selected from halogen, -OH, -NH₂、-CN、C _1-4Alkoxy radical, C_1-4Alkylamino, or di-C_1-4An alkylamino group;

   m is 0, 1,2,3,4, 5 or 6;

   each R²Independently selected from C_1-6Alkylcarbonyl, halo C_1-6Alkylcarbonyl group, C_1-6Alkoxycarbonyl group, C_1-6Alkylsulfonyl, -C (O) C ≡ CR^b、-SO ₂C≡CR ^b、-C(O)C(R ^a)＝C(R ^b) ₂or-SO₂C(R ^a)＝C(R ^b) ₂；

   Each R^aIndependently selected from H, halogen, or C_1-4An alkyl group;

   each R^bIndependently selected from H or optionally substituted with 1,2 or 3R^cSubstituted with the following groups: c_1-6Alkyl radical, C_1-4Alkoxy radical C_1-3Alkyl radical, C_1-4Alkylamino radical C_1-3Alkyl, di-C_1-4Alkylamino radical C_1-3Alkyl, 3-7 membered cycloalkyl C_1-3Alkyl, 4-7 membered heterocycloalkyl C_1-3An alkyl group;

   each R^cIndependently selected from halogen, -OH, -NH₂、-CN、C _1-6Alkyl radical, C_1-6Alkoxy, or halo C_1-6An alkyl group;

   x is selected from a single bond, -S-, -O-, -NH-, or-N (C)_1-3Alkyl) -;

   R ³selected from H or optionally substituted by 1,2,3 or 4R^dSubstituted with the following groups: c_1-6Alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, benzo 4-6 membered heterocyclyl, 4-7 membered heterocycloalkyl C_1-3Alkyl, or 5-6 membered heteroaryl C_1-3An alkyl group;

   each R^dIndependently selected from halogen, -OH, oxo, -NH₂、-CN、C _1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino, di-C_1-4Alkylamino, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl C_1-3Alkyl, wherein, said C_1-4Alkylamino, di-C_1-4Alkylamino is optionally substituted with a substituent selected from 1 or 2 cyano or 5-6 membered heteroaryl;

   y is selected from a single bond, -CH₂-, or a carbonyl group;

   b is selected from optionally substituted by 1,2,3,4, 5 or 6R^eSubstituted phenyl, naphthyl, 5-6 membered heteroaryl, benzo 5-6 membered cycloalkenyl, benzo 5-6 membered heterocyclyl, or benzo 5-6 membered heteroaryl;

   each R^eIndependently selected from halogen, -CN, -OH, -NH₂、C _1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, di-C_1-6Alkylamino, halogeno C_1-6Alkyl, halo C_1-6Alkoxy, halo C_1-6Alkylthio, halo C_1-6Alkylamino, di (halo C)_1-6Alkyl) amino, or optionally substituted by 1,2 or 3R^e1Substituted with the following groups: 3-7 membered cycloalkyl, 3-7 membered cycloalkyl C_1-3Alkyl, 4-7 membered heterocycloalkyl C_1-3An alkyl group;

   each R^e1Independently selected from halogen, -CN, -OH, -NH₂、C _1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino, di-C_1-4An alkylamino group;

   R ⁴、R ⁵independently selected from H, halogen, -OH, -NH₂、-CN、C _1-6Alkyl radical, C_1-6Alkoxy, or halo C_1-6Alkyl, or, R⁴And R⁵Together form a carbonyl, a 3-6 membered cycloalkyl or a 4-6 membered heterocycloalkyl;

   R ⁶、R ⁷independently selected from H, halogen, -OH, -NH₂、-CN、C _1-6Alkyl radical, C_1-6Alkoxy, or halo C_1-6Alkyl, or, R⁶And R⁷Together form a carbonyl group, a 3-to 6-membered cycloalkyl group or a 4-to 6-membered heterocycloalkyl group,

   with the proviso that said compound of formula (I) is not

   

   
2. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 wherein a-R²Part is selected from

   

   Wherein R is selected from H or C_1-6An alkyl group.
3. The method as claimed in any one of claims 1-2A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is¹Independently selected from halogen, oxo, -OH, -NH₂-CN, or optionally substituted by 1,2 or 3R⁰Substituted with the following groups: c_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino, or di-C_1-4Alkylamino, wherein R⁰Independently selected from halogen, -OH, -NH₂、-CN、C _1-3Alkoxy radical, C_1-3Alkylamino, or di-C_1-3An alkylamino group.
4. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-3 wherein R is²Selected from the group consisting of:

   

   
5. a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-4 wherein R is³Selected from the group consisting of optionally substituted by 1,2,3 or 4R^dSubstituted with the following groups: 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl C_1-3Alkyl, or 5-6 membered heteroaryl C_1-3An alkyl group; preferably, R³Selected from H or optionally substituted by 1,2,3 or 4R^dSubstituted with the following groups: tetrahydropyrrolemethyl, tetrahydropyrrolethyl, tetrahydropyrrolpropyl, morpholinylpropyl, tetrahydropyrrolethyl, tetrahydropyrrolylpropyl, tetrahydropyrrolyl, and tetrahydropyrrolyl,

   
6. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-5 wherein R is³Selected from H,

   

   

   
7. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-6, wherein B is selected from

   

   

   
8. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7, selected from compounds of the general formula or a pharmaceutically acceptable salt thereof,

   

   wherein R is¹、R ²、R ³、R ⁴、R ⁵、R ⁶、R ⁷The moieties X, m, a and B are as defined above in claims 1-10.
9. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-8, selected from the following compounds, or a pharmaceutically acceptable salt thereof,

   

   

   

   
10. a pharmaceutical composition comprising a compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof.
11. A method of treating a disease associated with KRas G12C in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10.