Cycloalkyl or haloalkyl-containing compounds

Abstract

The invention relates to a compound containing naphthenic base or halogenated alkyl, and particularly discloses a compound shown in the formula I, a stereoisomer or pharmaceutically acceptable salt of the compound, a preparation method of the compound, a pharmaceutical composition containing the compound and application of the pharmaceutical composition in tumor treatment.

Description

[0001] This application is a divisional application of the following application: application date November 30, 2022; application number 202280074056.4; invention title: "Compound containing cycloalkyl or haloalkyl".

[0002] Cross-reference to related applications

[0003] This application claims the priority and benefits of the following Chinese patent applications filed with the China National Intellectual Property Administration, the disclosures of which are incorporated herein by reference in their entirety:

[0004] Chinese Patent Application No. 202111441498.1 filed on November 30, 2021;

[0005] Chinese Patent Application No. 202111638379.5 filed on December 29, 2021;

[0006] Chinese Patent Application No. 202210564004.7 filed on May 23, 2022;

[0007] Chinese Patent Application No. 202210889925.0 filed on July 27, 2022; and

[0008] Chinese Patent Application No. 202211492694.6 filed on November 25, 2022. Technical field

[0009] This application relates to compounds containing cycloalkyl or haloalkyl, and specifically discloses compounds represented by formula I", their stereoisomers or pharmaceutically acceptable salts thereof, methods for their preparation, pharmaceutical compositions containing the compounds, and their use in the treatment of tumors. Background art

[0010] EGFR (epidermal growth factor receptor)-TKI (tyrosine kinase inhibitor), as a small molecule inhibitor, competitively binds to EGFR through endogenous ligands, inhibits the activation of tyrosine kinase, thereby blocking the EGFR signaling pathway, and ultimately produces a series of biological effects such as inhibiting the proliferation and metastasis of tumor cells and promoting apoptosis of tumor cells, and is one of the main targets for the treatment of lung cancer.

[0011] Osimertinib (Osimertinib, AZD9291) is a third-generation EGFR-TKI targeted drug. Although it has a high response rate to the drug resistance caused by the T790M mutation, patients will also develop drug resistance. According to the existing research on the drug resistance analysis of AZD9291, obtaining a third mutation, namely the EGFR C797S mutation, is one of the main mechanisms leading to the drug resistance of Osimertinib, accounting for about 40%. It has important research significance to provide a safer and more effective fourth-generation EGFR C797S / T790M inhibitor for patients. Summary of the Invention

[0012] On the one hand, the present application relates to a compound of formula I", its stereoisomer or its pharmaceutically acceptable salt,

[0013]

[0014] wherein,

[0015] R 1 is selected from C 3-5 cycloalkyl, C 3-5 cycloalkyl-C 1-3 alkyl-, halo C 1-6 alkyl or C 1-6 alkyl;

[0016] R 2 is selected from hydrogen, halogen, OH, NH 2 , C 1-8 alkyl or C 1-8 alkoxy, wherein C 1-8 alkyl or C 1-8 alkoxy is optionally substituted by one or more R';

[0017] R' is selected from halogen, OH, cyano, NH 2 or nitro;

[0018] R 3 is selected from halogen, cyano, nitro, NH 2 , OH, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -NHR b , -NR a R b , -OR a , -SR a , -C(O)H, -C(O)R a , COOH, -C(O)OR a , -C(O)NH2 、 -C(O)NR a R b 、 -OC(O)R a 、 -NHC(O)R a 、 -N(C 1-4 alkyl)C(O)R a 、 -S(O) 2 H, -S(O) 2 R a 、 -S(O) 2 NH 2 、 -S(O) 2 NR a R b 、 -NHS(O) 2 R a 、 -NHC(O)OR a 、 -N(C 1-4 alkyl)C(O)OR a or -NHC(O)NHR a ; said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3 - 10 membered heterocyclic group, C 6-10 aryl or 5 - 10 membered heteroaryl is optionally substituted by one or more R c ;

[0019] Said R c is selected from oxo, OH, NH 2 , halogen, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy, -N(C 1-8 alkyl) 2 , -NH(C 1-8 alkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -S(O) 2 R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , -C 1-6 alkyl - S(O) 2 - C 1-6 alkyl or optionally substituted by one or more independently selected from OH, halogen or C1-6 3- to 8-membered heterocycloalkyl substituted with an alkyl group;

[0020] R a and R b are each independently selected from the following groups optionally substituted with one or more R'': C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl;

[0021] R'' are each independently selected from halogen, oxo, deuterium, NH 2 , OH, cyano, nitro, C 1-8 alkyl, haloC 1-8 alkyl, C 1-8 alkoxy, -N(C 1-8 alkyl) 2 , -NH(C 1-8 alkyl), C 3-6 cycloalkyl or 3- to 10-membered heterocycloalkyl optionally substituted with C 1-8 alkyl;

[0022] n is selected from 0, 1, 2, 3 or 4;

[0023] R 4 is selected from C 1-6 alkyl or C 3-5 cycloalkyl,

[0024] provided that when R 1 is selected from C 1-6 alkyl, R 4 is selected from C 3-5 cycloalkyl.

[0025] On the other hand, the present application relates to a compound of formula I', its stereoisomers or its pharmaceutically acceptable salts,

[0026]

[0027] wherein,

[0028] R 1 is selected from C 3-5 cycloalkyl, C 3-5 cycloalkyl-C 1-3 alkyl-, haloC 1-6 alkyl or C 1-6 alkyl;

[0029] R 2 is selected from hydrogen, C 1-8 alkyl or C 1-8 alkoxy, wherein C1-8 An alkyl or C 1-8 The alkoxy group is optionally substituted by one or more R';

[0030] R' is selected from halogen, OH, cyano, NH 2 or nitro;

[0031] R 3 is selected from halogen, cyano, nitro, NH 2 , OH, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -NHR b , -NR a R b , -OR a , -SR a , -C(O)H, -C(O)R a , COOH, -C(O)OR a , -C(O)NH 2 , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -N(C 1-4 alkyl)C(O)R a , -S(O) 2 H, -S(O) 2 R a , -S(O) 2 NH 2 , -S(O) 2 NR a R b , -NHS(O) 2 R a , -NHC(O)OR a or -N(C 1-4 alkyl)C(O)OR a , and the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more R c ;

[0032] The said R c is selected from oxo, halogen, cyano, nitro, C 1-8 alkoxy, -N(C1-8 alkyl 2 -NH(C 1-8 alkyl), -C(O)R a -C(O)OR a -C(O)NR a R b -OC(O)R a -NHC(O)R a -S(O) 2 R a -S(O) 2 NR a R b -NHS(O) 2 R a or optionally a 3- to 8-membered heterocycloalkyl group substituted with one or more groups independently selected from OH, halogen, or C 1-6 alkyl;

[0033] R a and R b are each independently selected from the following groups, optionally substituted with one or more R'': C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl;

[0034] R'' are each independently selected from halogen, NH 2 , OH, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy, -N(C 1-8 alkyl) 2 , -NH(C 1-8 alkyl), C 3-6 cycloalkyl, or 3- to 10-membered heterocycloalkyl;

[0035] n is selected from 0, 1, 2, 3, or 4;

[0036] R 4 is selected from C 1-6 alkyl or C 3-5 cycloalkyl,

[0037] provided that when R 1 is selected from C 1-6 alkyl, R 4 is selected from C 3-5 cycloalkyl.

[0038] In some embodiments, R 1 is selected from C 3-5 cycloalkyl, C 3-5Cycloalkyl-C 1-3 alkyl- or halo-C 1-6 alkyl.

[0039] In some embodiments, said R 1 is selected from C 3-4 cycloalkyl, C 3-4 cycloalkyl-C 1-2 alkyl- or halo-C 1-3 alkyl.

[0040] In some embodiments, said R 1 is selected from cyclopropyl, cyclopropyl-CH 2 - or halo-methyl.

[0041] In some embodiments, said R 1 is selected from cyclopropyl, cyclopropyl-CH 2 - or one or more fluoro-substituted methyls.

[0042] In some embodiments, said R 1 is selected from cyclopropyl.

[0043] In some embodiments, said R 1 is selected from cyclopropyl-CH 2 -.

[0044] In some embodiments, said R 1 is selected from -CH 2 F, -CHF 2 or -CF 3 .

[0045] In some embodiments, said R 1 is selected from methyl.

[0046] In some embodiments, said R 1 is selected from C 3-4 cycloalkyl, C 3-4 cycloalkyl-C 1-2 alkyl-, halo-C 1-3 alkyl or C 1-3 alkyl.

[0047] In some embodiments, said R 1 is selected from cyclopropyl, cyclopropyl-CH 2 -, halo-methyl or methyl.

[0048] In some embodiments, said R 1 is selected from cyclopropyl, cyclopropyl-CH 2 -, one or more fluoro-substituted methyls or methyl.

[0049] In some embodiments, R2 Selected from hydrogen, halogen, OH, NH 2 , C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted by one or more R'.

[0050] In some embodiments, R 2 is selected from hydrogen, halogen, OH, NH 2 , C 1-3 alkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally substituted by one or more R'.

[0051] In some embodiments, R 2 is selected from hydrogen, fluorine, chlorine, bromine, C 1-3 alkyl or C 1-3 alkoxy.

[0052] In some embodiments, R 2 is selected from fluorine, chlorine, bromine or C 1-3 alkyl.

[0053] In some embodiments, R 2 is selected from fluorine or methyl.

[0054] In still other embodiments, R 2 is selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted by one or more R'. In still other embodiments, R 2 is selected from hydrogen, C 1-3 alkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally substituted by one or more R'.

[0055] In still other embodiments, R 2 is selected from hydrogen, C 1-3 alkyl or C 1-3 alkoxy.

[0056] In still other embodiments, R 2 is selected from C 1-3 alkyl.

[0057] In still other embodiments, R 2 is selected from methyl.

[0058] In some embodiments, R’ is selected from halogens.

[0059] In some embodiments, R 3 is selected from halogens, cyano, nitro, NH 2 , OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, 5-6 membered heteroaryl, -NHR b , -NR a R b , -OR a , -SR a , -C(O)H, -C(O)R a , COOH, -C(O)OR a , -C(O)NH 2 , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -N(C 1-4 alkyl)C(O)R a , -S(O) 2 H, -S(O) 2 R a , -S(O) 2 NH 2 , -S(O) 2 NR a R b , -NHS(O) 2 R a , -NHC(O)OR a , -N(C 1-4 alkyl)C(O)OR a or -NHC(O)NHR a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-6 membered heteroaryl is optionally substituted with one or more R c .

[0060] In some embodiments, R 3 is selected from halogens, cyano, nitro, NH 2 , OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6Cycloalkyl, 3- to 6-membered heteroalkyl, phenyl, 5- to 6-membered heteroaryl, -NHR b 、-NR a R b 、-OR a 、-SR a 、-C(O)H, -C(O)R a 、COOH, -C(O)OR a 、-C(O)NH 2 、-C(O)NR a R b 、-OC(O)R a 、-NHC(O)R a 、-N(C 1-4 alkyl)C(O)R a 、-S(O) 2 H, -S(O) 2 R a 、-S(O) 2 NH 2 、-S(O) 2 NR a R b 、-NHS(O) 2 R a 、-NHC(O)OR a 、-N(C 1-4 alkyl)C(O)OR a or -NHC(O)NHR a ,wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl, phenyl, 5- to 6-membered heteroaryl is optionally substituted with one or more R c substituents.

[0061] In some embodiments, R 3 is selected from halogen, cyano, NH 2 、OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, -NHR b 、-NR a R b 、-OR a 、-SR a 、-OC(O)R a 、-NHC(O)R a 、-N(C 1-4 alkyl)C(O)R a 、-NHS(O)2 R a 、 -NHC(O)OR a 、 -N(C 1-4 alkyl)C(O)OR a or -NHC(O)NHR a , where the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, or 3 - 8 - membered heterocyclic group is optionally substituted by one or more R c substituents.

[0062] In some embodiments, the R 3 is selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, 4 - 6 - membered heterocycloalkyl, -NHR b 、 -NR a R b 、 -OR a 、 -SR a 、 -OC(O)R a 、 -NHC(O)R a 、 -NHC(O)OR a 、 -N(C 1-4 alkyl)C(O)OR a or -NHC(O)NHR a ; where the C 1-4 alkyl, C 2-4 alkenyl or 4 - 6 - membered heterocycloalkyl is optionally substituted by one or more R c substituents.

[0063] In some embodiments, the R 3 is selected from fluorine, chlorine, bromine, C 1-3 alkyl, C 2-4 alkenyl, 4 - 5 - membered azacycloalkyl, -NHR b 、 -NR a R b 、 -OR a 、 -SR a 、 -OC(O)R a 、 -NHC(O)R a 、 -NHC(O)OR a 、 -N(C 1-4 alkyl)C(O)OR a or -NHC(O)NHR a ; where the C 1-3 alkyl, C 2-4 alkenyl or 4 - 5 - membered azacycloalkyl is optionally substituted by one or more R c substituents.

[0064] In some embodiments, the R 3 is selected from bromine, methyl, butenyl, azetidinyl, pyrrolidinyl, -NHR b , -NR a R b , -OR a , -NHC(O)R a , or -NHC(O)NHR a ; the methyl, butenyl, azetidinyl or pyrrolidinyl is optionally substituted with one or more R c substituents.

[0065] In some embodiments, the R 3 is selected from bromine, -NHR b , -NR a R b , -OR a , -NHC(O)R a or -NHC(O)NHR a .

[0066] In some specific embodiments, the R 3 is selected from -NHR b , -NR a R b , -OR a , -NHC(O)R a or -NHC(O)NHR a .

[0067] In some specific embodiments, the R 3 is selected from -NHR b or -NR a R b . In some specific embodiments, the R 3 is selected from -OR a . In some specific embodiments, the R 3 is selected from -NHC(O)R a or -NHC(O)NHR a .

[0068] In some embodiments, the R 3 is selected from bromine,

[0069]

[0070] Alternatively, R 3 is selected from

[0071]

[0072]

[0073] In some specific embodiments, said R 3 is selected from

[0074]

[0075] In some other embodiments, said R 3 is selected from fluorine, chlorine, bromine, C 1-4 alkyl, C 2-4 alkenyl, 5- to 6-membered heterocyclic group, -NHR b , -NR a R b , -OR a , -SR a , -OC(O)R a , -NHC(O)R a , -NHC(O)OR a , -N(C 1-4 alkyl)C(O)OR a or -NHC(O)NHR a ; said C 1-4 alkyl, C 2-4 alkenyl or 5- to 6-membered heterocyclic group is optionally substituted by one or more R c .

[0076] In some other embodiments, said R 3 is selected from bromine, methyl, butenyl, pyrrolidinyl, -NHR b , -NR a R b , -OR a , -NHC(O)R a , or -NHC(O)NHR a ; said methyl, butenyl or pyrrolidinyl is optionally substituted by one or more R c .

[0077] In some other embodiments, said R 3 is selected from bromine, -NHR b , -NR a R b , -OR a , -NHC(O)R aor -NHC(O)NHR a 。

[0078] In some other embodiments, said R 3 is selected from bromine,

[0079]

[0080] In some other embodiments, R 3 is selected from halogen, cyano, nitro, NH 2 , OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl, 5- to 6-membered heteroaryl, -NHR b , -NR a R b , -OR a , -SR a , -C(O)H, -C(O)R a , COOH, -C(O)OR a , -C(O)NH 2 , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -N(C 1-4 alkyl)C(O)R a , -S(O) 2 H, -S(O) 2 R a , -S(O) 2 NH 2 , -S(O) 2 , -SR a R b , -NHS(O) 2 R a , -NHC(O)OR a or -N(C 1-4 alkyl)C(O)OR a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 6-membered heteroaryl is optionally substituted with one or more R c .

[0081] In some other embodiments, R 3 is selected from halogen, cyano, nitro, NH 2 , OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -NHR b , -NR a R b , -OR a , -SR a , -C(O)H, -C(O)R a , COOH, -C(O)OR a , -C(O)NH 2 , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -N(C 1-4 alkyl)C(O)R a , -S(O) 2 H, -S(O) 2 R a , -S(O) 2 NH 2 , -S(O) 2 NR a R b , -NHS(O) 2 R a , -NHC(O)OR a or -N(C 1-4 alkyl)C(O)OR a , wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted with one or more R c .

[0082] In some other embodiments, R 3 is selected from halogen, cyano, nitro, NH 2 , OH, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -NHR b , -NR a R b , -OR a, -SR a , -C(O)H, -C(O)R a , COOH, -C(O)OR a , -C(O)NH 2 , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -N(C 1-3 alkyl)C(O)R a , -S(O) 2 H, -S(O) 2 R a , -S(O) 2 NH 2 , -S(O) 2 NR a R b , -NHS(O) 2 R a , -NHC(O)OR a or -N(C 1-3 alkyl)C(O)OR a , the C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, 3 - to 6 - membered heteroalkyl, phenyl or 5 - to 6 - membered heteroaryl is optionally substituted with one or more R c .

[0083] In some other embodiments, R 3 is selected from halogen, cyano, NH 2 , OH or -NHR b .

[0084] In some other embodiments, R 3 is selected from fluorine, chlorine, bromine or -NHR b .

[0085] In some other embodiments, R 3 is selected from bromine,

[0086] In some embodiments, the R c is selected from OH, NH 2 , oxo, halogen, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, -N(C 1-6 alkyl) 2 , -NH(C 1-8 alkyl), -C(O)R a , -C(O)ORa 、 -C(O)NR a R b 、 -OC(O)R a 、 -NHC(O)R a 、 -S(O) 2 R a 、 -S(O) 2 NR a R b 、 -NHS(O) 2 R a 、 -C 1-6 alkyl - S(O) 2 - C 1-6 alkyl or 3 - 6 - membered heterocycloalkyl optionally substituted with one or more groups independently selected from OH, halogen, or C 1-4 alkyl.

[0087] In some embodiments, said R c is selected from OH, NH 2 , oxo, halogen, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, -N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -S(O) 2 R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , -C 1-4 alkyl - S(O) 2 , -C 1-4 alkyl or 4 - 6 - membered heterocycloalkyl optionally substituted with one or more groups independently selected from OH, halogen, or C 1-3 alkyl.

[0088] In some embodiments, said R c is selected from OH, NH 2 , halogen, cyano, C 1-4 alkyl, -C 1-4 alkoxy, -N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), -C1-4 alkyl-S(O) 2 -C 1-4 alkyl or a 4-6 membered heterocycloalkyl optionally substituted with one or more groups independently selected from OH, halogen or C 1-3 alkyl.

[0089] In some embodiments, said R c is selected from OH, C 1-3 alkyl, -N(C 1-3 alkyl) 2 , -C 1-3 alkyl-S(O) 2 -C 1-3 alkyl or a 6 membered heterocycloalkyl optionally substituted with one or more groups independently selected from OH, halogen or C 1-3 alkyl.

[0090] In some embodiments, said R c is selected from OH, C 1-3 alkyl, -N(C 1-3 alkyl) 2 , -C 1-3 alkyl-S(O) 2 -C 1-3 alkyl or a piperazinyl optionally substituted with one or more C 1-3 alkyl.

[0091] In some embodiments, said R c is selected from OH, methyl,

[0092] In still other embodiments, said R c is selected from oxo, OH, NH 2 , halogen, cyano, nitro, C 1-8 alkoxy, -N(C 1-8 alkyl) 2 , -NH(C 1-8 alkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -S(O) 2 R a , -S(O) 2 , -S(O) a R b , -NHS(O) 2 R a or a group optionally substituted with one or more groups independently selected from OH, halogen or C 1-6A 3- to 8-membered heterocycloalkyl group substituted with an alkyl group.

[0093] In some other embodiments, said R c is selected from OH, NH 2 , oxo, halogen, cyano, nitro, C 1-6 alkoxy, -N(C 1-6 alkyl) 2 , -NH(C 1-8 alkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -S(O) 2 R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or a 3- to 6-membered heterocycloalkyl group optionally substituted with one or more groups independently selected from OH, halogen, or C 1-4 alkyl.

[0094] In some other embodiments, said R c is selected from OH, NH 2 , oxo, halogen, cyano, nitro, C 1-4 alkoxy, -N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -S(O) 2 R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or a 4- to 6-membered heterocycloalkyl group optionally substituted with one or more groups independently selected from OH, halogen, or C 1-3 alkyl.

[0095] In some other embodiments, said R c is selected from OH, NH 2 , halogen, cyano, C1-4 alkoxy, -N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), or a 4-6 membered heterocycloalkyl optionally substituted with one or more groups independently selected from OH, halogen, or C 1-3 alkyl.

[0096] In some further embodiments, said R c is selected from OH, -N(C 1-3 alkyl) 2 or a 6 membered heterocycloalkyl optionally substituted with one or more groups independently selected from OH, halogen, or C 1-3 alkyl.

[0097] In some further embodiments, said R c is selected from OH, -N(C 1-3 alkyl) 2 or a piperazinyl optionally substituted with one or more C 1-3 alkyl.

[0098] In some further embodiments, said R c is selected from OH,

[0099] In some further embodiments, said R c is selected from oxo, halogen, cyano, nitro, C 1-6 alkoxy, -N(C 1-6 alkyl) 2 , -NH(C 1-8 alkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -S(O) 2 R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or a 3-6 membered heterocycloalkyl optionally substituted with one or more groups independently selected from OH, halogen, or C 1-4 alkyl.

[0100] In some further embodiments, said R c is selected from oxo, halogen, cyano, nitro, C 1-4 alkoxy, -N(C 1-4 alkyl)2 , -NH(C 1-4 alkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -S(O) 2 R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or a 4-6 membered heteroalkyl group optionally substituted with one or more groups independently selected from OH, halogen, or C 1-3 alkyl.

[0101] In some additional embodiments, said R c is selected from oxo, halogen, cyano, C 1-4 alkoxy, -N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), or a 4-6 membered heteroalkyl group optionally substituted with one or more groups independently selected from OH, halogen, or C 1-3 alkyl.

[0102] In some embodiments, said R a and R b are each independently selected from the following groups optionally substituted with one or more R": C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-8 membered heteroalkyl, C 6-10 aryl, or 5-6 membered heteroaryl.

[0103] In some embodiments, said R a and R b are each independently selected from the following groups optionally substituted with one or more R": C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, or 3-8 membered heteroalkyl.

[0104] In some embodiments, said R a and R b are each independently selected from the following groups optionally substituted with one or more R": C 1-8 alkyl, C 3-8cycloalkyl or 3-8 membered heterocycloalkyl. In some specific embodiments, said R a and R b are each independently selected from the following groups optionally substituted with one or more R": C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl.

[0105] In some embodiments, said R a and R b are each independently selected from the following groups optionally substituted with one or more R": C 1-5 alkyl, C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl.

[0106] In some embodiments, said R a and R b are each independently selected from the following groups optionally substituted with one or more R": methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl or piperidinyl.

[0107] In some embodiments, said R a and R b are each independently selected from C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl optionally substituted with one or more R. In some embodiments, said R a and R b are each independently selected from C 1-5 alkyl optionally substituted with one or more R. In some embodiments, said R a and R b are each independently selected from C 3-6 cycloalkyl optionally substituted with one or more R. In some embodiments, said R a and R b are each independently selected from 4-6 membered heterocycloalkyl optionally substituted with one or more R. In some specific embodiments, said R a and R b are each independently selected from the following groups optionally substituted with one or more R": methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some specific embodiments, said R a and R b are each independently selected from the following groups optionally substituted with one or more R": propyl or cyclohexyl. In some specific embodiments, said R a and R bIndependently selected from propyl optionally substituted with one or more R″. In some specific embodiments, said R a and R b are independently selected from cyclohexyl optionally substituted with one or more R″.

[0108] In some other embodiments, said R a and R b are independently selected from the following groups optionally substituted with one or more R″: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl.

[0109] In some other embodiments, said R a and R b are independently selected from the following groups optionally substituted with one or more R″: C 1-4 alkyl or 3-6 membered heterocycloalkyl.

[0110] In some other embodiments, said R a and R b are independently selected from the following groups optionally substituted with one or more R″: propyl, ethyl or oxetanyl.

[0111] In some embodiments, -N(C 1-8 alkyl) 2 appearing in the definition of R″ is selected from -N(C 1-8 alkyl) 2 and -N(deuterated C 1-8 alkyl) 2 .

[0112] In some embodiments, R″ is independently selected from halogen, oxo, deuterium, NH 2 , OH, cyano, nitro, C 1-8 alkyl, halo C 1-8 alkyl, C 1-8 alkoxy, -N(C 1-8 alkyl) 2 , -N(deuterated C 1-8 alkyl) 2 , -NH(C 1-8 alkyl), C 3-6 cycloalkyl or 3-10 membered heterocycloalkyl optionally substituted with C 1-8 alkyl.

[0113] In some embodiments, R″ is independently selected from halogen, oxo, deuterium, NH 2, OH, cyano, nitro, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkoxy, -N(C 1-8 alkyl) 2 , -N(deuterated C 1-6 alkyl) 2 , -NH(C 1-8 alkyl), C 3-6 cycloalkyl or a 3- to 10-membered heterocycloalkyl optionally substituted with C 1-8 alkyl.

[0114] In some embodiments, each R” is independently selected from halogen, oxo, deuterium, NH 2 , OH, cyano, nitro, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, -N(C 1-6 alkyl) 2 , -N(deuterated C 1-6 alkyl) 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl or a 3- to 6-membered heterocycloalkyl optionally substituted with C 1-6 alkyl. In some specific embodiments, each R” is independently selected from C 1-6 alkyl, -N(C 1-6 alkyl) 2 , -N(deuterated C 1-6 alkyl) 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl or a 3- to 6-membered heterocycloalkyl optionally substituted with C 1-6 alkyl. In some specific embodiments, each R” is independently selected from C 1-6 alkyl, -N(C 1-6 alkyl) 2 , -N(deuterated C 1-6 alkyl) 2 or a 3- to 6-membered heterocycloalkyl optionally substituted with C 1-3 alkyl. In some specific embodiments, each R” is independently selected from C 1-4 alkyl, -N(C 1-4 alkyl) 2 , -N(deuterated C 1-4 alkyl) 2 , or a 4- to 6-membered heterocycloalkyl optionally substituted with C 1-3 alkyl.

[0115] In some embodiments, each R” is independently selected from halogen, oxo, deuterium, NH 2 、OH, cyano, nitro, C 1-3 alkyl, halo-C 1-3 alkyl, C 1-3 alkoxy, -N(C 1-3 alkyl) 2 、-N(deuterio-C 1-3 alkyl) 2 、-NH(C 1-3 alkyl), C 4-6 cycloalkyl or 3- to 6-membered heterocycloalkyl optionally substituted with C 1-3 alkyl.

[0116] In some embodiments, each R” is independently selected from fluorine, chlorine, bromine, oxo, deuterium, NH 2 、OH, cyano, C 1-4 alkyl, fluoro-C 1-4 alkyl, C 1-4 alkoxy, -N(C 1-4 alkyl) 2 、-N(deuterio-C 1-4 alkyl) 2 、-NH(C 1-4 alkyl), C 5-6 cycloalkyl or 4- to 6-membered heterocycloalkyl optionally substituted with C 1-4 alkyl.

[0117] In some embodiments, each R” is independently selected from fluorine, OH, oxo, deuterium, -NH 2 、methyl, ethyl, propyl, trifluoromethyl, -N(CH 3 ) 2 、-N(CD 3 ) 2 、-N(CH 2 CH 3 ) 2 、-NHCH 3 、morpholinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, 1,4-dioxanyl or oxetanyl optionally substituted with methyl or ethyl.

[0118] In some embodiments, R” are each independently selected from halogen, NH 2 、OH, oxo, deuterium, cyano, nitro, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkoxy, -N(C 1-8 alkyl), -NH(C 1-8 alkyl), C 3-6 cycloalkyl or optionally substituted with C1-8 Alkyl-substituted 3- to 10-membered heterocycloalkyl;

[0119] In some embodiments, each R″ is independently selected from halogen, oxo, deuterium, NH 2 , OH, cyano, nitro, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, -N(C 1-6 alkyl) 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl optionally substituted with C 1-6 alkyl. In some specific embodiments, each R″ is independently selected from C 1-6 alkyl, -N(C 1-6 alkyl) 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl optionally substituted with C 1-6 alkyl. In some specific embodiments, each R″ is independently selected from C 1-6 alkyl, -N(C 1-6 alkyl) 2 or 3- to 6-membered heterocycloalkyl optionally substituted with C 1-3 alkyl. In some specific embodiments, each R″ is independently selected from C 1-4 alkyl, -N(C 1-4 alkyl) 2 or 4- to 6-membered heterocycloalkyl optionally substituted with C 1-3 alkyl.

[0120] In some embodiments, each R″ is independently selected from halogen, oxo, deuterium, NH 2 , OH, cyano, nitro, C 1-3 alkyl, halo-C 1-3 alkyl, C 1-3 alkoxy, -N(C 1-3 alkyl) 2 , -NH(C 1-3 alkyl), C 4-6 cycloalkyl or 3- to 6-membered heterocycloalkyl optionally substituted with C 1-3 alkyl.

[0121] In some embodiments, each R″ is independently selected from fluorine, chlorine, bromine, oxo, deuterium, NH 2 , OH, cyano, C 1-4 alkyl, fluoro-C 1-4 alkyl, C 1-4 alkoxy, -N(C1-4 alkyl) 2 、 -NH(C 1-4 alkyl), C 5-6 cycloalkyl or 4 - 6 - membered heterocycloalkyl optionally substituted with C 1-4 alkyl.

[0122] In some embodiments, each R” is independently selected from fluorine, OH, oxo, deuterium, -NH 2 , methyl, ethyl, propyl, trifluoromethyl, -N(CH 3 ), 2 , -N(CH 2 CH 3 ), 2 , -NHCH 3 , morpholinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, 1,4 - dioxanyl or oxetanyl optionally substituted with methyl or ethyl.

[0123] In some specific embodiments, each R” is independently selected from halogen, OH, oxo, C 1-6 alkyl, halo - C 1-6 alkyl or -N(C 1-4 alkyl) 2 . In some specific embodiments, each R” is independently selected from halogen, OH, oxo, C 1-4 alkyl, halo - C 1-4 alkyl or -N(C 1-2 alkyl) 2 . In some specific embodiments, each R” is independently selected from fluorine, OH, oxo, methyl, ethyl, propyl, trifluoromethyl or -N(CH 3 ), 2 .

[0124] In some other embodiments, R” are each independently selected from halogen, NH 2 , OH, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy, -N(C 1-8 alkyl) 2 , -NH(C 1-8 alkyl), C 3-6 cycloalkyl or 3 - 10 - membered heterocycloalkyl.

[0125] In some other embodiments, each R” is independently selected from halogen, NH 2 , OH, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, -N(C 1-6 alkyl) 2 , -NH(C 1-6 alkyl), C3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0126] In some other embodiments, each R″ is independently selected from halogen, NH 2 , OH, cyano, nitro, C 1-3 alkyl, C 1-3 alkoxy, -N(C 1-3 alkyl) 2 , -NH(C 1-3 alkyl), C 4-6 cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0127] In some other embodiments, each R″ is independently selected from fluorine, chlorine, bromine, NH 2 , OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, -N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), C 5-6 cycloalkyl or 4- to 6-membered heterocycloalkyl. In some other embodiments, each R″ is independently selected from fluorine, -NH 2 , methyl, ethyl, propyl, -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -NHCH 3 , morpholinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, 1,4-dioxanyl or oxetanyl. In some other embodiments, each R″ is independently selected from halogen or 3- to 6-membered heterocycloalkyl.

[0128] In some other embodiments, each R″ is independently selected from fluorine, chlorine, bromine or 6-membered heterocycloalkyl.

[0129] In some other embodiments, each R″ is independently selected from fluorine or morpholinyl.

[0130] In some embodiments, each R a and R b are independently selected from methyl, CD 3 ,

[0131]

[0132] Alternatively, each R a and R b are independently selected from

[0133] In some other embodiments, said R a and R b are each independently selected from methyl,

[0134]

[0135] In some other embodiments, said R a and R b are each independently selected from

[0136] In some embodiments, n is selected from 0, 1, 2 or 3. In some embodiments, n is selected from 0, 1 or 2. In some embodiments, n is selected from 1 or 2; in some specific embodiments, n is selected from 1.

[0137] In some embodiments, R 4 is selected from C 1-3 alkyl or C 3-4 cycloalkyl.

[0138] In some embodiments, R 4 is selected from methyl, ethyl, cyclopropyl or cyclobutyl.

[0139] In some embodiments, R 4 is selected from methyl or cyclopropyl. In some specific embodiments, R 4 is selected from cyclopropyl.

[0140] In some specific embodiments, R 4 is selected from methyl.

[0141] In some embodiments, R 1 is selected from halo C 1-6 alkyl or C 3-4 cycloalkyl, or R 1 is selected from halomethyl or cyclopropyl;

[0142] R 2 is selected from C 1-3 alkyl, or R 2 is selected from methyl;

[0143] R 3 is selected from -NHR b or -NR a R b ;

[0144] R a and Rb are each independently selected from the following groups optionally substituted by one or more R": C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, or, R a and R b are each independently selected from the following groups optionally substituted by one or more R": C 1-5 alkyl, C 3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl; or, R a and R b are each independently selected from the following groups optionally substituted by one or more R": methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl or piperidinyl; or, R a and R b are each independently selected from the following groups optionally substituted by one or more R": methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or, R a and R b are each independently selected from the following groups optionally substituted by one or more R": propyl or cyclohexyl;

[0145] R" are each independently selected from fluorine, chlorine, bromine, oxo, deuterium, NH 2 , OH, cyano, C 1-4 alkyl, fluorinated C 1-4 alkyl, C 1-4 alkoxy, -N(C 1-4 alkyl) 2 , -N(deuterated C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), C 5-6 cycloalkyl or 4- to 6-membered heterocycloalkyl optionally substituted by C 1-4 alkyl; or, R" are each independently selected from fluorine, OH, oxo, deuterium, -NH 2 , methyl, ethyl, propyl, trifluoromethyl, -N(CH 3 ) 2 , -N(CD 3 ) 2 , -N(CH 2 CH 3 ) 2 , -NHCH 3 , morpholinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, 1,4-dioxanyl or oxetanyl optionally substituted by methyl or ethyl;

[0146] R 4 is selected from C1-3 alkyl, or R 4 is selected from methyl.

[0147] In some embodiments, the compound of formula I", its stereoisomers or its pharmaceutically acceptable salts are selected from the compound of formula I"A or the compound of formula I"B, its stereoisomers or its pharmaceutically acceptable salts,

[0148]

[0149] wherein n, R 1 , R 2 , R 3 or R 4 are as defined above.

[0150] In some embodiments, the compound of formula I', its stereoisomers or its pharmaceutically acceptable salts are selected from the compound of formula I'A or the compound of formula I'B, its stereoisomers or its pharmaceutically acceptable salts,

[0151]

[0152] wherein n, R 1 , R 2 , R 3 or R 4 are as defined above.

[0153] In some embodiments, the compound of formula I', its stereoisomers or its pharmaceutically acceptable salts are selected from the compound of formula I, its stereoisomers or its pharmaceutically acceptable salts,

[0154]

[0155] wherein n, R 1 , R 2 or R 3 are as defined above.

[0156] In some embodiments, in the compound of formula I:

[0157] R 1 is selected from C 3-5 cycloalkyl, C 3-5 cycloalkyl-C 1-3 alkyl- or halo C 1-6 alkyl;

[0158] R 2 is selected from hydrogen, C 1-8 alkyl or C 1-8 alkoxy, wherein C 1-8 alkyl or C 1-8 alkoxy is optionally substituted by one or more R';

[0159] R’ is selected from halogen, hydroxyl, cyano, amino or nitro;

[0160] R 3 is selected from halogen, cyano, nitro, NH 2 , OH, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -NHR b , -NR a R b , -OR a , -SR a , -C(O)H, -C(O)R a , COOH, -C(O)OR a , -C(O)NH 2 , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -N(C 1-4 alkyl)C(O)R a , -S(O) 2 H, -S(O) 2 R a , -S(O) 2 NH 2 , -S(O) 2 NR a R b , -NHS(O) 2 R a , -NHC(O)OR a or -N(C 1-4 alkyl)C(O)OR a , wherein the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more R c ;

[0161] The R c is selected from oxo, halogen, cyano, nitro, C 1-8 alkoxy, -N(C 1-8 alkyl) 2 , -NH(C 1-8 alkyl), -C(O)R a, -C(O)OR a , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -S(O) 2 R a , -S(O) 2 , -S(O) a NR b , -NHS(O) 2 R a , or optionally a 3- to 8-membered heterocycloalkyl group substituted with one or more hydroxyl groups, halogens or C 1-6 alkyl groups;

[0162] R a and R b are each independently selected from the following groups optionally substituted with one or more R": C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl;

[0163] R" are each independently selected from halogen, NH 2 , OH, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy, -N(C 1-8 alkyl) 2 , -NH(C 1-8 alkyl), C 3-6 cycloalkyl or 3- to 10-membered heterocycloalkyl;

[0164] n is selected from 0, 1, 2, 3 or 4.

[0165] In some embodiments, the heteroatoms in the heterocycloalkyl, heterocyclic or heteroaryl groups described in the present application are selected from N, O or S, and the remaining ring atoms are selected from carbon; in some embodiments, the heteroatoms in the heterocycloalkyl, heterocyclic or heteroaryl groups described in the present application are selected from N or O, and the remaining ring atoms are selected from carbon; in some embodiments, the number of heteroatoms in the heterocycloalkyl, heterocyclic or heteroaryl groups described in the present application is selected from 1, 2, 3, 4 or 5; in some embodiments, the number of heteroatoms in the heterocycloalkyl, heterocyclic or heteroaryl groups described in the present application is selected from 1, 2 or 3.

[0166] In some embodiments, the compound of formula I', the compound of formula I'A, the compound of formula I'B, the compound of formula I, its stereoisomers or its pharmaceutically acceptable salts described in the present application are selected from the compound of formula IA or the compound of formula IB, its stereoisomers or its pharmaceutically acceptable salts,

[0167]

[0168] Among them, n, R 1 , R 2 or R 3 are defined as described above.

[0169] In some embodiments, the compound of formula I', the compound of formula I'A, the compound of formula I'B, the compound of formula I, the compound of formula IA, the compound of formula IB, their stereoisomers or their pharmaceutically acceptable salts are selected from the compound of formula I-1, the compound of formula I-1A, the compound of formula I-1B, the compound of formula I-2, the compound of formula I-2A, the compound of formula I-2B, the compound of formula II, the compound of formula IIA, the compound of formula IIB, the compound of formula II-1, the compound of formula II-1A, the compound of formula II-1B, the compound of formula II-2, the compound of formula II-2A or the compound of formula II-2B, their stereoisomers or their pharmaceutically acceptable salts,

[0170]

[0171]

[0172] Among them, R b , R 1 , R 2 and R 3 are defined as described above.

[0173] In some embodiments, the compound of formula I', the compound of formula I'A, the compound of formula I'B, their stereoisomers or their pharmaceutically acceptable salts are selected from the compound of formula III-1, the compound of formula III-1A, the compound of formula III-1B, the compound of formula III-2, the compound of formula III-2A, the compound of formula III-2B, the compound of formula IV, the compound of formula IVA, the compound of formula IVB, the compound of formula IV-1, the compound of formula IV-1A, the compound of formula IV-1B, the compound of formula IV-2, the compound of formula IV-2A or the compound of formula IV-2B, their stereoisomers or their pharmaceutically acceptable salts,

[0174]

[0175]

[0176] Among them, R b , R 1 , R 2 and R 3 are defined as described above.

[0177] In some embodiments, the present application includes the variables and their embodiments defined above, as well as any combination thereof. It should be understood that any embodiment of the compounds of the present disclosure as described above and any specific substituents described herein with respect to specific n, R 1 、R 2 、R 3 and R 4 substituents may be independently combined with other embodiments of the present invention and / or substituents of the compounds to form embodiments of the present invention not specifically described above. Additionally, in specific embodiments and / or claims, with respect to any particular n, R 1 、R 2 、R 3 and R 4 substituents, in the case where a list of substituents is disclosed, it should be understood that one or more substituents may be deleted from the list, and the remaining list of substituents will be considered an embodiment of the present invention.

[0178] In some embodiments, the present application provides the following compounds, their stereoisomers, or their pharmaceutically acceptable salts:

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189] On the other hand, the present application relates to pharmaceutical compositions comprising the compounds of the present application (such as the compounds of Formula I", Formula I', or Formula I), their stereoisomers, or their pharmaceutically acceptable salts. In some embodiments, the pharmaceutical compositions of the present application further include pharmaceutically acceptable excipients.

[0190] On the other hand, the present application relates to a method for treating EGFR-mediated diseases in an individual (such as a mammal), including administering a therapeutically effective amount of a compound of the present application (such as a compound of formula I″, formula I′ or formula I), its stereoisomers or its pharmaceutically acceptable salts, or a pharmaceutical composition thereof to an individual in need of such treatment, preferably a human.

[0191] On the other hand, the present application relates to the use of a compound of the present application (such as a compound of formula I″, formula I′ or formula I), its stereoisomers or its pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating EGFR-mediated diseases.

[0192] On the other hand, the present application relates to the use of a compound of the present application (such as a compound of formula I″, formula I′ or formula I), its stereoisomers or its pharmaceutically acceptable salts, or a pharmaceutical composition thereof in preventing or treating EGFR-mediated diseases.

[0193] On the other hand, the present application relates to a compound of the present application (such as a compound of formula I″, formula I′ or formula I), its stereoisomers or its pharmaceutically acceptable salts, or a pharmaceutical composition thereof for preventing or treating EGFR-mediated diseases.

[0194] In some embodiments, the EGFR-mediated diseases described in the present application are selected from EGFR mutant-mediated diseases. The mutants are selected from one, two, three or four of L858R, T790M, d19, and C797S; in some embodiments, the mutants are selected from the two mutants L858R and T790M; in some embodiments, the mutants are selected from the double mutant d19 and T790M. Further, in some embodiments, the mutants include the C797S mutant; furthermore, the mutants are selected from the triple mutant L858R, T790M and C797S; or the mutants are selected from the triple mutant d19, T790M and C797S.

[0195] In some embodiments, the EGFR-mediated diseases described in the present application are selected from cancers.

[0196] In some embodiments, the EGFR-mediated diseases described in the present application are selected from lung cancers.

[0197] In some embodiments, the EGFR-mediated diseases described in the present application are selected from non-small cell lung cancers.

[0198] The compounds of the present application have one or more advantages such as good kinase and cell activities (including wild type and mutants, such as d19, T790M, C797S and L858R), stable metabolism in vivo and in vitro, and excellent in vivo drug efficacy.

[0199] Definition

[0200] Unless otherwise specified, the following terms used in this application have the following meanings. A particular term should not be considered indefinite or unclear without a special definition, but should be understood according to its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding commodity or its active ingredient.

[0201] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, provided that the valence state of the particular atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.

[0202] The term "optionally" or "optionally" means that the subsequent described event or situation may or may not occur, and this description includes the occurrence and non-occurrence of the described event or situation. For example, "optionally" substituted by a halogen for ethyl means that ethyl can be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), polysubstituted (such as CHFCH 2 F, CH 2 CHF 2 , etc.) or fully substituted (CF 2 CF 3 ). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible to exist and / or cannot be synthesized will be introduced.

[0203] In some embodiments, the "one or more" described in this application is selected from one, two, three, four, five, or six. In some embodiments, the "one or more" is selected from one, two, or three. In some embodiments, the "one or more" is selected from one, or two.

[0204] C m-n herein means that this part has an integer number of carbon atoms within a given range, and any carbon present in the substituents of this part is not included in the m to n carbons of C m-n . For example, "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0205] When any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted by 2 Rs, each R has an independent option.

[0206] When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent single bond.

[0207] When one of the variables is selected from a single bond, it means that the two groups it connects are directly linked.

[0208] When a substituent's bond cross-links to two atoms on a ring, this substituent can bond to any atom on this ring. For example, the structural unit means that it can be substituted at any position on cyclohexyl or cyclohexadiene.

[0209] means that the substituent is connected to other structures. For example, when the heterocyclic alkyl of R 1 is selected from , it means is connected to L:

[0210] The term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine. When a group in this application has a halogenated group, the number of halogenations is optionally selected from one or more. In some embodiments, the "one or more" in this application is selected from one, two, three, four, five, or six. In some embodiments, the "one or more" is selected from one, two, or three. In some embodiments, the "one or more" is selected from one, or two. For example, the halogenated C 1-6 alkyl in this application includes C 1-6 alkyl substituted with one, two, three, four, five, or six halogen atoms.

[0211] The term "hydroxy" refers to the -OH group.

[0212] The term "cyano" refers to the -CN group.

[0213] The term "amino" refers to the -NH 2 group.

[0214] The term "nitro" refers to the -NO 2 group.

[0215] The term "alkyl" refers to a hydrocarbon group with the general formula C n H 2n+1 . This alkyl can be straight-chain or branched-chain. For example, the term "C 1-6"Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl moiety (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above.

[0216] The term "alkoxy" refers to -O-alkyl.

[0217] The term "alkylamino" refers to -NH-alkyl.

[0218] The term "dialkylamino" refers to -N(alkyl) 2 。

[0219] The term "alkylsulfonyl" refers to -SO 2 -alkyl.

[0220] The term "alkenyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl can be a C 2-8 alkenyl having 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0221] The term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl can be a C 2-8 alkynyl having 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH 3 ), 2-propynyl (-CH 2 -C≡CH), 1,3-butadiynyl (-C≡C-C≡CH), etc.

[0222] The term "cycloalkyl" refers to a carbocyclic ring that is completely saturated and can exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocyclic ring is usually a 3- to 10-membered ring (such as 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.

[0223] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the heterocycle is usually a 3- to 10-membered (e.g., 3-, 4-, 5-, 6-, 7- or 8-membered) ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxiranyl, thiiranyl, aziridinyl; non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl; examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl; examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl; examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, thiepanyl. Preferred is a monocyclic heterocycloalkyl having 5 or 6 ring atoms.

[0224] The term "heterocyclyl" refers to a non-aromatic ring (such as heterocycloalkyl) that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the heterocycle is usually a 3- to 10-membered ring (e.g., 3-, 4-, 5-, 5-, 7- or 8-membered) containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. Non-limiting examples of heterocyclyl include, but are not limited to, oxiranyl, oxetanyl, tetrahydrofuranyl, 1,4-dioxanyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, etc.

[0225] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. For example, aryl can have 6 - 20 carbon atoms, 6 - 14 carbon atoms or 6 - 12 (e.g., 6, 7, 8, 9, 10, 11 or 12) carbon atoms. Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthryl and 1,2,3,4-tetrahydronaphthalene, etc.

[0226] The term "heteroaryl" refers to a monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 4- to 8-membered ring, especially a 5- to 8-membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, etc.

[0227] The term "treatment" means administering a compound or formulation described in the present application to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0228] (i) inhibiting a disease or disease state, i.e., curbing its development;

[0229] (ii) alleviating a disease or disease state, i.e., causing the disease or disease state to subside.

[0230] The term "prevention" means administering a compound or formulation described in the present application to prevent a disease or one or more symptoms associated with the disease, and includes preventing the occurrence of a disease or disease state in an individual (e.g., a mammal), especially when such a mammal is susceptible to the disease state but has not been diagnosed as having the disease state.

[0231] The term "effective amount" means (i) the amount of a compound of the present application for treating or preventing a specific disease, condition or disorder, (ii) reducing, improving or eliminating one or more symptoms of a specific disease, condition or disorder, or (iii) preventing or delaying the onset of one or more symptoms of a specific disease, condition or disorder described herein. The amount of the compound of the present application constituting an "effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0232] The term "pharmaceutically acceptable" pertains to those compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0233] As pharmaceutically acceptable salts, for example, mention may be made of metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic or acidic amino acids, etc.

[0234] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the present application to an organism.

[0235] The term "pharmaceutically acceptable excipients" refers to those excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0236] The term "individual" includes mammals such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In some embodiments, the individual is a human.

[0237] The words "comprise" or "comprising" and their English variants such as "comprises" or "comprising" should be understood in an open, non-exclusive sense, i.e., "including but not limited to".

[0238] The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. Specific examples of proton tautomers are imidazole moieties, where the proton can migrate between two ring nitrogens. Valence tautomers include interconversions through the reorganization of some bonding electrons.

[0239] The present application also includes isotopically labeled compounds of the present application that are the same as those described herein, but with one or more atoms replaced by atoms having an atomic weight or mass number different from that typically found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123I. 125 I and 36 Cl, etc.

[0240] Certain isotopically labeled compounds of the present application (e.g., those labeled with 3 H and 14 C) can be used in the analysis of the tissue distribution of compounds and / or substrates. Tritiation (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by substituting unlabeled reagents with isotopically labeled reagents through the following procedures similar to those disclosed in the schemes and / or examples below.

[0241] In addition, substitution with heavier isotopes (such as deuterium (i.e., 2 H)) can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirements), and may therefore be preferred in certain cases, where deuterium substitution can be partial or complete, and partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium.

[0242] The compounds of the present application can be asymmetric, for example, having one or more stereoisomers. Unless otherwise specified, all stereoisomers are included, such as enantiomers and diastereomers. Compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. The optically pure form can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0243] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, and aerosols, etc.

[0244] Typical routes of administration of the compounds of the present application or their pharmaceutically acceptable salts or their pharmaceutical compositions include but are not limited to oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0245] The pharmaceutical composition of the present application can be manufactured by methods well-known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill manufacturing methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0246] In all administration methods of the compounds described herein, the daily dose administered is from 0.01 to 200 mg / kg body weight, in the form of a single or divided dose.

[0247] The compounds of the present application can be prepared by a variety of synthetic methods well-known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination of these with other chemical synthesis methods, and equivalent replacement methods well-known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present application.

[0248] The chemical reactions of the specific embodiments of the present application are completed in a suitable solvent, which must be suitable for the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, sometimes those skilled in the art need to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0249] An important consideration in the synthesis route planning in the art is to select a suitable protecting group for the reactive functional groups. For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. All references cited in the present application are incorporated herein by reference in their entirety.

[0250] In some embodiments, the compounds of the general formula of the present application can be prepared by those skilled in the art of organic synthesis through the following route:

[0251]

[0252] wherein, R 1 , R 2 , R 3 , R 4 , and n are defined as described above.

[0253] Preparation of Intermediate I-2: Prepared by reacting Compound I-1 with (wherein R 1 is defined as in the present application) in the presence of a suitable solvent (such as N,N-dimethylformamide, etc.) and an inorganic base (such as potassium carbonate, etc.). This reaction is carried out at about 25 °C to about 50 °C.

[0254] Preparation of Intermediate I-3: It is prepared by reacting Compound I-2 in the presence of a suitable solvent (such as dichloromethane, etc.) and an organic base (such as triethylamine, etc.). This reaction is carried out at about 0 °C to about 20 °C.

[0255] Preparation of Intermediate I-4: It is prepared by reacting Compound I-3 with (where R 2 , R 4 as defined in this application) in the presence of a suitable solvent (such as N,N-dimethylformamide, etc.) and an inorganic base (such as potassium carbonate, etc.). This reaction is carried out at about 50 °C to about 80 °C.

[0256] Preparation of Intermediate I-5: It is prepared by reacting Compound I-4 in the presence of a suitable solvent (such as methanol, etc.) and a catalyst (such as Raney nickel, etc.). This reaction is carried out at about 0 °C to about 30 °C.

[0257] Preparation of Intermediate I-6: It is prepared by reacting Compound I-5 with cyanogen bromide in the presence of a suitable solvent (such as dichloromethane / tert-butanol, etc.). This reaction is carried out at about 0 °C to about 30 °C.

[0258] Preparation of Intermediate I-7: It is prepared by reacting Compound I-6 in the presence of a suitable solvent (such as tetrahydrofuran, etc.) and an inorganic base (such as sodium hydroxide, etc.). This reaction is carried out at about 0 °C to about 30 °C.

[0259] Preparation of Intermediate I-8: It is prepared by reacting Compound I-7 in the presence of a suitable solvent (such as dichloromethane, etc.) and a condensing agent (such as TBTU, etc.). This reaction is carried out at about 0 °C to about 30 °C.

[0260] Preparation of Intermediate I: It is prepared by reacting Compound I-8 in the presence of a suitable solvent (such as tert-amyl alcohol, etc.), a base (such as potassium tert-butoxide, etc.), a ligand (such as 2-(di-tert-butylphosphino)biphenyl, etc.) and a catalyst (such as Pd 2 (dba) 3 , etc.). This reaction is carried out at about 70 °C to about 110 °C.

[0261] The following abbreviations are used in this application:

[0262] Pd(dppf)Cl 2 CH 2 Cl 2 is dichloromethane complex of [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride; HATU represents 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate; TBTU represents O-benzotriazol-N,N,N',N'-tetramethyluronium tetrafluoroborate; Pd 2 (dba) 3Represents tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl 2 Represents dichloropalladium(II) bis(diphenylphosphino)ferrocene; X-Phos represents 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; SEM represents 2-(trimethylsilyl)ethoxymethyl; Boc represents tert-butoxycarbonyl; LiAlH 4 Represents lithium aluminum hydride; Cbz represents benzyloxycarbonyl. Detailed implementation mode

[0263] For clarity, the present application is further illustrated by examples, but the examples do not limit the scope of the present application. All reagents used in the present application are commercially available and can be used without further purification.

[0264] Example 1:

[0265]

[0266]

[0267] (1) Preparation method of compound A:

[0268] Dissolve methyl 2-chloro-6-methylisonicotinate (20.0 g), 1-methyl-5-hydroxypyrazole (21.4 g), Pd(dppf)Cl 2 CH 2 Cl 2 (2.64 g), and sodium carbonate (25.125 g) in anisole (400 mL). The reaction solution is purged with argon three times and stirred at 130 °C for about 10 h. After the reaction is complete, it is cooled to room temperature, filtered by suction, and the filter cake is rinsed with 80 mL of toluene. 60 mL of methanol is added to the filtrate, and 40 mL of 4 M hydrogen chloride dioxane solution is slowly added dropwise. After the addition is complete, it is stirred at room temperature for 2 h. After the stirring is completed, it is filtered by suction, and the filter cake is rinsed with 40 mL of toluene. The target compound is obtained and dried under vacuum at 50 °C for 8 h. Compound A (18.3 g) is obtained, ESI-MS: m / z = 248.26 [M + H] + .

[0269] (2) Preparation method of compound B:

[0270] (S)-4-Benzyl-2-oxazolidinone (10.0 g), cyclopropylacetic acid (7.3 g) and 4-dimethylaminopyridine (7.6 g) were dispersed in dichloromethane (150 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.6 g) was added at 20 - 25 °C. After the addition, the mixture was stirred at 20 - 25 °C for 12 h to complete the reaction. 50 mL of dichloromethane was added to the reaction solution. The dichloromethane phase was washed successively with water (100 mL), 1 M hydrochloric acid (100 mL × 2), and 1 M sodium bicarbonate solution (100 mL × 2). The dichloromethane phase was retained, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound B (7.65 g) was obtained by column chromatography. ESI-MS: m / z = 260.16 [M + H] + 。

[0271] (3) Preparation method of compound C:

[0272] Compound B (4.0 g) was dispersed in tetrahydrofuran (50 mL), and the system was purged with nitrogen three times and cooled (set temperature -78 °C). When the internal temperature reached -70 °C, sodium bis(trimethylsilyl)amide (2 M, 11.6 mL) was added dropwise over 15 min. After the addition, the mixture was stirred at -70 °C or below for 1 h. Then 3-bromopropene (3.7 g) was added dropwise, and after stirring at -70 °C or below for 1 h, the mixture was slowly warmed to room temperature and stirred for 12 h to complete the reaction. The reaction solution was poured into ammonium chloride solution (1 M, 400 mL), and extracted with ethyl acetate (30 mL × 2). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound C (2.8 g) was obtained by column chromatography. ESI-MS: m / z = 300.18 [M + H] + 。

[0273] (4) Preparation method of compound D:

[0274] Compound C (1.0 g) was dispersed in tetrahydrofuran (10 mL), cooled to 0 - 5 °C in an ice bath, and a solution of lithium hydroxide monohydrate (240 mg) in water (2 mL) was added. After stirring for 5 min, hydrogen peroxide (30%, 1.34 mL) was added, and the mixture was stirred at 0 - 5 °C for 1 h to complete the reaction. Sodium sulfite solution (1 M, 15 mL) and sodium bicarbonate solution (1 M, 15 mL) were added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL × 2). The aqueous phase was retained, and the pH of the aqueous phase was adjusted to 1 - 2 with 4 M hydrochloric acid and then extracted with dichloromethane (15 mL × 2). The dichloromethane phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound D (3.34 mmol) was obtained, which was directly used in the next step without further purification.

[0275] (5) Preparation method of compound E:

[0276] Dissolve compound D (3.34 mmol) in dichloromethane (10 mL). Successively add dibenzylamine (659 mg), N,N-diisopropylethylamine (1.3 g), and HATU (1.5 g). After addition, stir the reaction mixture at 20 - 25 °C for 12 h until the reaction is complete. Wash the reaction solution with water (10 mL × 2), retain the dichloromethane phase, dry it over anhydrous sodium sulfate, concentrate it until no more liquid flows out, and obtain compound E (800 mg) by column chromatography. ESI-MS: m / z = 320.30 [M + H] + 。

[0277] (6) Preparation method of compound F:

[0278] Disperse compound E (800 mg) in tetrahydrofuran (10 mL), add 9-borabicyclo[3.3.1]nonane (0.5 M, 12.5 mL), and stir the reaction mixture at 20 - 25 °C for 1 h. Cool the reaction mixture to 0 - 5 °C in an ice bath, and successively add an aqueous solution of sodium hydroxide (200 mg) in water (2 mL) and hydrogen peroxide (30%, 1.42 mL). Stir the reaction mixture at 20 - 25 °C for 2 h until the reaction is complete. Pour the reaction solution into water (30 mL), extract it with ethyl acetate (10 mL × 2), combine the ethyl acetate phases, dry it over anhydrous sodium sulfate, concentrate it until no more liquid flows out, and obtain compound F (700 mg), which can be directly used for the next step of the reaction without further purification. ESI-MS: m / z = 338.30 [M + H] + 。

[0279] (7) Preparation method of compound G:

[0280] Disperse compound F (700 mg) in tetrahydrofuran (10 mL), cool it to 0 - 5 °C, and slowly add lithium aluminum hydride (1 M, 4.1 mL). After addition, stir the reaction mixture at 20 - 25 °C for 2 h until the reaction is complete. Add saturated sodium sulfate solution dropwise to the reaction solution until no more gas is evolved, then add anhydrous sodium sulfate for drying, filter and concentrate until no more liquid flows out to obtain compound G (630 mg), which can be directly used for the next step of the reaction without further purification. ESI-MS: m / z = 324.35 [M + H] + 。

[0281] (8) Preparation method of compound H:

[0282] Disperse compound G (630 mg) in methanol (10 mL), add Pd / C (10%, 50 mg), replace the air with hydrogen three times, and stir the reaction mixture in a water bath at 40 - 45 °C for 2 h until the reaction is complete. Filter and concentrate the reaction solution until no more liquid flows out to obtain compound H (1.948 mmol), which can be directly used for the next step of the reaction without further purification.

[0283] (9) Preparation method of compound I:

[0284] Dissolve compound H (1.948 mmol) in N,N-dimethylformamide (10 mL). Sequentially add 4-bromo-1-fluoro-2-nitrobenzene (428 mg) and potassium carbonate (592 mg). Stir and react at 40 - 45 °C in a water bath for 6 h until the reaction is complete. Pour the reaction solution into 50 mL of water, extract with ethyl acetate (10 mL × 2). Combine the ethyl acetate phases, dry over anhydrous sodium sulfate, concentrate until no more liquid flows out, and obtain compound I (470 mg) by column chromatography. ESI-MS: m / z = 343.14 [M + H] + 。

[0285] (10) Preparation method of compound J:

[0286] Dissolve compound I (470 mg) in dichloromethane (8 mL), add triethylamine (208 mg) and cool to 0 - 5 °C. Dropwise add a solution of methanesulfonyl chloride (188 mg) in dichloromethane (2 mL). After the addition is complete, react at 20 - 25 °C for 1 h until the reaction ends. Wash the reaction solution with sodium bicarbonate solution (1 M, 10 mL × 2), retain the dichloromethane phase, dry over anhydrous sodium sulfate, concentrate until no more liquid flows out, and obtain compound J (1.369 mmol), which is directly used in the next step without further purification.

[0287] (11) Preparation method of compound K:

[0288] Disperse compound J (1.369 mmol), compound A (339 mg) and potassium carbonate (416 mg) in N,N-dimethylformamide (10 mL), react at 60 °C for 6 h until the reaction is complete. Pour the reaction solution into 50 mL of water, extract with ethyl acetate (10 mL × 2). Combine the ethyl acetate phases, wash the organic phase with water once, dry the organic phase over anhydrous sodium sulfate, concentrate until no more liquid flows out, and obtain compound K (650 mg) by column chromatography. ESI-MS: m / z = 572.16 [M + H] + 。

[0289] (12) Preparation method of compound L:

[0290] Dissolve compound K (650 mg) in methanol (5 mL), add Raney nickel (20 mg), displace with hydrogen 3 times, react at 25 °C for 5 h until the reaction is complete. Filter the reaction solution, dry the filtrate over anhydrous sodium sulfate, concentrate until no more liquid flows out, and obtain compound L (1.135 mmol), which is directly used in the next step without further purification.

[0291] (13) Preparation method of compound M:

[0292] Compound L (1.135 mmol) was dissolved in tert-butanol (1 mL) and dichloromethane (4 mL). A solution of cyanogen bromide (144 mg) in dichloromethane (1 mL) was added dropwise, and the reaction was carried out at 25 °C for 12 h until completion. Sodium bicarbonate solution (1 M, 10 mL) was added to the reaction mixture. After liquid separation, the dichloromethane phase was retained. The organic phase was washed with sodium bicarbonate solution (1 M, 10 mL × 2), dried over anhydrous sodium sulfate, and concentrated until no more liquid flowed out to obtain compound M (460 mg), which was directly used in the next reaction without further purification. ESI-MS: m / z = 567.17 [M+H] + 。(14) Preparation method of compound N:

[0293] Compound M (460 mg) was dissolved in tetrahydrofuran (3 mL). A solution of sodium hydroxide (130 mg) in water (3 mL) was added, and the reaction was stirred at 20 - 25 °C for 45 min until completion. The pH was adjusted to 5 - 6 with 6 M hydrochloric acid. Tetrahydrofuran and water were removed by distillation under reduced pressure. Dichloromethane (10 mL) and triethylamine (246 mg) were added and stirred until clear. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated until no more liquid flowed out to obtain compound N (0.811 mmol), which was directly used in the next reaction without further purification. ESI-MS: m / z = 553.16 [M+H] + 。

[0294] (15) Preparation method of compound O:

[0295] Compound N (0.811 mmol) was redissolved in dichloromethane (5 mL). TBTU (312 mg) was added, and the reaction was carried out at 20 - 25 °C for 16 h until completion. The reaction mixture was washed with water (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated until no more liquid flowed out, and purified by column chromatography to obtain compound O (310 mg). ESI-MS: m / z = 535.22 [M+H] + 。

[0296] (16) Preparation method of Example 1:

[0297] Compound O (100 mg), 3-oxetanamine (16 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), and potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h until completion. 30 mL of water was added to the reaction mixture. The mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated until no more liquid flowed out. Example 1 (20 mg) was obtained by preparative liquid chromatography purification. ESI-MS: m / z = 528.48 [M+H] + 。

[0298] 1 H NMR(500MHz,DMSO-d 6 )δ12.40(s,1H),8.33(s,1H),7.90(s,1H),7.54(d,J = 1.2Hz,1H),7.36(d,J = 8.7Hz,1H),6.64(d,J = 2.1Hz,1H),6.48(dd,J = 8.7,2.2Hz,1H),6.38(d,J = 6.0Hz,1H),4.85(t,J = 6.2Hz,2H),4.49(q,J = 6.2Hz,1H),4.44(td,J = 5.9,4.1Hz,2H),4.31–4.25(m,1H),4.21(dd,J = 14.0,3.5Hz,1H),4.07–3.98(m,2H),3.72(s,3H),2.54(s,3H),2.19(q,J = 6.7Hz,1H),2.13(dt,J = 10.4,5.1Hz,1H),1.97(dd,J = 11.7,6.5Hz,1H),1.80(t,J = 8.5Hz,1H),1.69(q,J = 6.9,5.5Hz,1H),0.62–0.53(m,1H),0.29(dt,J = 9.4,4.8Hz,1H), - 0.07(dq,J = 9.5,4.9Hz,1H), - 0.18(tt,J = 9.5,4.5Hz,1H), - 0.62(dq,J = 9.6,4.8Hz,1H).

[0299] Example 2:

[0300]

[0301] Dissolve compound O (100 mg), (S)–trifluoroisopropylamine hydrochloride (32 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), and potassium tert-butoxide (126 mg) in tert-amyl alcohol (10 mL). Replace the atmosphere with nitrogen three times and react at 100 °C for 2 h. After the reaction is completed, add 50 mL of water to the reaction solution, extract with ethyl acetate (50 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and purify by preparative liquid chromatography to obtain Example 2 (10 mg). ESI-MS: m / z = 568.48 [M+H] + .

[0302] 1 H NMR(500MHz,DMSO-d 6)δ12.44(s,1H),8.34(s,1H),7.91(s,1H),7.55(s,1H),7.37(d,J=8.7Hz,1H),6.93(d,J=2.2Hz,1H),6.73(dd,J=8.8,2.3Hz,1H),5.99(d,J=8.6Hz,1H),4.29(d,J=7.5Hz,1H),4.22(dq,J=8.1,5.1,4.3Hz,2H),4.03(td,J=9.5,4.3Hz,2H),3.73(s,3H),2.54(s,3H),2.20(q,J=6.7,6.3Hz,1H),2.13(dq,J=9.0,4.4,3.8Hz,1H),1.98(td,J=9.9,9.2,4.5Hz,1H),1.80(d,J=9.3Hz,1H),1.70(tt,J=8.6,3.7Hz,1H),1.33(d,J=6.7Hz,3H),0.59(tt,J=8.6,3.6Hz,1H),0.30(dt,J=8.9,4.4Hz,1H),-0.03–-0.09(m,1H),-0.18(dt,J=9.1,4.4Hz,1H),-0.61(dd,J=9.4,4.8Hz,1H).

[0303] Example 3:

[0304]

[0305] Compound O (110 mg), 4-(2-aminoethyl)morpholine (40 mg), Pd 2 (dba) 3 (47 mg), 2-(di-tert-butylphosphino)biphenyl (31 mg), potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (10 mL). After purging with nitrogen three times, the mixture was reacted at 100 °C for 2 h. After the reaction was completed, 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 3 (30 mg). ESI-MS: m / z = 585.49 [M+H] + .

[0306] 1 H NMR (500 MHz, DMSO-d 6)δ12.39(s,1H),8.34(s,1H),8.16(s,1H),7.91(s,1H),7.55(d,J=1.3Hz,1H),7.34(d,J=8.7Hz,1H),6.76(d,J=2.2Hz,1H),6.61(dd,J=8.7,2.2Hz,1H),4.33–4.26(m,1H),4.22(dd,J=13.9,3.4Hz,1H),4.02(dt,J=14.3,8.2Hz,2H),3.73(s,3H),3.61(t,J=4.6Hz,4H),3.13(t,J=6.7Hz,2H),2.54(s,6H),2.44(s,3H),2.21(t,J=6.8Hz,1H),2.14(dt,J=10.4,5.4Hz,1H),2.03–1.94(m,1H),1.80(d,J=10.0Hz,1H),1.70(dd,J=11.1,5.9Hz,1H),0.58(dt,J=9.8,5.2Hz,1H),0.30(dt,J=9.3,4.7Hz,1H),-0.06(dq,J=9.5,4.8Hz,1H),-0.17(dt,J=9.1,4.7Hz,1H),-0.61(dt,J=9.6,4.8Hz,1H).

[0307] Example 4:

[0308]

[0309]

[0310] (1) Preparation method of compound A-1-1:

[0311] Disperse cyclopropylhydrazine hydrochloride (5.0 g) in methanol (50 mL), dropwise add methyl trans-3-methoxyacrylate (5.34 g) at 20 - 25 °C, then raise the temperature to 50 - 60 °C and react for 3.5 h until the reaction is complete; concentrate the reaction solution, add tetrahydrofuran (60 mL) to the residue, stir at room temperature for 2 h, after stirring, filter by suction, wash the filter cake with 20 mL of tetrahydrofuran, and dry the filter cake in vacuo at 50 °C for 8 h. Obtain compound A-1-1 (6.4 g). ESI-MS: m / z = 125.08 [M + H] + .

[0312] (2) Preparation method of compound A-1-2:

[0313] Compound A-1-1 (6.0 g) and sodium methoxide (2.02 g) were dispersed in methanol (60 mL), and the mixture was stirred at 20 - 25 °C for 2 h; the reaction solution was concentrated, added with tetrahydrofuran (50 mL × 2) and evaporated to dryness, then added with tetrahydrofuran (100 mL), stirred at 20 - 25 °C for 1 h, filtered by suction, and concentrated to dryness; then successively added with tetrahydrofuran (60 mL), triphenylphosphine (12.7 g), and benzyl alcohol (4.85 g), cooled to 0 - 10 °C, and diisopropyl azodicarboxylate (10.6 g) was added dropwise, and the mixture was kept warm for reaction for 2 h to complete the reaction; water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, separated by liquid separation, the organic phase was dried with anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound A-1-2 (7.0 g) was obtained by column chromatography. ESI-MS: m / z = 215.10 [M + H] + 。

[0314] (3) Preparation method of compound A-1-3:

[0315] Compound A-1-2 (7.0 g) was dispersed in dichloromethane (70 mL), N-iodosuccinimide (7.35 g) was added, and the mixture was stirred at 20 - 25 °C for 2 h to complete the reaction; water (100 mL) was added to the reaction solution, extracted with dichloromethane (50 mL × 2), the organic phases were combined, dried with anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound A-1-3 (5.9 g) was obtained by column chromatography. ESI-MS: m / z = 341.04 [M + H] + 。

[0316] (4) Preparation method of compound A-1-4:

[0317] Compound A-1-3 (5.9 g) was dispersed in tetrahydrofuran (60 mL), under nitrogen protection, cooled to -20 - -10 °C, isopropylmagnesium chloride (2 mol / L, 17.34 mL) was added dropwise, kept warm for reaction for 2 h, isopropyl pinacol borate (8.07 g) was added dropwise, and after the addition, the mixture was kept warm for reaction for 2 h to complete the reaction; the reaction solution was poured into ammonium chloride solution (10%, 100 mL), extracted with ethyl acetate (100 mL × 2), the organic phases were combined, dried with anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound A-1-4 (7.2 g) was obtained, which was directly used for the next reaction without further purification. ESI-MS: m / z = 341.02 [M + H] + 。

[0318] (5) Preparation method of compound A-1-5:

[0319] Compound A-1-4 (3.6 g), methyl 2-bromo-6-methylisonicotinate (2.43 g), potassium carbonate (2.9 g), Pd(dppf)Cl 2(0.39 g) was dispersed in N,N-dimethylformamide (30 mL), purged with nitrogen three times, and reacted at 90 - 100 °C for 8 h. After the reaction was completed, water (300 mL) was added to the reaction solution, and it was extracted with ethyl acetate (150 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound A-1-5 (1.06 g) was obtained by column chromatography. ESI-MS: m / z = 364.25 [M+H] + 。

[0320] (6) Preparation method of compound A-1:

[0321] Compound A-1-5 (1.06 g) was dispersed in tetrahydrofuran (20 mL), Pd / C (10%, 200 mg) was added, purged with hydrogen three times, and stirred at 20 - 25 °C for 0.5 h. After the reaction was completed, the reaction solution was filtered and concentrated until no liquid flowed out to obtain compound A-1 (0.8 g), which was directly used in the next reaction without further purification. ESI-MS: m / z = 274.11 [M+H] + 。

[0322] (7) Preparation method of compound I-1:

[0323] (R)-5-Amino-4-methyl-1-pentanol (4.65 g), 2-fluoro-5-bromonitrobenzene (8.32 g), and potassium carbonate (11.50 g) were added to N,N-dimethylformamide (85 mL) and reacted at 50 °C for 4 h. After the reaction was complete, the reaction solution was poured into 500 mL of water, extracted with ethyl acetate (400 mL × 2), the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out to obtain compound I-1 (4.5 g), which was directly used in the next reaction without further purification. ESI-MS: m / z = 317.10 [M+H] + 。

[0324] (8) Preparation method of compound J-1:

[0325] Compound I-1 (4.31 g) was dissolved in dichloromethane (80 mL), triethylamine (2.75 g) was slowly added and the temperature was lowered to 0 - 5 °C, and then p-toluenesulfonyl chloride (2.86 g) was slowly added dropwise. After the addition was complete, the reaction was carried out at 20 - 25 °C for 3 h until the reaction was complete. The reaction solution was washed with sodium bicarbonate solution (1 M, 100 mL × 2), separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated until no liquid flowed out to obtain compound J-1 (5.1 g), which was directly used in the next reaction without further purification. ESI-MS: m / z = 471.10 [M+H] + 。

[0326] (9) Preparation method of compound K-1:

[0327] Compound J-1 (1.38 g), compound A-1 (0.8 g) and potassium carbonate (1.0 g) were added to N,N-dimethylformamide (10 mL), and the reaction was carried out at 70 °C for 2.5 h until the reaction was complete. The reaction solution was poured into 150 mL of water, extracted with ethyl acetate (150 mL × 2), the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound K-1 (0.8 g) was obtained by column chromatography. ESI-MS: m / z = 572.19 [M+H] + 。

[0328] (10) Preparation method of compound L-1:

[0329] Compound K-1 (0.8 g) was dissolved in methanol (30 mL), and Raney Ni (0.2 g) was slowly added. The reaction solution was purged with nitrogen twice and then with hydrogen three times, and the reaction was carried out at 25 °C for 2 h until the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated until no liquid flowed out to obtain compound L-1 (1.40 mmol), which was directly used in the next step without further purification. ESI-MS: m / z = 542.21 [M+H] + 。

[0330] (11) Preparation method of compound M-1:

[0331] Compound L-1 (1.40 mmol) was dissolved in methanol (30 mL), and a solution of cyanogen bromide (0.3 g) in acetonitrile (3 mL) was added dropwise. The reaction was carried out at 40 - 50 °C for 2 h until the reaction was complete. Sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL × 2). The dichloromethane phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound M-1 (0.7 g) was obtained by concentration, which was directly used in the next step without further purification. ESI-MS: m / z = 567.21 [M+H] + 。

[0332] (12) Preparation method of compound N-1:

[0333] Compound M-1 (0.7 g) was dissolved in tetrahydrofuran (30 mL), and a solution of sodium hydroxide (0.2 g) in water (6 mL) was added dropwise. The reaction was carried out at 20 - 25 °C for 3 h until the reaction was complete. The pH of the reaction solution was adjusted to 5 - 6 with 6 M hydrochloric acid, and tetrahydrofuran and water were removed under reduced pressure. Dichloromethane (50 mL) and triethylamine (2.25 g) were added and stirred until clear. After drying and filtration, a dichloromethane solution of compound N-1 (1.23 mmol) was obtained, which was directly used in the next step without further purification. ESI-MS: m / z = 553.18 [M+H] + 。

[0334] (13) Preparation method of compound O-1:

[0335] Add TBTU (0.47 g) to the dichloromethane solution of compound N-1 (1.23 mmol), react at 20 - 25 °C for 16 h until the reaction is complete; wash the reaction solution with water (20 mL * 3), dry the organic phase with anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain compound O-1 (0.48 g) by column chromatography. ESI-MS: m / z = 535.23 [M + H] + .

[0336] (14) Preparation method of Example 4:

[0337] Disperse compound O-1 (100 mg), 3 - oxetanamine (21 mg), Pd 2 (dba) 3 (37 mg), 2-(di-tert-butylphosphino)biphenyl (23 mg), and potassium tert-butoxide (126 mg) in tert-amyl alcohol (5 mL), displace with nitrogen 3 times, react at 70 - 75 °C for 2 h until the reaction is complete; add water (50 mL) to the reaction solution, extract with dichloromethane (50 mL * 2), combine the organic phases, dry with anhydrous sodium sulfate, concentrate until no liquid flows out, and purify by preparative liquid phase to obtain Example 4 (36 mg). ESI-MS: m / z = 528.43 [M + H] + .

[0338] 1 1H NMR (500 MHz, chloroform-d) δ 12.09 (s, 1H), 8.48 (d, J = 1.3 Hz, 1H), 8.09 (s, 1H), 7.63 (d, J = 1.4 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.56 (dd, J = 8.7, 2.2 Hz, 1H), 6.45 (d, J = 6.0 Hz, 1H), 5.30 (s, 1H), 4.99 (t, J = 6.2 Hz, 2H), 4.62–4.38 (m, 4H), 4.29 (d, J = 13.7 Hz, 1H), 4.02 (s, 1H), 3.58 (t, J = 11.8 Hz, 1H), 3.49 - 3.40 (m, 1H), 2.79 (s, 1H), 2.60 (s, 3H), 2.25 (d, J = 7.1 Hz, 1H), 1.93 (dtd, J = 19.1, 10.2, 9.5, 5.6 Hz, 2H), 1.48 (dq, J = 13.4, 7.1, 5.8 Hz, 1H), 1.40 - 1.32 (d, J = 10.5 Hz, 1H), 1.16 - 1.13 (m, 1H), 1.09–0.97 (m, 2H), 0.89 (d, J = 6.6 Hz, 3H).

[0339] Example 5:

[0340]

[0341] Compound O-1 (100 mg), 4-(2-aminoethyl)morpholine (46 mg), Pd 2 (dba) 3 (37 mg), 2-(di-tert-butylphosphino)biphenyl (23 mg), potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (5 mL). The mixture was purged with nitrogen three times and reacted at 70 - 75 °C for 2 h. After the reaction was completed, water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 5 (15 mg). ESI-MS: m / z = 585.36 [M+H] + .

[0342] 1 H NMR (500 MHz, DMSO-d 6 ) δ12.41 (s, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 7.87 (s, 1H), 7.55 (s, 1H), 7.44–7.41 (m, 1H), 6.77 (d, J = 2.3 Hz, 1H), 6.61 (dd, J = 8.6, 2.2 Hz, 1H), 4.39 (td, J = 9.2, 4.5 Hz, 1H), 4.12 (ddd, J = 25.9, 11.6, 4.0 Hz, 2H), 3.78 (dd, J = 13.6, 10.1 Hz, 1H), 3.60 (t, J = 4.5 Hz, 5H), 3.13 (t, J = 6.7 Hz, 2H), 2.78 (s, 1H), 2.54 (s, 4H), 2.52 (s, 1H), 2.43 (t, J = 4.7 Hz, 3H), 2.23 (t, J = 6.8 Hz, 1H), 2.03–1.95 (m, 1H), 1.93 (d, J = 10.9 Hz, 1H), 1.49–1.40 (m, 1H), 1.23 (d, J = 5.0 Hz, 1H), 1.17–1.14 (m, 1H), 1.03 (t, J = 5.5 Hz, 3H), 0.81 (d, J = 6.5 Hz, 3H).

[0343] Example 6:

[0344]

[0345] (1) Preparation method of compound K-2:

[0346] Compound J (600 mg), compound A-1 (400 mg) and potassium carbonate (433 mg) were added to N,N-dimethylformamide (10 mL), and the reaction was carried out at 60 °C for 5 h until the reaction was complete. The reaction solution was poured into 50 mL of water, extracted with ethyl acetate (30 mL × 2), the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound K-2 (610 mg) was obtained by column chromatography. ESI-MS: m / z = 598.21 [M+H]

[0347] (2) Preparation method of compound L-2:

[0348] Compound K-2 (600 mg) was dissolved in methanol (10 mL), and Raney Ni (0.1 g) was slowly added. The reaction solution was purged with nitrogen twice and then with hydrogen three times, and the reaction was carried out at 25 °C for 4 h until the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated until no liquid flowed out to obtain compound L-2 (1.003 mmol), which was directly used in the next step without further purification. ESI-MS: m / z = 568.22 [M+H] + 。

[0349] (3) Preparation method of compound M-2:

[0350] Compound L-2 (1.003 mmol) was dissolved in tert-butanol (2 mL) and dichloromethane (8 mL), and a solution of cyanogen bromide (128 mg) in dichloromethane (1 mL) was added dropwise. The reaction was carried out at 20 - 25 °C for 12 h until the reaction was complete. Sodium bicarbonate solution (1 M, 10 mL) was added to the reaction solution, and liquid separation was carried out. The dichloromethane phase was retained, and the organic phase was washed with sodium bicarbonate solution (1 M, 10 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated until no liquid flowed out to obtain compound M-2 (500 mg), which was directly used in the next step without further purification. ESI-MS: m / z = 593.24 [M+H] + 。

[0351] (4) Preparation method of compound N-2:

[0352] Compound M-2 (500 mg) was dissolved in tetrahydrofuran (10 mL), and a solution of sodium hydroxide (135 mg) in water (6 mL) was added dropwise. The reaction was carried out at 20 - 25 °C for 2 h until the reaction was complete. The reaction solution was adjusted to pH = 5 - 6 with 6 M hydrochloric acid, and tetrahydrofuran and water were removed under reduced pressure. Dichloromethane (20 mL) and triethylamine (250 mg) were added and stirred until clear. After drying and filtration, a dichloromethane solution of compound N-2 (0.842 mmol) was obtained, which was directly used in the next step without further purification. ESI-MS: m / z = 579.20 [M+H] + 。

[0353] (5) Preparation method of compound O'-2:

[0354] To the dichloromethane solution of compound N-2 (0.842 mmol), add TBTU (324 mg), react at 20 - 25 °C for 16 h until the reaction is complete; wash the reaction solution with water (20 mL * 3), dry the organic phase with anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain compound O'-2 (350 mg) by column chromatography. ESI-MS: m / z = 561.19 [M + H] + .

[0355] (6) Preparation method of Example 6:

[0356] Disperse compound O'-2 (100 mg), 3-oxetanamine (16 mg), Pd 2 (dba) 3 (41 mg), 2-(di-tert-butylphosphino)biphenyl (27 mg), and potassium tert-butoxide (120 mg) in tert-amyl alcohol (5 mL), displace with nitrogen 3 times, react at 70 - 75 °C for 2 h until the reaction is complete; add 50 mL of water to the reaction solution, extract with dichloromethane (50 mL * 2), combine the organic phases, dry with anhydrous sodium sulfate, concentrate until no liquid flows out, and purify by preparative liquid phase to obtain Example 6 (26 mg). ESI-MS: m / z = 554.31 [M + H] + .

[0357] Example 7:

[0358]

[0359] Disperse compound O'-2 (100 mg), 4-(2-aminoethyl)morpholine (28 mg), Pd 2 (dba) 3 (41 mg), 2-(di-tert-butylphosphino)biphenyl (27 mg), and potassium tert-butoxide (120 mg) in tert-amyl alcohol (5 mL), displace with nitrogen 3 times, react at 70 - 75 °C for 2 h until the reaction is complete; add 50 mL of water to the reaction solution, extract with dichloromethane (50 mL * 2), combine the organic phases, dry with anhydrous sodium sulfate, concentrate until no liquid flows out, and purify by preparative liquid phase to obtain Example 7 (15 mg). ESI-MS: m / z = 611.36 [M + H] + .

[0360] Example 8:

[0361]

[0362] (1) Preparation method of compound I-2:

[0363] Compound H (1.0 g), 2-fluoro-4-bromonitrobenzene (1.54 g) and potassium carbonate (2.12 g) were added to N,N-dimethylformamide (30 mL), and the mixture was stirred at 40 - 45 °C in a water bath for 6 h. The reaction was monitored by LC-MS until completion. The reaction solution was poured into 200 mL of water, extracted with ethyl acetate (30 mL × 2), and the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound I-2 (1.54 g) was obtained by column chromatography. ESI-MS: m / z = 343.15 [M+H] + 。

[0364] (2) Preparation method of compound J-2:

[0365] Compound I-2 (1.54 g) was dissolved in dichloromethane (20 mL), triethylamine (681 mg) was slowly added and the temperature was cooled to 0 - 5 °C, then ethylsulfonyl chloride (692 mg) was slowly added dropwise. After the addition was complete, the reaction was carried out at 20 - 25 °C for 3 h until the reaction was complete. The reaction solution was washed with sodium bicarbonate solution (1 M, 20 mL × 2), separated, the organic phase was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound J-2 was obtained, which was directly used in the next step without further purification.

[0366] (3) Preparation method of compound K-2:

[0367] The compound J-2 obtained in the previous step, compound A (1.10 g) and potassium carbonate (1.36 g) were added to N,N-dimethylformamide (20 mL), and the reaction was carried out at 70 °C for 2.5 h. The reaction was monitored by LC-MS until completion. The reaction solution was poured into 100 mL of water, extracted with ethyl acetate (20 mL × 2), and the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound K-2 (2.01 g) was obtained by column chromatography. ESI-MS: m / z = 572.20 [M+H] + 。

[0368] (4) Preparation method of compound L-2:

[0369] Compound K-2 (2.0 g) was dissolved in methanol (15 mL) and tetrahydrofuran (15 mL), Raney nickel (200 mg) was added, and the mixture was purged with hydrogen three times. The reaction was carried out at 25 °C for 5 h, and TLC showed that the reaction was complete. The reaction solution was filtered, the filtrate was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound L-2 was obtained, which was directly used in the next step without further purification. ESI-MS: m / z = 542.21 [M+H] + 。

[0370] (5) Preparation method of compound M-2:

[0371] Dissolve the compound L-2 obtained in the previous step in tert-butanol (5 mL) and dichloromethane (20 mL), add dropwise a solution of cyanogen bromide (444 mg) in dichloromethane (2 mL), react at 25 °C for 12 h, and LC-MS shows that the reaction is complete; add sodium bicarbonate solution (1 M, 30 mL) to the reaction solution, separate the layers, retain the dichloromethane phase, wash the organic phase with sodium bicarbonate solution (1 M, 30 mL * 2), dry the organic phase with anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain compound M-2 (1.80 g), which is directly used for the next reaction without further purification. ESI-MS: m / z = 567.19 [M + H]

[0372] (6) Preparation method of compound N-2:

[0373] Dissolve compound M-2 (1.80 g) in tetrahydrofuran (10 mL), add a solution of sodium hydroxide (507 mg) in water (10 mL), stir and react at 20 - 25 °C for 45 min, and monitor the reaction by LC-MS until it is complete; adjust the pH to 5 - 6 with 6 M hydrochloric acid, distill off tetrahydrofuran and water under reduced pressure, add dichloromethane (30 mL) and triethylamine (963 mg), stir until clear, dry with anhydrous sodium sulfate, filter and concentrate until no liquid flows out to obtain compound N-2, which is directly used for the next reaction without further purification. ESI-MS: m / z = 553.16 [M + H] + 。

[0374] (7) Preparation method of compound O-2:

[0375] Dissolve the compound N-2 obtained in the previous step in dichloromethane (30 mL), add TBTU (1.20 g), react at 20 - 25 °C for 16 h, and LC-MS shows that the reaction is complete; wash the reaction solution with water (30 mL * 3), dry the organic phase with anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain compound O-2 (900 mg) by column chromatography. ESI-MS: m / z = 535.21 [M + H] + 。

[0376] (8) Preparation method of compound P-2:

[0377] Add compound O-2 (100 mg) to N,N-dimethylformamide (2 mL), sequentially add dropwise 2-(trimethylsilyl)ethoxymethyl chloride (47 mg) and N,N-diisopropylethylamine (48 mg) at 20 - 25 °C, displace with nitrogen 3 times, react at 60 °C for 3 h, and LC-MS shows that the reaction is complete; pour the reaction solution into 15 mL of water, extract with ethyl acetate (10 mL * 2), combine the ethyl acetate phases, dry with anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain compound P-2 (90 mg) by column chromatography. ESI-MS: m / z = 665.20 [M + H] +。

[0378] (9) Preparation method of compound Q-2:

[0379] Add compound P-2 (90 mg), potassium trifluoro((4-methylpiperazin-1-yl)methyl)borate (52 mg), X-Phos (15 mg), palladium acetate (3.6 mg), and cesium carbonate (130 mg) into 1,4-dioxane (3 mL) and water (0.3 mL), displace with nitrogen three times, react at 100 °C for 2 h, and LC-MS shows that the reaction is complete; pour the reaction solution into 15 mL of water, extract with ethyl acetate (10 mL × 2), combine the ethyl acetate phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain compound Q-2 (70 mg) by column chromatography. ESI-MS: m / z = 699.38 [M+H] + 。

[0380] (10) Preparation method of Example 8:

[0381] Add compound Q-2 (20 mg) into dichloromethane (2 mL), dropwise add trifluoroacetic acid (0.3 mL) at 20 - 25 °C, react at 35 °C for 6 h, and LC-MS shows that the reaction is complete; concentrate the reaction solution until no liquid flows out, and purify by preparative liquid phase to obtain Example 8 (13 mg). ESI-MS: m / z = 569.35 [M+H] + 。

[0382] 1 H NMR (500 MHz, chloroform-d) δ 12.05 (s, 1H), 8.41 (s, 1H), 8.15 (s, 1H), 7.66 (s, 1H), 7.40 (s, 1H), 7.27 (d, J = 9.1 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 4.41 (dd, J = 14.2, 3.0 Hz, 1H), 4.38–4.32 (m, 1H), 4.03 (dd, J = 14.0, 7.2 Hz, 1H), 3.96 (dd, J = 9.6, 4.7 Hz, 1H), 3.79 (s, 3H), 3.62 (s, 2H), 2.64 (s, 3H), 2.57–2.40 (m, 6H), 2.30 (s, 3H), 2.28 (s, 1H), 2.21 (dd, J = 15.5, 7.9 Hz, 3H), 2.01 (d, J = 6.3 Hz, 1H), 1.64 (t, J = 7.5 Hz, 1H), 0.59–0.51 (m, 1H), 0.44 (dq, J = 8.9, 4.4 Hz, 1H), 0.04 (d, J = 7.2 Hz, 1H), -0.04 (q, J = 5.3, 4.8 Hz, 1H), -0.37 (dq, J = 9.7, 5.0 Hz, 1H).

[0383] Example 9:

[0384]

[0385] (1) Preparation method of compound A-2-1:

[0386] Add 1-methyl-5-hydroxypyrazole (30 g) and potassium carbonate (90 g) into acetonitrile (900 mL), and dropwise add 2-(trimethylsilyl)ethoxymethyl chloride (90 mL) at 25°C. After the addition, react at 20-25°C for 16 h until the reaction is complete. Filter the reaction solution, evaporate the filtrate to dryness, add methyl tert-butyl ether (300 mL) to the residue, heat to 65°C to dissolve it clearly, then add n-heptane (120 mL), cool naturally to crystallize, filter by suction, and dry the filter cake to obtain compound A-2-1. ESI-MS: m / z = 229.30 [M+H] + .

[0387] (2) Preparation method of compound A-2-2:

[0388] Add compound A-2-1 (26 g), N-iodosuccinimide (30.7 g), and benzoic acid (2.8 g) into dichloromethane (260 mL), and react at 20-25°C for 3 h until the reaction is complete. Wash the reaction solution with water (500 mL×2), separate the layers, dry the organic phase with anhydrous sodium sulfate, concentrate until no liquid flows out, and perform column chromatography to obtain compound A-2-2. ESI-MS: m / z = 355.20 [M+H] + .

[0389] (3) Preparation method of compound A-2-3:

[0390] Add 2-fluoroisonicotinic acid (20 g), iodomethane (40.2 g), and potassium carbonate (39 g) into N,N-dimethylformamide (200 mL), and react at 40°C for 16 h until the reaction is complete. Pour the reaction solution into 1500 mL of water, extract with ethyl acetate (500 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, concentrate until no liquid flows out, and perform column chromatography to obtain compound A-2-3. ESI-MS: m / z = 156.08 [M+H] + .

[0391] (4) Preparation method of compound A-2-4:

[0392] Add bis(pinacolato)diboron (14.8 g), methoxy(cycloocta-1,5-diene)iridium(III) dimer (570 mg), and 4,4'-di-tert-butyl-2,2'-bipyridine (468 mg) to cyclohexane (150 mL). Replace the air with nitrogen three times and stir at 25 °C for 1 h. Then, dropwise add a solution of compound A-2-3 (9 g) in cyclohexane (30 mL). After the addition is complete, react at 75 °C for 4 h until the reaction is complete. Evaporate the reaction solution to dryness to obtain compound A-2-4, which is directly used in the next step without further purification. ESI-MS: m / z = 199.99 [M+H] + 。

[0393] (5) Preparation method of compound A-2-5:

[0394] Add compound A-2-2 (5.9 g), compound A-2-4 (5.0 g), Pd(dppf)Cl 2 (1.3 g), and cesium carbonate (8.2 g) to N,N-dimethylformamide (50 mL). Replace the air with nitrogen three times and stir at 100 °C for 4 h until the reaction is complete. Pour the reaction solution into 300 mL of water and extract with dichloromethane (100 mL×2). Combine the organic phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and perform column chromatography to obtain compound A-2-5. ESI-MS: m / z = 382.34 [M+H] + 。

[0395] (6) Preparation method of compound A-2:

[0396] Add compound A-2-5 (5.9 g) to a 1,4-dioxane solution of hydrogen chloride (4 M, 20 mL) and stir at 25 °C for 3 h until the reaction is complete. Evaporate the reaction solution to dryness to obtain compound A-2, which is directly used in the next step without further purification. ESI-MS: m / z = 252.17 [M+H] + 。(7) Preparation method of compound K-3:

[0397] Add compound J (1.0 g), compound A-2 (596 mg), and potassium carbonate (721 mg) to N,N-dimethylformamide (20 mL) and react at 60 °C for 6 h. Monitor the reaction by LC-MS until completion. Pour the reaction solution into 100 mL of water and extract with ethyl acetate (30 mL×2). Combine the ethyl acetate phases, wash the organic phase with water once, dry the organic phase over anhydrous sodium sulfate, concentrate until no liquid flows out, and perform column chromatography to obtain compound K-3 (1.1 g). ESI-MS: m / z = 576.15 [M+H] + 。

[0398] (8) Preparation method of compound L-3:

[0399] Dissolve compound K-3 (1.1 g) in methanol (15 mL), add Raney nickel (100 mg), displace with hydrogen three times, react at 25 °C for 5 h, and TLC shows that the reaction is complete; filter the reaction solution, dry the filtrate with anhydrous sodium sulfate, concentrate until no liquid flows out to obtain compound L-3, which is directly used in the next reaction without further purification.

[0400] (9) Preparation method of compound M-3:

[0401] Dissolve the obtained compound L-3 from the previous step in tert-butanol (4 mL) and dichloromethane (16 mL), dropwise add a solution of cyanogen bromide (243 mg) in dichloromethane (1 mL), react at 25 °C for 12 h, and LC-MS shows that the reaction is complete; add sodium bicarbonate solution (1 M, 20 mL) to the reaction solution, separate the layers, retain the dichloromethane layer, wash the organic layer with sodium bicarbonate solution (1 M, 20 mL × 2), dry the organic layer with anhydrous sodium sulfate, concentrate until no liquid flows out to obtain compound M-3 (850 mg), which is directly used in the next reaction without further purification. ESI-MS: m / z = 571.13 [M + H] + 。

[0402] (10) Preparation method of compound N-3:

[0403] Dissolve compound M-3 (850 mg) in tetrahydrofuran (10 mL), add a solution of sodium hydroxide (238 mg) in water (3 mL), stir and react at 20 - 25 °C for 45 min, and monitor the reaction by LC-MS until it is complete; adjust the pH to 5 - 6 with 6 M hydrochloric acid, evaporate tetrahydrofuran and water under reduced pressure, add dichloromethane (10 mL) and triethylamine (456 mg), stir until clear, dry with anhydrous sodium sulfate, filter and concentrate until no liquid flows out to obtain compound N-3, which is directly used in the next reaction without further purification. ESI-MS: m / z = 557.15 [M + H] + 。

[0404] (11) Preparation method of compound O-3:

[0405] Dissolve the obtained compound N-3 from the previous step in dichloromethane (10 mL), add TBTU (573 mg), react at 20 - 25 °C for 16 h, and LC-MS shows that the reaction is complete; wash the reaction solution with water (10 mL × 3), dry the organic layer with anhydrous sodium sulfate, concentrate until no liquid flows out, and perform column chromatography to obtain compound O-3 as a grayish-brown solid (620 mg). ESI-MS: m / z = 539.16 [M + H] + 。

[0406] (12) Preparation method of Example 9:

[0407] Compound O-3 (100 mg), (S)–trifluoroisopropylamine hydrochloride (42 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were added to tert-amyl alcohol (10 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. LC-MS showed that the reaction was complete. 10 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 9 (12 mg). ESI-MS: m / z = 572.34 [M+H] + .

[0408] 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.52 (s, 1H), 8.43 (d, J = 2.2 Hz, 1H), 7.87 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 1.9 Hz, 1H), 6.93 (d, J = 2.2 Hz, 1H), 6.75 (dd, J = 8.7, 2.3 Hz, 1H), 6.03 (d, J = 8.6 Hz, 1H), 4.36–4.28 (m, 1H), 4.23 (dt, J = 14.1, 3.7 Hz, 2H), 4.06 (td, J = 9.3, 4.1 Hz, 2H), 3.74 (s, 3H), 2.21 (q, J = 6.8, 6.0 Hz, 1H), 2.15 (dt, J = 10.1, 5.0 Hz, 1H), 2.04–1.96 (m, 1H), 1.79 (s, 1H), 1.76–1.66 (m, 1H), 1.33 (d, J = 6.7 Hz, 3H), 0.63–0.56 (m, 1H), 0.30 (tt, J = 9.0, 4.7 Hz, 1H), -0.04 (dq, J = 9.7, 4.7 Hz, 1H), -0.18 (tt, J = 9.6, 4.8 Hz, 1H), -0.62 (dt, J = 9.5, 5.0 Hz, 1H).

[0409] Example 10:

[0410]

[0411] Compound O (100 mg), 4-amino-1-methylpiperidine (32 mg), Pd 2 (dba) 3(43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were added to tert-amyl alcohol (10 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 50 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 10 (30 mg). ESI-MS: m / z = 569.56 [M + H] + .

[0412] 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.35 (s, 1H), 8.33 (s, 1H), 8.21 (s, 1H), 7.90 (s, 1H), 7.54 (s, 1H), 7.32 (d, J = 8.6 Hz, 1H), 6.78 (d, J = 2.2 Hz, 1H), 6.59 (dd, J = 8.7, 2.2 Hz, 1H), 4.28 (q, J = 7.8 Hz, 1H), 4.21 (dd, J = 13.9, 3.5 Hz, 1H), 4.02 (td, J = 14.0, 13.4, 7.5 Hz, 2H), 3.73 (s, 3H), 3.24–3.14 (m, 1H), 2.89 (d, J = 11.3 Hz, 2H), 2.54 (s, 3H), 2.30 (s, 3H), 2.27–2.19 (m, 3H), 2.16–2.08 (m, 1H), 1.97 (dd, J = 13.7, 8.8 Hz, 3H), 1.81 (d, J = 9.2 Hz, 1H), 1.70 (dq, J = 13.7, 6.4, 5.5 Hz, 1H), 1.48 (q, J = 11.2 Hz, 2H), 0.58 (tt, J = 8.6, 3.6 Hz, 1H), 0.30 (tt, J = 9.3, 4.8 Hz, 1H), -0.06 (dq, J = 9.7, 4.9 Hz, 1H), -0.16 (dp, J = 9.4, 4.7 Hz, 1H), -0.59 (dt, J = 9.7, 4.9 Hz, 1H).

[0413] Example 11:

[0414]

[0415] Compound O-2 (60 mg), copper hydroxide (22 mg), and potassium carbonate (30 mg) were added to N,N-dimethylethanolamine (5 mL). The mixture was purged with nitrogen three times and reacted at 130 °C for 18 h. After the reaction was completed, 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Purification by preparative liquid chromatography gave Example 11 (15 mg). ESI-MS: m / z = 544.41 [M+H] + 。

[0416] 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.43 (s, 1H), 8.38 (s, 1H), 7.95 (s, 1H), 7.59 (s, 1H), 7.30 (d, J = 8.5 Hz, 1H), 6.81 (d, J = 2.1 Hz, 1H), 6.61 (dd, J = 8.5, 2.0 Hz, 1H), 4.33 (q, J = 8.1 Hz, 1H), 4.27 (dd, J = 14.1, 3.7 Hz, 1H), 4.09 (td, J = 9.5, 4.5 Hz, 2H), 3.99 (t, J = 5.3 Hz, 2H), 3.77 (s, 3H), 2.59 (s, 3H), 2.53 (t, J = 6.9 Hz, 2H), 2.28 (s, 1H), 2.25 (s, 6H), 2.18 (td, J = 9.6, 4.9 Hz, 1H), 2.04 (tt, J = 13.9, 10.5, 5.0 Hz, 1H), 1.89 (d, J = 9.5 Hz, 1H), 1.78 (tt, J = 13.2, 5.6 Hz, 1H), 0.66 (qd, J = 8.4, 4.2 Hz, 1H), 0.38 (dp, J = 9.2, 4.7 Hz, 1H), 0.00 (dq, J = 9.6, 5.0 Hz, 1H), -0.06 (dp, J = 9.4, 4.7 Hz, 1H), -0.55 (dt, J = 9.6, 4.9 Hz, 1H).

[0417] Example 12:

[0418]

[0419] Compound O-1 (100 mg), 4-amino-1-methylpiperidine (32 mg), Pd 2 (dba) 3(37 mg), 2-(di-tert-butylphosphino)biphenyl (23 mg), potassium tert-butoxide (126 mg) were added to tert-amyl alcohol (4 mL). The mixture was purged with nitrogen three times and reacted at 70 - 75 °C for 4 h. After the reaction was completed, water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 12 (47 mg). ESI-MS: m / z = 569.45 [M+H] + 。

[0420] 1 1H NMR (500 MHz, chloroform-d) δ 12.20 (s, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.15 (s, 1H), 7.90 (d, J = 1.3 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 6.58 (d, J = 9.5 Hz, 2H), 4.48 (td, J = 9.1, 5.0 Hz, 1H), 4.32 (dd, J = 13.7, 3.3 Hz, 1H), 4.06–4.01 (m, 1H), 3.85 (ddt, J = 15.4, 5.2, 3.3 Hz, 2H), 3.79–3.75 (m, 2H), 3.73 (s, 3H), 3.69–3.61 (m, 2H), 3.52–3.46 (m, 2H), 3.14 (dd, J = 12.4, 3.8 Hz, 1H), 3.05 (dd, J = 12.4, 7.5 Hz, 1H), 2.83 (s, 1H), 2.65 (s, 3H), 2.28 (d, J = 7.1 Hz, 1H), 2.12 (ddt, J = 14.1, 9.3, 4.5 Hz, 1H), 1.92 (dtd, J = 19.1, 10.2, 9.5, 5.6 Hz, 2H), 1.50 (dq, J = 13.4, 7.1, 5.8 Hz, 1H), 1.40–1.35 (m, 1H), 1.18–1.13 (m, 1H), 1.07–1.01 (m, 2H), 0.89 (d, J = 6.6 Hz, 3H).

[0421] Example 13:

[0422]

[0423] Compound O-1 (100 mg), (R)-3-aminotetrahydrofuran hydrochloride (35 mg), Pd 2 (dba) 3(37 mg), 2-(di-tert-butylphosphino)biphenyl (23 mg), potassium tert-butoxide (126 mg) were added to tert-amyl alcohol (4 mL). After displacing with nitrogen three times, the reaction was carried out at 70 - 75 °C for 4 h. After the reaction was completed, water (50 mL) was added to the reaction solution, and it was extracted with dichloromethane (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 13 (18 mg). ESI-MS: m / z = 542.39 [M+H] + 。

[0424] 1 1H NMR (500 MHz, chloroform-d) δ 11.93 (s, 1H), 8.51 (d, J = 1.4 Hz, 1H), 8.10 (s, 1H), 7.66 (d, J = 1.3 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.57 (d, J = 8.2 Hz, 2H), 4.47 (dt, J = 9.1, 4.5 Hz, 1H), 4.32 (dd, J = 13.7, 3.4 Hz, 1H), 4.10–4.02 (m, 2H), 4.00–3.91 (m, 2H), 3.85 (td, J = 8.6, 5.5 Hz, 1H), 3.74 (dd, J = 9.3, 2.8 Hz, 1H), 3.63 (dd, J = 13.7, 9.6 Hz, 1H), 3.48 (tt, J = 7.4, 3.9 Hz, 1H), 2.83 (s, 1H), 2.63 (s, 3H), 2.29 (dtd, J = 10.5, 5.7, 5.0, 2.5 Hz, 2H), 2.14 (td, J = 9.7, 4.9 Hz, 1H), 1.96 (dq, J = 9.6, 4.8 Hz, 1H), 1.89 (dddd, J = 13.0, 8.1, 5.6, 3.1 Hz, 1H), 1.56–1.47 (m, 1H), 1.37 (dtd, J = 7.5, 3.9, 2.0 Hz, 1H), 1.19–1.14 (m, 1H), 1.10–1.01 (m, 2H), 0.92 (d, J = 6.5 Hz, 3H).

[0425] Example 14:

[0426]

[0427] Compound O-1 (100 mg), (S)-1,4-dioxan-2-ylmethanamine hydrochloride (43 mg), Pd 2 (dba) 3(37 mg), 2-(di-tert-butylphosphino)biphenyl (23 mg), potassium tert-butoxide (126 mg) were added to tert-amyl alcohol (4 mL). After purging with nitrogen three times, the mixture was reacted at 70 - 75 °C for 4 h. The reaction was completed. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 14 (11 mg). ESI-MS: m / z = 572.41 [M + H] + 。

[0428] 1 H NMR (500 MHz, chloroform-d) δ 11.91 (s, 1H), 8.51 (d, J = 1.3 Hz, 1H), 8.09 (s, 1H), 7.66 (d, J = 1.4 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 6.61 (dd, J = 8.6, 2.1 Hz, 1H), 6.57 (d, J = 2.1 Hz, 1H), 4.48 (td, J = 9.1, 5.0 Hz, 1H), 4.32 (dd, J = 13.7, 3.3 Hz, 1H), 4.06–4.01 (m, 1H), 3.85 (ddt, J = 15.4, 5.2, 3.3 Hz, 2H), 3.79–3.72 (m, 2H), 3.68–3.60 (m, 2H), 3.51–3.45 (m, 2H), 3.16 (dd, J = 12.4, 3.8 Hz, 1H), 3.07 (dd, J = 12.4, 7.5 Hz, 1H), 2.83 (s, 1H), 2.63 (s, 3H), 2.27 (d, J = 7.1 Hz, 1H), 2.14 (ddt, J = 14.1, 9.3, 4.5 Hz, 1H), 1.96 (dtd, J = 19.1, 10.2, 9.5, 5.6 Hz, 2H), 1.51 (dq, J = 13.4, 7.1, 5.8 Hz, 1H), 1.40–1.35 (m, 1H), 1.18–1.13 (m, 1H), 1.07–1.01 (m, 2H), 0.91 (d, J = 6.6 Hz, 3H).

[0429] Example 15:

[0430]

[0431] (1) Preparation method of Compound I-4:

[0432] (R)-5-Amino-4-methyl-1-pentanol (5.58 g), 2-fluoro-4-bromonitrobenzene (9.98 g), and potassium carbonate (13.82 g) were added to N,N-dimethylformamide (85 mL), and the reaction was carried out at 50 °C for 4 h; after the reaction was complete, the reaction solution was poured into 500 mL of water, extracted with ethyl acetate (400 mL × 2), the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, and concentrated until no more liquid flowed out to obtain compound I-4 (5.52 g), which was used directly in the next step without further purification. ESI-MS: m / z = 317.10 [M+H] + 。

[0433] (2) Preparation method of compound J-4:

[0434] Compound I-4 (5.52 g) was dissolved in dichloromethane (80 mL), triethylamine (3.52 g) was slowly added and the temperature was lowered to 0 - 5 °C, then p-toluenesulfonyl chloride (3.66 g) was slowly added dropwise. After the addition was complete, the reaction was carried out at 20 - 25 °C for 3 h until the reaction was complete; the reaction solution was washed with sodium bicarbonate solution (1 M, 100 mL × 2), separated, the organic phase was dried over anhydrous sodium sulfate and concentrated until no more liquid flowed out to obtain compound J-4 (6.1 g), which was used directly in the next step without further purification. ESI-MS: m / z = 471.10 [M+H] + 。

[0435] (3) Preparation method of compound K-4:

[0436] Compound J-4 (1.38 g), compound A-1 (0.8 g), and potassium carbonate (1.0 g) were added to N,N-dimethylformamide (10 mL), and the reaction was carried out at 70 °C for 2.5 h until the reaction was complete; the reaction solution was poured into 150 mL of water, extracted with ethyl acetate (150 mL × 2), the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, and concentrated until no more liquid flowed out. Column chromatography was used to obtain compound K-4 (0.9 g). ESI-MS: m / z = 572.20 [M+H] + 。(4) Preparation method of compound L-4:

[0437] Compound K-4 (0.8 g) was dissolved in methanol (30 mL), Raney nickel (0.2 g) was slowly added, the reaction solution was purged with nitrogen twice and then with hydrogen three times, and the reaction was carried out at 25 °C for 2 h until the reaction was complete; the reaction solution was filtered, and the filtrate was concentrated until no more liquid flowed out to obtain compound L-4, which was used directly in the next step without further purification. ESI-MS: m / z = 542.24 [M+H] + 。

[0438] (5) Preparation method of compound M-4:

[0439] Dissolve the compound L-4 obtained in the previous step in methanol (30 mL), add dropwise a solution of cyanogen bromide (0.3 g) in acetonitrile (3 mL), react at 40 - 50 °C for 2 h until the reaction is complete; add sodium bicarbonate solution (1 M, 20 mL) to the reaction solution, extract with dichloromethane (15 mL × 2), combine the dichloromethane phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain compound M-4 (0.7 g). ESI-MS: m / z = 567.25 [M + H] + 。(6) Preparation method of compound N-4:

[0440] Dissolve compound M-4 (0.7 g) in tetrahydrofuran (30 mL), add dropwise a solution of sodium hydroxide (0.2 g) in water (6 mL), react at 20 - 25 °C for 3 h until the reaction is complete; adjust the pH of the reaction solution to 5 - 6 with 6 M hydrochloric acid, evaporate tetrahydrofuran and water under reduced pressure, add dichloromethane (50 mL) and triethylamine (2.25 g), stir until clear, dry and filter to obtain a dichloromethane solution of compound N-4, which is directly used in the next step without further purification. ESI-MS: m / z = 553.19 [M + H] + 。

[0441] (7) Preparation method of compound O-4:

[0442] Add TBTU (0.47 g) to the dichloromethane solution of compound N-4 obtained in the previous step, react at 20 - 25 °C for 16 h until the reaction is complete; wash the reaction solution with water (20 mL × 3), dry the organic phase over anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain compound O-4 (0.51 g) by column chromatography. ESI-MS: m / z = 535.27 [M + H] + 。

[0443] (8) Preparation method of Example 15:

[0444] Add compound O-4 (50 mg), 4-amino-1-methylpiperidine (13 mg), Pd 2 (dba) 3 (21 mg), 2-(di-tert-butylphosphino)biphenyl (14 mg), and potassium tert-butoxide (61 mg) to tert-amyl alcohol (3 mL), displace with nitrogen 3 times, react at 70 - 75 °C for 4 h until the reaction is complete; add water (10 mL) to the reaction solution, extract with ethyl acetate (10 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and purify by preparative liquid phase to obtain Example 15 (5 mg). ESI-MS: m / z = 569.49 [M + H] + 。

[0445] 1 H NMR(500MHz,DMSO-d6 )δ12.38(s,1H),8.44(s,1H),8.15(s,1H),7.87(s,1H),7.54(s,1H),7.23(d,J=8.6Hz,1H),6.68(d,J=2.0Hz,1H),6.54(dd,J=8.6,2.0Hz,1H),4.40(td,J=9.3,4.5Hz,1H),4.13(ddd,J=18.7,11.6,4.0Hz,2H),3.85–3.81(m,1H),3.64–3.62(m,1H),3.28(s,1H),2.81–2.73(m,3H),2.54(s,3H),2.24(s,1H),2.20(s,3H),2.09(t,J=11.2Hz,2H),2.03–1.98(m,1H),1.96–1.89(m,3H),1.46(s,1H),1.44–1.35(m,2H),1.20–1.14(m,1H),1.03(ddd,J=11.6,7.7,3.7Hz,3H),0.82(d,J=6.5Hz,3H).

[0446] Example 16:

[0447]

[0448] Compound O-4 (50 mg), (S)-3-pyrrolidinol (10 mg), Pd 2 (dba) 3 (21 mg), 2-(di-tert-butylphosphino)biphenyl (14 mg), potassium tert-butoxide (61 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 70 - 75 °C for 4 h. After the reaction was completed, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 16 (10 mg). ESI-MS: m / z = 542.26 [M+H] + .

[0449] 1 H NMR (500 MHz, DMSO-d 6)δ12.41(s,1H),8.35(s,1H),7.91(s,1H),7.55(s,1H),7.34(d,J=8.6Hz,1H),6.69(d,J=2.2Hz,1H),6.47(dd,J=8.7,2.2Hz,1H),4.98(s,1H),4.43(dq,J=7.0,3.4Hz,1H),4.29(q,J=8.2,7.6Hz,1H),4.22(dd,J=14.0,3.7Hz,1H),4.14(dd,J=13.8,9.1Hz,1H),4.04(dt,J=7.0,4.6Hz,1H),3.46(dd,J=10.0,5.0Hz,1H),3.12(dd,J=10.0,2.5Hz,1H),2.79(s,1H),2.60(s,3H),2.25(d,J=7.1Hz,1H),2.09(t,J=11.2Hz,2H),2.03–1.98(m,1H),1.96–1.89(m,3H),1.48(dq,J=13.4,7.1,5.8Hz,1H),1.40-1.32(d,J=10.5Hz,2H),1.16-1.13(m,1H),1.09–0.97(m,2H),0.89(d,J=6.6Hz,3H).

[0450] Example 17:

[0451]

[0452] Compound O-4 (70 mg), N,N-dimethylethylenediamine (23 mg), Pd 2 (dba) 3 (24 mg), 2-(di-tert-butylphosphino)biphenyl (16 mg), potassium tert-butoxide (88 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 80 °C for 2 h. After the reaction was completed, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 17 (20 mg). ESI-MS: m / z = 543.43 [M+H] + 。

[0453] 1 H NMR (500 MHz, DMSO-d 6)δ12.41(s,1H),8.45(s,1H),8.19(d,J=2.6Hz,1H),7.88(d,J=3.4Hz,1H),7.55(d,J=1.2Hz,1H),7.26(d,J=8.5Hz,1H),6.73(d,J=2.1Hz,1H),6.57(dd,J=8.6,2.1Hz,1H),4.40(dt,J=9.5,4.8Hz,1H),4.18–4.10(m,2H),3.84(dd,J=13.6,10.2Hz,1H),3.65–3.61(m,1H),3.21(t,J=6.4Hz,2H),2.81(s,1H),2.63(t,J=6.5Hz,2H),2.55(d,J=3.6Hz,3H),2.33(d,J=4.7Hz,6H),2.25(s,1H),2.01(d,J=13.8Hz,1H),1.97–1.89(m,1H),1.47(s,1H),1.16(ddd,J=9.1,4.6,2.7Hz,1H),1.09–1.01(m,3H),0.84(t,J=5.2Hz,3H).

[0454] Example 18:

[0455]

[0456] Compound O (100 mg), (R)-3-aminotetrahydropyran hydrochloride (31 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 18 (69 mg). ESI-MS: m / z = 556.46 [M+H] + 。

[0457] 1 H NMR(500MHz,DMSO-d 6)δ12.36(s,1H),8.34(s,1H),7.91(s,1H),7.54(d,J=1.2Hz,1H),7.24(d,J=8.6Hz,1H),6.82(d,J=2.1Hz,1H),6.58(dd,J=8.6,2.1Hz,1H),5.45(s,1H),4.28(td,J=8.5,5.2Hz,1H),4.21(dd,J=13.9,3.7Hz,1H),4.12–4.01(m,2H),3.92(ddd,J=10.9,4.0,1.6Hz,1H),3.73(s,3H),3.45(s,1H),3.38–3.33(m,1H),3.12(dd,J=11.0,8.4Hz,1H),2.54(s,3H),2.21(dd,J=13.3,6.6Hz,1H),2.13(tt,J=8.8,4.9Hz,1H),2.00(td,J=13.4,5.0Hz,2H),1.84(d,J=9.9Hz,1H),1.71(dq,J=12.2,3.7Hz,2H),1.59(dtd,J=17.7,10.0,8.3,4.4Hz,1H),1.50–1.42(m,1H),0.86–0.83(m,1H),0.67–0.58(m,1H),0.32(dp,J=9.2,4.7Hz,1H),-0.05(dq,J=9.6,4.8Hz,1H),-0.13(dq,J=9.3,4.9Hz,1H),-0.57(dt,J=9.6,4.8Hz,1H).

[0458] Example 19:

[0459]

[0460] Compound O (100 mg), (S)-1,4-dioxan-2-ylmethanamine hydrochloride (43 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), and potassium tert-butoxide (126 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 19 (13 mg). ESI-MS: m / z = 572.34 [M+H] + .

[0461] 11H NMR (500 MHz, chloroform-d) δ 11.93 (s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 7.65 (s, 1H), 7.15 (d, J = 9.1 Hz, 1H), 6.57 (d, J = 6.5 Hz, 2H), 4.35 (tt, J = 8.8, 4.5 Hz, 2H), 3.98–3.90 (m, 2H), 3.84 (ddd, J = 17.8, 9.9, 4.1 Hz, 3H), 3.78 (s, 3H), 3.76 (d, J = 10.1 Hz, 1H), 3.66 (td, J = 11.4, 3.0 Hz, 1H), 3.51 (dd, J = 11.4, 9.8 Hz, 1H), 3.22 (dd, J = 12.4, 3.8 Hz, 1H), 3.13 (dd, J = 12.3, 7.5 Hz, 1H), 2.64 (s, 3H), 2.27 (q, J = 7.8, 7.4 Hz, 1H), 2.18 (p, J = 9.2, 7.5 Hz, 2H), 1.81 (q, J = 7.8, 7.1 Hz, 2H), 0.87 (dtt, J = 10.5, 6.6, 3.0 Hz, 1H), 0.52 (dq, J = 8.6, 4.8, 3.6 Hz, 1H), 0.44 (tt, J = 8.9, 4.9 Hz, 1H), 0.12 (tt, J = 9.0, 5.1 Hz, 1H), -0.03 (d, J = 4.8 Hz, 1H), -0.32 (dq, J = 9.9, 5.1 Hz, 1H).

[0462] Example 20:

[0463]

[0464] Compound O-2 (100 mg), 4-amino-1-methylpiperidine (26 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 20 (35 mg). ESI-MS: m / z = 569.45 [M + H] + .

[0465] 1 1H NMR (500 MHz, DMSO-d 6)δ12.35(s,1H),8.33(s,1H),7.90(s,1H),7.54(s,1H),7.23(d,J=8.5Hz,1H),6.71(d,J=2.1Hz,1H),6.53(dd,J=8.8,1.9Hz,1H),5.35(s,1H),4.32–4.26(m,1H),4.22(dd,J=13.9,3.8Hz,1H),4.03(td,J=13.9,13.1,7.1Hz,2H),3.73(s,3H),3.24(d,J=9.9Hz,1H),2.75(d,J=11.4Hz,2H),2.54(s,3H),2.26–2.21(m,1H),2.17(s,3H),2.12(dq,J=9.2,4.3Hz,1H),2.07–1.98(m,3H),1.90(t,J=13.1Hz,2H),1.81(s,1H),1.72(dd,J=13.6,6.4Hz,1H),1.39(dtd,J=24.7,11.5,11.1,5.6Hz,2H),0.59(dq,J=8.5,5.1,3.5Hz,1H),0.33(td,J=9.1,5.0Hz,1H),-0.04(dt,J=9.4,4.6Hz,1H),-0.13(dp,J=9.5,4.6Hz,1H),-0.54(dq,J=9.6,4.8Hz,1H).

[0466] Example 21:

[0467]

[0468] Compound O-2 (60 mg), (S)-3-pyrrolidinol hydrochloride (17 mg), Pd 2 (dba) 3 (25 mg), 2-(di-tert-butylphosphino)biphenyl (16 mg), potassium tert-butoxide (75 mg) were added to tert-amyl alcohol (10 mL). The mixture was purged with nitrogen three times and reacted at 85 - 95 °C for 3 h. After the reaction was completed, the temperature was lowered to room temperature. The palladium catalyst was removed by filtration. 30 mL of water was added to the filtrate, and the mixture was extracted with ethyl acetate (10 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 21 (25 mg). ESI-MS: m / z = 542.41 [M + H] + .

[0469] 1 H NMR (500 MHz, DMSO-d 6)δ12.41(s,1H),8.35(s,1H),7.91(s,1H),7.55(s,1H),7.34(d,J=8.6Hz,1H),6.69(d,J=2.2Hz,1H),6.47(dd,J=8.7,2.2Hz,1H),4.98(s,1H),4.43(dq,J=7.0,3.4Hz,1H),4.29(q,J=8.2,7.6Hz,1H),4.22(dd,J=14.0,3.7Hz,1H),4.14(dd,J=13.8,9.1Hz,1H),4.04(dt,J=7.0,4.6Hz,1H),3.73(s,3H),3.46(dd,J=10.0,5.0Hz,1H),3.12(dd,J=10.0,2.5Hz,1H),2.54(s,3H),2.25–2.18(m,1H),2.16–2.06(m,2H),2.03–1.98(m,2H),1.94–1.84(m,2H),1.72(dt,J=13.6,6.1Hz,1H),1.50–1.42(m,1H),0.63(dd,J=9.8,5.3Hz,1H),0.31(tt,J=9.3,4.6Hz,1H),-0.05(dt,J=9.5,4.7Hz,1H),-0.14(tt,J=9.1,4.6Hz,1H),-0.56(dd,J=9.5,5.0Hz,1H).

[0470] Example 22:

[0471]

[0472] Compound O (70 mg), 4-(aminomethyl)tetrahydropyran (23 mg), Pd 2 (dba) 3 (30 mg), 2-(di-tert-butylphosphino)biphenyl (20 mg), potassium tert-butoxide (88 mg) were added to tert-amyl alcohol (5 mL). The mixture was purged with nitrogen three times and reacted at 90 °C for 2 h. After the reaction was completed, 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 22 (35 mg). ESI-MS: m / z = 570.41 [M+H] + .

[0473] 1 H NMR (500 MHz, DMSO-d 6)δ12.37(s,1H),8.34(s,1H),7.90(s,1H),7.54(s,1H),7.23(d,J=8.6Hz,1H),6.71(d,J=2.3Hz,1H),6.55(dd,J=8.6,2.0Hz,1H),4.28(q,J=7.7Hz,1H),4.22(dd,J=14.0,3.6Hz,1H),4.10–4.01(m,2H),3.89–3.83(m,2H),3.73(s,3H),3.25(td,J=9.3,4.6Hz,2H),2.96(qd,J=12.7,6.7Hz,2H),2.54(s,3H),2.21(q,J=7.7,6.4Hz,1H),2.13(dq,J=14.2,7.7,6.2Hz,1H),2.05–1.97(m,1H),1.87–1.77(m,2H),1.75–1.66(m,3H),1.29–1.20(m,2H),0.61(tq,J=8.4,4.4,3.4Hz,1H),0.32(dp,J=9.4,4.7Hz,1H),-0.04(dt,J=9.7,4.8Hz,1H),-0.13(tt,J=9.3,4.7Hz,1H),-0.57(dq,J=9.6,4.8Hz,1H).

[0474] Example 23 / 24:

[0475]

[0476] (1) Preparation method of compound (3-bromopropyl) triphenylphosphine:

[0477] Add 1,3-dibromopropane (90 mmol), triphenylphosphine (25 g), and toluene (260 mL) into the reaction flask in sequence, react at 110 °C for 4 h, filter the reaction solution by suction, and wash the filter cake with 40 mL of cyclohexane to obtain compound (3-bromopropyl) triphenylphosphine. It is directly used for the next reaction without further purification. ESI-MS: m / z = 383.01 [M] + .

[0478] (2) Preparation method of compound R:

[0479] Add compound (3-bromopropyl) triphenylphosphine (5 g), methanol (26 mL), and dimethylamine (40 mmol) into the reaction flask in sequence, stir at room temperature for 1 h, heat up to 65 °C and react for 4 h, concentrate the reaction solution until no liquid flows out to obtain compound R (4.0 g). It is directly used for the next reaction without further purification. ESI-MS: m / z = 348.40 [M] +。

[0480] (3) Preparation method of compound S:

[0481] Add compound O-2 (165 mg), N-formyl saccharin (131 mg), palladium acetate (7 mg), 1,4-bis(diphenylphosphino)butane (20 mg), triethylsilane (58 mg) and sodium carbonate (66 mg) into N,N-dimethylformamide (5 mL), displace with nitrogen for 3 times, react at 80 °C for 4 h; pour the reaction solution into 20 mL of water, extract with ethyl acetate (10 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out to obtain compound S, which is directly used for the next reaction without further purification. ESI-MS: m / z = 485.33 [M+H] + 。

[0482] (4) Preparation method of Example 23 / 24:

[0483] Add compound R (323 mg) into tetrahydrofuran (5 mL), displace with nitrogen for 3 times, cool down to -78 °C, add n-butyllithium (0.5 mL), stir at -78 °C for 3 h, add the tetrahydrofuran (5 mL) solution of compound S obtained in the previous step to the reaction solution, gradually warm up to 60 °C and react for 3 h, and the reaction is completed; cool down to room temperature, pour the reaction solution into 20 mL of ice water, evaporate tetrahydrofuran under reduced pressure, extract with dichloromethane (50 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and purify by preparative liquid phase to obtain Example 23 (15 mg), ESI-MS: m / z = 554.46 [M+H] + and Example 24 (20 mg), ESI-MS: m / z = 554.46 [M+H] + 。Example 23: 1 H NMR (500 MHz, DMSO-d 6)8.41(s,1H),8.25(s,1H),7.96(s,1H),7.60(dd,J=9.1,1.3Hz,2H),7.56(d,J=8.2Hz,1H),7.21(dd,J=8.3,1.4Hz,1H),6.61(dd,J=11.7,2.1Hz,1H),5.72(dt,J=11.6,6.6Hz,1H),4.38–4.32(m,2H),4.26–4.22(m,1H),4.10(d,J=5.6Hz,1H),3.78(s,3H),2.60(s,3H),2.52–2.45(m,2H),2.22(s,6H),2.05(ddt,J=14.1,10.8,5.0Hz,2H),1.90(s,1H),1.81–1.72(m,1H),1.34–1.25(m,3H),0.68(dd,J=11.7,7.1Hz,1H),0.34(dq,J=8.9,4.7Hz,1H),-0.00(dq,J=9.7,5.0Hz,1H),-0.19(tt,J=9.1,4.7Hz,1H),-0.63(dq,J=9.7,4.8Hz,1H). Example 24: 1 H NMR(500MHz,DMSO-d 6 )8.43(s,1H),8.34(s,1H),7.99(s,1H),7.77(d,J=1.5Hz,1H),7.63(d,J=1.2Hz,1H),7.53(d,J=8.2Hz,1H),7.32(dd,J=8.4,1.5Hz,1H),6.60(d,J=15.8Hz,1H),6.39(dt,J=15.8,6.8Hz,1H),4.39–4.33(m,2H),4.29–4.26(m,1H),4.14–4.10(m,1H),3.80(s,3H),3.45(t,J=6.5Hz,2H),2.62(s,3H),2.55(d,J=7.3Hz,1H),2.46(t,J=7.5Hz,2H),2.32(s,6H),2.08(dt,J=13.0,4.6Hz,1H),1.96(d,J=9.5Hz,1H),1.83–1.75(m,1H),1.64–1.54(m,1H),0.71(dq,J=9.8,5.3,4.2Hz,1H),0.37(dq,J=9.4,5.0Hz,1H),0.01(dt,J=9.7,5.0Hz,1H),-0.18(dq,J=9.0,4.7Hz,1H),-0.59(dq,J=9.5,4.8Hz,1H).

[0484] Example 25 / 26:

[0485]

[0486] Compound O (100 mg), N,N-dimethyl-1,4-cyclohexanediamine (30 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. It was obtained by preparation (liquid phase conditions: column: YMC-TA-C18 250x50 mm, 10 um; mobile phase: A: 0.1% formic acid / water, C: acetonitrile, gradient: 20% C - 50% C (0 - 60 min); flow rate: 60 mL / min; wavelength: 254 nm) to obtain Example 25 (13 mg, retention time 14.2 minutes), ESI-MS: m / z = 597.44 [M+H] + , and Example 26 (19 mg, retention time 19.6 minutes), ESI-MS: m / z = 597.44 [M+H] + . Example 25: 1 H NMR (500 MHz, chloroform-d) δ 12.15 (s, 1H), 8.51 (s, 1H), 8.41 (s, 1H), 8.15 (s, 1H), 7.70 (s, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.54 (d, J = 7.8 Hz, 2H), 4.40–4.32 (m, 2H), 3.95 (p, J = 5.9 Hz, 2H), 3.79 (s, 3H), 3.16 (d, J = 12.0 Hz, 1H), 2.92 (d, J = 12.4 Hz, 1H), 2.62 (d, J = 5.1 Hz, 3H), 2.60 (s, 6H), 2.27 (d, J = 12.3 Hz, 3H), 2.17–2.09 (m, 3H), 1.83–1.74 (m, 2H), 1.48 (t, J = 10.5 Hz, 2H), 1.26 (t, J = 6.0 Hz, 2H), 0.87 (dt, J = 14.0, 7.0 Hz, 1H), 0.57–0.48 (m, 1H), 0.45 (dq, J = 10.0, 5.1 Hz, 1H), 0.12 (dd, J = 10.2, 5.3 Hz, 1H), -0.02 (s, 1H), -0.31 (dq, J = 10.2, 5.0 Hz, 1H). Example 26:1 1H NMR (500 MHz, chloroform-d) δ 11.98 (s, 1H), 8.53 (s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 7.67 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.72 (dd, J = 8.7, 2.1 Hz, 1H), 6.60 (d, J = 2.1 Hz, 1H), 4.39–4.32 (m, 2H), 3.94 (dq, J = 13.9, 7.4, 6.2 Hz, 2H), 3.78 (s, 3H), 3.69–3.64 (m, 1H), 2.83 (d, J = 11.1 Hz, 1H), 2.69 (s, 6H), 2.64 (s, 3H), 2.31–2.25 (m, 1H), 2.22–2.15 (m, 2H), 2.12–2.06 (m, 2H), 1.97 (d, J = 21.7 Hz, 4H), 1.82–1.73 (m, 2H), 1.68–1.60 (m, 2H), 0.52 (d, J = 12.0 Hz, 1H), 0.44 (dq, J = 8.9, 4.5, 4.1 Hz, 1H), 0.17–0.09 (m, 1H), -0.04 (q, J = 4.8 Hz, 1H), -0.31 (dd, J = 9.8, 5.3 Hz, 1H).

[0487] Example 27:

[0488]

[0489] Compound O-2 (60 mg), 3-dimethylaminopropylamine (14 mg), Pd 2 (dba) 3 (25 mg), 2-(di-tert-butylphosphino)biphenyl (17 mg), and potassium tert-butoxide (75 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 27 (20 mg). ESI-MS: m / z = 279.36 [1 / 2M + H] + .

[0490] 1 1H NMR (500 MHz, DMSO-d 6)δ12.37(s,1H),8.34(s,1H),7.91(s,1H),7.54(d,J=1.2Hz,1H),7.25(d,J=8.6Hz,1H),6.70(d,J=2.0Hz,1H),6.53(dd,J=8.6,2.0Hz,1H),4.29(td,J=8.4,5.8Hz,1H),4.22(dd,J=14.0,3.6Hz,1H),4.08–4.00(m,2H),3.73(s,3H),3.07(t,J=6.9Hz,2H),2.54(d,J=1.2Hz,4H),2.33(t,J=7.1Hz,2H),2.22(dt,J=12.4,6.9Hz,1H),2.15(s,6H),2.00(td,J=7.8,4.6Hz,1H),1.84(d,J=9.3Hz,1H),1.71(h,J=6.7Hz,3H),0.60(td,J=8.2,3.5Hz,1H),0.32(tt,J=9.3,4.6Hz,1H),-0.05(dt,J=9.4,4.6Hz,1H),-0.12(tt,J=7.6,4.4Hz,1H),-0.57(dq,J=9.5,4.7Hz,1H).

[0491] Example 28:

[0492]

[0493] Compound O-2 (60 mg), N,N-dimethylethylenediamine (12 mg), Pd 2 (dba) 3 (25 mg), 2-(di-tert-butylphosphino)biphenyl (17 mg), potassium tert-butoxide (75 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 28 (25 mg). ESI-MS: m / z = 272.30 [1 / 2M + H] + .

[0494] 1 H NMR(500MHz,DMSO-d 6)δ 12.43 (s, 1H), 8.38 (s, 1H), 7.95 (s, 1H), 7.59 (s, 1H), 7.30 (d, J = 8.5 Hz, 1H), 6.81 (d, J = 2.1 Hz, 1H), 6.61 (dd, J = 8.5, 2.0 Hz, 1H), 5.41 (s, 1H), 4.33 (q, J = 8.1 Hz, 1H), 4.27 (dd, J = 14.1, 3.7 Hz, 1H), 4.09 (td, J = 9.5, 4.5 Hz, 2H), 3.77 (s, 3H), 3.20 (t, J = 5.3 Hz, 2H), 2.59 (s, 3H), 2.53 (t, J = 6.9 Hz, 2H), 2.28 (s, 1H), 2.25 (s, 6H), 2.18 (td, J = 9.6, 4.9 Hz, 1H), 2.05 (tt, J = 13.9, 10.5, 5.0 Hz, 1H), 1.89 (d, J = 9.5 Hz, 1H), 1.76 (tt, J = 13.2, 5.6 Hz, 1H), 0.65 (qd, J = 8.4, 4.2 Hz, 1H), 0.37 (dp, J = 9.2, 4.7 Hz, 1H), 0.00 (dq, J = 9.6, 5.0 Hz, 1H), -0.07 (dp, J = 9.4, 4.7 Hz, 1H), -0.51 (dt, J = 9.6, 4.9 Hz, 1H).

[0495] Example 29:

[0496]

[0497] Compound O (100 mg), 3 - methyloxetan - 3 - amine (20 mg), Pd 2 (dba) 3 (43 mg), 2 - (di - tert - butylphosphino) biphenyl (28 mg), potassium tert - butoxide (126 mg) were added to tert - amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 30 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 29 (20 mg). ESI - MS: m / z = 542.37 [M + H] + .

[0498] 1 H NMR (500 MHz, DMSO - d 6)δ12.38(s,1H),8.33(s,1H),7.90(s,1H),7.54(s,1H),7.29(d,J=8.5Hz,1H),6.40(dd,J=8.6,2.1Hz,1H),6.33(d,J=2.1Hz,1H),6.11(s,1H),4.63(dd,J=15.9,5.8Hz,2H),4.52(d,J=5.8Hz,2H),4.33–4.25(m,1H),4.22(dd,J=14.0,3.4Hz,1H),4.07–3.97(m,2H),3.72(s,3H),2.54(s,3H),2.22(dd,J=13.6,6.9Hz,1H),2.12(td,J=11.3,10.2,5.5Hz,1H),2.05–1.95(m,1H),1.81–1.69(m,2H),1.58(s,3H),0.57(tt,J=8.7,3.6Hz,1H),0.33(dp,J=9.3,4.7Hz,1H),-0.05(dt,J=9.7,4.8Hz,1H),-0.13(dp,J=9.5,4.7Hz,1H),-0.60(dq,J=9.7,4.8Hz,1H).

[0499] Example 30:

[0500]

[0501] Compound O (50 mg), 2,2-dimethyloxetan-3-amine (19 mg), Pd 2 (dba) 3 (21 mg), 2-(di-tert-butylphosphino)biphenyl (14 mg), potassium tert-butoxide (63 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 30 (10 mg). ESI-MS: m / z = 556.37 [M+H] + .

[0502] 1 H NMR (500 MHz, DMSO-d 6)δ 12.40 (s, 1H), 8.33 (s, 1H), 7.90 (s, 1H), 7.54 (d, J = 1.2 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 6.79–6.72 (m, 2H), 5.70 (d, J = 9.2 Hz, 1H), 4.44 (td, J = 5.9, 4.1 Hz, 2H), 4.29 (td, J = 8.7, 6.1 Hz, 1H), 4.23 (dd, J = 14.0, 3.5 Hz, 1H), 4.04 (t, J = 8.3 Hz, 2H), 3.97 (dd, J = 13.9, 9.6 Hz, 1H), 3.73 (s, 3H), 2.54 (s, 3H), 2.29–2.19 (m, 1H), 2.17–2.09 (m, 1H), 2.00–1.95 (m, 1H), 1.84 (t, J = 8.5 Hz, 1H), 1.77–1.67 (m, 1H), 1.46 (s, 3H), 1.44 (s, 3H), 0.55 (tt, J = 8.3, 3.1 Hz, 1H), 0.33 (dq, J = 9.5, 4.7 Hz, 1H), -0.04 (dt, J = 9.9, 4.9 Hz, 1H), -0.19 (dp, J = 9.7, 4.8 Hz, 1H), -0.62 (dq, J = 9.7, 4.9 Hz, 1H).

[0503] Example 31:

[0504]

[0505] Compound O (70 mg), 2,2,4,4 - tetramethyloxetan - 3 - amine hydrochloride (43 mg), Pd 2 (dba) 3 (24 mg), 2 - (di - tert - butylphosphino)biphenyl (16 mg), potassium tert - butoxide (88 mg) were added to tert - amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 30 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 31 (10 mg). ESI - MS: m / z = 584.34 [M + H] + .

[0506] 1 H NMR (500 MHz, DMSO - d 6)δ12.42(s,1H),8.33(s,1H),7.90(s,1H),7.54(d,J=1.2Hz,1H),7.28(d,J=8.5Hz,1H),6.78–6.70(m,2H),5.76(d,J=9.2Hz,1H),4.29(td,J=8.7,6.1Hz,1H),4.23(dd,J=14.0,3.5Hz,1H),4.04(t,J=8.3Hz,2H),3.97(dd,J=13.9,9.6Hz,1H),3.73(s,3H),2.54(s,3H),2.29–2.19(m,1H),2.17–2.09(m,1H),2.00–1.95(m,1H),1.84(t,J=8.5Hz,1H),1.77–1.67(m,1H),1.46(s,3H),1.44(s,3H),1.30(s,3H),1.19(s,3H),0.55(tt,J=8.3,3.1Hz,1H),0.33(dq,J=9.5,4.7Hz,1H),-0.04(dt,J=9.9,4.9Hz,1H),-0.19(dp,J=9.7,4.8Hz,1H),-0.62(dq,J=9.7,4.9Hz,1H).

[0507] Example 32:

[0508]

[0509] Compound O (70 mg), 1-Boc-3-aminocyclobutanamine (45 mg), Pd 2 (dba) 3 (24 mg), 2-(di-tert-butylphosphino)biphenyl (16 mg), potassium tert-butoxide (88 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The crude product obtained by concentrating the filtrate was directly dissolved in hydrogen chloride-methanol solution (4 M, 5 mL), stirred for 30 min, and monitored by LC-MS until the reaction was completed. After concentration of the reaction solution, it was purified by preparative liquid phase to obtain Example 32 (16 mg). ESI-MS: m / z = 527.37 [M+H] + .

[0510] 1 H NMR (500 MHz, DMSO-d 6)δ8.38(s,1H),8.33(s,1H),7.90(s,1H),7.54(s,1H),7.30(d,J=8.5Hz,1H),6.68–6.62(m,1H),6.51(dd,J=8.5,2.0Hz,1H),6.43(s,1H),4.35(s,1H),4.29(t,J=4.3Hz,1H),4.19(dd,J=14.6,5.6Hz,2H),4.10–4.01(m,2H),3.73(s,3H),3.67(td,J=9.8,4.8Hz,2H),2.54(s,3H),2.26–2.18(m,1H),2.13(dq,J=13.1,7.2,6.1Hz,1H),1.99(tt,J=12.4,5.5Hz,2H),1.82(d,J=9.6Hz,1H),1.71(q,J=9.0,6.1Hz,1H),0.60(dt,J=9.6,4.6Hz,1H),0.31(dt,J=9.2,4.5Hz,1H),-0.05(dq,J=9.9,5.0Hz,1H),-0.18(tt,J=9.4,4.7Hz,1H),-0.62(dq,J=9.5,4.8Hz,1H).

[0511] Example 33:

[0512]

[0513] Compound O (50 mg), 1-methylazetidin-3-amine (30 mg), Pd 2 (dba) 3 (21 mg), 2-(di-tert-butylphosphino)biphenyl (14 mg), and potassium tert-butoxide (63 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 33 (10 mg). ESI-MS: m / z = 541.41 [M+H] + .

[0514] 11H NMR (500 MHz, chloroform-d) δ 12.30 (s, 1H), 8.49 (s, 1H), 8.45 (s, 1H), 8.17 (s, 1H), 7.80 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.65 (dd, J = 8.7, 2.0 Hz, 1H), 6.30 (d, J = 2.1 Hz, 1H), 4.40–4.32 (m, 2H), 4.06–4.00 (m, 1H), 3.95–3.90 (m, 2H), 3.81 (s, 1H), 3.79 (s, 3H), 3.67 (t, J = 8.7 Hz, 1H), 2.66 (s, 3H), 2.64 (s, 3H), 2.28–2.10 (m, 3H), 1.78 (d, J = 14.6 Hz, 2H), 1.28 (dd, J = 18.1, 8.7 Hz, 2H), 0.49 (td, J = 9.0, 8.5, 4.1 Hz, 1H), 0.41 (dq, J = 8.7, 4.5, 4.0 Hz, 1H), 0.10–0.03 (m, 1H), -0.06 (dt, J = 9.7, 5.2 Hz, 1H), -0.40 (dq, J = 10.0, 5.1 Hz, 1H).

[0515] Example 34:

[0516]

[0517] Compound O (70 mg), 1-Boc-3-amino-3-methylacridine (31 mg), Pd 2 (dba) 3 (24 mg), 2-(di-tert-butylphosphino)biphenyl (16 mg), potassium tert-butoxide (88 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h until the reaction was completed. 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The crude product obtained by concentrating the filtrate was directly dissolved in hydrogen chloride-methanol solution (4 M, 5 mL), stirred for 30 min, and monitored by LC-MS until the reaction was completed. After concentration of the reaction solution, it was purified by preparative liquid phase to obtain Example 34 (6 mg). ESI-MS: m / z = 541.21 [M + H] + .

[0518] 1 1H NMR (500 MHz, DMSO-d 6)δ8.34(s,1H),8.29(s,2H),7.91(s,1H),7.54(d,J=1.2Hz,1H),7.31(d,J=8.4Hz,1H),6.50–6.43(m,2H),6.19(s,1H),4.32–4.27(m,1H),4.22(dd,J=14.0,3.6Hz,1H),4.16–4.11(m,1H),4.06(s,1H),3.92(s,2H),3.73(s,3H),2.64(s,3H),2.28–2.19(m,1H),2.17–2.10(m,1H),2.02–1.97(m,1H),1.81(s,1H),1.73(t,J=10.7Hz,1H),1.57(s,3H),1.24(t,J=4.6Hz,2H),0.65–0.57(m,1H),0.32(dt,J=10.4,5.3Hz,1H),-0.02–-0.08(m,1H),-0.19(d,J=9.4Hz,1H),-0.65(dd,J=9.6,5.0Hz,1H).

[0519] Example 35:

[0520]

[0521] Compound O (60 mg), (1-methylpyrrolidin-3-yl)methanamine (14 mg), Pd 2 (dba) 3 (26 mg), 2-(di-tert-butylphosphino)biphenyl (17 mg), potassium tert-butoxide (75 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 30 mL of water was added to the reaction solution. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 35 (20 mg). ESI-MS: m / z = 278.66 [1 / 2M + H] + 。

[0522] 1 H NMR (500 MHz, DMSO-d 6)δ12.40(s,1H),8.34(s,1H),8.24(d,J=2.3Hz,1H),7.91(d,J=2.3Hz,1H),7.54(s,1H),7.25(d,J=8.5Hz,1H),6.74(s,1H),6.54(d,J=8.5Hz,1H),4.30(t,J=7.9Hz,1H),4.21(dd,J=14.2,3.7Hz,1H),4.05(dt,J=9.5,6.0Hz,2H),3.73(s,3H),3.53(t,J=7.8Hz,2H),3.28–3.21(m,4H),2.78–2.70(m,1H),2.54(s,3H),2.39(s,3H),2.22(s,1H),2.14(s,1H),2.00(d,J=9.9Hz,1H),1.86(s,1H),1.70(d,J=14.3Hz,1H),0.61(q,J=7.2,5.4Hz,1H),0.32(dq,J=9.3,4.8Hz,1H),-0.05(dd,J=9.7,4.9Hz,1H),-0.14(dq,J=9.2,4.8Hz,1H),-0.59(dd,J=9.8,5.2Hz,1H).

[0523] Example 36:

[0524]

[0525] Compound O (70 mg), 3-aminomethyloxetane (14 mg), Pd 2 (dba) 3 (24 mg), 2-(di-tert-butylphosphino)biphenyl (16 mg), potassium tert-butoxide (88 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 36 (32 mg). ESI-MS: m / z = 542.35 [M + H] + 。

[0526] 1 H NMR (500 MHz, DMSO-d 6)δ12.39(s,1H),8.34(s,1H),7.91(s,1H),7.54(d,J=1.2Hz,1H),7.25(d,J=8.5Hz,1H),6.76(d,J=2.1Hz,1H),6.53(dd,J=8.6,2.0Hz,1H),4.68(ddd,J=7.5,5.9,1.6Hz,2H),4.34(td,J=5.9,2.2Hz,2H),4.29(dt,J=8.4,4.2Hz,1H),4.22(dd,J=14.0,3.6Hz,1H),4.10–4.01(m,2H),3.73(s,3H),3.36(d,J=7.4Hz,2H),3.24–3.19(m,1H),2.54(s,3H),2.21(dd,J=13.0,6.9Hz,1H),2.14(dq,J=9.7,4.9,4.3Hz,1H),2.04–1.97(m,1H),1.85(d,J=10.8Hz,1H),1.76–1.67(m,1H),0.67–0.58(m,1H),0.32(dp,J=9.2,4.5Hz,1H),-0.05(dq,J=9.5,4.9Hz,1H),-0.14(tt,J=9.3,4.7Hz,1H),-0.59(dq,J=9.7,5.0Hz,1H).

[0527] Example 37:

[0528]

[0529] Compound O (70 mg), 1-(oxetan-3-yl)ethan-1-amine (16 mg), Pd 2 (dba) 3 (24 mg), 2-(di-tert-butylphosphino)biphenyl (16 mg), potassium tert-butoxide (88 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 37 (10 mg). ESI-MS: m / z = 556.39 [M+H] + .

[0530] 1 H NMR (500 MHz, DMSO-d 6)δ12.40(s,1H),8.36(s,1H),7.93(s,1H),7.57(s,1H),7.26(d,J=8.5Hz,1H),6.86(d,J=12.8Hz,1H),6.58(d,J=8.3Hz,1H),5.36(dd,J=23.0,8.6Hz,1H),4.65(ddt,J=18.1,14.3,7.2Hz,2H),4.40(p,J=6.0Hz,2H),4.36–4.28(m,1H),4.24(d,J=13.7Hz,1H),4.15–4.03(m,2H),3.89(q,J=7.4,6.6Hz,1H),3.75(s,3H),3.07(p,J=7.8Hz,1H),2.56(s,3H),2.24(s,1H),2.16(s,1H),2.05–1.99(m,1H),1.86(s,1H),1.79–1.69(m,1H),1.05(dd,J=22.8,6.2Hz,3H),0.67–0.58(m,1H),0.35(dp,J=9.2,4.5Hz,1H),-0.05(dq,J=9.5,4.9Hz,1H),-0.14(tt,J=9.3,4.7Hz,1H),-0.59(dq,J=9.7,5.0Hz,1H).

[0531] Example 38 / 39:

[0532]

[0533] Prepared by resolving Example 37 (80 mg) (resolving conditions: column: YMC-SB 250 mm × 30 mm, 10 um; mobile phase: A: n-hexane B: ethanol, gradient: 20% C - 70% B (0 - 80 min); flow rate: 20 mL / min; wavelength: 254 nm) to obtain Example 38 (27 mg, retention time 31.0 minutes), ESI-MS: m / z = 556.39 [M + H] + , and Example 39 (30 mg, retention time 43.5 minutes), ESI-MS: m / z = 556.39 [M + H] + . Example 38: 1 H NMR (500 MHz, DMSO-d 6)δ12.38(s,1H),8.34(s,1H),7.91(s,1H),7.55(d,J=1.2Hz,1H),7.33(d,J=8.6Hz,1H),6.80(d,J=2.1Hz,1H),6.62(dd,J=8.8,2.2Hz,1H),5.38(d,J=8.8Hz,1H),4.62(ddd,J=10.9,7.9,6.1Hz,2H),4.38(td,J=6.2,4.5Hz,2H),4.29(q,J=7.7Hz,1H),4.22(dd,J=13.9,3.5Hz,1H),4.07–3.98(m,2H),3.73(s,3H),3.70(dt,J=8.9,6.2Hz,1H),3.05(dtd,J=14.4,8.1,6.3Hz,1H),2.54(s,3H),2.21(p,J=6.7,6.3Hz,1H),2.13(dq,J=13.8,8.3,6.7Hz,1H),2.02–1.95(m,1H),1.85–1.77(m,1H),1.69(h,J=7.2Hz,1H),1.04(d,J=6.2Hz,3H),0.63–0.55(m,1H),0.31(dq,J=9.3,5.1Hz,1H),-0.06(dq,J=9.5,4.8Hz,1H),-0.15(dp,J=9.4,4.6Hz,1H),-0.58(dq,J=9.7,4.9Hz,1H). Example 39: 1 H NMR(500MHz,DMSO-d 6)δ12.38(s,1H),8.34(s,1H),7.91(s,1H),7.55(s,1H),7.33(d,J=8.6Hz,1H),6.89–6.73(m,1H),6.62(d,J=8.7Hz,1H),5.37(d,J=8.8Hz,1H),4.63(dt,J=10.9,6.9Hz,2H),4.38(td,J=6.2,3.7Hz,2H),4.29(q,J=7.8Hz,1H),4.22(dd,J=14.1,3.5Hz,1H),4.02(td,J=13.7,12.1,7.2Hz,2H),3.73(s,3H),3.69(d,J=7.5Hz,1H),3.05(q,J=7.5Hz,1H),2.54(s,3H),2.26–2.17(m,1H),2.13(s,1H),2.03–1.94(m,1H),1.81(s,1H),1.69(d,J=14.8Hz,1H),1.04(d,J=6.2Hz,3H),0.59(d,J=9.7Hz,1H),0.30(tt,J=9.3,4.7Hz,1H),-0.06(dq,J=9.6,4.9Hz,1H),-0.14(dq,J=13.3,7.9,6.2Hz,1H),-0.59(dd,J=9.8,5.1Hz,1H).

[0534] Example 40:

[0535]

[0536] Compound O (70 mg), 3-methyl-3-aminomethyl-1-oxetane (16 mg), Pd 2 (dba) 3 (24 mg), 2-(di-tert-butylphosphino)biphenyl (16 mg), and potassium tert-butoxide (88 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 40 (41 mg). ESI-MS: m / z = 556.40 [M+H] + .

[0537] 1 H NMR (500 MHz, DMSO-d 6)δ12.40(s,1H),8.35(s,1H),7.92(s,1H),7.55(s,1H),7.25(d,J=8.5Hz,1H),6.80(d,J=2.1Hz,1H),6.62(dd,J=8.5,2.0Hz,1H),5.67(s,1H),4.44(d,J=5.5Hz,2H),4.31–4.19(m,4H),4.06(dd,J=14.2,9.1Hz,2H),3.73(s,3H),3.27(d,J=3.3Hz,2H),2.55(s,3H),2.22(dt,J=12.9,6.8Hz,1H),2.13(tt,J=8.8,4.7Hz,1H),1.99(ddt,J=14.2,9.5,5.0Hz,1H),1.85(p,J=9.3Hz,1H),1.72(dd,J=11.8,6.6Hz,1H),1.35(s,3H),0.60(tt,J=8.5,3.6Hz,1H),0.31(dp,J=9.3,4.6Hz,1H),-0.06(dq,J=9.7,4.9Hz,1H),-0.15(dq,J=9.1,4.6Hz,1H),-0.60(dq,J=9.7,4.8Hz,1H).

[0538] Example 41:

[0539]

[0540] Compound O (70 mg), 3-(methylamino)oxetane (14 mg), Pd 2 (dba) 3 (30 mg), 2-(di-tert-butylphosphino)biphenyl (20 mg), and potassium tert-butoxide (88 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 41 (30 mg). ESI-MS: m / z = 542.42 [M+H] + .

[0541] 1 H NMR (500 MHz, DMSO-d 6)δ12.49(s,1H),8.34(s,1H),7.90(s,1H),7.54(s,1H),7.37(d,J=8.7Hz,1H),6.89(s,1H),6.67(d,J=8.7Hz,1H),4.79(q,J=6.2,5.6Hz,2H),4.57(h,J=5.7Hz,2H),4.48(t,J=5.8Hz,1H),4.30(q,J=7.9Hz,1H),4.19(qd,J=14.1,6.4Hz,2H),4.02(q,J=7.3,6.8Hz,1H),3.73(s,3H),2.83(s,3H),2.54(s,3H),2.18(d,J=33.7Hz,2H),2.04–1.96(m,1H),1.83(s,1H),1.70(d,J=13.3Hz,1H),0.70–0.59(m,1H),0.29(tt,J=9.2,4.6Hz,1H),-0.08(dq,J=9.7,4.8Hz,1H),-0.25(tt,J=9.7,4.7Hz,1H),-0.70(dd,J=9.4,5.0Hz,1H).

[0542] Example 42:

[0543]

[0544] Compound O (70 mg), N,N-dimethylethylenediamine (23 mg), Pd 2 (dba) 3 (30 mg), 2-(di-tert-butylphosphino)biphenyl (20 mg), and potassium tert-butoxide (88 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 42 (15 mg). ESI-MS: m / z = 543.42 [M+H] + .

[0545] 11H NMR (500 MHz, chloroform-d) δ 8.41 (s, 1H), 8.15 (s, 1H), 7.72 (s, 1H), 7.13 (d, J = 8.7 Hz, 1H), 6.61 (dd, J = 8.6, 2.1 Hz, 1H), 6.49 (d, J = 2.1 Hz, 1H), 4.35 (dt, J = 10.1, 3.1 Hz, 2H), 3.97–3.88 (m, 2H), 3.79 (s, 3H), 3.11 (q, J = 6.4 Hz, 2H), 2.78 (t, J = 5.7 Hz, 2H), 2.63 (s, 3H), 2.42 (s, 6H), 2.30–2.23 (m, 1H), 2.20–2.11 (m, 2H), 1.83–1.74 (m, 2H), 0.50 (tq, J = 8.4, 5.0, 4.2 Hz, 1H), 0.42 (dq, J = 8.8, 4.5 Hz, 1H), 0.09 (tt, J = 9.1, 5.2 Hz, 1H), -0.05 (dt, J = 9.8, 4.8 Hz, 1H), -0.34 (dq, J = 10.0, 5.1 Hz, 1H).

[0546] Example 43:

[0547]

[0548] Compound O (100 mg), (R)-tetrahydrofuran-3-amine hydrochloride (28 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 43 (33 mg). ESI-MS: m / z = 542.39 [M + H] + .

[0549] 1 1H NMR (500 MHz, DMSO-d 6)δ12.41(s,1H),8.39(s,1H),7.96(s,1H),7.59(s,1H),7.31(d,J=8.5Hz,1H),6.78(s,1H),6.60(d,J=8.6Hz,1H),5.89(d,J=6.7Hz,1H),4.30(dd,J=31.8,11.0Hz,2H),4.10(d,J=9.4Hz,2H),4.01(t,J=7.4Hz,1H),3.87(q,J=7.7Hz,1H),3.78(s,3H),3.59(dd,J=8.9,3.9Hz,1H),3.47–3.28(m,2H),2.59(s,3H),2.33–2.11(m,3H),2.10–2.00(m,1H),1.92–1.71(m,3H),0.72–0.62(m,1H),0.36(dd,J=11.3,6.1Hz,1H),-0.00(dt,J=9.7,5.0Hz,1H),-0.05–-0.16(m,1H),-0.49–-0.60(m,1H).

[0550] Example 44:

[0551]

[0552] Compound O (100 mg), N,N-dimethyl-1,3-diaminopropane (23 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 44 (20 mg). ESI-MS: m / z = 557.44 [M+H] + 。

[0553] 11H NMR (500 MHz, chloroform-d) δ 8.47 (s, 1H), 8.41 (s, 1H), 8.15 (s, 1H), 7.72 (s, 1H), 7.13 (d, J = 8.6 Hz, 1H), 6.62 (dd, J = 8.7, 2.1 Hz, 1H), 6.48 (d, J = 2.1 Hz, 1H), 4.38–4.33 (m, 2H), 3.97–3.94 (m, 1H), 3.93–3.89 (m, 1H), 3.79 (s, 3H), 3.10 (dq, J = 13.4, 6.4 Hz, 2H), 3.02–2.95 (m, 2H), 2.65 (s, 6H), 2.64 (s, 3H), 2.31–2.25 (m, 1H), 2.17 (ddd, J = 23.0, 11.6, 5.1 Hz, 2H), 2.00 (q, J = 7.0 Hz, 2H), 1.78 (t, J = 8.9 Hz, 2H), 0.51 (td, J = 9.1, 4.6 Hz, 1H), 0.42 (tt, J = 9.1, 5.0 Hz, 1H), 0.08 (tt, J = 8.6, 5.0 Hz, 1H), -0.04 (dt, J = 9.6, 5.1 Hz, 1H), -0.35 (dq, J = 9.9, 5.1 Hz, 1H).

[0554] Example 45:

[0555]

[0556] Compound O-2 (100 mg), N,N,N'-trimethylethylenediamine (28 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), and potassium tert-butoxide (126 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The product was purified by preparative liquid chromatography to obtain Example 45 (23 mg). ESI-MS: m / z = 279.37 [1 / 2M + H] + .

[0557] 1 1H NMR (500 MHz, DMSO-d 6)δ12.42(s,1H),8.35(s,1H),7.91(s,1H),7.55(s,1H),7.34(d,J=8.7Hz,1H),6.89(d,J=2.3Hz,1H),6.66(dd,J=8.8,2.3Hz,1H),4.30(q,J=7.9Hz,1H),4.23(dd,J=13.9,3.6Hz,1H),4.14(dd,J=13.9,9.2Hz,1H),4.03(dt,J=9.0,5.8Hz,1H),3.73(s,3H),3.57–3.49(m,2H),3.42(ddd,J=14.6,8.5,6.0Hz,2H),2.94(s,3H),2.54(s,3H),2.43(qd,J=9.1,7.7,4.1Hz,2H),2.20(s,6H),2.01(td,J=9.5,4.5Hz,1H),1.84(d,J=9.5Hz,1H),1.72(tt,J=12.5,5.2Hz,1H),0.63(qt,J=8.6,5.0Hz,1H),0.31(tt,J=9.3,4.8Hz,1H),-0.05(dq,J=9.7,4.9Hz,1H),-0.17(dp,J=9.5,4.7Hz,1H),-0.60(dq,J=9.7,4.8Hz,1H).

[0558] Example 46:

[0559]

[0560] Compound O-2 (70 mg), N,N-diethylethylenediamine (18 mg), Pd 2 (dba) 3 (30 mg), 2-(di-tert-butylphosphino)biphenyl (20 mg), potassium tert-butoxide (88 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 46 (20 mg). ESI-MS: m / z = 571.41 [M + H] + .

[0561] 1 H NMR (500 MHz, DMSO-d 6)δ12.41(s,1H),8.34(s,1H),7.91(s,1H),7.54(s,1H),7.27(d,J=8.5Hz,1H),6.79(d,J=2.1Hz,1H),6.56(dd,J=8.6,2.1Hz,1H),4.33–4.26(m,1H),4.22(dd,J=14.1,3.6Hz,1H),4.10–4.01(m,2H),3.73(s,3H),3.21(t,J=6.7Hz,2H),2.77(t,J=6.7Hz,2H),2.69(q,J=7.2Hz,4H),2.54(s,3H),2.27–2.18(m,1H),2.13(tt,J=9.3,4.8Hz,1H),2.00(tq,J=8.9,4.4,3.8Hz,1H),1.86(d,J=10.2Hz,1H),1.71(tt,J=8.8,3.9Hz,1H),1.03(t,J=7.1Hz,6H),0.61(dt,J=9.4,4.9Hz,1H),0.31(dt,J=9.0,4.4Hz,1H),-0.05(dt,J=9.8,4.8Hz,1H),-0.15(dp,J=9.6,4.7Hz,1H),-0.59(dq,J=9.7,4.8Hz,1H).

[0562] Example 47:

[0563]

[0564] Compound O (75 mg), 1-isopropylpiperidin-4-amine (40 mg), Pd 2 (dba) 3 (32 mg), 2-(di-tert-butylphosphino)biphenyl (21 mg), potassium tert-butoxide (94 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 47 (20 mg). ESI-MS: m / z = 299.39 [1 / 2M + H] + 。

[0565] 11H NMR (500 MHz, chloroform-d) δ 8.49 (s, 1H), 8.42 (s, 1H), 8.15 (s, 1H), 7.73 (s, 1H), 7.14 (d, J = 8.5 Hz, 1H), 6.59–6.53 (m, 2H), 4.36 (dq, J = 8.6, 5.8, 4.6 Hz, 2H), 3.97–3.89 (m, 2H), 3.79 (s, 3H), 3.39–3.29 (m, 4H), 2.64 (s, 3H), 2.57 (s, 1H), 2.28 (dd, J = 13.4, 6.8 Hz, 1H), 2.24–2.13 (m, 4H), 1.98 (dd, J = 25.5, 12.2 Hz, 2H), 1.80 (d, J = 11.9 Hz, 2H), 1.28 (s, 3H), 1.26 (s, 3H), 0.87 (dt, J = 13.2, 6.6 Hz, 1H), 0.51 (dd, J = 10.5, 5.8 Hz, 1H), 0.44 (tt, J = 9.0, 4.9 Hz, 1H), 0.10 (tt, J = 8.8, 4.8 Hz, 1H), -0.01– -0.08 (m, 1H), -0.34 (dq, J = 10.1, 5.1 Hz, 1H).

[0566] Example 48:

[0567]

[0568] Compound O (75 mg), 1-ethylpiperidin-4-amine dihydrochloride (56 mg), Pd 2 (dba) 3 (32 mg), 2-(di-tert-butylphosphino)biphenyl (21 mg), potassium tert-butoxide (94 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 48 (10 mg). ESI-MS: m / z = 292.38 [1 / 2M + H] + .

[0569] 11H NMR (500 MHz, chloroform-d) δ 8.48 (s, 1H), 8.44 (s, 1H), 8.15 (s, 1H), 7.79 (s, 1H), 7.14 (d, J = 8.5 Hz, 1H), 6.58–6.50 (m, 2H), 4.41–4.33 (m, 2H), 3.96 (dt, J = 8.9, 5.9 Hz, 1H), 3.89 (dd, J = 13.9, 7.7 Hz, 1H), 3.79 (s, 3H), 3.30 (d, J = 13.3 Hz, 2H), 3.18 (s, 1H), 2.73 (q, J = 7.2 Hz, 2H), 2.64 (s, 3H), 2.34 (d, J = 10.9 Hz, 1H), 2.28 (q, J = 6.5 Hz, 1H), 2.25–2.19 (m, 2H), 2.11 (t, J = 8.8 Hz, 3H), 1.84–1.77 (m, 3H), 1.21 (t, J = 7.3 Hz, 3H), 0.89–0.86 (m, 1H), 0.51 (t, J = 8.5 Hz, 1H), 0.43 (tt, J = 9.1, 5.0 Hz, 1H), 0.09 (tt, J = 9.1, 5.3 Hz, 1H), -0.04 (p, J = 4.9 Hz, 1H), -0.34 (dt, J = 9.6, 5.0 Hz, 1H).

[0570] Example 49:

[0571]

[0572] Compound O (75 mg), 3-methylaminopropylamine (15 mg), Pd 2 (dba) 3 (32 mg), 2-(di-tert-butylphosphino)biphenyl (21 mg), and potassium tert-butoxide (94 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 49 (25 mg). ESI-MS: m / z = 272.30 [1 / 2M + H] + .

[0573] 1 1H NMR (500 MHz, DMSO-d 6)δ8.36(s,1H),8.33(s,1H),7.90(s,1H),7.54(s,1H),7.34(d,J=8.7Hz,1H),6.74(d,J=2.2Hz,1H),6.60–6.57(m,1H),4.32–4.26(m,1H),4.22(dd,J=13.9,3.5Hz,1H),4.02(dd,J=14.5,9.3Hz,2H),3.73(s,3H),3.06(t,J=6.9Hz,2H),2.73(t,J=7.0Hz,1H),2.67–2.62(m,1H),2.54(s,3H),2.52(d,J=2.1Hz,3H),2.23–2.18(m,1H),2.14(d,J=9.3Hz,1H),2.03–1.96(m,2H),1.83–1.76(m,2H),1.71(d,J=12.8Hz,1H),0.58(dd,J=10.5,5.8Hz,1H),0.30(tt,J=9.0,4.9Hz,1H),-0.06(tt,J=8.8,4.8Hz,1H),-0.10–-0.15(m,1H),-0.61(dq,J=10.1,5.1Hz,1H).

[0574] Example 50:

[0575]

[0576] Compound O (85 mg), tert-butyl (3-aminopropyl)carbamate (33 mg), Pd 2 (dba) 3 (34 mg), 2-(di-tert-butylphosphino)biphenyl (22 mg), and potassium tert-butoxide (100 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h until the reaction was completed. 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The crude product obtained by concentrating the filtrate was directly dissolved in hydrogen chloride-methanol solution (4 M, 5 mL), stirred for 30 min, and monitored by LC-MS until the reaction was completed. After concentration, the reaction mixture was purified by preparative liquid chromatography to obtain Example 50 (9 mg). ESI-MS: m / z = 529.31 [M+H] + .

[0577] 1 H NMR (500 MHz, DMSO-d 6)δ8.38(s,1H),8.34(s,1H),7.88(s,1H),7.52(s,1H),7.31(d,J=8.7Hz,1H),6.72(d,J=2.2Hz,1H),6.60–6.56(m,1H),4.33–4.27(m,1H),4.20(dd,J=13.9,3.5Hz,1H),4.01(dd,J=14.5,9.3Hz,2H),3.73(s,3H),3.04(t,J=6.9Hz,2H),2.76(t,J=7.0Hz,1H),2.66–2.61(m,1H),2.56(s,3H),2.23–2.18(m,1H),2.13(d,J=9.3Hz,1H),2.02–1.97(m,2H),1.82–1.76(m,2H),1.67(d,J=12.8Hz,1H),0.56(dd,J=10.5,5.8Hz,1H),0.31(tt,J=9.0,4.9Hz,1H),-0.05(tt,J=8.8,4.8Hz,1H),-0.10–-0.15(m,1H),-0.60(dq,J=10.1,5.1Hz,1H).

[0578] Example 51:

[0579]

[0580] Compound O (100 mg), 4-dimethylaminobutylamine (21 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 51 (10 mg). ESI-MS: m / z = 571.44 [M+H] + .

[0581] 11H NMR (500 MHz, chloroform-d) δ 8.46 (s, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 7.70 (s, 1H), 7.13 (d, J = 8.7 Hz, 1H), 6.60 (dd, J = 8.6, 2.1 Hz, 1H), 6.52 (d, J = 2.2 Hz, 1H), 4.40–4.31 (m, 2H), 3.97–3.94 (m, 1H), 3.90 (d, J = 6.4 Hz, 1H), 3.78 (s, 3H), 3.08 (td, J = 6.4, 3.3 Hz, 2H), 2.95–2.89 (m, 2H), 2.69 (s, 6H), 2.63 (s, 3H), 2.27 (dt, J = 13.5, 6.9 Hz, 1H), 2.16 (ddt, J = 21.9, 13.5, 7.2 Hz, 2H), 1.87–1.73 (m, 4H), 1.68 (p, J = 6.8 Hz, 2H), 0.50 (td, J = 9.8, 8.3, 3.4 Hz, 1H), 0.42 (tt, J = 8.9, 4.9 Hz, 1H), 0.09 (tt, J = 9.1, 4.9 Hz, 1H), -0.04 (dq, J = 9.8, 4.9 Hz, 1H), -0.34 (dq, J = 9.9, 5.1 Hz, 1H).

[0582] Example 52:

[0583]

[0584] Compound O (100 mg), tert-butyl (4-aminobutyl)(methyl)carbamate (47 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), and potassium tert-butoxide (126 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The crude product obtained by concentrating the filtrate was directly dissolved in hydrogen chloride-methanol solution (4 M, 5 mL), stirred for 30 min, and monitored by LC-MS until the reaction was completed. After concentration of the reaction solution, it was purified by preparative liquid chromatography to obtain Example 52 (22 mg). ESI-MS: m / z = 557.31 [M+H] + .

[0585] 11H NMR (500 MHz, chloroform-d) δ 8.35 (s, 2H), 8.32 (s, 1H), 8.14 (s, 1H), 7.59 (s, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.62–6.54 (m, 2H), 4.29–4.21 (m, 2H), 3.90–3.86 (m, 1H), 3.76 (d, J = 8.8 Hz, 1H), 3.73 (s, 3H), 3.02 (dt, J = 23.3, 7.0 Hz, 4H), 2.69 (s, 3H), 2.60 (s, 3H), 2.15 (q, J = 6.6 Hz, 1H), 2.08 (d, J = 6.1 Hz, 1H), 2.02–1.95 (m, 1H), 1.90 (t, J = 7.7 Hz, 2H), 1.74–1.65 (m, 4H), 0.41 (s, 1H), 0.35 (dq, J = 8.6, 4.6, 4.1 Hz, 1H), -0.00– -0.06 (m, 1H), -0.12 (dt, J = 9.7, 5.0 Hz, 1H), -0.45 (dd, J = 9.7, 5.1 Hz, 1H).

[0586] Example 53:

[0587]

[0588] Compound O (100 mg), 1,4-diaminobutane hydrochloride (61 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 53 (25 mg). ESI-MS: m / z = 543.42 [M+H] + 。

[0589] 1 1H NMR (500 MHz, Methanol-d 4)δ8.34(s,1H),8.02(s,1H),7.58(s,1H),7.24–7.17(m,1H),6.66(d,J=8.4Hz,2H),4.34–4.28(m,1H),4.27–4.20(m,1H),3.98(p,J=5.1Hz,1H),3.84(d,J=20.1Hz,1H),3.73(s,3H),3.17–3.09(m,2H),2.99(t,J=7.4Hz,2H),2.53(s,3H),2.19(d,J=13.0Hz,2H),2.00(d,J=17.1Hz,1H),1.76(ddd,J=36.2,13.9,6.7Hz,6H),0.52–0.43(m,1H),0.33(t,J=8.9Hz,1H),-0.08–-0.17(m,2H),-0.60(d,J=8.9Hz,1H).

[0590] Example 54:

[0591]

[0592] Compound O-2 (70 mg), 1-isopropylpiperidin-4-amine (22 mg), Pd 2 (dba) 3 (30 mg), 2-(di-tert-butylphosphino)biphenyl (20 mg), and potassium tert-butoxide (88 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 54 (43 mg). ESI-MS: m / z = 299.39 [1 / 2M + H] + .

[0593] 1 H NMR (500 MHz, DMSO-d 6)δ8.38(s,1H),8.29(s,1H),7.95(s,1H),7.58(s,1H),7.28(d,J=8.5Hz,1H),6.78(s,1H),6.60(d,J=8.6Hz,1H),4.35–4.31(m,1H),4.26(dd,J=13.8,3.5Hz,1H),4.10–4.06(m,2H),3.77(s,3H),3.42(t,J=10.0Hz,1H),3.03(p,J=8.0,6.7Hz,2H),2.62(d,J=10.6Hz,2H),2.58(s,3H),2.26(dd,J=13.0,6.6Hz,1H),2.21–2.14(m,1H),2.10–2.01(m,3H),1.91–1.84(m,1H),1.81–1.71(m,1H),1.53(q,J=13.9,13.0Hz,2H),1.13(d,J=6.6Hz,6H),0.63(qd,J=8.5,5.2,3.6Hz,1H),0.36(tt,J=9.4,4.6Hz,1H),0.03– -0.03(m,1H),-0.11(dt,J=9.3,4.3Hz,1H),-0.54(dt,J=9.7,4.9Hz,1H).

[0594] Example 55:

[0595]

[0596] Compound O-2 (70 mg), 1-ethylpiperidin-4-amine dihydrochloride (32 mg), Pd 2 (dba) 3 (30 mg), 2-(di-tert-butylphosphino)biphenyl (20 mg), potassium tert-butoxide (88 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 55 (35 mg). ESI-MS: m / z = 292.40 [1 / 2M + H] + 。

[0597] 1 H NMR (500 MHz, DMSO-d 6)δ12.42(s,1H),8.38(s,1H),8.27(s,1H),7.95(s,1H),7.58(s,1H),7.29(d,J=8.6Hz,1H),6.78(s,1H),6.60(d,J=8.6Hz,1H),4.33(d,J=8.2Hz,1H),4.29–4.24(m,1H),4.08(dt,J=13.2,6.7Hz,2H),3.77(s,3H),3.42(d,J=10.0Hz,1H),3.07(t,J=10.8Hz,2H),2.63(d,J=7.1Hz,2H),2.58(s,3H),2.43(d,J=12.6Hz,2H),2.31–2.23(m,1H),2.20–2.13(m,1H),2.05(d,J=14.8Hz,3H),1.86(s,1H),1.76(dt,J=13.6,6.6Hz,1H),1.51(t,J=12.9Hz,2H),1.12(t,J=7.1Hz,3H),0.64(q,J=8.1Hz,1H),0.37(td,J=9.5,9.0,4.6Hz,1H),0.00(dd,J=9.6,4.9Hz,1H),-0.09(dt,J=9.6,4.6Hz,1H),-0.52(dd,J=9.1,4.9Hz,1H).

[0598] Examples 56 / 57:

[0599]

[0600] Compound O-2 (70 mg), N-methylethylenediamine (15 mg), Pd 2 (dba) 3 (30 mg), 2-(di-tert-butylphosphino)biphenyl (20 mg), potassium tert-butoxide (88 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and obtained by preparation (liquid phase conditions: column: YMC AQ C18 250 mm × 30 mm, 10 um; mobile phase: A: 0.1% formic acid B: acetonitrile, gradient: 15% C - 25% B (0 - 90 min); flow rate: 25 mL / min; wavelength: 254 nm) to obtain Example 56 (12 mg, retention time 60.4 minutes) ESI-MS: m / z = 529.35 [M + H] +, and Example 57 (25 mg, retention time of 39.5 minutes), ESI-MS: m / z = 529.35 [M+H] + . Example 56: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.39 (s, 1H), 7.91 (s, 1H), 7.54 (s, 1H), 7.27 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 2.1 Hz, 1H), 6.56 (dd, J = 8.6, 2.0 Hz, 1H), 5.81 (s, 1H), 4.33–4.26 (m, 1H), 4.22 (dd, J = 14.0, 3.6 Hz, 1H), 4.12–4.01 (m, 2H), 3.73 (s, 3H), 3.28 (t, J = 6.3 Hz, 2H), 2.90 (t, J = 6.3 Hz, 2H), 2.54 (s, 3H), 2.44 (s, 3H), 2.21 (dt, J = 12.2, 5.9 Hz, 1H), 2.13 (tt, J = 8.6, 4.6 Hz, 1H), 2.01 (qd, J = 9.4, 6.1, 5.6 Hz, 1H), 1.85 (s, 1H), 1.76–1.66 (m, 1H), 0.62 (tq, J = 8.2, 4.9, 4.3 Hz, 1H), 0.31 (tt, J = 9.4, 4.7 Hz, 1H), -0.05 (dq, J = 9.6, 4.9 Hz, 1H), -0.14 (tt, J = 9.4, 4.6 Hz, 1H), -0.60 (dq, J = 9.7, 4.9 Hz, 1H). Example 57: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.44 (s, 1H), 7.91 (s, 1H), 7.55 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.00 (s, 1H), 6.72 (d, J = 8.8 Hz, 1H), 4.29 (t, J = 7.8 Hz, 1H), 4.21 (d, J = 7.7 Hz, 2H), 4.03 (p, J = 6.2 Hz, 1H), 3.73 (s, 3H), 3.50 (tt, J = 15.3, 8.1 Hz, 2H), 2.94 (s, 3H), 2.87 (t, J = 7.2 Hz, 2H), 2.54 (s, 3H), 2.27–2.19 (m, 1H), 2.15 (s, 1H), 2.02 (d, J = 15.6 Hz, 1H), 1.87 (s, 1H), 1.71 (s, 1H), 0.66 (s, 1H), 0.29 (s, 1H), -0.03– -0.13 (m, 1H), -0.21 (s, 1H), -0.65 (s, 1H).

[0601] Example 58:

[0602]

[0603] Compound O-2 (70 mg), ethylenediamine (20 mg), Pd 2 (dba) 3 (30 mg), 2-(di-tert-butylphosphino)biphenyl (20 mg), potassium tert-butoxide (88 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 58 (40 mg). ESI-MS: m / z = 258.34 [1 / 2M + H] + .

[0604] 1 1H NMR (500 MHz, DMSO-d 6 ) δ 8.43 (s, 1H), 8.34 (s, 1H), 7.91 (s, 1H), 7.54 (s, 1H), 7.27 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 2.1 Hz, 1H), 6.56 (dd, J = 8.5, 2.0 Hz, 1H), 4.29 (q, J = 7.9 Hz, 1H), 4.22 (dd, J = 14.1, 3.5 Hz, 1H), 4.13–4.00 (m, 2H), 3.73 (s, 3H), 3.27 (t, J = 6.4 Hz, 2H), 2.93 (t, J = 6.3 Hz, 2H), 2.54 (s, 3H), 2.21 (dt, J = 11.9, 5.9 Hz, 1H), 2.14 (dt, J = 13.4, 6.4 Hz, 1H), 2.04–1.96 (m, 1H), 1.84 (d, J = 9.7 Hz, 1H), 1.72 (dd, J = 12.1, 6.7 Hz, 1H), 0.63 (td, J = 9.5, 8.8, 4.1 Hz, 1H), 0.31 (dp, J = 9.4, 4.6 Hz, 1H), -0.05 (dq, J = 9.7, 4.9 Hz, 1H), -0.14 (td, J = 8.8, 4.5 Hz, 1H), -0.60 (dq, J = 9.9, 4.9 Hz, 1H).

[0605] Examples 59 / 60:

[0606]

[0607] (1) Preparation method of compound B-a:

[0608] Add titanium tetrachloride (43.9 g) to dichloromethane (300 mL), cool down to 0 - 2 °C, and dropwise add tetra-isopropyl titanate (19.7 g) while controlling the temperature at 0 - 2 °C; after maintaining the temperature and stirring for 10 min, dropwise add N,N-diisopropylethylamine (32.8 g) while controlling the temperature at 0 - 2 °C; after maintaining the temperature and stirring for 10 min, dropwise add a solution of compound B (30.0 g) in dichloromethane (100 mL) while controlling the temperature at 0 - 2 °C; after maintaining the temperature and stirring for 2 h, dropwise add tert-butyl acrylate (44.5 g) while controlling the temperature at 0 - 2 °C, and continue the reaction at 0 - 2 °C for 4 h, monitor the reaction by TLC until it is complete; pour the reaction solution into saturated ammonium chloride solution (600 mL), extract with dichloromethane (200 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain compound B-a (19.0 g) by column chromatography.

[0609] (2) Preparation method of compound B-b:

[0610] Add sodium borohydride (1.64 g) to tetrahydrofuran (70 mL), cool down to 0 - 2 °C, and dropwise add a solution of compound B-a (15.26 g) in tetrahydrofuran (30 mL) while controlling the temperature at 0 - 2 °C. After the addition is complete, remove the ice bath and stir the reaction at 20 - 25 °C for 6 h, monitor the reaction by TLC until it is complete; pour the reaction solution into saturated ammonium chloride solution (200 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain compound B-b (1.95 g) by column chromatography.

[0611] (3) Preparation method of compound B-c:

[0612] Add compound B-b (1.95 g) to tetrahydrofuran (50 mL), displace with nitrogen three times and cool down to 0 - 2 °C, dropwise add a solution of lithium aluminum hydride in tetrahydrofuran (1 M, 10.9 mL) while controlling the temperature at 0 - 2 °C. After the addition is complete, remove the ice bath and stir the reaction at 20 - 25 °C for 6 h, monitor the reaction by TLC until it is complete; control the temperature at 0 - 5 °C and sequentially add water (0.37 mL), 15% sodium hydroxide solution (0.37 mL) and water (1.11 mL) to the reaction solution, filter the reaction solution, wash the filter cake with tetrahydrofuran (20 mL), dry the filtrate over anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain compound B-c (1.44 g).

[0613] (4) Preparation method of compound B-d:

[0614] Dissolve compound B-c (1.44 g) in dichloromethane (50 mL), slowly add triethylamine (5.06 g) and 4-dimethylaminopyridine (10 mg), and cool the temperature to 0 - 5 °C. Then slowly add a solution of p-toluenesulfonyl chloride (5.72 g) in dichloromethane (10 mL). After the addition is complete, react at 20 - 25 °C for 3 h until the reaction is complete. Wash the reaction solution with sodium bicarbonate solution (1 M, 20 mL × 2), separate the layers, dry the organic phase with anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain compound B-d (1.89 g) by column chromatography.

[0615] (5) Preparation method of compound B-e1 / B-e2:

[0616] Add compound B-d (1.89 g), 5-bromo-1H-benzoimidazol-2-amine (888 mg), and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (1.8 mL) to acetonitrile (50 mL). Replace the air with nitrogen three times and react at 15 - 20 °C for 24 h. Monitor the reaction by TLC until it is complete. Add 1 M aqueous sodium bicarbonate solution (50 mL) to the reaction solution, extract with ethyl acetate (50 mL × 2), combine the organic phases, dry with anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain a mixture of compound B-e1 / B-e2 (1.44 g) by column chromatography. ESI-MS: m / z = 492.18 [M + H] + .

[0617] (6) Preparation method of compound B-f1 / B-f2:

[0618] Add compound B-e1 / B-e2 (1.44 g), compound A (673 mg), and potassium carbonate (601 mg) to acetonitrile (70 mL) and react at 80 °C for 16 h. Monitor the reaction by TLC until it is complete. Pour the reaction solution into 100 mL of water, extract with ethyl acetate (40 mL × 2), combine the ethyl acetate phases, wash the organic phase with water once, dry the organic phase with anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain a mixture of compound B-f1 / B-f2 (853 mg) by column chromatography. ESI-MS: m / z = 567.19 [M + H] + .

[0619] (7) Preparation method of compound B-g1 / B-g2:

[0620] Dissolve compound B-f1 / B-f2 (853 mg) in tetrahydrofuran (10 mL), add a solution of sodium hydroxide (183 mg) in water (3 mL), stir and react at 20 - 25 °C for 18 h, monitor the reaction by LC-MS until completion; adjust the pH to 5 - 6 with 6 M hydrochloric acid, evaporate tetrahydrofuran and water under reduced pressure, add dichloromethane (10 mL) and triethylamine (456 mg), stir to dissolve clearly, dry over anhydrous sodium sulfate, filter and concentrate until no liquid flows out to obtain a mixture of compound B-g1 / B-g2, which is directly used in the next reaction without further purification. ESI-MS: m / z = 553.16 [M+H] + 。

[0621] (8) Preparation method of compound B-h1 / B-h2:

[0622] Dissolve the compound B-g1 / B-g2 obtained in the previous step in dichloromethane (10 mL), add TBTU (593 mg), react at 20 - 25 °C for 16 h, LC-MS shows that the reaction is complete; wash the reaction solution with water (10 mL * 3), dry the organic phase over anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain a mixture of compound B-h1 / B-h2 (817 mg) by column chromatography; obtain compound B-h1 (253 mg, retention time is 11.6 minutes) by preparative SFC (liquid phase conditions: column: YMC SB 30 mm x 250 mm, 10 um; mobile phase: carbon dioxide: methanol = 40:60; flow rate: 80 mL / min; wavelength: 254 nm), ESI-MS: m / z = 535.16 [M+H] + , and compound B-h2 (207 mg, retention time is 14.0 minutes), ESI-MS: m / z = 535.16 [M+H] + 。Compound B-h1: 11H NMR (500 MHz, chloroform-d) δ 12.00 (s, 1H), 8.47 (s, 1H), 8.17 (s, 1H), 7.60 (s, 1H), 7.43 (d, J = 1.7 Hz, 1H), 7.35 (dd, J = 8.4, 1.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 4.22 (dd, J = 9.1, 4.1 Hz, 1H), 4.18–4.10 (m, 2H), 4.01 (ddd, J = 14.0, 9.5, 4.8 Hz, 1H), 3.82 (s, 3H), 2.61 (s, 3H), 2.31–2.23 (m, 1H), 2.09 (ddt, J = 12.6, 9.1, 4.5 Hz, 2H), 1.94 (ddd, J = 12.0, 7.4, 4.3 Hz, 1H), 1.08 (dq, J = 8.6, 4.4 Hz, 1H), 0.90 (dtd, J = 9.9, 5.6, 4.7, 2.3 Hz, 1H), 0.64 (tt, J = 9.0, 4.6 Hz, 1H), 0.56 (tt, J = 8.9, 4.7 Hz, 1H), 0.28 (dq, J = 9.6, 4.8 Hz, 1H), 0.21 (dq, J = 9.3, 4.7 Hz, 1H). Compound B-h2: 1 1H NMR (500 MHz, chloroform-d) δ 12.04 (s, 1H), 8.46 (s, 1H), 8.17 (s, 1H), 7.59 (s, 1H), 7.49 (s, 1H), 7.40 (dd, J = 8.5, 1.2 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 4.22 (dd, J = 9.2, 4.1 Hz, 1H), 4.19–4.09 (m, 2H), 4.00 (ddd, J = 14.1, 9.7, 5.0 Hz, 1H), 3.82 (s, 3H), 2.60 (s, 3H), 2.31–2.21 (m, 1H), 2.07 (tt, J = 11.3, 8.4, 3.9 Hz, 2H), 1.92 (ddd, J = 11.7, 7.5, 4.2 Hz, 1H), 1.07 (qt, J = 8.3, 4.3 Hz, 1H), 0.96–0.87 (m, 1H), 0.67–0.60 (m, 1H), 0.56 (ddt, J = 13.3, 8.9, 4.6 Hz, 1H), 0.28 (dq, J = 9.6, 4.9 Hz, 1H), 0.20 (dq, J = 9.3, 4.8 Hz, 1H).

[0623] (9) Preparation method of Example 59:

[0624] Compound B-h1 (100 mg), 3-oxetanamine (16 mg), Pd 2(dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 59 (22 mg). ESI-MS: m / z = 528.35 [M+H] + 。

[0625] 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.34 (s, 1H), 8.42 (s, 1H), 7.94 (s, 1H), 7.55 (s, 1H), 7.35 (d, J = 8.6 Hz, 1H), 6.64 (s, 1H), 6.47 (d, J = 8.5 Hz, 1H), 6.39 (d, J = 5.8 Hz, 1H), 4.85 (t, J = 6.3 Hz, 2H), 4.53–4.46 (m, 1H), 4.42 (t, J = 6.0 Hz, 2H), 4.23 (dd, J = 9.3, 4.1 Hz, 1H), 4.19–4.10 (m, 2H), 3.97 (s, 1H), 3.78 (s, 3H), 2.55 (s, 3H), 2.25–2.16 (m, 1H), 1.23 (d, J = 3.8 Hz, 3H), 1.14 (d, J = 4.1 Hz, 1H), 0.97 (tt, J = 8.5, 3.5 Hz, 1H), 0.54 (ddq, J = 17.6, 9.0, 4.5, 3.7 Hz, 2H), 0.34 (dq, J = 9.5, 4.7 Hz, 1H), 0.21 (dq, J = 8.9, 4.8 Hz, 1H).

[0626] (10) Preparation method of Example 60:

[0627] Compound B-h2 (100 mg), 3-oxetanamine (16 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 60 (35 mg). ESI-MS: m / z = 528.35 [M+H] + 。

[0628] 1 H NMR(500MHz, DMSO-d 6 ) δ 12.35 (s, 1H), 8.42 (s, 1H), 7.94 (s, 1H), 7.58–7.51 (m, 1H), 7.26 (d, J = 8.5 Hz, 1H), 6.60 (d, J = 1.9 Hz, 1H), 6.50 (dd, J = 8.6, 2.0 Hz, 1H), 6.40 (d, J = 7.1 Hz, 1H), 4.90 (t, J = 6.5 Hz, 2H), 4.63 (h, J = 6.7 Hz, 1H), 4.43 (td, J = 6.1, 1.6 Hz, 2H), 4.25 (dd, J = 9.2, 4.1 Hz, 1H), 4.21–4.11 (m, 2H), 4.01–3.94 (m, 1H), 3.78 (s, 3H), 2.55 (s, 3H), 2.29–2.19 (m, 1H), 1.98–1.89 (m, 2H), 1.15 (ddt, J = 15.7, 8.7, 3.0 Hz, 2H), 1.04–0.97 (m, 1H), 0.56 (dtt, J = 25.5, 8.8, 4.3 Hz, 2H), 0.36 (dt, J = 9.3, 4.6 Hz, 1H), 0.27–0.20 (m, 1H).

[0629] Example 61:

[0630]

[0631] (1) Preparation method of compound B-5:

[0632] Add (S)-4-benzyl-2-oxazolidinone (14.1 g), 3-cyclopropylpropionic acid (10 g) and 4-dimethylaminopyridine (10.7 g) to dichloromethane (200 mL). Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.6 g) at 20 - 25 °C. After addition, stir and react at 20 - 25 °C for 12 h until the reaction is complete. Add 75 mL of dichloromethane to the reaction solution. The dichloromethane phase is washed successively with water (150 mL), 1 M hydrochloric acid (150 mL × 2), and 1 M sodium bicarbonate solution (150 mL × 2). Retain the dichloromethane phase, dry it over anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain compound B-5 (19.1 g) by column chromatography. ESI-MS: m / z = 274.14 [M + H] + .

[0633] (2) Preparation method of compound C-5:

[0634] Compound B-5 (6.0 g) was added to tetrahydrofuran (60 mL), and the mixture was purged with nitrogen three times and cooled (set temperature: -78 °C). When the internal temperature reached -70 °C, sodium bis(trimethylsilyl)amide (2 M, 16.5 mL) was added dropwise over 15 min, and the mixture was stirred at -70 °C or below for 1 h. Then, 3-bromopropene (5.3 g) was added dropwise, and after stirring at -70 °C or below for 1 h, the mixture was slowly warmed to room temperature and stirred for 12 h to complete the reaction. The reaction mixture was poured into ammonium chloride solution (1 M, 400 mL), and extracted with ethyl acetate (50 mL × 2). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound C-5 (3.5 g) was obtained by column chromatography. ESI-MS: m / z = 314.19 [M+H] + 。

[0635] (3) Preparation method of compound D-5:

[0636] Compound C-5 (2.8 g) was added to tetrahydrofuran (30 mL), and the mixture was cooled to 0 - 5 °C in an ice bath. Aqueous solution of lithium hydroxide monohydrate (1.1 g) in water (10 mL) was added, and after stirring for 5 min, hydrogen peroxide (30 wt%, 3.65 mL) was added. The mixture was stirred at 0 - 5 °C for 1 h to complete the reaction. Sodium sulfite solution (1 M, 30 mL) and sodium bicarbonate solution (1 M, 30 mL) were added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 2). The aqueous phase was retained, and the pH of the aqueous phase was adjusted to 1 - 2 with 4 M hydrochloric acid and then extracted with dichloromethane (30 mL × 2). The dichloromethane phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound D-5 was obtained, which was directly used in the next reaction without further purification.

[0637] (4) Preparation method of compound E-5:

[0638] The compound D-5 obtained in the previous step was dissolved in dichloromethane (30 mL), and dibenzylamine (1.8 g), N,N-diisopropylethylamine (4.43 mL) and HATU (4.1 g) were added in sequence. After addition, the mixture was stirred at 20 - 25 °C for 12 h to complete the reaction. The reaction mixture was washed with water (30 mL × 2), the dichloromethane phase was retained, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound E-5 (2.8 g) was obtained by column chromatography. ESI-MS: m / z = 334.30 [M+H] + 。

[0639] (5) Preparation method of compound F-5:

[0640] Compound E-5 (2.8 g) was added to tetrahydrofuran (30 mL), and 9-borabicyclo[3.3.1]nonane (0.5 M, 42 mL) was added. The mixture was stirred at 20 - 25 °C for 1 h; the temperature was lowered to 0 - 5 °C in an ice bath, and a solution of sodium hydroxide (672 mg) in water (5 mL) and hydrogen peroxide (30 wt%, 4.29 mL) were added successively. The mixture was stirred at 20 - 25 °C for 2 h to complete the reaction; the reaction solution was poured into water (30 mL), and extracted with ethyl acetate (30 mL × 2). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound F-5 (2.08 g) was obtained by column chromatography. ESI-MS: m / z = 352.30 [M + H] + 。

[0641] (6) Preparation method of compound G-5:

[0642] Compound F-5 (2.08 g) was added to tetrahydrofuran (30 mL), and the temperature was lowered to 0 - 5 °C. Borane dimethyl sulfide (2 M, 10.22 mL) was added dropwise. After addition, the mixture was stirred at 60 °C for 4 h to complete the reaction; the temperature was lowered to 0 - 5 °C in an ice bath, and dilute hydrochloric acid (1 M) was added dropwise to the reaction solution to quench the reaction. The reaction solution was evaporated to dryness, and the concentrate was dissolved in ethyl acetate (50 mL). The organic phase was washed with saturated sodium bicarbonate solution (50 mL × 1) and saturated brine (50 mL × 1) respectively, dried and concentrated, and then separated by column chromatography to obtain G-5 (1.45 g). ESI-MS: m / z = 338.40 [M + H] + 。

[0643] (7) Preparation method of compound H-5:

[0644] Compound G-5 (510 mg) was added to methanol (10 mL), and Pd / C (10%, 51 mg) was added. The mixture was purged with hydrogen three times and stirred in a water bath at 40 - 45 °C for 2 h to complete the reaction. The reaction solution was filtered and concentrated until no liquid flowed out to obtain compound H-5, which was directly used in the next step without further purification.

[0645] (8) Preparation method of compound I-5:

[0646] The compound H-5 obtained in the previous step was dissolved in N,N-dimethylformamide (10 mL), 4-bromo-1-fluoro-2-nitrobenzene (333 mg) and potassium carbonate (460 mg) were added successively, and the mixture was stirred in a water bath at 40 - 45 °C for 6 h to complete the reaction; the reaction solution was poured into 50 mL of water, and extracted with ethyl acetate (10 mL × 2). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and compound I-5 (387 mg) was obtained by column chromatography. ESI-MS: m / z = 357.14 [M + H] + 。

[0647] (9) Preparation method of compound J-5:

[0648] Dissolve compound I-5 (387 mg) in dichloromethane (8 mL), add triethylamine (164 mg) and cool down to 0 - 5 °C. Dropwise add a solution of ethylsulfonyl chloride (168 mg) in dichloromethane (5 mL). After the addition is complete, react at 20 - 25 °C for 1 h to end the reaction. Wash the reaction solution with sodium bicarbonate solution (1 M, 30 mL × 2), retain the dichloromethane phase, dry it over anhydrous sodium sulfate, and concentrate until no more liquid flows out to obtain compound J-5, which is directly used for the next reaction without further purification.

[0649] (10) Preparation method of compound K-5:

[0650] Add the obtained compound J-5 from the previous step, compound A (306 mg), and potassium carbonate (416 mg) to N,N-dimethylformamide (20 mL), and react at 60 °C for 20 h until the reaction is complete. Pour the reaction solution into 50 mL of water, extract with ethyl acetate (30 mL × 2), combine the ethyl acetate phases, wash the organic phase with water once, dry the organic phase over anhydrous sodium sulfate, concentrate until no more liquid flows out, and obtain compound K-5 (450 mg) by column chromatography. ESI-MS: m / z = 586.22 [M + H] + 。

[0651] (11) Preparation method of compound L-5:

[0652] Dissolve compound K-5 (450 mg) in methanol (5 mL), add Raney nickel (20 mg), displace with hydrogen 3 times, and react at 25 °C for 2 h until the reaction is complete. Filter the reaction solution, dry the filtrate over anhydrous sodium sulfate, concentrate until no more liquid flows out to obtain compound L-5, which is directly used for the next reaction without further purification.

[0653] (12) Preparation method of compound M-5:

[0654] Dissolve the obtained compound L-5 from the previous step in tert-butanol (10 mL) and dichloromethane (10 mL), dropwise add a solution of cyanogen bromide (163 mg) in dichloromethane (5 mL), and react at 25 °C for 12 h until the reaction is complete. Add sodium bicarbonate solution (1 M, 10 mL) to the reaction solution, separate the layers, retain the dichloromethane phase, wash the organic phase with sodium bicarbonate solution (1 M, 10 mL × 2), dry the organic phase over anhydrous sodium sulfate, concentrate until no more liquid flows out to obtain compound M-5, which is directly used for the next reaction without further purification. ESI-MS: m / z = 581.19 [M + H] + 。

[0655] (13) Preparation method of compound N-5:

[0656] Dissolve the compound M-5 obtained in the previous step in tetrahydrofuran (5 mL), add a solution of sodium hydroxide (123 mg) in water (5 mL), stir and react at 20 - 25 °C for 45 min until the reaction is complete; adjust the pH to 5 - 6 with 6 M hydrochloric acid, evaporate tetrahydrofuran and water under reduced pressure, add dichloromethane (10 mL) and triethylamine (0.43 mL), stir until clear, dry over anhydrous sodium sulfate, filter and concentrate until no liquid flows out to obtain the compound N-5, which is directly used in the next reaction without further purification. ESI-MS: m / z = 567.18 [M + H] + 。

[0657] (14) Preparation method of compound O-5:

[0658] Dissolve the compound N-5 obtained in the previous step in dichloromethane (5 mL), add TBTU (297 mg), react at 20 - 25 °C for 16 h until the reaction is complete; wash the reaction solution with water (10 mL * 3), dry the organic phase over anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain the compound O-5 (240 mg) by column chromatography. ESI-MS: m / z = 549.20 [M + H] + 。

[0659] (15) Preparation method of Example 61:

[0660] Add the compound O-5 (60 mg), 3-oxetanamine (12 mg), Pd 2 (dba) 3 (25 mg), 2-(di-tert-butylphosphino)biphenyl (16 mg), and potassium tert-butoxide (73 mg) into tert-amyl alcohol (5 mL), displace with nitrogen 3 times, react at 90 °C for 2 h until the reaction is complete; add 30 mL of water to the reaction solution, extract with ethyl acetate (30 mL * 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and purify by preparative liquid phase to obtain Example 61 (8 mg). ESI-MS: m / z = 542.46 [M + H] + 。

[0661] 11H NMR (500 MHz, chloroform-d) δ 12.04 (s, 1H), 8.41 (s, 1H), 8.15 (s, 1H), 7.66 (s, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.50 (dd, J = 8.5, 2.1 Hz, 1H), 6.43 (d, J = 2.2 Hz, 1H), 5.04 (t, J = 6.6 Hz, 2H), 4.63 (d, J = 7.8 Hz, 1H), 4.55 (t, J = 6.1 Hz, 2H), 4.45–4.34 (m, 2H), 4.01 (q, J = 7.6 Hz, 1H), 3.79 (s, 3H), 2.73 (s, 1H), 2.64 (s, 3H), 2.34 (dt, J = 13.8, 6.9 Hz, 1H), 2.13–2.06 (m, 1H), 2.01 (d, J = 6.4 Hz, 1H), 1.86 (q, J = 7.2, 6.0 Hz, 2H), 1.31 (s, 2H), 0.65–0.57 (m, 1H), 0.41 (ddt, J = 13.3, 8.7, 4.6 Hz, 2H), -0.04 (t, J = 4.1 Hz, 1H), -0.09 (dq, J = 11.4, 6.6, 5.4 Hz, 1H).

[0662] Example 62:

[0663]

[0664] Compound O (50 mg), 1-(dimethylamino)-2-propanamine (14 mg), Pd 2 (dba) 3 (21 mg), 2-(di-tert-butylphosphino)biphenyl (14 mg), potassium tert-butoxide (63 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 62 (10 mg). ESI-MS: m / z = 557.45 [M+H] + .

[0665] 1 1H NMR (500 MHz, DMSO-d 6)δ12.40(s,1H),8.39(s,1H),8.00(s,1H),7.56(s,1H),7.30(d,J=8.8Hz,1H),6.85(s,1H),6.64(d,J=8.6Hz,1H),4.34(s,1H),4.27(d,J=13.5Hz,1H),4.04(d,J=22.0Hz,2H),3.77(s,3H),2.58(s,3H),2.41(d,J=12.0Hz,1H),2.22(s,6H),2.15(d,J=10.1Hz,2H),2.05(d,J=13.1Hz,2H),1.84(h,J=7.3,5.2Hz,1H),1.75(tt,J=12.6,5.9Hz,1H),1.21(d,J=6.3Hz,3H),0.91(s,1H),0.65(s dhept,J=8.5,5.0Hz,1H),0.37(tt,J=9.1,4.8Hz,1H),-0.01(dq,J=9.5,5.3,4.7Hz,1H),-0.09(tt,J=9.7,4.8Hz,1H),-0.55(dq,J=9.7,4.9Hz,1H).

[0666] Example 63:

[0667]

[0668] Compound O-2 (50 mg), 1-(dimethylamino)-2-propanamine (14 mg), Pd 2 (dba) 3 (21 mg), 2-(di-tert-butylphosphino)biphenyl (14 mg), potassium tert-butoxide (63 mg) were added to tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 1 M aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 63 (10 mg). ESI-MS: m / z = 557.47 [M+H] + 。

[0669] 11H NMR (500 MHz, chloroform-d) δ 11.91 (s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 7.65 (s, 1H), 7.13 (dd, J = 8.5, 1.4 Hz, 1H), 6.63 (t, J = 2.6 Hz, 1H), 6.59 (dt, J = 8.7, 2.4 Hz, 1H), 4.36 (ddt, J = 14.1, 9.6, 4.9 Hz, 2H), 3.94 (ddt, J = 20.6, 13.4, 4.0 Hz, 2H), 3.78 (s, 3H), 3.58–3.48 (m, 1H), 2.64 (s, 4H), 2.33 (d, J = 7.3 Hz, 6H), 2.17 (qd, J = 7.4, 4.2 Hz, 2H), 2.01 (d, J = 6.5 Hz, 1H), 1.85–1.76 (m, 2H), 1.33–1.30 (m, 1H), 1.27 (d, J = 6.2 Hz, 3H), 0.60–0.51 (m, 1H), 0.45 (tq, J = 9.8, 5.3 Hz, 1H), 0.14 (tt, J = 9.2, 5.2 Hz, 1H), -0.02 (d, J = 5.7 Hz, 1H), -0.25–-0.33 (m, 1H).

[0670] Example 64:

[0671]

[0672] (1) Preparation method of Example 64:

[0673] Compound O-2 (100 mg), (2-amino-1,1-dimethylethyl)dimethylamine dihydrochloride (42 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (3 mL), purged with nitrogen three times, and reacted at 95 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 64 (20 mg). ESI-MS: m / z = 571.42 [M+H] + .

[0674] Example 65:

[0675]

[0676] (1) Preparation method of Compound 65-a:

[0677] Dissolve compound BOC-D-alanine (10.0 g) in dichloromethane (150 mL). Sequentially add dimethylamine hydrochloride (6.5 g), HATU (22.1 g), and N,N-diisopropylethylamine (20.5 g). React at 25 °C for 16 h. TLC shows the reaction is complete. Wash the reaction solution with an aqueous NaHCO 3 aqueous solution (1 M, 100 mL * 2), retain the organic phase, dry it, and evaporate to dryness. Obtain compound 65-a (9.1 g) by column chromatography.

[0678] (2) Preparation method of compound 65-b:

[0679] Disperse compound 65-a (9.1 g) in tetrahydrofuran (100 mL). Cool the temperature to 0 - 5 °C, and dropwise add a tetrahydrofuran solution of LiAlH 4 (1 M, 105 mL) at this temperature. React at 0 - 5 °C for 2 h. TLC shows the reaction is complete. Sequentially add water (7 mL), NaOH aqueous solution (15%, 7 mL), and water (21 mL) to the reaction solution. Filter, dry the filtrate, and evaporate to dryness. Obtain compound 65-b (4.5 g) by column chromatography.

[0680] (3) Preparation method of compound 65-c:

[0681] Disperse compound 65-b (4.5 g) in a hydrogen chloride / 1,4-dioxane solution (4 M, 56 mL). React at 25 °C for 16 h. TLC shows the reaction is complete. Concentrate the reaction solution, add ethyl acetate (40 mL), stir at 25 °C for 1 h, filter, and dry the filter cake to obtain compound 65-c (2.2 g).

[0682] (4) Preparation method of Example 65:

[0683] Disperse compound O-2 (100 mg), compound 65-c (23 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), and potassium tert-butoxide (126 mg) in tert-amyl alcohol (3 mL). Replace the atmosphere with nitrogen three times, and react at 100 °C for 2 h. After the reaction is complete, add an aqueous sodium bicarbonate solution (1 M, 20 mL) to the reaction solution, extract with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, concentrate until no liquid flows out, and purify by preparative liquid chromatography to obtain Example 65 (8.6 mg). ESI-MS: m / z = 557.45 [M + H] + .

[0684] 1 H NMR (500 MHz, DMSO-d 6)δ 12.41 (s, 1H), 8.37 (s, 1H), 7.93 (d, J = 7.0 Hz, 1H), 7.57 (d, J = 6.9 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 6.80 (s, 1H), 6.59 (d, J = 8.1 Hz, 1H), 5.36 (s, 1H), 4.34–4.24 (m, 2H), 4.10–4.03 (m, 2H), 3.76 (s, 3H), 3.63 (d, J = 6.7 Hz, 1H), 2.58 (s, 3H), 2.45 (t, J = 6.1 Hz, 1H), 2.36–2.31 (m, 1H), 2.27 (s, 6H), 2.03 (qd, J = 11.8, 6.8, 6.1 Hz, 3H), 1.85 (s, 1H), 1.79–1.71 (m, 1H), 1.14 (d, J = 6.3 Hz, 3H), 0.64 (dhept, J = 8.5, 5.0 Hz, 1H), 0.37 (tt, J = 9.1, 4.8 Hz, 1H), 0.00 (dq, J = 9.5, 5.3, 4.7 Hz, 1H), -0.07 (tt, J = 9.7, 4.8 Hz, 1H), -0.52 (dq, J = 9.7, 4.9 Hz, 1H).

[0685] Example 66:

[0686]

[0687] (1) Preparation method of compound 66-a:

[0688] Disperse N-Boc-L-alanine (15.0 g) in dichloromethane (200 mL), and successively add dimethylamine hydrochloride (9.7 g), HATU (33.2 g) and N,N-diisopropylethylamine (30.7 g), and react at 25 °C for 16 h. TLC shows that the reaction is complete; wash the reaction solution with aqueous NaHCO 3 aqueous solution (1 M, 100 mL * 2), retain the organic phase, dry and evaporate to dryness, and obtain compound 66-a (13.3 g) by column chromatography.

[0689] (2) Preparation method of compound 66-b:

[0690] Disperse compound 66-a (13.3 g) in tetrahydrofuran (150 mL), cool down to 0 - 5 °C, and keep the temperature while dropwise adding LiAlH 4A tetrahydrofuran solution (1 M, 154 mL) was reacted at 0 - 5 °C for 2 h. TLC indicated the completion of the reaction. Water (11 mL), an aqueous NaOH solution (15%, 11 mL), and water (33 mL) were successively added dropwise to the reaction solution. After filtration, the filtrate was dried and evaporated to dryness, and compound 66-b (5.7 g) was obtained by column chromatography.

[0691] (3) Preparation method of compound 66-c:

[0692] Compound 66-b (5.7 g) was dispersed in a hydrogen chloride / 1,4-dioxane solution (4 M, 70 mL) and reacted at 25 °C for 16 h. TLC indicated the completion of the reaction. The reaction solution was concentrated, ethyl acetate (50 ml) was added, and the mixture was stirred at 25 °C for 1 h. After filtration, the filter cake was dried to obtain compound 66-c (3.0 g). (4) Preparation method of Example 66:

[0693] Compound O-2 (100 mg) from Example 8, compound 66-c (23 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), and potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (3 mL). The system was purged with nitrogen three times and reacted at 100 °C for 2 h until the reaction was completed. An aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 66 (13 mg). ESI-MS: m / z = 557.45 [M + H] + 。

[0694] 1 H NMR (500 MHz, DMSO-d 6)δ12.41(s,1H),8.38(s,1H),7.95(s,1H),7.58(s,1H),7.28(d,J=8.6Hz,1H),6.80(d,J=2.1Hz,1H),6.58(dd,J=8.6,2.0Hz,1H),5.30(d,J=7.7Hz,1H),4.33(td,J=8.6,6.0Hz,1H),4.26(dd,J=14.0,3.6Hz,1H),4.07(td,J=9.5,4.1Hz,2H),3.77(s,3H),3.60(p,J=7.0Hz,1H),2.58(s,3H),2.33(dd,J=12.0,5.5Hz,1H),2.27–2.23(m,1H),2.19(s,6H),2.19–2.13(m,2H),2.04(ddt,J=13.1,8.8,4.9Hz,1H),1.86(h,J=7.3,5.2Hz,1H),1.75(tt,J=12.6,5.9Hz,1H),1.20(d,J=6.2Hz,3H),0.64(dhept,J=8.5,5.0Hz,1H),0.36(tt,J=9.1,4.8Hz,1H),0.00(dq,J=9.5,5.3,4.7Hz,1H),-0.07(tt,J=9.7,4.8Hz,1H),-0.53(dq,J=9.7,4.9Hz,1H).

[0695] Example 67:

[0696]

[0697] Compound O (100 mg), compound 65-c (23 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (3 mL), purged with nitrogen three times, and reacted at 100 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 67 (10.1 mg). ESI-MS: m / z = 557.47 [M+H] + 。

[0698] 1 H NMR (500 MHz, DMSO-d 6)δ8.34(s,1H),8.22(s,1H),7.91(s,1H),7.54(d,J=1.2Hz,1H),7.32(d,J=8.7Hz,1H),6.79(d,J=2.2Hz,1H),6.60(dd,J=8.7,2.2Hz,1H),4.31–4.26(m,1H),4.22(dd,J=13.9,3.6Hz,1H),4.03(ddd,J=13.7,9.7,5.3Hz,2H),3.73(s,3H),3.46(d,J=6.7Hz,1H),2.54(s,3H),2.40(dd,J=12.1,6.0Hz,1H),2.23(s,6H),2.22–2.19(m,1H),2.14(dp,J=13.0,7.4,6.3Hz,1H),1.98(dq,J=19.2,7.5,6.1Hz,1H),1.80(s,1H),1.74–1.65(m,1H),1.25(dd,J=8.6,5.0Hz,1H),1.15(d,J=6.2Hz,3H),0.59(tt,J=8.6,3.7Hz,1H),0.31(tt,J=9.2,4.7Hz,1H),-0.05(dq,J=9.6,4.9Hz,1H),-0.14(tt,J=9.2,4.6Hz,1H),-0.58(dq,J=9.7,4.9Hz,1H).

[0699] Example 68:

[0700]

[0701] Compound O (100 mg), compound 66-c (23 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (3 mL), purged with nitrogen three times, and reacted at 100 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 68 (15 mg). ESI-MS: m / z = 557.47 [M+H] + 。

[0702] 1 H NMR (500 MHz, DMSO-d 6)δ12.44(s,1H),8.39(s,1H),7.96(s,1H),7.59(s,1H),7.37(d,J=8.8Hz,1H),6.83(s,1H),6.65(d,J=8.6Hz,1H),4.34(s,1H),4.27(d,J=13.5Hz,1H),4.06(d,J=22.0Hz,2H),3.78(s,3H),2.59(s,3H),2.40(d,J=12.0Hz,1H),2.25(s,6H),2.20(d,J=10.1Hz,2H),2.05(d,J=13.1Hz,2H),1.85(h,J=7.3,5.2Hz,1H),1.75(tt,J=12.6,5.9Hz,1H),1.21(d,J=6.3Hz,3H),0.91(s,1H),0.64(s dhept,J=8.5,5.0Hz,1H),0.36(tt,J=9.1,4.8Hz,1H),-0.00(dq,J=9.5,5.3,4.7Hz,1H),-0.09(tt,J=9.7,4.8Hz,1H),-0.53(dq,J=9.7,4.9Hz,1H).

[0703] Example 69:

[0704]

[0705] Compound O (70 mg), N,N,2,2 - tetramethyl - 1,3 - propanediamine (20 mg), Pd 2 (dba) 3 (30 mg), 2 - (di - tert - butylphosphino)biphenyl (19 mg), potassium tert - butoxide (88 mg) were dispersed in tert - amyl alcohol (5 mL). The mixture was purged with nitrogen three times and reacted at 95 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 69 (10 mg). ESI - MS: m / z = 585.41 [M + H] + .

[0706] 1 H NMR(500MHz,DMSO - d 6)δ12.36(s,1H),8.33(s,1H),7.90(s,1H),7.54(d,J=1.3Hz,1H),7.32(d,J=9.0Hz,1H),6.80(s,1H),6.72–6.62(m,2H),4.29(q,J=7.7Hz,1H),4.22(dd,J=14.0,3.5Hz,1H),4.06–4.00(m,2H),3.73(s,3H),3.51(d,J=3.0Hz,1H),2.87(s,2H),2.54(s,3H),2.51(s,6H),2.03–1.95(m,4H),1.81(d,J=11.1Hz,1H),1.73–1.68(m,1H),0.96(s,6H),0.61–0.56(m,1H),0.30(dd,J=9.5,5.5Hz,1H),-0.00(m,1H),-0.14–-0.19(m,1H),-0.60(dd,J=9.5,4.9Hz,1H).

[0707] Example 70:

[0708]

[0709] Compound O (75 mg), 1-(3-aminopropyl)pyrrolidine (36 mg), Pd 2 (dba) 3 (32 mg), 2-(di-tert-butylphosphino)biphenyl (21 mg), potassium tert-butoxide (94 mg) were dispersed in tert-amyl alcohol (5 mL). The mixture was purged with nitrogen three times and reacted at 90 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 70 (20 mg). ESI-MS: m / z = 583.40 [M+H] + .

[0710] 11H NMR (500 MHz, chloroform-d) δ 12.09 (s, 1H), 8.41 (s, 1H), 8.15 (s, 1H), 7.71 (s, 1H), 7.14 (d, J = 8.6 Hz, 1H), 6.62 (d, J = 8.7 Hz, 1H), 6.49 (s, 1H), 4.41–4.31 (m, 2H), 3.93 (dq, J = 20.6, 6.0 Hz, 2H), 3.79 (s, 3H), 3.23 (q, J = 5.8 Hz, 2H), 2.96 (t, J = 5.9 Hz, 2H), 2.86 (s, 4H), 2.64 (s, 3H), 2.27 (d, J = 7.3 Hz, 1H), 2.21–2.14 (m, 2H), 2.00 (q, J = 7.0 Hz, 2H), 1.92 (s, 4H), 1.83–1.76 (m, 2H), 0.51 (s, 1H), 0.46–0.38 (m, 1H), 0.09 (t, J = 10.5 Hz, 1H), -0.02–-0.10 (m, 1H), -0.34 (dd, J = 9.4, 5.1 Hz, 1H).

[0711] Example 71:

[0712]

[0713] Compound O (100 mg), 1-(3-aminopropyl)piperidine (54 mg), Pd 2 (dba) 3 (35 mg), 2-(di-tert-butylphosphino)biphenyl (23 mg), potassium tert-butoxide (128 mg) were dispersed in tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 90 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 71 (19 mg). ESI-MS: m / z = 597.42 [M+H] + .

[0714] 1 1H NMR (500 MHz, DMSO-d 6)δ12.36(s,1H),8.34(s,1H),7.90(s,1H),7.55(d,J=1.2Hz,1H),7.32(d,J=8.8Hz,1H),6.73(d,J=2.3Hz,1H),6.56(dd,J=8.7,2.2Hz,1H),4.33–4.26(m,1H),4.22(dd,J=13.9,3.5Hz,1H),4.07–3.97(m,2H),3.73(s,3H),3.02(t,J=6.9Hz,2H),2.54(s,3H),2.35(t,J=7.0Hz,3H),2.32(s,2H),2.21(p,J=6.6,6.1Hz,1H),2.13(dq,J=9.5,4.3Hz,1H),1.98(dp,J=13.2,4.8,4.3Hz,1H),1.81(d,J=9.3Hz,1H),1.71(h,J=6.3,5.7Hz,3H),1.51(p,J=5.6Hz,4H),1.39(q,J=6.0Hz,2H),1.25(td,J=10.8,9.2,4.7Hz,1H),0.57(tdd,J=10.1,6.5,4.0Hz,1H),0.30(dp,J=9.4,4.6Hz,1H),-0.06(dq,J=9.5,4.8Hz,1H),-0.16(tt,J=9.5,4.6Hz,1H),-0.61(dq,J=9.7,4.9Hz,1H).

[0715] Example 72:

[0716]

[0717] Compound O (75 mg), 1-(2-aminoethyl)pyrrolidine (32 mg), Pd 2 (dba) 3 (32 mg), 2-(di-tert-butylphosphino)biphenyl (21 mg), potassium tert-butoxide (94 mg) were dispersed in tert-amyl alcohol (5 mL). The mixture was purged with nitrogen three times and reacted at 90 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 72 (16 mg). ESI-MS: m / z = 569.46 [M+H] + .

[0718] 11H NMR (500 MHz, chloroform-d) δ 12.09 (s, 1H), 8.41 (s, 1H), 8.15 (s, 1H), 7.71 (s, 1H), 7.14 (d, J = 8.6 Hz, 1H), 6.62 (d, J = 8.7 Hz, 1H), 6.49 (s, 1H), 4.41–4.31 (m, 2H), 3.93 (dq, J = 20.6, 6.0 Hz, 2H), 3.79 (s, 3H), 3.23 (q, J = 5.8 Hz, 2H), 2.96 (t, J = 5.9 Hz, 2H), 2.86 (s, 4H), 2.64 (s, 3H), 2.27 (d, J = 7.3 Hz, 1H), 2.21–2.14 (m, 2H), 1.92 (s, 4H), 1.83–1.76 (m, 2H), 0.51 (s, 1H), 0.46–0.38 (m, 1H), 0.09 (t, J = 10.5 Hz, 1H), -0.02–-0.10 (m, 1H), -0.34 (dd, J = 9.4, 5.1 Hz, 1H).

[0719] Example 73:

[0720]

[0721] Compound O (75 mg), 1-(2-aminoethyl)piperidine (36 mg), Pd 2 (dba) 3 (32 mg), 2-(di-tert-butylphosphino)biphenyl (21 mg), potassium tert-butoxide (94 mg) were dispersed in tert-amyl alcohol (5 mL). After purging with nitrogen three times, the mixture was reacted at 90 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 73 (31 mg). ESI-MS: m / z = 583.40 [M+H] + .

[0722] 11H NMR (500 MHz, chloroform-d) δ 12.17 (s, 1H), 8.57 (s, 1H), 8.42 (s, 1H), 8.16 (s, 1H), 7.75 (d, J = 1.4 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 6.65 (dd, J = 8.7, 2.1 Hz, 1H), 6.45 (d, J = 2.1 Hz, 1H), 4.35 (dd, J = 13.6, 3.9 Hz, 2H), 3.93 (ddt, J = 21.8, 13.8, 6.5 Hz, 2H), 3.79 (s, 3H), 3.18 (dq, J = 12.2, 6.7, 6.2 Hz, 2H), 2.95 (q, J = 6.8 Hz, 2H), 2.81 (s, 4H), 2.64 (s, 3H), 2.21 (ddt, J = 30.1, 22.6, 7.5 Hz, 3H), 1.80 (p, J = 5.9 Hz, 6H), 1.56 (s, 2H), 0.50 (d, J = 8.0 Hz, 1H), 0.42 (dq, J = 8.9, 4.7 Hz, 1H), 0.14–0.05 (m, 1H), -0.05 (dq, J = 10.0, 4.9 Hz, 1H), -0.35 (dq, J = 9.9, 5.1 Hz, 1H).

[0723] Example 74:

[0724]

[0725] Compound O (75 mg), N-(3-aminopropyl)morpholine (40 mg), Pd 2 (dba) 3 (32 mg), 2-(di-tert-butylphosphino)biphenyl (21 mg), potassium tert-butoxide (94 mg) were dispersed in tert-amyl alcohol (5 mL). The mixture was purged with nitrogen three times and reacted at 90 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 74 (31 mg). ESI-MS: m / z = 599.45 [M+H] + .

[0726] 11H NMR (500 MHz, chloroform-d) δ 12.03 (s, 1H), 8.44–8.38 (m, 1H), 8.15 (s, 1H), 7.68 (d, J = 1.3 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.58 (dd, J = 8.6, 2.1 Hz, 1H), 6.53 (d, J = 2.1 Hz, 1H), 4.40–4.32 (m, 2H), 3.94 (ddd, J = 16.7, 12.6, 6.5 Hz, 2H), 3.80 (d, J = 4.5 Hz, 4H), 3.78 (s, 3H), 3.16 (td, J = 6.4, 1.9 Hz, 2H), 2.64 (s, 3H), 2.62 (s, 2H), 2.60 (d, J = 7.1 Hz, 4H), 2.27 (q, J = 6.5 Hz, 1H), 2.20–2.11 (m, 2H), 1.87 (p, J = 6.6 Hz, 2H), 1.79 (td, J = 13.2, 12.2, 7.8 Hz, 2H), 0.51 (dq, J = 12.6, 3.6 Hz, 1H), 0.43 (dq, J = 8.8, 4.6 Hz, 1H), 0.10 (tt, J = 9.0, 5.2 Hz, 1H), -0.04 (q, J = 4.9 Hz, 1H), -0.33 (dq, J = 9.9, 5.1 Hz, 1H).

[0727] Example 75:

[0728]

[0729] (1) Preparation method of compound 75-a:

[0730] Disperse compound O (1.0 g), tert-butyl carbamate (437 mg), Pd 2 (dba) 3 (430 mg), 2-(di-tert-butylphosphino)biphenyl (280 mg), and potassium tert-butoxide (1.26 g) in tert-amyl alcohol (20 mL). Replace the atmosphere with nitrogen three times and react at 100 °C for 2 h until the reaction is complete. Add an aqueous sodium bicarbonate solution (1 M, 100 mL) to the reaction solution, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain compound 75-a (480 mg) by column chromatography. ESI-MS: m / z = 572.30 [M + H] + .

[0731] (2) Preparation method of compound 75-b:

[0732] Compound 75-a (480 mg) was dispersed in dichloromethane (10 mL). Trifluoroacetic acid (5 mL) was added dropwise at 25 °C. After the addition was complete, the mixture was reacted at 25 °C for 2 h. The reaction was completed. The reaction solution was concentrated. An aqueous sodium bicarbonate solution (1 M, 20 mL) and ethyl acetate (30 mL) were added to the concentrate. The layers were separated, and the organic phase was retained and concentrated until no more liquid flowed out to obtain compound 75-b (350 mg). ESI-MS: m / z = 472.31 [M+H] + 。

[0733] (3) Preparation method of Example 75:

[0734] Compound 75-b (30 mg) and N,N-dimethylglycine (7 mg) were dispersed in dichloromethane (5 mL). HATU (29 mg) and triethylamine (19 mg) were added successively. The mixture was reacted at 25 °C for 2 h. The reaction was completed. The reaction solution was washed with an aqueous sodium bicarbonate solution (1 M, 5 mL), dried over anhydrous sodium sulfate, and concentrated until no more liquid flowed out. It was purified by preparative liquid phase to obtain Example 75 (15 mg). ESI-MS: m / z = 557.32 [M+H] + 。

[0735] 1 1H NMR (500 MHz, DMSO-d 6 ) δ 9.84 (s, 1H), 8.36 (s, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.93 (s, 1H), 7.57 (dd, J = 8.7, 2.0 Hz, 1H), 7.50–7.37 (m, 2H), 4.32–4.25 (m, 2H), 4.9–4.01 (m, 2H), 3.75 (s, 3H), 3.13 (t, J = 7.1 Hz, 2H), 2.57 (s, 3H), 2.33 (s, 6H), 2.24 (q, J = 6.3 Hz, 1H), 2.14 (dt, J = 9.3, 4.9 Hz, 1H), 1.99 (td, J = 11.6, 8.9, 5.3 Hz, 1H), 1.86–1.70 (m, 2H), 0.60 (dq, J = 12.8, 7.9, 5.7 Hz, 1H), 0.37 (tt, J = 9.4, 4.8 Hz, 1H), -0.01 (dt, J = 9.8, 5.1 Hz, 1H), -0.05 (dp, J = 9.4, 4.7 Hz, 1H), -0.51 (dq, J = 9.6, 4.9 Hz, 1H).

[0736] Example 76:

[0737]

[0738] Compound 75-b (30 mg), 3-dimethylaminopropionic acid hydrochloride (9 mg) were dispersed in dichloromethane (5 mL). HATU (29 mg) and triethylamine (19 mg) were added successively, and the reaction was carried out at 25 °C for 2 h until the reaction was completed. The reaction solution was washed with an aqueous sodium bicarbonate solution (1 M, 5 mL), dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 76 (14 mg). ESI-MS: m / z = 571.35 [M+H] + 。

[0739] 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.68 (s, 1H), 10.15 (s, 1H), 8.35 (s, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.91 (s, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.44 (dd, J = 8.7, 2.0 Hz, 1H), 4.32–4.25 (m, 2H), 4.13–4.08 (m, 1H), 4.05–4.01 (m, 1H), 3.73 (s, 3H), 2.70 (t, J = 7.1 Hz, 2H), 2.55 (s, 3H), 2.52 (d, J = 7.0 Hz, 2H), 2.28 (s, 6H), 2.21 (q, J = 6.3 Hz, 1H), 2.14 (dt, J = 9.3, 4.9 Hz, 1H), 1.99 (td, J = 11.6, 8.9, 5.3 Hz, 1H), 1.82 (d, J = 10.1 Hz, 1H), 1.76–1.68 (m, 1H), 0.60 (dq, J = 12.8, 7.9, 5.7 Hz, 1H), 0.29 (tt, J = 9.4, 4.8 Hz, 1H), -0.06 (dt, J = 9.8, 5.1 Hz, 1H), -0.23 (dp, J = 9.4, 4.7 Hz, 1H), -0.68 (dq, J = 9.6, 4.9 Hz, 1H).

[0740] Example 77:

[0741]

[0742] Compound 75-b (30 mg), 4-dimethylaminobutyric acid hydrochloride (10 mg) were dispersed in dichloromethane (5 mL). HATU (29 mg) and triethylamine (19 mg) were added successively, and the reaction was carried out at 25 °C for 2 h until the reaction was completed. The reaction solution was washed with an aqueous sodium bicarbonate solution (1 M, 5 mL), dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 77 (15 mg). ESI-MS: m / z = 585.35 [M+H] + 。

[0743] 1 H NMR(500MHz,DMSO-d 6 )δ12.67(s,1H),10.03(s,1H),8.35(s,1H),7.93(d,J=1.9Hz,1H),7.91(s,1H),7.55(d,J=9.1Hz,2H),7.45(dd,J=8.7,2.0Hz,1H),4.32–4.24(m,2H),4.13–4.08(m,1H),4.04(dt,J=8.7,5.8Hz,1H),3.73(s,3H),2.55(s,3H),2.46(t,J=7.4Hz,2H),2.36(t,J=7.4Hz,2H),2.31(s,6H),2.21(t,J=6.4Hz,1H),2.14(d,J=6.0Hz,1H),2.03–1.96(m,1H),1.82(d,J=10.1Hz,1H),1.79(p,J=7.4Hz,2H),1.74–1.67(m,1H),0.60(dt,J=9.1,5.0Hz,1H),0.30(tt,J=9.3,4.8Hz,1H),-0.06(dq,J=9.7,4.9Hz,1H),-0.23(tt,J=9.5,4.8Hz,1H),-0.67(dq,J=9.6,4.8Hz,1H).

[0744] Example 78:

[0745]

[0746] Dissolve compound O (75 mg), 4-(2-aminoethyl)tetrahydropyran (36 mg), Pd 2 (dba) 3 (32 mg), 2-(di-tert-butylphosphino)biphenyl (21 mg), and potassium tert-butoxide (94 mg) in tert-amyl alcohol (5 mL). Replace the atmosphere with nitrogen three times and react at 90 °C for 2 h until the reaction is complete. Add an aqueous sodium bicarbonate solution (1 M, 20 mL) to the reaction solution, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and purify by preparative liquid chromatography to obtain Example 78 (19 mg). ESI-MS: m / z = 584.44 [M+H] + .

[0747] 11H NMR (500 MHz, chloroform-d) δ 11.97 (s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 7.66 (d, J = 1.2 Hz, 1H), 7.16 (d, J = 8.6 Hz, 1H), 6.58 (dd, J = 8.6, 2.2 Hz, 1H), 6.55 (d, J = 2.1 Hz, 1H), 4.35 (ddd, J = 11.4, 5.6, 3.0 Hz, 2H), 4.02–3.91 (m, 4H), 3.78 (s, 3H), 3.41 (td, J = 11.8, 1.9 Hz, 2H), 3.16 (t, J = 7.2 Hz, 2H), 2.64 (s, 3H), 2.33–2.24 (m, 1H), 2.23–2.13 (m, 2H), 1.80–1.77 (m, 1H), 1.68–1.61 (m, 8H), 0.56–0.49 (m, 1H), 0.44 (dq, J = 9.3, 4.8 Hz, 1H), 0.11 (tt, J = 9.1, 5.1 Hz, 1H), -0.03 (dd, J = 10.1, 5.3 Hz, 1H), -0.31 (dq, J = 10.0, 5.2 Hz, 1H).

[0748] Example 79:

[0749]

[0750] Compound O (75 mg), cyclobutylamine (20 mg), Pd 2 (dba) 3 (32 mg), 2-(di-tert-butylphosphino)biphenyl (21 mg), potassium tert-butoxide (94 mg) were dispersed in tert-amyl alcohol (5 mL). The mixture was purged with nitrogen three times and reacted at 90 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The residue was purified by preparative liquid chromatography to obtain Example 79 (30 mg). ESI-MS: m / z = 526.39 [M+H] + .

[0751] 11H NMR (500 MHz, chloroform-d) δ 12.25 (s, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.91 (s, 1H), 7.57 (s, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.03–6.96 (m, 1H), 4.41 (d, J = 13.9 Hz, 1H), 4.23 (d, J = 7.7 Hz, 1H), 4.09 (d, J = 7.9 Hz, 1H), 3.94 (d, J = 8.0 Hz, 1H), 3.88 (s, 3H), 2.49 (s, 3H), 2.33 (d, J = 25.2 Hz, 4H), 2.30–2.21 (m, 3H), 1.94 (q, J = 10.2 Hz, 3H), 1.75 (dt, J = 16.3, 7.9 Hz, 2H), 0.54–0.46 (m, 1H), 0.35 (dd, J = 9.2, 4.6 Hz, 1H), -0.12 (d, J = 3.0 Hz, 1H), -0.20 (dt, J = 9.8, 4.9 Hz, 1H), -0.65 (s, 1H).

[0752] Example 80:

[0753]

[0754] Compound O-2 (50 mg), 1-(3-aminopropyl)piperidine (16 mg), Pd 2 (dba) 3 (20 mg), 2-(di-tert-butylphosphino)biphenyl (13 mg), potassium tert-butoxide (61 mg) were dispersed in tert-amyl alcohol (12 mL). The mixture was purged with nitrogen three times and reacted at 95 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 80 (25 mg). ESI-MS: m / z = 597.45 [M+H] + .

[0755] 1 1H NMR (500 MHz, DMSO-d 6)δ12.37(s,1H),8.34(s,1H),7.91(s,1H),7.54(d,J=1.2Hz,1H),7.25(d,J=8.6Hz,1H),6.68(d,J=2.1Hz,1H),6.53(dd,J=8.6,2.0Hz,1H),4.28(td,J=8.6,6.2Hz,1H),4.22(dd,J=14.0,3.6Hz,1H),4.08–4.01(m,2H),3.73(s,3H),3.07(t,J=6.8Hz,2H),2.54(s,3H),2.36(t,J=7.1Hz,2H),2.33–2.29(m,3H),2.22(p,J=6.7,6.3Hz,1H),2.13(tt,J=8.6,4.8Hz,1H),2.00(ddt,J=13.7,8.9,3.9Hz,1H),1.87–1.79(m,1H),1.72(p,J=7.1Hz,3H),1.50(h,J=5.1,4.6Hz,4H),1.39(q,J=5.9Hz,2H),1.26(dt,J=17.5,4.6Hz,1H),0.65–0.55(m,1H),0.32(tt,J=9.3,4.6Hz,1H),-0.04(dt,J=9.4,4.7Hz,1H),-0.11(dp,J=9.3,4.5Hz,1H),-0.55(dq,J=9.6,4.8Hz,1H).

[0756] Example 81:

[0757]

[0758] Compound O-2 (70 mg), N-(3-aminopropyl)morpholine (22 mg), Pd 2 (dba) 3 (30 mg), 2-(di-tert-butylphosphino)biphenyl (20 mg), potassium tert-butoxide (88 mg) were dispersed in tert-amyl alcohol (5 mL). After purging with nitrogen three times, the mixture was reacted at 95 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 81 (37 mg). ESI-MS: m / z = 599.42 [M+H] + .

[0759] 1 H NMR (500 MHz, DMSO-d 6)δ12.30(s,1H),7.91(s,1H),7.54(s,1H),7.25(d,J=8.5Hz,1H),6.69(d,J=2.0Hz,1H),6.53(dd,J=8.5,2.1Hz,1H),4.29(q,J=7.8Hz,1H),4.22(dd,J=14.1,3.6Hz,1H),4.09–4.01(m,2H),3.73(s,3H),3.58(t,J=4.5Hz,4H),3.09(t,J=6.8Hz,2H),2.54(s,3H),2.43–2.30(m,6H),2.25–2.20(m,1H),2.13(dq,J=14.5,7.8,6.2Hz,1H),2.04–1.96(m,1H),1.83(d,J=9.7Hz,1H),1.73(p,J=7.3Hz,3H),0.60(tt,J=8.5,3.6Hz,1H),0.32(dp,J=9.1,4.6Hz,1H),-0.04(dt,J=9.8,4.7Hz,1H),-0.12(tt,J=9.3,4.6Hz,1H),-0.56(dq,J=9.7,4.8Hz,1H).

[0760] Example 82:

[0761]

[0762] Compound O-2 (75 mg), 1-(2-aminoethyl)pyrrolidine (32 mg), Pd 2 (dba) 3 (32 mg), 2-(di-tert-butylphosphino)biphenyl (21 mg), potassium tert-butoxide (94 mg) were dispersed in tert-amyl alcohol (5 mL). The mixture was purged with nitrogen three times and reacted at 90 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 82 (25 mg). ESI-MS: m / z = 569.40 [M+H] + 。

[0763] 1 H NMR (500 MHz, DMSO-d 6)δ12.44(s,1H),8.39(s,1H),8.30(s,1H),7.96(s,1H),7.59(s,1H),7.31(d,J=8.6Hz,1H),6.83(s,1H),6.61(dd,J=8.5,2.0Hz,1H),4.34(d,J=7.8Hz,1H),4.27(dd,J=13.9,3.6Hz,1H),4.13–4.07(m,2H),3.78(s,3H),3.29(t,J=6.7Hz,2H),2.83(t,J=6.6Hz,2H),2.71(d,J=5.9Hz,4H),2.59(s,3H),2.26(q,J=6.8Hz,1H),2.18(tt,J=8.9,4.8Hz,1H),2.05(ddd,J=13.9,9.2,5.0Hz,1H),1.91–1.86(m,1H),1.80(q,J=3.4,3.0Hz,4H),1.75(d,J=14.2Hz,1H),0.67(tt,J=8.5,3.7Hz,1H),0.37(tt,J=9.4,4.9Hz,1H),0.00(dq,J=9.7,5.1Hz,1H),-0.08(dq,J=8.9,4.6Hz,1H),-0.53(dq,J=9.8,4.8Hz,1H).

[0764] Example 83:

[0765]

[0766] Compound O-2 (60 mg), 1-(2-aminoethyl)piperidine (18 mg), Pd 2 (dba) 3 (25 mg), 2-(di-tert-butylphosphino)biphenyl (16 mg), potassium tert-butoxide (74 mg) were dispersed in tert-amyl alcohol (15 mL). The mixture was purged with nitrogen three times and reacted at 95 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The product was purified by preparative liquid chromatography to obtain Example 83 (25 mg). ESI-MS: m / z = 583.41 [M+H] + .

[0767] 1 H NMR (500 MHz, DMSO-d 6)δ12.38(s,1H),8.34(s,1H),7.91(s,1H),7.54(s,1H),7.26(d,J=8.6Hz,1H),6.77(d,J=2.1Hz,1H),6.56(dd,J=8.6,2.0Hz,1H),4.30–4.27(m,1H),4.24–4.20(m,1H),4.05(dt,J=9.1,4.5Hz,2H),3.73(s,3H),3.20(t,J=6.7Hz,2H),2.58(t,J=6.7Hz,2H),2.54(s,3H),2.28(d,J=6.6Hz,1H),2.21(q,J=6.6,6.1Hz,1H),2.17–2.11(m,1H),2.02–1.98(m,1H),1.84(q,J=7.5Hz,1H),1.72(d,J=13.5Hz,1H),1.55(p,J=5.6Hz,4H),1.44–1.39(m,3H),1.24(dd,J=6.2,3.6Hz,2H),0.61(qd,J=10.4,8.3,5.1Hz,1H),0.31(dp,J=8.7,4.6Hz,1H),-0.03–-0.07(m,1H),-0.13(tt,J=9.2,4.5Hz,1H),-0.58(dq,J=9.6,4.9Hz,1H).

[0768] Example 84:

[0769]

[0770] Compound O-2 (50 mg), 1-(3-aminopropyl)pyrrolidine (14 mg), Pd 2 (dba) 3 (20 mg), 2-(di-tert-butylphosphino)biphenyl (13 mg), potassium tert-butoxide (61 mg) were dispersed in tert-amyl alcohol (12 mL). The mixture was purged with nitrogen three times and reacted at 95 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 84 (25 mg). ESI-MS: m / z = 583.41 [M+H] + .

[0771] 1 H NMR (500 MHz, DMSO-d 6)δ12.40(s,1H),8.36(s,1H),8.25(s,1H),7.99(s,1H),7.59(s,1H),7.36(d,J=8.6Hz,1H),6.80(s,1H),6.55(dd,J=8.5,2.0Hz,1H),4.37(d,J=7.8Hz,1H),4.29(dd,J=13.9,3.6Hz,1H),4.17–4.01(m,2H),3.77(s,3H),3.25(t,J=6.7Hz,2H),2.80(t,J=6.6Hz,2H),2.71(d,J=5.9Hz,4H),2.55(s,3H),2.28(q,J=6.8Hz,1H),2.20(tt,J=8.9,4.8Hz,1H),2.15(q,J=7.0Hz,2H),2.03(ddd,J=13.9,9.2,5.0Hz,1H),1.91–1.86(m,1H),1.80(q,J=3.4,3.0Hz,4H),1.75(d,J=14.2Hz,1H),0.67(tt,J=8.5,3.7Hz,1H),0.37(tt,J=9.4,4.9Hz,1H),0.00(dq,J=9.7,5.1Hz,1H),-0.08(dq,J=8.9,4.6Hz,1H),-0.53(dq,J=9.8,4.8Hz,1H).

[0772] Example 85:

[0773]

[0774] (1) Preparation method of compound 85-a:

[0775] Disperse compound BOC-N-methyl-L-alanine (10.0 g) in dichloromethane (150 mL), and successively add dimethylamine hydrochloride (6.0 g), HATU (20.6 g) and N,N-diisopropylethylamine (19.1 g), and react at 25 °C for 16 h. TLC shows that the reaction is complete; wash the reaction solution with an aqueous solution of NaHCO 3 (1 M, 100 mL * 2), retain the organic phase, dry and evaporate to dryness, and obtain compound 85-a (9.3 g) by column chromatography.

[0776] (2) Preparation method of compound 85-b:

[0777] Disperse compound 85-a (9.3 g) in tetrahydrofuran (120 mL), cool down to 0 - 5 °C, and keep the temperature while dropwise adding LiAlH 4A tetrahydrofuran solution (1 M, 101 mL) was reacted at 0 - 5 °C for 2 h. TLC indicated the completion of the reaction. Water (10 mL), an aqueous NaOH solution (15%, 10 mL), and water (30 mL) were successively added dropwise to the reaction solution. After filtration, the filtrate was dried and evaporated to dryness, and compound 85-b (4.6 g) was obtained by column chromatography.

[0778] (3) Preparation method of compound 85-c:

[0779] Compound 85-b (4.6 g) was dispersed in a hydrogen chloride / 1,4-dioxane solution (4 M, 53 mL) and reacted at 25 °C for 16 h. TLC indicated the completion of the reaction. The reaction solution was concentrated, ethyl acetate (50 mL) was added, and the mixture was stirred at 25 °C for 1 h. After filtration, the filter cake was dried to obtain compound 85-c (2.50 g).

[0780] (4) Preparation method of Example 85:

[0781] Compound O-2 (100 mg), compound 85-c (25 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), and potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 85 (10 mg). ESI-MS: m / z = 571.35 [M + H] + 。

[0782] 1 1H NMR (500 MHz, DMSO-d 6)δ12.55(s,1H),8.41(s,1H),7.96(s,1H),7.60(s,1H),7.47(d,J=8.8Hz,1H),7.25(d,J=2.3Hz,1H),6.96(dd,J=8.9,2.3Hz,1H),4.53–4.44(m,1H),4.37(dt,J=8.6,4.4Hz,1H),4.33–4.23(m,2H),4.08(dt,J=8.9,5.7Hz,1H),3.78(s,3H),3.54(dd,J=13.5,10.7Hz,1H),3.20(dd,J=13.7,4.3Hz,1H),2.86(s,6H),2.77(s,3H),2.60(s,3H),2.33–2.25(m,1H),2.20(tq,J=8.9,4.5Hz,1H),2.08(ddd,J=15.5,10.2,6.0Hz,1H),1.90(td,J=9.2,4.8Hz,1H),1.83–1.73(m,1H),1.06(d,J=6.5Hz,3H),0.69(tq,J=8.4,4.3,3.4Hz,1H),0.35(tt,J=9.2,4.7Hz,1H),-0.00(dq,J=9.6,5.0Hz,1H),-0.19(tt,J=9.3,4.7Hz,1H),-0.61(dq,J=9.6,4.9Hz,1H).

[0783] Example 86:

[0784]

[0785] (1) Preparation method of compound 86-a:

[0786] Disperse compound BOC-N-methyl-D-alanine (10.0 g) in dichloromethane (150 mL), and successively add dimethylamine hydrochloride (6.0 g), HATU (20.6 g) and N,N-diisopropylethylamine (19.1 g) and react at 25 °C for 16 h. TLC shows that the reaction is complete; wash the reaction solution with an aqueous solution of NaHCO 3 (1M, 100 mL * 2), retain the organic phase, dry and evaporate to dryness, and obtain compound 86-a (8.9 g) by column chromatography.

[0787] (2) Preparation method of compound 86-b:

[0788] Disperse compound 86-a (8.9 g) in tetrahydrofuran (100 mL), cool down to 0-5 °C, and keep the temperature and dropwise add LiAlH 4A tetrahydrofuran solution (1 M, 103 mL) was reacted at 0 - 5 °C for 2 h. TLC indicated the completion of the reaction. Water (7 mL), NaOH aqueous solution (15%, 7 mL), and water (21 mL) were successively added dropwise to the reaction solution. After filtration, the filtrate was dried and then evaporated to dryness. Compound 86-b (4.2 g) was obtained by column chromatography.

[0789] (3) Preparation method of compound 86-c:

[0790] Compound 86-b (4.2 g) was dispersed in a hydrogen chloride / 1,4-dioxane solution (4 M, 52 mL) and reacted at 25 °C for 16 h. TLC indicated the completion of the reaction. The reaction solution was concentrated, ethyl acetate (40 ml) was added, and the mixture was stirred at 25 °C for 1 h. After filtration, the filter cake was dried to obtain compound 86-c (2.0 g). (4) Preparation method of Example 86:

[0791] Compound O-2 (100 mg) from Example 8, compound 86-c (25 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), and potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (3 mL). The system was purged with nitrogen three times and reacted at 100 °C for 2 h until the reaction was completed. An aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no more liquid flowed out, and purified by preparative liquid phase to obtain Example 86 (11 mg). ESI-MS: m / z = 571.35 [M + H] + 。

[0792] Example 87:

[0793]

[0794] Compound O-2 (60 mg), cyclopentylamine (12 mg), Pd 2 (dba) 3 (25 mg), 2-(di-tert-butylphosphino)biphenyl (16 mg), and potassium tert-butoxide (74 mg) were dispersed in tert-amyl alcohol (17 mL). The system was purged with nitrogen three times and reacted at 95 °C for 2 h until the reaction was completed. An aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no more liquid flowed out, and purified by preparative liquid phase to obtain Example 87 (25 mg). ESI-MS: m / z = 540.45 [M + H] + 。

[0795] 1 1H NMR (500 MHz, DMSO-d 6)δ12.36(s,1H),8.34(d,J=1.2Hz,1H),7.90(s,1H),7.54(d,J=1.2Hz,1H),7.23(d,J=8.6Hz,1H),6.68(d,J=2.0Hz,1H),6.53(dd,J=8.6,2.0Hz,1H),5.57(s,1H),4.28(td,J=8.5,6.1Hz,1H),4.23(dd,J=13.9,3.6Hz,1H),4.08–4.00(m,2H),3.76(t,J=6.4Hz,1H),3.73(s,3H),2.54(s,3H),2.27–2.19(m,1H),2.13(tt,J=8.7,4.9Hz,1H),1.98(dddd,J=23.9,12.4,6.1,1.9Hz,3H),1.80(dq,J=9.1,4.5Hz,1H),1.70(dp,J=21.0,7.3,6.3Hz,3H),1.57(qd,J=7.7,3.5Hz,2H),1.51–1.39(m,2H),0.65–0.57(m,1H),0.33(tt,J=9.1,4.6Hz,1H),-0.04(dt,J=9.5,4.7Hz,1H),-0.10(td,J=8.6,4.3Hz,1H),-0.55(dq,J=9.5,4.8Hz,1H).

[0796] Example 88:

[0797]

[0798] Compound O (75 mg), 3-(trifluoromethyl)oxetan-3-amine (50 mg), Pd 2 (dba) 3 (32 mg), 2-(di-tert-butylphosphino)biphenyl (21 mg), potassium tert-butoxide (94 mg) were dispersed in tert-amyl alcohol (5 mL). After purging with nitrogen three times, the mixture was reacted at 90 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 88 (6 mg). ESI-MS: m / z = 596.20 [M+H] + .

[0799] 11H NMR (500 MHz, chloroform-d) δ 12.01 (s, 1H), 8.39 (d, J = 1.4 Hz, 1H), 8.15 (s, 1H), 7.65 (d, J = 1.4 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 6.54–6.47 (m, 2H), 4.95 (dd, J = 7.1, 1.2 Hz, 2H), 4.83 (d, J = 7.0 Hz, 2H), 4.35 (tt, J = 13.5, 4.8 Hz, 2H), 3.96 (dt, J = 8.4, 5.8 Hz, 2H), 3.78 (s, 3H), 3.35–3.27 (m, 2H), 2.64 (s, 3H), 2.26 (dt, J = 14.0, 6.1 Hz, 1H), 2.18 (td, J = 11.9, 11.0, 4.7 Hz, 2H), 0.52 (dt, J = 12.7, 5.6 Hz, 1H), 0.46 (dq, J = 8.2, 4.4, 3.5 Hz, 1H), 0.15–0.09 (m, 1H), -0.01 (d, J = 8.2 Hz, 1H), -0.31 (dq, J = 9.9, 5.1 Hz, 1H).

[0800] Example 89:

[0801]

[0802] Compound O (75 mg), 1-(3-methyloxetan-3-yl)ethan-1-amine hemioxalate (32 mg), Pd 2 (dba) 3 (32 mg), 2-(di-tert-butylphosphino)biphenyl (21 mg), potassium tert-butoxide (94 mg) were dispersed in tert-amyl alcohol (5 mL). The mixture was purged with nitrogen three times and reacted at 90 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 89 (16 mg). ESI-MS: m / z = 570.44 [M+H] + .

[0803] 11H NMR (500 MHz, chloroform-d) δ 11.95 (s, 1H), 8.40 (s, 1H), 8.16 (s, 1H), 7.67 (s, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.67–6.59 (m, 2H), 4.60 (dd, J = 6.2, 1.7 Hz, 1H), 4.55 (dd, J = 6.0, 2.6 Hz, 1H), 4.38 (dd, J = 6.2, 1.7 Hz, 2H), 4.36–4.33 (m, 1H), 3.95 (dt, J = 14.2, 7.5 Hz, 2H), 3.84 (q, J = 6.5 Hz, 1H), 3.78 (s, 3H), 3.72 (q, J = 7.0 Hz, 2H), 2.65 (s, 3H), 2.27 (q, J = 7.6 Hz, 1H), 2.19 (ddd, J = 12.3, 8.6, 5.3 Hz, 2H), 1.85–1.79 (m, 1H), 1.39 (s, 3H), 1.12 (dd, J = 6.4, 2.7 Hz, 3H), 0.58–0.49 (m, 1H), 0.45 (tt, J = 8.8, 4.2 Hz, 1H), 0.13 (tt, J = 8.9, 4.8 Hz, 1H), -0.00–-0.04 (m, 1H), -0.29 (dt, J = 9.5, 4.9 Hz, 1H).

[0804] Example 90:

[0805]

[0806] Compound O (75 mg), 3-ethyloxetan-3-amine hydrochloride (39 mg), Pd 2 (dba) 3 (32 mg), 2-(di-tert-butylphosphino)biphenyl (21 mg), and potassium tert-butoxide (94 mg) were dispersed in tert-amyl alcohol (5 mL). The mixture was purged with nitrogen three times and reacted at 90 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The product was purified by preparative liquid chromatography to obtain Example 90 (10 mg). ESI-MS: m / z = 556.42 [M+H] + .

[0807] 11H NMR (500 MHz, chloroform-d) δ 11.96 (s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 7.65 (s, 1H), 7.17 (d, J = 8.6 Hz, 1H), 6.45 (dd, J = 8.6, 2.2 Hz, 1H), 6.39 (d, J = 2.2 Hz, 1H), 4.77 (dd, J = 6.1, 2.7 Hz, 2H), 4.62 (d, J = 6.0 Hz, 2H), 4.34 (td, J = 13.0, 12.1, 5.3 Hz, 2H), 3.95 (dt, J = 18.1, 6.5 Hz, 2H), 3.78 (s, 3H), 2.64 (s, 3H), 2.28 (t, J = 6.9 Hz, 1H), 2.15 (dd, J = 13.9, 6.7 Hz, 3H), 1.82 (t, J = 7.5 Hz, 1H), 1.74 (s, 2H), 0.91 (t, J = 7.3 Hz, 3H), 0.52 (dq, J = 8.4, 4.2, 3.3 Hz, 1H), 0.46 (dq, J = 8.7, 4.4 Hz, 1H), 0.15 (tt, J = 9.4, 5.2 Hz, 1H), -0.02 (d, J = 5.2 Hz, 1H), -0.27 (dt, J = 9.6, 5.1 Hz, 1H).

[0808] Example 91:

[0809]

[0810] Compound O (75 mg), (2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidine hydrochloride (56 mg), Pd 2 (dba) 3 (32 mg), 2-(di-tert-butylphosphino)biphenyl (21 mg), and potassium tert-butoxide (94 mg) were dispersed in tert-amyl alcohol (5 mL). The mixture was purged with nitrogen three times and reacted at 90 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. The product of Example 91 (31 mg) was obtained by preparative liquid chromatography purification. ESI-MS: m / z = 618.39 [M+H] + 。

[0811] 11H NMR (500 MHz, chloroform-d) δ 12.01 (s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 7.67 (s, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.47 (dt, J = 8.5, 2.5 Hz, 1H), 6.44 (q, J = 2.8 Hz, 1H), 4.35 (td, J = 11.9, 9.8, 5.1 Hz, 2H), 4.25 (q, J = 8.0 Hz, 1H), 3.93 (dq, J = 14.0, 5.3, 4.5 Hz, 3H), 3.78 (s, 3H), 3.46 (dt, J = 14.0, 7.2 Hz, 1H), 3.28 (dq, J = 13.7, 5.7, 4.5 Hz, 2H), 3.00–2.96 (m, 1H), 2.95 (s, 3H), 2.63 (s, 3H), 2.27 (q, J = 6.4 Hz, 1H), 2.17 (dd, J = 16.8, 11.7 Hz, 2H), 1.79 (d, J = 15.3 Hz, 2H), 1.59 (d, J = 6.0 Hz, 3H), 0.56–0.48 (m, 1H), 0.43 (tt, J = 9.0, 5.0 Hz, 1H), 0.09 (tt, J = 9.1, 5.1 Hz, 1H), -0.04 (dt, J = 9.9, 4.8 Hz, 1H), -0.34 (dq, J = 9.9, 5.1 Hz, 1H).

[0812] Example 92:

[0813]

[0814] Compound O (75 mg), (3-ethyloxetan-3-yl)methanamine (32 mg), Pd 2 (dba) 3 (32 mg), 2-(di-tert-butylphosphino)biphenyl (21 mg), potassium tert-butoxide (94 mg) were dispersed in tert-amyl alcohol (5 mL). The mixture was purged with nitrogen three times and reacted at 90 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 92 (10 mg). ESI-MS: m / z = 570.20 [M + H] + .

[0815] 11H NMR (500 MHz, chloroform-d) δ 12.02 (s, 1H), 8.42 (s, 1H), 8.18 (s, 1H), 7.68 (s, 1H), 7.18 (d, J = 8.5 Hz, 1H), 6.65 (dd, J = 8.6, 2.2 Hz, 1H), 6.61 (d, J = 2.2 Hz, 1H), 4.51 (s, 4H), 4.35 (td, J = 12.0, 10.3, 5.2 Hz, 2H), 3.95 (dq, J = 9.3, 5.5 Hz, 2H), 3.79 (s, 3H), 3.31 (s, 2H), 2.65 (s, 3H), 2.21 (dtt, J = 30.7, 11.8, 5.6 Hz, 4H), 1.83–1.81 (m, 1H), 1.32 (d, J = 11.2 Hz, 1H), 0.95 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 6.8 Hz, 1H), 0.52 (tt, J = 8.6, 3.9 Hz, 1H), 0.44 (tt, J = 9.2, 5.0 Hz, 1H), 0.11 (tt, J = 9.2, 5.1 Hz, 1H), -0.00–-0.08 (m, 1H), -0.32 (dq, J = 10.1, 5.2 Hz, 1H).

[0816] Example 93:

[0817]

[0818] Compound O (75 mg), N 1 ,N 1 -dimethylcyclobutane-1,3-diamine (32 mg), Pd 2 (dba) 3 (32 mg), 2-(di-tert-butylphosphino)biphenyl (21 mg), potassium tert-butoxide (94 mg) were dispersed in tert-amyl alcohol (5 mL). After purging with nitrogen three times, the mixture was reacted at 90 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 93 (25 mg). ESI-MS: m / z = 569.43 [M+H] + .

[0819] 1 1H NMR (500 MHz, Methanol-d 4)δ8.46(s,1H),8.37(d,J=2.6Hz,1H),8.02(s,1H),7.57(t,J=8.5Hz,1H),7.26(t,J=9.6Hz,1H),6.67–6.57(m,2H),4.31(td,J=18.0,16.6,11.1Hz,2H),4.10–3.86(m,3H),3.74(s,3H),3.40(t,J=8.1Hz,1H),2.94–2.84(m,1H),2.76(d,J=10.0Hz,6H),2.68–2.61(m,1H),2.55(s,3H),2.38(dt,J=14.3,5.2Hz,1H),2.20(s,2H),2.05(dt,J=19.5,10.0Hz,2H),1.87–1.70(m,2H),0.51(d,J=8.5Hz,1H),0.34(dq,J=8.8,4.7Hz,1H),-0.11(dt,J=18.2,7.7Hz,2H),-0.58(dt,J=10.0,5.3Hz,1H).

[0820] Example 94:

[0821]

[0822] Compound O (75 mg), 3-fluorocyclobutanamine (25 mg), Pd 2 (dba) 3 (32 mg), 2-(di-tert-butylphosphino)biphenyl (21 mg), potassium tert-butoxide (94 mg) were dispersed in tert-amyl alcohol (5 mL). After purging with nitrogen three times, the mixture was reacted at 90 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 94 (15 mg). ESI-MS: m / z = 544.36 [M+H] + .

[0823] 1 H NMR (500 MHz, Methanol-d 4)δ8.46(s,1H),8.15(s,1H),7.70(d,J=4.5Hz,1H),7.31(d,J=8.6Hz,1H),6.71(d,J=8.3Hz,1H),6.67(s,1H),5.35(ddt,J=56.3,6.6,2.5Hz,1H),4.47–4.30(m,2H),4.19–4.05(m,2H),3.95(t,J=11.1Hz,1H),3.85(s,3H),2.73(ddd,J=19.7,10.0,6.0Hz,2H),2.66(s,3H),2.51–2.39(m,2H),2.34–2.24(m,2H),2.15–2.03(m,1H),1.85(s,2H),0.67–0.53(m,1H),0.44(d,J=8.5Hz,1H),0.01(q,J=6.7,6.1Hz,2H),-0.46(q,J=6.2,5.6Hz,1H).

[0824] Example 95:

[0825]

[0826] Compound O (100 mg), 3,3-difluorocyclobutanamine (55 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 90 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 95 (18 mg). ESI-MS: m / z = 562.36 [M+H] + .

[0827] 1 H NMR (500 MHz, Methanol-d 4)δ8.32(s,1H),8.01(s,1H),7.55(s,1H),7.26–7.16(m,1H),6.60(d,J=8.2Hz,2H),4.33–4.26(m,1H),4.22(s,1H),3.95(s,1H),3.88–3.74(m,2H),3.71(s,3H),3.01(dt,J=13.7,7.1Hz,2H),2.53(s,3H),2.45(d,J=14.7Hz,2H),2.22–2.09(m,2H),1.96(s,1H),1.72(s,2H),0.46(s,1H),0.31(d,J=8.8Hz,1H),-0.08–-0.19(m,2H),-0.54–-0.64(m,1H).

[0828] Example 96:

[0829]

[0830] Compound O (100 mg), 3,3-difluorocyclopentylamine (46 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 90 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 96 (30 mg). ESI-MS: m / z = 576.38 [M+H] + .

[0831] 1 H NMR (500 MHz, Methanol-d 4)δ8.35(s,1H),8.02(s,1H),7.58(s,1H),7.20(d,J=8.4Hz,1H),6.72–6.59(m,2H),4.30(q,J=7.5,6.9Hz,1H),4.23(d,J=12.6Hz,1H),4.02–3.89(m,2H),3.85(s,1H),3.72(s,3H),2.59(s,1H),2.54(s,3H),2.32–2.22(m,2H),2.21–2.06(m,3H),1.98(dt,J=15.1,7.3Hz,2H),1.74(dt,J=24.0,10.6Hz,3H),0.47(s,1H),0.32(d,J=9.3Hz,1H),-0.12(t,J=6.6Hz,2H),-0.58(s,1H).

[0832] Example 97:

[0833]

[0834] Compound O (100 mg), 4,4-difluorocyclohexylamine (51 mg), Pd 2 (dba) 3 (35 mg), 2-(di-tert-butylphosphino)biphenyl (23 mg), potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (3 mL), purged with nitrogen three times, and reacted at 90 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 97 (38 mg). ESI-MS: m / z = 590.42 [M+H] + .

[0835] 1 H NMR (500 MHz, Methanol-d 4)δ8.47(s,1H),8.15(s,1H),7.70(s,1H),7.30(d,J=8.6Hz,1H),6.86–6.75(m,2H),4.42(q,J=8.4,7.4Hz,1H),4.33(d,J=12.9Hz,1H),4.09(q,J=6.4Hz,1H),3.96(t,J=12.0Hz,1H),3.84(s,3H),3.48(d,J=11.6Hz,1H),2.66(s,3H),2.35–2.25(m,2H),2.23–2.14(m,4H),2.02(dt,J=42.9,13.2Hz,3H),1.84(s,2H),1.69(d,J=12.0Hz,2H),0.58(d,J=12.3Hz,1H),0.44(q,J=7.3,6.1Hz,1H),0.04–-0.05(m,2H),-0.45(q,J=6.6Hz,1H).

[0836] Example 98:

[0837]

[0838] Compound O-2 (100 mg), N 1 ,N 1 -dimethylcyclobutane-1,3-diamine (25 mg), Pd 2 (dba) 3 (18 mg), 2-(di-tert-butylphosphino)biphenyl (16 mg), potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (4 mL), purged with nitrogen three times, and reacted at 95 °C for 3 h. After the reaction was completed; water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 98 (13 mg). ESI-MS: m / z = 569.43 [M+H] + .

[0839] 1 1H NMR (500 MHz, DMSO-d 6)δ12.37(s,1H),8.33(s,1H),8.22(s,1H),7.90(s,1H),7.54(s,1H),7.24(d,J=8.5Hz,1H),6.64(d,J=2.1Hz,1H),6.50(dd,J=8.6,2.1Hz,1H),4.29(d,J=7.1Hz,1H),4.22(dd,J=14.0,3.7Hz,1H),4.04(td,J=9.1,4.0Hz,2H),3.73(s,3H),2.63–2.56(m,2H),2.54(s,3H),2.43–2.39(m,1H),2.22(dd,J=12.8,6.6Hz,1H),2.14(q,J=5.4,4.8Hz,1H),2.06(s,6H),2.00–1.97(m,1H),1.81(d,J=8.6Hz,1H),1.77–1.69(m,1H),1.66–1.55(m,2H),1.46(t,J=7.3Hz,1H),0.61(tt,J=8.4,3.5Hz,1H),0.33(dq,J=9.0,4.8Hz,1H),-0.05(dq,J=9.4,4.8Hz,1H),-0.14(tt,J=9.4,4.6Hz,1H),-0.58(dq,J=9.7,4.9Hz,1H).

[0840] Example 99:

[0841]

[0842] Compound O-2 (100 mg), cis-N 1 ,N 1 -dimethylcyclohexane-1,4-diamine dihydrochloride (48 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (4 mL). The mixture was purged with nitrogen three times and reacted at 95 °C for 3 h. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 99 (15 mg). ESI-MS: m / z = 597.49 [M+H] + .

[0843] 1 1H NMR (500 MHz, DMSO-d 6)δ12.40(s,1H),8.38(s,1H),8.31(s,1H),7.95(s,1H),7.58(d,J=1.1Hz,1H),7.28(d,J=8.6Hz,1H),6.79(d,J=2.0Hz,1H),6.66(dd,J=8.7,2.0Hz,1H),4.32(dd,J=8.9,2.8Hz,1H),4.26(dd,J=14.0,3.7Hz,1H),4.11–4.04(m,2H),3.77(s,3H),2.58(s,3H),2.39–2.36(m,1H),2.33(s,6H),2.26(q,J=6.7,6.2Hz,1H),2.17(dq,J=9.1,4.7,3.9Hz,1H),2.04(dq,J=14.9,5.0,4.3Hz,2H),1.87–1.72(m,6H),1.66–1.57(m,4H),0.68–0.61(m,1H),0.37(tt,J=9.2,4.6Hz,1H),0.00(dq,J=9.5,4.9Hz,1H),-0.08(tt,J=9.4,4.6Hz,1H),-0.50(dq,J=9.5,4.8Hz,1H).

[0844] Example 100:

[0845]

[0846] Compound O-2 (100 mg), trans-N 1 ,N 1 -dimethylcyclohexane-1,4-diamine hydrochloride (40 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (4 mL). The mixture was purged with nitrogen three times and reacted at 95 °C for 3 h. After the reaction was completed, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 100 (20 mg). ESI-MS: m / z = 597.49 [M+H] + .

[0847] 1 H NMR (500 MHz, DMSO-d 6)δ12.40(s,1H),8.37(s,1H),8.31(s,1H),7.94(s,1H),7.58(s,1H),7.26(d,J=8.6Hz,1H),6.75(d,J=2.0Hz,1H),6.56(dd,J=8.5,2.0Hz,1H),4.32(td,J=8.4,5.8Hz,1H),4.26(dd,J=14.0,3.7Hz,1H),4.08(td,J=9.0,3.8Hz,2H),3.77(s,3H),2.58(s,3H),2.48–2.39(m,1H),2.35(s,6H),2.26(dt,J=12.1,5.9Hz,1H),2.17(dq,J=8.8,4.2,3.5Hz,1H),2.14–1.99(m,4H),1.95–1.84(m,3H),1.80–1.72(m,1H),1.49–1.38(m,2H),1.18(ddt,J=23.8,13.0,6.5Hz,2H),0.68–0.58(m,1H),0.37(tt,J=9.2,4.6Hz,1H),-0.00(dt,J=9.5,4.7Hz,1H),-0.08(dp,J=9.4,4.7Hz,1H),-0.48–-0.54(m,1H).

[0848] Example 101:

[0849]

[0850] Compound 75-b (30 mg) and morpholin-4-ylacetic acid (8 mg) were dispersed in dichloromethane (5 mL). HATU (29 mg) and triethylamine (19 mg) were added successively, and the reaction was carried out at 25 °C for 2 h until the reaction was completed. The reaction solution was washed with an aqueous sodium bicarbonate solution (1 M, 5 mL), dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 101 (12 mg). ESI-MS: m / z = 599.35 [M + H] + 。

[0851] 1 1H NMR (500 MHz, DMSO-d 6)δ12.69(s,1H),9.84(s,1H),8.35(s,1H),7.98(d,J=2.0Hz,1H),7.91(s,1H),7.57(d,J=9.8Hz,2H),7.45(dd,J=8.8,2.0Hz,1H),4.33–4.24(m,2H),4.17–4.09(m,1H),4.04(dt,J=8.9,5.8Hz,1H),3.73(s,3H),3.65(t,J=4.5Hz,4H),3.15(s,2H),2.55(s,3H),2.53(t,J=4.3Hz,4H),2.25–2.18(m,1H),2.18–2.11(m,1H),2.03–1.96(m,1H),1.84(t,J=8.9Hz,1H),1.70(q,J=5.9Hz,1H),0.60(dq,J=8.5,5.0,3.4Hz,1H),0.30(tt,J=9.2,4.9Hz,1H),-0.06(dq,J=9.8,5.0Hz,1H),-0.23(tt,J=9.3,4.8Hz,1H),-0.68(dq,J=9.6,4.8Hz,1H).

[0852] Example 102:

[0853]

[0854] Compound O (70 mg), 3-aminocyclopentanol hydrochloride (22 mg), Pd 2 (dba) 3 (30 mg), 2-(di-tert-butylphosphino)biphenyl (20 mg), potassium tert-butoxide (88 mg) were dispersed in tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 102 (10 mg). ESI-MS: m / z = 556.36 [M+H] + .

[0855] Example 103:

[0856]

[0857] Compound O (70 mg), 4-aminocyclohexanol (18 mg), Pd 2 (dba) 3(30 mg), 2-(di-tert-butylphosphino)biphenyl (20 mg), potassium tert-butoxide (88 mg) were dispersed in tert-amyl alcohol (3 mL), purged with nitrogen three times, and reacted at 100 °C for 2 h. After the reaction was completed, 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 103 (12 mg). ESI-MS: m / z = 570.35 [M+H] + 。

[0858] Example 104:

[0859]

[0860] Compound O (70 mg), 4-aminocyclohexanone hydrochloride (23 mg), Pd 2 (dba) 3 (30 mg), 2-(di-tert-butylphosphino)biphenyl (20 mg), potassium tert-butoxide (88 mg) were dispersed in tert-amyl alcohol (3 mL), purged with nitrogen three times, and reacted at 100 °C for 2 h. After the reaction was completed, 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 104 (8 mg). ESI-MS: m / z = 568.35 [M+H] + 。

[0861] 1 H NMR (500 MHz, chloroform-d) δ 12.11 (s, 1H), 8.61 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.71 (s, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.52 (d, J = 7.8 Hz, 2H), 4.45–4.37 (m, 2H), 3.98 (p, J = 5.9 Hz, 2H), 3.77 (s, 3H), 3.16 (d, J = 12.0 Hz, 1H), 2.92 (d, J = 12.4 Hz, 1H), 2.54 (s, 3H), 2.29 (ddd, J = 24.9, 15.6, 6.9 Hz, 2H), 2.17–2.09 (m, 2H), 2.02 (s, 2H), 1.83–1.74 (m, 2H), 1.48 (t, J = 10.5 Hz, 2H), 1.26 (t, J = 6.0 Hz, 2H), 0.47–0.39 (m, 1H), 0.28 (dq, J = 10.0, 5.1 Hz, 1H), 0.10 (dd, J = 10.2, 5.3 Hz, 1H), -0.07 (s, 1H), -0.51 (dq, J = 10.2, 5.0 Hz, 1H).

[0862] Example 105:

[0863]

[0864] Disperse compound O (70 mg), (1R,2S)-2-fluorocyclopropylamine p-toluenesulfonate (39 mg), Pd 2 (dba) 3 (30 mg), 2-(di-tert-butylphosphino)biphenyl (20 mg), and potassium tert-butoxide (88 mg) in tert-amyl alcohol (3 mL). Replace the gas with nitrogen three times and react at 100 °C for 2 h. After the reaction is completed, add 30 mL of water to the reaction solution, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and purify by preparative liquid chromatography to obtain Example 105 (8 mg). ESI-MS: m / z = 530.31 [M+H] + .

[0865] Example 106:

[0866]

[0867] Disperse compound O (100 mg), 3-aminocyclobutanol (20 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), and potassium tert-butoxide (126 mg) in tert-amyl alcohol (3 mL). Replace the gas with nitrogen three times and react at 100 °C for 2 h. After the reaction is completed, add an aqueous sodium bicarbonate solution (1 M, 20 mL) to the reaction solution, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and purify by preparative liquid chromatography to obtain Example 106 (15 mg). ESI-MS: m / z = 542.30 [M+H] + .

[0868] Example 107:

[0869]

[0870] Disperse compound O (100 mg), 3-aminocyclobutanone (20 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), and potassium tert-butoxide (126 mg) in tert-amyl alcohol (3 mL). Replace the gas with nitrogen three times and react at 100 °C for 2 h. After the reaction is completed, add an aqueous sodium bicarbonate solution (1 M, 20 mL) to the reaction solution, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and purify by preparative liquid chromatography to obtain Example 107 (10 mg). ESI-MS: m / z = 540.31 [M+H] + .

[0871] Example 108:

[0872]

[0873] Compound O (100 mg), 1-methyl-4-(methylamino)piperidine (29 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 108 (15 mg). ESI-MS: m / z = 583.40 [M+H] + .

[0874] 1 1H NMR (500 MHz, chloroform-d) δ 12.18 (s, 1H), 8.41 (s, 1H), 8.15 (s, 1H), 7.69 (s, 1H), 7.22 (d, J = 9.1 Hz, 1H), 6.82 (dd, J = 6.5, 2.6 Hz, 2H), 4.42–4.32 (m, 2H), 3.95 (tt, J = 14.1, 6.4 Hz, 2H), 3.79 (s, 3H), 3.57 (td, J = 10.9, 4.7 Hz, 1H), 3.30 (d, J = 11.8 Hz, 2H), 2.79 (s, 3H), 2.62 (s, 3H), 2.58 (s, 3H), 2.52 (d, J = 12.0 Hz, 2H), 2.27 (q, J = 6.6 Hz, 1H), 2.22–2.08 (m, 4H), 1.82 (dd, J = 30.8, 9.5 Hz, 4H), 0.52 (dt, J = 12.6, 6.6 Hz, 1H), 0.44 (dq, J = 8.6, 4.7, 4.1 Hz, 1H), 0.10 (tt, J = 9.3, 5.2 Hz, 1H), -0.01–-0.07 (m, 1H), -0.33 (dq, J = 9.9, 5.1 Hz, 1H).

[0875] Example 109:

[0876]

[0877] Compound O (100 mg), N 1 ,N 1 -dimethylcyclopentane-1,3-diamine (29 mg), Pd 2 (dba) 3(43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (3 mL), purged with nitrogen three times, and reacted at 100 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 109 (23 mg). ESI-MS: m / z = 583.41 [M+H] + 。

[0878] Example 110:

[0879]

[0880] Compound O (100 mg), N 1 ,N 1 ,N 4 -trimethylcyclohexane-1,4-diamine (35 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (3 mL), purged with nitrogen three times, and reacted at 100 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 110 (10 mg). ESI-MS: m / z = 611.43 [M+H] + 。

[0881] Example 111:

[0882]

[0883] (1) Preparation method of compound 111-a:

[0884] Compound O-2 (1.0 g), tert-butyl carbamate (437 mg), Pd 2 (dba) 3 (430 mg), 2-(di-tert-butylphosphino)biphenyl (280 mg), potassium tert-butoxide (1.26 g) were dispersed in tert-amyl alcohol (20 mL), purged with nitrogen three times, and reacted at 100 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by column chromatography to obtain compound 111-a (420 mg). ESI-MS: m / z = 572.31 [M+H] + 。

[0885] (2) Preparation method of Compound 111-b:

[0886] Disperse Compound 111-a (420 mg) in dichloromethane (10 mL), add trifluoroacetic acid (5 mL) dropwise at 25 °C. After the addition, react at 25 °C for 2 h until the reaction is complete. Concentrate the reaction solution, add aqueous sodium bicarbonate solution (1 M, 20 mL) and ethyl acetate (30 mL) to the concentrate, separate the layers, retain the organic phase, and concentrate until no liquid flows out to obtain Compound 111-b (300 mg). ESI-MS: m / z = 472.32 [M+H] + .

[0887] (3) Preparation method of Example 111:

[0888] Disperse Compound 111-b (30 mg) and N,N-dimethylglycine (7 mg) in dichloromethane (5 mL), successively add HATU (29 mg) and triethylamine (19 mg), and react at 25 °C for 2 h until the reaction is complete. Wash the reaction solution with aqueous sodium bicarbonate solution (1 M, 5 mL), dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and purify by preparative liquid phase to obtain Example 111 (13 mg). ESI-MS: m / z = 557.34 [M+H] + .

[0889] 1 1H NMR (500 MHz, DMSO-d 6 ) δ 12.66 (s, 1H), 9.85 (s, 1H), 8.34 (s, 1H), 8.07 (d, J = 1.9 Hz, 1H), 7.91 (s, 1H), 7.56 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.40 (dd, J = 8.6, 1.8 Hz, 1H), 4.32–4.26 (m, 2H), 4.07–4.04 (m, 1H), 4.00 (dd, J = 13.9, 8.6 Hz, 1H), 3.73 (s, 3H), 3.15 (d, J = 1.3 Hz, 2H), 2.55 (s, 3H), 2.34 (s, 6H), 2.23 (dt, J = 13.2, 6.8 Hz, 1H), 2.13 (q, J = 6.7, 5.4 Hz, 1H), 2.02 (dq, J = 13.9, 7.6, 6.3 Hz, 1H), 1.76 (ddt, J = 20.9, 13.0, 4.8 Hz, 2H), 0.58 (q, J = 8.1, 7.2 Hz, 1H), 0.35 (tt, J = 8.7, 4.5 Hz, 1H), 0.01– -0.04 (m, 1H), -0.07 (dt, J = 8.8, 4.4 Hz, 1H), -0.52 (dq, J = 9.5, 4.7 Hz, 1H).

[0890] Example 112:

[0891]

[0892] Compound 111-b (30 mg) and 3-dimethylaminopropionic acid hydrochloride (9 mg) were dispersed in dichloromethane (5 mL). HATU (29 mg) and triethylamine (19 mg) were added successively, and the reaction was carried out at 25 °C for 2 h until the reaction was completed. The reaction solution was washed with an aqueous sodium bicarbonate solution (1 M, 5 mL), dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 112 (15 mg). ESI-MS: m / z = 571.36 [M+H] + .

[0893] 1 1H NMR (500 MHz, DMSO-d 6 ) δ 12.67 (s, 1H), 10.19 (s, 1H), 8.34 (s, 1H), 8.07 (d, J = 1.9 Hz, 1H), 7.91 (s, 1H), 7.56 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.23 (dd, J = 8.6, 1.8 Hz, 1H), 4.28 (dt, J = 14.7, 5.4 Hz, 2H), 4.06 (dt, J = 7.3, 5.0 Hz, 1H), 3.98 (dd, J = 14.0, 8.4 Hz, 1H), 3.73 (s, 3H), 2.70 (t, J = 7.1 Hz, 2H), 2.55 (s, 3H), 2.52 (d, J = 6.9 Hz, 2H), 2.28 (s, 6H), 2.22 (h, J = 6.1, 5.3 Hz, 1H), 2.12 (td, J = 8.8, 4.3 Hz, 1H), 2.06–2.00 (m, 1H), 1.76 (qd, J = 14.0, 13.1, 8.5 Hz, 2H), 0.55 (qd, J = 8.0, 4.0 Hz, 1H), 0.36 (dp, J = 8.9, 4.4 Hz, 1H), -0.00 (q, J = 5.1, 4.5 Hz, 1H), -0.06 (tt, J = 9.8, 5.1 Hz, 1H), -0.51 (dq, J = 9.5, 4.7 Hz, 1H).

[0894] Example 113:

[0895]

[0896] Compound 111-b (30 mg) and 4-dimethylaminobutyric acid hydrochloride (10 mg) were dispersed in dichloromethane (5 mL). HATU (29 mg) and triethylamine (19 mg) were added successively, and the reaction was carried out at 25 °C for 2 h until the reaction was completed. The reaction solution was washed with an aqueous sodium bicarbonate solution (1 M, 5 mL), dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 113 (13 mg). ESI-MS: m / z = 585.39 [M+H] + 。

[0897] 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.82–12.47 (m, 1H), 10.05 (s, 1H), 8.34 (s, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.56 (s, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 4.28 (q, J = 8.7 Hz, 2H), 4.04 (d, J = 7.0 Hz, 1H), 3.98 (dd, J = 13.9, 8.3 Hz, 1H), 3.73 (s, 3H), 2.55 (s, 3H), 2.35 (dd, J = 16.8, 8.8 Hz, 4H), 2.20 (s, 6H), 2.13 (t, J = 7.5 Hz, 1H), 2.05 (s, 1H), 1.75 (d, J = 11.7 Hz, 5H), 0.56 (s, 1H), 0.39–0.33 (m, 1H), -0.01 (q, J = 4.9 Hz, 1H), -0.06 (s, 1H), -0.47– -0.55 (m, 1H).

[0898] Example 114:

[0899]

[0900] Compound 111-b (30 mg) and morpholin-4-ylacetic acid (8 mg) were dispersed in dichloromethane (5 mL). HATU (29 mg) and triethylamine (19 mg) were added successively, and the reaction was carried out at 25 °C for 2 h until the reaction was completed. The reaction solution was washed with an aqueous sodium bicarbonate solution (1 M, 5 mL), dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 114 (15 mg). ESI-MS: m / z = 599.36 [M+H] + 。

[0901] 11H NMR (500 MHz, chloroform-d) δ 9.24 (s, 1H), 8.40 (d, J = 1.3 Hz, 1H), 8.30 (d, J = 1.9 Hz, 1H), 8.15 (s, 1H), 7.65 (d, J = 1.3 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.5, 1.9 Hz, 1H), 4.41 (dd, J = 13.8, 3.2 Hz, 1H), 4.37–4.32 (m, 1H), 4.04 (dd, J = 13.9, 7.5 Hz, 1H), 3.98–3.94 (m, 1H), 3.81 (t, J = 4.6 Hz, 4H), 3.79 (s, 3H), 3.20 (d, J = 1.3 Hz, 2H), 2.67 (t, J = 4.7 Hz, 4H), 2.64 (s, 3H), 2.29 (dt, J = 13.3, 6.6 Hz, 1H), 2.21–2.16 (m, 2H), 1.84–1.78 (m, 2H), 0.58 (dq, J = 13.1, 7.3, 5.4 Hz, 1H), 0.44 (tt, J = 9.0, 4.9 Hz, 1H), 0.13 (tt, J = 9.0, 5.1 Hz, 1H), -0.04 (dt, J = 10.0, 4.9 Hz, 1H), -0.33 (dq, J = 9.9, 5.0 Hz, 1H).

[0902] Example 115:

[0903]

[0904] Compound O-2 (100 mg), N 1 -cyclopropyl-N 2 ,N 2 -dimethyl ethane-1,2-diamine dihydrochloride (45 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 115 (10 mg). ESI-MS: m / z = 583.40 [M+H] + .

[0905] 1 1H NMR (500 MHz, DMSO-d 6)δ12.46(s,1H),8.38(s,1H),7.94(s,1H),7.59(s,1H),7.39(d,J=8.9Hz,2H),7.17(s,1H),6.95(d,J=9.0Hz,1H),4.30(d,J=23.1Hz,2H),4.11(d,J=27.2Hz,2H),3.76(s,3H),2.58(s,3H),2.43(s,4H),2.17(s,6H),2.05(s,2H),1.88–1.73(m,3H),0.90(s,3H),0.66(s,1H),0.63–0.57(m,1H),0.49(s,1H),0.35(s,1H),0.00(s,1H),-0.06–-0.14(m,1H),-0.56(s,1H).

[0906] Example 116:

[0907]

[0908] Compound O-2 (100 mg), N 1 ,N 1 -dimethyl-N2-(methyl-d 3 )ethane-1,2-diamine dihydrochloride (34 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 116 (22 mg). ESI-MS: m / z = 560.42 [M+H] + .

[0909] 1 1H NMR (500 MHz, DMSO-d 6)δ12.45(s,1H),8.39(s,1H),7.96(s,1H),7.60(s,1H),7.39(d,J=8.8Hz,1H),6.93(d,J=2.3Hz,1H),6.70(dd,J=8.8,2.3Hz,1H),4.34(q,J=7.9Hz,1H),4.28(dd,J=14.0,3.6Hz,1H),4.18(dd,J=13.9,9.2Hz,1H),4.08(dt,J=8.7,5.7Hz,1H),3.78(s,3H),3.57(s,1H),3.47(d,J=2.3Hz,1H),2.59(s,3H),2.44(ddd,J=15.3,10.5,6.1Hz,2H),2.26(dd,J=9.5,4.6Hz,1H),2.23(s,6H),2.19(td,J=9.2,8.3,3.7Hz,1H),2.06(td,J=12.6,9.3,5.4Hz,1H),1.87(d,J=10.0Hz,1H),1.81–1.72(m,1H),0.68(tt,J=8.3,3.3Hz,1H),0.36(tt,J=9.2,4.7Hz,1H),0.00(dq,J=9.6,4.9Hz,1H),-0.11(dp,J=9.5,4.8Hz,1H),-0.55(dq,J=9.6,4.9Hz,1H).

[0910] Example 117:

[0911]

[0912] Compound O-2 (100 mg), 1-methyl-4-(methylamino)piperidine (29 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (3 mL). The mixture was purged with nitrogen three times and reacted at 100 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 117 (12 mg). ESI-MS: m / z = 583.40 [M+H] + 。

[0913] 1 H NMR (500 MHz, DMSO-d 6)δ12.47(s,1H),8.39(s,1H),8.27(s,1H),7.95(s,1H),7.59(s,1H),7.39(d,J=8.7Hz,1H),7.06(s,1H),6.84(d,J=8.9Hz,1H),4.33(q,J=7.8Hz,1H),4.28(dd,J=14.0,3.4Hz,1H),4.20(dd,J=13.9,8.9Hz,1H),4.10–4.05(m,1H),3.77(s,3H),3.03–2.93(m,2H),2.78(s,3H),2.58(s,3H),2.31(s,3H),2.27–2.14(m,4H),2.06(dq,J=13.0,4.7,3.9Hz,1H),1.90–1.73(m,4H),1.71–1.61(m,2H),1.27(d,J=10.5Hz,1H),0.67(dq,J=9.4,5.2,4.4Hz,1H),0.35(tt,J=9.4,4.8Hz,1H),0.03– -0.04(m,1H),-0.14(tt,J=9.2,4.7Hz,1H),-0.54(dq,J=9.7,4.8Hz,1H).

[0914] Example 118:

[0915]

[0916] Compound O-2 (100 mg), N 1 ,N 1 -dimethylcyclopentane-1,3-diamine (29 mg), Pd 2 (dba) 3 (43 mg), 2-(di-tert-butylphosphino)biphenyl (28 mg), potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (3 mL), purged with nitrogen three times, and reacted at 100 °C for 2 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 118 (30 mg). ESI-MS: m / z = 583.41 [M+H] + .

[0917] Example 119:

[0918]

[0919] Compound O (70 mg), 3-(oxan-4-yl)propan-1-amine (22 mg), Pd 2 (dba)3 (30 mg), 2-(di-tert-butylphosphino)biphenyl (20 mg), potassium tert-butoxide (88 mg) were dispersed in tert-amyl alcohol (3 mL), purged with nitrogen three times, and reacted at 100 °C for 2 h. The reaction was completed. An aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 119 (10 mg). ESI-MS: m / z = 598.39 [M+H] + 。

[0920] Example 120:

[0921]

[0922] Compound O (70 mg), tert-butylamine (30 mg), Pd 2 (dba) 3 (30 mg), 2-(di-tert-butylphosphino)biphenyl (20 mg), potassium tert-butoxide (88 mg) were dispersed in tert-amyl alcohol (3 mL), purged with nitrogen three times, and reacted at 60 °C for 5 h. The reaction was completed. An aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 120 (8 mg). ESI-MS: m / z = 528.36 [M+H] + 。

[0923] Example 121:

[0924]

[0925] Compound O (70 mg), cyclopropylamine (25 mg), Pd 2 (dba) 3 (30 mg), 2-(di-tert-butylphosphino)biphenyl (20 mg), potassium tert-butoxide (88 mg) were dispersed in tert-amyl alcohol (3 mL), purged with nitrogen three times, and reacted at 60 °C for 5 h. The reaction was completed. An aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 121 (6 mg). ESI-MS: m / z = 512.34 [M+H] + 。

[0926] Example 122:

[0927]

[0928] Compound O-2 (70 mg), cyclopropylamine (25 mg), Pd 2 (dba)3 (30 mg), 2-(di-tert-butylphosphino)biphenyl (20 mg), potassium tert-butoxide (88 mg) were dispersed in tert-amyl alcohol (3 mL), purged with nitrogen three times, and reacted at 60 °C for 5 h. After the reaction was completed, an aqueous sodium bicarbonate solution (1 M, 20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 122 (8 mg). ESI-MS: m / z = 512.34 [M+H] + 。

[0929] Example 123:

[0930]

[0931] (1) Preparation method of compound 123-a:

[0932] Compound N-benzyloxycarbonyl-L-alanine (3.82 g) was dispersed in dichloromethane (50 mL). At 0 - 5 °C, dimethyl-d6-amine hydrochloride (1.65 g), TBTU (6.05 g) and N,N-diisopropylethylamine (8.5 mL) were added successively. After addition, the reaction was carried out at 25 °C for 16 h. TLC showed that the reaction was completed. The reaction solution was washed with sodium hydroxide solution (1 M, 100 mL × 2), the organic phase was retained, dried and evaporated to dryness, and compound 123-a (3.93 g) was obtained by column chromatography.

[0933] (2) Preparation method of compound 123-b:

[0934] Compound 123-a (3.93 g) was dispersed in tetrahydrofuran (20 mL). The temperature was lowered to 0 - 5 °C, and borane (1 M in THF, 46 mL) was added dropwise while maintaining the temperature. The reaction was carried out at 0 - 5 °C for 2 h. TLC showed that the raw materials had reacted completely. Hydrochloric acid (12 M, 3.0 mL) was slowly added dropwise to the reaction solution at 0 - 5 °C. After the addition was completed, the mixture was heated at 60 °C for 2 h. TLC showed that the intermediate state had disappeared. The reaction solution was cooled to 20 - 25 °C, poured into water (50 mL), and the pH was adjusted to 9 - 10 with saturated sodium bicarbonate solution. The layers were separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried and evaporated to dryness, and compound 123-b (1.52 g) was obtained by column chromatography.

[0935] (3) Preparation method of compound 123-c:

[0936] Compound 123-b (1.52 g) was dispersed in methanol (40 mL), hydrochloric acid (12 M, 3.8 mL) and Pd / C (10%, 0.15 g) were added. The mixture was purged with hydrogen three times and heated at 50 °C for 5 h. TLC showed that the reaction was complete. The reaction solution was filtered through diatomaceous earth on filter paper, and the filtrate was evaporated to dryness to obtain colorless oily liquid 123-c (0.83 g).

[0937] (4) Preparation method of Example 123:

[0938] 123-c (68 mg) and potassium tert-butoxide (126 mg) were dispersed in tert-amyl alcohol (5 mL), stirred at 20 - 25 °C for 5 min, and then compound O-2 (100 mg) from Example 8, Pd 2 (dba) 3 (26 mg) and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl (30 mg) were added. The mixture was purged with nitrogen 3 times and reacted at 100 °C for 2 h. LC-MS showed that the reaction was completed. 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 123 (25 mg). ESI-MS: m / z = 563.55 [M + H] + 。

[0939] 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.43 (s, 1H), 8.38 (s, 1H), 7.95 (s, 1H), 7.58 (s, 1H), 7.30 (d, J = 8.5 Hz, 1H), 6.86 (s, 1H), 6.61 (d, J = 8.5 Hz, 1H), 4.37–4.31 (m, 1H), 4.30–4.24 (m, 1H), 4.09 (dd, J = 13.7, 8.8 Hz, 2H), 3.77 (s, 3H), 3.55 (s, 2H), 2.58 (s, 3H), 2.26 (d, J = 9.8 Hz, 1H), 2.18 (s, 1H), 2.04 (d, J = 7.1 Hz, 2H), 1.87 (s, 1H), 1.75 (d, J = 12.4 Hz, 1H), 1.20 (d, J = 6.2 Hz, 3H), 0.64 (s, 1H), 0.35 (d, J = 10.2 Hz, 1H), 0.00 (q, J = 4.9 Hz, 1H), -0.09 (s, 1H), -0.51– -0.58 (m, 1H).

[0940] Example 124:

[0941]

[0942] Disperse 123-c (102 mg) and potassium tert-butoxide (189 mg) in tert-amyl alcohol (5 mL), stir at 20 - 25 °C for 5 min, then add compound O (100 mg), Pd 2 (dba) 3 (26 mg) and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl (30 mg), displace with nitrogen for 3 times, react in an oil bath at 100 °C for 2 h, LC-MS shows that the reaction is completed; add 30 mL of water to the reaction solution, extract with ethyl acetate (20 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and purify by preparative liquid phase to obtain Example 124 (22 mg). ESI-MS: m / z = 563.48 [M+H] + 。

[0943] 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.41 (s, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 7.54 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.81 (s, 1H), 6.63 (d, J = 8.8 Hz, 1H), 4.29 (q, J = 7.8 Hz, 1H), 4.22 (dd, J = 14.2, 3.6 Hz, 1H), 4.04 (q, J = 6.2, 5.3 Hz, 2H), 3.73 (s, 3H), 3.50 (s, 2H), 2.54 (s, 3H), 2.20 (s, 1H), 2.14 (s, 1H), 2.00 (d, J = 13.8 Hz, 2H), 1.81 (s, 1H), 1.73–1.66 (m, 1H), 1.15 (d, J = 6.2 Hz, 3H), 0.59 (s, 1H), 0.30 (dq, J = 9.2, 4.6 Hz, 1H), -0.06 (dd, J = 9.5, 5.0 Hz, 1H), -0.16 (s, 1H), -0.59 (q, J = 5.1 Hz, 1H).

[0944] Example 125:

[0945]

[0946] Dissolve compound O (120 mg), cis-N 1 ,N 1 -dimethylcyclobutane-1,3-diamine (31 mg), Pd 2 (dba) 3(30 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl (35 mg), potassium tert-butoxide (148 mg) were dispersed in tert-amyl alcohol (5 mL), purged with nitrogen three times, and reacted in an oil bath at 100 °C for 3.0 h. LC-MS showed that the reaction was complete; 30 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 125 (25 mg). ESI-MS: m / z = 569.44 [M+H] + 。

[0947] 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.38 (s, 1H), 8.40 (s, 1H), 7.97 (s, 1H), 7.61 (s, 1H), 7.39 (d, J = 8.7 Hz, 1H), 6.77 (s, 1H), 6.59 (d, J = 8.6 Hz, 1H), 4.35 (q, J = 7.8 Hz, 1H), 4.28 (dd, J = 14.0, 3.5 Hz, 1H), 4.09 (dq, J = 14.0, 4.6 Hz, 2H), 3.81 (d, J = 9.8 Hz, 1H), 3.79 (s, 3H), 2.91 (d, J = 7.5 Hz, 1H), 2.61 (s, 3H), 2.48 (t, J = 7.5 Hz, 1H), 2.30–2.24 (m, 1H), 2.20 (d, J = 13.1 Hz, 1H), 2.12 (s, 6H), 2.05 (d, J = 7.7 Hz, 2H), 1.87 (t, J = 8.5 Hz, 1H), 1.81–1.74 (m, 1H), 1.69 (q, J = 9.9, 9.1 Hz, 2H), 0.64 (h, J = 8.5, 7.3 Hz, 1H), 0.37 (tt, J = 9.1, 4.8 Hz, 1H), 0.00 (dq, J = 9.8, 5.0 Hz, 1H), -0.09 (dq, J = 8.8, 4.5 Hz, 1H), -0.53 (dt, J = 9.9, 5.1 Hz, 1H).

[0948] Example 126:

[0949]

[0950] Compound O (120 mg), trans-N 1 ,N 1 -dimethylcyclobutane-1,3-diamine (31 mg), Pd 2 (dba) 3(30 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl (35 mg), potassium tert-butoxide (148 mg) were dispersed in tert-amyl alcohol (5 mL), purged with nitrogen three times, and reacted in an oil bath at 100 °C for 3.0 h. LC-MS showed that the reaction was completed. 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 126 (20 mg). ESI-MS: m / z = 569.46 [M+H] + 。

[0951] 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.42 (s, 1H), 8.40 (s, 1H), 7.97 (s, 1H), 7.61 (d, J = 1.2 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 6.72 (d, J = 2.1 Hz, 1H), 6.56 (dd, J = 8.6, 2.2 Hz, 1H), 6.01 (d, J = 5.3 Hz, 1H), 4.35 (q, J = 7.8 Hz, 1H), 4.28 (dd, J = 14.0, 3.5 Hz, 1H), 4.13–4.05 (m, 2H), 3.81 (d, J = 9.8 Hz, 1H), 3.79 (s, 3H), 2.85 (p, J = 6.6 Hz, 1H), 2.61 (s, 3H), 2.28 (ddd, J = 13.0, 7.5, 5.7 Hz, 3H), 2.20 (dq, J = 8.8, 4.3, 3.4 Hz, 1H), 2.14 (s, 6H), 2.07–1.99 (m, 3H), 1.88 (d, J = 9.3 Hz, 1H), 1.77 (dd, J = 11.3, 6.0 Hz, 1H), 0.65 (ddt, J = 13.0, 8.6, 4.6 Hz, 1H), 0.37 (tt, J = 9.3, 4.8 Hz, 1H), 0.00 (dq, J = 9.6, 5.0 Hz, 1H), -0.09 (dq, J = 9.4, 4.9 Hz, 1H), -0.53 (dq, J = 9.8, 5.0 Hz, 1H).

[0952] Example 127:

[0953]

[0954] Compound O-2 (60 mg), cis-N 1 ,N 1 -dimethylcyclobutane-1,3-diamine (31 mg), Pd 2 (dba) 3(30 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl (35 mg), potassium tert-butoxide (148 mg) were dispersed in tert-amyl alcohol (5 mL). After purging with nitrogen three times, the mixture was reacted in an oil bath at 100 °C for 3.0 h. LC-MS showed that the reaction was completed. 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 127 (50 mg). ESI-MS: m / z = 569.46 [M+H] + 。

[0955] 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.38 (s, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.97 (d, J = 1.2 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 6.60–6.49 (m, 2H), 4.33–4.25 (m, 2H), 4.06 (d, J = 5.7 Hz, 2H), 3.81 (d, J = 9.8 Hz, 1H), 3.77 (s, 3H), 3.08 (p, J = 6.6 Hz, 1H), 2.61 (s, 3H), 2.28 (ddd, J = 13.0, 7.5, 5.7 Hz, 3H), 2.20 (dq, J = 8.8, 4.3, 3.4 Hz, 1H), 2.26 (s, 6H), 2.10–1.98 (m, 3H), 1.84 (q, J = 8.0, 7.6 Hz, 1H), 1.80–1.73 (m, 1H), 0.65 (dq, J = 17.8, 8.2, 6.6 Hz, 1H), 0.36 (tt, J = 9.3, 4.5 Hz, 1H), -0.01 (dq, J = 9.8, 5.0 Hz, 1H), -0.09 (dq, J = 9.1, 4.4 Hz, 1H), -0.55 (dt, J = 9.8, 4.8 Hz, 1H).

[0956] Example 128:

[0957]

[0958] Compound O-2 (120 mg), trans-N 1 ,N 1 -dimethylcyclobutane-1,3-diamine (31 mg), Pd 2 (dba) 3(30 mg), 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl (35 mg), potassium tert-butoxide (148 mg) were dispersed in tert-amyl alcohol (5 mL), purged with nitrogen three times, and reacted in an oil bath at 100 °C for 3 h. LC-MS showed that the reaction was complete; 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 128 (35 mg). ESI-MS: m / z = 569.49 [M+H] + 。

[0959] 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.42 (s, 1H), 8.38 (s, 1H), 8.32 (s, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 6.60–6.49 (m, 2H), 4.33–4.25 (m, 2H), 4.06 (d, J = 5.7 Hz, 2H), 3.81 (d, J = 9.8 Hz, 1H), 3.77 (s, 3H), 3.08 (p, J = 6.6 Hz, 1H), 2.61 (s, 3H), 2.28 (ddd, J = 13.0, 7.5, 5.7 Hz, 3H), 2.20 (dq, J = 8.8, 4.3, 3.4 Hz, 1H), 2.26 (s, 6H), 2.10–1.98 (m, 3H), 1.84 (q, J = 8.0, 7.6 Hz, 1H), 1.80–1.73 (m, 1H), 0.64 (dq, J = 17.8, 8.2, 6.6 Hz, 1H), 0.37 (tt, J = 9.3, 4.5 Hz, 1H), 0.00 (dq, J = 9.8, 5.0 Hz, 1H), -0.07 (dq, J = 9.1, 4.4 Hz, 1H), -0.50 (dt, J = 9.8, 4.8 Hz, 1H).

[0960] Example 129:

[0961]

[0962] (1) Preparation method of compound 129-a:

[0963] (1S,3R)-3-Aminocyclopentanol hydrochloride (500 mg) was dispersed in tetrahydrofuran (10 mL). Aqueous solution of sodium hydroxide (363 mg) in water (3 mL) and di-tert-butyl dicarbonate (833 mg) were added successively. The reaction was carried out at 20 - 25 °C for 3 h. TLC showed that the reaction was complete. 20 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out to obtain compound 129-a (731 mg), which was directly used for the next step without purification.

[0964] (2) Preparation method of compound 129-b:

[0965] Compound 129-a (731 mg) was dispersed in ethyl acetate (20 mL). Triethylamine (735 mg) and ethylsulfonyl chloride (513 mg) were added successively to the reaction solution while controlling the temperature at 5 - 15 °C. The reaction was carried out at 5 - 15 °C for 0.5 h. TLC showed that the reaction was complete. The reaction solution was washed with water (20 mL × 2), and the ethyl acetate phase was retained, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out to obtain compound 129-b (1.06 g), which was directly used for the next step without purification.

[0966] (3) Preparation method of compound 129-c:

[0967] Compound 129-b (1.06 g) was dispersed in N,N-dimethylformamide (20 mL). Potassium carbonate (1.51 g), 4-dimethylaminopyridine (44 mg) and dimethylamine hydrochloride (5.92 g) were added successively. The reaction was carried out at 80 °C for 6 h. TLC was used to monitor until the reaction was complete. 100 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (50 mL × 2). The organic phases were combined and washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Then, column chromatography was carried out to obtain liquid 129-c (238 mg).

[0968] (4) Preparation method of compound 129-d:

[0969] Compound 129-c (238 mg) was dispersed in hydrochloric acid methanol solution (4 M, 15 mL). The reaction was stirred at 20 - 25 °C for 1 h. TLC showed that the reaction was complete; the reaction solution was concentrated until no liquid flowed out, redissolved in methanol (15 mL) and then concentrated until no liquid flowed out to obtain compound 129-d (150 mg).

[0970] (5) Preparation method of Example 129:

[0971] Compound O (50 mg), 129-d (25 mg), Pd 2 (dba) 3(29 mg), 2 - Di - tert - butylphosphino - 2',4',6' - triisopropylbiphenyl (27 mg), potassium tert - butoxide (141 mg) were dispersed in tert - amyl alcohol (5 mL). After purging with nitrogen three times, the reaction was carried out in an oil bath at 100 °C for 2 h. LC - MS showed that the reaction was completed. 30 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 129 (22 mg). ESI - MS: m / z = 583.51 [M + H] + 。

[0972] 1 H NMR (500 MHz, chloroform - d) δ 12.05 (s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 7.67 (s, 1H), 7.16 (d, J = 8.5 Hz, 1H), 6.55 (d, J = 9.4 Hz, 2H), 4.37–4.33 (m, 2H), 3.99–3.93 (m, 2H), 3.78 (s, 3H), 3.42 (t, J = 8.6 Hz, 1H), 2.73 (s, 1H), 2.71–2.66 (m, 6H), 2.63 (s, 3H), 2.38 (dt, J = 15.9, 7.9 Hz, 2H), 2.28 (dd, J = 13.9, 6.9 Hz, 1H), 2.21–2.12 (m, 3H), 2.02–1.93 (m, 2H), 1.82–1.73 (m, 2H), 1.59 (p, J = 6.8 Hz, 1H), 0.51 (d, J = 9.6 Hz, 1H), 0.43 (tt, J = 8.8, 4.7 Hz, 1H), 0.11 (d, J = 10.1 Hz, 1H), -0.01– -0.07 (m, 1H), -0.32 (dt, J = 10.2, 5.2 Hz, 1H).

[0973] Example 130:

[0974]

[0975] Compound O - 2 (50 mg), 129 - d (25 mg) in Example 8, Pd 2 (dba) 3(29 mg), 2 - Di - tert - butylphosphino - 2',4',6' - triisopropylbiphenyl (27 mg), potassium tert - butoxide (141 mg) were dispersed in tert - amyl alcohol (5 mL). After three - time nitrogen replacement, the reaction was carried out in an oil bath at 100 °C for 2 h. LC - MS showed that the reaction was completed. 30 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 130 (20 mg). ESI - MS: m / z = 583.53 [M + H] + 。

[0976] 1 H NMR (500 MHz, chloroform - d) δ8.39 (d, J = 4.4 Hz, 3H), 8.15 (s, 1H), 7.64 (s, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.59 (s, 1H), 6.51 (d, J = 8.5 Hz, 1H), 4.35 (tt, J = 8.7, 4.4 Hz, 2H), 4.05 (h, J = 6.1, 5.4 Hz, 1H), 4.00–3.91 (m, 2H), 3.78 (s, 3H), 3.46 (t, J = 8.5 Hz, 1H), 2.74 (d, J = 13.9 Hz, 6H), 2.63 (s, 3H), 2.42 (q, J = 9.2, 8.2 Hz, 2H), 2.30–2.11 (m, 4H), 2.08–1.94 (m, 2H), 1.86–1.75 (m, 2H), 1.65–1.55 (m, 1H), 0.55 (dq, J = 12.8, 6.6 Hz, 1H), 0.42 (tq, J = 9.0, 4.5 Hz, 1H), 0.06 (td, J = 8.6, 4.6 Hz, 1H), - 0.05 (dq, J = 9.1, 4.7 Hz, 1H), - 0.37 (ddt, J = 32.8, 9.7, 5.0 Hz, 1H).

[0977] Example 131:

[0978]

[0979] (1) Preparation method of compound 131 - a:

[0980] (1S,3S)-3-Aminocyclopentanol hydrochloride (500 mg) was dispersed in tetrahydrofuran (10 mL). Aqueous solution of sodium hydroxide (363 mg) in water (3 mL) and di-tert-butyl dicarbonate (833 mg) were added successively. The reaction was carried out at 20 - 25 °C for 3 h. TLC indicated that the reaction was complete. 20 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out to obtain compound 131-a (720 mg), which was directly used in the next step without purification.

[0981] (2) Preparation method of compound 131-b:

[0982] Compound 131-a (720 mg) was dispersed in ethyl acetate (20 mL). Triethylamine (721 mg) and ethylsulfonyl chloride (505 mg) were added successively to the reaction solution while controlling the temperature at 5 - 15 °C. The reaction was carried out at 5 - 15 °C for 0.5 h. TLC indicated that the reaction was complete. The reaction solution was washed with water (20 mL × 2), and the ethyl acetate phase was retained, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out to obtain compound 131-b (1.01 g), which was directly used in the next step without purification.

[0983] (3) Preparation method of compound 131-c:

[0984] Compound 131-b (1.01 g) was dispersed in N,N-dimethylformamide (20 mL). Potassium carbonate (1.44 g), 4-dimethylaminopyridine (42 mg) and dimethylamine hydrochloride (5.64 g) were added successively. The reaction was carried out at 80 °C for 6 h. TLC was used to monitor until the reaction was complete. 100 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (50 mL × 2). The organic phases were combined and washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Then, column chromatography was carried out to obtain liquid 131-c (215 mg).

[0985] (4) Preparation method of compound 131-d:

[0986] Compound 131-c (215 mg) was dispersed in hydrochloric acid-methanol solution (4 M, 15 mL). The reaction was stirred at 20 - 25 °C for 1 h. TLC indicated that the reaction was complete; the reaction solution was concentrated until no liquid flowed out, redissolved in methanol (15 mL) and then concentrated until no liquid flowed out to obtain compound 131-d (140 mg).

[0987] (5) Preparation method of Example 131:

[0988] Compound O (50 mg), 131-d (25 mg), Pd 2 (dba) 3(29 mg), 2 - Di - tert - butylphosphino - 2',4',6' - triisopropylbiphenyl (27 mg), potassium tert - butoxide (141 mg) were dispersed in tert - amyl alcohol (5 mL). After three - time nitrogen replacement, the reaction was carried out in an oil bath at 100 °C for 2 h. LC - MS showed that the reaction was completed. 30 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 131 (15 mg). ESI - MS: m / z = 583.53 [M + H] + 。

[0989] 1 H NMR (500 MHz, chloroform - d) δ 8.46 (s, 1H), 8.40 (d, J = 8.5 Hz, 1H), 8.15 (s, 1H), 7.70 (d, J = 24.2 Hz, 1H), 7.14 (dd, J = 18.5, 8.5 Hz, 1H), 6.65–6.44 (m, 2H), 4.35 (dt, J = 13.9, 4.1 Hz, 2H), 3.99–3.89 (m, 3H), 3.78 (s, 3H), 3.42–3.35 (m, 1H), 2.68 (d, J = 15.3 Hz, 6H), 2.64 (s, 3H), 2.40–2.31 (m, 1H), 2.27 (q, J = 6.6 Hz, 1H), 2.22–2.11 (m, 3H), 1.96 (dtd, J = 26.5, 18.1, 16.5, 10.2 Hz, 3H), 1.78 (q, J = 10.6, 9.1 Hz, 2H), 1.63–1.53 (m, 1H), 0.55–0.47 (m, 1H), 0.43 (dp, J = 9.1, 4.7 Hz, 1H), 0.10 (tt, J = 9.4, 4.9 Hz, 1H), - 0.01– - 0.08 (m, 1H), - 0.33 (dt, J = 8.8, 4.5 Hz, 1H).

[0990] Example 132:

[0991]

[0992] Compound O - 2 (50 mg) in Example 8, 131 - d (25 mg), Pd 2 (dba) 3(29 mg), 2 - di - tert - butylphosphino - 2',4',6' - triisopropylbiphenyl (27 mg), potassium tert - butoxide (141 mg) were dispersed in tert - amyl alcohol (5 mL). After purging with nitrogen three times, the reaction was carried out in an oil bath at 100 °C for 2 h. LC - MS showed that the reaction was completed. 30 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 132 (23 mg). ESI - MS: m / z = 583.51 [M + H] + 。

[0993] 1 H NMR (500 MHz, chloroform - d) δ 11.93 (s, 1H), 8.39 (d, J = 4.5 Hz, 1H), 8.15 (s, 1H), 7.65 (s, 1H), 7.13 (dd, J = 8.5, 6.1 Hz, 1H), 6.63–6.47 (m, 2H), 4.35 (dd, J = 10.6, 4.2 Hz, 2H), 4.08–4.05 (m, 1H), 3.98–3.93 (m, 2H), 3.78 (s, 3H), 3.37 (q, J = 8.3 Hz, 1H), 2.71 (d, J = 34.9 Hz, 6H), 2.63 (s, 3H), 2.47–2.38 (m, 1H), 2.32–2.24 (m, 1H), 2.24–2.12 (m, 3H), 2.09–1.88 (m, 3H), 1.85–1.77 (m, 2H), 1.60 (dq, J = 13.7, 7.1 Hz, 1H), 0.55 (d, J = 14.4 Hz, 1H), 0.44 (tt, J = 9.0, 4.4 Hz, 1H), 0.12 (ddt, J = 39.2, 8.8, 4.2 Hz, 1H), - 0.04 (q, J = 5.3, 4.6 Hz, 1H), - 0.30 (ddq, J = 28.3, 9.8, 5.1 Hz, 1H).

[0994] Example 133:

[0995]

[0996] (1) Preparation method of compound 133 - a:

[0997] (1R,3R)-3-Aminocyclopentanol hydrochloride (500 mg) was dispersed in tetrahydrofuran (10 mL). Aqueous solution of sodium hydroxide (363 mg) in water (3 mL) and di-tert-butyl dicarbonate (833 mg) were added successively. The reaction was carried out at 20 - 25 °C for 3 h. TLC showed that the reaction was complete. 20 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out to obtain compound 133-a (730 mg), which was directly used in the next step without purification.

[0998] (2) Preparation method of compound 133-b:

[0999] Compound 133-a (730 mg) was dispersed in ethyl acetate (20 mL). Triethylamine (731 mg) and ethylsulfonyl chloride (512 mg) were added successively to the reaction solution while controlling the temperature at 5 - 15 °C. The reaction was carried out at 5 - 15 °C for 0.5 h. TLC showed that the reaction was complete. The reaction solution was washed with water (20 mL × 2), and the ethyl acetate phase was retained, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out to obtain compound 133-b (1.05 g), which was directly used in the next step without purification.

[1000] (3) Preparation method of compound 133-c:

[1001] Compound 133-b (1.05 g) was dispersed in N,N-dimethylformamide (20 mL). Potassium carbonate (1.50 g), 4-dimethylaminopyridine (44 mg) and dimethylamine hydrochloride (5.86 g) were added successively. The reaction was carried out at 80 °C for 6 h. TLC was used to monitor until the reaction was complete. 100 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (50 mL × 2). The organic phases were combined and washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Then, column chromatography was carried out to obtain liquid 133-c (230 mg).

[1002] (4) Preparation method of compound 133-d:

[1003] Compound 133-c (230 mg) was dispersed in hydrochloric acid - methanol solution (4 M, 15 mL). The reaction was stirred at 20 - 25 °C for 1 h. TLC showed that the reaction was complete; the reaction solution was concentrated until no liquid flowed out, redissolved in methanol (15 mL), and then concentrated until no liquid flowed out to obtain compound 133-d (155 mg).

[1004] (5) Preparation method of Example 133:

[1005] Compound O (50 mg), 133-d (25 mg), Pd 2 (dba) 3(29 mg), 2 - Di - tert - butylphosphino - 2',4',6' - triisopropylbiphenyl (27 mg), potassium tert - butoxide (141 mg) were dispersed in tert - amyl alcohol (5 mL). After three nitrogen purges, the reaction was carried out in an oil bath at 100 °C for 2 h. LC - MS showed that the reaction was completed. 30 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid chromatography to obtain Example 133 (18 mg). ESI - MS: m / z = 583.53 [M + H] + 。

[1006] 1 H NMR (500 MHz, chloroform - d) δ 8.51 (s, 1H), 8.42 (d, J = 8.5 Hz, 1H), 8.13 (s, 1H), 7.71 (d, J = 24.2 Hz, 1H), 7.14 (dd, J = 18.5, 8.5 Hz, 1H), 6.62–6.49 (m, 2H), 4.35 (dt, J = 13.9, 4.1 Hz, 2H), 3.99–3.89 (m, 3H), 3.77 (s, 3H), 3.41–3.35 (m, 1H), 2.68 (d, J = 15.3 Hz, 6H), 2.61 (s, 3H), 2.38–2.31 (m, 1H), 2.28 (q, J = 6.6 Hz, 1H), 2.20–2.11 (m, 3H), 1.96 (dtd, J = 26.5, 18.1, 16.5, 10.2 Hz, 3H), 1.78 (q, J = 10.6, 9.1 Hz, 2H), 1.63–1.53 (m, 1H), 0.55–0.47 (m, 1H), 0.43 (dp, J = 9.1, 4.7 Hz, 1H), 0.10 (tt, J = 9.4, 4.9 Hz, 1H), - 0.01– - 0.08 (m, 1H), - 0.33 (dt, J = 8.8, 4.5 Hz, 1H).

[1007] Example 134:

[1008]

[1009] The compound O - 2 (50 mg), 133 - d (25 mg) in Example 8, Pd 2 (dba) 3(29 mg), 2 - bis - tert - butylphosphino - 2',4',6' - triisopropylbiphenyl (27 mg), potassium tert - butoxide (141 mg) were dispersed in tert - amyl alcohol (5 mL). After three - time nitrogen replacement, the reaction was carried out in an oil bath at 100 °C for 2 h. LC - MS showed that the reaction was completed. 30 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 134 (20 mg). ESI - MS: m / z = 583.51 [M + H] + 。

[1010] 1 H NMR (500 MHz, chloroform - d) δ 8.42 (d, J = 4.4 Hz, 3H), 8.14 (s, 1H), 7.68 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.59 (s, 1H), 6.50 (d, J = 8.5 Hz, 1H), 4.33 (tt, J = 8.7, 4.4 Hz, 2H), 4.09 (h, J = 6.1, 5.4 Hz, 1H), 4.00–3.92 (m, 2H), 3.78 (s, 3H), 3.45 (t, J = 8.5 Hz, 1H), 2.70 (d, J = 13.9 Hz, 6H), 2.61 (s, 3H), 2.41 (q, J = 9.2, 8.2 Hz, 2H), 2.30–2.13 (m, 4H), 2.04–1.92 (m, 2H), 1.84–1.74 (m, 2H), 1.65–1.55 (m, 1H), 0.56 (dq, J = 12.8, 6.6 Hz, 1H), 0.40 ...

Claims

1. A compound of formula I”, its stereoisomers or its pharmaceutically acceptable salts, wherein, R 1 selected from C 3-5 cycloalkyl, C 3-5 cycloalkyl-C 1-3 alkyl-, halo-C 1-6 alkyl or C 1-6 alkyl; R 2 selected from hydrogen, halogen, OH, NH 2 , C 1-8 alkyl or C 1-8 alkoxy, wherein the C 1-8 alkyl or C 1-8 alkoxy is optionally substituted by one or more R'; R’ is selected from halogen, OH, cyano, NH 2 or nitro; R 3 Selected from halogen, cyano, nitro, NH 2 , OH, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -NHR b , -NR a R b , -OR a , -SR a , -C(O)H, -C(O)R a , COOH, -C(O)OR a , -C(O)NH 2 , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -N(C 1-4 alkyl)C(O)R a , -S(O) 2 H, -S(O) 2 R a , -S(O) 2 NH 2 , -S(O) 2 NR a R b , -NHS(O) 2 R a , -NHC(O)OR a , -N(C 1-4 alkyl)C(O)OR a or -NHC(O)NHR a ; the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more R c ; The R c is selected from oxo, OH, NH 2 , halogen, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy, -N(C 1-8 alkyl) 2 , -NH(C 1-8 alkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -S(O) 2 R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , -C 1-6 alkyl-S(O) 2 , -C 1-6 alkyl or a 3-8 membered heteroalkyl optionally substituted with one or more groups independently selected from OH, halogen or C 1-6 alkyl; R a and R b are each independently selected from the following groups optionally substituted with one or more R": C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl; "R" are each independently selected from halogen, NH 2 , OH, oxo, deuterium, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkyl, -N(C 1-8 alkyl) 2 , -NH(C 1-8 alkyl), C 3-6 cycloalkyl or a 3- to 10-membered heterocycloalkyl optionally substituted with C 1-8 alkyl; n is selected from 0, 1, 2, 3 or 4; R 4 selected from C 1-6 alkyl or C 3-5 cycloalkyl, Provided that when R 1 is selected from C 1-6 alkyl, R 4 is selected from C 3-5 cycloalkyl.

2. The compound of formula I” according to claim 1, its stereoisomers or its pharmaceutically acceptable salts, which are selected from the compounds of formula I’, its stereoisomers or its pharmaceutically acceptable salts, wherein, R 1 selected from C 3-5 cycloalkyl, C 3-5 cycloalkyl-C 1-3 alkyl-, halo-C 1-6 alkyl or C 1-6 alkyl; R 2 selected from hydrogen, C 1-8 alkyl or C 1-8 alkoxy, wherein the C 1-8 alkyl or C 1-8 alkoxy is optionally substituted by one or more R'; R' is selected from halogen, hydroxy, cyano, amino or nitro; R 3 Selected from halogen, cyano, nitro, NH 2 , OH, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -NHR b , -NR a R b , -OR a , -SR a , -C(O)H, -C(O)R a , COOH, -C(O)OR a , -C(O)NH 2 , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -N(C 1-4 alkyl)C(O)R a , -S(O) 2 H, -S(O) 2 R a , -S(O) 2 NH 2 , -S(O) 2 NR a R b , -NHS(O) 2 R a , -NHC(O)OR a or -N(C 1-4 alkyl)C(O)OR a , wherein the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more R c ; The R c is selected from oxo, halogen, cyano, nitro, C 1-8 alkoxy, -N(C 1-8 alkyl) 2 , -NH(C 1-8 alkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -S(O) 2 R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or optionally a 3-8 membered heterocycloalkyl group substituted with one or more groups independently selected from hydroxy, halogen or C 1-6 alkyl; R a and R b are each independently selected from the following groups, optionally substituted with one or more R": C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl; "R” are each independently selected from halogen, NH 2 , OH, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy, -N(C 1-8 alkyl) 2 , -NH(C 1-8 alkyl), C 3-6 cycloalkyl or 3- to 10-membered heterocycloalkyl; n is selected from 0, 1, 2, 3 or 4; R 4 selected from C 1-6 alkyl or C 3-5 cycloalkyl, Provided that when R 1 is selected from C 1-6 alkyl, R 4 is selected from C 3-5 cycloalkyl.

3. The compound, its stereoisomers or its pharmaceutically acceptable salts according to claim 1 or 2, wherein R 1 is selected from C 3-4 cycloalkyl, C 3-4 cycloalkyl-C 1-2 alkyl-, halo-C 1-3 alkyl or C 1-3 alkyl; Optionally, said R 1 is selected from cyclopropyl, cyclopropyl-CH 2 -, halomethyl or methyl; Optionally, said R 1 is selected from cyclopropyl, cyclopropyl-CH 2 -, one or more fluorine-substituted methyl or methyl.

4. The compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1-3, wherein R 2 is selected from hydrogen, halogen, OH, NH 2 , C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted by one or more R'; Optionally, R 2 is selected from hydrogen, halogen, OH, NH 2 , C 1-3 alkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally substituted by one or more R'; Optionally, R 2 is selected from hydrogen, fluorine, chlorine, bromine, C 1-3 alkyl or C 1-3 alkoxy; Optionally, R 2 is selected from fluorine, chlorine, bromine or C 1-3 alkyl; Optionally, R 2 is selected from fluorine or methyl; Alternatively, R 2 is selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more R'; Optionally, R 2 is selected from hydrogen, C 1-3 alkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl or C 1-3 alkoxy is optionally substituted by one or more R'; Optionally, R 2 is selected from hydrogen, C 1-3 alkyl or C 1-3 alkoxy; Optionally, R 2 is selected from C 1-3 alkyl; Optionally, R 2 is selected from methyl; and / or, the R’ is selected from halogen.

5. The compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1-4, R 3 is selected from halogen, cyano, nitro, NH 2 , OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl, 5- to 6-membered heteroaryl, -NHR b , -NR a R b , -OR a , -SR a , -C(O)H, -C(O)R a , COOH, -C(O)OR a , -C(O)NH 2 , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -N(C 1-4 alkyl)C(O)R a , -S(O) 2 H, -S(O) 2 R a , -S(O) 2 NH 2 , -S(O) 2 , -S(O) a NR b , -NHS(O) 2 R a , -NHC(O)OR a , -N(C 1-4 alkyl)C(O)OR a or -NHC(O)NHR a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 6-membered heteroaryl is optionally substituted by one or more R c ; Optionally, R 3 is selected from halogen, cyano, nitro, NH 2 , OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heteroalkyl, phenyl, 5-6 membered heteroaryl, -NHR b , -NR a R b , -OR a , -SR a , -C(O)H, -C(O)R a , COOH, -C(O)OR a , -C(O)NH 2 , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -N(C 1-4 alkyl)C(O)R a , -S(O) 2 H, -S(O) 2 R a , -S(O) 2 NH 2 , -S(O) 2 NR a R b , -NHS(O) 2 R a , -NHC(O)OR a , -N(C 1-4 alkyl)C(O)OR a or -NHC(O)NHR a , wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heteroalkyl, phenyl, 5-6 membered heteroaryl are optionally substituted by one or more R c ; Optionally, R 3 is selected from halogen, cyano, NH 2 , OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, -NHR b , -NR a R b , -OR a , -SR a , -OC(O)R a , -NHC(O)R a , -N(C 1-4 alkyl)C(O)R a , -NHS(O) 2 R a , -NHC(O)OR a , -N(C 1-4 alkyl)C(O)OR a or -NHC(O)NHR a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocyclic group is optionally substituted by one or more R c ; Optionally, said R 3 is selected from fluorine, chlorine, bromine, C 1-4 alkyl, C 2-4 alkenyl, 4-6 membered heterocyclic group, -NHR b , -NR a R b , -OR a , -SR a , -OC(O)R a , -NHC(O)R a , -NHC(O)OR a , -N(C 1-4 alkyl)C(O)OR a or -NHC(O)NHR a ; said C 1-4 alkyl, C 2-4 alkenyl or 4-6 membered heterocyclic group is optionally substituted by one or more R c ; Optionally, said R 3 is selected from fluorine, chlorine, bromine, C 1-3 alkyl, C 2-4 alkenyl, 4-5 membered azacycloalkyl, -NHR b , -NR a R b , -OR a , -SR a , -OC(O)R a , -NHC(O)R a , -NHC(O)OR a , -N(C 1-4 alkyl)C(O)OR a or -NHC(O)NHR a ; said C 1-3 alkyl, C 2-4 alkenyl or 4-5 membered azacycloalkyl is optionally substituted by one or more R c ; Optionally, said R 3 is selected from bromine, methyl, butenyl, azetidinyl, pyrrolidinyl, -NHR b , -NR a R b , -OR a , -NHC(O)R a , or -NHC(O)NHR a ; said methyl, butenyl, azetidinyl or pyrrolidinyl is optionally substituted by one or more R c ; Optionally, said R 3 is selected from bromine, -NHR b 、-NR a R b 、-OR a 、-NHC(O)R a or -NHC(O)NHR a ; Optionally, said R 3 is selected from -NHR b , -NR a R b , -OR a , -NHC(O)R a or -NHC(O)NHR a ; Optionally, said R 3 is selected from -NHR b or -NR a R b ; Optionally, said R 3 is selected from -OR a ; Optionally, said R 3 is selected from -NHC(O)R a or -NHC(O)NHR a ; Alternatively, R 3 is selected from halogen, cyano, nitro, NH 2 , OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl, 5- to 6-membered heteroaryl, -NHR b , -NR a R b , -OR a , -SR a , -C(O)H, -C(O)R a , COOH, -C(O)OR a , -C(O)NH 2 , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -N(C 1-4 alkyl)C(O)R a , -S(O) 2 H, -S(O) 2 R a , -S(O) 2 NH 2 , -S(O) 2 NR a R b , -NHS(O) 2 R a , -NHC(O)OR a or -N(C 1-4 alkyl)C(O)OR a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 6-membered heteroaryl is optionally substituted by one or more R c ; Optionally, R 3 is selected from halogen, cyano, nitro, NH 2 , OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, -NHR b , -NR a R b , -OR a , -SR a , -C(O)H, -C(O)R a , COOH, -C(O)OR a , -C(O)NH 2 , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -N(C 1-4 alkyl)C(O)R a , -S(O) 2 H, -S(O) 2 R a , -S(O) 2 NH 2 , -S(O) 2 NR a R b , -NHS(O) 2 R a , -NHC(O)OR a or -N(C 1-4 alkyl)C(O)OR a , wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl is optionally substituted with one or more R c ; Optionally, R 3 is selected from halogen, cyano, nitro, NH 2 , OH, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -NHR b , -NR a R b , -OR a , -SR a , -C(O)H, -C(O)R a , COOH, -C(O)OR a , -C(O)NH 2 , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -N(C 1-3 alkyl)C(O)R a , -S(O) 2 H, -S(O) 2 R a , -S(O) 2 NH 2 , -S(O) 2 NR a R b , -NHS(O) 2 R a , -NHC(O)OR a or -N(C 1-3 alkyl)C(O)OR a , wherein the C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted by one or more R c ; Optionally, R 3 is selected from halogen, cyano, NH 2 , OH or -NHR b ; Optionally, R 3 is selected from fluorine, chlorine, bromine or -NHR b ; Optionally, R 3 is selected from bromine, and / or, n is selected from 0, 1, 2 or 3; optionally, n is selected from 0, 1 or 2; optionally, n is selected from 1 or 2; optionally, n is selected from 1.

6. The compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1-5, wherein R c is selected from OH, NH 2 , oxo, halogen, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, -N(C 1-6 alkyl) 2 , -NH(C 1-8 alkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -S(O) 2 R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , -C 1-6 alkyl-S(O) 2 , -C 1-6 alkyl or a 3-6 membered heterocycloalkyl optionally substituted with one or more groups independently selected from OH, halogen or C 1-4 alkyl; Optionally, said R c is selected from OH, NH 2 , oxo, halogen, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, -N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -S(O) 2 R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , -C 1-4 alkyl-S(O) 2 , -C 1-4 alkyl or optionally substituted with one or more groups independently selected from OH, halogen or C 1-3 alkyl substituted 4-6 membered heteroalkyl; Optionally, said R c is selected from OH, NH 2 , halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, -N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), -C 1-4 alkyl-S(O) 2 -C 1-4 alkyl or a 4-6 membered heterocycloalkyl optionally substituted with one or more groups independently selected from OH, halogen or C 1-3 alkyl; optionally, said R c is selected from OH, C 1-3 alkyl, -N(C 1-3 alkyl) 2 , -C 1-3 alkyl-S(O) 2 -C 1-3 alkyl or a 6 membered heterocycloalkyl optionally substituted with one or more groups independently selected from OH, halogen or C 1-3 alkyl; Optionally, said R c is selected from OH, C 1-3 alkyl, -N(C 1-3 alkyl) 2 , -C 1-3 alkyl-S(O) 2 -C 1-3 alkyl or a piperazinyl group optionally substituted with one or more C 1-3 alkyl; Optionally, said R c is selected from OH, methyl, Alternatively, said R c is selected from oxo, OH, NH 2 , halogen, cyano, nitro, C 1-8 alkoxy, -N(C 1-8 alkyl) 2 , -NH(C 1-8 alkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -S(O) 2 R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or optionally a 3-8 membered heterocycloalkyl group substituted with one or more groups independently selected from OH, halogen or C 1-6 alkyl; Optionally, said R c is selected from oxo, halogen, cyano, nitro, C 1-6 alkoxy, -N(C 1-6 alkyl) 2 , -NH(C 1-8 alkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -S(O) 2 R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or optionally a 3- to 6-membered heterocycloalkyl group substituted with one or more groups independently selected from hydroxy, halogen, or C 1-4 alkyl; Optionally, said R c is selected from oxo, halogen, cyano, nitro, C 1-4 alkoxy, -N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R b , -OC(O)R a , -NHC(O)R a , -S(O) 2 R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or a 4- to 6-membered heterocycloalkyl optionally substituted by one or more groups independently selected from hydroxy, halogen, or C 1-3 alkyl; Optionally, said R c is selected from oxo, halogen, cyano, C 1-4 alkoxy, -N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), or a 4-6 membered heterocycloalkyl optionally substituted with one or more groups independently selected from hydroxy, halogen or C 1-3 alkyl; and / or, said R a and R b are each independently selected from the following groups optionally substituted with one or more R": C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-8 membered heteroalkyl, C 6-10 aryl or 5-6 membered heteroaryl; Optionally, said R a and R b are each independently selected from the following groups optionally substituted with one or more R": C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl; Optionally, said R a and R b are each independently selected from the following groups which are optionally substituted by one or more R": C 1-8 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl; Optionally, said R a and R b are each independently selected from the following groups optionally substituted by one or more R": C 1-5 alkyl, C 3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl; Optionally, said R a and R b are each independently selected from the following groups which are optionally substituted by one or more R": methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl or piperidinyl; Alternatively, said R a and R b are each independently selected from the following groups optionally substituted with one or more R": C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heteroalkyl, phenyl or 5- to 6-membered heteroaryl; Optionally, said R a and R b are each independently selected from the following groups which are optionally substituted by one or more R": C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl; and / or, said R” is independently selected from halogen, oxo, deuterium, NH 2 , OH, cyano, nitro, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkoxy, -N(C 1-8 alkyl) 2 , -N(deuterio-C 1-8 alkyl) 2 , -NH(C 1-8 alkyl), C 3-6 cycloalkyl or a 3- to 10-membered heterocycloalkyl optionally substituted with C 1-8 alkyl; Optionally, each of said R” is independently selected from halogen, oxo, deuterium, NH 2 , OH, cyano, nitro, halo-C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, -N(C 1-6 alkyl) 2 , -N(deuterio-C 1-6 alkyl) 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with C 1-6 alkyl; Optionally, each of said R” is independently selected from halogen, oxo, deuterium, NH 2 , OH, cyano, nitro, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, -N(C 1-3 alkyl) 2 , -N(deuterated C 1-3 alkyl) 2 , -NH(C 1-3 alkyl), C 4-6 cycloalkyl or a 3-6 membered heterocycloalkyl optionally substituted with C 1-3 alkyl; Optionally, each of said R” is independently selected from fluorine, chlorine, bromine, oxo, deuterium, NH 2 , OH, cyano, C 1-4 alkyl, fluorinated C 1-4 alkyl, C 1-4 alkoxy, -N(C 1-4 alkyl) 2 , -N(deuterated C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), C 5-6 cycloalkyl or a 4-6 membered heterocycloalkyl optionally substituted with C 1-4 alkyl; Optionally, each of said R” is independently selected from fluorine, OH, oxo, deuterium, -NH 2 , methyl, ethyl, propyl, trifluoromethyl, -N(CH 3 ) 2 , -N(CD 3 ) 2 , -N(CH 2 CH 3 ) 2 , -NHCH 3 , morpholinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, 1,4-dioxanyl or oxetanyl optionally substituted with methyl or ethyl; Alternatively, the R” are each independently selected from halogen or 3- to 6-membered heterocycloalkyl; optionally, the R” are each independently selected from fluorine, chlorine, bromine or 6-membered heterocycloalkyl; optionally, the R” are each independently selected from fluorine or morpholinyl.

7. The compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1-6, R 4 is selected from C 1-3 alkyl or C 3-4 cycloalkyl; Optionally, R 4 is selected from methyl, ethyl, cyclopropyl or cyclobutyl; Optionally, R 4 is selected from methyl or cyclopropyl; Optionally, R 4 is selected from cyclopropyl; Optionally, R 4 is selected from methyl.

8. The compound, its stereoisomers or its pharmaceutically acceptable salts according to any one of claims 1-7, wherein the compound of formula I” is selected from compound I’A, formula I’B, formula I, formula IA, formula IB, formula I-1, formula I-1A, formula I-1B, formula I-2, formula I-2A, formula I-2B, formula II, formula IIA, formula IIB, formula II-1, formula II-1A, formula II-1B, formula II-2, formula II-2A, formula II-2B, formula III-1, formula III-1A, formula III-1B, formula III-2, formula III-2A, formula III-2B, formula IV, formula IVA, formula IVB, formula IV-1, formula IV-1A, formula IV-1B, formula IV-2, formula IV-2A or formula IV-2B, 9. The following compounds, their stereoisomers or their pharmaceutically acceptable salts:

10. A pharmaceutical composition comprising the compound, its stereoisomers or its pharmaceutically acceptable salts according to any one of claims 1-9.

11. Use of the compound, its stereoisomers or its pharmaceutically acceptable salts according to any one of claims 1-9, or the pharmaceutical composition according to claim 10 in the preparation of a drug for preventing or treating cancer; optionally, the cancer is selected from lung cancer; optionally, the cancer is selected from non-small cell lung cancer.

Images