CN117580836A

CN117580836A - Pyrimidine ring structure derivative and application thereof

Info

Publication number: CN117580836A
Application number: CN202280044402.4A
Authority: CN
Inventors: 陈寿军; 强晓明; 宁德争; 丁兆
Original assignee: Sichuan Huiyu Haiyue Pharmaceutical Technology Co ltd; SICHUAN HUIYU PHARMACEUTICAL CO Ltd
Current assignee: Sichuan Huiyu Haiyue Pharmaceutical Technology Co ltd; SICHUAN HUIYU PHARMACEUTICAL CO Ltd
Priority date: 2021-06-24
Filing date: 2022-06-24
Publication date: 2024-02-20
Also published as: WO2022268209A1

Abstract

The compound has obvious inhibition effect on SOS1 protein activity, can be used as an SOS1 protein inhibitor, has good pharmacy, can be used for preparing medicines for treating diseases such as cancers, pathogenic rash and the like mediated by SOS1 protein, and has wide application prospect.

Description

Pyrimidine ring structure derivative and application thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a compound serving as an SOS1 protein inhibitor and application thereof.

Background

SOS1 (son of sevenless homolog 1) protein is a regulatory protein widely expressed in cells, and plays an important role in regulating intracellular Ras or Rac1 signal transduction pathways as a guanine nucleotide exchange factor of Ras or Rac1 protein (Baltans, F.C.; zarich, N.; rojas;)J.m.; santos, e.biochem.biophys.acta.rev.cancer.2020, 1874, 188445). The SOS1 protein plays a role in the Ras signal transduction pathway in promoting the release of GDP from Ras, binding GTP, and converting the Ras protein from an inactive state to an active state.

The currently known RAS family shares three genes: KRAS, NRAS and HRAS. Mutations in RAS enzymes are closely related to tumorigenesis, with about 25% of all tumors detected (de Castro J.；Belda-Iniesta C.；Transl Lung Cancer Res.20132 (2), 142-51.), among different types of tumors, the RAS mutation type is also different. RAS mutations (KRAS, NRAS, HRAS) are present in 90% of pancreatic cancers, 45% of colon cancers and 35% of lung cancers. Non-small cell lung Cancer (NSCLC) accounts for 80% of all lung Cancer cases (Jemal, B.; et al, CA Cancer J.Clin.2011, 61 (2), 69-90), ras proto-oncogene is the most common mutant gene in NSCLC (Prior, L.et al, cancer Res.2012, 72 (10), 2457-2467;Li,L.et al,J Exp Clin Cancer Res.2018, 37 (1), 178), where v-Ki-Ras2Kirsten rat sarcoma viral oncogene (Kras) accounts for 90% of lung adenocarcinoma RAS mutations (Hunter, J.C.; et al, mol. Cancer Res.2015, 13 (9), 1325-35).

SOS1 plays an important regulatory role in many signal transduction pathways within cells as a "cardiac pacemaker" of Kras. Studies have shown that inhibition of SOS1 activity has a potent inhibitory effect on cancer cell proliferation based on all major Kras gene mutations (Kessler, D.; gerlach, D.; kraut, N.; mcConnell, D.B.Curr.Opin.Chem.Biol.2021, 62, 109-118). In addition, a clinical study in 62 ovarian cancer patients showed that RAS mutation and SOS1 mutation were significantly elevated in ovarian cancer tissue expression and that both prognosis were associated with patient PFS shortening, suggesting that RAS and SOS1 targeted therapy would be potentially valuable in ovarian cancer patients. At the same time, SOS1 gene mutations are also found in many other cancer cells, such as embryonal rhabdomyosarcoma, celtoli cell testicular tumor, cutaneous granulocytoma (denyer et al, genes Chromosomes Cancer,2010, 49 (3): 242-52), and lung adenocarcinoma (Cancer Genome AtIas Research network, nature 2014, 511 (7511), 543-50). In addition, SOS1 gene was found to be highly expressed in bladder cancer (Watanabe et al, IUBMB Life, 2000, 49 (4), 317-20) and prostate cancer (Timofeeva et al, int.J.Oncol.,2009, 35 (4): 751-60). During the development of chronic myeloid leukemia, BCR-ABL activates GRB2 by phosphorylation, recruiting SOS1, thereby continuously activating the Ras/MAPK signaling pathway, leading to malignant proliferation of hematopoietic stem cells. Thus, SOS1 protein is also a potential new target for chronic myeloid leukemia treatment. In addition to cancer, studies have shown that genetic SOS1 gene mutations are also closely associated with some pathogenic rashes such as Noonan Syndrome (NS), cardiac skin syndrome (CFC) and type I hereditary gum fibromatosis (Pierre et al, biochem. Phacol., 2011, 82 (9): 1049-56).

SOS1 inhibition was quite similar in mechanism to SHP2 inhibition (Nichols, R.J.; et al Nat Cell biol.2018, 20 (9), 1064-1073), suggesting that SOS1 inhibition could also enhance KRAS ^G12C And the efficacy of MEK inhibitors. Preliminary data shows that there is a significant synergy between SOS1 and MEK inhibition in PDX models of multiple G12 and G13 KRAS mutations (Hofmann, M.H.; et al; cancer discovery.2020, 10.1158/2159-8290. CD-20-0142.). In addition to inhibiting Kras ^wt Due to KRAS in addition to feedback activation of (C) ^G12C Allosteric inhibitors can only bind to KRAS ^GDP Binding, inhibition of SOS1 has been achieved by increasing mutant KRAS ^G12C Directly increasing KRAS ^G12C Potential advantages of the efficacy of inhibitors (hillg, r.c., et al, proc Natl Acad Sci U S a.2019, 116 (7), 2551-2560). Although still to be further studied, inhibition of SOS1 has great potential for clinical use as a strategy for combination therapy.

At present, no medicine aiming at SOS1 targets is marketed on the global scale, and the compounds are in early clinical or preclinical research stages. Although there are a few pharmaceutical companies or research institutions that have studied SOS1 inhibitors and have been published in related patents, for example, boringer Johnsongahn discloses a class of benzyl amine substituted quinazoline derivatives as SOS1 inhibitors (US 20190358230A 1) and Bayer pharmacy discloses a class of 2-methyl-aza quinazoline compounds as SOS1 inhibitors (WO 2019201848A 1), the SOS1 inhibitors developed at the present stage still have very broad clinical application prospects, but the SOS1 inhibitors developed at the present stage still do not meet the clinical requirements.

Disclosure of Invention

The invention mainly solves the technical problem of providing a pyrimido ring derivative which has a strong selective inhibition effect on SOS 1.

In order to solve the technical problems, the invention provides a compound which has a structure shown in a formula I or a tautomer, a meso, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable hydrate, solvate or salt thereof, or,

having a structure represented by formula I or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt or co-crystal thereof:

wherein:

A ¹ selected from CH, CH ₂ Or N, NR ²⁸ 、O、S，A ² Selected from C or N, A ³ Selected from CH, CH ₂ 、N、NR ²⁸ 、O、S，A ⁴ Selected from CH, CH ₂ Or a bond; preferably, A ⁴ Selected from CH, CH ₂ Or a single bond;

y is selected from bond, CR ⁶ R ⁷ 、O、NR ⁵ S, S (O); when A is ¹ 、A ³ 、A ⁴ Is CH and A ² When C (i.e., when ring A is a benzene ring structure), Y is not a bond;

R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ²⁸ each independently selected from H, alkyl; preferably, R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ²⁸ Each independently selected from H, C to C6 alkyl, more preferably H, C to C3 alkyl, even more preferably H, methyl;

ar is selected from aryl, heteroaryl, and alicyclic, and when ring A is not aromatic, the heteroaryl is not pyridinyl, wherein the aryl, heteroaryl, and alicyclic are optionally substituted with one or more R ⁸ Substitution;

R ⁸ independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, aryl, heteroaryl, -OR ^a 、-NR ^b R ^c 、-SR ^d 、-C(O)R ¹⁰ 、-C(O)NR ^b R ^c 、-C(O)OR ^a Wherein alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more R ¹¹ Substitution;

R ¹¹ independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, aryl, heteroaryl, -OR ^a 、-NR ^b R ^c 、-SR ^d 、-C(O)R ¹² 、-C(O)NR ^b R ^c 、-C(O)OR ^a Wherein the alkyl, cycloalkyl, alicyclic, aryl, heteroaryl is optionally substituted with one or more R ¹³ Substitution;

R ¹³ independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, -OR ^a 、-NR ^b R ^c 、-SR ^d 、-C(O)R ¹⁴ 、-C(O)NR ^b R ^c 、-C(O)OR ^a ；

R ¹ Selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, alicyclic, aryl, -OR ^e 、-NR ^f R ^g 、-SR ^h 、-C(O)R ¹⁵ 、-C(O)NR ^f R ^g 、-C(O)OR ^e Wherein the alkyl, cycloalkyl, and alicyclic groups are optionally substituted with one or more R ¹⁶ Substitution;

R ¹⁶ independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, -OR ^e 、-NR ^f R ^g 、-SR ^h 、-C(O)R ¹⁷ 、-C(O)NR ^f R ^g 、-C(O)OR ^e ；

Ring E is selected from cycloalkyl, alicyclic, aryl, heteroaryl, wherein cycloalkyl, alicyclic, aryl, heteroaryl are optionally substituted with one or more R ¹⁸ Substitution;

R ¹⁸ independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, aryl, heteroaryl, -OR ⁱ 、-NR ^j R ^k 、-SR ^m 、-C(O)R ¹⁹ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ Or two adjacent R ¹⁸ The ring atoms of the ring E to which they are attached together form cycloalkyl, alicyclic, aryl, heteroaryl, wherein the alkyl, cycloalkyl, alicyclic, aryl, heteroaryl are optionally substituted with one or more R ²⁵ Substitution;

preferably, R ¹⁸ Independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, -OR ⁱ 、-NR ^j R ^k 、-SR ^m 、-C(O)R ¹⁹ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ Or two adjacent R ¹⁸ The atoms to which they are attached together form cycloalkyl, alicyclic, aryl, heteroaryl, wherein the alkyl, cycloalkyl, alicyclic, aryl, heteroaryl are optionally substituted with one or more R ²⁵ Substitution;

R ²⁵ independently at each occurrence selected from halogen, cyano, alkyl, -NR ^j R ^k Substituted alkyl, cycloalkyl, alicyclic, -OR ⁱ 、-NR ^j R ^k 、-SR ^m 、-C(O)R ²⁶ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ ；

R ²⁵ Independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, -OR ⁱ 、-NR ^j R ^k 、-SR ^m 、-C(O)R ²⁶ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ ；

R ^a 、R ^b 、R ^c 、R ^d 、R ^e 、R ^f 、R ^g 、R ^h 、R ⁱ 、R ^j 、R ^k 、R ^m Independently at each occurrence selected from H, alkyl, cycloalkyl, alicyclic, -C (O) R ²⁰ Or R is ^b 、R ^c Together with the N atom to which it is attached, constitutes a cycloaliphatic radical, wherein said alkyl, cycloalkyl, cycloaliphatic radical is optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, alkyl, cycloalkyl, alicyclic;

R ¹⁰ 、R ¹² 、R ¹⁴ 、R ¹⁵ 、R ¹⁷ 、R ¹⁹ 、R ²⁰ 、R ²⁶ Each occurrence is independently selected from H, alkyl, cycloalkyl, and alicyclic, said alkyl, cycloalkyl, and alicyclic being optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, alkyl, cycloalkyl, and alicyclic.

In one embodiment, the invention provides a compound having the structure of formula I or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, a pharmaceutically acceptable hydrate, solvate, or salt thereof, or,

in one embodiment, having a structure of formula I or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt or co-crystal thereof, wherein,

A ¹ selected from CH, CH ₂ Or N, NR ²⁸ 、O、S，A ² Selected from C or N, A ³ Selected from CH, CH ₂ 、N、NR ²⁸ 、O、S，A ⁴ Selected from CH, CH ₂ Or a bond; preferably, A ⁴ Selected from CH、CH ₂ Or a single bond;

y is selected from bond, CR ⁶ R ⁷ 、O、NR ⁵ S, S (O); when A is ¹ 、A ³ 、A ⁴ Is CH and A ² When C, Y is not a bond;

ar is selected from aryl or heteroaryl, and when ring A is not aromatic, the heteroaryl is not pyridinyl, wherein the aryl or heteroaryl is optionally substituted with one or more R ⁸ Substitution;

R ¹³ independently at each occurrence selected from halogen, cyano, and,Alkyl, cycloalkyl, alicyclic, -OR ^a 、-NR ^b R ^c 、-SR ^d 、-C(O)R ¹⁴ 、-C(O)NR ^b R ^c 、-C(O)OR ^a ；

R ¹⁸ independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, -OR ⁱ 、-NR ^j R ^k 、-SR ^m 、-C(O)R ¹⁹ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ Wherein the alkyl, cycloalkyl, and alicyclic are optionally substituted with one or more R ²⁵ Substitution;

R ^a 、R ^b 、R ^c 、R ^d 、R ^e 、R ^f 、R ^g 、R ^h 、R ⁱ 、R ^j 、R ^k 、R ^m Independently at each occurrence selected from H, alkyl, cycloalkyl, alicyclic, -C (O) R ²⁰ Wherein the alkyl, cycloalkyl, alicyclic are optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, alkyl, cycloalkyl, alicyclic;

Further, R ^a 、R ^b 、R ^c 、R ^d Independently at each occurrence selected from H, alkyl, -C (O) R ²⁰ Wherein the alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, alkyl;

further, R ^a 、R ^b 、R ^c 、R ^d Independently at each occurrence selected from H, C1-C6 alkyl, -C (O) R ²⁰ Wherein the alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, C1-C6 alkyl;

further, R ^a 、R ^b 、R ^c 、R ^d Independently at each occurrence, a H, C1-C3 alkyl group, wherein the alkyl group is optionally substituted with one or more of the following substituents: halogen, C1-C3 alkyl;

Further, R ^a 、R ^b 、R ^c 、R ^d Each occurrence ofWhen independently selected from H, methyl, preferably R ^b 、R ^c Is methyl.

Further, R ⁱ 、R ^j 、R ^k 、R ^d Independently at each occurrence selected from H, alkyl, -C (O) R ²⁰ Wherein the alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, alkyl;

further, R ⁱ 、R ^j 、R ^k 、R ^d Independently at each occurrence selected from H, C1-C6 alkyl, -C (O) R ²⁰ Wherein the alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, C1-C6 alkyl;

further, R ⁱ 、R ^j 、R ^k 、R ^d Independently at each occurrence, a H, C1-C3 alkyl group, wherein the alkyl group is optionally substituted with one or more of the following substituents: halogen, C1-C3 alkyl;

further, R ⁱ 、R ^j 、R ^k 、R ^d Each occurrence is independently selected from H, methyl, difluoromethyl, preferably H, methyl, preferably H.

The "when ring a is not aromatic, the heteroaryl group is not pyridinyl", it being understood that in this case the heteroaryl group is not only unsubstituted pyridinyl, but also pyridinyl substituted with substituents of any structure in the art.

“R ⁸ Independently at each occurrence "means when R ⁸ When the number of (C) is greater than 1, R is different ⁸ May be selected from the same or different groups. For example, R ⁸ When the number of (2), one R ⁸ May be selected from alkyl, another R ⁸ May be selected from halogen; alternatively, two R ⁸ May all be selected from alkyl groups; the rest of the similar situation is the same. Further, A ¹ Selected from CH, CH ₂ Or N. Preferably CH.

Further, A ² Selected from C or N, preferably C.

Further, A ³ Selected from CH, CH ₂ 、N、NR ²⁸ O, S, where R ²⁸ Selected from H, alkyl, preferably H, C1 to C6 alkyl, more preferably H, C to C3 alkyl, more preferably H, methyl; further, A ³ Selected from CH or N.

Further, A ⁴ Selected from CH, CH ₂ Or a bond, more preferably CH, CH ₂ Or a single bond, more preferably CH.

Further, the method comprises the steps of,selected from the following groups:

preferably selected from the following groups:

more preferablyMore preferably

In a specific embodiment of the invention, R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ²⁸ Are respectively and independently selected from H, C to C6 alkyl,preferably H, C to C3 alkyl, more preferably H or methyl.

Further, R ⁵ Is a C1-C6 alkyl group, preferably a C1-C3 alkyl group, more preferably a methyl group.

Further, the compounds of the present invention have the structure shown in formula II or isomers, tautomers, meso, racemates, enantiomers, diastereomers or mixtures thereof, pharmaceutically acceptable hydrates, solvates or salts thereof, or,

Having a structure represented by formula II or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal thereof:

ring E is selected from C3-C6 cycloalkyl, 4-7 membered alicyclic heterocyclic group, phenyl, 5-6 membered heteroaryl, preferably 5-7 membered alicyclic heterocyclic group, phenyl, further preferably N-containing 6 membered alicyclic heterocyclic group, phenyl, more preferably phenyl; wherein cycloalkyl, alicyclic, phenyl, heteroaryl are optionally substituted with one or more R ¹⁸ Substituted, R ¹⁸ Is as defined above;

n ¹ an integer selected from 0 to 5, preferably an integer from 1 to 3, preferably 1, 2, more preferably 2.

Preferably, ring E is selected from phenyl, 5-6 membered N heteroaryl, 5-6 membered thiaheteroaryl, more preferably phenyl, 6 membered N heteroaryl, 5 membered thiaheteroaryl, more preferably phenyl, pyridinyl or thienyl; wherein the phenyl, 5-6 membered N heteroaryl, 5-6 membered S heteroaryl, 6 membered N heteroaryl, 5 membered S heteroaryl, pyridinyl, thienyl is optionally substituted with one or more R ¹⁸ Substituted, R ¹⁸ As defined above.

Preferably, ring E is selected from phenyl, 5-6 membered N heteroaryl, preferably phenyl, 6 membered N heteroaryl, more preferably phenyl or pyridinyl; wherein phenyl, pyridinyl, N heteroaryl are optionally substituted with one or more R ¹⁸ Substituted, R ¹⁸ As defined above.

In a particular embodiment of the invention, ring E is phenyl, piperidinyl, where phenyl, piperidinyl are optionally substituted with one or more R ¹⁸ Substitution, said R ¹⁸ As defined above.

Further, when ring E is piperidinyl, R ¹⁸ Is C1-C6 alkyl, wherein the alkyl is optionally substituted with 1-3 alkyl groups, halogen, hydroxy, amino, cyano.

In a specific embodiment of the invention, when ring E is piperidinyl, R ¹⁸ Is C1-C3 alkyl which is unsubstituted or substituted by hydroxy.

Further, when ring E is piperidinyl, it has the following structure:the following structure is preferred:

n ² an integer selected from 1 to 3, preferably 2.

Further, ring E is selected from phenyl, 5-6 membered N heteroaryl, preferably phenyl, 6 membered N heteroaryl, more preferably phenyl or pyridinyl; wherein phenyl, pyridinyl, N heteroaryl are optionally substituted with one or more R ¹⁸ Substitution; n is n ¹ An integer selected from 0 to 5, preferably an integer from 1 to 3, preferably 1, 2, more preferably 2.

Further, the compounds of the present invention have the structure shown in formula III or isomers, tautomers, meso, racemates, enantiomers, diastereomers or mixtures thereof, pharmaceutically acceptable hydrates, solvates or salts thereof, or,

Having a structure represented by formula III or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt or co-crystal thereof:

further, R ²³ Selected from C1-C3 alkyl, C1-C3 alkyl substituted by halogen and/or hydroxy, preferably methyl, difluoromethyl, trifluoromethyl, CF ₂ CH ₂ OH、C(OH)CH ₃ CH ₃ More preferably trifluoromethyl;

further, the compounds of the present invention have the structure shown in formula III' or an isomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt thereof, or,

having the structure shown in III' or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt or co-crystal thereof:

in one embodiment, R ¹⁸ Independently at each occurrence selected from halogen, cyano, alkyl, aryl, heteroaryl, -OR ⁱ 、-NR ^j R ^k 、-C(O)R ¹⁹ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ Or two adjacent R ¹⁸ The ring atoms of the ring E to which they are attached together form cycloalkyl, alicyclic, aryl, heteroaryl, wherein the cycloalkyl, alicyclic, aryl, heteroaryl are optionally substituted with one or more R ²⁵ Substitution;

in one embodiment, further, R ¹⁸ Independently at each occurrence selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -OH, phenyl, -NR ^j R ^k Or two adjacent R ¹⁸ The ring atoms of the ring E to which they are attached together form a C5-C10 cycloalkyl, 5-C10-membered alicyclic, C5-C10-aryl, 5-C10-membered heteroaryl group, wherein the alkyl, alkoxy, phenyl, cycloalkyl, alicyclic, aryl, heteroaryl groups are optionally substituted with 1 to 4R ²⁵ Substituted, R ^j 、R ^k Independently at each occurrence selected from H, C1 to C6 alkyl.

In one embodiment, R ¹⁸ Independently at each occurrence selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, -OH, phenyl, -NR ^j R ^k Or two adjacent R ¹⁸ The ring atoms of the ring E to which they are attached together form a C5-C6 cycloalkyl, 5-6 membered alicyclic, 5-6 membered heteroaryl group, wherein the alkyl, alkoxy, phenyl, cycloalkyl, alicyclic, heteroaryl groups are optionally substituted with 1-3R ²⁵ Substituted, R ^j 、R ^k Each occurrence of which is independently selected from H, C1 to C3 alkyl;

in one embodiment, further, R ¹⁸ Independently at each occurrence selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, -OH, phenyl, -NR ^j R ^k Or two adjacent R ¹⁸ The ring atoms of the ring E to which they are attached together form a cyclopentane, tetrahydrofuran, pyrrole radical, where the C1-C3 alkyl, C1-C3 alkoxy, phenyl, cyclopentylalkyl, tetrahydrofuran, pyrrole radical is optionally substituted with 1 to 3R ²⁵ Substituted, R ^j 、R ^k All are H;

further, R ¹⁸ Independently at each occurrence selected from halogen, cyano, alkyl, -OR ⁱ 、-NR ^j R ^k 、-C(O)R ¹⁹ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ Or two adjacent R ¹⁸ The atoms to which they are attached together form cycloalkyl, alicyclic, aryl, heteroaryl, wherein the alkyl, cycloalkyl, alicyclic, aryl, heteroaryl are optionallyGeodesic one or more R ²⁵ Substitution;

further, R ¹⁸ Independently at each occurrence selected from halogen, cyano, C1-C6 alkyl, -NR ^j R ^k Or two adjacent R ¹⁸ The atoms to which they are attached together form a C5-C10 cycloalkyl, 5-C10 membered alicyclic, C5-C10 aryl, 5-C10 membered heteroaryl group, wherein the alkyl, cycloalkyl, alicyclic, aryl, heteroaryl groups are optionally substituted with 1 to 4R ²⁵ Substituted, R ^j 、R ^k Each occurrence of which is independently selected from H, C1 to C6 alkyl;

further, R ¹⁸ Independently at each occurrence selected from halogen, cyano, C1-C3 alkyl, -NR ^j R ^k Or two adjacent R ¹⁸ The atoms to which they are attached together form a C5-C6 cycloalkyl, 5-6 membered alicyclic, 5-6 membered heteroaryl group, wherein the alkyl, cycloalkyl, alicyclic, heteroaryl groups are optionally substituted with 1-3R ²⁵ Substituted, R ^j 、R ^k Each occurrence of which is independently selected from H, C1 to C3 alkyl;

further, R ¹⁸ Independently at each occurrence selected from halogen, cyano, C1-C3 alkyl, -NR ^j R ^k Or two adjacent R ¹⁸ The atoms to which they are attached together form a cyclopentane, tetrahydrofuran, pyrrole radical, where the C1-C3 alkyl, cyclopentane, tetrahydrofuran, pyrrole radicals are optionally substituted with 1-3R ²⁵ Substituted, R ^j 、R ^k All are H.

Further, R ¹⁸ Independently at each occurrence selected from halogen, cyano, alkyl, -OR ⁱ 、-NR ^j R ^k 、-C(O)R ¹⁹ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ Wherein the alkyl is optionally substituted with one or more R ²⁵ Substitution;

further, R ¹⁸ Independently at each occurrence selected from halogen, cyano, and,C1-C6 alkyl, -OR ⁱ 、-NR ^j R ^k Wherein the alkyl is optionally substituted with one or more R ²⁵ Substitution;

further, R ¹⁸ Independently at each occurrence selected from halogen, C1-C3 alkyl, -NR ^j R ^k Wherein the alkyl is optionally substituted with one or more R ²⁵ And (3) substitution.

In one embodiment, R ¹⁸ Independently at each occurrence selected from halogen, cyano, hydroxy, amino, methyl, CF ₃ 、-CF ₂ CH ₃ 、-CF ₂ H、-CF ₂ CH ₂ OH、-C(CH ₃ ) ₂ OH、-OCF ₂ H、-CH ₂ NHCH ₃ Substituted phenyl or pyridyl, or, alternatively, two adjacent R ¹⁸ The ring atoms on the ring E to which they are attached together form a cyclopentanyl, tetrahydrofuranyl, pyrrolyl group, wherein the cyclopentanyl, tetrahydrofuranyl, pyrrolyl groups are optionally substituted with one or more F atoms.

In one embodiment, R ²⁵ Independently at each occurrence selected from halogen, C1-C6 alkyl, -OR ⁱ 、-CH ₂ NR ^j R ^k 、-NR ^j R ^k ；

Further, R ²⁵ Independently at each occurrence selected from halogen, C1-C6 alkyl, -OR ⁱ 、-NR ^j R ^k Preferably halogen, C1-C3 alkyl, -OR ⁱ More preferably halogen OR-OR ⁱ More preferably halogen, wherein R ⁱ 、R ^j 、R ^k As defined hereinbefore, preferably R ⁱ 、R ^j 、R ^k Independently selected from H, alkyl, more preferably R ⁱ 、R ^j 、R ^k Is H; further, R ²⁵ Independently at each occurrence selected from F, cl, methyl, ethyl, propyl, hydroxy, preferably F, methylHydroxyl, more preferably F, hydroxyl.

Further, R ¹⁸ Each occurrence is independently selected from F, CN, -NH ₂ 、-CH ₃ 、-CHF ₂ 、-CF ₃ 、-CF ₂ CH ₃ 、-CF ₂ CH ₂ OH、-C(OH)CH ₃ CH ₃ Or two adjacent R ¹⁸ To which atoms are attached to form together

In one embodiment, R ¹⁸ Independently at each occurrence selected from the group consisting of-F, -CN, -NH ₂ 、-OH、-CH ₃ 、-CHF ₂ 、-CF ₃ 、-CF ₂ CH ₃ 、-CF ₂ CH ₂ OH、-OCF ₂ H、 Or two adjacent R ¹⁸ To which atoms are attached to form together

Further, R ¹⁸ Each occurrence is independently selected from F, CN, -NH ₂ 、-CH ₃ 、-CHF ₂ 、-CF ₃ 、-CF ₂ CH ₃ 、-CF ₂ CH ₂ OH, or two adjacent R' s ¹⁸ To which atoms are attached to form together

Further, the compound has the structureIs thatWherein R is ²² 、R ²³ 、R ²⁴ Independently selected from H, halogen, cyano, C1-C6 alkyl, -OR ⁱ 、-NR ^j R ^k 、-C(O)R ¹⁹ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ Wherein the alkyl is optionally substituted with one or more R ²⁵ Substitution;

further, R ²² 、R ²³ 、R ²⁴ Are independently selected from H, halogen, C1-C3 alkyl, -NR ^j R ^k Wherein the alkyl is optionally substituted with one or more R ²⁵ And (3) substitution.

Further, R ²² Selected from H or halogen, preferably H or F, more preferably H;

R ²³ selected from C1-C3 alkyl, C1-C3 alkyl substituted by halogen and/or hydroxy, preferably methyl, difluoromethyl, trifluoromethyl, CF ₂ CH ₂ OH、C(OH)CH ₃ CH ₃ More preferably trifluoromethyl;

R ²⁴ selected from H, NH ₂ Preferably NH ₂ 。

In one embodiment, ring E is selected from the following structures:

further, ring E is selected from the following structures:

y is selected from bond, CR ⁶ R ⁷ 、O、NR ⁵ When A is ¹ 、A ³ 、A ⁴ Is CH and A ² In the case of C, Y is not a bond.

In a particular embodiment of the invention, Y is selected from the group consisting of a bond, O, NR ⁵ When A is ¹ 、A ³ 、A ⁴ Is CH and A ² In the case of C, Y is not a bond. Wherein R is ⁵ 、R ⁶ 、R ⁷ Each independently selected from H, alkyl, preferably H, C to C6 alkyl, more preferably H, C to C3 alkyl, more preferably H, methyl;

further, the methodR in (B) ¹⁸ Is not fixed, meaning R ¹⁸ Any substitutable site on the benzene ring is possible, and the rest of the similar conditions are the same.

Further, Y is selected from the group consisting of bond, CR ⁶ R ⁷ 、O、NR ⁵ When A is ¹ 、A ³ 、A ⁴ Is CH and A ² In the case of C, Y is not a bond.

In a particular embodiment of the invention, Y is selected from the group consisting of a bond, O, NR ⁵ When A is ¹ 、A ³ 、A ⁴ Is CH and A ² In the case of C, Y is not a bond. Wherein R is ⁵ Selected from H, alkyl, preferably H, C1 to C6 alkyl, more preferably H, C to C3 alkyl, more preferably H, methyl; alternatively, R ⁵ Is a C1-C6 alkyl group, preferably a C1-C3 alkyl group, more preferably a methyl group;

further, Y is selected from O, NR ⁵ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ⁵ Selected from H, alkyl, preferably H, C1 to C6 alkyl, more preferably H, C to C3 alkyl, more preferably H, methyl; alternatively, R ⁵ Is a C1-C6 alkyl group, preferably a C1-C3 alkyl group, more preferably a methyl group.

Further Ar is selected from C6-C10 aryl, 5-10 membered heteroaryl, 3-10 membered alicyclic, wherein said aryl, heteroaryl, alicyclic are optionally substituted with one or more R ⁸ Substitution;

further Ar is selected from phenyl, 6-9 membered heteroaryl, 5-6 membered alicyclic, wherein said phenyl, heteroaryl, alicyclic are optionally substituted with one or more R ⁸ Substitution;

further, ar is selected from phenyl, 6-membered N-heteroaryl, 9-membered N-heteroaryl, N-heterocycloalkylene, wherein the phenyl, 6-membered N-heteroaryl, 9-membered N-heteroaryl, N-heterocycloalkylene are optionally substituted with one or more R ⁸ Substitution;

further, ar is selected from phenyl, 6-membered N-heteroaryl, N-heterocycloalkylene, wherein the phenyl, 6-membered N-heteroaryl, N-heterocycloalkylene are optionally substituted with one or more R ⁸ Substitution;

further, ar is selected from phenyl, pyridyl,Wherein the phenyl group, the pyridyl group,Optionally by one or more R ⁸ Substitution;

further, ar is selected from phenyl, pyridyl,Wherein the phenyl group, the pyridyl group, Optionally by one or more R ⁸ And (3) substitution.

Further Ar is selected from phenyl or a 5-to 10-membered heteroaryl, preferably phenyl or a 6-to 9-membered heteroaryl, more preferably phenyl or N-hetero 6-to 9-membered heteroaryl, more preferably phenyl, pyridinyl, 9-membered N-heteroaryl, wherein the phenyl, pyridinyl, heteroaryl are optionally substituted with one or more R ⁸ Substitution, said R ⁸ As defined above.

According to the foregoing definition "when ring a does not possess aromaticity, the heteroaryl is not pyridinyl", then when Ar is pyridinyl, it is to be understood that ring a possesses aromaticity.

Further Ar is optionally substituted with 1 to 3R ⁸ Substitution; further Ar is optionally substituted with 1 to 2R ⁸ And (3) substitution.

Further, R ⁸ Independently at each occurrence selected from halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 alicyclic heterocyclyl, -OR ^a 、-NR ^b R ^c Wherein the alkyl, cycloalkyl, and alicyclic groups are optionally substituted with one or more R ¹¹ Substitution, said R ^a 、R ^b 、R ^c 、R ¹¹ As defined above.

Further, R ⁸ Independently at each occurrence selected from C1-C3 alkyl, -OR ^a 、-NR ^b R ^c Wherein the alkyl is optionally substituted with one or more R ¹¹ Substitution, said R ^a 、R ^b 、R ^c 、R ¹¹ As defined above.

Further, R ⁸ Independently at each occurrence selected from C1-C3 alkyl, -OR ^a 、-NR ^b R ^c Wherein R is ^a Selected from H, alkyl, R ^b 、R ^c Independently selected from H, alkyl, or R ^b 、R ^c Together with the N atom to which they are attached form a cycloaliphatic radical, said alkyl, cycloaliphatic radical optionally being substituted with one or more R ¹¹ Substitution;

further, R ⁸ Independently at each occurrence selected from methyl, ethyl, propyl, -OR ^a 、-NR ^b R ^c Wherein R is ^a Selected from H, C-C6 alkyl, R ^b 、R ^c Are independently selected from C1-C6 alkyl, or R ^b 、R ^c Together with the N atom to which they are attached form a 5-membered alicyclic ring, said methyl, ethyl, propyl, alkyl, alicyclic ring optionally being substituted with one or more R ¹¹ Substitution;

further, R ⁸ Independently at each occurrence selected from methyl, ethyl, -OR ^a 、-NR ^b R ^c Wherein R is ^a Selected from H, C-C3 alkyl, R ^b 、R ^c Are independently selected from C1-C3 alkyl, or R ^b 、R ^c Is co-formed with N atomsThe methyl, ethyl, alkyl,Optionally by one or more R ¹¹ And (3) substitution.

Further, R ⁸ Each occurrence of which is independently selected from-OH, -OCH ₃ 、-N(CH ₃ ) ₂ 、-NHCH ₃ 、-CH ₂ C(O)N(CH ₃ ) ₂ 、-CH ₂ CH ₂ C(O)N(CH ₃ ) ₂ 、-CH ₂ CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CN、

Further, R ⁸ Each occurrence of which is independently selected from-OH, -OCH ₃ 、-N(CH ₃ ) ₂ 、-CH ₂ C(O)N(CH ₃ ) ₂ 、-CH ₂ CH ₂ C(O)N(CH ₃ ) ₂ 、-CH ₂ CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CN、

Further, R ⁸ Each occurrence of which is independently selected from-OCH ₃ 、-OH、 -CH ₂ C(O)N(CH ₃ ) ₂ 、 -CH ₂ CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CN、-CH ₃ ；

Further, R ⁸ Each occurrence of which is independently selected from-OCH ₃ 、-OH、 -CH ₂ C(O)N(CH ₃ ) ₂ 、 -CH ₂ CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CN。

In one embodiment, R ¹¹ Independently at each occurrence selected from halogen, cyano, alkyl, aryl, heteroaryl, -OR ^a 、-NR ^b R ^c 、-C(O)R ¹² 、-C(O)NR ^b R ^c 、-C(O)OR ^a Wherein the alkyl, aryl, heteroaryl are optionally substituted with one or more R ¹³ Substitution;

further, R ¹¹ Independently at each occurrence selected from halogen, cyano, C1-C6 alkyl, 6-to 10-membered aryl, 5-to 9-membered heteroaryl, -OR ^a 、-NR ^b R ^c 、-C(O)R ¹² 、-C(O)NR ^b R ^c 、-C(O)OR ^a Wherein the alkyl, aryl, heteroaryl are optionally substituted with one or more R ¹³ Substitution;

further, R ¹¹ Independently at each occurrence selected from halogen, cyano, C1-C6 alkyl, 5-6 membered heteroaryl, -OR ^a 、-NR ^b R ^c 、-C(O)R ¹² 、-C(O)NR ^b R ^c 、-C(O)OR ^a Wherein the alkyl, aryl, heteroaryl are optionally substituted with 1 to 3R ¹³ Substitution;

further, R ¹¹ Independently at each occurrence selected from cyano, C1-C3 alkyl, 5 membered heteroaryl, -NR ^b R ^c 、-C(O)NR ^b R ^c Wherein the alkyl, aryl, heteroaryl are optionally substituted with 1 to 3R ¹³ Substitution;

further, R ¹¹ The 5 membered heteroaryl group of (2) is selected from thiazolyl and imidazolyl, wherein the thiazolyl and imidazolyl are optionally substituted with 1-2R ¹³ Substitution;

further, R ¹¹ Independently at each occurrence selected from cyano, methyl, ethyl, propyl, -N(CH ₃ ) ₂ 、-C(O)N(CH ₃ ) ₂ 、

In one embodiment, R ¹¹ Independently at each occurrence selected from alkyl, 6-10 membered aryl, 5-9 membered heteroaryl, -C (O) R ¹² 、-C(O)NR ^b R ^c 、-C(O)OR ^a Wherein the alkyl, aryl, heteroaryl are optionally substituted with one or more R ¹³ Substitution, said R ^a 、R ^b 、R ^c 、R ¹² 、R ¹³ As defined above.

Further, R ¹¹ Independently at each occurrence selected from 5-6 membered heteroaryl, -C (O) R ¹² 、-C(O)NR ^b R ^c 、-C(O)OR ^a Wherein the heteroaryl is optionally substituted with one or more R ¹³ Substitution, said R ^a 、R ^b 、R ^c 、R ¹² 、R ¹³ As defined above.

Further, the method，R ¹¹ Independently at each occurrence selected from 5 membered heteroaryl, -C (O) NR ^b R ^c preferably-C (O) NR ^b R ^c Wherein the heteroaryl is optionally substituted with one or more R ¹³ Substitution, said R ^b 、R ^c 、R ¹³ As defined above.

In a specific embodiment of the invention, R ¹¹ Independently at each occurrence selected from thiazolyl, imidazolyl, -C (O) NR ^b R ^c Wherein the thiazolyl, imidazolyl are optionally substituted with one or more R ¹³ Substitution, said R ^b 、R ^c 、R ¹³ As defined above.

Further, R ¹¹ The optional thiazolyl and imidazolyl are of the following structures:

further, R ¹³ Independently at each occurrence selected from halogen, C1-C6 alkyl, -OR ^a 、-NR ^b R ^c 、-C(O)R ¹⁴ 、-C(O)NR ^b R ^c 、-C(O)OR ^a The R is ^a 、R ^b 、R ^c 、R ¹⁴ As defined above.

In a specific embodiment of the invention, R ¹³ Independently for each occurrence selected from halogen, C1-C6 alkyl, preferably C1-C3 alkyl, preferably methyl.

Further, R ^a 、R ^b 、R ^c 、R ^d Independently at each occurrence selected from H, C1-C6 alkyl, -C (O) R ²⁰ Wherein the alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, C1-C6 alkyl.

Further, R ^a 、R ^b 、R ^c 、R ^d Independently at each occurrence, a H, C1-C3 alkyl group, wherein the alkyl group is optionally substituted with one or more of the following substituents: halogen, C1-C3 alkyl.

Further, in a specific embodiment of the present invention, R ^a 、R ^b 、R ^c 、R ^d Independently at each occurrence selected from H, methyl, preferably R ^b 、R ^c Is methyl.

In one embodiment, ar is selected from the following groups:

further, ar is selected from the following groups:

ar is selected from the following groups:

further, ar is selected from the following groups:

further, the compounds of the present invention have a structure of formula IV or formula V or formula VI or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt thereof, or,

a compound having a structure of formula IV or formula V or formula VI or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt or co-crystal thereof:

A ⁵ 、A ⁶ Are respectively and independently selected from CR ²⁷ Or N, wherein R ²⁷ Selected from H, C-C3 alkyl, preferably H;

R ²¹ selected from H, C-C6 alkyl, -OR ^a 、-NR ^b R ^c Preferably C1-C3 alkyl, -OR ^a 、-NR ^b R ^c Preferably methyl, ethyl, -OR ^a 、-NR ^b R ^c More preferably-OR ^a 。

In a specific embodiment of the present invention, the structure of formula IV is further of formula IV':

the structure of formula V is further of formula V':

the structures of formula IV 'and formula V' represent A in formula IV ¹ 、A ³ 、A ⁴ Is CH, A ² C, it is to be understood that the above is satisfied when A ¹ 、A ³ 、A ⁴ Is CH and A ² Y is not a bond limitation in the case of C.

Further, in formula IV or formula IV ', formula V or formula V', Y is NR ⁵ The method comprises the steps of carrying out a first treatment on the surface of the In formula VI, Y is selected from the group consisting of a bond, O, NR ⁵ 。

In a particular embodiment of the invention, a compound of formula IV or formula IVSelected from the following structures:

in the formula V or V',selected from the following structures:

in formula VISelected from the following structures:

further, in formula IV or formula IV',selected from the following structures:in the formula V or V',in the formula VI, the compound of formula VI,is that

Further, the method comprises the steps of,selected from the following structures:

preferably is

Further, R ¹⁸ Independently at each occurrence selected from halogen, cyano, alkyl, -OR ⁱ 、-NR ^j R ^k 、-C(O)R ¹⁹ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ Wherein the alkyl is optionally substituted with one or more R ²⁵ Substitution, said R ⁱ 、R ^j 、R ^k 、R ¹⁹ 、R ²⁵ As defined above.

Further, R ¹⁸ Independently at each occurrence selected from halogen, cyano, C1-C6 alkyl, -OR ⁱ 、-NR ^j R ^k Wherein the alkyl is optionally substituted with one or more R ²⁵ Substitution, said R ⁱ 、R ^j 、R ^k 、R ²⁵ As defined above.

Further, R ¹⁸ Independently at each occurrence selected from halogen, C1-C3 alkyl, -NR ^j R ^k Wherein the alkyl is optionally substituted with one or more R ²⁵ Substitution, said R ^j 、R ^k 、R ²⁵ As defined above.

In a specific embodiment of the present invention,the structure is as follows:wherein R is ²² 、R ²³ 、R ²⁴ Independently selected from H, halogen, cyano, C1-C6 alkyl, -OR ⁱ 、-NR ^j R ^k 、-C(O)R ¹⁹ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ Wherein the alkyl is optionally substituted with one or more R ²⁵ Substitution, said R ⁱ 、R ^j 、R ^k 、R ¹⁹ 、R ²⁵ As defined above.

Further, R ²² 、R ²³ 、R ²⁴ Are independently selected from H, halogen, C1-C3 alkyl, -NR ^j R ^k Wherein the alkyl is optionally substituted with one or more R ²⁵ Substitution, said R ^j 、R ^k 、R ²⁵ As defined above.

In a specific embodiment of the invention, R ²⁵ Independently at each occurrence selected from halogen, C1-C6 alkyl, -OR ⁱ 、-NR ^j R ^k Preferably halogen, C1-C3 alkyl, -OR ⁱ More preferably halogen; r is R ⁱ 、R ^j 、R ^k As defined above.

In a specific embodiment of the invention, R ⁱ 、R ^j 、R ^k 、R ^d Each occurrence is independently selected from H, methyl, preferably H.

In a specific embodiment of the invention, R ²² Selected from H or halogen, preferably H or F, more preferably H; r is R ²³ Selected from C1-C3 alkyl, C1-C3 alkyl substituted by halogen and/or hydroxy, preferably methyl, difluoromethyl, trifluoromethyl, CF ₂ CH ₂ OH、C(OH)CH ₃ CH ₃ More preferably trifluoromethyl; r is R ²⁴ Selected from H, NH ₂ Preferably NH ₂ 。

Further, the compounds of the present invention have a structure represented by formula VII or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable hydrate, solvate or salt thereof, or,

having a structure represented by formula VII or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal thereof:

further, R ¹ Selected from hydrogen, halogen, cyano, C1-C6 alkyl, 6-10 membered aryl, -OR ^e 、-NR ^f R ^g 、-C(O)R ¹⁵ 、-C(O)NR ^f R ^g 、-C(O)OR ^e Wherein the alkyl is optionally substituted with one or more R ¹⁶ Substitution, said R ^e 、R ^f 、R ^g 、R ¹⁵ 、R ¹⁶ As defined above;

further, R ¹ Selected from hydrogen, halogen, cyano, C1-C3 alkyl, -OR ^e 、-NR ^f R ^g Wherein the alkyl is optionally substituted with one or more R ¹⁶ Substitution, said R ^e 、R ^f 、R ^g 、R ¹⁶ As defined above;

in a specific embodiment of the invention, R ¹ Selected from halogen and C1-C3 alkyl.

In one embodiment, R ¹ Selected from hydrogen, halogen, C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more R ¹⁶ And (3) substitution.

Further, R ¹⁶ Independently at each occurrence selected from halogen, cyano, C1-C6 alkyl, -OR ^e 、-NR ^f R ^g 、-C(O)R ¹⁷ 、-C(O)NR ^f R ^g 、-C(O)OR ^e 。

Further, R ¹⁶ Independently at each occurrence selected from halogen, C1-C3 alkyl, -OR ^e 、-NR ^f R ^g 。

Further, R ¹⁶ is-OR ^e 。

Further, R ^e 、R ^f 、R ^g 、R ^h Independently at each occurrence selected from H, C1-C6 alkyl, -C (O) R ²⁰ Wherein the alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, C1-C6 alkyl.

Further, R ^e 、R ^f 、R ^g 、R ^h Independently at each occurrence, a H, C1-C3 alkyl group, wherein the alkyl group is optionally substituted with one or more of the following substituents: halogen, C1-C3 alkyl.

Further, R ^e 、R ^f 、R ^g 、R ^h Independently at each occurrence selected from H, methyl, ethyl.

Further, R ^e H.

Further, R ¹ Selected from H, cl, br, I, hydroxy, cyano, methyl, difluoromethyl, ethyl, -CH ₂ OH、-CH ₂ NH ₂ 、-NHCH ₃ 、-OCH ₂ CH ₃ Preferably methyl or Cl. Further, the method comprises the steps of,is of the configuration of

In one embodiment, R ¹ Selected from H, cl, br, I, hydroxy, cyano, methyl, difluoromethyl, ethyl, -CH ₂ OH、-CH ₂ NH ₂ 、-NHCH ₃ 、-OCH ₂ CH ₃ More preferably H, cl, methyl, ethyl, -CH ₂ CH ₂ OH; more preferably methyl or Cl;

preferably, R ¹ Selected from Cl, methyl, -CH ₂ CH ₂ OH、-CH ₂ CH ₃ A cyclopropane group;

further, the method comprises the steps of,is of the configuration of

Further, R ¹⁰ 、R ¹² 、R ¹⁴ 、R ¹⁵ 、R ¹⁷ 、R ¹⁹ 、R ²⁰ 、R ²⁶ Each occurrence is independently selected from H, C1 to C6 alkyl groups, said alkyl groups optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, C1-C6 alkyl.

Further, R ¹⁰ 、R ¹² 、R ¹⁴ 、R ¹⁵ 、R ¹⁷ 、R ¹⁹ 、R ²⁰ 、R ²⁶ Each occurrence is independently selected from H, C1 to C3 alkyl groups, said alkyl groups optionally substituted with one or more of the following substituents: halogen, hydroxy, amino, C1-C3 alkyl.

In a specific embodiment of the invention, the compound structure is selected from one of the following:

in another aspect of the present invention, there is provided a process for the preparation of the above compound, comprising the steps selected from the following synthetic schemes:

synthesis scheme 1:

the compound of formula 1-1 and the compound of formula 1-2 are subjected to cyclization reaction to obtain the compound of formula 1-3, the compound of formula 1-3 and POX ₃ Carrying out a reaction to obtain compounds of formulas 1-4;

wherein X represents halogen, preferably selected from chlorine or bromine; A. a is that ¹ 、A ² 、A ³ 、A ⁴ Is defined as a compound of formula (I);

synthesis scheme 2:

route a: the compound of formula 2-1 is subjected to substitution reaction with the compound of formula 2-2 to obtain a compound of formula 2-3, and then the compound of formula 2-3 is subjected to substitution reaction with the compound of formula 2-4 to obtain a compound of formula (I'); or alternatively, the first and second heat exchangers may be,

route B: the compound of the formula 2-1 is subjected to substitution reaction with the compound of the formula 2-4 to obtain a compound of the formula 2-3, and then the compound of the formula 2-3 is subjected to substitution reaction with the compound of the formula 2-4 to obtain a compound of the formula (I');

wherein X represents halogen, preferably selected from chlorine or bromine; r is R ¹ 、R ² 、R ³ 、R ⁴ 、A、A ¹ 、A ² 、A ³ 、A ⁴ Y is defined as a compound of formula (I); m and M 'are selected from X or Y, provided that M and M' are not X or Y at the same time;

e ', R1', ar ' are each defined as E, R, ar in the compound of formula (I), provided that when the substituents in the three in the compound of formula (I) comprise a hydroxy group, the hydroxy group is optionally substituted with OTBS; optionally, steps A and B are followed by a step of removing TBS from the compound of formula (I');

when the substituents in the three of the compounds of (I) comprise amino groups, said amino groups are optionally substituted by-NO ₂ or-C (O) OCH ₂ CH ₃ Substitution; optionally, steps A and B are followed by addition of-NH-to the compound of formula (I') ₂ Reduction to-NO ₂ Is subjected to the step of removing-C (O) OCH ₂ CH ₃ A protecting group step;

when the substituents in the three of the compounds of (I) includeWhen in use, theOptionally is covered bySubstitution; optionally, step A and step B are followed by the step of adding a compound of formula (I')Is reduced toIs carried out by the steps of (a);

when the substituents in the three of the compounds of (I) includeOr ethyl, theOr ethyl optionally beingSubstitution; optionally, step A and step B are followed by the step of adding a compound of formula (I')Is reduced toOr an ethyl group;

synthesis scheme 3:

compounds of formula 3-2 in Cs ₂ CO ₃ Cyclizing with 18-crown ether-6 to obtain a compound of formula 3-2;

wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、A、A ¹ 、A ² 、A ³ 、A ⁴ Y, ar are as defined for compounds of formula (I);

synthesis scheme 4:

compounds of formula 4-1 and BBr ₃ Carrying out demethylation reaction to obtain a compound of formula 4-2;

wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、A、A ¹ 、A ² 、A ³ 、A ⁴ The definition of E ring and Y is the same as that of the compound of formula (I); the N-ring is selected from phenyl or pyridyl.

The invention also provides a medicinal composition, and the active ingredient of the medicinal composition is selected from one or more than two of the compounds or stereoisomers, solvates, hydrates, pharmaceutically acceptable salts or eutectic crystals thereof.

The invention also provides application of the compound or tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt or eutectic crystal thereof and a pharmaceutical composition in preparing an SOS1 inhibitor.

The invention also provides application of the compound or tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt or eutectic crystal thereof and a pharmaceutical composition in preparing medicines for treating SOS 1-mediated diseases.

Further, the disease is selected from: cancer and pathogenic rash.

Further, the cancer is selected from: non-small cell lung cancer, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, chronic myelogenous leukemia, colorectal cancer, brain cancer, liver cancer, kidney cancer, stomach cancer, and breast cancer.

The pathogenic rash is selected from the group consisting of: noonan syndrome, cardio-facial skin syndrome, hereditary gingival fibromatosis type I.

The invention also provides application of the compound or tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt or eutectic crystal thereof and a pharmaceutical composition in preparing medicines for treating diseases causing over-expression of SOS1 protein.

The invention also provides application of the compound or tautomer, stereoisomer, solvate, metabolite, isotope label, pharmaceutically acceptable salt or eutectic crystal thereof and a pharmaceutical composition in preparing medicines for treating diseases caused by over-expression of SOS1 protein.

The pharmaceutical composition containing the compound or the tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt or eutectic crystal of the compound can contain pharmaceutically acceptable auxiliary materials.

"tautomer" as used herein refers to a functional group isomer that results from the movement of an atom in a molecule at two positions, particularly the presence of mobile hydrogen atoms in the molecule, such as keto and enol tautomers.

As used herein, "stereoisomers" refers to isomers produced by the same order of interconnection of atoms or groups of atoms in a molecule, but in different spatial arrangements, and include cis-trans isomers, optical isomers, conformational isomers. Stereoisomers according to the invention also include mixtures of two or more stereoisomers, such as mixtures of enantiomers and/or diastereomers in any ratio.

The term "isotopic label" as used herein means that one or more atoms in a molecule are replaced by atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, such as but not limited to ² H、 ³ H、 ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹³ N、 ¹⁵ N、 ¹⁵ O、 ¹⁷ O、 ¹⁸ O、 ³⁵ S、 ¹⁸ F、 ³⁶ Cl、 ¹²³ I and ¹²⁵ I. certain isotopically-labeled compounds of the present invention are useful in drug and/or substrate tissue distribution studies, the radioisotope tritium being ³ H and carbon-14, i.e ¹⁴ C is particularly useful for this purpose because of its ease of incorporation and convenient detection means, e.g., the compounds of the present invention may be enriched in 1%, 2%, 5%, 10%, 25%, 50%, 75%, 90%, 95% or 99% of the designated isotope. Furthermore, substitution of the compounds of the invention with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages.

The term "pharmaceutically acceptable salt" as used herein refers to salts of the compounds of the present invention with acids or bases that are suitable for use as medicaments. The acid base is a broad Lewis acid base. Suitable salts forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and benzenesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid. The "pharmaceutically acceptable salt" of the present invention is preferably hydrochloride or formate.

The term "solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention that is suitable for use as a drug. Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N-dimethylformamide, dimethylsulfoxide, and the like.

The term "pharmaceutically acceptable" as used herein is meant to include any material which does not interfere with the effectiveness of the biological activity of the active ingredient and which is not toxic to the host to which it is administered.

The pharmaceutically acceptable auxiliary materials are the general names of all additional materials except the main drugs in the medicine, and the auxiliary materials have the following properties: (1) no toxic or side effect to human body; (2) The chemical property is stable, and is not easily influenced by temperature, pH, preservation time and the like; (3) No incompatibility with the main medicine, and no influence on the curative effect and quality inspection of the main medicine; (4) does not interact with the packaging material. Adjuvants in the present invention include, but are not limited to, fillers (diluents), lubricants (glidants or anti-adherents), dispersants, wetting agents, binders, conditioning agents, solubilizing agents, antioxidants, bacteriostats, emulsifiers, disintegrants, and the like. The binder comprises syrup, acacia, gelatin, sorbitol, tragacanth, cellulose and its derivatives (such as microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose or hydroxypropyl methylcellulose), gelatin slurry, syrup, starch slurry or polyvinylpyrrolidone; the filler comprises lactose, sugar powder, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salt (such as calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, etc.), sorbitol or glycine, etc.; the lubricant comprises aerosil, magnesium stearate, talcum powder, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol and the like; disintegrants include starch and its derivatives (e.g., sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, etc.), polyvinylpyrrolidone, microcrystalline cellulose, etc.; the wetting agent comprises sodium dodecyl sulfate, water or alcohol, etc.; the antioxidant comprises sodium sulfite, sodium bisulphite, sodium metabisulfite, dibutyl benzoic acid and the like; the bacteriostat comprises 0.5% phenol, 0.3% cresol, 0.5% chlorobutanol and the like; the regulator comprises hydrochloric acid, citric acid, potassium hydroxide (sodium), sodium citrate, buffer (including sodium dihydrogen phosphate and disodium hydrogen phosphate), etc.; the emulsifier comprises polysorbate-80, sorbitan without acid, pluronic F-68, lecithin, soybean lecithin, etc.; the solubilizer comprises Tween-80, bile, glycerol, etc. The term "pharmaceutically acceptable salt" refers to salts of the compounds of the invention with acids or bases that are suitable for use as medicaments. The acid base is a broad Lewis acid base. Suitable salts forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and the like; acidic amino acids such as aspartic acid and glutamic acid.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.

In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.

The compounds of the invention can likewise be used in injectable formulations. Wherein the injection is selected from liquid injection (water injection), sterile powder for injection (powder injection) or tablet for injection (refers to a stamped tablet or a machine pressed tablet prepared by a sterile operation method for medicines), and is dissolved by water for injection when in use for subcutaneous or intramuscular injection.

Wherein the powder for injection contains at least an excipient in addition to the above-mentioned compounds. The excipients described in the present invention, which are components intentionally added to a drug, should not have pharmacological properties in the amounts used, however, the excipients may aid in processing, dissolution or dissolution of the drug, delivery by targeted route of administration, or stability.

"optionally substituted with one or more …" means that it may be substituted with one or more specified substituents, or it may be unsubstituted; the "plurality" of "one or more" is not limited, and the minimum value is 2, and the maximum value is the number of substitutable sites of a substituted group.

"substituted" means that a hydrogen atom in the molecule is replaced by a different group.

"Yuan" means the number of skeleton atoms constituting a ring.

"Ring" refers to any covalently closed structure, including, for example, carbocycles (e.g., aryl or cycloalkyl), heterocycles (e.g., heteroaryl or heterocycloalkyl), aromatic groups (e.g., aryl or heteroaryl), non-aromatic groups (e.g., cycloalkyl or heterocycloalkyl). The "ring" in the present invention may be a single ring or multiple rings, and may be a parallel ring, a spiro ring or a bridged ring.

Heteroatoms include, but are not limited to O, S, N, P, si and the like.

The term "key" in the present invention means only one connecting key, and is also understood as "none". For example, in formula I when Y is a bond, ar is directly attached to the A ring.

"alkyl" refers to an aliphatic hydrocarbon group, and to a saturated hydrocarbon group. The alkyl moiety may be a straight chain alkyl group or a branched alkyl group. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.

The C1 to Cn used in the present invention includes C1 to C2, C1 to C3.. The prefix as a substituent means minimum and maximum values of the number of carbon atoms in the substituent, for example, "C1 to C6 alkyl" means a straight-chain or branched alkyl group having 1 to 6 carbon atoms.

"heteroalkyl" refers to an alkyl group containing a heteroatom.

"cycloalkyl" refers to a saturated cyclic hydrocarbon substituent.

"alicyclic" refers to a substituent formed by a compound having at least one heteroatom in the ring skeleton and not having aromatic properties. Typical alicyclic groups include, but are not limited to:

"aryl" refers to an aromatic, monocyclic or multicyclic radical whose planar ring has a delocalized pi electron system and contains 4n+2 pi electrons, where n is an integer; typical aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthracyl, fluorenyl, indenyl, and the like.

"heteroaryl" refers to a monocyclic or polycyclic group containing heteroatoms and having aromaticity. Typical heteroaryl groups include, but are not limited to:

in some embodiments of the invention, ar is selected from tautomers of heteroaryl groups, e.gTautomers of (C)

"N-Heterodienonyl" means a substituent on the ring skeleton of a cyclohexadienone containing at least one N atom, e.g

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

"cyano" refers to-CN.

"amino" means-NH ₂ 。

"hydroxy" refers to-OH.

"(O)" means =O, e.g., -C (O) R ¹² Refers toThe rest of the similar situation is the same.

The pyridine structure is

The structural formula of the pyrazole is

The piperidine structure is

The thiazole structure is

The imidazole structure is

The beneficial effects of the invention are as follows: the invention provides a series of compounds with obvious inhibition effect on SOS1 protein, provides a new scheme for treating diseases taking SOS1 as a target point of treatment, such as cancers, pathogenic rash and the like, can be used for preparing medicaments for treating related diseases, and has wide application prospect.

Detailed Description

The following description of the present invention will be made clearly and fully, and it is apparent that the embodiments described are some, but not all, of the embodiments of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). The chemical shift (delta) of NMR is given in parts per million (ppm). NMR was performed using an AVANCE NEO 400MHz Bruker instrument with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard is Tetramethylsilane (TMS). The MS was determined using an ISQ-EC Thermo Fisher LC-MS instrument. Prep-HPLC is a GX-281 Gilson chromatograph, and the separation method is as follows: (method 1) Sun Fire Prep C18 OBDTM 5 μm,30X 150mm Column,0.04%HCl aqueous solution/acetonitrile; (method 2) Sun Fire Prep C18 OBDTM 5 μm,30x 150mm Column,0.06% formic acid in water/acetonitrile; (method 3) Xbridge Prep C18 OBDTM 5 μm,30x 150mm Column,10mM NH ₄ HCO ₃ Aqueous solution/acetonitrile.

The starting materials in the examples of the present invention are known and commercially available or may be synthesized according to methods known in the art.

The solvent used in the present invention is commercially available unless otherwise specified.

Unless otherwise specified, the reaction temperature was room temperature and was 20℃to 30 ℃.

The chemical abbreviations referred to in the present invention have the following meanings:

DMF: n, N-dimethylformamide

THF: tetrahydrofuran (THF)

DMSO: dimethyl sulfoxide

DIPEA: n, N-diisopropylethylamine

HATU: o- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea

DBU:1, 8-diazabicyclo [5.4.0] undec-7-ene

BOP: benzotriazol-1-yloxy tris (dimethylamino) phosphonium salt

DAST: diethylaminosulfur trifluoride

DMF-DMA: n, N-dimethylformamide dimethyl acetal

LiHMDS: lithium bis (trimethylsilyl) amide

Prep-HPLC: preparation type high performance liquid chromatograph

TBS: tertiary butyl dimethylsilyl group

CHFN: tetrabutylammonium fluoride

Example 1

Preparation of (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

Step a): preparation of 2- (5-bromo-2-hydroxyphenyl) -N, N-dimethylacetamide

2- (5-bromo-2-hydroxyphenyl) acetic acid (8.0 g,34.625 mmol), dimethylamine hydrochloride (3.7 g,45.012 mmol), DIPEA (13.4 g,103.875 mmol) and DMF (160 mL) were added to the reaction flask, HATU (19.7 g,51.938 mmol) was added with stirring at room temperature and the reaction was maintained at room temperature for 3h. After the reaction, water (200 mL) was added to quench, extraction was performed with ethyl acetate (200 mL. Times.2), the organic phases were combined, washed successively with saturated aqueous sodium bicarbonate (50 mL. Times.1), saturated brine (100 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2- (5-bromo-2-hydroxyphenyl) -N, N-dimethylacetamide in 98.0% yield; ESI-MS (m/z): 258.0[ M+H ] ] ⁺ 。

Step b): preparation of 2- (5-bromo-2-methoxyphenyl) -N, N-dimethylacetamide

2- (5-bromo-2-hydroxyphenyl) -N, N-dimethylacetamide (8.8 g,33.933 mmol), potassium carbonate (14.1 g,101.799 mmol) and DMF (150 mL) were added to the reaction flask, methyl iodide (7.2 g,50.900 mmol) was added with stirring at room temperature, and the reaction was allowed to stir at room temperature overnight. After the reaction, quench with water (100 mL), extract with ethyl acetate (100 ml×3), combine the organic phases, wash with saturated brine (100 ml×2), concentrate the organic phases to dryness under reduced pressure, purify the residue with a silica gel column (eluent: petroleum ether/ethyl acetate=5/1), give 2- (5-bromo-2-methoxyphenyl) -N, N-dimethylacetamide in a yield of 51.4%; ESI-MS (m/z): 272.0[ M+H ] +.

Step c): preparation of (3- (2- (dimethylamino) -2-oxoethyl) -4-methoxyphenyl) carbamic acid tert-butyl ester

2- (5-bromo-2-methoxyphenyl) -N, N-dimethylacetamide (4.7 g,17.426 mmol), tert-butyl carbamate (3.1 g,26.496 mmol), X-Phos (1.7 g,3.564 mmol), cs ₂ CO ₃ (17.0 g,52.147 mmol), toluene (95 mL) and Pd (dba) ₂ (1.0 g,1.739 mmol) was successively added to the reaction flask, replaced with nitrogen three times, and the reaction was continued with stirring at 110℃for 3 hours. After the reaction, water (100 mL) was added to quench, extraction was performed with ethyl acetate (100 ml×2), the organic phases were combined, washed with saturated brine (100 mL), concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=7/3) to give tert-butyl (3- (2- (dimethylamino) -2-oxoethyl) -2-methoxyphenyl) carbamate in 60.5% yield; ESI-MS (m/z): 253.0[ M+H-Bu ] ^t ]+。

Step d): preparation of 2- (5-amino-2-methoxyphenyl) -N, N-dimethylacetylamide hydrochloride

Tert-butyl (3- (2- (dimethylamino) -2-oxyethyl) -2-methoxyphenyl) carbamate (330 mg,1.055 mmol) and ethyl acetate (3.0 mL) are added into a reaction bottle, stirred and dissolved, ethyl hydrogen chloride acetate solution (4M, 5.0 mL) is added, stirring is carried out at room temperature for 1h, a large amount of solid is separated out, the solvent is removed by decompression concentration, and the 2- (5-amino-2-methoxyphenyl) -N, N-dimethyl acetamide hydrochloride is obtained, the yield is high99.9％；ESI-MS(m/z)：209.2[M+H] ⁺ 。

Step e): preparation of 6-bromo-4-chloro-2-methylquinazoline

6-bromo-2-methylquinazolin-4 (3H) -one (4.8 g,20.168 mmol) was added to 1, 2-dichloroethane (100 mL) and DIPEA (18.1 g,140.310 mmol) and POCl were added with stirring ₃ (18.4 g,120.261 mmol) under nitrogen protection, heating to 90 ℃ for reaction overnight, cooling to room temperature after the reaction is finished, evaporating solvent under reduced pressure, adding methylene chloride (100 mL) to dissolve the residue, pouring the mixture into a mixed solution of ice cubes and sodium bicarbonate for quenching, separating liquid, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying the residue by a silica gel chromatographic column (eluent: petroleum ether/ethyl acetate=20/1 to 10/1) to obtain 6-bromo-4-chloro-2-methyl quinazoline, and the yield is 87.2%; ESI-MS (m/z): 257.1[ M+H ] ] ⁺ 。

Step f): preparation of (R) -6-bromo-2-methyl-N- (1- (3-nitro-5-) trifluoromethyl) phenyl) ethyl) quinazolin-4-amine

6-bromo-4-chloro-2-methyl quinazoline (2.2 g,8.594 mmol), (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethane-1-amine hydrochloride (2.6 g, 9.457 mmol), DIPEA (3.3 g,25.581 mmol) and DMSO (20 mL) were added sequentially to the reaction flask, and the temperature was raised to 80℃under nitrogen and the reaction was stirred for 2h. After the reaction, saturated ammonium chloride solution (30 mL) was added, extracted with ethyl acetate (50 ml×2), the organic phases were combined, washed with saturated brine (100 ml×1), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 to 3/1) to give (R) -6-bromo-2-methyl-N- (1- (3-nitro-5-) trifluoromethyl) phenyl) ethyl) quinazolin-4-amine in 94.8% yield; ESI-MS (m/z): 455.0[ M+H ]] ⁺ 。

Step g): preparation of (R) -2- (2-methoxy-5- ((2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide

(R) -6-bromo-2-methyl-N- (1- (3-nitro-5-) trifluoromethyl) phenyl) ethyl) quinazolin-4-amine (300 mg,0.659 mmol), 2- (5-amino-2-methoxyphenyl) -N, N-dimethylacetylamide hydrochloride (193 mg,0.791 mmol), X- Phos(63mg，0.132mmol)、Cs ₂ CO ₃ (430 mg,1.318 mmol), toluene (5 mL) and Pd (dba) ₂ (61 mg,0.066 mmol) was added sequentially to the flask, replaced with nitrogen three times, and the mixture was warmed to reflux and stirred for 3 hours. After the reaction, quench the reaction with water (10 mL), extract with ethyl acetate (20 ml×2), combine the organic phases, wash with saturated brine (30 ml×1), concentrate the organic phases under reduced pressure, purify the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 to 1/1), give (R) -2- (2-methoxy-5- ((2-methyl-4- ((1- (3-nitro-5-) trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) -N, N-dimethylacetamide in 72.1% yield; ESI-MS (m/z): 583.2[ M+H ]] ⁺ 。

Step h): preparation of (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

(R) -2- (2-methoxy-5- ((2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide (100 mg,0.172 mmol) was dissolved in methanol (2 mL), iron powder (48 mg,0.859 mmol) and saturated aqueous ammonium chloride solution (1 mL) were added, the reaction solution was warmed to reflux for 1h, ethyl acetate (10 mL) and water (10 mL) were added after the reaction solution cooled to room temperature, suction filtration, the filtrate was separated, the aqueous phase was extracted with ethyl acetate (10 ml×1), the organic phases were combined, washed with saturated brine (10 ml×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by preparative thin layer chromatography (developer: dichloromethane/methanol=15/1) to give (R) -2- (5- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6-quinazolin) -N-dimethylacetamide in 80.0 yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.10(s，1H)，8.01(s，1H)，7.77(s，1H)，7.47(d，J＝8.8Hz，1H)，7.36(d，J＝8.8Hz，1H)，7.04(d，J＝8.4Hz，1H)，6.98(s，1H)，6.95-6.82(m，3H)，6.68(s，1H)，5.59-5.49(m，3H)，3.74(s，3H)，3.58(s，2H)，3.00(s，3H)，2.79(s，3H)，2.36(s，3H)，1.53(d，J＝6.4Hz，3H)；ESI-MS(m/z)：553.1[M+H] ⁺ 。

Example 2

Preparation of (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide

(R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl quinazoline-6-yl) amino) -2-methoxy phenyl) -N, N-dimethyl acetamide (27 mg,0.049 mmol) and dichloromethane (1 mL) are added into a reaction bottle, stirred and dissolved, nitrogen is replaced 3 times, stirred for 5min at 0 ℃ C., BBr is added ₃ (60 mg,0.239 mmol) and ethyl acetate (5 mL) were added, stirred at room temperature for 30min, the aqueous phase was extracted with ethyl acetate (5 mL. Times.1), the organic phases were combined, washed with saturated brine (5 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting crude product was purified by preparative thin layer chromatography (developing solvent: dichloromethane/methanol=9/1) to give (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide in a yield of 30.8%; ¹ H NMR(400MHz，DMSO-d ₆ )δ9.26(s，1H)，8.13(s，1H)，8.00(s，1H)，7.70(s，1H)，7.45(d，J＝8.8Hz，1H)，7.33(d，J＝8.8Hz，1H)，6.96(s，1H)，6.91(d，J＝8.8Hz，1H)，6.88(s，1H)，6.84(s，1H)，6.77(d，J＝8.4Hz，1H)，6.68(s，1H)，5.61-5.46(m，3H)，3.57(s，2H)，3.02(s，3H)，2.80(s，3H)，2.36(s，3H)，1.53(d，J＝6.4Hz，3H)；ESI-MS(m/z)：539.1[M+H] ⁺ 。

example 3

Preparation of (R) -2- (4- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide formate salt

Step a): preparation of 2- (4-bromo-2-methoxyphenyl) -N, N-dimethylacetamide

2- (4-bromo-2-methoxyphenyl) acetic acid (1.10 g,4.489 mmol), dimethylamine hydrochloride (439 mg, 5.383 mmol) and DIPEA (1.74 g,13.467 mmol) and dichloromethane (20 mL) were added to the reaction flask, and T was added with stirring at room temperature ₃ P (4.28 g, 6.284 mmol,50% ethyl acetate solution) was stirred at room temperature for 2h. After the completion of the reaction, the reaction was quenched with water (20 mL), extracted with dichloromethane (20 ml×3), the organic phases were combined, washed with saturated aqueous sodium bicarbonate (20 ml×1) and saturated brine (20 ml×1) in this order, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/3) to give 2- (4-bromo-2-methoxyphenyl) -N, N-dimethylacetamide in 90.8% yield; ESI-MS (m/z): 272.0[ M+H ]] ⁺ 。

Step b): preparation of 2- (4-amino-2-methoxyphenyl) -N, N-dimethylacetamide

Toluene (30 mL), 2- (4-bromo-2-methoxyphenyl) -N, N-dimethylacetamide (1.10 g,4.042 mmol), tert-butyl carbamate (710 mg,6.063 mmol), X-Phos (3836 mg, 0.178 mmol), cs ₂ CO ₃ (3.95 g,12.126 mmol) and Pd ₂ (dba) ₃ (370 mg,0.404 mmol) was added sequentially to the flask, replaced with nitrogen three times, and the reaction was stirred at 110℃for 3 hours. After completion of the reaction, the reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine (20 mL. Times.1), concentrated under reduced pressure, and the residue was dissolved in 4M ethyl hydrogen chloride solution (20 mL) and stirred at room temperature for 2h. After the reaction was completed, the reaction was quenched by adding water (20 mL) and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. Extraction with ethyl acetate (20 mL. Times.3), washing the combined organic phases with saturated brine (20 mL. Times.1), concentrating the organic phase under reduced pressure, and purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/5) to give 2- (4-ammonia) 1, yield 77.3% of 2-methoxyphenyl-NN-dimethylacetamide; ESI-MS (m/z): 209.0[ M+H ]] ⁺ 。

Step c): preparation of (R) -2- (2-methoxy-4- ((2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide

Toluene (5 mL), 2- (4-amino-2-methoxyphenyl) -N, N, dimethylacetamide (75 mg,0.360 mmol), (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine (136.5 mg,0.300 mmol), X-Phos (57 mg,0.120 mmol), cs ₂ CO ₃ (195 mg,0.600 mmol) and Pd (dba) ₂ (34.5 mg,0.060 mmol) was added sequentially to the flask, replaced with nitrogen three times and the reaction was stirred at 90℃for 3h. After the reaction, quench the reaction with water (10 mL), extract with ethyl acetate (10 ml×3), combine the organic phases, wash with saturated brine (10 ml×1), concentrate the organic phases dry under reduced pressure, purify the residue by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give (R) -2- (2-methoxy-4- ((2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide in 95.3% yield; ESI-MS (m/z): 583.0[ M+H ] ] ⁺ 。

Step d): preparation of (R) -2- (4- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide formate salt

Methanol (3 mL), water (2 mL), and (R) -2- (2-methoxy-4- ((2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide (116 mg,0.200 mmol), iron powder (56 mg,1.000 mmol), and saturated aqueous ammonium chloride solution (3 mL) were sequentially added to a reaction flask, and the reaction was stirred at 90℃for 2h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, the solid was rinsed with ethyl acetate (5 mL. Times.3), the filtrate was separated, the aqueous phase was extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine (10 mL. Times.1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by Prep-HPLC (method 2), to give(R) -2- (4- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl quinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide formate salt in 35.3% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.37(s，1H)8.22(d，J＝8.0Hz，1H)，8.15(s，1H)，8.08(s，1H)，7.51(d，J＝8.0Hz，1H)，7.42(d，J＝8.0Hz，1H)，6.95(d，J＝8.0Hz，1H)，6.89(s，1H)，6.84(s，2H)，6.68(s，1H)，6.61(d，J＝8.0Hz，1H)，5.52(m，3H)，3.72(s，3H)，3.49(s，2H)，3.00(s，3H)，2.83(s，3H)，2.36(s，3H)，1.51(d，J＝4.0Hz，3H)；ESI-MS(m/z)：553.1[M+H] ⁺ 。

example 4

Preparation of (R) -2- (4- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide formate salt

(R) -2- (4- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl quinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide (110 mg,0.200 mmol) and dichloromethane (4 mL) were added to a reaction flask, and boron tribromide (250 mg,1.000 mmol) was slowly added dropwise under an ice water bath. After the completion of the dropwise addition, the mixture was slowly warmed to room temperature and stirred for reaction for 1 hour. After the reaction, quench the reaction with water (5 mL), extract with dichloromethane (10 ml×2), combine the organic phases, wash with saturated brine (10 ml×1), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, dissolve the resulting crude product with methanol (2 mL), purify via Prep-HPLC (method 2) to give (R) -2- (4- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl quinazolin-6-yl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide formate in 64.0% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ9.63(brs，1H)，8.16(s，2H)，8.14(s，1H)，7.93(s，1H)，7.54-7.40(m，2H)，6.90(s，2H)，6.85(s，1H)，6.68(s，1H)，6.59(s，1H)，6.54(d，J＝8.0Hz，1H)，5.53(m，3H)，3.48(s，2H)，3.02(s，3H)，2.83(s，3H)，2.36(s，3H)，1.52(d，J＝5.5Hz，3H)；ESI-MS(m/z)：539.1[M+H] ⁺ 。

example 5

Preparation of (R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

Step a): preparation of methyl 2- (3-bromo-2-hydroxyphenyl) acetate

Tert-butylamine (1.35 mL,0.94g, 12.850 mmol) and toluene (43 mL) were added to the flask, cooled to-30deg.C, bromine (1.08 g,6.740 mmol) was added dropwise, and the reaction was maintained at-30deg.C for 1h after completion of the dropwise addition. The reaction mixture was cooled to-78℃and a methylene chloride solution (7 mL) of methyl 2-hydroxyphenylacetate (1.40 g,8.425 mmol) was slowly added dropwise thereto. After the completion of the dropwise addition, the reaction solution was slowly warmed to room temperature and reacted overnight. After the reaction, adding water (50 mL) to quench the reaction, extracting with dichloromethane (50 mL×3), combining organic phases, washing with saturated sodium sulfite aqueous solution (50 mL×1), saturated saline solution (50 mL×1), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain 2- (3-bromo-2-hydroxyphenyl) methyl acetate, and directly using the obtained crude product in the next reaction without purification; ESI-MS (m/z): 245.0[ M+H ] ] ⁺ 。

Step b): 2- (3-bromo-2-methoxyphenyl) acetic acid methyl ester

Methyl 2- (3-bromo-2-hydroxyphenyl) acetate (2.10 g,8.569 mmol), potassium carbonate (2.37 g,17.138 mmol) and DMF (40 mL) were added to methyl iodide (1.82 g,12.853 mmol) under stirring at room temperature, the reaction was maintained at room temperature for 3 hours under stirring, water (100 mL) was added to quench the reaction, extraction was performed with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with saturated brine (50 mL. Times.2), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/acetic acid)Ethyl=3/1) to give methyl 2- (3-bromo-2-methoxyphenyl) acetate in a yield of 63.1%; ESI-MS (m/z): 259.0[ M+H ]] ⁺ 。

Step c): preparation of 2- (3-bromo-2-methoxyphenyl) acetic acid

Methyl 2- (3-bromo-2-methoxyphenyl) acetate (1.40 g,5.403 mmol), THF (15 mL) and water (15 mL) were added to the reaction flask, dissolved with stirring, and LiOH. H was slowly added ₂ O (1.13 g,27.017 mmol) was stirred at room temperature for 2h. After the reaction is finished, 1N dilute hydrochloric acid is added dropwise, the pH value of the reaction solution is regulated to be 2-3, solid precipitation is carried out, filtration is carried out, a filter cake is leached by water (10 mL multiplied by 2), and the filter cake is dried at room temperature under reduced pressure, thus obtaining 2- (3-bromo-2-methoxyphenyl) acetic acid, and the yield is 83.1%; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.36(s，1H)，7.53(d，J＝8.0Hz，1H)，7.28(d，J＝7.6Hz，1H)，7.04(t，J＝7.6Hz 1H)，3.74(s，3H)，3.63(s，2H)。

step d): preparation of 2- (3-bromo-2-methoxyphenyl) -N, N-dimethylacetamide

2- (3-bromo-2-methoxyphenyl) acetic acid (1.10 g, 4.4819 mmol), dimethylamine hydrochloride (439 mg, 5.383 mmol) and DIPEA (1.74 g,13.488 mmol) were added to the reaction flask, T3P (4.28 g, 6.284 mmol,50% ethyl acetate solution) was added with stirring at room temperature, and the reaction was maintained at room temperature with stirring for 2h. After the reaction, water (20 mL) was added to quench the reaction, dichloromethane was used to extract (20 mL. Times.3), the organic phases were combined, washed with saturated aqueous sodium bicarbonate (20 mL. Times.1) and saturated brine (20 mL. Times.1) in this order, and the organic phases were concentrated under reduced pressure to give 2- (3-bromo-2-methoxyphenyl) -N, N-dimethylacetamide in a yield of 90.8%; ESI-MS (m/z): 272.0[ M+H ]] ⁺ 。

Step e): preparation of (3- (2- (dimethylamino) -2-oxoethyl) -2-methoxyphenyl) carbamic acid tert-butyl ester

Toluene (22 mL), 2- (3-bromo-2-methoxyphenyl) -N, N-dimethylacetamide (1.10 g,4.042 mmol), tert-butyl carbamate (710 mg,6.063 mmol), X-Phos (3836 mg, 0.178 mmol), cs ₂ CO ₃ (3.95 g,12.126 mmol) and Pd ₂ (dba) ₃ (370 mg,0.404 mmol) was added sequentially to the reactionIn the flask, the reaction was stirred for 3 hours at 110℃with nitrogen gas replaced three times. After the completion of the reaction, the reaction was quenched with water (20 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine (20 ml×1), concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/7) to give tert-butyl (3- (2- (dimethylamino) -2-oxoethyl) -2-methoxyphenyl) carbamate in a yield of 72.3%; ESI-MS (m/z): 253.0[ M+H-Bu ] ^t ] ⁺ 。

Step f): preparation of 2- (3-amino-2-methoxyphenyl) -N, N-dimethylacetylamide hydrochloride

A solution of tert-butyl (3- (2- (dimethylamino) -2-oxoethyl) -2-methoxyphenyl) carbamate (200 mg,0.649 mmol) and 4N ethyl hydrogen chloride acetate (4 mL) was added to the reaction flask, and the reaction was stirred at room temperature for 1h. After the reaction is finished, the reaction solution is decompressed and concentrated to obtain 2- (3-amino-2-methoxyphenyl) -N, N-dimethyl acetamide hydrochloride, and the yield is 98.8%; ESI-MS (m/z): 209.0[ M+H ]] ⁺ 。

Step g): preparation of (R) -2- (2-methoxy-3- ((2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide

Toluene (9 mL), 2- (3-amino-2-methoxyphenyl) -N, N-dimethylacetylamide hydrochloride (157 mg,0.641 mmol), and (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine (292 mg,0.641 mmol), X-Phos (61 mg,0.128 mmol), cs ₂ CO ₃ (627 mg,1.923 mmol) and Pd (dba) ₂ (37 mg,0.064 mmol) was successively added to the reaction flask, replaced with nitrogen three times, and the reaction was stirred at 90℃for 3 hours. After the reaction, quench the reaction with water (10 mL), extract with ethyl acetate (10 ml×3), combine the organic phases, wash with saturated brine (20 ml×1), concentrate the organic phases dry under reduced pressure, purify the residue by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give (R) -2- (2-methoxy-3- ((2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide in 96.0% yield; ESI-MS m/z)：583.0[M+H] ⁺ 。

Step h): preparation of (R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

Ethanol (2 mL), water (2 mL), and (R) -2- (2-methoxy-3- ((2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide (100 mg,0.172 mmol), iron powder (29 mg,0.515 mmol), and anhydrous ammonium chloride (37 mg,0.688 mmol) were added sequentially to a reaction flask, and the reaction was stirred for 2h at 80 ℃. After the reaction is finished, the reaction solution is cooled to room temperature, filtered, a filter cake is leached by ethyl acetate (5 mL multiplied by 3), the filtrate is separated, an aqueous phase is extracted by ethyl acetate (5 mL multiplied by 1), organic phases are combined, the mixture is washed by saturated sodium chloride aqueous solution (10 mL multiplied by 1), anhydrous sodium sulfate is dried and filtered, the filtrate is concentrated under reduced pressure, and the obtained crude product is purified by Prep-HPLC (method 3) to obtain (R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl quinazoline-6-yl) amino) -2-methoxy phenyl) -N, N-dimethyl acetamide with the yield of 24.2 percent; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.08(d，J＝7.2Hz，1H)，7.92(s，1H)，7.75(s，1H)，7.50(s，2H)，7.14(d，J＝8.0Hz，1H)，6.90-6.96(m，2H)，6.84(s，1H)，6.69(d，J＝9.6Hz，2H)，5.51(s，3H)，3.67(s，2H)，3.64(s，3H)，3.05(s，3H)，2.84(s，3H)，2.36(s，3H)，1.52(d，J＝6.4Hz，3H)；ESI-MS(m/z)：553.1[M+H] ⁺ 。

example 6

Preparation of (R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide formate salt

(R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl quinazoline-6-yl) amino) -2-methoxybenzeneRadical) -N, N-dimethylacetamide (100 mg,0.181 mmol) and dichloromethane (4 mL) were added to the reaction flask and boron tribromide (2.50 g,10.000 mmol) was slowly added dropwise under an ice water bath. After the completion of the dropwise addition, the reaction was stirred at room temperature for 1 hour. After the reaction, quench the reaction with water (5 mL), extract with dichloromethane (5 ml×2), combine the organic phases, wash with saturated brine (10 ml×1), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, purify the resulting crude product by Prep-HPLC (method 2) to give (R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide formate in 59.5% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ9.63(s，1H)，8.14(s，1H)，8.03(s，1H)，7.81(s，1H)，7.47(s，2H)，7.37(s，1H)，7.13(s，1H)，6.89(s，1H)，6.84(s，1H)，6.75(s，2H)，6.68(s，1H)，5.50(s，3H)，3.72(s，2H)，3.12(s，3H)，3.03(s，3H)，2.03(s，3H)，1.52(s，3H)；ESI-MS(m/z)：538.8[M+H] ⁺ 。

example 7

Preparation of (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide formate salt

Step a): preparation of (3- (2- (dimethylamino) -2-oxoethyl) -4-methoxyphenyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl (3- (2- (dimethylamino) -2-oxoethyl) -4-methoxyphenyl) carbamate (400 mg,1.297 mmol) and tetrahydrofuran (10 mL) were added to a reaction flask, dissolved by stirring, replaced with nitrogen 3 times, stirred at 0℃for 5min, naH (207 mg,5.175 mmol) was added, stirred at 0℃for 30min, methyl iodide (276 mg,1.944 mmol) was added, the mixture was warmed to room temperature and reacted for 1h, ethyl acetate (20 mL) and saturated aqueous ammonium chloride solution (20 mL) were added, the mixture was separated, the aqueous phase was extracted with ethyl acetate (10 mL. Times.1), and the organic phases were combined to form a saturated diet Brine is washed (10 mL multiplied by 1), anhydrous sodium sulfate is dried and filtered, the filtrate is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain (3- (2- (dimethylamino) -2-oxyethyl) -4-methoxyphenyl) (methyl) carbamic acid tert-butyl ester with the yield of 63.7%; ¹ H NMR(400MHz，DMSO-d ₆ )δ7.09(d，J＝8.8Hz，1H)，6.97(s，1H)，6.91(d，J＝8.4Hz，1H)，3.75(s，3H)，3.56(s，2H)，3.11(s，3H)，3.00(s，3H)，2.83(s，3H)，1.37(s，9H)；ESI-MS(m/z)：267.1[M+H] ⁺ 。

step b): preparation of 2- (2-methoxy-5- (methylamino) phenyl) -N, N-dimethylacetylamide hydrochloride

Tert-butyl (3- (2- (dimethylamino) -2-oxoethyl) -4-methoxyphenyl) (methyl) carbamate (260 mg,0.806 mmol) was dissolved in ethyl hydrogen chloride solution (4 m,2 ml), reacted at room temperature for 4h, concentrated to dryness under reduced pressure to give 2- (2-methoxy-5- (methylamino) phenyl) -N, N-dimethylacetylamide hydrochloride in 98.6% yield; ESI-MS (m/z): 223.1[ M+H ]] ⁺ 。

Step c): preparation of (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide

2- (2-methoxy-5- (methylamino) phenyl) -N, N-dimethylacetylamide hydrochloride (206 mg,0.796 mmol) was added to toluene (10 mL), and (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine (369 mg, 0.81mmol), cesium carbonate (792 mg,2.431 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (154 mg,0.323 mmol), tris (dibenzylideneacetone) dipalladium (93 mg,0.102 mmol) was added to toluene (10 mL) with stirring, and after the reaction was completed, the resulting crude product was purified by silica gel column chromatography (eluent: methanol/methylene chloride=1/20) to give (R) -2- (2-methoxy-5- (- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazolin-6) amino) phenyl) -N-dimethylacetamide in 8.84% yield; ESI-MS (m/z): 597.2[ M+H ] ] ⁺ 。

Step d): preparation of (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide formate salt

(R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide (403 mg,0.675 mmol) was dissolved in methanol (6 mL), iron powder (189 mg, 3.284 mmol) and saturated aqueous ammonium chloride solution (6 mL) were added, the reaction solution was warmed to reflux for 1h, cooled to room temperature, ethyl acetate (20 mL) and water (10 mL) were added, filtered, the filtrate was partitioned, the aqueous phase was extracted with ethyl acetate (10 mL. Times.1), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product which was purified by Prep-HPLC (method 2) to give (R) -2- (5- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-6-yl) (methyl) amino) -2-dimethylphenylacetamide, N, yield was 77.0%; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.17(s，1H)，8.1δ-8.11(m，2H)，7.62(s，1H)，7.35(d，J＝8.8Hz，1H)，7.07(d，J＝9.6Hz，1H)，7.03(s，1H)，6.96-7.01(m，1H)，6.91(s，2H)，6.88(s，1H)，6.70(s，1H)，5.52-5.63(m，3H)，3.76(s，3H)，3.57(s，2H)，3.33(s，3H)，2.99(s，3H)，2.78(s，3H)，2.35(s，3H)，1.57(d，J＝6.0Hz，3H)；ESI-MS(m/z)：567.2[M+H] ⁺ 。

example 8

Preparation of (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide formate salt

(R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl quinazolin-6-yl) (methyl) amino) -2-methoxyphenyl)) -N, N-dimethylacetamide (100 mg,0.176 mmol) was dissolved in dichloromethane (2 mL), nitrogen was displaced 3 times, stirred for 5min at 0 ℃, boron tribromide (200 mg,0.789 mmol) was added, warmed to room temperature for 2h, saturated aqueous sodium bicarbonate solution (10 mL) and ethyl acetate (10 mL) were added, the aqueous phase was extracted with ethyl acetate (10 ml×1), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the resulting crude Prep-HPLC (method 2) was purified to give (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide formate in 33.0% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.16(s，1H)，9.55(s，1H)，8.15-8.13(m，1H)，7.54(s，1H)，7.33(d，J＝9.2Hz，1H)，7.02(d，J＝9.2Hz，1H)，6.89(d，J＝9.6Hz，4H)，6.85-6.80(m，1H)，6.70(s，1H)，5.65-5.50(m，3H)，3.56(s，2H)，3.31(s，3H)，3.01(s，3H)，2.80(s，3H)，2.35(s，3H)，1.61-1.51(m，3H)；ESI-MS(m/z)：553.1[M+H] ⁺ 。

example 9

Preparation of (R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

Step a): preparation of (3- (2- (dimethylamino) -2-oxoethyl) -2-methoxyphenyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl (3- (2- (dimethylamino) -2-oxoethyl) -2-methoxyphenyl) carbamate (308 mg,1.000 mmol), naH (120 mg,3.000mmol, 60%) and tetrahydrofuran (10 mL) were added to the reaction flask, methyl iodide (142 mg,1.000 mmol) was added under ice-bath stirring, and after 30min, the mixture was slowly warmed to room temperature and stirred for 2h. After completion of the reaction, the mixture was quenched with water (30 mL), extracted with ethyl acetate (40 mL. Times.3), and the organic phase was combined, washed with saturated brine (50 mL. Times.2), and dried The phases were concentrated under reduced pressure and the residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate=3/1) to give tert-butyl (3- (2- (dimethylamino) -2-oxoethyl) -2-methoxyphenyl) (methyl) carbamate in 68.3% yield; ESI-MS (m/z): 323.0[ M+H ]] ⁺ 。

Step b): preparation of 2- (2-methoxy-3- (methylamino) phenyl) -N, N-dimethylacetylamide hydrochloride

Tert-butyl (3- (2- (dimethylamino) -2-oxyethyl) -2-methoxyphenyl) (methyl) carbamate (220 mg,0.682 mmol) and ethyl acetate (2.5 mL) are added into a reaction bottle, stirred and dissolved, ethyl hydrogen acetate solution (4M, 2.5 mL) is added, stirring is carried out at room temperature for 1h, a large amount of solid is separated out, and decompression concentration is carried out, so that 2- (3-methoxy-4- (methylamino) phenyl) -N, N-dimethylacetamide is obtained, and the yield is 99.9%; ESI-MS (m/z): 223.0M+H] ⁺ 。

Step c): preparation of (R) -2- (2-methoxy-3- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide

(R) -6-bromo-2-methyl-N- (1- (3-nitro-5-) trifluoromethyl) phenyl) ethyl) quinazolin-4-amine (163 mg, 0.399 mmol), 2- (2-methoxy-3- (methylamino) phenyl) -N, N-dimethylacetylamide hydrochloride (93 mg, 0.399 mmol), X-Phos (34 mg,0.072 mmol), cs ₂ CO ₃ (235 mg,0.720 mmol), toluene (10 mL) and Pd (dba) ₂ (21 mg,0.036 mmol) was successively added to the reaction flask, replaced with nitrogen three times, and the temperature was raised to 100℃and the reaction was stirred for 3 hours. After the completion of the reaction, the reaction was quenched with water (30 mL), extracted with ethyl acetate (30 ml×2), the organic phases were combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give (R) -2- (2-methoxy-3- (methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide in a yield of 75.0%; ESI-MS (m/z): 597.3[ M+H ]] ⁺ 。

Step d): preparation of (R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

(R) -2- (2-methoxy-3- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide (160 mg,0.270 mmol) was dissolved in methanol (2 mL), iron powder (75 mg,1.350 mmol) and saturated aqueous ammonium chloride solution (2 mL) were added, the reaction solution was warmed to reflux for 1h, ethyl acetate (10 mL) and water (10 mL) were added after the reaction solution cooled to room temperature, suction filtration, the filtrate was separated, the aqueous phase was extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product, which was purified by Prep-HPLC (method 3) to give (R) -2- (3- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl-quinazolin-6-yl) (methyl) amino) -N, N-dimethylacetamide in 78.5% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.08(d，J＝8.0Hz，1H)，7.53(s，1H)，7.33(d，J＝8.0Hz，1H)，7.09-7.04(m，3H)，6.90(d，J＝12.0Hz，3H)，6.70(s，1H)，5.64-5.57(m，1H)，5.54(s，2H)，3.68(s，2H)，3.52(s，3H)，3.35(s，3H)，3.05(s，3H)，2.85(s，3H)，2.35(s，3H)，1.58(d，J＝8.0Hz，3H)；ESI-MS(m/z)：567.3[M+H] ⁺ 。

Example 10

Preparation of (R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide

(R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl quinazoline-6-yl) (methyl) amino) -3-methoxy phenyl) -N, N-dimethyl acetamide (60 mg,0.106 mmol) and methylene chloride (4 mL) are added into a reaction bottle, stirred and dissolved, nitrogen is replaced for 3 times, stirred for 5min at 0 ℃ C. And BBr is added ₃ (2 mL), room temperatureStirring for 30min. After the reaction, saturated aqueous sodium hydrogencarbonate (50 mL) and ethyl acetate (50 mL) were added, the solution was separated, the aqueous phase was extracted with ethyl acetate (50 ml×2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by Prep-HPLC (method 3) to give (R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide in a yield of 30.2%; ¹ H NMR(400MHz，DMSO-d ₆ )δ9.30(s，1H)，8.12(brs，1H)，7.48(s，1H)，7.31(d，J＝8.0Hz，1H)，7.05(d，J＝8.0Hz，1H)，6.97(d，J＝8.0Hz，1H)，6.92(s，1H)，6.88(s，1H)，6.82(t，J＝8.0Hz，1H)，6.75-6.71(m，2H)，5.65-5.58(m，1H)，5.54(s，2H)，3.70(s，2H)，3.24(s，3H)，3.08(s，3H)，2.86(s，3H)，2.35(s，3H)，1.58(d，J＝4.0Hz，3H)；ESI-MS(m/z)：553.3[M+H] ⁺ 。

example 11

Preparation of (R) -2- (4- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -3-methoxyphenyl) -N, N-dimethylacetamide

Step a): preparation of diethyl 2- (3-methoxy-4-nitrophenyl) malonate

4-bromo-2-methoxy-1-nitrobenzene (2.32 g,10.000 mmol), diethyl malonate (1.92 g,12.000 mmol), X-Phos (954 mg,2.000 mmol), cs ₂ CO ₃ (6.52 g,20.000 mmol), 1, 4-dioxane (50 mL), and Pd ₂ (dba) ₃ (575 mg,1.000 mmol) was added sequentially to the flask, replaced with nitrogen three times, and the mixture was warmed to reflux and stirred for 2h. After completion of the reaction, the mixture was quenched with water (200 mL), extracted with ethyl acetate (200 mL. Times.2), and the organic phases were combined, washed with saturated brine (100 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressureThe residue was purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give diethyl 2- (3-methoxy-4-nitrophenyl) malonate in 96.4% yield; ESI-MS (m/z): 312.0[ M+H ]] ⁺ 。

Step b): preparation of 2- (3-methoxy-4-nitrophenyl) acetic acid

Diethyl 2- (3-methoxy-4-nitrophenyl) malonate (3.0 g, 9.640 mmol), lithium hydroxide monohydrate (1.6 g, 38.284 mmol), methanol (10 mL), tetrahydrofuran (10 mL) and water (20 mL) were added to the reaction flask, and the reaction was stirred at room temperature for 2 hours. The organic solvent was removed by concentrating under reduced pressure, concentrated hydrochloric acid (20 mL) was slowly added dropwise under ice bath stirring, and the temperature was raised to 60℃and the reaction was stirred for 4h. After the reaction, concentrating under reduced pressure, diluting with water (100 mL), extracting with ethyl acetate (100 mL. Times.3), mixing the organic phases, washing with saturated saline (100 mL. Times.2), concentrating the organic phases under reduced pressure to dryness, purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1), to obtain 2- (3-methoxy-4-nitrophenyl) acetic acid, yield 17.2%; ESI-MS (m/z): 212.0[ M+H ] ] ⁺ 。

Step c): preparation of 2- (3-methoxy-4-nitrophenyl) -N, N-dimethylacetamide

2- (3-methoxy-4-nitrophenyl) acetic acid (350 mg, 1.618 mmol), dimethylamine hydrochloride (161 mg,1.989 mmol), DIPEA (641 mg,4.974 mmol) and DMF (5 mL) were added to the reaction flask, HATU (945 mg,2.487 mmol) was added with stirring at room temperature and the reaction was maintained at room temperature for 1h. After the reaction was completed, water (20 mL) was added to quench, extraction was performed with ethyl acetate (20 ml×2), the organic phases were combined, washed successively with saturated aqueous sodium bicarbonate (20 mL), saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to give 2- (3-methoxy-4-nitrophenyl) -N, N-dimethylacetamide in 88.7% yield; ESI-MS (m/z): 239.0[ M+H ]] ⁺ 。

Step d): preparation of 2- (4-amino-3-methoxyphenyl) -N, N-dimethylacetamide

2- (3-methoxy-4-nitrophenyl) -N, N-dimethylacetamide (350 mg,1.470 mmol), palladium on carbon (50 mg,5Sequentially adding ethanol (10 mL) and ethanol (10 mL) into a reaction bottle, stirring for dissolution, replacing hydrogen for 3 times, and stirring for 2h at room temperature in a hydrogen atmosphere. After the reaction is finished, filtering, concentrating the filtrate under reduced pressure to obtain 2- (4-amino-3-methoxyphenyl) -N, N-dimethylacetamide, and directly using the 2- (4-amino-3-methoxyphenyl) -N, N-dimethylacetamide in the next reaction without further purification; ESI-MS (m/z): 209.0[ M+H ] ] ⁺ 。

Step e): preparation of (4- (2- (dimethylamino) -2-oxoethyl) -2-methoxyphenyl) carbamic acid tert-butyl ester

2- (4-amino-3-methoxyphenyl) -N, N-dimethylacetamide (306 mg,1.470 mmol), DIPEA (569 mg,4.410 mmol) and tetrahydrofuran (10 mL) were sequentially added to a reaction flask, dissolved with stirring, and Boc was added dropwise ₂ O (352 mg, 1.611 mmol), was heated to 60℃and reacted for 4h with stirring. After the reaction is finished, concentrating under reduced pressure to obtain (4- (2- (dimethylamino) -2-oxyethyl) -2-methoxyphenyl) carbamic acid tert-butyl ester which is directly used for the next reaction without further purification; ESI-MS (m/z): 309.0[ M+H ]] ⁺ 。

Step f): preparation of (4- (2- (dimethylamino) -2-oxoethyl) -2-methoxyphenyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl (4- (2- (dimethylamino) -2-oxoethyl) -2-methoxyphenyl) carbamate (457 mg,1.470 mmol), naH (176.4 mg,4.41mmol, 60%) and tetrahydrofuran (10 mL) were added to the reaction flask, methyl iodide (209 mg,1.470 mmol) was added under ice-bath stirring, and after 30min the reaction was slowly warmed to room temperature and stirred for 2h. After the completion of the reaction, water (30 mL) was added to quench, extraction was performed with ethyl acetate (40 ml×3), the organic phases were combined, washed with saturated brine (50 ml×2), and the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) to give tert-butyl (4- (2- (dimethylamino) -2-oxoethyl) -2-methoxyphenyl) (methyl) carbamate in 46.5% yield; ESI-MS (m/z): 323.0[ M+H ] ] ⁺ 。

Step g): preparation of 2- (3-methoxy-4- (methylamino) phenyl) -N, N-dimethylacetylamide hydrochloride

(4- (2- (dimethylamino) -2-oxoethyl) -2-methoxyphenyl) (methyl) carbamic acid tert-butyl ester (220 mg,0.683 mmol) and ethyl acetateAdding ester (2.5 mL) into a reaction bottle, stirring for dissolving, adding ethyl hydrogen chloride solution (4M, 2.5 mL) and stirring at room temperature for 1h, wherein a large amount of solid is separated out, and concentrating under reduced pressure to obtain 2- (3-methoxy-4- (methylamino) phenyl) -N, N-dimethylacetamide which can be directly used for the next reaction without further purification; ESI-MS (m/z): 223.0M+H] ⁺ 。

Step h): preparation of (R) -2- (3-methoxy-4- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide

(R) -6-bromo-2-methyl-N- (1- (3-nitro-5-) trifluoromethyl) phenyl) ethyl) quinazolin-4-amine (184 mg,0.404 mmol), 2- (3-methoxy-4- (methylamino) phenyl) -N, N-dimethylacetylamide hydrochloride (87 mg,0-336 mmol), X-Phos (31 mg,0.066 mmol), cs ₂ CO ₃ (220 mg,0.672 mmol), toluene (10 mL) and Pd (dba) ₂ (19 mg,0.033 mmol) was successively added to the reaction flask, replaced with nitrogen three times, and the temperature was raised to 100℃and the reaction was stirred for 3 hours. After the completion of the reaction, the reaction was quenched with water (10 mL), extracted with ethyl acetate (40 ml×2), the organic phases were combined, washed with saturated brine (30 mL), and the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give (R) -2- (3-methoxy-4- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide in a yield of 83.4%; ESI-MS (m/z): 597.3[ M+H ] ] ⁺ 。

Step i): preparation of (R) -2- (4- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -3-methoxyphenyl) -N, N-dimethylacetamide

(R) -2- (3-methoxy-4- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide (167 mg,0.280 mmol) was dissolved in methanol (2 mL), iron powder (157 mg,2.800 mmol) and saturated aqueous ammonium chloride solution (2 mL) were added, the reaction solution was warmed to reflux for 1h, after the reaction solution cooled to room temperature, ethyl acetate (10 mL) and water (10 mL) were added, suction filtration was performed, and the solution was filteredThe aqueous phase was extracted with ethyl acetate (20 ml×2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude product which was purified by Prep-HPLC (method 3) to give (R) -2- (4- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -3-methoxyphenyl) -N, N-dimethylacetamide in 75.7% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.07(brs，1H)，7.44(s，1H)，7.29(d，J＝8.0Hz，1H)，7.11(d，J＝8.0Hz，1H)，7.01(d，J＝8.0Hz，1H)，6.92(s，1H)，6.88(s，1H)，6.85(d，J＝8.0Hz，1H)，6.72(d，J＝12.0Hz，2H)，5.64-5.57(m，1H)，5.55(s，2H)，3.72(s，2H)，3.69(s，3H)，3.27(s，3H)，3.05(s，3H)，2.86(s，3H)，2.23(s，3H)，1.58(d，J＝8.0Hz，3H)；ESI-MS(m/z)：567.3[M+H] ⁺ 。

example 12

Preparation of (R) -2- (4- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -3-hydroxyphenyl) -N, N-dimethylacetamide

(R) -2- (4- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl quinazoline-6-yl) (methyl) amino) -3-methoxy phenyl) -N, N-dimethyl acetamide (60 mg,0.106 mmol) and methylene chloride (4 mL) are added into a reaction bottle, stirred and dissolved, nitrogen is replaced for 3 times, stirred for 5min at 0 ℃ C. And BBr is added ₃ (2 ml), and stirred at room temperature for 30min. After completion of the reaction, saturated aqueous sodium hydrogencarbonate (50 mL) and ethyl acetate (50 mL) were added, the solution was separated, the aqueous phase was extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting crude product was purified by Prep-HPLC (method 3) to give (R) -2- (4- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -3-hydroxyphenyl) -N, N-diMethylacetamide in 10.5% yield; ¹ H NMR(4((MHz，DMSO-d ₆ )δ9.39(s，1H)，8.06(d，J＝8.0Hz，1H)，7.43(s，1H)，7.29(d，J＝8.0Hz，1H)，7.02(d，J＝8.0Hz，1H)，6.92(s，1H)，6.88(s，1H)，6.84(s，1H)，6.76-6.70(m，3H)，5.64-5.56(m，1H)，5.54(s，2H)，3.63(s，2H)，3.26(s，3H)，3.02(s，3H)，2.85(s，3H)，2.34(s，3H)，1.58(d，J＝8.0Hz，3H)；ESI-MS(m/z)：553.3[M+H] ⁺ 。

example 13

Preparation of (R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinolin-6-yl) (methyl) amino) -4-methoxyphenyl) -N, N-dimethylacetamide formate salt

Step a): preparation of (5- (2- (dimethylamino) -2-oxoethyl) -2-methoxyphenyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl (5- (2- (dimethylamino) -2-oxoethyl) -2-methoxyphenyl) carbamate (500 mg, 1.6271 mmol) and tetrahydrofuran (10 mL) were added to the reaction flask, nitrogen was replaced 3 times, cooled to 0℃and NaH (207 mg,5.175mmol, 60%) was added, stirred at 0℃for 30min, methyl iodide (276 mg,1.944 mmol) was added dropwise, and the mixture was warmed naturally to room temperature and reacted for 1h. After the reaction was completed, the mixture was added to a saturated aqueous ammonium chloride solution (20 mL), extracted with ethyl acetate (15 ml×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to give t-butyl (5- (2- (dimethylamino) -2-oxoethyl) -2-methoxyphenyl) (methyl) carbamate in 78.6% yield; ESI-MS (m/z): 267.1[ M+H ] ] ⁺ 。

Step b): preparation of 2- (4-methoxy-3- (methylamino) phenyl) -N, N-dimethylacetamide

(5- (2- (dimethylamino) -2-oxoethyl) -2-methoxylTert-butyl (methyl) carbamate (410 mg, 1.275 mmol) was dissolved in ethyl hydrogen chloride acetate solution (4M, 5 mL) and the reaction was stirred at room temperature for 2h. After the reaction, saturated aqueous sodium bicarbonate (50 mL) was added for extraction, ethyl acetate (15 mL. Times.3) was used for extraction, the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2- (4-methoxy-3- (methylamino) phenyl) -N, N-dimethylacetamide in a yield of 89.5%; ESI-MS (m/z): 223.1[ M+H ]] ⁺ 。

Step c): preparation of (R) -2- (4-methoxy-3- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide

(R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine (127 mg,1.139 mmol), 2- (4-methoxy-3- (methylamino) phenyl) -N, N-dimethylacetamide (255 mg,1.139 mmol), cs ₂ CO ₃ (743mg，2.278mmol)、XPhos(218mg，0.456mmol)、Pd ₂ (dba) ₃ (208 mg,0.228 mmol) and toluene (8 mL) were added to the reaction flask, nitrogen was replaced three times, and the temperature was maintained at 90℃and the reaction was stirred for 16h. After the reaction, quench the reaction with water (15 mL), extract with ethyl acetate (10 ml×3), combine the organic phases, wash with saturated brine (10 mL), concentrate the organic phases dry under reduced pressure, purify the residue by silica gel column chromatography (eluent: dichloromethane/methanol=20/1), to give (R) -2- (4-methoxy-3- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide in 39.4% yield; ESI-MS (m/z): 597.2[ M+H ] ] ⁺ 。

Step d): preparation of (R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinolin-6-yl) (methyl) amino) -4-methoxyphenyl) -N, N-dimethylacetamide formate salt

(R) -2- (4-methoxy-3- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide (254 mg,0.426 mmol) was dissolved in methanol (3 mL), and iron powder (119 mg,2.131 mm) was addedol) and saturated aqueous ammonium chloride (3 mL), and the reaction was warmed to reflux for 2h. After the reaction was completed, the reaction solution was cooled to room temperature, ethyl acetate (20 mL) and water (10 mL) were added, filtration was performed, the filtrate was extracted with ethyl acetate (15 ml×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20), and the obtained crude product was purified by Prep-HPLC (method 2) to obtain (R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinolin-6-yl) (methyl) amino) -4-methoxyphenyl) -N, N-dimethylacetamide formate, and the yield was 95.1%; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.77(s，1H)，8.15(s，1H)，8.06(d，J＝8.0Hz，1H)，7.45(s，1H)，7.29(d，J＝9.2Hz，1H)，7.13-7.06(m，2H)，7.04(s，1H)，6.91(s，1H)，6.88(s，1H)，6.75(d，J＝11.6Hz，1H)，6.70(s，1H)，5.64-5.57(m，1H)，5.54(s，2H)，3.70(s，3H)，3.61(s，2H)，3.28(s，3H)，2.98(s，3H)，2.80(s，3H)，2.34(s，3H)，1.58(d，J＝7.2Hz，3H)；ESI-MS(m/z)：567.2[M+H] ⁺ 。

example 14

Preparation of (R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -4-hydroxyphenyl) -N, N-dimethylacetamide formate salt

(R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinolin-6-yl) (methyl) amino) -4-methoxyphenyl) -N, N-dimethylacetamide (100 mg,0.176 mmol) was added to dichloromethane (2 mL) and BBr was added with stirring at 0deg.C ₃ (300 mg,1.200 mmol) was added and reacted at room temperature for 16 hours. Pouring the reaction solution into ice water for quenching, extracting with dichloromethane (20 mL multiplied by 3), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the obtained crude product by Prep-HPLC (method 2) to obtain (R) -2- (3- ((4- (. About.)1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl quinazolin-6-yl) (methyl) amino) -4-hydroxyphenyl) -N, N-dimethylacetamide formate salt; yield 35.0%; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.71(s，1H)，9.31(s，1H)，8.15(s，1H)，8.07(d，J＝8.0Hz，1H)，7.44(s，1H)，7.30(d，J＝9.2Hz，1H)，6.99-6.85(m，5H)，6.78(d，J＝8.8Hz，1H)，6.70(s，1H)，5.62(d，J＝7.2Hz，1H)，5.54(s，2H)，3.56(s，2H)，3.26(s，3H)，2.96(s，3H)，2.79(s，3H)，2.34(s，3H)，1.58(d，J＝7.2Hz，3H)；ESI-MS(m/z)：553.2[M+H] ⁺ 。

example 15

Preparation of (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino-2-methyl quinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate salt

Step a): preparation of diethyl 2- (2-methoxy-5-nitropyridin-3-yl) malonate

3-bromo-2-methoxy-5-nitropyridine (5.00 g,21.457 mmol), diethyl malonate (13.75 g,85.829 mmol), cuprous bromide (12.31 g,85.829 mmol), 1, 4-dioxane (100 mL) were added to the reaction flask, naH (3.43 g,85.829 mmol) was added at 0deg.C, stirred for 15min, and the mixture was warmed to 100deg.C and stirred for 2h. After the reaction is finished, cooling to room temperature, carrying out suction filtration, adding saturated ammonium chloride aqueous solution (100 mL), extracting by ethyl acetate (100 mL), washing an organic phase by saturated saline solution (50 mL), drying by anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the obtained crude product by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/10), and obtaining diethyl 2- (2-methoxy-5-nitropyridin-3-yl) malonate with the yield of 74.6%; ESI-MS (m/z): 313.0[ M+H ] ] ⁺ 。

Step b): preparation of ethyl 2- (2-methoxy-5-nitropyridin-3-yl) acetate

2- (2-methoxy) radicalDiethyl-5-nitropyridin-3-yl-malonate (5.01 g,16.043 mmol), lithium chloride (2.921 g,68.919 mmol), DMSO (60 mL) and water (3 mL) were added to a reaction flask and reacted at 100℃for 24h. Cooling to room temperature, diluting with water (100 mL), extracting with ethyl acetate (100 mL), washing the organic phase with saturated saline (50 mL. Times.2), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the crude product by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/5), to obtain ethyl 2- (2-methoxy-5-nitropyridin-3-yl) acetate, yield 33.7%; ¹ H NMR(400MHz，DMSO-d ₆ )δ9.03(s，1H)，8.52(s，1H)，4.13-4.08(m，2H)，4.00(s，3H)，3.77(s，2H)，1.20-1.18(m，3H)；ESI-MS(m/z)：241.0[M+H] ⁺ 。

step c): preparation of 2- (2-methoxy-5-nitropyridin-3-yl) acetic acid

Ethyl 2- (2-methoxy-5-nitropyridin-3-yl) acetate (1.30 g,5.417 mmol), aqueous lithium hydroxide (4M, 5.4 mL), methanol (2 mL) and THF (6 mL) were added to the reaction flask and reacted at room temperature for 0.5h. After the reaction, adjusting the pH to be 1-2 with 1N hydrochloric acid, extracting with ethyl acetate (20 mL), washing with saturated saline (10 mL), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain 2- (2-methoxy-5-nitropyridin-3-yl) acetic acid, and directly using the 2- (2-methoxy-5-nitropyridin-3-yl) acetic acid in the next reaction without further purification, wherein the yield is 83.3%; ESI-MS (m/z): 213.1[ M+H ] ] ⁺ 。

Step d): preparation of 2- (2-methoxy-5-nitropyridin-3-yl) -N, N-dimethylacetamide

2- (2-methoxy-5-nitropyridin-3-yl) acetic acid (957 mg,4.511 mmol), dimethylamine hydrochloride (441 mg,5.413 mmol), DIPEA (1.455 g,11.277 mmol), dichloromethane (10 mL) and T ₃ P (3.4475 g,5.413 mmol) was added to the flask and reacted at room temperature for 2h. After the reaction, water (20 mL) was added for dilution, extraction with ethyl acetate (30 ml×2), washing with saturated brine (20 mL), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, purification of the crude product by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=2/1) to give 2- (2-methoxy-5-nitropyridin-3-yl) -N, N-dimethylacetamide in a yield of 59.3%; ESI-MS (m/z): 240.0[ M+H ]] ⁺

Step e): preparation of 2- (5-amino-2-methoxypyridin-3-yl) -N, N-dimethylacetamide

2- (2-methoxy-5-nitropyridin-3-yl) -N, N-dimethylacetamide (640 mg,2.675 mmol), iron powder (747 mg,13.376 mmol), saturated aqueous ammonium chloride (6 mL), methanol (12 mL) were added to the reaction flask and reacted under reflux for 0.5h. After the reaction is finished, cooling to room temperature, adding saturated sodium chloride aqueous solution (10 mL) and acetonitrile (30 mL), filtering, separating liquid, extracting aqueous phase with acetonitrile (20 mL multiplied by 3), combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure to obtain 2- (5-amino-2-methoxypyridin-3-yl) -N, N-dimethylacetamide, and directly using the 2- (5-amino-2-methoxypyridin-3-yl) -N, N-dimethylacetamide in the next reaction without further use; ESI-MS (m/z): 210.1[ M+H ] ] ⁺ 。

Step f): preparation of (5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyridin-3-yl) carbamic acid tert-butyl ester

2- (5-amino-2-methoxypyridin-3-yl) -N, N-dimethylacetamide (547 mg, 2.015 mmol), di-tert-butyl dicarbonate (552 mg,2.667 mmol) and dioxane (12 mL) were sequentially added to a reaction flask, and the mixture was stirred for 20min at 100 ℃. Cooling to room temperature, concentrating under reduced pressure, purifying the crude product by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=3/1) to obtain (5- (2- (dimethylamino) -2-oxyethyl) -6-methoxypyridin-3-yl) carbamic acid tert-butyl ester, yield 98.9%; ESI-MS (m/z): 254.1[ M+H-Bu ^t ]+。

Step g): preparation of (5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyridin-3-yl) (methyl) carbamic acid tert-butyl ester

Tert-butyl (5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyridin-3-yl) carbamate (400 mg,1.293 mmol) was dissolved in THF (8 mL), naH (207 mg,5.172 mmol) was added at 0deg.C, stirred for 15min, methyl iodide (220 mg,1.552 mmol) was added, stirred at room temperature for 30min, quenched with saturated ammonium chloride (10 mL), extracted with ethyl acetate (20 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/1) to give (5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyrazole) T-butyl pyridin-3-yl) (methyl) carbamate in 66.2% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ7.97(s，1H)，7.43(s，1H)，3.83(s，3H)3.59(s，2H)，3.14(s，3H)，3.04(s，3H)，2.83(s，3H)，1.38(s，9H)；ESI-MS(m/z)：268.1[M+H-Bu ^t ]+。

step h): preparation of 2- (2-methoxy-5- (methylamino) pyridin-3-yl) -N, N-dimethylacetylamide hydrochloride

Tert-butyl (5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyridin-3-yl) (methyl) carbamate (272 mg,0.841 mmol) and ethyl acetate hydrochloride (4M, 4 mL) were added to the reaction flask and reacted at room temperature for 1.5h. Concentrating under reduced pressure to obtain 2- (2-methoxy-5- (methylamino) pyridin-3-yl) -N, N-dimethyl acetamide hydrochloride, wherein the obtained crude product is directly used for the next reaction without purification, and the yield is 65.0%; ESI-MS (m/z): 224.1[ M+H ]] ⁺

Step i): preparation of (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -N, N-dimethylacetamide

2- (2-methoxy-5- (methylamino) pyridin-3-yl) -N, N-dimethylacetylamide hydrochloride (162 mg, 0.264 mmol), (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine (293 mg, 0.640 mmol), X-Phos (238 mg,0.499 mmol), cs ₂ CO ₃ (1.220g，3.744mmol)、Pd ₂ (dba) ₃ (229 mg,0.250 mmol) and toluene (20 mL) were added sequentially to the flask, and the reaction was stirred at 105℃for 2h with three nitrogen substitutions. Cooling to room temperature, concentrating under reduced pressure, purifying the crude product by silica gel column chromatography (eluent: methanol/dichloromethane=1/20) to obtain (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -N, N-dimethylacetamide with a yield of 92.3%; ESI-MS (m/z): 598.2[ M+H ] ] ⁺ 。

Step j): preparation of (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino-2-methyl quinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate salt

(R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -N, N-dimethylacetamide (344 mg,0.576 mmol) was dissolved in methanol (8 mL), iron powder (161 mg, 2.88mmol) and saturated aqueous ammonium chloride solution (4 mL) were added and the mixture was refluxed for 0.5h. Cooling to room temperature, adding ethyl acetate (20 mL) and water (10 mL), suction filtering, separating the filtrate to obtain an organic phase, washing (10 mL) with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the obtained crude product by Prep-HPLC (method 2) to obtain (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino-2-methyl quinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate, and the yield is 5.2%; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.73(s，1H)，8.22(s，1H)，8.13(s，1H)，7.94(s，1H)，7.70(s，1H)，7.41(d，J＝8.8Hz，1H)，7.35(s，1H)，7.11(d，J＝9.2Hz，1H)， 6.90(s，1H)，6.87(s，1H)，6.70(s，1H)，5.66-5.49(m，3H)，3.85(s，3H)，3.59(s，2H)，3.36(s，3H)，3.02(s，3H)，2.80(s，3H)，2.38(s，3H)1.57(d，J＝6.8Hz，3H)；ESI-MS(m/z)：568.0[M+H] ⁺ 。

example 16

Preparation of (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino-2-methyl quinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide

(R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino-2-methyl quinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide (150 mg,0.264 mmol), a solution of hydrogen bromide in acetic acid (33%, 5 mL) were added to a reaction flask, stirred at 80℃for 1h, cooled to room temperature, saturated aqueous sodium bicarbonate (100 mL) was added to adjust pH 7-8, ethyl acetate was extracted (20 mL), and saturated brine was added(10 mL) washing, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the resulting crude product by Prep-HPLC (method 3) to give (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino-2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide in a yield of 5.3%; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.59(s，1H)，8.06(s，1H)，7.52(s，1H)，7.39(d，J＝9.2Hz，1H)，7.25(s，1H)，7.17(s，1H)，7.07(d，J＝8.8Hz，1H)，6.89(s，1H)，6.87(s，1H)，6.70(s，1H)，5.65-5.47(m，3H)，3.41(s，2H)，3.26(s，3H)，3.00(s，3H)，2.78(s，3H)，2.35(s，3H)，1.57(d，J＝6.8Hz，3H)；ESI-MS(m/z)：554.0[M+H] ⁺ 。

example 17

Preparation of (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-chloroquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

Step a): preparation of (R) -6-bromo-2-chloro-N- (1- (3-nitro-5-trifluoromethylphenyl) ethyl) quinazolin-4-amine

6-bromo-2, 4-dichloroquinazoline (618 mg,2.222 mmol), (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethane-1-amine hydrochloride (500 mg, 1.850 mmol), DIPEA (7197 mg, 5.552 mmol) and DMSO (10 mL) were added sequentially to a reaction flask, and the mixture was heated to 80℃under nitrogen and stirred for 1h. After the completion of the reaction, saturated aqueous ammonium chloride solution (30 mL) was added, extracted with ethyl acetate (50 ml×2), the organic phases were combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 to 5/1) to give (R) -6-bromo-2-chloro-N- (1- (3-nitro-5-trifluoromethylphenyl) ethyl) quinazolin-4-amine in 92.0% yield; ESI-MS (m/z): 475.0[ M+H ] ] ⁺ 。

Step b): preparation of (R) -2- (5- (2-chloro-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) (methylamino) -2-methoxyphenyl) -N, N-dimethylacetamide

(R) -6-bromo-2-chloro-N- (1- (3-nitro-5-trifluoromethylphenyl) ethyl) quinazolin-4-amine (143 mg,0.300 mmol), 2- (2-methoxy-5- (methylamino) phenyl) -N, N-dimethylacetylamide hydrochloride (78 mg,0.300 mmol), X-Phos (28 mg,0.060 mmol), cs ₂ CO ₃ (195 mg,0.6 mmol), toluene (5 mL) and Pd (dba) ₂ (17 mg,0.030 mmol) was successively added to a reaction flask, replaced with nitrogen three times, and the temperature was raised to 100℃and the reaction was stirred for 3 hours. After the completion of the reaction, the reaction was quenched with water (30 mL), extracted with ethyl acetate (30 ml×2), the organic phases were combined, washed with saturated brine (30 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give (R) -2- (5- (2-chloro-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) (methylamino) -2-methoxyphenyl) -N, N-dimethylacetamide in a yield of 37.8%; ESI-MS (m/z): 617.0[ M+H ]] ⁺ 。

Step c): preparation of (R) -2- (5- (4- (1- (3-amino-5- (trifluoromethylphenyl) ethyl) amino) -2-chloroquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

(R) -2- (5- (2-chloro-4- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) (methylamino) -2-methoxyphenyl) -N, N-dimethylacetamide (70 mg,0.113 mmol) was dissolved in methanol (1.5 mL), iron powder (32 mg, 0.560 mmol) and an aqueous ammonium chloride solution (1.5 mL) were added to the reaction flask, and the reaction was stirred at 90℃for 2h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, the solid was rinsed with ethyl acetate (5 ml×3), the filtrate was separated, the aqueous phase was extracted with ethyl acetate (10 ml×2), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by Prep-HPLC (method 3), (R) -2- (5- (4- (1- (3-amino-5- (trifluoromethylphenyl) ethyl) amino) -2-chloroquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide in a yield of 37.7%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.64(d，J＝8.0Hz，1H)，7.62(s，1H)，7.36(d，J＝8.0Hz，1H)，7.10-7.07(m，2H)，7.01(d，J＝8.0Hz，1H)，6.95(s，1H)，6.88(s，1H)，6.85(s，1H)，6.73(s，1H)，5.95(s，2H)，5.52-5.45(m，1H)，3.78(s，3H)，3.52(s，2H)，3.33(s，3H)，3.00(s，3H)，2.80(s，3H)，1.59(d，J＝8.0Hz，3H)；ESI-MS(m/z)：587.0[M+H] ⁺ 。

example 18

Step a): preparation of (R) -2- (4- ((2-chloro-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

(R) -6-bromo-2-chloro-N- (1- (3-nitro-5-trifluoromethylphenyl) ethyl) quinazolin-4-amine (300 mg,0.63 mmol), 2- (4-amino-2-methoxyphenyl) -N, N-dimethylacetylamide hydrochloride (154 mg,0.63 mmol), X-Phos (60 mg,0.126 mmol), cs ₂ CO ₃ (410 mg,1.260 mmol), toluene (50 mL), and Pd (dba) ₂ (36 mg,0.063 mmol) was added to the flask in this order, nitrogen was replaced three times, and the temperature was raised to 100℃and the reaction was stirred for 3 hours. After the reaction, quench the reaction with water (50 mL), extract with ethyl acetate (50 ml×2), combine the organic phases, wash with saturated brine (50 ml×1), concentrate the organic phases under reduced pressure, and purify the residue by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to give (R) -2- (4- ((2-chloro-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide in a yield of 21.0%; ESI-MS (m/z): 603.0[ M+H ]] ⁺ 。

Step b): preparation of (R) -2- (4- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-chloroquinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

((R) -2- (4- ((2-chloro-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide (80 mg,0.132 mmol) was dissolved in methanol (1.5 mL), iron powder (37 mg,0.66 mmol) and aqueous ammonium chloride (1.5 mL) were added to the reaction flask, and 90℃was maintained under stirring for 2h after completion of the reaction, the reaction was cooled to room temperature, filtered, the solid was rinsed with ethyl acetate (5 mL. Times.3), the filtrate was separated, the aqueous phase was extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude (R) -2- (4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-chloro-6-quinazolin) -N-dimethylacetamide purified by Prep-HPLC (method 3), yield 7.66; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.75(d，J＝8.0Hz，1H)，8.53(s，1H)，8.42(s，1H)，7.54-7.46(m，2H)，6.98(d，J＝8.0Hz，1H)，6.88(s，1H)，6.86(s，1H)，6.81(s，1H)，6.71(s，1H)，6.64(d，J＝8.0Hz，1H)，5.54(s，2H)，5.46-5.39(m，1H)，3.72(s，3H)，3.50(s，2H)，3.01(s，3H)，2.83(s，3H)，1.53(d，J＝8.0Hz，3H)；ESI-MS(m/z)：573.0[M+H] ⁺ 。

Example 19

Preparation of (R) -2- (4- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-chloroquinazolin-6-yl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide

(R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl quinazoline-6-yl) (methyl) amino) -3-methoxy phenyl) -N, N-dimethyl acetamide (40 mg,0.070 mmol) and dichloromethane (2 mL) are added into a reaction bottle, stirred and dissolved, nitrogen is replaced for 3 times, stirred at 0 ℃ for 5min, and BCl is added ₃ (1M, 2 mL), room temperatureStirring for 30min. After the reaction, saturated aqueous sodium hydrogencarbonate (20 mL) and ethyl acetate (20 mL) were added, the solution was separated, the aqueous phase was extracted with ethyl acetate (20 ml×2), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by Prep-HPLC (method 3) to give (R) -2- (4- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-chloroquinazolin-6-yl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide in a yield of 51.2%; ¹ H NMR(400MHz，DMSO-d ₆ )δ9.48(s，1H)，8.72(d，J＝8.0Hz，1H)，8.32(s，1H)，7.97(s，1H)，7.51(s，2H)，6.94(d，J＝8.0Hz，1H)，6.88(s，1H)，6.84(s，1H)，6.70(s，1H)，6.63(s，1H)，6.59(d，J＝8.0Hz，1H)，5.54(s，2H)，5.39-5.46(m，1H)，3.50(s，2H)，3.03(s，3H)，2.83(s，3H)，1.54(d，J＝8.0Hz，3H)；ESI-MS(m/z)：559.0[M+H] ⁺ 。

example 20

Preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

Step a): preparation of 1-bromo-3-difluoromethyl-2-fluorobenzene

3-bromo-2-fluorobenzaldehyde (20.0 g,98.522 mmol) and methylene chloride (200 mL) were added to a reaction flask, dissolved by stirring, replaced with nitrogen 3 times, cooled to 0℃and diethylaminosulfur trifluoride (24.1 g,147.789 mmol) was added dropwise, and after the dropwise addition was completed, the mixture was naturally warmed to room temperature and stirred for 16 hours. After the reaction, saturated aqueous sodium bicarbonate solution is slowly added dropwise to adjust the pH to be 7-8 for extraction and deactivation, dichloromethane (150 mL multiplied by 3) is used for extraction, the organic phases are combined, the mixture is washed with 200mL of saturated saline solution, dried with anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure, and the residue is purified by a silica gel column (eluent: petroleum ether/ethyl acetate=100/1) to obtain 1-bromo-3-difluoromethyl-2-fluorobenzene with the yield of 88.0%; ¹ H NMR(400MHz，CDCl ₃ )δ7.68(t，J＝8.0Hz，8.0Hz 1H)，7.55(t，J＝7.0Hz，7.0Hz 1H)，7.14(d，J＝8.0Hz，2H)，6.89(t，J＝54.8Hz，1H)；19FNMR(376MHz，CDCl ₃ )δ-114.27(s，1F)，-114.26(s，1F)，-113.08(s，1F)。

step b): preparation of 1- (3- (difluoromethyl) -2-fluorophenyl) ethyl-1-one

1-bromo-3-difluoromethyl-2-fluorobenzene (19.5 g,87.053 mmol), tributyl (1-ethoxyvinyl) stannane (40.8 g,113.170 mmol), pd (PPh ₃ ) ₂ Cl ₂ (611 mg,0.871 mmol) and triethylamine (17.6 g,174.106 mmol) were added to 1, 4-dioxane (200 mL), and the reaction mixture was continuously purged with nitrogen for 5min and then heated to 100℃in an autoclave overnight. After the reaction was completed, the reaction solution was cooled to room temperature, 2M of diluted hydrochloric acid was added to adjust to ph=2-3, stirring was carried out at room temperature for 1h, the solvent was removed by concentration, saturated aqueous sodium bicarbonate solution was added to the mixture, extraction was carried out with ethyl acetate (150 ml×3), the organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=100/1) to give 1- (3- (difluoromethyl) -2-fluorophenyl) ethyl-1-one in 72.1% yield; ¹ H NMR(400MHz，CDCl ₃ )δ8.00(t，J＝7.2Hz，1H)，7.79(t，J＝7.2Hz，6.4Hz，1H)，7.34(t，J＝7.6Hz，1H)，6.95(t，J＝54.8Hz，1H)，2.67(d，J＝5.2Hz，3H)。

Step c): preparation of (R, E) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylene) -2-methylpropane-2-sulfinamide

1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-one (12.1 g,64.362 mmol) and (R) - (+) -tert-butylsulfinamide (9.3 g,77.234 mmol) and THF (150 mL) were added to a reaction flask, dissolved with stirring, tetraethyltitanate (33.8 g, 96.4819 mmol, 65%) was added at room temperature, and after the addition, the flask was closed and stirred at 80℃for 3h. After the reaction was completed, the mixture was cooled to room temperature, water (200 mL) was added to precipitate a large amount of solid, the solid was filtered, the cake was washed with ethyl acetate (50 mL), the filtrate was extracted with ethyl acetate (150 mL. Times.3), and the organic phases were combined to saturateBrine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give (R, E) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylene) -2-methylpropane-2-sulfinamide in 81.0% yield; ESI-MS (m/z): 292.1[ M+H ]] ⁺ 。

Step d): preparation of (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl-1-amine hydrochloride

(R, E) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethylene) -2-methylpropane-2-sulfinamide (15.1 g,51.546 mmol) and tetrahydrofuran/water mixture (160 mL, v/v=15/1) were added into a reaction flask, stirred and dissolved, and NaBH was slowly added under stirring at-78 DEG C ₄ (2.4 g,63.158 mmol) and was reacted at-78℃for 1h. After the reaction, naturally heating to room temperature, quenching the reaction by adding saturated saline (100 mL), separating the solution, washing the organic phase once again by using saturated saline (100 mL), drying and concentrating, purifying the residue by silica gel column chromatography, collecting the target component, dissolving the obtained intermediate in THF (80 mL), adding dioxane hydrochloride solution (4M, 30 mL), stirring at room temperature for 3h, concentrating the solvent under reduced pressure to dryness, adding ethyl acetate/petroleum ether (100 mL, v/v=1/1) into the obtained solid, pulping at room temperature for 1h, filtering, drying the obtained solid under reduced pressure to obtain (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl-1-amine hydrochloride with the yield of 78.1%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.80(s，3H)，7.94(t，J＝7.6Hz，1H)，7.66(t，J＝7.2Hz，1H)，7.44(t，J＝7.6Hz，1H)，7.25(t，J＝54.0Hz，1H)，4.65(q，J＝6.0Hz，1H)，1.55(d，J＝6.8Hz，3H)；ESI-MS(m/z)：190.1[M+H] ⁺ 。

step e) (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-4-amine preparation

6-bromo-4-chloro-2-methylquinazoline (200 mg,0.733 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl-1-amine hydrochloride (165 mg,0.733 mmol) and DIPEA (284 mg, 2.198mmol) were dissolved in DMSO (5 mL), the reaction solution was heated to 80℃and stirred for 1h, after the reaction was completed, the reaction solution was cooled to room temperature, water (50 mL) was added to extract, and ethyl acetate was used to extractThe organic phases were combined (30 ml×3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=1/1) to give (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-4-amine in 95.1% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.72(s，1H)，8.55(d，J＝7.2Hz，1H)，7.84(d，J＝8.4Hz，1H)，7.68(t，J＝7.6Hz，1H)，7.53(d，J＝8.8Hz，1H)，7.50(t，J＝7.2Hz，1H)，7.29(t，J＝7.6Hz，1H)，7.23(t，J＝54.4Hz，1H)，5.81-5.74(m，1H)，2.34(s，3H)，1.60(d，J＝6.8Hz，3H)；ESI-MS(m/z)：411.2[M+H] ⁺ 。

Step f): preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-4-amine (260 mg,0.636 mmol), 2- (2-methoxy-5- (methylamino) phenyl) -N, N-dimethylacetylamide hydrochloride (164 mg,0.636 mmol), cs ₂ CO ₃ (622mg，1.908mmol)、X-Phos(61mg，0.127mmol)、Pd ₂ (dba) ₃ (59 mg,0.064 mmol) and toluene (7 mL) were added to the flask, nitrogen was replaced three times, and the temperature was raised to 90℃and the reaction was stirred for 16h. After the reaction was completed, the reaction was quenched with water (15 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 mL), and the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by Prep-HPLC (method 3) to give (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide in 39.9% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.18(d，J＝7.6Hz，1H)，7.70(t，J＝7.6Hz，1H)，7.65(s，1H)，7.49(t，J＝7.2Hz，1H)，7.35(d，J＝9.2Hz，1H)，7.29(t，J＝7.6Hz，1H)，7.24(t，J＝54.4Hz，1H)，7.10-7.02(m，2H)，6.99(d，J＝8.8Hz，1H)，6.91(s，1H)，5.87-5.80(m，1H)，3.77(s，3H)，3.57(s，2H)，3.35(s，3H)，2.99(s，3H)，2.79(s，3H)，2.29(s，3H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：552.2[M+H] ⁺ 。

example 21

Preparation of (S) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide formate salt

Step a): preparation of (S) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-4-amine

6-bromo-4-chloro-2-methylquinazoline (200 mg,0.777 mmol), (S) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl-1-amine hydrochloride (175 mg,0.777 mmol) and DIPEA (301 mg,2.331 mmol) were dissolved in DMSO (5 mL), the reaction was heated to 80 ℃ and stirred for 1h, after the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (50 mL), extracted with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to give (S) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-4-amine in 90.8% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.72(s，1H)，8.56(d，J＝7.2Hz，1H)，7.85(d，J＝6.8Hz，1H)，7.68(t，J＝7.6Hz，1H)，7.53(d，J＝9.2Hz，1H)，7.49(d，J＝7.2Hz，1H)，7.29(t，J＝7.6Hz，1H)，7.23(t，J＝54.4Hz，1H)，5.81-5.74(m，1H)，2.34(s，3H)，1.60(d，J＝6.8Hz，3H)；ESI-MS(m/z)：411.2[M+H] ⁺ 。

step b): preparation of (S) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide formate salt

(S) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl)) Ethyl) -2-methylquinazolin-4-amine (260 mg,0.636 mmol), 2- (2-methoxy-5- (methylamino) phenyl) -N, N-dimethylacetylamide hydrochloride (164 mg,0.636 mmol), cs ₂ CO ₃ (622mg，1.908mmol)、X-Phos(121mg，0.254mmol)、Pd(dba) ₂ (76 mg,0.127 mmol) and toluene (7 mL) were added to the flask, nitrogen was replaced three times, and the temperature was maintained at 90℃and the reaction was stirred for 16h. After the reaction was completed, the reaction was quenched with water (15 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 2) to give (S) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide formate in 55.1% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.75(s，1H)，8.20(d，J＝7.6Hz，1H)，8.14(s，1H)，7.70(t，J＝7.5Hz，1H)，7.65(s，1H)，7.49(t，J＝7.2Hz，1H)，7.35(d，J＝9.2Hz，1H)，7.30(t，J＝7.6Hz，1H)，7.24(t，J＝54.4Hz，1H)，7.10-7.02(m，2H)，6.99(d，J＝8.8Hz，1H)，6.91(s，1H)，5.87-5.80(m，1H)，3.77(s，3H)，3.57(s，2H)，3.35(s，3H)，2.99(s，3H)，2.79(s，3H)，2.30(s，3H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：552.2[M+H]+。

Example 22

Preparation of (R) -2- (4- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

Step a): preparation of (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) quinazolin-4-amine

6-bromo-4-chloroquinazoline (300 mg,1.240 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine hydrochloride (426 mg,1.612 mmol) and dimethyl sulfoxide (5 mL) were added to a reaction flask and stirredDissolving, adding DIPEA (481 mg,3.720 mmol), heating the reaction solution to 80 ℃ for 2h, cooling the reaction solution to room temperature after the reaction is finished, adding water (20 mL), diluting, extracting with ethyl acetate (20 mL multiplied by 2), merging organic phases, washing with saturated saline water (30 mL multiplied by 3), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 to 5/1), and obtaining (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) quinazoline-4-amine with a yield of 81.7%; ESI-MS (m/z): 396.0[ M+H ]] ⁺ 。

Step b): preparation of (R) -2- (4- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) quinazolin-4-amine (200 mg,0.506 mmol), 2- (4-amino-2-methoxyphenyl) -N, N-dimethylacetylamide hydrochloride (136 mg,0.557 mmol), X-Phos (48 mg,0.0.102 mmol), cs ₂ CO ₃ (803 mg,1.113 mmol), toluene (5 mL) and Pd ₂ (dba) ₃ (46 mg,0.0.051 mmol) was added sequentially to the flask, replaced with nitrogen three times, and the reaction was stirred for 4 hours at 100 ℃. After the completion of the reaction, the reaction was quenched with water (10 mL), extracted with ethyl acetate (20 ml×2), the organic phases were combined, washed with saturated brine (30 mL), and the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 to 1/1) to give (R) -2- (4- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide in 67.9% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.50(s，1H)，8.38(d，J＝8.0Hz，1H)，8.23(s，1H)，8.16(s，1H)，7.66-7.59(m，2H)，7.48(d，J＝8.0Hz，2H)，7.37-7.10(m，2H)，6.99(d，J＝8.0Hz，1H)，6.92(s，1H)，6.66(d，J＝8.0Hz，1H)，5.82-5.75(m，1H)，3.76(s，3H)，3.51(s，2H)，3.02(s，3H)，2.84(s，3H)，1.57(d，J＝8.0Hz，3H)；ESI-MS(m/z)：524.2[M+H] ⁺ 。

example 23

Preparation of (R) -2- (4- ((2-chloro-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetylamide hydrochloride

Step a): preparation of methyl 2- ((Boc) amino) -5- ((4- (2- (dimethylamino) -2-oxoethyl) -3-methoxyphenyl) amino) benzoate

Methyl 5-bromo-2- ((tert-butoxycarbonyl) amino) benzoate (3.0 g, 8.480 mmol), 2- (4-amino-2-methoxyphenyl) -N, N-dimethylacetamide (1.81 g,8.163 mmol), X-Phos (780 mg, 1.630 mmol), cs ₂ CO ₃ (5.3 g,16.326 mmol), toluene (30 mL) and Pd (dba) ₂ (470 mg,0.816 mmol) was successively added to the reaction flask, replaced with nitrogen three times, and the temperature was raised to 110℃and the reaction was stirred for 3 hours. After the reaction was completed, cooled to room temperature, filtered with celite under reduced pressure, the cake was washed once with ethyl acetate (30 mL), the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 to 1/1) to give methyl 2- ((tert-butoxycarbonyl) amino) -5- ((4- (2- (dimethylamino) -2-oxoethyl) -3-methoxyphenyl) amino) benzoate, yield 48.6%; ¹ H NMR(400MHz，CDCl ₃ )δ10.02(s，1H)，8.34(d，J＝8.0Hz，1H)，7.77(s，1H)，7.30-7.26(m，2H)，7.07(d，J＝8.0Hz，1H)，6.53(s，1H)，3.89(s，3H)，3.74(s，3H)，3.62(s，2H)，3.00(s，6H)，1.52(s，9H)；ESI-MS(m/z)：458.2[M+H] ⁺ 。

step b): preparation of methyl 2-amino-5- ((4- (2- (dimethylamino) -2-oxoethyl) -3-methoxyphenyl) amino) benzoate

Methyl 2- ((Boc) amino) -5- ((4- (2- (dimethylamino) -2-oxoethyl) -3-methoxyphenyl) amino) benzoate (1.8 g,3.939 mmol) was dissolved in ethyl acetate (5 mL), ethyl hydrogen chloride solution (4M, 15 mL) was added, reacted overnight at room temperature, the organic solvent was removed by concentration, and the residue was saturated with Sodium bicarbonate solution ph=8-9, extraction with ethyl acetate (50 ml×2), combining the organic phases, drying over anhydrous sodium sulfate, filtration, concentrating the filtrate under reduced pressure to give methyl 2-amino-5- ((4- (2- (dimethylamino) -2-oxoethyl) -3-methoxyphenyl) amino) benzoate, yield 78.6%; ESI-MS (m/z): 358.2[ M+H ]] ⁺ 。

Step c): preparation of 2- (4- ((2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

Methyl 2-amino-5- ((4- (2- (dimethylamino) -2-oxyethyl) -3-methoxyphenyl) amino) benzoate (1.8 g,3.939 mmol) and urea (5 g,83.333 mmol) are mixed and added into a reaction bottle, the reaction is placed in an oil bath at 160 ℃ and heated and stirred for 3 hours, after the reaction is finished, cooled to room temperature, added with water (30 mL) and stirred for 1 hour for beating treatment, filtration is carried out, a filter cake is washed once with water (30 mL), filter cakes are collected, and the filter cake is dried under reduced pressure to obtain 2- (4- ((2, 4-dioxy-1, 2,3, 4-tetrahydroquinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide, and the yield is 43.3%; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.17(s，1H)，10.96(s，1H)，8.21(s，1H)，7.56(s，1H)，7.39(d，J＝12.0Hz，1H)，7.09(d，J＝8.0Hz，1H)，6.93(d，J＝8.0Hz，1H)，6.61-6.57(m，2H)，3.71(s，3H)，3.49(s，2H)，3.00(s，3H)，2.83(s，3H)；ESI-MS(m/z)：369.1[M+H] ⁺ 。

step d): preparation of 2- (4- ((2, 4-dichloroquinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

2- (4- ((2, 4-Dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide (100 mg, 0.279 mmol) was added to toluene (5 mL) and POCl was added at room temperature ₃ (208 mg,1.365 mmol) and DIPEA (211 mg, 1.618 mmol), heating and stirring the reaction in an oil bath at 90deg.C for 20min, cooling to room temperature after the reaction, pouring the reaction solution into ice water, adjusting pH to 8-9 with saturated sodium bicarbonate aqueous solution, extracting with ethyl acetate (20 mL), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain 2- (4- ((2, 4-dichloroquinazolin-6-yl) amino) -2-methoxyphenyl) -NN-dimethylacetamide was used directly in the next reaction without purification.

Step e): preparation of (R) -2- (4- ((2-chloro-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetylamide hydrochloride

2- (4- ((2, 4-Dichloroquinazolin-6-yl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide (63 mg,0.156 mmol) was added to DMSO (5 mL), and (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine hydrochloride (42 mg,0.172 mmol) and DIPEA (60 mg, 0.268 mmol) were added at room temperature, the reaction was warmed to 80 ℃ with stirring for 30min, after completion of the reaction, cooled to room temperature, the reaction solution was poured into saturated ammonium chloride aqueous solution, extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated brine (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by Prep-HPLC (method 1) to give (R) -2- (4- ((2-chloro-4- ((1- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide hydrochloride in a yield of 13.13%; ¹ H NMR(400MHz，DMSO-d ₆ )δ14.71(s，1H)，8.87(d，J＝8.0Hz，1H)，8.57(s，1H)，8.16(s，1H)，7.67-6.89(m， 8H)，6.66(s，1H)，5.76-5.69(m，1H)，3.74(s，3H)，3.51(s，2H)，3.02(s，3H)，2.84(s，3H)，1.58(d，J＝8.0Hz，3H)；ESI-MS(m/z)：558.0[M+H] ⁺ 。

Example 24

Preparation of (R) -2- (4- ((2-chloro-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetylamide hydrochloride

Step a): preparation of methyl 2- ((Boc) amino) -5- ((4- (2- (dimethylamino) -2-oxoethyl) -3-methoxyphenyl) (methyl) amino) benzoate

5-bromo-2- ((tert)Boc) amino benzoic acid methyl ester (560 mg,1.727 mmol), 2- (4-amino-2-methoxyphenyl) -N, N-dimethylacetamide (190 mg,1.900 mmol), pd ₂ (dba) ₃ (158mg，0.173mmol)、Cs ₂ CO ₃ (1.1 g,3.545 mmol), toluene (5 mL), and X-Phos (165 mg,0.346 mmol) were sequentially added to a reaction flask, nitrogen was replaced three times, and the temperature was raised to 110℃and the reaction was stirred for 3 hours. After the reaction was completed, cooled to room temperature, filtered with celite under reduced pressure, the cake was washed once with ethyl acetate (20 mL), the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 to 1/1) to give methyl 2- ((tert-butoxycarbonyl) amino) -5- ((4- (2- (dimethylamino) -2-oxoethyl) -3-methoxyphenyl) (methyl) amino) benzoate in 52.9% yield; ESI-MS (m/z): 472.2[ M+H ]] ⁺ 。

Step b): preparation of methyl 2-amino-5- ((4- (2- (dimethylamino) -2-oxoethyl) -3-methoxyphenyl) (methyl) amino) benzoate

Methyl 2- ((tert-butoxycarbonyl) amino) -5- ((4- (2- (dimethylamino) -2-oxoethyl) -3-methoxyphenyl) (methyl) amino) benzoate (430 mg,0.913 mmol) was dissolved in ethyl acetate (5 mL), ethyl acetate solution (4 m,8 mL) containing hydrogen chloride was added, and the reaction was carried out at room temperature overnight, and the solvent was distilled off under reduced pressure to give methyl 2-amino-5- ((4- (2- (dimethylamino) -2-oxoethyl) -3-methoxyphenyl) (methyl) amino) benzoate in 99.9% yield; ESI-MS (m/z): 358.2[ M+H ]] ⁺ 。

Step c): preparation of 2- (4- ((2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

Methyl 2-amino-5- ((4- (2- (dimethylamino) -2-oxoethyl) -3-methoxyphenyl) (methyl) amino) benzoate (340 mg, 0.803 mmol) and urea (2.0 g,33.333 mmol) were mixed and added to a reaction flask, and the reaction was warmed to 160℃and reacted for 3 hours. Cooling to room temperature after the reaction is finished, adding water (30 mL), stirring for 1h, pulping, filtering, washing a filter cake once with water (20 mL), collecting the filter cake, and drying under reduced pressure to obtain 2- (4- ((2, 4-dioxy-1, 2,3, 4-tetrahydroquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-diMethylacetamide in 80.8% yield; ESI-MS (m/z): 383.2[ M+H ] ] ⁺ 。

Step d): preparation of 2- (4- ((2, 4-dichloroquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

2- (4- ((2, 4-Dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide (250 mg, 0.650 mmol) was added to toluene (5 mL) and POCl was added at room temperature ₃ (150 mg,0.981 mmol) and DIPEA (140 mg,1.046 mmol), and was reacted at 90℃for 30min. After the reaction was completed, cooled to room temperature, the reaction solution was poured into ice water, adjusted to ph=8-9 with saturated sodium bicarbonate, extracted with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2- (4- ((2, 4-dichloroquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide, which was used directly for the next reaction without purification.

Step e): preparation of (R) -2- (4- (2-chloro-4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetylamide hydrochloride

2- (4- ((2, 4-dichloropquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide (35 mg,0.084 mmol) was added to DMSO (3 mL), and (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine hydrochloride (21 mg,0.092 mmol) and DIPEA (24 mg,0.185 mmol) were added at room temperature, reacted at 80 ℃ for 30min, cooled to room temperature after the reaction was completed, the reaction solution was poured into saturated ammonium chloride aqueous solution, extracted with ethyl acetate (20 ml×2), the organic phases were combined, washed with saturated brine (20 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by Prep-HPLC (method 1) to give (R) -2- (4- ((2-chloro-4- ((1- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -quinazolin-6-yl) -N, N-dimethylacetamide hydrochloride in 10.6 yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ14.72(s，1H)，8.89(d，J＝8.0Hz，1H)，7.90(s，1H)，7.73(s，1H)，7.56-7.04(m，6H)，6.76(s，1H)， 6.66(d，J＝8.0Hz，1H)，5.79-5.73(m，1H)，3.71(s，3H)，3.55(s，2H)，3.46(s，3H)，3.02(s，3H)，2.84(s，3H)，1.64(d，J＝8.0Hz，3H)；ESI-MS(m/z)：572.0[M+H] ⁺ 。

Example 25

Preparation of (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide formate salt

Step a): preparation of (R, E) -2-methyl-N- (1- (3- (trifluoromethyl) phenyl) ethylene) propane-2-sulfinamide

M-trifluoromethyl acetophenone (5.00 g,26.574 mmol), (R) - (+) -tert-butylsulfonamide (3.86 g,31.848 mmol), tetraethyltitanate (13.99 g,39.864 mmol) and THF (100 mL) were added to the reaction flask and the temperature was raised to 80℃for 3h. After the reaction, cooling to room temperature, adding ice water (100 mL) and ethyl acetate (100 mL), mixing evenly, carrying out suction filtration, separating filtrate, extracting aqueous phase with ethyl acetate (30 mL), combining organic phases, washing saturated saline (50 mL), drying with anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure, purifying obtained crude product by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/10), and obtaining (R, E) -2-methyl-N- (1- (3- (trifluoromethyl) phenyl) ethylene) propane-2-sulfinamide with the yield of 63.0%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.19(d，J＝7.6Hz，1H)，8.16(s，1H)，7.96-7.90(m，1H)，7.79-7.71(m，1H)，2.78(s，3H)，1.23(s，9H)；ESI-MS(m/z)：292.0[M+H] ⁺ 。

step b): preparation of (R) -2-methyl-N- ((R) -1- (3- (trifluoromethyl) phenyl) ethyl) propane-2-sulfinamide

(R, E) -2-methyl-N- (1- (3- (trifluoromethyl) phenyl) ethylene) propane-2-sulfinamide (4.9 g,16.747 mmol) was dissolved in THF (50 mL) and water (1 mL), cooled to-78deg.C, sodium borohydride (950 mg,25.112 mmol) was added, and reacted at room temperature for 1h. After the reaction, ice water (50 mL) was added for dilution Ethyl acetate extraction (100 mL), washing the organic phase with saturated brine (50 mL), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the obtained crude product by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/3), obtaining (R) -2-methyl-N- ((R) -1- (3- (trifluoromethyl) phenyl) ethyl) propane-2-sulfinamide, yield 54.8%; ¹ H NMR(400MHz，DMSO-d ₆ )δ7.79(s，1H)，7.71(d，J＝7.2Hz，1H)，7.62-7.54(m，2H)，5.85(d，J＝8.0Hz，1H)，4.49(m，1H)，1.42(d，J＝6.8Hz，3H)，1.12(s，9H)；ESI-MS(m/z)：294.1[M+H] ⁺ 。

step c): preparation of (R) -1- (3- (trifluoromethyl) phenyl) ethyl-1-amine hydrochloride

(R) -2-methyl-N- ((R) -1- (3- (trifluoromethyl) phenyl) ethyl) propane-2-sulfinamide (2.7 g,9.177 mmol) was dissolved in dioxane (5 mL), dioxane hydrochloride solution (4M, 5 mL) was added and reacted at room temperature for 1h. Concentrating under reduced pressure, pulping (30 mL, v/v=5:1) with petroleum ether/ethyl acetate mixed solvent, filtering, and vacuum drying under reduced pressure to obtain (R) -1- (3- (trifluoromethyl) phenyl) ethyl-1-amine hydrochloride with yield of 92.0%; ESI-MS (m/z): 190.0[ M+H ]] ⁺ 。

Step d): preparation of (R) -6-bromo-2-methyl-N- (1- (3- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine

6-bromo-4-chloro-2-methyl quinazoline (200 mg,0.777 mmol), (R) -1- (3- (trifluoromethyl) phenyl) ethan-1-amine hydrochloride (165 mg,0.731 mmol), DIPEA (283 mg,2.190 mmol), and DMSO (4 mL) were added sequentially to the reaction flask, and the mixture was heated to 80℃under nitrogen and stirred for 3h. After the reaction was completed, cooled to room temperature, saturated brine (20 mL) was added, extracted with ethyl acetate (20 ml×2), the organic phases were combined, washed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/3) to give (R) -6-bromo-2-methyl-N- (1- (3- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine in 89.7% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.67(s，1H)，8.53(d，J＝7.6Hz，1H)，7.87-7.80(m，2H)，7.76(d，J＝7.2Hz，1H)，7.63-7.50(m，3H)，5.63(m，1H)，2.38(s，3H)，1.61(d，J＝7.2Hz，3H)；ESI-MS(m/z)：410.0[M+H] ⁺ 。

Step e): preparation of (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide formate salt

(R) -6-bromo-2-methyl-N- (1- (3- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine (267 mg, 0.650 mmol), 2- (2-methoxy-5- (methylamino) phenyl) -N, N-dimethylacetylamide hydrochloride (170 mg,0.657 mmol), X-Phos (126 mg,0.264 mmol), cs ₂ CO ₃ (645mg，1.980mmol)、Pd ₂ (dba) ₃ (119 mg,0.130 mmol) and toluene (20 mL) were successively added to the reaction flask, replaced with nitrogen three times, and the temperature was raised to 105℃and the reaction was stirred for 1 hour. After the reaction, cooling to room temperature, concentrating under reduced pressure, purifying the obtained crude product by silica gel column chromatography (eluent: methanol/dichloromethane=1:20), and purifying by Prep-HPLC (method 2) to obtain (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide formate with a yield of 39.2%; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.73(s，1H)，8.17(s，1H)，8.14(s，1H)，7.83(s，1H)，7.78(d，J＝6.4Hz，1H)，7.62-7.54(m，3H)，7.35(d，J＝9.2Hz，1H)，7.10-6.97(m，3H)，6.91(s，1H)，5.73-5.64(m，1H)，3.77(s，3H)，3.57(s，2H)，3.34(s，3H)，2.99(s，3H)，2.78(s，3H)，2.33(s，3H)，1.64(d，J＝7.2Hz，3H)；ESI-MS(m/z)：552.2[M+H] ⁺ 。

example 26

Preparation of (R) -2- (2-hydroxy-5- (methyl (2-methyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide formate salt

(R) -2-/v2-methoxy-5- (methyl (2-methyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide (100 mg,0.181 mmol) and dichloromethane (4 mL) were added to a reaction flask, stirred and dissolved, replaced with nitrogen for 3 times, and boron tribromide (200 mg,0.789 mmol) was added to the flask after cooling to 0℃and reacted at room temperature for 1h. After the reaction was completed, saturated aqueous sodium hydrogencarbonate (20 mL) and ethyl acetate (20 mL) were added, the solution was separated, the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained crude product was purified by Prep-HPLC (method 2) to give (R) -2- (2-hydroxy-5- (methyl (2-methyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide formate in a yield of 21.2%; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.79(s，1H)，9.53(s，1H)，8.16(s，1H)，8.13(s，1H)，7.83(s，1H)，7.78(d，J＝6.0Hz，1H)，7.62-7.55(m，2H)，7.52(s，1H)，7.32(d，J＝9.2Hz，1H)，7.02(d，J＝9.2Hz，1H)，6.94-6.88(m，2H)，6.82(d，J＝8.4Hz，1H)，5.74-5.63(m，1H)，3.56(s，2H)，3.31(s，3H)，3.01(s，3H)，2.80(s，3H)，2.33(s，3H)，1.64(d，J＝7.2Hz，3H)；ESI-MS(m/z)：538.2[M+H] ⁺ 。

Example 27

Preparation of (S) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide formate salt

Step a): preparation of (R) -2-methyl-N- ((S) -1- (3- (trifluoromethyl) phenyl) ethyl) propane-2-sulfinamide

(R, E) -2-methyl-N- (1- (3- (trifluoromethyl) phenyl) ethylene) propane-2-sulfinamide (4.879 g,16.747 mmol) was dissolved in THF (50 mL) and water (1 mL), cooled to-78℃and sodium borohydride (0.950 g,25.112 mmol) was added and reacted at room temperature for 1h. After the reaction, add ice water (50 mL) to quenchEster extraction (100 mL), washing the organic phase with saturated brine (50 mL), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the crude product by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/1), obtaining (R) -2-methyl-N- ((S) -1- (3- (trifluoromethyl) phenyl) ethyl) propane-2-sulfinamide, yield 17.7%; ¹ H NMR(400MHz，DMSO-d ₆ )δ7.72(s，1H)，7.67(d，J＝7.2Hz，1H)，7.65-7.61(m，2H)，5.52(d，J＝5.2Hz，1H)，4.60-4.49(m，1H)，1.48(d，J＝6.8Hz，3H )，1.11(s，9H)；ESI-MS(m/z)：294.1[M+H] ⁺

step b): preparation of (S) -1- (3- (trifluoromethyl) phenyl) ethyl-1-amine hydrochloride

(R) -2-methyl-N- ((S) -1- (3- (trifluoromethyl) phenyl) ethyl) propane-2-sulfinamide (0.87 g,2.966 mmol) was dissolved in 1, 4-dioxane (2 mL), dioxane hydrochloride solution (4M, 2 mL) was added, and the mixture was reacted at room temperature for 1h. Concentrating under reduced pressure, pulping (10 mL, v/v= 5;1) with petroleum ether/ethyl acetate mixed solvent, filtering, and vacuum drying the obtained solid under reduced pressure to obtain (S) -1- (3- (trifluoromethyl) phenyl) ethyl-1-amine hydrochloride with a yield of 80.8%; ESI-MS (m/z): 190.0[ M+H ] ] ⁺ 。

Step c): preparation of (S) -6-bromo-2-methyl-N- (1- (3- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine

6-bromo-4-chloro-2-methylquinazoline (189 mg, 0.284 mmol), (S) -1- (3- (trifluoromethyl) phenyl) ethan-1-amine hydrochloride (165 mg,0.731 mmol), DIPEA (283 mg,2.190 mmol) and DMSO (4 mL) were added sequentially to the reaction flask, and the mixture was heated to 80℃under nitrogen and stirred for 2h. After the reaction was completed, cooled to room temperature, saturated brine (20 mL) was added, extracted with ethyl acetate (20 ml×2), the organic phases were combined, washed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/3) to give (S) -6-bromo-2-methyl-N- (1- (3- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine in 84.7% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.67(s，1H)，8.53(d，J＝7.6Hz，1H)，7.86-7.80(m，2H)，7.76(d，J＝7.2Hz，1H)，7.61-7.52(m，3H)，5.63(m，1H)2.38(s，3H)，1.61(d，J＝7.2Hz，3H)；ESI-MS(m/z)：410.0[M+H] ⁺ 。

step d): preparation of (S) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide formate salt

(S) -6-bromo-2-methyl-N- (1- (3- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine (250 mg, 0.319 mmol), 2- (2-methoxy-5- (methylamino) phenyl) -N, N-dimethylacetylamide hydrochloride (158 mg, 0.319 mmol), X-Phos (116 mg,0.244 mmol), cs ₂ CO ₃ (595g，1.827mmol)、Pd ₂ (dba) ₃ (111 mg,0.122 mmol) and toluene (20 mL) were sequentially added to the reaction flask, replaced with nitrogen three times, and the temperature was raised to 105℃and the reaction was stirred for 1h. After the reaction, cooling to room temperature, concentrating under reduced pressure, diluting with water (20 mL) and ethyl acetate (20 mL), filtering, separating filtrate, washing an organic phase with saline solution (10 mL multiplied by 2), drying with anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure, purifying the obtained crude product by Prep-HPLC (method 2), and obtaining (S) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide formate with the yield of 33.5%; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.78(s，1H)，8.19-8.13(m，2H)，7.83(s，1H)，7.78(d，J＝6.0Hz，1H)，7.62-7.56(m，3H)，7.35(d，J＝9.2Hz，1H)，7.10-7.02(m，2H)，7.01-7.10(m，1H)，6.91(s，1H)，5.74-5.64(m，1H)，3.77(s，3H)，3.57(s，2H)，3.33(s，3H)，2.99(s，3H)，2.78(s，3H)，2.33(s，3H)，1.64(d，J＝7.2Hz，3H)；ESI-MS(m/z)：552.2[M+H] ⁺ 。

example 28

Preparation of (S) -2- (2-hydroxy-5- (methyl (2-methyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide formate salt

(S) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide (150 mg,0.272 mmol) was dissolved in dichloromethane (4 mL), replaced with nitrogen 3 times, boron tribromide (300 mg, 1.197mmol) was added at 0deg.C, and the temperature was raised to room temperature for reaction for 1h. After the reaction, saturated aqueous sodium bicarbonate (20 mL) and ethyl acetate (20 mL) are added to quench the reaction, the organic phase is washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the obtained crude product is purified by Prep-HPLC (method 2) to obtain (S) -2- (2-hydroxy-5- (methyl (2-methyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide formate with a yield of 4.4%; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.78(s，1H)，9.57(s，1H)，8.13(s，1H)，7.84(s，1H)，7.78(d，J＝6.8Hz，1H)，7.63-7.51(m，4H)，7.35(d，J＝8.5Hz，1H)，7.06(d，J＝8.4Hz，1H)，6.95-6.88(m，2H)，6.84(d，J＝8.4Hz，1H)，5.73(s，1H)，3.57(s，2H)，3.31(s，3H)，3.01(s，3H)，2.80(s，3H)，2.37(s，3H)，1.66(d，J＝7.2Hz，3H)；ESI-MS(m/z)：538.2[M+H] ⁺ 。

Example 29

Preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl)) -N, N-dimethylacetamide formate salt

Step a): preparation of 1-bromo-3- (difluoromethyl) -2-methylbenzene

3-bromo-2-methylbenzaldehyde (5.00 g,25.119 mmol) was dissolved in dichloromethane (50 mL), diethylaminosulfur trifluoride (DAST, 8.10g,50.251 mmol) was added dropwise at 0℃and the mixture was reacted at room temperature for 24 hours. After the reaction, the reaction solution was poured into saturated carbonIn aqueous sodium hydrogen carbonate solution (50 mL), the organic phase is separated, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the crude product obtained is purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=100/1) to obtain 1-bromo-3- (difluoromethyl) -2-methylbenzene with a yield of 86.6%; ¹ H NMR(400MHz，DMSO-d ₆ )δ7.79(d，J＝8.0Hz，1H)，7.57(d，J＝8.0Hz，1H)，7.38-7.15(m，2H)，2.44(s，3H)。

step b): preparation of 1- (3- (difluoromethyl) -2-methylphenyl) ethyl-1-one

1-bromo-3- (difluoromethyl) -2-methylbenzene (4.809 g, 21.751 mmol), tributyl (1-ethoxyethylene) tin (9.428 g,26.107 mmol), pd (PPh) ₃ )Cl ₂ (0.764 g,1.088 mmol), triethylamine (5.493 g,54.284 mmol) and dioxane (50 mL) were added to the reaction flask, and the reaction was closed at 100deg.C for 16h. After the reaction, cooling to room temperature, adding saturated potassium fluoride aqueous solution (50 mL) and ethyl acetate (50 mL), stirring for 0.5h, carrying out suction filtration, separating filtrate, drying with anhydrous sodium sulfate, filtering, concentrating to about the volume (30 mL), adding ethyl acetate hydrochloride (4M, 20 mL), stirring for 0.5h, concentrating under reduced pressure, purifying the obtained crude product by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/100), and obtaining 1- (3- (difluoromethyl) -2-methylphenyl) ethyl-1-ketone with the yield of 90.4%; ESI-MS (m/z): 185.0[ M+H ] ] ⁺ 。

Step c): preparation of (R, E) -N- (1- (3- (difluoromethyl) -2-methylphenyl) ethylene) -2-methylpropane-2-sulfinamide

1- (3- (difluoromethyl) -2-methylphenyl) ethyl-1-one (3.264 g, 19.6755 mmol), (R) - (+) -tert-butylsulfinamide (2.862 g,23.610 mmol), tetraethyl titanate (10.357 g,29.512 mmol) and THF (70 mL) were added to a reaction flask, reacted at 80℃for 16h, cooled to room temperature after the reaction was completed, water (100 mL) and ethyl acetate (100 mL) were added to mix well, suction filtration was performed, the organic phase of the filtrate was separated, the aqueous phase was extracted with ethyl acetate (30 mL), the organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/10) to obtain (R, E) -N- (1- (3- (di-mL)Fluoromethyl) -2-methylphenyl) ethylene) -2-methylpropane-2-sulfinamide in 88.4% yield; ESI-MS (m/z): 288.1[ M+H ]] ⁺ 。

Step d): preparation of (R) -N- ((R) -1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -2-methylpropane-2-sulfinamide

(R, E) -N- (1- (3- (difluoromethyl) -2-methylphenyl) ethylene) -2-methylpropane-2-sulfinamide (5.00 g,17.399 mmol) was dissolved in THF (50 mL) and water (1 mL), cooled to-78 ℃, sodium borohydride (0.987 g,26.099 mmol) was added, the reaction was carried out at room temperature for 1h, ice water (50 mL) was added for quenching, ethyl acetate was extracted (100 mL), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/3) to give (R) -N- ((R) -1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -2-methylpropane-2-sulfinamide in 37.8% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ7.65(d，J＝7.6Hz，1H)，7.45-7.38(m，1H)，7.38-7.32(m，1H)，7.32-7.05(m，1H)，5.71(d，J＝6.4Hz，1H)，4.69(m，1H)，2.36(s，3H)，1.37(d，J＝6.8Hz，3H)，1.08(s，9H)；ESI-MS(m/z)：290.1[M+H] ⁺

Step e): preparation of (R) -1- (3- (difluoromethyl) -2-methylphenyl) ethyl-1-amine hydrochloride

(R) -N- ((R) -1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -2-methylpropane-2-sulfinamide (1.906 g,6.586 mmol) was dissolved in dioxane (5 mL), dioxane hydrochloride solution (4M, 5 mL) was added, reaction was carried out at room temperature for 0.5h, petroleum ether (20 mL) was added, and the solid was collected by filtration to give (R) -1- (3- (difluoromethyl) -2-methylphenyl) ethyl-1-amine hydrochloride in 98.1% yield; ESI-MS (m/z): 186.1[ M+H ]] ⁺ 。

Step f): preparation of (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -2-methylquinazolin-4-amine

6-bromo-4-chloro-2-methylquinazoline (400 mg,1.553 mmol), (R) -1- (3- (difluoromethyl) -2-methylphenyl) ethan-1-amine hydrochloride (324 mg, 1.463mmol), DIPEA (567 mg, 4.383 mmol), DMSO (8 mL) were added sequentially to the reaction flask, nitrogenThe reaction was stirred at 80℃under protection for 1h. After the reaction was completed, the mixture was cooled to room temperature, saturated brine (20 mL) was added, ethyl acetate was extracted (20 ml×2), the organic phases were combined, washed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/3) to give (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -2-methylquinazolin-4-amine in 82.5% yield; ESI-MS (m/z): 406.0[ M+H ] ] ⁺ 。

Step g): preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl)) -N, N-dimethylacetamide formate salt

(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -2-methylquinazolin-4-amine (300 mg,0.738 mmol), 2- (2-methoxy-5- (methylamino) phenyl) -N, N-dimethylacetylamide hydrochloride (191 mg,0.738 mmol), X-Phos (141 mg, 0.025 mmol), cs ₂ CO ₃ (721g，2.214mmol)、Pd ₂ (dba) ₃ (135 mg,0.147 mmol) and toluene (10 mL) were added sequentially to the reaction flask, replaced with nitrogen three times, and stirred at 105℃for 24h. After the reaction, cooling to room temperature, concentrating under reduced pressure, purifying the obtained crude product by silica gel column chromatography (eluent: methanol/dichloromethane=1/20), and purifying by Prep-HPLC (method 2) to obtain (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -2-methyl quinazolin-6-yl) (methyl) amino) -2-methoxyphenyl)) -N, N-dimethylacetamide formate with the yield of 3.2%; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.78(s，1H)，8.22(s，1H)，8.14(s，1H)，7.70(d，J＝7.6Hz，1H)，7.65(s，1H)，7.40-7.22(m，4H)，7.09-7.02(m，2H)，7.00-6.97(m，1H)，6.90(s，1H)，5.84-5.74(m，1H)，3.77(s，3H)，3.57(s，2H)，3.35(s，3H)，2.99(s，3H)，2.79(s，3H)，2.57(s，3H)，2.31(s，3H)，1.56(d，J＝7.2Hz，3H)；ESI-MS(m/z)：548.2[M+H] ⁺ 。

example 30

Preparation of (S) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl)) -N, N-dimethylacetamide formate salt

Step a): preparation of (R) -N- ((S) -1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -2-methylpropane-2-sulfinamide

(R, E) -N- (1- (3- (difluoromethyl) -2-methylphenyl) ethylene) -2-methylpropane-2-sulfinamide (5.00 g,17.399 mmol) was dissolved in THF (50 mL) and water (1 mL), cooled to-78deg.C, and sodium borohydride (0.987 g,26.099 mmol) was added and reacted at room temperature for 1h. Ice water (50 mL) was added to quench, extraction was performed with ethyl acetate (100 mL), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the crude product obtained was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/1) to give (R) -N- ((S) -1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -2-methylpropane-2-sulfinamide in 40.0% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ7.59(d，J＝7.6Hz，1H)，7.44-7.37(m，1H)，7.37-7.32(m，1H)，7.30-7.05(m，1H)，5.37(d，J＝5.2Hz，1H)，4.72(m，1H)，2.36(s，3H)，1.45(d，J＝6.8Hz，3H)，1.10(s，9H)；ESI-MS(m/z)：290.1[M+H] ⁺ 。

step b): preparation of (S) -1- (3- (difluoromethyl) -2-methylphenyl) ethyl-1-amine hydrochloride

(R) -N- ((S) -1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -2-methylpropane-2-sulfinamide (2.014 g,6.959 mmol) was dissolved in dioxane (5 mL), dioxane hydrochloride solution (4M, 5 mL) was added and reacted at room temperature for 0.5h. Adding petroleum ether (20 mL), pulping, filtering and drying to obtain (S) -1- (3- (difluoromethyl) -2-methylphenyl) ethyl-1-amine hydrochloride with the yield of 87.2%; ESI-MS (m/z): 186.1[ M+H ] ] ⁺ 。

Step c): preparation of (S) -6-bromo-N- (1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -2-methylquinazolin-4-amine

6-bromo-4-chloro-2-methylquinazoline (400 mg,1.553 mmol), (S) -1- (3- (difluoromethyl) -2-methylphenyl) ethyl-1-amine hydrochloride (324 mg, 1.463mmol), DIPEA (567 mg, 4.383 mmol) and DMSO (8 mL) were added sequentially to the reaction flask and stirred at 80℃for 1h under nitrogen. After the reaction was completed, cooled to room temperature, saturated brine (20 mL) was added, extracted with ethyl acetate (20 ml×2), the organic phases were combined, washed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/3) to give (S) -6-bromo-N- (1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -2-methylquinazolin-4-amine in 74.5% yield; ESI-MS (m/z): 406.0[ M+H ]] ⁺ 。

Step d): preparation of (S) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl)) -N, N-dimethylacetamide formate salt

(S) -6-bromo-N- (1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -2-methylquinazolin-4-amine (200 mg,0.492 mmol), 2- (2-methoxy-5- (methylamino) phenyl) -N, N-dimethylacetylamide hydrochloride (127 mg,0.492 mmol), X-Phos (94 mg, 0.197mmol), cs ₂ CO ₃ (481g，1.476mmol)、Pd ₂ (dba) ₃ (90 mg,0.098 mmol) and toluene (20 mL) were sequentially added to the reaction flask, and the reaction was stirred at 105℃for 24 hours with three nitrogen substitutions. After the reaction, cooling to room temperature, concentrating under reduced pressure, purifying the obtained crude product by silica gel column chromatography (eluent: methanol/dichloromethane=1/20), and purifying by Prep-HPLC (method 2) to obtain (S) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl)) -N, N-dimethylacetamide formate in a yield of 4.9%; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.78(s，1H)，8.25(s，1H)，8.13(s，1H)，7.70(d，J＝7.6Hz，1H)，7.65(s，1H)，7.40-7.22(m，4H)，7.10-7.03(m，2H)，7.01-6.96(m，1H)，6.91(s，1H)，5.84-5.73(m，1H)，3.77(s，3H)，3.57(s，2H)，3.35(s，3H)，2.99(s，3H)，2.79(s，3H)，2.57(s，3H)，2.32(s，3H)，1.56(d，J＝6.8Hz，3H)；ESI-MS(m/z)：548.2[M+H] ⁺ 。

example 31

Preparation of (R) -2- (5- ((4- ((1- (3- (1, 1-difluoroethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

Step a): preparation of 1- (1, 1-difluoroethyl) -3-iodobenzene

3-iodoacetophenone (2.46 g,9.998 mmol) and THF (30 mL) were added to the reaction flask, dissolved with stirring, replaced with nitrogen 3 times, cooled to 0deg.C, diethylaminosulfur trifluoride (8.1 g,49.990 mmol) was added dropwise, methanol (0.5 mL) was added dropwise after the addition was completed, and the mixture was naturally warmed to room temperature and stirred for 1h. The temperature was raised to 80℃and the reaction was carried out overnight. After the completion of the reaction, the reaction was quenched by slowly dropping a saturated aqueous sodium bicarbonate solution to ph=7-8, extracted with dichloromethane (150 ml×3), the organic phases were combined, washed with saturated brine (50 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=100/1) to give 1- (1, 1-difluoroethyl) -3-iodobenzene in 85.0% yield.

Step b): preparation of 1- (3- (1, 1-difluoroethyl) phenyl-1-one

1- (1, 1-difluoroethyl) -3-iodobenzene (2.3 g,8.498 mmol), tributyl (1-ethoxyvinyl) stannane (3.99 g,11.047 mmol), pd (PPh) ₃ )Cl ₂ (298 mg,0.425 mmol) and triethylamine (1.716 g,16.996 mmol) were added to 1, 4-dioxane (30 mL), and the reaction mixture was continuously purged with nitrogen for 5min and then heated to 100℃in a hydrothermal reactor to react overnight. After the reaction, the reaction mixture was cooled to room temperature, 2N diluted hydrochloric acid was added to adjust the pH to 2-3, the mixture was stirred at room temperature for 1 hour, the solvent was removed by concentration under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added to the mixture, extraction was performed with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was reducedThe residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=50/1) to give 1- (3- (1, 1-difluoroethyl) phenyl-1-one in 72.0% yield.

Step c): preparation of (R) -N- (1- (3- (1, 1-difluoroethyl) phenyl) ethylene) -2-methylpropane-2-sulfinamide

1- (3- (1, 1-difluoroethyl) phenyl-1-one (0.7 g,3.800 mmol) and (R) - (+) -tert-butylsulfinamide (0.69 g,5.700 mmol) and THF (15 mL) were added to a reaction flask, dissolved with stirring, tetraethyltitanate (2.6615 g,7.600mmol, 65%) was added at room temperature and stirred for 3h at 80℃after completion of the reaction, cooled to room temperature, water (20 mL) was added, a large amount of solids was precipitated, filtered, the filter cake was washed with ethyl acetate (50 mL), the filtrate was extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give ((R) -N- (1, 1-difluoroethyl) phenyl) -2-methylpropane-2-sulfinamide, 97.0%; ESI-MS (m 3M: 288 H+3/M ] ⁺ 。

Step d): preparation of (R) -N- ((R) -1- (3- (1, 1-difluoroethyl) phenyl) ethyl) -2-methylpropane-2-sulfinamide

((R) -N- (1- (3- (1, 1-difluoroethyl) phenyl) ethylene) -2-methylpropane-2-sulfinamide (1.059 g,3.686 mmol) and THF/water mixture (15 mL, v/v=50/1) were added to a reaction flask, stirred and dissolved, and NaBH was slowly added under stirring at-78deg.C ₄ (0.278 g,7.372 mmol) and was reacted at-78℃for 1 hour. After the reaction, naturally heating to room temperature, adding saturated saline (100 mL) to quench the reaction, separating the solution, washing the organic phase with saturated saline (100 mL), drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain (R) -N- ((R) -1- (3- (1, 1-difluoroethyl) phenyl) ethyl) -2-methylpropane-2-sulfinamide with a yield of 70.3%; ESI-MS (m/z): 290.3[ M+H ]] ⁺ 。

Step e): preparation of (R) -1- (3- (1, 1-difluoroethyl) phenyl) ethyl-1-amine hydrochloride

(R) -N- ((R) -1- (3- (1, 1-difluoroethyl) phenyl) ethyl) -2-methylpropane-2-sulfinamide (0.75 g,2.592 mmol) and THF (2 mL) are added into a reaction bottle, stirred and dissolved, hydrogen chloride 1,4 dioxane solution (3 mL, 4M) is slowly added under the stirring condition of 0 ℃ and the addition is completed, and the temperature is naturally raised to room temperature for reaction for 1h. Concentrating under reduced pressure after the reaction is finished, dissolving the residue with a small amount of ethyl acetate, adding a large amount of petroleum ether in batches under stirring to separate out a large amount of white precipitate, filtering, washing with petroleum ether to obtain (R) -1- (3- (1, 1-difluoroethyl) phenyl) ethyl-1-amine hydrochloride, wherein the yield is 95.7%; ESI-MS (m/z): 186.2[ M+H ] ] ⁺ 。

Step f): preparation of (R) -6-bromo-N- (1- (3- (1, 1-difluoroethyl) phenyl) ethyl) -2-methylquinazolin-4-amine

6-bromo-4-chloro-2-methylquinazoline (200 mg,0.733 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl-1-amine hydrochloride (162 mg,0.733 mmol) and DIPEA (284 mg, 2.198mmol) were dissolved in DMSO (5 mL), the reaction solution was heated to 80 ℃ and stirred for 1h, after the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (50 mL), extracted with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to give (R) -6-bromo-N- (1- (3- (1, 1-difluoroethyl) phenyl) ethyl) -2-methylquinazolin-4-amine in 95.0 yield; ESI-MS (m/z): 406.2[ M+H ]] ⁺ 。

Step g): preparation of((R) -2- (5- ((4- ((1- (3- (1, 1-difluoroethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

(R) -6-bromo-N- (1- (3- (1, 1-difluoroethyl) phenyl) ethyl) -2-methylquinazolin-4-amine (120 mg,0.300 mmol), 2- (2-methoxy-5- (methylamino) phenyl) -N, N-dimethylacetylamide hydrochloride (77 mg,0.300 mmol), cs ₂ CO ₃ (217mg，0.600mmol)、X-Phos(28mg，0.060mmol)、Pd(dba) ₂ (17 mg, 0.003mmol) and toluene (7 mL) were added to the reaction flask, and the nitrogen was replaced three timesThe temperature is raised to 90 ℃ and the reaction is stirred for 16h. After the reaction was completed, the reaction was quenched with water (25 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1), and the crude product was purified by Prep-HPLC (method 3) to give ((R) -2- (5- ((4- ((1- (3- (1, 1-difluoroethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide in a yield of 49.8%; ¹ H NMR(400MHz，CD3OD)δ7.63(d，J＝8.0Hz，1H)，7.55(d，J＝4.0Hz，1H)，7.41-7.38(m，2H)，7.26-7.21(m，2H)，7.12-7.09(m，1H)，7.02-6.97(m，3H)，5.89-5.84(m，1H)，3.85(s，3H)，3.69(s，2H)，3.38(s，3H)，3.11(s，3H)，2.94(s，3H)，2.60(s，3H)，2.41(t，J＝12.0Hz，，3H)，1.63(d，J＝8.0Hz，3H)；ESI-MS(m/z)：548.6[M+H] ⁺ 。

example 32

Preparation of (R) -2- (5- ((4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

Step a): preparation of (R) -6-bromo-N- (1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-4-amine

6-bromo-4-chloro-2-methylquinazoline (172 mg, 0.6278 mmol), (R) -1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethane-1-amine hydrochloride (150 mg, 0.6278 mmol), DIPEA (244 mg,1.884 mmol) and DMSO (5 mL) were sequentially added to the reaction flask, and the mixture was heated to 80℃under nitrogen and stirred for 2 hours. After the completion of the reaction, the mixture was quenched with saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/acetic acid) Ethyl ester=10/1), to give (R) -6-bromo-N- (1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-4-amine in 93.9% yield; ESI-MS (m/z): 424.0[ M+H ]] ⁺ 。

Step b): preparation of (R) -2- (5- ((4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

(R) -6-bromo-N- (1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-4-amine (90 mg,0.212 mmol), 2- (2-methoxy-5- (methylamino) phenyl) -N, N-dimethylacetylamide hydrochloride (61 mg,0.233 mmol), X-Phos (42 mg,0.085 mmol), cs ₂ CO ₃ (208mg，0.636mmol)、Pd(dba) ₂ (25 mg,0.043 mmol) and toluene (5 mL) were added sequentially to the flask, nitrogen was replaced three times, and the temperature was raised to 105℃and the reaction was stirred overnight. After the reaction was completed, the reaction was quenched with water (20 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 3) to give (R) -2- (5- ((4- ((1- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide in a yield of 33.3%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.18(d，J＝7.2Hz，1H)，7.68-7.61(m，2H)，7.42(t，J＝7.6Hz，1H)，7.35(d，J＝9.2Hz，1H)，7.24(t，J＝7.6Hz，1H)，7.11-7.02(m，2H)，6.98(d，J＝8.8Hz，1H)，6.91(d，J＝2.8Hz，1H)，5.86-5.78(m，1H)，3.76(s，3H)，3.57(s，2H)，3.37(s，3H)，2.99(s，3H)，2.78(s，3H)，2.29(s，3H)，2.04(t，J＝18.8Hz，3H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：566.3[M+H] ⁺ 。

Example 33

Preparation of (R) -2- (5- ((4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide formate salt

Step a): preparation of 2- (2-hydroxy-5- (methylamino) phenyl) -N, N-dimethylacetamide

2- (2-methoxy-5- (methylamino) phenyl) -N, N-dimethylacetamide (300 mg,1.110 mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, boron tribromide (1 mL) was added dropwise, the temperature was raised to room temperature after the addition was completed, the reaction solution was stirred for 16h, quenched with water (10 mL), adjusted to ph=8 to 9 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (20 ml×3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give 2- (2-hydroxy-5- (methylamino) phenyl) -N, N-dimethylacetamide in a yield of 81.4%; ESI-MS (m/z): 209.1[ M+H ]] ⁺ 。

Step b): preparation of 2- (2- ((tert-butyldimethylsilyl) oxy) -5- (methylamino) phenyl) -N, N-dimethylacetamide

2- (2-hydroxy-5- (methylamino) phenyl) -N, N-dimethylacetamide (188 mg,0.899 mmol), t-butyldimethylchlorosilane (163 mg,1.079 mmol), triethylamine (137 mg,1.349 mmol) and methylene chloride (5 mL) were successively added to the reaction flask, and the reaction mixture was stirred at room temperature for 16h. After the reaction, concentrating under reduced pressure, purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:4) to obtain 2- (2- ((tert-butyldimethylsilyl) oxy) -5- (methylamino) phenyl) -N, N-dimethylacetamide with a yield of 82.6%; ESI-MS (m/z): 323.2[ M+H ] ] ⁺ 。

Step c): preparation of (R) -2- (2- ((tert-butyldimethylsilyl) oxy) -5- ((4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) phenyl) -N, N-dimethylacetamide

(R) -6-bromo-N- (1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-4-amine (92 mg,0.21 mmol), 2- (2- ((tert-butyldimethylsilyl) oxy) -5- (methylamino) phenyl) -N, N-dimethylacetamide (70 mg,0.21 mmol), X-Phos (42 mg, 0.08)6mmol)、Cs ₂ CO ₃ (141mg，0.434mmol)、Pd(dba) ₂ (25 mg,0.043 mmol) and toluene (5 mL) were added sequentially to the flask, nitrogen was replaced three times, and the temperature was raised to 105℃and the reaction was stirred overnight. After the reaction was completed, the reaction was quenched with water (20 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give (R) -2- (2- ((tert-butyldimethylsilyl) oxy) -5- ((4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) phenyl) -N, N-dimethylacetamide in 79.7% yield; ESI-MS (m/z): 666.3[ M+H ] ] ⁺ 。

Step d): preparation of (R) -2- (5- ((4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide formate salt

(R) -2- (2- ((tert-Butyldimethylsilyl) oxy) -5- ((4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) phenyl) -N, N-dimethylacetamide (115 mg,0.171 mmol) was dissolved in THF (3 mL), tetrabutylammonium fluoride (0.26 mL, 1M) was added and stirred at room temperature for 30min. After completion of the reaction, the reaction was quenched with water (20 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by Pre-HPLC (method 2) to give (R) -2- (5- ((4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide formate in 15.9% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.60(s，1H)，9.53(s，1H)，8.16(s，1H)，8.14(s，1H)，7.65(t，J＝6.4Hz，1H)，7.57(s，1H)，7.42(t，J＝7.6Hz，1H)，7.32(d，J＝9.2Hz，1H)，7.25(t，J＝7.6Hz，1H)，7.02(m，1H)，6.94-6.87(m，2H)，6.83(d，J＝8.4Hz，1H)，5.83(q，J＝7.2Hz，1H)，3.57(s，2H)，3.33(s，3H)，3.01(s，3H)，2.80(s，3H)，2.29(s，3H)，2.04(t，J＝18.8Hz，3H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：552.2[M+H] ⁺ 。

example 34

Preparation of (R) -2- (5- ((4- ((1- (3- (1, 1-difluoroethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide

Preparation method referring to example 33, purification by Prep-HPLC (method 3) gave (R) -2- (5- ((4- ((1- (3- (1, 1-difluoroethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide in 45.7% yield; ¹ H NMR(400MHz，CD3OD)δ7.56(d，J＝8.0Hz，1H)，7.40(d，J＝4.0Hz，1H)，7.33-7.29(m，2H)，7.20-7.16(m，1H)，7.12-7.09(m，1H)，6.92-6.89(m，3H)，6.81-6.78(m，1H)，5.83-5.78(m，1H)，3.64(s，2H)，3.29(s，3H)，3.06(s，3H)，2.88(s，3H)，2.53(s，3H)，2.34(t，J＝12.0Hz，3H)，，1.55(d，J＝8.0Hz，3H)；ESI-MS(m/z)：534.6[M+H] ⁺ 。

Example 35

(R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridine) -3-

Preparation of the formate of yl) -N, N-dimethylacetamide

(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-4-amine (413 mg, 1.399 mmol), 2- (2-methoxy-5- (methylamino) pyridin-3-yl) -N, N-dimethylacetamide (150 mg,0.673 mmol), X-Phos (128 mg,0.269 mmol), cs ₂ CO ₃ (439mg，1.346mmol)、Pd(dba) ₂ (76 mg,0.134 mmol) and toluene (8 mL) were added sequentially to the flask, nitrogen was replaced three times, and the temperature was raised to 105℃and the reaction was stirred overnight. After the reaction was completed, the reaction was quenched with water (20 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 2) to give (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate in 53.7% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.60(s，1H)，8.21(d，J＝7.2Hz，1H)，8.14(s，1H)，7.94(d，J＝2.8Hz，1H)，7.73(s，1H)，7.69(t，J＝7.6Hz，1H)，7.49(t，J＝7.2Hz，1H)，7.39(d，J＝9.2Hz，1H)，7.35(s，1H)，7.29(t，J＝7.6Hz，1H)，7.24(s，1H)，7.10(m，1H)，5.82(q，J＝7.2Hz，1H)，3.85(s，3H)，3.59(s，2H)，3.38(s，3H)，3.02(s，3H)，2.80(s，3H)，2.30(s，3H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：553.2[M+H] ⁺ 。

example 36

Preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin) -3-yl) -N, N-dimethylacetamide formate salt

Preparation method referring to example 35, (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin) -3-yl) -N, N-dimethylacetamide formate was obtained in 2.3% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.70(s，1H)，8.31(s，1H)，8.14(s，1H)，7.94-7.95(m，1H)，7.77-7.67(m，2H)，7.40-7.08(m，6H)，5.80(s，1H)，3.85(s，3H)，3.60(s，2H)，3.38(s，3H)，3.02(s，3H)，2.81(s，3H)，2.57(s，3H)，2.33(s，3H)，1.57(d，J＝7.2Hz，3H)；ESI-MS(m/z)：549.3[M+H] ⁺ 。

example 37

Preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin) -3-yl) -N, N-dimethylacetamide formate salt

(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -2-methylquinazolin-4-amine (616 mg,1.540 mmol), 2- (2-hydroxy-5- (methylamino) pyridin-3-yl) -N, N-dimethylacetylamide hydrochloride (161 mg,0.770 mmol), cs ₂ CO ₃ (753mg，2.310mmol)、X-Phos(294mg，0.616mmol)、Pd(dba) ₂ (175 mg,0.308 mmol) and toluene (10 mL) were added to the flask, the mixture was replaced with nitrogen three times, and the reaction was stirred at 105℃for 16h. Cooling to room temperature, concentrating under reduced pressure, purifying the residue by silica gel column chromatography (eluent: methanol/dichloromethane=1/20), purifying the crude product obtained by Prep-HPLC (method 2) to give (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin) -3-yl) -N, N-dimethylacetamide formate in 4.7% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.70(s，1H)，11.60(s，1H)，8.17(s，1H)，8.20(d，J＝7.2Hz，1H)，7.70(d，J＝7.6Hz，1H)，7.55(m，1H)，7.41-7.34(m，2H)，7.33-7.13(m，4H)，7.07-7.04(m，1H)，5.79(m 1H)，3.42(s，2H)，3.29(s，3H)，3.02(s，3H)，2.79(s，3H)，2.57(s，3H)，2.31(s，3H)，1.56(d，J＝7.2Hz，3H)；ESI-MS(m/z)：535.0[M+H] ⁺ 。

Example 38

Preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide

(R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin) -3-yl) -N, N-dimethylacetamide (200 mg, 0.803 mmol), an acetic acid solution of hydrogen bromide (5 mL, 33%) was sequentially added to the reaction flask, and the mixture was stirred for 20 minutes at 80 ℃. After the reaction was completed, the reaction was quenched by adding saturated aqueous sodium bicarbonate (50 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 3) to give (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide in a yield of 25.5%; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.60(s，1H)，8.20(s，1H)，7.68(t，J＝7.6Hz，1H)，7.55(s，1H)，7.49(t，J＝7.2Hz，1H)，7.39(d，J＝9.2Hz，1H)，7.31-7.26(m，2H)，7.24(t，J＝54.4Hz，1H)，7.19(d，J＝2.8Hz，1H)，7.08(m，1H)，5.82(q，J＝7.2Hz，1H)，3.42(s，2H)，3.28(s，3H)，3.01(s，3H)，2.78(s，3H)，2.30(s，3H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：539.2[M+H] ⁺ 。

example 39

Preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin) -3-yl) -1- (pyrrolidin-1-yl) ethyl-1-one formate

Step a): preparation of 2- (5-bromo-2-methoxypyridin-3-yl) acetic acid hydrochloride

2- (5-bromo-2-methoxypyridin-3-yl) ethylEthyl acetate (500 mg, 1.284 mmol), aqueous lithium hydroxide (4M, 1.8 mL), THF (1.5 mL) and methanol (0.5 mL) were added to the reaction flask and reacted at room temperature for 15min. Adding 0.2N hydrochloric acid to adjust pH to 2-3, adding ethyl acetate for extraction (20 mL multiplied by 2), combining organic phases, washing with saturated saline (10 mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain 2- (5-bromo-2-methoxypyridin-3-yl) acetic acid hydrochloride, and obtaining the yield of 91.5%; ESI-MS (m/z): 246.0[ M+H ]] ⁺ 。

Step b): preparation of 2- (5-bromo-2-methoxypyridin-3-yl) -1- (pyrrolidin-1-yl) ethyl-1-one

2- (5-bromo-2-methoxypyridin-3-yl) acetate (471.0 mg,1.667 mmol), tetrahydropyrrole (163.5 mg,2.299 mmol), DIPEA (618.2 mg,4.783 mmol), HATU (1.1 g,2.893 mmol) and dichloromethane (5 mL) were added to a reaction flask and stirred at room temperature for 1h. After the reaction was completed, saturated aqueous sodium hydrogencarbonate (20 mL) and ethyl acetate (20 mL) were added and stirred, the solution was separated, the organic phase was washed with saturated aqueous ammonium chloride (20 mL), saturated aqueous brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate/petroleum ether=1/1) to give 2- (5-bromo-2-methoxypyridin-3-yl) -1- (pyrrolidin-1-yl) ethyl-1-one in 94.4% yield; ESI-MS (m/z): 299.0[ M+H ] ] ⁺ 。

Step c): preparation of (6-methoxy-5- (2-oxo-2- (pyrrolidin-1-yl) ethyl) pyridin-3-yl) carbamic acid tert-butyl ester

Tert-butyl 2- (5-bromo-2-methoxypyridin-3-yl) -1- (pyrrolidin-1-yl) ethyl-1-one (220.0 mg, 0.730 mmol), carbamic acid (103.3 mg,0.882 mmol), pd (dba) ₂ (83.5mg，0.147mmol)，X-Phos(140.1mg，0.294mmol)，Cs ₂ CO ₃ (479.6 mg,1.472 mmol) and toluene (5 mL) were sequentially added to the reaction flask, nitrogen was replaced three times, and the temperature was raised to 110℃and the reaction was stirred for 2 hours. Filtering, leaching the filter cake with ethyl acetate (10 mL), concentrating the filtrate under reduced pressure, and purifying the obtained crude product by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/2) to obtain (6-methoxy-5- (2-oxo-2- (pyrrolidin-1-yl) ethyl) pyridin-3-yl) carbamic acid tert-butyl ester; yield 73.6%；ESI-MS(m/z)：280.2[M+H-But] ⁺ 。

Step d): preparation of tert-butyl (6-methoxy-5- (2-oxo-2- (pyrrolidin-1-yl) ethyl) pyridin-3-yl) (meth) carbamate

Tert-butyl (6-methoxy-5- (2-oxo-2- (pyrrolidin-1-yl) ethyl) pyridin-3-yl) carbamate (181.0 mg,0.539 mmol), naH (86.3 mg,2.157mmol, 60%) and tetrahydrofuran (3 mL) were added to the reaction flask and methyl iodide (92.5 mg,0.651 mmol) was added with stirring in ice bath and stirred at room temperature for 0.5h. After the reaction, saturated aqueous ammonium chloride (10 mL) was added to quench the reaction, extracted with ethyl acetate (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=2:1) to give tert-butyl (6-methoxy-5- (2-oxo-2- (pyrrolidin-1-yl) ethyl) pyridin-3-yl) (methyl) carbamate in 52.9% yield; ESI-MS (m/z): 294.2[ M+H ] ] ⁺ 。

Step e): preparation of 2- (2-methoxy-5- (methylamino) pyridin-3-yl) -1- (pyrrolidin-1-yl) ethyl-1-one

Tert-butyl (6-methoxy-5- (2-oxo-2- (pyrrolidin-1-yl) ethyl) pyridin-3-yl) (methyl) carbamate (100.0 mg, 0.284 mmol), trifluoroacetic acid (130.3 mg,1.143 mmol) and dichloromethane (1 mL) were added to the reaction flask and stirred at room temperature for 3h. The reaction solution was concentrated to dryness under reduced pressure, methylene chloride (15 mL) and saturated aqueous sodium bicarbonate solution (10 mL) were added and stirred, the aqueous phase was separated, extracted with methylene chloride (10 ml×2), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2- (2-methoxy-5- (methylamino) pyridin-3-yl) -1- (pyrrolidin-1-yl) ethyl-1-one in 70.4% yield; ESI-MS (m/z): 250.1[ M+H ]] ⁺ 。

Step f): preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin) -3-yl) -1- (pyrrolidin-1-yl) ethyl-1-one formate

2- (2-methoxy-5- (methylamino) pyridin-3-yl) -1- (pyrrolidin-1-yl) ethyl-1-one (50 mg,0.200 mmol), (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-quinazolin-4-amine (82 mg,0.201 mmol), pd (dba) ₂ (24mg，0.041mmol)，X-Phos(39mg，0.081mmol)，Cs ₂ CO ₃ (130 mg,0.399 mmol) and toluene (2 mL) were sequentially added to the reaction flask, nitrogen was replaced three times, and the temperature was raised to 90℃and stirred for 16h. Filtering, eluting the filter cake with ethyl acetate (10 mL), concentrating the filtrate under reduced pressure to dryness, purifying the residue by silica gel column chromatography (eluent: methanol/dichloromethane=1/25), purifying the obtained crude product by Prep-HPLC (method 2) to obtain (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -1- (pyrrolidin-1-yl) ethyl-1-one formate in 35.3% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.74(s，1H)，8.21(d，J＝7.6Hz，1H)，8.14(s，1H)，7.94(s，1H)，7.75-7.65(m，2H)，7.49(t，J＝6.8Hz，1H)，7.41-7.36(m，2H)，7.29(t，J＝7.6Hz，1H)，7.38-7.11(m，1H)，7.12(s，1H)，5.83(s，1H)，3.85(s，3H)，3.54(s，2H)，3.47(t，J＝6.8Hz，2H)，3.38(s，3H)，3.25(t，J＝6.8Hz，2H)，2.30(s，3H)，1.90-1.83(m，2H)，1.75(m，2H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：579.4[M+H] ⁺ 。

example 40

Preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -1- (pyrrolidin-1-yl) ethyl-1-one formate salt

Preparation method referring to example 38, purification by Pre-HPLC (method 2) afforded (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -1- (pyrrolidin-1-yl) ethyl-1-one formate in 51.7% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.76(s，1H)，11.59(s，1H)，8.16(d，J＝6.8Hz，1H)，8.14(s，1H)，7.69(t，J＝7.2Hz，1H)，7.55(s，1H)，7.49(t，J＝6.8Hz，1H)，7.39(d，J＝9.2Hz，1H)，7.38-7.10(m，1H)，7.32-7.25(m，2H)，7.22-7.21(m，1H)，7.09-7.07(m，1H)，5.83(d，J＝7.2Hz，1H)，3.48(t，J＝6.8Hz，2H)，3.37(s，2H)，3.29(s，3H)，3.23(t，J＝6.8Hz，2H)，2.29(s，3H)，1.86(s，2H)，1.74(s，2H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：565.3[M+H] ⁺ 。

example 41

Preparation of (R) -2- (6- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin) -3-yl) -N, N-dimethylacetamide

Step a): preparation of 6-methoxy-N-methyl-5-nitropyridin-2-amine

2-methoxy-3-nitro-6-chloropyridine (5.0 g,26.511 mmol), dimethylamine hydrochloride (3.6 g,53.022 mmol), potassium carbonate (7.3 g, 53.022) and DMF (50 mL) were added to a closed reaction flask, heated to 80℃and stirred for 3h. After the reaction, cooling to room temperature, adding water (100 mL) to quench the reaction, extracting with ethyl acetate (50 mL. Times.3), combining organic phases, washing with saturated saline (30 mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain 6-methoxy-N-methyl-5-nitropyridin-2-amine with a yield of 98.2%; ESI-MS (m/z): 184.0[ M+H ]] ⁺ 。

Step b): preparation of benzyl (6-methoxy-5-nitropyridin-2-yl) (meth) carbamate

6-methoxy-N-methyl-5-nitropyridin-2-amine (4.8 g,26.229 mmol) was dissolved in tetrahydrofuran (60 mL) and DMF (10 mL), sodium hydride (2.3 g,57.703mmol, 60%) was added under ice-bath, the reaction was stirred for 15min, benzyl chloroformate (5.4 g,31.475 mmol) was added dropwise, and the mixture was warmed to room temperature and stirred for 30min. After the completion of the reaction, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (50 mL. Times.)3) The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=8/1), to give benzyl (6-methoxy-5-nitropyridin-2-yl) (methyl) carbamate in a yield of 87.8%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.34(d，J＝9.2Hz，1H)，7.47-7.35(m，5H)，7.31(d，J＝9.2Hz，1H)，5.26(s，2H)，3.47(s，3H)，3.02(d，J＝4.8Hz，3H)；ESI-MS(m/z)：318.1[M+H] ⁺ 。

Step c): preparation of benzyl (5-amino-6-methoxypyridin-2-yl) (meth) carbamate

Benzyl (6-methoxy-5-nitropyridin-2-yl) (methyl) carbamate (2.5 g,7.886 mmol) was dissolved in methanol (20 mL) and water (10 mL), iron powder (2.2 g,39.433 mmol) and ammonium chloride (2.1 g,39.433 mmol) were added, warmed to reflux, and stirred for 2h. After the reaction, cooling to room temperature, adding water (50 mL) and ethyl acetate (30 mL), stirring and mixing uniformly, filtering, separating filtrate, extracting aqueous phase with ethyl acetate (30 mL multiplied by 2), mixing organic phases, washing with saturated saline (100 mL), drying with anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure to obtain (5-amino-6-methoxypyridin-2-yl) (methyl) benzyl carbamate; yield 99.1%; ESI-MS (m/z): 288.1[ M+H ]] ⁺ 。

Step d): preparation of benzyl (5-bromo-6-methoxypyridin-2-yl) (meth) carbamate

Copper bromide (2.1 g,9.198 mmol) and acetonitrile (20 mL) were added to the flask, nitrogen was replaced 3 times, cooled to 0deg.C, an acetonitrile solution (10 mL) of isoamyl nitrite (13 g,11.498 mmol) was added, stirred for 15min, and an acetonitrile solution (10 mL) of benzyl (5-bromo-6-methoxypyridin-2-yl) (methyl) carbamate (2.2 g,7.665 mmol) was added dropwise, and stirring was continued for 1h at 0deg.C after the addition. After the completion of the reaction, the reaction was quenched with water (100 mL), extracted with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give (5-bromo-6-methoxypyridin-2-yl) (methyl) aminomethyl Benzyl acid ester, yield 35.0%; ¹ H NMR(400MHz，CDCl ₃ )δ7.72(d，J＝8.4Hz，1H)，7.42-7.33(m，5H)，7.31(d，J＝8.4Hz，1H)，5.24(s，2H)，3.96(s，3H)，3.46(s，3H)；ESI-MS(m/z)：350.0[M+H] ⁺ 。

step e): preparation of benzyl (5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyridin-2-yl) (methyl) carbamate

Benzyl (5-bromo-6-methoxypyridin-2-yl) (methyl) carbamate (900 mg,2.571 mmol) and a solution of (2- (dimethylamino) -2-oxoethyl) magnesium bromide in tetrahydrofuran (5.2 mL,5.141mmol, 1M), pd (dba) ₂ (148 mg,0.257 mmol), X-phos (244 mg,0.514 mmol) and tetrahydrofuran (15 mL) were added to the reaction flask, nitrogen was replaced three times, and the temperature was raised to 80℃and the reaction was stirred for 2h. After the reaction, cooling to room temperature, filtering, concentrating the filtrate under reduced pressure, purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain benzyl (5- (2- (dimethylamino) -2-oxyethyl) -6-methoxypyridin-2-yl) (methyl) carbamate, yield 95.3%; ESI-MS (m/z): 357.1[ M+H ]] ⁺ 。

Step f): preparation of 2- (2-methoxy-6- (methylamino) pyridin-3-yl) -N, N-dimethylacetamide

Benzyl (5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyridin-2-yl) (methyl) carbamate (900 mg,2.549 mmol) was dissolved in methanol (15 mL), palladium on carbon (270.0 mg,0.255 mmol) was added, hydrogen was replaced three times, and stirring was performed at room temperature for 3h. Filtering, concentrating the filtrate under reduced pressure to obtain 2- (2-methoxy-6- (methylamino) pyridin-3-yl) -N, N-dimethylacetamide with a yield of 93.2%; ESI-MS (m/z): 224.1[ M+H ] ] ⁺ 。

Step g): preparation of (R) -2- (6- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin) -3-yl) -N, N-dimethylacetamide

(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-4-amine (187 mg,0.455 mmol), 2- (2-methoxy-6- (methylamino) pyridin-3-yl) -N, N-dimethylacetamide (102 mg,0.455 mmol), cs ₂ CO ₃ (297mg，0.910mmol)、X-Phos(43mg，0.091mmol)、Pd ₂ (dba) ₃ (26 mg,0.045 mmol) and toluene (7 mL) were added to the flask, nitrogen was replaced three times, and the temperature was raised to 105℃and the reaction was stirred for 16h. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give (R) -2- (6- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin) -3-yl) -N, N-dimethylacetamide in 43.8% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.41-8.31(m，2H)，7.70-7.65(m，2H)，7.58(d，J＝8.8Hz，1H)，7.49(t，J＝6.8Hz，1H)，7.28(t，J＝7.6Hz，1H)，7.24(s，1H)，7.22(t，J＝60.4Hz，1H)，6.15(d，J＝8.0Hz，1H)，5.81(m，1H)，3.75(s，3H)，3.51(s，3H)，3.45(s，2H)，3.01(s，3H)，2.82(s，3H)，2.35(s，3H)，1.58(d，J＝7.2Hz，3H)；ESI-MS(m/z)：553.2[M+H] ⁺ 。

example 42

Preparation of (R) -2- (6- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide

Preparation method referring to example 38, (R) -2- (6- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide was obtained in 43.8% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ10.52(s，1H)，8.37(d，J＝7.2Hz，1H)，8.23(s，1H)，7.67(t，J＝7.6Hz，1H)，7.57(s，2H)，7.49(t，J＝7.2Hz，1H)，7.28(t，J＝7.6Hz， 1H)，7.23(t，J＝54.4Hz，1H)，7.15(d，J＝8.0Hz，1H)，5.81(p，J＝7.2Hz，2H)，3.43(s，3H)，3.39(s，2H)，3.01(s，3H)，2.82(s，3H)，2.34(s，3H)，1.59(d，J＝7.2Hz，3H)；ESI-MS(m/z)：539.2[M+H] ⁺ 。

Example 43

Preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide formate salt

(R) -N ⁴ - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -N ⁶ 2-Dimethylquinazoline-4, 6-diamine (100 mg,0.273 mmol), 2- (5-bromo-2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide (108 mg,0.417 mmol), sodium t-butoxide (80 mg,0.833 mmol), X-phos (88 mg,0.222 mmol), pd (dba) ₂ (64 mg,0.111 mmol) and toluene (2 ml) were added to the reaction flask, nitrogen was substituted 3 times, and the mixture was stirred at 110℃for 16 hours. After the reaction was completed, cooled to room temperature, ethyl acetate (10 mL) was added and stirred at room temperature for 10min, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 2) to give (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide formate in 2.8% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.14(s，2H)，7.68(t，J＝12.0Hz，1H)，7.57(s，2H)，7.51-7.47(m，1H)，7.42(s，1H)，7.39(s，1H)，7.29(t，J＝15.2Hz，1H)，7.24(t，J＝54.4Hz，1H)，7.11(d，J＝12.0Hz，1H)，6.46(d，J＝8.0Hz，1H)，5.85-5.81(m，1H)，4.79(s，2H)，3.30(s，3H)，3.04(s，3H)，2.85(s，3H)，2.29(s，3H)，1.63(d，J＝8.0Hz，3H)；ESI-MS(m/z)：539.0[M+H] ⁺ 。

example 44

Preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- (2-hydroxyethyl) quinazolin-6-yl) (methyl) amino)) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate salt

Step a): preparation of ethyl 2- (6-bromo-4-oxo-3, 4-dihydro-quinazolin-2-yl) acetate

Methyl 2-amino-5-bromobenzoate (5.0 g,0.022 mol), ethyl cyanoacetate (2.7 g,0.024 mol) and a solution of hydrogen chloride in dioxane (4M, 50 mL) were charged into a constant volume reactor and reacted at 100℃for 16 hours. After the reaction is finished, cooling to room temperature, concentrating under reduced pressure, adding water (100 mL) and saturated sodium bicarbonate aqueous solution (20 mL) into the residue to adjust the pH to be neutral, stirring for 5min at room temperature, filtering, adding petroleum ether/ethyl acetate mixed solvent (100 mL, v/v=10:1) into the filter cake, stirring for 10min at room temperature, filtering, and drying the filter cake under reduced pressure to obtain ethyl 2- (6-bromo-4-oxo-3, 4-dihydro-quinazolin-2-yl) acetate, wherein the yield is 59.2%; ESI-MS (m/z): 311.0[ M+H ]] ⁺ 。

Step b): preparation of ethyl (R) -2- (6-bromo-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinazolin-2-yl) acetate

Ethyl 2- (6-bromo-4-oxo-3, 4-dihydroquinazolin-2-yl) acetate (1.6 g,5.142 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine hydrochloride (1.3 g,5.761 mmol), BOP (2.8 g,6.331 mmol), DBU (2.0 g,13.137 mmol) and DMF (16 mL) were added to a reaction flask and reacted at room temperature for 1h. Ethyl acetate (80 mL) and saturated sodium chloride solution (60 mL) were added to the reaction solution, the solution was separated, the aqueous phase was extracted with ethyl acetate (50 ml×2), the organic phases were combined, washed with saturated brine (50 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/5) to give ethyl (R) -2- (6-bromo-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinazolin-2-yl) acetate, yield 43.9%; ESI-MS (m/z): 482.1[ M+H ] ] ⁺ 。

Step c): preparation of ethyl (R) -2- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- ((5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyridin-3-yl) (meth) amino) quinazolin-2-yl) acetate

(R) -ethyl 2- (6-bromo-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinazolin-2-yl) acetate (200.0 mg, 0.015 mmol), 2- (2-methoxy-5- (methylamino) pyridin-3-yl) -N, N-dimethylacetamide (93.5 mg, 0.319 mmol), X-Phos (79.0 mg,0.166 mmol), cs ₂ CO ₃ (270.3 mg,0.830 mmol), pd (dba) 2 (47.1 mg,0.083 mmol) and toluene (4 mL) were added sequentially to the reaction flask, and the reaction was stirred at 95℃for 2h with nitrogen substitution three times. The reaction solution was cooled to room temperature, filtered, the filter cake was rinsed with ethyl acetate (10 mL), the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20) to give ethyl (R) -2- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- ((5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyridin-3-yl) (methyl) amino) quinazolin-2-yl) acetate in 87.3% yield; ESI-MS (m/z): 625.3[ M+H ]] ⁺ 。

Step d): preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- (2-hydroxyethyl) quinazolin-6-yl) (methyl) amino)) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate salt

(R) -ethyl 2- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- ((5- (2- (dimethylamino) -2-oxyethyl) -6-methoxypyridin-3-yl) (methyl) amino) quinazolin-2-yl) acetate (226.0 mg,0.362 mmol), sodium borohydride (18.1 mg, 0.178 mmol), boron trifluoride diethyl etherate (56.2 mg, 0.3996 mmol) and THF (4 mL) were sequentially added to the reaction flask, and the mixture was replaced with nitrogen three times and reacted at room temperature with stirring for 2 hours. Ethyl acetate (20 mL) and saturated sodium bicarbonate (20 mL) were added to the reaction solution, the solution was separated, the organic phase was washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20), the crude product obtained was further purified by Prep-HPLC (method 2) to give (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- (2-hydroxyethyl) quinazolin-6-yl) (methyl) amino)) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate, yield 4.7%; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.68(s，1H)，8.25(d，J＝6.8Hz，1H)，8.14(s，1H)，7.93-7.92(s，1H)，7.75(s，1H)，7.67(t，J＝7.2Hz，1H)，7.53-7.46(m，2H)，7.42(d，J＝9.2Hz，1H)，7.29(t，J＝7.6Hz，1H)，7.37-7.10(m，1H)，7.14(d，J＝9.2Hz，1H)，5.79(s，1H)，4.44(s，1H)，3.90(s，3H)，3.74-3.61(m，2H)，3.38(s，2H)，2.89(s，3H)，2.75-2.69(m，2H)，2.55(s，6H)，1.63(d，J＝7.2Hz，3H)；ESI-MS(m/z)：583.0[M+H] ⁺ 。

example 45

Preparation of (R) -2- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- ((5- (2- (dimethylamino) ethyl) -6-methoxypyridin-3-yl) (methyl) amino) quinazolin-2-yl) ethyl-1-ol

(R) -ethyl 2- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- ((5- (2- (dimethylamino) -2-oxyethyl) -6-methoxypyridin-3-yl) (methyl) amino) quinazolin-2-yl) acetate (958.0 mg, 1.284 mmol), sodium borohydride (580.3 mg,15.340 mmol), boron trifluoride diethyl etherate (2.2 g,15.501 mmol) and THF (20 mL) were sequentially added to the reaction flask, nitrogen was replaced three times, and the reaction was stirred at 0deg.C for 1h. After the reaction was completed, ethyl acetate (50 mL) and saturated sodium bicarbonate (50 mL) were added, the solution was separated, the organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20), and the crude product was purified by Prep-HPLC (method 3) to give (R) -2- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- ((5- (2- (dimethylamino) ethyl) -6-methoxypyridin-3-yl) (methyl) amino) quinazolin-2-yl) ethyl-1-ol in a yield of 6.3%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.24(d，J＝6.8Hz，1H)，7.89(s，1H)，7.72(s，1H)，7.67(t，J＝7.2Hz，1H)，7.49(t，J＝6.8Hz，1H)，7.45(s，1H)，7.40(d，J＝9.2Hz，1H)，7.28(t，J＝7.6Hz，1H)，7.37-7.10(m，1H)，7.13(d，J＝9.2Hz，1H)，5.79(s，1H)，4.44(m，1H)，3.88(s，3H)，3.75-3.59(m，2H)，3.38(s，3H)，2.76-2.62(m，4H)，2.44-2.39(m，2H)，2.14(s，6H)，1.63(d，J＝7.2Hz，3H)；ESI-MS(m/z)：569.0[M+H] ⁺ 。

example 46

(R)-N ⁴ - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -N ⁶ - (5- (2- (dimethylamino) ethyl) -6-methoxypyridin-3-yl) -2-ethyl-N ⁶ Preparation of methyl quinazoline-4, 6-dicarbamate

(R) -ethyl 2- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- ((5- (2- (dimethylamino) -2-oxyethyl) -6-methoxypyridin-3-yl) (methyl) amino) quinazolin-2-yl) acetate (958 mg, 1.284 mmol), sodium borohydride (580 mg,15.340 mmol), boron trifluoride diethyl etherate (2.2 g,15.501 mmol) and THF (20 mL) were sequentially added to the reaction flask, nitrogen was replaced three times, and the reaction was stirred at 0℃for 1h. After the reaction, ethyl acetate (50 mL) and saturated sodium bicarbonate (50 mL) are added and stirred for dilution, the solution is separated, the organic phase is washed by saturated sodium chloride aqueous solution (50 mL), dried by anhydrous sodium sulfate, filtered, the filtrate is concentrated to dryness under reduced pressure, the residue is purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20), and the crude product is purified by Prep-HPLC (method 2) to obtain (R) -N ⁴ - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -N ⁶ - (5- (2- (dimethylamino) ethyl) -6-methoxypyridin-3-yl) -2-ethyl-N ⁶ -methyl quinazoline-4, 6-dicarbamate in 2.0% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.76(s，1H)，8.23(d，J＝6.8Hz，1H)，8.15(s，1H)，7.89(s，1H)，7.73(s，1H)，7.66(t，J＝7.2Hz，1H)，7.51-7.44(m，2H)，7.40(d，J＝9.2Hz，1H)，7.27(t，J＝7.6Hz，1H)，7.36-7.09(m，1H)，7.11(d，J＝9.2Hz，1H)，5.78(s，1H)，3.88(s，3H)，3.38(s，3H)，2.76-2.63(m，2H)，2.61-2.52(m，4H)，2.20(s，6H)，1.63(d，J＝7.2Hz，3H)，1.05(t，J＝7.6Hz，3H)；ESI-MS(m/z)：553.3[M+H] ⁺ 。

example 47

Preparation of (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) oxy) -2-methoxyphenyl) -N, N-dimethylacetamide

Step a): preparation of 2- (5-bromo-2-methoxyphenyl) -N, N-dimethylacetamide

2- (5-bromo-2-methoxyphenyl) acetic acid (2.70 g,11.017 mmol) and methylene chloride (50 mL) were added to the reaction flask, and dimethylamine hydrochloride (1.17 g,14.322 mmol), DIPEA (4.27 g,33.051 mmol) and HATU (6.28 g,16.526 mmol) were slowly added in this order at room temperature and the reaction was maintained at room temperature with stirring for 2h. After the completion of the reaction, the reaction was quenched with water (50 mL), extracted with methylene chloride (50 mL. Times.3), and the organic phases were combined, washed with a saturated aqueous sodium hydrogencarbonate solution (50 mL) and a saturated brine (50 mL) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give 2- (5-bromo-2-methoxyphenyl) -N, N-dimethylacetamide in a yield of 98.7%. Directly used in the next reaction without further purification; ESI-MS (m/z) =272.1 [ M+H ] ] ⁺ 。

Step b): preparation of 2- (2-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaboren-2-yl) phenyl) -N, N-dimethylacetamide

2- (5-bromo-2-methoxyphenyl) -N, N-dimethylacetamide (2.96 g, 9.2793 mmol), potassium acetate (2.73 g,27.819 mmol), pinacol biborate (3.53 g,13.910 mmol) and 1, 4-dioxane (45 mL) were added to the reaction flask, and finally Pd (dppf) Cl was added ₂ (399 mg, 0.460 mmol) was replaced with nitrogen three times, and the reaction was stirred at 80℃for 6 hours. After the reaction, the reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined and saturatedBrine (30 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated to dryness under reduced pressure, and the residue purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/3) to give 2- (2-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -N, N-dimethylacetamide in 89.3% yield; ESI-MS (m/z) =320.3 [ M+H ]] ⁺ 。

Step c): preparation of 2- (5-hydroxy-2-methoxyphenyl) -N, N-dimethylacetamide

2- (2-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -N, N-dimethylacetamide (3.10 g,9.71 mmol) and tetrahydrofuran (90 mL) were added to a reaction flask, and hydrogen peroxide (2.00 g,19.423mmol, 33%) was added dropwise with stirring at 0 ℃. After the completion of the dropwise addition, the reaction was stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by a silica gel column (eluent: petroleum ether/ethyl acetate=1/1) to give 2- (5-hydroxy-2-methoxyphenyl) -N, N-dimethylacetamide in a yield of 54.1%; ESI-MS (m/z): 210.2[ M+H ] ] ⁺ 。

Step d): preparation of methyl 5- (3- (2- (dimethylamino) -2-oxoethyl) -4-methoxyphenoxy) -2-nitrobenzoate

2- (5-hydroxy-2-methoxyphenyl) -N, N-dimethylacetamide (900 mg,4.301 mmol), methyl 5-fluoro-2-nitrobenzoate (867 mg,4.301 mmol), potassium carbonate (1.19 g,8.602 mmol) and DMF (18 mL) were added to the reaction flask and the reaction was stirred at room temperature for 2h. After the completion of the reaction, the reaction was quenched with water (20 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the residue was purified by silica gel column (eluent: petroleum ether/ethyl acetate=1/1) to give methyl 5- (3- (2- (dimethylamino) -2-oxoethyl) -4-methoxyphenoxy) -2-nitrobenzoate in 95.8% yield; ESI-MS (m/z): 389.0[ M+H ]] ⁺ 。

Step e): preparation of methyl 2-amino-5- (3- (2- (dimethylamino) -2-oxoethyl) -4-methoxyphenoxy) benzoate

Methanol (32 mL), 5- (3- (2- (dimethylamino) -2-oxoethyl) -4-methoxyphenoxy)) Methyl-2-nitrobenzoate (1.60 g,4.120 mmol) and palladium on carbon (160 mg, 5%) were added sequentially to the reaction flask, replaced with hydrogen 3 times, and stirred at room temperature for 2h under a hydrogen atmosphere. After the reaction is finished, filtering, concentrating the filtrate under reduced pressure to obtain 2-amino-5- (3- (2- (dimethylamino) -2-oxyethyl) -4-methoxyphenoxy) methyl benzoate, which is directly used for the next reaction without further purification; ESI-MS (m/z): 359.2[ M+H ] ] ⁺ 。

Step f): preparation of 2- (5- ((4-hydroxy-2-methylquinazolin-6-yl) oxy) -2-methoxyphenyl) -N, N-dimethylacetamide

Methyl 2-amino-5- (3- (2- (dimethylamino) -2-oxoethyl) -4-methoxyphenoxy) benzoate (1.1 g,3.069 mmol), acetonitrile (22 mL) and 4M dioxane hydrochloride solution (22 mL) were added to a constant volume reaction flask and the reaction stirred at 110℃for 16h. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure, the residue was slurried with 4N aqueous ammonia (30 mL) at room temperature for 1h, filtered, and the solid was dissolved in DMF (10 mL) and purified by C18 column (eluent: water/acetonitrile=3/2) to give 2- (5- ((4-hydroxy-2-methylquinazolin-6-yl) oxy) -2-methoxyphenyl) -N, N-dimethylacetamide in 17.7% yield; ESI-MS (m/z): 368.2[ M+H ]] ⁺ 。

Step g): preparation of (R) -2- (2-methoxy-5- ((2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) oxy) phenyl) -N, N-dimethylacetamide

2- (5- ((4-hydroxy-2-methylquinazolin-6-yl) oxy) -2-methoxyphenyl) -N, N-dimethylacetamide (200 mg,0.544 mmol) and DMF (5 mL) were added to the reaction flask, and (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethan-1-amine hydrochloride (177 mg,0.653 mmol), DBU (248 mg,1.632 mmol) and BOP (481mg, 1.088 mmol) were added slowly in sequence at room temperature and the reaction stirred at room temperature for 16h. After the completion of the reaction, the reaction was quenched with water (10 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=15/1) to give (R) -2- (2-methoxy-5- ((2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) oxy) Phenyl) -N, N-dimethylacetamide in a yield of 47.2%; ESI-MS (m/z): 584.2[ M+H ]] ⁺ 。

Step h): preparation of (R) -2- (2-methoxy-5- ((2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) oxy) phenyl) -N, N-dimethylacetamide

Ethanol (2 mL), water (2 mL), and (R) -2- (2-methoxy-5- ((2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) oxy) phenyl) -N, N-dimethylacetamide (150 mg,0.257 mmol), iron powder (58 mg,1.028 mmol), anhydrous ammonium chloride (55 mg,1.028 mmol) were added sequentially to a reaction flask, and the reaction was stirred for 2h at 80 ℃. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, the solid was rinsed with ethyl acetate (5 ml×3), the filtrate was separated, the aqueous phase was extracted with ethyl acetate (5 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by Prep-HPLC (method 3) to give (R) -2- (2-methoxy-5- ((2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) oxy) phenyl) -N, N-dimethylacetamide in 24.2% yield; 1H NMR (400 mhz, dmso-d 6) delta 8.28 (d, j=8.0 hz, 1H), 8.20 (s, 1H), 7.64 (d, j=9.2 hz, 1H), 7.44 (d, j=8.8 hz, 1H), 7.05 (d, j=8.4 hz, 1H), 6.89 (s, 1H), 6.85 (s, 1H), 6.72 (s, 1H), 6.69 (s, 1H), 6.45 (d, j=8.0 hz, 1H), 5.57-5.49 (m, 3H), 3.72 (s, 3H), 3.54 (s, 2H), 3.01 (s, 3H), 2.83 (s, 3H), 2.40 (s, 3H), 1.52 (d, j=7.2 hz, 3H); ESI-MS (m/z): 554.0[ M+H ] ] ⁺ 。

Example 48

Preparation of (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) oxy) -2-hydroxyphenyl) -N, N-dimethylacetamide

(R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl)) ethyl)Group) amino) -2-methylquinazolin-6-yl) oxy) -2-methoxyphenyl) -N, N-dimethylacetamide (50 mg,0.093 mmol) and dichloromethane (2 mL) were added to the reaction flask, and boron tribromide (232 mg,0.927 mmol) was slowly added dropwise under ice water bath. After the completion of the dropwise addition, the reaction was stirred at room temperature for 1 hour. After the reaction, methanol (5 mL) is added for quenching reaction, the reaction solution is concentrated to dryness under reduced pressure, and the obtained crude product is purified by Pre-HPLC (method 3) to obtain (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl quinazoline-6-yl) oxy) -2-hydroxyphenyl) -N, N-dimethylacetamide with the yield of 59.5 percent; 1H NMR (400 MHz, DMSO-d 6) δ9.70 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.64 (d, J=9.2 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 6.89 (s, 1H), 8.17 (s, 1H), 6.84 (s, 1H), 6.69 (s, 1H), 6.42-6.39 (m, 2H), 5.54-5.51 (m, 3H), 3.52 (s, 2H), 3.02 (s, 3H), 2.83 (s, 3H), 2.41 (s, 3H), 1.52 (d, J=7.2 Hz, 3H); ESI-MS (m/z): 540.0[ M+H ] ] ⁺ 。

Example 49

Preparation of (R) -1- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -3-methylimidazolidin-2-one

Step a): preparation of 1- (2-methoxy-5-nitropyridin-3-yl) imidazolidin-2-one

Toluene (20 mL), 3-bromo-2-methoxy-5-nitropyridine (1.00 g,4.29 mmol), imidazolidin-2-one (447 mg,5.150 mmol), X-Phos (205 mg,0.429 mmol), cs ₂ CO ₃ (4.20 g,12.874 mmol) and Pd (dba) ₂ (123 mg,0.215 mmol) was added sequentially to the reaction flask, nitrogen was replaced three times, and the reaction was stirred at 110℃for 3 hours. After completion of the reaction, the reaction mixture was quenched with water (30 mL), extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was taken upPurifying by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/7) to obtain 1- (2-methoxy-5-nitropyridin-3-yl) imidazolidin-2-one with a yield of 78.3%; ESI-MS (m/z) =239.1 [ M+H ]] ⁺ 。

Step b): preparation of 1- (2-methoxy-5-nitropyridin-3-yl) -3-methylimidazolidin-2-one

1- (2-methoxy-5-nitropyridin-3-yl) imidazolidin-2-one (800 mg, 3.399 mmol), naH (403 mg,10.076mmol, 60%) and THF (16 mL) were added to the reaction flask, stirred for 20min under ice bath conditions, methyl iodide (142 mg,1.000 mmol) was added while maintaining an ice-water bath, and the mixture was slowly warmed to room temperature and stirred for 2h. After the reaction was completed, water (30 mL) was added to quench, extraction was performed with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine (20 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained crude product was directly used for the next reaction; ESI-MS (m/z): 252.1[ M+H ] ] ⁺ 。

Step c): preparation of 1- (5-amino-2-methoxypyridin-3-yl) -3-methylimidazolidin-2-one

Ethanol (8 mL), water (8 mL), 1- (5-amino-2-methoxypyridin-3-yl) -3-methylimidazolidin-2-one (800 mg,3.172 mmol), iron powder (710 mg,12.687 mmol), and anhydrous ammonium chloride (679 mg,12.687 mmol) were sequentially added to the reaction flask, and the reaction was stirred at 80℃for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, the solid was rinsed with ethyl acetate (10 ml×3), the filtrate was separated, the aqueous phase was extracted with ethyl acetate (10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, and the obtained product was used for the next reaction without further purification; ESI-MS (m/z): 223.1[ M+H ]] ⁺ 。

Step d): preparation of (6-methoxy-5- (3-methyl-2-oxoimidazolin-1-yl) pyridin-3-yl) carbamic acid tert-butyl ester

1- (5-amino-2-methoxypyridin-3-yl) -3-methylimidazolidin-2-one (500 mg,2.250 mmol), DIPEA (871 mg,6.749 mmol) and methylene chloride (10 mL) were successively added to a reaction flask, dissolved by stirring, and Boc was further added dropwise ₂ O (729 mg,3.375 mmol) was stirred at room temperature for 4h. After the reaction, concentrating under reduced pressure to dryPurifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to give tert-butyl (6-methoxy-5- (3-methyl-2-oxoimidazolin-1-yl) pyridin-3-yl) carbamate in 24.8% yield; ESI-MS (m/z): 323.2[ M+H ] ] ⁺ 。

Step e): preparation of tert-butyl (6-methoxy-5- (3-methyl-2-oxoimidazolin-1-yl) pyridin-3-yl) (meth) carbamate

Tert-butyl (6-methoxy-5- (3-methyl-2-oxoimidazolin-1-yl) pyridin-3-yl) carbamate (180 mg, 0.578 mmol), naH (67 mg,1.675mmol,60%) and tetrahydrofuran (5 mL) were added to the reaction flask, stirred for 20min under ice bath conditions, methyl iodide (119 mg,0.838 mmol) was added while maintaining an ice-water bath, and the mixture was slowly warmed to room temperature and stirred for 2h. After the completion of the reaction, the reaction was quenched with water (10 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to give tert-butyl (6-methoxy-5- (3-methyl-2-oxoimidazol-1-yl) pyridin-3-yl) (methyl) carbamate in 79.7% yield; ESI-MS (m/z): 337.2[ M+H ]] ⁺ 。

Step f): preparation of 1- (2-methoxy-5- (methylamino) pyridin-3-yl) -3-methylimidazolidin-2-one hydrochloride salt

Tert-butyl (6-methoxy-5- (3-methyl-2-oxoimidazolin-1-yl) pyridin-3-yl) (methyl) carbamate (150 mg, 0.4476 mmol) and ethyl hydrogen chloride solution (4 ml,4 m) were added to the reaction flask and reacted at room temperature with stirring for 1h. After the reaction is finished, the reaction solution is decompressed and concentrated to dryness to obtain 1- (2-methoxy-5- (methylamino) pyridin-3-yl) -3-methylimidazolidin-2-one hydrochloride with the yield of 98.8%; ESI-MS (m/z): 237.1[ M+H ] ] ⁺ 。

Step g): preparation of (R) -1- (2-methoxy-5- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -3-methylimidazolidin-2-one

Toluene (5 mL), 1- (2-methoxy-5- (methylamino) pyridin-3-yl) -3-methylimidazolidin-2-one hydrochloride(157 mg, 0.640 mmol), (R) -6-bromo-2-methyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine (292 mg, 0.640 mmol), X-Phos (61 mg,0.128 mmol), cs ₂ CO ₃ (627 mg,1.923 mmol) and Pd (dba) 2 (37 mg,0.064 mmol) were sequentially added to the reaction flask, and the reaction was stirred for 3 hours after the temperature was raised to 90℃by nitrogen substitution three times. After the completion of the reaction, the reaction was quenched with water (10 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give (R) -1- (2-methoxy-5- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -3-methylimidazolidin-2-one in 66.1% yield; ESI-MS (m/z): 611.2[ M+H ]] ⁺ 。

Step h): preparation of (R) -1- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -3-methylimidazolidin-2-one

Ethanol (2 mL), water (2 mL), tert-butyl (3- (2- (dimethylamino) -2-oxoethyl) -2-methoxyphenyl) carbamate (180 mg,0.295 mmol), iron powder (66 mg,1.180 mmol), and anhydrous ammonium chloride (63 mg,1.180 mmol) were added sequentially to the reaction flask, and the reaction was stirred at 80℃for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, the solid was rinsed with ethyl acetate (5 ml×3), the filtrate was separated, the aqueous phase was extracted with ethyl acetate (5 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and the resulting crude product was purified by Prep-HPLC (method 3) to give (R) -1- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -3-methylimidazolidin-2-one in 28.3% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.11(d，J＝8.0Hz，1H)，7.88(s，1H)，7.74(s，1H)，7.55(s，1H)，7.42(d，J＝9.2Hz，1H)，7.20(d，J＝8.0Hz，1H)，6.90(s，1H)，6.87(s，1H)，6.70(s，1H)，5.62-5.56(m，1H)，5.53(brs，2H)，3.89(s，3H)，3.75-3.71(m，2H)，3.42-3.38(m，2H)，3.37(s，3H)，2.70(s，3H)，2.36(s，3H)，1.56(d，J＝6.8Hz，3H)；ESI-MS(m/z)：581.0[M+H] ⁺ 。

example 50

Preparation of (R) -1- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -3-methylimidazolidin-2-one

Preparation method referring to example 48, (R) -1- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl quinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -3-methylimidazolidin-2-one is obtained in 61.6% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.83(brs，1H)，8.20(brs，1H)，7.54(s，1H)，7.47(s，1H)，8.41(d，J＝9.2Hz，1H)，7.23(s，1H)，7.15(d，J＝9.2Hz，1H)，6.90(s，1H)，6.86(s，1H)，6.70(s，1H)，5.62-5.58(m，1H)，5.54(s，2H)，3.91-3.85(m，2H)，3.37-3.35(m，2H)，3.27(s，3H)，2.69(s，3H)，2.37(s，3H)，1.57(d，J＝5.2Hz，3H)；ESI-MS(m/z)：567.0[M+H] ⁺ 。

Example 51

Preparation of (R) -2- (5- ((4- ((1- (6- (difluoromethyl) pyridin-3-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

Preparation method referring to example 32, (R) -2- (5- ((4- ((1- (6- (difluoromethyl) pyridin-3-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide was obtained in 43.0% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.79(s，1H)，8.18(d，J＝8.0Hz，1H)，8.04(d，J＝8.0Hz，1H)，7.67(d，J＝8.0Hz，1H)，7.60(s，1H)，7.35(d，J＝9.2Hz，1H)，7.09-7.03(m，2H)，6.98(d，J＝8.8Hz，1H)，6.92(t，J＝56.0Hz，1H)，6.91(s，1H)，5.71-5.61(m，1H)，3.77(s，3H)，3.57(s，2H)，3.34(s，3H)，2.99(s，3H)，2.78(s，3H)，2.33(s，3H)，1.66(d，J＝7.2Hz，3H)；ESI-MS(m/z)：535.4[M+H] ⁺ 。

example 52

Preparation of (R) -2- (5- ((4- ((1- (6- (difluoromethyl) pyridin-2-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

Preparation method referring to example 32, (R) -2- (5- ((4- ((1- (6- (difluoromethyl) pyridin-2-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide was obtained in 33.3% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.22(d，J＝7.6Hz，1H)，7.94(t，J＝8.0Hz，1H)，7.64-7.61(m，2H)，7.56(d，J＝7.6Hz，1H)，7.36(d，J＝9.2Hz，1H)，7.10-7.04(m，2H)，6.99(d，J＝8.8Hz，1H)，6.92(s，1H)，6.82(d，J＝52.0Hz，1H)，5.72-5.64(m，1H)，3.77(s，3H)，3.57(s，2H)，3.34(s，3H)，2.99(s，3H)，2.78(s，3H)，2.30(s，3H)，1.65(d，J＝7.2Hz，3H)；ESI-MS(m/z)：535.0[M+H] ⁺ 。

example 53

Preparation of (R) -2- (5- ((4- ((1- (6- (difluoromethyl) pyridin-2-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide

Preparation method referring to example 35, purification by Pre-HPLC (method 3) gives (R) -2- (5- ((4- ((1- (6- (difluoromethyl) pyridin-2-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide in 14.0% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.25(d，J＝8.0Hz，1H)，7.96-7.92(m，2H)，7.72(s，1H)，7.62(d，J＝8.0Hz，1H)，7.56(d，J＝8.0Hz，1H)，7.40(d，J＝12.0Hz，1H)，7.36(s，1H)，7.12(d，J＝8.0Hz，1H)，6.95(t，J＝56.0Hz，1H)，5.71-5.64(m，1H)，3.85(s，3H)，3.59(s，2H)，3.36(s，3H)，3.02(s，3H)，2.80(s，3H)，2.31(s，3H)，1.65(d，J＝8.0Hz，3H)；ESI-MS(m/z)：536.3[M+H] ⁺ 。

Example 54

Preparation of (R) -2- (5- ((4- ((1- (6- (difluoromethyl) pyridin-2-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -NN-dimethylacetamide

Preparation method referring to example 38, (R) -2- (5- ((4- ((1- (6- (difluoromethyl) pyridin-2-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide was obtained in a yield of 84.0%; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.60(s，1H)，8.21(d，J＝8.0Hz，1H)，7.94(t，J＝8.0Hz，1H)，7.61(d，J＝8.0Hz，1H)，7.57-7.54(m，2H)，7.40(d，J＝12.0Hz，1H)，7.26(s，1H)，7.19(s，1H)，7.09(d，J＝8.0Hz，1H)，6.95(t，J＝52.0Hz，1H)，5.72-5.65(m，1H)，3.42(s，2H)，3.27(s，3H)，3.01(s，3H)，2.78(s，3H)，2.30(s，3H)，1.65(d，J＝8.0Hz，3H)；ESI-MS(m/z)：522.0[M+H] ⁺ 。

example 55

Preparation of (R) -2- (5- ((4- ((1- (5- (difluoromethyl) pyridin-2-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide

Preparation method referring to example 35, purification by Pre-HPLC (method 3) gives (R) -2- (5- ((4- ((1- (5- (difluoromethyl) pyridin-2-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide in 15.0% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.79(s，1H)，8.21(d，J＝8.0Hz，1H)，8.04(d，J＝8.0Hz，1H)，7.94(s，1H)，7.68-7.66(m，2H)，7.40(d，J＝8.0Hz，1H)，7.35(s，1H)，7.10(d，J＝8.0Hz，1H)，6.92(t，J＝56.0Hz，1H)，5.71-5.65(m，1H)，3.84(s，3H)，3.59(s，2H)，3.36(s，3H)，3.02(s，3H)，2.80(s，3H)，2.34(s，3H)，1.66(d，J＝8.0Hz，3H)；ESI-MS(m/z)：536.0[M+H] ⁺ 。

example 56

Preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d ] pyrimidin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

Step a): preparation of 6-chloro-2-methylpyrido [3,4-d ] pyrimidin-4 (3H) -one

Methyl 3-amino-6-chloropicolinate (1.00 g, 5.399 mmol), hydrogen chloride dioxane solution (4M, 2.5 mL) and acetonitrile (2.5 mL) were added to the autoclave, and the temperature was raised to 100℃and the reaction was stirred for 16h. After the reaction is finished, cooling to room temperature, concentrating the reaction solution under reduced pressure, diluting the residue with water (30 mL), dropwise adding ammonia water under stirring to adjust the pH to be neutral, continuously stirring for 1h, filtering, washing the filter cake with water (30 mL), collecting the filter cake, and drying under reduced pressure to obtain 6-chloro-2-methylPyrido [3,4-d ] radicals]Pyrimidin-4 (3H) -one in 85.7% yield; ESI-MS (m/z): 196.0[ M+H ]] ⁺ 。

Step b): preparation of 4, 6-dichloro-2-methylpyrido [3,4-d ] pyrimidine

By reacting 6-chloro-2-methylpyrido [3,4-d ]]Pyrimidin-4 (3H) -one (350 mg,1.795 mmol) was added to 1, 2-dichloroethane (20 mL), and DIPEA (1.6 g,12.403 mmol) and POCl were added with stirring ₃ (1.6 g, 10.458 mmol) was reacted overnight at 90℃under nitrogen protection, after the reaction was completed, cooled to room temperature, the solvent was distilled off under reduced pressure, the residue was dissolved in methylene chloride (100 mL), the mixture was poured into a mixture of ice cubes and sodium hydrogencarbonate, quenched, separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 4, 6-dichloro-2-methylpyrido [3,4-d ] ]Pyrimidine was used directly in the next reaction without further purification; ESI-MS (m/z): 214.0[ M+H ]] ⁺ 。

Step c): preparation of (R) -6-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [3,4-d ] pyrimidin-4-amine

4, 6-dichloro-2-methylpyrido [3,4-d ]]Pyrimidine (385 mg,1.799 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl-1-amine hydrochloride (405 mg,1.800 mmol), DIPEA (697 mg, 5.399mmol) and DMSO (8 mL) were added sequentially to the reaction flask, and the temperature was raised to 80℃under nitrogen and the reaction was stirred for 1h. After the completion of the reaction, a saturated ammonium chloride solution (30 mL) was added to dilute, and extracted with ethyl acetate (50 mL. Times.2), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 to 5/1) to give (R) -6-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [3, 4-d)]Pyrimidin-4-amine in 48.9% yield; ¹ H NMR(400MHz，CDCl ₃ )δ8.98(s，1H)，7.61(s，1H)，7.56-7.51(m，2H)，7.23(t，J＝8.0Hz，1H)，7.39(s，1H)，6.92(t，J＝56.0Hz，1H)，6.11(s，1H)，5.83-5.76(m，1H)，2.59(s，3H)，1.73(d，J＝8.0Hz，3H)；ESI-MS(m/z)：367.1[M+H] ⁺ 。

step d): preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3,4-d ] pyrimidin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

(R) -6-chloro-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [3,4-d]Pyrimidin-4-amine (100 mg, 0.279 mmol), 2- (2-methoxy-5- (methylamino) phenyl) -N, N-dimethylacetamide, (80 mg,0.310 mmol), cs ₂ CO ₃ (245mg，0.754mmol)、Pd(dba) ₂ (30 mg,0.052 mmol), X-phos (50 mg,0.105 mmol) and toluene (6 mL) were sequentially added to the reaction flask, nitrogen was replaced three times, and the temperature was raised to 105℃and the reaction was stirred for 3 hours. After the completion of the reaction, the reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting crude product was purified by Pre-HPLC (method 3) to give (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [3, 4-d)]Pyrimidin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide in 77.0% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.60(s，1H)，8.38(s，1H)，7.64(t，J＝8.0Hz，1H)，7.49(t，J＝8.0Hz，1H)，7.39(s，1H)，7.28(t，J＝8.0Hz，1H)，7.23(t，J＝52.0Hz，1H)，7.16(d，J＝8.0Hz，1H)，7.03-6.99(m，2H)，5.60-5.73(m，1H)，3.79(s，3H)，3.59(s，2H)，3.42(s，3H)，3.01(s，3H)，2.79(s，3H)，2.30(s，3H)，1.59(d，J＝8.0Hz，3H)；ESI-MS(m/z)：553.4[M+H] ⁺ 。

example 57

Preparation of (R) -2- (5- (4- (1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethylamino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide formate salt

Step a): preparation of ethyl 2- (3-bromo-2-fluorophenyl) -2, 2-difluoroacetate

1-bromo-2-fluoro-3-iodobenzene (7.5 g,24.926 mmol), ethyl 2-bromo-2, 2-difluoroacetate (15.15 g,74.780 mmol) and THF (100 mL) were added to the reaction flask, dissolved with stirring, replaced with nitrogen 3 times, copper powder (4.77 g,74.780 mmol) was added, and the mixture was heated to 80℃to react overnight. After the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL), slowly dropped with water (400 mL) under ice bath to conduct extraction, filtered, the filtrate was extracted with ethyl acetate (200 ml×2), the organic phases were combined, washed with saturated brine (100 ml×2), dried over anhydrous sodium sulfate, filtered under reduced pressure, the organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=100/1) to give ethyl 2- (3-bromo-2-fluorophenyl) -2, 2-difluoroacetate in a yield of 87.3%.

Step b): preparation of ethyl 2- (3-acetyl-2-fluorophenyl) -2, 2-difluoroacetate

Ethyl 2- (3-bromo-2-fluorophenyl) -2, 2-difluoroacetate (6.46 g,21.746 mmol), tributyl (1-ethoxyvinyl) stannane (10.207 g,28.276 mmol), pd (PPh) ₃ )Cl ₂ (763 mg,1.087 mmol), triethylamine (4.39 g,43.492 mmol), 1, 4-dioxane (100 mL) were added to the reaction flask, nitrogen was replaced 3 times, and the temperature was raised to 100℃to react overnight. After the completion of the reaction, the reaction solution was cooled to room temperature, 2N diluted hydrochloric acid was added to adjust to ph=2-3, stirring was carried out at room temperature for 1h, the solvent was removed by concentration, a saturated aqueous sodium hydrogencarbonate solution was added to the mixture to adjust to ph=7-8, extraction was carried out with ethyl acetate (100 ml×3), the organic phases were combined, washed with saturated brine (150 mLl ×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=50/1) to give ethyl 2- (3-acetyl-2-fluorophenyl) -2, 2-difluoroacetate in 44.3% yield.

Step c): preparation of (R) -2- (3- (1- ((tert-butylsulfinyl) imino) ethyl) -2-fluorophenyl) -2, 2-difluoroacetic acid ethyl ester

Ethyl 2- (3-acetyl-2-fluorophenyl) -2, 2-difluoroacetate (2.5 g, 9.015 mmol) and (R) - (+) -tert-butylsulfinamide (2.327 g,19.230 mmol) and THF (50 mL) were added to a reaction flask, dissolved with stirring, and added at room temperature Tetraethyltitanate (10.117 g,28.845mmol, 65%) was added and stirred for 3h at 80 ℃. After the reaction was completed, cooled to room temperature, water (20 mL) was added to precipitate a large amount of solid, the solid was filtered, the filter cake was washed with ethyl acetate (50 mL), the filtrate was extracted with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine (50 ml×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give (R) -2- (3- (1- ((tert-butylsulfinyl) imino) ethyl) -2-fluorophenyl) -2, 2-difluoroethyl acetate in 67.5% yield; ESI-MS (m/z): 364.4[ M+H ]] ⁺ 。

Step d): preparation of (R) -2- (3- (1- ((tert-butylsulfinyl) imino) ethyl) -2-fluorophenyl) -2, 2-difluoroacetic acid ethyl ester

Ethyl (R) -2- (3- (1- ((tert-butylsulfinyl) imino) ethyl) -2-fluorophenyl) -2, 2-difluoroacetate (2.35 g,6.474 mmol) and THF (15 mL) were added to the reaction flask, dissolved with stirring, and a solution of DIBAL-H (19.422 mL,19.422 mmol) in THF (1.0M) was slowly added with stirring at-78deg.C and the reaction was maintained at-78deg.C for 1H. After the reaction, naturally heating to room temperature, adding saturated saline (100 mL) to quench the reaction, precipitating a large amount of solid, filtering, washing a filter cake with ethyl acetate (50 mL), extracting the filtrate with ethyl acetate (50 mL multiplied by 3), combining organic phases, washing with saturated saline (50 mL multiplied by 1), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1), and obtaining (R) -2- (3- (1- ((tert-butylsulfinyl) imino) ethyl) -2-fluorophenyl) -2, 2-difluoroethyl acetate with the yield of 71.8%; ESI-MS (m/z): 366.4[ M+H ] ] ⁺ 。

Step e): preparation of (R) -2- (3- (1-aminoethyl) -2-fluorophenyl) -2, 2-difluoroacetic acid ethyl ester hydrochloride

Ethyl (R) -2- (3- (1- ((tert-butylsulfinyl) imino) ethyl) -2-fluorophenyl) -2, 2-difluoroacetate (1.7 g,4.652 mmol) and THF (10 mL) were added to a reaction flask, stirred and dissolved, and 1,4 dioxane solution (20 mL, 4M) of hydrogen chloride was slowly added under stirring at 0℃and the addition was naturally warmed to room temperature to react for 1h. After the reaction is finished, the pressure is reduced and concentratedThe residue is dissolved by a small amount of ethyl acetate, a large amount of petroleum ether is added in batches under stirring to separate out a large amount of white precipitate, the white precipitate is filtered, a filter cake is washed by a proper amount of petroleum ether, and the mixture is dried in vacuum to obtain (R) -2- (3- (1-amino ethyl) -2-fluorophenyl) -2, 2-difluoro ethyl acetate hydrochloride, and the yield is 86.6%; ESI-MS (m/z): 262.2[ M+H ]] ⁺ 。

Step f): preparation of (R) -2- (3- (1- (6-bromo-2-yl-quinazolin-4-yl) aminoethyl) -2, 2-difluoroacetic acid ethyl ester

6-bromo-4-chloro-2-methylquinazoline (577 mg,2.240 mmol), (R) -2- (3- (1-aminoethyl) -2-fluorophenyl) -2, 2-difluoroacetic acid ethyl ester hydrochloride (800 mg,2.680 mmol) and DIPEA (870 mg,6.720 mmol) and DMSO (10 mL) were added to a reaction flask, the reaction was heated to 80℃and stirred for 1h, after the reaction was completed, the reaction was cooled to room temperature, water (50 mL) was added to quench, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to give (R) -2- (3- (1- (6-bromo-2-yl quinazolin-4-yl) aminoethyl) -2, 2-difluoroacetic acid ethyl ester in 90.0% yield: ESI-MS (m/z): 482.2 M+H ] ⁺ 。

Step g): preparation of ethyl (R) -2- (3- (1- ((6- ((3- (2- (dimethylamino) -2-oxoethyl) -4-methoxyphenyl) (methyl) amino) -2-methylquinazolin-4-yl)) amino) ethyl) -2-fluorophenyl) -2, 2-difluoroacetate

((R) -2- (3- (1- (6-bromo-2-methylquinazolin-4-yl) aminoethyl) -2, 2-difluoroacetic acid ethyl ester (150 mg,0.310 mmol), 2- (2-methoxy-5- (methylamino) phenyl) -N, N-dimethylacetoamide hydrochloride (80 mg,0.310 mmol), cs2CO3 (202 mg,0.620 mmol), X-Phos (30 mg,0.062 mmol), pd (dba) 2 (18 mg, 0.003mmol) and toluene (7 mL) were added to a reaction flask, nitrogen was displaced three times, the reaction was stirred at 90℃for 16h, after completion of the reaction, water (25 mL) was added, the reaction was quenched with ethyl acetate, the (20 mL. Times.3) was extracted, the organic phases were combined, concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to give (R) -2- (3- ((6- ((3- (2- (dimethylamino) -2-oxoethyl) -4-methoxy) (methyl) amino) -2-difluoroethyl) 2-fluoroacetate, yield 59.9%; ESI-MS (m/z): 624.6[ M+H ] +.

Step h): preparation of (R) -2- (5- (4- (1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethylamino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide formate salt

Ethyl (R) -2- (3- (1- ((6- ((3- (2- (dimethylamino) -2-oxoethyl) -4-methoxyphenyl) (methyl) amino) -2-methylquinazolin-4-yl)) amino) ethyl) -2-fluorophenyl) -2, 2-difluoroacetate (100 mg,0.160 mmol) and THF/H2O mixture (5 ml, v/v=50/1) were added to the reaction flask, stirred and dissolved, naBH4 (12.13 mg,0.320 mmol) was slowly added with stirring at-78 ℃ and the reaction was maintained at-78 ℃ for 1H. After the reaction was completed, the temperature was naturally raised to room temperature, saturated brine (10 mL) was added to quench the reaction, the reaction was extracted with ethyl acetate (20 ml×3), the organic phase was then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 2) to give (R) -2- (5- (4- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethylamino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide formate in a yield of 85.7%;1HNMR (400 mhz, dmso-d 6) delta 8.19 (d, j=8.0 hz, 1H), 8.15 (s, 1H), 7.69-7.65 (m, 2H), 7.43-7.40 (m, 1H), 7.35 (d, j=8.0 hz, 1H), 7.26 (t, j=8.0 hz, 1H), 7.10-7.04 (m, 2H), 6.99 (d, j=8.0 hz, 1H), 6.92 (s, 1H), 5.88-5.81 (m, 1H), 5.72 (s, 1H), 3.95 (t, j=12.0 hz, 2H), 3.77 (s, 3H), 3.58 (s, 2H), 3.36 (s, 3H), 3.00 (s, 3H), 2.79 (s, 3H), 2.31 (s, 3H), 1.62 (s, j=8.0 hz, 1H). ESI-MS (m/z): 582.6[ M+H ] ] ⁺ 。

Example 58

Preparation of((R) -2- (5- (4- (4- (1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide formate salt

Step a): preparation of (R) -2- (3- (1- ((6- ((4- ((tert-butyldimethylsilyl) oxy) -3- (2- (dimethylamino) -2-oxoethyl) phenyl) (methyl) amino) -2-methylquinazolin-4-yl) amino) ethyl) -2-fluorophenyl) -2, 2-difluoroethyl acetate

(R) -2- (3- (1- (6-bromo-2-ylquinazolin-4-yl) aminoethyl) -2, 2-difluoroacetic acid ethyl ester (241 mg,0.500 mmol), 2- (2- ((tert-butyldimethylsilyl) oxy) -5- (methylamino) phenyl) -N, N-dimethylacetamide (161 mg,0.500 mmol), cs ₂ CO ₃ (326mg，1.000mmol)、X-Phos(48mg，1.000mmol)、Pd(dba) ₂ (29 mg,0.050 mmol) and toluene (10 mL) were added to the reaction flask, nitrogen was replaced three times, and the temperature was raised to 90℃and the reaction was stirred for 16h. After the completion of the reaction, the reaction was quenched with water (25 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to give ethyl (R) -2- (3- (1- ((6- ((4- ((tert-butyldimethylsilyl) oxy) -3- (2- (dimethylamino) -2-oxoethyl) phenyl) (methyl) amino) -2-methylquinazolin-4-yl) amino) ethyl) -2, 2-difluoroacetate in 45.5% yield; ESI-MS (m/z): 724.9[ M+H ] ] ⁺ 。

Step b): preparation of ethyl (R) -2- (3- (1- ((6- ((3- (2- (dimethylamino) -2-oxoethyl) -4-hydroxyphenyl) (methyl) amino) -2-methylquinazolin-4-yl)) amino) ethyl) -2-fluorophenyl) -2, 2-difluoroacetate

Ethyl (R) -2- (3- (1- ((6- ((4- ((tert-butyldimethylsilyl) oxy) -3- (2- (dimethylamino) -2-oxoethyl) phenyl) (methyl) amino) -2-methylquinazolin-4-yl) amino) ethyl) -2-fluorophenyl) -2, 2-difluoroacetate (170 mg,0.235 mmol) and THF (5 mL) were added to the reaction flask, dissolved by stirring, and a THF solution of TBAF (0.305 mL,1.0 m) was slowly added under stirring at 0 ℃ and the reaction was carried out at room temperature by naturally warming to room temperature after the addition. Concentrating under reduced pressure after the reaction is finished, and passing the residue through a silica gel columnChromatography purification (eluent: dichloromethane/methanol=20/1) afforded (R) -2- (3- (1- ((6- ((3- (2- (dimethylamino) -2-oxoethyl) -4-hydroxyphenyl) (methyl) amino) -2-methylquinazolin-4-yl) amino) ethyl) -2-fluorophenyl) -2, 2-difluoroacetic acid ethyl ester in 85.7% yield; ESI-MS (m/z): 610.6[ M+H ]] ⁺ 。

Step c): preparation of((R) -2- (5- (4- (4- (1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide formate salt

Ethyl (R) -2- (3- (1- ((6- ((3- (2- (dimethylamino) -2-oxoethyl) -4-hydroxyphenyl) (methyl) amino) -2-methylquinazolin-4-yl)) amino) ethyl) -2-fluorophenyl) -2, 2-difluoroacetate (97 mg,0.160 mmol) and THF/water mixture (5 ml, v/v=50/1) were added to the reaction flask, stirred and dissolved, naBH4 (12.13 mg,0.320 mmol) was slowly added with stirring at-78 ℃ and the reaction was maintained at-78 ℃ for 1h. After the reaction was completed, the temperature was naturally raised to room temperature, saturated brine (10 mL) was added to quench the reaction, the reaction was extracted with ethyl acetate (20 ml×3), the organic phase was washed with saturated brine (100 ml×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 2) to give ((R) -2- (4- (4- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide formate, yield 85.0%;1H NMR (400 MHz, DMSO-d 6) delta 9.55 (s, 1H), 8.16-8.13 (m, 2H), 7.69-7.66 (m, 1H), 7.57 (s, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.33 (d, J=12.0 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.04-7.01 (m, 1H), 6.94-6.89 (m, 2H), 6.83 (d, J=8.0 Hz, 1H), 5.88-5.80 (m, 1H), 5.72 (s, 1H), 3.95 (t, J=12.0 Hz, 2H), 3.57 (s, 2H), 3.33 (s, 3H), 3.01 (s, 3H), 2.81 (s, 3H) 2.30 (s, 3H), 1.62 (d, j=8.0 hz, 3H); ESI-MS (m/z): 568.6[ M+H ] ] ⁺ 。

Example 59

Preparation of (R) -2- (5- (4- (4- (1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methyl quinazolin-6-yl (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate salt

The preparation method was carried out by referring to the procedure of example 58, to give (R) -2- (5- (4- (4- (1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate in 83.8% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.22(d，J＝8.0Hz，1H)，8.15(s，1H)，7.94(s，1H)，7.74(s，1H)，7.67(t，J＝8.0Hz，1H)，7.44-7.39(m，2H)，7.35(d，J＝8.0Hz，1H)，7.26(t，J＝8.0Hz，1H)，7.13-7.10(q，J＝4.0Hz，1H)，5.87-5.80(m，1H)，5.72(s，1H)，3.95(t，J＝12.0Hz，2H)，3.86(s，3H)，3.60(s，2H)，3.36(s，3H)，3.03(s，3H)，2.81(s，3H)，2.32(s，3H)，1.62(d，J＝8.0Hz，3H)；ESI-MS(m/z)：583.6[M+H] ⁺ 。

example 60

Preparation of (R) -2- (5- (4- (4- (1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide formate salt

(R) -2- (5- (4- (4- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide (20 mg,0.034 mmol) was placed in a reaction flask, and an aqueous solution of HBr (5 mL, 24%) was added under stirring at 0℃and the reaction was stirred at 90℃until the addition was completed. After the completion of the reaction, the reaction was quenched with water (25 mL), extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated under reduced pressure, and the obtained crude product was purified by Prep-HPLC (method 2) to give (R) -2- (5- (4- (4- (1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) -2-methyl quinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide formate salt, yield 25.3%; ¹ H NMR(400MHz，CD ₃ OD)δ8.54(s，1H)，7.60-7.53(m，2H)，7.49-7.42(m，3H)，7.37(s，1H)，7.20(t，J＝8.0Hz，1H)，5.95-5.89(m，1H)，5.18(s，1H)，4.02(t，J＝12.0Hz，2H)，3.62(s，2H)，3.38(s，3H)，3.17(s，3H)，2.97(s，3H)，2.45(s，3H)，1.70(d，J＝8.0Hz，3H)；ESI-MS(m/z)：569.6[M+H] ⁺ 。

example 61

Preparation of (R) -2- (5- ((4- ((1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl-N, N-dimethylacetamide formate salt

(R) -2- (5- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl-N, N-dimethylacetamide (2910 mg,0.500 mmol) and tetrahydrofuran (3 mL) were added to a reaction flask, dissolved with stirring, and Cs was added ₂ CO ₃ (326 mg,1.000 mmol), 18-crown-6 (66 mg,0.250 mmol), nitrogen substitution 3 times, and heating to 80℃for reaction overnight. After the reaction was completed, cooled to room temperature, quenched by slowly dropping water (10 mL), extracted with dichloromethane (15 ml×3), combined organic phases, dried with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the residue purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1), the crude product obtained was purified by Prep-HPLC (method 2) to obtain (R) -2- (5- ((4- ((1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl-N, N-dimethylacetamide formate, yield 49.8%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.15(s，1H)，8.05(d，J＝8.0Hz，1H)，7.87(s，1H)，7.66(s，1H)，7.54(d，J＝8.0Hz，1H)，7.43(d，J＝8.0Hz，1H)，7.33(d，J＝8.0Hz，1H)，7.27(s，1H)，7.06-7.00(m，2H)，5.75-5.68(m，1H)，4.81(t，J＝16.0Hz，2H)，3.78(s，3H)，3.52(s，2H)，3.31(s，3H)，2.95(s，3H)，2.73(s，3H)，2.24(s，3H)，1.53(d，J＝8.0Hz，3H)；ESI-MS(m/z)：563.6[M+H] ⁺ 。

Example 62

Preparation of (R) -2- (4- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide formate salt

Step a): preparation of (R) -6-bromo-N- (1- (3- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-4-amine

(R) -2- (3- (1- ((6-bromo-2-methylquinazolin-4-yl) amino) ethyl) -2-fluorophenyl) -2, 2-difluoroethane-1-ol (90 mg,0.204 mmol), t-butyldimethylchlorosilane (92 mg,0.613 mmol), triethylamine (103 mg,1.021 mmol) and dichloromethane (5 mL) were added to the reaction flask and stirred at room temperature for 1h. After the reaction, concentrating under reduced pressure, purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1), to obtain (R) -6-bromo-N- (1- (3- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-4-amine in 99.0% yield; ESI-MS (m/z): 505.3[ M+H ]] ⁺ 。

Step b): (R) -N ⁴ - (1- (3- (2- (tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -N ⁶ Preparation of 2-dimethylquinazoline-4, 6-diamine

(R) -6-bromo-N- (1- (3- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-4-amine @ 100mg,0.180 mmol), methylamine hydrochloride (122 mg,1.803 mmol), cesium carbonate (881 mg,2.702 mmol), X-phos (17 mg,0.036 mmol), pd (dba) ₂ (10 mg,0.018 mmol) and toluene (2 ml) were added to the flask, nitrogen was replaced 3 times and the reaction was stirred at 110℃for 16h. After completion of the reaction, the reaction mixture was cooled to room temperature, ethyl acetate (5 mL) was added, stirred at room temperature for 10min, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give (R) -N ⁴ - (1- (3- (2- (tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -N ⁶ 2-dimethylquinazoline-4, 6-diamine in a yield of 87.9%; ESI-MS (m/z): 505.3[ M+H ]] ⁺ 。

Step c): preparation of (R) -2- (4- ((4- ((1- (3- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide

(R) -N ⁴ - (1- (3- (2- (tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -N ⁶ 2-Dimethylquinazoline-4, 6-diamine (80 mg,0.159 mmol), 2- (4-bromo-2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide (62 mg,0.238 mmol), cesium carbonate (104 mg,0.318 mmol), X-phos (16 mg,0.032 mmol), pd (dba) 2 (10 mg,0.016 mmol) and toluene (2 ml) were added to the reaction flask, nitrogen was substituted 3 times, and the reaction was stirred at 110℃for 16 hours. After completion, the reaction solution was cooled to room temperature, ethyl acetate (5 mL) was added, stirred at room temperature for 10min, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give (R) -2- (4- ((4- ((1- (3- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide in a yield of 74.1%; ESI-MS (m/z): 683.3[ M+H ] ] ⁺ 。

Step d): preparation of (R) -2- (4- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide formate salt

A solution of ((R) -2- (4- ((1- (3- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide (80 mg,0.117 mmol) and tetra-N-butylammonium fluoride in tetrahydrofuran (1 mL) was added to the reaction flask, stirred at room temperature for 30min, the reaction quenched by the addition of dilute hydrochloric acid (10 mL, 1N), extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 2) to give (R) -2- (4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -N, N-dimethylacetamide in 23.4% yield (1H.; 1.4 MHz (1.70.73 s) (1.73S.),400.12.12.3H, 8.40 (s, 1H), 8.13 (s, 1H), 7.69-7.64 (m, 3H), 7.42 (t, j=7.2 hz, 1H), 7.28-7.21 (m, 2H), 5.84-5.81 (m, 1H), 5.70 (t, j=12.0 hz, 1H), 5.66-5.63 (m, 1H), 5.47 (d, j=4.0 hz, 1H), 4.65 (s, 2H), 3.98-3.89 (m, 2H), 3.33 (s, 3H), 3.02 (s, 3H), 2.83 (s, 3H), 2.41 (s, 3H), 1.60 (d, j=4.0 hz, 3H). ESI-MS (m/z): 569.2[ M+H ] +.

Example 63

Preparation of (R) -2- (4- ((4- ((1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -NN-dimethylacetamide formate salt

Step a): preparation of (R) -6-bromo-N- (1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethyl) -2-methylquinazolin-4-amine

(R) -2- (3- (1- (6-bromo-2-methylquinazolin-4-yl) aminoethyl) -2-fluorophenyl) -2, 2-difluoroethan-1-ol (480.0 mg,1.100 mmol) and tetrahydrofuran (5 mL) were added to a reaction flask, dissolved with stirring, and Cs was added ₂ CO ₃ (717.0mg，2.200mmol)、18-Crown-6 (145.0 mg,0.550 mmol), nitrogen substitution 3 times, and reaction was carried out at 80℃overnight. The reaction solution was cooled to room temperature, water (30 mL) was slowly added dropwise to extract and quench the reaction, dichloromethane was used to extract (30 ml×3), the organic phases were combined, washed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1) to give (R) -6-bromo-N- (1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethyl) -2-methylquinazolin-4-amine in 79.8% yield, ESI-MS (m/z): 421.0[ M+H ]] ⁺ 。

Step b-c): preparation of (R) -2- (4- ((4- ((1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide formate salt

Preparation method referring to steps b-c of example 62, the yield was 49.0% of (R) -2- (4- ((4- ((1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide formate; 1H NMR (400 mhz, dmso-d 6) delta 12.50 (s, 1H), 8.41-8.37 (m, 2H), 8.13 (s, 1H), 7.66 (d, j=8.0 hz, 1H), 7.61-7.56 (m, 2H), 7.49 (d, j=8.0 hz, 1H), 7.21 (d, j=8.0 hz, 1H), 7.08 (d, j=8.0 hz, 1H), 5.77-5.70 (m, 1H), 5.62 (dd, j=8.0 hz, 1H), 5.45 (d, j=4.0 hz, 1H), 4.87 (t, j=16.0 hz, 2H), 4.64 (s, 2H), 3.33 (s, 3H), 3.02 (s, 3H), 2.83 (s, 3H), 2.37 (s, 3H), 1.57 (j=8.0 hz, 1H). ESI-MS (m/z): 549.6[ M+H ]] ⁺ 。

Example 64

Preparation of (R) -2- (5- ((4- ((1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide formate salt

Preparation method reference to step c of example 62To obtain (R) -2- (5- ((4- ((1- (3, 3-difluoro-2, 3-dihydrobenzofuran-7-yl) ethyl) amino) -2-methyl quinazoline-6-yl) (methyl) amino) -2-oxygen pyridine-1 (2H) -group) -N, N-dimethyl acetamide formate, the yield is 47.6%;1H NMR (400 MHz, DMSO-d 6) delta 8.15 (s, 1H), 8.13 (s, 1H), 7.59 (t, J=4.0 Hz, 3H), 7.50 (d, J=8.0 Hz, 1H), 7.42-7.39 (m, 2H), 7.14-7.07 (m, 2H), 6.47 (d, J=8.0 Hz, 1H), 5.83-5.75 (m, 1H), 4.88 (t, J=16.0 Hz, 2H), 4.79 (s, 2H), 3.29 (s, 3H), 3.04 (s, 3H), 2.85 (s, 3H), 2.32 (s, 3H), 1.60 (d, J=8.0 Hz, 3H). ESI-MS (m/z): 549.6[ M+H1 ] ⁺ 。

Example 65

Preparation of (R) -2- (3- (1- ((6- ((5- (2- (dimethylamino) ethyl) -6-methoxypyridin-3-yl) (methyl) amino) -2-methylquinazolin-4-yl)) amino) ethyl) -2-fluorophenyl) -2, 2-difluoroethanol-1-carboxylate

(R) -2- (5- ((4- ((1- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl-N, N-dimethylacetamide (146 mg,0.250 mmol) and tetrahydrofuran (3 mL) were added to a reaction flask, stirred and dissolved, lithium aluminum hydride (18.9 mg,0.500 mmol) was added to cool to 0deg.C, the reaction was stirred at 0deg.C for 2h, after completion of the reaction, water (10 mL) was slowly added dropwise to quench the reaction, extracted with dichloromethane (15 mL. Times.3), the combined organic phases were washed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, the organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to give crude product, which was purified by Prep-HPLC (method 2) to give (R) -2- (3- ((6- ((5- (dimethylamino) ethyl) -6-methoxypyridin-3-methyl) -2-fluoro) amino) -2-quinazolin-2-ethyl-fluoro-2-ethyl) ethyl-fluoro-2-fluoro-ethyl-methyl-1-fluoro-ethyl-1-fluoro-methyl-1-ethyl-methyl-1-methyl-ethyl-methyl-1-methyl-ethyl-methyl-2-methyl-1-carboxylate, yield 38.8%;1H NMR (400 MHz, DMSO-d 6) δ8.23 (d, J=8.0 Hz, 1H), 8.18 (s, 2H), 7.90 (d, J=4.0 Hz, 1H), 7.72 (d, J=4.0 Hz, 1H), 7.65 (t，J＝4.0Hz，1H)，7.46-7.38(m，3H)，7.25(t，J＝8.0Hz，1H)，7.12(dd，J＝8.0Hz，1H)，5.87-5.80(m，1H)，4.94(t，J＝16.0Hz，2H)，3.88(s，3H)，3.38(s，3H)，2.68(t，J＝4.0Hz，2H)，2.52(t，J＝4.0Hz，2H)，2.31(s，3H)，2.22(s，6H)，1.60(d，J＝8.0Hz，3H)；ESI-MS(m/z)：569.6[M+H] ⁺ 。

Example 66

Preparation of 2- (5- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide formate salt

The preparation was carried out in accordance with steps c to h of example 57 to give 2- (5- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide formate in 20.1% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.66(s，1H)，8.15(s，1H)，8.13(s，1H)，7.65(s，1H)，7.63-7.58(m，2H)，7.47-7.42(m，1H)，7.41-7.33(m，2H)，7.10-7.02(m，2H)，7.02-6.96(m，1H)，6.91-6.90(m，1H)，5.73-5.66(m，1H)，5.58(s，1H)，3.87-3.80(m，2H)，3.76(s，3H)，3.57(s，2H)，3.33(s，3H)，2.99(s，3H)，2.78(s，3H)，2.35(s，3H)，1.63(d，J＝7.2Hz，3H)；ESI-MS(m/z)：564.2[M+H] ⁺ 。

example 67

Preparation of 2- (5- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetylamide hydrochloride

Preparation method referring to example 58, purification by Pre-HPLC (method 1) gives 2- (5- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetylamide hydrochloride in 55.4% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ14.09(s，1H)，9.89(s，1H)，9.72(s，1H)，7.71(m，1H)，7.68(s，1H)，7.64(d，J＝8.0Hz，1H)，7.53-7.43(m，3H)，7.18(s，1H)，7.00-6.93(m，2H)，6.89(d，J＝8.4Hz，1H)，5.88(s，1H)，5.63(s，1H)，3.91-3.83(m，2H)，3.59(s，2H)，3.35(s，3H)，3.03(s，3H)，2.82(s，3H)，2.56(s，3H)，1.73(d，J＝7.2Hz，3H)；ESI-MS(m/z)：550.3[M+H] ⁺ 。

example 68

Preparation of (R) -2- (5- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylquinolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate salt

Step a): preparation of (R) -2- (3- (1- ((6- ((5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyridin-3-yl) (methyl) amino) -2-methylquinazolin-4-yl) amino) ethyl) phenyl) -2, 2-difluoroacetic acid ethyl ester

Ethyl (R) -2- (3- (1- ((6-bromo-2-methyl-piperidin-4-yl) amino) ethyl) phenyl) -2, 2-difluoroacetate (150 mg,0.323 mmol), 2- (2-methoxy-5- (methylamino) pyridin-3-yl) -N, N-dimethylacetamide (60 mg, 0.263 mmol), cs ₂ CO ₃ (175mg，0.538mmol)、Pd(dba) ₂ (31 mg,0.054 mmol), X-phos (52 mg,0.108 mmol) and toluene (6 mL) were sequentially added to the reaction flask, nitrogen was replaced three times, and the temperature was raised to 105℃and the reaction was stirred for 3 hours. After completion of the reaction, the reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified over silica gelColumn chromatography purification (eluent: dichloromethane/methanol=20/1) afforded (R) -2- (3- (1- ((6- ((5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyridin-3-yl) (methyl) amino) -2-methylquinazolin-4-yl) amino) ethyl) phenyl) -2, 2-difluoroacetic acid ethyl ester in 84.0% yield; ESI-MS (m/z): 607.3[ M+H ]] ⁺ 。

Step b): preparation of (R) -2- (5- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylquinolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate salt

(R) -2- (3- (1- ((6- ((5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyridin-3-yl) (methyl) amino) -2-methyl quinazolin-4-yl) amino) ethyl) phenyl) -2, 2-difluoroacetic acid ethyl ester (200 mg,0.330 mmol) was dissolved in THF (10 mL), sodium borohydride (25 mg,0.659 mmol) was added and the reaction was stirred at room temperature for 16h. After the reaction was completed, the reaction was quenched with water (20 mL), extracted with ethyl acetate (20 ml×2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 2) to give (R) -2- (5- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylquinolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate in a yield of 90.0%; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.72(s，1H)，8.13(s，2H)，7.94(s，1H)，7.70(s，1H)，7.65(s，1H)，7.60(s，1H)，7.46-7.34(m，4H)，7.10(d，J＝8.0Hz，1H)，5.75-5.66(m，1H)，5.60(t，J＝8.0Hz，1H)，3.88-3.79(m，5H)，3.59(s，2H)，3.36(s，3H)，3.02(s，3H)，2.80(s，3H)，2.36(s，3H)，1.63(d，J＝8.0Hz，3H)；ESI-MS(m/z)：565.3[M+H] ⁺ 。

Example 69

Preparation of (R) -2- (5- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide formate salt

Preparation method referring to example 38, purification by Pre-HPLC (method 2) afforded (R) -2- (5- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide formate in 54.0% yield; ¹ H NMR(400MHz，CD ₃ OD)δ8.54(s，1H)，7.62(s，1H)，7.57-7.50(m，3H)，7.42-7.36(m，4H)，7.33(s，1H)，5.76-5.71(m，1H)，3.86(t，J＝16.0Hz，2H)，3.56(s，2H)，3.34(s，3H)，3.14(s，3H)，2.93(s，3H)，2.45(s，3H)，1.67(d，J＝8.0Hz，3H)；ESI-MS(m/z)：551.4[M+H] ⁺ 。

example 70

Preparation of (R) -2- (3- (1- ((6- ((5- (2- (dimethylamino) ethyl) -6-methoxypyridin-3-yl) (methyl) amino) -2-methylquinazolin-4-yl)) amino) ethyl) phenyl) -2, 2-difluoroethanol-1-ol

(R) -2- (3- (1- ((6- ((5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyridin-3-yl) (methyl) amino) -2-methyl-quinazolin-4-yl) amino) ethyl) phenyl) -2, 2-difluoroacetic acid ethyl ester (100.0 mg,0.165 mmol) was dissolved in THF (10 mL), lithium aluminum hydride (31.3 mg, 0.025 mmol) was added and stirred at room temperature for 30min. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL. Times.3), the organic phases combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was purified by Prep-HPLC (method 3) to give (R) -2- (3- (1- ((6- ((5- (2- (dimethylamino) ethyl) -6-methoxypyridin-3-yl) (methyl) amino) -2-methylquinazolin-4-yl) amino) ethyl) phenyl) -2, 2-difluoroethanol-1-ol in 90.0% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.19(s，1H)，8.16(s，1H)，7.88(s，1H)，7.68(s，1H)，7.65(s，1H)，7.59(d，J＝8.0Hz，1H)，7.46-7.42(m，2H)，7.39-7.36(m，2H)，7.09(d，J＝8.0Hz，1H)，5.73-5.66(m，1H)，3.88(s，3H)，3.83(t，J＝12.0Hz，2H)，3.35(m，3H)，2.67-2.64(m，2H)，2.49(t，J＝12.0Hz，2H)，2.35(s，3H)，2.19(s，6H)，1.62(d，J＝8.0Hz，3H)；ESI-MS(m/z)：551.5[M+H] ⁺ 。

Example 71

Preparation of (R) -2- (5- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) acetonitrile formate salt

Step a): preparation of (R) -2- (3- (1- ((6-bromo-2-methylquinazolin-4-yl) amino) ethyl) phenyl) -2, 2-difluoroethane-1-ol

(R) -2- (3- (1- ((6-bromo-2-methylquinazolin-4-yl) amino) ethyl) phenyl) -2, 2-difluoroacetic acid ethyl ester (300 mg, 0.488 mmol), THF (5 mL) and water (0.1 mL) were added to a reaction flask, sodium borohydride (54 mg, 1.298 mmol) was added, stirring at room temperature for 1h, the reaction was quenched by adding water (5 mL), extracted with ethyl acetate (20 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to give (R) -2- (3- (1- ((6-bromo-2-methylquinazolin-4-yl) amino) ethyl) phenyl) -2, 2-difluoroethane-1-ol in 50.6% yield; ESI-MS (m/z): 422.1[ M+H ]] ⁺ 。

Step b): preparation of (R) -6-bromo-N- (1- (3- (2- ((tert-butyldimethylsilyloxy) -1, 1-difluoroethyl) phenyl) ethyl) -2-methylquinazolin-4-amine

(R) -2- (3- (1- ((6-bromo-2-methylquinazolin-4-yl) amino) ethyl) phenyl) -2, 2-difluoroethane-1-ol (150 mg,0.355 mmol), triethylamine (173 mg,0.666 mmol), t-butyldimethylchlorosilane (290 mg,0.888 mmol), 4-dimethylaminopyridine (4.3 mg,0.035 mmol) and dichloromethane (5 mL) were added to the reaction flask and stirred at room temperature for 5h. Concentrating the reaction solution under reduced pressure, and collecting residue Purifying the product by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain (R) -6-bromo-N- (1- (3- (2- ((tert-butyldimethylsilyloxy) -1, 1-difluoroethyl) phenyl) ethyl) -2-methylquinazolin-4-amine in 97.6% yield, ESI-MS (m/z): 536.2[ M+H)] ⁺ 。

Step c): (R) -N ⁴ - (1- (3- (2- (tert-butyldimethylsilyloxy) -1, 1-difluoroethyl) phenyl) ethyl) -N ⁶ Preparation of 2-dimethylquinazoline-4, 6-diamine

(R) -6-bromo-N- (1- (3- (2- ((tert-butyldimethylsilyloxy) -1, 1-difluoroethyl) phenyl) ethyl) -2-methylquinazolin-4-amine (190 mg,0.354 mmol), methylamine hydrochloride (239 mg,3.541 mmol), cesium carbonate (1.7 g,5.312 mmol), X-phos (34 mg,0.071 mmol), pd (dba) ₂ (22 mg,0.035 mmol) and toluene (10 ml) were charged into a constant volume reactor, and after nitrogen bubbling for 2 minutes, the temperature was raised to 120℃and stirred for 16 hours. The reaction mixture was cooled to room temperature, ethyl acetate (20 mL) was added and stirred at room temperature for 10min, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give (R) -N ⁴ - (1- (3- (2- (tert-butyldimethylsilyloxy) -1, 1-difluoroethyl) phenyl) ethyl) -N ⁶ 2-dimethylquinazoline-4, 6-diamine in 81.9% yield; ESI-MS (m/z): 487.3[ M+H ] ] ⁺ 。

Step d): preparation of ethyl (R) -2- (5- ((4- ((1- (3- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) acetate

(R) -N ⁴ - (1- (3- (2- (tert-butyldimethylsilyloxy) -1, 1-difluoroethyl) phenyl) ethyl) -N ⁶ 2-Dimethylquinazolin-4, 6-diamine (100 mg,0.205 mmol), ethyl 2- (5-bromo-2-methoxypyridin-3-yl) acetate (86 mg,0.308 mmol), cesium carbonate (135 mg,0.411 mmol), X-phos (20 mg,0.041 mmol), pd (dba) ₂ (12.1 mg,0.021 mmol) and toluene (10 ml) were added to the reaction flask, nitrogen was substituted 3 times, and the mixture was stirred at 100℃for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, ethyl acetate (20 mL) was added thereto, and the mixture was stirred at room temperature for 10 minutes, filtered, and the filtrate was reducedConcentrating under pressure, and purifying the residue by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give ethyl (R) -2- (5- ((4- ((1- (3- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) acetate in 71.6% yield; ESI-MS (m/z): 680.3[ M+H ]] ⁺ 。

Step e): preparation of (R) -2- (5- ((4- ((1- (3- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) acetic acid

Ethyl (R) -2- (5- ((4- ((1- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) acetate (100 mg,0.147 mmol), THF (2 mL), methanol (2 mL), and water (4 mL) were added to the reaction flask, then lithium hydroxide monohydrate (31 mg,0.735 mmol) was added and stirred at room temperature for 2h, ph=5 to 6 was adjusted with 1N aqueous hydrochloric acid solution, ethyl acetate was added to extract (20 ml×2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give (R) -2- (5- ((1- (3- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) phenyl) amino) -2-methyl quinazolin-6-yl) (methyl) amino) -2-methoxypyridin 61.1% yield; ESI-MS (m/z): 652.3[ M+H ]] ⁺ 。

Step f): preparation of (R) -2- (5- ((4- ((1- (3- (2- ((tert-butyldimethylsilyloxy) -1, 1-difluoroethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) acetamide

(R) -2- (5- ((4- ((1- (3- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) acetic acid (80 mg,0.123 mmol), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (70 mg,0.184 mmol), N, N-diisopropylethylamine (32 mg, 0.248 mmol), 1mol/L methanolic ammonia solution (0.8 mL) and N, N-dimethylformamide (2 mL) were added to the reaction In a bottle, stirring at room temperature for 3h, extracting with water (5 mL) and ethyl acetate (10 mL), drying the organic phase over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the residue by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give (R) -2- (5- ((4- ((1- (3- (2- ((tert-butyldimethylsilyloxy) -1, 1-difluoroethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) acetamide in 99.9% yield, ESI-MS (m/z): 651.3[ M+H ]] ⁺ 。

Step g): preparation of (R) -2- (5- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) acetonitrile formate salt

N, N-dimethylformamide (3 mL) was added to the reaction flask, thionyl chloride (0.5 mL) was added with stirring in ice bath, stirring in ice bath was maintained for 30min, and (R) -2- (5- ((1- (3- (2- ((tert-butyldimethylsiloxy) -1, 1-difluoroethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) acetamide (60 mg,0.092 mmol) was added dropwise, stirred for 1h, quenched with water (5 mL) and extracted with dichloromethane (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 2) to give (R) -2- (5- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) acetonitrile, yield 37.8%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.31(s，1H)，8.13(s，1H)，8.03(s，1H)，7.78(s，1H)，7.65(s，1H)，7.60-7.59(m，2H)，7.46-7.42(m，2H)，7.38(d，J＝8.0Hz，1H)，7.18(d，J＝8.0Hz，1H)，5.74-5.67(m，1H)，5.60(t，J＝12.0Hz，1H)，3.93(s，3H)，3.88-3.79(m，4H)，3.37(s，3H)，2.37(s，3H)，1.62(d，J＝8.0Hz，3H)；ESI-MS(m/z)：519.3[M+H] ⁺ 。

Example 72

Preparation of (R) -2- (5- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate salt

Preparation method referring to step g and step h of example 57, (R) -2- (5- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-methylphenyl) ethyl) amino) -2-methyl quinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate was obtained in 90.0% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.26(s，1H)，8.16(s，1H)，7.93(s，1H)，7.73(s，1H)，7.67(s，1H)，7.37(d，J＝8.0Hz，1H)，7.34-7.32(m，2H)，7.25(t，J＝8.0Hz，1H)，7.09(d，J＝8.0Hz，1H)，5.82-5.75(m，1H)，5.65(s，1H)，3.94-3.87(m，2H)，3.85(s，3H)，3.59(s，2H)，3.38(s，3H)，3.02(s，3H)，2.80(s，3H)，2.60(s，3H)，2.31(s，3H)，1.55(d，J＝8.0Hz，3H)；ESI-MS(m/z)：579.3[M+H] ⁺ 。

example 73

Preparation of (R) -2- (5- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide formate salt

Preparation method referring to example 38, purification by Pre-HPLC (method 2) gives (R) -2- (5- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide formate in 46.0% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.61(s，1H)，8.22(d，J＝8.0Hz，1H)，8.14(s，1H)，7.66(d，J＝8.0Hz，1H)，7.55(s，1H)，7.37(d，J＝12.0Hz，1H)，7.33(d，J＝8.0Hz，1H)，7.26-7.22(m，2H)，7.18(s，1H)，7.05(d，J＝8.0Hz，1H)，5.82-5.75(m，1H)，5.65(s，1H)，3.90(t，J＝12.0Hz，2H)，3.42(s，2H)，3.28(s，3H)，3.01(s，3H)，2.79(s，3H)，2.60(s，3H)，2.31(s，3H)，1.55(d，J＝8.0Hz，3H)；ESI-MS(m/z)：565.3[M+H] ⁺ 。

example 74

Preparation of (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (6-methylpyridin-2-yl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide formate salt

Step a): preparation of (R, E) -2-methyl-N- (1- (6-methylpyridin-2-yl) ethylene) propane-2-sulfinamide

1- (6-methylpyridin-2-yl) -ethan-1-one (5.0 g,0.037 mol), (R) -tert-butylsulfinamide (9.0 g,0.074 mol), tetraethyltitanate (25.3 g,0.111 mol) and THF (100 mL) were added to the reaction flask, and the mixture was warmed to reflux and stirred for 3h. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (100 mL) and ethyl acetate (100 mL), stirred at room temperature for 10min, filtered, the filtrate was separated, the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered under pressure and suction, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give (R, E) -2-methyl-N- (1- (6-methylpyridin-2-yl) ethylene) propane-2-sulfinamide in 62.4% yield; ESI-MS (m/z): 239.1[ M+H ]] ⁺ 。

Step b): preparation of (R) -2-methyl-N- ((R) -1- (6-methylpyridin-2-yl) ethyl) propane-2-sulfinamide

(R, E) -2-methyl-N- (1- (6-methylpyridin-2-yl) ethylene) propane-2-sulfinamide (5.0 g,0.021 mol) and THF (100 mL) water (2 mL) were added to the reaction flask, stirred and dissolved, cooled to-78deg.C and stirred for 10 min. Sodium borohydride (1.2 g,0.032 mol) was added in portions, stirred at 78℃for 1h, then slowly warmed to room temperature and stirred for a further 30min. The reaction was quenched with water (50 ml), extracted with ethyl acetate (50 ml) and the organic phase was used Saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered under suction under pressure, and the filtrate concentrated under reduced pressure, and the residue purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give 3.4g of (R) -2-methyl-N- ((R) -1- (6-methylpyridin-2-yl) ethyl) propane-2-sulfinamide in 66.7% yield; ESI-MS (m/z): 241.1[ M+H ]] ⁺ 。

Step c): preparation of (R) -1- (6-methylpyridin-2-yl) ethane-1-amine

(R) -2-methyl-N- ((R) -1- (6-methylpyridin-2-yl) ethyl) propane-2-sulfinamide (2.4 g, 0.010m0l) and THF (10 ml) were added to the reaction flask, dissolved with stirring, and then added with 1, 4-dioxane solution of hydrogen chloride (30 mL, 4M) and stirred at room temperature for 3h. Concentrating the reaction solution under reduced pressure, adding ethyl acetate (10 mL) and petroleum ether (100 mL), pulping at room temperature for 30min, filtering, and drying the obtained solid under reduced pressure to obtain (R) -1- (6-methylpyridin-2-yl) ethane-1-amine with a yield of 95.6%; ESI-MS (m/z): 137.1[ M+H ]] ⁺ 。

Step d): preparation of (R) -6-bromo-2-methyl-N- (1- (6-methylpyridin-2-yl) ethyl) quinazolin-4-amine

(R) -1- (6-methylpyridin-2-yl) ethan-1-amine (100 mg, 0.284 mmol) and 6-bromo-4-chloro-2-methyl quinazoline (227 mg,0.881 mmol) were dissolved in DMF (2 mL), DIPEA (284 mg,2.203 mmol) was added, and the mixture was stirred at 80℃for 3h. After the reaction was completed, the reaction solution was cooled to room temperature, water (2 mL) and ethyl acetate (4 mL) were added to extract, and the organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to give (R) -6-bromo-2-methyl-N- (1- (6-methylpyridin-2-yl) ethyl) quinazolin-4-amine in 57.2% yield; ESI-MS (m/z): 357.0[ M+H ] ] ⁺ 。

Step e): preparation of (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (6-methylpyridin-2-yl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide formate salt

(R) -6-bromo-2-methyl-N- (1- (6-methylpyridin-2-yl) ethyl) quinazolin-4-amine (55 mg,0.154 mmol), 2- (2-methoxy-5- (methylamino) phenyl) -NN-dimethylacetylamide hydrochloride (52 mg,0.200 mmol), cesium carbonate (101 mg,0.308 mmol), X-phos (15 mg,0.031 mmol), pd (dba) ₂ (9 mg,0.015 mmol) and toluene (2 ml) were added to the flask, nitrogen was replaced 3 times, and the mixture was stirred at reflux with warming for 16h. After the reaction, cooling to room temperature, adding ethyl acetate (5 mL) and stirring at room temperature for 10min, filtering, concentrating the filtrate under reduced pressure, purifying the residue by silica gel column chromatography (eluent: dichloromethane/methanol=20/1), purifying the obtained crude product by Prep-HPLC (method 2), and obtaining (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (6-methylpyridin-2-yl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide formate with the yield of 13.4%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.16(s，1H)，8.14(s，1H)，8.13(s，1H)，7.64-7.61(m，2H)，7.37(d，J＝12.0Hz，1H)，7.25(d，J＝8.0Hz，1H)，7.12-7.05(m，3H)，7.00(d，J＝8.0Hz，1H)，6.93(s，1H)，5.66-5.59(m，1H)，3.78(s，3H)，3.58(s，2H)，3.34(s，3H)，2.99(s，3H)，2.79(s，3H)，2.48(s，3H)，2.34(s，3H)，1.62(d，J＝8.0Hz，3H)；ESI-MS(m/z)：499.2[M+H] ⁺ 。

example 75

Preparation of (R) -2- (5- (4- (1- (5-aminopyridin-3-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate salt

Step a): preparation of 1- (5-nitropyridin-3-yl) ethyl-1-one

3-bromo-5-nitropyridine (1.725 g,8.498 mmol), tributyl (1-ethoxyvinyl) stannane (3.989 g,11.047 mmol), pd (PPh ₃ )Cl ₂ (298 mg,0.425 mmol), triethylamine (1.716 g,16.996 mmol) and 1, 4-dioxane (30 mL) were added to a reaction flask, nitrogen was replaced three times, and the temperature was raised to 90℃and the reaction was stirred for 16h. After the reaction, the reaction solution was cooled to room temperature, added with 2N of diluted hydrochloric acid to adjust the pH to 2-3, stirred at room temperature for 1h, concentrated and removedRemoving solvent, adding saturated sodium bicarbonate aqueous solution into the mixture, extracting with ethyl acetate (50 mL×3), mixing organic phases, washing with saturated saline (150 mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1), to obtain 1- (5-nitropyridin-3-yl) ethyl-1-one, yield 42.0%; ESI-MS (m/z): 167.1[ M+H ]] ⁺ 。

Step b): preparation of (R, E) -2-methyl-N- (1- (5-nitropyridin-3-yl) ethylene) propane-2-sulfinamide

1- (5-nitropyridin-3-yl) ethyl-1-one (630 mg,3.800 mmol) and (R) - (+) -tert-butylsulfonamide (0.69 g,5.700 mmol) and THF (15 mL) were added to a reaction flask, dissolved with stirring, tetraethyltitanate (2.6615 g,7.600mmol, 65%) was added at room temperature, and the temperature was raised to 80℃after the addition and stirred for 3h. After the reaction was completed, cooled to room temperature, water (20 mL) was added to precipitate a large amount of solid, the solid was filtered, the cake was washed with ethyl acetate (50 mL), the filtrate was extracted with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to give (R, E) -2-methyl-N- (1- (5-nitropyridin-3-yl) ethylene) propane-2-sulfinamide in 99.0% yield; ESI-MS (m/z): 270.3[ M+H ] ] ⁺ 。

Step c): preparation of (R) -2-methyl-N- ((R) -1- (5-nitropyridin-3-yl) ethyl) propane-2-sulfinamide

(R) -2-methyl-N- (1- (5-nitropyridin-3-yl) ethylene) propane-2-sulfinamide (942 mg,3.500 mmol) and THF (15 mL) were added to the reaction flask and dissolved with stirring, DIBAL-H in THF (1M, 10.5mL,10.500 mmol) was slowly added with stirring at-78deg.C and the reaction was maintained at-78deg.C for 1 hour. After the completion of the reaction, the reaction was naturally warmed to room temperature, saturated brine (50 mL) was added to quench the reaction, a large amount of solids was precipitated, filtered, the cake was washed with ethyl acetate (50 mL), the filtrate was extracted with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:petroleum ether/ethyl acetate=2/1), to give (R) -2-methyl-N- ((R) -1- (5-nitropyridin-3-yl) ethyl) propane-2-sulfinamide in 90.0% yield; ESI-MS (m/z): 272.3[ M+H ]] ⁺ 。

Step d): preparation of (R) -1- (5-nitropyridin-3-yl) ethyl-1-amine hydrochloride

(R) -2-methyl-N- ((R) -1- (5-nitropyridin-3-yl) ethyl) propane-2-sulfinamide (854 mg,3.150 mmol) and THF (5 mL) were added to a reaction flask, stirred and dissolved, and a hydrogen chloride dioxane solution (4M, 10 mL) was slowly added under stirring at 0℃and the addition was completed, and the temperature was naturally raised to room temperature for reaction for 1h. Concentrating under reduced pressure after the reaction is finished, dissolving the residue with a small amount of ethyl acetate, adding a large amount of petroleum ether in batches under stirring to separate out a large amount of white precipitate, filtering, washing with petroleum ether to obtain (R) -1- (5-nitropyridin-3-yl) ethyl-1-amine hydrochloride, and obtaining the yield of 95.5%; ESI-MS (m/z): 168.1[ M+H ] ] ⁺ 。

Step e): preparation of (R) -6-bromo-2-methyl-N- (1- (5-nitropyridin-3-yl) ethyl) quinazolin-4-amine

6-bromo-4-chloro-2-methyl quinazoline (200 mg,0.733 mmol), (R) -1- (5-nitropyridin-3-yl) ethyl-1-amine hydrochloride (150 mg,0.733 mmol) and DIPEA (283 mg, 2.198mmol) were dissolved in DMSO (5 mL), the reaction solution was heated to 80 ℃ and stirred for 1h, after the reaction was completed, the reaction solution was cooled to room temperature, water (50 mL) was added to extract it, ethyl acetate was used to extract it (30 ml×3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/1) to give (R) -6-bromo-2-methyl-N- (1- (5-nitropyridin-3-yl) ethyl) quinazolin-4-amine in 92.3% yield; ESI-MS (m/z): 389.2[ M+H ]] ⁺ 。

Step f): preparation of (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (5-nitropyridin-3-yl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -N, N-dimethylacetamide

(R) -6-bromo-2-methyl-N- (1- (5-nitropyridin-3-yl) ethyl) quinazolin-4-amine (120 mg,0.310 mmol), 2- (2-methoxy-5- (methylamino) pyridin-3-yl) -N, N-dimethylacetamide (70 m) g，0.310mmol)、Cs ₂ CO ₃ (203mg，0.620mmol)、X-Phos(30mg，0.062mmol)、Pd(dba) ₂ (18 mg, 0.003mmol) and toluene (7 mL) were added to the reaction flask, nitrogen was replaced three times, and the temperature was raised to 90℃and the reaction was stirred for 16h. After the completion of the reaction, the reaction was quenched with water (25 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to give (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (5-nitropyridin-3-yl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -N, N-dimethylacetamide in a yield of 60.9%; ESI-MS (m/z): 531.6[ M+H ]] ⁺ 。

Step g): preparation of (R) -2- (5- (4- (1- (5-aminopyridin-3-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate salt

(R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (5-nitropyridin-3-yl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -N, N-dimethylacetamide (143 mg,0.270 mmol) was dissolved in methanol (2 mL), iron powder (75 mg,1.350 mmol) and saturated aqueous ammonium chloride solution (2 mL) were added, the reaction solution was warmed to reflux for 1h, ethyl acetate (10 mL) and water (10 mL) were added after the reaction solution cooled to room temperature, suction filtration, the filtrate was separated, the aqueous phase was extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by Prep-HPLC (method 2) to give (R) -2- (5- (4- (1- (5-aminopyridin-3-yl) ethyl) amino) -2-methoxypyridin-3-N, N-dimethylacetamide in 48.5% yield; 1H NMR (400 MHz, DMSO-d 6) delta 8.16 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.94 (s, 1H), 7.87 (s, 1H), 7.79 (s, 1H), 7.70 (s, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.33 (s, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.95 (s, 1H), 5.63-5.56 (m, 1H), 5.25 (s, 2H), 3.85 (s, 3H), 3.59 (s, 2H), 3.35 (s, 3H), 3.02 (s, 3H), 2.80 (s, 3H), 2.37 (s, 3H), 1.5 8(d，J＝8.0Hz，3H)；ESI-MS(m/z)：501.6[M+H] ⁺ 。

Example 76

Preparation of (R) -2- (5- ((4- ((1- (5-aminopyridin-3-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide formate salt

Preparation method referring to step f and step g of example 75, (R) -2- (5- ((4- ((1- (5-aminopyridin-3-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide formate was obtained in 39.8% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.16(s，1H)，8.09(d，J＝8.0Hz，1H)，7.87(s，1H)，7.78(s，1H)，7.63(s，1H)，7.35(d，J＝12.0Hz，1H)，7.09-7.03(m，2H)，6.99(d，J＝8.0Hz，1H)，6.95(s，1H)，6.90(s，1H)，5.63-5.56(m，1H)，5.25(s，2H)，3.77(s，3H)，3.57(s，2H)，3.33(s，3H)，2.99(s，3H)，2.79(s，3H)，2.36(s，3H)，1.58(d，J＝8.0Hz，3H)；ESI-MS(m/z)：500.6[M+H] ⁺ 。

example 77

Preparation of (R) -2- (5- ((4- ((1- (3-cyano-2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide

Step a): preparation of 3-acetyl-2-methylbenzonitrile

3-bromo-2-methylbenzonitrile (3.0 g,15.302 mmol), tributyl (1-ethoxyvinyl) stannane (7.2 g,19.893 mmol), pd (PPh) ₃ ) ₂ Cl ₂ (537.0 mg,0.765 mmol), triethylamine (3.1 g,30.604 mmo)l) was added to 1, 4-dioxane (45 mL), and the mixture was stirred at 100℃for 2h. Cooling to room temperature, adding ethyl acetate (80 mL) and potassium fluoride aqueous solution (5 g/50 mL), stirring for 30min, filtering, eluting a filter cake with ethyl acetate (20 mL multiplied by 2), mixing the filtrates, separating the filtrate, washing with saturated saline solution (30 mL), adding ethyl hydrogen chloride solution (30 mL, 4M) into an organic phase, stirring for 30min at room temperature, adding saturated sodium bicarbonate aqueous solution, adjusting the pH value of the reaction solution to be neutral, separating the liquid, washing the organic phase with saturated saline solution (30 mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the obtained crude product by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/10), and obtaining 3-acetyl-2-methylbenzonitrile with the yield of 66%;1H NMR (400 MHz, DMSO-d 6) δ8.06 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 2.58 (s, 3H), 2.56 (s, 3H).

Step b): preparation of N- (1- (3-cyano-2-methylphenyl) ethylene) -2-methylpropane-2-sulfinamide

3-acetyl-2-methylbenzonitrile (1.6 g,10.051 mmol), (R) - (+) -tert-butylsulfinamide (1.46 g,12.061 mmol), tetraethyltitanate (4.6 g,13.066mmol, 65%) and THF (25 mL) were added to the reaction flask and reacted at 80℃for 2h. After the reaction was completed, cooled to room temperature, ethyl acetate (30 mL) and water (30 mL) were added, stirred for 10min, filtered, the filter cake was washed with ethyl acetate (10 ml×2), the filtrates were combined, the aqueous phase was extracted with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/5) to give N- (1- (3-cyano-2-methylphenyl) ethylene) -2-methylpropan-2-sulfinamide in 64% yield; ESI-MS (m/z): 263.2[ M+H ]] ⁺ 。

Step c): preparation of N- ((R) -1- (3-cyano-2-methylphenyl) ethyl) -2-methylpropane-2-sulfinamide

N- (1- (3-cyano-2-methylphenyl) ethylene) -2-methylpropane-2-sulfinamide (1.7 g,6.479 mmol) and tetrahydrofuran/water mixture (18 mL, v/v=8/1) were added to a reaction flask, naBH4 (615.4 mg,16.196 mmol) was added with stirring at-78℃and reaction 1 was carried out at-78 ℃ h, quenching the reaction with water (10 mL), extracting with ethyl acetate (20 mL. Times.2), combining the organic phases, washing with saturated brine (20 mL), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the crude product by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/3), to give N- ((R) -1- (3-cyano-2-methylphenyl) ethyl) -2-methylpropane-2-sulfinamide in 25% yield; ESI-MS (m/z): 265.1[ M+H ]] ⁺ 。

Step d): preparation of (R) -3- (1-aminoethyl) -2-methylbenzonitrile hydrochloride

N- ((R) -1- (3-cyano-2-methylphenyl) ethyl) -2-methylpropane-2-sulfinamide (400.0 mg,1.513 mmol) was dissolved in ethyl acetate (3.5 mL), and a hydrogen chloride dioxane solution (4M, 3.5 mL) was added and reacted at room temperature for 2h. The reaction solution was concentrated to dryness under reduced pressure, and the obtained crude product was directly subjected to the next reaction.

Step e): preparation of (R) -3- (1- ((6-bromo-2-methylquinazolin-4-yl) amino) ethyl) -2-methylbenzonitrile

6-bromo-4-chloro-2-methyl quinazoline (428.5 mg,1.664 mmol), (R) -3- (1-aminoethyl) -2-methylbenzonitrile hydrochloride (298.0 mg,1.513 mmol), DIPEA (585.5 mg,4.539 mmol) and DMF (10 mL) were added to the reaction flask and stirred at 80℃for 1h. After the reaction is finished, cooling to room temperature, dropwise adding the mixture into an ice-water mixture (50 mL) under the stirring condition, stirring at room temperature for 30min, filtering, leaching a filter cake with water (10 mL multiplied by 2), and drying the filter cake to obtain (R) -3- (1- ((6-bromo-2-methylquinazolin-4-yl) amino) ethyl) -2-methylbenzonitrile, wherein the yield is 93%; ESI-MS (m/z): 381.0[ M+H ] ] ⁺ 。

Step f): preparation of (R) -2- (5- ((4- ((1- (3-cyano-2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide

(R) -3- (1- ((6-bromo-2-methylquinazolin-4-yl) amino) ethyl) -2-methylbenzonitrile (200.0 mg,0.525 mmol), 2- (2-methoxy-5- (methylamino) pyridin-3-yl) -N, N-dimethylacetamide (128.8 mg,0.577 mmol), cs ₂ CO ₃ (513.4mg，1.575mmol)，X-Phos(25.1mg，0.053mmol)，Pd(dba) ₂ (15.0 mg,0.026 mmol) and toluene (4 mL) were added to the reactionIn the flask, nitrogen was replaced three times and the reaction was stirred at 110℃for 2h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/10), and the crude product obtained was purified by Prep-HPLC (method 3) to give (R) -2- (5- ((4- ((1- (3-cyano-2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide 32%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.28(d，J＝6.8Hz，1H)，7.93(s，1H)，7.82(d，J＝8.0Hz，1H)，7.71(s，1H)，7.63(d，J＝7.6Hz，1H)，7.39-7.33(m，3H)，7.09(d，J＝9.2Hz，1H)，5.70-5.63(m，1H)，3.85(s，3H)，3.59(s，2H)，3.38(s，3H)，3.02(s，3H)，2.80(s，3H)，2.73(s，3H)，2.31(s，3H)，1.56(d，J＝7.2Hz，3H)；ESI-MS(m/z)：524.5[M+H] ⁺ 。

example 78

Preparation of (R) -2- (5- ((4- ((1- (3-cyano-2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide

Preparation method referring to example 38, (R) -2- (5- ((4- ((1- (3-cyano-2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide was obtained in 32% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.58(brs，1H)，8.22(d，J＝6.8Hz，1H)，7.81(d，J＝8.0Hz，1H)，7.62(d，J＝7.6Hz，1H)，7.53(s，1H)，7.39-7.34(m，2H)，7.25(s，1H)，7.16(s，1H)，7.06(d，J＝9.2Hz，1H)，5.70-5.63(m，1H)，3.42(s，2H)，3.28(s，3H)，3.01(s，3H)，2.78(s，3H)，2.73(s，3H)，2.30(s，3H)，1.56(d，J＝7.2Hz，3H)；ESI-MS(m/z)：510.5[M+H] ⁺ 。

Example 79

Preparation of (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -N, N-dimethylacetamide formate salt

Preparation method referring to example 77, purification by Pre-HPLC (method 2) afforded (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -N, N-dimethylacetamide formate in 49.2% yield; ¹ H NMR (400MHz，DMSO-d ₆ )δ12.74(s，1H)，8.31(d，J＝7.2Hz，1H)，8.14(s，1H)，7.94(s，1H)，7.81(d，J＝7.6Hz，1H)，7.72(s，1H)，7.53(d，J＝7.2Hz，1H)，7.40-7.31(m，3H)，7.09(d，J＝9.2Hz，1H)，5.75(s，1H)，3.85(s，3H)，3.59(s，2H)，3.38(s，3H)，3.02(s，3H)，2.80(s，3H)，2.64(s，3H)，2.30(s，3H)，1.58(d，J＝7.2Hz，3H)；ESI-MS(m/z)：567.2[M+H] ⁺ 。

example 80

Preparation of (R) -2- (2-hydroxy-5- (methyl (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -N, N-dimethylacetamide formate salt

Preparation method referring to example 38, purification by Pre-HPLC (method 2) afforded (R) -2- (2-hydroxy-5- (methyl (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -N, N-dimethylacetamide formate in 66.7% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.64(s，1H)，11.64(s，1H)，8.41(d，J＝7.2Hz，1H)，8.14(s，1H)，7.81(d，J＝7.6Hz，1H)，7.58-7.51(m，2H)，7.41-7.33(m，2H)，7.27(s，1H)，7.19(s，1H)，7.08(d，J＝9.2Hz，1H)，5.76(s，1H)，3.42(s，2H)，3.29(s，3H)，3.01(s，3H)，2.79(s，3H)，2.64(s，3H)，2.30(s，3H)，1.59(d，J＝7.2Hz，3H)；ESI-MS(m/z)：553.4[M+H] ⁺ 。

example 81

Preparation of (R) -2- (5- ((4- ((1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide

Step a): preparation of 2-fluoro-N-methoxy-N-methyl-3- (trifluoromethyl) benzamide

2-fluoro-3- (trifluoromethyl) benzoic acid (5.0 g,24.035 mmol), dimethylhydroxylamine hydrochloride (2.8 g,28.841 mmol), HATU (13.5 g, 35.227 mmol), DIPEA (9.3 g,71.925 mmol) and dichloromethane (100 mL) were added to the reaction flask and stirred at room temperature for 1h. After the reaction, adding water (150 mL), quenching the reaction, extracting with dichloromethane (150 mL. Times.3), combining organic phases, washing with water (200 mL. Times.2) in sequence, saturated saline (200 mL), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 2-fluoro-N-methoxy-N-methyl-3- (trifluoromethyl) benzamide; yield 87.0%; ESI-MS (m/z): 252.0[ M+H ]] ⁺ 。

Step b): preparation of 2-fluoro-3- (trifluoromethyl) acetophenone

2-fluoro-N-methoxy-N-methyl-3- (trifluoromethyl) benzamide (6.3 g,25.099 mmol) was dissolved in tetrahydrofuran (60 mL), and methyl bromomagnesium bromide (16.7 mL,50.199mmol, 3M) was added dropwise under ice, and after the dropwise addition was completed, the mixture was warmed to room temperature and stirred for 1h. After the reaction was completed, the reaction mixture was quenched by dropwise addition to an ice-water mixture (100 mL), extracted with ethyl acetate (100 ml×3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give 2-fluoro-3- (trifluoromethyl) acetophenone; the yield thereof was found to be 79.4%.

Step c-g): preparation of (R) -2- (5- ((4- ((1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide

Preparation method referring to steps b to f of example 77, (R) -2- (5- ((4- ((1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl quinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide was obtained in 44.7% yield; ¹ H NMR(400MHz，DMSO-d ₆ ) δ8.25(s，1H)，7.94(d，J＝2.8Hz，1H)，7.82(t，J＝7.2Hz，1H)，7.72(d，J＝2.4Hz，1H)，7.63(t，J＝7.2Hz，1H)，7.41-7.33(m，3H)，7.11(m，1H)，5.79(q，J＝7.2Hz，1H)，3.85(s，3H)，3.59(s，2H)，3.38(s，3H)，3.02(s，3H)，2.80(s，3H)，2.28(s，3H)，1.64(d，J＝7.2Hz，3H)；ESI-MS(m/z)：571.2[M+H] ⁺ 。

example 82

Preparation of (R) -2- (5- ((4- ((1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide

Preparation method referring to example 38, (R) -2- (5- ((4- ((1- (2-fluoro-3- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide was obtained in 37.6% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.59(s，1H)，8.20(d，J＝7.2Hz，1H)，7.81(t，J＝6.8Hz，1H)，7.63(t，J＝7.2Hz，1H)，7.54(d，J＝2.4Hz，1H)，7.39(d，J＝9.2Hz，1H)，7.35(t，J＝7.6Hz，1H)，7.26(d，J＝2.8Hz，1H)，7.19(d，J＝2.8Hz，1H)，7.08(d J＝9.2，1H)，5.78(m，1H)，3.42(s，2H)，3.29(s，3H)，3.01(s，3H)，2.78(s，3H)，2.27(s，3H)，1.64(d，J＝7.2Hz，3H)；ESI-MS(m/z)：557.2[M+H] ⁺ 。

example 83

Preparation of 2- (5- ((4- ((1- (1, 1-difluoro-2, 3-dihydro-1H-inden-4-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -NN-dimethylacetamide formate salt

Preparation method referring to example 77, purification by Pre-HPLC (method 2) afforded 2- (5- ((4- ((1- (1, 1-difluoro-2, 3-dihydro-1H-inden-4-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate in 24.2% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.75(s，1H)，8.23(d，J＝7.2Hz，1H)，8.14(s，1H)，7.93(s，1H)，7.70(s，1H)，7.67(d，J＝8.0Hz，1H)，7.40-7.36(m，3H)，7.33(s，1H)，7.09(d，J＝9.2Hz，1H)，5.62-5.55(m，1H)，3.84(s，3H)，3.59(s，2H)，3.37(s，3H)，3.18-3.11(m，2H)，3.02(s，3H)，2.80(s，3H)，2.69-2.58(m，2H)，2.32(s，3H)，1.60(d，J＝6.8Hz，3H)；ESI-MS(m/z)：561.2[M+H] ⁺ 。

Example 84

Preparation of (R) -2- (5- ((4- ((1- (1, 1-difluoro-2, 3-dihydro-1H-inden-4-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetylamide hydrochloride

Preparation method referring to example 33, purification by Pre-HPLC (method 1) gives (R) -2- (5- ((4- ((1- (1, 1-difluoro-2, 3-dihydro-1H-inden-4-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetylamide hydrochloride in 8.5% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ14.22(s，1H)，11.73(s，1H)，10.08(d，J＝6.4Hz，1H)，7.80(s，1H)，7.75(d，J＝6.4Hz，1H)，7.56(d，J＝9.2Hz，1H)，7.51-7.41(m，2H)，7.36(s，1H)，7.26(d，J＝9.2Hz，1H)，7.20(s，1H)，5.79(m，1H)，3.43(s，2H)，3.33(s，3H)，3.28-3.11(m，2H)，3.03(s，3H)，2.80(s，3H)，2.70-2.59(m，2H)，2.54(s，3H)，1.71(d，J＝7.2Hz，3H)；ESI-MS(m/z)：547.0[M+H] ⁺ 。

example 85

Preparation of (R) -2- (4- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide formate salt

Step a): (R) -N ⁶ -2-dimethyl-N ⁴ Preparation of- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazoline-4, 6-diamine

(R) -6-bromo-2-methyl-N- (1- (3-nitro-5-) trifluoromethyl) phenyl) ethyl) quinazolin-4-amine (200 mg,0.439 mmol), methylamine hydrochloride (298 mg,4.390 mmol), cesium carbonate (2148 mg,6.591 mmol), X-phos (42 mg,0.088 mmol), pd (dba) ₂ (29 mg,0.052 mmol) and toluene (10 ml) were added to the flask, and after 3min of nitrogen bubbling, the temperature was raised to 120℃and stirred for 16h. After the reaction, cooling to room temperature, adding ethyl acetate (5 mL), stirring at room temperature for 10min, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain (R) -N ⁶ -2-dimethyl-N ⁴ - (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazoline-4, 6-diamine in 73.0% yield; ESI-MS (m/z): 406.1[ M+H ]] ⁺ 。

Step b): preparation of (R) -N, N-dimethyl-2- (4- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) -2-oxopyridin-1 (2H) -yl) acetamide

(R) -N ⁶ -2-dimethyl-N ⁴ - (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazoline-4, 6-diamine (120 mg, 0.298 mmol), 2- (4-bromo-2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide (115 mg,0.444 mmol), caesium carbonate (193 mg,0, 592 mmol), X-phos (28 mg,0.059 mmol), pd (dba) ₂ (17 mg,0.030 mmol) and toluene (2 ml) were charged into a reaction flask, and after 3 times of nitrogen substitution, the mixture was heated under reflux and stirred for 16 hours. The reaction solution was cooled to room temperature, ethyl acetate (10 mL) was added and stirred at room temperature for 10min, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give (R) -N, N-dimethyl-2- (4- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) -2-oxopyridin-1 (2H) -yl) acetamide in 26.2% yield; ESI-MS (m/z): 584.2[ M+H ] ] ⁺ 。

Step c): preparation of (R) -2- (4- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide formate salt

(R) -N, N-dimethyl-2- (4- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) -2-oxopyridin-1 (2H) -yl) acetamide (45 mg,0.077 mmol), iron powder (150 mg), saturated aqueous ammonium chloride (5 mL) and methanol (5 mL) were added to the reaction flask and stirred at 100deg.C for 1H. After the reaction, cooling to room temperature, filtering, eluting a filter cake with methanol, combining filtrate, concentrating under reduced pressure to remove methanol, adding water for dilution, extracting (10 mL multiplied by 2) with dichloromethane, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the obtained crude product by Prep-HPLC (method 2) to obtain (R) -2- (4- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methyl quinazolin-6-yl) (methyl) amino) -2-oxo-pyridin-1 (2H) -yl) -N, N-dimethyl acetamide formate, and the yield is 25.1%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.36(d，J＝8.0Hz，1H)，8.33(s，1H)，8.17(s，2H)，7.66(d，J＝8.0Hz，1H)，7.60-7.57(m，1H)，7.20(d，J＝8.0Hz，1H)，6.90(s，1H)，6.86(s，1H)，6.70(s，1H)，5.63-5.61(m，1H)，5.58-5.52(m，3H)，5.45(s，1H)，4.64(s，2H)，3.32(s，3H)，3.03(s，3H)，2.83(s，3H)，2.42(s，3H)，1.54(d，J＝8.0Hz，3H)；ESI-MS(m/z)：554.3[M+H] ⁺ 。

example 86

Preparation of (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-carbonylpyridin-1 (2H) -yl) -N, N-dimethylacetamide formate salt

Preparation method referring to example 85, (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-carbonylpyridin-1 (2H) -yl) -N, N-dimethylacetamide formate was obtained in 90.7% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.26(s，1H)，8.13(s，1H)，7.59(s，1H)，7.56(s，1H)，7.43-7.38(m，2H)，7.12(d，J＝9.2Hz，1H)，6.90(s，1H)，6.87(s，1H)，6.71(s，1H)，6.46(d，J＝9.6Hz，1H)，5.66-5.58(m，1H)，5.54(s，2H)，4.78(s，2H)，3.27(s，3H)，3.04(s，3H)，2.85(s，3H)，2.38(s，3H)，1.58(d，J＝7.2Hz，3H)；ESI-MS(m/z)：554.6[M+H] ⁺ 。

example 87

(R)-N ⁴ - (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -N ⁶ - (5- (2- (dimethylamino) ethyl) -6-methoxypyridin-3-yl) -N ⁶ Preparation of 2-dimethylquinazoline-4, 6-diamine formate

(R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (3-nitro-5- (trifluoromethyl)) benzene)Group) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -N, N-dimethylacetamide (300 mg,0.502 mmol) and THF (5 ml) were added to the reaction flask, lithium aluminum hydride (95 mg,2.510 mmol) was added in portions and stirred at room temperature for 16h. After the completion of the reaction, the reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 2) to give (R) -N ⁴ - (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -N6- (5- (2- (dimethylamino) ethyl) -6-methoxypyridin-3-yl) -N6, 2-dimethylquinazolin-4, 6-diamine formate salt, yield 28.6%;1H NMR (400 MHz, DMSO-d 6) delta 8.17 (s, 2H), 8.13 (d, J=8.0 Hz, 2H), 7.88 (s, 1H), 7.68 (s, 1H), 7.44 (s, 1H), 7.39 (d, J=8.0 Hz, 1H), 6.90 (s, 1H), 6.87 (s, 1H), 6.70 (s, 1H), 5.61-5.58 (m, 1H), 5.53 (s, 1H), 3.88 (s, 3H), 3.35 (s, 3H), 2.67-2.63 (m, 2H), 2.47-2.45 (m, 2H), 2.36 (s, 3H), 2.18 (s, 6H), 1.57 (d, J=8.0 Hz, 3H). ESI-MS (m/z): 554.2[ M+H ] ] ⁺ 。

Example 88

Preparation of (R) -5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -3- (2- (dimethylamino) ethyl) pyridin-2-ol formate salt

Preparation method referring to example 38, purification by Pre-HPLC (method 2) gives (R) -5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -3- (2- (dimethylamino) ethyl) pyridin-2-ol formate in 44.2% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.18(s，2H)，8.09(d，J＝8.0Hz，1H)，7.52(d，J＝4.0Hz，1H)，7.39(d，J＝12.0Hz，1H)，7.26(s，1H)，7.21(s，1H)，7.06(s，1H)，6.90(s，1H)，6.87(s，1H)，6.70(s，1H)，5.63-5.56(m，2H)，5.53(s，1H)，3.25(s，3H)，2.54-2.52(m，4H)，2.35(s，3H)，2.23(s，6H)，1.57(d，J＝4.0Hz，3H)；ESI-MS(m/z)：540.3[M+H] ⁺ 。

example 89

Preparation of (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (6-methylpyridin-2-yl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -N, N-dimethylacetamide

Preparation method referring to example 35, (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (6-methylpyridin-2-yl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -N, N-dimethylacetamide was obtained in a yield of 64.2%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.17(d，J＝8.0Hz，1H)，7.95(s，1H)，7.69(s，1H)，7.62(m，1H)，7.41(d，J＝7.6Hz，1H)，7.36(s，1H)，7.25(d，J＝8.4Hz，1H)，7.14-7.10(m，2H)，5.66-5.59(m，1H)，3.85(s，3H)，3.60(s，2H)，3.37(s，3H)，3.02(s，3H)，2.80(s，3H)，2.48(s，3H)，2.34(s，3H)，1.61(d，J＝7.2Hz，3H)；ESI-MS(m/z)：500.0[M+H] ⁺ 。

example 90

Preparation of (R) -2- (2-hydroxy-5- (methyl (2-methyl-4- ((1- (6-methylpyridin-2-yl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -N, N-dimethylacetamide

Preparation method referring to example 38, (R) -2- (2-hydroxy-5- (methyl (2-methyl-4- ((1- (6-methylpyridin-2-yl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -N, N-dimethylacetamide was obtained in 37.8% yield; 1H NMR (400 MHz, DMSO-d 6) δ11.61 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.62 (t, J=16.0 Hz, 1H), 7.52 (s, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.2-7.23 (m, 2H), 7.20 (s, 1) H)，7.12-7.08(m，2H)，5.64-5.59(m，1H)，3.57(s，2H)，3.27(s，3H)，3.01(s，3H)，2.80(s，3H)，2.48(s，3H)，2.33(s，3H)，1.62(d，J＝4.0Hz，3H)；ESI-MS(m/z)：486.0[M+H] ⁺ 。

Example 91

Preparation of (R) -2- (4- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide formate salt

Step a): (R) -N ⁴ - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -N ⁶ Preparation of 2-dimethylquinazoline-4, 6-diamine (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-4-amine (360 mg,0.878 mmol), methylamine hydrochloride (560 mg,8.780 mmol), cesium carbonate (4.30 g,13.171 mmol), X-phos (84 mg,0.176 mmol), pd (dba) ₂ (50 mg,0.088 mmol) and toluene (2 ml) were added to the reaction flask, nitrogen was replaced 3 times, and the mixture was warmed to reflux and stirred for 16h. After the reaction, cooling to room temperature, adding ethyl acetate (5 mL), stirring at room temperature for 10min, filtering, concentrating the filtrate under reduced pressure, purifying the residue by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain (R) -N4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -N6, 2-dimethylquinazoline-4, 6-diamine with a yield of 50.6%; ESI-MS (m/z): 361.2[ M+H ]] ⁺ 。

Step b): preparation of (R) -2- (4- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide formate salt

(R) -N ⁴ - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -N ⁶ 2-Dimethylquinazoline-4, 6-diamine, (160 mg,0.444 mmol), 2- (4-bromo-2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide (173 mg,0.666 mmol), cesium carbonate (290 mg,0.888 mmol), X-phos (4)2mg,0.088 mmol), bis (dibenzylideneacetone) palladium (25 mg,0.044 mmol) and toluene (2 mL) were added to the reaction flask, nitrogen was replaced 3 times, and the mixture was warmed to reflux and stirred for 16h. The reaction solution was cooled to room temperature, ethyl acetate (10 mL) was added and stirred at room temperature for 10min, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1), and the crude product obtained was purified by Prep-HPLC (method 2) to give (R) -2- (4- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide formate in 21.0% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.72(s，1H)，8.48(d，J＝8.0Hz，1H)，8.36(s，1H)，8.14(s，1H)，7.70-7.65(m，2H)，7.61-7.59(m，1H)，7.50(t，J＝12.0Hz，1H)，7.38-7.10(m，1H)，7.29(s，1H)，7.23(d，J＝8.0Hz，1H)，5.80(s，1H)，5.63(s，1H)，5.46(d，J＝4.0Hz，1H)，4.65(s，2H)，3.33(s，3H)，3.03(s，3H)，2.84(s，3H)，2.37(s，3H)，1.59(d，J＝8.0Hz，3H)；ESI-MS(m/z)：539.1[M+H] ⁺ 。

example 92

Preparation of (R) -2- (3- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-carbonylpyridazin-1 (6H) -yl) -N, N-dimethylacetamide formate salt

Step a): 2- (3-bromo-6-carbonylpyridazin-1 (6H) -yl) acetic acid ethyl ester

6-bromopyridazin-3 (2H) -one (5.0 g,28.573 mmol), ethyl 2-bromoacetate (5.2 g,31.437 mmol) and DMF (5 mL) were added sequentially to the reaction flask, cooled to 0deg.C, then added anhydrous potassium carbonate (4.7 g, 34.292 mmol) and stirred at 0deg.C for 1.5H. The reaction solution was filtered, the filter cake was rinsed with ethyl acetate (30 mL. Times.3), the filtrate was washed with saturated brine (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give ethyl 2- (3-bromo-6-carbonylpyridazin-1 (6H) -yl) acetate, yield The rate is 95.2%; ESI-MS (m/z): 262.1[ M+H ]] ⁺ 。

Step b): preparation of 2- (3-bromo-6-carbonylpyridazin-1 (6H) -yl) acetic acid

Ethyl 2- (3-bromo-6-carbonylpyridazin-1 (6H) -yl) acetate (1.0 g,3.830 mmol) was dissolved in a mixed solvent of THF (10 mL) and methanol (2 mL), and an aqueous lithium hydroxide solution (4.5 mL,3 mol/L) was added thereto to react under stirring at 25℃for 1H. Concentrating under reduced pressure, adjusting the pH of the residue to be 2.0 with 15% hydrochloric acid, stirring at room temperature for 10min, filtering, washing the filter cake with water (20 mL×2), and vacuum drying to obtain 2- (3-bromo-6-carbonyl pyridazin-1 (6H) -yl) acetic acid with a yield of 72.4 °; ESI-MS (m/z): 234.0[ M+H ]] ⁺ 。

Step c): preparation of 2- (3-bromo-6-carbonylpyridazin-1 (6H) -yl) -N, N-dimethylacetamide

2- (3-bromo-6-carbonylpyridazin-1 (6H) -yl) acetic acid (640.0 mg,2.746 mmol), dimethylamine hydrochloride (335.9 mg,4.120 mmol), 2- (3H- [1,2, 3)]Triazole [4,5-b ]]Pyridin-3-yl) -1, 3-tetramethylurea hexafluorophosphate (1.6 g,4.120 mmol), DIPEA (887.2 mg,6.865 mmol) and dichloromethane (10 mL) were added sequentially to the reaction flask and reacted under stirring at 25℃for 30min. Quenching reaction with water (20 mL), separating, washing organic phase with saturated saline (20 mL×2), drying with anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure to obtain 2- (3-bromo-6-carbonyl pyridazin-1 (6H) -yl) -N, N-dimethylacetamide with yield of 91.3%; ESI-MS (m/z): 261.1[ M+H ] ] ⁺ 。

Step d): preparation of (R) -2- (3- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-carbonylpyridazin-1 (6H) -yl) -N, N-dimethylacetamide formate salt

(R) -N ⁴ - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -N ⁶ 2-Dimethylquinazoline-4, 6-diamine (100.0 mg,0.277 mmol), 2- (3-bromo-6-carbonylpyridazin-1 (6H) -yl) -N, N-dimethylacetamide (108.2 mg,0.416 mmol), X-Phos (52.8 mg,0.111 mmol), cs ₂ CO ₃ (241.4mg，0.741mmol)，Pd(dba) ₂ (42.6 mg,0.074 mmol) and toluene (5 mL) were sequentially added to a reaction flask, nitrogen was replaced three times, and the temperature was raisedThe reaction was carried out at 105℃for 5h. After the reaction was completed, cooled to room temperature, quenched with water (30 mL), extracted with ethyl acetate (30 ml×2), the organic phases were combined, washed with saturated brine (30 mL), and the organic phase was concentrated under reduced pressure, and the resulting crude product was purified by Prep-HPLC (method 2) to give (R) -2- (3- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-carbonylpyridazin-1 (6H) -yl) -N, N-dimethylacetamide formate in 42.4% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.40(d，J＝7.6Hz，1H)，8.22(s，1H)，8.13(s，1H)，7.67(t，J＝7.2Hz，1H)，7.62-7.56(m，2H)，7.49(t，J＝6.8Hz，1H)，7.28(t，J＝8.0Hz，1H)，7.23(s，1H)，7.09(d，J＝10.0Hz，1H)，6.79(d，J＝10.0Hz，1H)，5.84-5.76(m，1H)，4.82(s，2H)，3.33(s，3H)，3.04(s，3H)，2.86(s，3H)，2.34(s，3H)，1.59(d，J＝7.2Hz，3H)；ESI-MS(m/z)：540.6[M+H] ⁺ 。

example 93

Preparation of (R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-carbonylpyridazin-1 (6H) -yl) -N, N-dimethylacetamide formate salt

Preparation method referring to example 85, (R) -2- (3- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-carbonylpyridazin-1 (6H) -yl) -N, N-dimethylacetamide formate was obtained in 92.8% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.63(s，1H)，8.31(d，J＝8.0Hz，1H)，8.19(s，1H)，8.13(s，1H)，7.61-7.55(m，2H)，7.08(d，J＝9.6Hz，1H)，6.89(s，1H)，6.85(s，1H)，6.77(d，J＝10.0，1H)，6.70(s，1H)，5.60-5.54(m，1H)，5.52(s，2H)，4.82(s，2H)，3.32(s，3H)，3.04(s，3H)，2.86(s，3H)，2.40(s，3H)，1.54(d，J＝7.2Hz，3H)；ESI-MS(m/z)：555.6[M+H] ⁺ 。

example 94

Preparation of (R) -2- (3- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide formate salt

Step a): preparation of (R) -2- (3- ((4- ((1- (3- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide

(R) -N ⁴ - (1- (3- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) phenyl) ethyl) -N ⁶ 2-Dimethylquinazoline-4, 6-diamine (70.0 mg,0.144 mmol), 2- (3-bromo-6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide (56 mg,0.216 mmol), cs ₂ CO ₃ (140mg，0.432mmol)，Pd(dba) ₂ (33 mg,0.058 mmol), X-phos (55 mg,0.115 mmol) and toluene (5 mL) were added sequentially to the flask, nitrogen was replaced three times, and the temperature was raised to 105℃and the reaction was stirred for 16h. After the reaction was completed, the reaction was cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give (R) -2- (3- ((4- ((1- (3- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide in a yield of 84.0%; ESI-MS (m/z): 666.4[ M+H ] ] ⁺ 。

Step b): preparation of (R) -2- (3- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide formate salt

(R) -2- (3- ((4- ((1- (3- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide (84 mg,0.126 mmol) was dissolved in THF (5 mL), tetrabutylammonium fluoride (42 mg,0.152 mmol) was added and stirred at room temperature for 2H. The reaction solution was concentrated under reduced pressure, and the crude product obtained was purified by Prep-HPLC (method 2) to give (R) -2- (3- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide formate in a yield of 35.0%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.38(d，J＝8.0Hz，1H)，8.18(s，1H)，8.13(s，1H)，7.63(s，1H)，7.61-7.55(m，3H)，7.45-7.36(m，2H)，7.07(d，J＝12.0Hz，1H)，6.77(d，J＝12.0Hz，1H)，5.70-5.62(m，1H)，5.59(t，J＝8.0Hz，1H)，4.82(s，2H)，3.87-3.78(s，2H)，3.32(s，3H)，3.04(s，3H)，2.86(s，3H)，2.40(s，3H)，1.59(d，J＝8.0Hz，3H)；ESI-MS(m/z)：552.1[M+H] ⁺ 。

example 95

Preparation of (R) -2- (4- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide

Preparation method referring to example 91, purification by Prep-HPLC (method 3) yielded (R) -2- (4- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -N, N-dimethylacetamide in 11.5% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ7.95(d，J＝8.0Hz，1H)，7.75(s，1H)，7.65-7.61(m，1H)，7.48(s，2H)，7.34(t，J＝7.6Hz，2H)，7.09(d，J＝8.8Hz，1H)，7.04(s，1H)，5.96-5.90(m，2H)，5.84-5.81(m，1H)，5.72-5.64(m，1H)，4.68-4.57(m，4H)，3.02(s，3H)，2.83(s，3H)，2.81(d，J＝4.8Hz，3H)，2.31(s，3H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：551.2[M+H] ⁺ 。

Example 96

Preparation of (R) -2- (5- ((4- ((1- (4- (difluoromethyl) -1H-indol-6-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate salt

Step a): preparation of 2-methyl-3-nitrobenzaldehyde

2-methyl-3-nitrobenzyl alcohol (5.0 g,29.911 mmol) and methylene chloride (50 mL) were added to the flask, and dess-martin reagent (15.22 g,35.894 mmol) was added in portions at 0deg.C and reacted at room temperature for 15min. Filtering, concentrating the filtrate under reduced pressure, diluting with ethyl acetate (50 mL), filtering, concentrating the filtrate under reduced pressure, and purifying the obtained crude product by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/10) to obtain 2-methyl-3-nitrobenzaldehyde with a yield of 97.5%.

Step b): preparation of 5-bromo-2-methyl-3-nitrobenzaldehyde

2-methyl-3-nitrobenzaldehyde (4.82 g, 29.178 mmol), NBS (6.23 g,35.015 mmol), concentrated sulfuric acid (15 mL) and trifluoroacetic acid (50 mL) were added to the reaction flask and reacted at 60℃for 3 hours. Cooling to room temperature, concentrating under reduced pressure, adding methyl tert-butyl ether (200 mL), saturated sodium thiosulfate aqueous solution (200 mL) and saturated sodium bicarbonate aqueous solution to adjust to pH=7, stirring at room temperature for 1h, separating liquid, extracting aqueous phase with methyl tert-butyl ether (100 mL), combining organic phases, washing with saturated saline (100 mL), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying the obtained crude product by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/15), obtaining 5-bromo-2-methyl-3-nitrobenzaldehyde with a yield of 47.9%; ¹ H NMR(400MHz，DMSO-d ₆ )δ10.25(s，1H)，8.42(s，1H)，8.25(s，1H)，2.60(s，3H)。

Step c): preparation of 5-bromo-1- (difluoromethyl) -2-methyl-3-nitrobenzene

5-bromo-2-methyl-3-nitrobenzaldehyde (3.41 g,13.981 mmol) and methylene chloride (34 mL) were added to the flask, DAST (3.38 g,20.972 mmol) was added at 0deg.C, and the mixture was reacted at room temperature for 0.5h. Saturated aqueous sodium thiosulfate (50 mL) was added, the pH was adjusted to 6 with saturated sodium bicarbonate solution, dichloromethane (50 mL) was added, the liquid separated, the aqueous phase was extracted with dichloromethane (50 mL), the organic phases were combined, washed with saturated brine (50 ml×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/20) to give 5-bromo-1- (difluoromethyl) -2-methyl-3-nitrobenzene in 90.2% yield.

Step d): preparation of 2- (4-bromo-2- (difluoromethyl) -6-nitrophenyl) -N, N-dimethylvinyl-1-amine

5-bromo-1- (difluoromethyl) -2-methyl-3-nitrobenzene (3.35 g,12.607 mmol), DMF-DMA (3.0 g,25.214 mmol) and DMF (33 mL) were added to the reaction flask and reacted at 140℃for 1h. Cooled to room temperature, saturated brine (100 mL) was added, extracted with ethyl acetate (50 ml×2), the organic phases were combined, washed with saturated brine (50 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/10) to give 2- (4-bromo-2- (difluoromethyl) -6-nitrophenyl) -N, N-dimethylvinyl-1-amine in 69.5% yield.

Step e): preparation of 6-bromo-4- (difluoromethyl) -1H-indole

2- (4-bromo-2- (difluoromethyl) -6-nitrophenyl) -N, N-dimethylvinyl-1-amine (2.01 g,6.275 mmol), iron powder (1.05 g, 18.8235 mmol) and acetic acid (20 mL) were added to a reaction flask and stirred under nitrogen at 90deg.C for 1h. Cooled to room temperature, ethyl acetate (50 mL) was added, filtration was performed, the filter cake was rinsed with ethyl acetate (20 ml×2), the filtrates were combined, concentrated under reduced pressure, diluted with saturated aqueous sodium bicarbonate (100 mL) and ethyl acetate (100 mL), the aqueous phase was extracted with ethyl acetate (50 mL), the organic phases were combined, washed with saturated brine (50 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/20) to give 6-bromo-4- (difluoromethyl) -1H-indole in 54.0% yield.

Step f): preparation of benzyl 6-bromo-4- (difluoromethyl) -1H-indole-1-carboxylate

6-bromo-4- (difluoromethyl) -1H-indole (814 mg,3.308 mmol), 4-dimethylaminopyridine (40 mg,0.331 mmol), triethylamine (502 mg, 4.962mmol) and dichloromethane (8 mL) were added to a reaction flask, benzyl chloroformate (677 mg,3.970 mmol) was added dropwise at 0deg.C, and reacted for 0.5H at room temperature. Saturated sodium bicarbonate (30 mL) and dichloromethane (30 mL) are added, stirred and mixed evenly, the solution is separated, the organic phase is washed by saturated saline (30 mL), dried by anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/20) to obtain 6-bromo-4- (difluoromethyl) -1H-indole-1-carboxylic acid benzyl ester with the yield of 54.1%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.45(s，1H)，7.95-7.94(m，1H)，7.71(s，1H)，7.60(d，J＝7.2Hz，2H)7.51-7.24(m，4H)，6.96-6.91(m，1H)，5.55(s，2H)。

Step g): preparation of benzyl 6-acetyl-4- (difluoromethyl) -1H-indole-1-carboxylate

Benzyl 6-bromo-4- (difluoromethyl) -1H-indole-1-carboxylate (681 mg,1.791 mmol), tributyl (1-ethoxyvinyl) stannane (776 mg,2.149 mmol), pd (PPh) ₃ ) ₂ Cl ₂ (63 mg,0.089 mmol) and triethylamine (457 mg,4.477 mmol) were added to 1, 4-dioxane (7 mL), and the reaction was stirred at 100deg.C for 2h. Cooling to room temperature, adding ethyl acetate (50 mL), potassium fluoride (1 g,17.21 mmol) and water (10 mL), stirring for 30min, filtering, eluting the filter cake with ethyl acetate (20 mL. Times.2), separating the filtrate, washing with saturated saline (20 mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, dissolving the residue with ethyl acetate (50 mL), adding ethyl acetate chloride solution (10 mL, 4M) at room temperature, stirring for 10min, adding saturated sodium bicarbonate aqueous solution to adjust the pH of the reaction solution to neutral, separating the solution, washing the organic phase with saturated saline (30 mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the obtained crude product by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/10), to obtain 6-acetyl-type-4- (difluoromethyl) -1H-indole-1-carboxylic acid benzyl ester in 99.2% yield; ESI-MS (m/z): 344.0[ M+H ] ] ⁺ 。

Step h): preparation of ethyl 6- (1- (((R) -tert-butylsulfinyl) imino) ethyl) -4- (difluoromethyl) -1H-indole-1-carboxylate

Benzyl 6-acetyl-4- (difluoromethyl) -1H-indole-1-carboxylate (610 mg,1.777 mmol), (R) - (+) -tert-butylsulfinamide (360 mg,2.971 mmol), tetraethyltitanate (2.09 g,5.943mmol, 65%) and THF (7 mL) were added to the reaction flask and reacted at 80℃for 1H. The reaction solution was cooled to room temperature, ethyl acetate (50 mL) and water (50 mL) were added, stirred at room temperature for 10min, filtered, the filter cake was rinsed with ethyl acetate (20 ml×2), the filtrates were combined, the aqueous phase was extracted with ethyl acetate (30 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/5) to give ethyl 6- (1- (((R) -tert-butylsulfinyl) imino) ethyl) -4- (difluoromethyl) -1H-indole-1-carboxylate, yield 49.3%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.88(s，1H)，8.09-8.01(m，2H)，7.55-7.28(m，1H)，6.95-6.94(m，1H)，4.53-4.47(m，2H)，2.82(s，3H)，1.45-1.40(m，3H)，1.26(s，9H)；ESI-MS(m/z)：385.1[M+H] ⁺ 。

step i): preparation of (R) -6- (1- (((R) -tert-butylsulfinyl) amino) ethyl) -4- (difluoromethyl) -1H-indole-1-carboxylic acid ethyl ester

Ethyl 6- (1- (((R) -tert-butylsulfinyl) imino) ethyl) -4- (difluoromethyl) -1H-indole-1-carboxylate (317 mg, 0.823mmol) and THF/water mixture (4.5 ml, v/v=8/1) were added to the reaction flask, naBH4 (62 mg,1.649 mmol) was added with stirring at-78 ℃ and reacted at room temperature for 0.5H. The reaction was quenched with water (10 mL), extracted with ethyl acetate (15 ml×2), the organic phases combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/3) to give (R) -6- (1- (((R) -tert-butylsulfinyl) amino) ethyl) -4- (difluoromethyl) -1H-indole-1-carboxylic acid ethyl ester, yield 78.1%; ESI-MS(m/z)：387.1[M+H] ⁺ 。

Step j): preparation of (R) -6- (1-aminoethyl) -4- (difluoromethyl) -1H-indole-1-carboxylic acid ethyl ester hydrochloride

(R) -6- (1- (((R) -tert-butylsulfinyl) amino) ethyl) -4- (difluoromethyl) -1H-indole-1-carboxylic acid ethyl ester (145 mg,0.375 mmol) was dissolved in ethyl acetate (3.5 mL), ethyl acetate hydrochloride solution (4M, 0.5 mL) was added, reacted at room temperature for 3H, concentrated under reduced pressure to dryness, and the obtained crude product was directly subjected to the next reaction.

Step k): preparation of (R) -6- (1- ((6-bromo-2-methylquinazolin-4-yl) amino) ethyl) -4- (difluoromethyl) -1H-indole-1-carboxylic acid ethyl ester

6-bromo-4-chloro-2-methyl quinazoline (89 mg,0.345 mmol), (R) -6- (1-aminoethyl) -4- (difluoromethyl) -1H-indole-1-carboxylic acid ethyl ester hydrochloride (110 mg,0.345 mmol), DIPEA (134 mg,1.035 mmol) and DMF (2 mL) were added to the reaction flask and stirred under nitrogen at 80℃for 1H. After the reaction was completed, the reaction was cooled to room temperature, quenched with saturated brine (15 mL), extracted with ethyl acetate (20 ml×2), the organic phases were combined, washed with saturated brine (15 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the crude product obtained was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/1) to give (R) -6- (1- ((6-bromo-2-methylquinazolin-4 yl) amino) ethyl) -4- (difluoromethyl) -1H-indole-1-carboxylic acid ethyl ester, 75.4% yield; ESI-MS (m/z): 503.1[ M+H ] ] ⁺ 。

Step l): preparation of (R) - (4- (difluoromethyl) -6- (1- ((6- ((5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyridin-3-yl) (methyl) amino) -2-methylquinazolin-4-yl) amino) ethyl-1H-indole-1-carboxylic acid ethyl ester

(R) -6- (1- ((6-bromo-2-methylquinazolin-4 yl) amino) ethyl) -4- (difluoromethyl) -1H-indole-1-carboxylic acid ethyl ester (130 mg,0.258 mmol), 2- (2-methoxy-5- (methylamino) phenyl) -N, N-dimethylacetylamide hydrochloride (58 mg,0.258 mmol), cs ₂ CO ₃ (168mg，0.516mmol)、X-Phos(49mg，0.103mmol)、Pd(dba) ₂ (29 mg,0.052 mmol) and toluene (2 mL) were added to the flask, replaced with nitrogen three times, and the reaction was stirred at 90℃for 1h.After the reaction was completed, cooled to room temperature, concentrated under reduced pressure, and the crude product obtained was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/10) to give ethyl (R) - (4- (difluoromethyl) -6- (1- ((6- ((5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyridin-3-yl) (methyl) amino) -2-methylquinazolin-4-yl) amino) ethyl-1H-indole-1-carboxylate, yield 91.9%; ESI-MS (m/z): 646.2[ m+h ]] ⁺ 。

Step m): preparation of (R) -2- (5- ((4- ((1- (4- (difluoromethyl) -1H-indol-6-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide formate salt

(R) - (4- (difluoromethyl) -6- (1- ((6- ((5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyridin-3-yl) (methyl) amino) -2-methylquinazolin-4-yl) amino) ethyl-1H-indole-1-carboxylate (153 mg,0.237 mmol), lithium hydroxide monohydrate (40 mg,0.948 mmol), THF (3 mL) and water (1 mL) were added to the reaction flask, warmed to reflux and stirred for 1H after the reaction, cooled to room temperature, the reaction solution was adjusted to ph=2 to 3 with 1N hydrochloric acid, extracted with ethyl acetate (20 ml×2), the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude product purified by Prep-HPLC (method 2) to give (R) -2- (5- ((1- (4- (difluoromethyl) -1H-indol-6-yl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) -2-methoxypyridin-3.33.7-yl acetamide in yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.64(s，1H)，11.32(s，1H)，8.20(d，J＝8.0Hz，1H)，8.14(s，1H)，7.93(s，1H)，7.73(s，1H)，7.63(s，1H)，7.44-7.33(m，4H)，7.32-7.12(m，1H)，7.10-7.08(m，1H)，6.53(s，1H)，5.83-5.79(m，1H)，3.84(s，3H)，3.58(s，2H)，3.36(s，3H)，3.01(s，3H)，2.79(s，3H)，2.36(s，3H)，1.67(d，J＝7.2Hz，3H)；ESI-MS(m/z)：574.2[M+H] ⁺ 。

example 97

Preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluoro-5-hydroxyphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide formate salt

Step a): preparation of 3-bromo-2-fluoro-5-iodobenzoic acid

3-bromo-2-fluorobenzoic acid (7.0 g,0.032 mol) and concentrated sulfuric acid (50 mL) are added into a reaction bottle, stirred in ice bath, N-iodosuccinimide (7.6 g,0.034 mol) is added in batches, the mixture is naturally warmed to room temperature and stirred for 2h, the reaction solution is poured into ice water (100 mL), stirred for 30min at room temperature, filtered, the filter cake is added with saturated sodium thiosulfate aqueous solution (50 mL), stirred for 30min at room temperature, filtered, and the filter cake is rinsed with a proper amount of water and dried in vacuum to obtain 3-bromo-2-fluoro-5-iodobenzoic acid with 99.4% yield.

Step b): preparation of 3-bromo-2-fluoro-5-hydroxybenzoic acid

3-bromo-2-fluoro-5-iodobenzoic acid (150.0 mg,0.355 mmol), sodium hydroxide (6.4 g,0.164 mol), cuprous oxide (665.3 mg,4.633 mmol) and water (110 mL) were added to the reaction flask and reacted at 100deg.C with stirring for 16h. After the reaction, cooling to room temperature, adjusting the pH to be 1-2 with 1N hydrochloric acid aqueous solution, filtering, extracting the filtrate with ethyl acetate (100 mL), drying the organic phase anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, adding petroleum ether (100 mL) into the residue, stirring for 30min at room temperature, filtering, and vacuum drying the filter cake to obtain the 3-bromo-2-fluoro-5-hydroxybenzoic acid with the yield of 69.3%.

Step c): preparation of 3-bromo-5- ((tert-butyldimethylsilyl) oxy) -2-fluorobenzoic acid

3-bromo-2-fluoro-5-hydroxybenzoic acid (5.2 g,0.022 mol), triethylamine (5.6 g,0.055 mol), t-butyldimethylsilyl chloride (5.0 g,0.033 mol) and dichloromethane (100 mL) were added to a reaction flask, stirred at room temperature for 2 hours, aqueous 1N hydrochloric acid (50 mL) was added, the separated solution was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=50/1) to give 3-bromo-5- ((t-butyldimethylsilyl) oxy) -2-fluorobenzoic acid in a yield of 64.9%.

Step d): preparation of methyl 3-bromo-5- ((tert-butyldimethylsilyl) oxy) -2-fluorobenzoate

3-bromo-5- ((tert-butyldimethylsilyl) oxy) -2-fluorobenzoic acid (4.6 g,0.013 mol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.3 g,0.017 mol), 4-dimethylaminopyridine (3.2 g,0.026 mol), methanol (5 mL) and methylene chloride (50 mL) were added to a reaction flask, the reaction was replaced 3 times with nitrogen, stirred at room temperature for 2 hours, diluted with water (50 mL) and stirred, the separated organic phase was washed successively with 1N aqueous hydrochloric acid (50 mL), water (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give methyl 3-bromo-5- ((tert-butyldimethylsilyl) oxy) -2-fluorobenzoate in 71.6% yield.

Step e): preparation of 3-bromo-5- ((tert-butyldimethylsilyloxy) -2-fluorophenyl) methanol

Methyl 3-bromo-5- ((tert-butyldimethylsilyl) oxy) -2-fluorobenzoate (2.1 g,0.005 mol) and THF (25 mL) were added to the reaction flask, lithium aluminum hydride (0.6 g,0.016 mol) was added in portions, and stirred at room temperature for 1h. Saturated ammonium chloride solution (20 mL) and methylene chloride (20 mL) were added and the reaction was quenched by stirring for 10 min. Filtering, eluting the filter cake with dichloromethane, separating the filtrate, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain 3-bromo-5- ((tert-butyldimethylsilyloxy) -2-fluorophenyl) methanol in a yield of 51.6%.

Step f): preparation of 3-bromo-5- ((tert-butyldimethylsilyl) oxy) -2-fluorobenzaldehyde

3-bromo-5- ((tert-butyldimethylsilyloxy) -2-fluorophenyl) methanol (2.1 g, 0.006mol), dessert-martin oxidant (4.0 g,0.009 mol) and dichloromethane (20 mL) were added to a reaction flask, stirred at room temperature for 1h, filtered, the filtrate was washed with saturated aqueous sodium bicarbonate (20 mL), the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure and the residue purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1) to give 3-bromo-5- ((tert-butyldimethylsilyloxy) -2-fluorobenzaldehyde in 47.6% yield.

Step g): preparation of (3-bromo-5- (difluoromethyl) -4-fluorophenoxy) (tert-butyl) dimethylsilane

3-bromo-5- ((tert-butyldimethylsilyl) oxy) -2-fluorobenzaldehyde (1.5 g,0.005 mol) and methylene chloride (15 mL) were added to the reaction flask, and diethylaminosulfur trifluoride (1.5 g, 0.010mol) was added dropwise under stirring in an ice bath, and the reaction was stirred in an ice bath for 30 minutes after the addition, and then warmed to room temperature and stirred for 2 hours. After the completion of the reaction, the reaction was quenched by slowly dropping a saturated aqueous sodium bicarbonate solution (5 mL), extracting with methylene chloride (20 mL), drying the organic phase over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=50/1) to obtain (3-bromo-5- (difluoromethyl) -4-fluorophenoxy) (tert-butyl) dimethylsilane in 42.7% yield.

Step h): preparation of 1- (5- ((tert-butyldimethylsilyl) oxy) -3- (difluoromethyl) -2-fluorophenyl) ethan-1-one

(3-bromo-5- (difluoromethyl) -4-fluorophenoxy) (tert-butyl) dimethylsilane (500 mg,1.408 mmol), triethylamine (284 mg,2.817 mmol), tri-n-butyl (vinyl) tin (670 mg, 1.830 mmol), bis (triphenylphosphine) palladium (II) dichloride (100 mg,0.141 mmol) and 1, 4-dioxane (10 mL) were added to a reaction flask, nitrogen was replaced 3 times, warmed to 100 ℃ and stirred for 3h, after the reaction was completed, cooled to room temperature, saturated aqueous potassium fluoride (20 mL) was added, stirred at room temperature for 10min, filtered, the filter cake was rinsed with ethyl acetate (20 mL), the filtrate was extracted with ethyl acetate (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (5 mL), ethyl acetate solution (10 mL,4 m) of hydrogen chloride was added, stirred at room temperature for 10min, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was eluted through silica gel (5 m ethyl acetate/1-4 m) to give 1-fluoro-1- ((1-ethyl-1-tert-butyl) fluoroketone) as a 1-fluoro-ether-containing 1- ((1.45% of ethyl acetate).

Step i): preparation of (R, Z) -N- (1- (5- (tert-butyldimethylsilyl) oxy) -3- (difluoromethyl) -2-fluorophenyl) ethylene) -2-methylpropane-2-sulfonamide

1- (5- ((tert-Butyldimethylsilyl) oxy) -3- (difluoromethyl) -2-fluorophenyl) ethan-1-one (350 mg,1.099 mmol), (R) -tert-butylsulfinamide (160 mg,1.322 mmol), tetraethyl titanate (380 mg,1.667 mmol) and tetrahydrofuran (4 mL) were added to the reaction flask, and the mixture was stirred at 80℃under nitrogen. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) and ethyl acetate (10 mL) were added and stirred at room temperature for 10 minutes, and the mixture was filtered, and the organic phase was separated, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give (R, Z) -N- (1- (5- (tert-butyldimethylsilyl) oxy) -3- (difluoromethyl) -2-fluorophenyl) ethylene) -2-methylpropane-2-sulfonamide in 36.8% yield; ESI-MS (m/z): 422.2[ M+H ]] ⁺ 。

Step j): preparation of (R) -N- ((R) -1- (5- ((tert-butyldimethylsilyl) oxy) -3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide

(R, Z) -N- (1- (5- (tert-butyldimethylsilyl) oxy) -3- (difluoromethyl) -2-fluorophenyl) ethylene) -2-methylpropane-2-sulfonamide (120 mg, 0.284 mmol), THF (2 mL) and water (0.1 mL) were added to the reaction flask, sodium borohydride (17 mg,0.428 mmol) was added thereto, the reaction was stirred at-78deg.C for 1 hour, the reaction was warmed to room temperature and stirred for 30min, water (10 mL) and ethyl acetate (20 mL) were added for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1), to give (R) -N- ((R) -1- (5- ((tert-butyldimethylsilyl) oxy) -3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide in 72.5% yield; ESI-MS (m/z): 424.2[ M+H ] ] ⁺ 。

Step k): preparation of (R) -1- (5- ((tert-butyldimethylsilyl) oxy) -3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine

(R) -N- ((R) -1- (5- ((tert-Butyldimethylsilyl) oxy) -3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide (87 mg,0.206 mmol) and THF (1 mL) were added to a reaction flask, and then a 1, 4-dioxane solution (2 mL, 4N) of hydrogen chloride was added thereto, and the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressureThe (R) -1- (5- ((tert-butyldimethylsilyl) oxy) -3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine was obtained and used in the next reaction without purification. ESI-MS (m/z): 320.2[ M+H ]] ⁺ 。

Step l): preparation of (R) -6-bromo-N- (1- (5- ((tert-butyldimethylsilyl) oxy) -3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-4-amine

(R) -1- (5- ((tert-butyldimethylsilyl) oxy) -3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine (80 mg,0.225 mmol), 6-bromo-4-chloro-2-methylquinazoline (87 mg,0.337 mmol), DIPEA (232 mg,1.798 mmol) and N, N-dimethylformamide (2 mL) were added to the reaction flask, the reaction mixture was stirred at 80 ℃ for 1h, water (10 mL) and ethyl acetate (20 mL) were added to stir the mixture, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (R) -6-bromo-N- (1- (5- ((tert-butyldimethylsilyl) oxy) -3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-4-amine in 82.5% yield by silica gel column chromatography purification (eluent: petroleum ether/ethyl acetate=5/1); ESI-MS (m/z): 540.1[ M+H ] ] ⁺

Step m): preparation of (R) -2- (5- ((4- ((1- (5- ((tert-butyldimethylsilyl) oxy) -3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide

(R) -6-bromo-N- (1- (5- ((tert-butyldimethylsilyl) oxy) -3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylquinazolin-4-amine (45 mg,0.083 mmol), cesium carbonate (55 mg,0.167 mmol), X-phos (8.3 mg,0.017 mmol), pd (dba) ₂ (5.0 mg,0.008 mmol), 2- (2-methoxy-5- (methylamino) pyridin-3-yl) -N, N-dimethylacetamide (28 mg,0.125 mmol) and toluene (2 mL) were added to the reaction flask, and after 3 times nitrogen substitution, stirred at 100℃for 3h. After the reaction was completed, cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give (R) -2- (5- ((4- ((1- (5- ((tert-butyldimethylsilyl) oxy) -3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide,yield 81.6%; ESI-MS (m/z): 683.3[ M+H ]] ⁺ 。

Step n): preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluoro-5-hydroxyphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide formate salt

(R) -2- (5- ((4- ((1- (5- ((tert-butyldimethylsilyl) oxy) -3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl quinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide (40 mg,0.059 mmol), THF (2 mL) and tetrabutylammonium fluoride in THF (1 m,2 mL) were added to the reaction flask, stirred at room temperature for 30min, dichloromethane (20 mL) was added, washed with 1N aqueous hydrochloric acid (10 mL), the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 2) to give (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluoro-5-hydroxyphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide in 27.8% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.38(s，1H)，8.15(d，J＝8.0Hz，1H)，8.14(s，1H)，7.95(d，J＝4.0Hz，1H)，7.74(s，1H)，7.40(d，J＝8.0Hz，1H)，7.35(s，1H)，7.14(t，J＝56.0Hz，1H)，7.11(d，J＝8.0Hz，1H)，7.03(s，1H)，6.79(s，1H)，5.79-5.75(m，1H)，3.85(s，3H)，3.59(s，2H)，3.38(s，3H)，3.02(s，3H)，2.80(s，3H)，2.31(s，3H)，1.34-1.28(m，3H)；ESI-MS(m/z)：569.2[M+H] ⁺ 。

example 98

Preparation method referring to example 38, purification by Pre-HPLC (method 2) gives (R) -2- (5- (. About.4- ((1- (3- (difluoromethyl) -2-fluoro-5-hydroxyphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide formate salt, yield 33.6%; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.63(s，1H)，9.70(s，1H)，8.13(s，2H)，7.59(s，1H)，7.42(s，1H)，7.28(s，1H)，7.19(s，1H)，7.15(t，J＝56.0Hz，1H)，7.13(s，1H)，7.01(s，1H)，6.81(s，1H)，5.80(m，1H)，3.42(s，2H)，3.31(s，3H)，3.02(s，3H)，2.79(s，3H)，2.34(s，3H)，1.60(d，J＝8.0Hz，3H)；ESI-MS(m/z)：555.2[M+H] ⁺ 。

Example 99

Preparation of (R) -2- (5- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide

Step a): preparation of 2-bromo-6-methyl-4-nitroaniline

2-methyl-4-nitroaniline (1.5 g,9.859 mmol) and glacial acetic acid (20 mL) are added to the reaction flask, bromine (1.8 g,12.953 mmol) is added at room temperature and the reaction is stirred at room temperature for 1.5h. The reaction solution was poured into ice water (100 mL), stirred for 10min, filtered, and the filter cake was rinsed with water (20 mL) and saturated aqueous sodium bicarbonate (20 mL) in this order, dried in vacuo to give 2-bromo-6-methyl-4-nitroaniline in 97.0% yield.

Step b): preparation of 1- (2-bromo-6-methyl-4-nitrophenyl) -2-diazonium fluoroborate

2-bromo-6-methyl-4-nitroaniline (6.0 g,26.087 mmol) and aqueous fluoroboric acid (30 mL, 50%) were added to the reaction flask, the reaction mixture was cooled to 0-5℃and an aqueous solution (4.0 mL) of sodium nitrite (2.0 g,25.986 mmol) was slowly added dropwise, and the mixture was reacted at 0-10℃for 1h. After the reaction, the mixture was filtered, and the filter cake was rinsed with an aqueous solution of fluoroboric acid (30 mL, 50%) and ethyl acetate (10 mL. Times.2), and the filter cake was dried under vacuum to give 1- (2-bromo-6-methyl-4-nitrophenyl) -2-diazonium fluoroborate in 78.6% yield.

Step c): preparation of 1-bromo-2-fluoro-3-methyl-5-nitrobenzene

1- (2-bromo-6-methyl-4-nitrophenyl) -2-diazonium fluoroborate (7.0 g,21.277 mmol) was added to the reaction flask and reacted for 30min with stirring at 155 ℃. The reaction solution was cooled to room temperature and the crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=100/1 to 30/1) to give 1-bromo-2-fluoro-3-methyl-5-nitrobenzene in 44.3% yield.

Step d-j): preparation of (R) -2- (5- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide

Preparation method referring to steps a-g of example 75, (R) -2- (5- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide was isolated by Prep-HPLC (method 3) in 16.9% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.07(brs，1H)，7.94(s，1H)，7.78(s，1H)，7.40(d，J＝8.0Hz，1H)，7.34(s，1H)，7.12(d，J＝8.0Hz，1H)，6.47-6.44(m，1H)，6.28-6.26(m，1H)，5.77-5.73(m，1H)，4.77(s，2H)，3.85(s，3H)，3.59(s，2H)，3.38(s，3H)，3.02(s，3H)，2.80(s，3H)，2.33(s，3H)，2.11(s，3H)，1.54(d，J＝8.0Hz，3H)；ESI-MS(m/z)：532.0[M+H] ⁺ 。

example 100

Preparation of (R) -2- (5- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide

(R) -2- (5- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methyl quinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethyl Acetamide (60 mg,0.113 mmol) and aqueous hydrogen bromide (2 mL, 48%) were added to the reaction flask and the reaction stirred at 80℃for 0.5h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product obtained was purified by Prep-HPLC (method 3) to give (R) -2- (5- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide in a yield of 35.9%; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.50(s，1H)，7.99(d，J＝8.0Hz，1H)，7.58(s，1H)，7.39(d，J＝8.0Hz，1H)，7.25(s，1H)，7.17(d，J＝4.0Hz，1H)，7.08(d，J＝8.0Hz，1H)，6.46-6.44(m，1H)，6.28-6.26(m，1H)，5.76-5.73(m，1H)，4.76(s，2H)，3.42(s，2H)，3.28(s，3H)，3.01(s，3H)，2.78(s，3H)，2.32(s，3H)，2.11(s，3H)，1.54(d，J＝8.0Hz，3H)；ESI-MS(m/z)：518.3[M+H] ⁺ 。

example 101

Preparation of (R) -N, N-dimethyl-2- (3- (methyl (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) -6-oxopyridazin-1 (6H) -yl) acetamide

(R) -N ⁶ 2-dimethyl-N ⁴ - (1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) quinazoline-4, 6-diamine (120 mg,0.321 mmol), 2- (3-bromo-6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide (125 mg,0.481 mmol), cs ₂ CO ₃ (312mg，0.961mmol)、Pd(dba) ₂ (37 mg,0.064 mmol), X-phos (61 mg,0.128 mmol) and toluene (5 mL) were sequentially added to the reaction flask, nitrogen was replaced three times, and the temperature was raised to 105℃and the reaction was stirred for 5 hours. The reaction mixture was cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting crude product was purified by Prep-HPLC (method 3) to give (R) -N, N-dimethyl-2- (3- (methyl (2-methyl-4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) amino) -6-oxopyridazin-1 (6H) -yl) acetamide in 74.5% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.50(d，J＝8.0Hz，1H)，8.21(s，1H)，7.76(d，J＝8.0Hz，1H)，7.60-7.50(m，3H)，7.34(t，J＝8.0Hz，1H)，7.08(d，J＝8.0Hz，1H)，6.79(d，J＝8.0Hz，1H)，5.76-5.68(m，1H)，4.83(s，2H)，3.31(s，3H)，3.04(s，3H)，2.86(s，3H)，2.65(s，3H)，2.34(s，3H)，1.54(d，J＝6.8Hz，3H)；ESI-MS(m/z)：554.0[M+H] ⁺ 。

example 102

Preparation of (R) -2- (3- ((4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide

Step a): (R) -N ⁴ - (1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -N ⁶ Preparation of 2-dimethylquinazoline-4, 6-diamine

(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -2-methylquinazolin-4-amine (300 mg,0.739 mmol), methylamine hydrochloride (495mg, 7.389 mmol), cs ₂ CO ₃ (2.9g，8.867mmol)、X-Phos(70mg，0.148mmol)、Pd(dba) ₂ (42 mg,0.074 mmol) and toluene (20 mL) were added to the reaction flask, and nitrogen was purged into the flask for 1min, and the mixture was stirred at 110℃under sealed conditions to react for 16h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give (R) -N ⁴ - (1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -N ⁶ 2-dimethylquinazoline-4, 6-diamine in 50.1% yield; ESI-MS (m/z): 357.2[ M+H ]] ⁺ 。

Step b): preparation of (R) -2- (3- ((4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide

(R) -N ⁴ - (1- (3- (difluoromethyl) -2-methylphenyl) ethyl) -N ⁶ 2-Dimethylquinazoline-4, 6-diamine (65 mg, 0.183mmol), 2- (3-bromo-6-oxopyridazin-1 (6H) -yl-N, N-dimethylacetamide (48 mg, 0.183mmol), cs ₂ CO ₃ (119mg，0.366mmol)、X-Phos(17.1mg，0.037mmol)、Pd(dba) ₂ (10 mg,0.018 mmol) and toluene (5 mL) were added to the flask, nitrogen was replaced 3 times, and the reaction was stirred at 105℃for 16h. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 3) to give (R) -2- (3- ((4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide in 40.8% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.47(s，1H)，8.22(s，1H)，7.65(d，J＝7.6Hz，1H)，7.62-7.51(m，2H)，7.38(d，J＝7.6Hz，1H)，7.28(t，J＝7.6Hz，1H)，7.21(t，J＝54.8Hz，1H)，7.07(d，J＝9.6Hz，1H)，6.79(d，J＝10.0Hz，1H)，5.75(p，J＝7.2Hz，1H)，4.82(s，2H)，3.33(s，3H)，3.04(s，3H)，2.86(s，3H)，2.56(s，3H)，2.36(s，3H)，1.53(d，J＝7.2Hz，3H)；ESI-MS(m/z)：536.2[M+H] ⁺ 。

example 103

Preparation of (R) -2- (3- ((4- ((1- (3-cyano) -2-methylphenyl) ethyl) amino) -2-methyl quinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide

Steps a-b): preparation of (R) -2- (3- ((4- ((1- (3-cyano) -2-methylphenyl) ethyl) amino) -2-methyl quinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide

Preparation method referring to example 102, the crude product obtained was purified by silica gel column chromatography (eluent/methanol/dichloromethane=1/10) followed by Prep-HPLC (method 3) to give (R) -2- (3- ((4- ((1- (3-cyano) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide in 17.2% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.48(d，J＝6.8Hz，1H)，8.20(s，1H)，7.78(d，J＝7.6Hz，1H)，7.63-7.54(m，3H)，7.36(t，J＝7.6Hz，1H)，7.07(d，J＝10.0Hz，1H)，6.79(d，J＝9.6Hz，1H)，5.68-5.61(m，1H)，4.82(s，2H)，3.33(s，3H)，3.04(s，3H)，2.86(s，3H)，2.72(s，3H)，2.36(s，3H)，1.53(d，J＝6.8Hz，3H)；ESI-MS(m/z)：511.0[M+H] ⁺ 。

Example 104

Preparation of (R) -2- (4- ((4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin) -1 (2H) -yl) -N, N-dimethylacetamide

Preparation method referring to example 101, purification by Pre-HPLC (method 3) yielded (R) -2- (4- ((4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin) -1 (2H) -yl) -N, N-dimethylacetamide in 36.7% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.51(d，J＝7.2Hz，1H)，8.35(s，1H)，7.69-7.61(m，2H)，7.57(d，J＝8.8，1H)，7.38(d，J＝7.6Hz，1H)，7.28(t，J＝7.6Hz，1H)，7.21(d，J＝7.6Hz，1H)，7.21(t，J＝54.8Hz，1H)，5.76(p，J＝7.2Hz，1H)，5.61(d，J＝7.6，1H)，5.44(s，1H)，4.64(s，2H)，3.32(s，3H)，3.02(s，3H)，2.83(s，3H)，2.56(s，3H)，2.37(s，3H)，1.52(d，J＝7.2Hz，3H)；ESI-MS(m/z)：535.2[M+H] ⁺ 。

example 105

Preparation of (R) -2- (3- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide

Step a): preparation of (R) -2- (3- ((4- ((1- (3- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide

Preparation method referring to example 101, the crude product obtained was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20) to give (R) -2- (3- ((4- ((1- (3- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide in a yield of 68.0%; ESI-MS (m/z): 684.3[ M+H ] ] ⁺ 。

Step b): preparation of (R) -2- (3- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide

(R) -2- (3- ((4- ((1- (3- (2- ((tert-butyldimethylsilyl) oxy) -1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide (70 mg,0.102 mmol), tetrabutylammonium fluoride in THF (153.0. Mu.L, 0.153mmol, 1M) and THF (1 mL) were added to a reaction flask and reacted at room temperature for 5min. Ethyl acetate (20 mL), saturated brine (10 mL) and 1M aqueous hydrogen chloride (10 mL) were added sequentially, the solution was separated, the organic phase was washed sequentially with saturated aqueous sodium bicarbonate (20 mL), saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 3) to give (R) -2- (3- ((4- ((1- (3- (1, 1-difluoro-2-hydroxyethyl)) 1- (1, 1-difluoro-2-hydroxyethyl) ethyl)-2-fluorophenyl) ethyl) amino) -2-methyl quinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N, N-dimethylacetamide in a yield of 17.2%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.39(d，J＝7.2Hz，1H)，8.22(s，1H)，7.66-7.54(m，3H)，7.44-7.37(m，1H)，7.24(t，J＝7.6Hz，1H)，7.09(d，J＝10.0Hz，1H)，6.79(d，J＝10.0Hz，1H)，5.84-5.76(m，1H)，5.70(t，J＝6.4Hz，1H)，4.82(s，2H)，3.99-3.87(m，2H)，3.33(s，3H)，3.04(s，3H)，2.86(s，3H)，2.35(s，3H)，1.58(d，J＝7.2Hz，3H)；ESI-MS(m/z)：570.0[M+H] ⁺ 。

example 106

Preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyrimidin-1 (2H) -yl) -N, N-dimethylacetylamide hydrochloride

Step a): (R) -N ⁴ - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -N ⁶ - (2-methoxypyrimidin-5-yl) -N ⁶ Preparation of 2-dimethylquinazoline-4, 6-diamine

(R) -N ⁴ - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -N ⁶ 2-Dimethylquinazoline-4, 6-diamine (209 mg,0.583 mmol), 5-bromo-2-methoxypyrimidine (132 mg,0.696 mmol), cs ₂ CO ₃ (382mg，1.166mmol)、X-Phos(58mg，0.120mmol)、Pd(dba) ₂ (33 mg,0.058 mmol) and toluene (4 mL) were added to the flask, nitrogen was replaced three times, and the temperature was raised to 105℃and the reaction was stirred for 3h. After the reaction, cooling to room temperature, filtering, eluting the filter cake with ethyl acetate (20 mL), combining the filtrates, concentrating under reduced pressure, and purifying the crude product by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 to 1/1) to obtain (R) -N ⁴ - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -N ⁶ - (2-methoxypyrimidin-5-yl) -N ⁶ 2-dimethylquinazoline-4, 6-diamine in 58.9% yield; ESI-MS (m/z): 469.2[ M+H ]] ⁺ 。

Step b): preparation of (R) -5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) pyrimidin-2 (1H) -one

(R) -N at room temperature ⁴ - (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -N ⁶ - (2-methoxypyrimidin-5-yl) -N ⁶ 2-Dimethylquinazoline-4, 6-diamine (160 mg,0.340 mmol) and 33wt% hydrogen bromide acetic acid solution (4 mL) were sequentially added to the reaction flask, and the temperature was raised to 80℃for 30min. After the reaction is finished, cooling to room temperature, and concentrating under reduced pressure to obtain (R) -5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl quinazoline-6-yl) (methyl) amino) pyrimidine-2 (1H) -ketone, wherein the yield is 100.0%; ESI-MS (m/z): 455.1[ M+H ] ] ⁺ 。

Step c): preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyrimidin-1 (2H) -yl) -N, N-dimethylacetylamide hydrochloride

(R) -5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) pyrimidin-2 (1H) -one (160 mg,0.350 mmol) was dissolved in DMF (3 mL), followed by the addition of potassium carbonate (145 mg,1.050 mmol), 2-bromo-N, N-dimethylacetamide (69 mg,0.420 mmol), and the reaction was warmed to 60℃for 1H. After the reaction was completed, cooling to room temperature, filtering, quenching the filtrate with saturated ammonium chloride (10 mL), extracting with ethyl acetate (15 mL), washing twice with saturated brine (15 ml×2), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the residue by Prep-HPLC (method 1) to obtain (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyrimidin-1 (2H) -yl) -N, N-dimethylacetylamide hydrochloride in 9.5% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ14.38(s，1H)，10.22(s，1H)，8.61(s，1H)，8.20(s，1H)，7.92(s，1H)，7.82-7.79(m，1H)，7.60-7.51(m，2H)，7.34-7.29(m，2H)，7.13-7.00(m，1H)，5.99-5.93(m，1H)，4.76(s，2H)，3.34(s，3H)，3.00(s，3H)，2.83(s，3H)，2.50(s，3H)，1.70(d，J＝6.8Hz，3H)；ESI-MS(m/z)：540.4[M+H] ⁺ 。

example 107

Preparation of (R) -6- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2- (2- (dimethylamino) ethyl) pyridazin-3 (2H) -one dihydrochloride

Preparation method referring to example 101, purification by Prep-HPLC (method 1) afforded (R) -6- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2- (2- (dimethylamino) ethyl) pyridazin-3 (2H) -one dihydrochloride in 74.5% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ14.80(s，1H)，10.49(s，1H)，10.15(s，1H)，8.79(d，J＝10.8Hz，1H)，7.99(d，J＝7.6Hz，1H)，7.90(s，1H)，7.81(t，J＝7.6Hz，1H)，7.55(t，J＝7.6Hz，1H)，7.37-7.32(m，1H)，7.24(s，1H)，7.21(t，J＝44.0Hz，1H)，6.91(d，J＝10.0Hz，1H)，6.04-5.97(m，1H)，4.42-4.28(m，2H)，3.55-3.47(m，2H)，3.43(s，3H)，2.87(d，J＝4.8Hz，6H)，2.59(s，3H)，1.72(d，J＝7.2Hz，3H)；ESI-MS(m/z)：526.3[M+H] ⁺ 。

example 108

Preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) -N, N-dimethylacetylamide hydrochloride

Preparation method referring to example 101, purification by Prep-HPLC (method 1) gives (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -2-fluoro)Phenyl) ethyl) amino) -2-methyl-quinazolin-6-yl) (methyl) amino) -1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) -N, N-dimethylacetylamide hydrochloride in 42.3% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ14.38(s，1H)，10.19-10.04(m，1H)，7.88-7.81(m，2H)，7.78(s，1H)，7.59-7.56(m，2H)，7.39-7.31(m，2H)，7.25-7.11(m，2H)，6.03-5.96(m，1H)，3.46(s，2H)，3.45(s，3H)，3.35(s，3H)，3.04(s，3H)，2.80(s，3H)，2.54(s，3H)，1.74(d，J＝6.8Hz，3H)；ESI-MS(m/z)：553.6[M+H] ⁺ 。

example 109

Preparation of (R) -6- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2- (2- (dimethylamino) ethyl) pyridazin-3 (2H) -one hydrochloride

Step a): preparation of (R) -2- (2- (dimethylamino) ethyl) -6- ((4- ((1- (2-fluoro-3-methyl-5-nitrophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) pyridazin-3 (2H) -one

Preparation method referring to example 101, the crude product obtained was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/6) to give (R) -2- (2- (dimethylamino) ethyl) -6- ((4- ((1- (2-fluoro-3-methyl-5-nitrophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) pyridazin-3 (2H) -one in a yield of 90.2%; ESI-MS (m/z): 535.2[ M+H ]] ⁺ 。

Step b): preparation of (R) -6- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2- (2- (dimethylamino) ethyl) pyridazin-3 (2H) -one hydrochloride

(R) -2- (2- (dimethylamino) ethyl) -6- ((4- ((1- (2-fluoro-3-methyl-5-nitrophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) pyridazin-3 (2H) -one (68 mg,0.127 mmol) was dissolved in methanol (3 mL), iron powder (35 mg,0.635 mmol) and saturated ammonium chloride water were addedThe solution (1.5 mL) was reacted at 90℃for 0.5h. The reaction solution was cooled to room temperature, ethyl acetate (20 mL) and water (10 mL) were added, filtration was carried out, the filtrate was separated, the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtration was carried out, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by Prep-HPLC (method 1) to give (R) -6- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2- (2- (dimethylamino) ethyl) pyridazin-3 (2H) -one hydrochloride in a yield of 7.8%; ¹ H NMR(400MHz，DMSO-d ₆ )δ14.79(s，1H)，10.42(s，1H)，8.76(s，1H)，8.08-7.92(m，1H)，7.83(d，J＝9.2Hz，1H)，7.25(d，J＝10.0Hz，2H)，7.05-6.87(m，2H)，5.96-5.87(m，1H)，4.50-4.21(m，2H)，3.55-3.48(m，2H)，3.45(s，3H)，2.86(s，6H)，2.60(s，3H)，2.49(s，2H)，2.24(s，3H)，1.68(d，J＝6.8Hz，3H)；ESI-MS(m/z)：505.3[M+H] ⁺ 。

Example 110

(R)-N ⁴ - (1- (5-amino-2-fluoro-3-methylphenyl) ethyl) -N ⁶ - (5- (2- (dimethylamino) ethyl) -6-methoxypyridin-3-yl) -N ⁶ Preparation of 2-dimethylquinazoline-4, 6-diamine

Step a): preparation of 2- (5- ((4- ((1- (2-fluoro-3-methyl-5-nitrophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide

Preparation method referring to example 101, 2- (5- ((4- ((1- (2-fluoro-3-methyl-5-nitrophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide was obtained in a yield of 85.8%; ESI-MS (m/z): 562.2[ M+H ]] ⁺ 。

Step b): (R) -N ⁴ - (1- (5-amino-2-fluoro-3-methylphenyl) ethyl) -N ⁶ - (5- (2- (dimethylamino) ethyl) -6-methoxypyridin-3-yl) -N ⁶ Preparation of 2-dimethylquinazoline-4, 6-diamine

2- (5- ((4- ((1- (2-fluoro-3-methyl-5-nitrophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide (123 mg,0.219 mmol), lithium aluminum hydride (42 mg,1.115 mmol) and THF (3 mL) were added to a reaction flask and reacted at 50 ℃ with stirring for 1h. The reaction solution was cooled to 0℃and ethyl acetate (20 mL) was added, the reaction was quenched by addition of crystalline sodium sulfate solid (3 g), filtered, the cake was rinsed with ethyl acetate (10 mL), the filtrates were combined, concentrated under reduced pressure, and the crude product was purified by Prep-HPLC (method 3) to give (R) -N ⁴ - (1- (5-amino-2-fluoro-3-methylphenyl) ethyl) -N ⁶ - (5- (2- (dimethylamino) ethyl) -6-methoxypyridin-3-yl) -N ⁶ 2-dimethylquinazoline-4, 6-diamine. Yield 81.8%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.05(d，J＝7.2Hz，1H)，7.88(s，1H)，7.75(s，1H)，7.44(s，1H)，7.38(d，J＝9.2Hz，1H)，7.09(d，J＝9.2，1H)，6.46(d，J＝6.0，1H)，6.27(d，J＝6.4，1H)，5.74(t，J＝7.2Hz，1H)，5.1-4.52(s，2H)，3.88(s，3H)，3.38(s，3H)，2.70-2.63(m，2H)，2.49(s，3H)，2.33(s，3H)，2.21-2.15 (m，5H)，2.11(s，3H)，1.53(d，J＝7.2Hz，3H)；ESI-MS(m/z)：518.0[M+H] ⁺ 。

example 111

Preparation of (R) -5- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -3- (2- (dimethylamino) ethyl) pyridin-2-ol

(R) -N ⁴ - (1- (5-amino-2-fluoro-3-methylphenyl) ethyl) -N ⁶ - (5- (2- (dimethylamino) ethyl) -6-methoxypyridin-3-yl) -N ⁶ 2-Dimethylquinazoline-4, 6-diamine (60 mg,0.116 mmol) and a solution of hydrogen bromide in acetic acid (33%, 2 mL) were added to a reaction flask, and the temperature was raised to 80 ℃The reaction was carried out for 20min. After the reaction is finished, the reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by Prep-HPLC (method 3) to obtain (R) -5- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methyl quinazoline-6-group) (methyl) amino) -3- (2- (dimethylamino) ethyl) pyridine-2-alcohol, and the yield is 9.9%; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.50(s，1H)，8.00(d，J＝8.0Hz，1H)，7.58(s，1H)，7.37(d，J＝9.2Hz，1H)，7.24(s，1H)，7.18(s，1H)，7.05(d，J＝9.2Hz，1H)，6.45(d，J＝6.0Hz，1H)，6.27(d，J＝6.0Hz，1H)，5.80-5.68(m，1H)，4.76(s，2H)，3.27(s，3H)，2.46-2.38(m，4H)，2.32(s，3H)，2.14(s，6H)，2.11(s，3H)，1.53(d，J＝7.2Hz，3H)；ESI-MS(m/z)：504.0[M+H] ⁺ 。

example 112

Preparation of (R) -1- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin) -3-yl) -3-methylimidazolin-2-one

Preparation method referring to example 101, purification by Prep-HPLC (method 3) yielded (R) -1- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin) -3-yl) -3-methylimidazolin-2-one in 21.7% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.19(d，J＝7.2Hz，1H)，7.90(s，1H)，7.78(s，1H)，7.70(t，J＝7.2Hz，1H)，7.57(s，1H)，7.49(t，J＝7.2Hz，1H)，7.42(d，J＝9.2Hz，1H)，7.28(t，J＝7.6Hz，1H)，7.24(t，J＝54.4Hz，1H)，7.22(d，J＝9.2，1H)，5.81(q，J＝7.2Hz，1H)，3.90(s，3H)，3.79-3.69(m，2H)，3.42-3.38(m，5H)，2.71(s，3H)，2.30(s，3H)，1.61(d，J＝7.2Hz，3H)；ESI-MS(m/z)：566.2[M+H] ⁺ 。

Example 113

Preparation of (R) -5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -1- (2- (dimethylamino) ethyl) pyridin-2 (1H) -one hydrochloride

Preparation method referring to example 106, purification by Prep-HPLC (method 1) afforded (R) -5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -1- (2- (dimethylamino) ethyl) pyridin-2 (1H) -one hydrochloride in 27.2% yield; ¹ H NMR(400 MHz，Methanol-d4)δ7.89(d，J＝9.2Hz，2H)，7.77(t，J＝6.4Hz，1H)，7.62-7.51(m，4H)，7.33(t，J＝7.6Hz，1H)，7.04(t，J＝54.4Hz，1H)，6.74(d，J＝9.6Hz，1H)，6.12-6.06(m，1H)，4.49-4.45(m，2H)，3.66(t，J＝5.6Hz，2H)，3.46(s，3H)，3.07(s，6H)，2.63(s，3H)，1.83(d，J＝7.2Hz，3H)；ESI-MS(m/z)：525.2[M+H]+。

example 114

Preparation of (R) -1- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -3-methylimidazolin-2-one

Preparation method referring to example 111, purification by Prep-HPLC (method 3) yielded (R) -1- (5- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -3-methylimidazolin-2-one in 48.6% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.83(s，1H)，8.13(d，J＝7.6Hz，1H)，7.69(t，J＝7.6Hz，1H)，7.56(s 1H)，7.51-7.46(m，2H)，7.40(d，J＝9.2Hz，1H)，7.28(t，J＝7.6Hz，1H)，7.24(t，J＝54.4Hz，1H)，7.23(s，1H)，7.15(d，J＝9.2，1H)，5.82(p，J＝7.2Hz，1H)，3.94-3.83(m，2H)，3.36(t，J＝8.0Hz，2H)，3.29(s，3H)，2.69(s，3H)，2.29(s，3H)，1.61(d，J＝7.2Hz，3H)；ESI-MS(m/z)：552.2[M+H] ⁺ 。

example 115

Preparation of (R) -1- (5- ((4- ((1- (3- (difluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -3-dimethylimidazolin-2-one

Preparation method referring to example 101, purification by Pre-HPLC (method 3) yielded (R) -1- (5- ((4- ((1- (3- (difluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -3-dimethylimidazolin-2-one in 64.5% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.17(d，J＝7.6Hz，1H)，7.89(s，1H)，7.74(s，1H)，7.67(s，1H)，7.64(d，J＝7.8Hz，1H)，7.56(s，1H)，7.48(t，J＝7.6Hz，1H)，7.43(s，1H)，7.41(s，1H)，7.21(d，J＝9.2，1H)，7.03(t，J＝56.0Hz，1H)，5.68(p，J＝7.2Hz，1H)，3.90(s，3H)，3.78-3.69(m，2H)，3.42-3.38(m，5H)，2.71(s，3H)，2.35(s，3H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：548.2[M+H] ⁺ 。

Example 116

Preparation of (R) -1- (5- ((4- ((1- (3- (difluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -3-methylimidazolin-2-one

Preparation method reference example 111, purification by Prep-HPLC (method 3) gives (R) -1- (5- ((4- ((1- (3- (difluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridine-3-yl) -3-methylimidazolin-2-one in 44.1% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.83(s，1H)，8.11(d，J＝8.0Hz，1H)，7.66(s，1H)，7.63(d，J＝7.6Hz，1H)，7.53(s，1H)，7.50-7.44(m，2H)，7.43-7.38(m，2H)，7.22(s，1H)，7.14(d，J＝9.2，1H)，7.02(t，J＝56.0Hz，1H)，5.67(p，J＝7.2Hz，1H)，3.93-3.83(m，2H)，3.35(t，J＝8.0Hz，2H)，3.27(s，3H)，2.68(s，3H)，2.33(s，3H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：534.2[M+H] ⁺ 。

example 117

Preparation of (R) -2- (5- ((4- ((1- (3-amino-5- (difluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxybenzyl) -N, N-dimethylacetamide

Preparation method referring to example 109, prep-HPLC purification (method 3) afforded 2- (5- ((4- (((1R) -1- (3-amino-5- (difluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide in 19.3% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.07(d，J＝8.0Hz，1H)，7.63(s，1H)，7.34(d，J＝9.2Hz，1H)，7.08-7.02(m，2H)，6.99(s，1H)，6.90(s，1H)，6.83(t，J＝56.4Hz，1H)，6.78(s，2H)，6.58(s，1H)，5.64-5.57(m，1H)，5.34(s，2H)，3.76(s，3H)，3.57(s，2H)，3.33(s，3H)，2.98(s，3H)，2.78(s，3H)，2.35(s，3H)，1.56(d，J＝6.8Hz，3H)；ESI-MS(m/z)：549.0[M+H] ⁺ 。

example 118

Preparation of (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (5- (2- ((methylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -N, N-dimethylacetamide

Step a): preparation of benzyl (R) - (2- (5- (1- ((6- ((5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyridin-3-yl) (methyl) amino) -2-methylquinazolin-4-yl) amino) ethyl) thiophen-2-yl) benzyl) (methyl) carbamate

Preparation method referring to example 101, benzyl (R) - (2- (5- (1- ((6- ((5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyridin-3-yl) (methyl) amino) -2-methylpquinazolin-4-yl) amino) ethyl) thiophen-2-yl) benzyl) (methyl) carbamate was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) in 75.3% yield; ESI-MS (m/z): 744.3[ M+H ]] ⁺ 。

Step b): preparation of (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (5- (2- ((methylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -N, N-dimethylacetamide

Benzyl (R) - (2- (5- (1- ((6- ((5- (2- (dimethylamino) -2-oxoethyl) -6-methoxypyridin-3-yl) (methyl) amino) -2-methylquinazolin-4-yl) amino) ethyl) thiophen-2-yl) benzyl) (methyl) carbamate (140 mg,0.181 mmol) was dissolved in methanol (3 mL), 10% Pd/C (39 mg) was added, hydrogen was replaced three times, and stirring was performed at room temperature overnight. Filtering, concentrating the filtrate under reduced pressure, and purifying the residue by Prep-HPLC (method 3) to obtain (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (5- (2- ((methylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) quinazolin-6-yl) amino) pyridin-3-yl) -N, N-dimethylacetamide; the yield was 55.4%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.30(d，J＝8.4Hz，1H)，7.93(s，1H)，7.63(s，1H)，7.49(d，J＝7.6Hz，1H)，7.41(d，J＝9.2Hz，1H)，7.35-7.24(m，4H)，7.15(s，1H)，7.12-7.07(m，2H)，5.99(p，J＝7.2Hz，1H)，3.84(s，3H)，3.66(s，2H)，3.58(s，2H)，3.33(s，3H)，3.00(s，3H)，2.79(s，3H)，2.44(s，3H)，2.25(s，3H)，1.73(d，J＝6.8Hz，3H)；ESI-MS(m/z)：610.3[M+H] ⁺ 。

Example 119

Preparation of (R) -1- (5- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -3-methylimidazolin-2-one

Preparation method referring to example 109, purification by Pre-HPLC (method 3) yielded (R) -1- (5- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methyl quinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -3-methylimidazolin-2-one; yield 32.5%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.15(s，1H)，7.90(s，1H)，7.82(s，1H)，7.56(s，1H)，7.42(d，J＝9.2Hz，1H)，7.21(d，J＝9.2， 1H)，6.46-6.43(m，1H)，6.28-6.25(m，1H)，5.74(p，J＝7.2Hz，1H)，4.79(s，2H)，3.90(s，3H)，3.78-3.69(m，2H)，3.43-3.38(m，5H)，2.70(s，3H)，2.34(s，3H)，2.10(d，J＝2.0Hz，3H)，1.52(d，J＝7.2Hz，3H)；ESI-MS(m/z)：545.3[M+H] ⁺ 。

example 120

Preparation of (R) -1- (5- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -3-methylimidazolin-2-one

Preparation method referring to example 111, purification by Prep-HPLC (method 3) yielded ((R) -1- (5- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methyl quinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -3-methylimidazolin-2-one in 38.8% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.85(s，1H)，8.00(d，J＝7.6Hz，1H)，7.60(s，1H)，7.47(s，1H)，7.39(d，J＝9.2Hz，1H)，7.22(d，J＝2.8Hz，1H)，7.13(d，J＝9.2，1H)，6.45-6.43(m，1H)，6.27-6.25(m，1H)，5.73(p，J＝7.2Hz，1H)，4.77(s，2H)，3.94-3.82(m，2H)，3.36(d，J＝8.0Hz，2H)，3.29(s，3H)，2.68(s，3H)，2.31(s，3H)，2.10(s，3H)，1.52(d，J＝7.2Hz，3H)；ESI-MS(m/z)：531.3[M+H] ⁺ 。

example 121

Preparation of (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (5- (2- ((methylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide

Preparation method referring to example 118, purification by Prep-HPLC (method 3) yielded (R) -2- (2-methoxy-5- (methyl (2-methyl-4- ((1- (5- (2- ((methylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide; the yield was 80.3%; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.27(d，J＝8.4Hz，1H)，7.56(s，1H)，7.50(d，J＝7.2Hz，1H)，7.37(d，J＝9.2Hz，1H)，7.35-7.26(m，3H)，7.15(s，1H)，7.10-7.02(m，3H)，6.98(d，J＝8.8Hz，1H)，6.90(s，1H)，5.99(p，J＝7.2Hz，1H)，3.76(s，3H)，3.68(s，2H)，3.56(s，2H)，3.29(s，3H)，2.98(s，3H)，2.78(s，3H)，2.43(s，3H)，2.26(s，3H)，1.74(d，J＝6.8Hz，3H)；ESI-MS(m/z)：609.3[M+H] ⁺ 。

Example 122

Preparation of (R) -2- (5- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

Preparation method referring to example 109, purified by Prep-HPLC (method 3) in 73.1% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.02(d，J＝6.4Hz，1H)，7.69(s，1H)，7.34(d，J＝9.2Hz，1H)，7.10-7.02(m，2H)，7.01-6.95(m，1H)，6.90(s，1H)，6.46(d，J＝6.0Hz，1H)，6.27(d，J＝6.0Hz，1H)，5.79-5.70(m，1H)，4.78(s，2H)，3.77(s，3H)，3.57(s，2H)，3.35(s，3H)，2.99(s，3H)，2.78(s，3H)，2.32(s，3H)，2.11(s，3H)，1.53(d，J＝7.2Hz，3H))；ESI-MS(m/z)：531.0[M+H] ⁺ 。

example 123

Preparation of (R) -2- (5- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide

(R) -2- (5- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methyl quinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide (200 mg,0.377 mmol) and dichloromethane (15 mL) were added to a reaction flask, boron tribromide (480 mg,1.916 mmol) was added at 0deg.C, and the reaction was carried out at room temperature for 0.5h. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (30 mL), extracted with ethyl acetate (40 mL), the organic phase was washed with saturated brine (20 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting crude product was purified by Prep-HPLC (method 3) to give (R) -2- (5- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide in a yield of 50.1%; ¹ H NMR(400MHz，DMSO-d ₆ )δ9.54(s，1H)，7.99(d，J＝8.0Hz，1H)，7.61(s，1H)，7.31(d，J＝9.2Hz，1H)，7.01(d，J＝9.2Hz，1H)，6.93-6.90(m，1H)，6.88(s，1H)，6.83(d，J＝8.4Hz，1H)，6.46(d，J＝6.0Hz，1H)，6.27(d，J＝6.0Hz，1H)，5.77-5.72(m，1H)，4.78(s，2H)，3.56(s，2H)，3.32(s，3H)，3.01(s，3H)，2.80(s，3H)，2.31(s，3H)，2.11(s，3H)，1.53(d，J＝7.2Hz，3H)；ESI-MS(m/z)：517.0[M+H] ⁺ 。

Example 124

Preparation of (R) -2- (2-hydroxy-5- (methyl (2-methyl-4- ((1- (5- (2- ((methylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide

Preparation method referring to example 111, purification by Prep-HPLC (method 3) gave (R) -2- (2-hydroxy-5- (methyl (2-methyl-4- ((1- (5- (2- ((methylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) quinazolin-6-yl) amino) phenyl) -N, N-dimethylacetamide in a yield of 38.8%; ¹ H NMR(400MHz，DMSO-d ₆ )δ9.55(s，1H)，8.24(d，J＝8.4Hz，1H)，7.51-7.46(m，2H)，7.38-7.19(m，5H)，7.15(s，1H)，7.09(s，1H)，7.01(d，J＝9.2，1H)，6.92-6.86(m，2H)，6.82(d，J＝8.4Hz，1H)，5.98(p，J＝7.2Hz，1H)，3.65(s，2H)，3.56(s，2H)，3.26(s，3H)，3.00(s，3H)，2.79(s，3H)，2.42(s，3H)，2.25(s，3H)，1.73(d，J＝7.2Hz，3H)；ESI-MS(m/z)：595.3[M+H] ⁺ 。

example 125

Preparation of 2- (5- ((4- ((1- (2-amino-3- (difluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

Step a): preparation of 2- (5- ((4- ((1- (3- (difluoromethyl) -2-nitrophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

Preparation method referring to example 101, (eluent: methanol/dichloromethane=1/19) was purified by silica gel column chromatography to give (R) -2- (5- ((4- ((1- (2-fluoro-3-methyl-5-nitrophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide in a yield of 86.4%; ESI-MS (m/z): 578.2[ M+H ] ] ⁺ 。

Step b): preparation of 2- (5- ((4- ((1- (2-amino-3- (difluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

2- (5- ((4- ((1- (3- (difluoromethyl) -2-nitrophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide (120 mg,0.207 mmol) was dissolved in ethyl acetate (2 mL), 10% pd/C (120 mg) was added, hydrogen was replaced three times, and the reaction was carried out at room temperature under a hydrogen atmosphere for 2h. The reaction solution is filtered, the filter cake is leached by ethyl acetate (10 mL), the filtrate is combined and concentrated under reduced pressure, and the obtained crude product is purified by Prep-HPLC (method 3) to obtain 2- (5- ((4- ((1- (2-amino-3- (difluoromethyl) phenyl) ethyl) amino) -2-methyl quinazoline-6-yl) (methyl) amino) -2-methoxy phenyl) -N, N-dimethyl acetamide with the yield of 26.0 percent; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.04(d，J＝8.0Hz，1H)，7.55(s，1H)，7.49(d，J＝7.6Hz，1H)，7.35(d，J＝9.2Hz，1H)，7.24-7.18(m，1H)，7.12-6.90(m，4H)，6.88(s，1H)，6.70(t，J＝7.6Hz，1H)，5.82-5.73(m，1H)，5.67(s，2H)，3.76(s，3H)，3.56(s，2H)，3.29(s，3H)，2.97(s，3H)，2.77(s，3H)，2.42(s，3H)，1.62(d，J＝6.8Hz，3H)；ESI-MS(m/z)：549.0[M+H] ⁺ 。

example 126

Preparation of 2- (5- ((4- ((1- (2-amino-3- (difluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide formate salt

Step a): preparation of 2- (2- ((tert-butyldimethylsilyl) oxy) -5- ((4- ((1- (3- (difluoromethyl) -2-nitrophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) phenyl) -N, N-dimethylacetamide

Preparation method referring to example 101, the crude product obtained was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/19) to give 2- (2- ((tert-butyldimethylsilyl) oxy) -5- ((4- ((1- (3- (difluoromethyl) -2-nitrophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) phenyl) -N, N-dimethylacetamide in a yield of 87.5%; ESI-MS (m/z): 679.3[ M+H ]] ⁺ 。

Step b): preparation of 2- (5- ((4- ((1- (3- (difluoromethyl) -2-nitrophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide

2- (2- ((tert-Butyldimethylsilyl) oxy) -5- ((4- ((1- (3- (difluoromethyl) -2-nitrophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) phenyl) -N, N-dimethylacetamide (190 mg,0.280 mmol), tetrabutylammonium fluoride in THF (310.0. Mu.L, 0.310mmol, 1M) and THF (3 mL) were added to the reaction flask and reacted at room temperature for 5min. The reaction mixture was quenched with saturated brine (20 mL) and aqueous hydrogen chloride (10 mL, 1M), extracted with ethyl acetate (30 mL), the organic phase was washed successively with saturated aqueous sodium bicarbonate (20 mL), saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the crude product obtained was directly subjected to the next reaction in 88.6% yield; ESI-MS m/z=565.2 [ m+h ] ] ⁺ 。

Step c): preparation of 2- (5- ((4- ((1- (2-amino-3- (difluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide formate salt

Preparation method referring to step b of example 125, purification by Prep-HPLC (method 2) afforded 2- (5- ((4- ((1- (2-amino-3- (difluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxyphenyl) -N, N-dimethylacetamide formate in 22.4% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ12.68(s，1H)，9.54(s，1H)，8.13(s，1H)，8.05(s，1H)，7.52-7.45(m，2H)，7.33(d，J＝9.2Hz，1H)，7.22(d，J＝7.6Hz，1H)，7.12-6.96(m，2H)，6.93-6.84(m，2H)，6.84-6.78(m，1H)，6.71(t，J＝7.6Hz，1H)，5.85-5.70(s，1H)，5.66(s，2H)，3.55(s，2H)，3.27(s，3H)，2.99(s，3H)，2.79(s，3H)，2.42(s，3H)，1.62(d，J＝6.8Hz，3H)；ESI-MS(m/z)：535.4[M+H] ⁺ 。

example 127

Preparation of (R) -6- ((4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2- (2- (dimethylamino) ethyl) pyridazin-3 (2H) -one

Preparation method referring to example 101, purification by Prep-HPLC (method 3) yielded (R) -6- ((4- ((1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2- (2- (dimethylamino) ethyl) pyridazin-3 (2H) -one in 19.9% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.41(d，J＝7.2Hz，1H)，8.21(s，1H)，7.64(d，J＝7.6Hz，1H)，7.57(s，2H)，7.38(d，J＝7.6Hz，1H)，7.28(t，J＝7.6Hz，1H)，7.21(t，J＝54.8Hz，1H)，7.04(d，J＝10.0Hz，1H)，6.76(d，J＝10.0Hz，1H)，5.75(p，J＝7.2Hz，1H)，4.06(s，2H)，3.36(s，3H)，2.63(t，J＝6.8Hz，2H)，2.55(s，3H)，2.35(s，3H)，2.21(s，6H)，1.52(d，J＝7.2Hz，3H)；ESI-MS(m/z)：522.3[M+H] ⁺ 。

example 128

Preparation of (R) -2- (5- ((4- ((1- (3-amino-5- (difluoromethoxy) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide

Preparation method referring to example 109, (method 3) was purified by Prep-HPLC to give (R) -2- (5- ((4- ((1- (3-amino-5- (difluoromethoxy) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxyphenyl) -N, N-dimethylacetamide in 36.8% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.03(d，J＝8.4Hz，1H)，7.63(s，1H)，7.36-7.25(m，2H)，7.08-7.02(m，2H)，6.98(d，J＝8.8Hz，1H)，6.90-6.88(m，1H)，6.50(s，1H)，6.39(s，1H)，6.19(s，1H)，5.59-5.52(m，1H)，5.36(s，2H)，3.76(s，3H)，3.57(s，2H)，3.32(s，3H)，2.98(s，3H)，2.78(s，3H)，2.36(s，3H)，1.54(d，J＝7.2Hz，3H)；ESI-MS(m/z)：565.3[M+H] ⁺ 。

Example 129

Preparation of (R) -2- (5- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -1-methyl-2-oxa-1, 2-dihydropyridin-3-yl) -N, N-dimethylacetamide

Preparation method referring to example 109, prep-HPLC purification (method 3) yielded (R) -2- (5- ((4- ((1- (5-amino-2-fluoro-3-methylphenyl) ethyl) amino) -2-methyl quinazolin-6-yl) (methyl) amino) -1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) -N, N-dimethylacetamide in 38.4% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.00(d，J＝8.0Hz，1H)，7.67(s，1H)，7.61(s，1H)，7.39(d，J＝9.2Hz，1H)，7.19(s，1H)，7.11-7.08(m，1H)，6.46-6.44(m，1H)，6.28-6.26(m，1H)，5.78-5.71(m，1H)，4.77(s，2H)，3.45(s，5H)，3.30(s，3H)，3.02(s，3H)，2.78(s，3H)，2.32(s，3H)，2.11(s，3H)，1.53(d，J＝7.2Hz，3H)；ESI-MS(m/z)：532.3[M+H] ⁺ 。

example 130

Preparation of (R) -2- (6- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -4-methoxypyridin-3-yl) -N, N-dimethylacetamide

Preparation method referring to example 101, purification by Prep-HPLC (method 3) gave (R) -2- (6- ((4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -4-methoxypyridin-3-yl) -N, N-dimethylacetamide in 18.1% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.42(d，J＝7.2Hz，1H)，8.35(s，1H)，7.76(s，1H)，7.69-7.64(m，2H)，7.60(d，J＝8.8Hz，1H)，7.49(t，J＝6.8Hz，1H)，7.28(t，J＝7.6Hz，1H)，7.23(t，J＝54.4Hz，1H)，6.20(s，1H)，5.81(p，J＝7.2Hz，1H)，3.59(s，3H)，3.51(s，3H)，3.45(s，2H)，3.04(s，3H)，2.82(s，3H)，2.35(s，3H)，1.58(d，J＝7.2Hz，3H)；ESI-MS(m/z)：553.0[M+H] ⁺ 。

example 131

Preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide

Preparation method referring to example 102, purification by Prep-HPLC (method 3) yielded (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide in 87.8% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.24(d，J＝7.6Hz，1H)，8.02(d，J＝12.4Hz，2H)，7.94(s，1H)，7.79(s，1H)，7.65(s，1H)，7.40(d，J＝9.2Hz，1H)，7.35(s，1H)，7.15(t，J＝55.6Hz，1H)，7.11(d，J＝9.2，1H)，5.68(p，J＝7.2Hz，1H)，3.84(s，3H)，3.59(s，2H)，3.37(s，3H)，3.02(s，3H)，2.80(s，3H)，2.33(s，3H)，1.66(d，J＝7.2Hz，3H)；ESI-MS(m/z)：603.2[M+H] ⁺ 。

example 132

Preparation of (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide

Preparation method referring to example 111, purification by Prep-HPLC (method 3) yielded (R) -2- (5- ((4- ((1- (3- (difluoromethyl) -5- (trifluoromethyl) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide in 26.2% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.61(s，1H)，8.19(d，J＝7.6Hz，1H)，8.02(s，1H)，7.99(s，1H)，7.79(s，1H)，7.48(s，1H)，7.40(d，J＝9.2Hz，1H)，7.27(s，1H)，7.18(s，1H)，7.15(t，J＝55.2Hz，1H)，7.08(d，J＝9.2，1H)，5.68(p，J＝7.2Hz，1H)，3.41(s，2H)，3.27(s，3H)，3.01(s，3H)，2.78(s，3H)，2.32(s，3H)，1.66(d，J＝7.2Hz，3H)；ESI-MS(m/z)：589.2[M+H] ⁺ 。

example 133

Preparation of (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-cyclopropylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide

Step a): preparation of (R) -6-bromo-2-cyclopropyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine

6-bromo-4-chloro-2-cyclopropylquinazoline (200 mg,0.709 mmol), (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethan-1-amine hydrochloride (191 mg, 0.09 mmol), DIPEA (274 mg,2.127 mmol) and DMF (10 mL) were added sequentially to the reaction flask, and the mixture was stirred at 80℃under nitrogen. The reaction solution was cooled to room temperature, quenched with saturated aqueous ammonium chloride (30 mL), extracted with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to give (R) -6-bromo-2-cyclopropyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine in a yield of 81.3%; ESI-MS (m/z): 481.0[ M+H ] ] ⁺ 。

Step b): preparation of (R) -2- (5- ((2-cyclopropyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide

(R) -6-bromo-2-cyclopropyl-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinazolin-4-amine (200 mg,0.417 mmol), 2- (2-methoxy-5- (methylamino) pyridin-3-yl) -N, N-dimethylacetamide (93 mg,0.417 mmol), cs ₂ CO ₃ (407mg，1.251mmol)、Pd(dba) ₂ (48 mg,0.083 mmol), X-phos (79 mg,0.166 mmol) and toluene (6 mL) were sequentially added to the reaction flask, nitrogen was replaced three times, and the temperature was raised to 105℃and the reaction was stirred for 2 hours. The reaction mixture was cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (20 ml×3), the organic phases combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give (R) -2- (5- ((2-cyclopropyl-4- ((1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) amino) quinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide in 80.1% yield; ESI-MS (m/z): 624.2[ M+H ]] ⁺ 。

Step c): preparation of (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-cyclopropylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide

Preparation method referring to step b of example 109, purification by Prep-HPLC (method 3) yielded (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-cyclopropylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -N, N-dimethylacetamide in 73.0% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ8.12(d，J＝7.2Hz，1H)，7.92(s，1H)，7.70(s，1H)，7.37(d，J＝9.2Hz，1H)，7.32(s，1H)，7.09(d，J＝9.2Hz，1H)，6.84(s，1H)，6.81(s，1H)，6.68(s，1H)，5.50(s，2H)，5.35-5.30(m，1H)，3.84(s，3H)，3.58(s，2H)，3.36(s，3H)，3.01(s，3H)，2.80(s，3H)，1.89-1.84(m，1H)，1.55(d，J＝7.2Hz，3H)，1.02-0.96(m，1H)，0.83-0.77(m，1H)，0.73-0.63(m，2H)；ESI-MS(m/z)：594.0[M+H] ⁺ 。

example 134

Preparation of (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-cyclopropylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide

Preparation method referring to example 111, purification by Prep-HPLC (method 3) gave (R) -2- (5- ((4- ((1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -2-cyclopropylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N, N-dimethylacetamide in 54.0% yield; ¹ H NMR(400MHz，DMSO-d ₆ )δ11.55(s，1H)，8.07(d，J＝7.2Hz，1H)，7.51(s，1H)，7.36(d，J＝9.2Hz，1H)，7.24(s，1H)，7.17(s，1H)，7.05(d，J＝9.2Hz，1H)，6.84(s，1H)，6.80(s，1H)，6.68(s，1H)，5.50(s，2H)，5.35-5.28(m，1H)，3.41(s，2H)，3.26(s，3H)，3.01(s，3H)，2.78(s，3H)，1.89-1.82(m，1H)，1.55(d，J＝7.2Hz，3H)，1.00-0.94(m， 1H)，0.83-0.76(m，1H)，0.74-0.61(m，2H)；ESI-MS(m/z)：580.0[M+H] ⁺ 。

biological Activity test

Test example 1: SOS1 inhibitory Activity assay

The effect of SOS1 inhibitors on the interaction between SOS1 and KRAS proteins was examined by Homogeneous Time Resolved Fluorescence (HTRF) to assess the level of inhibition of SOS1 proteins. The protein and the detection reagent are KRAS-G12D/SOS1 BINDING ASSAY KITS (Cisbio), firstly 2mM of the mother solution of the test compound is diluted 20 times (100 mu M) by a reagent (5% DMSO), and then the concentration gradient dilution is sequentially carried out by 5 times by the reagent, so that 8 concentrations of the working solution of the test compound are obtained. In 384 well plates, 4. Mu.L of tag2-KRAS was added sequentially per well ^G12D Protein (50. Mu.M GTP), 2. Mu.L of test compound (10X), 4. Mu.L of tag1-SOS1 protein, double wells, and incubation at room temperature for 15min. Adding Anti-tag1-Tb into each hole in turn ³⁺ Working solution and Anti-tag2-XL665 working solution were each 5. Mu.L and incubated at 4℃for 3h. The 384-well plate was placed on a multifunctional microplate reader to read the values, the excitation light wavelength was set to 337nm, and the read values at 620nm and 665nm were recorded. The data results are presented as the ratio of 665nm signal value per well to 620nm signal value, i.e.: ratio=104×665nm signal values/620 nm signal values. The inhibition was calculated by the following formula:

IC ₅₀ the inhibition was calculated by GraphPad Prism software. Each compound was assayed in 2 duplicate wells at a time and each set of experiments was independently repeated three times.

The compounds of examples 1 to 30 were measured in a first batch, and the test data are shown in Table 1; the compounds of examples 31 to 100 were measured in the second batch, and the test data are shown in Table 2; the compounds of examples 101 to 134 were measured in the third batch, and the test data are shown in Table 3.

TABLE 1 SOS1 inhibitory Activity of Compounds examples 1 to 30

TABLE 2 SOS1 inhibitory Activity of Compounds 31 to 100

TABLE 3 SOS1 inhibitory Activity of Compounds of examples 101 to 134

The positive control used was the following structural compound (BI-3406):

Test example 2: CYP3A4 inhibition activity assay

The main site of drug metabolism is the liver, and the main component of the mixed-function oxidase system present in the liver is the CYP450 enzyme, which causes the interaction of most drugs clinically, and thus leads to an increased incidence of adverse drug reactions. CYP450 is a large family of supergenes consisting of many isoenzymes, with CYP3A4 as the primary metabolizing enzyme involved in the metabolism of nearly half of the drugs in the clinic. Therefore, the inhibition activity of the compound on CYP3A4 can be tested in early stage, so that the risk of drug-drug interaction can be judged, and the medication safety is improved.

In the present invention, human liver microsomes are usedAs a source of CYP3A4 enzyme, testosterone as a specific probe substrate for CYP3A4 (indicated by CYP3 A4-T) was incubated with a range of concentrations of the test compound in the presence of cofactor NADPH. Determination of the production of metabolites of the probe substrate in the incubation System Using LC-MS/MS, calculation of IC of the test Compound to CYP3A4 ₅₀ The value was evaluated for inhibition of CYP3A 4. In the experiment, 49 mu L of PBS,50 mu L of probe substrate and 50 mu L of human liver microsome working solution are sequentially added into an incubation system, then 1 mu L of tested compound working solution with each concentration is added, and the mixture is uniformly mixed; after 5min of pre-incubation at 37℃50. Mu.L of NADPH was added to initiate the reaction. After incubation for a corresponding time, adding a proper amount of glacial acetonitrile containing an internal standard to terminate the reaction, vortex uniformly mixing, centrifuging to obtain supernatant, and detecting the generation amount of metabolites of the probe substrate by sample injection LC-MS/MS. The percentage of enzyme activity remaining for the metabolites at the different test compound concentrations was calculated using the 0 concentration point enzyme activity (characterized by metabolite production) as 100%. IC (integrated circuit) ₅₀ Calculation was performed by Graphpad Prism software by residual enzyme activity. The test data for the compounds in the examples are shown in table 4:

TABLE 4 Table 4

Examples numbering

CYP3A4-T inhibitory Activity (IC 50, mu M)

Example 37	＞10
Example 38	＞10
Example 59	＞10
Example 60	＞10
Example 62	＞10
Example 91	＞10
Example 104	＞10
Example 106	＞10
Example 108	7.6
Example 109	＞10
Example 111	＞10
Example 118	＞10
Example 120	8.0
BI-3406	4.1

BI-3406 has been reported to have SOS1 inhibitory activity, and the combination with trametinib (MEKi) can inhibit the growth of colorectal cancer and pancreatic cancer mutated by different subtypes of KRAS, and has better therapeutic effect than SOSi or MEKi alone (the university of AACR in 2020: DOI:10.1158/1538-7445.AM2020-1091 Published August 2020;DOI:10.1158/2159-8290. CD-20-0142).

From the data, the compound has obvious inhibition effect on SOS1, and partial compounds have the activity equivalent to or better than that of positive compounds, can be used as SOS1 inhibitors, and have wide application prospects in the fields of SOS1 protein-mediated cancers, pathogenic rash and other diseases. In addition, the representative compound of the invention has no obvious inhibition activity on CYP3A4-T, is obviously superior to a reference compound BI-3406, and is beneficial to reducing the risk of drug-drug interaction.

Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims

A compound having a structure of formula I or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal thereof:

wherein:

A ¹ selected from CH, CH ₂ Or N, NR ²⁸ 、O、S，A ² Selected from C or N, A ³ Selected from CH, CH ₂ 、N、NR ²⁸ 、O、S，A ⁴ Selected from CH, CH ₂ Or a bond, preferably A ⁴ Selected from CH, CH ₂ Or a single bond;

y is selected from bond, CR ⁶ R ⁷ 、O、NR ⁵ S, S (O); when A is ¹ 、A ³ 、A ⁴ Is CH and A ² When C, Y is not a bond;

R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ²⁸ each independently selected from H, alkyl; preferably, R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ²⁸ Each independently selected from H, C to C6 alkyl, more preferably H, C to C3 alkyl, even more preferably H, methyl;

ar is selected from aryl, heteroaryl, and alicyclic, and when ring A is not aromatic, the heteroaryl is not pyridinyl, wherein the aryl, heteroaryl, and alicyclic are optionally substituted with one or more R ⁸ Substitution;

R ⁸ independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, aryl, heteroaryl, -OR ^a 、-NR ^b R ^c 、-SR ^d 、-C(O)R ¹⁰ 、-C(O)NR ^b R ^c 、-C(O)OR ^a Wherein alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more R ¹¹ Substitution;

R ¹¹ independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, aryl, heteroaryl, -OR ^a 、-NR ^b R ^c 、-SR ^d 、-C(O)R ¹² 、-C(O)NR ^b R ^c 、-C(O)OR ^a Wherein the alkyl, cycloalkyl, alicyclic, aryl, heteroaryl is optionally substituted with one or more R ¹³ Substitution;

R ¹³ independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, -OR ^a 、-NR ^b R ^c 、-SR ^d 、-C(O)R ¹⁴ 、-C(O)NR ^b R ^c 、-C(O)OR ^a ；

R ¹ Selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, alicyclic, aryl, -OR ^e 、-NR ^f R ^g 、-SR ^h 、-C(O)R ¹⁵ 、-C(O)NR ^f R ^g 、-C(O)OR ^e Wherein the alkyl, cycloalkyl, and alicyclic groups are optionally substituted with one or more R ¹⁶ Substitution;

R ¹⁶ independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, -OR ^e 、-NR ^f R ^g 、-SR ^h 、-C(O)R ¹⁷ 、-C(O)NR ^f R ^g 、-C(O)OR ^e ；

Ring E is selected from cycloalkyl, alicyclic, aryl, heteroaryl, wherein cycloalkyl, alicyclic, aryl, heteroaryl are optionally substituted with one or more R ¹⁸ Substitution;

R ¹⁸ independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, aryl, heteroaryl, -OR ⁱ 、-NR ^j R ^k 、-SR ^m 、-C(O)R ¹⁹ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ Or two adjacent R ¹⁸ The ring atoms of the ring E to which they are attached together form cycloalkyl, alicyclic, aryl, heteroaryl, wherein the alkyl, cycloalkyl, alicyclic Optionally substituted with one or more R ²⁵ Substitution;

preferably, R ¹⁸ Independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, -OR ⁱ 、-NR ^j R ^k 、-SR ^m 、-C(O)R ¹⁹ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ Or two adjacent R ¹⁸ The ring atoms of the ring E to which they are attached together form cycloalkyl, alicyclic, aryl, heteroaryl, wherein the alkyl, cycloalkyl, alicyclic, aryl, heteroaryl are optionally substituted with one or more R ²⁵ Substitution;

R ²⁵ independently at each occurrence selected from halogen, cyano, alkyl, -NR ^j R ^k Substituted alkyl, cycloalkyl, alicyclic, -OR ⁱ 、-NR ^j R ^k 、-SR ^m 、-C(O)R ²⁶ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ ；

Preferably, R ²⁵ Independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, -OR ⁱ 、-NR ^j R ^k 、-SR ^m 、-C(O)R ²⁶ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ ；

R ^a 、R ^b 、R ^c 、R ^d 、R ^e 、R ^f 、R ^g 、R ^h 、R ⁱ 、R ^j 、R ^k 、R ^m Independently at each occurrence selected from H, alkyl, cycloalkyl, alicyclic, -C (O) R ²⁰ Or R is ^b 、R ^c Together with the N atom to which it is attached, form a cycloaliphatic radical, wherein the alkyl, cycloalkyl, and cycloaliphatic radicalsOptionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, alkyl, cycloalkyl, alicyclic;

R ¹⁰ 、R ¹² 、R ¹⁴ 、R ¹⁵ 、R ¹⁷ 、R ¹⁹ 、R ²⁰ 、R ²⁶ each occurrence is independently selected from H, alkyl, cycloalkyl, and alicyclic, said alkyl, cycloalkyl, and alicyclic being optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, alkyl, cycloalkyl, and alicyclic.
A compound having a structure of formula I or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal thereof:

wherein:

A ¹ selected from CH, CH ₂ Or N, NR ²⁸ 、O、S，A ² Selected from C or N, A ³ Selected from CH, CH ₂ 、N、NR ²⁸ 、O、S，A ⁴ Selected from CH, CH ₂ Or a bond, preferably A ⁴ Selected from CH, CH ₂ Or a single bond;

y is selected from bond, CR ⁶ R ⁷ 、O、NR ⁵ S, S (O); when A is ¹ 、A ³ 、A ⁴ Is CH and A ² When C, Y is not a bond;

R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ²⁸ each independently selected from H, alkyl; excellent (excellent)Optionally R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ²⁸ Each independently selected from H, C to C6 alkyl, more preferably H, C to C3 alkyl, even more preferably H, methyl;

ar is selected from aryl or heteroaryl, and when ring A is not aromatic, the heteroaryl is not pyridinyl, wherein the aryl or heteroaryl is optionally substituted with one or more R ⁸ Substitution;

R ⁸ independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, aryl, heteroaryl, -OR ^a 、-NR ^b R ^c 、-SR ^d 、-C(O)R ¹⁰ 、-C(O)NR ^b R ^c 、-C(O)OR ^a Wherein alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more R ¹¹ Substitution;

R ¹¹ independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, aryl, heteroaryl, -OR ^a 、-NR ^b R ^c 、-SR ^d 、-C(O)R ¹² 、-C(O)NR ^b R ^c 、-C(O)OR ^a Wherein the alkyl, cycloalkyl, alicyclic, aryl, heteroaryl is optionally substituted with one or more R ¹³ Substitution;

R ¹³ independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, -OR ^a 、-NR ^b R ^c 、-SR ^d 、-C(O)R ¹⁴ 、-C(O)NR ^b R ^c 、-C(O)OR ^a ；

R ¹ Selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, alicyclic, aryl, -OR ^e 、-NR ^f R ^g 、-SR ^h 、-C(O)R ¹⁵ 、-C(O)NR ^f R ^g 、-C(O)OR ^e Wherein the alkyl, cycloalkyl, and alicyclic groups are optionally substituted with one or more R ¹⁶ Substitution;

R ¹⁶ independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, -OR ^e 、-NR ^f R ^g 、-SR ^h 、-C(O)R ¹⁷ 、-C(O)NR ^f R ^g 、-C(O)OR ^e ；

Ring E is selected from cycloalkyl, alicyclic, aryl, heteroaryl, wherein cycloalkyl, alicyclic, aryl, heteroaryl are optionally substituted with one or more R ¹⁸ Substitution;

R ¹⁸ independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, -OR ⁱ 、-NR ^j R ^k 、-SR ^m 、-C(O)R ¹⁹ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ Wherein the alkyl, cycloalkyl, and alicyclic are optionally substituted with one or more R ²⁵ Substitution;

R ²⁵ independently at each occurrence selected from halogen, cyano, alkyl, cycloalkyl, alicyclic, -OR ⁱ 、-NR ^j R ^k 、-SR ^m 、-C(O)R ²⁶ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ ；

R ^a 、R ^b 、R ^c 、R ^d 、R ^e 、R ^f 、R ^g 、R ^h 、R ⁱ 、R ^j 、R ^k 、R ^m Independently at each occurrence selected from H, alkyl, cycloalkyl, alicyclic, -C (O) R ²⁰ Wherein, saidThe alkyl, cycloalkyl, and alicyclic groups are optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, alkyl, cycloalkyl, alicyclic;

R ¹⁰ 、R ¹² 、R ¹⁴ 、R ¹⁵ 、R ¹⁷ 、R ¹⁹ 、R ²⁰ 、R ²⁶ each occurrence is independently selected from H, alkyl, cycloalkyl, and alicyclic, said alkyl, cycloalkyl, and alicyclic being optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, alkyl, cycloalkyl, and alicyclic.
A compound according to claim 1 or 2, wherein R ^a 、R ^b 、R ^c 、R ^d Independently at each occurrence selected from H, alkyl, -C (O) R ²⁰ Wherein the alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, alkyl;

further, R ^a 、R ^b 、R ^c 、R ^d Independently at each occurrence selected from H, C1-C6 alkyl, -C (O) R ²⁰ Wherein the alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, C1-C6 alkyl;

further, R ^a 、R ^b 、R ^c 、R ^d Independently at each occurrence, a H, C1-C3 alkyl group, wherein the alkyl group is optionally substituted with one or more of the following substituents: halogen, C1-C3 alkyl;

further, R ^a 、R ^b 、R ^c 、R ^d Independently at each occurrence selected from H, methyl, preferably R ^b 、R ^c Is methyl.
A compound according to claim 1 or 2, wherein R ⁱ 、R ^j 、R ^k 、R ^d Independently at each occurrence selected from H, alkyl, -C (O) R ²⁰ Wherein the alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, alkyl;

further, R ⁱ 、R ^j 、R ^k 、R ^d Independently at each occurrence selected from H, C1-C6 alkyl, -C (O) R ²⁰ Wherein the alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, C1-C6 alkyl;

Further, R ⁱ 、R ^j 、R ^k 、R ^d Independently at each occurrence, a H, C1-C3 alkyl group, wherein the alkyl group is optionally substituted with one or more of the following substituents: halogen, C1-C3 alkyl;

further, R ⁱ 、R ^j 、R ^k 、R ^d Each occurrence is independently selected from H, methyl, difluoromethyl, preferably H, methyl, preferably H.
A compound according to claim 1 or 2, wherein a ¹ Selected from CH, CH ₂ Or N, preferably CH;

preferably, A ² Selected from C or N, more preferably C;

preferably, A ³ Selected from CH, CH ₂ 、N、NR ²⁸ O, S, where R ²⁸ Selected from H, alkyl, more preferably H, C1 to C6 alkyl, more preferably H, C to C3 alkyl, more preferably H, methyl; further, A ³ Selected from CH or N;

preferably, A ⁴ Selected from CH, CH ₂ Or a bond, more preferably CH, CH ₂ Or a single bond,more preferably CH.
The compound according to any one of claims 1 to 5, wherein in its structureSelected from the following groups:

preferably selected from the following groups:

more preferably

More preferably

Wherein R is ²⁸ As defined in any one of claims 1, 2, 5.
The compound of any one of claims 1 to 6, having a structure represented by formula II or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal thereof:

Ring E is selected from C3-C6 cycloalkyl, 4-7 membered alicyclic heterocyclic group, phenyl, 5-6 membered heteroaryl, preferably 5-7 membered alicyclic heterocyclic group, phenyl, further preferably N-containing 6 membered alicyclic heterocyclic group, phenyl, more preferably phenyl; wherein cycloalkyl, alicyclic, phenyl, heteroaryl are optionally substituted with one or more R ¹⁸ Substituted, R ¹⁸ As defined in claim 1 or 2;

preferably, ring E is selected from phenyl, 5-6 membered N heteroaryl, 5-6 membered thiaheteroaryl, more preferably phenyl, 6 membered N heteroaryl, 5 membered thiaheteroaryl, more preferably phenyl, pyridinyl or thienyl; wherein the phenyl, 5-6 membered N heteroaryl, 5-6 membered S heteroaryl, 6 membered N heteroaryl, 5 membered S heteroaryl, pyridinyl, thienyl is optionally substituted with one or more R ¹⁸ Substituted, R ¹⁸ As defined in claim 1 or 2;

preferably, ring E is selected from phenyl, 5-6 membered N heteroaryl, preferably phenyl, 6 membered N heteroaryl, more preferably phenyl or pyridinyl; wherein phenyl, pyridinyl, N heteroaryl are optionally substituted with one or more R ¹⁸ Substituted, R ¹⁸ As defined in claim 1 or 2;

preferably, ring E is phenyl, piperidinyl, wherein phenyl, piperidinyl are optionally substituted with one or more R ¹⁸ Substituted, R ¹⁸ As defined in claim 1 or 2;

Further, when ring E is piperidinyl, R ¹⁸ Is C1-C6 alkyl, wherein the alkyl is optionally substituted by 1-3 alkyl groups, halogen, hydroxy, amino, cyano;

further, when ring E is piperidinyl, R ¹⁸ C1-C3 alkyl which is unsubstituted or substituted by hydroxy;

further, when ring E is piperidinyl, it has the following structure:the following structure is preferred:

n ² an integer selected from 1 to 3, preferably 2;

further, when ring E is thienyl, R ¹⁸ Is aryl, wherein the aryl is optionally substituted with 1 to 3 alkyl groups, the alkyl groups being optionally substituted with one or more-NR groups ^j R ^k Substitution;

n ¹ an integer selected from 0 to 5, preferably an integer from 1 to 3, preferably 1, 2, more preferably 2.
The compound of any one of claims 1-7, wherein the compound has a structure of formula III or formula III' or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal thereof:

wherein each substituent is as defined in any one of claims 1 to 7;

preferably, the method comprises the steps of,is thatWherein R is ²² 、R ²³ 、R ²⁴ Independently selected from H, halogen, cyano, C1-C6 alkyl, -OR ⁱ 、-NR ^j R ^k 、-C(O)R ¹⁹ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ Wherein the alkyl group is optionally substituted with oneOne or more R ²⁵ Substitution;

further, R ²² 、R ²³ 、R ²⁴ Are independently selected from H, halogen, C1-C3 alkyl, -NR ^j R ^k Wherein the alkyl is optionally substituted with one or more R ²⁵ Substitution;

wherein the R is ⁱ 、R ^j 、R ^k 、R ¹⁹ 、R ²⁵ As defined in any one of claims 1 to 7;

preferably, R ²² Selected from H or halogen, preferably H or F, more preferably H;

R ²³ selected from C1-C3 alkyl, C1-C3 alkyl substituted by halogen and/or hydroxy, preferably methyl, difluoromethyl, trifluoromethyl, CF ₂ CH ₂ OH、C(OH)CH ₃ CH ₃ More preferably trifluoromethyl;

R ²⁴ selected from H, NH ₂ Preferably NH ₂ 。
A compound according to any one of claims 1 to 8, wherein R ¹⁸ Independently at each occurrence selected from halogen, cyano, alkyl, aryl, heteroaryl, -OR ⁱ 、-NR ^j R ^k 、-C(O)R ¹⁹ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ Or two adjacent R ¹⁸ The ring atoms of the ring E to which they are attached together form cycloalkyl, alicyclic, aryl, heteroaryl, wherein the cycloalkyl, alicyclic, aryl, heteroaryl are optionally substituted with one or more R ²⁵ Substitution;

further, R ¹⁸ Independently at each occurrence selected from halogen, cyano, alkyl, -OR ⁱ 、-NR ^j R ^k 、-C(O)R ¹⁹ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ Or two adjacent R ¹⁸ The atoms to which they are attached together form cycloalkyl, alicyclic, aryl, heteroaryl, wherein the alkyl, cycloalkyl, alicyclic, aryl, heteroaryl are optionally substituted with one or more R ²⁵ Substitution;

further, R ¹⁸ Independently at each occurrence selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -OH, phenyl, -NR ^j R ^k Or two adjacent R ¹⁸ The ring atoms of the ring E to which they are attached together form a C5-C10 cycloalkyl, 5-C10-membered alicyclic, C5-C10-aryl, 5-C10-membered heteroaryl group, wherein the alkyl, alkoxy, phenyl, cycloalkyl, alicyclic, aryl, heteroaryl groups are optionally substituted with 1 to 4R ²⁵ Substituted, R ^j 、R ^k Each occurrence of which is independently selected from H, C1 to C6 alkyl;

further, R ¹⁸ Independently at each occurrence selected from halogen, cyano, C1-C6 alkyl, -NR ^j R ^k Or two adjacent R ¹⁸ The atoms to which they are attached together form a C5-C10 cycloalkyl, 5-C10 membered alicyclic, C5-C10 aryl, 5-C10 membered heteroaryl group, wherein the alkyl, cycloalkyl, alicyclic, aryl, heteroaryl groups are optionally substituted with 1 to 4R ²⁵ Substituted, R ^j 、R ^k Each occurrence of which is independently selected from H, C1 to C6 alkyl;

further, R ¹⁸ Independently at each occurrence selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, -OH, phenyl, -NR ^j R ^k Or two adjacent R ¹⁸ The ring atoms of the ring E to which they are attached together form a C5-C6 cycloalkyl, 5-6 membered alicyclic, 5-6 membered heteroaryl group, wherein the alkyl, alkoxy, phenyl, cycloalkyl, alicyclic, heteroaryl groups are optionally substituted with 1-3R ²⁵ Substituted, R ^j 、R ^k At each occurrence independentlyAnd is selected from H, C to C3 alkyl;

further, R ¹⁸ Independently at each occurrence selected from halogen, cyano, C1-C3 alkyl, -NR ^j R ^k Or two adjacent R ¹⁸ The atoms to which they are attached together form a C5-C6 cycloalkyl, 5-6 membered alicyclic, 5-6 membered heteroaryl group, wherein the alkyl, cycloalkyl, alicyclic, heteroaryl groups are optionally substituted with 1-3R ²⁵ Substituted, R ^j 、R ^k Each occurrence of which is independently selected from H, C1 to C3 alkyl;

further, R ¹⁸ Independently at each occurrence selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, -OH, phenyl, -NR ^j R ^k Or two adjacent R ¹⁸ The ring atoms of the ring E to which they are attached together form a cyclopentane, tetrahydrofuran, pyrrole radical, where the C1-C3 alkyl, C1-C3 alkoxy, phenyl, cyclopentylalkyl, tetrahydrofuran, pyrrole radical is optionally substituted with 1 to 3R ²⁵ Substituted, R ^j 、R ^k All are H;

further, R ¹⁸ Independently at each occurrence selected from halogen, cyano, C1-C3 alkyl, -NR ^j R ^k Or two adjacent R ¹⁸ The atoms to which they are attached together form a cyclopentane, tetrahydrofuran, pyrrole radical, where the C1-C3 alkyl, cyclopentane, tetrahydrofuran, pyrrole radicals are optionally substituted with 1-3R ²⁵ Substituted, R ^j 、R ^k All are H;

preferably, R ¹⁸ Independently at each occurrence selected from halogen, cyano, alkyl, -OR ⁱ 、-NR ^j R ^k 、-C(O)R ¹⁹ 、-C(O)NR ^j R ^k 、-C(O)OR ⁱ Wherein the alkyl is optionally substituted with one or more R ²⁵ Substitution;

further, R ¹⁸ Independently at each occurrence selected from halogen, cyano, C1-C6 alkyl, -OR ⁱ 、-NR ^j R ^k Wherein the alkyl is optionally substituted with one or more R ²⁵ Substitution;

further, R ¹⁸ Independently at each occurrence selected from halogen, C1-C3 alkyl, -NR ^j R ^k Wherein the alkyl is optionally substituted with one or more R ²⁵ Substitution;

preferably, R ¹⁸ Independently at each occurrence selected from halogen, cyano, hydroxy, amino, methyl, CF ₃ 、-CF ₂ CH ₃ 、-CF ₂ H、-CF ₂ CH ₂ OH、-C(CH ₃ ) ₂ OH、-OCF ₂ H、-CH ₂ NHCH ₃ Substituted phenyl or pyridyl, or, alternatively, two adjacent R ¹⁸ The ring atoms on the ring E to which they are attached together form a cyclopentanyl, tetrahydrofuranyl, pyrrolyl group, wherein the cyclopentanyl, tetrahydrofuranyl, pyrrolyl groups are optionally substituted with one or more F atoms.
The compound of claim 9, wherein R ²⁵ Independently at each occurrence selected from halogen, C1-C6 alkyl, -OR ⁱ 、-CH ₂ NR ^j R ^k 、-NR ^j R ^k Preferably halogen, C1-C6 alkyl, -OR ⁱ 、-NR ^j R ^k Preferably halogen, C1-C3 alkyl, -OR ⁱ More preferably halogen OR-OR ⁱ More preferably halogen, wherein R ⁱ 、R ^j 、R ^k As defined in claim 1, preferably R ⁱ 、R ^j 、R ^k Independently selected from H, alkyl, more preferably R ⁱ 、R ^j 、R ^k Is H; further, the method comprises the steps of,R ²⁵ independently at each occurrence selected from F, cl, methyl, ethyl, propyl, hydroxy, preferably F, hydroxy, -CH ₂ NHCH ₃ Preferably F, methyl, hydroxy, more preferably F, hydroxy.
A compound according to any one of claims 1 to 10, wherein R ¹⁸ Independently at each occurrence selected from the group consisting of-F, -CN, -NH ₂ 、-OH、-CH ₃ 、-CHF ₂ 、-CF ₃ 、-CF ₂ CH ₃ 、-CF ₂ CH ₂ OH、-OCF ₂ H、 Or two adjacent R ¹⁸ The connected atoms are combined

Further, R ¹⁸ Independently at each occurrence selected from the group consisting of-F, -CN, -NH ₂ 、-CH ₃ 、-CHF ₂ 、-CF ₃ 、-CF ₂ CH ₃ 、-CF ₂ CH ₂ OH、-C(OH)CH ₃ CH ₃ Or two adjacent R ₁₈ To which atoms are attached to form together

Further, R ¹⁸ Independently at each occurrence selected from the group consisting of-F, -CN, -NH ₂ 、-CH ₃ 、-CHF ₂ 、-CF ₃ 、-CF ₂ CH ₃ 、-CF ₂ CH ₂ OHOr two adjacent R ¹⁸ To which atoms are attached to form together
A compound according to any one of claims 1 to 11, wherein ring E is selected from the following structures:

further, ring E is selected from the following structures:

further, ring E is selected from the following structures:
a compound according to any one of claims 1 to 12 wherein Y is selected from the group consisting of a bond, -CR ⁶ R ⁷ -、-O-、-NR ⁵ -, when A ¹ 、A ³ 、A ⁴ Is CH and A ² When C, Y is not a bond; wherein R is ⁵ 、R ⁶ 、R ⁷ Independently selected from H, alkyl, preferably H, C to C6 alkyl, more preferably H, C to C3 alkyl, More preferably H, methyl;

further, Y is selected from the group consisting of bond, O, NR ⁵ When A is ¹ 、A ³ 、A ⁴ Is CH and A ² When C, Y is not a bond; wherein R is ⁵ Selected from H, alkyl, preferably H, C1 to C6 alkyl, more preferably H, C to C3 alkyl, more preferably H, methyl; alternatively, R ⁵ Is a C1-C6 alkyl group, preferably a C1-C3 alkyl group, more preferably a methyl group;

further, Y is selected from O, NR ⁵ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ⁵ Selected from H, alkyl, preferably H, C1 to C6 alkyl, more preferably H, C to C3 alkyl, more preferably H, methyl; alternatively, R ⁵ Is a C1-C6 alkyl group, preferably a C1-C3 alkyl group, more preferably a methyl group;

preferably Y is selected from-NH-, -O-or-NCH ₃ -。
A compound according to any one of claims 1 to 13 wherein Ar is selected from C6 to C10 aryl, 5 to 10 membered heteroaryl, 3 to 10 membered alicyclic heterocyclyl wherein said aryl, heteroaryl, alicyclic heterocyclyl is optionally substituted with one or more R ⁸ Substitution;

further Ar is selected from phenyl, 6-9 membered heteroaryl, 5-6 membered alicyclic, wherein said phenyl, heteroaryl, alicyclic are optionally substituted with one or more R ⁸ Substitution;

further, ar is selected from phenyl, 6-membered N-heteroaryl, 9-membered N-heteroaryl, N-heterocycloalkylene, wherein the phenyl, 6-membered N-heteroaryl, 9-membered N-heteroaryl, N-heterocycloalkylene are optionally substituted with one or more R ⁸ Substitution;

further, ar is selected from phenyl, 6-membered N-heteroaryl, N-heterocycloalkylene, wherein the phenyl, 6-membered N-heteroaryl, N-heterocycloalkylene are optionally substituted with one or more R ⁸ Substitution;

further, ar is selected from phenyl, pyridyl,Wherein the phenyl group, the pyridyl group,Optionally by one or more R ⁸ Substitution;

further, ar is selected from phenyl, pyridyl,Wherein the phenyl group, the pyridyl group, Optionally by one or more R ⁸ Substitution;

preferably Ar is selected from phenyl or a 5-to 10-membered heteroaryl, more preferably phenyl or a 6-to 9-membered heteroaryl, more preferably phenyl or N-hetero 6-to 9-membered heteroaryl, more preferably phenyl, pyridinyl, 9-membered N-heteroaryl, wherein the phenyl, pyridinyl, heteroaryl are optionally substituted with one or more R ⁸ Substitution, said R ⁸ As defined in claim 1.
A compound according to any one of claims 1 to 14, wherein Ar is optionally substituted with 1 to 3R ⁸ Substitution; further Ar is optionally substituted with 1 to 2R ⁸ And (3) substitution.
A compound according to any one of claims 1 to 15, wherein R ⁸ Independently at each occurrence selected from halogen, cyano, C1-C6 alkyl, C3-to-ultrahighC6-membered cycloalkyl, 3-6-membered alicyclic heterocyclic group, -OR ^a 、-NR ^b R ^c Wherein the alkyl, cycloalkyl, and alicyclic groups are optionally substituted with one or more R ¹¹ Substitution, said R ^a 、R ^b 、R ^c 、R ¹¹ As defined in claim 1;

further, R ⁸ Independently at each occurrence selected from C1-C3 alkyl, -OR ^a 、-NR ^b R ^c Wherein the alkyl is optionally substituted with one or more R ¹¹ Substitution, said R ^a 、R ^b 、R ^c 、R ¹¹ As defined in claim 1;

further, R ⁸ Independently at each occurrence selected from C1-C3 alkyl, -OR ^a 、-NR ^b R ^c Wherein R is ^a Selected from H, alkyl, R ^b 、R ^c Independently selected from H, alkyl, or R ^b 、R ^c Together with the N atom to which they are attached form a cycloaliphatic radical, said alkyl, cycloaliphatic radical optionally being substituted with one or more R ¹¹ Substitution;

further, R ⁸ Independently at each occurrence selected from methyl, ethyl, propyl, -OR ^a 、-NR ^b R ^c Wherein R is ^a Selected from H, C-C6 alkyl, R ^b 、R ^c Are independently selected from C1-C6 alkyl, or R ^b 、R ^c Together with the N atom to which they are attached form a 5-membered alicyclic ring, said methyl, ethyl, propyl, alkyl, alicyclic ring optionally being substituted with one or more R ¹¹ Substitution;

further, R ⁸ Independently at each occurrence selected from methyl, ethyl, -OR ^a 、-NR ^b R ^c Wherein R is ^a Selected from H, C-C3 alkyl, R ^b 、R ^c Are independently selected from C1-C3 alkyl, or R ^b 、R ^c Is co-formed with N atomsThe methyl, ethyl, alkyl, Optionally by one or more R ¹¹ Substitution;

further, R ⁸ Each occurrence of which is independently selected from-OH, -OCH ₃ 、-N(CH ₃ ) ₂ 、-NHCH ₃ 、-CH ₂ C(O)N(CH ₃ ) ₂ 、-CH ₂ CH ₂ C(O)N(CH ₃ ) ₂ 、-CH ₂ CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CN、

Further, R ⁸ Each occurrence of which is independently selected from-OH, -OCH ₃ 、-N(CH ₃ ) ₂ 、-CH ₂ C(O)N(CH ₃ ) ₂ 、-CH ₂ CH ₂ C(O)N(CH ₃ ) ₂ 、-CH ₂ CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CN、

Further, R ⁸ Each occurrence of which is independently selected from-OCH ₃ 、-OH、 -CH ₂ C(O)N(CH ₃ ) ₂ 、 -CH ₂ CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CN、-CH ₃ ；

Further, R ⁸ Each occurrence of which is independently selected from-OCH ₃ 、-OH、 -CH ₂ C(O)N(CH ₃ ) ₂ 、 -CH ₂ CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CN。
A compound according to any one of claims 1 to 16, wherein R ¹¹ Independently at each occurrence selected from halogen, cyano, alkyl, aryl, heteroaryl, -OR ^a 、-NR ^b R ^c 、-C(O)R ¹² 、-C(O)NR ^b R ^c 、-C(O)OR ^a Wherein the alkyl, aryl, heteroaryl are optionally substituted with one or more R ¹³ Substitution;

further, R ¹¹ Independently at each occurrence selected from halogen, cyano, C1-C6 alkyl, 6-to 10-membered aryl, 5-to 9-membered heteroaryl, -OR ^a 、-NR ^b R ^c 、-C(O)R ¹² 、-C(O)NR ^b R ^c 、-C(O)OR ^a Wherein the alkyl, aryl, heteroaryl are optionally substituted with one or more R ¹³ Substitution;

further, R ¹¹ Independently at each occurrence selected from halogen, cyano, C1-C6 alkyl, 5-6 membered heteroaryl, -OR ^a 、-NR ^b R ^c 、-C(O)R ¹² 、-C(O)NR ^b R ^c 、-C(O)OR ^a Wherein the alkyl, aryl, heteroaryl are optionally substituted with 1 to 3R ¹³ Substitution;

further, R ¹¹ Independently at each occurrence selected from cyano, C1-C3 alkyl, 5 membered heteroaryl, -NR ^b R ^c 、-C(O)NR ^b R ^c Wherein the alkyl, aryl, heteroaryl are optionally substituted with 1 to 3R ¹³ Substitution;

Further, R ¹¹ The 5 membered heteroaryl group of (2) is selected from thiazolyl and imidazolyl, wherein the thiazolyl and imidazolyl are optionally substituted with 1-2R ¹³ Substitution; alternatively, R ¹¹ The thiazolyl and imidazolyl of the formula are as follows:

further, R ¹¹ Independently at each occurrence selected from cyano, methyl, ethyl, propyl,-N(CH ₃ ) ₂ 、-C(O)N(CH ₃ ) ₂ 、

Preferably, R ¹¹ Independently at each occurrence selected from alkyl, 6-10 membered aryl, 5-9 membered heteroaryl, -C (O) R ¹² 、-C(O)NR ^b R ^c 、-C(O)OR ^a Wherein the alkyl, aryl, heteroaryl are optionally substituted with one or more R ¹³ Substitution, said R ^a 、R ^b 、R ^c 、R ¹² 、R ¹³ As defined in claim 1;

further, R ¹¹ Independently at each occurrence selected from 5-6 membered heteroaryl, -C (O) R ¹² 、-C(O)NR ^b R ^c 、-C(O)OR ^a Wherein the heteroaryl is optionally substituted with one or more R ¹³ Substitution, said R ^a 、R ^b 、R ^c 、R ¹² 、R ¹³ As defined in claim 1;

further, R ¹¹ Independently at each occurrence selected from 5 membered heteroaryl, -C (O) NR ^b R ^c preferably-C (O) NR ^b R ^c Wherein the heteroaryl is optionally substituted with one or more R ¹³ Substitution, said R ^b 、R ^c 、R ¹³ As defined in claim 1;

further, R ¹¹ Independently at each occurrence selected from thiazolyl, imidazolyl, -C (O) NR ^b R ^c Wherein the thiazolyl, imidazolyl are optionally substituted with one or more R ¹³ Substitution, said R ^b 、R ^c 、R ¹³ As defined in claim 1;

Further, R ¹¹ The optional thiazolyl and imidazolyl are of the following structures:
a compound according to any one of claims 1 to 17, wherein R ¹³ Independently at each occurrence selected from halogen, C1-C6 alkyl, -OR ^a 、-NR ^b R ^c 、-C(O)R ¹⁴ 、-C(O)NR ^b R ^c 、-C(O)OR ^a The R is ^a 、R ^b 、R ^c 、R ¹⁴ As defined in claim 1;

further, R ¹³ Independently for each occurrence selected from halogen, C1-C6 alkyl, preferably C1-C3 alkyl, preferably methyl.
A compound according to any one of claims 1 to 18, wherein R ¹¹ Independently at each occurrence selected from alkyl, -C (O) NR ^b R ^c 、-NR ^b R ^c Cyano, wherein R ^b 、R ^c Independently selected from H, alkyl, or R ^b 、R ^c The N atoms to which they are attached together form a cycloaliphatic radical;

further, R ¹¹ Independently at each occurrence selected from C1-C6 alkyl, -C (O) NR ^b R ^c 、-NR ^b R ^c Cyano, wherein R ^b 、R ^c Are independently selected from H, C-C6 alkyl, or R ^b 、R ^c Together with the N atom, a 5-6 membered alicyclic heterocyclic group is formed;

further, R ¹¹ Independently at each occurrence selected from C1-C3 alkyl, -C (O) NR ^b R ^c 、-NR ^b R ^c Cyano, wherein R ^b 、R ^c Are respectively and independently selected fromC1-C3 alkyl, or R ^b 、R ^c Together with the N atom, a 5-membered alicyclic heterocyclic group;

further, R ¹¹ Independently at each occurrence selected from methyl, -C (O) NR ^b R ^c 、-NR ^b R ^c Cyano, wherein R ^b 、R ^c Are all methyl, or R ^b 、R ^c Together with the N atom, a tetrahydropyrrole group;

further, R ¹¹ Independently at each occurrence selected from methyl, -C (O) N (CH) ³ ) ² 、 -N(CH ³ ) ² Cyano group.
A compound according to any one of claims 1 to 19, wherein Ar is selected from the group consisting of:

further, ar is selected from the following groups:

further, ar is selected from the following groups:
the compound of any one of claims 1 to 20, having a structure of formula IV or formula V or formula VI or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal thereof:

wherein A is ¹ 、A ² 、A ³ 、A ⁴ 、R ¹ 、R ¹¹ 、R ¹⁸ 、R ^a 、R ^b 、R ^c Y is as defined in claim 1;

A ⁵ 、A ⁶ are respectively and independently selected from CR ²⁷ Or N, wherein R ²⁷ Selected from H, C-C3 alkyl, preferably H;

R ²¹ selected from H, C-C6 alkyl, -OR ^a 、-NR ^b R ^c Preferably C1-C3 alkyl, -OR ^a 、-NR ^b R ^c Preferably methyl, ethyl, -OR ^a 、-NR ^b R ^c More preferably-OR ^a ；

Preferably, R ^a 、R ^b 、R ^c Each independently selected from H or methyl; preferably methyl;

preferably, the structure of formula IV is further of formula IV':

the structure of formula V is further of formula V':

wherein each group is as defined in any one of claims 1 to 20;

preferably; in formula IV or formula IV ', formula V or formula V', Y is NR ⁵ The method comprises the steps of carrying out a first treatment on the surface of the In formula VI, Y is selected from the group consisting of a bond, O, NR ⁵ 。
A compound according to claim 21 wherein,

in the formula IV or formula IV',selected from the following structures:

in the formula V or V',selected from the following structures:

in the formula VI, the compound of formula VI,selected from the following structures:
the compound of claim 22, wherein,

in the formula IV or formula IV',selected from the following structures:

in the formula V or V',is that

In the formula VI, the compound of formula VI,is that
A compound according to claim 21 or 23, characterized in that,selected from the following structures:

preferably is
A compound according to any one of claims 1 to 24, having a structure of formula VII or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt, co-crystal thereof:

wherein each group is as defined in any one of claims 1 to 24.
A compound according to any one of claims 1 to 25, wherein R ¹ Selected from hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, 6-10 membered aryl, -OR ^e 、-NR ^f R ^g 、-C(O)R ¹⁵ 、-C(O)NR ^f R ^g 、-C(O)OR ^e Wherein the alkyl is optionally substituted with one or more R ¹⁶ Substitution;

further, R ¹ Selected from hydrogen, halogen, cyano, C1-C3 alkyl, cyclopropane, -OR ^e 、-NR ^f R ^g Wherein the alkyl is optionally substituted with one or more R ¹⁶ Substitution;

further, R ¹ Selected from halogen and C1-C3 alkyl;

further, R ¹ Selected from hydrogen, halogen, C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more R ¹⁶ Substitution;

preferably, R ¹ Selected from H, cl, br, I, hydroxy, cyano, methyl, difluoromethyl, ethyl, -CH ₂ OH、-CH ₂ NH ₂ 、-NHCH ₃ 、-OCH ₂ CH ₃ More preferably H, cl, methyl, ethyl, -CH ₂ CH ₂ OH; more preferably methyl or Cl;

preferably, R ¹ Selected from Cl, methyl, -CH ₂ CH ₂ OH、-CH ₂ CH ₃ A cyclopropane group;

preferably, R ¹⁶ Independently at each occurrence selected from halogen, cyano, C1-C6 alkyl, -OR ^e 、-NR ^f R ^g 、-C(O)R ¹⁷ 、-C(O)NR ^f R ^g 、-C(O)OR ^e ；

Further, R ¹⁶ Independently at each occurrence selected from halogen, C1-C3 alkyl, -OR ^e 、-NR ^f R ^g ；

Further, R ¹⁶ is-OR ^e 。
A compound according to any one of claims 1 to 26, wherein R ^e 、R ^f 、R ^g 、R ^h Independently at each occurrence selected from H, C1-C6 alkyl, -C (O) R ²⁰ Wherein the alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, C1-C6 alkyl;

further, R ^e 、R ^f 、R ^g 、R ^h At each occurrenceIndependently selected from H, C to C3 alkyl groups, wherein the alkyl groups are optionally substituted with one or more of the following substituents: halogen, C1-C3 alkyl;

Further, R ^e 、R ^f 、R ^g 、R ^h Independently at each occurrence selected from H, methyl, ethyl;

further, R ^e H.
A compound according to any one of claims 1 to 27,

is of the configuration ofFurther, the method comprises the steps of,is of the configuration of
A compound according to any one of claims 1 to 28, wherein R ¹⁰ 、R ¹² 、R ¹⁴ 、R ¹⁵ 、R ¹⁷ 、R ¹⁹ 、R ²⁰ 、R ²⁶ Each occurrence is independently selected from H, C1 to C6 alkyl groups, said alkyl groups optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, amino, C1-C6 alkyl;

further, R ¹⁰ 、R ¹² 、R ¹⁴ 、R ¹⁵ 、R ¹⁷ 、R ¹⁹ 、R ²⁰ 、R ²⁶ Each occurrence is independently selected from H, C1 to C3 alkyl groups, said alkyl groups optionally substituted with one or more of the following substituents: halogen, hydroxy, amino, C1-C3 alkyl.
A compound according to claim 1 or 2, wherein the compound structure is selected from one of the following:
a process for the preparation of a compound according to any one of claims 1 to 30, comprising the steps of: performing cyclization reaction on the compound of the formula 1-1 and the compound of the formula 1-2 to obtain a compound of the formula 1-3, and performing reaction on the compound of the formula 1-3 and POX3 to obtain a compound of the formula 1-4;

wherein X represents halogen; A. a is that ¹ 、A ² 、A ³ 、A ⁴ Is defined as formula (I), R ^1’ Is defined as R in the compound of formula (I) ¹ 。
A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of claims 1 to 30 or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt or co-crystal thereof, or a combination of two or more.
Use of a compound according to any one of claims 1 to 30, or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutical composition according to claim 32, for the preparation of a SOS1 inhibitor.
Use of a compound according to any one of claims 1 to 30, or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutical composition according to claim 32, for the manufacture of a medicament for the treatment of a SOS1 mediated disease;

preferably, the disease is selected from: cancer, pathogenic rash;

more preferably, the cancer is selected from: non-small cell lung cancer, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, chronic myelogenous leukemia, colorectal cancer, brain cancer, liver cancer, kidney cancer, stomach cancer, and breast cancer;

More preferably, the pathogenic rash is selected from the group consisting of: noonan syndrome, cardio-facial skin syndrome, hereditary gingival fibromatosis type I.
Use of a compound according to any one of claims 1 to 30, or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutical composition according to claim 32, for the manufacture of a medicament for the treatment of a disease causing overexpression of SOS1 protein.
Use of a compound according to any one of claims 1 to 30 or a tautomer, stereoisomer, solvate, metabolite, isotopic label, pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutical composition according to claim 32 for the manufacture of a medicament for the treatment of a disease caused by overexpression of SOS1 protein.