Heterocyclic-substituted five-six-membered heteroaryl derivative, pharmaceutical composition thereof, application and preparation method of heterocyclic-substituted five-six-membered heteroaryl derivative

Abstract

The invention discloses a heterocyclic-substituted five-and six-membered heteroaryl derivative. The structure of the heterocyclic-substituted five-and six-membered heteroaryl derivative is shown as a formula (I). In addition, the invention also discloses pharmaceutically acceptable salts, stereoisomers, pharmaceutical compositions and applications of the derivatives. The compound provided by the invention has remarkable AAK1 selective inhibitory activity, lower hERG inhibitory effect and more excellent central nervous system permeability, and has very practical value. # imgabs0 #

Description

Heterocyclic substituted pentahedral and hexa-membered heteroaryl derivatives, pharmaceutical compositions thereof, and applications and preparation methods

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on December 13, 2022, with application number 202211604460.6 and invention name “Heterocyclic substituted five- and six-membered heteroaryl derivatives, their pharmaceutical compositions, applications and preparation methods”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present application relates to the field of medical technology, and in particular to a heterocyclic substituted five- and six-membered heteroaryl derivative, a pharmaceutically acceptable salt, a stereoisomer, a pharmaceutical composition, and an application and preparation method thereof. Background Art

[0003] The adaptor protein complex 2 (AP-2) is a heterotetramer composed of α, β, μ, and σ subunits. Clathrin-mediated endocytosis is initiated by recruiting the AP-2 complex to saturated protease-sensitive sites on the cell membrane. AAK1 (AP-2 associated kinase 1) was originally discovered as a phosphorylation-regulated kinase of AP-2, and both are involved in the formation of clathrin-coated vesicles. AAK1 changes the molecular conformation of AP-2 by phosphorylating the μ2 subunit of AP-2, enhancing the affinity of AP-2 for endocytic receptors, accelerating the formation of clathrin-coated vesicles, and thus improving endocytosis efficiency. AAK1 is widely expressed in the brain and spinal cord, including the dorsal root ganglia. GABA A Receptor (γ-aminobutyric acid type A receptor) related chloride ion channel is related to nociception, presumably reducing GABA A Increased cell surface levels of the μ2 receptor, and thus reduced endocytosis, are associated with the analgesic effects of AAK1 inhibitors. Phenotypic screening of AAK1 knockout mice revealed that AAK1 knockout mice are highly resistant to neuropathic pain, suggesting that targeting the adaptor-associated kinase 1 (AAK1) gene is a potential therapeutic target for neuropathic pain. Currently, only one small molecule AAK1 inhibitor is under development: LX9211, developed by Lexicon and Bristol-Myers Squibb, is in Phase II clinical trials. Preclinical studies have shown that LX9211 exhibits central nervous system penetration and reduced pain behavior in neuropathic pain models without affecting opioid pathways. However, previous studies have shown that LX9211 has relatively rapid clearance in rats, resulting in suboptimal in vivo exposure levels, severe hERG (human ether-à-go-go related gene) suppression, and potential cardiotoxicity. Therefore, the development of highly active AAK1 inhibitors with superior in vivo pharmacokinetic parameters and reduced hERG inhibition is of great clinical significance.

[0004] Summary of the Invention

[0005] The purpose of the present application is to provide a heterocyclic substituted five- and six-membered heteroaryl derivative having high activity as an AAK1 kinase inhibitor, excellent pharmacokinetic parameters, reduced hERG inhibitory effect, and excellent central nervous system penetration.

[0006] In a first aspect, the present application provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0007] In formula (I),

[0008] Z is C or N;

[0009] When Z is C,

[0010] R a For hydrogen, deuterium, -NR a0 R b0 , halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 alkyl), halogen (preferably fluorine, chlorine or bromine), 5 or 6 membered heteroaryl, cyano, hydroxy, carboxyl, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8 Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), halogenated C 1-8 Alkoxy (preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkoxy), -C(O)C 1-8 Alkyl (preferably -C(O)C 1-6 Alkyl, more preferably -C(O)C 1-3 alkyl), halo-C(O)C 1-8 Alkyl (preferably halo-C(O)C 1-6 Alkyl, more preferably halo-C(O)C 1-3 alkyl), -C(O)OC 1-8 Alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 Alkyl (preferably -OC(O)C 1-6 Alkyl, more preferably -OC(O)C 1-3 Alkyl), C2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl or -C(O)NR a1 R b1 The 5- or 6-membered heteroaryl group is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl;

[0011] R b is hydrogen, halogen (preferably fluorine or chlorine), halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 alkyl), cyano, hydroxyl, carboxyl, C 3-6 Cycloalkyl, C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8 Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), -C(O)C 1-8 Alkyl (preferably -C(O)C 1-6 Alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 Alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 Alkyl (preferably -OC(O)C 1-6 Alkyl, more preferably -OC(O)C 1-3 alkyl) or -C(O)NR a1 R b1 ;

[0012] or R a With R b connected to form a 5- or 6-membered heteroaryl ring, a benzene ring or a 5- or 6-membered heterocycloalkyl ring; wherein the 5- or 6-membered heteroaryl ring, the benzene ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl; the 5 or 6 membered heterocycloalkyl ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, oxo, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl;

[0013] When Z is N,

[0014] R a For hydrogen, deuterium, -NR a0 R b0 , halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 alkyl), halogen (preferably fluorine or chlorine), cyano, hydroxy, carboxyl, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, C1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8 Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), halogenated C 1-8 Alkoxy (preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkoxy), -C(O)C 1-8 Alkyl (preferably -C(O)C 1-6 Alkyl, more preferably -C(O)C 1-3 alkyl), halo-C(O)C 1-8 Alkyl (preferably halo-C(O)C 1-6 Alkyl, more preferably halo-C(O)C 1-3 alkyl), -C(O)OC 1-8 Alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 Alkyl (preferably -OC(O)C 1-6 Alkyl, more preferably -OC(O)C 1-3 Alkyl), C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl or -C(O)NR a1 R b1 ;

[0015] R b does not exist;

[0016] or R a With R b connected to form a 5- or 6-membered heteroaryl ring, or a 5- or 6-membered heterocycloalkyl ring; wherein the 5- or 6-membered heteroaryl ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)C 1-3 Alkyl, -SC 1-3 Alkyl and C 3-6 Cycloalkyl; the 5 or 6 membered heterocycloalkyl ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, oxo, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl; the C 2-4 The alkenyl group is substituted by 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) or haloC 1-3 Alkyl; the C 2-4 The alkynyl group is substituted by 0 or 1 substituents selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) or haloC 1-3 alkyl;

[0017] R a0 、R b0 are independently hydrogen, C 1-3 Alkyl, -C(O)C 1-8 Alkyl, -C(O)OC 1-8 Alkyl, halogenated C 1-8 alkyl, 5- or 6-membered heteroaryl, -C(O)C 3-6 Cycloalkyl, -C(O)NR a1 R b1 or -C(O)R, R is a 5- or 6-membered heteroaryl group; or R a0 、R b0 Together with the connected nitrogen atom, it forms a 4- to 6-membered saturated monocyclic heterocyclic ring; the 5- or 6-membered heteroaryl group and the 4- to 6-membered saturated monocyclic heterocyclic ring are each independently unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl;

[0018] R c 、R d are independently hydrogen, halogen (preferably fluorine or chlorine), halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 alkyl), cyano, hydroxyl, carboxyl, C 3-6 Cycloalkyl, C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), -NR a1 R b1 or C 1-8 Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 alkoxy);

[0019] U1 and U2 are N or C; and U1 and U2 are not N or C at the same time;

[0020] Ring A is a 5-membered heteroaryl ring;

[0021] (R1) n Indicates that the hydrogen on ring A is replaced by n R1, n is 0, 1, 2 or 3; each R1 is the same or different and is independently cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -NR a1 R b1 、C 3-6 Cycloalkyl, C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8 Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), -C(O)C 1-8 Alkyl (preferably -C(O)C 1-6 Alkyl, more preferably -C(O)C 1-3alkyl), -C(O)OC 1-8 Alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 Alkyl (preferably -OC(O)C 1-6 Alkyl, more preferably -OC(O)C 1-3 alkyl) or -C(O)NR a1 R b1 ; wherein said C 1-8 Alkyl, the C 1-8 Each alkoxy group is independently unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl;

[0022] R0 is hydrogen or C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 alkyl);

[0023] R2 and R3 are each independently C 1-3 Alkyl; or R2, R3 and the connected carbon atom together form C 3-6 cycloalkyl ring;

[0024] R a1 、R b1 are independently hydrogen, C 1-3 Alkyl or acetyl; or R a1 、R b1 Together with the nitrogen atom to which it is connected, it forms a 4- to 6-membered saturated monocyclic heterocycle; the 4- to 6-membered saturated monocyclic heterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl;

[0025] The heteroatoms on the heteroaryl or heteroaryl ring, heterocycloalkyl or heterocycloalkyl ring, and saturated monocyclic heterocycle are independently selected from N, O, and S.

[0026] In some embodiments, the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof is:

[0027] In formula (I),

[0028] Z is C or N;

[0029] When Z is C,

[0030] R a For hydrogen, deuterium, -NR a0 R b0 , halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 alkyl), halogen (preferably fluorine or chlorine), 5- or 6-membered heteroaryl, cyano, hydroxy, carboxyl, C 3-6 Cycloalkyl, C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8 Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), halogenated C 1-8 Alkoxy (preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkoxy), -C(O)C 1-8 Alkyl (preferably -C(O)C 1-6 Alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 Alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC1-3 alkyl), -OC(O)C 1-8 Alkyl (preferably -OC(O)C 1-6 Alkyl, more preferably -OC(O)C 1-3 alkyl) or -C(O)NR a1 R b1 wherein the 5- or 6-membered heteroaryl group is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl;

[0031] R b is hydrogen, halogen (preferably fluorine or chlorine), halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 alkyl), cyano, hydroxyl, carboxyl, C 3-6 Cycloalkyl, C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8 Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), -C(O)C 1-8 Alkyl (preferably -C(O)C 1-6 Alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 Alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 Alkyl (preferably -OC(O)C 1-6 Alkyl, more preferably -OC(O)C 1-3 alkyl) or -C(O)NR a1R b1 ;

[0032] or R a With R b connected to form a 5- or 6-membered heteroaryl ring, a benzene ring or a 5- or 6-membered heterocycloalkyl ring; wherein the 5- or 6-membered heteroaryl ring, the benzene ring is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl; the 5 or 6 membered heterocycloalkyl ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, oxo, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl;

[0033] When Z is N,

[0034] R a For hydrogen, deuterium, -NR a0 R b0 , halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 alkyl), halogen (preferably fluorine or chlorine), cyano, hydroxy, carboxyl, C 3-6 Cycloalkyl, C1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8 Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), halogenated C 1-8 Alkoxy (preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkoxy), -C(O)C 1-8 Alkyl (preferably -C(O)C 1-6 Alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 Alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 Alkyl (preferably -OC(O)C 1-6 Alkyl, more preferably -OC(O)C 1-3 alkyl) or -C(O)NR a1 R b1 ;

[0035] R b does not exist;

[0036] or R a With R b connected to form a 5- or 6-membered heteroaryl ring, or a 5- or 6-membered heterocycloalkyl ring; wherein the 5- or 6-membered heteroaryl ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)C 1-3 Alkyl, -SC 1-3 Alkyl and C 3-6Cycloalkyl; the 5 or 6 membered heterocycloalkyl ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, oxo, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl; the C 2-4 The alkenyl group is substituted by 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) or haloC 1-3 Alkyl; the C 2-4 The alkynyl group is substituted by 0 or 1 substituents selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) or haloC 1-3 alkyl;

[0037] R a0 、R b0 are independently hydrogen, C 1-3 Alkyl, -C(O)C 1-8 Alkyl, -C(O)OC 1-8 Alkyl, halogenated C 1-8 alkyl, 5- or 6-membered heteroaryl, -C(O)C 3-6 Cycloalkyl, -C(O)NR a1 R b1 or -C(O)R, R is a 5- or 6-membered heteroaryl group; or R a0 、R b0 Together with the nitrogen atom connected thereto, they form a 4- to 6-membered saturated monocyclic heterocycle; the 5- or 6-membered heteroaryl group and the 4- to 6-membered saturated monocyclic heterocycle are each independently unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl;

[0038] R c 、R d are independently hydrogen, halogen (preferably fluorine or chlorine), halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 alkyl), cyano, hydroxyl, carboxyl, C 3-6 Cycloalkyl, C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), -NR a1 R b1 or C 1-8 Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 alkoxy);

[0039] U1 and U2 are N or C; and U1 and U2 are not N or C at the same time;

[0040] Ring A is a 5-membered heteroaryl ring;

[0041] (R1) n Indicates that the hydrogen on ring A is replaced by n R1, n is 0, 1, 2 or 3; each R1 is the same or different and is independently cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -NR a1 R b1 、C 3-6 Cycloalkyl, C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8 Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), -C(O)C 1-8 Alkyl (preferably -C(O)C 1-6 Alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 Alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C1-8 Alkyl (preferably -OC(O)C 1-6 Alkyl, more preferably -OC(O)C 1-3 alkyl) or -C(O)NR a1 R b1 ; wherein said C 1-8 Alkyl, the C 1-8 Each alkoxy group is independently unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl;

[0042] R0 is hydrogen or C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 alkyl);

[0043] R2 and R3 are each independently C 1-3 Alkyl; or R2, R3 and the connected carbon atom together form C 3-6 cycloalkyl ring;

[0044] R a1 、R b1 are independently hydrogen, C 1-3 Alkyl or acetyl; or R a1 、R b1 Together with the nitrogen atom to which it is connected, it forms a 4- to 6-membered saturated monocyclic heterocycle; the 4- to 6-membered saturated monocyclic heterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl;

[0045] The heteroatoms on the heteroaryl or heteroaryl ring, heterocycloalkyl or heterocycloalkyl ring, and saturated monocyclic heterocycle are independently selected from N, O, and S.

[0046] In some embodiments, the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof is:

[0047] In formula (I),

[0048] Z is C or N;

[0049] When Z is C,

[0050] R a -NR a0 R b0 , halogenated C 3-6 Cycloalkyl, halo-C(O)C 1-8 Alkyl (preferably halo-C(O)C 1-6 Alkyl, more preferably halo-C(O)C 1-3 Alkyl), C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl or halogenated C 2-6 Alkynyl;

[0051] R a0 、R b0 Together with the nitrogen atom to which it is connected, it forms a 4- to 6-membered saturated monocyclic heterocyclic ring; the 4- to 6-membered saturated monocyclic heterocyclic ring is independently unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of oxo;

[0052] R b is hydrogen, halogen (preferably fluorine or chlorine), halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 alkyl), cyano, hydroxyl, carboxyl, C 3-6 Cycloalkyl, C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), -C(O)C 1-8 Alkyl (preferably -C(O)C 1-6 Alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 Alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 Alkyl (preferably -OC(O)C 1-6 Alkyl, more preferably -OC(O)C 1-3 alkyl) or -C(O)NR a1 R b1 ;

[0053] When Z is N,

[0054] R a Halogenated C 3-6 Cycloalkyl, halo-C(O)C 1-8 Alkyl (preferably halo-C(O)C 1-6 Alkyl, more preferably halo-C(O)C 1-3 Alkyl), C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl or halogenated C 2-6 Alkynyl;

[0055] R b does not exist;

[0056] R c 、R d are independently hydrogen, halogen (preferably fluorine or chlorine), halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 alkyl), cyano, hydroxyl, carboxyl, C 3-6 Cycloalkyl, C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), -NR a1 R b1 or C 1-8 Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 alkoxy);

[0057] U1 and U2 are N or C; and U1 and U2 are not N or C at the same time;

[0058] Ring A is a 5-membered heteroaryl ring;

[0059] (R1) n Indicates that the hydrogen on ring A is replaced by n R1, n is 0, 1, 2 or 3; each R1 is the same or different and is independently cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -NR a1 R b1 、C 3-6 Cycloalkyl, C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8 Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), -C(O)C 1-8 Alkyl (preferably -C(O)C 1-6 Alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 Alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 Alkyl (preferably -OC(O)C 1-6 Alkyl, more preferably -OC(O)C 1-3 alkyl) or -C(O)NR a1 R b1 ; wherein said C 1-8 Alkyl, the C 1-8 Each alkoxy group is independently unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl;

[0060] R0 is hydrogen or C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3alkyl);

[0061] R2 and R3 are each independently C 1-3 Alkyl; or R2, R3 and the connected carbon atom together form C 3-6 cycloalkyl ring;

[0062] R a1 、R b1 are independently hydrogen, C 1-3 Alkyl or acetyl; or R a1 、R b1 Together with the nitrogen atom to which it is connected, it forms a 4- to 6-membered saturated monocyclic heterocycle; the 4- to 6-membered saturated monocyclic heterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl;

[0063] The heteroatom in the saturated monocyclic heterocycle is selected from N, O, and S.

[0064] In some embodiments, when Z is C, R a is tetrahydropyrrolyl, oxazolidin-2-one, pyrrolidin-2-one, fluoro C 3-6 Cycloalkyl, fluoro-C(O)C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 2-4 Alkenyl or halogenated C 2-4 Alkynyl.

[0065] In some embodiments, when Z is C, R a is tetrahydropyrrolyl, oxazolidin-2-onyl, pyrrolidin-2-onyl, fluorocyclopropyl, fluoroacetyl, vinyl, ethynyl, fluorovinyl or fluoroethynyl.

[0066] In some embodiments, when Z is C, Ra It is tetrahydropyrrolyl, oxazolidin-2-one, pyrrolidin-2-one, difluorocyclopropyl, difluoroacetyl, vinyl, monofluorovinyl or difluorovinyl.

[0067] In some embodiments, when Z is N, R a is tetrahydropyrrolyl, oxazolidin-2-one, pyrrolidin-2-one, fluoro C 3-6 Cycloalkyl, fluoro-C(O)C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 2-4 Alkenyl or halogenated C 2-4 Alkynyl.

[0068] In some embodiments, when Z is N, R a is tetrahydropyrrolyl, oxazolidin-2-onyl, pyrrolidin-2-onyl, fluorocyclopropyl, fluoroacetyl, vinyl, ethynyl, fluorovinyl or fluoroethynyl.

[0069] In some embodiments, when Z is N, R a It is tetrahydropyrrolyl, oxazolidin-2-one, pyrrolidin-2-one, difluorocyclopropyl, difluoroacetyl, vinyl, monofluorovinyl or difluorovinyl.

[0070] In some embodiments, the compound of formula (I) is represented by formula (II):

[0071] In some embodiments, the structure A structure selected from one of the following groups:

[0072] In some embodiments, the structure A structure selected from one of the following groups:

[0073] In some embodiments, Z is C; R a For hydrogen, deuterium, -NR a0 R b0 , halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl), halogenated C 1-8 Alkoxy (preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkoxy), C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3alkyl), halogen (preferably fluorine or chlorine), C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, -C(O)NR a1 R b1 , halogenated-C(O)C 1-8 Alkyl (preferably halo-C(O)C 1-6 Alkyl, more preferably halo-C(O)C 1-3 wherein the 5- or 6-membered heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl;

[0074] R a0 、R b0 are independently hydrogen, C 1-3 Alkyl, -C(O)C 1-8 Alkyl, -C(O)OC 1-8 Alkyl, halogenated C 1-8 alkyl, 5- or 6-membered heteroaryl, -C(O)C 3-6 Cycloalkyl, -C(O)NR a1 R b1 or -C(O)R, R is a 5- or 6-membered heteroaryl; wherein each occurrence of the 5- or 6-membered heteroaryl is independently unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NH2, -C(O)NH(C1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl;

[0075] R b is hydrogen or halogen (preferably fluorine or chlorine).

[0076] In some embodiments, Z is C; R a For hydrogen, deuterium, -NR a0 R b0 , halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl), C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), halogenated C 1-8 Alkoxy (preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 alkoxy), halogen (preferably fluorine or chlorine), -C(O)NR a1 R b1 、C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, halo-C(O)C 1-8 Alkyl (preferably halo-C(O)C 1-6 Alkyl, more preferably halo-C(O)C 1-3 wherein the pyrazolyl and thiazolyl are each independently unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, C 1-3 Alkyl and halogenated C 1-3 alkyl;

[0077] R a0 、R b0 are independently hydrogen, C 1-3 Alkyl, -C(O)C 1-8 Alkyl, -C(O)OC 1-8 Alkyl, halogenated C 1-8 Alkyl, pyrazolyl, thiazolyl, -C(O)C 3-6 Cycloalkyl, -C(O)NR a1 R b1or -C(O)R, R is pyrazolyl or thiazolyl; wherein each occurrence of the pyrazolyl and thiazolyl groups is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen, C 1-3 Alkyl and halogenated C 1-3 alkyl;

[0078] R b is hydrogen or halogen (preferably fluorine or chlorine).

[0079] In some embodiments, Z is C; R a For hydrogen, deuterium, -NR a0 R b0 , halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl), C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), halogenated C 1-8 Alkoxy (preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 alkoxy), halogen (preferably fluorine or chlorine), -C(O)NR a1 R b1 , cyclopropyl, fluorocyclopropyl, fluoroacetyl, pyrazolyl or thiazolyl; wherein the pyrazolyl and thiazolyl are each independently unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, C 1-3 Alkyl and halogenated C 1-3 alkyl;

[0080] R a0 、R b0 are independently hydrogen, C 1-3 Alkyl, -C(O)C 1-8 Alkyl, -C(O)OC 1-8 Alkyl, halogenated C 1-8 Alkyl, pyrazolyl, thiazolyl, -C(O)C 3-6 Cycloalkyl, -C(O)NR a1 R b1 or -C(O)R, R is pyrazolyl or thiazolyl; wherein each occurrence of the pyrazolyl and thiazolyl groups is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen, C 1-3 Alkyl and halogenated C 1-3 alkyl;

[0081] R b is hydrogen or halogen (preferably fluorine or chlorine).

[0082] In some embodiments, Z is C; R a is hydrogen, deuterium, halogen, -NH2, -NHCH3, -NH-difluoroethyl, difluoromethyl, trifluoromethyl, monofluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, monofluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, methyl, ethyl, propyl, isopropyl, -NHCOCH3, -NHCOOCH3, -NHCO-cyclopropyl, -NHCO-thiazole, -NHCO-tetrahydropyrrole, -NHCONHCH2CH3, pyrazolyl, methylpyrazolyl, -NH-methylpyrazol, -NH-thiazole, -NH-methylthiazole, -CONH2, cyclopropyl, difluorocyclopropyl, difluoroacetyl, tetrahydropyrrolyl, oxazolidin-2-onyl or pyrrolidin-2-onyl;

[0083] R b is hydrogen, fluorine or chlorine.

[0084] In some embodiments, Z is C; R a With R b connected to form a 5- or 6-membered heteroaryl ring, a benzene ring or a 5- or 6-membered heterocycloalkyl ring; the 5- or 6-membered heteroaryl ring, the benzene ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl; the 5 or 6 membered heterocycloalkyl ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, oxo, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl.

[0085] In some embodiments, Z is C; R a With R b Connected to form:

[0086] (i) a benzene ring or a 5- or 6-membered heteroaryl ring selected from the group consisting of a thiophene ring, a furan ring, a thiazole ring, an isothiazole ring, an imidazole ring, an oxazole ring, a pyrrole ring, a pyrazole ring, a triazole ring (including a 1,2,3-triazole ring, a 1,2,4-triazole ring, a 1,2,5-triazole ring, and a 1,3,4-triazole ring), a tetrazole ring, an isoxazole ring, an oxadiazole ring (including a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, a 1,2,5-oxadiazole ring, and a 1,3,4-oxadiazole ring), a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, and a tetrazine ring; the 5- or 6-membered heteroaryl ring and the benzene ring are unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2、-C(O)NH2、-C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 cycloalkyl; or

[0087] (ii) a 5- or 6-membered heterocycloalkyl ring selected from the group consisting of a tetrahydrofuran ring, a tetrahydrothiophene ring, a tetrahydropyrrole ring, a piperidine ring, a pyrroline ring, an oxazolidine ring, a piperazine ring, a dioxolane ring, a dioxane ring, a morpholine ring, a thiomorpholine ring, a thiomorpholine-1,1-dioxide ring, and a tetrahydropyran ring; the 5- or 6-membered heterocycloalkyl ring being unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from the group consisting of deuterium, oxo, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl.

[0088] In some embodiments, Z is N; R a With R b The 5-membered heteroaryl ring is connected to form a 5-membered heteroaryl ring, wherein the 5-membered heteroaryl ring is selected from the group consisting of: thiazole ring, isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring (including 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring), isoxazole ring, oxadiazole ring (including 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring) and thiadiazole ring; the 5-membered heteroaryl ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -C(O)NH2、-C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)C 1-3 Alkyl, -SC 1-3 Alkyl and C 3-6 Cycloalkyl; the C 2-4 The alkenyl group is substituted by 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) or haloC1-3 Alkyl; the C 2-4 The alkynyl group is substituted by 0 or 1 substituents selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) or haloC 1-3 alkyl.

[0089] In some embodiments, Z is N; R a For hydrogen, deuterium, -NR a0 R b0 , halogenated C 1-3 Alkyl, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, -C(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, C 3-6 Cycloalkyl, C 2-4 Alkenyl or -OC(O)C 1-3 alkyl;

[0090] R a0 、R b0 are independently hydrogen, C 1-3 Alkyl, -C(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, halogenated C 1-3 Alkyl, -C(O)NR a1 R b1 .

[0091] In some embodiments, Z is N; R a For hydrogen, deuterium, halogen, fluorinated C 1-3 Alkyl, chloro C 1-3 Alkyl, C 1-3 Alkyl, amino, hydroxy, -NHC(O)C 1-3 Alkyl, -NHC(O)OC 1-3 Alkyl, cyclopropyl, vinyl or -NHC(O)NR a1 R b1 .

[0092] In some embodiments, Z is N; R a is hydrogen, deuterium, fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, dichloroethyl, trichloroethyl, methyl, ethyl, fluorine, chlorine, -NH2, -NHCOOCH3, -NHCOOCH2CH3, -NHCOCH3, -NHCOCH2CH3, -NHC(O)NH2, cyclopropyl, vinyl or

[0093] In some embodiments, the structure Select one of the following structures:

[0094] where R s1 、R s2 、R s3 、R s4 、R s5 、R s6 、R s7 、R s8 、R s9 、R s10 、R s11 、R s12 、R s13 、R s14 、R s15 、R s16 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -SC 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)C 1-3 Alkyl or C 3-6 Cycloalkyl; the C 2-4 The alkenyl group is substituted by 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) or haloC 1-3 Alkyl; the C 2-4 The alkynyl group is substituted by 0 or 1 substituents selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) or haloC 1-3 alkyl;

[0095] m1, m3, m6, and m10 are each independently 0, 1, or 2; m2 is 0, 1, 2, 3, or 4; m4, m7, m8, m9, m11, m12, m13, and m14 are each independently 0 or 1; and m5 is 0, 1, 2, or 3.

[0096] In some embodiments, the structure A structure selected from one of the following groups:

[0097] where R s1 、R s2 、R s3 、R s4 、R s5 、R s6 、R s7 、R s8 、R s9 、R s10 、R s11 、R s12 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -SC 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)C 1-3 Alkyl or C 3-6 Cycloalkyl; the C 2-4 The alkenyl group is substituted by 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) or haloC 1-3 Alkyl; the C 2-4 The alkynyl group is substituted by 0 or 1 substituents selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) or haloC 1-3 alkyl;

[0098] m1, m3, m6, and m10 are each independently 0, 1, or 2; m2 is 0, 1, 2, 3, or 4; m4, m7, m8, and m9 are each independently 0 or 1; and m5 is 0, 1, 2, or 3.

[0099] In some embodiments, R s1 、R s2 、R s3 、R s4 、R s5、 Rs6、 R s7、 R s8、 R s9、 R s10、 R s11、 R s12 Each is independently hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, ethynyl, propynyl, butynyl, vinyl, 1-fluorovinyl, 1-trifluoromethylvinyl, 2,2-difluorovinyl, -SCH3, -SC2H5, -SC3H7, -SCH(CH3)2, methoxy, ethoxy, n-propoxy, isopropoxy, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -C(O)NH2、-C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl)2, -C(O)CH3, -C(O)OCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0100] In some embodiments, R c is hydrogen, halogen, -NR a1 R b1 or halogenated C 1-3 Further, R c is hydrogen, chlorine, fluorine, amino or difluoromethyl.

[0101] In some embodiments, R d is hydrogen or halogen. Further, R d is hydrogen, fluorine or chlorine.

[0102] In some embodiments, the compound of formula (I) is a compound of formula (XII):

[0103] In some embodiments, the compound of formula (I) is a compound of formula (III):

[0104] where R s5 Each occurrence is independently hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -SC 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)C 1-3 Alkyl or C 3-6 Cycloalkyl; the C 2-4 The alkenyl group is substituted by 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) or haloC 1-3 alkyl;

[0105] m3 is 0, 1, or 2;

[0106] R c 、R d are independently hydrogen, fluorine, chlorine, halogenated C 1-3 Alkyl, cyano, hydroxyl, carboxyl, C 3-6 Cycloalkyl, C 1-3 Alkyl, -NR a1 R b1 or C 1-3 alkoxy;

[0107] (R1) n Indicates that the hydrogen on ring A is replaced by n R1, n is 0, 1 or 2; each R1 is the same or different and is independently cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -NR a1 R b1 、C 3-6 Cycloalkyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -C(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl or -C(O)NR a1 R b1 ;

[0108] R0 is hydrogen or C 1-3 alkyl;

[0109] R2 and R3 are each independently C 1-3 Alkyl; or R2, R3 and the connected carbon atom together form C 3-6 Cycloalkyl ring.

[0110] In some embodiments, R2 and R3 are each independently methyl; or R2, R3 and the carbon atom to which they are attached together form a cyclopropyl ring.

[0111] In some embodiments, the structure A structure selected from one of the following groups:

[0112] In some embodiments, the structure A structure selected from one of the following groups:

[0113] In some embodiments, the structure A structure selected from one of the following groups:

[0114] In some embodiments, the structure A structure selected from one of the following groups:

[0115] In some embodiments, the structure A structure selected from one of the following groups:

[0116] In some embodiments, the structure A structure selected from one of the following groups:

[0117] In some embodiments, the structure A structure selected from one of the following groups:

[0118] In some embodiments, in the above structural formulas, the 5- or 6-membered heteroaryl (ring) in each group is independently selected from the group consisting of: thienyl, furyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl), tetrazolyl, isoxazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl.

[0119] In some embodiments, in the above structural formulas, the 3- to 6-membered heterocycloalkyl group in each group is a 4- to 6-membered heterocycloalkyl group, each independently selected from the group consisting of: azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, oxazolidinyl, dioxolane, piperidinyl, piperazinyl, morpholinyl, dioxane, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetrahydropyranyl, pyrrolidin-2-one, dihydrofuran-2(3H)-one, morpholin-3-one, piperazin-2-one and piperidin-2-one.

[0120] In some embodiments, R a With R b The 5- or 6-membered heterocycloalkyl rings formed by connecting are independently selected from the group consisting of a tetrahydrofuran ring, a tetrahydrothiophene ring, a tetrahydropyrrole ring, a piperidine ring, a piperazine ring, a morpholine ring, and a tetrahydropyran ring.

[0121] In some embodiments, in each of the above structural formulas, the 4- to 6-membered saturated monocyclic heterocycle is independently selected from: an azetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a tetrahydropyrrole ring, a piperidine ring, a piperazine ring, a morpholine ring, a thiomorpholine ring, a thiomorpholine-1,1-dioxide and a tetrahydropyran ring.

[0122] In some embodiments, R0 is hydrogen or C 1-3 Alkyl; further, R0 is hydrogen or methyl.

[0123] In some embodiments, R2 is methyl.

[0124] In some embodiments, R3 is methyl.

[0125] In some embodiments, R2, R3 and the carbon atom to which they are attached together form a cyclopropyl ring.

[0126] In some embodiments, the compound of formula (I) is any one of the following compounds:

[0127] In some embodiments, the compound of formula (I) is any one of the following compounds:

[0128] The second aspect of the present application provides a pharmaceutical composition comprising the compound described in the first aspect of the present application, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0129] The third aspect of the present application provides use of the compound described in the first aspect of the present application, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition described in the second aspect of the present application in the preparation of an AAK1 activity inhibitor.

[0130] In some embodiments, the AAK1 activity inhibitor is used to treat or manage a disease or condition associated with or mediated by AAK1 activity.

[0131] In some embodiments, the disease or condition is pain. In some embodiments, the pain is neuropathic pain. In some embodiments, the neuropathic pain is fibromyalgia or peripheral neuropathy.

[0132] A fourth aspect of the present application provides a method for treating or controlling a disease or condition mediated by AAK1 activity, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof. In some embodiments, the disease or condition is pain. In some embodiments, the pain is neuropathic pain. In some embodiments, the neuropathic pain is fibromyalgia or peripheral neuropathy.

[0133] In a fifth aspect, the present application provides a compound represented by formula (IV), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0134] In formula (IV), Z, U1, U2, ring A, R a 、R b 、R c 、R d 、(R1) n As described in the instructions.

[0135] In some embodiments, the compound of formula (IV) is any one of the following compounds:

[0136] The sixth aspect of the present application provides a method for preparing the compound represented by formula (IV) according to the fifth aspect, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, comprising the following steps:

[0137] S100: performing a coupling reaction between the compound represented by formula (III-A) and the compound represented by formula (III-B) to obtain the compound represented by formula (III);

[0138] in,

[0139] Z, U1, U2, Ring A, R a 、R b 、Rc 、R d 、(R1) n As stated in the instructions,

[0140] R G1 、R G2 A pair of groups that can undergo coupling reaction,

[0141] R4 is a hydroxyl protecting group;

[0142] S200: reacting the compound represented by formula (III) to obtain the compound represented by formula (IV).

[0143] in,

[0144] Z, U1, U2, Ring A, R a 、R b 、R c 、R d 、(R1) n As stated in the instructions,

[0145] R4 is a hydroxyl protecting group.

[0146] It is understandable that the compound of formula (III) obtained in step S100 can be modified by methods well known in the art (such as modifying the amino group through an acylation reaction, or converting the halogen into an amino group, or alkylating the amino group, etc.). The modification method is not particularly limited, as long as it does not conflict with the purpose of the invention of this application, and it should be understood that it is within the scope of protection of this application.

[0147] In some embodiments, the hydroxyl protecting group is a common hydroxyl protecting group commonly used by those skilled in the art, including but not limited to C 1-6 Alkyl (preferably C 1-3 alkyl), benzyl, -Cbz, -Boc, etc.

[0148] In some embodiments, R G1 、R G2 A pair of groups that can undergo Suzuki coupling reaction.

[0149] In some embodiments, R G1 and R G2 One of them is a halogen and one is (HO)2B- or a borate group (including a pinacol borate group).

[0150] In some embodiments, R G1 is Br, Cl or I; R G2 is (HO)2B- or a borate group (including a pinacol borate group).

[0151] In some embodiments, RG2 is Br, Cl or I; R G1 is (HO)2B- or a borate group (including a pinacol borate group).

[0152] In some embodiments, R G1 、R G2 A pair of groups that can undergo Stille coupling reaction.

[0153] In some embodiments, R G1 and R G2 One of them is halogen and the other is -SnBu3 or -SnMe3.

[0154] In some embodiments, R G1 is Br, Cl or I; R G2 is -SnBu3 or -SnMe3.

[0155] In some embodiments, R G2 is Br, Cl or I; R G1 is -SnBu3 or -SnMe3.

[0156] In some embodiments, step S100 includes the following steps:

[0157] S110: Mixing the compound represented by formula (III-A), the compound represented by formula (III-B), a solvent, a catalyst and a base to react to obtain the compound represented by formula (I).

[0158] In some embodiments, step S100 includes the following steps:

[0159] S120: Mixing the compound represented by formula (III-A), the compound represented by formula (III-B), a solvent and a catalyst to react to obtain the compound represented by formula (I).

[0160] In some embodiments, in step S110 or step S120, the solvent is selected from: toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, ethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, methanol, ethanol, propanol, isopropanol, butanol, water and combinations thereof.

[0161] In some embodiments, in step S110 or step S120, the solvent is a mixed solvent consisting of 1,4-dioxane and water; further, the volume ratio of 1,4-dioxane to water is about (2-12):1.

[0162] In some embodiments, in step S110 or step S120, the catalyst is a palladium catalyst; further, the palladium catalyst is selected from the group consisting of palladium on carbon, tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (PddppfCl2), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, XPhos Pd G2, palladium acetate, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, triphenylphosphine palladium acetate, bis(tri-o-phenylmethylphosphine)palladium dichloride, 1,2-bis(diphenylphosphino)ethanepalladium dichloride, bis(triphenylphosphine)palladium chloride, and combinations thereof. Further, the catalyst is Pd(PPh3)4, bis(triphenylphosphine)palladium chloride, or PddppfCl2.

[0163] In some embodiments, in step S110, the base is an inorganic base or an organic base; further, the base is selected from the group consisting of triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, N-methylmorpholine, pyridine, and combinations thereof. Further, the base is potassium carbonate, sodium carbonate, potassium acetate, or cesium carbonate.

[0164] In some embodiments, in step S110 or step S120, the reaction temperature is about 60°C to about 180°C; further, the reaction temperature is about 80°C to about 150°C.

[0165] In some embodiments, step S110 or step S120 is reacted under microwave conditions.

[0166] In some embodiments, step S200 includes the following steps:

[0167] S210: Mixing the compound represented by formula (III) and an acid to react to obtain the compound represented by formula (IV).

[0168] In some embodiments, the acid in step S210 is an aqueous solution of hydrobromic acid.

[0169] In some embodiments, in step S210, the reaction temperature is about 60°C to about 150°C; further, the reaction temperature is about 80°C to about 130°C.

[0170] In some embodiments, step S200 is to react the compound of formula (III-1) to obtain the compound of formula (IV-1):

[0171] In some embodiments, step S200 includes the following steps:

[0172] S220: The compound represented by formula (III) is subjected to a hydroxyl protecting group removal reaction to obtain a compound represented by formula (IV).

[0173] In some embodiments, in step S220, when R4 is benzyl, the compound represented by formula (III) reacts under a hydrogen atmosphere and palladium-carbon catalysis to obtain the compound represented by formula (IV-1).

[0174] In a seventh aspect, the present application provides a compound represented by formula (X), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0175] In formula (X), R6 is an amino protecting group,

[0176] U1, U2, Ring A, (R1) n , R0, R2, and R3 are as described in the specification.

[0177] In some embodiments, the compound of formula (X) is selected from the following structures:

[0178] In an eighth aspect of the present application, a method for preparing the compound of formula (I) according to the first aspect of the present application is provided, comprising the following steps:

[0179] S310: subjecting the compound represented by formula (IV) to an etherification reaction to obtain a compound represented by formula (V):

[0180] Among them, Z, U1, U2, ring A, R a 、R b 、R c 、R d , (R1)n, R0, R2, R3 are as described in the specification,

[0181] R5 is an amino protecting group;

[0182] S410: Deprotecting the compound represented by formula (V) to obtain the compound represented by formula (I):

[0183] Among them, Z, U1, U2, ring A, R a 、R b 、R c 、R d 、(R1) n , R0, R2, R3 are as described in the specification,

[0184] R5 is an amino protecting group.

[0185] In some embodiments, when the compound of formula (I) has a structure represented by formula (XII), the preparation method thereof comprises the following steps:

[0186] S320: Reacting the compound represented by formula (X) with compound A to obtain a compound represented by formula (XI):

[0187] S420: Deprotecting the compound represented by formula (XI) to obtain the compound represented by formula (XII):

[0188] Among them, U1, U2, ring A, R c 、R d 、(R1) n 、R0、R2、R3、(R s5 ) m3 As described in the instructions;

[0189] R6 is an amino protecting group.

[0190] It is understood that the compound of formula (V) obtained in step S310 or the compound of formula (XI) obtained in step S320 can be modified by methods well known in the art (such as modifying the amino group by acylation reaction (such as modifying -NH2 to C2H5NHC(O)NH-, or modifying -NH2 to CH3OC(O)NH-, or modifying -NH2 to Or the carboxyl group is modified into an amide through an acylation reaction, or the halogen is converted into an amino group, or the amino group is alkylated, etc.), the modification method is not particularly limited, as long as it does not conflict with the purpose of the invention of this application, it should be understood that all of them are within the scope of protection of this application.

[0191] In some embodiments, the amino protecting group is a common amino protecting group commonly used by those skilled in the art, including but not limited to -Cbz, -Boc, and the like.

[0192] In some embodiments, in step S310, the compound of formula (IV) reacts with a suitable intermediate (such as intermediate a, intermediate b, intermediate d, intermediate e, intermediate f, etc.) in the presence of a base to obtain a compound of formula (V).

[0193] In some embodiments, in step S310, the base is an inorganic base or an organic base; further, the base is selected from the group consisting of triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, N-methylmorpholine, pyridine, and combinations thereof. Further, the base is potassium carbonate, sodium carbonate, potassium acetate, or cesium carbonate.

[0194] In some embodiments, in step S310, the reaction temperature is 20-150°C, further 30-150°C, and further 50-100°C.

[0195] In some embodiments, in step S320, R s5 is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, monofluoromethyl, monofluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, acetyl, -CO2CH2CH3, -CO2CH3 or -C(O)NH2; m3 is 0, 1 or 2.

[0196] In some embodiments, in step S320, the compound of formula (A) is selected from the following structures:

[0197] In some embodiments, in step S320, the reaction is carried out in acetic acid.

[0198] In some embodiments, in step S320, the reaction temperature is 50-150°C, preferably 60-120°C.

[0199] In some embodiments, the reaction in step S410 or step S420 is a common reaction for removing amino protecting groups (e.g., when the amino protecting group is -Cbz, the conditions for removing the protecting group are H2 / Pd-C; when the amino protecting group is -Boc, the conditions for removing the protecting group are to react in the presence of TFA). The method for removing the protecting group is not particularly limited, as long as it does not conflict with the purpose of the invention of this application, and it should be understood that it is within the scope of protection of this application.

[0200] The ninth aspect of the present application provides a compound of formula (I) prepared according to the method for preparing the compound of formula (I) described in the eighth aspect of the present application.

[0201] It should be understood that within the scope of this application, the above-mentioned technical features of this application and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one.

[0202] After extensive and in-depth research, the inventors unexpectedly discovered a class of heterocyclic-substituted pentacyclic and hexacyclic heteroaryl derivatives that exhibit significant AAK1 kinase inhibitory activity and excellent in vivo pharmacokinetic activity. Furthermore, these compounds exhibit weaker hERG inhibition and improved central nervous system penetration. Therefore, these compounds are expected to be developed as AAK1 kinase inhibitors for the treatment or management of diseases or conditions mediated by AAK1 activity. Based on this, the inventors completed the present application. DETAILED DESCRIPTION

[0203] To make the objectives, technical solutions, and advantages of this application more clearly understood, the following examples are given to further describe this application in detail. It is apparent that the described examples are only a portion of the embodiments of this application, and not all of them. All other embodiments derived by persons of ordinary skill in the art based on the examples in this application are intended to fall within the scope of protection of this application.

[0204] Definition of terms

[0205] In order to more clearly understand the technical content of this application, the terms of this application are further explained below.

[0206] "Alkyl" refers to straight-chain and branched saturated aliphatic hydrocarbon groups. 1-8 "Alkyl" refers to an alkyl group having 1 to 8 carbon atoms, preferably C 1-6 Alkyl, more preferably C 1-3Alkyl; Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl pentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof.

[0207] "Alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group having one or more carbon-carbon double bonds (C=C). 2-8 "Alkenyl" refers to an alkenyl group having 2 to 8 carbon atoms, preferably C 2-6 Alkenyl, more preferably C 2-4 Alkenyl is similarly defined; non-limiting examples of alkenyl include ethenyl, propenyl, isopropenyl, n-butenyl, isobutenyl, pentenyl, hexenyl, and the like.

[0208] "Alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. 2-8 "Alkynyl" refers to an alkynyl group having 2 to 8 carbon atoms, preferably C 2-6 Alkynyl, more preferably C 2-4 Alkynyl is similarly defined; non-limiting examples of alkynyl include ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, hexynyl, and the like.

[0209] "Cycloalkyl" and "cycloalkyl ring" are used interchangeably and refer to a saturated monocyclic, bicyclic or polycyclic hydrocarbon group, which may be fused to an aryl or heteroaryl group. The cycloalkyl ring may be optionally substituted. In certain embodiments, the cycloalkyl ring contains one or more carbonyl groups, such as an oxo group. "C 3-8"Cycloalkyl" refers to a monocyclic cycloalkyl group having 3 to 8 carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc. Preferably, C 3-6 Cycloalkyl, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 8-10 "Cycloalkyl" refers to a fused bicyclic hydrocarbon radical having 8 to 10 ring atoms, C 8-10 Non-limiting examples of cycloalkyl groups include

[0210] "Cycloalkenyl" and "cycloalkenyl ring" are used interchangeably and refer to a monocyclic, bicyclic, or polycyclic hydrocarbon group containing one or more carbon-carbon double bonds within the ring, which may be fused to an aryl or heteroaryl group. The cycloalkenyl ring may be optionally substituted. In certain embodiments, the cycloalkenyl ring contains one or more carbonyl groups, such as an oxo group. "C 3-8 "Cycloalkenyl" refers to a cycloalkenyl group having a monocyclic structure of 3 to 8 carbon atoms. 3-6 Cycloalkenyl. Non-limiting examples of cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, cyclopentyl-2-en-1-one, cyclohexyl-2,5-dien-1-one, cyclohexyl-2-en-1-one, cyclohex-2-ene-1,4-dione, and the like.

[0211] "Heterocycloalkyl" and "heterocycloalkyl ring" are used interchangeably and both refer to a cycloalkyl group comprising at least one heteroatom selected from nitrogen, oxygen and sulfur, which group may be fused to an aryl or heteroaryl group. The heterocycloalkyl ring may be optionally substituted. In certain embodiments, the heterocycloalkyl ring contains one or more carbonyl or thiocarbonyl groups, such as groups comprising oxo and thio. "3 to 8 membered heterocycloalkyl" refers to a monocyclic cyclic hydrocarbon group having 3 to 8 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, preferably 4 to 8 membered heterocycloalkyls. More preferably, 3 to 6 membered heterocycloalkyls have 3 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. More preferably, 4 to 6 membered heterocycloalkyls have 4 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples include aziridine, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, oxazolidinyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxane, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetrahydropyranyl, azetidin-2-onyl, oxetan-2-onyl, dihydrofuran-2(3H)-onyl, pyrrolidin-2-onyl, pyrrolidin-2,5-dionyl, dihydrofuran-2,5-dionyl, piperidin-2-onyl, tetrahydro-2H-pyran-2-onyl, piperazin-2-onyl, morpholin-3-onyl, and the like. "6- to 12-membered heterocycloalkyl" and "6- to 12-membered fused heterocycloalkyl" are used interchangeably and refer to fused bicyclic cyclic hydrocarbon groups having 6 to 12 ring atoms, of which 1, 2, or 3 ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur. "8- to 10-membered heterocycloalkyl" and "8- to 10-membered fused heterocycloalkyl" are used interchangeably and refer to fused bicyclic cyclic hydrocarbon groups having 8 to 10 ring atoms, of which 1, 2, or 3 ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples include hexahydro-1H-furo[3,4-c]pyrrole, octahydro-1H-cyclopenta[c]pyridine, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, octahydropyrrolo[1,2-a]pyrazine, hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one, octahydrocyclopenta[c]pyrrole, and the like. In fused bicyclic heterocycloalkyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as valence permits.Bicyclic heterocycloalkyl systems may include one or more heteroatoms in one or both rings.

[0212] "Aryl" and "aryl ring" are used interchangeably to refer to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated π electron system, which may be fused to a cycloalkyl ring, a heterocycloalkyl ring, a cycloalkenyl ring, a heterocycloalkenyl ring, or a heteroaryl ring. 6-10The term "aryl" refers to a monocyclic or bicyclic aromatic group having 6 to 10 carbon atoms. Non-limiting examples of aryl include phenyl, naphthyl, and the like.

[0213] "Heteroaryl" and "heteroaryl ring" and "heteroaromatic ring" are used interchangeably and refer to a group of a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system (for example, having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In this application, heteroaryl also includes a ring system in which the above-mentioned heteroaryl ring is fused to one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings. The heteroaryl ring may be optionally substituted. "5 to 10 membered heteroaryl" refers to a monocyclic or bicyclic heteroaryl group having 5 to 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms. "5- to 6-membered heteroaryl" refers to a monocyclic heteroaryl group having 5 to 6 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms, non-limiting examples of which include thienyl, furanyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl. "8- to 10-membered heteroaryl" refers to a bicyclic heteroaryl group having 8 to 10 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms, non-limiting examples of which include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, The term "heteroatom" refers to nitrogen, oxygen, or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings.

[0214] "Fused" refers to structures in which two or more rings share one or more bonds.

[0215] "Benzoheterocycloalkyl" refers to a group in which a benzene ring is fused to a heterocycloalkyl ring to form a bicyclic, tricyclic, or polycyclic ring system, wherein the heterocycloalkyl ring is as defined above. "7- to 11-membered phenylheterocycloalkyl" refers to a bicyclic cyclic group having 7 to 11 ring atoms, of which 1, 2, 3, or 4 are heteroatoms selected from nitrogen, oxygen, and sulfur. Preferably, it is an 8- to 10-membered phenylheterocycloalkyl group having 8 to 10 ring atoms, of which 1, 2, or 3 are heteroatoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples include indoline, benzo[d][1,3]dioxazole, 1,2,3,4-tetrahydroisoquinoline, 3,4-dihydro-2H-benzo[b][1,4]oxazine, and the like.

[0216] "Heteroarylheterocycloalkyl" refers to a group in which a heteroaryl ring is fused to a heterocycloalkyl ring to form a bicyclic, tricyclic, or polycyclic ring system, wherein the heterocycloalkyl ring is as defined above. "7- to 11-membered heteroarylheterocycloalkyl" refers to a bicyclic cyclic group having 7 to 11 ring atoms, of which 1, 2, 3, or 4 are heteroatoms selected from nitrogen, oxygen, and sulfur. Preferably, it is an 8- to 10-membered heteroarylheterocycloalkyl group having 8 to 10 ring atoms, of which 1, 2, 3, or 4 are heteroatoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples include 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, [1,3]dioxolane[4,5-b]pyridine, 2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine, 2,3,4,6-tetrahydropyrrolo[3,4-b][1,4]oxazine, 2,4,5,6-tetrahydropyrano[2,3-c]pyrazole, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, and the like.

[0217] "Alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined above. Preferably C 1-8 Alkoxy, more preferably C 1-6 Alkoxy, most preferably C 1-3 Alkoxy. Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, and the like.

[0218] "Cycloalkyloxy" refers to an -O-cycloalkyl group, wherein the cycloalkyl group is as defined above. Preferably C 3-8 Cycloalkyloxy, more preferably C 3-6 Cycloalkyloxy. Non-limiting examples of cycloalkyloxy include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0219] "A bond" means that the two groups connected thereto are connected by one covalent bond.

[0220] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0221] "Halo" refers to a group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms are replaced by a halogen.

[0222] For example, "haloalkyl" refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, wherein alkyl is as defined above. 1-8 Alkyl, more preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 Examples of haloalkyl groups include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.

[0223] For another example, "haloalkoxy" refers to an alkoxy group substituted by one or more (such as 1, 2, 3, 4 or 5) halogens, wherein the definition of alkoxy is as described above. 1-8 Alkoxy, more preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkoxy. Haloalkoxy includes, but is not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.

[0224] For another example, "halocycloalkyl" refers to a cycloalkyl group substituted by one or more (such as 1, 2, 3, 4 or 5) halogens, wherein the definition of cycloalkyl is as described above. 3-8 Cycloalkyl, more preferably halogenated C 3-6 Cycloalkyl. Halocycloalkyl includes, but is not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.

[0225] "Deuterated alkyl" refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, or 5) deuterium atoms, wherein the definition of alkyl is as described above. 1-8 Alkyl, more preferably deuterated C 1-6 Alkyl, more preferably deuterated C 1-3 Examples of deuterated alkyl groups include, but are not limited to, monodeuterated methyl, monodeuterated ethyl, dideuterated methyl, dideuterated ethyl, trideuterated methyl, trideuterated ethyl, and the like.

[0226] "Amino" refers to -NH2, "cyano" refers to -CN, "nitro" refers to -NO2, "benzyl" refers to -CH2-phenyl, "oxo" refers to =O, "carboxyl" refers to -C(O)OH, "acetyl" refers to -C(O)CH3, "hydroxymethyl" refers to -CH2OH, "hydroxyethyl" refers to -CH2CH2OH or -CHOHCH3, "hydroxy" refers to -OH, "mercapto" refers to -SH, "Me" refers to methyl, "Bu" refers to butyl, and the structure of "cyclopropylene" is:

[0227] "Ms" refers to methylsulfonyl.

[0228] "Saturated or partially unsaturated monocyclic ring" refers to a saturated or partially unsaturated all-carbon monocyclic ring system, wherein "partially unsaturated" refers to a ring portion including at least one double bond or triple bond, and "partially unsaturated" is intended to cover rings with multiple unsaturated sites, but is not intended to include aryl or heteroaryl moieties as defined herein. In certain embodiments, the saturated or partially unsaturated monocyclic ring contains one or more carbonyl groups, such as an oxo group. "3 to 7 membered saturated or partially unsaturated monocyclic ring" has 3 to 7 ring carbon atoms, preferably a saturated or partially unsaturated monocyclic ring with 3 to 6 ring carbon atoms, more preferably a saturated monocyclic ring with 3 to 6 ring carbon atoms. Non-limiting examples of saturated or partially unsaturated monocyclic rings include cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring, cycloheptyl ring, cycloheptatrienyl ring, cyclopentanone ring, cyclopentane-1,3-dione ring, etc.

[0229] "Saturated or partially unsaturated monocyclic heterocycle" means a saturated or partially unsaturated monocyclic ring in which one, two or three carbon atoms are selected from nitrogen, oxygen or S(O) t(wherein t is an integer of 0, 1 or 2) is substituted with a heteroatom, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. A "3- to 7-membered saturated or partially unsaturated monocyclic heterocycle" has 3 to 7 ring atoms, of which 1, 2 or 3 ring atoms are the above-mentioned heteroatoms. Preferably, the 3- to 6-membered saturated or partially unsaturated monocyclic heterocycle has 3 to 6 ring atoms, of which 1 or 2 ring atoms are the above-mentioned heteroatoms, more preferably, the 5- to 6-membered saturated or partially unsaturated monocyclic heterocycle has 5 to 6 ring atoms, of which 1 or 2 ring atoms are the above-mentioned heteroatoms, and most preferably, the 5- or 6-membered saturated monocyclic heterocycle. Non-limiting examples of saturated monocyclic heterocycles include an oxetane ring, an azetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a tetrahydropyrrole ring, a piperidine ring, a pyrroline ring, an oxazolidine ring, a piperazine ring, a dioxolane ring, a dioxane ring, a morpholine ring, a thiomorpholine ring, a thiomorpholine-1,1-dioxide, a tetrahydropyran ring, an azetidine-2-one ring, an oxetane-2-one ring, a pyrrolidine-2-one ring, a pyrrolidine-2,5-dione ring, a piperidin-2-one ring, a dihydrofuran-2(3H)-one ring, a dihydrofuran-2,5-dione ring, a tetrahydro-2H-pyran-2-one ring, a piperazin-2-one ring, and a morpholine-3-one ring. Non-limiting examples of partially unsaturated monocyclic heterocycles include 1,2-dihydroazetidine, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H -pyran ring, 1,2,3,6-tetrahydropyridine ring, 4,5-dihydro-1H-imidazole ring, 1,4,5,6-tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazolidine ring, 1,6-dihydropyrimidine ring, 4,5,6,7-tetrahydro-1H-1,3-diazepine ring, 2,5,6,7-tetrahydro-1,3,5-oxadiazepine ring, etc.

[0230] "Substituted" means that one or more hydrogen atoms, preferably 1 to 5 hydrogen atoms, and more preferably 1 to 3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0231] Unless otherwise defined, the "substituents independently selected from..." mentioned herein means that when more than one hydrogen on a group is replaced by a substituent, the substituents may be of the same or different types, and the substituents selected are of independent types.

[0232] Unless otherwise defined, the phrase "...same or different, and each independently is..." in this application means that when there are more than one identical substituent group in the general formula, the groups may be the same or different and are each independent species. For example, L is (CR L1 R L2 ) s , when s is 2, that is, L is (CR L1 R L2 )-(CR L1 R L2 ), where two R L1 Can be the same or different, two R L2 They can be the same or different and are independent species. For example, L can be C(CH3)(CN)-C(CH2CH3)(OH), C(CH3)(CN)-C(CH3)(OH) or C(CN)(CH2CH3)-C(OH)(CH2CH3).

[0233] Unless otherwise defined, any group herein may be substituted or unsubstituted. When the above groups are substituted, the substituents are preferably 1 to 5 groups independently selected from cyano, halogen (preferably fluorine or chlorine), C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8 Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl), C 3-8 Cycloalkyl (preferably C 3-6 Cycloalkyl), halogenated C 1-8 Alkoxy (preferably halogenated C 1-6 Alkoxy, more preferably halo C 1-3 Alkoxy), C 1-8 Alkyl-substituted amino, halogenated C 1-8 Alkyl-substituted amino, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl, nitro, C 6-10 Aryl (preferably phenyl), C 3-8 Cycloalkyloxy (preferably C 3-6 Cycloalkyloxy), C 2-8 Alkenyl (preferably C 2-6 Alkenyl, more preferably C 2-4 alkenyl), C 2-8 Alkynyl (preferably C 2-6 Alkynyl, more preferably C 2-4 Alkynyl), -CONR a0`R b0 `、-C(O)OC 1-10 Alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl), -CHO, -OC(O)C 1-10 Alkyl (preferably -OC(O)C 1-6 Alkyl, more preferably -OC(O)C 1-3 Alkyl), -SO2C 1-10 Alkyl (preferably -SO2C 1-6 Alkyl, more preferably -SO2C 1-3 Alkyl), -SO2C 6-10 Aryl (preferably -SO2C6 aryl, such as -SO2-phenyl), -COC 6-10 Aryl (preferably -COC6 aryl, such as -CO-phenyl), 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring, 4 to 6-membered saturated or unsaturated monocyclic ring, 5 to 6-membered monocyclic heteroaryl ring, 8 to 10-membered bicyclic heteroaryl ring, spiro ring, spiroheterocycle, bridged ring or bridged heterocycle, wherein R a0 `、R b0 `Each independently is hydrogen or C 1-3 alkyl.

[0234] In this application, when two or more “preferably” appear in one solution, any two “preferably” may be independent of each other.

[0235] In the present application, when the number of substituents is greater than 1, any two substituents may be the same or different. For example, the substituents may be two halogens that are the same or different, or one halogen and one hydroxyl group.

[0236] Each type of substituent group described herein above can itself be substituted with the groups described herein.

[0237] When the 4- to 6-membered saturated monocyclic heterocycle described herein is substituted, the substituents may be positioned at their possible chemical positions. Representative substitutions of exemplary monocyclic heterocycles are shown below:

[0238] Wherein "Sub" represents various substituents described herein; Indicates the connection position with other atoms.

[0239] This article involves numerical ranges, unless otherwise specified, including every integer between the minimum value (inclusive) and the maximum value (inclusive) of the range. 1-8 The "1-8" in the alkyl group may refer to 1, 2, 3, 4, 5, 6, 7 or 8.

[0240] Pharmaceutical composition

[0241] Generally, the compounds of the present application or their pharmaceutically acceptable salts, or solvates, or stereoisomers, or prodrugs can be administered in a suitable dosage form with one or more pharmaceutical carriers. These dosage forms are suitable for oral, rectal, topical, oral, and other parenteral administrations (e.g., subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups. The compounds of the present application contained in these preparations can be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, etc. The above dosage forms can be prepared from the active compound and one or more carriers or excipients via common pharmaceutical methods. The above carriers need to be compatible with the active compound or other excipients. For solid preparations, commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, etc. Carriers for liquid preparations include water, physiological saline, aqueous glucose solution, ethylene glycol, and polyethylene glycol, etc. The active compound can form a solution or suspension with the above carriers.

[0242] "Pharmaceutically acceptable carrier" means a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating material or auxiliary formulation or any type of excipient that is compatible with a patient, preferably a mammal, more preferably a human, and is suitable for delivering an active agent to a target site without terminating the activity of the agent.

[0243] The "active substance of the present application" or "active compound of the present application" refers to the compound of formula (I) of the present application, or a pharmaceutically acceptable salt, or a solvate, or a stereoisomer, or a prodrug thereof, which has high AAK1 selective inhibitory activity.

[0244] The compositions of the present application are formulated, dosed and administered in a manner consistent with medical practice. The "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.

[0245] "Therapeutically effective amount" refers to the amount of the compound of the present invention that will induce a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease.

[0246] The therapeutically effective amount of the compound of the present application or its pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug contained in the pharmaceutical composition or pharmaceutical composition of the present application is preferably 0.1 mg / kg to 5 g / kg (body weight).

[0247] "Patient" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.

[0248] "Treatment" refers to alleviating, slowing the progression of, attenuating, preventing, or maintaining an existing disease or condition (eg, cancer). Treatment also includes curing, preventing the development of, or alleviating to some extent, one or more symptoms of a disease or condition.

[0249] The term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Pharmaceutically acceptable acid addition salts are salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. These salts can be prepared by methods known in the art. The pharmaceutically acceptable salts can be freed by methods known in the art to obtain the corresponding free form of the compound.

[0250] "Pharmaceutically acceptable base addition salts" include, but are not limited to, salts with inorganic bases such as sodium, potassium, calcium, and magnesium salts. They also include, but are not limited to, salts with organic bases such as ammonium, triethylamine, lysine, and arginine salts. These salts can be prepared by methods known in the art.

[0251] Asymmetric centers may be present in the compounds of the present invention. It should be understood that the present invention encompasses all stereochemical isomeric forms or mixtures thereof that have the ability to inhibit AAK1. Individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products followed by separation (such as conversion into a mixture of diastereoisomers followed by separation or recrystallization, chromatography techniques, or direct separation of enantiomers on a chiral chromatographic column). Starting compounds of specific stereochemistry are commercially available or can be prepared and resolved by techniques known in the art. Certain compounds of the present invention may also exist in separable different stable conformations. Torsional asymmetry due to restricted rotation around an asymmetric single bond, for example due to steric hindrance or ring stress, can allow the separation of different conformers. The present invention includes each conformer of these compounds and mixtures thereof. The term "compound of the present invention" and equivalent expressions are intended to encompass compounds of formula (I) and pharmaceutically acceptable salts thereof, and enantiomers and diastereomers thereof. Similarly, references to intermediates are intended to encompass their salts where the context permits.

[0252] Preparation method

[0253] The application provides a preparation method of a compound of formula (I), which can be synthesized using standard synthesis techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein. The solvent, temperature, and other reaction conditions provided herein can be changed according to the art. The reactions can be used in sequence to provide compounds of the application, or they can be used to synthesize fragments, which are subsequently added by methods described herein and / or methods known in the art.

[0254] The compound described in this application can use the illustrative method described in the following similar method or embodiment, or the relevant open literature used by those skilled in the art, by using appropriate selectable starting material synthetic compound.The starting material for synthesizing the compound described in this application can be synthesized or can be obtained from commercial sources.The compound described in this application and other related compounds with different substituents can be synthesized using technology and raw materials known to those skilled in the art.The general method for preparing compounds disclosed in this application can be from reaction known in the art, and the reaction can be modified by those skilled in the art to consider appropriate reagents and conditions to introduce the various parts in the molecule provided by the application.

[0255] The main advantages of this application include:

[0256] Provides a series of novel heterocyclic substituted five- and six-membered heteroaryl derivatives, which have high selective inhibitory activity against AAK1, excellent in vivo pharmacokinetic activity and weak hERG inhibition, and the inhibitory activity IC of AAK1 kinase is 50 The values ​​ranged from 50 nM to 100 nM, and the IC values ​​of some compounds were 50 The values ​​ranged from 10 nM to 50 nM, and the IC values ​​of some compounds were 50 The values ​​are 0.1 nM to 10 nM, and thus can be used as drugs for treating or controlling diseases or conditions mediated by AAK1 activity. These compounds have superior central nervous system penetration, higher AAK1 selectivity, and weaker hERG inhibition, thus potentially having superior therapeutic effects and lower toxicity for central nervous system diseases mediated by AAK1 activity.

[0257] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present application only and are not intended to limit the scope of the present application. The experimental methods for which specific conditions are not specified in the following examples are generally based on conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight. Unless otherwise defined, the terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar or equivalent to the described content can be applied to the present application.

[0258] Known starting materials can be synthesized by methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0259] Unless otherwise specified, the reactions in the examples were carried out under nitrogen or argon atmosphere.

[0260] DCM: dichloromethane, TEA: triethylamine, TFA: trifluoroacetic acid, NaHMDS: sodium bis(trimethylsilyl)amide, DMF: dimethylformamide, DMSO: dimethyl sulfoxide, THF: tetrahydrofuran, DIEA: N,N-diisopropylethylamine, EA: ethyl acetate, EtOAc: ethyl acetate, PE: petroleum ether, MeOH: methanol, IPA: isopropanol, NMP: N-methylpyrrolidone, DMAP: 4-dimethylaminopyridine, TsCl: 4-toluenesulfonyl chloride, HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, DMF-DMA: N,N-dimethylformamide dimethyl acetal, LDA: lithium diisopropylamide, MCPBA: m-chloroperbenzoic acid, TMSCN: trimethylsilyl cyanide, TMSCl: trimethylchlorosilane, BINAP: (2R,3S)-2,2 '-Bis(diphenylphosphino)-1,1'-binaphthyl, NBS: N-bromosuccinimide, NCS: N-chlorosuccinimide, Pd2(dba)3: tris(dibenzylideneacetone)dipalladium, Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, Pd(PPh3)4: tetrakis(triphenylphosphine)palladium, P d(PPh3)2Cl2: bistriphenylphosphine palladium dichloride, DPPA: diphenylphosphoryl azide, Grubb's2 catalyst: 1,3-bis(2,4,6-trimethylphenyl)-2-(imidazolidinylidene)(dichlorobenzylidene)(tricyclohexylphosphine)ruthenium, PMBCl: p-methoxybenzyl chloride, TfOH: trifluoromethanesulfonic acid, DBU: 1,8-diazabicycloundec-7-ene, TBAF: tetrabutylammonium fluoride, Na Ascorbate: sodium ascorbate, t-BuXPhosPd-G3: methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II), XPhos Pd G2: chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), tBuXPhos: 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, DAST: diethylaminosulfur trifluoride, ACN: acetonitrile, Pd / C: palladium on carbon, BBr3: boron tribromide, NH4HCO3: ammonium bicarbonate.

[0261] LC-MS: liquid chromatography-mass spectrometry; combiflash: flash chromatography.

[0262] The present invention is obtained by purification by prep.HPLC (preparative high performance liquid chromatography) and then freeze-dried.

[0263] The percentages mentioned in this application, unless otherwise specified, refer to mass percentages for solid-liquid mixtures and solid-solid mixtures, and volume percentages for liquid-liquid mixtures. Unless otherwise specified, the solvent is water.

[0264] As used herein, room temperature refers to about 20-30° C.; “overnight” refers to about 10 h to 16 h; 1 M / 1 N is 1 mol / L, and 1 mM is 1 mmol / L; eq: equivalent.

[0265] Yield = actual mass of synthesized product / theoretical mass of synthesized product × 100%.

[0266] Preparation of intermediate a

[0267] Step 1: Dissolve imidazole (25.90 g, 380.41 mmol) and triethylamine (21.17 g, 209.22 mmol, 29.18 mL) in dichloromethane (300 mL). Cool to -60°C under nitrogen. Slowly add thionyl chloride (1 M, 104.61 mL) dropwise at -60°C. After complete addition, stir the reaction at -60°C for 15 min. Then, cool the reaction mixture to -78°C and slowly add a solution of (S)-tert-butyl (1-hydroxy-2,4-dimethylpentan-2-yl)carbamate (22 g, 95.10 mmol) in dichloromethane (100 mL). After complete addition, warm the reaction mixture to room temperature and stir for 16 h. After the reaction, water (200 mL) was added to the reaction solution to quench the mixture, followed by extraction with dichloromethane (300 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a light yellow oily substance (4S)-tert-butyl-4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (26 g, 93.73 mmol, 98.56% yield). MS m / z (ESI): 222.1 [M-56+H] + .

[0268] Step 2: Dissolve (4S)-tert-Butyl-4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (26 g, 93.73 mmol) in a mixture of acetonitrile (270 mL) and water (108 mL). Then add ruthenium chloride trihydrate (100 mg, 382.45 μmol). Finally, slowly add sodium periodate (25 g, 115.79 mmol) at room temperature. Stir the reaction for 2 h. After completion of the reaction, filter, and wash the filter cake with ethyl acetate. The filtrate is concentrated under reduced pressure, and water (100 mL) is added. Extraction is then performed with ethyl acetate (150 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using a solvent system (petroleum ether / ethyl acetate: 1 / 0 to 10 / 1) to afford Intermediate a (14.5 g, colorless oil) in a yield of 52.73%. 1 H NMR (400MHz, CDCl3) δ (ppm): 4.44 (d, J = 9.2Hz, 1H), 4.19 (d, J = 9.2Hz, 1H), 2.09-1.9 4(m,1H),1.82-1.67(m,2H),1.58(s,3H),1.55(s,9H),0.98(dd,J=7.9,6.5Hz,6H).

[0269] Preparation of intermediate b

[0270] Under ice, (S)-2-amino-2,4-dimethylpentan-1-ol (20 g, 152.42 mmol) and di-tert-butyl dicarbonate (49.90 g, 228.63 mmol) were added to dichloromethane (50 mL), followed by triethylamine (46.27 g, 457.26 mmol, 63.78 mL). The reaction mixture was stirred at room temperature for 16 hours. LC-MS monitored the reaction completion, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a solvent system (petroleum ether / ethyl acetate: 1 / 0 to 2 / 1) (phosphomolybdic acid as a colorimetric tool) to afford intermediate b (22 g, 95.10 mmol, 62.39% yield) as a white solid. MS m / z (ESI): 176.1 [M-56+H] + .

[0271] Preparation of intermediate c

[0272] Under argon, thiazole-2-carboxylic acid (258 mg, 2.00 mmol) was dissolved in tetrahydrofuran (6 mL), oxalyl chloride (507.17 mg, 4.00 mmol, 338.11 μL) was added, and N,N-dimethylformamide (0.1 mL) was added dropwise. The reaction was stirred at 20°C for 1 hour and dried under reduced pressure to afford Intermediate c (290 mg, 1.96 mmol) in a 98.35% yield. The crude product was used directly in the next step.

[0273] Preparation of intermediate d

[0274] Step 1: Dissolve imidazole (25.7 g, 378 mmol) and triethylamine (21.0 g, 207 mmol) in anhydrous dichloromethane (350 mL). Cool to -60°C under nitrogen. Slowly add thionyl chloride (12.2 g, 102 mmol) dropwise at -60°C. After the addition is complete, stir the reaction at -60°C for 30 minutes. Then, cool the reaction mixture to -70°C and slowly add a dichloromethane solution (60 mL) of N-tert-butyloxycarbonyl-L-leucinol (20.3 g, 93.6 mmol). After the addition is complete, heat the reaction mixture to 20°C and stir for 12 hours. The reaction solution was quenched with water (200 mL), and then extracted with dichloromethane (200 mL × 2). The organic phases were combined, washed with water (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain (4S)-4-isobutyl-1,2,3-oxathiazolidine-3-carboxylic acid-2-oxo-tert-butyl ester (25.3 g, yellow oil). The crude product was used directly in the next reaction.

[0275] Step 2: Dissolve tert-butyl (4S)-2-oxo-4-isobutyl-1,2,3-oxathiazolidine-3-carboxylate (27.3 g, 103 mmol) in a mixture of acetonitrile (270 mL) and water (100 mL). Then, add ruthenium trichloride (18 mg, 86.7 μmol μmol). Finally, slowly add sodium periodate (24.4 g, 114 mmol) at 20°C and stir for 2 hours. The reaction mixture was quenched with water (180 mL) and extracted with ethyl acetate (350 mL x 2). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (1 / 0 to 24 / 1) as the eluent to afford Intermediate d (12.0 g, white solid) in a yield of 41.4%. 1H NMR (400MHz, CDCl3) δ (ppm): 4.65 (dd, J = 9.2, 5.6Hz, 1H), 4.38-4.26 (m, 2H), 1. 85-1.68(m,2H),1.66-1.58(m,1H),1.56(s,9H),0.98(dd,J=12.4,6.4Hz,6H).

[0276] Preparation of intermediate e

[0277] Step 1: Dissolve (S)-2-amino-3-cyclopropylpropionic acid (12.5 g, 96.78 mmol) in a 1 M sodium hydroxide solution (325.00 mL). Slowly add benzyl chloroformate (19.81 g, 116.14 mmol). Stir and react at 20°C for 16 hours. The reaction mixture is extracted with dichloromethane (200 mL x 3). The aqueous phase is adjusted to pH 3 with hydrochloric acid and then extracted with dichloromethane (200 mL x 3). The combined organic phases are washed with saturated brine (300 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (S)-2-(((benzyloxy)carbonyl)amino)-3-cyclopropylpropionic acid (17.5 g, colorless gum) in a yield of 68.6%. MS m / z (ESI): 263.9 [M+H] + .

[0278] Step 2: (S)-2-(((Benzyloxy)carbonyl)amino)-3-cyclopropylpropanoic acid (17 g, 64.57 mmol) was dissolved in tetrahydrofuran (300 mL). Borane in tetrahydrofuran (1 M, 83.94 mL) was slowly added dropwise at 0°C under a nitrogen atmosphere. The mixture was stirred at 20°C under a nitrogen atmosphere for 4 hours. The reaction mixture was quenched by the addition of aqueous hydrochloric acid (1 M, 300 mL) at 0°C until bubbling occurred. The mixture was then stirred at 20°C for 10 hours. The mixture was then extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated aqueous sodium bicarbonate (300 mL x 2) and saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (S)-benzyl(1-cyclopropyl-3-hydroxypropan-2-yl)aminomethyl ester (14.0 g, colorless gum) in an 86.9% yield. MS m / z(ESI):249.9[M+H] + .

[0279] Step 3: Dissolve imidazole (16.38 g, 240.67 mmol) in dichloromethane (150 mL). Add thionyl chloride (8.59 g, 72.20 mmol) in dichloromethane (30 mL) slowly dropwise to the reaction mixture at -5°C under a nitrogen atmosphere. Stir at -5°C for 1 hour. Then, add (S)-benzyl(1-cyclopropyl-3-hydroxypropan-2-yl)aminomethyl ester (10.0 g, 40.11 mmol) in dichloromethane (60 mL) slowly dropwise to the reaction mixture at -10°C under a nitrogen atmosphere. After the addition is complete, stir the mixture at 20°C under a nitrogen atmosphere for 2 hours. Cool to 10°C, add 20 mL of water, and extract with dichloromethane (10 mL x 3). The extract was washed with 10% aqueous citric acid solution (20 mL) and saturated brine (20 mL), respectively, dried over anhydrous sodium sulfate, and separated by column chromatography (PE:EA=100:0-80:20) to give (4S)-4-(cyclopropylmethyl)-1,2,3-oxathiazolidine-3-carboxylic acid benzyl ester 2-oxide (4.90 g, colorless oil) in a yield of 41.3%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.33-7.42 (m, 5H), 5.18-5.32 (m, 2H), 4.90-5.07 (m, 1H), 4.82 (dd, J = 9.03, 8. 28Hz,1H),4.07-4.43(m,1H),1.43-1.79(m,2H),0.58-0.75(m,1H),0.31-0.45(m,2H),-0.06-0.14(m,2H).

[0280] Step 4: Dissolve (4S)-benzyl 4-(cyclopropylmethyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (4.80 g, 16.25 mmol) in acetonitrile (50 mL) and water (50 mL). Add trichloromethane (67.42 mg, 325.03 μmol) and sodium periodate (8.69 g, 40.63 mmol) separately in an ice bath at 0°C. Stir at room temperature for 2 hours. Cool to 0°C, add water (60 mL), and extract with dichloromethane (60 mL x 2). The extract is washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and isolated by column chromatography (PE:EA = 100:0 to 80:20) to afford intermediate e (2.90 g, white solid) in a 56.0% yield. 1H NMR (400MHz, CDCl3) δ (ppm) 7.30-7.48 (m, 5H), 5.23-5.41 (m, 2H), 4.72 (dd, J=9.29, 5.77Hz, 1H), 4.54 (dd, J=9.29, 2.01H z,1H),4.39-4.50(m,1H),1.81-1.91(m,1H),1.67-1.77(m,1H),0.59-0.71(m,1H),0.44-0.59(m,2H),0.07-0.24(m,2H).

[0281] Preparation of intermediate f

[0282] Step 1: Dissolve p-chlorobenzaldehyde (101 g, 716 mmol) and DL-alanine methyl ester hydrochloride (100 g, 716 mmol) in anhydrous dichloromethane (1000 mL). Add anhydrous magnesium sulfate (345 g, 2.87 mol) and triethylamine (254 g, 2.51 mmol). React at 40°C under nitrogen for 32 hours. Filter, rinse the filter cake with dichloromethane (500 mL x 1). Combine the filtrates and wash sequentially with water (1000 mL x 1) and saturated brine (1000 mL x 1). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to obtain (E)-methyl 2-((4-chlorobenzylidene)amino)propanoate (26.5 g, light yellow liquid), which is used directly in the next step with a yield of 78.0%. 1 H NMR (400MHz, CDCl3) δ (ppm) 8.22-8.37 (m, 1H), 7.68-7.79 (m, 2H), 7.36-7.4 6(m,2H),4.17(q,J=6.80Hz,1H),3.69-3.82(m,3H),1.54(d,J=6.80Hz,3H).

[0283] Step 2: To a solution of methyl (E)-2-((4-chlorobenzylidene)amino)propanoate (50.0 g, 222 mmol) in anhydrous tetrahydrofuran (500 mL) at 25°C under nitrogen was added sodium hydride (9.75 g, 244 mmol, 60% purity). The mixture was allowed to react at 25°C for 30 minutes. Bromomethylcyclopropane (29.9 g, 222 mmol) was then slowly added. The temperature was naturally raised to 25°C and the reaction continued for 16 hours. The reaction solution was added dropwise to 50 mL of water and extracted with ethyl acetate (700 mL x 3). The combined organic phases were washed with 500 mL of saturated sodium chloride water, dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude methyl (E)-2-((4-chlorobenzylidene)amino)-3-cyclopropyl-2-methylpropanoate (40.0 g, light yellow liquid) in a yield of 64.5%. MS m / z(ESI):280.0[M+H] + . 1 H NMR (400MHz, CDCl3) δ (ppm) 8.16 (s, 1H), 7.61-7.63 (m, 2H), 7.28-7.30 (m, 2H), 3.66 (s, 3H) ,1.74-1.80(m,2H),1.49(s,3H),0.75-0.80(m,1H),0.34-0.39(m,2H),0.00-0.02(m,2H).

[0284] Step 3: Dissolve (E)-2-((4-chlorobenzylidene)amino)-3-cyclopropyl-2-methylpropanoic acid methyl ester (40.0 g, 143 mmol) in anhydrous tetrahydrofuran (200 mL), cool to 0°C, add 178 mL of 1 M aqueous hydrogen chloride solution, and stir the reaction at 0°C for 1.5 hours. The reaction solution was extracted with ethyl acetate (350 mL × 1), and the retained aqueous phase was adjusted to pH = 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (350 mL × 2). The organic phases were combined, washed with saturated sodium chloride water (150 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 2-amino-3-cyclopropyl-2-methylpropanoic acid methyl ester (6.25 g, light yellow liquid) in a yield of 27.8%. 1 H NMR (400MHz, CDCl3) δ (ppm) 3.70 (s, 3H), 1.87 (br s,2H),1.70(dd,J=14.0,6.80Hz,1H),1.41-1.51(m,1H),1.32(s,3H),0.55-0.67(m,1H),0.36-0.50(m,2H),-0.05-0.15(m,2H).

[0285] Step 4: Methyl 2-amino-3-cyclopropyl-2-methylpropanoate (6.00 g, 38.2 mmol) was dissolved in anhydrous dichloromethane (60 mL). N,N-diisopropylethylamine (5.43 g, 42.0 mmol) was added, and benzyl chloroformate (5.43 g, 42.0 mmol) was slowly added dropwise at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using an eluent (PE / EA = 1 / 0 to 5 / 1) to give methyl 2-(((benzyloxy)carbonyl)amino)-3-cyclopropyl-2-methylpropanoate (6.00 g, colorless oily liquid) in a 54.0% yield. MS m / z (ESI): 292.0 [M+H]. + .

[0286] Step 5: Methyl 2-(((benzyloxy)carbonyl)amino)-3-cyclopropyl-2-methylpropanoate (6.10 g, 20.9 mmol) was dissolved in 150 mL of anhydrous tetrahydrofuran. A 1 M solution of lithium aluminum hydroxide in tetrahydrofuran (25.1 mL) was added dropwise at 0°C under nitrogen. The ice bath was removed and the mixture was allowed to react at 25°C for 3 hours. Water (100 mL) was added at 0°C and stirred for 30 minutes. The mixture was filtered through celite and the filtrate was extracted with ethyl acetate (120 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (150 mL x 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by neutral alumina column chromatography using an eluent (PE / EA = 1 / 0 to 5 / 4) to give benzyl (1-cyclopropyl-3-hydroxy-2-methylpropan-2-yl)carbamate (3.15 g, colorless oily liquid) in a yield of 57.1%. MS m / z(ESI):263.9[M+H] + .

[0287] Step 6: Benzyl (1-cyclopropyl-3-hydroxy-2-methylpropan-2-yl)carbamate (2.80 g, 10.6 mmol) was purified by chiral HPLC (preparative column: DAICEL CHIRALPAK AD (250 mm × 50 mm, 10 μm); mobile phase: [0.1% NH3H2O ​​IPA]; B%: 20%-20% per minute) to afford benzyl (S)-(1-cyclopropyl-3-hydroxy-2-methylpropan-2-yl)carbamate (980 mg, colorless oily liquid) in a 35.0% yield. MS m / z (ESI): 263.9 [M+H] + . 1H NMR (400MHz, CDCl3) δ (ppm) 7.28-7.44 (m, 5H), 5.07 (s, 2H), 4.98-5.07 (m, 1H), 3.60-3.80 (m, 2H), 1.57 -1.68(m,1H),1.47-1.57(m,1H),1.31(s,3H),0.62-0.78(m,1H),0.39-0.56(m,2H),0.04-0.15(m,2H).

[0288] Step 7: Under nitrogen, thionyl chloride (339 mg, 2.85 mmol) was added to acetonitrile (3 mL). The mixture was cooled to -40°C and slowly added dropwise a solution of (S)-(1-cyclopropyl-3-hydroxy-2-methylpropan-2-yl)carbamic acid benzyl ester (300 mg, 1.14 mmol) dissolved in 1.5 mL of acetonitrile. Immediately after the addition, pyridine (451 mg, 5.70 mmol) was added. The temperature was slowly raised to 25°C and stirred for 1 hour. The reaction mixture was stripped of solvent under reduced pressure, and ethyl acetate (30 mL) was added. The mixture was stirred for 2 minutes and allowed to stand for 10 minutes. A solid precipitated and was collected by filtration and dried under reduced pressure to afford crude (4S)-4-(cyclopropylmethyl)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid benzyl ester 2-oxide (328 mg, light yellow gum) in a yield of 93.2%. MS m / z (ESI): 309.9 [M+H]. + .

[0289] Step 8: Benzyl (4S)-4-(cyclopropylmethyl)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (100 mg, 323 μmol) was dissolved in a mixture of acetonitrile (1.2 mL) and water (0.6 mL). Ruthenium trichloride (670 μg, 3.23 μmol) and sodium periodate (76.0 mg, 356 μmol) were added, and the mixture was stirred at 20°C for 2 hours. Water (5 mL) and saturated aqueous sodium sulfite solution (2 mL) were added, and the mixture was stirred for 1 minute. The mixture was extracted with ethyl acetate (5 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by neutral alumina column chromatography using an eluent (PE / EA = 1 / 0 to 7 / 1) to obtain intermediate f (52.0 mg, colorless oily liquid) in a yield of 48.7%. MS m / z(ESI):347.9[M+Na + ]. 1H NMR (400MHz, CDCl3) δ (ppm) 7.31-7.48 (m, 5H), 5.24-5.39 (m, 2H), 4.66 (d, J = 9.20Hz, 1H), 4.27 (d, J = 9.20Hz, 1H), 1.98 (dd, J =14.40,6.80Hz,1H),1.78(dd,J=14.40,6.80Hz,1H),1.63(s,3H),0.59-0.73(m,1H),0.48-0.59(m,2H),0.04-0.16(m,2H).

[0290] Preparation of intermediate 1

[0291] Step 1: Dissolve 2,4,6-trimethylbenzenesulfonyl chloride (15 g, 68.59 mmol) and tert-butyl N-hydroxycarbamate (9.13 g, 68.59 mmol) in methyl tert-butyl ether (100 mL). Cool the reaction mixture to 0°C, then add triethylamine (8.33 g, 82.30 mmol, 11.48 mL). Stir the reaction mixture at 0°C for 2 hours. Monitor the reaction by LC-MS. After completion of the reaction, filter and spin dry to obtain (tert-butyloxycarbonylamino) 2,4,6-trimethylbenzenesulfonate (14 g, white solid). Yield: 64.72%. MS m / z (ESI): 333.1 [M+18] + .

[0292] Step 2: Dissolve (tert-Butyloxycarbonylamino) 2,4,6-trimethylbenzenesulfonate (12.6 g, 39.95 mmol) in trifluoroacetic acid (25 mL). Cool the reaction mixture to 0°C and stir at 0°C for 2 hours. Monitor the reaction by LC-MS. After completion of the reaction, add ice water and filter to obtain amino 2,4,6-trimethylbenzenesulfonate (8.6 g, white solid). Yield: 100%. MS m / z (ESI): 233.1 [M+18] + .

[0293] Step 3: Dissolve amino 2,4,6-trimethylbenzenesulfonate (8.59 g, 39.89 mmol) and 2-bromo-5-methoxypyridine (5 g, 26.59 mmol) in dichloromethane (50 mL). Stir the reaction mixture at room temperature for 2 hours. After completion of the reaction, spin dry to obtain 2,4,6-trimethylbenzenesulfonate of 2-bromo-5-methoxypyridin-1-bromo-1-amine (5.43 g, yellow oil). Yield: 100%. MS m / z (ESI): 205.0 [M+H] + .

[0294] Step 4: Dissolve 2-bromo-5-methoxypyridin-1-bromo-1-amine (5.43 g, 26.61 mmol) and methyl propiolate (4.47 g, 53.22 mmol) in N,N-dimethylformamide (50 mL). Cool the reaction mixture to 0°C, then add potassium carbonate (5.52 g, 39.92 mmol). Stir the mixture at room temperature for 16 hours. After completion, filter the mixture and dry it through a column (PE / EtOAc = 3 / 1) to obtain methyl 7-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (2.1 g, yellow solid). Yield: 27.68%. MS m / z (ESI): 285.0 [M+H]. + .

[0295] Step 5: Dissolve methyl 7-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (500 mg, 1.75 mmol) in hydrobromic acid (5 mL, 48%). Heat the reaction mixture to 100°C and stir for 2 hours. After completion of the reaction, spin dry to obtain 7-bromo-4-methoxypyrazolo[1,5-a]pyridine (330 mg, purple solid). Yield: 82.87%. MS m / z (ESI): 229.0 [M+H] + .

[0296] Step 6: 7-Bromo-4-methoxypyrazolo[1,5-a]pyridine (80 mg, 352.33 μmol), 2-aminopyridine-4-boronic acid pinacol ester (116.31 mg, 528.50 μmol), tetrakis(triphenylphosphine)palladium (40.71 mg, 35.23 μmol), and cesium carbonate (137.76 mg, 422.80 μmol) were added to 1,4-dioxane (5 mL) and water (0.5 mL). The reaction solution was stirred at 100°C for 4 hours. After completion of the reaction, the product was spin-dried and filtered through a column (DCM / MeOH = 19 / 1) to afford 4-(4-methoxypyrazolo[1,5-a]pyridin-7-yl)pyridin-2-amine (80 mg, yellow solid). Yield: 94.50%. MS m / z (ESI): 241.1 [M+H]. + .

[0297] Step 7: Dissolve 4-(4-methoxypyrazolo[1,5-a]pyridin-7-yl)pyridin-2-amine (80 mg, 332.97 μmol) in hydrobromic acid (5 mL, 48%). Stir the reaction mixture at 120°C for 48 hours. After completion of the reaction, the mixture was dried to afford Intermediate 1 (70 mg, yellow solid). Yield: 92.93%. MS m / z (ESI): 227.1 [M+H] + .

[0298] Preparation of intermediate 2

[0299] Step 1: 7-Bromo-4-methoxypyrazolo[1,5-a]pyridine (110 mg, 484.46 μmol), 2-difluoromethyl-4-pyridinium boronic acid pinacol ester (185.35 mg, 726.69 μmol), tetrakis(triphenylphosphine)palladium (55.98 mg, 48.45 μmol), and cesium carbonate (189.42 mg, 581.35 μmol) were added to 1,4-dioxane (5 mL) and water (0.5 mL). The reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, the mixture was dried and filtered through a column (PE / EtOAc = 2 / 1) to afford 7-[2-(difluoromethyl)-4-pyridinyl]-4-methoxypyrazolo[1,5-a]pyridine (110 mg, yellow solid). Yield: 82.49%. MS m / z(ESI):276.1[M+H] + .

[0300] Step 2: Dissolve 7-[2-(difluoromethyl)-4-pyridyl]-4-methoxypyrazolo[1,5-a]pyridine (110 mg, 399.63 μmol) in hydrobromic acid (5 mL, 48%). Stir the reaction at 120°C for 48 hours. After completion of the reaction, the solvent was evaporated to afford Intermediate 2 (100 mg, yellow solid). Yield: 95.79%. MS m / z (ESI): 262.1 [M+H] + .

[0301] Preparation of intermediate 3

[0302] Step 1: Dissolve 6-bromopyridin-3-ol (1.74 g, 10.00 mmol) and benzyl bromide (2.05 g, 12.00 mmol) in N,N-dimethylformamide (20 mL), then add potassium carbonate (2.07 g, 15.00 mmol). Stir the reaction mixture at 60°C for 2 hours. After completion, the reaction mixture was dried and passed through a column (PE / EtOAC = 4 / 1) to afford 5-benzyloxy-2-bromopyridine (2.4 g, white solid). Yield: 90.87%. MS m / z (ESI): 264.0 [M+H] +

[0303] Step 2: Dissolve amino 2,4,6-trimethylbenzenesulfonate (2.15 g, 10.00 mmol) and 5-benzyloxy-2-bromopyridine (1.32 g, 5.00 mmol) in dichloromethane (20 mL). Stir the reaction mixture at room temperature for 2 hours. After the reaction is complete, spin dry to obtain 5-benzyloxy-2-bromopyridin-1-bromo-1-amine 2,4,6-trimethylbenzenesulfonate (1.40 g, white solid). Yield: 100%. MS m / z (ESI): 281.0 [M+H]+ .

[0304] Step 3: Dissolve 2,4,6-trimethylbenzenesulfonate (1.4 g, 5.00 mmol) of 5-benzyloxy-2-bromopyridin-1-bromo-1-amine and methyl propiolate (840.31 mg, 10.00 mmol) in N,N-dimethylformamide (20 mL). The reaction mixture was cooled to 0°C, and potassium carbonate (1.73 g, 12.49 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was dried and column chromatography (PE / EtOAc = 2 / 1) to afford methyl 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylate (1.4 g, white solid). Yield: 77.56%. MS m / z (ESI): 363.0 [M+H]. + .

[0305] Step 4: 4-Benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (180 mg, 498.35 μmol), 7-azaindole-4-boronate (145.98 mg, 598.02 μmol), tetrakis(triphenylphosphine)palladium (28.79 mg, 24.92 μmol), and potassium carbonate (68.88 mg, 498.35 μmol) were added to 1,4-dioxane (5 mL) and water (0.5 mL). The reaction solution was stirred at 100°C for 4 hours. After completion of the reaction, the product was dried and passed through a column (PE / EtOAc = 1 / 4) to afford 4-benzyloxy-7-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (180 mg, yellow solid). Yield: 90.66%. MS m / z(ESI):399.2[M+H] + .

[0306] Step 5: Dissolve methyl 4-benzyloxy-7-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (180 mg, 451.79 μmol) in hydrobromic acid (10 mL, 48%). Stir the reaction at 100°C for 4 hours. After completion of the reaction, the product was dried to afford Intermediate 3 (100 mg, yellow solid). Yield: 88.45%. MS m / z (ESI): 251.1 [M+H] + .

[0307] Preparation of intermediate 4

[0308] Step 1: 4-Benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (540 mg, 1.50 mmol), 2-(tert-butoxycarbonylamino)pyridinium-4-boronic acid pinacol ester (478.70 mg, 1.50 mmol), tetrakis(triphenylphosphine)palladium (86.38 mg, 74.75 μmol), and potassium carbonate (206.63 mg, 1.50 mmol) were added to 1,4-dioxane (5 mL) and water (0.5 mL). The reaction solution was stirred at 100°C for 16 hours. After completion of the reaction, the product was dried and passed through a column (PE / EtOAc = 2 / 1) to afford 4-benzyloxy-7-[2-(tert-butoxycarbonylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (600 mg, yellow solid). Yield: 84.58%. MS m / z(ESI):475.1[M+H] + .

[0309] Step 2: Dissolve methyl 4-benzyloxy-7-[2-(tert-butoxycarbonylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridine-3-carboxylate (100 mg, 210.74 μmol), iodomethane (59.83 mg, 421.49 μmol), and potassium carbonate (43.69 mg, 316.12 μmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was dried and passed through a column (PE / EtOAc = 2 / 1) to afford methyl 4-benzyloxy-7-[2-[tert-butoxycarbonyl(methyl)amino]-4-pyridinyl]pyrazolo[1,5-a]pyridine-3-carboxylate (95 mg, yellow solid). Yield: 92.27%. MS m / z (ESI): 489.3 [M+H]. + .

[0310] Step 3: Dissolve methyl 4-benzyloxy-7-[2-[tert-butyloxycarbonyl(methyl)amino]-4-pyridyl]pyrazolo[1,5-a]pyridine-3-carboxylate (95 mg, 194.46 μmol) in hydrobromic acid (5 mL, 48%). Stir the reaction at 100°C for 4 hours. After completion of the reaction, the mixture was dried to afford Intermediate 4 (40 mg, yellow solid). Yield: 85.61%. MS m / z (ESI): 241.1 [M+H]. + .

[0311] Preparation of intermediate 5

[0312] Step 1: Dissolve methyl 4-benzyloxy-7-[2-(tert-butoxycarbonylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridine-3-carboxylate (100 mg, 210.74 μmol), 1,1-difluoro-2-iodoethane (80.90 mg, 421.49 μmol), and potassium carbonate (58.25 mg, 421.49 μmol) in N,N-dimethylformamide (5 mL). Stir the reaction at 70°C for 16 hours. After completion, the reaction was dried and column chromatography (PE / EtOAc = 2 / 1) to afford methyl 4-benzyloxy-7-[2-[tert-butoxycarbonyl(2,2-difluoroethyl)amino]-4-pyridinyl]pyrazolo[1,5-a]pyridine-3-carboxylate (90 mg, yellow solid). Yield: 79.30%. MS m / z(ESI):539.2[M+H] + .

[0313] Step 2: Dissolve methyl 4-benzyloxy-7-[2-[tert-butyloxycarbonyl(2,2-difluoroethyl)amino]-4-pyridyl]pyrazolo[1,5-a]pyridine-3-carboxylate (90 mg, 167.12 μmol) in hydrobromic acid. Stir the reaction mixture at 100°C for 4 hours. After completion of the reaction, the mixture was dried to afford Intermediate 5 (40 mg, yellow solid). Yield: 82.46%. MS m / z (ESI): 291.1 [M+H] + .

[0314] Preparation of intermediate 6

[0315] Step 1: Dissolve 8-iodo-5-methoxyimidazo[1,2-a]pyridine (1 g, 3.65 mmol) in tetrahydrofuran (20 mL), cool to -70°C, and under argon, add n-butyllithium (2.5 M, 2.63 mL) dropwise. Stir at low temperature for 10 minutes. Slowly add a solution of triisopropyl borate (1.37 g, 7.30 mmol) in tetrahydrofuran, and continue stirring for 1.5 hours. The reaction is quenched with water and concentrated. The remaining yellow oil is purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford (5-methoxyimidazo[1,2-a]pyridin-8-yl)boronic acid (0.6 g, yield: 85.7%) as a colorless oil. MS m / z (ESI): 193.1 [M+H] + .

[0316] Step 2: (5-Methoxyimidazo[1,2-a]pyridin-8-yl)boronic acid (191 mg, 1 mmol), 7-chloropyrazolo[1,5-a]pyrimidine (152 mg, 1 mmol), and bis(triphenylphosphine)palladium chloride (36.40 mg, 0.05 mmol) were dissolved in 1,4-dioxane (15 mL). Potassium carbonate (412 mg, 3 mmol) was added, and the atmosphere was replaced with argon three times. The reaction mixture was heated to 150°C under microwave conditions for 1 hour. After cooling, the mixture was filtered and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford 7-(5-methoxyimidazo[1,2-a]pyridin-8-yl)pyrazolo[1,5-a]pyrimidine (100 mg, yield: 37.9%) as a yellow oil. MS m / z (ESI): 266.1 [M+H] + .

[0317] Step 3: Dissolve 7-(5-methoxyimidazo[1,2-a]pyridin-8-yl)pyrazolo[1,5-a]pyrimidine (60 mg, 0.27 mmol) in N,N-dimethylformamide (10 mL), add p-toluenesulfonic acid (78 mg, 0.45 mmol) and lithium chloride (19 mg, 0.45 mmol), heat to 120°C, stir for 0.5 hour, cool, filter, and concentrate. The residue is purified by column chromatography (methanol / dichloromethane = 1 / 10) to give Intermediate 6 (40 mg, yield: 70.39%). MS m / z (ESI): 252.1 [M+H] + .

[0318] Preparation of intermediate 7

[0319] Step 1: (5-methoxyimidazo[1,2-a]pyridin-8-yl)boronic acid (191 mg, 1 mmol), 4-chloro-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (168 mg, 1 mmol) and bis(triphenylphosphine)palladium chloride (36.40 mg, 0.05 mmol) were dissolved in 1,4-dioxane (15 mL), potassium carbonate (413 mg, 3 mmol) was added, and the atmosphere was replaced with argon three times. The temperature was raised to 150 ° C. under microwave conditions, the reaction was carried out for 1 hour, the reaction was cooled, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (120 mg, yield: 43.0%). MS m / z(ESI):281.1[M+H] + .

[0320] Step 2: Dissolve 4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (100 mg, 0.356 mmol) in N,N-dimethylformamide (10 mL), add p-toluenesulfonic acid (123 mg, 0.713 mmol) and lithium chloride (30 mg, 0.713 mmol), heat to 120°C, stir for 0.5 hour, cool, filter, and concentrate. The residue is purified by column chromatography (methanol / dichloromethane = 1 / 10) to give Intermediate 7 (80 mg, yield: 83.6%). MS m / z (ESI): 267.1 [M+H] + .

[0321] Preparation of intermediate 8

[0322] Step 1: Dissolve (5-methoxyimidazo[1,2-a]pyridin-8-yl)boronic acid (120 mg, 0.63 mmol), 3-chloro-4-iodo-2-pyridinamine (159 mg, 0.63 mmol), and bis(triphenylphosphine)palladium chloride (23 mg, 0.03 mmol) in 1,4-dioxane (6 mL). Add potassium carbonate (259 mg, 1.88 mmol). Replace the atmosphere with argon three times. Heat to 150°C under microwave conditions for 1 hour. After cooling, filter, and concentrate. The residue is purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford 3-chloro-4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)pyridin-2-amine (100 mg, yield: 58.2%) as a yellow oil. MS m / z (ESI): 275.1 [M+H] + .

[0323] Step 2: Dissolve 3-chloro-4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)pyridin-2-amine (100 mg, 0.364 mmol) in N,N-dimethylformamide (10 mL), add p-toluenesulfonic acid (125 mg, 0.73 mmol) and lithium chloride (31 mg, 0.73 mmol), heat to 120°C, stir for 0.5 hour, cool, filter, and concentrate. The residue is purified by column chromatography (methanol / dichloromethane = 1 / 10) to give yellow solid intermediate 8 (40 mg, yield: 41.8%). MS m / z (ESI): 261.1 [M+H] + .

[0324] Preparation of intermediate 9

[0325] Step 1: Dissolve (5-methoxyimidazo[1,2-a]pyridin-8-yl)boronic acid (150 mg, 0.78 mmol), 5-fluoro-4-iodo-2-pyridinamine (186 mg, 0.78 mmol), and bis(triphenylphosphine)palladium chloride (28.6 mg, 0.04 mmol) in 1,4-dioxane (6 mL). Add potassium carbonate (324 mg, 2.34 mmol). Replace the atmosphere with argon three times. Heat to 150°C under microwave conditions for 1 hour. After cooling, filter, and concentrate. The residue is purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford 5-fluoro-4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)pyridin-2-amine (150 mg, yield: 74.3%) as a yellow oil. MS m / z (ESI): 259.1 [M+H] + .

[0326] Step 2: Dissolve 5-fluoro-4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)pyridin-2-amine (150 mg, 0.58 mmol) in N,N-dimethylformamide (10 mL), add p-toluenesulfonic acid (200 mg, 1.16 mmol) and lithium chloride (49 mg, 1.16 mmol), heat to 120°C, stir for 0.5 hour, cool, filter, and concentrate. The residue is purified by column chromatography (methanol / dichloromethane = 1 / 10) to give yellow solid intermediate 9 (140 mg, yield: 98.7%). MS m / z (ESI): 245.1 [M+H] + .

[0327] Preparation of intermediate 10

[0328] Step 1: Dissolve 7-bromo-4-methoxypyrazolo[1,5-a]pyridine (454 mg, 2 mmol) in tetrahydrofuran (25 mL), cool to -70°C, and under argon, add n-butyllithium (2.5 M, 1.44 mL) dropwise. Stir at low temperature for 10 minutes. Slowly add a solution of tributyltin chloride (1.13 g, 4 mmol) in tetrahydrofuran, and continue stirring for 1.5 hours. The reaction is quenched with water and concentrated. The remaining yellow oil is purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to afford 4-methoxy-7-(tributyltinyl)pyrazolo[1,5-a]pyridine (0.8 g, yield: 91.5%) as a colorless oil. MS m / z (ESI): 439.0 [M+H] + .

[0329] Step 2: Dissolve 4-methoxy-7-(tributylstannyl)pyrazolo[1,5-a]pyridine (451 mg, 1 mmol), 5-fluoro-4-iodo-2-pyridinamine (238 mg, 1 mmol), and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) in toluene (20 mL). The atmosphere was replaced with argon three times. The reaction mixture was heated to 150°C under microwave conditions for 2 hours. After cooling, the mixture was filtered and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 5-fluoro-4-(4-methoxypyrazolo[1,5-a]pyridin-7-yl)pyridin-2-amine (120 mg, yield: 46.47%). MS m / z (ESI): 259.1 [M+H] + .

[0330] Step 3: Dissolve 5-fluoro-4-(4-methoxypyrazolo[1,5-a]pyridin-7-yl)pyridin-2-amine (120 mg, 0.465 mmol) in 40% aqueous hydrobromic acid (15 mL), heat to 120°C, stir for 2 hours, cool, and concentrate to yield yellow solid Intermediate 10 (95 mg, yield: 83.7%), which was used directly in the next step. MS m / z (ESI): 245.1 [M+H] + .

[0331] Preparation of intermediate 11

[0332] Step 1: Dissolve 4-methoxy-7-(tributylstannyl)pyrazolo[1,5-a]pyridine (226 mg, 0.5 mmol), 4-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (106 mg, 0.5 mmol), and bis(triphenylphosphine)palladium chloride (17.6 mg, 0.025 mmol) in 1,4-dioxane (10 mL). The atmosphere was replaced with argon three times. The reaction mixture was heated to 150°C under microwave conditions for 1 hour. After cooling, the mixture was filtered and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 4-(4-methoxypyrazolo[1,5-a]pyridin-7-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine (90 mg, yield: 64.7%). MS m / z (ESI): 279.1 [M+H] + .

[0333] Step 2: Dissolve 4-(4-methoxypyrazolo[1,5-a]pyridin-7-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine (90 mg, 0.32 mmol) in 40% aqueous hydrobromic acid (10 mL). Heat to 120°C, stir for 2 hours, cool, and concentrate to yield the remaining yellow solid Intermediate 11 (80 mg, yield: 93.6%), which was used directly in the next step. MS m / z (ESI): 265.1 [M+H] + .

[0334] Preparation of intermediate 12

[0335] 5-Chloro-8-iodoimidazo[1,2-a]pyridine (663 mg, 2.38 mmol) and (2-(difluoromethyl)pyridin-4-yl)boronic acid (729.30 mg, 2.86 mmol) were dissolved in a mixture of 1,4-dioxane (10 mL) and water (2 mL). Potassium carbonate (663.00 mg, 4.80 mmol) and tetrakis(triphenylphosphine)palladium (142.07 mg, 122.95 μmol) were then added. The reaction was heated to 90°C under nitrogen and stirred for 5 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a solvent system (petroleum ether / ethyl acetate: 1 / 0 to 2 / 1) to afford Intermediate 12 (330 mg, yellow solid) in a 49.56% yield. MS m / z (ESI): 280.1 [M+H]. + .

[0336] Preparation of intermediate 13

[0337] Step 1: Add methyl 4-(benzyloxy)-7-bromopyrazolo[1,5-a]pyridine-3-carboxylate (500 mg, 1.38 mmol) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (980.81 mg, 2.77 mmol) to acetonitrile (20 mL) and stir at room temperature under argon for 16 hours. Add saturated sodium bicarbonate solution and extract with dichloromethane (30 mL x 3). The organic phase is dried, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using a solvent system (petroleum ether / ethyl acetate: 1 / 0 to 3 / 1) to afford methyl 4-(benzyloxy)-7-bromo-2-fluoropyrazolo[1,5-a]pyridine-3-carboxylate (200 mg, light yellow oil) in a yield of 38.10%. MS m / z(ESI):379.0[M+H] + .

[0338] Step 2: Add methyl 4-(benzyloxy)-7-bromo-2-fluoropyrazolo[1,5-a]pyridine-3-carboxylate (200 mg, 527.45 μmol), 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (201.81 mg, 791.18 μmol), tetrakis(triphenylphosphine)palladium (60.95 mg, 52.75 μmol), and potassium carbonate (87.48 mg, 632.94 μmol) to water (1 mL) and 1,4-dioxane (10 mL). Stir the reaction at 90°C for 6 hours. Filter and spin dry the solvent. The resulting residue was purified by silica gel column chromatography using a 1 / 0 to 1 / 1 solvent system (petroleum ether / ethyl acetate) to afford methyl 4-(benzyloxy)-7-(2-(difluoromethyl)pyridin-4-yl)-2-fluoropyrazolo[1,5-a]pyridine-3-carboxylate (75 mg, yellow solid) in a 33.27% yield. MS m / z (ESI): 428.1 [M+H] + .

[0339] Step 3: Dissolve methyl 4-(benzyloxy)-7-(2-(difluoromethyl)pyridin-4-yl)-2-fluoropyrazolo[1,5-a]pyridine-3-carboxylate (75 mg, 175.49 μmol) in ethanol (10 mL). Add 10% palladium on carbon (40 mg, 175.49 μmol). Stir the reaction mixture at room temperature for 1 hour under a hydrogen atmosphere. Filter and concentrate under reduced pressure to obtain intermediate 13 (53 mg, yellow oil). The crude product was used directly in the next step. MS m / z (ESI): 338.0 [M+H] + .

[0340] Preparation of Intermediate 14-1

[0341] Step 1: Add (4-methoxyphenyl)methanamine (1.20 g, 8.76 mmol), 2,6-dichloro-4-iodo-pyridine (1.2 g, 4.38 mmol), and N,N-diisopropylethylamine (1.70 g, 13.14 mmol, 2.29 mL) to N-methylpyrrolidone (10 mL). The reaction mixture was stirred at 155°C for 6 hours. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using a solvent system (petroleum ether / ethyl acetate: 1 / 0 to 5 / 1) to afford 6-chloro-4-iodo-N-(4-methoxybenzyl)pyridin-2-amine (840 mg, white solid) in a 51.18% yield. MS m / z (ESI): 375.0 [M+H] + .

[0342] Step 2: 6-Chloro-4-iodo-N-(4-methoxybenzyl)pyridin-2-amine (840 mg, 2.24 mmol), pinacol bis(boron) (626.36 mg, 2.47 mmol), potassium acetate (550.18 mg, 5.61 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (82.04 mg, 112.12 μmol) were added to 1,4-dioxane (20 mL). Under argon, the reaction mixture was stirred at 80°C for 16 hours. The mixture was filtered and concentrated under reduced pressure to afford (2-chloro-6-((4-methoxybenzyl)amino)pyridin-4-yl)boronic acid (840 mg, black oil). The crude product was used directly in the next step. MS m / z (ESI): 293.1 [M+H] + .

[0343] Step 3: Add methyl 4-(methyloxy)-7-bromopyrazolo[1,5-a]pyridine-3-carboxylate (639.17 mg, 2.24 mmol), (2-chloro-6-((4-methoxybenzyl)amino)pyridin-4-yl)boronic acid (840 mg, 2.24 mmol), tetrakis(triphenylphosphine)palladium (129.54 mg, 112.10 μmol), and potassium carbonate (619.73 mg, 4.48 mmol) to water (1 mL) and 1,4-dioxane (10 mL). Stir the reaction at 100°C for 16 hours. Filter and spin dry the solvent. The resulting residue was purified by silica gel column chromatography with an eluent system (petroleum ether / ethyl acetate: 1 / 0 to 1 / 1) to provide methyl 7-(2-chloro-6-((4-methoxybenzyl)amino)pyridin-4-yl)-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (520 mg, yellow solid, 1.15 mmol, 51.21% yield) in a 51.21% yield. MS m / z (ESI): 453.2 [M+H] + .

[0344] Step 4: Methyl 7-(2-chloro-6-((4-methoxybenzyl)amino)pyridin-4-yl)-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (520 mg, 1.15 mmol) was added to a 48% aqueous solution of hydrogen bromide (12 mL). The reaction mixture was stirred at 130°C for 48 hours. The mixture was concentrated under reduced pressure to afford Intermediate 14 (210 mg, brown solid). The crude product was used directly in the next step. MS m / z (ESI): 261.1 [M+H] + .

[0345] Preparation of Intermediate 14-2

[0346] Step 1: Dissolve methyl 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylate (1.1 g, 3.05 mmol) in 1,4-dioxane (30 mL). Add (2,6-dichloro-4-pyridyl)boronic acid (584.15 mg, 3.05 mmol), potassium carbonate (841.84 mg, 6.09 mmol), tetrakis(triphenylphosphine)palladium (351.92 mg, 304.55 μmol), and water (3 mL). Stir at 100°C overnight. LC-MS confirmed the reaction was complete. Concentrate under reduced pressure to yield a brown solid. The solid was purified by combiflash (0-60% EA / PE) to afford methyl 4-benzyloxy-7-(2,6-dichloro-4-pyridyl)pyrazolo[1,5-a]pyridine-3-carboxylate (600 mg, yellow solid) in a yield of 46.00%. MS m / z(ESI):428.1[M+H] + .

[0347] Step 2: Dissolve methyl 4-benzyloxy-7-(2,6-dichloro-4-pyridinyl)pyrazolo[1,5-a]pyridine-3-carboxylate (600 mg, 1.40 mmol) in N-methylpyrrolidone (10 mL). Add 4-methoxybenzylamine (192.19 mg, 1.40 mmol) and N,N-diisopropylethylamine (543.19 mg, 4.20 mmol). Stir at 150°C for 2 hours. The reaction is complete as determined by LC-MS. Concentrate under reduced pressure to obtain a brown solid. The solid is purified by combiflash (0-100% EA / PE) to afford methyl 4-benzyloxy-7-[2-chloro-6-[(4-methoxyphenyl)methylamine]-4-pyridinyl]pyrazolo[1,5-a]pyridine-3-carboxylate (500 mg, yellow solid) in a 67.47% yield. MS m / z(ESI):529.1[M+H] + .

[0348] Step 3: Dissolve methyl 4-benzyloxy-7-[2-chloro-6-[(4-methoxyphenyl)methylamine]-4-pyridyl]pyrazolo[1,5-a]pyridine-3-carboxylate (700 mg, 1.32 mmol) in water (10 mL). Add aqueous hydrogen bromide (428.28 mg, 40%) and stir at 100°C for 4 hours. LC-MS confirmed the reaction was complete. Concentrate under reduced pressure to afford Intermediate 14 (300 mg, brown solid) in an 86.97% yield. MS m / z (ESI): 261.1 [M+H]. + .

[0349] Preparation of Intermediate 14-3

[0350] Step 1: Dissolve 2-amino-6-chloropyridine (2.56 g, 19.91 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.06 g, 23.90 mmol) in tetrahydrofuran (20 mL). Stir at room temperature for 1 hour. Then, add pinacol diboron (2.53 g, 9.96 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (94.11 mg, 398.26 μmol), and bis[(1,2,5,6-η)-1,5-cyclooctadiene]di-μ-methoxyiridium (130.39 mg, 199.13 μmol). The reaction mixture is stirred at 80°C under nitrogen for 16 hours. The product was dried and passed through a column (DCM / MeOH = 20 / 1) to give 2-amino-6-chloro-pyridine-4-boronic acid pinacol ester (2.46 g, yellow solid) in a yield of 48.54%. MS m / z (ESI): 255.1 [M+H] + .

[0351] Step 2: Methyl 4-benzyloxy-7-bromopyrazolo[1,5-a]pyridine-3-carboxylate (1 g, 2.77 mmol), 2-amino-6-chloro-pyridinium-4-boronic acid pinacol ester (845.61 mg, 3.32 mmol), tetrakis(triphenylphosphine)palladium (159.97 mg, 138.43 μmol), and potassium carbonate (459.18 mg, 3.32 mmol) were added to 1,4-dioxane (50 mL) and water (5 mL). The reaction mixture was stirred at 100°C for 16 hours. The mixture was then dried and purified by column chromatography (DCM / MeOH = 20 / 1) to afford methyl 7-(2-amino-6-chloro-4-pyridinyl)-4-benzyloxypyrazolo[1,5-a]pyridine-3-carboxylate (850 mg, yellow solid) in a yield of 75.09%. MS m / z(ESI):409.2[M+H] + .

[0352] Step 3: Methyl 7-(2-amino-6-chloro-4-pyridinyl)-4-benzyloxypyrazolo[1,5-a]pyridine-3-carboxylate (850 mg, 2.08 mmol) was dissolved in aqueous hydrobromic acid (50 mL, 40%). The reaction mixture was stirred at 120°C for 5 hours. The mixture was dried and purified by column chromatography (DCM / MeOH = 4 / 1) to afford Intermediate 14 (541 mg, yellow solid) in a 99.82% yield. MS m / z (ESI): 261.1 [M+H] + .

[0353] Preparation of intermediate 15

[0354] Step 1: Dissolve 2,3-difluoro-4-iodopyridine (2 g, 8.30 mmol) in aqueous ammonia (20 mL). Stir the reaction at 135°C for 12 hours. Cool to room temperature, filter, and dry the solid under reduced pressure to yield 3-fluoro-4-iodopyridin-2-amine (1.5 g, 6.30 mmol, white solid). Yield: 75.94%. MS m / z (ESI): 238.9 [M+H]. + .

[0355] Step 2: Dissolve 3-fluoro-4-iodopyridin-2-amine (1 g, 4.20 mmol), tert-butyl tert-butoxycarbonyl carbonate (1.83 g, 8.40 mmol), and triethylamine (848.74 mg, 424.37 mmol, 1.17 mL) in dichloromethane (10 mL). Stir the reaction at 40°C for 3 hours. Concentrate under reduced pressure and purify the resulting residue by silica gel column chromatography using a 2 / 1 system of petroleum ether / ethyl acetate to afford tert-butyl (3-fluoro-4-iodopyridin-2-yl)carbamate (1.3 g, 3.84 mmol) in a 91.51% yield. MS m / z (ESI): 282.9 [M-56+H]. + .

[0356] Step 3: Under argon, tert-butyl (3-fluoro-4-iodopyridin-2-yl)carbamate (200 mg, 591.51 μmol) and (5-methoxyimidazo[1,2-a]pyridin-8-yl)boronic acid (113.56 mg, 591.51 μmol) were dissolved in 1,4-dioxane (6 mL) and water (2 mL). Tetrakis(triphenylphosphine)palladium (68.35 mg, 59.15 μmol) and potassium carbonate (163.26 mg, 1.18 mmol) were then added. The reaction was stirred at 100°C for 5 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using a 5 / 1 dichloromethane / methanol system as the eluent to yield 3-fluoro-4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)pyridin-2-amine (100 mg, 387.22 μmol) in a 65.46% yield. MS m / z (ESI): 259.1 [M+H] + .

[0357] Step 4: Dissolve 3-fluoro-4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)pyridin-2-amine (70 mg, 271.05 μmol), tert-butyl tert-butoxycarbonyl carbonate (118.31 mg, 542.11 μmol), and N,N-dimethylpyridin-4-amine (3.31 mg, 27.11 μmol) in dichloromethane (10.02 mL). The reaction was stirred at 40°C for 3 hours. The solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (dichloromethane / methanol: 5 / 1) to afford tert-butyl N-tert-butoxycarbonyl-N-[3-fluoro-4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)-2-pyridinyl]carbamate (85 mg, 185.39 μmol) in a 68.40% yield. MS m / z(ESI):459.2[M+H] + .

[0358] Step 5: Dissolve tert-butyl N-tert-butoxycarbonyl-N-[3-fluoro-4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)-2-pyridinyl]carbamate (80 mg, 174.49 μmol), lithium chloride (14.79 mg, 348.98 μmol), and 4-methylbenzenesulfonic acid (60.09 mg, 348.98 μmol) in N,N-dimethylformamide (6 mL). The reaction was stirred at 120°C for 0.5 h. The solvent was evaporated under reduced pressure. The crude product was purified by prep.HPLC to afford Intermediate 15 (10 mg, 40.95 μmol) in a 23.47% yield. MS m / z (ESI): 245.1 [M+H]. + .

[0359] Preparation of Intermediate 16-1

[0360] Step 1: Under argon protection, 2,6-difluoropyridine-4-boronic acid (571.91 mg, 3.60 mmol) and 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (1 g, 2.77 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL), and then potassium carbonate (764.14 mg, 5.54 mmol) and tetrakis(triphenylphosphine)palladium (159.97 mg, 138.43 μmol) were added. The reaction was stirred at 100°C for 12 hours, and the crude product was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using a 4 / 1 system of petroleum ether / ethyl acetate as eluent to afford methyl 4-benzyloxy-7-(2,6-difluoro-4-pyridyl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.5 g, 1.26 mmol) in a 45.68% yield. MS m / z (ESI): 396.0 [M+H] + .

[0361] Step 2: Methyl 4-benzyloxy-7-(2,6-difluoro-4-pyridinyl)pyrazolo[1,5-a]pyridine-3-carboxylate (440 mg, 1.11 mmol) and (4-methoxyphenyl)methanamine (198.47 mg, 1.45 mmol) were dissolved in N-methylpyrrolidone (8 mL), and N,N-diisopropylethylamine (287.67 mg, 2.23 mmol, 387.70 μL) was added. The reaction was stirred at 120°C for 2 hours. The residue was concentrated under reduced pressure and purified by silica gel column chromatography using a 3 / 1 system of petroleum ether / ethyl acetate as eluent to afford methyl 4-(benzyloxy)-7-(2-fluoro-6-((4-methoxybenzyl)amino)pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.35 g, 801.95 μmol) in a 72.06% yield. MS m / z (ESI): 513.2 [M+H] + .

[0362] Step 3: Methyl 4-(benzyloxy)-7-(2-fluoro-6-((4-methoxybenzyl)amino)pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.35 g, 682.89 μmol) was dissolved in hydrobromic acid (8 mL, 48%). The reaction was stirred at 100°C for 12 hours. The product was evaporated to dryness under reduced pressure to afford Intermediate 16 (160 mg, 655.14 μmol) in a 95.94% yield. The crude product was used directly in the next step. MS m / z (ESI): 245.1 [M+H] + .

[0363] Preparation of Intermediate 16-2

[0364] Step 1: Dissolve 2-amino-6-fluoropyridine (1.12 g, 9.99 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.53 g, 11.99 mmol) in tetrahydrofuran (20 mL). Stir at room temperature for 1 hour. Then, add pinacol diboron (1.27 g, 5.00 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (47.22 mg, 199.81 μmol), and bis[(1,2,5,6-η)-1,5-cyclooctadiene]di-μ-methoxyiridium (65.42 mg, 99.91 μmol). The reaction mixture is stirred at 80°C under nitrogen for 16 hours. The product was dried and passed through a column (DCM / MeOH = 20 / 1) to give 2-amino-6-fluoro-pyridine-4-boronic acid pinacol ester (1.38 g, yellow solid) in a yield of 58.02%. MS m / z (ESI): 239.2 [M+H] + .

[0365] Step 2: Methyl 4-benzyloxy-7-bromopyrazolo[1,5-a]pyridine-3-carboxylate (0.5 g, 1.38 mmol), 2-amino-6-fluoro-pyridinium-4-boronic acid pinacol ester (395.47 mg, 1.66 mmol), tetrakis(triphenylphosphine)palladium (79.98 mg, 69.22 μmol), and potassium carbonate (229.59 mg, 1.66 mmol) were added to 1,4-dioxane (50 mL) and water (5 mL). The reaction mixture was stirred at 100°C for 16 hours. The mixture was then dried and purified by column chromatography (DCM / MeOH = 20 / 1) to afford methyl 7-(2-amino-6-fluoro-4-pyridinyl)-4-benzyloxypyrazolo[1,5-a]pyridine-3-carboxylate (420 mg, yellow solid) in a yield of 77.32%. MS m / z(ESI):393.2.

[0366] Step 3: Dissolve methyl 7-(2-amino-6-fluoro-4-pyridyl)-4-benzyloxypyrazolo[1,5-a]pyridine-3-carboxylate (420 mg, 1.07 mmol) in 40% aqueous hydrobromic acid (50 mL). Stir the reaction mixture at 120°C for 5 hours. Dry the mixture and purify it with a column chromatography (DCM / MeOH = 4 / 1) to obtain Intermediate 16 (261 mg, yellow solid) in a 99.84% yield. MS m / z (ESI): 245.1 [M+H] + .

[0367] Preparation of intermediate 17

[0368] Step 1: Dissolve 6-chloro-3-iodopyridin-2-amine (4 g, 15.72 mmol) in isopropanol (30 mL), add 2-bromo-1,1-diethoxyethane (3.72 g, 18.86 mmol) and hydrogen bromide solution (2.54 g, 31.44 mmol, 48%), stir at 90°C overnight, and concentrate under reduced pressure to obtain a yellow solid. The solid was washed with diethyl ether and filtered to obtain 5-chloro-8-iodoimidazo[1,2-a]pyridine (4 g, 14.36 mmol, 91.37% yield) as a yellow solid. MS m / z (ESI): 279.1 [M+H] + .

[0369] Step 2: Dissolve 5-chloro-8-iodoimidazo[1,2-a]pyridine (5 g, 17.95 mmol) in methanol (100 mL), add sodium methoxide (2.91 g, 53.86 mmol), stir at 65°C for 6 hours, and concentrate under reduced pressure to obtain a white solid. The solid was purified by combiflash (0-100% EA / PE) to obtain 8-iodo-5-methoxyimidazo[1,2-a]pyridine (4.9 g, 17.88 mmol, 99.58% yield) as a white solid. MS m / z (ESI): 275.1 [M+H] + .

[0370] Step 3: Dissolve 8-iodo-5-methoxyimidazo[1,2-a]pyridine (1 g, 3.65 mmol) in water (2 mL). Add 1,4-dioxane (20 mL), potassium carbonate (1.01 g, 7.30 mmol), Pd(dppf)2Cl2 (295.77 mg, 364.89 μmol), and 2-aminopyridine-4-boronic acid pinacol ester (803.03 mg, 3.65 mmol). Microwave under nitrogen at 120°C and stir for 1 hour. Filter and concentrate under reduced pressure to obtain a black solid. The solid was purified by combiflash (0-30% DCM / MeOH) to afford 4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)pyridin-2-amine (400 mg, 1.66 mmol, 45.63% yield) as a yellow solid. MS m / z(ESI):241.1[M+H] + .

[0371] Step 4: Dissolve 4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)pyridin-2-amine (400 mg, 1.66 mmol) in N,N-dimethylformamide (2 mL), add lithium chloride (141.16 mg, 3.33 mmol) and p-toluenesulfonic acid (573.38 mg, 3.33 mmol), and stir at 120°C for 30 minutes. Concentrate under reduced pressure to obtain a brown solid. The solid is purified by combiflash (0-20% DCM / MeOH) to obtain intermediate 17 (280 mg, 1.24 mmol, 74.34% yield) as a yellow solid. MS m / z (ESI): 227.1 [M+H] + .

[0372] Preparation of intermediate 18

[0373] Step 1: Dissolve 4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)pyridin-2-amine (180 mg, 749.19 μmol) in dichloromethane (8 mL). Add acetyl chloride (117.62 mg, 1.50 mmol) and triethylamine (227.43 mg, 2.25 mmol, 313.48 μL) at 0°C and stir at 0°C for 1 hour. Add dichloromethane, wash with anhydrous sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give N-acetyl-N-[4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)-2-pyridinyl]acetamide (160 mg, 493.32 μmol) as a yellow solid in a yield of 65.85%. Use directly in the next reaction. MS m / z (ESI): 325.1 [M+H] + .

[0374] Step 2: Dissolve N-acetyl-N-[4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)-2-pyridinyl]acetamide (120 mg, 369.99 μmol) in N,N-dimethylformamide (5 mL). Add lithium chloride (15.69 mg, 369.99 μmol) and p-toluenesulfonic acid (63.71 mg, 369.99 μmol). Stir at 120°C for 30 minutes. Concentrate under reduced pressure to obtain a yellow solid. Pre-HPLC analysis of the solid afforded Intermediate 18 (50 mg, 186.38 μmol, 50.37% yield) as a yellow solid. MS m / z (ESI): 269.1 [M+H] + .

[0375] Preparation of intermediate 19

[0376] Step 1: Dissolve 5-chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine (0.2 g, 0.72 mmol) in anhydrous methanol (6 mL). Potassium hydroxide (0.12 g, 2.15 mmol) was added and the reaction was stirred at 65°C for 16 h. After completion of the reaction, the solvent was removed under reduced pressure. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to afford 8-(2-(difluoromethyl)pyridin-4-yl)-5-methoxyimidazo[1,2-a]pyridine (0.14 g, yellow solid) in a yield of 64%. MS m / z (ESI): 276.1 [M+H]. + .

[0377] Step 2: 8-(2-(Difluoromethyl)pyridin-4-yl)-5-methoxyimidazo[1,2-a]pyridine (0.14 g, 0.51 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). p-Toluenesulfonic acid (0.48 g, 2.54 mmol) and lithium chloride (0.11 g, 2.54 mmol) were added. The reaction was stirred at 120°C under nitrogen for 0.5 h. After completion, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford Intermediate 19 (70 mg, light yellow solid) in a yield of 44.8%. MS m / z (ESI): 262.1 [M+H]. + .

[0378] Preparation of intermediate 20

[0379] Step 1: Dissolve methyl 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylate (720 mg, 1.99 mmol), (2-chloro-4-pyridyl)boronic acid (313.69 mg, 1.99 mmol), potassium carbonate (275.51 mg, 1.99 mmol), and tetrakis(triphenylphosphine)palladium (2.30 g, 1.99 mmol) in 1,4-dioxane (10 mL) and water (2 mL). Stir the reaction mixture at 100°C for 16 hours. After completion, the reaction mixture was dried and passed through a column (PE / EtOAC = 2 / 1) to afford methyl 4-benzyloxy-7-(2-chloro-4-pyridyl)pyrazolo[1,5-a]pyridine-3-carboxylate (420 mg, yellow solid). Yield: 53.50%. MS m / z (ESI): 394.2 [M+H]. + .

[0380] Step 2: 4-Benzyloxy-7-(2-chloro-4-pyridinyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (420 mg, 1.07 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (221.90 mg, 1.07 mmol), potassium carbonate (176.88 mg, 1.28 mmol) and tetrakis(triphenylphosphine)palladium (123.18 mg, 106.65 μmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL), and the reaction solution was stirred under microwave conditions at 120 ° C for 1 hour. After the reaction was complete, the product was dried and passed through a column (DCM / MeOH = 19 / 1) to afford methyl 4-benzyloxy-7-[2-(1-methylpyrazol-4-yl)-4-pyridinyl]pyrazolo[1,5-a]pyridine-3-carboxylate (100 mg, yellow solid). Yield: 21.34%. MS m / z (ESI): 440.2 [M+H] + .

[0381] Step 3: Dissolve methyl 4-benzyloxy-7-[2-(1-methylpyrazol-4-yl)-4-pyridinyl]pyrazolo[1,5-a]pyridine-3-carboxylate (100 mg, 227.55 μmol) in 40% aqueous hydrobromic acid (5 mL). Stir the reaction at 120°C for 2 hours. After completion of the reaction, the mixture was dried to afford Intermediate 20 (66 mg, yellow solid). Yield: 99.57%. MS m / z (ESI): 292.1 [M+H] + .

[0382] Preparation of intermediate 21

[0383] Step 1: Dissolve 2-bromo-4-chloropyridine (1.92 g, 10 mmol) and 1-methylpyrazol-4-amine (971 mg, 10 mmol) in 1,4-dioxane (60 mL). Add tris(dibenzylideneindeneacetone)dipalladium (275 mg, 0.3 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (347 mg, 0.6 mmol), and cesium carbonate (6.52 g, 20 mmol). Replace the atmosphere with argon three times, heat to 100°C, and stir for 2 hours. After cooling, filter, concentrate, and purify by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford 4-chloro-N-(1-methylpyrazol-4-yl)pyridin-2-amine (1.7 g, yield: 81.5%) as a yellow oil. MS m / z (ESI): 209.1 [M+H] + .

[0384] Step 2: 4-Chloro-N-(1-methylpyrazol-4-yl)pyridin-2-amine (1.5 g, 7.19 mmol) and biboronic acid pinacol ester (3.65 g, 14.38 mmol) were dissolved in 1,4-dioxane (50 mL), and tris(dibenzylideneindeacetone)dipalladium (197.50 mg, 0.215 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (205 mg, 0.43 mmol) and potassium acetate (2.12 g, 21.6 mmol) were added. The mixture was replaced with argon three times, heated to 100 ° C, stirred for 2 hours, cooled, filtered, and concentrated to give crude (2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)boronic acid (black solid, 1.5 g, yield: 95.7%), which was used directly in the next step. MS m / z(ESI):219.1[M+H] + .

[0385] Step 3: Dissolve (2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)boronic acid (1.4 g, 6.42 mmol) and methyl 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylate (2.32 g, 6.42 mmol) in 1,4-dioxane (50 mL), add potassium acetate (1.89 g, 19.26 mmol) and 1,1-bis(diphenylphosphino)diphenylferric chloride. Palladium chloride (235 mg, 0.32 mmol) was added, the atmosphere was replaced with argon three times, the mixture was heated to 100°C, stirred for 4 hours, cooled, filtered, and concentrated. The residue was purified by column chromatography (methanol / dichloromethane = 1 / 10) to give methyl 4-(benzyloxy)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.85 g, yield: 29.3%) as a yellow solid. MS m / z (ESI): 455.2 [M+H] + .

[0386] Step 4: Dissolve methyl 4-(benzyloxy)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.2 g, 440.06 μmol) in 40% aqueous hydrobromic acid (10 mL), heat to 120°C, stir for 4 hours, cool, and concentrate to afford crude intermediate 21 (black solid, 0.13 g, yield: 96.4%), which was used directly in the next step. MS m / z (ESI): 307.0 [M+H] + .

[0387] Preparation of intermediate 22

[0388] Step 1: Dissolve 4-bromo-6-fluoroquinoline (2.26 g, 10.00 mmol) in DCM (30 mL) and add m-chloroperbenzoic acid (6.09 g, 29.99 mmol, 85% purity). The reaction mixture was stirred at room temperature for 16 hours. Saturated sodium sulfite was added and stirred for half an hour, followed by saturated sodium bicarbonate and stirred for half an hour. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and dried to give 4-bromo-6-fluoroquinoline N-oxide (2.3 g, yellow solid) in a 95.05% yield. MS m / z (ESI): 244.0 [M+H] + .

[0389] Step 2: Dissolve 4-bromo-6-fluoroquinoline N-oxide (2.3 g, 9.50 mmol) in chloroform (30 mL). Add p-toluenesulfonic anhydride (9.30 g, 28.51 mmol) and tert-butylamine (3.47 g, 47.51 mmol) under ice-cooling. Stir the reaction mixture at room temperature for 48 hours. LC-MS analysis revealed approximately 75% product, with some starting material remaining. The product was purified by silica gel column chromatography (EA / PE = 1 / 2) to afford 4-bromo-N-tert-butyl-6-fluoroquinolin-2-amine (920 mg, yellow oil) in a 32.58% yield. MS m / z (ESI): 299.1 [M+H] + .

[0390] Step 3: 4-Bromo-N-tert-butyl-6-fluoroquinolin-2-amine (920 mg, 3.10 mmol), pinacol boronate (943.40 mg, 3.72 mmol), Pd(dppf)Cl2 (226.53 mg, 309.59 μmol), and potassium acetate (911.50 mg, 9.29 mmol) were added to 1,4-dioxane (10 mL). The reaction mixture was stirred at 80°C for 16 hours. Filtered and dried to give 4-pinacol boronate-N-tert-butyl-6-fluoroquinolin-2-amine (1.05 g, yellow solid) in a 98.53% yield. MS m / z (ESI): 345.2 [M+H] + .

[0391] Step 4: 4-Benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (0.5 g, 1.38 mmol), 4-pinacol boronate-N-tert-butyl-6-fluoroquinolin-2-amine (524.18 mg, 1.52 mmol), Pd(PPh3)4 (47.99 mg, 41.53 μmol), and potassium carbonate (229.59 mg, 1.66 mmol) were added to dioxane (10 mL) and water (1 mL). The reaction solution was stirred at 100°C for 16 hours. The product was dried and passed through a column (PE / EA = 3 / 1) to give 4-benzyloxy-7-[2-(tert-butylamino)-6-fluoro-4-quinolinyl]pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (620 mg, yellow solid) in a yield of 89.84%. MS m / z(ESI):499.3[M+H] + .

[0392] Step 5: Methyl 4-benzyloxy-7-[2-(tert-butylamino)-6-fluoro-4-quinolyl]pyrazolo[1,5-a]pyridine-3-carboxylate (620 mg, 1.24 mmol) was dissolved in aqueous hydrogen bromide (10 mL, 40%). The reaction mixture was stirred at 120°C for 4 hours. The mixture was dried and purified by column chromatography (DCM / MeOH = 4 / 1) to afford Intermediate 22 (365 mg, yellow solid) in a 99.73% yield. MS m / z (ESI): 295.1 [M+H] + .

[0393] Preparation of intermediate 23

[0394] Step 1: Dissolve 4-bromoquinoline (2.08 g, 10.00 mmol) in DCM (30 mL), then add m-chloroperbenzoic acid (6.09 g, 29.99 mmol, 85% purity). Stir the reaction mixture at room temperature for 16 hours. Add saturated sodium sulfite and stir for half an hour. Then add saturated sodium bicarbonate and stir for half an hour. Extract with dichloromethane, dry over anhydrous sodium sulfate, and spin dry to obtain 4-bromoquinoline N-oxide (2.1 g, yellow solid) in a 93.75% yield. MS m / z (ESI): 224.1 [M+H] + .

[0395] Step 2: Dissolve 4-bromoquinoline N-oxide (1 g, 4.46 mmol) in chloroform (20 mL). Add p-toluenesulfonic anhydride (4.37 g, 13.39 mmol) and tert-butylamine (1.63 g, 22.32 mmol) under ice. Stir the reaction mixture at room temperature for 48 hours. LC-MS analysis revealed approximately 75% product, with some starting material remaining. The product was purified by silica gel column chromatography (EA / PE = 1 / 2) to afford 4-bromo-N-tert-butylquinolin-2-amine (430 mg, yellow oil) in a 34.51% yield. MS m / z (ESI): 279.1 [M+H] + .

[0396] Step 3: 4-Bromo-N-tert-butylquinolin-2-amine (430 mg, 1.54 mmol), pinacol boronate (469.35 mg, 1.85 mmol), Pd(dppf)Cl2 (112.70 mg, 154.03 μmol), and potassium acetate (453.48 mg, 4.62 mmol) were added to 1,4-dioxane (10 mL). The reaction mixture was stirred at 80°C for 16 hours. Filtered and dried to give 4-pinacol boronate-N-tert-butylquinolin-2-amine (500 mg, yellow solid) in a 99.50% yield. MS m / z (ESI): 327.3 [M+H] + .

[0397] Step 4: 4-Benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (0.5 g, 1.38 mmol), 4-pinacol boronate-N-tert-butylquinolin-2-amine (496.78 mg, 1.52 mmol), Pd(PPh3)4 (47.99 mg, 41.53 μmol), and potassium carbonate (229.59 mg, 1.66 mmol) were added to dioxane (10 mL) and water (1 mL). The reaction mixture was stirred at 100°C for 16 hours. The product was then dried and purified by column chromatography (PE / EA = 3 / 1) to afford 4-benzyloxy-7-[2-(tert-butylamino)-4-quinolinyl]pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (600 mg, yellow solid) in a 90.19% yield. MS m / z (ESI): 481.2 [M+H] + .

[0398] Step 5: Methyl 4-benzyloxy-7-[2-(tert-butylamino)-4-quinolyl]pyrazolo[1,5-a]pyridine-3-carboxylate (600 mg, 1.25 mmol) was dissolved in aqueous hydrogen bromide (10 mL, 40%). The reaction mixture was stirred at 120°C for 4 hours. The mixture was dried and purified by column chromatography (DCM / MeOH = 4 / 1) to afford Intermediate 23 (344 mg, yellow solid) in a 99.72% yield. MS m / z (ESI): 277.1 [M+H] + .

[0399] Preparation of intermediate 24

[0400] Step 1: Dissolve 4-bromo-2-(difluoromethyl)pyridine (0.9 g, 4.33 mmol) in dichloromethane (35 mL), add m-chloroperbenzoic acid (1.49 g, 8.65 mmol), and stir at room temperature for 18 hours. Concentrate under reduced pressure, and purify the resulting residue by silica gel column chromatography using an eluent system (PE / EA = 1 / 1) to obtain 4-bromo-2-(difluoromethyl)pyridine 1-oxide (0.8 g) in an 82.54% yield. MS m / z (ESI): 225.9 [M+H] + .

[0401] Step 2: Dissolve 4-bromo-2-(difluoromethyl)pyridine 1-oxide (0.7 g, 3.12 mmol) in chloroform (30 mL). Add 4-toluenesulfonic anhydride (3.06 g, 9.37 mmol) and tert-butylamine (1.14 g, 15.62 mmol) under ice-cooling. Stir the reaction mixture at room temperature for 48 hours. Filter, concentrate the filtrate, and purify the resulting residue by silica gel column chromatography using an eluent system (PE / EA = 2 / 1) to afford 4-bromo-N-(tert-butyl)-6-(difluoromethyl)pyridin-2-amine (0.8 g) in a 91.72% yield. MS m / z (ESI): 281.0 [M+H] + .

[0402] Step 3: Dissolve 4-bromo-N-(tert-butyl)-6-(difluoromethyl)pyridin-2-amine (0.4 g, 1.43 mmol) and bis(pinacol)boronate (727.81 mg, 2.87 mmol) in 1,4-dioxane (50 mL). Add 1,1'-bis(diphenylphosphinoferrocenepalladium chloride) (52.43 mg, 71.65 μmol). Heat to 100°C under argon and stir for 3 hours. Filter and concentrate to obtain crude (2-(tert-butylamino)-6-(difluoromethyl)pyridin-4-yl)boronic acid (0.25 g), which is used directly in the next step. MS m / z (ESI): 245.1 [M+H] + .

[0403] Step 4: Dissolve (2-(tert-butylamino)-6-(difluoromethyl)pyridin-4-yl)boronic acid (0.25 g, 1.02 mmol) and methyl 4-(benzyloxy)-7-bromopyrazolo[1,5-a]pyridine-3-carboxylate (370.00 mg, 1.02 mmol) in 1,4-dioxane (30 mL). Add potassium carbonate (283.16 mg, 2.05 mmol). Heat to 100°C under argon and stir overnight. Filter, concentrate the filtrate, and purify the resulting residue by silica gel column chromatography with an eluent system (PE / EA = 3 / 1) to afford methyl 4-(benzyloxy)-7-(2-(tert-butylamino)-6-(difluoromethyl)pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.15 g) in a 30.47% yield. MS m / z(ESI):481.2[M+H] + .

[0404] Step 5: Dissolve methyl 4-(benzyloxy)-7-(2-(tert-butylamino)-6-(difluoromethyl)pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.15 g, 312.17 μmol) in 40% aqueous hydrobromic acid (20 mL), heat to 120°C, and stir for 3 hours. Concentrate under reduced pressure to give the crude intermediate 24 (70 mg), which is used directly in the next step. MS m / z (ESI): 277.0 [M+H] + .

[0405] Preparation of intermediate 25

[0406] Step 1: 4-Bromopyrimidin-2-amine (174 mg, 1.00 mmol) and 4-methoxy-7-(tributyltriphenylstannyl)pyrazolo[1,5-a]pyridine (437.21 mg, 1.00 mmol) were placed in a single-necked flask. NMP (5 mL) was added, followed by the addition of Pd(PPh3)4 (115.56 mg, 100.00 μmol). The reaction was stirred at 100°C for 12 hours. The product was then dried and purified by column chromatography (PE / EA = 2 / 1) to afford 4-(4-methoxypyrazolo[1,5-a]pyridin-7-yl)pyrimidin-2-amine (90 mg, yellow solid) in a 37.31% yield. MS m / z (ESI): 242.1 [M+H]. + .

[0407] Step 2: 4-(4-Methoxypyrazolo[1,5-a]pyridin-7-yl)pyrimidin-2-amine (60 mg, 248.71 μmol) was added to aqueous hydrogen bromide (5 mL, 40%), and the reaction mixture was stirred at 120°C for 12 hours. The product was dried and purified by column chromatography (DCM / MeOH = 10 / 1) to afford Intermediate 25 (20 mg, yellow solid) in a 35.39% yield. MS m / z (ESI): 228.1 [M+H] + .

[0408] Preparation of intermediate 26

[0409] Step 1: 4-Bromopicolinonitrile (1.5 g, 8.20 mmol), pinacol diboronate (4.16 g, 16.39 mmol), potassium acetate (2.01 g, 20.49 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (599.74 mg, 819.65 μmol) were added to 1,4-dioxane (30 mL). Under argon, the reaction mixture was stirred at 100°C for 16 hours. The mixture was filtered and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 3 / 1) to obtain 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (1.8 g, light yellow oil) in a yield of 95.45%. MS m / z(ESI):149.1[M+H] + .

[0410] Step 2: Under argon, methyl 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylate (700 mg, 1.94 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (700 mg, 3.04 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (335.93 mg, 290.71 μmol), and potassium carbonate (535.71 mg, 3.88 mmol) were added to 1,4-dioxane (50 mL) and water (5 mL). The reaction mixture was stirred at 110°C for 16 hours. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using an eluent system (DCM / MeOH = 1 / 0 to 10 / 1) to provide methyl 4-benzyloxy-7-(2-cyano-4-pyridinyl)pyrazolo[1,5-a]pyridine-3-carboxylate (520 mg, off-white solid) in a 69.80% yield. MS m / z (ESI): 385.1 [M+H] + .

[0411] Step 3: Add 4-benzyloxy-7-(2-cyano-4-pyridinyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (520 mg, 1.35 mmol) to 40% aqueous hydrogen bromide (30 mL). The reaction mixture was stirred at 110°C for 3 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using an eluent system (DCM / MeOH = 1 / 0 to 2 / 1) to afford Intermediate 26 (310 mg, orange-red solid) in an 89.78% yield. MS m / z (ESI): 256.1 [M+H] + .

[0412] Preparation of intermediate 27

[0413] Step 1: Dissolve methyl 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylate (2 g, 5.54 mmol) in water (3 mL). Add (2-chloro-4-pyridyl)boronic acid (871.36 mg, 5.54 mmol), potassium carbonate (2.30 g, 16.61 mmol), Pd(dppf)Cl2 (405.16 mg, 553.73 μmol), and dioxane (30 mL). Stir at 100°C overnight under nitrogen. Filter and concentrate to obtain a black solid. The solid was combiflashed (0-60% EA / PE) to afford methyl 4-benzyloxy-7-(2-chloro-4-pyridyl)pyrazolo[1,5-a]pyridine-3-carboxylate (1.5 g, 68.79% yield, yellow solid). MS m / z (ESI): 394.1 [M+H] + .

[0414] Step 2: Methyl 4-benzyloxy-7-(2-chloro-4-pyridyl)pyrazolo[1,5-a]pyridine-3-carboxylate (1.2 g, 3.05 mmol) was added to 48% aqueous hydrobromic acid (15 mL). The reaction mixture was stirred at 110°C for 3 hours. The mixture was concentrated under reduced pressure to afford a black solid. The residue was purified by silica gel column chromatography using an eluent system (DCM / MeOH = 1 / 0 to 10 / 1) to afford Intermediate 27 (550 mg, 73.48% yield, as a yellow oil). MS m / z (ESI): 246.1 [M+H] + .

[0415] Preparation of intermediate 28

[0416] Step 1: Dissolve 4-chloro-2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (220 mg, 997.38 μmol) in dioxane (10 mL). Add bispinacol boronate (253.27 mg, 997.38 μmol), potassium acetate (97.88 mg, 997.38 μmol), and Pd(dppf)Cl2 (72.98 mg, 99.74 μmol). Stir overnight at 100°C under nitrogen. Filter and concentrate under reduced pressure to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (250 mg, 80.31% yield, black solid), which was used directly in the next reaction. MS m / z(ESI):313.1[M+H] + .

[0417] Step 2: Dissolve 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (200 mg, 640.83 μmol) in dioxane (8 mL). Add methyl 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylate (231.46 mg, 640.83 μmol), potassium carbonate (88.57 mg, 640.83 μmol), Pd(dppf)Cl2 (46.89 mg, 64.08 μmol), and water (0.8 mL). Stir at 100°C overnight under nitrogen. Filter and concentrate to obtain a black solid. The solid was combiflashed (0-60% EA / PE) to give methyl 4-benzyloxy-7-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]pyrazolo[1,5-a]pyridine-3-carboxylate (200 mg, yield 66.91%, yellow solid). MS m / z (ESI): 467.1 [M+H] + .

[0418] Step 3: Methyl 4-benzyloxy-7-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]pyrazolo[1,5-a]pyridine-3-carboxylate (200 mg, 643.21 μmol) was added to a 48% aqueous solution of hydrobromic acid (15 mL). The reaction mixture was stirred at 120°C overnight. The mixture was concentrated under reduced pressure to afford Intermediate 28 (100 mg, black solid, 48.85% yield). MS m / z (ESI): 319.1 [M+H] + .

[0419] Preparation of intermediate 29

[0420] Step 1: Methyl 4-(benzyloxy)-7-bromopyrazolo[1,5-a]pyridine-3-carboxylate (1 g, 2.77 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine (1.14 g, 4.15 mmol), Pd(dppf)Cl2 (40.18 mg, 55.37 μmol) and potassium carbonate (765.30 mg, 5.54 mmol) were dissolved in dioxane (20 mL) and water (2 mL). Under nitrogen protection, the reaction solution was stirred at 110°C for 16 hours. After the reaction was complete, the product was dried and passed through a column (PE / EA = 1 / 4) to obtain methyl 4-(benzyloxy)-7-(2-(trifluoromethyl)pyrimidin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (1 g, yellow solid, yield 84.32%). MS m / z (ESI): 429.1 [M+H] + .

[0421] Step 2: Methyl 4-(benzyloxy)-7-(2-(trifluoromethyl)pyrimidin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (900 mg, 2.10 mmol) was added to 48% aqueous hydrobromic acid (20 mL), and the reaction solution was stirred at 120°C for 3 hours. After completion of the reaction as monitored by LC-MS, the product was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using an eluent system (DCM / MeOH = 1 / 0 to 10 / 1) to afford Intermediate 29 (420 mg, yellow solid, yield 71.34%). MS m / z (ESI): 281.0 [M+H] + .

[0422] Preparation of intermediate 30

[0423] Step 1: 4-Bromo-2-(difluoromethyl)pyrimidine (95 mg, 454.56 μmol) and tributyl-(4-methoxypyrazolo[1,5-a]pyridin-7-yl)stannane (258.36 mg, 590.93 μmol) were placed in a microwave vial, DMF (10 mL) was added, and then Pd(PPh3)4 (52.53 mg, 45.46 μmol) was added. The reaction was stirred at 135°C in a microwave reactor for 60 minutes. LC-MS monitored the reaction for completion. The product was evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (petroleum ether containing 45% ethyl acetate) to afford 7-[2-(difluoromethyl)pyrimidin-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine (85 mg, 67.69% yield). MS m / z (ESI): 277.0 [M+H]. + .

[0424] Step 2: 7-[2-(Difluoromethyl)pyrimidin-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine (85.00 mg, 307.70 μmol) was dissolved in 48% aqueous hydrobromic acid (5 mL). The reaction was stirred at 120°C for 12 hours. The reaction was monitored for completion by LC-MS. The crude product was purified by column chromatography (dichloromethane containing 15% methanol) to afford intermediate 30 (50 mg, yield 61.97%). MS m / z (ESI): 263.0 [M+H] + .

[0425] Preparation of intermediate 31

[0426] Step 1: Dissolve intermediate 27 (500 mg, 2.04 mmol) and benzyl bromide (417.73 mg, 2.44 mmol) in DMF (10 mL) and add potassium carbonate (421.95 mg, 3.05 mmol). The reaction mixture was stirred at room temperature for 12 hours. After completion, it was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 1 / 9) to obtain 4-(benzyloxy)-7-(2-chloropyridin-4-yl)pyrazolo[1,5-a]pyridine (400 mg, yellow solid, yield 58.53%). MS m / z (ESI): 336.1 [M+H] + .

[0427] Step 2: Dissolve 4-(benzyloxy)-7-(2-chloropyridin-4-yl)pyrazolo[1,5-a]pyridine (400 mg, 1.19 mmol), tBuXPhos (25.29 mg, 59.56 μmol), Pd2(dba)3 (21.82 mg, 23.82 μmol), and potassium hydroxide (133.68 mg, 2.38 mmol) in 1,4-dioxane (10 mL) and water (2 mL). Under nitrogen, the reaction mixture was microwaved at 120°C for 2 hours. After completion of the reaction, the mixture was dried and passed through a column (MeOH / DCM = 1 / 15) to afford 4-(4-(benzyloxy)pyrazolo[1,5-a]pyridin-7-yl)pyridin-2-ol (100 mg, yellow solid, yield 26.45%). MS m / z (ESI): 318.1 [M+H] + .

[0428] Step 3: Dissolve 4-(4-(Benzyloxy)pyrazolo[1,5-a]pyridin-7-yl)pyridin-2-ol (100 mg, 315.12 μmol) and sodium difluorochloroacetate (72.06 mg, 472.68 μmol) in DMF (5 mL), and add potassium carbonate (87.11 mg, 630.24 μmol). The reaction mixture was stirred at 60°C for 12 hours. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 1 / 9) to afford 4-(benzyloxy)-7-(2-(difluoromethoxy)pyridin-4-yl)pyrazolo[1,5-a]pyridine (80 mg, yellow solid, 69.11% yield). MS m / z (ESI): 368.1 [M+H] + .

[0429] Step 4: Dissolve 4-(benzyloxy)-7-(2-(difluoromethoxy)pyridin-4-yl)pyrazolo[1,5-a]pyridine (80 mg, 217.78 μmol) in MeOH (10 mL) and add 10% Pd / C (10 mg). Under a hydrogen atmosphere, the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to afford Intermediate 31 (75 mg, yellow oil), which was used directly in the next step without purification. MS m / z (ESI): 278.1 [M+H] + .

[0430] Preparation of intermediate 32

[0431] Step 1: Dissolve methyl 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylate (700 mg, 1.94 mmol) in water (1.5 mL). Add (2-bromo-4-pyridyl)boronic acid (391.12 mg, 1.94 mmol), sodium carbonate (205.41 mg, 1.94 mmol), Pd(dppf)Cl2 (1.42 g, 1.94 mmol), and dioxane (15 mL). Stir the mixture at 100°C overnight under nitrogen. Filter, check, and concentrate to obtain a black solid. The solid was purified by combiflash (0-60% EA / PE) to afford methyl 4-benzyloxy-7-(2-bromo-4-pyridyl)pyrazolo[1,5-a]pyridine-3-carboxylate (80 mg, 9.42% yield, as a yellow solid). MS m / z (ESI): 438.1 [M+H] + .

[0432] Step 2: Methyl 4-benzyloxy-7-(2-bromo-4-pyridyl)pyrazolo[1,5-a]pyridine-3-carboxylate (80 mg, 182.53 μmol) was added to a 48% aqueous solution of hydrobromic acid (10 mL). The reaction mixture was stirred at 110°C for 3 hours. The mixture was concentrated under reduced pressure to afford intermediate 32 (42 mg, 79.31% yield, brown solid). This product was used directly in the next reaction. MS m / z (ESI): 290.1 ​​[M+H] + .

[0433] Preparation of intermediate 33

[0434] Step 1: (2-Methyl-4-pyridyl)boronic acid (400 mg, 2.92 mmol), methyl 4-benzyloxy-7-bromopyrazolo[1,5-a]pyridine-3-carboxylate (1.05 g, 2.92 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (213.72 mg, 292.09 mmol), and potassium carbonate (807.40 mg, 5.84 mmol) were added to 1,4-dioxane (10 mL) and water (1 mL). The atmosphere was replaced with argon three times and the mixture was stirred at 100°C overnight. The reaction mixture was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (3 x 30 mL), and the organic phase was dried by evaporation. The resulting residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 2 / 1) (detection at 254 nm) to give methyl 4-benzyloxy-7-(2-methyl-4-pyridyl)pyrazolo[1,5-a]pyridine-3-carboxylate (670 mg, brown oil, yield 61.43%). MS m / z (ESI): 374.2 [M+H] + .

[0435] Step 2: Dissolve methyl 4-benzyloxy-7-(2-methyl-4-pyridyl)pyrazolo[1,5-a]pyridine-3-carboxylate (70 mg, 187.46 μmol) in 48% aqueous hydrogen bromide (2 mL) and react at 120°C for 2 hours. Cool the reaction mixture to room temperature and adjust the pH to 8 by adding saturated sodium bicarbonate (15 mL). The mixture is extracted with ethyl acetate (3 × 20 mL), and the organic phase is concentrated under reduced pressure to obtain intermediate 33 (50 mg, yellow solid, crude product). MS m / z (ESI): 226.1 [M+H] + Preparation of Intermediate 34

[0436] Step 1: Under argon, 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (555.79 mg, 2.49 mmol), methyl 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylate (600 mg, 1.66 mmol), XPhos Pd G2 (130.54 mg, 166.12 μmol), and potassium carbonate (459.18 mg, 3.32 mmol) were added to 1,4-dioxane (30 mL) and water (3 mL). The reaction mixture was stirred at 120°C for 20 hours. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 0 / 1) to give methyl 4-benzyloxy-7-(3-fluoro-4-pyridyl)pyrazolo[1,5-a]pyridine-3-carboxylate (550 mg, yellow solid, yield 87.74%). MS m / z (ESI): 378.1 [M+H] + .

[0437] Step 2: Add methyl 4-benzyloxy-7-(3-fluoro-4-pyridyl)pyrazolo[1,5-a]pyridine-3-carboxylate (550 mg, 1.46 mmol) to 48% aqueous hydrogen bromide (10 mL). The reaction mixture was stirred at 120°C for 2 hours. The mixture was concentrated under reduced pressure to afford Intermediate 34 (330 mg, brown solid, 98.78% yield). The crude product was used directly in the next step. MS m / z (ESI): 230.1 [M+H] + .

[0438] Preparation of intermediate 35

[0439] Step 1: Dissolve 4-pyridineboronic acid (100 mg, 813.55 μmol) and methyl 4-benzyloxy-7-bromopyrazolo[1,5-a]pyridine-3-carboxylate (195.90 mg, 542.37 μmol) in 1,4-dioxane (3 mL) and water (0.3 mL) at room temperature. Add Pd(dppf)Cl2 (39.69 mg, 54.24 μmol). Reaction was carried out at 100°C under nitrogen for 12 hours. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 100 / 1) to afford methyl 4-benzyloxy-7-(4-pyridyl)pyrazolo[1,5-a]pyridine-3-carboxylate (170 mg, yellow solid, yield 87.22%). MS m / z (ESI): 360.1 [M+H]. + .

[0440] Step 2: Methyl 4-benzyloxy-7-(4-pyridyl)pyrazolo[1,5-a]pyridine-3-carboxylate (170 mg, 473.04 μmol) was dissolved in 48% aqueous hydrogen bromide (20 mL) at room temperature. The reaction mixture was heated at 100°C for 12 h. The mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using an eluent system (DCM / MeOH = 1 / 0 to 20 / 1) to afford Intermediate 35 (128 mg, yellow solid, 92.63% yield). MS m / z (ESI): 212.1 [M+H] + .

[0441] Preparation of intermediate 36

[0442] Step 1: 4-Bromo-2-chloro-pyrimidine (400 mg, 2.07 mmol), 4-methoxy-7-(tributyltinyl)pyrazolo[1,5-a]pyridine (904.11 mg, 2.07 mmol), and Pd(PPh3)4 (23.90 mg, 20.68 μmol) were added to DMF (10 mL). The atmosphere was replaced with argon three times and stirred at 120°C for 5 h. The reaction was monitored by LC-MS. The reaction mixture was cooled to room temperature, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The solid was purified by combiflash (0-30% EA / PE) to give 7-(2-chloropyrimidin-4-yl)-4-methoxy-pyrazolo[1,5-a]pyridine (420 mg, yield 77.91%). MS m / z (ESI): 261.1 [M+H] + .

[0443] Step 2: Dissolve 7-(2-chloropyrimidin-4-yl)-4-methoxy-pyrazolo[1,5-a]pyridine (100 mg, 383.61 μmol) in dioxane (4 mL). Add 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborane (48.16 mg, 383.61 μmol), potassium carbonate (53.02 mg, 383.61 μmol), Pd(dppf)Cl2 (28.07 mg, 38.36 μmol), and water (0.4 mL). Stir at 100°C overnight under nitrogen. Filter and concentrate to obtain a black solid. This solid was then purified by combiflash (0-60% EA / PE) to afford 4-methoxy-7-(2-methylpyrimidin-4-yl)pyrazolo[1,5-a]pyridine (30 mg, 32.55% yield, as a yellow solid). MS m / z(ESI):241.1[M+H] + .

[0444] Step 3: Dissolve 4-methoxy-7-(2-methylpyrimidin-4-yl)pyrazolo[1,5-a]pyridine (30 mg, 124.86 μmol) in 48% aqueous hydrogen bromide (30.31 mg, 374.59 μmol) and stir overnight at 140°C. Concentrate under reduced pressure to afford Intermediate 36 (25 mg, 88.50% yield, yellow solid). Use directly in the next reaction. MS m / z (ESI): 227.1 [M+H] + .

[0445] Preparation of intermediate 37

[0446] Step 1: Dissolve intermediate 26 (600 mg, 2.35 mmol) in methanol (5 mL) and add thionyl chloride (839.04 mg, 7.05 mmol) dropwise under ice-cooling. Stir for 30 minutes, then raise the temperature to 60°C and stir overnight. The reaction mixture was concentrated under reduced pressure and dried by rotary evaporation. The resulting residue was purified by silica gel column chromatography using an eluent system (DCM / MeOH = 1 / 0 to 4 / 1) (254 nm detection) to obtain intermediate 37 (220 mg, yellow solid, yield 34.76%). MS m / z (ESI): 270.1 [M+H] + .

[0447] Preparation of intermediate 38

[0448] Step 1: 4-(Benzyloxy)-7-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (210 mg, 581.41 μmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (220.14 mg, 639.55 μmol), Pd(dppf)Cl2 (8.44 mg, 11.63 μmol) and K2CO3 (160.71 mg, 1.16 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). Under nitrogen protection, the reaction solution was stirred at 100 ° C for 16 hours. After the reaction was complete, the product was dried and passed through a column (PE / EA = 1 / 10) to give methyl 4-(benzyloxy)-7-(1H-pyrrolo[3,2-b]pyridin-7-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (110 mg, yellow solid, yield 47.49%). MS m / z (ESI): 399.2 [M+H] + .

[0449] Step 2: Methyl 4-(benzyloxy)-7-(1H-pyrrolo[3,2-b]pyridin-7-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (110 mg, 276.10 μmol) was added to a 48% aqueous HBr solution (5 mL). The reaction was stirred at 120°C for 12 hours. After completion of the reaction as monitored by LC-MS, the product was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using an eluent system (DCM / MeOH = 1 / 0 to 10 / 1) to afford Intermediate 38 (60 mg, yellow solid, 86.84% yield). MS m / z (ESI): 251.1 [M+H] + .

[0450] Preparation of intermediate 39

[0451] Step 1: 4-Benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (150 mg, 415.29 μmol), 4-(tributyltinyl)pyrimidine (229.95 mg, 622.94 μmol), and tetrakis(triphenylphosphine)palladium (47.99 mg, 41.53 μmol) were added to N,N-dimethylformamide (15 mL). Under argon, the reaction mixture was stirred at 120°C for 16 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 1 / 1) to afford 4-(benzyloxy)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (137 mg, yellow solid, 91.54% yield). MS m / z (ESI): 361.1 [M+H]. + .

[0452] Step 2: Methyl 4-(benzyloxy)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (137 mg, 380.17 μmol) was added to a 48% aqueous solution of hydrogen bromide (10 mL). The reaction mixture was stirred at 110°C for 3 hours and concentrated under reduced pressure. This afforded Intermediate 39 (75 mg, brown solid, 91.54% yield). The crude product was used directly in the next reaction. MS m / z (ESI): 213.1 [M+H] + .

[0453] Preparation of intermediate 40

[0454] Step 1: Dissolve 7-bromo-4-methoxypyrazolo[1,5-a]pyridine (300 mg, 1.32 mmol) in DCM (10 mL) and add BBr3 (662.01 mg, 2.64 mmol). The reaction mixture is stirred at room temperature for 12 hours. After completion, the reaction is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography using an eluent system (DCM / MeOH = 1 / 0 to 1 / 9) to provide 7-bromopyrazolo[1,5-a]pyridin-4-ol (170 mg, yellow solid, 60.40% yield). MS m / z (ESI): 213.0 [M+H] + .

[0455] Step 2: Dissolve 7-bromopyrazolo[1,5-a]pyridin-4-ol (140 mg, 657.18 μmol) and benzyl bromide (168.60 mg, 985.77 μmol) in DMF (5 mL). Add KCO (272.49 mg, 1.97 mmol). Stir the reaction mixture at room temperature for 12 hours. After completion, concentrate under reduced pressure, and purify the residue by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 2 / 1) to obtain 4-(benzyloxy)-7-bromopyrazolo[1,5-a]pyridine (120 mg, yellow solid, 55.21% yield). MS m / z (ESI): 305.1 [M+H] + .

[0456] Step 3: Dissolve 4-(benzyloxy)-7-bromopyrazolo[1,5-a]pyridine (120 mg, 395.84 μmol), 2-fluoropyridin-4-ylpinacol boronic acid (105.95 mg, 475.01 μmol), Pd(dppf)Cl2 (5.74 mg, 7.92 μmol), and K2CO3 (109.42 mg, 791.68 μmol) in 1,4-dioxane (5 mL) and water (1 mL). Under nitrogen, the reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, the product was dried and passed through a column (PE / EA = 1 / 4) to afford 4-(benzyloxy)-7-(2-fluoropyridin-4-yl)pyrazolo[1,5-a]pyridine (110 mg, yellow solid, 87.02% yield). MS m / z(ESI):320.2[M+H] + .

[0457] Step 4: Dissolve 4-(benzyloxy)-7-(2-fluoropyridin-4-yl)pyrazolo[1,5-a]pyridine (110 mg, 344.47 μmol) in DCM (10 mL) and add BBr3 (172.59 mg, 688.94 μmol). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (DCM / MeOH = 1 / 0 to 1 / 9) to obtain Intermediate 40 (60 mg, orange solid, 75.99% yield). MS m / z (ESI): 230.01 [M+H] + .

[0458] Example 1: Preparation of Compound H-1

[0459] Step 1: Dissolve intermediate 1 (70 mg, 309.41 μmol) and intermediate d (86.44 mg, 309.41 μmol) in DMF (5 mL), then add potassium carbonate (85.53 mg, 618.83 μmol). The reaction mixture was stirred at 50°C for 2 hours. After completion of the reaction, the mixture was dried and passed through a column (DCM / MeOH = 3 / 1) to obtain compound H-1-a (120 mg, yellow solid). Yield: 91.14%. MS m / z (ESI): 426.3 [M+H] + .

[0460] Step 2: Compound H-1-a (30 mg, 70.50 μmol) was dissolved in 4 M HCl in 1,4-dioxane (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was dried and the resulting residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain the desired product H-1 (1.17 mg). Yield: 5.10%. MS m / z (ESI): 326.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.97 (d, J = 6.0 Hz, 2H), 7.05 (s, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 6.0 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 6.71(d,J=8.0Hz,1H),6.04(s,2H),4.01-3.87(m,2H),3.11(m,1H),1.88-1.78(m,1H),1.34-1.21(m,2H),0.89(dd,J=12.0,6.0Hz,6H).

[0461] Example 2: Preparation of Compound H-2

[0462] Step 1: Dissolve intermediate 1 (180 mg, 795.64 μmol) and intermediate a (233.42 mg, 795.64 μmol) in N,N-dimethylformamide (5 mL), then add potassium carbonate (219.93 mg, 1.59 mmol). The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the mixture was dried and passed through a column (DCM / MeOH = 3 / 1) to obtain compound H-2-a (200 mg, yellow solid). Yield: 57.19%. MS m / z (ESI): 440.3 [M+H] + .

[0463] Step 2: Dissolve compound H-2-a (50 mg, 113.75 μmol) in dichloromethane (5 mL), then add trifluoroacetic acid (2 mL). Stir the reaction mixture at room temperature for 2 hours. The solvent was dried and the resulting residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain the desired product H-2 (5 mg). Yield: 12.10%. MS m / z (ESI): 340.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.98 (d, J = 4.0Hz, 2H), 7.05 (s, 1H), 7.00 (d, J = 8.0Hz, 1H), 6.92 (dd, J = 6.0, 2.0Hz, 1H), 6.84 (d, J = 2.0Hz, 1H) ,6.71(d,J=8.0Hz,1H),6.03(s,2H),3.90(s,2H),1.85-1.75(m,1H),1.43(dd,J=14.0,8.0Hz,2H),1.17(s,3H),0.91(dd,J=8.0,6.0Hz,6H).

[0464] Example 3: Preparation of Compound H-3

[0465] Step 1: Dissolve intermediate 2 and intermediate d (80.20 mg, 287.11 μmol) in N,N-dimethylformamide (5 mL), then add potassium carbonate (85.53 mg, 618.83 μmol). Stir the reaction mixture at 50°C for 2 hours. After completion, the mixture was dried and passed through a column (DCM / MeOH = 3 / 1) to afford compound H-3-a (45 mg, yellow solid). Yield: 51.05%. MS m / z (ESI): 461.3 [M+H] + .

[0466] Step 2: Compound H-3-a (45 mg, 97.72 μmol) was dissolved in 4 M HCl / 1,4-dioxane (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was dried and the resulting residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain the desired product H-3 (13 mg). Yield: 36.52%. MS m / z (ESI): 361.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.81 (d, J = 6.0 Hz, 1H), 8.37 (s, 1H), 8.16 (d, J = 6.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 8.0, 1H), 7.04 (t, J=56,,1H),6.97(d,J=2.0Hz,1H),6.83(d,J=8.0Hz,1H),4.21-4.11(m,2H),3.40(m,1H),1.84-1.77(m,1H),1.45(m,2H),0.93-0.89(m,6H).

[0467] Example 4: Preparation of Compound H-4

[0468] Step 1: Dissolve intermediate 2 (50 mg, 191.40 μmol) and intermediate a (84.23 mg, 287.11 μmol) in N,N-dimethylformamide (5 mL), then add potassium carbonate (52.91 mg, 382.81 μmol). Stir the reaction mixture at 80°C for 16 hours. After completion of the reaction, the solvent was evaporated, water was added, and the mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. Compound H-4-a (45 mg, yellow solid) was obtained by spin drying. Yield: 49.54%. MS m / z (ESI): 475.3 [M+H] + .

[0469] Step 2: Compound H-4-a (45 mg, 94.83 μmol) was dissolved in 4 M HCl / 1,4-dioxane (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the resulting residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain the desired product H-4 (5 mg, white solid). Yield: 13.64%. MS m / z (ESI): 375.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ (ppm): 8.75 (d, J = 4.0Hz, 1H), 8.16 (s, 1H), 8.05 (s, 1H), 7.95 (d, J = 2.1Hz, 1H), 6.91-6.44(m,4H),3.95(s,2H),1.86-1.79(m,1H),1.38-1.24(m,7H),0.98(dd,J=12.0,6.0Hz,6H).

[0470] Example 5: Preparation of Compound H-5

[0471] Step 1: Dissolve compound H-1-a (80 mg, 188.00 μmol) and triethylamine (38.05 mg, 376.01 μmol, 52.44 μL) in dichloromethane (5 mL), then add acetyl chloride (22.14 mg, 282.01 μmol). Stir the reaction mixture at room temperature for 2 hours. Dry the mixture and pass it through a column (DCM / MeOH = 3 / 1) to obtain compound H-5-a (50 mg, yellow solid). Yield: 56.88%. MS m / z (ESI): 468.3 [M+H] + .

[0472] Step 2: Dissolve compound H-5-a in dichloromethane (10 mL), then add trifluoroacetic acid (2 mL). Stir the reaction mixture at room temperature for 2 hours. The solvent was dried and the resulting residue was purified by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain the target product H-5 (20 mg). Yield: 48.27%. MS m / z (ESI): 368.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.62 (s, 1H), 8.61 (s, 1H), 8.41 (d, J = 6.0Hz, 1H) ,8.02(d,J=2.1Hz,1H),7.62(dd,J=8.0,2.0Hz,1H),7.10(d,J=8.0Hz,1H),7.00 (d,J=2.0Hz,1H),6.83(d,J=8.0Hz,1H),4.37-4.35(m,1H),4.22-4.18(m,1H),3 .65(m,1H),2.09(s,3H),1.83-1.72(m,1H),1.57(m,2H),0.92(t,J=6.0Hz,6H).

[0473] Example 6: Preparation of Compound H-6

[0474] Step 1: Dissolve compound H-2-a (50 mg, 113.75 μmol) and acetyl chloride (17.86 mg, 227.51 μmol) in dichloromethane (5 mL), then add triethylamine (23.02 mg, 227.51 μmol, 31.73 μL). Stir the reaction mixture at room temperature for 2 hours. Dry the mixture and pass it through a column (DCM / MeOH = 10 / 1) to obtain compound H-6-a (45 mg, yellow solid). Yield: 82.14%. MS m / z (ESI): 482.3 [M+H] + .

[0475] Step 2: Dissolve compound H-6-a (45 mg, 93.44 μmol) in dichloromethane (5 mL), then add trifluoroacetic acid (2 mL). Stir the reaction mixture at room temperature for 2 hours. The solvent was dried and the resulting residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain the target product H-6 (5 mg). Yield: 13.88%. MS m / z (ESI): 382.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.59 (s, 1H), 8.60 (s, 1H), 8.40 (d, J = 6.0Hz, 1H) ,7.98(d,J=2.0Hz,1H),7.63(dd,J=6.0,2.0Hz,1H),7.07(d,J=8.0Hz,1H),6.85( d,J=2.0Hz,1H),6.75(d,J=8.0Hz,1H),3.89(s,2H),2.10(s,3H),1.80(dt,J=18 .0,6.0Hz,1H),1.41(dd,J=16.0,8.0Hz,2H),1.15(s,3H),0.91(t,J=6.0Hz,6H).

[0476] Example 7: Preparation of Compound H-7

[0477] Step 1: Dissolve intermediate 3 (50 mg, 0.2 mmol) and intermediate d (55.81 mg, 199.80 μmol) in N,N-dimethylformamide (5 mL), then add potassium carbonate (55.23 mg, 399.59 μmol). The reaction mixture was stirred at 50°C for 2 hours. After completion of the reaction, the mixture was dried and passed through a column (DCM / MeOH = 2 / 1) to obtain compound H-7-a (60 mg, yellow solid). Yield: 66.80%. MS m / z (ESI): 450.3 [M+H] + .

[0478] Step 2: Dissolve compound H-7-a (60 mg, 133.47 μmol) in dichloromethane (4 mL), then add trifluoroacetic acid (2 mL). Stir the reaction mixture at room temperature for 2 hours. The solvent was dried and the resulting residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain the desired product H-7 (16 mg). Yield: 34.17%. MS m / z (ESI): 350.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ (ppm): 11.81 (s, 1H), 8.31 (d, J = 4.0Hz, 1H), 7.93 (d, J = 2.0Hz, 1H), 7.61-7.47 (m, 2H), 7.08 (d, J = 8.0Hz, 1H), 6.83-6. 77(m,2H),6.28(d,J=4.0Hz,1H),4.08-4.04(m,1H),3.99-3.90(m,1H) ,3.18(m,1H),1.90-1.78(m,1H),1.39-1.25(m,2H),0.93-0.83(m,6H).

[0479] Example 8: Preparation of Compound H-8

[0480] Step 1: Dissolve intermediate 3 (50 mg, 199.80 μmol) and intermediate a (58.62 mg, 199.80 μmol) in N,N-dimethylformamide (5 mL), then add potassium carbonate (55.23 mg, 399.59 μmol). The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the product was dried and column chromatography (DCM / MeOH = 3 / 1) to afford compound H-8-a (50 mg, yellow solid). Yield: 53.98%. MS m / z (ESI): 464.3 [M+H]. + .

[0481] Step 2: Dissolve compound H-8-a (50 mg, 107.86 μmol) in dichloromethane (4 mL), then add trifluoroacetic acid (2 mL). Stir the reaction mixture at room temperature for 2 hours. The solvent was dried and the residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain the desired product H-8 (15 mg, white solid). Yield: 37.21%. MS m / z (ESI): 364.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ (ppm): 11.82 (s, 1H), 8.31 (d, J = 6.0Hz, 1H), 7.93 (d, J = 2.0Hz, 1H), 7.58-7.47 (m, 2H), 7.08 (d, J = 8.0Hz, 1H), 6.85 (d, J=2.0Hz,1H),6.76(d,J=8.0Hz,1H),6.28(s,1H),3.91(s,2H),1.86-1.79(m,1H),1.45(t,J=4.0Hz,2H),1.17(s,3H),0.93(t,J=6.0Hz,6H).

[0482] Example 9: Preparation of Compound H-9

[0483] Step 1: Dissolve compound H-1-a (200 mg, 470.01 μmol) and triethylamine (95.12 mg, 940.02 μmol, 131.11 μL) in dichloromethane (10 mL), then add methyl chloroformate (66.62 mg, 705.02 μmol). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the product was dried and column chromatography (DCM / MeOH = 3 / 1) to afford compound H-9-a (180 mg, yellow solid). Yield: 79.20%. MS m / z (ESI): 484.3 [M+H]. + .

[0484] Step 2: Dissolve compound H-9-a (180 mg, 372.24 μmol) in dichloromethane (4 mL), then add trifluoroacetic acid (2 mL). Stir the reaction mixture at room temperature for 2 hours. The solvent was dried and the resulting residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain the desired product H-9 (92 mg). Yield: 63.51%. MS m / z (ESI): 384.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.33 (s, 1H), 8.45-8.29 (m, 2H), 7.99 (d, J = 2.0Hz, 1H), 7.58 (dd, J = 6.0, 2.0Hz, 1H), 7.09 (d, J = 8.0Hz, 1H), 6 .83-6.75(m,2H),4.03-3.89(m,2H),3.66(s,3H),3.17-3.04(m,1H), 1.87-1.79(m,1H),1.64(s,2H),1.36-1.19(m,2H),0.92-0.87(m,6H).

[0485] Example 10: Preparation of Compound H-10

[0486] Step 1: Dissolve compound H-2-a (200 mg, 455.01 μmol) and triethylamine (92.09 mg, 910.02 μmol, 126.93 μL) in dichloromethane (10 mL), then add methyl chloroformate (64.50 mg, 682.52 μmol). Stir the reaction mixture at room temperature for 2 hours. After completion of the reaction, dry the mixture and pass it through a column (DCM / MeOH = 3 / 1) to obtain compound H-10-a (170 mg, yellow solid). Yield: 75.09%. MS m / z (ESI): 498.3 [M+H] + .

[0487] Step 2: Dissolve compound H-10-a (170 mg, 341.65 μmol) in dichloromethane (4 mL), then add trifluoroacetic acid (2 mL). Stir the reaction mixture at room temperature for 2 hours. The solvent was dried and the resulting residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain the desired product H-10 (73 mg). Yield: 53.55%. MS m / z (ESI): 398.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.33 (s, 1H), 8.45-8.31 (m, 2H), 8.00 (d, J = 2.0Hz, 1H), 7.59-7.58 (m, 1H), 7.09 (d, J = 8.0Hz, 1H), 6.86 (d, J=2.0Hz,1H),6.75(d,J=8.0Hz,1H),3.88(s,2H),3.66(s,3H),2.11-1.76(m,3H),1.49-1.32(m,2H),1.14(s,3H),0.91(t,J=6.8Hz,6H).

[0488] Example 11: Preparation of Compound H-11

[0489] Step 1: Dissolve intermediate 4 (40 mg, 166.49 μmol), intermediate a (39.50 mg, 166.49 μmol), and potassium carbonate (23.01 mg, 166.49 μmol) in N,N-dimethylformamide (5 mL). Stir the reaction at 80°C for 16 hours. After completion, the reaction was dried and column chromatography (DCM / MeOH = 4 / 1) to afford compound H-11-a (50 mg, yellow solid). Yield: 66.21%. MS m / z (ESI): 454.3 [M+H]. + .

[0490] Step 2: Dissolve compound H-11-a (50 mg, 110.24 μmol) in trifluoroacetic acid (1 mL) and dichloromethane (4 mL). Stir the reaction mixture at 22°C for 2 hours. The solvent was evaporated and the resulting residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain the desired product H-11 (5 mg). Yield: 12.71%. MS m / z (ESI): 354.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ(ppm):8.05(d,J=6.0Hz,1H),7.96(d,J=2.0Hz,1H),7.05(s,1H), 7.01(d,J=8.0Hz,1H),6.91(dd,J=6.0,2.0Hz,1H),6.81(d,J=2.0Hz,1H),6.69(d,J=8.0H z,1H),6.62(dd,J=8.0,4.0Hz,1H),3.84(s,2H),2.79(d,J=4.0Hz,3H),1.81(dt,J=12.0, 6.0Hz, 1H), 1.58 (s, 2H), 1.40 (dd, J = 6.0, 2.0Hz, 2H), 1.13 (s, 3H), 0.90 (t, J = 6.0Hz, 6H).

[0491] Example 12: Preparation of Compound H-12

[0492] Step 1: Intermediate 5 (40 mg, 137.80 μmol), intermediate a (32.70 mg, 137.80 μmol), and potassium carbonate (19.05 mg, 137.80 μmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was stirred at 80°C for 16 hours. After completion of the reaction, the product was dried and passed through a column (DCM / MeOH = 9 / 1) to afford compound H-12-a (40 mg, yellow solid). Yield: 57.64%. MS m / z (ESI): 504.3 [M+H] + .

[0493] Step 2: Compound H-12-a (40 mg, 79.43 μmol) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (4 mL). The reaction mixture was stirred at 22°C for 2 hours. The solvent was dried and the resulting residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain the target product H-12 (2 mg). Yield: 6.17%. MS m / z (ESI): 404.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ (ppm): 8.08 (d, J = 6.0Hz, 1H), 7.97 (d, J = 2.0Hz, 1H), 7.21 (s, 1H), 7.12 (t, J = 6.0Hz, 1H), 7.07-7.00 (m, 2H), 6.84 (d, J = 2.0Hz, 1 H),6.71(d,J=8.0Hz,1H),6.26-5.97(m,1H),3.88(s,2H),3.77-3.67(m,2H ), 1.84-1.76 (m, 1H), 1.46-1.38 (m, 2H), 1.15 (s, 3H), 0.91 (t, J = 6.0Hz, 6H).

[0494] Example 13: Preparation of Compound H-13

[0495] Step 1: Dissolve intermediate 6 (40 mg, 0.16 mmol) in N,N-dimethylformamide (8 mL), add intermediate d (57 mg, 0.32 mmol) and potassium carbonate (22 mg, 0.16 mmol), heat to 40°C and stir overnight, cool, filter, and concentrate. The residue is purified by column chromatography (methanol / dichloromethane = 1 / 10-1 / 5) to obtain compound H-13-a (40 mg, yield: 55.77%). MS m / z (ESI): 395.2 [M-56+1] + .

[0496] Step 2: Add trifluoroacetic acid (2 mL) to a solution of compound H-13-a (30 mg, 0.066 mmol) in dichloromethane (8 mL), stir at room temperature for 1 hour, concentrate, and purify the residue by preparative HPLC to obtain compound H-13 (9.67 mg, yield: 40.83%). MS m / z (ESI): 351.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.89 (d, J = 8.3Hz, 1H), 8.65 (d, J = 4.5Hz, 1H), 8.29-8.20 (m, 2H), 8.11 (d, J = 1.4Hz, 1H), 7.65 (d, J = 1.4Hz, 1H), 6.83 (d, J =2.4Hz,1H),6.66(d,J=8.3Hz,1H),4.30-4.28(m,1H),4.16-4.14(m,1H),3 .20-3.18(m,1H),2.13-1.79(m,3H),1.33-1.31(m,2H),0.92-0.90(m,6H).

[0497] Example 14: Preparation of Compound H-14

[0498] Step 1: Dissolve intermediate 7 (60 mg, 0.22 mmol) in N,N-dimethylformamide / ethyl acetate (4 mL / 4 mL), add intermediate d (80 mg, 0.45 mmol) and potassium carbonate (62 mg, 0.45 mmol), stir at room temperature overnight, cool, filter, and concentrate. The residue is purified by column chromatography (methanol / dichloromethane = 1 / 10-1 / 5) to obtain compound H-14-a (70 mg, yield: 67.2%). MS m / z (ESI): 410.2 [M-56+1] + .

[0499] Step 2: To a solution of compound H-14-a (50 mg, 0.107 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL), stirred at room temperature for 1 hour, concentrated, and the residue was purified by preparative HPLC to give compound H-14 (6.01 mg, yield: 15.31%). MS m / z (ESI): 366.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 11.00 (s, 1H), 8.11 (d, J = 5.5Hz, 1H), 8.02 (d, J=1.4Hz,1H),7.62(d,J=1.4Hz,1H),7.54(d,J=7.9Hz,1H),7.35(d,J=5.5Hz, 1H),6.48(d,J=7.9Hz,1H),4.23-4.21(m,1H),4.10-4.08(m,1H),3.70(s,2H) ,3.17-3.15(m,1H),1.87-1.85(m,3H),1.32-1.30(m,2H),0.92-0.90(m,6H).

[0500] Example 15: Preparation of Compound H-15

[0501] Step 1: Dissolve intermediate 8 (70 mg, 0.27 mmol) in N,N-dimethylformamide / ethyl acetate (3 mL / 3 mL), add intermediate d (144 mg, 0.80 mmol) and potassium carbonate (111 mg, 0.80 mmol), stir at room temperature overnight, cool, filter, and concentrate. The residue is purified by column chromatography (methanol / dichloromethane = 1 / 10-1 / 5) to obtain yellow solid compound H-15-a (40 mg, yield: 32.4%). MS m / z (ESI): 404.2 [M-56+1] + .

[0502] Step 2: To a solution of compound H-15-a (20 mg, 0.043 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL), stirred at room temperature for 1 hour, concentrated, and the residue was purified by preparative HPLC to give compound H-15 (3.84 mg, yield: 24.51%). MS m / z (ESI): 360.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.97 (d, J = 1.3Hz, 1H), 7.91 (d, J = 5.0Hz, 1H), 7.52(d,J=1.3Hz,1H),7.25(d,J=7.7Hz,1H),6.66(d,J=5.0Hz,1H),6.43(d,J =7.8Hz,1H),6.31(s,2H),4.21-4.19(m,1H),4.07-4.05(m,1H),3.21-3.12( m,1H),2.08(s,2H),1.86-1.84(m,1H),1.32-1.30(m,2H),0.91-0.89(m,6H).

[0503] Example 16: Preparation of Compound H-16

[0504] Step 1: Dissolve intermediate 9 (120 mg, 0.49 mmol) in N,N-dimethylformamide (4 mL), add compound d (176 mg, 0.98 mmol) and potassium carbonate (135 mg, 0.98 mmol), stir at room temperature overnight, cool, filter, and concentrate. The residue is purified by column chromatography (methanol / dichloromethane = 1 / 10-1 / 5) to obtain yellow solid compound H-16-a (180 mg, yield: 82.6%). MS m / z (ESI): 388.2 [M-56+1] + .

[0505] Step 2: To a solution of compound H-16-a (100 mg, 0.225 mmol) in dichloromethane (9 mL) was added trifluoroacetic acid (3 mL), stirred at room temperature for 1 hour, concentrated, and the residue was purified by preparative HPLC to give compound H-16 (55.5 mg, yield: 71.7%). MS m / z (ESI): 344.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ (ppm): 8.00 (d, J = 1.3Hz, 1H), 7.93 (d, J = 2.6Hz, 1H), 7.58 (d, J = 1.3Hz, 1H), 7.44-7.43 (m, 1H), 7.02 (d, J = 5.3Hz, 1H), 6.46 (d,J=7.9Hz,1H),5.89(s,2H),4.21-4.19(m,1H),4.07-4.05(m,1H),3.2 0-3.10(m,1H),1.85-1.83(m,3H),1.31-1.29(m,2H),0.91-0.89(m,6H).

[0506] Example 17: Preparation of Compound H-17

[0507] Step 1: Dissolve intermediate 10 (95 mg, 0.389 mmol) in N,N-dimethylformamide / ethyl acetate (4 mL / 4 mL), add intermediate d (139 mg, 0.778 mmol) and potassium carbonate (108 mg, 0.778 mmol), heat to 40°C and stir overnight, cool, filter, and concentrate. The residue is purified by column chromatography (methanol / dichloromethane = 1 / 10-1 / 5) to obtain yellow solid compound H-17-a (100 mg, yield: 57.96%). MS m / z (ESI): 388.2 [M-56+1] + .

[0508] Step 2: Add trifluoroacetic acid (2 mL) to a solution of compound H-17-a (50 mg, 0.112 mmol) in dichloromethane (8 mL), stir at room temperature for 1 hour, concentrate, and purify the residue by preparative HPLC to obtain compound H-17 (7.13 mg, yield: 18.2%). MS m / z (ESI): 344.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.95-7.93 (m, 2H), 6.92 (d, J = 7.8Hz, 1H), 6.78 (d, J = 2.3Hz, 1H), 6.73-6.63 (m, 2H), 6.03 ( s,2H),4.02-4.00(m,1H),3.91-3.89(m,1H),3.15-3.08(m,1H),1.91-1.76(m,2H),1.37-1.16(m,3H),0.90-0.88(m,6H).

[0509] Example 18: Preparation of Compound H-18

[0510] Step 1: Dissolve intermediate 11 (40 mg, 0.15 mmol) in N,N-dimethylformamide (5 mL), add intermediate a (89 mg, 0.3 mmol) and potassium carbonate (42 mg, 0.3 mmol), heat to 80°C and stir overnight, cool, filter, and concentrate. The residue is purified by column chromatography (methanol / dichloromethane = 1 / 10-1 / 5) to obtain yellow solid compound H-18-a (30 mg, yield: 42.8%). MS m / z (ESI): 422.2 [M-56+1] + .

[0511] Step 2: To a solution of compound H-18-a (20 mg, 0.042 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (1.5 mL), stirred at room temperature for 1 hour, concentrated, and the residue was purified by preparative HPLC to give compound H-18 (6.5 mg, yield: 40.5%). MS m / z (ESI): 378.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 11.64 (s, 1H), 8.18 (d, J = 5.1Hz, 1H), 7.92 (d ,J=2.2Hz,1H),7.46(d,J=5.0Hz,1H),7.04(d,J=7.8Hz,1H),6.82(d,J=2.2H z,1H),6.73(d,J=7.9Hz,1H),5.99(s,1H),3.86(s,2H),2.37(s,3H),1.84-1 .82(m,1H),1.59(s,2H),1.43-1.41(m,2H),1.15(s,3H),0.91-0.89(m,6H).

[0512] Example 19: Preparation of Compound H-19

[0513] Step 1: Dissolve intermediate 11 (35 mg, 0.132 mmol) in N,N-dimethylformamide (3 mL), add intermediate d (74 mg, 0.264 mmol) and potassium carbonate (37 mg, 0.264 mmol), heat to 40°C and stir overnight, cool, filter, and concentrate. The residue is purified by column chromatography (methanol / dichloromethane = 1 / 10-1 / 5) to obtain yellow solid compound H-19-a (30 mg, yield: 48.9%). MS m / z (ESI): 464.3 [M+H] + .

[0514] Step 2: To a solution of compound H-19-a (30 mg, 0.065 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (1.5 mL), stirred at room temperature for 1 hour, concentrated, and the residue was purified by preparative HPLC to give compound H-19 (6.58 mg, yield: 27.98%). MS m / z (ESI): 364.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 11.64 (s, 1H), 8.18 (d, J = 5.1Hz, 1H), 7.92 (d, J = 2.2Hz, 1H), 7.46 (d, J = 5.0Hz, 1H), 7.04 (d, J = 7.8Hz, 1H), 6.83-6. 72(m,2H),5.98(s,1H),4.03-4.01(m,1H),3.93-3.91(m,1H),3.15-3.13 (m,1H),2.37(s,3H),1.85(s,2H),1.30-1.28(m,3H),0.91-0.89(m,6H).

[0515] Example 20: Preparation of Compound H-20

[0516] Step 1: Intermediate b (545.92 mg, 2.36 mmol), intermediate 12 (330 mg, 1.18 mmol), allylpalladium(II) chloride dimer (20 mg, 54.66 μmol), 2-(di-tert-butylphosphino)-3-methoxy-6-methyl-2'4'6'-triisopropyl-biphenyl (30 mg, 64.01 μmol), and cesium carbonate (576.68 mg, 1.77 mmol) were added to toluene (10 mL). Under argon, the reaction mixture was heated to 90°C and stirred for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography using a dichloromethane / methanol system (1 / 0 to 10 / 1) to afford compound H-20-a (180 mg, yellow oil) in a 32.15% yield. MS m / z (ESI): 475.1 [M+H] + .

[0517] Step 2: Dissolve compound H-20-a (180 mg, 379.31 μmol) in dichloromethane (3 mL) and add trifluoroacetic acid (3 mL). Stir the reaction mixture at room temperature for 1 hour. The solvent was evaporated under reduced pressure, neutralized by adding ammonia in methanol, and then concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography using a 10 / 1 dichloromethane / methanol system to obtain a pale yellow oil. Further purification was performed by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain compound H-20 (15 mg) in a yield of 10.56%. MS m / z (ESI): 375.1 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ(ppm):8.72(d,J=5.5Hz,2H),8.39(d,J=5.2Hz,1H),8.09(d,J=1.2Hz,1H),7.97(d,J=8.0Hz,1H),7.70(d,J=1.2Hz,1H ), 7.00 (t, J = 55.0Hz, 1H), 6.54 (d, J = 8.1Hz, 1H), 4.08 (s, 2H), 1.89-1.70 (m, 3H), 1.44-1.42 (m, 2H), 1.16 (s, 3H), 0.92 (dd, J = 11.1, 6.6Hz, 6H).

[0518] Example 21: Preparation of Compound H-21

[0519] Step 1: Dissolve intermediate 1 (390 mg, 1.72 mmol) in N,N-dimethylformamide (10 mL), add potassium carbonate (476.52 mg, 3.45 mmol), and then add (S)-tert-butyl 4-isobutyl-1,2,3-oxothiazolidine-3-carboxylate-2,2-dioxide (481.57 mg, 1.72 mmol). The reaction mixture was stirred at 50°C for 4 hours. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol: 1 / 0 to 3 / 1) to afford compound H-21-a (563 mg, yellow solid) in a 64.60% yield. MS m / z (ESI): 506.3 [M+H] + .

[0520] Step 2: Compound H-21-a (100 mg, 197.79 μmol) was added to dichloromethane (15 mL), followed by triethylamine (60.04 mg, 593.37 μmol, 82.76 μL), and then cyclopropanecarbonyl chloride (62.03 mg, 593.37 μmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, methanol (10 mL) and water (1 mL) were added, followed by sodium hydroxide (10 mg), and the reaction mixture was stirred at room temperature for 30 minutes. The pH was adjusted to 7 with 1 M hydrochloric acid solution, and the mixture was concentrated under reduced pressure to obtain the crude product compound H-21-b (110 mg, yellow oil), which was used directly in the next step. MS m / z (ESI): 574.3 [M+H] + .

[0521] Step 3: Compound H-21-b (110 mg, 191.75 μmol) was added to trifluoroacetic acid (5 mL) and dichloromethane (5 mL), and the reaction mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, ammonia in methanol was added for neutralization, and further concentration under reduced pressure was performed. The resulting residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain compound H-21 (45.07 mg) in a yield of 59.73%. MS m / z (ESI): 394.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.91 (s, 1H), 8.61 (s, 1H), 8.40 (d, J = 5.2Hz, 1H), 7.98 (d, J = 2.2H z,1H),7.63(dd,J=5.3,1.4Hz,1H),7.07(d,J=7.9Hz,1H),6.82(d,J=2.2Hz,1H),6.75(d,J=8.0Hz ,1H),4.01(dd,J=9.4,5.0Hz,1H),3.96-3.87(m,1H),3.15-3.09(m,1H),2.03-1.99(m,1H),1.88- 1.80(m,1H),1.71(s,2H),1.35-1.21(m,2H),0.89(dd,J=13.7,6.6Hz,6H),0.80(d,J=6.1Hz,4H).

[0522] Example 22: Preparation of Compound H-22

[0523] Step 1: Compound H-2-a (100 mg, 227.51 μmol) was added to dichloromethane (15 mL), followed by triethylamine (69.06 mg, 682.52 μmol, 95.19 μL), and then cyclopropanecarbonyl chloride (71.35 mg, 682.52 μmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, methanol (10 mL) and water (1 mL) were added, followed by sodium hydroxide (10 mg), and the reaction mixture was stirred at room temperature for 30 minutes. The pH was adjusted to 7 with 1 M hydrochloric acid solution, and the mixture was concentrated under reduced pressure to obtain the crude product, compound H-22-a (100 mg, yellow oil), which was used directly in the next step. MS m / z (ESI): 508.3 [M+H] + .

[0524] Step 2: Compound H-22-a (100 mg, 197 μmol) was added to trifluoroacetic acid (5 mL) and dichloromethane (5 mL), and the reaction mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, ammonia in methanol was added for neutralization, and further concentration under reduced pressure was performed. The resulting residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain compound H-22 (61.02 mg) in a yield of 75.25%. MS m / z (ESI): 408.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.92 (s, 1H), 8.61 (d, J = 0.7Hz, 1H), 8.43-8.37 (m, 1 H),7.98(d,J=2.2Hz,1H),7.63(dd,J=5.3,1.6Hz,1H),7.06(d,J=7.9Hz,1H),6.84( d,J=2.3Hz,1H),6.73(d,J=8.0Hz,1H),3.86(s,2H),2.04-1.97(m,1H),1.83-1.77( m,3H),1.41-1.29(m,2H),1.13(s,3H),0.90(t,J=6.6Hz,6H),0.80(d,J=6.1Hz,4H).

[0525] Example 23: Preparation of Compound H-23

[0526] Step 1: Dissolve intermediate 13 (53 mg, 157.15 μmol) in ethyl acetate (5 mL) and N,N-dimethylformamide (1 mL). Add potassium carbonate (43.44 mg, 314.30 μmol) and then add (S)-tert-butyl 4-isobutyl-1,2,3-oxothiazolidine-3-carboxylate-2,2-dioxide (52.68 mg, 188.58 μmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to afford compound H-23-a (84 mg, yellow oil). The crude product was used directly in the next step. MS m / z (ESI): 481.2 [M-56+H] + .

[0527] Step 2: Compound H-23-a (84 mg, 156.56 μmol) was dissolved in tetrahydrofuran (5 mL), and lithium hydroxide monohydrate (9.85 mg, 234.84 μmol) and water (0.5 mL) were added. The reaction mixture was stirred at room temperature for 1 hour. After adjusting the acidity with trifluoroacetic acid, the mixture was concentrated under reduced pressure. Trifluoroacetic acid (2 mL) and dichloromethane (2 mL) were added to the residue. The reaction mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the mixture was neutralized with 7N ammonia in methanol and concentrated again under reduced pressure. The residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain compound H-23 (11.94 mg) in a yield of 19.81%. MS m / z(ESI):379.2[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.79 (d, J = 5.2Hz, 1H), 8.44 (d, J = 8.8Hz, 1H), 8.35 (s, 1H), 8.23 ​​(d, J = 5.1Hz, 1H), 7.84 (d, J = 8.9Hz, 1H) ,7.21-6.89(m,2H),4.16-4.06(m,1H),3.98-3.86(m,1H),3.09-3.04(m,1H),1.83-1.78(m,1H),1.33-1.18(m,2H),0.93-0.75(m,6H).

[0528] Example 24: Preparation of Compound H-24

[0529] Step 1: Dissolve intermediate 14 (100 mg, 383.61 μmol) in N,N-dimethylformamide (10 mL), add potassium carbonate (106.04 mg, 767.23 μmol), and then add (S)-tert-butyl 4-isobutyl-4-methyl-1,2,3-oxothiazolidine-3-carboxylate-2,2-dioxide (112.54 mg, 383.61 μmol). The reaction mixture was stirred at 80°C for 2 hours. Filter and concentrate under reduced pressure to obtain compound H-24-a (110 mg, brown oil). The crude product was used directly in the next step. MS m / z (ESI): 474.3 [M+H] + .

[0530] Step 2: Compound H-24-a (110 mg, 232.07 μmol) was added to trifluoroacetic acid (4 mL) and dichloromethane (4 mL), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. After neutralization with 7N ammonia in methanol, the mixture was concentrated under reduced pressure again. The residue was purified by preparative liquid chromatography (preparative column: water-sunfire; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254 / 214 nm; gradient: 5% to 30% acetonitrile) to obtain compound H-24 (5.74 mg) in a yield of 5.89%. MS m / z (ESI): 374.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.33 (s, 1H), 8.00 (d, J = 2.2Hz, 1H), 7.09 (d, J = 7.9Hz, 1H), 7.01 ( dd,J=13.2,1.1Hz,2H),6.87(d,J=2.2Hz,1H),6.71(d,J=8.0Hz,1H),6.55(s,2H),3.91(s,2H), 1.84-1.78(m,1H),1.46-1.43(m,2H),1.17(s,3H),0.91(dd,J=9.1,6.7Hz,6H).

[0531] Example 25: Preparation of Compound H-25

[0532] Step 1: Intermediate 15 (10 mg, 40.95 μmol) and intermediate d (11.44 mg, 40.95 μmol) were dissolved in ethyl acetate (6 mL) and N,N-dimethylformamide (1 mL), and potassium carbonate (11.30 mg, 81.89 μmol) was added. The reaction was stirred at 50°C for 12 hours. The solvent was evaporated under reduced pressure. Prep.HPLC analysis of the crude product afforded compound H-25-a (10 mg, 22.55 μmol) in a 55.07% yield. MS m / z (ESI): 388.2 [M-56+H]. + .

[0533] Step 2: Compound H-25-a (10 mg, 22.55 μmol) was dissolved in 4 M hydrochloric acid / 1,4-dioxane solution. The reaction was stirred at 23°C for 1 hour. The product was evaporated to dryness under reduced pressure. The crude product was purified by Prep.HPLC to yield compound H-25 (1.1 mg, 3.20 μmol, 100% purity) in a 14.21% yield. MS m / z (ESI): 344.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.04(d,J=1.2Hz,1H),7.77(d,J=5.2Hz,1H),7.5 7(d,J=1.2Hz,1H),7.41(d,J=7.6Hz,1H),6.92(t,J=4.9Hz,1H),6.47(d,J=7.9Hz ,1H),6.18(s,2H),4.27(dd,J=9.4,4.0Hz,1H),4.19-4.09(m,1H),3.31(m,1H),1 .82(dd,J=13.3,6.7Hz,1H), 1.37(t,J=6.6Hz,2H), 0.90(dd,J=11.0,6.6Hz,6H).

[0534] Example 26: Preparation of Compound H-26

[0535] Step 1: Dissolve intermediate c (29.19 mg, 197.79 μmol) and compound H-2-a (50 mg, 98.90 μmol) in dichloromethane (10 mL), then add triethylamine (29.97 mg, 296.69 μmol). Stir the reaction at 20°C for 1 hour. Adjust the pH to approximately 7 with dilute hydrochloric acid. Dry the mixture under reduced pressure to afford compound H-26-a (60 mg, 97.29 μmol), which was used directly in the next step. Yield: 98.38%. MS m / z (ESI): 551.24 [M+H] + .

[0536] Step 2: Compound H-26-a (45 mg, 85.95 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The reaction was stirred at 23°C for 1 hour, dried under reduced pressure, and the pH was adjusted to approximately 8 with methanolic ammonia solution. The crude product was dried under reduced pressure to afford compound H-26 (17.83 mg, 39.49 μmol) using prep HPLC. The yield was 62.26% and the purity was 99.78%. MS m / z (ESI): 451.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.74 (s, 1H), 8.51 (d, J = 5.2Hz, 1H), 8.20 (d, J = 3.0Hz, 1H),8.14(d,J=3.0Hz,1H),8.02(d,J=2.2Hz,1H),7.79(dd,J=5.3,1.4Hz,1H),7.18( d,J=7.9Hz,1H),6.87(d,J=2.3Hz,1H),6.77(d,J=8.0Hz,1H),3.88(s,2H),1.81(dd, J=12.6, 6.2Hz, 1H), 1.41 (dd, J=5.5, 2.4Hz, 2H), 1.14 (s, 3H), 0.91 (t, J=6.5Hz, 6H).

[0537] Example 27: Preparation of Compound H-27

[0538] Step 1: Intermediate 16 (40 mg, 163.78 μmol) and intermediate d (45.75 mg, 163.78 μmol) were dissolved in N,N-dimethylformamide (8 mL), and potassium carbonate (45.20 mg, 327.57 μmol) was added. The reaction was stirred at 50°C for 3 hours. The mixture was filtered and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (dichloromethane / methanol = 2 / 1) to afford compound H-27-a (45 mg, 85.95 μmol) in a yield of 52.48%. MS m / z (ESI): 524.2 [M+H] + .

[0539] Step 2: Compound H-27-a (45 mg, 85.95 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The reaction was stirred at 23°C for 1 hour. The mixture was evaporated to dryness under reduced pressure, and the pH was adjusted to approximately 8 with methanolic ammonia solution. The crude product was evaporated to dryness under reduced pressure. The crude product was purified by prep.HPLC to obtain compound H-27 (5.13 mg, 14.20 μmol) with a yield of 16.52% and a purity of 95.07%. MS m / z (ESI): 344.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ (ppm): 7.92 (s, 1H), 6.95 (s, 1H), 6.81 (d, J = 8.1Hz, 2H), 6.70 (s, 1H), 6.41 (d, J = 7.8Hz, 1H), 4.64 (s,2H),4.20-4.09(m,1H),4.02-3.89(m,1H),3.45(s,1H),1.79(d,J=6.5Hz,1H),1.46(m,2H),0.95(t,J=7.2Hz,6H).

[0540] Example 28: Preparation of Compound H-28

[0541] Step 1: Dissolve intermediate 17 (180 mg, 795.64 μmol) and (S)-tert-butyl 4-isobutyl-1,2,3-oxathiozolidine-3-carboxylate-2,2-dioxide (222.26 mg, 795.64 μmol) in N,N-dimethylformamide (10 mL). Add potassium carbonate (329.88 mg, 2.39 mmol) and stir at 100°C for 4 hours. Concentrate under reduced pressure to obtain a yellow solid. The solid was purified by combiflash (0-30% DCM / MeOH) to afford compound H-28-a (100 mg, 235.01 μmol, 29.54% yield) as a brown solid. MS m / z (ESI): 426.1 [M+H] + .

[0542] Step 2: Dissolve compound H-28-a (100 mg, 235.01 μmol) in dichloromethane (5 mL). Add cyclopropane chloride (29.48 mg, 282.01 μmol) and triethylamine (71.34 mg, 705.02 μmol, 98.33 μL) at 0°C. Stir at 0°C for 30 minutes. Concentrate under reduced pressure to obtain compound H-28-b (100 mg, 202.59 μmol, 86.21% yield) as a yellow solid. MS m / z (ESI): 494.1 [M+H] + .

[0543] Step 3: Compound H-28-b (100 mg, 235.01 μmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (2 mL, 4 N) and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to yield a yellow solid. The solid was purified by pre-HPLC (preparative column: 21.2 × 250 mm C18 column, system: 10 mM NH4HCO3H2O, wavelength: 254 / 214 nm, gradient: 30% to 60% acetonitrile) to yield compound H-28 (11.07 mg, 27.74 μmol, 13.69% yield). MS m / z (ESI): 394.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.39 (s, 1H), 8.61-8.55 (m, 1H), 8.30 (dd, J = 5.5, 1.8Hz, 1H), 8.05 ( dd,J=5.5,0.7Hz,1H),7.74(s,1H),7.53(d,J=1.3Hz,1H),7.49(d,J=8.5Hz,1H),7.17(d,J=1.3Hz, 1H),4.42-4.33(m,1H),3.83-3.77(m,1H),3.48-3.38(m,1H),2.00(q,J=7.6,6.9Hz,2H),1.68-1.5 7(m,1H),1.39(ddd,J=13.3,7.3,5.9Hz,1H),1.23(s,2H),0.85(d,J=6.9Hz,6H),0.83-0.75(m,4H).

[0544] Example 29: Preparation of Compound H-29

[0545] Step 1: Dissolve compound H-28-a (100 mg, 235.01 μmol) in dichloromethane (5 mL). Add thiazole-2-carbonyl chloride (34.68 mg, 235.01 μmol) and triethylamine (71.34 mg, 705.02 μmol, 98.33 μL) at 0°C. Stir at 0°C for 1 hour. Concentrate under reduced pressure to obtain compound H-29-a (80 mg, 149.07 μmol, 63.43% yield) as a yellow solid. MS m / z (ESI): 537.1 [M+H] + .

[0546] Step 2: Compound H-29-a (80 mg, 149.07 μmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (50.99 mg, 447.22 μmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to yield a yellow solid. The solid was purified by pre-HPLC (preparative column: 21.2 × 250 mm C18 column, system: 10 mM NH4HCO3H2O, wavelength: 254 / 214 nm, gradient: 30%-60% acetonitrile) to yield compound H-29 (10.23 mg, 23.43 μmol, 15.72% yield, 100% purity). MS m / z (ESI): 437.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.97 (d, J = 1.9 Hz, 1H), 8.47 (d, J = 5.3 Hz, 1H), 8.21 (d, J=3.0Hz,1H),8.16(d,J=3.1Hz,1H),8.11-8.04(m,2H),7.80(d,J=8.0Hz,1H),7.69( d,J=1.5Hz,1H),6.57(d,J=8.0Hz,1H),4.20(ddd,J=57.5,9.3,5.4Hz,2H),3.21(q,J =6.2Hz, 1H), 1.90-1.83 (m, 1H), 1.34 (t, J = 6.7Hz, 2H), 0.92 (dd, J = 12.5, 6.6Hz, 6H).

[0547] Example 30: Preparation of Compound H-30

[0548] Step 1: Dissolve compound H-28-a (1 g, 2.35 mmol) in dichloromethane (20 mL). Add methyl chloroformate (382.55 mg, 3.53 mmol) and triethylamine (713.40 mg, 7.05 mmol, 983.33 μL) at 0°C and stir at 0°C for 1 hour. Concentrate under reduced pressure to obtain compound H-30-a (0.8 g, 1.65 mmol, 70.40% yield) as a yellow solid. MS m / z (ESI): 484.1 [M+H] + .

[0549] Step 2: Dissolve compound H-30-a (0.8 g, 1.65 mmol) in dichloromethane (30 mL), add trifluoroacetic acid (565.90 mg, 4.96 mmol), and stir at room temperature for 2 hours. Concentrate under reduced pressure to obtain a yellow solid. The solid was purified by pre-HPLC (preparative column: 21.2 × 250 mm C18 column, system: 10 mM NH4HCO3H2O, wavelength: 254 / 214 nm, gradient: 30% to 60% acetonitrile) to obtain compound H-30 (33 mg, 85.78 μmol, 5.18% yield, 99.67% purity). MS m / z (ESI): 384.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.20 (s, 1H), 8.61 (d, J = 1.8 Hz, 1H), 8.31 (d, J = 5. 3Hz,1H),8.06(d,J=1.5Hz,1H),7.86(dd,J=5.3,1.7Hz,1H),7.71-7.64(m,2H),6. 53(d,J=8.0Hz,1H),4.18(ddd,J=56.9,9.2,5.4Hz,2H),3.69(s,3H),3.19(d,J=8 .5Hz,1H),1.90-1.74(m,1H),1.33(t,J=7.1Hz,2H),0.92(dd,J=12.7,6.6Hz,6H).

[0550] Examples 31-32: Preparation of Compounds H-31 and H-32

[0551] Step 1: Dissolve intermediate 18 (300 mg, 1.33 mmol) and intermediate d (370.44 mg, 1.33 mmol) in N,N-dimethylformamide (10 mL), add potassium carbonate (549.81 mg, 3.98 mmol), and stir at 100°C for 4 hours. Concentrate under reduced pressure to obtain a yellow solid. The solid is purified by column chromatography through a combiflash (0-30% DCM / MeOH) to obtain compound H-31-a (300 mg, 705.02 μmol, 53.17% yield) as a brown solid. MS m / z (ESI): 468.1 [M+H] + .

[0552] Step 2: Compound H-31-a (20 mg, 42.78 μmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (3 mL, 4 M) and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to yield a yellow solid. Pre-HPLC (preparative conditions: preparative column: 21.2 × 250 mm C18 column, system: 10 mM NH4HCO3H2O, wavelength: 254 / 214 nm, gradient: 30% to 60% acetonitrile) yielded compound H-31 (2.57 mg, 6.99 μmol, 16.35% yield, 100% purity). MS m / z (ESI): 368.1 [M+H] + .

[0553] Step 3: Compound H-31 (20 mg, 42.78 μmol) was dissolved in H₂O (1 mL), potassium hydroxide (7.20 mg, 128.33 μmol) and ethanol (2 mL) were added, and the mixture was stirred at 85°C for 4 hours. The mixture was then concentrated under reduced pressure to yield a yellow solid. The solid was purified by pre-HPLC (preparative column: 21.2 × 250 mm C₁ₒ column, system: 10 mM NH₄HCO₃H₂O, wavelength: 254 / 214 nm, gradient: 30% to 60% acetonitrile) to yield compound H-32 (1.10 mg, 3.37 μmol, 7.88% yield). MS m / z (ESI): 326.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.03 (d, J = 1.4Hz, 1H), 7.95 (d, J = 5.4Hz, 1H), 7.63 (d, J = 1 .5Hz,1H),7.61(d,J=7.9Hz,1H),7.41(d,J=1.8Hz,1H),7.16-7.12(m,1H),6.48(d,J=8. 0Hz, 1H), 5.93 (s, 2H), 4.22 (dd, J=9.4, 4.4Hz, 1H), 4.08 (dd, J=9.3, 6.7Hz, 1H), 3.21-3. 17(m,1H),1.89-1.85(m,1H),1.32(td,J=6.9,3.7Hz,2H),0.91(dd,J=12.9,6.6Hz,6H).

[0554] Example 33: Preparation of Compound H-33

[0555] Step 1: Intermediate 19 (60 mg, 0.23 mmol) and intermediate d (87 mg, 0.31 mmol) were dissolved in a mixture of ethyl acetate (3 mL) and N,N-dimethylformamide (0.3 mL). Potassium carbonate (127 mg, 0.92 mmol) was added and the reaction was stirred at room temperature for 16 h. After completion of the reaction, the solid was filtered and washed with ethyl acetate. The filtrate was dried and purified by column chromatography (dichloromethane:methanol = 15:1) to afford compound H-33-a (80 mg) in a yield of 71.8%. MS m / z (ESI): 461.2 [M+H] + .

[0556] Step 2: Dissolve compound H-33-a (80 mg, 0.17 mmol) in anhydrous dichloromethane (3 mL), then add trifluoroacetic acid (0.5 mL). Stir the reaction at room temperature for 2 h. After the reaction, add saturated aqueous sodium bicarbonate to adjust the pH to a weak base. Extract with dichloromethane (10 mL x 2). The combined organic phases are washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound H-33 (30 mg). Yield: 49%. MS m / z (ESI): 361.1 [M+H]. + . 1 H NMR (400MHz, CDCl3) δ (ppm): 8.73 (d, J = 5.2Hz, 1H), 8.27 (d, J = 5.2Hz, 1H), 8.25 (s, 1H), 7.80 ( d,J=1.2Hz,1H),7.70(d,J=1.2Hz,1H),7.54(d,J=7.8Hz,1H),6.72(t,J=55.6Hz,1H),6.21(d ,J=7.8Hz,1H),4.26(dd,J=9.0,3.8Hz,1H),4.12(dd,J=9.0,7.2Hz,1H),3.55-3.38(m,1H),1 .84(dt,J=13.8,6.8Hz,1H), 1.45(t,J=7.0Hz,2H), 1.26(s,2H), 1.00(dd,J=9.8,6.6Hz,6H).

[0557] Example 34: Preparation of Compound H-34

[0558] Step 1: Dissolve methyl 3-hydroxypyridine-2-carboxylate (4.15 g, 27.1 mmol) in water (240 mL). Slowly add liquid bromine (4.33 g, 27.1 mmol) dropwise at 20°C until complete. Stir the reaction at 20°C for 3 hours. The reaction mixture is extracted with dichloromethane (150 mL x 2), washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure to afford methyl 6-bromo-3-hydroxypyridine-2-carboxylate (5.18 g, 83.1% purity, pale yellow solid) in a 68.5% yield. MS m / z (ESI): 231.9 / 233.9 [M+H] + .

[0559] Step 2: Methyl 6-bromo-3-hydroxypyridine-2-carboxylate (3.00 g, 12.9 mmol) was dissolved in a mixed solvent of ethyl acetate (75 mL) and N,N-dimethylformamide (7.5 mL), followed by the addition of potassium carbonate (7.15 g, 51.7 mmol) and intermediate d (4.88 g, 17.4 mmol). The reaction was stirred at 50 °C for 2 h. The reaction mixture was diluted with ethyl acetate (60 mL) and washed with water (150 mL). The aqueous phase was extracted with ethyl acetate (70 mL). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude compound was then dissolved in ethyl acetate (50 mL), and 0.1 M aqueous citric acid (40 mL) was added. The mixture was stirred for 5 minutes. After separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (19 / 1 to 9 / 1) as eluent to obtain compound H-34-a (3.98 g, 97.7% purity, as a light yellow, transparent, viscous gel) in a 69.7% yield. MS m / z (ESI): 375.0 / 377.0 [M-56+H]. + ; 431.0 / 433.0[M+H] + .

[0560] Step 3: Dissolve compound H-34-a (3.94 g, 9.13 mmol) in tetrahydrofuran (80 mL). Cool the reaction mixture to ~0°C and add a 1M solution of lithium triethylborohydride in tetrahydrofuran (45 mL) dropwise. Stir the reaction at 15°C for 3 hours. Cool the reaction mixture to approximately 0°C, add water (150 mL) and stir for 30 minutes. Extract the mixture with ethyl acetate (120 mL), wash with saturated brine (150 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the resulting residue by silica gel column chromatography with petroleum ether / ethyl acetate (9 / 1 to 6 / 1) to obtain compound H-34-b (2.15 g, 99.5% purity, colorless viscous gel) in a 58.1% yield. MS m / z (ESI): 402.9 / 404.9 [M+H] + .

[0561] Step 4: Dissolve compound H-34-b (2.15 g, 5.33 mmol) in dichloromethane (80 mL) and add manganese dioxide (9.27 g, 106 mmol). Stir the reaction at 15°C for 36 hours. Filter through a layer of celite and concentrate the filtrate under reduced pressure to obtain compound H-34-c (1.50 g, white solid) in a 70.1% yield. MS m / z (ESI): 401.0 / 403.0 [M+H] + .

[0562] Step 5: Compound H-34-c (1.50 g, 3.74 mmol) was dissolved in 15 mL of N,N-dimethylformamide, and glycine (309 mg, 4.12 mmol) was added. The atmosphere was purged with nitrogen three times, followed by the addition of elemental iodine (948 mg, 3.74 mmol) and sodium carbonate (792 mg, 7.48 mmol). The reaction was stirred at 60°C for 9 hours. 240 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (9 / 1 to 9 / 2) as the eluent to afford compound H-34-d (686 mg, 99.5% purity, as a yellow, transparent viscous gel) in a 40.9% yield. MS m / z (ESI): 412.0 / 414.0 [M+H] + . 1H NMR (400MHz, CDCl3) δ (ppm): 8.27 (s, 1H), 7.67 (s, 1H), 6.70 (d, J = 7.6Hz, 1H), 5.98 (br d, J = 7.6Hz, 1H), 4.68 (br d,J=7.6Hz,1H),4.14-4.01(m,2H),1.78-1.69(m,2H),1.54(br d,J=6.4Hz,1H),1.45(s,9H),0.97(t,J=6.8Hz,6H).

[0563] Step 6: 1H-Pyrrolo[2,3-b]pyridine-4-boronic acid (50 mg, 308 μmol) and compound H-34-d (138 mg, 91.9% purity, 308 μmol) were dissolved in a mixture of dioxane (10 mL) and water (2 mL). Potassium carbonate (107 mg, 774 μmol) was added, and the atmosphere was purged with nitrogen three times. Xphos-Pd-G2 (12.5 mg, 15.89 μmol) was added, and the atmosphere was purged with nitrogen three times. The reaction was stirred at 85°C for 2 hours. The mixture was diluted with ethyl acetate (15 mL), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography on silica gel using a developing solvent (petroleum ether / ethyl acetate = 0 / 1) to afford compound H-34-e (52.9 mg, 94.6% purity, yellow solid) in a 36.0% yield. MS m / z(ESI):450.3[M+H] + .

[0564] Step 7: Dissolve compound H-34-e (22.4 mg, 49.8 μmol) in 0.2 mL of dioxane and add 0.47 mL of 4 M hydrogen chloride / dioxane dropwise in an ice bath. Stir the mixture at 15°C for 1 hour. The dioxane is removed by vortexing the reaction mixture under reduced pressure. Acetonitrile is added to remove the remaining dioxane, and the mixture is lyophilized with water to yield 26 mg of a yellow solid. This solid is then slurried in 1.5 mL of acetonitrile for 10 minutes, filtered, and the filter cake is pumped dry to yield the hydrochloride salt of compound H-34 (13.2 mg, 96.5% purity). Yield: 66.2%. MS m / z (ESI): 350.2 [M+H]. + . 1H NMR(400MHz,CD3OD)δ(ppm):9.49(s,1H),8.63(br d,J=6.0Hz,1H),8.52(s,1H),7.92(d,J=6.0Hz,1H),7.84(d,J=3.6Hz,1H), 7.55(d,J=7.6Hz,1H),6.96(d,J=7.6Hz,1H),6.76(d,J=3.2Hz,1H),4.63(br dd,J=2.4,10.4Hz,1H),4.47(br dd,J=10.4,6.4Hz,1H),3.89(br d,J=3.2Hz,1H),1.91-1.82(m,1H),1.82-1.70(m,2H),1.07(t,J=6.0Hz,6H).

[0565] Example 35: Preparation of Compound H-35

[0566] Step 1: Dissolve 2-amino-4-bromopyridine (5.00 g, 28.9 mmol, 1 eq) in 50 mL of dichloromethane. Slowly add acetic anhydride (4.43 g, 43.35 mmol, 4.06 mL, 1.50 eq) and 4-dimethylaminopyridine (353.07 mg, 2.89 mmol, 0.1 eq). Stir the mixture at room temperature under a nitrogen atmosphere for 16 hours. Add 50 mL of dichloromethane to the reaction mixture. Wash the organic layer with saturated sodium bicarbonate (60 mL x 3) and saturated brine (60 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain N-(4-bromopyridin-2-yl)acetamide (5.40 g, off-white solid) in an 83.5% yield. MS m / z (ESI): 216.7 [M+H] + .

[0567] Step 2: Dissolve N-(4-bromopyridin-2-yl)acetamide (2.00 g, 9.30 mmol, 1.00 eq) in 20 mL of dioxane. Add bis(1,1-bis(diphenylphosphino)ferrocene)palladium dichloride (2.41 g, 9.49 mmol, 1.02 eq), potassium acetate (2.74 g, 27.90 mmol, 3.00 eq), and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride in dichloromethane (379.75 mg, 465.01 μmol, 0.05 eq) sequentially. Degas the mixture with nitrogen and stir at 100°C under a nitrogen atmosphere for 16 hours. Cool to room temperature, concentrate under reduced pressure to remove the solvent, and dilute and dissolve the mixture with 20 mL of ethyl acetate. Filter the mixture through a silica gel pad. Wash the filter cake with ethyl acetate (20 mL x 4). Concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was recrystallized from n-hexane:ethyl acetate = 5:1 (10 mL x 3) to give 2-acetamidopyridine-4-boronic acid (1.20 g, off-white solid). Yield: 49.2%. MS m / z (ESI): 180.8 [M+H] + .

[0568] Step 3: Dissolve compound H-34-d (100 mg, 242.53 μmol, 1.00 eq) in 2 mL of dioxane and 0.2 mL of water. Add 2-acetamidopyridine-4-boronic acid (76.28 mg, 291.04 μmol, 1.20 eq), potassium carbonate (83.80 mg, 606.32 μmol, 2.50 eq), and (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) chloride (9.54 mg, 12.13 μmol, 0.05 eq) sequentially. Degas the mixture with nitrogen and stir at 85°C under a nitrogen atmosphere for 2 hours. Cool to room temperature, add 5 mL of water, and extract with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (8 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using an eluent (dichloromethane / methanol = 100 / 0 to 95 / 5) to obtain compound H-35-a (100 mg, light yellow solid) in a 44.0% yield. MS m / z (ESI): 468.1 [M+H] + .

[0569] Step 4: Dissolve compound H-35-a (95.0 mg, 203.18 μmol, 1 eq) in 0.5 mL of dioxane and slowly add 4 M hydrochloric acid in ethyl acetate (0.5 mL) dropwise at 0°C. Stir the mixture at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, yielding compound H-35 (50 mg) in a 64.4% yield. MS m / z (ESI): 368.0 [M+H]+ . 1 H NMR(DMSO-d6)δ(ppm):10.84(s,1H),9.39(br s,1H),8.55(br s,1H),8.52(d,J=5.02Hz,2H),8.48(br s,1H),8.37(s,1H),7.49(dd,J=5.27,1.51Hz,1H),7.15(d,J=7.78Hz,1H),6.73(d,J=7.78Hz,1H),4.49-4.42(m,2H),4.30(br dd,J=10.54,5.77Hz,1H),2.14(s,3H),1.86-1.77(m,1H),1.68-1.59(m,2H),0.94(dd,J=6.53,4.27Hz,6H).

[0570] Example 36: Preparation of Compound H-36

[0571] Step 1: Dissolve methyl 6-bromo-3-[(2S)-2-(tert-butylcarbonylamino)-4-methylpentyloxy]pyridine-2-carboxylate (1.70 g, 3.94 mmol) and 2-(difluoromethyl)pyridine-4-boronic acid pinacol ester (1.11 g, 4.34 mmol) in a mixture of dioxane (20 mL) and water (4 mL). Add potassium carbonate (1.36 g, 9.85 mmol) and tetrakis(triphenylphosphine)palladium (228 mg, 197 μmol). Replace the atmosphere with nitrogen three times. Stir and react at 80°C for 3 hours. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The mixture was extracted twice with ethyl acetate (25 mL). The combined organic phases were washed with brine (25 mL). The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with an eluent (petroleum ether / ethyl acetate = 1 / 0 to 20 / 9) to obtain compound H-36-a (1.52 g, 77.0% purity, light yellow solid) in a yield of 61.9%. MS m / z (ESI): 480.2 [M+H] + .

[0572] Step 2: Compound H-36-a (1.52 g, 3.17 mmol) was dissolved in tetrahydrofuran (30 mL). The reaction mixture was cooled to 0°C and a 1M solution of lithium triethylborohydride in tetrahydrofuran (15.9 mL) was added dropwise. The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was cooled to 0°C, water (10 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered through celite and extracted twice with ethyl acetate (10 mL). The combined organic phases were washed with brine (15 mL). The organic phases were separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (0 / 1 to 4 / 1) as eluent to afford compound H-36-b (750 mg, 100% purity, as a light yellow gum) in a yield of 52.4%. MS m / z (ESI): 452.2 [M+H] + .

[0573] Step 3: Dissolve compound H-36-b (750 mg, 1.66 mmol) in dichloromethane (30 mL) and add manganese dioxide (2.89 g, 33.2 mmol). Stir the reaction at 25°C for 5 hours. Filter through celite and concentrate the filtrate under reduced pressure to obtain compound H-36-c (480 mg, 95.8% purity, light yellow gum) in a 61.6% yield. MS m / z (ESI): 450.2 [M+23] + .

[0574] Step 4: Dissolve compound H-36-c (480 mg, 1.07 mmol) in 5 mL of N,N-dimethylformamide, add glycine (88.2 mg, 1.17 mmol), iodine (271 mg, 1.07 mmol) and sodium carbonate (226 mg, 2.14 mmol), and stir the reaction at 60 °C for 6 hours. The reaction mixture was added with 30 mL of water and 10 mL of saturated sodium sulfite, and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by basic preparative HPLC (preparative column: Phenomenex C18 80 × 40 mm × 3 μm; mobile phase: [water (ammonia)-acetonitrile]; B%: 33%-63%, 8 min) and lyophilized to afford compound H-36-d (405 mg, 78.9% purity, white solid) in a 65.0% yield. MS m / z (ESI): 461.1 [M+H]. + .

[0575] Step 5: Compound H-36-d (400 mg, 868 μmol) was dissolved in 5 mL of ethyl acetate and 10 mL of 4 M hydrogen chloride / dioxane was added dropwise under ice. The reaction mixture was stirred at 25°C for 3 hours. The dioxane was removed by vortexing under reduced pressure. The residue was purified by preparative alkaline HPLC (preparative column: Phenomenex C18 80 × 40 mm × 3 μm; mobile phase: [water (ammonia)-acetonitrile]; B%: 38%-68%, 8 min) and lyophilized to afford compound H-36 (75.0 mg, 97.6% purity, light yellow solid) in a 23.4% yield. MS m / z (ESI): 361.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.84 (d, J = 5.02Hz, 1H), 8.47 (s, 1H), 7.99 (s, 1H), 7.96 (br d,J=4.77Hz,1H),7.62(s,1H),7.21-6.92(m,1H),6.92-6.82(m,1H),6.38(d,J=7.53Hz,1H),4.05(dd,J=9.41,4.89 Hz,1H),3.99-3.90(m,1H),3.20-3.13(m,1H),1.87-1.84(m,1H),1.37-1.30(m,2H),0.92(dd,J=13.05,6.53Hz,6H).

[0576] Example 37: Preparation of Compound H-37

[0577] Step 1: Dissolve intermediate 20 (33 mg, 113.28 μmol) and potassium carbonate (23.49 mg, 169.92 μmol) in N,N-dimethylformamide (5 mL), then add intermediate d (31.65 mg, 113.28 μmol). The reaction mixture was stirred at 50°C for 2 hours. After completion of the reaction, the mixture was dried and passed through a column (DCM / MeOH = 4 / 1) to afford compound H-37-a (50 mg, yellow solid). Yield: 89.97%. MS m / z (ESI): 491.3 [M+H] + .

[0578] Step 2: Dissolve compound H-37-a (50 mg, 101.92 μmol) in dichloromethane (8 mL), then add trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion, the solvent was evaporated and the residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain the target product, compound H-37 (5.73 mg). Yield: 13.97%. MS m / z (ESI): 391.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.59 (d, J = 6.0Hz, 1H), 8.33 (s, 1H), 8.13 (s, 1 H),8.05-7.99(m,2H),7.77(d,J=6.0Hz,1H),7.22(d,J=8.0Hz,1H),6.85(d, J=2.0Hz,1H),6.79(d,J=8.0Hz,1H),4.08-4.03(m,1H),3.97-3.93(m,1H),3 .88(s,3H),3.17(s,1H),1.84(s,1H),1.35-1.28(m,2H),0.92-0.87(m,6H).

[0579] Example 38: Preparation of Compound H-38

[0580] Step 1: Dissolve intermediate 21 (80 mg, 261.16 μmol) and intermediate a (153.24 mg, 522.33 μmol) in N,N-dimethylformamide (5 mL), add potassium carbonate (72.19 mg, 522.33 μmol), warm to 80°C, and stir for 18 hours. Cool, filter, concentrate, and purify by column chromatography (methanol / dichloromethane = 1 / 10) to give compound H-38-a (100 mg, yield: 73.7%). MS m / z (ESI): 520.2 [M+H] + .

[0581] Step 2: Dissolve compound H-38-a (70 mg, 134.71 μmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 1 hour. Concentrate the mixture, and purify the residue by preparative HPLC to obtain compound H-38 (13.7 mg, yield: 24.1%). MS m / z (ESI): 420.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ (ppm): 8.98 (s, 1H), 8.18 (d, J = 5.4Hz, 1H), 8.02-7.94 (m, 2H), 7.43-7.34 (m, 2H), 7.11-7.01 (m, 2H), 6.83 (d, J = 2.2H) z,1H),6.72(d,J=8.0Hz,1H),3.85(s,2H),3.79(s,3H),1.82-1.80(m,1H),1.59(s,2H),1.41-1.39(m,2H),1.13(s,3H),0.92-0.90(m,6H).

[0582] Examples 39 to 70, 90 to 91

[0583] Compounds H-39 to H-70, H-90 to H-91 can be prepared by referring to the methods of the above examples.

[0584] Example 71 Preparation of Compound HY-71 (H-71 Hydrochloride)

[0585] Step 1: Dissolve intermediate 1 (115 mg, 508.32 μmol) and intermediate e (189.92 mg, 609.99 μmol) in anhydrous DMF (5 mL). Add cesium carbonate (662.49 mg, 2.03 mmol) at room temperature. Stir the reaction at 50°C for 5 hours. After cooling, filter, wash the filter cake with tetrahydrofuran (3 mL x 2), and concentrate the filtrate under reduced pressure to obtain H-71-a (220 mg, brown oil) in a 94.6% yield. MS m / z (ESI): 458.0 [M+H] + .

[0586] Step 2: Dissolve H-71-a (100 mg, 218.57 μmol) and triethylamine (66.35 mg, 655.70 μmol) in anhydrous dichloromethane (2 mL). Add methyl chloroformate (24.78 mg, 262.28 μmol) dropwise in an ice-water bath. Stir at room temperature for 3 hours. Quench with water (2 mL) and extract with dichloromethane (2 mL x 3). The combined organic phases are washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford H-71-b (100 mg, light yellow solid) in a 79.7% yield. MS m / z (ESI): 574.0 [M+H] + .

[0587] Step 3: Dissolve H-71-b (80.0 mg, 139.47 μmol) in 2 mL of methanol and add sodium hydroxide (11.16 mg, 278.94 μmol) at room temperature. Stir at room temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford H-71-c (40.0 mg, yellow solid) in a 55.6% yield. MS m / z (ESI): 516.0 [M+H] + .

[0588] Step 4: Dissolve H-71-c (40.0 mg, 77.59 μmol) in 1 mL of methanol, add palladium on carbon (4.00 mg, 10% purity), and stir under a hydrogen atmosphere at room temperature for 5 hours. Filter, concentrate the filtrate under reduced pressure, and purify it by preparative separation (preparative column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water(HCl)-ACN]; B%: 12%-42%, 10 min) to obtain HY-71 (20.0 mg, light yellow powder) in a 67.5% yield. MS m / z (ESI): 382.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.50 (s, 1H), 8.45 (s, 1H), 8.39 (d, J = 5.52Hz, 1H), 8.02-8.06 (m, 1H), 7.65 (dd, J = 5.27, 1.51Hz, 1H), 7.17 (d, J = 8.03Hz, 1H),6.98(d,J=2.26Hz,1H),6.82(d,J=8.03Hz,1H),4.52-4.63(m,2H),3.7 8-3.87(m,1H),3.70(s,3H),1.80-1.96(m,2H),0.72-0.86(m,1H),0.43(br d,J=8.03Hz,2H),-0.02-0.13(m,2H).

[0589] Example 72 Preparation of Compound HY-72 (H-72 Hydrochloride)

[0590] Step 1: Dissolve compound H-71-a (100 mg, 218.57 μmol) and triethylamine (66.35 mg, 655.70 μmol) in anhydrous dichloromethane (3 mL). Add cyclopropanecarbonyl chloride (27.42 mg, 262.28 μmol) dropwise in an ice-water bath. Stir at room temperature for 16 hours. Quench with water (2 mL) and extract with dichloromethane (2 mL x 3). The combined organic phases are washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford H-72-a (100 mg, yellow solid) in a 77.0% yield. MS m / z (ESI): 594.0 [M+H] + .

[0591] Step 2: Dissolve H-72-a (100 mg, 168.44 μmol) in 2 mL of methanol and add sodium hydroxide (13.47 mg, 336.89 μmol) at room temperature. Stir at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude H-72-b (40.0 mg, yellow solid) in a 45.1% yield. MS m / z (ESI): 526.0 [M+H] + .

[0592] Step 3: Dissolve H-72-b (40.0 mg, 76.10 μmol) in 2 mL of methanol, add palladium on carbon (4 mg, 10% purity), and stir under a hydrogen atmosphere at room temperature for 3 hours. Filter, concentrate the filtrate under reduced pressure, and purify it by preparative separation (preparative column: Xtimate C18 150 × 40 mm × 5 μm; mobile phase: [water (HCl)-ACN]; B%: 10%-40%, 10 min) to obtain HY-72 (10.0 mg, light yellow powder) in a yield of 29.8%. MS m / z (ESI): 392.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ(ppm)11.63(br s,1H),8.66(s,1H),8.56(br s,3H),8.44(d,J=5.52Hz,1H),8.06(d,J=2.26Hz,1H),7.80(dd,J=5.65,1.38 Hz,1H),7.25(d,J=7.78Hz,1H),7.15(d,J=2.26Hz,1H),6.89(d,J=8.03Hz,1H ),4.40-4.54(m,2H),3.97(dd,J=8.53,6.02Hz,1H),2.04-2.12(m,1H),1.59- 1.84(m,2H),1.42-1.51(m,1H),1.18-1.30(m,1H),0.82-0.92(m,5H),0.48(br d,J=8.03Hz,2H),0.08-0.21(m,2H).

[0593] Example 73 Preparation of Compound HY-73 (Hydrochloride Salt of Compound H-73)

[0594] Step 1: Intermediate 1 (160 mg, 708 μmol) was dissolved in anhydrous N,N-dimethylformamide (2.5 mL). Intermediate f (278 mg, 854 μmol) and cesium carbonate (921 mg, 2.83 mmol) were added and the reaction was stirred at 50°C for 2 hours. The reaction mixture was filtered, and the filter cake was rinsed with dichloromethane (5 mL x 3). The filtrate was concentrated and purified by silica gel column chromatography using an eluent (DCM / MeOH = 1 / 0 to 9 / 1) to obtain H-73-a (100 mg, brown-black viscous gum; 70.0 mg, yellow solid) in a 50.9% yield. MS m / z (ESI): 472.2 [M+H] + .

[0595] Step 2: H-73-a (25.0 mg, 53.0 μmol) was dissolved in anhydrous dichloromethane (2 mL). Triethylamine (16.1 mg, 159 μmol) and cyclopropanecarbonyl chloride (11.0 mg, 106.0 μmol) were added under nitrogen. The reaction was stirred at 25°C for 2 hours. 2 mL of water was added, and the mixture was extracted with dichloromethane (2 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product H-73-b (32.0 mg, light yellow gum) in a yield of 99.0%. The crude product was used directly in the next step. MS m / z (ESI): 608.1 [M+H] + .

[0596] Step 3: Dissolve H-73-b (32.0 mg, 52.7 μmol) in anhydrous methanol (2 mL), add sodium hydroxide (4.20 mg, 52.7 μmol), and react at 60°C for 3 hours. Then, add sodium hydroxide (4.20 mg, 52.7 μmol), and react at 60°C for 6 hours. Filter and spin dry to obtain crude H-73-c (35.0 mg, light yellow oil), which is used directly in the next step. MS m / z (ESI): 540.1 [M+H] + .

[0597] Step 4: H-73-c (35.0 mg, 64.9 μmol) was dissolved in anhydrous methanol (5 mL), and Pd / C (30 mg, 10% purity) was added. The mixture was replaced with hydrogen three times and reacted at 20°C under a hydrogen atmosphere (15 psi) for 0.5 h. The mixture was filtered through a layer of celite. The filtrate was concentrated and preparatively analyzed by HPLC (preparative column: Phenomenex C18 150 × 40 mm × 5 μm; mobile phase: [water (HCl)-ACN]; B%: 5%-35%, 10 min). The product was lyophilized to afford HY-73 (3.5 mg, light yellow solid) in a 13.3% yield. MS m / z (ESI): 406.1 [M+H] + . 1 H NMR(400MHz,MeOD)δ(ppm)8.72(s,1H),8.40(br d,J=6.80Hz,1H),8.06-8.21(m,2H),7.60(d,J=8.00Hz,1H),7.13-7.24(m,1H),6.91-7.06(m,1H),4.35-4.65(m,2H),1 .94-2.05(m,1H),1.72-1.94(m,2H),1.63(s,3H),1.09-1.23(m,4H),0.87(m,1H),0.56-0.72(m,2H),0.16-0.31(m,2H).

[0598] Example 74 Preparation of Compound H-74

[0599] Step 1: Dissolve H-2-a (130 mg, 295.76 μmol) in acetonitrile (5 mL), add ethanediisocyanate (63.07 mg, 887.27 μmol) and triethylamine (149.64 mg, 1.48 mmol), stir overnight at 90°C, and concentrate under reduced pressure to obtain a yellow solid. The solid was combiflashed (0-20% MeOH / DCM) to obtain H-74-a (60 mg, yellow solid) in a yield of 39.73%. MS m / z (ESI): 511.1 [M+H] + .

[0600] Step 2: H-74-a (60 mg, 117.50 μmol) was dissolved in DCM (4 mL), and trifluoroacetic acid (40.19 mg, 352.51 μmol) was added. The mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, the mixture was purified by pre-HPLC (preparative column: 21.2 × 250 mm C18 column, system: 10 mM NH4HCO3H2O, wavelength: 254 / 214 nm, gradient: 30%-60% acetonitrile) to obtain H-74 (9.98 mg, purity 98.9%) in a yield of 20.46%. MS m / z (ESI): 411.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.24 (s, 1H), 8.28 (d, J = 5.4Hz, 1H), 8.13 (s, 1H), 8.03 (d, J = 2.2Hz, 1H), 7.97(s,1H),7.43(dd,J=5.4,1.5Hz,1H),7.15-7.02(m,2H),6.84(d,J=8.0Hz,1H),4.20(dd,J=29.2, 10.4Hz,2H),3.16(dd,J=9.0,3.3Hz,2H),1.78(ddd,J=28.9,13.3,6.1Hz,2H),1.60(dd,J=14.0,5.2H z, 1H), 1.38 (s, 3H), 1.21 (s, 2H), 1.08 (t, J = 7.2Hz, 3H), 0.95 (d, J = 6.5Hz, 3H), 0.89 (d, J = 6.4Hz, 3H).

[0601] Example 75 Preparation of Compound HY-75 (Hydrochloride Salt of Compound H-75)

[0602] Step 1: In a 250 mL three-necked flask, add 50 mL of anhydrous DMF and methyl 4-(benzyloxy)-7-bromopyrazolo[1,5-a]pyridine-3-carboxylate (5.75 g, 13.84 mmol). The system is purged with nitrogen three times, and tributyl(1-ethoxyethylene)tin (6.50 g, 18.00 mmol) is slowly injected into the system via syringe. After the addition is complete, the system is heated to 120°C and reacted for 1 hour. After the reaction is completed, the reaction solution is cooled to room temperature and quenched by slowly adding saturated potassium fluoride solution (40 mL). After quenching, the reaction solution is stirred at room temperature for 30 minutes, filtered, and the filter cake is rinsed with ethyl acetate (3 mL x 2). The filtrate was diluted with water (100 mL × 1) and ethyl acetate (100 mL × 1), and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product H-75-a (9.00 g, brown solid), which was used directly in the next reaction. MS m / z (ESI): 352.9 [M+H] + .

[0603] Step 2: To a 250 mL three-necked flask, add hydrochloric acid (2M, 40 mL) and tetrahydrofuran (60 mL), then add crude H-75-a (9.00 g, 10.22 mmol, 40% purity). The reaction mixture was allowed to react at 25°C for 1 hour. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (PE / EA = 90 / 10 to 85 / 15) afforded H-75-b (1.80 g, brown solid) in a 54.3% yield. MS m / z (ESI): 324.8 [M+H] + .

[0604] Step 3: To a 100 mL three-necked flask, add aqueous hydrogen bromide (50 mL, 48%) and H-75-b (1.00 g, 3.08 mmol). The reaction mixture was allowed to react at 110°C for 48 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated to remove most of the HBr. The concentrate was extracted with ethyl acetate (20 mL x 4). The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford H-75-c (500 mg, yellow solid) in a yield of 92.1%. MS m / z (ESI): 176.8 [M+H] + .

[0605] Step 4: To an 8 mL AK vial, add anhydrous DMF (3 mL), H-75-c (250 mg, 1.42 mmol) and intermediate e (530.20 mg, 1.70 mmol), and cesium carbonate (3.70 g, 11.35 mmol). The reaction mixture was heated to 50°C and reacted for 2 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to obtain crude product H-75-d (300 mg, yellow solid), which was used directly in the next reaction. MS m / z (ESI): 407.9 [M+H] + .

[0606] Step 5: To a 50 mL single-necked flask, add N,N-dimethylformamide dimethyl acetal (5.38 g, 45.17 mmol) and H-75-d (300 mg, crude). The reaction mixture was heated to 110°C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated, and purified by column chromatography (DCM / MeOH = 100 / 0 to 98 / 2) to obtain H-75-e (170 mg, yellow solid) in a 49.9% yield. MS m / z (ESI): 463.0 [M+H] + .

[0607] Step 6: To a 5 mL thumb flask, add 2 mL of acetic acid, H-75-e (170 mg, 367.54 μmol) and 1H-pyrazol-5-amine (30.54 mg, 367.54 μmol). The reaction mixture was heated to 110°C for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into 10 mL of ice water. After stirring for two minutes, the mixture was filtered and the filter cake was washed with water (2 mL x 1). The filter cake was collected and concentrated to obtain H-75-f (80.0 mg, yellow solid) in a yield of 45.1%. MS m / z (ESI): 483.0 [M+H] + .

[0608] Step 7: In a 5 mL vial, anhydrous tetrahydrofuran (2 mL) was added, followed by H-75-f (50 mg, 103.62 μmol) and palladium hydroxide (50.0 mg, 356.04 μmol). The system was degassed three times with a hydrogen balloon (15 psi). The reaction mixture was allowed to react at 25°C under a hydrogen atmosphere for 1.5 hours. After completion of the reaction, the mixture was filtered, and the filtrate was purified by HPLC (preparative column: Xtimate C18 150 × 40 mm × 5 μm; mobile phase: [water (HCl)-ACN]; B%: 1%-30%, 10 min) to afford HY-75 (11.0 mg, yellow solid) in a 27.6% yield. MS m / z (ESI): 348.9 [M+H] + . 1H NMR(400MHz,CD3OD)δ(ppm)8.68(br s,1H),8.10(br s,1H),7.87(br s,1H),7.40(br s,2H),7.02(br s,1H),6.81-6.94(m,2H),4.46-4.66(m,2H),3.88(br s,1H),1.81(br s,2H),0.89(br s,1H),0.64(br d,J=8.00Hz,2H),0.24(br s,2H).

[0609] Example 76 Preparation of Compound H-76

[0610] Step 1: Dissolve H-75-c (190 mg, 1.08 mmol) and potassium carbonate (223.59 mg, 1.62 mmol) in DMF (5 mL), then add intermediate a (379.69 mg, 1.29 mmol). The reaction mixture was stirred at 80°C for 16 hours. After completion, the mixture was dried and purified by column chromatography (DCM / MeOH = 4 / 1) to obtain H-76-a (280 mg, yellow solid) in a 66.66% yield. MS m / z (ESI): 390.3 [M+H] + .

[0611] Step 2: H-76-a (280 mg, 0.72 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (8.57 g, 72.0 mmol). The reaction mixture was stirred at 110°C for 16 hours. The mixture was dried to give H-76-b (280 mg, yellow solid) in an 87.59% yield. MS m / z (ESI): 445.3 [M+H] + .

[0612] Step 3: H-76-b (280 mg, 629.83 μmol) and 3-trifluoromethyl-1H-pyrazol-5-amine (95.16 mg, 629.83 μmol) were dissolved in acetic acid (5 mL). The reaction mixture was stirred at 80°C for 4 hours. The solvent was evaporated, and the product was dissolved in dichloromethane (8 mL). Trifluoroacetic acid (2 mL) was then added, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was evaporated, and the residue was purified by preparative liquid chromatography (preparative column: water-sunfire; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254 / 214 nm; gradient: 5% to 30% acetonitrile) to obtain H-76 (32.22 mg) in an 11.59% yield. MS m / z (ESI): 433.2 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.89 (d, J = 4.0Hz, 1H), 7.92 (s, 1H), 7.74 (d, J = 4.0Hz, 1H), 7.48 (d, J = 8.0Hz, 1H), 7.44 (s, 1H), 7.00 (d,J=2.0Hz,1H),6.90(d,J=8.0Hz,1H),4.16-4.04(m,2H),1.89-1.79(m,1H),1.62-1.49(m,2H),1.28(s,3H),0.97-0.92(m,6H).

[0613] Example 77 Preparation of Compound H-77

[0614] Step 1: H-76-b (280 mg, 629.83 μmol) and 3-chloro-1H-pyrazol-5-amine (74.03 mg, 629.83 μmol) were dissolved in acetic acid (5 mL). The reaction mixture was stirred at 80°C for 4 hours. The solvent was evaporated, and the residue was dissolved in dichloromethane (8 mL). Trifluoroacetic acid (2 mL) was then added, and the reaction mixture was stirred at room temperature for 2 hours. The residue was evaporated and purified by preparative liquid chromatography (preparative column: water-sunfire; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-30% acetonitrile) to obtain H-77 (20.46 mg, yellow solid) in a yield of 7.86%. MS m / z (ESI): 399.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.76 (d, J = 4.0Hz, 1H), 7.92 (s, 1H), 7.54 (d, J = 4.3Hz, 1H), 7.42 (d, J = 8.0Hz, 1H), 7.05-6.95 ( m,2H),6.87(d,J=8.0Hz,1H),4.08(q,J=10.0Hz,2H),1.87-1.79(m,1H),1.62-1.48(m,2H),1.27(s,3H),0.96-0.91(m,6H).

[0615] Example 78 Preparation of Compound H-78

[0616] Step 1: Dissolve H-76-b (0.25 g, 562.35 μmol) and 3-amino-5-bromopyrazole (91.09 mg, 562.35 μmol) in acetic acid (10 mL). Stir the reaction at 80°C for 2 hours. The solvent is evaporated, and DCM (8 mL) is added. The reaction is stirred at room temperature for 2 hours. This solution is evaporated to give H-78-a (150 mg, yellow solid) in a yield of 49.08%. MS m / z (ESI): 445.1 [M-100+H]. + .

[0617] Step 2: H-78-a (50 mg, 92.00 μmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (31.47 mg, 276.01 μmol) was added. The mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, the mixture was purified by pre-HPLC (preparative column: 21.2 × 250 mm C18 column, system: 10 mM NH4HCO3H2O, wavelength: 254 / 214 nm, gradient: 30%-60% acetonitrile) to obtain H-78 (7.83 mg, purity 100%) in a yield of 19.20%. MS m / z (ESI): 443.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.73 (d, J = 4.3Hz, 1H), 7.91 (d, J = 2.1Hz, 1H), 7.51 (d, J = 4.3Hz, 1H), 7.42 (d, J = 7.8Hz, 1H), 7.07 (s, 1H), 6.86(dd,J=27.3,5.1Hz,2H),3.95(s,2H),1.90-1.76(m,1H),1.45(t,J=4.9Hz,2H),1.22(s,2H),1.18(s,3H),0.93(t,J=6.9Hz,6H).

[0618] Example 79 Preparation of Compound H-79

[0619] Step 1: Dissolve H-76-b (50 mg, 112.47 μmol) in acetic acid (4 mL) and add 3-methyl-1H-pyrazol-5-amine (10.92 mg, 112.47 μmol). Stir at 80°C for 1 hour. Concentrate under reduced pressure to obtain a yellow solid. Purify the solid by combiflash (0-50% EA / PE) to obtain H-79-a (40 mg, yellow solid) in a yield of 74.31%. MS m / z (ESI): 479.1 [M+H]. + .

[0620] Step 2: H-79-a (40 mg, 83.58 μmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (50.03 mg, 438.79 μmol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to yield a yellow solid. The solid was purified by pre-HPLC (preparative column: 21.2 × 250 mm C18 column, system: 10 mM NH4HCO3H2O, wavelength: 254 / 214 nm, gradient: 30%-60% acetonitrile) to obtain H-79 (6.90 mg, purity 95.91%) in a yield of 11.95%. MS m / z (ESI): 379.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.59 (d, J = 4.2Hz, 1H), 7.88 (d, J = 2.0Hz, 1H), 7.39 (d, J = 7.9Hz, 1H), 7.34 (d, J = 4.2Hz, 1H), 6.86 (d, J = 2.1Hz, 1H), 6 .79(d,J=7.9Hz,1H),6.63(s,1H),3.92(s,2H),2.30(s,3H),1.84(dt,J= 12.6, 6.2Hz, 1H), 1.46-1.39 (m, 2H), 1.16 (s, 3H), 0.93 (t, J = 6.3Hz, 6H).

[0621] Example 80 Preparation of Compound H-80

[0622] Step 1: Dissolve H-76-b (100 mg, 224.94 μmol) in acetic acid (5 mL), add 3-(difluoromethyl)-1H-pyrazol-5-amine (29.94 mg, 224.94 μmol), and stir at 80°C for 1 hour. Concentrate under reduced pressure to obtain a yellow solid, which is purified by combiflash (0-50% EA / PE) to afford H-80-a (80 mg, yellow solid) in a yield of 69.12%. MS m / z (ESI): 515.1 [M+H]. + .

[0623] Step 2: H-80-a (80 mg, 155.47 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (53.18 mg, 466.41 μmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to yield a yellow solid. The solid was purified by pre-HPLC (preparative column: 21.2 × 250 mm C18 column, system: 10 mM NH4HCO3H2O, wavelength: 254 / 214 nm, gradient: 30%-60% acetonitrile) to obtain H-80 (21.55 mg, 100% purity) in a yield of 33.44%. MS m / z (ESI): 415.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.81(d,J=4.2Hz,1H),7.88(d,J=2.2Hz,1H),7.60 (d,J=4.2Hz,1H),7.43(d,J=7.9Hz,1H),7.14(s,1H),6.88(d,J=2.3Hz,1H),6.8 2(d,J=8.0Hz,1H),3.93(s,2H),1.98(dd,J=14.8,6.8Hz,1H),1.83(dt,J=12.4, 6.3Hz, 1H), 1.46-1.40 (m, 2H), 1.21 (s, 2H), 1.16 (s, 3H), 0.93 (t, J = 6.6Hz, 6H).

[0624] Example 81 Preparation of Compound H-81

[0625] Step 1: Phthalic anhydride (15 g, 101.27 mmol) and 5-amino-1H-pyrazol-3-ol (10 g, 100.92 mmol) were added to acetic acid (400 mL). The reaction mixture was stirred at 130°C for 2 hours. After cooling to room temperature, a solid precipitated, which was filtered and washed with ether. Drying afforded 2-(3-hydroxy-1H-pyrazol-5-yl)isoindole-1,3-dione (12 g, yellow solid) in a 51.88% yield. MS m / z (ESI): 230.1 [M+H] + .

[0626] Step 2: Add 2-(3-hydroxy-1H-pyrazol-5-yl)isoindole-1,3-dione (4 g, 17.45 mmol) to water (10 mL) and DMF (40 mL), followed by the addition of cesium carbonate (11.37 g, 34.91 mmol) and sodium difluorochloroacetate (6.39 g, 41.89 mmol). The reaction mixture was stirred at 110°C for 22 hours. The mixture was carefully quenched with saturated sodium bicarbonate solution (100 mL) and extracted with dichloromethane (100 mL x 3). The organic phase was washed with saturated brine, dried, filtered, and concentrated under reduced pressure. The concentrate was dissolved in ethanol (10 mL), hydrazine hydrate (1 mL) was added, and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using an eluent system (DCM / MeOH = 1 / 0 to 10 / 1) (214 nm detection) to provide 3-(difluoromethoxy)-1H-pyrazol-5-amine (510 mg, pale yellow solid / liquid) in a 19.60% yield. MS m / z (ESI): 150.1 [M+H] + .

[0627] Step 3: Add 3-(difluoromethoxy)-1H-pyrazol-5-amine (70.43 mg, 472.37 μmol) and H-76-b (140 mg, 314.91 μmol) to acetic acid (10 mL). The reaction mixture was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 1 / 1). H-81-a (85 mg, yellow oil) was obtained in a 50.87% yield. MS m / z (ESI): 531.3 [M+H] + .

[0628] Step 4: H-81-a (85 mg, 160.21 μmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (4 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. After dissolving in dichloromethane, 7N ammonia in methanol was added for neutralization and the mixture was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain H-81 (22.23 mg, yellow solid) in a yield of 32.07%. MS m / z (ESI): 431.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ(ppm)8.71(d,J=4.4Hz,1H),7.91(d,J=2.2Hz,1H),7 .54(d,J=4.5Hz,1H),7.46(d,J=7.9Hz,1H),7.35(t,J=72Hz,1H),6.88(d,J=2 .2Hz,1H),6.81(d,J=8.0Hz,1H),6.61(s,1H),3.92(s,2H),1.82(dd,J=12.7 ,6.2Hz,3H),1.43(dd,J=5.5,2.8Hz,2H),1.16(s,3H),0.92(t,J=6.5Hz,6H).

[0629] Example 82 Preparation of Compound H-82

[0630] Step 1: 2-(3-Hydroxy-1H-pyrazol-5-yl)isoindole-1,3-dione (1.16 g, 5.06 mmol) and 3,3-dimethyl-1-(trifluoromethyl)-1,2-benzoiodooxolane (2 g, 6.06 mmol) were added to DMF (10 mL). The reaction mixture was stirred at 60°C for 6 hours. Saturated sodium bicarbonate solution (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was dried, filtered, and concentrated under reduced pressure. The concentrate was dissolved in ethanol (10 mL), hydrazine hydrate (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The resulting residue was purified by silica gel column chromatography using an eluent system (DCM / MeOH = 1 / 0 to 10 / 1) (monitoring at 214 nm) to provide 3-(trifluoromethoxy)-1H-pyrazol-5-amine (60 mg, pale yellow oil) in a yield of 7.09%. MS m / z(ESI):168.0[M+H] + .

[0631] Step 2: 3-(Trifluoromethoxy)-1H-pyrazol-5-amine (60 mg, 359.09 μmol) and H-76-b (140 mg, 314.91 μmol) were added to acetic acid (10 mL). The reaction mixture was stirred at 80°C for 1 hour and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 1 / 1) to afford H-82-a (50 mg, light yellow oil) in a yield of 28.94%. MS m / z (ESI): 549.3 [M+H] + .

[0632] Step 3: H-82-a (50 mg, 91.15 μmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (4 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. After dissolving in dichloromethane, 7N ammonia in methanol was added for neutralization and the mixture was concentrated under reduced pressure again. The residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain H-82 (17.63 mg, yellow solid) in a yield of 43.09%. MS m / z (ESI): 449.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.79 (d, J = 4.4Hz, 1H), 7.90 (d, J = 2.2Hz, 1H), 7.63 (d, J = 4.4Hz, 1H), 7.45 (d, J = 7.9Hz, 1H), 6.89 (d, J = 2.3Hz, 1 H), 6.83 (dd, J = 10.4, 4.4Hz, 2H), 3.93 (s, 2H), 1.83 (dt, J = 12.3, 6.0Hz, 3H), 1.43 (dd, J = 5.5, 2.9Hz, 2H), 1.16 (s, 3H), 0.92 (t, J = 6.6Hz, 6H).

[0633] Example 83 Preparation of Compound H-83

[0634] Step 1: Dissolve potassium tert-butoxide (6.09 g, 54.30 mmol) in tetrahydrofuran (50 mL), cool to 0°C, and add ethyl 2,2-difluoropropionate (5 g, 36.20 mmol) and acetonitrile (2.23 g, 54.30 mmol). Allow the reaction mixture to warm to room temperature and stir for 16 hours. Add water (100 mL) and adjust the pH to <2 with dilute hydrochloric acid. Extract with ethyl acetate (100 mL x 3). The organic phase is dried, filtered, and concentrated under reduced pressure to yield 4,4-difluoro-3-oxopentanonitrile (4 g, yellow oil) in an 83.02% yield. The crude product is used directly in the next step. MS m / z (ESI): no product ion current.

[0635] Step 2: 4,4-Difluoro-3-oxopentanonitrile (4 g, 30.05 mmol) and hydrazine hydrate (5 mL) were added to ethanol (20 mL). The reaction mixture was stirred at 90°C for 4 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using an eluent system (DCM / MeOH = 1 / 0 to 10 / 1) to afford 3-(1,1-difluoroethyl)-1H-pyrazol-5-amine (1.1 g, yellow oil) in a yield of 24.88%. MS m / z (ESI): 148.1 [M+H] + .

[0636] Step 3: 3-(1,1-Difluoroethyl)-1H-pyrazol-5-amine (99.28 mg, 674.82 μmol) and H-76-b (150 mg, 337.41 μmol) were added to acetic acid (10 mL). The reaction mixture was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 1 / 1) to afford H-83-a (98 mg, yellow oil) in a 54.95% yield. MS m / z (ESI): 529.3 [M+H] + .

[0637] Step 4: H-83-a (98 mg, 185.40 μmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (4 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. After dissolving in dichloromethane, 7N ammonia in methanol was added for neutralization and the mixture was concentrated under reduced pressure again. The residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain H-83 (34.46 mg, yellow solid) in a yield of 43.38%. MS m / z (ESI): 429.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.78 (d, J = 4.3Hz, 1H), 7.91 (d, J = 2.3Hz, 1H), 7.63 (d, J = 4.3Hz, 1H), 7.51 (d, J = 7.9Hz, 1H), 7.11 (s, 1H), 6.93 (d, J = 2. 3Hz,1H),6.85(d,J=8.0Hz,1H),4.01(s,2H),1.90(t,J=20Hz,3H),1.85- 1.77(m,1H),1.53-1.45(m,2H),1.22(s,3H),0.93(dd,J=9.3,6.6Hz,6H).

[0638] Example 84 Preparation of Compound HY-84 (Formate Salt of Compound H-84)

[0639] Step 1: Dissolve H-78-a (150 mg, 276.01 μmol) and zinc cyanide (64.82 mg, 552.02 μmol) in DMF (5 mL), then add Pd(PPh3)4 (159.40 mg, 138.01 μmol). Stir the reaction mixture under microwave conditions at 120°C for 1 hour. Dry the mixture and filter through a column (PE / EA = 2 / 1) to afford H-84-a (70 mg, yellow solid) in a 51.80% yield. MS m / z (ESI): 434.2 [M-56+H]. + .

[0640] Step 2: H-84-a (30 mg, 61.28 μmol) was added to trifluoroacetic acid (2 mL) and dichloromethane (8 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. After neutralization with 7N ammonia in methanol, the mixture was concentrated under reduced pressure again. The residue was purified by preparative liquid chromatography (preparative column: water-sunfire; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254 / 214 nm; gradient: 5% to 30% acetonitrile) to obtain HY-84 (5.15 mg, yellow solid) in a yield of 21.58%. MS m / z (ESI): 390.1 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.93 (d, J = 4.3 Hz, 1H), 8.04 (s, 2H), 7.95 (d, J = 2. 1Hz,1H),7.77(d,J=4.2Hz,1H),7.69(s,1H),7.48(d,J=7.9Hz,1H),7.12(d,J= 2.2Hz,1H),6.95(d,J=8.0Hz,1H),4.27(dd,J=31.2,10.4Hz,2H),1.85-1.74(m ,2H),1.63(dd,J=14.1,5.2Hz,1H),1.41(s,3H),0.95(dd,J=19.7,6.5Hz,6H).

[0641] Example 85 Preparation of Compound HY-85 (Formate Salt of Compound H-85)

[0642] Step 1: H-84-a (30 mg, 61.28 μmol) was dissolved in DMSO (3 mL), followed by the addition of potassium carbonate (8.47 mg, 61.28 μmol) and aqueous H₂O₂ (4.17 mg, 30%). The reaction mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture, and the ethyl acetate layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. The mixture was spin-dried to afford H-85-a (20 mg, yellow solid) in a 64.30% yield. MS m / z (ESI): 452.2 [M-56+H] + .

[0643] Step 2: H-85-a (20 mg, 39.45 μmol) was added to trifluoroacetic acid (2 mL) and dichloromethane (8 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. After neutralization with 7N ammonia in methanol, the mixture was concentrated under reduced pressure again. The residue was purified by preparative liquid chromatography (preparative column: water-sunfire; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-30% acetonitrile) to obtain HY-85 (1.15 mg, yellow solid) in a yield of 4.38%. MS m / z (ESI): 408.1 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ(ppm)8.76(d,J=4.2Hz,1H),8.27(s,1H),7.93(d,J=2.2Hz,1H),7.68-7.60(m,2H),7.52(s,1H),7.22(s,1H),6.9 9(d,J=2.2Hz,1H),6.87(d,J=7.8Hz,1H),4.09(d,J=4.7Hz,2H),2.01-1.97(m,2H),1.54(d,J=5.4Hz,1H),1.28(s,3H),0.94(dd,J=12.0, 6.6Hz, 6H).

[0644] Example 86 Preparation of Compound H-86

[0645] Step 1: Dissolve H-78-a (45 mg, 82.80 μmol), cyclopropylboronic acid (21.34 mg, 248.41 μmol), Pd(dppf)Cl2 (6.06 mg, 8.28 μmol), and potassium carbonate (13.73 mg, 99.36 μmol) in dioxane (8 mL) and water (2 mL). Stir the reaction mixture at 100°C for 16 hours. Dry the mixture and pass it through a column (PE / EA = 2 / 1) to afford H-86-a (35 mg, yellow solid) in an 83.76% yield. MS m / z (ESI): 505.3 [M+H] + .

[0646] Step 2: H-86-a (35 mg, 69.36 μmol) was added to trifluoroacetic acid (2 mL) and dichloromethane (8 mL), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. After neutralization with 7N ammonia in methanol, the mixture was concentrated under reduced pressure again. The residue was purified by preparative liquid chromatography (preparative column: water-sunfire; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-30% acetonitrile) to obtain H-86 (12.09 mg, yellow solid) in a yield of 42.57%. MS m / z (ESI): 405.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.57 (d, J = 4.0Hz, 1H), 7.93 (d, J = 2.0Hz, 1H), 7.44 (d, J = 8.0Hz, 1H), 7.33 (d, J = 4.0Hz, 1H), 7.07 (d, J = 2.0Hz, 1H), 6.90 ( d,J=8.0Hz,1H),6.51(s,1H),4.25(dd,J=28.0,10.0Hz,2H),1.95-1.74(m, 3H),1.64-1.59(m,1H),1.40(s,3H),1.02-0.87(m,8H),0.73-0.67(m,2H).

[0647] Example 87 Preparation of Compound H-87

[0648] Step 1: Dissolve H-78-a (100 mg, 184.01 μmol), triisopropylsilyl acetylene (67.12 mg, 368.02 μmol), Pd(PPh3)2Cl2 (6.46 mg, 9.20 μmol), TEA (93.10 mg, 920.04 μmol), and cuprous iodide (3.50 mg, 18.40 μmol) in DMF (5 mL). Under nitrogen, the reaction mixture was microwaved at 160°C for 1.5 hours. The product was dried and purified by column chromatography (PE / EA = 5 / 1) to afford H-87-a (80 mg, yellow solid) in a 67.41% yield. MS m / z (ESI): 645.2 [M+H]. + .

[0649] Step 2: Dissolve H-87-a (80 mg, 124.05 μmol) in THF (5 mL) and add TBAF (64.87 mg, 248.09 μmol). Stir the reaction mixture at room temperature for 1 hour. Purify the mixture by column chromatography (PE / EA = 1 / 5) to obtain H-87-b (50 mg, yellow solid) in an 82.50% yield. MS m / z (ESI): 489.2 [M+H] + .

[0650] Step 3: H-87-b (50 mg, 102.34 μmol) was added to trifluoroacetic acid (2 mL) and dichloromethane (8 mL), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. After neutralization with 7N ammonia in methanol, the mixture was concentrated under reduced pressure again. The residue was purified by preparative liquid chromatography (preparative column: water-sunfire; system: A: water + 0.045% ammonium bicarbonate, B: acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-60% acetonitrile) to obtain H-87 (15.60 mg, yellow solid) in a yield of 24.47%. MS m / z (ESI): 389.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.75 (d, J = 4.2Hz, 1H), 7.89 (d, J = 2.3Hz, 1H), 7.54 (d, J = 4.2Hz, 1H), 7.41 (d, J = 7.9Hz, 1H), 7.10 (s, 1H), 6.88 ( d,J=2.3Hz,1H),6.82(d,J=8.0Hz,1H),4.44(s,1H),3.93(s,2H),1.89-1.78(m,1H),1.50-1.37(m,2H),1.16(s,3H),0.93(t,J=6.5Hz,6H).

[0651] Example 88 Preparation of Compound H-88

[0652] Step 1: Dissolve H-78-a (50 mg, 92.00 μmol) in DMF (4 mL), add tetrakis(triphenylphosphine)palladium (10.63 mg, 9.20 μmol) and tributyl(1-ethoxyvinyl)tin (33 mg, 92.00 μmol), and react at 100°C overnight under nitrogen. Add a saturated potassium fluoride solution and stir for 1 hour. Extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a yellow solid. Add 3 mL of 3N hydrochloric acid solution and stir for 1 hour. Concentrate under reduced pressure to obtain a yellow solid. The solid was then purified by combiflash (0-40% EA / PE) to afford H-88-a (40 mg, yellow solid) in a yield of 85.82%. MS m / z (ESI): 507.1 [M+H]. + .

[0653] Step 2: H-88-a (40 mg, 78.96 μmol) was dissolved in DCM (4 mL), and trifluoroacetic acid (27.01 mg, 236.88 μmol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to yield a yellow solid. The solid was purified by pre-HPLC (preparative column: 21.2 × 250 mm C18 column, system: 10 mM NH4HCO3H2O, wavelength: 254 / 214 nm, gradient: 30%-60% acetonitrile) to obtain H-88 (7.90 mg, 100% purity) in a yield of 24.61%. MS m / z (ESI): 407.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.80(d,J=4.2Hz,1H),7.92(d,J=2.1Hz,1H),7 .70(d,J=4.2Hz,1H),7.56(d,J=7.9Hz,1H),7.27(s,1H),6.92(d,J=2.2Hz,1 H),6.85(d,J=8.0Hz,1H),3.97(s,2H),2.40(s,3H),1.83(dd,J=12.5,6.6Hz ,1H),1.45(t,J=4.9Hz,2H),1.22(s,2H),1.18(s,3H),0.93(t,J=7.0Hz,6H).

[0654] Example 89 Preparation of Compound H-89

[0655] Step 1: Dissolve H-78-a (45 mg, 82.80 μmol), pyrrolidone (14.09 mg, 165.61 μmol), Pd2(dba)3 (7.58 mg, 8.28 μmol), Xantphos (9.58 mg, 16.56 μmol), and cesium carbonate (32.37 mg, 99.36 μmol) in dioxane (5 mL). Stir the reaction at 110°C for 16 hours. The mixture was then dried and purified by column chromatography (PE / EA = 2 / 1) to afford H-89-a (40 mg, yellow solid) in an 88.21% yield. MS m / z (ESI): 548.1 [M+H] + .

[0656] Step 2: H-89-a (40 mg, 73.04 μmol) was added to trifluoroacetic acid (2 mL) and dichloromethane (8 mL), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. After neutralization with 7N ammonia in methanol, the mixture was concentrated under reduced pressure again. The residue was purified by preparative liquid chromatography (preparative column: water-sunfire; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-30% acetonitrile) to obtain H-89 (11.92 mg, yellow solid) in a yield of 36.20%. MS m / z (ESI): 448.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.64 (d, J = 4.0Hz, 1H), 7.94 (d, J = 2.0Hz, 1H), 7.54 (d, J = 8.0Hz, 1H), 7. 45(d,J=4.0Hz,1H),7.15(s,1H),7.05(d,J=2.0Hz,1H),6.89(d,J=8.0Hz,1H),4.19(dd,J=20.0,10.0 Hz,2H),3.58(t,J=8.0Hz,2H),2.50-2.46(m,2H),2.05-1.95(m,2H),1.84(dt,J=12.0,6.0Hz,1H),1 .69(dd,J=14.0,6.0Hz,1H), 1.58(dd,J=16.0,6.0Hz,1H), 1.36(s,3H), 0.95(dd,J=16.0,6.0Hz,6H).

[0657] Example 92 Preparation of Compound H-92

[0658] Step 1: Dissolve intermediate 27 (550 mg, 2.24 mmol) in DMF (10 mL), add potassium carbonate (928.29 mg, 6.72 mmol), and then add intermediate a (985.24 mg, 3.36 mmol). The reaction mixture was stirred at 80°C for 16 hours. Concentrate under reduced pressure to obtain a yellow solid. The residue was purified by silica gel column chromatography using an eluent system (DCM / MeOH = 1 / 0 to 10 / 1) to obtain H-92-a (0.65 g, 63.26% yield, yellow oil). MS m / z (ESI): 459.1 [M+H] + .

[0659] Step 2: H-92-a (650 mg, 1.42 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. After dissolving in dichloromethane, 7 mol / L ammonia in methanol (5 mL) was added for neutralization, and the mixture was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain H-92 (yellow oil, 80 mg, yield 15.31%, purity 97.24%). MS m / z (ESI): 359.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.51 (d, J = 5.3Hz, 1H), 8.20 (s, 1H), 8.08-7.95 (m, 2H), 7.33 (d, J = 8.0Hz, 1H), 6.88 (d, J = 2.0Hz, 1H), 6.76 ( d,J=8.0Hz,1H),3.88(s,2H),1.81(dt,J=12.5,6.2Hz,1H),1.74-1.58(m,2H),1.39(t,J=9.9Hz,2H),1.13(s,3H),0.90(t,J=6.6Hz,6H).

[0660] Example 93 Preparation of Compound H-93

[0661] Step 1: Dissolve intermediate 29 (420 mg, 1.50 mmol) and intermediate a (527.70 mg, 1.80 mmol) in DMF (10 mL) and add potassium carbonate (517.91 mg, 3.75 mmol). The reaction mixture was stirred at 80°C for 12 hours. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 1 / 4) to obtain H-93-a (200 mg, yellow oil, yield 24.04%). MS m / z (ESI): 494.2 [M+H] + .

[0662] Step 2: H-93-a (200 mg, 405.25 μmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (4 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion, it was concentrated under reduced pressure, dissolved in dichloromethane, neutralized with 7 mol / L ammonia in methanol, and concentrated again under reduced pressure. The resulting residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain H-93 (46 mg, yield 28.85%). MS m / z (ESI): 394.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.35 (d, J = 5.4Hz, 1H), 9.21 (d, J = 5.5Hz, 1H), 8.18 (d, J = 2.3Hz, 1H), 8.10 (d, J = 8.2Hz, 1H), 7.01 (d, J = 2.3Hz ,1H),6.93(d,J=8.2Hz,1H),3.94(s,2H),1.90-1.76(m,J=6.4Hz,1H),1.64(s,2H),1.50-1.36(m,2H),1.16(s,3H),0.92(t,J=6.6Hz,6H).

[0663] Example 94 Preparation of Compound H-94

[0664] Step 1: Under argon, H-78-a (200 mg, 368.02 μmol) and bis-pinacol boronate (186.91 mg, 736.03 μmol) were dissolved in 1,4-dioxane (20 mL), followed by the addition of potassium acetate (108.35 mg, 1.10 mmol) and Pd(dppf)Cl2 (26.71 mg, 36.80 μmol). The reaction was stirred at 100°C for 12 hours. LC-MS confirmed the reaction was complete. The filtrate was filtered and dried under reduced pressure to afford H-94-a (200 mg, 59.06% purity, 32.09% yield). The crude product was used directly in the next step. MS m / z (ESI): 509.3 [M+H] + .

[0665] Step 2: Under argon, 2,2-difluorovinyl 4-methylbenzenesulfonate (95.19 mg, 406.42 μmol) and H-94-a (200 mg, 59.06% purity) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). Pd(dppf)Cl2 (24.58 mg, 33.87 μmol) and potassium carbonate (140.43 mg, 1.02 mmol) were then added. The reaction was stirred at 100°C for 12 hours. LC-MS monitored the reaction completion. The filtrate was filtered, dried under reduced pressure, and purified by column chromatography to afford H-94-b (100 mg, 81.68% yield). MS m / z (ESI): 527.3 [M+H] + .

[0666] Step 3: H-94-b (100 mg, 189.91 μmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion, it was concentrated under reduced pressure to obtain a red oil. 7 mol / L ammonia / methanol solution (3 mL) was added and the mixture was concentrated under reduced pressure to obtain a yellow solid. The residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain H-94 (38.29 mg, 47.28% yield). MS m / z (ESI): 427.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.70 (d, J = 4.2Hz, 1H), 7.89 (d, J = 2.3Hz, 1H), 7.46 (d, J = 4.2Hz, 1H), 7.42 (d, J = 7.9Hz, 1H), 6.87 (dd, J = 6.3, 2.6Hz, 2H), 6 .81(d,J=8.0Hz,1H),5.90(dd,J=27.4,2.5Hz,1H),3.94(s,2H),1.92-1.79 (m,1H),1.74(s,2H),1.51-1.38(m,2H),1.18(s,3H),0.95(t,J=6.5Hz,6H).

[0667] Example 95 Preparation of Compound H-95

[0668] Step 1: Dissolve 6-chloro-2-iodopyridin-3-ol (1 g, 3.91 mmol) in DMF (20 mL), add potassium carbonate (1.08 g, 7.83 mmol), and then add intermediate a (1.72 g, 5.87 mmol). The reaction mixture was stirred at 80°C for 1 hour. Filter and concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 3 / 1) to obtain H-95-a (1.8 g, colorless oil, 98.09% yield). MS m / z (ESI): 469.1 [M+H] + .

[0669] Step 2: H-95-a (1.5 g, 3.20 mmol), tributyl(prop-1-ynyl)stannane (1.05 g, 3.20 mmol), tetrakis(triphenylphosphine)palladium (250.00 mg, 216.35 μmol), and cuprous iodide (72.22 mg, 379.22 μmol) were added to toluene (25 mL). Under argon, the reaction mixture was stirred at 60°C for 1.5 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 3 / 1) to afford H-95-b (1.2 g, yellow oil, 98.45% yield). MS m / z (ESI): 381.2 [M+H] + .

[0670] Step 3: Add H-95-b (150 mg, 393.80 μmol) and cuprous chloride (77.97 mg, 787.59 μmol) to triethylamine (1 mL) and N,N-dimethylacetamide (7 mL). Under argon, in the dark, heat to 130°C and stir for 16 hours. Filter. Concentrate under reduced pressure. Purify the resulting residue by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 10 / 1) to obtain H-95-c (22 mg, colorless oil, 14.67% yield). MS m / z (ESI): 381.1 [M+H] + .

[0671] Step 4: H-95-c (120 mg, 315.04 μmol), 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (160.71 mg, 630.07 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (25.54 mg, 31.50 μmol), and potassium carbonate (87.08 mg, 630.07 μmol) were added to 1,4-dioxane (20 mL) and water (2 mL). Under argon, the reaction mixture was stirred at 115°C for 18 hours. The mixture was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 5 / 1) to afford H-95-d (95 mg, yellow oil, 63.68% yield). MS m / z(ESI):474.3[M+H] + .

[0672] Step 5: H-95-d (50 mg, 91.15 μmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. After dissolving in dichloromethane, 7 mol / L ammonia in methanol was added for neutralization and the mixture was concentrated under reduced pressure again. The residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain H-95 (45 mg, yellow oil, yield 60.07%). MS m / z (ESI): 374.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.81 (d, J = 5.2Hz, 1H), 7.91 (s, 1H), 7.87 (d, J = 4.7Hz, 1H), 7.53 (s, 1H), 7.03 (t, J = 52Hz, 1H),, 6.76-6.64 (m ,3H),6.27(d,J=7.7Hz,1H),3.81(s,2H),1.85-1.75(m,1H),1.52(s,2H),1.41(d,J=5.1Hz,2H),1.13(s,3H),0.91(dd,J=6.5,5.0Hz,6H).

[0673] Example 96 Preparation of Compound H-96

[0674] Step 1: Dissolve intermediate 37 (220 mg, 817.07 μmol), intermediate a (287.65 mg, 980.48 μmol), and potassium carbonate (112.93 mg, 817.07 μmol) in DMF (5 mL) and stir at room temperature overnight. The reaction solution was spin-dried. The resulting residue was purified by silica gel column chromatography using an eluent system (DCM / MeOH = 1 / 0 to 5 / 1) (254 nm detection) to obtain H-96-a (250 mg, green liquid, 63.40% yield). MS m / z (ESI): 483.3 [M+H] + .

[0675] Step 2: H-96-a (200 mg, 414.45 μmol) was dissolved in MeOH (3 mL), and sodium borohydride (62.71 mg, 1.66 mmol) was added. The atmosphere was replaced with nitrogen three times, and the mixture was stirred at room temperature for 1 hour, then refluxed at 60°C overnight. The reaction mixture was cooled to room temperature, quenched with water, and the reaction solution was spin-dried. The resulting residue was purified by silica gel column chromatography using an eluent system (DCM / MeOH = 1 / 0 to 5 / 1) (254 nm detection) to obtain H-96-b (100 mg, yellow solid, 53.08% yield). MS m / z (ESI): 455.3 [M+H] + .

[0676] Step 3: H-96-b (100 mg, 219.99 μmol) was dissolved in dichloromethane (3 mL). DAST (70.92 mg, 439.98 μmol) was added dropwise at -78°C, stirred for 2 hours, and allowed to react overnight at room temperature. The reaction solution was quenched with 10% sodium bicarbonate solution, extracted with DCM, and the organic phase was dried by spin drying. The resulting residue was purified by silica gel column chromatography using an eluent system (DCM / MeOH = 1 / 0 to 8 / 1) (254 nm detection) to obtain H-96-c (20 mg, black oil, 19.91% yield). MS m / z (ESI): 457.3 [M+H] + .

[0677] Step 4: H-96-c (20 mg, 43.81 μmol) was dissolved in DCM (2 mL), trifluoroacetic acid (0.2 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure. After dissolving in dichloromethane, 7 mol / L ammonia in methanol was added for neutralization, and the mixture was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to afford H-96 (1 mg, yellow oil, 6.15% yield). MS m / z (ESI): 357.2 [M+H] + .

[0678] Example 97 Preparation of Compound H-97

[0679] Step 1: Dissolve H-76-b (470 mg, 1.06 mmol) in ethanol (5 mL), add urea (126.98 mg, 2.11 mmol) and sodium ethoxide (215.83 mg, 3.17 mmol), and stir at 100°C for 2 hours. Filter and concentrate under reduced pressure to obtain a yellow solid. The solid was combiflashed (0-60% EA / PE) to obtain H-97-a (250 mg, 53.56% yield, yellow solid). MS m / z (ESI): 442.1 [M+H] + .

[0680] Step 2: H-97-a (200 mg, 452.98 μmol) was dissolved in POCl₃ (5 mL) and stirred at 105°C overnight. The mixture was concentrated under reduced pressure to yield a yellow solid. The solid was added to ice water and extracted with DCM / MeOH (10 / 1). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the crude product. The crude product was purified by pre-HPLC (preparative column: 21.2 × 250 mm C₁₄ column, system: 10 mM NH₄HCO₃H₂O, wavelength: 254 / 214 nm, gradient: 30%-60% acetonitrile) to yield H-97 (1.24 mg, yield 0.7%, purity 93.99%). MS m / z (ESI): 360.1 [M+H] + .

[0681] Examples 98 to 112

[0682] Compounds H-98 to H-112 can be prepared by referring to the methods of the above examples.

[0683] Example 112 Preparation of Compound H-112

[0684] Step 1: Compound 40 (60 mg, 261.77 μmol) and (S)-tert-butyl 4-isobutyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (92.16 mg, 314.12 μmol) were dissolved in DMF (5 mL). K2CO3 (90.45 mg, 654.42 μmol) was added, and the reaction mixture was stirred at 80°C for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a solvent system (petroleum ether / ethyl acetate: 1 / 0 to 1 / 4) to obtain compound H-112-a (60 mg, yellow solid) in a 51.80% yield. MS m / z (ESI): 443.3 [M+H] + .

[0685] Step 2: Compound H-112-a (60 mg, 135.59 μmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion, it was concentrated under reduced pressure, dissolved in dichloromethane, neutralized with 7N ammonia in methanol, and concentrated again under reduced pressure. The residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3H2O; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain compound H-112 (20 mg, yellow solid) in a yield of 43.08%.

[0686] Example 113 Preparation of Compound H-113

[0687] Step 1: Dissolve H-76-b (200 mg, 449.88 μmol) in EtOH (10 mL), add cyclopropanecarboxamide (75.69 mg, 899.75 μmol) and sodium ethoxide (91.84 mg, 1.35 mmol), and stir at 100°C for 2 hours. Filter and concentrate under reduced pressure to obtain a yellow solid. The solid is purified by combiflash (0-60% EA / PE) to obtain H-113-a (150 mg, 71.61% yield, yellow solid). MS m / z (ESI): 466.1 [M+H] + .

[0688] Step 2: H-113-a (150 mg, 322.17 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (110.20 mg, 966.52 μmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to yield a yellow solid. 7N methanolic ammonia solution (5 mL) was added and the mixture was concentrated under reduced pressure to yield the crude product. The crude product was purified by pre-HPLC (preparative column: 21.2 × 250 mm C18 column, system: 10 mM NH4HCO3H2O, wavelength: 254 / 214 nm, gradient: 30%-60% acetonitrile) to yield H-113 (3.95 mg, yield 3.23%, purity 96.17%). MS m / z (ESI): 366.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.75 (dd, J = 18.0, 5.3Hz, 2H), 8.10 (d, J = 2.3Hz, 1H), 7.95 (d, J = 8.1Hz, 1H), 6.98 (d, J = 2.3Hz, 1H), 6.87 (d, J = 8.2Hz, 1H ),3.98(s,2H),2.32-2.19(m,1H),1.98(dd,J=14.5,6.8Hz,1H),1.52-1.3 9(m,2H),1.21(d,J=6.7Hz,8H),1.07(s,1H),0.91(dd,J=10.5,6.6Hz,6H).

[0689] Example 114 Preparation of Compound H-114

[0690] Step 1: Dissolve H-97 (70 mg, 194.52 μmol) in water (0.5 mL), add 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (59.92 mg, 389.05 μmol), potassium carbonate (53.77 mg, 389.05 μmol), Pd(dppf)Cl2 (14.23 mg, 19.45 μmol) and 1,4-dioxane (5 mL), and stir at 100 °C overnight under nitrogen protection. The crude product was concentrated under reduced pressure and purified by Pre-HPLC (preparative column: 21.2×250 mm C18 column, system: 10 mM NH4HCO3H2O, wavelength: 254 / 214 nm, gradient: 30%-60% acetonitrile) to obtain H-114 (0.75 mg, yield: 1.03%, purity 94.31%). MS m / z (ESI): 352.1 [M+H] + .

[0691] Examples 115 to 128

[0692] Compounds H-115 to H-128 can be prepared by referring to the preparation methods of the above examples.

[0693] Test Example 1: AAK1 Enzyme Assay

[0694] 1. Reagents Required for the Experiment

[0695] 2. Boards and instruments required for the experiment

[0696] 3. Experimental Process

[0697] 1. Prepare 1× enzyme reaction buffer: Tris (pH 7.5) 10 mM, MgCl2 10 mM, 0.01% Tween 20, 0.01% Brij TM -35, DTT 2mM;

[0698] 2. Prepare the compound with DMSO to obtain a stock solution corresponding to 100 times the final concentration of the compound to be tested. Then dilute it with 1× buffer to 5 times the final concentration of the compound to be tested, with a DMSO content of 5%, and store it for future use.

[0699] 3. Add 2 μL of the prepared compound and centrifuge at 1000 rpm for 1 min. Add 5% DMSO in 1× buffer to both positive and negative control wells.

[0700] 4. Prepare AAK1 enzyme solution with 1× buffer to a final reaction concentration of 10 nM. Then, add 4 μL of enzyme solution to the positive control wells and compound wells in the reaction plate, and add 4 μL of 1× buffer to the negative control wells.

[0701] 5. Centrifuge at 1000 rpm for 1 min and let stand at room temperature for 30 min;

[0702] 6. Use 1× buffer to prepare a mixed solution of ATP and Micro2peptide with final concentrations of 1μM and 0.1μM respectively, and add 4μL of this mixed solution to the reaction plate;

[0703] 7. Centrifuge at 1000 rpm for 1 min and allow to react at room temperature for 3 h.

[0704] 8. Add 10ul of ATP depletion solution from the ADP-GLO kit;

[0705] 9. Centrifuge at 1000 rpm for 1 minute and let stand at room temperature for 40 minutes;

[0706] 10. Add 20 μL of ADP detection solution from the ADP-GLO kit, centrifuge at 1000 rpm for 1 min, and let stand at room temperature for 30 min;

[0707] 11. Then use Envision to read the fluorescence signal value (Signal) of each well.

[0708] 4. Test Results

[0709] 1. Calculation of compound inhibition rate (Inhibition%)

[0710] Max: positive control well, i.e., the maximum value well (blank control well with enzyme activity); Min: negative control well, i.e., the minimum value well (blank control well with no enzyme activity); Compound: compound well.

[0711] 2. XLFIT 5.0 software (IDBS, UK) was used for fitting, with the logarithm of compound concentration as the X-axis and the inhibition rate as the Y-axis, and the half-maximal inhibitory concentration (IC) of the compound was calculated using a...

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: In formula (I), Z is C or N; When Z is C, R a For hydrogen, deuterium, -NR a0 R b0 , halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 alkyl), halogen (preferably fluorine, chlorine or bromine), 5 or 6 membered heteroaryl, cyano, hydroxy, carboxyl, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8 Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), halogenated C 1-8 Alkoxy (preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkoxy), -C(O)C 1-8 Alkyl (preferably -C(O)C 1-6 Alkyl, more preferably -C(O)C 1-3 alkyl), halo-C(O)C 1-8 Alkyl (preferably halo-C(O)C 1-6 Alkyl, more preferably halo-C(O)C 1-3 alkyl), -C(O)OC 1-8 Alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 Alkyl (preferably -OC(O)C 1-6 Alkyl, more preferably -OC(O)C 1-3 Alkyl), C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl or -C(O)NR a1 R b1 The 5- or 6-membered heteroaryl group is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl; R b is hydrogen, halogen (preferably fluorine or chlorine), halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 alkyl), cyano, hydroxyl, carboxyl, C 3-6 Cycloalkyl, C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8 Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), -C(O)C 1-8 Alkyl (preferably -C(O)C 1-6 Alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 Alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 Alkyl (preferably -OC(O)C 1-6 Alkyl, more preferably -OC(O)C 1-3 alkyl) or -C(O)NR a1 R b1 ; or R a With R b are connected to form a 5- or 6-membered heteroaryl ring, a benzene ring or a 5- or 6-membered heterocycloalkyl ring; wherein, The 5- or 6-membered heteroaryl ring and the phenyl ring are unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl; the 5 or 6 membered heterocycloalkyl ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, oxo, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl; When Z is N, R a For hydrogen, deuterium, -NR a0 R b0 , halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 alkyl), halogen (preferably fluorine or chlorine), cyano, hydroxy, carboxyl, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8 Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), halogenated C 1-8 Alkoxy (preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 Alkoxy), -C(O)C 1-8 Alkyl (preferably -C(O)C 1-6 Alkyl, more preferably -C(O)C 1-3 alkyl), halo-C(O)C 1-8 Alkyl (preferably halo-C(O)C 1-6 Alkyl, more preferably halo-C(O)C 1-3 alkyl), -C(O)OC 1-8 Alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 Alkyl (preferably -OC(O)C 1-6 Alkyl, more preferably -OC(O)C 1-3 Alkyl), C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkenyl, halogenated C 2-6 Alkynyl or -C(O)NR a1 R b1 ; R b does not exist; or R a With R b connected to form a 5- or 6-membered heteroaryl ring, or a 5- or 6-membered heterocycloalkyl ring; wherein the 5- or 6-membered heteroaryl ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)C 1-3 Alkyl, -SC 1-3 Alkyl and C 3-6 Cycloalkyl; the 5 or 6 membered heterocycloalkyl ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, oxo, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl; the C 2-4 The alkenyl group is substituted by 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) or haloC 1-3 Alkyl; the C 2-4 The alkynyl group is substituted by 0 or 1 substituents selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) or haloC 1-3 alkyl; R a0 、R b0 are independently hydrogen, C 1-3 Alkyl, -C(O)C 1-8 Alkyl, -C(O)OC 1-8 Alkyl, halogenated C 1-8 alkyl, 5- or 6-membered heteroaryl, -C(O)C 3-6 Cycloalkyl, -C(O)NR a1 R b1 or -C(O)R, R is a 5- or 6-membered heteroaryl group; or R a0 、R b0 Together with the connected nitrogen atom, it forms a 4- to 6-membered saturated monocyclic heterocyclic ring; the 5- or 6-membered heteroaryl group and the 4- to 6-membered saturated monocyclic heterocyclic ring are each independently unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl; R c 、R d are independently hydrogen, halogen (preferably fluorine or chlorine), halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 alkyl), cyano, hydroxyl, carboxyl, C 3-6 Cycloalkyl, C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), -NR a1 R b1 or C 1-8 Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 alkoxy); U1 and U2 are N or C; and U1 and U2 are not N or C at the same time; Ring A is a 5-membered heteroaryl ring; (R1) n Indicates that the hydrogen on ring A is replaced by n R1, n is 0, 1, 2 or 3; each R1 is the same or different and is independently cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -NR a1 R b1 、C 3-6 Cycloalkyl, C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), C 1-8 Alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy), -C(O)C 1-8 Alkyl (preferably -C(O)C 1-6 Alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 Alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 Alkyl (preferably -OC(O)C 1-6 Alkyl, more preferably -OC(O)C 1-3 alkyl) or -C(O)NR a1 R b1 wherein said C 1-8 Alkyl, the C 1-8 Each alkoxy group is independently unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl; R0 is hydrogen or C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 alkyl); R2 and R3 are each independently C 1-3 Alkyl; or R2, R3 and the connected carbon atom together form C 3-6 cycloalkyl ring; R a1 、R b1 are independently hydrogen, C 1-3 Alkyl or acetyl; or R a1 、R b1 Together with the nitrogen atom to which it is connected, it forms a 4- to 6-membered saturated monocyclic heterocycle; the 4- to 6-membered saturated monocyclic heterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl; The heteroatoms on the heteroaryl or heteroaryl ring, heterocycloalkyl or heterocycloalkyl ring, and saturated monocyclic heterocycle are independently selected from N, O, and S.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound of formula (I) has the structure shown in formula (II):

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: structure A structure selected from one of the following groups:

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: structure A structure selected from one of the following groups:

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Z is C; R a For hydrogen, deuterium, -NR a0 R b0 , halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl), C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), halogenated C 1-8 Alkoxy (preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 alkoxy), halogen (preferably fluorine or chlorine), C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, -C(O)NR a1 R b1 , halogenated-C(O)C 1-8 Alkyl (preferably halo-C(O)C 1-6 Alkyl, more preferably halo-C(O)C 1-3 wherein the 5- or 6-membered heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl; R a0 、R b0 are independently hydrogen, C 1-3 Alkyl, -C(O)C 1-8 Alkyl, -C(O)OC 1-8 Alkyl, halogenated C 1-8 alkyl, 5- or 6-membered heteroaryl, -C(O)C 3-6 Cycloalkyl, -C(O)NR a1 R b1 or -C(O)R, R is a 5- or 6-membered heteroaryl; wherein each occurrence of the 5- or 6-membered heteroaryl is independently unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl; R b is hydrogen or halogen (preferably fluorine or chlorine).

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Z is C; R a For hydrogen, deuterium, -NR a0 R b0 , halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl), C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), halogenated C 1-8 Alkoxy (preferably halogenated C 1-6 Alkoxy, more preferably halogenated C 1-3 alkoxy), halogen (preferably fluorine or chlorine), -C(O)NR a1 R b1 、C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, halo-C(O)C 1-8 Alkyl (preferably halo-C(O)C 1-6 Alkyl, more preferably halo-C(O)C 1-3 wherein the pyrazolyl and thiazolyl groups are each independently unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, C 1-3 Alkyl and halogenated C 1-3 alkyl; R a0 、R b0 are independently hydrogen, C 1-3 Alkyl, -C(O)C 1-8 Alkyl, -C(O)OC 1-8 Alkyl, halogenated C 1-8 Alkyl, pyrazolyl, thiazolyl, -C(O)C 3-6 Cycloalkyl, -C(O)NR a1 R b1 or -C(O)R, R is pyrazolyl or thiazolyl; wherein each occurrence of the pyrazolyl and thiazolyl groups is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen, C 1-3 Alkyl and halogenated C 1-3 alkyl; R b is hydrogen or halogen (preferably fluorine or chlorine).

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Z is C; R a is hydrogen, deuterium, halogen, -NH2, -NHCH3, -NH-difluoroethyl, difluoromethyl, trifluoromethyl, monofluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, monofluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, methyl, ethyl, propyl, isopropyl, -NHCOCH3, -NHCOOCH3, -NHCO-cyclopropyl, -NHCO-thiazole, -NHCO-tetrahydropyrrole, -NHCONHCH2CH3, pyrazolyl, methylpyrazolyl, -NH-methylpyrazole, -NH-thiazole, -NH-methylthiazole, -CONH2, cyclopropyl, difluorocyclopropyl, difluoroacetyl, tetrahydropyrrolyl, oxazolidin-2-onyl or pyrrolidin-2-onyl; R b is hydrogen, fluorine or chlorine.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Z is C; R a With R b connected to form a 5- or 6-membered heteroaryl ring, a benzene ring or a 5- or 6-membered heterocycloalkyl ring; the 5- or 6-membered heteroaryl ring, the benzene ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl; the 5 or 6 membered heterocycloalkyl ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, oxo, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NR a1 R b1 、-SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl.

9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Z is C; R a With R b Connected to form: (i) a benzene ring or a 5- or 6-membered heteroaryl ring selected from the group consisting of a thiophene ring, a furan ring, a thiazole ring, an isothiazole ring, an imidazole ring, an oxazole ring, a pyrrole ring, a pyrazole ring, a triazole ring (including a 1,2,3-triazole ring, a 1,2,4-triazole ring, a 1,2,5-triazole ring, and a 1,3,4-triazole ring), a tetrazole ring, an isoxazole ring, an oxadiazole ring (including a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, a 1,2,5-oxadiazole ring, and a 1,3,4-oxadiazole ring), a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, and a tetrazine ring; the 5- or 6-membered heteroaryl ring and the benzene ring are unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2、-C(O)NH2、-C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 cycloalkyl; or (ii) a 5- or 6-membered heterocycloalkyl ring selected from the group consisting of a tetrahydrofuran ring, a tetrahydrothiophene ring, a tetrahydropyrrole ring, a piperidine ring, a pyrroline ring, an oxazolidine ring, a piperazine ring, a dioxolane ring, a dioxane ring, a morpholine ring, a thiomorpholine ring, a thiomorpholine-1,1-dioxide ring, and a tetrahydropyran ring; the 5- or 6-membered heterocycloalkyl ring being unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from the group consisting of deuterium, oxo, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl and C 3-6 Cycloalkyl.

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Z is N; R a With R b The 5-membered heteroaryl ring is connected to form a 5-membered heteroaryl ring, wherein the 5-membered heteroaryl ring is selected from the group consisting of: thiazole ring, isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring (including 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring), isoxazole ring, oxadiazole ring (including 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring) and thiadiazole ring; the 5-membered heteroaryl ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -C(O)NH2、-C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)C 1-3 Alkyl, -SC 1-3 Alkyl and C 3-6 Cycloalkyl; the C 2-4 The alkenyl group is substituted by 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) or haloC 1-3 Alkyl; the C 2-4 The alkynyl group is substituted by 0 or 1 substituents selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) or haloC 1-3 alkyl.

11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Z is N; R a For hydrogen, deuterium, -NR a0 R b0 , halogenated C 1-3 Alkyl, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, -C(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, C 3-6 Cycloalkyl, C 2-4 Alkenyl or -OC(O)C 1-3 alkyl; R a0 、R b0 are independently hydrogen, C 1-3 Alkyl, -C(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, halogenated C 1-3 Alkyl, -C(O)NR a1 R b1 .

12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: structure Select one of the following structures: where R s1 、R s2 、R s3 、R s4 、R s5 、R s6 、R s7 、R s8 、R s9 、R s10 、R s11 、R s12 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -SC 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)C 1-3 Alkyl or C 3-6 Cycloalkyl; the C 2-4 The alkenyl group is substituted by 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) or haloC 1-3 Alkyl; the C 2-4 The alkynyl group is substituted by 0 or 1 substituents selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) or haloC 1-3 alkyl; m1, m3, m6, and m10 are each independently 0, 1, or 2; m2 is 0, 1, 2, 3, or 4; m4, m7, m8, and m9 are each independently 0 or 1; and m5 is 0, 1, 2, or 3.

13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound of formula (I) is a compound of formula (XII):

14. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound of formula (I) is a compound of formula (III): where R s5 Each occurrence is independently hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, -SO2C 1-3 Alkyl, -S(O)C 1-3 Alkyl, -SC 1-3 Alkyl, -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl)2, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)C 1-3 Alkyl or C 3-6 Cycloalkyl; the C 2-4 The alkenyl group is substituted by 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) or haloC 1-3 alkyl; m3 is 0, 1, or 2; R c 、R d are independently hydrogen, fluorine, chlorine, halogenated C 1-3 Alkyl, cyano, hydroxyl, carboxyl, C 3-6 Cycloalkyl, C 1-3 Alkyl, -NR a1 R b1 or C 1-3 alkoxy; (R1) n Indicates that the hydrogen on ring A is replaced by n R1, n is 0, 1 or 2; each R1 is the same or different and is independently cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -NR a1 R b1 、C 3-6 Cycloalkyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, -C(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl or -C(O)NR a1 R b1 ; R0 is hydrogen or C 1-3 alkyl; R2 and R3 are each independently C 1-3 Alkyl; or R2, R3 and the connected carbon atom together form C 3-6 Cycloalkyl ring.

15. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R2 and R3 are each independently a methyl group; or R2, R3 and the carbon atom to which they are connected together form a cyclopropyl ring.

16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: structure A structure selected from one of the following groups:

17. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: structure A structure selected from one of the following groups:

18. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound of formula (I) is any one of the following compounds:

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and a pharmaceutically acceptable carrier.

20. Use of the compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition according to claim 19 in the preparation of an AAK1 activity inhibitor.

21. The use according to claim 20, characterized in that The AAK1 activity inhibitor is used to treat or control diseases or conditions associated with or mediated by AAK1 activity.

22. The use according to claim 21, characterized in that The disease or condition is pain.

23. A compound represented by formula (IV), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: In formula (IV), Z, U1, U2, ring A, R a 、R b 、R c 、R d 、(R1) n As claimed in claim 1.

24. A compound represented by formula (X), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: In formula (X), R6 is an amino protecting group, U1, U2, ring A, (R1) n , R0, R2, R3 as described in claim 1.

25. A method for preparing the compound of formula (XII), comprising the following steps: S320: Reacting the compound represented by formula (X) with compound A to obtain a compound represented by formula (XI): S420: Deprotecting the compound represented by formula (XI) to obtain the compound represented by formula (XII): Among them, U1, U2, ring A, R c 、R d 、(R1) n , R0, R2, R3 as described in claim 1; (R s5 ) m3 As claimed in claim 12; R6 is an amino protecting group.

26. A method for preparing the compound of formula (I), comprising the following steps: S310: subjecting the compound represented by formula (IV) to an etherification reaction to obtain a compound represented by formula (V): S410: Deprotecting the compound represented by formula (V) to obtain the compound represented by formula (I): Among them, Z, U1, U2, ring A, R a 、R b 、R c 、R d 、(R1) n , R0, R2, R3 as described in claim 1; R5 is an amino protecting group.

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