Heterocyclic-substituted nitrogen-containing heterocyclic derivative, pharmaceutical composition thereof, application and preparation method of heterocyclic-substituted nitrogen-containing heterocyclic 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 obvious selective inhibition of AAK1 kinase activity, weaker hERG inhibition effect and more excellent central nervous system permeability, and has very practical value. # imgabs0 #

Description

Heterocyclic substituted nitrogen-containing heterocyclic derivatives, pharmaceutical compositions thereof, and applications and preparation methods

[0001] This application claims priority to the Chinese patent application filed with the Patent Office of China on January 16, 2023, with application number 202310074810.0 and the invention name “Heterocycle-substituted nitrogen-containing heterocyclic derivatives, their pharmaceutical compositions, applications and preparation methods”, and the Chinese patent application filed with the Patent Office of China on April 24, 2023, with application number 202310451341.X and the invention name “Heterocycle-substituted nitrogen-containing heterocyclic 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 invention relates to the field of medical technology, and in particular to a heterocyclic-substituted nitrogen-containing heterocyclic 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 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-associated chloride channels are involved in nociception and are hypothesized to reduce GABA A Increased cell surface levels of the μ2 receptor, and thus reduced endocytosis, are associated with the analgesic effects of AAK1 inhibitors. Through phenotypic screening of gene knockout mice, Lexicon discovered 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 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 invention is to provide a heterocyclic-substituted nitrogen-containing heterocyclic derivative that selectively inhibits AAK1 kinase activity, has excellent pharmacokinetic parameters, has a weaker hERG inhibitory effect, and has excellent central nervous system penetration.

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

[0007] In formula (I),

[0008] Z1 and Z2 are each independently C or N;

[0009] R a 、R b Each independently represents absence, 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), -SC 1-8 Alkyl (preferably -SC 1-6 Alkyl, more preferably -SC 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 Rb1 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, -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 3-6 Cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl;

[0010] 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 1-3 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, C3-6 Cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl;

[0011] or R a With R b and Z1 and Z2 connected thereto together 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, 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, -SC 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl, saturated or partially unsaturated 3- to 7-membered monocyclic heterocycle, and 6- to 10-membered aryl (preferably phenyl or naphthyl); 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, -SC 1-3 Alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, 5- to 10-membered heteroaryl, saturated or partially unsaturated 3- to 7-membered monocyclic heterocycle, and 6- to 10-membered aryl (preferably phenyl or naphthyl); the C 2-4The alkenyl group is substituted with 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) and 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) and haloC 1-3 alkyl; the 5- to 10-membered heteroaryl, the saturated or partially unsaturated 3- to 7-membered monocyclic heterocycle or the 6- to 10-membered aryl is substituted by 0, 1, 2 or 3 substituents each independently selected from the group consisting of halogen (preferably fluorine, chlorine or bromine), oxo, C 1-6 Alkyl (preferably C 1-3 Alkyl), C 1-6 Alkoxy (preferably C 1-3 Alkoxy), -SC 1-6 Alkyl (preferably -SC 1-3 Alkyl), halogenated C 1-6 Alkyl (preferably halogenated C 1-3 Alkyl), halogenated C 1-6 Alkoxy (preferably 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, and -OC(O)C 1-3 alkyl;

[0012] R c 、R d are each independently hydrogen, deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, -NR a1 R b1 、C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl), halogenated C 1-8 Alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl), -SC 1-8 Alkyl (preferably -SC 1-6 Alkyl, more preferably -SC 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 1-3Alkoxy) or C 3-6 Cycloalkyl;

[0013] Ring A is a benzopyrazole ring, a pyrazine ring, a piperidine ring or a benzopyrrole ring;

[0014] (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), -SC 1-8 Alkyl (preferably -SC 1-6 Alkyl, more preferably -SC 1-3 alkyl), -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, -SC 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;

[0015] R0 is hydrogen or C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-3 alkyl);

[0016] 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;

[0017] R a1 、R b1 Each occurrence is 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, -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 3-6 Cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl.

[0018] In some embodiments, the compound of formula (I) is represented by formula (II):

[0019] In some embodiments, Ring A is

[0020] In some embodiments, the structure Select one of the following structures:

[0021] In some embodiments, (R1) n Indicates that the hydrogen on ring A is replaced by n R1, n is 0 or 1; each R1 is the same or different and is independently C 1-3 Alkyl; wherein the C 1-3 Alkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen.

[0022] In some embodiments, each R1 is the same or different and is independently monofluoromethyl, difluoromethyl, or trifluoromethyl.

[0023] In some embodiments, R1 is cyano, hydroxy, carboxyl, halogen (preferably fluorine, chlorine or bromine), -NH2, C 1-3 Alkyl, 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)NH2; wherein the C 1-3 Alkyl, the C 1-3 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, hydroxy and carboxyl.

[0024] In some embodiments, R1 is halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 Alkoxy.

[0025] In some embodiments, R1 is fluoro, fluoro-C 1-3 Alkyl or fluorinated C 1-3 Alkoxy.

[0026] In some embodiments, R1 is fluoro, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, or trifluoroethoxy.

[0027] In some embodiments, R1 is difluoromethyl.

[0028] In some embodiments, R1 is C 3-6 Cycloalkyl.

[0029] In some embodiments, R1 is cyclopropyl.

[0030] In some embodiments, the structure Select one of the following structures:

[0031] In some embodiments, n is 1.

[0032] In some embodiments, n is 0.

[0033] In some embodiments, Z1 and Z2 are both C;

[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), 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)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 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(C1-3 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;

[0035] Preferably, R a For hydrogen, halogen, C 1-8 Alkyl, halogenated C 1-8 Alkyl or C 3-6 Cycloalkyl;

[0036] 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 ;

[0037] Preferably, R b is hydrogen;

[0038] or R a With R b and Z1 and Z2 connected thereto together 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, 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, -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 3-6 cycloalkyl, 5- to 10-membered heteroaryl, saturated or partially unsaturated 3- to 7-membered monocyclic heterocycle, and 6- to 10-membered aryl (preferably phenyl or naphthyl); 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, C 3-6 Cycloalkyl, 5- to 10-membered heteroaryl, saturated or partially unsaturated 3- to 7-membered monocyclic heterocycle, and 6- to 10-membered aryl (preferably phenyl or naphthyl); the C 2-4 The alkenyl group is substituted with 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) and 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) and haloC 1-3 alkyl; the 5- to 10-membered heteroaryl, the saturated or partially unsaturated 3- to 7-membered monocyclic heterocycle or the 6- to 10-membered aryl is substituted by 0, 1, 2 or 3 substituents each independently selected from the group consisting of halogen (preferably fluorine, chlorine or bromine), oxo C 1-6 Alkyl (preferably oxo-C 1-3 Alkyl), C 1-6 Alkoxy (preferably C 1-3 Alkoxy), -SC 1-6 Alkyl (preferably -SC 1-3Alkyl), halogenated C 1-6 Alkyl (preferably halogenated C 1-3 Alkyl), halogenated C 1-6 Alkoxy (preferably 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 and -OC(O)C 1-3 alkyl.

[0039] In some embodiments, Z1 and Z2 are both C;

[0040] 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, -C(O)NR a1 R b1 or 5- or 6-membered heteroaryl; 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;

[0041] R b is hydrogen or halogen (preferably fluorine or chlorine).

[0042] In some embodiments, Z1 and Z2 are both C;

[0043] 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, -C(O)NR a1 R b1 , 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;

[0044] R b is hydrogen or halogen (preferably fluorine or chlorine).

[0045] In some embodiments, Z1 and Z2 are both C;

[0046] 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, cyclopropyl, -NHCOCH3, -NHCOOCH3, -NHCO-cyclopropyl, -NHCO-thiazole, -NHCO-tetrahydropyrrole, -NHCONHCH2CH3, pyrazolyl, methylpyrazolyl, -NH-methylpyrazole, -NH-thiazole, -NH-methylthiazole or -CONH2;

[0047] R b is hydrogen, fluorine or chlorine.

[0048] In some embodiments, Z1 and Z2 are both C; R a is hydrogen, halogen, difluoromethyl or cyclopropyl; R bis hydrogen, fluorine or chlorine.

[0049] In some embodiments, Z1 and Z2 are both C; R a is hydrogen, halogen or difluoromethyl; R b is hydrogen, fluorine or chlorine.

[0050] In some embodiments, Z1 and Z2 are both C; R a is fluorine, chlorine, bromine, methyl, cyclopropyl, trifluoromethyl, difluoromethyl or monofluoromethyl; R b For hydrogen.

[0051] In some embodiments, Z1 is C, Z2 is N;

[0052] 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, 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)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] R b does not exist;

[0054] or R a With R band Z1 and Z2 connected thereto together 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, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl, saturated or partially unsaturated 3- to 7-membered monocyclic heterocycle, and 6- to 10-membered aryl (preferably phenyl or naphthyl); 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, C 3-6 Cycloalkyl, 5- to 10-membered heteroaryl, saturated or partially unsaturated 3- to 7-membered monocyclic heterocycle, and 6- to 10-membered aryl (preferably phenyl or naphthyl); the C 2-4 The alkenyl group is substituted with 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) and 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) and haloC 1-3alkyl; the 5- to 10-membered heteroaryl, the saturated or partially unsaturated 3- to 7-membered monocyclic heterocycle or the 6- to 10-membered aryl is substituted by 0, 1, 2 or 3 substituents each independently selected from the group consisting of halogen (preferably fluorine, chlorine or bromine), oxo C 1-6 Alkyl (preferably oxo-C 1-3 Alkyl), C 1-6 Alkoxy (preferably C 1-3 Alkoxy), -SC 1-6 Alkyl (preferably -SC 1-3 Alkyl), halogenated C 1-6 Alkyl (preferably halogenated C 1-3 Alkyl), halogenated C 1-6 Alkoxy (preferably 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, and -OC(O)C 1-3 alkyl.

[0055] In some embodiments, Z1 is C, Z2 is N;

[0056] R a With R b and Z1 and Z2 connected thereto together form a 5-membered heteroaryl ring, wherein the 5-membered heteroaryl ring is selected from: 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, a 1,3,4-triazole 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, a 1,3,4-oxadiazole ring) and a 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、-NC(O)(CH2)3、-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(O)C 1-3 Alkyl, -SC 1-3 Alkyl and C 3-6 Cycloalkyl; the C 2-4 The alkenyl group is substituted with 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) and 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) and haloC 1-3 alkyl.

[0057] In some embodiments, Z1 is C, Z2 is N;

[0058] R a With R b and Z1 and Z2 connected thereto together form a 5-membered heteroaryl ring, wherein the 5-membered heteroaryl ring is a pyrazole ring; the pyrazole ring is unsubstituted or substituted by 1 or 2 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、-NC(O)(CH2)3、-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 with 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) and 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) and haloC 1-3 alkyl.

[0059] In some embodiments, Z1 is C, Z2 is N; R a With R b and Z1 and Z2 connected thereto together form a 5-membered heteroaryl ring, wherein the 5-membered heteroaryl ring is a pyrazole ring; the pyrazole ring is unsubstituted or substituted by 1 or 2 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 and -SC 1-3 Alkyl; the C 2-4 The alkenyl group is substituted with 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) and 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) and haloC 1-3 alkyl.

[0060] In some embodiments, Z1 is C, Z2 is N; R a With R b and Z1 and Z2 connected thereto together form a 5-membered heteroaryl ring, wherein the 5-membered heteroaryl ring is a pyrazole ring; the pyrazole ring is unsubstituted or substituted by 1 or 2 substituents each independently selected from the group consisting of deuterium, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy and -SC 1-3 alkyl.

[0061] In some embodiments, Z1 is C, Z2 is N; R a With R b and Z1 and Z2 to which they are connected together form a 5-membered heteroaryl ring, wherein the 5-membered heteroaryl ring is a pyrazole ring; the pyrazole ring is unsubstituted or substituted by 1 or 2 substituents each independently selected from the group consisting of deuterium, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, -SCH3 and -SCH2CH3.

[0062] In some embodiments, Z1 is C, Z2 is N; R a With R band Z1 and Z2 connected thereto together form a 5-membered heteroaryl ring, wherein the 5-membered heteroaryl ring is a pyrazole ring; the pyrazole ring is unsubstituted or substituted by 1 or 2 substituents each independently selected from the group consisting of bromine, difluoromethyl, and trifluoromethyl.

[0063] In some embodiments, Z1 is C, Z2 is N; R a With R b and Z1 and Z2 connected thereto together form a 5-membered heteroaryl ring, wherein the 5-membered heteroaryl ring is a pyrazole ring; the pyrazole ring is unsubstituted or substituted by one substituent independently selected from the group consisting of bromine and trifluoromethyl.

[0064] In some embodiments, the structure for:

[0065] Among them, R s1 Each occurrence is independently 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, -NC(O)(CH2)3, -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 with 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) and 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) and haloC 1-3 alkyl;

[0066] m1 is 0, 1, or 2.

[0067] In some embodiments, R s1 Each occurrence is independently deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3Alkyl, 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, -NC(O)(CH2)3, -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 with 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) and haloC 1-3 alkyl;

[0068] m1 is 0, 1, or 2.

[0069] In some embodiments, R s1 Each occurrence is independently 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、-NC(O)(CH2)3、-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, or cyclohexyl;

[0070] m1 is 0, 1, or 2.

[0071] In some embodiments, R s1Each occurrence is independently deuterium, halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy;

[0072] m1 is 0, 1, or 2.

[0073] In some embodiments, R s1 Each occurrence is independently bromo or trifluoromethyl;

[0074] m1 is 0, 1, or 2.

[0075] In some embodiments, Z1 is C, Z2 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 3-6 Cycloalkyl, -C(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl or -OC(O)C 1-3 alkyl;

[0076] 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 ;

[0077] Preferably, R a is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoropropyl, difluoropropyl, trifluoropropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, monofluoropropoxy, difluoropropoxy or trifluoropropoxy;

[0078] Preferably, R a is hydrogen, fluorine, chlorine, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl or cyclopropyl;

[0079] Preferably, R a is hydrogen, fluorine, chlorine, methyl, monofluoromethyl, difluoromethyl or trifluoromethyl.

[0080] In some embodiments, Z1 is C, Z2 is N; Ra For hydrogen, deuterium, halogen, fluorinated C 1-3 Alkyl, C 1-3 Alkyl, fluorinated C 1-3 Alkoxy, cyclopropyl or C 1-3 Alkoxy.

[0081] In some embodiments, Z1 is C, Z2 is N; R a is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoropropyl, difluoropropyl, trifluoropropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, monofluoropropoxy, difluoropropoxy or trifluoropropoxy.

[0082] In some embodiments, Z1 is C, Z2 is N; R a is methyl, cyclopropyl, trifluoromethyl, difluoromethyl or monofluoromethyl.

[0083] In some embodiments, the structure A structure selected from one of the following groups:

[0084] In some embodiments, the structure A structure selected from one of the following groups:

[0085] In some embodiments, the structure A structure selected from one of the following groups:

[0086] In some embodiments, the structure A structure selected from one of the following groups:

[0087] In some embodiments, in the above structural formulas, the 5- to 10-membered heteroaryl groups in each group are independently selected from the group consisting of pyridyl, indazolyl, 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, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazine d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, 1,8-naphthyridinyl, 1,7-naphthyridinyl, 1,6-naphthyridinyl, 1,5-naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0088] In some embodiments, in the above structural formulas, the saturated or partially unsaturated 3- to 7-membered monocyclic heterocycles in each group are independently selected from the group consisting of: oxetane, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, piperidinyl, pyrrolinyl, oxazolidinyl, piperazinyl, dioxolanyl, dioxane, morpholinyl, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetrahydropyranyl, azetidin-2-one, oxetane-2-one, pyrrolidine-2-one, pyrrolidine-2,5-dione, piperidin-2-one, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, tetrahydro-2H-pyran-2 oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl, 2-oxazolidinyl,

[0089] 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.

[0090] 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.

[0091] In some embodiments, R a With R b and the 5- or 6-membered heterocycloalkyl ring formed together with Z1 and Z2 connected thereto is 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.

[0092] 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.

[0093] 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.

[0094] In some embodiments, R d is hydrogen or halogen. Further, R d is hydrogen, fluorine or chlorine.

[0095] In some embodiments, R c 、R d are each independently hydrogen, fluorine or chlorine.

[0096] In some embodiments, R c For hydrogen.

[0097] In some embodiments, R d For hydrogen.

[0098] In some embodiments, R0 is hydrogen or C 1-3 Further, R0 is hydrogen or methyl.

[0099] In some embodiments, R2 is methyl.

[0100] In some embodiments, R3 is methyl.

[0101] In some embodiments, R2, R3 and the carbon atom to which they are attached together form a cyclopropyl ring.

[0102] In some embodiments, the compound of formula (I) is any one of the following compounds:

[0103] The second aspect of the present invention provides a pharmaceutical composition comprising the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0104] The third aspect of the present invention provides use of the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition according to the second aspect of the present invention in the preparation of an AAK1 activity inhibitor.

[0105] In some embodiments, the AAK1 activity inhibitor is used to treat or manage a disease or condition associated with or mediated by AAK1 activity.

[0106] 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.

[0107] A fourth aspect of the present invention provides a method for treating or managing 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.

[0108] The fifth aspect of the present invention provides a compound represented by formula (III), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0109] In formula (III), Z1, Z2, R a 、R b 、R c 、R d As described in the instructions;

[0110] R4 is OH, OTs, OMs, C 1-6 Alkoxy or halogen;

[0111] Select from any of the following structures:

[0112] In some embodiments, the compound of formula (III) is any one of the following compounds:

[0113] A sixth aspect of the present invention provides a method for preparing a compound represented by formula (IV), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, comprising the following steps:

[0114] S100: performing a coupling reaction between the compound represented by formula (IV-A) and the compound represented by formula (IV-B) to obtain the compound represented by formula (IV);

[0115] in,

[0116] Z1, Z2, ring A, Ra, Rb, Rc, Rd, (R1) n , R4 as described in the instructions;

[0117] R G1 、R G2 A pair of groups that can undergo coupling reaction.

[0118] It is understandable that the compound of formula (IV) 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.

[0119] It is understandable that the compound of formula (IV) obtained in step S100 can be modified with respect to R4 by methods well known in the art, for example, converting -OH into a halogen, converting an alkoxy group into a hydroxyl group, activating the hydroxyl group into a sulfonate, 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 all of them are within the scope of protection of this application.

[0120] In some embodiments, R G1 、RG2 A pair of groups that can undergo Suzuki coupling reaction.

[0121] 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).

[0122] In some embodiments, R G1 is Br, Cl or I; R G2 is (HO)2B- or a borate group (including a pinacol borate group).

[0123] In some embodiments, R G2 is Br, Cl or I; R G1 is (HO)2B- or a borate group (including a pinacol borate group).

[0124] In some embodiments, R G1 、R G2 A pair of groups that can undergo Stille coupling reaction.

[0125] In some embodiments, R G1 and R G2 One of them is halogen and the other is -SnBu3 or -SnMe3.

[0126] In some embodiments, R G1 is Br, Cl or I; R G2 is -SnBu3 or -SnMe3.

[0127] In some embodiments, R G2 is Br, Cl or I; R G1 is -SnBu3 or -SnMe3.

[0128] In some embodiments, step S100 includes the following steps:

[0129] S110: Mixing and reacting the compound represented by formula (IV-A), the compound represented by formula (IV-B), a solvent, a catalyst and a base to obtain the compound represented by formula (IV).

[0130] In some embodiments, in step S110, 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.

[0131] In some embodiments, in step S110, the solvent is a mixed solvent consisting of 1,4-dioxane and water; further, the volume ratio of 1,4-dioxane and water is about (2-12):1; further, the volume ratio of 1,4-dioxane and water can be 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1 or 12:1.

[0132] In some embodiments, in step S110, the catalyst is a palladium catalyst; further, the palladium catalyst is selected from: palladium 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.

[0133] In some embodiments, in step S110, the base is an inorganic base or an organic base; further, the base is selected from: 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.

[0134] In some embodiments, in step S110, the reaction temperature is 0-180°C; further, the reaction temperature is 20°C-150°C; further, the reaction temperature is 30-120°C.

[0135] In some embodiments, step S110 is reacted under microwave conditions.

[0136] The seventh aspect of the present invention provides a method for preparing the compound of formula (I) according to the first aspect of the present invention, comprising the following steps:

[0137] S210: subjecting the compound represented by formula (IV) to an etherification reaction to obtain a compound represented by formula (V):

[0138] Among them, Z1, Z2, ring A, R a 、R b 、Rc 、R d 、(R1) n , R0, R2, R3 are as described in the specification,

[0139] R5 is an amino protecting group;

[0140] S310: Deprotecting the compound represented by formula (V) to obtain the compound represented by formula (I):

[0141] Among them, Z1, Z2, ring A, R a 、R b 、R c 、R d 、(R1) n , R0, R2, R3 are as described in the specification;

[0142] R5 is an amino protecting group.

[0143] It is understandable that the compound of formula (V) obtained in step S210 can be modified by methods well known in the art (such as modifying the amino group by an acylation reaction (such as converting the amino group into an amide, or modifying the carboxyl group into an amide by 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.

[0144] 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.

[0145] In some embodiments, in step S210, 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).

[0146] In some embodiments, in step S210, the base is an inorganic base or an organic base; further, the base is selected from: 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, sodium hydride and combinations thereof; further, the base is potassium carbonate, sodium carbonate, potassium acetate, sodium hydride or cesium carbonate.

[0147] In some embodiments, in step S210, the reaction temperature is -20-150°C; further -10-130°C; further 70-120°C or -10-40°C.

[0148] In some embodiments, the reaction in step S310 is a common reaction for removing amino protecting groups (for example, 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.

[0149] The eighth aspect of the present invention provides a compound of formula (I) prepared by the method for preparing the compound of formula (I) according to the seventh aspect of the present invention.

[0150] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention 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.

[0151] After extensive and in-depth research, the inventors unexpectedly discovered a class of heterocyclic-substituted nitrogen-containing heterocyclic derivatives that exhibit remarkable selectivity in inhibiting AAK1 kinase 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 discovery, the inventors completed the present invention. DETAILED DESCRIPTION

[0152] Definition of terms

[0153] In order to more clearly understand the technical content of the present invention, the terms of the present invention are further explained below.

[0154] "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.

[0155] "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.

[0156] "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.

[0157] "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

[0158] "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.

[0159] "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.

[0160] "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 the present invention, 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, of which 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, benzothiadiazolyl, indanyl, purinyl, Pyrido[3,2-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, 1,8-naphthyridinyl, 1,7-naphthyridinyl, 1,6-naphthyridinyl, 1,5-naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. "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.

[0161] "Fused" refers to structures in which two or more rings share one or more bonds.

[0162] "Alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined above. Preferably C 1-8 Alkoxy, more preferably C 1-6Alkoxy, 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.

[0163] "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.

[0164] "A bond" means that the two groups connected thereto are connected by one covalent bond.

[0165] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0166] "Halo" refers to a group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms are replaced by a halogen.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] "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, and the structure of "cyclopropylene" is:

[0171] "Ms" refers to methylsulfonyl, and "Ts" refers to p-toluenesulfonyl.

[0172] "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, it is a 3- to 6-membered saturated or partially unsaturated monocyclic heterocycle having 3 to 6 ring atoms, of which 1 or 2 ring atoms are the above-mentioned heteroatoms. More preferably, it is a 5- to 6-membered saturated or partially unsaturated monocyclic heterocycle having 5 to 6 ring atoms, of which 1 or 2 ring atoms are the above-mentioned heteroatoms. Most preferably, it is a 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.

[0173] "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.

[0174] Unless otherwise defined, the "substituents independently selected from..." described in the present invention means that when more than one hydrogen on a group is replaced by a substituent, the substituents may be the same or different, and the substituents selected are independently of each other.

[0175] Unless otherwise defined, the phrase "...same or different, and each independently is..." in the present invention means that when there are more than one identical substituent group in the general formula, the substituent group 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).

[0176] 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 C1-6 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.

[0177] In the present invention, when two or more “preferably” appear in one embodiment, any two “preferably” may be independent of each other.

[0178] In the present invention, 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.

[0179] Each type of substituent group described herein above can itself be substituted with the groups described herein.

[0180] 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:

[0181] Wherein "Sub" represents various substituents described herein; Indicates the connection position with other atoms.

[0182] 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.

[0183] In the present invention, the term "about" is defined as close to as understood by those of ordinary skill in the art. In a non-limiting embodiment, the term is defined as within 10%, preferably within 5%, more preferably within 1%, and further preferably within 0.5%.

[0184] Pharmaceutical composition

[0185] Generally, the compounds of the present invention 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 invention 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 using common pharmaceutical methods. The above carriers need to be compatible with the active compound or other excipients. "Pharmaceutically acceptable carrier" refers to a non-toxic, inert, solid, semi-solid substance or liquid filling machine, diluent, encapsulating material or auxiliary preparation or any type of excipient that is compatible with the patient, preferably a mammal, more preferably a human, and is suitable for delivering the active agent to the target site without terminating the activity of the agent.

[0186] "Active substance of the present invention" or "active compound of the present invention" refers to the compound of formula (I) of the present invention, or a pharmaceutically acceptable salt, or a solvate, or a stereoisomer, or a prodrug thereof, which has higher AAK1 selective inhibitory activity.

[0187] The compositions of the present invention are formulated, dosed and administered in a manner consistent with standard 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.

[0188] "Therapeutically effective amount" refers to the amount of the compound of the present invention that will elicit 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.

[0189] The therapeutically effective amount of the compound of the present invention or its pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug contained in the pharmaceutical composition or pharmaceutical use composition of the present invention is preferably 0.1 mg / kg to 5 g / kg (body weight).

[0190] "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.

[0191] "Treatment" refers to alleviating, slowing the progression of, diminishing, preventing, or maintaining an existing disease or condition (e.g., cancer, pain, etc.). Treatment also includes curing, preventing the development of, or alleviating to some extent, one or more symptoms of a disease or condition.

[0192] 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.

[0193] "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.

[0194] Asymmetric centers may be present in the compounds of the present invention. It should be understood that the present invention encompasses all stereochemically 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 to a mixture of diastereoisomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the 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 different separable stable conformations. Torsional asymmetry due to restricted rotation around an asymmetric single bond, for example due to steric hindrance or ring strain, can allow for 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, as well as enantiomers and diastereomers thereof. Similarly, references to intermediates are intended to encompass their salts where the context permits.

[0195] Preparation method

[0196] The present invention provides methods for preparing compounds of formula (I), which can be synthesized using standard synthetic techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein. The solvents, temperatures, and other reaction conditions provided herein can be varied according to the skill in the art. The reactions can be used sequentially to provide compounds of the present invention, or they can be used to synthesize fragments that are subsequently added by the methods described herein and / or methods known in the art.

[0197] The compound described in the present invention 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 the present invention can be synthesized or can be obtained from commercial sources.The compound described in the present invention 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 the compound disclosed in the present invention 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 present invention.

[0198] The main advantages of the present invention include:

[0199] Provides a series of novel heterocyclic substituted nitrogen-containing heterocyclic derivatives, which selectively inhibit AAK1 kinase activity and have excellent in vivo pharmacokinetic activity and weak hERG inhibition. The inhibitory activity IC of AAK1 kinase is50 The values ​​ranged from 0.1 nM to 100 nM, and the IC values ​​of some compounds were 50 The values ​​ranged from 0.1 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. In addition, these compounds have better central nervous system penetration, and thus have potential excellent therapeutic effects on central nervous system diseases mediated by AAK1 activity.

[0200] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, 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 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 methods and materials similar or equivalent to those described herein may be applied to the present invention.

[0201] 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.

[0202] FA: formic acid, THF: tetrahydrofuran, DCM: dichloromethane, DMSO: dimethyl sulfoxide, PE: petroleum ether, EA: ethyl acetate, DMF: N,N-dimethylformamide, DMA: N,N-dimethylacetamide, TFA: trifluoroacetic acid, K2CO3: potassium carbonate, Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, PdCl2(dppf): [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, NH4HCO3: ammonium bicarbonate, H2O: water, LDA: lithium diisopropylamide.

[0203] Unless otherwise specified, percentages used in the present invention refer to percentages by mass for solid-liquid mixtures and solid-solid mixtures, and percentages by volume for liquid-liquid mixtures. Unless otherwise specified, the solvent used is water.

[0204] As used herein, room temperature refers to about 20-30°C.

[0205] As used herein, "overnight" refers to about 10 h to 16 h.

[0206] Preparation of intermediate a

[0207] 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, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (4S)-tert-butyl-4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (26 g, light yellow oil, yield: 98.56%). MS m / z (ESI): 222.1 [M-56+H] + .

[0208] 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. The reaction is stirred at room temperature 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. The mixture is then extracted with ethyl acetate (150 mL x 3). The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 10 / 1) to afford Intermediate a (14.5 g, colorless oil, yield: 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).

[0209] Preparation of intermediate b

[0210] Step 1: Under ice-cooling, (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 an eluent system (PE / EA = 1 / 0 to 2 / 1) to afford Intermediate b (22 g, white solid, yield: 62.39%). MS m / z (ESI): 176.1 [M-56+H] + .

[0211] Preparation of intermediate Z1

[0212] Step 1: 4-Bromopyrimidin-2-amine (1.5 g, 8.62 mmol) was dissolved in THF (20 mL), followed by the addition of isoamyl nitrite (3.03 g, 25.86 mmol), diiodomethane (3.46 g, 12.93 mmol), and cuprous iodide (492.55 mg, 2.59 mmol). The reaction was stirred at 80°C for 6 hours. LC-MS monitored the reaction completion. The mixture was cooled to room temperature and stirred with aqueous sodium sulfite for half an hour. The mixture was extracted with ethyl acetate, and the organic phase was evaporated to dryness under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 2 / 1) to afford Z1-1 (1.5 g, white solid, 48.86% yield). MS m / z (ESI): 284.8 [M+H] + .

[0213] Step 2: Dissolve Z1-1 (500 mg, 1.76 mmol) in THF (10 mL), cool to -78°C, and add methylmagnesium chloride (3 M, 877.56 μL) dropwise. The reaction is stirred at -78°C for 0.5 h. DMF (846.71 mg, 11.58 mmol, 896.93 μL) is added and the mixture is gradually warmed to room temperature. Stir for 2 h. The reaction is monitored for completion by LC-MS. The mixture is quenched with aqueous solution, extracted with ethyl acetate, and the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. Purification by silica gel column chromatography using an eluent system (PE / EA = 2 / 1) affords Z1-2 (100 mg, 30.57% yield). MS m / z (ESI): 186.9 [M+H] + .

[0214] Step 3: Z1-2 (550 mg, 2.94 mmol) was dissolved in THF (6 mL), and N-ethyl-N-(trifluorosulfanyl)ethanamine (711.15 mg, 4.41 mmol) was added. The reaction was stirred at 23°C for 12 hours. The reaction was monitored for completion by LC-MS. The reaction was quenched with water, and the organic phase was washed with aqueous sodium bicarbonate, washed with water, dried, and evaporated to dryness under reduced pressure to afford the crude product. The crude product was purified by column chromatography (petroleum ether containing 35% ethyl acetate) to afford Z1-3 (400 mg, 65.07% yield).

[0215] Step 4: Under argon protection, 7-bromo-4-methoxy-1H-indazole (100 mg, 440.42 μmol) and bis-pinacol boronate (167.76 mg, 660.63 μmol) were dissolved in dioxane (5 mL), and then Pd(dppf)Cl2 (31.96 mg, 44.04 μmol) and potassium acetate (86.44 mg, 880.83 μmol) were added. The reaction was stirred at 100°C for 12 hours. The reaction was monitored for completion by LC-MS. Filtered, the filtrate was used directly in the next step. The resulting Z1-A (120 mg, 99.40% yield) was obtained. MS m / z (ESI): 275.0 [M+H] + .

[0216] Step 5: Under argon, Z1-3 (90 mg, 430.64 μmol) and Z1-A (118.05 mg, 430.64 μmol) were dissolved in water (1 mL) and dioxane (8 mL). Pd(dppf)Cl2 (31.25 mg, 43.06 μmol) and K2CO3 (118.86 mg, 861.28 μmol) were then added. The reaction was stirred at 100°C for 12 hours. The reaction was monitored for completion by LC-MS. The product was evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (petroleum ether containing 35% ethyl acetate) to afford Z1-4 (85 mg, 71.45% yield). MS m / z (ESI): 276.7 [M+H] + .

[0217] Step 6: Dissolve Z1-4 (85 mg, 307.70 μmol) in aqueous hydrobromic acid (5 mL, 48%). The reaction was stirred at 100°C for 12 hours. The reaction was monitored for completion by LC-MS. The solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (dichloromethane containing 15% methanol) to obtain intermediate Z1 (50 mg, 61.97% yield). MS m / z (ESI): 263.0 [M+H] + .

[0218] Preparation of intermediate Z2

[0219] Step 1: Dissolve 2-difluoromethyl-4-bromopyridine (100 mg, 0.45 mmol) in dioxane (5 mL). Add pinacol diboronate (171 mg, 0.67 mmol), potassium acetate (110 mg, 1.12 mmol), and Pd(dppf)Cl2 (32.6 mg, 0.045 mmol) in this order. Replace the atmosphere with argon three times and stir in an oil bath at 100°C for 5 hours. Cool to room temperature, filter the reaction mixture, dilute with water (5 mL), and extract with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification was performed using a reverse phase column (1% OFA) to obtain 2-difluoromethylpyridine-4-boronic acid (65 mg, yellow oil, yield: 78.3%). MS m / z (ESI): 174.2 [M+H] + .

[0220] Step 2: Place methyl 3-amino-6-bromopyrazine-2-carboxylate (20 g, 0.086 mol) in a clean 3-L three-necked flask, add 120 mL of sulfuric acid, cool to 0°C, slowly add sodium nitrite (12 g, 0.17 mol) in portions, maintain stirring at 0°C for 30 min, pour the mixture into 1 L of methanol, heat under reflux for 5 h, and monitor by LCMS. The reaction mixture is cooled to room temperature and concentrated under reduced pressure to remove the methanol. The residual solution is adjusted to pH 7 with saturated sodium bicarbonate and extracted with ethyl acetate (300 mL x 3). The organic phases are combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. Purification by silica gel column chromatography with an eluent (PE / EA = 5:1) affords Z2-1 (6.4 g, white solid, yield: 30%). MS m / z (ESI): 246.9 [M+H] + .

[0221] Step 3: Z2-1 (5.4 g, 21.8 mmol) was placed in a clean 250 mL three-necked flask, and 80 mL of dichloromethane was added. The temperature was cooled to -78°C, and diisobutylaluminum hydride (44 mL, 43.7 mmol) was added dropwise. After the addition was complete, the mixture was stirred at -78°C for 1.5 hours. LCMS sampling indicated that the reaction was complete. The reaction mixture was poured directly into 100 mL of saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification was performed by silica gel column chromatography using an eluent (PE / EA = 2:1) to obtain Z2-2 (3.7 g, brown solid, yield: 78%). MS m / z (ESI): 218.1 [M+H] + .

[0222] Step 4: Dissolve Z2-2 (100 mg, 0.46 mmol) in dichloromethane (3 mL) and heat in an ice-water bath. Add diethylaminosulfur trifluoride (222 mg, 1.38 mmol) under argon and continue the reaction for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (3 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography with PE / EA = 3:1 eluent afforded Z2-3 (25 mg, colorless oil, yield: 22.7%). MS m / z (ESI): 239.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.66 (s, 1H), 7.05 (t, J = 53.0Hz, 1H), 4.00 (s, 3H).

[0223] Step 5: Dissolve Z2-3 (300 mg, 1.25 mmol) and 2-difluoromethylpyridine-4-boronic acid (285 mg, 1.51 mmol) in dioxane (6 mL) and water (1.5 mL). Add Pd(dppf)Cl2 (90.6 mg, 0.125 mmol) and sodium carbonate (265 mg, 2.5 mmol). Replace the atmosphere with argon three times in an oil bath at 100°C and react for 5 hours. Cool to room temperature, filter the reaction mixture, dilute with water (20 mL), and extract with dichloromethane (25 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography using PE / EA = 2:1 as eluent afforded Z2-4 (211 mg, brown solid, 58.6% yield). MS m / z (ESI): 288.1 [M+H] + .

[0224] Step 6: Dissolve Z2-4 (200 mg, 0.7 mmol) in acetic acid (3 mL) and add hydrogen bromide (3 mL, 48% acetic acid solution). Under argon, react in an oil bath at 65°C for 1 hour. Cool to room temperature, add the reaction solution dropwise to saturated aqueous sodium bicarbonate (100 mL), and extract with dichloromethane (30 mL x 4). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. Purify by silica gel column chromatography using PE / EA = 1:1 as eluent to afford Z2-5 (115 mg, off-white solid, yield: 60.5%). 1H NMR (400MHz, DMSO-d6) δ (ppm) 13.43 (s, 1H), 8.72 (d, J = 5.2Hz, 1H), 8.65 (s, 1H), 8.16 (d, J = 5.7Hz, 1H), 8.04 (dd, J = 13.8, 5.2Hz, 1H), 7.18-6.80 (m, 2H).

[0225] Step 7: Dissolve Z2-5 (50 mg, 0.2 mmol) in phosphorus oxychloride (3 ml) under argon protection and stir in an oil bath at 100°C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove excess phosphorus oxychloride. The pH was adjusted to approximately 8 with icy saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by TLC (PE:EA = 3:1) to obtain intermediate Z2 (25 mg, white solid, yield: 46.9%).

[0226] Preparation of intermediate Z3

[0227] Step 1: Benzyl bromide (1 g, 5.85 mmol) and 4-bromo-3-nitrophenol (1 g, 4.59 mmol) were added to acetone (30 mL), followed by the addition of KCO (1.27 g, 9.17 mmol). The reaction mixture was refluxed for 16 hours. The mixture was filtered and 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 Z3-1 (1.35 g, yellow oil, 95.51% yield). MS m / z (ESI): no ionization.

[0228] Step 2: Dissolve Z3-1 (1.35 g, 4.38 mmol) in anhydrous THF (20 mL) and cool to -60°C under argon. Add vinylmagnesium bromide (1 M, 13.14 mL). After the addition is complete, stir the reaction mixture at -60°C to -40°C for 1 hour. Add saturated ammonium chloride solution (30 mL) and extract with ethyl acetate (30 mL x 2). The organic phase is washed with saturated sodium chloride solution, dried, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 5 / 1) to obtain Z3-2 (611 mg, yellow oil, 46.15% yield). MS m / z (ESI): 302.1 [M+H] + .

[0229] Step 3: Z3-2 (230 mg, 761.17 μmol), 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (291.23 mg, 1.14 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (61.70 mg, 76.12 μmol), and KCO (210.40 mg, 1.52 mmol) were added to water (1.5 mL) and 1,4-dioxane (15 mL). Under argon, the reaction mixture was stirred at 110°C for 18 hours. The mixture was 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 Z3-3 (235 mg, yellow solid, 88.12% yield). MS m / z(ESI):351.1[M+H] + .

[0230] Step 4: Dissolve Z3-3 (50 mg, 142.71 μmol) in ethanol (10 mL) and add palladium on carbon (30 mg, 10% purity). Stir the reaction mixture at room temperature under a hydrogen atmosphere for 3 hours. Filter and concentrate under reduced pressure to obtain intermediate Z3 (35 mg, yellow oil, 94.24% yield). MS m / z (ESI): 261.1 [M+H] + .

[0231] Preparation of intermediate Z4

[0232] Step 1: 2-Chloropyridine-4-boronic acid pinacol ester (150.31 mg, 627.57 μmol), 5-bromo-3-(difluoromethyl)-2-methoxypyrazine (150 mg, 627.57 μmol), bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (50.87 mg, 62.76 μmol), and K2CO3 (173.47 mg, 1.26 mmol) were added to 1,4-dioxane (10 mL) and water (1 mL). The reaction mixture was heated to 100°C under argon and stirred for 16 hours. 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 3 / 1) to afford Z4-1 (162 mg, white solid, 95.03% yield). MS m / z (ESI): 272.1 [M+H] + .

[0233] Step 2: Z4-1 (162 mg, 596.36 μmol) was added to aqueous hydrogen bromide (8 mL, 48%). The reaction mixture was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure to afford Z4-2 (150 mg, orange solid, 97.63% yield). The crude product was used directly in the next step. MS m / z (ESI): 258.1 [M+H] + .

[0234] Step 3: Add Z4-2 (150 mg, 582.24 μmol) to phosphorus oxychloride (8 mL). The reaction mixture was stirred at 110°C for 5 hours. The mixture was concentrated under reduced pressure. Saturated sodium bicarbonate solution was added for neutralization, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (PE / EA = 1 / 0 to 5 / 1) to obtain Z4 (134 mg, yellow solid, yield 83.36%). MS m / z (ESI): 276.0 [M+H] + .

[0235] Preparation of intermediate Z5

[0236] Step 1: Add pinacol diboronate (239.05 mg, 941.35 μmol), 5-bromo-3-(difluoromethyl)-2-methoxypyrazine (150 mg, 627.57 μmol), potassium acetate (153.97 mg, 1.57 mmol), and bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (50.87 mg, 62.76 μmol) to 1,4-dioxane (20 mL). Under argon, the reaction mixture was stirred at 80°C for 16 hours. Intermediate Z5-1 (128 mg) was obtained and the solution was used directly in the next step without post-treatment. MS m / z (ESI): 205.1 [M+H] + .

[0237] Step 2: 4-Chloro-2-(difluoromethyl)pyrimidine (102.95 mg, 625.69 μmol), bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (50.72 mg, 62.57 μmol), Z5-1 (128 mg, 625.69 μmol), and K2CO3 (172.95 mg, 1.25 mmol) were added to 1,4-dioxane (10 mL) and water (1 mL). Under argon, the reaction mixture was stirred at 105°C for 16 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 10 / 1) to afford Z5-2 (145 mg, pale yellow solid) in an 80.41% yield. MS m / z (ESI): 289.1 [M+H] + .

[0238] Step 3: Z5-2 (145 mg, 503.12 μmol) was added to aqueous hydrogen bromide (8 mL, 48%), and the reaction mixture was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure to afford Z5-3 (137 mg, yellow solid). The crude product was used directly in the next step without purification. MS m / z (ESI): 275.0 [M+H] + .

[0239] Step 4: Add Z5-3 (137 mg, 499.68 μmol) to phosphorus oxychloride (16 mL), and stir the reaction at 110°C for 16 hours. Concentrate under reduced pressure. Neutralize with saturated sodium bicarbonate solution, extract with dichloromethane (30 mL x 3), dry the organic phase, filter, and concentrate under reduced pressure. Purify by silica gel column chromatography with an eluent system (PE / EA = 1 / 0 to 5 / 1) to obtain intermediate Z5 (135 mg, yellow oil) in a yield of 92.33%. MS m / z (ESI): 293.0 [M+H] + .

[0240] Preparation of intermediate Z6

[0241] Step 1: Add 5-bromo-3-(difluoromethyl)-2-methoxypyrazine (500 mg, 2.09 mmol), tributyl(1-ethoxyvinyl)stannane (982.13 mg, 2.72 mmol), and [bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (169.57 mg, 209.19 μmol) to 1,4-dioxane (20 mL). Under argon, the reaction mixture was heated to 100°C and stirred for 16 hours. After cooling to room temperature, hydrochloric acid solution (2 mol / L) was added and stirred for 1 hour. The mixture was concentrated under reduced pressure. Neutralization was performed with methanolic ammonia solution (7 mol / L), and the mixture was concentrated under reduced pressure. Purification was performed by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 10 / 1) to obtain Z6-1 (335 mg, colorless oil) in a yield of 79.22%. MS m / z(ESI):203.1[M+H] + .

[0242] Step 2: Z6-1 (335 mg, 1.66 mmol) was added to DMF-DMA (8.97 g, 10 mL), and the reaction mixture was stirred at 100°C for 16 hours. The mixture was concentrated under reduced pressure to afford Z6-2 (410 mg, yellow solid) in a 96.18% yield. The crude product was used directly in the next step. MS m / z (ESI): 258.2 [M+H] + .

[0243] Step 3: Z6-2 (410 mg, 1.59 mmol) and 3-(trifluoromethyl)-1H-pyrazol-5-amine (481.63 mg, 3.19 mmol) were added to acetic acid (10 mL). The reaction mixture was stirred at 80°C for 3 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 10 / 1) to obtain Z6-3 (350 mg, yellow solid) in a 63.61% yield. MS m / z (ESI): 346.1 [M+H] + .

[0244] Step 4: Z6-3 (350 mg, 1.01 mmol) was added to aqueous hydrogen bromide (10 mL, 48%). The reaction mixture was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure to afford Z6-4 (335 mg, yellow solid). The crude product was used directly in the next step. MS m / z (ESI): 332.1 [M+H] + .

[0245] Step 5: Add phosphorus oxychloride (10 mL) to Z6-4 (335 mg, 1.01 mmol). Stir the reaction mixture at 110°C for 5 hours. Concentrate under reduced pressure. Neutralize with saturated sodium bicarbonate solution and extract with dichloromethane (30 mL x 3). Dry the organic phase, filter, and concentrate under reduced pressure. Purify by silica gel column chromatography with an eluent system (PE / EA = 1 / 0 to 5 / 1) to obtain intermediate Z6 (247 mg, yellow solid) in a yield of 69.84%. MS m / z (ESI): 350.0 [M+H] + .

[0246] Preparation of intermediate Z7

[0247] Step 1: Diboronic acid pinacol ester (226.91 mg, 893.55 μmol), 4-benzyloxy-7-bromo-1H-indole (180 mg, 595.70 μmol), potassium acetate (146.16 mg, 1.49 mmol), and bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (48.29 mg, 59.57 μmol) were added to 1,4-dioxane (15 mL). Under argon, the reaction mixture was stirred at 105°C for 16 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 5 / 1) to afford Z7-1 (112 mg, white solid) in a 53.84% yield. MS m / z (ESI): 350.2 [M+H] + .

[0248] Step 2: 4-Chloro-2-(difluoromethyl)pyrimidine (52.77 mg, 320.71 μmol), bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (26.00 mg, 32.07 μmol), Z7-1 (112 mg, 320.71 μmol), and K2CO3 (88.65 mg, 641.41 μmol) were added to water (1 mL) and 1,4-dioxane (10 mL). Under argon, the reaction mixture was stirred at 105°C for 16 hours. The mixture was then concentrated under reduced pressure. Purification by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 2 / 1) afforded Z7-2 (54 mg, light yellow solid) in a 47.92% yield. MS m / z (ESI): 352.1 [M+H] + .

[0249] Step 3: Dissolve Z7-2 (54 mg, 153.69 μmol) in ethanol (10 mL) and add palladium on carbon (30 mg, 10% purity). Stir the reaction mixture at room temperature under a hydrogen atmosphere for 3 hours. Filter and concentrate under reduced pressure to obtain Z7 (40 mg, yellow solid). Yield: 99.63%. MS m / z (ESI): 262.1 [M+H]. + .

[0250] Preparation of intermediate Z8

[0251] Step 1: 4-Bromo-2-(fluoromethyl)pyridine (155 mg, 815.73 μmol), compound Z5-1 (230 mg, 803.97 μmol), bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (65.17 mg, 80.40 μmol), and K2CO3 (222.22 mg, 1.61 mmol) were added to 1,4-dioxane (20 mL) and water (2 mL). Under argon, the reaction mixture was heated to 110°C and stirred for 16 hours. The product was concentrated under reduced pressure and purified by column chromatography (PE / EA = 1 / 0 to 3 / 1) to afford Z8-1 (185 mg, pale yellow solid) in an 85.47% yield. MS m / z (ESI): 270.1 [M+H] + .

[0252] Step 2: Z8-1 (185 mg, 687.16 μmol) was added to aqueous hydrogen bromide (5 mL, 48%). The reaction mixture was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure to afford Z8-2 (175 mg, pale yellow solid) in a 99.79% yield. The crude product was used directly in the next step. MS m / z (ESI): 256.1 [M+H] + .

[0253] Step 3: Add Z8-2 (163.48 mg, 640.59 μmol) to phosphorus oxychloride (8 mL). Stir the reaction mixture at 110°C for 3 hours. Concentrate under reduced pressure. Neutralize with saturated sodium bicarbonate solution and extract with dichloromethane (30 mL x 3). The organic phase is dried, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 1 / 0 to 2 / 1) to obtain intermediate Z8 (75 mg, light yellow solid) in a yield of 42.79%. MS m / z (ESI): 274.1 [M+H] + .

[0254] Preparation of intermediate Z9

[0255] Step 1: 2-Fluoropyridine-4-boronic acid pinacol ester (403.14 mg, 1.81 mmol), 5-bromo-3-(difluoromethyl)-2-methoxypyrazine (288 mg, 1.20 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (97.67 mg, 120.49 μmol), and K2CO3 (333.07 mg, 2.41 mmol) were added to 1,4-dioxane (30 mL) and water (3 mL). The reaction mixture was heated to 110°C and stirred for 16 hours under argon. The product was concentrated under reduced pressure and purified by column chromatography (PE / EA = 1 / 0 to 5 / 1) to afford Z9-1 (292 mg, white solid) in a 94.96% yield. MS m / z (ESI): 256.1 [M+H] + .

[0256] Step 2: Z9-1 (292 mg, 1.14 mmol) was added to aqueous hydrogen bromide (10 mL, 48%). The reaction mixture was stirred at 60°C for 0.5 h. The mixture was concentrated under reduced pressure to afford Z9-2 (270 mg, pale yellow solid) in a 97.84% yield. The crude product was used directly in the next step. MS m / z (ESI): 242.1 [M+H] + .

[0257] Step 3: Add Z9-2 (270 mg, 1.12 mmol) to phosphorus oxychloride (12 mL). Stir the reaction mixture at 110°C for 4 hours. Concentrate under reduced pressure. Neutralize with saturated sodium bicarbonate solution and extract with dichloromethane (30 mL x 3). The organic phase is dried, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 1 / 0 to 5 / 1) to obtain intermediate Z9 (280 mg, light yellow solid) in a yield of 96.34%. MS m / z (ESI): 260.1 [M+H] + .

[0258] Preparation of intermediate Z10

[0259] Step 1: Methyl 6-bromo-3-chloropyrazine-2-carboxylate (361 mg, 1.44 mmol), 2-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (351.90 mg, 1.44 mmol), PdCl2(dppf) (20.83 mg, 28.71 μmol), and K2CO3 (297.62 mg, 2.15 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL). Under nitrogen, the reaction mixture was stirred at 50°C for 4 hours. After completion of the reaction, the mixture was concentrated and purified by column chromatography (PE / EA = 1 / 4) to afford Z10-1 (310 mg, yellow solid) in a 74.53% yield. MS m / z (ESI): 290.1 ​​[M+H] + .

[0260] Step 2: Dissolve Z10-1 (310 mg, 1.07 mmol) in anhydrous DCM (10 mL) and cool to -78°C under argon. Slowly add diisobutylaluminum hydride (1 M in toluene, 1.28 mL) dropwise. After complete addition, continue stirring at -78°C for 1 hour. After the reaction is complete, add saturated aqueous ammonium chloride, stir for a while, add celite, and filter. The filtrate is extracted with dichloromethane (30 mL x 2). The organic phase is dried, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 1 / 2) to obtain Z10-2 (170 mg, yellow solid) in a 61.18% yield. MS m / z (ESI): 260.1 [M+H] + .

[0261] Step 3: Dissolve Z10-2 (170 mg, 654.63 μmol) in DCM (10 mL), cool to 0°C, and add diethylaminosulfur trifluoride (211.04 mg, 1.31 mmol) dropwise. Stir the reaction mixture for 2 hours. After completion, quench with saturated sodium bicarbonate solution (10 mL) and extract with dichloromethane (20 mL x 3). The organic phase is dried, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 1 / 1) to afford intermediate Z10 (160 mg, yellow solid) in an 86.77% yield. MS m / z (ESI): 282.1 [M+H] + .

[0262] Preparation of intermediate Z11

[0263] Step 1: 5-Bromo-3-(difluoromethyl)-2-methoxypyrazine (500 mg, 2.09 mmol) and aqueous hydrobromic acid (10 mL, 48%) were added to a single-necked flask and stirred at 40°C for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to afford Z11-1 (450 mg, yellow solid) in an 84.99% yield. The crude product was used directly in the next step. MS m / z (ESI): 221.0 (non-molecular ion peak).

[0264] Step 2: Dissolve Z11-1 (450 mg, 2.00 mmol) in anhydrous DMF (15 mL), add benzyl bromide (444.71 mg, 2.60 mmol) and K2CO3 (414.65 mg, 3.00 mmol), and allow the reaction to proceed overnight at room temperature. After completion, the reaction solution was concentrated and purified by column chromatography (PE / EA = 1 / 2) to afford Z11-2 (32 mg, yellow oil) in a 50.77% yield. MS m / z (ESI): 315.0 [M+H] + .

[0265] Step 3: Dissolve Z11-2 (320 mg, 1.02 mmol), pinacol diboronate (386.81 mg, 1.52 mmol), PdCl2(dppf) (14.74 mg, 20.31 μmol), and potassium acetate (179.39 mg, 1.83 mmol) in 1,4-dioxane (15 mL). Under nitrogen, the reaction mixture was stirred at 100°C for 16 hours. After the reaction was complete, the mixture was filtered and the filtrate was concentrated to obtain Z11-3 (360 mg, black solid). The crude product was used directly in the next step. MS m / z (ESI): 363.3 [M+H] + .

[0266] Step 4: Z11-3 (360 mg, 993.99 μmol), 4-chloro-2-cyclopropylpyrimidine (153.67 mg, 993.99 μmol), PdCl2(dppf) (14.43 mg, 19.88 μmol), and K2CO3 (274.76 mg, 1.99 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL). Under nitrogen, the reaction mixture was stirred at 110°C for 2 hours. After completion of the reaction, the product was concentrated and purified by column chromatography (PE / EA = 1 / 1) to afford Z11-4 (110 mg, yellow solid) in a 31.32% yield. MS m / z (ESI): 355.3 [M+H] + .

[0267] Step 5: Z11-4 (110 mg, 310.43 μmol) and aqueous hydrobromic acid (5 mL, 48%) were added to a single-necked flask and stirred at 40°C for 0.5 hours. After the reaction was complete, the product was concentrated under reduced pressure to afford Z11-5 (75 mg, yellow solid) in a 91.44% yield. The crude product was used directly in the next step. MS m / z (ESI): 265.1 [M+H] + .

[0268] Step 6: Dissolve Z11-5 (75 mg, 283.84 μmol) in phosphorus oxychloride (5 mL), and stir the reaction mixture at 110°C for 2 hours. After completion, concentrate under reduced pressure, neutralize with saturated sodium bicarbonate solution, and extract with dichloromethane (20 mL x 3). The organic phase is dried, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 3 / 1) to obtain intermediate Z11 (60 mg, yellow solid) in a yield of 74.78%. MS m / z (ESI): 283.1 [M+H] + .

[0269] Preparation of intermediate Z12

[0270] Step 1: Dissolve 5-bromo-2-chloro-3-(difluoromethyl)pyrazine (166.67 mg, 684.66 μmol), 2-methylpyridine-4-boronic acid pinacol ester (150 mg, 684.66 μmol), PdCl2(dppf) (9.94 mg, 13.69 μmol), and K2CO3 (189.25 mg, 1.37 mmol) in THF (10 mL) and H2O (1 mL). Under nitrogen, the reaction mixture was stirred at 40°C for 3 hours. After completion of the reaction, the product was concentrated and purified by column chromatography (PE / EA = 1 / 1) to afford Intermediate Z12 (40 mg, yellow solid) in a 22.85% yield. MS m / z (ESI): 256.1 [M+H] + .

[0271] Preparation of intermediate Z13

[0272] Step 1: Dissolve 3-bromo-5-chloro-pyrazin-2-amine (1 g, 4.80 mmol) in water (2 mL), add KCO (1.33 g, 9.59 mmol), cyclopropylboronic acid (535.71 mg, 6.24 mmol), PdCl(dppf) (351.03 mg, 479.75 μmol), and dioxane (20 mL), and stir at 100°C overnight under nitrogen. Concentrate under reduced pressure to obtain the crude product, which is purified by combiflash chromatography (0-60% EA / 100-40% PE) to afford Z13-1 (450 mg, yellow oil) in a 55.30% yield. MS m / z (ESI): 170.1 [M+H]. + .

[0273] Step 2: Dissolve Z13-1 (0.45 g, 2.65 mmol) in dioxane (18 mL), add [2-(difluoromethyl)-4-pyridyl]boronic acid (458.79 mg, 2.65 mmol), potassium carbonate (733.35 mg, 5.31 mmol), PdCl2(dppf) (194.13 mg, 265.31 μmol), and water (2 mL). Stir overnight at 100°C under nitrogen. Concentrate under reduced pressure to obtain the crude product, which is then purified by combiflash (0-60% EA / PE) to afford Z13-2 (200 mg, yellow oil) in a yield of 28.74%. MS m / z (ESI): 263.1 [M+H]. + .

[0274] Step 3: Dissolve Z13-2 (200 mg, 762.61 μmol) in concentrated hydrochloric acid (10 mL). Add sodium nitrite (263.08 mg, 3.81 mmol) at 0°C and stir at 0°C for 30 minutes. Add potassium carbonate to adjust the pH to 8. Extract the organic phase with dichloromethane to remove impurities. Concentrate the aqueous phase under reduced pressure to obtain intermediate Z13 (60 mg, yellow solid) in a yield of 27.93%, which was used directly in the next reaction. MS m / z (ESI): 264.1 [M+H] + .

[0275] Example 1 Preparation of Compound H-1

[0276] Step 1: Intermediate Z1 (50 mg, 190.68 μmol) and intermediate a (83.91 mg, 286.03 μmol) were dissolved in DMF (6 mL), and K2CO3 (52.63 mg, 381.37 μmol) was added. The reaction was stirred at 80°C for 12 hours. The reaction was monitored for completion by LC-MS. The solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (dichloromethane containing 25% methanol) to give H-1-a (21 mg, 22.06% yield). MS m / z (ESI): 476.1 [M+H] + .

[0277] Step 2: H-1-a (21 mg, 44.16 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The reaction was stirred at 23°C for 2 hours. The reaction was monitored for completion by LC-MS. The crude product was evaporated to dryness under reduced pressure, and prep.HPLC was performed to obtain H-1 (1.22 mg, purity: 100%, yield: 7.36%). MS m / z (ESI): 376.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ (ppm) 13.28 (s, 1H), 8.94 (d, J = 5.6Hz, 1H), 8.30 (d, J = 7.6Hz, 2H), 7.44 (t, J = 54.0Hz, 2H),6.77(d,J=8.3Hz,1H),3.95(s,2H),1.85-1.78(m,1H),1.49-1.40(m,2H),1.17(s,3H),1.06-0.76(m,6H).

[0278] Example 2: Preparation of Compound H-2

[0279] Step 1: Add intermediate b (8 mg, 0.034 mmol) to a clean 25 mL three-necked flask and dissolve in THF (1 mL). Cool to 0°C, add sodium hydride (5 mg, 0.204 mmol), and stir at 0°C for 30 min. Add intermediate Z2 (10 mg, 0.034 mmol), and stir at 0°C for 1 h. LC-MS monitoring indicates complete reaction of the starting material. Add saturated ammonium chloride (1.5 mL) to quench the reaction, extract with ethyl acetate (5 mL x 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain H-2-a (30 mg, green oil, crude product), which is used directly in the next step. MS m / z (ESI): 487.3 [M+H]. + .

[0280] Step 2: H-2-a (30 mg, 0.062 mmol) was placed in a clean 25 mL three-necked flask, dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL, 0.183 mmol) was added. The mixture was stirred at room temperature for 0.5 h and monitored by LC-MS sampling. After the reaction was complete, saturated sodium bicarbonate was added to adjust the pH to 7. The mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by preparative liquid chromatography afforded H-2 (8.9 mg, 37.43% yield). MS m / z (ESI): 387.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ (ppm) 9.24 (s, 1H), 8.81 (d, J = 5.2Hz, 1H), 8.29 (d, J = 1.6Hz, 1H), 8.22 (d, J = 5.2Hz, 1H), 7.38 (t, J = 53.0Hz, 1 H),7.03(t,J=54.8Hz,1H),4.39(s,2H),1.77(dt,J=12.5,6.2Hz,1H),1.65-1.44(m,2H),1.29(s,3H),0.89(dd,J=15.0,6.6Hz,6H).

[0281] Example 3: Preparation of Compound H-3

[0282] Step 1: Dissolve intermediate Z3 (35 mg, 134.49 μmol) in DMF (10 mL), add K2CO3 (37.18 mg, 268.98 μmol), and then add intermediate a (59.19 mg, 201.74 μmol). The reaction mixture was stirred at 80°C for 3 hours. Filter and concentrate under reduced pressure to obtain H-3-a (60 mg, brown oil, yield: 94.21%). The crude product was used directly in the next step without purification. MS m / z (ESI): 474.3 [M+H] + .

[0283] Step 2: H-3-a (60 mg, 126.70 μmol) was added to dichloromethane (10 mL), followed by trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, dissolved in dichloromethane, neutralized with 7 mol / L ammonia in methanol, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (preparative column: 21.2 x 250 mm C18 column; system: mobile phase A: 10 mM NH4HCO3 / H2O, mobile phase B: acetonitrile (10 mM NH4HCO3 / H2O-acetonitrile); wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to afford H-3 (21.52 mg, 45.26% yield). MS m / z (ESI): 374.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.26 (s, 1H), 8.72 (d, J = 5.1Hz, 1H), 7.83 (s, 1 H),7.78(d,J=5.4Hz,1H),7.27(t,J=2.8Hz,1H),7.23(d,J=8.0Hz,1H),6.99 (t,J=52Hz,1H),,6.65-6.59(m,2H),3.82(s,2H),1.86-1.78(m,1H),1.69(s ,2H),1.42(dd,J=5.5,2.1Hz,2H),1.14(s,3H),0.91(dd,J=6.6,5.0Hz,6H).

[0284] Example 4: Preparation of Compound H-4

[0285] Step 1: Dissolve 4-bromo-3-fluorophenol (0.5 g, 2.62 mmol) and intermediate a (768.02 mg, 2.62 mmol) in DMF (10 mL). Add K2CO3 (361.81 mg, 2.62 mmol). Stir the reaction mixture at 80°C for 12 hours. After completion of the reaction, concentrate under reduced pressure. The residue is purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 5 / 1) to obtain H-4-a (700 mg, yellow oil, 66.14% yield). MS m / z (ESI): 404.3 [M+H] + .

[0286] Step 2: H-4-a (361.81 mg, 2.62 mmol) was dissolved in anhydrous THF (15 mL). The mixture was cooled to -78°C under nitrogen, and LDA (2.0 M in THF, 3.46 mL) was added dropwise. The reaction system was stirred at -78°C for 2 hours, and then DMF (8.66 mmol, 670.25 μL) was added. The reaction was continued at low temperature for 1 hour. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 2 / 1) to afford H-4-b (500 mg, yellow oil, 66.80% yield). MS m / z (ESI): 334.1 [M-100] + .

[0287] Step 3: Dissolve H-4-b (500 mg, 1.16 mmol) in 1,4-dioxane (20 mL) and add 85% hydrazine hydrate (5 mL). Stir the reaction mixture at 130°C for 16 hours. After completion of the reaction, concentrate under reduced pressure. The residue is purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 3 / 1) to obtain H-4-c (420 mg, yellow oil, 85.18% yield). MS m / z (ESI): 426.1 [M+1] + .

[0288] Step 4: H-4-c (90 mg, 211.10 μmol), 2-difluoromethyl-4-pyridineboronic acid pinacol ester (59.23 mg, 232.21 μmol), Pd(dppf)Cl2 (3.06 mg, 4.22 μmol), and K2CO3 (29.18 mg, 211.10 μmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). Under nitrogen, the reaction solution was stirred at 110°C for 16 hours. After the reaction was complete, the product was dried and purified by column chromatography (PE / EA = 1 / 1) to afford H-4-d (60 mg, yellow solid, 59.90% yield). MS m / z (ESI): 475.3 [M+H] + .

[0289] Step 5: H-4-d (60 mg, 126.44 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 7 mol / L ammonia in methanol, and concentrated again under reduced pressure. The residue was purified by preparative liquid chromatography (preparative column: 21.2 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain H-4 (24.72 mg, 51.73% yield). MS m / z (ESI): 375.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 13.50 (s, 1H), 8.73 (d, J = 5.1Hz, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 7.89 (d, J = 5.2Hz, 1H), 7.58 (d, J = 7.9 Hz,1H),7.00(t,1H),6.68(d,J=8.0Hz,1H),3.88(s,2H),2.01-1.70(m,3H),1.50-1.36(m,2H),1.15(s,3H),0.91(t,J=6.9Hz,6H).

[0290] Example 5: Preparation of Compound H-5

[0291] Step 1: Dissolve H-4-c (90 mg, 211.10 μmol), 2-trifluoromethyl-4-pyrimidineboronic acid pinacol ester (86.78 mg, 316.64 μmol), Pd(dppf)Cl2 (3.06 mg, 4.22 μmol), and K2CO3 (29.18 mg, 211.10 μmol) in 1,4-dioxane (5 mL) and water (1 mL). Under nitrogen, the reaction mixture was stirred at 110°C for 16 hours. After completion of the reaction, the product was concentrated and purified by column chromatography (PE / EA = 1 / 1) to afford H-5-a (65 mg, yellow solid, 62.39% yield). MS m / z (ESI): 494.2 [M+H] + .

[0292] Step 2: H-5-a (65 mg, 131.71 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 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 x 250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain H-5 (15.7 mg, 30.30% yield). MS m / z (ESI): 394.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.83 (s, 1H), 9.03 (d, J = 5.5Hz, 1H), 8.46 (d, J = 5.6Hz, 1H), 8.37 (s, 1H), 8.30 (d, J = 8.2Hz, 1H),6.79(d,J=8.3Hz,1H),3.95(s,2H),2.04-1.75(m,3H),1.50-1.36(m,2H),1.16(s,3H),0.91(dd,J=8.0,6.6Hz,6H).

[0293] Example 6: Preparation of Compound H-6

[0294] Step 1: H-4-c (50 mg, 117.28 μmol), 2-chloro-pyridine-4-boronic acid pinacol ester (30.90 mg, 129.00 μmol), Pd(dppf)Cl2 (1.70 mg, 2.35 μmol), and K2CO3 (32.42 mg, 234.55 μmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). Under nitrogen, the reaction mixture was stirred at 110°C for 16 hours. After completion of the reaction, the product was concentrated and purified by column chromatography (PE / EA = 1 / 1) to afford H-6-a (40 mg, yellow solid, 74.31% yield). MS m / z (ESI): 459.3 [M+H] + .

[0295] Step 2: H-6-a (40 mg, 87.15 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, the mixture 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 NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to afford H-6 (15.06 mg, 48.15% yield). MS m / z (ESI): 359.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 13.51 (s, 1H), 8.45 (d, J = 5.2Hz, 1H), 8.28 (s, 1H), 7.81 (s, 1H), 7.73 (d, J = 5.8Hz, 1H), 7.57 (d, J = 7.9Hz, 1H),6.66(d,J=8.0Hz,1H),3.87(s,2H),2.03-1.74(m,3H),1.51-1.36(m,2H),1.15(s,3H),0.91(t,J=6.9Hz,6H).

[0296] Example 7: Preparation of Compound H-7

[0297] Step 1: Dissolve H-4-c (140 mg, 328.37 μmol), pinacol diboronate (125.08 mg, 492.56 μmol), Pd(dppf)Cl2 (4.77 mg, 6.57 μmol), and potassium acetate (64.45 mg, 656.74 μmol) in 1,4-dioxane (10 mL). Under nitrogen, the reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, the product was concentrated and purified by column chromatography (PE / EA = 1 / 1) to afford H-7-a (120 mg, yellow solid, 77.19% yield). MS m / z (ESI): 474.3 [M+H] + .

[0298] Step 2: H-7-a (120 mg, 253.48 μmol), 7-chloro-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (61.78 mg, 278.83 μmol), Pd(dppf)Cl2 (3.68 mg, 5.07 μmol), and K2CO3 (70.07 mg, 506.96 μmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL). Under nitrogen, the reaction mixture was stirred at 110°C for 16 hours. After completion of the reaction, the product was concentrated and purified by column chromatography (PE / EA = 1 / 2) to afford H-7-b (90 mg, yellow solid, 66.67% yield). MS m / z (ESI): 533.3 [M+H] + .

[0299] Step 3: H-7-b (90 mg, 169.00 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, the mixture was concentrated under reduced pressure, dissolved in dichloromethane, neutralized with 7 mol / L 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 NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain H-7 (46.72 mg, 63.93% yield). MS m / z (ESI): 433.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.88 (s, 1H), 8.78 (d, J = 4.4Hz, 1H), 8.25 (s, 1H), 7.83 (d, J = 8.0Hz, 1H), 7.48 (d, J = 4.4Hz, 1H), 7.37 (s, 1H),6.77(d,J=8.1Hz,1H),3.92(s,2H),1.90-1.76(m,1H),1.74-1.70(m,2H),1.49-1.37(m,2H),1.16(s,3H),0.93(t,J=6.7Hz,6H).

[0300] Example 8: Preparation of Compound H-8

[0301] Step 1: Dissolve intermediate b (100 mg, 432.28 μmol) in DMF (10 mL), cool to 0°C, add sodium hydride (20 mg, 521.97 μmol, 60% purity), and stir for 30 minutes. Then add intermediate Z6 (100 mg, 286.00 μmol). The reaction mixture was stirred at 0°C for 1.5 hours. The reaction mixture was concentrated and purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 5 / 1) to obtain H-8-a (140 mg, light yellow oil) in an 89.90% yield. MS m / z (ESI): 445.2 [M-100+H] + .

[0302] Step 2: H-8-a (140 mg, 257.11 μmol) was added to DCM (10 mL), followed by TFA (5 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The product was dissolved in dichloromethane and neutralized with 7 mol / L ammonia in methanol. The product was then concentrated. Purification by preparative liquid chromatography afforded H-8 (35 mg, 27.74% yield). MS m / z (ESI): 445.2 [M+H] + .

[0303] Example 9: Preparation of Compound H-9

[0304] Step 1: Dissolve intermediate Z7 (40 mg, 153.12 μmol) in DMF (10 mL), add K2CO3 (42.33 mg, 306.25 μmol), and then add intermediate a (67.38 mg, 229.69 μmol). The reaction mixture was stirred at 80°C for 3 hours. Filter and concentrate the filtrate to obtain H-9-a (72 mg, brown oil). The crude product was used directly in the next step without purification. MS m / z (ESI): 475.3 [M+H] + .

[0305] Step 2: H-9-a (72 mg, 151.73 μmol) was added to DCM (6 mL), followed by TFA (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The product was dissolved in dichloromethane and neutralized with 7 mol / L ammonia in methanol, followed by concentration. The product was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-30% acetonitrile) to afford H-9 (46.32 mg, yield 79.06%). MS m / z (ESI): 375.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ (ppm) 11.48 (s, 1H), 8.91 (d, J = 5.6Hz, 1H), 8.28 (d, J = 5.8Hz, 1H), 8.06(d,J=8.5Hz,1H),7.42(dd,J=5.1,2.4Hz,1H),7.28(t,J=56Hz,1H),6.82-6.79(m,1H ),6.76(d,J=8.5Hz,1H),4.11(q,J=9.9Hz,2H),1.82(dt,J=12.3,6.2Hz,1H),1.67(dd,J= 14.1,5.6Hz,1H),1.55(dd,J=14.1,5.5Hz,1H),1.32(s,3H),0.91(dd,J=19.3,6.6Hz,6H).

[0306] Example 10: Preparation of Compound H-10

[0307] Step 1: Dissolve intermediate b (83.01 mg, 358.83 μmol) in DMF (10 mL), cool to 0°C, add sodium hydride (13.75 mg, 358.83 μmol, 60% purity), and stir for 30 minutes. Then add intermediate Z5 (70 mg, 239.22 μmol). The reaction mixture was stirred at 0°C for 1.5 hours. The reaction mixture was concentrated and purified by silica gel column chromatography using an eluent system (PE / EA = 1 / 0 to 4 / 1) to obtain H-10-a (61 mg, red oil, 52.31% yield). MS m / z (ESI): 388.2 [M-100+H] + Step 2: Add H-10-a (61 mg, 125.13 μmol) to DCM (6 mL), followed by TFA (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. Dissolved in dichloromethane, the mixture was neutralized with 7 mol / L ammonia in methanol, and concentrated. Purification was performed by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-30% acetonitrile) to obtain H-10 (29.60 mg, yield: 60.69%). MS m / z (ESI): 388.1 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ (ppm) 9.31 (s, 1H), 9.13 (d, J = 5.3Hz, 1H), 8.33 (d, J = 5.3Hz, 1H), 7.42 (t, J = 56Hz, 1H), 7.07 (t, J = 56Hz, 1H), 4.43 ( s,2H),1.80(dt,J=12.4,6.0Hz,1H),1.63(dd,J=14.3,5.5Hz,1H),1.52(dd,J=14.3,5.6Hz,1H),1.30(s,3H),0.92(dd,J=13.8,6.6Hz,6H).

[0308] Example 11: Preparation of Compound H-11

[0309] Step 1: H-7-a (26.18 mg, 55.30 μmol), 2-bromo-7-chloropyrazolo[1,5-a]pyrimidine (15.43 mg, 66.36 μmol), Pd(dppf)Cl2 (3.68 mg, 5.07 μmol), and K2CO3 (15.29 mg, 110.60 μmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). Under nitrogen, the reaction mixture was stirred at 110°C for 16 hours. After completion of the reaction, the product was concentrated and purified by column chromatography (PE / EA = 1 / 1) to afford H-11-a (22 mg, yellow solid, 73.21% yield). MS m / z (ESI): 545.2 [M+H] + .

[0310] Step 2: H-11-a (22 mg, 40.48 μmol) was dissolved in DCM (3 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, it was concentrated under reduced pressure, dissolved in dichloromethane, neutralized with 7 mol / L ammonia in methanol, and concentrated again under reduced pressure. Purification was performed by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain H-11 (6.40 mg, yield 35.10%). MS m / z (ESI): 445.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ (ppm) 12.90 (s, 1H), 8.63 (d, J = 4.4Hz, 1H), 8.25 (s, 1H), 7.79 (d, J = 8.0Hz, 1H), 7.27 (d, J = 4.4Hz, 1H) ,7.02(s,1H),6.75(d,J=8.1Hz,1H),3.92(s,2H),1.92-1.72(m,3H),1.49-1.38(m,2H),1.16(s,3H),0.92(t,J=6.7Hz,6H).

[0311] Example 12: Preparation of Compound H-12

[0312] Step 1: Dissolve intermediate b (50 mg, 216.14 μmol) in DMF (10 mL), cool to 0°C, add sodium hydride (10.41 mg, 271.67 μmol, 60% purity), and stir for 30 minutes. Then add intermediate Z4 (50 mg, 181.11 μmol). The color turns black, and the reaction mixture is stirred at 0°C for 1.5 hours. The reaction mixture is concentrated to obtain H-12-a (85 mg, brown oil). The crude product is used directly in the next step without purification. MS m / z (ESI): 471.2 [M+H] + .

[0313] Step 2: H-12-a (85 mg, 180.49 μmol) was added to DCM (6 mL), followed by TFA (3 mL). The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The product was dissolved in dichloromethane and neutralized with 7 mol / L ammonia in methanol, followed by concentration under reduced pressure. Purification by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254 / 214 nm; gradient: 5% to 30% acetonitrile) afforded H-12 (45.19 mg, 66.80% yield). MS m / z (ESI): 371.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.23 (s, 1H), 8.56 (d, J = 5.2Hz, 1H), 8.16 (s, 1H), 8.07 (dd, J = 5.2, 1.5Hz, 1H), 7.40 (t, J = 56 Hz, 1H), 4.43 (s, 2H), 1.85-1.74 (m, 1H), 1.69-1.61 (m, 1H), 1.58-1.50 (m, 1H), 1.32 (s, 3H), 0.92 (dd, J = 15.2, 6.6Hz, 6H).

[0314] Example 13: Preparation of Compound H-13

[0315] Step 1: H-7-a (69.81 mg, 147.46 μmol), 4-chloro-2-methylpyrimidine (28.44 mg, 221.20 μmol), PdCl2(dppf) (3.68 mg, 5.07 μmol), and K2CO3 (40.76 mg, 294.93 μmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). Under argon, the reaction mixture was stirred at 110°C for 16 hours. After completion of the reaction, the product was concentrated and purified by column chromatography (PE / EtOAc = 1 / 50) to afford H-13-a (50 mg, yellow solid, 77.14% yield). MS m / z (ESI): 440.3 [M+H] + .

[0316] Step 2: H-13-a (50 mg, 113.75 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, the mixture was concentrated under reduced pressure, dissolved in dichloromethane, neutralized with 7 mol / L 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 NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile) to obtain H-13 (15.02 mg, 38.90% yield). MS m / z (ESI): 340.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 13.15 (s, 1H), 8.65 (d, J = 5.5Hz, 1H), 8.25 (s, 1H), 8.16 (d, J = 8.2Hz, 1H), 7.92 (d, J = 5.6Hz, 1H) ,6.70(d,J=8.2Hz,1H),3.91(s,2H),2.79(s,3H),1.88-1.72(m,3H),1.48-1.37(m,2H),1.15(s,3H),0.91(t,J=6.9Hz,6H).

[0317] Example 16: Preparation of Compound H-16

[0318] Step 1: Dissolve intermediate b (95.11 mg, 411.12 μmol) in DMF (10 mL), cool to 0°C, add sodium hydride (15.75 mg, 411.12 μmol, 60% purity), and stir for 30 minutes. Then add intermediate Z8 (75 mg, 274.08 μmol). The reaction mixture turns black, and the temperature is naturally raised to room temperature and stirred for 3 hours. Saturated sodium chloride solution (30 mL) is added, and the mixture is extracted with dichloromethane (50 mL x 3). The organic phase is dried, filtered, and concentrated under reduced pressure. Purification by column chromatography (PE / EA = 1 / 0 to 5 / 1) affords H-16-a (80 mg, colorless oil) in a 62.30% yield. MS m / z (ESI): 469.2 [M+H] + .

[0319] Step 2: H-16-a (80 mg, 170.75 μmol) was added to DCM (5 mL), followed by trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in dichloromethane and neutralized with 7N ammonia in methanol, then concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254 / 214 nm; gradient: 5% to 30% acetonitrile) to afford H-16 (18 mg, colorless oil) in a yield of 28.38%. MS m / z (ESI): 369.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.17 (s, 1H), 8.71 (d, J = 5.1Hz, 1H), 8.13 (s, 1H), 8.03 (d, J = 4.9Hz, 1H), 7.24 (t, J = 5 6Hz, 1H), 5.55 (d, J = 46.9Hz, 2H), 4.15 (s, 2H), 1.86-1.68 (m, 3H), 1.36 (s, 2H), 1.09 (s, 3H), 0.90 (t, J = 6.2Hz, 6H).

[0320] Example 14-Example 15, Example 17-Example 28

[0321] The compounds listed in the following table can be prepared by referring to the above preparation method:

[0322] Example 29: Preparation of Compound H-29

[0323] Step 1: Dissolve intermediate b (292.71 mg, 1.27 mmol) in DMF (20 mL), cool to 0°C, add sodium hydride (48.48 mg, 1.27 mmol, 60% purity), and stir for 30 minutes. Then add intermediate Z9 (219 mg, 843.56 μmol). The color turns black, and the reaction mixture is stirred at 0°C for 1.5 hours. Saturated sodium chloride solution (20 mL) is added, and the mixture is extracted with dichloromethane (30 mL x 3). The organic phase is dried, filtered, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 1 / 0 to 3 / 1) to afford H-29-a (271 mg, colorless oil) in a 70.69% yield. MS m / z (ESI): 455.3 [M+H] + .

[0324] Step 2: H-29-a (271 mg, 596.28 μmol) was added to DCM (10 mL), followed by trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in dichloromethane and neutralized with 7N ammonia in methanol, then concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254 / 214 nm; gradient: 5% to 30% acetonitrile) to afford H-29 (96.08 mg) in a 45.47% yield. MS m / z (ESI): 355.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.18 (s, 1H), 8.37 (d, J = 5.3Hz, 1H), 8.00 (d, J = 5.2Hz, 1H), 7.79 (s, 1H), 7.22 (t, J = 56Hz, 1 H),4.16(d,J=1.4Hz,2H),1.83-1.73(m,1H),1.58(s,2H),1.35(dd,J=5.5,2.7Hz,2H),1.09(s,3H),0.94-0.84(m,6H).

[0325] Example 30: Preparation of Compound H-30

[0326] Step 1: H-7-a (80 mg, 168.99 μmol), 4-chloro-2-fluoropyridine (33.34 mg, 253.48 μmol), PdCl2(dppf) (2.45 mg, 3.38 μmol), and K2CO3 (46.71 mg, 337.97 μmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). Under nitrogen, the reaction mixture was stirred at 110°C for 16 hours. After completion of the reaction, the product was concentrated and purified by column chromatography (PE / EA = 5 / 1) to afford H-30-a (60 mg, yellow solid) in an 80.23% yield. MS m / z (ESI): 443.3 [M+H] + .

[0327] Step 2: H-30-a (60 mg, 135.59 μmol) was dissolved in DCM (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 NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain H-30 (14.56 mg) in a 30.99% yield. MS m / z (ESI): 343.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 13.48 (s, 1H), 8.29 (d, J = 4.9Hz, 2H), 7.70-7.64 (m, 1H), 7.59 (d, J = 7.9Hz, 1H), 7.48 (s ,1H),6.66(d,J=8.0Hz,1H),3.86(s,2H),2.02-1.62(m,3H),1.49-1.35(m,2H),1.14(s,3H),0.90(t,J=6.9Hz,6H).

[0328] Example 31: Preparation of Compound H-31

[0329] Step 1: Dissolve intermediate b (197.10 mg, 852.01 μmol) in anhydrous DMF (10 mL), cool to 0°C, and add sodium hydride (45.44 mg, 1.14 mmol, 60% purity) dropwise. After a half-hour reaction, add intermediate Z10 (160 mg, 568.00 μmol), causing the mixture to turn black. Stir the reaction at 0°C for 1.5 hours. After completion of the reaction, concentrate the mixture and purify it by column chromatography (PE / EA = 2 / 1) to obtain H-31-a (120 mg, yellow oil) in a 44.33% yield. MS m / z (ESI): 477.3 [M+H]. + .

[0330] Step 2: H-31-a (120 mg, 251.81 μmol) was dissolved in DCM (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 NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain H-31 (30 mg, yellow oil) in a yield of 31.65%. MS m / z (ESI): 377.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.11 (s, 1H), 8.50 (d, J = 5.2Hz, 1H), 7.92 (s, 1H), 7.73 (dd, J = 5.2, 1.7Hz, 1H), 7.22 (t, 1H), 4.20-4 .12(m,2H),2.18(p,J=6.7Hz,1H),1.84-1.65(m,3H),1.40-1.31(m,2H),1.09(s,3H),1.00-0.94(m,4H),0.89(t,J=6.3Hz,6H).

[0331] Example 32: Preparation of Compound H-32

[0332] Step 1: Dissolve intermediate b (58.92 mg, 254.71 μmol) in anhydrous DMF (5 mL), cool to 0°C, and add sodium hydride (16.98 mg, 424.51 μmol, 60% purity) dropwise. After a half-hour reaction, add intermediate Z11 (60 mg, 212.26 μmol), causing the mixture to turn black. Stir the reaction at 0°C for 1.5 hours. After completion of the reaction, concentrate the mixture and purify it by column chromatography (PE / EtOAc = 3 / 1) to obtain H-32-a (30 mg, yellow oil) in a 29.60% yield. MS m / z (ESI): 478.3 [M+H] + .

[0333] Step 2: H-32-a (30 mg, 62.82 μmol) was dissolved in DCM (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-acetonitrile; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain H-32 (11 mg, yellow oil) in a yield of 44.73%. MS m / z (ESI): 378.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.28(d,J=1.1Hz,1H),8.77(d,J=5.2Hz,1H),7.89(d,J=5.2Hz,1H),7.23(t,1H),4.18 (d,J=1.5Hz,2H),2.33-2.22(m,1H),1.84-1.67(m,3H),1.43-1.29(m,2H),1.14-1.02(m,7H),0.90(t,J=6.3Hz,6H).

[0334] Example 33: Preparation of Compound H-33

[0335] Step 1: Dissolve intermediate b (54.29 mg, 234.69 μmol) in anhydrous DMF (5 mL), cool to 0°C, and add sodium hydride (11.49 mg, 287.20 μmol, 60% purity) dropwise. After a half-hour reaction, add intermediate Z12 (40 mg, 156.46 μmol), causing the mixture to turn black. Stir the reaction at 0°C for 1.5 hours. After completion of the reaction, concentrate the mixture and purify it by column chromatography (PE / EA = 3 / 1) to obtain H-33-a (35 mg, yellow oil) in a 49.65% yield. MS m / z (ESI): 451.3 [M+H] + .

[0336] Step 2: H-33-a (35 mg, 77.69 μmol) was dissolved in DCM (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 NH4HCO3 / H2O-acetonitrile; wavelength: 254 / 214 nm; gradient: 30%-60% acetonitrile) to obtain H-33 (22.97 mg, yellow oil) in an 84.38% yield. MS m / z (ESI): 351.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ(ppm)9.10(d,J=1.2Hz,1H),8.56(dd,J=5.3,0.8Hz,1H),7.91-7.86(m,1H),7.81(dd,J=5.3,1.7Hz, 1H),7.22(t,1H),4.21-4.11(m,2H),2.55(s,3H),1.98-1.69(m,3H),1.43-1.30(m,2H),1.10(s,3H),0.90(t,J=6.3Hz,6H).

[0337] Example 34: Preparation of Compound H-34

[0338] Step 1: Intermediate Z13 (60 mg, 227.93 μmol) was dissolved in DMF (10 mL), and intermediate a (66.87 mg, 227.93 μmol) and K2CO3 (94.51 mg, 683.78 μmol) were added. The mixture was stirred at 80°C overnight. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by combiflash chromatography (0-20% MeOH / 100-80% DCM) to afford H-34-a (60 mg, yellow solid). Yield: 55.24%, MS m / z (ESI): 477.1 [M+H] + .

[0339] Step 2: H-34-a (60 mg, 125.90 μmol) was dissolved in DCM (3 mL), trifluoroacetic acid (43.07 mg, 377.71 μmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a yellow solid. 10 mL of 7N methanolic ammonia solution was added and the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by pre-HPLC (preparative column: 21.2 × 250 mm C18 column, preparation conditions: system: 10 mM NH4HCO3 / H2O-acetonitrile, wavelength: 254 / 214 nm, gradient: 30% to 60% acetonitrile) to obtain H-34 (8.75 mg, purity: 100%), yield: 18.46%, MS m / z (ESI): 377.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.75 (d, J = 7.0Hz, 2H), 8.22 (d, J = 1.7Hz, 1H), 8.18-8.10 (m, 1H), 7.01 (t, J = 54.9Hz, 1H), 4.13 (d, J = 2.1Hz, 2H),2.58-2.52(m,1H),1.86-1.76(m,1H),1.49-1.34(m,2H),1.21(s,2H),1.15(s,3H),1.13-1.08(m,4H),0.92(dd,J=6.6,5.6Hz,6H).

[0340] Test Example 1: AAK1 Enzyme Assay

[0341] 1. Reagents Required for the Experiment

[0342] 2. Boards and instruments required for the experiment

[0343] 3. Experimental Process

[0344] 1. Prepare 1× buffer for enzyme reaction: Tris hydrochloride (pH 7.5) 10 mM, MgCl2 10 mM, 0.01% Tween 20, 0.01% Brij 35, DTT 2 mM.

[0345] 2. Prepare the compound stock solution with DMSO to 100 times the final concentration of the test compound, then dilute it with 1x buffer to 5 times the final concentration of the test compound. The DMSO content in the compound solution is now 5%, and store it for future use.

[0346] 3. Add 2 μL of the compound solution prepared in step (2) to the compound wells, centrifuge at 1000 rpm for 1 min, and add 5% DMSO prepared in 1x buffer to both the positive and negative control wells;

[0347] 4. Prepare AAK1 enzyme solution with 1x buffer to a final reaction concentration of 10 nM. Then, add 4 μL of AAK1 enzyme solution to the positive control wells and compound wells in the reaction plate, and add 4 μL of 1x buffer to the negative control wells.

[0348] 5. Centrifuge at 1000 rpm for 1 min and let stand at room temperature for 30 min;

[0349] 6. Use 1x buffer to prepare a mixed solution of ATP and Micro2 peptide with final concentrations of 1 μM and 0.1 μM, respectively, and add 4 μL of this mixed solution to the reaction plate;

[0350] 7. Centrifuge at 1000 rpm for 1 min and allow to react at room temperature for 3 h.

[0351] 8. Add 10 μL of ATP depletion solution from the ADP-GLO kit;

[0352] 9. Centrifuge at 1000 rpm for 1 minute and let stand at room temperature for 40 minutes;

[0353] 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;

[0354] 11. Then use Envision to read the fluorescence signal value of each well.

[0355] 4. Data Calculation

[0356] 1. Calculation of compound inhibition rate

[0357] Wherein, Inhibition% is the inhibition percentage of the compound on AAK1 kinase; Max is the positive control well, i.e., the maximum value well; Min is the negative control well, i.e., the minimum value well; Compound is the compound well; Signal is the fluorescence signal value of each well.

[0358] 2. XLFIT 5.0 software (IDBS, UK) was used for fitting, with the logarithm of the 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 four-parameter model. 50 The results are shown in Table 1.

[0359] Table 1 Inhibitory activity of compounds against AAK1 enzyme

[0360] As shown in Table 1, the compounds of the present invention have high inhibitory activity against AAK1 enzyme.

[0361] Test Example 2: BMP2K Enzyme Assay

[0362] 1. Reagents Required for the Experiment

[0363] 2. Boards and instruments required for the experiment

[0364] 3. Experimental Process

[0365] 1. Prepare 1x enzymatic reaction buffer: Tris hydrochloride (pH 7.5) 10 mM, MgCl2 10 mM, 0.01% Tween 20, 0.01% Brij 35, DTT 2 mM;

[0366] 2. Prepare the compound stock solution with DMSO to 100 times the final concentration of the test compound, then dilute it with 1x buffer to 5 times the final concentration of the test compound. The DMSO content in the compound solution is now 5%, and store it for future use.

[0367] 3. Add 2 μL of the compound solution prepared in step (2) to the compound wells, centrifuge at 1000 rpm for 1 min, and add 5% DMSO prepared in 1x buffer to both the positive and negative control wells;

[0368] 4. Prepare BMP2K enzyme solution with 1x buffer to a final reaction concentration of 7.5nM. Then, add 4μL of BMP2K enzyme solution to the positive control wells and compound wells in the reaction plate, and add 4μL of 1x buffer to the negative control wells.

[0369] 5. Centrifuge at 1000 rpm for 1 minute and let stand at room temperature for 15 minutes;

[0370] 6. Use 1x buffer to prepare a mixed solution with a final concentration of 1 μM ATP and 0.1 μM Micro2 peptide, and add 4 μL of this mixed solution to the reaction plate;

[0371] 7. Centrifuge at 1000 rpm for 1 min and allow to react at room temperature for 3 h.

[0372] 8. Add 10 μL of ADP-Glo ​​from the ADP-Glo ​​kit TM Reagent;

[0373] 9. Centrifuge at 1000 rpm for 1 minute and let stand at room temperature for 40 minutes;

[0374] 10. Add 20 μL of Kinase Detection Reagent from the ADP-Glo ​​kit, centrifuge at 1000 rpm for 1 min, and let stand at room temperature for 30 min.

[0375] 11. Use Tecan M1000pro microplate reader to read the luminescence value and perform data calculation.

[0376] 4. Data Calculation

[0377] 1. Calculation of compound inhibition rate

[0378] Wherein, Inhibition% is the inhibition percentage of the compound on BMP2K enzyme; Max is the positive control well, i.e., the maximum value well; Min is the negative control well, i.e., the minimum value well; Compound is the compound well; Signal is the fluorescence signal value of each well.

[0379] 2. XLFIT 5.0 software (IDBS, UK) was used for fitting, with the logarithm of the 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 four-parameter model. 50 The results are shown in Table 2.

[0380] Table 2 Inhibitory activity of compounds on BMP2K enzyme

[0381] As can be seen from Table 2, the compounds of the present application have relatively low inhibitory activity against BMP2K enzyme.

[0382] Test Example 3: Manual patch clamp detection of hERG potassium channel function test

[0383] 1. Experimental Materials

[0384] 1.1. Positive Control Compound Information: Name: Cisapride. Source: Sigma, Cat. No. C4740-10mg. Molecular Weight: 483.96. Storage: Store in a sealed container in the dark at -40°C in DMSO.

[0385] 1.2. Solvent: Name: DMSO (dimethyl sulfoxide). Source: Purchased from Sigma, Cat. No. 276855-100 mL. Molecular weight: 78.13. Storage: Store in a sealed container at room temperature, away from light.

[0386] 1.3. Cell Information: Species & Strain: CHO-hERG cell line (Chinese Hamster Ovary) (Chinese Hamster Ovary cells stably expressing the hERG channel). Source: In-house constructed. Culture Conditions: 5% CO2 (volume fraction, balance air), 37°C incubator. Cryopreservation Conditions: Liquid nitrogen.

[0387] 1.4. Solutions and Reagents: Extracellular solution (mM): 140% NaCl, 5% KCl, 1% CaCl₂, 1.25% MgCl₂, 10% HEPES, and 10% glucose. Adjust pH to 7.4 with NaOH. Intracellular solution (mM): 140% KCl, 1% MgCl₂, 1% CaCl₂, 10% EGTA, and 10% HEPES. Adjust pH to 7.2 with KOH. HEPES: 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid, N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid). EGTA: ethylene glycol bis(2-aminoethyl ether) tetraacetic acid.

[0388] 2. Experimental Methods

[0389] 2.1 Cell culture and treatment

[0390] CHO cells stably expressing hERG were cultured in 35 mm diameter cell culture dishes in a 37°C, 5% CO2 incubator. The cells were passaged every 48 hours at a 1:5 ratio. The culture medium consisted of 90% F12 medium (Invitrogen), 10% fetal bovine serum (Gibco), 100 μg / mL G418 antibiotic (Invitrogen), and 100 μg / mL Hygromycin B antibiotic (Invitrogen). On the day of the experiment, the cell culture medium was aspirated, the cells were rinsed once with extracellular medium, and then digested in 0.25% trypsin-EDTA (Invitrogen) for 3-5 minutes at room temperature. The digestion medium was aspirated, the cells were resuspended in extracellular medium, and then transferred to a dish for electrophysiological recording.

[0391] 2.2 Compound preparation

[0392] On the day of the test, the compound was prepared with DMSO to the stock concentration, and then serially diluted 3-fold with DMSO. That is, 10 μL was added to 20 μL of DMSO, and then 10 μL of the serially diluted compound DMSO solution was added to 4990 μL of extracellular fluid, and the final concentration to be tested was obtained by 500-fold dilution.

[0393] Prepare the positive control compound, cisapride: Add 10 μL of a 150 μM cisapride DMSO stock solution to 4990 μL of extracellular fluid and dilute 500-fold to a final concentration of 300 nM. The DMSO content in the final test concentration should not exceed 0.2%, as this concentration has no effect on hERG potassium channels.

[0394] 2.3 Electrophysiological recording process

[0395] hERG potassium channel currents were recorded using the whole-cell patch-clamp technique at room temperature in CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. After perfusion with electrode solution, the tip resistance was approximately 2-5 MΩ. The microelectrodes were connected to the patch-clamp amplifier by inserting them into the amplifier headstage. Clamp voltage and data recording were controlled and recorded by a computer using pClamp software with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After whole-cell recordings were obtained, cells were clamped at -80 mV. To elicit hERG potassium currents (I hERG ), a 2-second depolarization step from -80 mV to +20 mV was applied, followed by repolarization to -50 mV, which was maintained for 1 second before returning to -80 mV. This voltage stimulus was applied every 10 seconds, and drug administration was initiated after confirming the stability of the hERG potassium current (1 minute). Compounds were administered for at least 1 minute to steady state of action or for a maximum of 3 minutes at each test concentration, and at least two cells (n≥2) were tested at each concentration.

[0396] 2.4 Data Processing

[0397] Data were analyzed using pClamp 10, GraphPad Prism 8, and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current evoked at -50 mV) by different compound concentrations was calculated using the following formula: Inhibition% = [1-(I / Io)] × 100%, where Inhibition% represents the percentage of inhibition of the hERG potassium current by the compound, and I and Io represent the amplitude of the hERG potassium current before and after drug addition, respectively. Compound IC 50Calculated using GraphPad Prism 8 software by fitting the following equation:

[0398] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 =(X)*HillSlope), where X is the Log value of the compound concentration tested, Y is the inhibition percentage at the corresponding concentration, Bottom and Top are the minimum and maximum inhibition percentages measured at each compound concentration during the test, and HillSlope is the slope factor. The test results are shown in Table 3.

[0399] Table 3 IC of compounds inhibiting hERG potassium channel current 50 value

[0400] As shown in Table 3, the compounds of the present application have the effect of reducing hERG inhibition.

[0401] Test Example 4: In vivo pharmacokinetic study in rats after single administration

[0402] The pharmacokinetic characteristics of the test compounds following intravenous and oral administration in rodents were evaluated using a standard protocol. The test compounds were prepared as clear solutions or homogeneous suspensions in a solvent, depending on the dose and concentration, and administered to Sprague-Dawley rats as single intravenous and oral doses. Sprague-Dawley rats (source: Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., male, 200-300 g, 7-9 weeks old) were randomly assigned to each group. The intravenous group had free access to food and water before dosing; the oral group fasted overnight before dosing and resumed food four hours after dosing (except under special circumstances). Water was available ad libitum.

[0403] The intravenous and oral administration groups used a vehicle consisting of a 5:10:85 volume ratio of dimethyl sulfoxide (DMSO), polyethylene glycol-15-hydroxystearate (PEG-15Hydroxystearate), and 20 mol / L citric acid buffer. The compound was dissolved by vortexing and sonication to prepare solutions with concentrations of 5 mg / mL, 1 mg / mL, or other concentrations (e.g., 0.5 mg / mL, depending on the compound's solubility). Solutions were required to be clear for the intravenous injection group and a homogenous suspension or clear solution for the oral administration group. Following intravenous administration of 1 mg / kg (mpk) or oral administration of 5 mg / kg (mpk) or 10 mg / kg (mpk), rats were subjected to collection of whole blood samples, brain homogenate samples, and cerebrospinal fluid samples. Whole blood samples were centrifuged at 3700 rpm for 15 minutes, and the supernatant was separated to obtain plasma samples. Plasma, brain homogenate, and cerebrospinal fluid samples were added with a certain volume of acetonitrile solution containing internal standard to precipitate protein. The supernatant was centrifuged and added with a certain volume of diluent (such as pure water, methanol / water solution, etc., which can be adjusted according to the situation). After mixing, the blood drug concentration C was quantitatively analyzed by LC-MS / MS analysis method. plasma and brain drug concentration C brain The pharmacokinetic parameters, such as peak concentration Cmax, time to peak concentration Tmax, clearance rate CL, half-life T1 / 2, area under the concentration-time curve AUC, and bioavailability F, were calculated using Data Analysie System software (Shanghai Bojia Pharmaceutical Technology Co., Ltd., version 3.0).

[0404] The results of the plasma and brain drug concentration tests 4 hours after a single oral administration in the oral group are shown in Table 4:

[0405] Table 4 Plasma and brain drug concentrations 4 hours after single administration in rats

[0406] As can be seen from Table 4, the compounds of the present application have a high drug penetration rate into the brain and have good brain penetration.

[0407] The structure of the positive compound D1 in Test Example 1 is: (D1, CAS No.: 2092891-50-2), the structure of the positive compound D2 in Test Example 1-4 is: (D2, CAS No.: 1815613-42-3), D1 and D2 can be prepared according to the existing technology, or can be obtained through commercial channels.

[0408] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

[0409] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0410] The embodiments described above only express several implementation methods of the present invention, which are convenient for understanding the technical solutions of the present invention in a specific and detailed manner, but they cannot be understood as limiting the scope of protection of the invention patent. It should be pointed out that for ordinary technicians in this field, without departing from the concept of the present invention, several variations and improvements can be made, which all fall within the scope of protection of the present invention. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided by the present invention are all within the scope of protection of the claims attached to the present invention. Therefore, the scope of protection of the patent of the present invention shall be based on the content of the attached claims, and the description can be used to interpret the content of the claims.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: In formula (I), Z1 and Z2 are each independently C or N; R a and R b are each independently absent, hydrogen, deuterium, -NR a0 R b0 , halo-C 1-8 alkyl (preferably halo-C 1-6 alkyl, more preferably halo-C 1-3 alkyl), halogen (preferably fluorine or chlorine), a 5- or 6-membered heteroaryl, cyano, hydroxy, carboxy, C 3-6 cycloalkyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -SC 1-8 alkyl (preferably -SC 1-6 alkyl, more preferably -SC 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halo-C 1-8 alkoxy (preferably halo-C 1-6 alkoxy, more preferably halo-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 ; the 5- or 6-membered heteroaryl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo-C 1-3 alkyl, halo-C 1-3 alkoxy, -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 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl; R a0 and R b0 are each independently hydrogen, C 1-3 alkyl, -C(O)C 1-8 alkyl, -C(O)OC 1-8 alkyl, halo C 1-8 alkyl, a 5- or 6-membered heteroaryl, -C(O)C 3-6 cycloalkyl, -C(O)NR a1 R b1 or -C(O)-R, where R is a 5- or 6-membered heteroaryl; or R a0 and R b0 together with the attached nitrogen atom form a 4- to 6-membered saturated monocyclic heterocycle; the 5- or 6-membered heteroaryl and the 4- to 6-membered saturated monocyclic heterocycle are each independently unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-3 alkyl, halo 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; or R a Together with R b and Z1 and Z2 connected thereto 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 benzene ring are unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo-C 1-3 alkyl, halo-C 1-3 alkoxy, -NR a1 R b1 、-SO2C 1-3 alkyl, -S(O)C 1-3 alkyl, -SC 1-3 alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl, saturated or partially unsaturated 3- to 7-membered monocyclic heterocycles, and 6- to 10-membered aryl (preferably phenyl or naphthyl); the 5- or 6-membered heterocycloalkyl ring is unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: deuterium, oxo, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo-C 1-3 alkyl, halo-C 1-3 alkoxy, -NR a1 R b1 、-SO2C 1-3 alkyl, -S(O)C 1-3 alkyl, -SC 1-3 alkyl, -C(O)NR a1 R b1 、-C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl, saturated or partially unsaturated 3- to 7-membered monocyclic heterocycles, and 6- to 10-membered aryl (preferably phenyl or naphthyl); the C 2-4 alkenyl is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of: deuterium, halogen (preferably fluorine, chlorine, or bromine), and halo-C 1-3 alkyl; The C 2-4 alkynyl group is substituted with 0 or 1 substituent selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine), and halo C 1-3 alkyl; the 5- to 10-membered heteroaryl, the saturated or partially unsaturated 3- to 7-membered monocyclic heterocycle, or the 6- to 10-membered aryl is substituted with 0, 1, 2 or 3 substituents each independently selected from the group consisting of halogen (preferably fluorine, chlorine or bromine), oxo, C 1-6 alkyl (preferably C 1-3 alkyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), -SC 1-6 alkyl (preferably -SC 1-3 alkyl), halo C 1-6 alkyl (preferably halo C 1-3 alkyl), halo C 1-6 alkoxy (preferably halo 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, and -OC(O)C 1-3 alkyl; R c and R d are each independently hydrogen, deuterium, a halogen (preferably fluorine or chlorine), a halo-C 1-8 alkyl (preferably a halo-C 1-6 alkyl, more preferably a halo-C 1-3 alkyl), cyano, hydroxy, carboxy, a C 3-6 cycloalkyl, a C 1-8 alkyl (preferably a C 1-6 alkyl, more preferably a C 1-3 alkyl), -SC 1-8 alkyl (preferably -SC 1-6 alkyl, more preferably -SC 1-3 alkyl), -NR a1 R b1 , a halo-C 1-8 alkoxy (preferably a halo-C 1-6 alkoxy, more preferably a halo-C 1-3 alkoxy) or a C 1-8 alkoxy (preferably a C 1-6 alkoxy, more preferably a C 1-3 alkoxy); ring A is a benzopyrazole ring, a pyrazine ring, a piperidine ring or a benzopyrrole ring; (R1) n represents that the hydrogen on ring A is substituted by n R1 groups, where n is 0, 1, 2, or 3; each R1 is the same or different and independently is cyano, hydroxy, carboxy, 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), -SC 1-8 alkyl (preferably -SC 1-6 alkyl, more preferably -SC 1-3 alkyl), -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 the C 1-8 alkyl and the C 1-8 alkoxy are each independently unsubstituted or substituted by 1, 2, or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-3 alkyl, halo C 1-3 alkoxy, -NR a1 R b1 、-SO2C 1-3 alkyl, -S(O)C 1-3 alkyl, -SC 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 and R3 together with the adjacent carbon atom form a C 3-6 cycloalkyl ring; R a1 and R b1 each occurrence, independently of one another, is hydrogen, C 1-3 alkyl or acetyl; or R a1 and R b1 together with the attached nitrogen atom form a 4- to 6-membered saturated monocyclic heterocycle; the 4- to 6-membered saturated monocyclic heterocycle is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxy, carboxy, oxo, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-3 alkyl, halo C 1-3 alkoxy, -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 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3- to 6-membered heterocycloalkyl.

2. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, 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, characterized in that, Structure selected from one of the following groups of structures: Preferably, (R1) n represents that the hydrogen on ring A is substituted by n R1s, where n is 0 or 1; each R1 is the same or different and is independently a C 1-3 alkyl group; wherein the C 1-3 alkyl group is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of: halogen; Preferably, each R1 is the same or different and is independently a fluoromethyl group, a difluoromethyl group or a trifluoromethyl group; Preferably, R1 is a difluoromethyl group; Preferably, R1 is C 3-6 cycloalkyl; Preferably, R1 is a cyclopropyl group; Preferably, the structure Selected from one of the following groups of structures:

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that both Z1 and Z2 are C; R a is hydrogen, deuterium, -NR a0 R b0 , halo-C 1-8 alkyl (preferably halo-C 1-6 alkyl, more preferably halo-C 1-3 alkyl), halogen (preferably fluorine or chlorine), a 5- or 6-membered heteroaryl, cyano, hydroxy, carboxy, 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), halo-C 1-8 alkoxy (preferably halo-C 1-6 alkoxy, more preferably halo-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 ; the 5- or 6-membered heteroaryl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo-C 1-3 alkyl, halo-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; Preferably, R a is hydrogen, halogen, C 1-8 alkyl, halo-C 1-8 alkyl or C 3-6 cycloalkyl; R b is hydrogen, a halogen (preferably fluorine or chlorine), a halo-C 1-8 alkyl (preferably a halo-C 1-6 alkyl, more preferably a halo-C 1-3 alkyl), cyano, hydroxy, carboxy, 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 ; Preferably, R b is hydrogen; or R a and R b together with Z1 and Z2 connected thereto form a 5- or 6-membered heteroaryl ring, benzene ring or 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, hydroxy, carboxy, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-3 alkyl, haloC 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 3-6 cycloalkyl, 5- to 10-membered heteroaryl, saturated and optionally partially unsaturated 3- to 7-membered monocyclic heterocycles, and 6- to 10-membered aryl groups (preferably phenyl or naphthyl); the 5- or 6-membered heterocycloalkyl ring is unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from the group consisting of: deuterium, oxo, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-3 alkyl, haloC 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 3-6 cycloalkyl, 5- to 10-membered heteroaryl, saturated or partially unsaturated 3- to 7-membered monocyclic heterocycles, and 6- to 10-membered aryl groups (preferably phenyl or naphthyl); the C 2-4 alkenyl is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of: deuterium, halogen (preferably fluorine, chlorine, or bromine), and haloC 1-3 alkyl; the C 2-4 alkynyl is substituted with 0 or 1 substituent selected from the group consisting of: deuterium, halogen (preferably fluorine, chlorine, or bromine), and haloC 1-3 alkyl; the 5- to 10-membered heteroaryl, the saturated or partially unsaturated 3- to 7-membered monocyclic heterocycle, or the 6- to 10-membered aryl group is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of: halogen (preferably fluorine, chlorine, or bromine), oxoC 1-6 alkyl (preferably oxoC 1-3 alkyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), -SC 1-6 alkyl (preferably -SC 1-3 alkyl), haloC 1-6 alkyl (preferably haloC 1-3 alkyl), haloC 1-6 alkoxy (preferably haloC 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 and -OC(O)C 1-3 alkyl group.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that both Z1 and Z2 are C; R a is hydrogen, deuterium, -NR a0 R b0 , halo-C 1-8 alkyl (preferably halo-C 1-6 alkyl, more preferably halo-C 1-3 alkyl), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halo-C 1-8 alkoxy (preferably halo-C 1-6 alkoxy, more preferably halo-C 1-3 alkoxy), halogen (preferably fluorine or chlorine), C 3-6 cycloalkyl, -C(O)NR a1 R b1 or a 5- or 6-membered heteroaryl; wherein the 5- or 6-membered heteroaryl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo-C 1-3 alkyl, halo-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; Preferably, R a is hydrogen, deuterium, a halogen, -NH2, -NHCH3, -NH-difluoroethyl, difluoromethyl, trifluoromethyl, fluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, fluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, -NHCOCH3, -NHCOOCH3, -NHCO-cyclopropyl, -NHCO-thiazole, -NHCO-pyrrolidine, -NHCONHCH2CH3, pyrazolyl, methylpyrazolyl, -NH-methylpyrazole, -NH-thiazole, -NH-methylthiazole or -CONH2; Preferably, R a is hydrogen, halogen, difluoromethyl or cyclopropyl; Preferably, R a is hydrogen, a halogen or difluoromethyl; R b is hydrogen or a halogen; Preferably, R b is hydrogen, fluorine or chlorine.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that Z1 is C and Z2 is N; R a is hydrogen, deuterium, -NR a0 R b0 , halo C 1-8 alkyl (preferably halo C 1-6 alkyl, more preferably halo C 1-3 alkyl), halogen (preferably fluorine or chlorine), cyano, hydroxy, carboxy, 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), halo C 1-8 alkoxy (preferably halo C 1-6 alkoxy, more preferably halo 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 ; R b Does not exist; or R a together with R b and Z1 and Z2 connected thereto 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 with 1, 2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-3 alkyl, halo 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, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl, saturated or partially unsaturated 3- to 7-membered monocyclic hetero, and 6- to 10-membered aryl (preferably phenyl or naphthyl); the 5- or 6-membered heterocycloalkyl ring is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of: deuterium, oxo, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-3 alkyl, halo 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 3-6 cycloalkyl, 5- to 10-membered heteroaryl, saturated or partially unsaturated 3- to 7-membered monocyclic hetero, and 6- to 10-membered aryl (preferably phenyl or naphthyl); the C 2-4 alkenyl is substituted with 0, 1, 2 or 3 substituents each independently selected from the group consisting of: deuterium, halogen (preferably fluorine, chlorine or bromine) and halo C 1-3 alkyl; the C 2-4 The alkynyl group is substituted with 0 or 1 substituent selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine), and halo C 1-3 alkyl; the 5- to 10-membered heteroaryl group, the saturated or partially unsaturated 3- to 7-membered monocyclic heterocycle, or the 6- to 10-membered aryl group is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halogen (preferably fluorine, chlorine or bromine), oxo C 1-6 alkyl (preferably oxo C 1-3 alkyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), -SC 1-6 alkyl (preferably -SC 1-3 alkyl), halo C 1-6 alkyl (preferably halo C 1-3 alkyl), halo C 1-6 alkoxy (preferably halo 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, and -OC(O)C 1-3 alkyl.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that Z1 is C and Z2 is N; R a Together with R b and Z1 and Z2 connected thereto form a 5-membered heteroaryl ring, and the 5-membered heteroaryl ring is a pyrazole ring; the pyrazole ring is unsubstituted or substituted by 1 or 2 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-3 alkyl, halo C 1-3 alkoxy and -SC 1-3 alkyl; the C 2-4 alkenyl is substituted by 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) and halo C 1-3 alkyl; the C 2-4 alkynyl is substituted by 0 or 1 substituent selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) and halo C 1-3 alkyl; Preferably, the 5-membered heteroaryl ring is a pyrazole ring; the pyrazole ring is unsubstituted or substituted by 1 or 2 substituents each independently selected from the group consisting of deuterium, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -SCH3 and -SCH2CH3; Preferably, the pyrazole ring is unsubstituted or substituted by 1 or 2 substituents each independently selected from the group consisting of bromine, difluoromethyl, trifluoromethyl.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, Structure is as follows: wherein R s1 each occurrence, independently, is deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-3 alkyl, halo C 1-3 alkoxy, -NH2, -NHC 1-3 alkyl, -N(C 1-3 alkyl)2, -NC(O)(CH2)3, -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; said C 2-4 alkenyl is substituted with 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) and halo-C 1-3 alkyl; said C 2-4 alkynyl is substituted with 0 or 1 substituent selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) and halo-C 1-3 alkyl; Preferably, R s1 each occurrence, independently, is deuterium, a halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethoxy, difluoromethoxy or fluoromethoxy; Preferably, R s1 is, independently each occurrence, bromine or trifluoromethyl; m1 is 0, 1 or 2.

9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that Z1 is C, Z2 is N; R a is hydrogen, deuterium, -NR a0 R b0 , halogenated C 1-3 alkyl, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, -C(O)C 1-3 alkyl, -C(O)OC 1-3 alkyl or -OC(O)C 1-3 alkyl; R a0 and R b0 are each independently hydrogen, C 1-3 alkyl, -C(O)C 1-3 alkyl, -C(O)OC 1-3 alkyl, halo-C 1-3 alkyl, -C(O)NR a1 R b1 ; Preferably, R a is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoropropyl, difluoropropyl, trifluoropropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, monofluoropropoxy, difluoropropoxy or trifluoropropoxy; Preferably, R a is hydrogen, fluorine, chlorine, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl or cyclopropyl; Preferably, R a is hydrogen, fluorine, chlorine, methyl, monofluoromethyl, difluoromethyl or trifluoromethyl.

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that Structure A structure selected from one of the following groups: Preferably, the structure A structure selected from one of the following groups:

11. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, R c is hydrogen, chlorine, fluorine, amino or difluoromethyl.

12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, R d is hydrogen, fluorine or chlorine.

13. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, R2 and R3 are each independently methyl.

14. The compound as claimed in 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:

15. A pharmaceutical composition, characterized in that, Comprising the compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and a pharmaceutically acceptable carrier.

16. Use of the compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition according to claim 15 in the preparation of an AAK1 activity inhibitor.

17. The use according to claim 16, characterized in that, The AAK1 activity inhibitor is used for treating or controlling a disease or disorder associated with or mediated by AAK1 activity.

18. The use according to claim 17, wherein The disease or disorder is pain.

Images