Monocyclic GPR6 inverse agonist and use thereof

Abstract

The present invention relates to the field of medicine. Disclosed are a monocyclic GPR6 inverse agonist and a use thereof. Specifically, provided are a GPR6 inverse agonist as shown in formula (I), a preparation method, a pharmaceutical composition, and a use of the compound in the treatment of GPR6-mediated related diseases.

Description

Monocyclic gpr6 inverse agonists and uses thereof

[0001] This application claims priority to Chinese patent application No. 2024110750224 with a filing date of August 6, 2024, Chinese patent application No. 2024114795474 with a filing date of October 22, 2024, Chinese patent application No. 2025101004898 with a filing date of January 21, 2025, Chinese patent application No. 2025105413634 with a filing date of April 27, 2025, and Chinese patent application No. 2025110651685 with a filing date of July 30, 2025. This application incorporates the entire contents of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present disclosure belongs to the field of medicine, in particular to a structurally novel GPR6 inverse agonist, its pharmaceutically acceptable salts, isomers, its pharmaceutical preparations, compositions, pharmaceutical uses and treatment methods. BACKGROUND

[0003] GPR6 (English name: G-protein coupled receptors 6) is a highly active G-protein coupled receptor (GPCR) belonging to the G protein-coupled receptor A family, which also includes GPR3, GPR12 receptors, and the three receptors have about 60% amino acid identity. Since GPR3, GPR6 and GPR12 have no identified endogenous ligand, they are still classified as orphan receptors. The receptors of this family have been shown to have constitutive activity, which can mediate signal transduction through Gs protein or non-Gs protein mechanism, and Gs protein can activate the production of cyclic adenosine monophosphate (cAMP). The first cloning experiment in the mid-1990s showed that GPR6 is mainly expressed in the central nervous system and only has a small amount of expression in the periphery. In the central tissue, the striatum shows the highest GPR6 protein level. Functionally, the striatum, as the main input structure of the basal ganglia, regulates the motor control system and participates in the reward pathway, affecting learning and memory. The cAMP level in the striatal tissue of GPR6 knockout mice is reduced, which is consistent with GPR6-Gs protein coupling and cAMP signal transduction in vivo. Pharmacological targeting of GPR6 can be shown to be useful for the treatment of striatum-related neurological and neuropsychiatric diseases, such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, autism spectrum disorder, schizophrenia and drug addiction.

[0004] Parkinson's disease (PD) is a chronic progressive movement disorder, the pathological hallmark of which is neurodegeneration and loss of dopamine-producing neurons in the substantia nigra compacta and resulting depletion of striatal dopamine (DA). Currently, dopaminergic therapies, including the DA precursor drug levodopa (L-DOPA), catechol-O-methyl transferase (COMT) inhibitors, monoamine oxidase B (MAO) inhibitors, and dopamine receptor agonists, are effective methods for treating PD, but long-term use can lead to severe dyskinesia and a variety of side effects. In addition, a variety of non-dopaminergic therapies have been applied in the clinic, such as the adenosine A2A antagonist istradefylline (KW6002), which has been approved in the United States and Japan as an adjunct to L-DOPA, and can significantly improve the motor symptoms of PD. Developing a drug that selectively targets the indirect pathway of PD can avoid invasive deep brain stimulation (DBS) while not increasing the risk of drug-induced dyskinesia.

[0005] CVN424 developed by Cerevance is a non-dopaminergic oral GPCR6 inverse agonist, indicated for Parkinson's disease, and is currently in clinical phase II. Unlike the dopamine replacement therapy (L-DOPA) commonly used in the clinic for Parkinson's disease, CVN424 selectively targets the dopamine D2 receptor-dependent indirect signaling pathway associated with Parkinson's disease, producing the same positive results as levodopa or deep brain stimulation while avoiding adverse reactions. In a phase 2 study, CVN424 as an adjunct to levodopa was safe and effective in reducing the "off" period (the period when patients still have symptoms of Parkinson's disease even after treatment) of patients with Parkinson's disease. Although there are currently inverse agonist drugs targeting GPR6 in the clinical stage, given the complexity, uncertainty, and high risk of the drug development process, it is still important to continue to develop this targeted drug and increase the number of clinical drug candidates. SUMMARY

[0006] The present disclosure provides a GPR6-targeted inverse agonist with high selectivity relative to other subtypes, good in vivo and in vitro activity, pharmacokinetic properties, and can be used for GRP6-mediated related diseases.

[0007] The present disclosure provides a compound represented by formula (I), a pharmaceutically acceptable salt thereof, and an isomer, characterized in that,

[0008] X 1 selected from N, CR X1 ;

[0009] X 2 selected from N, CR X2 ;

[0010] X3 Selected from N, CR X3 ;

[0011] X 4 Selected from N, CR X4 ;

[0012] Ring B is selected from C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups;

[0013] The ring C is selected from phenyl and 5-6-membered heteroaryl groups;

[0014] R X1 R X2 R X3 R X4 Each group is independently selected from hydrogen, hydroxyl, cyano, carboxyl, oxo, amino, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, (R a (R) b N-, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R a (R) b )NC(O)-、C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -L 3 -R 5 6-8 fused heterocyclic groups, C 2-6 alkenyl, C 2-6 alkynyl group; wherein, the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, (R a (R) b N-, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R a (R) b )NC(O)-、C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, 6-8 membered fused heterocyclic, C 2-6 alkenyl, C 2-6 The alkynyl group is optionally surrounded by one or more R groups. 1A The R that was replaced 1A Selected from halogens, hydroxyl groups, cyano groups, (R a(R) b N-, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, (R a (R) b )NC(O)-、C 1-6 Alkyl-C(O)-, Oxygenated, C 2-6 alkenyl, C 2-6 alkynyl group;

[0015] L 3 Selected from -C(R) L3a (R) L3b )-、-N(R L3c )-、-O-;

[0016] R L3a R L3b Each element is independently selected from hydrogen, hydroxyl, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy, or R L3a R L3b Together with the carbon atoms it is attached to, they form C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-9 Spirocycloalkyl; the C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-9 Spirocycloalkyl groups may be optionally surrounded by one or more groups selected from hydroxyl, cyano, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 The alkoxy group is replaced;

[0017] R L3c Selected from hydrogen, C 1-6 alkyl;

[0018] R 5 Selected from hydrogen, hydroxyl, cyano, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, (R a (R) b )NC(O)-、(R a (R) b N-, C 3-6cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-S(O)2-, C 2-6 alkenyl, C 2-6 alkynyl; said C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 alkyl-S(O)2-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-S(O)2-, C 2-6 alkenyl, C 2- 6alkynyl is optionally substituted with one or more R 5A , R 5A is selected from the group consisting of hydroxy, cyano, halogen, =NR c , C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, oxo, (R d )(R e )N-;

[0019] R a , R b , R c , R d , R e are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkyl-C(O)-, or R a , R b and the nitrogen atom to which they are attached together form a 3-6 membered heterocyclyl;

[0020] R 2 is selected from the group consisting of hydrogen, deuterium, hydroxy, cyano, amino, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy;

[0021] R 3 is selected from the group consisting of hydrogen, hydroxy, cyano, amino, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy;

[0022] L 1 is selected from the group consisting of -O-, -N(R L1a-, -N=, -(CR) L1a R L1b )q-、-C(R L1a )=, -C(O)-, -S-, -S(O)2-, -S(O)-;

[0023] R L1a R L1b Each element is independently selected from hydrogen, halogen, and C. 1-6 alkyl;

[0024] L 2 Selected from chemical bonds, -O-, -N(R) L2a -, -C(O)-, -C(O)-N(R) L2a )-、-C(R L2a R L2b )-、-C(R L2a R L2b )-N(R L2a )-、-N=C(R L2a )-、-N(R L2a )-O-;

[0025] R L2a R L2b Each element is independently selected from hydrogen, hydroxyl, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy;

[0026] R 4 Selected from one or more R 4A The following groups are substituted: hydroxyl group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclic groups, 6-8 membered bridged heterocyclic groups, 7-11 membered spirocyclic groups, 6-10 membered fused heterocyclic groups, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, phenyl; R 4A Selected from hydroxyl, cyano, amino, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1- 6-alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkylene, C 3-6 Cycloalkyl-(CH2) t - 3-6 membered heterocyclic group -(CH2) t -、(R a (R) b N-, oxo, deuterated C1-6 alkyl;

[0027] n, p, q, t are independently selected from 0, 1, 2, 3, 4.

[0028] In another embodiment of the present disclosure, the present disclosure provides a compound represented by formula (I), a pharmaceutically acceptable salt thereof, isomers, characterized in that,

[0029] X 1 selected from N, CR X1 ;

[0030] X 2 selected from N, CR X2 ;

[0031] X 3 selected from N, CR X3 ;

[0032] X 4 selected from N, CR X4 ;

[0033] ring B is selected from C 3-6 cycloalkyl, 3-6 membered heterocyclyl;

[0034] ring C is selected from phenyl, 5-6 membered heteroaryl;

[0035] R X1 , R X2 , R X3 , R X4 are independently selected from hydrogen, hydroxyl, cyano, carboxyl, oxo, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, (R a )(R b )N-, C 1-6 alkyl-C(O)-, C 1-6 alkyl-S(O)2-, C 1-6 alkoxy-C(O)-, (R a )(R b )N-C(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -L 3 -R 5 , 6-8 membered fused heterocyclyl, C 2-6 alkenyl, C 2-6 alkynyl; wherein, the C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6Alkoxy, (R a (R) b N-, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R a (R) b )NC(O)-、C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, 6-8 membered fused heterocyclic, C 2-6 alkenyl, C 2-6 The alkynyl group is optionally surrounded by one or more R groups. 1A The R that was replaced 1A Selected from halogens, hydroxyl groups, cyano groups, (R a (R) b N-, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, (R a (R) b )NC(O)-、C 1-6 Alkyl-C(O)-, Oxygenated, C 2-6 alkenyl, C 2-6 alkynyl group;

[0036] L 3 Selected from -C(R) L3a (R) L3b )-;

[0037] R L3a R L3b Each element is independently selected from hydrogen, hydroxyl, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy, or R L3a R L3b Together with the carbon atoms it is attached to, they form C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-9 Spirocycloalkyl; the C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-9 Spirocycloalkyl groups may be optionally surrounded by one or more groups selected from hydroxyl, cyano, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 The alkoxy group is replaced;

[0038] R 5hydrogen, hydroxy, cyano, halogen, C 1-6 alkyl, halogen-C 1-6 alkyl, C 1-6 alkoxy, halogen-C 1-6 alkoxy, C 1-6 alkyl-C(O)-, C 1-6 alkyl-S(O)2-, (R a )(R b )N-C(O)-, (R a )(R b )N-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-S(O)2-, C 2-6 alkenyl, C 2-6 alkynyl; said C 1-6 alkyl, halogen-C 1-6 alkyl, C 1-6 alkoxy, halogen-C 1-6 alkoxy, C 1-6 alkyl-S(O)2-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-S(O)2-, C 2-6 alkenyl, C 2- 6alkynyl is optionally substituted by one or more R 5A , R 5A is selected from the group consisting of hydroxy, cyano, halogen, =NR c , C 1-6 alkyl, halogen-C 1-6 alkyl, C 1-6 alkoxy, halogen-C 1-6 alkoxy, oxo, (R d )(R e )N-;

[0039] R a , R b , R c , R d , R e are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen-C 1-6 alkyl, C 1-6 alkyl-C(O)-, or R a , R b together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclyl;

[0040] R 2 is selected from the group consisting of hydrogen, hydroxy, cyano, amino, halogen, C 1-6 alkyl, halogen-C 1-6 alkyl, C 1-6Alkoxy, halogenated C 1-6 Alkoxy;

[0041] R 3 Selected from hydrogen, hydroxyl, cyano, amino, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy;

[0042] L 1 Selected from -O-, -N(R) L1a -, -N=, -(CR) L1a R L1b )q-、-C(R L1a )=, -C(O)-, -S-, -S(O)2-, -S(O)-;

[0043] R L1a R L1b Each element is independently selected from hydrogen, halogen, and C. 1-6 alkyl;

[0044] L 2 Selected from chemical bonds, -O-, -N(R) L2a -, -C(O)-, -C(O)-N(R) L2a )-、-C(R L2a R L2b )-、-C(R L2a R L2b )-N(R L2a )-、-N=C(R L2a )-、-N(R L2a )-O-;

[0045] R L2a R L2b Each element is independently selected from hydrogen, hydroxyl, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy;

[0046] R 4 Selected from one or more R 4A The following groups are substituted: hydroxyl group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclic groups, 6-8 membered bridged heterocyclic groups, 7-11 membered spirocyclic groups, 6-10 membered fused heterocyclic groups, C 3-6 cycloalkyl, 5-6 membered heteroaryl, phenyl; R 4A Selected from hydroxyl, cyano, amino, halogen, C1-6 alkyl, haloC 1-6 alkyl, C 1- alkoxy, haloC 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkylene, C 3-6 cycloalkyl-(CH2) t -, 3-6 membered heterocyclyl-(CH2) t -, (R a )(R b )N-, oxo, deuterated C 1-6 alkyl;

[0047] n, p, q, t are independently selected from 0, 1, 2, 3, 4.

[0048] In another embodiment of the present disclosure, the present disclosure provides a compound represented by formula (I), a pharmaceutically acceptable salt thereof, isomers, characterized in that,

[0049] X 1 is selected from N, CR X1 ;

[0050] X 2 is selected from N, CR X2 ;

[0051] X 3 is selected from N, CR X3 ;

[0052] X 4 is selected from N, CR X4 ;

[0053] ring B is selected from C 3-6 cycloalkyl, 3-6 membered heterocyclyl;

[0054] ring C is selected from phenyl, 5-6 membered heteroaryl;

[0055] R X1 , R X2 , R X3 , R X4 are independently selected from hydrogen, hydroxyl, cyano, carboxyl, oxo, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, (R a )(R b )N-, C 1-6 alkyl-C(O)-, C 1-6 alkyl-S(O)2-, C 1-6 alkoxy-C(O)-, (Ra (R) b )NC(O)-、C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -L 3 -R 5 6-8 fused heterocyclic groups; wherein, the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, (R a (R) b N-, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R a (R) b )NC(O)-、C 3-6 Cycloalkyl, 3-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl, 6-8-membered fused heterocyclic groups are optionally surrounded by one or more R groups. 1A The R that was replaced 1A Selected from halogens, hydroxyl groups, cyano groups, (R a (R) b N-, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, (R a (R) b )NC(O)-、C 1-4 Alkyl-C(O)-;

[0056] L 3 Selected from -C(R) L3a (R) L3b )-;

[0057] R L3a R L3b Each element is independently selected from hydrogen, hydroxyl, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy, or R L3a R L3b Together with the carbon atoms it is attached to, they form C 3-6 cycloalkyl, 3-6 membered heterocyclic groups; the C 3-6 Cycloalkyl, 3-6 membered heterocyclic group optionally selected by one or more hydroxyl, cyano, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6alkyl, haloC 1-6 alkyl, haloC

[0058] R 5 selected from hydrogen, hydroxy, cyano, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkyl-C(O)-, C 1-6 alkyl-S(O)2-, (R a )(R b )N-C(O)-, (R a )(R b )N-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-S(O)2-; said C 1-6 alkyl-S(O)2-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-S(O)2- optionally substituted with one or more R 5A selected from hydroxy, cyano, halogen, =NR 5A , C c alkyl, haloC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, haloC 1-6 alkyl, C

[0059] R a , R b , R c are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkyl-C(O)-, or R a , R b and the nitrogen atom to which they are attached form a 3-6 membered heterocyclyl ring;

[0060] R 2 selected from hydrogen, hydroxy, cyano, amino, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkyl, haloC 1-6 alkyl, C

[0061] R 3 selected from hydrogen, hydroxy, cyano, amino, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkyl, haloC1-6 Alkoxy;

[0062] L 1 Selected from -O-, -N(R) L1a -, -N=, -(CR) L1a R L1b )q-、-C(R L1a )=, -C(O)-, -S-, -S(O)2-, -S(O)-;

[0063] R L1a R L1b Each element is independently selected from hydrogen, halogen, and C. 1-6 alkyl;

[0064] L 2 Selected from chemical bonds, -O-, -N(R) L2a -, -C(O)-, -C(O)-N(R) L2a )-、-C(R L2a R L2b )-、-C(R L2a R L2b )-N(R L2a )-、-N=C(R L2a )-、-N(R L2a )-O-;

[0065] R L2a R L2b Each element is independently selected from hydrogen, hydroxyl, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy;

[0066] R 4 Selected from one or more R 4A The following groups are substituted: hydroxyl group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclic groups, 6-8 membered bridged heterocyclic groups, 7-11 membered spirocyclic groups, 6-10 membered fused heterocyclic groups, C 3-6 cycloalkyl, 5-6 membered heteroaryl, phenyl; R 4A Selected from hydroxyl, cyano, amino, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1- 6-alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkylene, C 3-6 Cycloalkyl-(CH2) t-, 3-6 membered heterocyclyl-(CH2) t -, (R a )(R b )N-;

[0067] n, p, q, t are independently selected from 0, 1, 2, 3, 4.

[0068] In another embodiment of the present disclosure, the present disclosure provides a compound represented by formula (I), a pharmaceutically acceptable salt thereof, isomers, characterized in that,

[0069] X 1 is selected from N, CR X1 ;

[0070] X 2 is selected from N, CR X2 ;

[0071] X 3 is selected from N, CR X3 ;

[0072] X 4 is selected from N, CR X4 ;

[0073] ring B is selected from C 3-6 cycloalkyl, 3-6 membered heterocyclyl;

[0074] ring C is selected from phenyl, 5-6 membered heteroaryl;

[0075] R X1 , R X2 , R X3 , R X4 are independently selected from hydrogen, hydroxyl, cyano, carboxyl, oxo, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, (R a )(R b )N-, C 1-6 alkyl-C(O)-, C 1-6 alkyl-S(O)2-, C 1-6 alkoxy-C(O)-, (R a )(R b )N-C(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -L 3 -R 5 ; wherein the C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC1-6 Alkoxy, (R a (R) b N-, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R a (R) b )NC(O)-、C 3-6 Cycloalkyl, 3-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl, optionally with one or more R 1A The R that was replaced 1A Selected from halogens, hydroxyl groups, cyano groups, (R a (R) b N-, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0076] L 3 Selected from -C(R) L3a (R) L3b )-;

[0077] R L3a R L3b Each element is independently selected from hydrogen, hydroxyl, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy, or R L3a R L3b Together with the carbon atoms it is attached to, they form C 3-6 cycloalkyl, 3-6 membered heterocyclic groups; the C 3-6 Cycloalkyl, 3-6 membered heterocyclic group optionally selected by one or more hydroxyl, cyano, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 The alkoxy group is replaced;

[0078] R 5 Selected from hydrogen, hydroxyl, cyano, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, (R a (R) b )NC(O)-、C3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl; said C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl optionally substituted with one or more R 5A substituents, R 5A is selected from the group consisting of hydroxy, cyano, halogen, =NR c , C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy;

[0079] R a , R b , R c are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, or R a , R b together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclyl;

[0080] R 2 is selected from the group consisting of hydrogen, hydroxy, cyano, amino, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy;

[0081] R 3 is selected from the group consisting of hydrogen, hydroxy, cyano, amino, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy;

[0082] L 1 is selected from the group consisting of -O-, -N(R L1a )-, -N=, -(CR L1a R L1b )q-, -C(R L1a )=, -C(O)-, -S-, -S(O)2-, -S(O)-;

[0083] R L1a , R L1b are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl;

[0084] L 2 is selected from the group consisting of a bond, -O-, -N(R L2a )-, -C(O)-, -C(O)-N(R L2a )-, -C(R L2a R L2b)-, -C(R L2a R L2b )-N(R L2a )-, -N=C(R L2a )-, -N(R L2a )-O-;

[0085] R L2a , R L2b are each independently selected from hydrogen, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy;

[0086] R 4 is selected from the group consisting of hydroxyl, C 4A alkyl, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-C(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 6-8 membered bridged heterocyclyl, 7-11 membered spiroheterocyclyl, 6-10 membered fused heterocyclyl, 5-6 membered heteroaryl, phenyl; R 3-6 is selected from the group consisting of hydroxyl, cyano, amino, halogen, C 4A alkyl, C 1-6 haloalkyl, C 1-6 alkyl, C 1- 6alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxy-C 1-6 alkylene, C 3-6 cycloalkyl-(CH2) t -, 3-6 membered heterocyclyl-(CH2) t -;

[0087] m, n, p, q, t are each independently selected from 0, 1, 2, 3, 4.

[0088] In another embodiment of the present disclosure, the heteroatoms in the "heteroaryl", "heterocyclyl", "fused heterocyclyl", "bridged heterocyclyl", and "spiroheterocyclyl" are independently selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0089] In another embodiment of the present disclosure, the "isomers" are stereoisomers.

[0090] In another embodiment of the present disclosure, in ring B, the C 3-6 cycloalkyl is a 5-6 membered saturated monocyclic carbocyclic ring, for example

[0091] In another embodiment of the present disclosure, in ring B, the 3-6 membered heterocyclyl is a 5-6 membered saturated monocyclic ring having 1 or 2 heteroatoms selected from N and O, preferably the heteroatom is N, and the 6 membered saturated monocyclic ring having 1 heteroatom is, for example,

[0092] In another embodiment of the present disclosure, each of the 5-6 membered heteroaryl is independently a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms selected from N and O, for example,

[0093] In another embodiment of the present disclosure, each of the C 1-6 alkyl is independently C 1-4 alkyl, for example methyl, ethyl, n-propyl, or i-propyl, preferably methyl.

[0094] In another embodiment of the present disclosure, each of the C 1-4 alkyl is independently methyl, ethyl, n-propyl, or i-propyl, preferably methyl.

[0095] In another embodiment of the present disclosure, each of the haloC 1-6 alkyl is independently C 1-6 alkyl substituted with halo, the halo being F, CI, or Br, preferably F; and the C 1-6 alkyl is C 1-4 alkyl, preferably methyl; for example -OCF3or -OCHF2.

[0096] In another embodiment of the present disclosure, each of the C 1-6 alkoxy is independently C 1-4 alkoxy, for example methoxy, ethoxy, n-propoxy, or i-propoxy, preferably methoxy.

[0097] In another embodiment of the present disclosure, each of the haloC 1-6 alkoxy is independently C 1-6 alkoxy substituted with halo, the halo being F, CI, or Br, preferably F; and the C 1-6 alkoxy is C 1-4 alkoxy, preferably methoxy; for example -OCF3or -OCHF2.

[0098] In another embodiment of the present disclosure, each of the C 3-6 cycloalkyl is independently monocyclic cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, preferably cyclopropyl.

[0099] In another embodiment of the present disclosure, each of the 6-8 membered fused heterocyclyl is independently a 6-8 membered fused heterocyclyl having 1 heteroatom selected from N, for example

[0100] In another embodiment of the present disclosure, each of said 3-6 membered heterocyclyl is independently a saturated or partially saturated 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms selected from N and O, preferably N, for example

[0101] In another embodiment of the present disclosure, each of said C 2-6 alkenyl is independently C 2-4 alkenyl, for example vinyl.

[0102] In another embodiment of the present disclosure, each of said C 2-6 alkynyl is independently C 2-4 alkynyl, for example ethynyl or propynyl.

[0103] In another embodiment of the present disclosure, each of said halogen is independently F, Cl, Br or I, preferably F.

[0104] In another embodiment of the present disclosure, L 3 , R L3a , R L3b and the carbon atom to which they are attached together form a C 3-6 cycloalkyl, said C 3-6 cycloalkyl is preferably

[0105] In another embodiment of the present disclosure, L 3 , R L3a , R L3b and the carbon atom to which they are attached together form a 3-6 membered heterocyclyl, said 3-6 membered heterocyclyl is saturated, 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatoms selected from N and O, for example

[0106] In another embodiment of the present disclosure, L 3 , R L3a , R L3b and the carbon atom to which they are attached together form a C 5-9 spirocycloalkyl, said C 5-9 spirocycloalkyl is saturated, preferably a 3-membered spiro 3-membered carbocyclic ring, for example

[0107] In another embodiment of the present disclosure, each of said 6-10 membered fused heterocyclyl is independently a 5-membered fused 6-membered heterocyclyl having 1 or 2 heteroatoms selected from N and O, for example

[0108] In another embodiment of this disclosure, when R a R b When the nitrogen atom to which it is attached forms a 3-6 membered heterocyclic group, the 3-6 membered heterocyclic group is saturated or partially saturated, the heteroatom is selected from N and O, and the number of heteroatoms is 1 or 2.

[0109] In another embodiment of this disclosure, X 1 X 4 Both are N, X 2 For CR X2 X 3 For CR X3 .

[0110] In another embodiment of this disclosure, the structural unit Selected from The asterisk (*) indicates that it is connected to ring B.

[0111] In another embodiment of this disclosure, the structural unit Selected from The asterisk (*) indicates that it is connected to ring B.

[0112] In another embodiment of this disclosure, the structural unit Selected from

[0113] In another embodiment of this disclosure, the structural unit Selected from More preferably

[0114] In another embodiment of this disclosure, R X1 R X2 R X3 R X4 Each group is independently selected from hydrogen, hydroxyl, cyano, carboxyl, amino, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -L 3 -R 5 、(R a (R) b )NC(O)-, 6-8 fused heterocyclic group, C 2-4 alkenyl, C 2-4 alkynyl group; wherein, the C 1-4Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, (R a (R) b )NC(O)-, 6-8 fused heterocyclic group, C 2-4 alkenyl, C 2-4 The alkynyl group is optionally surrounded by one or more R groups. 1A The R that was replaced 1A Selected from halogen, hydroxyl, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, (R a (R) b )NC(O)-、C 1-4 Alkyl-C(O)-, Oxygenated, C 2-4 alkenyl, C 2-4 alkynyl group;

[0115] L 3 Selected from -C(R) L3a (R) L3b )-、-N(R L3c )-、-O-;

[0116] R L3a R L3b Each is independently selected from hydrogen, halogen, or R. L3a R L3b Together with the carbon atoms it is attached to, they form C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-7 Spirocycloalkyl; the C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-7 Spirocycloalkyl groups may be optionally surrounded by one or more groups selected from hydroxyl, cyano, halogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 The alkoxy group is replaced;

[0117] R L3c Selected from hydrogen, C 1-4 alkyl;

[0118] R 5 Selected from hydrogen, hydroxyl, cyano, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C1-4 alkyl-C(O)-, C 1-4 alkyl-S(O)2-, (R a )(R b )N-C(O)-, (R a )(R b )N-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-S(O)2-, C 2-4 alkenyl, C 2-4 alkynyl, said C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkyl-S(O)2-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-S(O)2-, C 2-4 alkenyl, C 2-4 alkynyl optionally substituted with one or more R 5A selected from the group consisting of hydroxy, cyano, halogen, =NR 5A , C c alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, oxo, (R 1-4 )(R d )N-;

[0119] R e , R a , R b , R c , R d , R e are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkyl-C(O)-, or R a , R b and the nitrogen atom to which they are attached collectively form a 3-6 membered heterocyclyl.

[0120] In another embodiment of the present disclosure, wherein R X1 , R X2 , R X3 , R X4 are each independently selected from the group consisting of hydrogen, hydroxy, cyano, carboxy, amino, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -L 3 -R 5 , (R a )(R b )N-C(O)-, 6-8 membered fused heterocyclyl, C 2-4 alkenyl, C 2-4 alkynyl; wherein said C 1-4 ycloalkyl, haloC 1-4 ycloalkyl, C 1-4 ycloalkyl, haloC 1-4 ycloalkyl, C 3-6 ycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, (R a )(R b )N-C(O)-, 6-8 membered fused heterocyclyl, C 2-4 alkenyl, C 2-4 alkynyl optionally substituted with one or more R 1A selected from halogen, hydroxy, cyano, amino, C 1A alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy, (R 1-4 )(R a )N-C(O)-, C b alkyl-C(O)-, oxo, C 1-4 alkenyl, C 2-4 alkynyl;

[0121] L 2-4 is selected from -C(R 3 )(R L3a )-;

[0122] R L3b , R L3a are each independently selected from hydrogen, halogen, or R L3b , R L3a together with the carbon atom to which they are attached form a C L3b ycloalkyl, 3-6 membered heterocyclyl, C 3-6 spirocycloalkyl; said C 5-7 ycloalkyl, 3-6 membered heterocyclyl, C 3-6 spirocycloalkyl optionally substituted with one or more groups selected from hydroxy, hydroxy, cyano, halogen, C 5-7 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, C 1-4 alkoxy;

[0123] R 5hydrogen, hydroxy, cyano, halogen, =NR 1-4 alkyl, halogen-C 1-4 alkyl, C 1-4 alkoxy, halogen-C 1-4 alkoxy, C 1-4 alkyl-C(O)-, C 1-4 alkyl-S(O)2-, (R a )(R b )N-C(O)-, (R a )(R b )N-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-S(O)2-, C 2-4 alkenyl, C 2-4 alkynyl, the C 1-4 alkyl, halogen-C 1-4 alkyl, C 1-4 alkoxy, halogen-C 1-4 alkoxy, C 1-4 alkyl-S(O)2-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-S(O)2-, C 2-4 alkenyl, C 2-4 alkynyl optionally substituted by one or more R 5A , R 5A is selected from the group consisting of hydroxy, cyano, halogen, =NR c , C 1-4 alkyl, halogen-C 1-4 alkyl, C 1-4 alkoxy, halogen-C 1-4 alkoxy, oxo, (R d )(R e )N-;

[0124] R a , R b , R c , R d , R e are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, halogen-C 1-4 alkyl, C 1-4 alkyl-C(O)-, or R a , R b together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclyl.

[0125] In another embodiment of the present disclosure, wherein R X1 , R X2 , R X3 , R X4Each group is independently selected from hydrogen, hydroxyl, cyano, carboxyl, amino, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -L 3 -R 5 、(R a (R) b )NC(O)-, 6-8 fused heterocyclic group; wherein, the C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, (R a (R) b )NC(O)-, 6-8 fused heterocyclic groups are optionally coupled with one or more R 1A The R that was replaced 1A Selected from halogen, hydroxyl, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, (R a (R) b )NC(O)-、C 1-4 Alkyl-C(O)-;

[0126] L 3 Selected from -C(R) L3a (R) L3b )-;

[0127] R L3a R L3b Each is independently selected from hydrogen, halogen, or R. L3a R L3b Together with the carbon atoms it is attached to, they form C 3-6 cycloalkyl, 3-6 membered heterocyclic groups; the C 3-6 Cycloalkyl, 3-6 membered heterocyclic group optionally selected by one or more hydroxyl, cyano, halogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 The alkoxy group is replaced;

[0128] R 5 Selected from hydrogen, hydroxyl, cyano, C 1-4 Alkyl-C(O)-, C 1-4Alkyl-S(O)2-, (R a (R) b )NC(O)-、(R a (R) b N-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, C 3-6 cycloalkyl-S(O)2-, the C 1-4 Alkyl-S(O)2-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, C 3-6 Cycloalkyl-S(O)2- optionally substituted with one or more R 5A Replaced by, R 5A Selected from hydroxyl, cyano, halogen, =NR c C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0129] R a R b R c Selected independently from hydrogen and C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkyl-C(O)-, or R a R b Together with the nitrogen atom it is attached to, they form 3-6 membered heterocyclic groups.

[0130] In another embodiment of this disclosure, R X1 R X2 R X3 R X4 Each group is independently selected from hydrogen, hydroxyl, cyano, carboxyl, amino, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -L 3 -R 5 ; wherein, the C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl, optionally with one or more R 1A The R that was replaced 1A Selected from halogen, hydroxyl, cyano, amino, C1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy;

[0131] L 3 Selected from -C(R) L3a (R) L3b )-, R L3a R L3b Each is independently selected from hydrogen, or R L3a R L3b Together with the carbon atoms it is attached to, they form C 3-6 cycloalkyl, 3-6 membered heterocyclic groups; the C 3-6 Cycloalkyl, 3-6 membered heterocyclic group optionally selected by one or more hydroxyl, cyano, halogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 The alkoxy group is replaced;

[0132] R 5 Selected from hydrogen, hydroxyl, cyano, C 1-4 Alkyl-C(O)-, C 1-4 Alkyl-S(O)2-, (R a (R) b )NC(O)-、C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, optionally enclosed by one or more R 5A Replaced by, R 5A Selected from hydroxyl, cyano, halogen, =NR c C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0133] R a R b R c Selected independently from hydrogen and C 1-4 Alkyl, Halogenated C 1-4 Alkyl, or R a R b Together with the nitrogen atom it is attached to, they form 3-6 membered heterocyclic groups.

[0134] In another embodiment of this disclosure, R X2 Selected from hydrogen, cyano, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, (R a (R)b )N-C(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -L 3 -R 5 , C 2-6 alkenyl and C 2-6 alkynyl; wherein said 3-6 membered heterocyclyl is optionally substituted with one or more R 1A ; said R 1A is selected from halo;

[0135] L 3 is -C(R L3a )(R L3b )-;

[0136] R L3a , R L3b and the carbon atom to which they are attached together form a C 3-6 cycloalkyl or C 5-9 spirocycloalkyl;

[0137] R 5 is selected from cyano, (R a )(R b )N-C(O)- and 5-6 membered heteroaryl; said 5-6 membered heteroaryl is optionally substituted with one or more C 1-6 alkyl;

[0138] R a and R b are each independently selected from hydrogen and C 1-6 alkyl.

[0139] In another embodiment of the disclosure, wherein R X3 is selected from hydrogen, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, -L 3 -R 5 and 6-8 membered fused heterocyclyl; wherein said C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 6-8 membered fused heterocyclyl is optionally substituted with one or more R 1A ; said R 1A is selected from halo, hydroxy, cyano, C 1-6 alkyl, (R a )(R b )N-C(O)-, C 1-6 alkyl-C(O)- and oxo;

[0140] L 3 is selected from -C(R L3a )(R L3b )-;

[0141] R L3a , R L3b are each independently selected from hydrogen, halogen, and C 1-6 alkyl, or R L3a and R L3b together with the carbon atom to which they are attached form a C 3- 6cycloalkyl, 3-6 membered heterocyclyl, C 5-9 spirocycloalkyl; said C 3-6 6cycloalkyl, 3-6 membered heterocyclyl, C 5-9 spirocycloalkyl is optionally substituted with one or more groups selected from halogen and C 1-6 alkyl;

[0142] R 5 is selected from hydroxy, cyano, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-C(O)-, C 1-6 alkyl-S(O)2-, (R a )(R b )N-C(O)-, (R a )(R b )N-, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl-S(O)2-, and C 2-6 alkynyl; said C 1-6 alkyl, C 1-6 alkyl-S(O)2-, 3-6 membered heterocyclyl, or 5-6 membered heteroaryl is optionally substituted with one or more R 5A ; R 5A is selected from cyano, halogen, =NR c , C 1-6 alkyl, C 1-6 alkoxy, oxo, and (R d )(R e )N-;

[0143] R a , R b , R c , R d , R e are each independently selected from hydrogen, C 1-6 alkyl, and C 1-6 alkyl-C(O)-.

[0144] In another embodiment of the disclosure, wherein R X2 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, and -L 3 -R 5 ;

[0145] L 3 -C(R) L3a (R) L3b )-;

[0146] R L3a R L3b Together with the carbon atoms it is attached to, they form C 3-6 cycloalkyl;

[0147] R 5 Selected from cyano, (R a (R) b )NC(O)- and 5-6-membered heteroaryl; said 5-6-membered heteroaryl is optionally surrounded by one or more C 1-6 Alkyl groups are substituted;

[0148] R a and R b Selected independently from C 1-6 Alkyl group. In another embodiment of this disclosure, R... X3 Selected from hydrogen, C 3-6 cycloalkyl and -L 3 -R 5 The aforementioned C 3-6 The cycloalkyl group may be optionally replaced by one or more halogens;

[0149] L 3 Selected from -C(R) L3a (R) L3b )-;

[0150] R L3a R L3b Selected independently from hydrogen and C respectively 1-6 Alkyl, or R L3a R L3b Together with the carbon atoms it is attached to, they form C 3-6 cycloalkyl;

[0151] R 5 Selected from cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-S(O)2-, (R a (R) b )NC(O)-, 3-6 membered heterocyclic groups, 5-6 membered heteroaryl groups and C 2-6 alkynyl group; the C group mentioned above 1-6 Alkyl, 3-6 membered heterocyclic or 5-6 membered heteroaryl, optionally enclosed by one or more R 5A Replaced by, R 5A Selected from C 1-6 Alkyl, C1-6 alkoxy and oxo;

[0152] R a and R b are each independently selected from C 1-6 alkyl.

[0153] In another embodiment of the disclosure, wherein R X3 is selected from C 3-6 cycloalkyl and -L 3 -R 5 ; said C 3-6 cycloalkyl is optionally substituted with one or more halogen;

[0154] L 3 is selected from -C(R L3a )(R L3b )-;

[0155] R L3a , R L3b and the carbon atom to which they are attached together form a C 3-6 cycloalkyl;

[0156] R 5 is selected from cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-S(O)2-, (R a )(R b )N-C(O)-, 3-6 membered heterocyclyl, 5-6 membered heteroaryl and C 2-6 alkynyl; said C 1-6 alkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted with one or more R 5A , R 5A is selected from C 1-6 alkyl, C 1-6 alkoxy and oxo;

[0157] R a and R b are each independently selected from C 1-6 alkyl.

[0158] In another embodiment of the disclosure, wherein R X3 is selected from C 3-6 cycloalkyl and -L 3 -R 5 ; said C 3-6 cycloalkyl is optionally substituted with one or more halogen;

[0159] L 3 is selected from -C(R L3a )(RL3b

[0160] R L3a , R L3b and the carbon atom to which they are attached together form a C 3-6 cycloalkyl;

[0161] R 5 is selected from cyano and haloC 1-6 alkyl.

[0162] In another embodiment of the present disclosure, wherein R X1 , R X2 , R X3 , R X4 are each independently selected from H, -CHF2, -CN,

[0163] In another embodiment of the present disclosure, wherein R X1 , R X2 , R X3 , R X4 are each independently selected from

[0164] In another embodiment of the present disclosure, wherein R X1 , R X2 , R X3 , R X4 are each independently selected from -CH3, -CH2CH3, -CH(CH3)2, -CF3, -CH=CH2, -CºCH, -CºCCH3,

[0165] In another embodiment of the present disclosure, wherein R X1 , R X2 , R X3 , R X4 are each independently selected from -NH2,

[0166] In another embodiment of the present disclosure, R X1 is H.

[0167] In another embodiment of the present disclosure, R X2 is H, -NH2, -OCH3, -CN, -CHF2, -CH2CH3, -CH(CH3)2, -CF3, -CH=CH2, -CH3, -CºCH, -CºCCH3, is preferably H, -CH3,​ or -CH=CH2.

[0168] In another embodiment of the present disclosure, R X3 is H, -CN, -CF3,

[0169] is H,

[0170] In another embodiment of the present disclosure, R X2 is selected from H.

[0171] In another embodiment of the present disclosure, R X4 is H.

[0172] In another embodiment of the present disclosure, wherein ring B is selected from 5-6 membered heterocyclyl, C 4-6 cycloalkyl.

[0173] In another embodiment of the present disclosure, wherein ring B is selected from 5-6 membered heterocyclyl with 1 heteroatom being N, preferably 6 membered heterocyclyl with 1 heteroatom being N.

[0174] In another embodiment of the present disclosure, wherein ring B is selected from “*” indicates the connection to L 1 .

[0175] In another embodiment of the present disclosure, wherein ring B is selected from “*” indicates the connection to L 1 .

[0176] In another embodiment of the present disclosure, wherein R 2 is selected from H, OH, F, Cl, -CH3, -CH2CH3; n is selected from 0 or 1.

[0177] In another embodiment of the present disclosure, wherein R 2 is deuterium; n is 0 or 1.

[0178] In another embodiment of the present disclosure, wherein L 1 is selected from -O-, -N(R L1a )-, -C(R L1a R L1b )-, -C(R L1a )=; R L1a , R L1b are each independently selected from H, halogen, C 1-4 alkyl;

[0179] Preferably, R L1a , R L1b are independently from each other selected from H, F, CI, -CH3.

[0180] In another embodiment of the present disclosure, wherein L 1 is selected from -O-, -NH-, -CHF-, -CF2-, -CH2-, -CH=, -CF=.

[0181] In another embodiment of the present disclosure, wherein L 1 is selected from -O-, -N(R L1a )-, -C(R L1a R L1b )-, -C(R L1a )=; R L1a , R L1b are independently from each other selected from H, halogen, C 1-4 alkyl; the “*” end indicates the attachment to ring C.

[0182] In another embodiment of the present disclosure, L 1 is selected from -O-, -NH-, -CHF-, -CF2-, -CH2-, -CH=, -CF=; the “*” end indicates the attachment to ring C.

[0183] In another embodiment of the present disclosure, L 1 is selected from -O-, -CH2- or -CH=; the “*” end indicates the attachment to ring C.

[0184] In another embodiment of the present disclosure, wherein L 1 is selected from -O-.

[0185] In another embodiment of the present disclosure, wherein ring C is selected from phenyl.

[0186] In another embodiment of the present disclosure, R 3 is selected from halogen, C 1-4 alkyl, halogenated C 1-4 alkyl.

[0187] In another embodiment of the present disclosure, R 3 is selected from halogen or C 1-6 alkyl, preferably halogen.

[0188] In another embodiment of the present disclosure, wherein R 3 is selected from F, CI, -CH3, -CF3.

[0189] In another embodiment of the present disclosure, wherein the structural unit is

[0190] In another embodiment of the present disclosure, wherein the structural unit is

[0191] In another embodiment of the present disclosure, wherein the structural unit is

[0192] In another embodiment of the present disclosure, wherein the structural unit is

[0193] In another embodiment of the present disclosure, wherein L 2 is selected from the group consisting of a chemical bond, -N(R L2a )-, -C(O)-, -C(O)-N(R L2a )-, -C(R L2a R L2b )-, -C(R L2a R L2a )-N(R L2a )-, -N=C(R L2a )-, -N(R L2b )-O-; R 1-4 , R 1-4 are each independently selected from the group consisting of H, OH, halogen, C 2 alkyl, C 2 alkoxy.

[0194] In another embodiment of the present disclosure, wherein L 2 is selected from the group consisting of a chemical bond, -NH-, -CH2-NH-, -C(O)-NH-, -C(O)-, -N=C(CH3)-, -NH-O-.

[0195] In another embodiment of the present disclosure, wherein L 2 is selected from the group consisting of a chemical bond, -NH-.

[0196] In another embodiment of the present disclosure, wherein L 2 is selected from the group consisting of a chemical bond, -NH- or -C(O)-NH-, preferably a chemical bond.

[0197] In another embodiment of the present disclosure, wherein L 2 is selected from the group consisting of a chemical bond, -N(R L2a )-, -C(O)-, -C(O)-N(R L2a )-, -C(R L2a R L2b )-, -C(R L2a R L2b )-N(R L2a )-, -N=C(R L2a )-, -N(RL2a )-O-; R L2a , R L2b are each independently selected from H, OH, halo, C 1-4 alkyl, C 1-4 alkoxy; the asterisked end indicates attachment to R 4 .

[0198] In another embodiment of the disclosure, L 2 is selected from a bond, -NH-, *-CH2-NH-, *-C(O)-NH-, -C(O)-, *-N=C(CH3)-, *-NH-O-; the asterisked end indicates attachment to R 4 .

[0199] In another embodiment of the disclosure, R 4 is selected from C 4A alkyl, C 1-6 cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered fused heterocyclyl, 5-6 membered heteroaryl, and phenyl, optionally substituted with one or more R 3-6 ; R 4A is independently selected from hydroxyl, cyano, amino, halo, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, (R a )(R b )N-, oxo, and deuterated C 1-6 alkyl.

[0200] In another embodiment of the disclosure, R 4 is selected from 3-6 membered heterocyclyl and 5-6 membered heteroaryl, optionally substituted with one or more R 4A ; R 4A is independently selected from amino, halo, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, oxo, and deuterated C 1-6 alkyl.

[0201] In another embodiment of the disclosure, R 4 is selected from 3-6 membered heterocyclyl, optionally substituted with one or more R 4A ; R 4A is independently selected from C 1-6 alkyl, haloC 1-6 alkyl, oxo, and deuterated C 1-6 alkyl.

[0202] In another embodiment of the disclosure, R 4 is selected from 3-6 membered heterocyclyl, optionally substituted with one or more R 4Asubstituted C 1-4 alkyl, haloC 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 fused heterocyclyl, phenyl;

[0203] R 4A selected from hydrogen, hydroxyl, cyano, amino, halogen, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, (R a )(R b )N-, oxo, deuterated C 1-4 alkyl;

[0204] R a , R b are each independently selected from hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkyl-C(O)-.

[0205] In another embodiment of the disclosure, R 4 is selected from the following groups, optionally substituted with one or more R 4A substituted C 1-4 alkyl, haloC 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 fused heterocyclyl, phenyl;

[0206] R 4A selected from hydroxyl, cyano, amino, halogen, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, (R a )(R b )N-, oxo, deuterated C 1-4 alkyl;

[0207] R a , R b are each independently selected from hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkyl-C(O)-.

[0208] In another embodiment of the disclosure, wherein R 4 is selected from the following groups, optionally substituted with one or more R 4A substituted C 1-4 alkyl, haloC 1-4 alkyl, C3-6 cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl;

[0209] R 4A Selected from hydroxyl, cyano, amino, halogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, (R a (R) b )N-;

[0210] R a R b Selected independently from hydrogen and C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkyl-C(O)-.

[0211] In another embodiment of this disclosure, R 4 Selected from one or more R 4A The following groups are substituted: C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl;

[0212] R 4A Selected from hydroxyl, cyano, amino, halogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl group.

[0213] In another embodiment of this disclosure, R 4 Selected from one or more R 4A Substituted 5-6 membered heterocyclic groups; R 4A As defined by any of the aforementioned schemes.

[0214] In another embodiment of this disclosure, R 4 Selected from -CH3, -CH2CH3, -CH(CH3)2,

[0215] In another embodiment of this disclosure, R 4 Selected from

[0216] In another embodiment of this disclosure, R 4 Selected from

[0217] In another embodiment of the present disclosure, wherein R 4 is selected from

[0218] In another embodiment of the present disclosure, wherein R 4 is selected from

[0219] In another embodiment of the present disclosure, wherein R 4 is selected from

[0220] In another embodiment of the present disclosure, the compound of formula (I), pharmaceutically acceptable salts, isomers thereof, having the structure as shown below:

[0221] X 1 , X 2 , X 4 , R x2 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , R 5 , ring B, ring C, n, p are as defined in any of the preceding embodiments.

[0222] In another embodiment of the present disclosure, the compound of formula (I), pharmaceutically acceptable salts, isomers thereof, having the structure as shown below:

[0223] R 4-1 is as defined as R 4 ;

[0224] Preferably R 4-1 is selected from the following groups optionally substituted with one or more R 4A ; 3-6 membered heterocyclyl, 5-6 membered heteroaryl;

[0225] R x2 , R 2 , R 3 , R 4A , L 1 , L 3 , R L3a , R L3b , R 5 , n, p are as defined in any of the preceding embodiments.

[0226] In another embodiment of the present disclosure of formula (I-B), (I-B-2), R 4-1 is selected from optionally substituted 5-6 membered heterocyclyl; R 4A is selected from optionally substituted 5-6 membered heterocyclyl; R 4A is as defined in any of the preceding embodiments.

[0227] In another embodiment of the present disclosure of formula (I-B), (I-B-2), R 4-1 is selected from optionally substituted 5-6 membered heterocyclyl; R 4A is selected from optionally substituted 5-6 membered heterocyclyl; R 4A is as defined in any of the preceding embodiments.

[0228] In one embodiment of the present disclosure of formula (I-B-2), R 3 is selected from halogen;

[0229] R 4-1 is selected from optionally substituted 5-6 membered heterocyclyl; R 4A is selected from optionally substituted 5-6 membered heterocyclyl; R

[0230] R 4A is selected from hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl;

[0231] R L3a , R L3b are each independently selected from hydrogen, halogen, C 1-4 alkyl, or R L3a , R L3b together with the atom to which they are attached form a C 3-6 cycloalkyl;

[0232] R 5 is selected from cyano, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl.

[0233] In another embodiment of the present disclosure of formula (I-B), (I-B-2), R 4-1 is selected from

[0234] In one embodiment of the present disclosure of formula (I-B-3), R 3 is selected from halogen;

[0235] R 4A is selected from hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, halogenated C1-4 Alkoxy, deuterated C 1-4 alkyl;

[0236] R L3a R L3b Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, or R L3a R L3b Together with the atoms it is attached to, they form C 3-6 cycloalkyl;

[0237] R 5 Selected from cyano, halogen, C 1-4 Alkyl, Halogenated C 1-4 alkyl.

[0238] In another embodiment of this disclosure, the compound of formula (I), its pharmaceutically acceptable salt, and its isomers have the following structure:

[0239] Among them, R X2 Selected from H, C 1-4 alkyl;

[0240] R X3 Selected from C 3-6 cycloalkyl, 3-6 membered heterocyclic groups, -L 3 -R 5 The C mentioned above 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, optionally surrounded by one or more R groups 1A The R that was replaced 1A Selected from cyano, halogen, C 1-4 Alkyl, Halogenated C 1-4 alkyl;

[0241] L 3 Selected from -C(R) L3a (R) L3b )-;

[0242] R L3a R L3b Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, or R L3a R L3b Together with the atoms it is attached to, they form C 3-6 cycloalkyl;

[0243] R 5 Selected from cyano, halogen, C 1-4 Alkyl, Halogenated C 1-4 alkyl.

[0244] R 4-1 Selected from one or more R 4Asubstituted 5-6 membered heterocyclyl;

[0245] R 4A selected from hydrogen, oxo, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, deuterated C 1-4 alkyl;

[0246] R 3 selected from halogen, C 1-4 alkyl, haloC 1-4 alkyl; p is selected from 1, 2, 3.

[0247] In another embodiment of the present disclosure, the compound of formula (I-B-4) has the structure shown below: 4-1 selected from

[0248] R 4A selected from hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, deuterated C 1-4 alkyl.

[0249] In another embodiment of the present disclosure, the compound of formula (I), a pharmaceutically acceptable salt thereof, or an isomer thereof, has the structure shown below:

[0250] wherein R 2 is H or deuterium;

[0251] R 3 is H or F;

[0252] R X2 and R X3 are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, and -L 3 -R 5 ; said C 3-6 cycloalkyl is optionally substituted with one or more halogens;

[0253] L 3 is -C(R L3a )(R L3b )-;

[0254] R L3a , R L3b are each independently selected from hydrogen and C 1-6 alkyl, or R L3a , RL3b together with the carbon atom to which it is attached forms C 3-6 cycloalkyl;

[0255] R 5 selected from cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-S(O)2-, (R a )(R b )N-C(O)-, 3-6 membered heterocyclyl, 5-6 membered heteroaryl and C 2-6 alkynyl; said C 1-6 alkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted with one or more R 5A substituents, R 5A selected from C 1-6 alkyl, C 1-6 alkoxy and oxo;

[0256] R a and R b are each independently selected from C 1-6 alkyl; L 2 is selected from a single bond, -NH- and -C(O)-NH-;

[0257] R 4 is selected from the group consisting of 3-6 membered heterocyclyl and 5-6 membered heteroaryl optionally substituted with one or more R 4A substituents; R 4A is independently selected from amino, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, oxo and deuterated C 1-6 alkyl.

[0258] In another embodiment of the disclosure, the compound of formula (I), a pharmaceutically acceptable salt thereof, or an isomer thereof, has the structure shown below:

[0259] wherein,

[0260] R X2 is selected from hydrogen and C 1-6 alkyl, preferably hydrogen;

[0261] R X3 is selected from C 3-6 cycloalkyl (preferably cyclopropyl) and -L 3 -R 5 ; said C 3-6 cycloalkyl is optionally substituted with one or more halogen (preferably fluorine);

[0262] L 3 Selected from -C(R) L3a (R) L3b )-;

[0263] R L3a R L3b Together with the carbon atoms it is attached to, they form C 3-6 Cycloalkyl groups (preferably 3-membered saturated carbon rings);

[0264] R 5 Selected from cyano and halogenated C 1-6 Alkyl groups (preferably methyl groups substituted with 1, 2, or 3 fluorine atoms);

[0265] R 4 Selected from one or more R 4A The following groups can be substituted: 3-6 membered heterocyclic groups (preferably 6-membered partially saturated monocyclic rings with N heteroatoms and 1 or 2 heteroatoms); R 4A Selected independently from C 1-6 Alkyl (preferably methyl), halogenated C 1-6 Alkyl groups (preferably methyl groups substituted with 1, 2, or 3 fluorine atoms), oxo and deuterated C atoms 1-6 Alkyl group (preferably a methyl group substituted with 1, 2 or 3 deuterium atoms).

[0266] In another embodiment of this disclosure, the compound of formula (I), its pharmaceutically acceptable salt, or its isomer has the following structure:

[0267] R X2 Selected from hydrogen and C 1-6 Alkyl groups, preferably hydrogen;

[0268] R X3 Selected from C 3-6 cycloalkyl (preferably cyclopropyl) and -L 3 -R 5 The C mentioned above 3-6 The cycloalkyl group may optionally be replaced by one or more halogens (preferably fluorine);

[0269] L 3 Selected from -C(R) L3a (R) L3b )-;

[0270] R L3a R L3b Together with the carbon atoms it is attached to, they form C 3-6 Cycloalkyl groups (preferably 3-membered saturated carbon rings);

[0271] R 5 Selected from cyano and halogenated C 1-6alkyl (preferably methyl) substituted with 1, 2 or 3 fluorines, deuterated C1-4alkyl (preferably methyl substituted with 1, 2 or 3 deuteriums) and C1-4alkoxy (preferably methoxy);

[0272] R 4 is selected from the group consisting of 5-6 membered heteroaryl (preferably heteroatoms are N and O, number of heteroatoms is 1 or 2 or 3) or 3-6 membered heterocyclyl (preferably heteroatoms are N, number of heteroatoms is 1 or 2 of 6 membered partially saturated monocyclic ring); preferably 3-6 membered heterocyclyl; 4A is selected from the group consisting of 5-6 membered heteroaryl (preferably heteroatoms are N and O, number of heteroatoms is 1 or 2 or 3) or 3-6 membered heterocyclyl (preferably heteroatoms are N, number of heteroatoms is 1 or 2 of 6 membered partially saturated monocyclic ring); preferably 3-6 membered heterocyclyl;

[0273] R 4A is independently selected from the group consisting of oxo, halogen, cyano, (R a )(R b )N-, C 1-6 alkyl (preferably methyl), haloC 1-6 alkyl (preferably methyl substituted with 1, 2 or 3 fluorines), deuterated C1-4alkyl (preferably methyl substituted with 1, 2 or 3 deuteriums) and C1-4alkoxy (preferably methoxy); 1-6 alkyl (preferably methyl substituted with 1, 2 or 3 fluorines), deuterated C1-4alkyl (preferably methyl substituted with 1, 2 or 3 deuteriums) and C1-4alkoxy (preferably methoxy); 1-6 alkyl (preferably methyl substituted with 1, 2 or 3 fluorines), deuterated C1-4alkyl (preferably methyl substituted with 1, 2 or 3 deuteriums) and C1-4alkoxy (preferably methoxy);

[0274] R a , R b are each independently selected from the group consisting of hydrogen, C 1-6 alkyl.

[0275] In another embodiment of the present disclosure, there is provided a compound as shown below, a pharmaceutically acceptable salt, isomer thereof,

[0276] The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) as described above, a pharmaceutically acceptable salt, isomer thereof and one or more pharmaceutically acceptable carriers.

[0277] In another embodiment of the present disclosure, the content of the compound, isomer or pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from 0.1 mg-1000 mg.

[0278] In another embodiment of the present disclosure, the content of the compound, pharmaceutically acceptable salt, isomer thereof in the pharmaceutical composition is 1%-95% (weight percent).

[0279] In another embodiment of the present disclosure, the pharmaceutically acceptable carrier in the pharmaceutical composition comprises one or more of a filler, a disintegrant, a binder, a glidant, a lubricant.

[0280] The present disclosure also provides the use of the above-mentioned compound of formula (I), pharmaceutically acceptable salts, isomers thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating a GPR6-mediated disease.

[0281] In another embodiment of the present disclosure, the GPR6-mediated disease includes Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, drug addiction, eating disorder, cognitive disorder, schizophrenia, bipolar disorder, epilepsy, Alzheimer's disease, anxiety and depression. Preferably, the GPR6-mediated disease is Parkinson's disease.

[0282] The present disclosure also provides the use of the above-mentioned compound of formula (I), pharmaceutically acceptable salts, isomers thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating a GPR6-mediated disease.

[0283] The present disclosure also provides a method for treating a GPR6-mediated disease, which is characterized in that a therapeutically effective amount of the above-mentioned compound of formula (I), pharmaceutically acceptable salts, isomers thereof is provided to a subject. Preferably, the GPR6-mediated disease is as described above.

[0284] Explanation and Definition

[0285] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indefinite or unclear if not specifically defined, but should be interpreted in accordance with the ordinary meaning in the art.

[0286] The term "pharmaceutically acceptable" means those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0287] The term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds prepared by reacting the compounds with a suitable inorganic or organic acid or base. These salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting a purified compound with a suitable inorganic or organic acid or base, and then isolating the salt. When the compound contains a relatively acidic moiety, such as -COOH, -OH, -SO3H, etc., base addition salts can be prepared by contacting the neutral form of the compound with a suitable inorganic or organic base, such as a metal cation or an amine, to provide a salt. When the compound contains a relatively basic moiety, such as -NH2, etc., acid addition salts can be prepared by contacting the neutral form of the compound with a suitable inorganic or organic acid, such as a metal cation or an amine, to provide a salt.

[0288] The term "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for the delivery of biologically active agents to animals, particularly mammals, and more particularly humans, and includes, for example, adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow conditioners, disintegrants, wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents, and dispersing agents, depending upon the nature of the dosage form and the means of administration. Pharmaceutically acceptable carriers are formulated in accordance with routine procedures, such as those described in Remington's Pharmaceutical Sciences, 19thEd. (Mack Publishing Company, 1995). The appropriate formulation is chosen to suit the mode of delivery and the nature of the active agent(s) to be delivered. The pharmaceutically acceptable carrier includes both aqueous and nonaqueous media, as well as solid and semi-solid dosage forms. Such carriers include a wide variety of ingredients and additives, which are well known in the art, and are included in the formulation for a variety of reasons, such as to stabilize the active agent(s), to bind agents together, etc.

[0289] The term "effective prophylactic or therapeutic amount" refers to the amount of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or an isomer thereof, which is sufficient to treat a disorder at a reasonable benefit / risk ratio applicable to any medical treatment and / or prophylaxis. It will be appreciated that the appropriate amount of the compound of Formula I or a pharmaceutically acceptable salt thereof and compositions of the present disclosure to be administered will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.

[0290] The term "enantiomer" refers to a stereoisomer whose mirror image is not superimposable. The term "tautomer" refers to a functional group isomer that has different hydrogen bonding sites and exists in equilibrium with another structure that is not superimposable mirror image. The term "diastereomer" refers to a stereoisomer that has two or more chiral centers and is not a mirror image of itself. The term "cis-trans isomer" refers to different spatial configurations of a molecule that exist due to the inability of a double bond or ring-forming carbon atom single bond to rotate freely. The term "stereoisomer" refers mainly to isomers containing chiral centers, including enantiomers, diastereomers, and racemates, non-racemic mixtures; "stereoisomer" includes, but is not limited to, absolute configuration R and absolute configuration S containing one chiral center, a mixture of R and S configuration isomers containing one chiral center, and diastereomers containing 2-4 chiral centers. The term "atropisomer" refers to a stereoisomer that can be separated due to the hindrance or very slow rotation of a single bond. The stereoisomers of the compounds of the present disclosure can be prepared by chiral synthesis or chiral reagents or other conventional techniques. For example, one enantiomer of a compound of the present disclosure can be prepared by asymmetric catalysis techniques or chiral auxiliary derivatization techniques. Or by chiral resolution techniques, to obtain a single stereoisomer from a mixture. Or directly prepared using chiral starting materials. The separation of optically pure compounds in the present disclosure is usually achieved using preparative chromatography, using chiral chromatographic columns to separate chiral compounds.

[0291] The absolute stereochemistry of the compounds can be confirmed by conventional techniques. For example, single crystal X-ray diffraction, or by the chiral structure of the starting material and the reaction mechanism of asymmetric synthesis. Or after resolution, by comparison with the product of absolute configuration. The compounds marked as "absolute configuration unknown / undetermined" in this paper are usually resolved from racemic compounds by chiral preparative SFC into single isomers, and then characterized and tested.

[0292] The compounds of the present disclosure can exist in the form of one of the isomers, or in the form of a mixture of isomers, and the compounds of the present disclosure include various isomers and mixtures thereof.

[0293] The term "optionally substituted" in the present disclosure refers to two cases: one or more hydrogen atoms of the substituent group can be "substituted" or "not substituted" by one or more substituents.

[0294] When a bond in a substituent structure is interrupted by a broken line, it indicates that the bond is the point of attachment of the substituent, for example indicates that the pyrimidine ring is attached to the given group or given formula through a C atom. The occurrence of a dash "-" in a substituent structure indicates the point of attachment for the substituent, for example -SCH3is attached to the given group or given formula through the sulfur atom.

[0295] indicates the absolute configuration of a stereogenic center, i.e. R or S configuration. indicates the cis or trans configuration, a double solid bond or a double dashed bond indicates the cis configuration, a solid-dashed bond indicates the trans configuration.

[0296] When a bond of a substituent can cross-link to a ring, it indicates that the substituent can bond to any atom on the ring. For example, the structural element indicates that the substituent R can be substituted at any position on the benzene ring. In the compounds of the present disclosure, the L group can be attached to any bondable site in the target structure.

[0297] When a listed substituent is not specified as to its attachment point to the given group or given formula, then the substituent can be attached by any bondable atom thereof.

[0298] When any variable (e.g. R d ) occurs more than one time in a compound or substituent or group of compounds or substituents, its definition in each occurrence is independent of its definition at every other occurrence. For example, indicates that the cyclopentyl group is substituted with 3 R d groups, and each R d group has independent options. For example, the substituent group "(R a )(R b )N-", which can be an optional group for R X1 , R X2 , R X3 , R X4 , R 5 , R 4A , where the definitions of R a , R b are independent of each other in each variable.

[0299] Unless otherwise specified, the term "halogen" or "halo" means a fluorine, chlorine, bromine, or iodine atom.

[0300] Unless otherwise specified, the term "alkyl" means a straight or branched chain saturated aliphatic hydrocarbon radical derived from an alkane by removal of one hydrogen. For example "C 1-10"alkyl" refers to a straight or branched hydrocarbon group having 1 to 20 carbon atoms, including "Ci, C2, C3, C4, C5, C6, C7, C8, C9, C10, Cn, C12, C13, C14, C15, C16, C17, C18, C19, and C20alkyl". Specific examples include, but are not limited to: methyl, ethyl, n-propyl, i-propyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, and the like. 10 "alkyl", "C 1-6 "alkyl", "C 1- "alkyl", "C 1-3 "alkyl"; specific examples include, but are not limited to: methyl, ethyl, n-propyl, i-propyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, and the like.

[0301] Unless otherwise specified, the term "alkenyl" means a straight or branched chain hydrocarbon group having at least one carbon-carbon double bond, derived by the removal of one hydrogen atom from a straight or branched chain alkene, including "Ci, C2, C3, C4, C5, C6, C7, C8, C9, C10, Cn, C12, C13, C14, C15, C16, C17, C18, C19, and C20alkenyl". Specific examples include, but are not limited to: -CH=CH2, -CH=CHCH3, -C(CH2)=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, and the like. 2-6 "alkenyl", "C 2-5 "alkenyl", "C 2-4 "alkenyl", "C 2-3 "alkenyl"; specific examples include, but are not limited to: -CH=CH2, -CH=CHCH3, -C(CH2)=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, and the like.

[0302] Unless otherwise specified, the term "alkynyl" means a straight or branched chain hydrocarbon group having at least one carbon-carbon triple bond, derived by the removal of one hydrogen atom from a straight or branched chain alkyne, including "Ci, C2, C3, C4, C5, C6, C7, C8, C9, C10, Cn, C12, C13, C14, C15, C16, C17, C18, C19, and C20alkynyl". Specific examples include, but are not limited to: -C≡CH, -C≡CHCH3, HC≡CHCH2-, HC≡C-C≡C-, and the like. 2-5 "alkynyl", "C 2-4 "alkynyl", "C 2-3 "alkynyl"; specific examples include, but are not limited to: -C≡CH, -C≡CHCH3, HC≡CHCH2-, HC≡C-C≡C-, and the like.

[0303] Unless otherwise specified, the term "haloalkyl" means an alkyl group in which one or more hydrogen atoms have been replaced by a halogen atom. Preferably, the haloalkyl group is a haloC 1-6 alkyl, more preferably a haloC 1-4 alkyl. Examples of haloalkyl groups include, but are not limited to monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like. Alkyl groups are as previously defined.

[0304] Unless otherwise specified, the term "alkoxy" means an alkyl group, as defined herein, attached to the parent molecular group by an oxygen atom, i.e., "alkyl-O-". Includes "Ci, C2, C3, C4, C5, C6, C7, C8, C9, C10, Cn, C12, C13, C14, C15, C16, C17, C18, C19, and C20alkoxy". Specific examples include, but are not limited to methoxy, ethoxy, propyloxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropyloxy, 1,2-dimethylpropyloxy, and the like; preferably, the "alkoxy" groups of the present disclosure are C 1-6 alkoxy" (structure C 1-6 alkoxy" (structure C 1-4 alkoxy"; specific examples include, but are not limited to methoxy, ethoxy, propyloxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropyloxy, 1,2-dimethylpropyloxy, and the like; preferably, the "alkoxy" groups of the present disclosure are C 1-4 alkoxy", more preferably C1-3 alkoxy.

[0305] Unless otherwise specified, the term "haloalkoxy" means an alkoxy group in which one or more hydrogen atoms are replaced by a halogen atom, i.e., "alkyl-O-". Included within this term are "haloC 1-6 alkoxy", "haloC 1-4 alkoxy", "haloC 1-4 alkoxy", "haloC

[0306] Unless otherwise specified, the term "ring" means a saturated, partially saturated, or unsaturated monocyclic ring, and polycyclic rings, including spiro, fused, or bridged rings. A group derived from a ring by removal of a hydrogen atom is referred to as a "ring group", which includes monovalent rings, divalent rings (often referred to as alyl rings), trivalent rings, tetravalent rings, etc., depending on the number of substituents attached to the ring. The present disclosure does not specifically distinguish the valence of the ring group for the description of "ring groups". Representative "ring groups" include substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. The term "hetero" means substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms (also referred to as heteroatom groups), which are generally selected from N, O, S, P, and oxidized forms generally include NO, SO, S(O)2, P(O), and the nitrogen atom can be substituted, i.e., NR (R is H or other substituents as defined herein). The number of atoms in a ring is often defined as the number of members of the ring, e.g., "3-6 membered heterocycloalkyl" means a ring of 3-6 atoms arranged in a ring, each ring optionally containing 1-3 heteroatoms and / or heteroatom groups, i.e., N, O, S, NO, SO, S(O)2, P(O), or NR, each ring optionally substituted with R groups, R being a group as defined herein.

[0307] Unless otherwise specified, the term "cycloalkyl" means a saturated cyclic group derived from a monocyclic cycloalkane by removal of a hydrogen atom. The carbon atoms in the cycloalkyl group are optionally further oxidized, i.e., to form C(O). The cycloalkyl group includes "C 3-8 cycloalkyl", "C 3-6 cycloalkyl", "C 3-5 cycloalkyl", "C 4-6 cycloalkyl". Specific examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

[0308] Unless otherwise specified, the term "spirocycloalkyl" means a cyclic structure formed from two or more cycloalkyl groups sharing a ring atom with each other, and the carbon atoms in the spirocycloalkyl group can be further oxidized, i.e., to form C(O). The spirocycloalkyl group includes "6-11 membered spirocycloalkyl", "7-11 membered spirocycloalkyl", "7-9 membered spirocycloalkyl", and specific examples include, but are not limited to

[0309] Unless otherwise specified, the term "heterocyclyl" refers to non-aromatic, saturated and partially saturated monocyclic groups having at least one ring atom which is a heteroatom or heteroatom group, i.e., including heterocycloalkyl, heterocycloalkenyl. Ring carbon atoms in the heterocyclyl group are optionally oxo, i.e., -C(O). Preferably, the heteroatoms are independently selected from 1-3 N and / or O. Preferably, the heterocyclyl group is a "nitrogen-containing heterocyclyl" group, meaning that at least one ring atom is N, and optionally containing one or more additional heteroatoms; preferably, the "nitrogen-containing heterocyclyl" group contains 1 N atom and 0-2 atoms selected from N and / or O and / or S. Preferably, the "nitrogen-containing heterocyclyl" group contains 1 N atom and 0-1 atoms selected from O and / or S. Preferably, the heterocyclyl group is an "oxygen-containing heterocyclyl" group, meaning that at least one ring atom is O, and optionally containing one or more additional heteroatoms; preferably, the "oxygen-containing heterocyclyl" group contains 1 O atom and 0-2 atoms selected from N and / or O. Heterocyclyl groups according to the present disclosure include "5-10 membered heterocycloalkenyl," "6-10 membered heterocycloalkenyl," "5-6 membered heterocyclyl," "5-8 membered heterocycloalkenyl," "5-7 membered heterocycloalkenyl," "6-7 membered heterocycloalkenyl," "6-7 membered nitrogen-containing heterocycloalkenyl," "5-6 membered nitrogen-containing heterocycloalkenyl," "5-6 membered oxygen-containing heterocycloalkenyl." Specific examples of heterocyclyl groups include, but are not limited to: azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl,

[0310] Unless otherwise specified, the term "fused heterocyclyl" refers to a saturated or partially saturated, non-aromatic ring group having at least one ring atom which is a heteroatom, formed by two or more cyclic structures sharing two adjacent atoms with each other; ring carbon atoms in the fused heterocyclyl group can be further oxo, forming C(O). Fused heterocyclyl groups according to the present disclosure include "6-14 membered fused heterocyclyl," "6-10 membered fused heterocyclyl," "6-8 membered fused heterocyclyl," "8-9 membered fused heterocyclyl"; the manner of fusion can be 5-6 membered heterocyclyl and 5-6 membered heterocyclyl, 5-6 membered heterocyclyl and 5-6 membered cycloalkyl, benzo 5-6 membered heterocyclyl, benzo 5-6 membered saturated heterocyclyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered saturated heterocyclyl, benzo 5-6 membered heterocyclyl and 5-6 membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl and 5-6 membered heterocyclyl, benzo 5-6 membered cycloalkyl and 5-6 membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered cycloalkyl and 5-6 membered heterocyclyl; specific examples of fused heterocyclyl groups include, but are not limited to: , and the like.

[0311] Unless otherwise specified, the term "bridged heterocyclyl" refers to a saturated or partially saturated (i.e., bridged heterocycloalkenyl) ring structure formed from two or more cyclic structures sharing two non-adjacent ring atoms with each other, and wherein at least one ring is a heterocyclic ring. Ring carbon atoms in a bridged heterocyclyl group are optionally oxidized, i.e., form -C(O). "Bridged heterocyclyl" includes, for example, "5-11 membered bridged heterocyclyl," "6-11 membered bridged heterocyclyl," "5-10 membered bridged heterocyclyl," "7-10 membered bridged heterocyclyl," "6-9 membered bridged heterocyclyl," "7-8 membered bridged heterocyclyl," "9-10 membered bridged heterocyclyl," "6-10 membered bridged heterocycloalkenyl," "6-8 membered bridged heterocycloalkenyl," and the like. Preferably, the heteroatoms are independently selected from 1-3 N and / or O. Preferably, the bridged heterocyclyl is a "nitrogen-containing bridged heterocyclyl," which refers to a bridged heterocyclyl having at least one ring atom that is N, and optionally having one or more additional heteroatoms; preferably, the "nitrogen-containing bridged heterocyclyl" has 1 N atom and 0-2 atoms selected from N and / or O and / or S. Preferably, the "nitrogen-containing bridged heterocyclyl" has 1 N atom and 0-1 atoms selected from O and / or S. Preferably, the bridged heterocyclyl is an "oxygen-containing bridged heterocyclyl," which refers to a bridged heterocyclyl having at least one ring atom that is O, and optionally having one or more additional heteroatoms; preferably, the "oxygen-containing bridged heterocyclyl" has 1 O atom and 0-2 atoms selected from N and / or O. Specific examples of bridged (hetero)cyclyl groups include, but are not limited to: and the like.

[0312] Unless otherwise specified, the term "spiroheterocyclyl" refers to a saturated or partially saturated ring structure formed from two or more cyclic structures sharing one carbon atom with each other, and wherein at least one ring is a heterocyclic ring. Ring carbon atoms in a spiroheterocyclyl group are optionally oxidized, i.e., form -C(O). It includes, but is not limited to, ring structures formed from a heterocyclyl spiroheterocyclyl, a heterocyclyl spirocycloalkyl. The spiroheterocyclyl preferably contains 1-2 heteroatoms selected from N and / or O, more preferably 1 N and 0-1 NR or O heteroatoms. The spiroheterocyclyl is preferably a "nitrogen-containing spiroheterocyclyl," which refers to a spiroheterocyclyl having at least one ring atom that is N. The spiroheterocyclyl includes "7-11 membered spiroheterocyclyl," "7-9 membered spiroheterocyclyl," "7-11 membered nitrogen-containing spiroheterocyclyl," "7-9 membered nitrogen-containing spiroheterocyclyl." Specific examples include, but are not limited to: and the like.

[0313] Unless otherwise indicated, the term "heteroaryl" refers to monocyclic groups having aromaticity, with at least one ring atom being a heteroatom and / or heteroatomic group, preferably the heteroatom(s) is / are independently selected from 1-3 N and / or O. The heteroaryl group includes "5-6 membered heteroaryl" and "5-6 membered nitrogen-containing heteroaryl", the latter refers to at least one ring atom being N, and optionally containing one or more other heteroatoms; specific examples include, but are not limited to, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl.

[0314] Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture and purification, formulation into an effective therapeutic agent.

[0315] The preparation methods of some compounds in the present disclosure refer to the preparation methods of the aforementioned analogous compounds. Those skilled in the art should know that when using or referring to using the preparation methods cited, the feeding ratio of reactants, reaction solvents, reaction temperature, etc. can be appropriately adjusted according to the different reactants. DETAILED DESCRIPTION

[0316] The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by the combination of the specific embodiments with other chemical synthetic methods well known to those skilled in the art, and equivalent alternatives well known to those skilled in the art, preferred embodiments include but are not limited to the examples of the present disclosure.

[0317] 1. Instruments and materials used

[0318] The structures of the compounds of the present disclosure are determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS), or ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The NMR chemical shift (δ) is given in units of parts per million (ppm). The NMR is measured by Bruker Neo400M or Bruker Ascend 400 nuclear magnetic instrument, and the measuring solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), heavy water (D2O), and the internal standard is tetramethylsilane (TMS).

[0319] LC-MS determination with Agilent 1260-6125B single quadrupole mass spectrometer, mass spectrometer (ion source is electrospray ionization).

[0320] UPLC-MS determination with Waters UPLC H-class SQD mass spectrometer (ion source is electrospray ionization).

[0321] HPLC determination uses Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.

[0322] Preparation HPLC uses Waters 2555-2489 (10 μm, ODS250 cm x 5 cm) or GILSON C 281.

[0323] Chiral HPLC determination uses waters acquity UPC2; column is Daicel chiralpak AD-H (5um, 4.6*250mm) and (3um, 4.6*100mm).

[0324] Supercritical fluid chromatography (SFC) uses waters SFC 150MGM.

[0325] The starting materials and intermediates directly used in the present disclosure can be synthesized according to methods known in the art, or purchased commercially; the experimental methods in the examples without specific conditions are generally according to conventional conditions, or according to the conditions suggested by the raw material or commodity manufacturers. The reagents without specific sources are conventional reagents purchased on the market.

[0326] The monitoring of the reaction progress in the examples can use conventional methods such as thin layer chromatography (TLC), LC-MS, etc., and the eluent system used for column chromatography and the developing agent system used for thin layer chromatography can be composed of one or more of the following solvents: dichloromethane, methanol, n-hexane, ethyl acetate, petroleum ether, ethyl acetate, acetone, dichloromethane, etc., and the volume ratio of the solvents is adjusted according to the different polarity of the compounds, and a small amount of basic or acidic reagents can also be added for adjustment, such as triethylamine, acetic acid, trifluoroacetic acid, etc.

[0327] In the examples of the present disclosure, when "M" appears, it means "mol / L", which is the concentration of the reagent.

[0328] The abbreviations used in the examples of the present disclosure and their corresponding chemical names are as follows:

[0329] 2. Example

[0330] Intermediate INT-1: 4-(2,4-difluorophenoxy)piperidine hydrochloride

[0331] Operation steps:

[0332] Step A: 2,4-difluorophenol (1.0 g, 7.69 mmol) was dissolved in THF (20 mL) at room temperature, and 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (3.09 g, 15.37 mmol) and triphenylphosphine (3.0 g, 11.45 mmol) were added. The mixture was cooled to 0 °C under nitrogen protection, and then DEAD (2.32 g, 13.32 mmol) was added dropwise. The reaction solution was heated to 60 °C and stirred for 16 hours. After cooling to room temperature, water was added for quenching, and ethyl acetate (10 mL x 3 times) was used for extraction. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained after concentration was purified by silica gel column chromatography to obtain 1.3 g of compound 4-(2,4-difluorophenoxy)piperidine-1-carboxylic acid tert-butyl ester.

[0333] MS (ESI) M / Z: 258.0 [M+H-56] + .

[0334] 1 H NMR (400 MHz, CDCl3) δ 6.92-6.86 (m, 1H), 6.81-6.76 (m, 1H), 6.74-6.67 (m, 1H), 4.27-4.22 (m, 1H), 3.69-3.63 (m, 2H), 3.25-3.18 (m, 2H), 1.85-1.78 (m, 2H), 1.72-1.63 (m, 2H), 1.40 (s, 9H).

[0335] Step B: 4-(2,4-difluorophenoxy)piperidine-1-carboxylic acid tert-butyl ester (2.06 g, 6.57 mmol) was dissolved in ethyl acetate (40 mL) at room temperature, and hydrochloric acid / dioxane (10 mL, 4 mol / L) was added. The mixture was stirred at 25 °C for 4 hours. The reaction solution was concentrated and filtered to obtain 2.09 g of compound 4-(2,4-difluorophenoxy)piperidine hydrochloride.

[0336] MS (ESI) M / Z: 214.0 [M+H] + .

[0337] 1H NMR (400 MHz, DMSO-d6) δ 9.03 - 8.93 (m, 2H), 7.35 - 7.31 (m, 1H), 7.32 - 7.28 (m, 1H), 7.08 - 7.00 (m, 1H), 4.62 - 4.53 (m, 1H), 3.20 (br, 2H), 3.05 (br, 2H), 2.13 - 2.04 (m, 2H), 1.89 - 1.81 (m, 2H).

[0338] Intermediate INT-2: 2-(tert-Butoxycarbonyl)-amino-6-tri-n-butylstannyl-pyridine

[0339] Step A: 6-Bromo-pyridin-2-amine (2.0 g, 11.56 mmol), TEA (3.5 g, 34.68 mmol), 4-dimethylaminopyridine (0.70 g, 5.78 mmol) and di-tert-butyl dicarbonate (7.56 g, 34.68 mmol) were dissolved in DCM (20 mL) and heated to 50 °C and stirred for 16 h. The reaction was cooled to room temperature, diluted with DCM (100 mL) and water (100 mL), extracted with DCM (100 mL x 2 times), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3.01 g of compound N,N-bis-tert-butoxycarbonyl-6-bromo-pyridin-2-amine.

[0340] 1 H NMR (400 MHz, CDCl3) δ 7.58 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 1.46 (s, 18H).

[0341] Step B: N,N-bis-tert-butoxycarbonyl-6-bromo-pyridin-2-amine (500 mg, 1.34 mmol), tri-n-butyltin (777 mg, 1.34 mmol) and Pd(PPh3)4(77 mg, 0.07 mmol) were dissolved in 1,2-dichloroethane (5 mL) and the reaction was heated to 80 °C and stirred for 20 h. The reaction was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3 times), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 330 mg of compound 2-(tert-butoxycarbonyl)-amino-6-tri-n-butylstannyl-pyridine.

[0342] MS (ESI) M / Z: 585 [M+H] + .

[0343] Intermediate INT-3: (R)-1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6- ((tetrahydrofuran-3-yl)amino)pyrazin-2-yl)cyclopropane-1-carboxylic acid

[0344] Operation steps:

[0345] Step A: Compound 2,5-dichloropyrazine (4 g, 26.85 mmol) and 1-tert-butyl-3- ethyl propanediolate (5.56 g, 29.54 mmol) were dissolved in DMSO (40 mL) at room temperature, and cesium carbonate (17.50 g, 53.7 mmol) was added to the above reaction solution. After the reaction system was protected by nitrogen, it was heated to 100°C and stirred for 4 hours. After cooling to room temperature, water (40 mL) was added to quench the reaction, and EA (50 mL x 3 times) was used for extraction. The combined organic phase was washed with saturated sodium chloride aqueous solution (20 mL x 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 7.5 g of compound 1-tert-butyl-3-ethyl-2-(5-chloropyrazin-2-yl) propanediolate.

[0346] MS (ESI) M / Z: 245.1 [M-55] + .

[0347] Step B: Compound 1-tert-butyl-3-ethyl-2-(5-chloropyrazin-2-yl) propanediolate (8.2 g, 27.27 mmol) was dissolved in DCM (80 mL) at room temperature, and trifluoroacetic acid (62.19 g, 545.4 mmol) was added dropwise to the above reaction solution. The reaction system was stirred for 4 hours under nitrogen protection. Water (40 mL) was added to quench the reaction, and DCM (50 mL x 3 times) was used for extraction. The combined organic phase was washed with sodium chloride aqueous solution (20 mL x 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 5 g of compound 2-(5-chloropyrazin-2-yl) ethyl acetate.

[0348] MS (ESI) M / Z: 201.1 [M+H] + .

[0349] Step C: Compound ethyl 2-(5-chloropyrazin-2-yl)acetate (4.5 g, 22.43 mmol) and diphenyl(vinyl)sulfonium triflate (0.43 g, 1.2 mmol) were dissolved in DMSO (45 mL) at room temperature, then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 g, 2 mmol) was added, and the reaction system was continuously stirred for 0.5 h under nitrogen protection. Water (50 mL) was added to quench the reaction, and the mixture was extracted with EA (50 mL x 3 times), and the combined organic phase was washed with sodium chloride aqueous solution (20 mL x 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 4.2 g of compound ethyl 1-(5-chloropyrazin-2-yl)cyclopropane-1-carboxylate.

[0350] MS (ESI) M / Z: 227.1 [M+H] + .

[0351] Step D: Compound ethyl 1-(5-chloropyrazin-2-yl)cyclopropane-1-carboxylate (1 g, 4.41 mmol), potassium fluoride (0.26 g, 4.41 mmol) and DIEA (1.14 g, 8.82 mmol) were dissolved in DMSO (3 mL) at room temperature. The reaction system was heated to 100°C and stirred for 2 h under nitrogen protection. After cooling to room temperature, water (10 mL) was added to quench the reaction, and the mixture was extracted with EA (10 mL x 3 times), and the combined organic phase was washed with sodium chloride aqueous solution (20 mL x 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 0.6 g of compound ethyl 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carboxylate.

[0352] MS (ESI) M / Z: 404.2 [M+H] + .

[0353] Step E: Compound 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1- carboxylate (0.48 g, 1.19 mmol) and 1-bromopyrrolidine-2,5-dione (0.21 g, 1.19 mmol) were dissolved in DMF (5 mL) and acetic acid (5 mL) at room temperature, the reaction system was continued to stir for 2 hours under nitrogen protection. To the reaction solution, saturated sodium bicarbonate (20 mL) was added to quench, extracted with ethyl acetate (30 mL x 3 times), the combined organic phase was washed with sodium chloride aqueous solution (20 mL x 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 0.48 g of compound 1-(6-bromo-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carboxylate.

[0354] MS (ESI) M / Z: 482.1 [M+H] + .

[0355] Step F: Compound 1-(6-bromo-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1- carboxylate (0.35 g, 0.73 mmol), (R)-3-aminotetrahydrofuran (0.13 g, 1.46 mmol), Pd2(dba)3 (0.067 g, 0.073 mmol), XPhos (0.042 g, 0.088 mmol) and sodium tert-butoxide (0.14 g, 1.46 mmol) were dissolved in toluene (7 mL) at room temperature, the reaction system was heated to 100°C and continued to stir for 2 hours under nitrogen protection. After cooling to room temperature, water (10 mL) was added to the reaction solution to quench, the mixture was extracted with ethyl acetate (20 mL x 3 times), the combined organic phase was washed with sodium chloride aqueous solution (20 mL x 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 0.05 g of compound (R)-1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-((tetrahydrofuran-3-yl)amino)pyrazin-2-yl)cyclopropane-1-carboxylate.

[0356] MS (ESI) M / Z: 461.2 [M+H] + .

[0357] Intermediate INT-4: (R)-1-(6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazin-2-yl)cyclopropane-1-carboxylic acid

[0358] Procedure steps:

[0359] Step A: Compound 1 -(5-chloropyrazin-2-yl)cyclopropane-1 -carboxylate (1 g, 4.41 mmol), (R)-3-aminotetrahydrofuran (0.38 g, 4.41 mmol), potassium fluoride (0.26 g, 4.41 mmol) and DIEA (1.14 g, 8.82 mmol) were dissolved in DMSO (3 mL) at room temperature. The reaction was heated to 130 °C in a microwave and stirred for 4 h under nitrogen. After cooling to room temperature, the crude product was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel to give 0.22 g of 1 -(5-{[(3R)-oxolanyl-3-yl]amino}pyrazin-2-yl)cyclopropane-1 - carboxylic acid ethyl ester.

[0360] MS (ESI) M / Z: 278.2 [M+H] + .

[0361] Step B: Compound 1 -(5-{[(3R)-oxolanyl-3-yl]amino}pyrazin-2-yl)cyclopropane-1 - carboxylic acid ethyl ester (0.35 g, 1.26 mmol) and 1 -bromopyrrolidine-2,5-dione (0.22 g, 1.26 mmol) were dissolved in DMF (3 mL) and acetic acid (3 mL) at room temperature. The reaction was stirred for 2 h under nitrogen. The reaction was quenched by adding saturated sodium bicarbonate (20 mL) and the mixture was extracted with ethyl acetate (20 mL x 3 times). The combined organic phase was washed with aqueous sodium chloride solution (20 mL x 2 times), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 0.35 g of 1 -(6-bromo-5-{[(3R)-oxolanyl-3-yl]amino}pyrazin-2-yl)cyclopropane-1 - carboxylic acid ethyl ester.

[0362] MS (ESI) M / Z: 356.1 [M+H] + .

[0363] Step C: Compound 1-(6-bromo-5-{[(3R)-oxolan-3-yl]amino}pyrazin-2-yl)cyclopropane- 1 -carboxylate (0.35 g, 0.98 mmol), 4-(2,4-difluorophenoxy)piperidine (0.21 g, 0.98 mmol), Pd2(dba)3(0.090 g, 0.098 mmol), XPhos (0.056 g, 0.12 mmol) and sodium tert-butoxide (0.19 g, 1.96 mmol) were dissolved in toluene (6 mL) and the reaction mixture was heated to 100 °C under nitrogen atmosphere for 2 h. After cooling to room temperature, the reaction was quenched by adding water (10 mL) and the mixture was extracted with ethyl acetate (10 mL x 3 times). The combined organic phase was washed with aqueous sodium chloride solution (20 mL x 2 times), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 0.1 g of compound 1-(6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-{[(3R)-oxolan-3-yl]amino}pyrazin-2-yl)cyclopropane-1-carboxylic acid.

[0364] MS (ESI) M / Z: 461.2 [M+H] + .

[0365] Intermediate INT-5: 1-(5-chloro-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile

[0366] Procedure:

[0367] Step A: 2,6-dichloropyrazine (3 g, 20.14 mmol) was dissolved in dimethyl sulfoxide (30 mL) under ice water bath, then cesium carbonate (19.7 g, 60.42 mmol) and tert-butyl 2-cyanoacetate (3.13 g, 22.15 mmol) were added portionwise successively. The reaction mixture was heated to 100 °C for 2 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was extracted with ethyl acetate (50 mL x 3 times). The combined organic phase was washed with water (100 mL x 3 times) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4.6 g of crude tert-butyl 2-(6-chloropyrazin-2-yl)-2-cyanoacetate.

[0368] MS (ESI) M / Z: 254.3 [M+H] + .

[0369] Step B: tert-Butyl 2-(6-chloropyrazin-2-yl)-2-cyanoacetate (8.5 g, 33.56 mmol) was dissolved in dimethyl sulfoxide (85 mL) at room temperature, and a saturated aqueous solution of sodium chloride (8.5 mL) was added. The reaction was heated to 120 °C for 2 hours. After the reaction was returned to room temperature, it was concentrated under reduced pressure, quenched with water (300 mL), extracted with ethyl acetate (150 mL x 3 times), and the combined organic phases were washed with water (450 mL) and saturated brine (300 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 4.7 g of the target molecule 2-(6-chloropyrazin-2-yl)acetonitrile.

[0370] MS (ESI) M / Z: 154.1 [M+H] + .

[0371] 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 0.7 Hz, 1H), 8.68 (s, 1H), 4.37 (d, J = 0.7 Hz, 2H).

[0372] Step C: 2-(6-Chloropyrazin-2-yl)acetonitrile (800 mg, 5.21 mmol) was dissolved in DMF (17 mL) in an ice water bath, and then diphenyl(vinyl)sulfonium trifluoromethanesulfonate (3.78 g, 10.42 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.38 g, 15.63 mmol) were added sequentially to the reaction. The reaction was allowed to react at room temperature for 2 hours. The reaction was quenched by adding water (50 mL), extracted with ethyl acetate (20 mL x 3 times), and the combined organic phases were washed with water (50 mL x 2 times) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 830 mg of the target molecule 1-(6-chloropyrazin-2-yl)cyclopropane-1-carbonitrile.

[0373] MS (ESI) M / Z: 180.1 [M+H] + .

[0374] 1 H NMR (400 MHz, DMSO-d6) δ 8.82-8.55 (m, 2H), 1.99-1.92 (m, 2H), 1.81-1.73 (m, 2H).

[0375] Step D: 4-(2,4-difluorophenoxy)piperidin-l-(5H)-one (2.15 g, 10.0 mmol), l-(6-chloropyrazin-2-yl)cyclopropane-l-carbonitrile (1.80 g, 10.0 mmol), Pd2(dba)3 (920 mg, 1.0 mmol), 2-dicyclohexylphospho-2',4',6'-triisopropylbiphenyl (960 mg, 2.01 mmol) and cesium carbonate (6.55 g, 20.11 mmol) were dissolved in 1,4-dioxane (36 mL) and the reaction mixture was heated to 90 °C for 2 h. After the reaction mixture was cooled to room temperature, it was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 1.95 g of l-(6-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropane-l- carbonitrile.

[0376] MS (ESI) M / Z: 357.2 [M+H] + .

[0377] 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.96 (s, 1H), 7.36 - 7.25 (m, 2H), 7.05 - 6.98 (m, 1H), 4.64 - 4.53 (m, 1H), 3.99 - 3.87 (m, 2H), 3.47 - 3.36 (m, 2H), 2.01 - 1.94 (m, 2H), 1.79 - 1.73 (m, 2H), 1.68 - 1.59 (m, 4H).

[0378] Step E: l-(6-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropane-l- carbonitrile (1 g, 2.81 mmol) was dissolved in DMF (20 mL) and acetic acid (20 mL) at room temperature, and NCS (412.6 mg, 3.09 mmol) was added. The reaction mixture was heated to 50 °C for 16 h. After the reaction mixture was cooled to room temperature, water (50 mL) was added to quench the reaction, and the pH was adjusted to 7 with saturated aqueous NaHC03solution. The mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with water (150 mL) and saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 120 mg of l-(5-chloro-6-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropane-l- carbonitrile.

[0379] MS (ESI) M / Z: 391.1 [M+H] + .

[0380] 1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.36 - 7.25 (m, 2H), 7.05 - 6.98 (m, 1H), 4.62 - 4.53 (m, 1H), 3.76 - 3.67 (m, 2H), 3.32 - 3.26 (m, 2H), 2.08 - 2.00 (m, 2H), 1.88 - 1.81 (m, 2H), 1.80 - 1.68 (m, 4H).

[0381] Example 1:

[0382] (R)-1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-((tetrahydrofuran-3-yl)amino)pyrazin-2-yl)cyclopropane-1-carbonitrile

[0383] Procedure:

[0384] Step A: 2-chloro-5-methylpyrazine (2 g, 15.56 mmol), NBS (2.77 g, 15.56 mmol) and AIBN (0.26 g, 1.56 mmol) were added into carbon tetrachloride (20 mL) at room temperature, the reaction was heated to 100 °C for 4 hours. After the reaction was returned to room temperature, saturated aqueous sodium thiosulfate solution (50 mL) was added to quench, extracted with ethyl acetate (50 mL x 3 times), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography to give 1.50 g of the target molecule 2-(bromomethyl)-5-chloropyrazine.

[0385] 1 H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 1.4 Hz, 1H), 8.49 (d, J = 1.4 Hz, 1H), 4.55 (s, 2H).

[0386] Step B: 2-(bromomethyl)-5-chloropyrazine (500 mg, 2.41 mmol), TMSCN (263.01 mg, 2.65 mmol) and TBAF (3.62 mL, 1M) were added into THF (10 mL) at room temperature, the reaction was carried out at room temperature for 1 hour. Quench with water (30 mL), extracted with ethyl acetate (30 mL x 3 times), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography to give 198 mg of the target molecule 2-(5-chloropyrazin-2-yl)acetonitrile.

[0387] 1 H NMR (400 MHz, CDCl3) δ 8.59 (t, J = 1.7 Hz, 1H), 8.51 - 8.47 (m, 1H), 3.96 (s, 2H).

[0388] Step C: 2-(5-chloropyrazin-2-yl)acetonitrile (198 mg, 1.29 mmol), diphenyl(ethenyl)sulfonium triflate (560.98 mg, 1.55 mmol) and DBU (589.17 mg, 3.87 mmol) were dissolved in DMSO (5 mL) at room temperature, and the mixture was reacted at room temperature for 1 h. Water (30 mL) was added for quenching, and the mixture was extracted with ethyl acetate (20 mL x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 151.2 mg of the target compound 1-(5-chloropyrazin-2-yl)cyclopropane-1-carbonitrile.

[0389] 1 H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 1.4 Hz, 1H), 8.43 (d, J = 1.5 Hz, 1H), 1.88-1.74 (m, 4H).

[0390] Step D: 1-(5-chloropyrazin-2-yl)cyclopropane-1-carbonitrile (100 mg, 0.56 mmol), 4-(2,4-difluorophenoxy)piperidine (143.28 mg, 0.67 mmol), Pd2(dba)3 (51.28 mg, 0.056 mmol) and xPhos (32.04 mg, 0.067 mmol) and sodium tert-butoxide (161.45 mg, 1.68 mmol) were added to toluene (5 mL) at room temperature, and the mixture was heated to 90 °C in a sealed tube for 2 h. Water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 109.3 mg of the target compound 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile.

[0391] MS (ESI) M / Z: 357.2 [M+H] + .

[0392] Step E: 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1- carbonitrile (55 mg, 0.15 mmol), NBS (29.37 mg, 0.17 mmol) were dissolved in a mixed solvent of DMF (1 mL) and acetic acid (1 mL) at room temperature, and the reaction solution was heated to 40 °C for 1 h. The reaction was quenched by adding saturated sodium thiosulfate (20 mL), extracted with ethyl acetate (20 mL x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 50 mg of the target compound 1-(6-bromo-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile.

[0393] MS (ESI) M / Z: 435.1 [M+H] + .

[0394] Step F: 1-(6-bromo-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1- carbonitrile (50 mg, 0.11 mmol), Pd2(dba)3 (10 mg, 0.011 mmol) and xPhos (6.3 mg, 0.013 mmol) were added to anhydrous toluene (2 mL), and then (3R)-oxapentan-3-amine (14.37 mg, 0.17 mmol) and sodium tert-butoxide (31.71 mg, 0.33 mmol) were added. The reaction solution was heated to 90 °C for 2 h in a sealed tube. Water (10 mL) was added to quench the system, extracted with ethyl acetate (10 mL x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to obtain 15.1 mg of the target product 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-{[(3R)-oxapentan-3-yl]amino}pyrazin-2-yl)cyclopropane-1-carbonitrile.

[0395] MS (ESI) M / Z: 442.2 [M+H] + .

[0396] 1H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 7.33-7.22 (m, 2H), 7.06-6.95 (m, 1H), 6.18 (d, J = 5.6 Hz, 1H), 4.57-4.44 (m, 1H), 4.38-4.23 (m, 1H), 3.93-3.81 (m, 2H), 3.73-3.69 (m, 1H), 3.57-3.54 (m, 1H), 3.35-3.28 (m, 2H), 2.96-2.88 (m, 2H), 2.23-2.14 (m, 1H), 2.13-2.00 (m, 2H), 1.99-1.92 (m, 1H), 1.91-1.82 (m, 2H), 1.71-1.54 (m, 4H).

[0397] Example 2:

[0398] (R)-1-(6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazin-2-yl)cyclopropane-1-carbonitrile

[0399] Procedure:

[0400] Step A: 1-(5-chloropyrazin-2-yl)cyclopropane-1-carbonitrile (250 mg, 1.39 mmol), Pd2(dba)3 (127.29 mg, 0.14 mmol) and XPhos (79.52 mg, 0.17 mmol) were added into anhydrous toluene (10 mL) at room temperature, then (R)-tetrahydrofuran-3-amine (181.65 mg, 2.08 mmol) and sodium tert-butoxide (400.74 mg, 0.15 mmol) were added, and the tube was heated to 90 °C for 2 hours. After the reaction solution returned to room temperature, water (10 mL) was added to quench the system, and ethyl acetate (10 mL x 3 times) was extracted, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 104 mg of the target product (R)-1-(5-(tetrahydrofuran-3-yl)amino)pyrazin-2-yl)cyclopropane-1-carbonitrile.

[0401] MS (ESI) M / Z: 231.2 [M+H] + .

[0402] Step B: (R)-1-(5-(tetrahydrofuran-3-yl)amino)pyrazin-2-yl)cyclopropane-1- carbonitrile (104 mg, 0.45 mmol) was dissolved in a mixture solvent of DMF (3 mL) and acetic acid (3 mL) at room temperature, NBS (80.09 mg, 0.45 mmol) was added, and the reaction was heated to 40 °C for 1 h. After the reaction was cooled to room temperature, saturated sodium thiosulfate (2 mL) was added to quench the reaction, and ethyl acetate (20 mL x 3 times) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 63.5 mg of the target product (R)-1-(6-bromo-5-(tetrahydrofuran-3-yl)amino)pyrazin-2-yl)cyclopropane-1-carbonitrile.

[0403] MS (ESI) M / Z: 309.1 [M+H] + .

[0404] Step C: (R)-1-(6-bromo-5-(tetrahydrofuran-3-yl)amino)pyrazin-2-yl)cyclopropane-1- carbonitrile (32 mg, 0.13 mmol), 4-(2,4-difluorophenoxy)piperidine (36.03 mg, 0.17 mmol), Pd2(dba)3 (11.90 mg, 0.013 mmol), XPhos (7.44 mg, 0.016 mmol), and sodium tert-butoxide (37.48 mg, 0.39 mmol) were added to anhydrous toluene (2 mL) at room temperature, and the reaction was heated to 90 °C in a sealed tube for 2 h. After the reaction was cooled to room temperature, water (5 mL) was added to quench the reaction, and ethyl acetate (20 mL x 3 times) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to obtain 9.5 mg of the target product (R)-1-(6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazin-2-yl)cyclopropane-1-carbonitrile

[0405] MS (ESI) M / Z: 442.2 [M+H]+.

[0406] 1H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.33-7.25 (m, 2H), 7.03-6.98 (m, 1H), 6.06 (d, J = 6.0 Hz, 1H), 4.56-4.51 (m, 1H), 4.42-4.38 (m, 1H), 3.93-3.81 (m, 2H), 3.71-3.66 (m, 1H), 3.59-3.55 (m, 1H), 3.42 (s, 2H), 3.00-2.91 (m, 2H), 2.21-2.13 (m, 1H), 2.07-2.01 (m, 2H), 1.99-1.94 (m, 1H), 1.89-1.79 (m, 2H), 1.64-1.61 (m, 2H), 1.53-1.50 (m, 2H).

[0407] Example 3:

[0408] 1-(6-(6-aminopyridin-2-yl)-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile

[0409] Procedure:

[0410] Step A: 1-(6-bromo-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile (50 mg, 0.115 mmol) was dissolved in toluene (1 mL) at room temperature, (6-(tributylstannyl)pyridin-2-yl)carbamic acid tert-butyl ester (270 mg, 0.46 mmol), dichlorobis(triphenylphosphine)palladium (16.23 mg, 0.02 mmol), lithium chloride (15 mg, 0.33 mmol) were added, the reaction was heated to 110 °C and stirred for 4 hours. The reaction was cooled to room temperature and filtered, the organic phase was concentrated under reduced pressure, the crude product was purified by silica gel column chromatography to obtain 44 mg of (6-(6-(1-cyanocyclopropyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)pyridin-2-yl)carbamic acid tert-butyl ester.

[0411] MS (ESI) M / Z: 649.5 [M+H] + .

[0412] Step B: (6-(6-(1-cyanocyclopropyl)-3-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)pyridin-2- yl)amino bis-methylate tert-butyl ester (44 mg, 0.68 mmol) was dissolved in dichloromethane / trifluoroacetic acid (1 mL / 1 mL) at room temperature, the reaction was stirred at room temperature for 5 hours. The pH was adjusted to weak alkaline by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, dried, the crude product was purified by silica gel column to obtain 16.45 mg of target molecule 1-(6-(6-aminopyridin-2-yl)-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropane-l-carbonitrile.

[0413] MS (ESI) M / Z: 449.5 [M+H] + .

[0414] 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.53 - 7.46 (m, 1H), 7.29 - 7.22 (m, 2H), 7.01 - 6.94 (m, 1H), 6.86 (d, J = 7.0 Hz, 1H), 6.45 (d, J = 8.2 Hz, 1H), 6.09 (s, 2H), 4.49 - 4.43 (m, 1H), 3.52 - 3.42 (m, 2H), 3.06 - 3.01 (m, 2H), 1.94 - 1.84 (m, 2H), 1.74 - 1.71 (m, 2H), 1.63 - 1.55 (m, 4H).

[0415] Example 4:

[0416] (R)-3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-(l-methyl-lH-l,2,4-triazol-5-yl)cyclopropyl)-N- (tetrahydrofuran-3-yl)pyrazin-2-amine

[0417] Procedure:

[0418] Step A: To ethyl l-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropane-l-carboxylate (630 mg, 1.56 mmol) in mixed solvent DMF (3 mL), acetic acid (3 mL) was added NCS (271 mg, 2.03 mmol) at room temperature, the reaction was stirred at room temperature overnight. Water was added to the reaction, extracted with ethyl acetate, the organic phase was combined and washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated. The obtained residue was purified by silica gel column chromatography to obtain 540 mg of target molecule ethyl l-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropane-l-carboxylate.

[0419] MS (ESI) M / Z: 438.6 [M+H] + .

[0420] 1 H NMR (400 MHz, CDC13) δ 8.32 (s, 1H), 7.04-6.97 (m, 1H), 6.90-6.84 (m, 1H), 6.83-6.76 (m, 1H), 4.45-4.38 (m, 1H), 4.20-4.12 (m, 2H), 3.81-3.68 (m, 2H), 3.38-3.25 (m, 2H), 2.16-2.06 (m, 2H), 2.03-1.92 (m, 2H), 1.68 (q, J = 4.1 Hz, 2H), 1.44-1.38 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H).

[0421] Step B: Compound 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l- yl)pyrazin-2-yl)cyclopropane-l-carboxylate (540 mg, 1.24 mmol) was dissolved in a mixture solution of tetrahydrofuran / methanol / water (2 mL / 2 mL / 1 mL) at room temperature, then lithium hydroxide (60 mg, 2.48 mmol) was added to the reaction solution, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate, washed, dried, and concentrated under reduced pressure to give 480 mg of the target product 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l- yl)pyrazin-2-yl)cyclopropane-l-carboxylic acid.

[0422] MS (ESI) M / Z: 410.3 [M+H] + .

[0423] Step C: 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2- yl)cyclopropane-l-carboxylic acid (200 mg, 0.49 mmol), ammonium chloride (52 mg, 0.98 mmol), 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (281 mg, 0.74 mmol), and DIEA (190 mg, 1.47 mmol) were dissolved in DMF (3 mL) at room temperature, and the reaction was allowed to proceed at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel to give 180 mg of the target molecule 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l- yl)pyrazin-2-yl)cyclopropane-l-carboxamide.

[0424] MS (ESI) M / Z: 409.3 [M+H] + .

[0425] Step D: To a solution of 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1- yl)pyrazin-2-yl)cyclopropane-1-carboxamide (150 mg, 0.37 mmol) in tetrahydrofuran (2.5 mL) was added N,N-dimethylformamide dimethyl acetal (3 mL) at room temperature, the reaction was heated to 50 °C and stirred for 1 h. The reaction was concentrated to give 170 mg of the target molecule (E)-1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)-N-((dimethylamino)methylene)cyclopropane-1-carboxamide as a crude product.

[0426] MS (ESI) M / Z: 464.4 [M+H] + .

[0427] Step E: To a solution of (E)-1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1- yl)pyrazin-2-yl)-N-((dimethylamino)methylene)cyclopropane-1-carboxamide (150 mg, 0.37 mmol) in acetic acid (2 mL) was added methylhydrazine sulfate (59 mg, 0.41 mmol) at room temperature, the reaction was heated to 80 °C and stirred for 1 h. After the reaction was cooled to room temperature, water was added, and the reaction was extracted with ethyl acetate. The organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give 60 mg of the target product 3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(1-(1-methyl-1H-1,2,4-triazol-5-yl)cyclopropyl)pyrazine.

[0428] MS (ESI) M / Z: 447.3 [M+H] + .

[0429] 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.71 (s, 1H), 7.35 - 7.24 (m, 2H), 7.07 - 6.97 (m, 1H), 4.60 - 4.51 (m, 1H), 3.74 (s, 3H), 3.66 - 3.55 (m, 2H), 3.23 - 3.16 (m, 2H), 2.08 - 1.97 (m, 2H), 1.82 - 1.71 (m, 2H), 1.63 - 1.56 (m, 2H), 1.53 - 1.47 (m, 2H).

[0430] Step F: 3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(l-(l-methyl-lH- l,2,4-triazol-5-yl)cyclopropyl)pyrazine (60 mg, 0.13 mmol), (R)-tetrahydrofuran-3- amine (23 mg, 0.26 mmol), palladium acetate (3 mg, 0.013 mmol), 1,1'-binaphthalene- 2,2'-diphenylphosphine (16 mg, 0.026 mmol) and cesium carbonate (127 mg, 0.39 mmol) were dissolved in anhydrous toluene (3 mL) and heated to 100 °C under nitrogen protection for 2 hours. After the reaction was cooled to room temperature, it was filtered and concentrated. The resulting residue was purified by silica gel column chromatography to obtain 16.48 mg of the target molecule (R)-3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-(l-methyl-lH-l,2,4-triazol-5- yl)cyclopropyl)-N-(tetrahydrofuran-3-yl)pyrazin-2-amine.

[0431] MS (ESI) M / Z: 498.3 [M+H] + .

[0432] 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.34 - 7.24 (m, 2H), 7.04 - 6.97 (m, 1H), 6.80 (s, 1H), 6.08 (d, J = 5.5 Hz, 1H), 4.55 - 4.46 (m, 1H), 4.30 - 4.22 (m, 1H), 3.86 - 3.80 (m, 2H), 3.73 (s, 3H), 3.72 - 3.66 (m, 1H), 3.53 (dd, J = 8.8, 4.7 Hz, 1H), 3.28 - 3.23 (m, 2H), 2.92 - 2.81 (m, 2H), 2.20 - 2.08 (m, 1H), 2.09 - 1.99 (m, 2H), 1.99 - 1.92 (m, 1H), 1.91 - 1.80 (m, 2H), 1.65 - 1.50 (m, 2H), 1.40 - 1.33 (m, 2H).

[0433] Example 5:

[0434] (R)-1-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-((tetrahydrofuran-3-yl)amino)pyrazin- 2-yl)-N,N-dimethylcyclopropane-1-carboxamide

[0435] Procedure:

[0436] Step A: 1-(6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-{[(3R)-oxolanyl-3- yl]amino}pyrazin-2-yl)cyclopropane-1-carboxylic acid (15 mg, 0.033 mmol) and ethylenediamine (2.98 mg, 0.066 mmol) were dissolved in DMF (1 mL) at room temperature, followed by the addition of HATU (15.06 mg, 0.040 mmol) and DIEA (12.79 mg, 0.099 mmol), and the reaction mixture was stirred at room temperature for 3 hours under nitrogen protection. After the reaction solution was concentrated, 5.34 mg of the target product (R)-1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-((tetrahydrofuran-3-yl)amino)pyrazin-2-yl)-N,N-dimethylcyclopropane-1-carboxamide was obtained after high performance liquid chromatography purification.

[0437] MS (ESI) M / Z: 488.3 [M+H] + .

[0438] 1H NMR (400 MHz, DMSO-d6) δ 7.33 - 7.25 (m, 2H), 7.22 (s, 1H), 7.03 - 6.98 (m, 1H), 6.03 (d, J = 5.6 Hz, 1H), 4.54 - 4.48 (m, 1H), 4.32 - 4.27 (m, 1H), 3.90 - 3.80 (m, 2H), 3.73 - 3.67 (m, 1H), 3.56 - 3.52 (m, 1H), 3.30 - 3.28 (m, 2H), 2.90 - 2.83 (m, 2H), 2.88 (s, 6H), 2.18 - 2.13 (m, 1H), 2.06 - 2.03 (m, 2H), 1.99 - 1.93 (m, 1H), 1.92 - 1.83 (m, 2H), 1.35 - 1.25 (m, 2H), 1.23 - 1.17 (m, 2H).

[0439] Example 6:

[0440] (R)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1-(methylsulfonyl)cyclopropyl)-N- (tetrahydrofuran-3-yl)pyrazin-2-amine

[0441] Procedure:

[0442] Step A: 2-(Bromomethyl)-5-chloropyrazine (1 g, 2.41 mmol) was dissolved in acetonitrile (20 mL) at room temperature, sodium methanesulfinate (0.74 g, 7.23 mmol) was added at room temperature, after the addition was completed, the reaction was heated to 60 °C for 4 hours. After the reaction was cooled to room temperature, water (40 mL) was added, diatomite was filtered, extracted with ethyl acetate (10 mL x 3 times), the combined organic phase was dried, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 0.4 g of the target product 2-chloro-5-(methylsulfonylmethyl)pyrazine.

[0443] MS (ESI) M / Z: 207.1 [M+H] + .

[0444] Step B: 2-Chloro-5-(methylsulfonylmethyl)pyrazine (320 mg, 1.55 mmol) and 4-(2,4-difluorophenoxy)piperidine (330.49 mg, 1.55 mmol) were dissolved in DMSO (5 mL) at room temperature, potassium fluoride (180.11 mg, 3.1 mmol) and DIEA (600.97 mg, 4.65 mmol) were added, and the reaction was heated to 110 °C under microwave protection for 0.5 hours. After the reaction was cooled to room temperature, water (30 mL) was added, extracted with ethyl acetate (10 mL x 3 times), the combined organic phase was dried, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 300 mg of the target product 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(methylsulfonylmethyl)pyrazine.

[0445] MS (ESI) M / Z: 384.1 [M+H] + .

[0446] Step C: 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(methylsulfonylmethyl)pyrazine (260 mg, 0.68 mmol) was dissolved in DMF (2 mL) and acetic acid (1 mL) in an ice bath, NBS (133.13 mg, 0.75 mmol) was added, and the reaction was heated to 40 °C under nitrogen protection for 2 hours. After the reaction was cooled to room temperature, water (30 mL) was added, extracted with ethyl acetate (10 mL x 3 times), the combined organic phase was dried, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 160 mg of the target product 3-bromo-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(methylsulfonylmethyl)pyrazine.

[0447] MS (ESI) M / Z: 462.0 [M+H] + .

[0448] Step D: 3-bromo-2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(l- methanesulfonylcyclopropyl)pyrazine (30 mg, 0.061 mmol) and (R)-3- aminotetrahydrofuran (5.31 mg, 0.061 mmol) were dissolved in DMSO (1 mL) at room temperature. After the addition of potassium fluoride (7.09 mg, 0.12 mmol) and diisopropylethylamine (23.65 mg, 0.18 mmol), the reaction was heated to 140 °C in a microwave reactor under nitrogen for 1.5 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by HPLC to give 7.1 mg of the target product (R)-3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l- (methanesulfonyl)cyclopropyl)-N-(tetrahydrofuran-3-yl)pyrazin-2-amine.

[0449] MS (ESI) M / Z: 488.1 [M+H] + .

[0450] Step D: 3-bromo-2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(l- methanesulfonylcyclopropyl)pyrazine (30 mg, 0.061 mmol) and (R)-3- aminotetrahydrofuran (5.31 mg, 0.061 mmol) were dissolved in DMSO (1 mL) at room temperature. After the addition of potassium fluoride (7.09 mg, 0.12 mmol) and diisopropylethylamine (23.65 mg, 0.18 mmol), the reaction was heated to 140 °C in a microwave reactor under nitrogen for 1.5 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by HPLC to give 7.1 mg of the target product (R)-3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l- (methanesulfonyl)cyclopropyl)-N-(tetrahydrofuran-3-yl)pyrazin-2-amine.

[0451] MS (ESI) M / Z: 495.2 [M+H] + .

[0452] 1H NMR (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.34 - 7.25 (m, 2H), 7.04 - 6.98 (m, 1H), 6.16 (d, J = 6.0 Hz, 1H), 4.56 - 4.51 (m, 1H), 4.42 - 4.35 (m, 1H), 3.93 (dd, J = 8.8, 6.0 Hz, 1H), 3.88 - 3.82 (m, 1H), 3.74 - 3.69 (m, 1H), 3.60 (dd, J = 8.8, 4.8 Hz, 1H), 3.39 - 3.36 (m, 2H), 3.08 (s, 3H), 2.98 - 2.91 (m, 2H), 2.23 - 2.14 (m, 1H), 2.07 - 1.96 (m, 3H), 1.91 - 1.83 (m, 2H), 1.62 - 1.55 (m, 2H), 1.39 - 1.32 (m, 2H).

[0453] Example 7:

[0454] N-(6-(1-cyanocyclopropyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)-2- methoxynicotinamide

[0455] Procedure:

[0456] Step A: 1-(6-bromo-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1- carbonitrile (40 mg, 0.092 mmol) and 2-methoxypyridine-3-carboxamide (16.80 mg, 0.11 mmol) were dissolved in toluene (1 mL) at room temperature, Pd2(dba)3(16.85 mg, 0.018 mmol), Xphos (21.29 mg, 0.037 mmol) and cesium carbonate (89.93 mg, 0.28 mmol) were added, the reaction was heated to 110 °C under microwave irradiation for 0.5 h under nitrogen protection. The reaction was cooled to room temperature and concentrated under reduced pressure, and 16.64 mg of the target product N-(6-(1-cyanocyclopropyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)-2- methoxynicotinamide was obtained after purification by high performance liquid chromatography.

[0457] MS (ESI) M / Z: 507.2 [M+H] + .

[0458] 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 8.19 (s, 1H), 8.17-8.15 (m, 1H), 7.34-7.25 (m, 2H), 7.19 (dd, J = 7.2, 4.8 Hz, 1H), 7.03-6.98 (m, 1H), 4.58-4.52 (m, 1H), 3.91 (s, 3H), 3.63-3.60 (m, 2H), 3.20-3.13 (m, 2H), 2.06-2.02 (m, 2H), 1.81-1.73 (m, 2H), 1.67-1.66 (m, 2H), 1.33-1.23 (m, 2H).

[0459] Example 8:

[0460] (R)-1-(6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazin-2-yl)-N,N-dimethylcyclopropane-1-carboxamide

[0461] Procedure:

[0462] Step A: 1-(6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-{[(3R)-oxolanyl-3-yl]amino}pyrazin-2-yl)cyclopropane-1-carboxylic acid (30 mg, 0.065 mmol) and ethylenediamine (5.86 mg, 0.13 mmol) were dissolved in DMF (1 mL) at room temperature, HATU (29.66 mg, 0.078 mmol) and DIEA (25.20 mg, 0.20 mmol) were added, the reaction was stirred at room temperature under nitrogen protection for 3 hours. After concentration under reduced pressure, 11.56 mg of the target product (R)-1-(6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazin-2-yl)-N,N-dimethylcyclopropane-1-carboxamide was obtained after purification by high performance liquid chromatography.

[0463] MS (ESI) M / Z: 488.3 [M+H] + .

[0464] 1H NMR (400 MHz, DMSO-d6) δ 7.41 (s, 1H), 7.34 - 7.25 (m, 2H), 7.03 - 6.98 (m, 1H), 5.85 (d, J = 6.0 Hz, 1H), 4.56 - 4.50 (m, 1H), 4.39 - 4.32 (m, 1H), 3.89 - 3.81 (m, 2H), 3.72 - 3.67 (m, 1H), 3.57 - 3.54 (m, 1H), 3.37 - 3.32 (m, 2H), 2.97 - 2.92 (m, 2H), 2.88 (s, 6H), 2.20 - 2.11 (m, 1H), 2.05 - 2.02 (m, 2H), 1.97 - 1.91 (m, 1H), 1.86 - 1.80 (m, 2H), 1.25 - 1.20 (m, 2H), 1.18 - 1.14 (m, 2H).

[0465] Example 9:

[0466] (R)-3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(2-(methylsulfonyl)prop-2-yl)-N- (tetrahydrofuran-3-yl)pyrazin-2-amine

[0467] Procedure:

[0468] Step A: 3-bromo-2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(methylsulfonylmethyl)pyrazine (25 mg, 0.054 mmol) was dissolved in tetrahydrofuran (0.5 mL) under ice bath, followed by the addition of potassium tert-butoxide (12.12 mg, 0.108 mmol) and iodomethane (15.33 mg, 0.11 mmol), the reaction was stirred under ice bath for 0.5 hour. The reaction was quenched by the addition of water (10 mL), extracted by ethyl acetate (2 mL x 3 times), the organic phase was combined and dried, concentrated, the residue was purified by silica gel column to give 15 mg of the target product 3-bromo-2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(2-(methylsulfonyl)prop-2-yl)pyrazine.

[0469] MS (ESI) M / Z: 490.1 [M+H] + .

[0470] Step B: 3-bromo-2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(2-(methylsulfonyl)prop-2- yl)pyrazine (15 mg, 0.031 mmol) and (R)-3-aminotetrahydrofuran (2.70 mg, 0.031 mmol) were dissolved in DMSO (1 mL) at room temperature, potassium fluoride (3.60 mg, 0.062 mmol) and DIEA (12.02 mg, 0.093 mmol) were added, the reaction was heated to 140 °C in a microwave with nitrogen protection for 1.5 hours. After the reaction was cooled to room temperature, 2.17 mg of the target product (R)-3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(2-(methylsulfonyl)prop-2-yl)-N-(tetrahydrofuran-3-yl)pyrazin-2-amine was obtained after purification by high performance liquid chromatography.

[0471] MS (ESI) M / Z: 497.2 [M+H] + .

[0472] 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.34 - 7.25 (m, 2H), 7.03 - 6.99 (m, 1H), 6.12 (d, J = 5.6 Hz, 1H), 4.56 - 4.50 (m, 1H), 4.40 - 4.33 (m, 1H), 3.95 (dd, J = 8.8, 6.0 Hz, 1H), 3.87 - 3.82 (m, 1H), 3.74 - 3.68 (m, 1H), 3.60 (dd, J = 8.8, 4.4 Hz, 1H), 3.43 - 3.36 (m, 2H), 2.99 - 2.92 (m, 2H), 2.85 (s, 3H), 2.24 - 2.15 (m, 1H), 2.08 - 2.05 (m, 2H), 2.02 - 1.95 (m, 1H), 1.90 - 1.85 (m, 2H), 1.69 (s, 6H).

[0473] Example 10:

[0474] 3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-(methylsulfonyl)ethyl)-N-((R)- tetrahydrofuran-3-yl)pyrazin-2-amine

[0475] Procedure:

[0476] Step A: 3-Bromo-2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5- (methylsulfonylmethyl)pyrazine (25 mg, 0.054 mmol) was dissolved in tetrahydrofuran (0.5 mL) under ice bath, followed by the addition of potassium tert-butoxide (6.06 mg, 0.054 mmol) and iodomethane (7.66 mg, 0.054 mmol), and the reaction was stirred for 0.5 h under ice bath. The reaction was quenched by the addition of water (10 mL), extracted with ethyl acetate (2 mL x 3), and the combined organic phase was dried, filtered, and concentrated. The residue was purified by column chromatography on silica gel to give 15 mg of the target product 3-bromo-2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(l- (methylsulfonyl)ethyl)pyrazine.

[0477] MS (ESI) M / Z: 476.1 [M+H] + .

[0478] Step B: 3-Bromo-2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(l- (methylsulfonyl)ethyl)pyrazine (15 mg, 0.031 mmol) and (R)-3-aminotetrahydrofuran (2.70 mg, 0.031 mmol) were dissolved in DMSO (1 mL) at room temperature, followed by the addition of potassium fluoride (3.60 mg, 0.062 mmol) and DIEA (12.02 mg, 0.093 mmol), and the reaction was heated to 140 °C under microwave irradiation for 1.5 h under nitrogen. The reaction was cooled and purified by high performance liquid chromatography to give 3.02 mg of the target product 3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l- (methylsulfonyl)ethyl)-N-((R)-tetrahydrofuran-3-yl)pyrazin-2-amine.

[0479] MS (ESI) M / Z: 483.2 [M+H] + .

[0480] 1H NMR (400 MHz, DMSO-d6) δ 7.55 (s, 1H), 7.33-7.25 (m, 2H), 7.03-7.01 (m, 1H), 6.15-6.13 (m, 1H), 4.57-4.49 (m, 1H), 4.39-4.32 (m, 2H), 3.98-3.91 (m, 1H), 3.87-3.82 (m, 1H), 3.74-3.68 (m, 1H), 3.59-3.56 (m, 1H), 3.40-3.36 (m, 2H), 2.99-2.91 (m, 5H), 2.23-2.16 (m, 1H), 2.08-2.05 (m, 2H), 2.01-1.95 (m, 1H), 1.90-1.86 (m, 2H), 1.64-1.61 (m, 3H).

[0481] Example 11:

[0482] (R)-3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-(5-methyl-l,3,4-oxadiazol-2- yl)cyclopropyl)-N-(tetrahydrofuran-3-yl)pyrazine-2-amine

[0483] Procedure:

[0484] Step A: l-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropane- 1-carboxylic acid (180 mg, 0.44 mmol), acetic hydrazide (39 mg, 0.53 mmol), 1- hydroxybenzotriazole (72 mg, 0.53 mmol), carbodiimide (102 mg, 0.53 mmol), triethylamine (89 mg, 0.88 mmol) were added into DMF (2 mL) at room temperature, the reaction was stirred at room temperature for 2 hours. Water was added into the reaction, the product was extracted by ethyl acetate, the organic phase was combined and washed by brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to give 86 mg of the target molecule N'-acetyl-l-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropane-l-carbohydrazide.

[0485] MS (ESI) M / Z: 466.3 [M+H] + .

[0486] Step B: To a solution of N'-acetyl-l-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l- yl)pyrazin-2-yl)cyclopropane-l-carbohydrazide (86 mg, 0.18 mmol) in pyridine (2 mL) was added phosphorus oxychloride (1 mL) at room temperature, and the reaction was heated to 80 °C overnight. The reaction was cooled to room temperature and quenched with water. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with dilute hydrochloric acid, saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel to give 30 mg of the target molecule 2-(l-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l- yl)pyrazin-2-yl)cyclopropyl)-5-methyl-l,3,4-oxadiazole.

[0487] MS (ESI) M / Z: 448.3 [M+H] + .

[0488] Step C: To a solution of 2-(l-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l- yl)pyrazin-2-yl)cyclopropyl)-5-methyl-l,3,4-oxadiazole (30 mg, 0.067 mmol), (R)- tetrahydrofuran-3-amine (12 mg, 0.13 mmol), palladium acetate (2 mg, 0.007 mmol), 1,1'- binaphthalene-2,2'-diphenylphosphine (9 mg, 0.014 mmol) and cesium carbonate (66 mg, 0.20 mmol) in anhydrous toluene (2 mL) was added at room temperature under nitrogen protection, and the reaction was heated to 100 °C for 2 hours. The reaction was cooled to room temperature and filtered. The residue was purified by preparative high performance liquid chromatography to give 7.14 mg of the target product (R)-3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-(5-methyl-l,3,4- oxadiazol-2-yl)cyclopropyl)-N-(tetrahydrofuran-3-yl)pyrazin-2-amine.

[0489] MS (ESI) M / Z: 499.3 [M+H] + .

[0490] 1H NMR (400 MHz, DMSO-d6) δ 7.45 (s, 1H), 7.37-7.25 (m, 2H), 7.05-6.97 (m, 1H), 6.12 (d, J = 5.6 Hz, 1H), 4.57-4.47 (m, 1H), 4.33-4.23 (m, 1H), 3.87-3.79 (m, 2H), 3.73-3.66 (m, 1H), 3.54 (dd, J = 8.8, 4.8 Hz, 1H), 3.33-3.26 (m, 2H), 2.94-2.84 (m, 2H), 2.47 (s, 3H), 2.19-2.11 (m, 1H), 2.10-2.02 (m, 2H), 2.01-1.93 (m, 1H), 1.93-1.84 (m, 2H), 1.65-1.54 (m, 2H), 1.53-1.47 (m, 2H).

[0491] Example 12:

[0492] 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile

[0493] Operation steps

[0494] Step A: 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile (400 mg, 1.12 mmol) was dissolved in mixed solvent (DMF / acetic acid = 1 / 1, 3 mL) at room temperature, then NCS (195 mg, 1.46 mmol) was added thereto, and the reaction solution was heated to 40°C and stirred for 16 hours. After the reaction solution was cooled to room temperature, water was added for quenching, and ethyl acetate was extracted three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 346 mg of the target molecule 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile.

[0495] MS (ESI) M / Z: 391.3 [M+H] + .

[0496] Step B: To a solution of 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1- yl)pyrazin-2-yl)cyclopropane-1-carbonitrile (40 mg, 0.102 mmol), (1-methyl-1H- pyrazol-4-yl)boronic acid (26 mg, 0.204 mmol), [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium (8 mg, 0.01 mmol) and cesium carbonate (48 mg, 0.204 mmol) in 1,4-dioxane / water (0.4 mL / 0.04 mL) was heated to 110 °C under nitrogen protection for 3 h. The reaction was allowed to cool to room temperature, quenched with water and extracted with ethyl acetate (3x). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The residue was purified by preparative high performance liquid chromatography to give 5.37 mg of 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazin-2-yl)cyclopropane-1-carbonitrile.

[0497] MS (ESI) M / Z: 437.3 [M+H] + .

[0498] 1 H NMR (400 MHz, DMSO-d6) d 8.35 (s, 1H), 8.21 (s, 1H), 8.07 (d, J = 0.4 Hz, 1H), 7.34 - 6.98 (m, 2H), 7.06 - 6.96 (m, 1H), 4.60 - 4.48 (m, 1H), 3.92 (s, 3H), 3.41 - 3.34 (m, 2H), 3.03 - 2.94 (m, 2H), 2.10 - 2.04 (m, 2H), 1.88 - 1.82 (m, 1H), 1.79 - 1.74 (m, 2H), 1.72 - 1.68 (m, 2H).

[0499] Example 13:

[0500] 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3- yl)pyrazin-2-yl)cyclopropane-1-carbonitrile

[0501] Procedure:

[0502] Step A: 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropane- 1-carbonitrile (40 mg, 0.102 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin- 2(lH)-one (48 mg, 0.204 mmol), [l,l'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (8 mg, 0.01 mmol) and cesium carbonate (48 mg, 0.204 mmol) were dissolved in 1,4-dioxane / water (0.4 mL / 0.04 mL) and the reaction was heated to 110 °C for 3 h under nitrogen protection. The reaction was allowed to cool to room temperature and quenched with water. The reaction was extracted with ethyl acetate (3x) and the combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered and concentrated to give a crude product. The residue was purified by preparative high performance liquid chromatography to give 27.53 mg of the target molecule 1-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)pyrazin-2-yl)cyclopropane-l-carbonitrile.

[0503] MS (ESI) M / Z: 463.9 [M+H] + .

[0504] 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 2.6 Hz, 1H), 8.25 (s, 1H), 8.07 (dd, J = 9.5, 2.6 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.03 - 6.97 (m, 1H), 6.51 (d, J = 9.5 Hz, 1H), 4.53 - 4.46 (m, 1H), 3.53 (s, 3H), 3.46 - 3.41 (m, 2H), 3.06 - 2.98 (m, 2H), 2.03 - 1.95 (m, 2H), 1.80 - 1.68 (m, 6H).

[0505] Example 14:

[0506] 1-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)pyrazin-2-yl)cyclopropane-l-carbonitrile

[0507] Detailed procedure:

[0508] Preparation Method Reference Example 12, with 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropane-l-carbonitrile and l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole as starting materials, to give 32.53 mg of compound 1-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-ethyl-lH-pyrazol-4-yl)pyrazin-2-yl)cyclopropane-l-carbonitrile.

[0509] MS (ESI) M / Z: 451.3 [M+H] + .

[0510] 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.21 (s, 1H), 8.08 (s, 1H), 7.38 - 7.22 (m, 2H), 7.07 - 6.94 (m, 1H), 4.63 - 4.43 (m, 1H), 4.25 - 4.20 (m, 2H), 3.42 - 3.32 (m, 2H), 3.02 - 2.95 (m, 2H), 2.13 - 2.01 (m, 2H), 1.88 - 1.81 (m, 2H), 1.79 - 1.74 (m, 2H), 1.74 - 1.67 (m, 2H), 1.40 (t, J=7.2 Hz, 3H).

[0511] Example 15:

[0512] 1-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-[(pyridin-4-yl)amino]pyrazin-2-yl)cyclopropane-l- carbonitrile

[0513] Procedure:

[0514] To a 10 mL microwave tube was added 1-(6-bromo-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropane-l-carbonitrile (50 mg, 0.11 mmol), Pd2(dba)3(10 mg, 0.011 mmol) and Xphos (6.3 mg, 0.013 mmol) at room temperature, anhydrous toluene (1 mL) was added, followed by pyridin-4-amine (20.15 mg, 0.13 mmol) and sodium tert-butoxide (31.71 mg, 0.33 mmol), the reaction was heated to 90 °C in the microwave for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 1-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(pyridin-4-ylamino)pyrazin-2-yl)cyclopropane-l-carbonitrile. oC was reacted for 2 hours. After returning to room temperature, water (10 mL) was added to the system, which was washed with ethyl acetate (10 mL x 3 times), and the organic phase was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography, and freeze-dried under reduced pressure to obtain 7.6 mg of the target molecule 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-[(pyridin-4-yl)amino]pyrazin-2-yl)cyclopropane-1-carbonitrile.

[0515] MS (ESI) M / Z: 449.2 [M+H] +

[0516] 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.35-8.34 (m, 2H), 7.93 (s, 1H), 7.68-7.67 (m, 2H), 7.35-7.26 (m, 2H), 7.04-6.99 (m, 1H), 4.59-4.53 (m, 1H), 3.43-3.38 (m, 2H), 3.06-3.00 (m, 2H), 2.10-2.07 (m, 2H), 1.94-1.89 (m, 2H), 1.79-1.76 (m, 2H), 1.65-1.62 (m, 2H).

[0517] Example 16:

[0518] (R)-1-(1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-((tetrahydrofuran-3-yl)amino)pyrazin-2-yl)cyclopropyl)pyrrolidin-2-one

[0519] Operation steps:

[0520] Step A: 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carboxylic acid ethyl ester (500 mg, 1.241 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature, and lithium hydroxide (156.3 mg, 3.722 mmol, dissolved in 3 mL of water) was added thereto. The reaction liquid was heated to 50°C and stirred overnight. After the reaction liquid was cooled to room temperature, it was concentrated under reduced pressure, diluted with water (10 mL), adjusted to a pH of 3 with a (1M) aqueous hydrochloric acid solution, extracted with ethyl acetate (40 mL x 3 times), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 438 mg of the target molecule 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carboxylic acid.

[0521] MS (ESI) M / Z: 376.4 [M+H] + .

[0522] 1 H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.23 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H) 7.41 - 7.21 (m, 2H), 7.05 - 6.99 (m, 1H), 4.65 - 4.52 (m, 1H), 4.00 - 3.91 (m, 2H), 3.42 - 3.35 (m, 2H), 2.04 - 1.99 (m, 2H), 1.71 - 1.58 (m, 2H), 1.48 - 1.42 (m, 2H), 1.30 - 1.22 (m, 2H).

[0523] Step B: 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1- carboxylic acid (620 mg, 1.649 mmol) was dissolved in tert-butanol (8 mL), diphenyl phosphorazide (544.5 mg, 1.979 mmol) and triethylamine (0.3 mL, 2.144 mmol) were added, the reaction was heated to 100 °C under nitrogen protection for 4 hours. Water (100 mL) was added to quench and extracted with ethyl acetate (60 mL x 3 times), the organic phase was combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 212 mg of tert-butyl (1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropyl)carbamate.

[0524] MS (ESI) M / Z: 447.3 [M+H] + .

[0525] 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.00 (s, 1H), 7.73 (s, 1H), 7.34 - 7.26 (m, 2H), 7.05 - 6.99

[0526] (m, 1H), 4.59 - 4.52 (m, 1H), 3.98 - 3.86 (m, 2H), 3.29 - 3.22 (m, 2H), 2.00 - 1.95 (m,

[0527] 2H), 1.41 (s, 9H), 1.25 - 1.23 (m, 2H), 1.05 - 1.02 (m, 2H).

[0528] Step C: To a solution of (l-(5-(4-(2,4-difluorophenoxy)piperidin-l- yl)pyrazin-2-yl)cyclopropyl)carbamic acid tert-butyl ester (190 mg, 0.426 mmol) in hydrochloric acid / dioxane (4 mol / L, 1.05 mL, 4.26 mmol) was added water (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give 131 mg of 1-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2- yl)cyclopropane-l -amine.

[0529] MS (ESI) M / Z: 347.3 [M+H] + .

[0530] Step D: To a solution of l-(5-(4-(2,4-difluorophenoxy)piperidin-l- yl)pyrazin-2-yl)cyclopropane-l -amine (100 mg, 0.289 mmol) in anhydrous methanol (4 mL) and acetic acid (0.4 mL) was added methyl 4-oxobutanoate (33.6 mg, 0.289 mmol) slowly at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0 °C and sodium cyanoborohydride (54.5 mg, 0.867 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 82 mg of methyl 4-(l-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropyl)amino)butanoate.

[0531] MS (ESI) M / Z: 447.3 [M+H] + .

[0532] Step E: To a solution of methyl 4-(l-(5-(4-(2,4-difluorophenoxy)piperidin-l- yl)pyrazin-2-yl)cyclopropyl)amino)butanoate (80 mg, 0.179 mmol) in anhydrous toluene (1 mL) was added triethylamine (54.4 mg, 0.538 mmol) at room temperature. The reaction mixture was heated to 110 °C under nitrogen overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography to give 63 mg of the target compound l-(l-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropyl)pyrrolidin-2-one.

[0533] MS (ESI) M / Z: 415.2 [M+H] + .

[0534] 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 1.4 Hz, 1H), 7.93 (d, J = 1.4 Hz, 1H), 7.41 - 7.19 (m, 2H), 7.08 - 6.94 (m, 1H), 4.66 - 4.50 (m, 1H), 4.04 - 3.83 (m, 2H), 3.44 (t, J = 7.0 Hz, 2H), 3.41 - 3.34 (m, 2H), 2.32 (t, J = 8.0 Hz, 2H), 2.04 - 1.93 (m, 4H), 1.69 - 1.57 (m, 2H), 1.33 - 1.27 (m, 2H), 1.23 - 1.18 (m, 2H).

[0535] Step F: 1 -(1 -(5-(4-(2,4-difluorophenoxy)piperidin-1 -yl)pyrazin-2-yl)cyclopropyl)- pyrrolidin-2-one (60 mg, 0.145 mmol) was dissolved in DMF (2 mL) and acetic acid (0.5 mL) at room temperature, NCS (23 mg, 0.174 mmol) was added, the reaction was heated to 50 °C for 16 h. The reaction was cooled to room temperature, quenched with water (20 mL) and the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (30 mL x 3 times), the organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 43.3 mg of the target molecule 1 -(1 -(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1 - yl)pyrazin-2-yl)cyclopropyl)pyrrolidin-2-one.

[0536] MS (ESI) M / Z: 449.2 [M+H] + .

[0537] 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.38 - 7.25 (m, 2H), 7.06 - 6.98 (m, 1H), 4.64 - 4.48 (m, 1H), 3.66 - 3.54 (m, 2H), 3.46 (t, J = 7.0 Hz, 2H), 3.24 - 3.15 (m, 2H), 2.34 (t, J = 8.0 Hz, 2H), 2.07 - 1.97 (m, 4H), 1.82 - 1.73 (m, 2H), 1.38 - 1.34 (m, 2H), 1.33 - 1.29 (m, 2H).

[0538] Step G: 1-(1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropyl)pyrrolidin-2-one (40 mg, 0.097 mmol), (R)-tetrahydrofuran-3-amine (16.8 mg, 0.193 mmol), BINAP (9 mg, 0.0145 mmol), Pd2(dba)3(13.0 mg, 0.0145 mmol) and sodium tert-butoxide (23.2 mg, 0.242 mmol) were all dissolved in anhydrous toluene (0.8 mL) and the reaction was heated to 90 °C in a sealed tube for 2 hours.

[0539] After the reaction was cooled to room temperature, it was filtered, the filter cake was washed with ethyl acetate (5 mL x 4 times), the resulting filtrate was concentrated under reduced pressure, and the resulting crude product was purified by preparative high performance liquid chromatography. This resulted in 10.2 mg of the target molecule (R)-1-(1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-((tetrahydrofuran-3-yl)amino)pyrazin-2-yl)cyclopropyl)pyrrolidin-2-one.

[0540] MS (ESI) M / Z: 500.3 [M+H] + .

[0541] 1 H NMR (400 MHz, DMSO-d6) δ 7.38 - 7.23 (m, 3H), 7.05 - 6.96 (m, 1H), 6.03 (d, J = 5.6 Hz, 1H), 4.59 - 4.45 (m, 1H), 4.31 - 4.23 (m, 1H), 3.92 - 3.79 (m, 2H), 3.73 - 3.67 (m, 1H), 3.54 (dd, J = 8.8, 4.8 Hz, 1H), 3.45 (t, J = 7.0 Hz, 2H), 3.29 - 3.21 (m, 2H), 2.91 - 2.83 (m, 2H), 2.33 - 2.94 (m, 2H), 2.20 - 2.11 (m, 1H), 2.08 - 1.94 (m, 5H), 1.91 - 1.83 (m, 2H), 1.44 - 1.37 (m, 1H), 1.36 - 1.31 (m, 1H), 1.21 - 1.17 (m, 2H).

[0542] Example 17:

[0543] 1-(6-(6-(difluoromethyl)pyridin-2-yl)-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile

[0544] Procedure:

[0545] Step A: 2-Bromo-6-(difluoromethyl)pyridine (300 mg, 1.44 mmol), hexamethylditin (567 mg, 1.73 mmol) were dissolved in 1,4-dioxane (5 mL) under nitrogen at room temperature, followed by the addition of Pd(PPh3)4(166 mg, 0.14 mmol), and the reaction was heated to 115 °C in a microwave reactor for 1.5 h. After the reaction was cooled to room temperature, it was filtered, the filter cake was washed with ethyl acetate, and the combined organic phases were concentrated under reduced pressure to give 200 mg of the crude product 2-(difluoromethyl)-6-(trimethylstannyl)pyridine which was used directly in the next step.

[0546] MS (ESI) M / Z: 294.0 [M+H] + .

[0547] Step B: Compound 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile (30 mg, 0.077 mmol), 2-(difluoromethyl)-6-(trimethylstannyl)pyridine crude (200 mg, 0.68 mmol), Pd(dtbpf)Cl2(5 mg, 0.008 mmol), cesium carbonate (50 mg, 0.15 mmol) were dissolved in 1,4-dioxane (1.5 mL), and the reaction was heated to 110 °C for 2 h. After the reaction was cooled to room temperature, it was filtered and concentrated, and the product was purified by preparative high-performance liquid chromatography to give 9.97 mg of the target product 1-(6-(6-(difluoromethyl)pyridin-2-yl)-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile.

[0548] MS (ESI) M / Z: 484.2 [M+H] + .

[0549] 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.17 (t, J = 7.8 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.30 - 7.21 (m, 2H), 7.00 (t, J = 54.8 Hz, 1H), 7.00 - 6.92 (m, 1H), 4.53 - 4.42 (m, 1H), 3.49 - 3.36 (m, 2H), 3.11 - 3.00 (m, 2H), 1.93 - 1.82 (m, 2H), 1.80 - 1.72 (m, 2H), 1.68 - 1.63 (m, 2H), 1.63 - 1.53 (m, 2H).

[0550] Example 18:

[0551] 2-(1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)cyclopropyl)-5-methyl-1,3,4-oxadiazole

[0552] Procedure:

[0553] Step A: 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carboxylic acid ethyl ester (1000 mg, 2.48 mmol) was dissolved in anhydrous ethanol (8 mL) at room temperature, to which hydrazine hydrate (4 mL) was added, and the reaction was heated to 95 °C for 48 hours. After the reaction was cooled to room temperature, it was concentrated under reduced pressure, the residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3 times), the organic phase was combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to obtain 860 mg of the target molecule 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbohydrazide.

[0554] MS (ESI) M / Z: 390.3 [M+H] + .

[0555] 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.27 (d, J = 1.4 Hz, 1H), 8.04 (d, J = 1.4 Hz, 1H), 7.36 - 7.26 (m, 2H), 7.08 - 6.97 (m, 1H), 4.68 - 4.54 (m, 1H), 4.38 - 4.23 (m, 2H), 4.04 - 3.89 (m, 2H), 3.43 - 3.35 (m, 2H), 2.03 - 1.96 (m, 2H), 1.70 - 1.61 (m, 2H), 1.34 - 1.27 (m, 2H), 1.08 - 1.02 (m, 2H).

[0556] Step B: 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1- carbohydrazide (800 mg, 2.056 mmol) was dissolved in dichloromethane (16 mL) at room temperature, triethylamine (415.4 mg, 4.113 mmol) and acetic anhydride (209.8 mg, 2.056 mmol) were added, the reaction was stirred at room temperature for 2 hours. The reaction was quenched with water (100 mL) and extracted with dichloromethane (60 mL x 3 times), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and the residue was concentrated under reduced pressure and purified by silica gel column chromatography to give 813 mg of the target molecule N'-acetyl-1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbohydrazide.

[0557] MS (ESI) M / Z: 432.3 [M+H] + .

[0558] 1 H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 0.8H), 9.40 (s, 0.1H), 9.26 (s, 0.8H), 8.85 (s, 0.1H), 8.31-8.27 (m, 1H), 8.19-8.09 (m, 1H), 7.36-7.26 (m, 2H), 7.05-7.00 (m, 1H), 4.65-4.52 (m, 1H), 4.05-3.92 (m, 2H), 3.45-3.35 (m, 2H), 2.01-1.96 (m, 2H), 1.82 (s, 2.55H), 1.72 (s, 0.45H), 1.69-1.59 (m, 2H), 1.36-1.30 (m, 2H), 1.18-1.12 (m, 2H).

[0559] Step C: N'-acetyl-1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1- carbohydrazide (800 mg, 1.856 mmol) was dissolved in dichloromethane (8 mL) at room temperature, then triethylamine (1.2 mL, 7.425 mmol) and p-toluenesulfonyl chloride (707.7 mg, 3.71 mmol) were added to the reaction, the reaction was heated to 30 °C and stirred overnight. The reaction was concentrated under reduced pressure, the residue was purified by silica gel column chromatography to give 558 mg of the target molecule 2-(1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropyl)-5-methyl-1,3,4-oxadiazole.

[0560] MS (ESI) M / Z: 414.3 [M+H] + .

[0561] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 1.5 Hz, 1H), 8.18 (d, J = 1.5 Hz, 1H), 7.39 - 7.23 (m, 2H), 7.09 - 6.96 (m, 1H), 4.68 - 4.50 (m, 1H), 4.07 - 3.86 (m, 2H), 3.47 - 3.37 (m, 2H), 2.44 (s, 3H), 2.02 - 1.96 (m, 2H), 1.73 - 1.59 (m, 2H), 1.55 (s, 4H).

[0562] Step D: 2-(l-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropyl)-5- methyl-l,3,4-oxadiazole (550 mg, 1.332 mmol) was dissolved in DMF (10 mL) and acetic acid (3 mL) at room temperature, N-chlorosuccinimide (231.2 mg, 1.73 mmol) was added, the reaction was heated at 50 °C for 16 hours. After cooling to room temperature, water (50 mL) was added to quench and the pH value was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (60 mL x 3 times), the organic phase was combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 350 mg of the target molecule 2-(l-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l- yl)pyrazin-2-yl)cyclopropyl)-5-methyl-l,3,4-oxadiazole.

[0563] MS (ESI) M / Z: 448.2 [M+H] + .

[0564] 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 0.8H), 7.95 (s, 0.2H), 7.39 - 7.21 (m, 2H), 7.11 - 6.96 (m, 1H), 4.69 - 4.50 (m, 1H), 3.79 - 3.57 (m, 2H), 3.29 - 3.21 (m, 2H), 2.46 (s, 3H), 2.12 - 2.00 (m, 2H), 1.82 - 1.74 (m, 2H), 1.67 - 1.62 (m, 4H).

[0565] Step E: 2-(l-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2- yl)cyclopropyl)-5-methyl-l,3,4-oxadiazole (60 mg, 0.134 mmol), l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (55.8 mg, 0.268 mmol), Pd(dtbpf)Cl2 (8.75 mg, 0.0134 mmol) and cesium carbonate (87.5 mg, 0.268 mmol) were all dissolved in dioxane (1 mL) and pure water (0.1 mL), the reaction was sealed and heated to 110 °C for 3 hours. After the reaction was cooled to room temperature, it was filtered, the filter cake was washed with ethyl acetate (5 mL x 4 times), the resulting filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative high performance liquid chromatography to obtain 12.2 mg of the target molecule 2-(l-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazin-2-yl)cyclopropyl)-5-methyl-l,3,4-oxadiazole.

[0566] MS (ESI) M / Z: 494.2 [M+H] + .

[0567] 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.35-7.25 (m, 2H), 7.06-6.96 (m, 1H), 4.55-4.49 (m, 1H), 3.92 (s, 3H), 3.39-3.36 (m, 2H), 3.01-2.94 (m, 2H), 2.47 (s, 3H), 2.09-2.04 (m, 2H), 1.89-1.78 (m, 2H), 1.75 - 1.67 (m, 2H), 1.64-1.57 (m, 2H).

[0568] Example 19:

[0569] 5-(3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-(5-methyl-l,3,4-oxadiazol-2-yl)cyclopropyl)pyrazin-2-yl)-l-methylpyridin-2(lH)-one

[0570] Procedure:

[0571] With 2-(1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropyl)-5-methyl-1,3,4-oxadiazole and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one as raw materials, 15.3 mg of the target molecule 5-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1-(5-methyl-1,3,4-oxadiazol-2-yl)cyclopropyl)pyrazin-2-yl)-1-methylpyridin-2(1H)-one was prepared by referring to the preparation method of Example 18.

[0572] MS (ESI) M / Z: 521.2 [M+H] + .

[0573] 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 2.5 Hz, 1H), 8.23 (s, 1H), 8.07 (dd, J = 9.5, 2.6 Hz, 1H), 7.36-7.22 (m, 2H), 7.06-6.94 (m, 1H), 6.51 (d, J = 9.5 Hz, 1H), 4.59-4.42 (m, 1H), 3.54 (s, 3H), 3.48-3.37 (m, 2H), 3.07-2.94 (m, 2H), 2.47 (s, 3H), 2.04-1.95 (m, 2H), 1.79-1.67 (m, 4H), 1.64-1.56 (m, 2H).

[0574] Example 20:

[0575] 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(4-fluoro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile

[0576] Operation steps:

[0577] Step A: 5-bromo-4-fluoropyridin-2(1H)-one (450 mg, 2.34 mmol) and potassium carbonate (646.8 mg, 4.68 mmol) were dissolved in DMF (13 mL), then methyl iodide (399 mg, 2.8 mmol) was added, and the reaction was reacted at room temperature for 2 hours. Water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3 times), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 261 mg of the target molecule 5-bromo-4-fluoro-1-methylpyridin-2(1H)-one.

[0578] MS (ESI) M / Z: 206.0 [M+H] + .

[0579] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 9.2 Hz, 1H), 6.42 (d, J = 11.1 Hz, 1H), 3.41 (s, 3H).

[0580] Step B: Under nitrogen protection, 5-bromo-4-fluoro-l-methylpyridin-2(lH)-one (120 mg, 0.58 mmol), bis(pinacolato)diboron (666 mg, 2.62 mmol) and potassium acetate (199.2 mg, 2.03 mmol) were dissolved in anhydrous 1,4-dioxane (5 mL), then Pd(PPh3)2Cl2 (40.7 mg, 0.058 mmol) was added, and the reaction was heated to 90 °C in a tube under nitrogen protection for 2.5 hours. After the reaction was cooled to room temperature, it was concentrated under reduced pressure, washed with n-hexane (8 mL x 3 times), filtered, and the obtained filtrate was concentrated under reduced pressure to obtain 147 mg of the target molecule 4-fluoro-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one.

[0581] MS (ESI) M / Z: 254.3 [M+H] + .

[0582] Step C: With (l-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropane-l- carbonitrile and 4-fluoro-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one as raw materials, 18.67 mg of the target molecule l-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(4-fluoro-l-methyl-6-oxo-l,6-dihydropyridin-3-yl)pyrazin-2-yl)cyclopropane-l-carbonitrile was prepared according to the method in Example 18.

[0583] MS (ESI) M / Z: 482.3 [M+H] + .

[0584] 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.25 (d, J = 9.4 Hz, 1H), 7.32-7.20 (m, 2H), 7.07-6.95 (m, 1H), 6.36 (d, J = 12.4 Hz, 1H), 4.58-4.41 (m, 1H), 3.55-3.48 (m, 5H), 3.11-3.04 (m, 2H), 1.96-1.87 (m, 2H), 1.81-1.73 (m, 2H), 1.69-1.54 (m, 4H).

[0585] Example 21:

[0586] 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(5-methoxy-1-methyl-6-oxo-1,6- dihydropyridin-3-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile

[0587] Procedure:

[0588] Starting from 5-bromo-3-methoxypyridin-2(1H)-one and 1-(6-chloro-5-(4-(2,4- difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile, 24.47 mg of the target molecule 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(5-methoxy-1-methyl-6- oxo-1, 6-dihydropyridin-3-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile was prepared by referring to the procedure of Example 20.

[0589] MS (ESI) M / Z: 494.3 [M+H] + .

[0590] 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.34-7.23 (m, 2H), 7.07-6.95 (m, 1H), 4.56-4.44 (m, 1H), 3.77 (s, 3H), 3.55 (s, 3H), 3.47-3.40 (m, 2H), 3.07-2.99 (m, 2H), 2.04-1.93 (m, 2H), 1.80-1.76 (m, 2H), 1.75-1.66 (m, 4H).

[0591] Example 22:

[0592] 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3- yl)pyrazin-2-yl)cyclobutan-1-one

[0593] Operation steps

[0594] Step A: 2-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)acetonitrile (200 mg, 0.604 mmol), 1,3-dibromopropane (182.9 mg, 0.906 mmol) were dissolved in DMF (3 mL) and added dropwise to a solution of 60% sodium hydride (72.5 mg, 1.812 mmol) in DMF (2 mL) at room temperature. The reaction was stirred at 20 °C for 10 min. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3 times). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 100 mg of the target molecule 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclobutan-1-one.

[0595] 1 H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 1.5 Hz, 1H), 8.19 (d, J = 1.5 Hz, 1H), 7.03-6.95 (m, 1H), 6.91-6.84 (m, 1H), 6.83-6.75 (m, 1H), 4.49-4.41 (m, 1H), 4.00-3.89 (m, 2H), 3.64-3.54 (m, 2H), 2.84-2.68 (m, 4H), 2.45-2.31 (m, 1H), 2.17-2.06 (m, 1H), 2.04-1.98 (m, 2H), 1.95-1.85 (m, 2H).

[0596] Step B and C: 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclobutan-1-one was used as the raw material, and the preparation method was referred to Example 12 and Example 13 to give 4.24 mg of the target molecule 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazin-2-yl)cyclobutan-1-one.

[0597] MS (ESI) M / Z: 478.0 [M+H] + .

[0598] 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 2.5 Hz, 1H), 8.31 (s, 1H), 8.09 (dd, J = 9.5, 2.6 Hz, 1H), 7.39 - 7.20 (m, 2H), 7.00 (m, 1H), 6.54 (d, J = 9.5 Hz, 1H), 4.60 - 4.40 (m, 1H), 3.55 (s, 3H), 3.51 - 3.41 (m, 2H), 3.10 - 3.00 (m, 2H), 2.85 - 2.66 (m, 4H), 2.33 - 2.20 (m, 1H), 2.14 - 1.93 (m, 3H), 1.83 - 1.65 (m, 2H).

[0599] Example 23:

[0600] 1-(6-(1-(diifluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile

[0601] Procedure:

[0602] With 5-bromo-1-(difluoromethyl)-1,2-dihydropyridin-2-one and 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile as starting materials, the preparation method is referred to Example 12 and Example 13 to obtain 80 mg of target molecule 1-(6-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile.

[0603] MS (ESI) M / Z: 500.2 [M+H] + ;

[0604] 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.5 Hz, 1H), 8.32 (s, 1H), 8.19 (dd, J = 9.8, 2.5 Hz, 1H), 7.95 (t, J = 59.6 Hz, 1H), 7.36 - 7.24 (m, 2H), 7.06 - 6.97 (m, 1H), 6.70 (d, J = 9.8 Hz, 1H), 4.59 - 4.45 (m, 1H), 3.52 - 3.39 (m, 2H), 3.10 - 2.98 (m, 2H), 2.06 - 1.96 (m, 2H), 1.85 - 1.78 (m, 2H), 1.78 - 1.69 (m, 4H).

[0605] Example 24:

[0606] 5-(6-(1-(di fluoromethyl)cyclopropyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)-1- methylpyridin-2(1H)-one

[0607] Operation steps

[0608] Step A: 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1- carbonitrile (500 mg, 1.28 mmol) was dissolved in DCM (7.5 mL), cooled to -78 °C, then diisobutylaluminum hydride (2.56 mL, 3.85 mmol) was added dropwise slowly, the reaction solution was stirred at -78 °C for 1 h. After the reaction solution was returned to room temperature, sodium sulfate decahydrate was added slowly, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 116 mg of 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1- carbaldehyde.

[0609] MS (ESI) M / Z: 394.1 [M+H] + .

[0610] 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.46 (s, 1H), 7.36-7.26 (m, 2H), 7.02 (t, J = 8.7 Hz, 1H), 4.63-4.50 (m, 1H), 3.71-3.58 (m, 2H), 3.26-3.20 (m, 2H), 2.10-2.00 (m, 2H), 1.84-1.72 (m, 2H), 1.69-1.65 (m, 2H), 1.64-1.59 (m, 2H).

[0611] Step B: 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1- carbaldehyde (116 mg, 0.29 mmol) was dissolved in DCM (1.5 mL), then diethylamine trifluoride (142 mg, 0.88 mmol) was added, and the reaction solution was stirred at room temperature for 3 h. The reaction solution was quenched by pouring into ice water (10 mL), extracted with ethyl acetate (10 mL x 2 times), the combined organic phase was washed with water (20 mL), saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 37 mg of 3-chloro-5-(1-(difluoromethyl)cyclopropyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazine.

[0612] MS (ESI) M / Z: 416.1 [M+H] + .

[0613] 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.36 - 7.25 (m, 2H), 7.05 - 6.97 (m, 1H), 6.22 (t, J = 55.8 Hz, 1H), 4.60 - 4.53 (m, 1H), 3.70 - 3.61 (m, 2H), 3.25 - 3.20 (m, 2H), 2.11 - 2.00 (m, 2H), 1.82 - 1.72 (m, 2H), 1.25 - 1.16 (m, 4H).

[0614] Step C: 3-chloro-5-(1-(difluoromethyl)cyclopropyl)-2-(4-(2,4-difluorophenoxy)piperidin-1- yl)pyrazine (37 mg, 0.09 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin- 2(1H)-one (42 mg, 0.18 mmol), Pd(dtbpf)Cl2(5.8 mg, 0.009 mmol) and cesium carbonate (58 mg, 0.18 mmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL) in a sealed tube under nitrogen protection, and heated to 110 °C for 3 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by thin layer chromatography and preparative high performance liquid chromatography to obtain 19.48 mg of the target molecule 5-(6-(1-(difluoromethyl)cyclopropyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)-1- methylpyridin-2(1H)-one.

[0615] MS (ESI) M / Z: 489.2 [M+H] + .

[0616] 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 2.5 Hz, 1H), 8.20 (s, 1H), 8.09 (dd, J = 9.5, 2.6 Hz, 1H), 7.33 - 7.23 (m, 2H), 7.04 - 6.96 (m, 1H), 6.53 - 6.22 (m, 2H), 4.53 - 4.42 (m, 1H), 3.54 (s, 3H), 3.46 - 3.37 (m, 2H), 3.05 - 2.96 (m, 2H), 2.04 - 1.95 (m, 2H), 1.77 - 1.67 (m, 2H), 1.31 - 1.26 (m, 2H), 1.22 - 1.18 (m, 2H).

[0617] Example 25:

[0618] 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1-(methyl-d3)-6-oxo-1,6- dihydropyridin-3-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile

[0619] Procedure

[0620] Step A: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-ol (600 mg, 2.71 mmol) was dissolved in acetonitrile (12 mL) solution, then potassium carbonate (1.87 g, 13.57 mmol) and iodomethane-d3 (786 mg, 5.43 mmol) were added, the reaction was heated to 50 °C for 16 hours. After the reaction was returned to room temperature, it was filtered, the filter cake was washed with ethyl acetate (20 mL), the filtrate was added with water (20 mL), ethyl acetate was extracted (20 mL x 3 times), the combined organic phase was dried over anhydrous sodium sulfate, filtered, then concentrated under reduced pressure to obtain 615 mg of 1-(methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one crude product.

[0621] MS (ESI) M / Z: 239.1 [M+H] + .

[0622] 1 H NMR (400 MHz, CDCl3) d 7.76 (d, J = 1.7 Hz, 1H), 7.60 (dd, J = 9.1, 2.0 Hz, 1H), 6.53 (d, J = 9.1 Hz, 1H), 1.31 (s, 12H).

[0623] Step B: 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1- carbonitrile (200 mg, 0.51 mmol) was dissolved in 1,4 dioxane / water (2 mL / 0.2 mL) under nitrogen protection at room temperature, to which was added 1-(methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (600 mg, 2.71 mmol), Pd(dtbpf)Cl2(33.2 mg, 0.051 mmol) and cesium carbonate (240.5 mg, 1.02 mmol), and the reaction was heated to 90 °C for 1 hour. After the reaction was returned to room temperature, it was filtered, the filtrate was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3 times), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain 115.06 mg of the target molecule 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1-(methyl-d3)-6-oxo-1,6-dihydropyridin-3-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile.

[0624] MS (ESI) M / Z: 466.9 [M+H] + .

[0625] 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 2.4 Hz, 1H), 8.25 (s, 1H), 8.07 (dd, J = 9.5, 2.6 Hz, 1H), 7.32 - 7.26 (m, 2H), 7.00 (s, 1H), 6.51 (d, J = 9.5 Hz, 1H), 4.58 - 4.42 (m, 1H), 3.49 - 3.39 (m, 2H), 3.05 - 2.95 (m, 2H), 2.06 - 1.95 (m, 2H), 1.79 - 1.69 (m, 6H).

[0626] Example 26:

[0627] 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(6-methylpyridin-2-yl)pyrazin-2-yl)cyclopropane-1- carbonitrile

[0628] Reaction Scheme:

[0629] Procedure:

[0630] With 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1- carbonitrile and (6-methylpyridin-2-yl)boronic acid as raw materials, the preparation method is reference to Example 12 and Example 13 to obtain 29.55 mg of target molecule 1-(5-(4-(2,4- difluorophenoxy)piperidin-1-yl)-6-(6-methylpyridin-2-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile.

[0631] MS (ESI) M / Z: 448.2 [M+H] + ;

[0632] 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.28 - 7.19 (m, 2H), 7.00 - 6.94 (m, 1H), 4.52 - 4.40 (m, 1H), 3.47 - 3.34 (m, 2H), 3.07 - 2.96 (m, 2H), 2.53 (s, 3H), 1.92 - 1.83 (m, 2H), 1.78 - 1.72 (m, 2H), 1.67 - 1.54 (m, 4H).

[0633] Example 27:

[0634] 5-(3-(4-(2,4-Difluorophenoxy)piperidin-1-yl)-6-(1-(trifluoromethyl)cyclopropyl)pyrazin-2-yl)-1- methylpyridin-2(1H)-one

[0635] Operation steps:

[0636] Step A: 2-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazine (20 mg, 0.06 mmol) was dissolved in 1,4-dioxane / water (0.5 mL / 0.05 mL) under nitrogen protection at room temperature, then 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-l-en-2-yl)-l,3,2-dioxaborolane (27.26 mg, 0.12 mmol), Pd(dtbpf)Cl2(3.9 mg, 0.006 mmol), cesium carbonate (39.1 mg, 0.12 mmol) were added, and the reaction was heated to 110 °C for 16 h. After the reaction was cooled to room temperature, it was filtered, the filter cake was washed with ethyl acetate (5 mL x 3 times), and the filtrate was directly concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 20 mg of the target molecule 2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(3,3,3-trifluoroprop-l-en-2-yl)pyrazine.

[0637] MS (ESI) M / Z: 386.2 [M+H] + .

[0638] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 1.4 Hz, 1H), 8.32 (s, 1H), 7.38 - 7.25 (m, 2H), 7.08 - 6.98 (m, 1H), 6.37 (d, J = 1.7 Hz, 1H), 6.01 (s, 1H), 4.68 - 4.56 (m, 1H), 4.09 - 3.97 (m, 2H), 3.59 - 3.46 (m, 2H), 2.07 - 1.95 (m, 2H), 1.74 - 1.59 (m, 2H).

[0639] Step B: 2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(3,3,3-trifluoroprop-l-en-2-yl)pyrazine (50 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL) under ice bath, then freshly prepared diazomethane in ether (2.8 mL, 1.3 mmol) was added, and after the addition was completed, the reaction was stirred at room temperature for 2 h. The reaction was quenched by adding 5 drops of acetic acid, and concentrated under reduced pressure. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (10 mL x 3 times), the organic phase was combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 55.6 mg of the target molecule 2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(3-(trifluoromethyl)-4,5-dihydro-3H-pyrazol-3-yl)pyrazine.

[0640] MS (ESI) M / Z: 428.1 [M+H]+.

[0641] Step C: 2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(3-(trifluoromethyl)-4,5- dihydro-3H-pyrazol-3-yl)pyrazine (55.6 mg, 0.13 mmol) was dissolved in xylene (3 mL) under nitrogen protection at room temperature, and the reaction was heated to 130 °C and stirred overnight. After the reaction was returned to room temperature, the obtained residue was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 46 mg of the target molecule 2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(l-(trifluoromethyl)cyclopropyl)pyrazine.

[0642] MS (ESI) M / Z: 400.3 [M+H] + .

[0643] 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 1.5 Hz, 1H), 8.19 (s, 1H), 7.37 - 7.25 (m, 2H), 7.06 - 6.99 (m, 1H), 4.66 - 4.54 (m, 1H), 4.05 - 3.92 (m, 2H), 3.50 - 3.38 (m, 2H), 2.06 - 1.93 (m, 2H), 1.72 - 1.58 (m, 2H), 1.26 - 1.19 (m, 4H).

[0644] Step D: 2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(l-(trifluoromethyl)cyclopropyl)pyrazine (173 mg, 0.43 mmol) was dissolved in a mixed solvent (DMF / acetic acid = 1 / 1, 7 mL) at room temperature, and then NCS (75.2 mg, 0.56 mmol) was added thereto, and the reaction was heated to 50 °C for 16 hours. After the reaction was returned to room temperature, water (10 mL) was added to quench the reaction, and extraction was performed using ethyl acetate (10 mL x 3 times), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 140 mg of the target molecule 3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(l-(trifluoromethyl)cyclopropyl)pyrazine.

[0645] MS (ESI) M / Z: 434.2 [M+H] + .

[0646] 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.38 - 7.25 (m, 2H), 7.07 - 6.97 (m, 1H), 4.64 - 4.53 (m, 1H), 3.77 - 3.64 (m, 2H), 3.32 - 3.25 (m, 2H), 2.11 - 2.01 (m, 2H), 1.84 - 1.70 (m, 2H), 1.43 - 1.38 (m, 2H), 1.33 - 1.27 (m, 2H).

[0647] Step E: 3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(l- (trifluoromethyl)cyclopropyl)pyrazine (50 mg, 0.12 mmol) was dissolved in 1,4- dioxane / water (1 mL / 0.1 mL) under nitrogen at room temperature, then 1-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (54.2 mg, 0.23 mmol), Pd(dtbpf)Cl2(7.48 mg, 0.012 mmol), cesium carbonate (74.9 mg, 0.23 mmol) were added, and the reaction was heated to 110 °C for 3 hours. The reaction was cooled to room temperature, and the resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography and preparative high performance liquid chromatography to obtain 56.06 mg of 5-(3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l- (trifluoromethyl)cyclopropyl)pyrazin-2-yl)-l-methylpyridin-2(lH)-one.

[0648] MS (ESI) M / Z: 507.1 [M+H] + .

[0649] 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 2.5 Hz, 1H), 8.24 (s, 1H), 8.04 (dd, J = 9.5, 2.6 Hz, 1H), 7.32 - 7.24 (m, 2H), 7.03 - 6.97 (m, 1H), 6.51 (d, J = 9.5 Hz, 1H), 4.54 - 4.44 (m, 1H), 3.54 (s, 3H), 3.49 - 3.41 (m, 2H), 3.09 - 2.99 (m, 2H), 2.04 - 1.93 (m, 2H), 1.78 - 1.66 (m, 2H), 1.40 (s, 4H).

[0650] Example 28:

[0651] 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-methyl-6-(1-methyl-6-oxo-1,6- dihydropyridin-3-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile

[0652] Operation steps

[0653] Step A: Methyl 3,5-dichloropyrazine-2-carboxylate (5 g, 24.15 mmol) was dissolved in DMF (75 mL) under ice bath, N,N-diisopropyl ethylamine (6.23 g, 48.3 mmol) and 4-(2,4-difluorophenoxy)piperidine (5.15 g, 24.15 mmol) were added into the above solution, the reaction was kept under ice bath for 1.5 hours. The reaction was quenched by adding water (50 mL) after returning to room temperature, extracted with ethyl acetate, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, then purified by silica gel column chromatography to obtain 7 g of the target molecule methyl 3-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazine-2-carboxylate.

[0654] MS (ESI) M / Z: 384.4 [M+H] + .

[0655] Step B: Methyl 3-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazine-2-carboxylate (5.3 g, 13.81 mmol) was dissolved in tetrahydrofuran (138 mL) and methanol (15.3 mL) under ice bath, then lithium borohydride tetrahydrofuran solution (7.6 mL, 15.19 mmol) was added, the reaction was kept under ice bath for 2 hours. After returning to room temperature, water (100 mL) was added to quench the reaction, extracted with ethyl acetate (50 mL x 3 times), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, then the obtained residue was purified by silica gel column chromatography to obtain 2.5 g of the target molecule (3-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)methanol.

[0656] MS (ESI) M / Z: 356.2 [M+H] + .

[0657] 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.37-7.26 (m, 2H), 7.09-6.98 (m, 1H), 5.16-5.07 (m, 1H), 4.63-4.55 (m, 1H), 4.49 (s, 2H), 3.98-3.91 (m, 2H), 3.49-3.41 (m, 2H), 2.05-1.99 (m, 2H), 1.71-1.61 (m, 2H).

[0658] Step C: (3-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)methanol (1 g, 2.81 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL) under nitrogen protection at room temperature, then methylboronic acid (504.6 mg, 8.43 mmol), Pd(dppf)Cl2(205.6 mg, 0.28 mmol) and potassium carbonate (776.7 mg, 5.62 mmol) were added, and the reaction was heated to 110 °C for 16 hours. After the reaction was cooled to room temperature, it was filtered with diatomite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 600 mg of (5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-3-methylpyrazin-2-yl)methanol.

[0659] MS (ESI) M / Z: 336.2 [M+H] + .

[0660] 1 H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.36-7.25 (m, 2H), 7.08-6.93 (m, 1H), 4.94 (t, J = 5.5 Hz, 1H), 4.61-4.52 (m, 1H), 4.46 (d, J = 5.5 Hz, 2H), 4.01-3.87 (m, 2H), 3.40-3.33 (m, 2H), 2.40 (s, 3H), 2.04-1.92 (m, 2H), 1.70-1.56 (m, 2H).

[0661] Step D: (5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-3-methylpyrazin-2-yl)methanol (760 mg, 2.27 mmol) was dissolved in DCM (20 mL) at room temperature, then triethylamine (688 mg, 6.8 mmol) and methylsulfonyl chloride (389 mg, 3.4 mmol) were added, the reaction was returned to room temperature and reacted for 2 hours. Quench with water (30 mL), the mixture was extracted with ethyl acetate (20 mL x 3 times), the organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was dissolved in acetonitrile (10 mL). Tetra-n-butylammonium fluoride (4.53 mL, 4.53 mmol) and trimethylsilyl cyanide (567 mg, 4.53 mmol) were added to the above reaction solution under ice water bath, and the reaction was reacted at room temperature for 16 hours. Quench with water (30 mL). The mixture was extracted with ethyl acetate (20 mL x 3 times), the organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 100 mg of the target molecule 2-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-3-methylpyrazin-2-yl)acetonitrile

[0662] MS (ESI) M / Z: 345.2 [M+H] + .

[0663] 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.37-7.24 (m, 2H), 7.08-6.97 (m, 1H), 4.64-4.50 (m, 1H), 4.05 (d, J = 8.2 Hz, 2H), 4.02-3.93 (m, 2H), 3.44-3.35 (m, 2H), 2.35 (s, 3H), 2.02-1.97 (m, 2H), 1.68-1.59 (m, 2H).

[0664] Step E: 2-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-3-methylpyrazin-2-yl)acetonitrile (100 mg, 0.29 mmol) was dissolved in dimethyl sulfoxide (3 mL) at room temperature, then diphenyl(vinyl)sulfonium trifluoromethanesulfonate (210.2 mg, 0.58 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (132.4 mg, 0.87 mmol) were added, and the reaction was stirred at 30 °C for 16 h. Water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3), and the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 90 mg of the target molecule 1-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-3-methylpyrazin-2-yl)cyclopropane-l-carbonitrile.

[0665] MS (ESI) M / Z: 371.2 [M+H] + .

[0666] 1 H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.37 - 7.23 (m, 2H), 7.08 - 6.95 (m, 1H), 4.66 - 4.48 (m, 1H), 4.06 - 3.90 (m, 2H), 3.48 - 3.35 (m, 2H), 2.51 (s, 3H), 2.08 - 1.92 (m, 2H), 1.72 - 1.58 (m, 4H), 1.48 - 1.40 (m, 2H).

[0667] Step F: 1-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-3-methylpyrazin-2-yl)cyclopropane-l-carbonitrile (90 mg, 0.24 mmol) was dissolved in DMF (2 mL) and acetic acid (2 mL) at room temperature, then NCS (42.2 mg, 0.32 mmol) was added, and the reaction was heated to 50 °C for 16 h. Water (10 mL) was added to quench the reaction, and the mixture was made basic with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (10 mL x 3), and the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 65 mg of the target molecule 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-3-methylpyrazin-2-yl)cyclopropane-l-carbonitrile.

[0668] MS (ESI) M / Z: 405.2 [M+H] + .

[0669] 1H NMR (400 MHz, DMSO-d6) δ 7.38 - 7.22 (m, 2H), 7.10 - 6.97 (m, 1H), 4.69 - 4.44 (m, 1H), 3.79 - 3.62 (m, 2H), 3.29 - 3.22 (m, 2H), 2.57 (s, 3H), 2.11 - 1.98 (m, 2H), 1.84 - 1.70 (m, 4H), 1.58 - 1.48 (m, 2H).

[0670] Step G: l-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-3-methylpyrazin-2- yl)cyclopropane-l-carbonitrile (35 mg, 0.086 mmol) and l-methyl-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (40.6 mg, 0.173 mmol) were dissolved in a solution of 1,4-dioxane / water (0.8 mL / 0.08 mL) under nitrogen at room temperature, then Pd(dtbpf)Cl2(5.6 mg, 0.0086 mmol) and cesium carbonate (56 mg, 0.172 mmol) were added to the above reaction solution, and the reaction solution was heated to 110 °C for 2 hours. After the reaction solution was returned to room temperature, it was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography and preparative high performance liquid chromatography to obtain 13.84 mg of the target molecule l-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-3-methyl-6-(l-methyl-6-oxo- 1,6-dihydropyridin-3-yl)pyrazin-2-yl)cyclopropane-l-carbonitrile.

[0671] MS (ESI) M / Z: 478.2 [M+H] + .

[0672] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 2.5 Hz, 1H), 8.01 (dd, J = 9.5, 2.6 Hz, 1H), 7.36 - 7.20 (m, 2H), 7.05 - 6.94 (m, 1H), 6.49 (d, J = 9.5 Hz, 1H), 4.54 - 4.42 (m, 1H), 3.53 (s, 3H), 3.49 - 3.39 (m, 2H), 3.07 - 3.01 (t, J = 9.4 Hz, 2H), 2.59 (s, 3H), 2.02 - 1.93 (m, 2H), 1.76 - 1.66 (m, 4H), 1.63 - 1.58 (m, 2H).

[0673] Example 29:

[0674] N-(6-(1-cyanocyclopropyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)-3- methoxy-1-methyl-1H-pyrazole-4-carboxamide

[0675] Operation steps

[0676] Step A: 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid (30 mg, 0.19 mmol) was dissolved in DMF (1 mL) at room temperature, followed by the addition of ammonium chloride (30.8 mg, 0.58 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (86.7 mg, 0.23 mmol), N,N-diisopropylethylamine (49.12 mg, 0.38 mmol), and the reaction was allowed to react at room temperature for 2 hours. The reaction was concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography to obtain 20 mg of the target molecule 3-methoxy-1-methyl-1H-pyrazole-4-carboxamide.

[0677] MS (ESI) M / Z: 156.0 [M+H] + .

[0678] 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.05 (s, 1H), 6.53 (s, 1H), 3.87 (s, 3H), 3.69 (s, 3H).

[0679] Step B: 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1- carbonitrile (25 mg, 0.064 mmol) and 3-methoxy-1-methyl-1H-pyrazole-4-carboxamide (10 mg, 0.064 mmol) were dissolved in anhydrous 1,4-dioxane (0.5 mL) under nitrogen protection at room temperature, followed by the addition of Pd2(dba)3(5.86 mg, 0.0064 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (6.10 mg, 0.0128 mmol), and cesium carbonate (41.7 mg, 0.128 mmol), and the reaction was heated to 90°C in a sealed tube for 4 hours. After the reaction was returned to room temperature, the obtained crude product was purified by silica gel thin layer chromatography, and was slurried with methanol (5 mL), filtered, and the filter cake was dried to obtain 4.74 mg of the target molecule N-(6-(1-cyanocyclopropyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)-3- methoxy-1-methyl-1H-pyrazole-4-carboxamide.

[0680] MS (ESI) M / Z: 510.1 [M+H]+ .

[0681] 1 H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.18(s,1H),8.15(s,1H),7.35-7.25(m,2H),7.04-6.98(m,1H),4.61-4.50(m,1H ),4.00(s,3H),3.76(s,3H),3.49-3.36(m,2H),3.04(m,2H),2.06-1.96(m,2H),1.83-1.71(m,4H),1.64-1.56(m,2H).

[0682] Example 30:

[0683] 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)cyclopropane-1-onitrile

[0684] Operating steps:

[0685] Step A: Under nitrogen protection at room temperature, 1 g (6.94 mmol) of 6-chloro-2-methylpyridazin-3(2H)-one, 2.64 g (10.42 mmol) of bis(pinacol)diboron (2.04 g (20.82 mmol) and 2.04 g (20.82 mmol) of potassium acetate were added to 1,4-dioxane (15 mL), along with palladium acetate (154.56 mg (0.69 mmol) and X-phos (657.87 mg (1.38 mmol)). The reaction mixture was heated to 100 °C for 3 hours. The reaction mixture was then cooled to room temperature and quenched with water. The reaction mixture was extracted three times with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.5 g of the target molecule, 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridazin-3(2H)-one.

[0686] MS(ESI)M / Z: 236.9 [M+H] + .

[0687] Step B: Under nitrogen atmosphere, 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1- yl)pyrazin-2-yl)cyclopropane-1-carbonitrile (40 mg, 0.1 mmol), cesium carbonate (65 mg, 0.2 mmol), Pd(dtbpf)Cl2(6.52 mg, 0.01 mmol) and 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine-3(2H)-one (236 mg, 1.0 mmol) were added into a mixture of 1,4-dioxane (2 mL) and water (0.2 mL), the reaction mixture was heated to 80 °C for 1 h. The reaction was quenched by adding water (5 mL), extracted with ethyl acetate for three times, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative high performance liquid chromatography to give 34.17 mg of the target molecule 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile.

[0688] MS (ESI) M / Z: 465.2 [M+H] + .

[0689] 1 H NMR (400 MHz, DMSO-d6) d 8.33 (s, 1H), 7.95 (d, J = 9.7 Hz, 1H), 7.37 - 7.22 (m, 2H), 7.08 (d, J = 9.7 Hz, 1H), 7.04 - 6.97 (m, 1H), 4.58 - 4.47 (m, 1H), 3.72 (s, 3H), 3.60 - 3.47 (m, 2H), 3.21 - 3.05 (m, 2H), 2.03 - 1.90 (m, 2H), 1.79 - 1.75 (m, 2H), 1.73 - 1.56 (m, 4H).

[0690] Example 31:

[0691] 2-(1-(6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)cyclopropyl)-5-methyl-1,3,4-oxadiazole

[0692] Procedure:

[0693] Step A: 2-(l-(5-chloro-6-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2- yl)cyclopropyl)-5-methyl-l,3,4-oxadiazole (23 mg, 0.051 mmol), l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (53.51 mg, 0.25 mmol) and cesium carbonate (33.25 mg, 0.10 mmol) were added to a mixture of 1,4-dioxane (0.8 mL) and water (0.08 mL) under nitrogen at room temperature, then Pd(dtbpf)Cl2(3.32 mg, 0.0051 mmol) was added, the reaction mixture was heated to 90 °C for 1 h. The reaction mixture was cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (3x), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative high performance liquid chromatography to give 6 mg of the target molecule 2-(l-(6-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(l-methyl-lH-pyrazol-4-yl)pyrazin-2- yl)cyclopropyl)-5-methyl-l,3,4-oxadiazole.

[0694] MS (ESI) M / Z: 494.2 [M+H] + .

[0695] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.21 (s, 1H), 8.02 (s, 1H), 7.33-7.26 (m, 2H), 7.06-6.95 (m, 1H), 4.52-4.49 (m, 1H), 3.92 (s, 3H), 3.39-3.35 (m, 2H), 3.02-2.96 (m, 2H), 2.48 (s, 3H), 2.06-2.02 (m, 2H), 1.82-1.72 (m, 4H), 1.66-1.61 (m, 2H).

[0696] Example 32:

[0697] 1-(5-(6-aminopyridin-2-yl)-6-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropane-l-carbonitrile

[0698] Procedure

[0699] Starting from 2-(tert-butoxycarbonyl)-amino-6-tri-n-butylstannyl-pyridine and 1-(5-chloro-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile, the preparation method refers to INT-2, INT-5 and Example 3 to obtain 8.13 mg of target molecule 1-(5-(6-aminopyridin-2-yl)-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile.

[0700] MS (ESI) M / Z: 449.0 [M+H] + .

[0701] 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.56-7.42 (m, 1H), 7.33-7.19 (m, 2H), 7.02-6.94 (m, 1H), 6.86 (d, J = 7.3 Hz, 1H), 6.43 (d, J = 8.2 Hz, 1H), 6.05 (s, 2H), 4.47 (s, 1H), 3.46 (s, 2H), 3.09-2.99 (m, 2H), 1.90-1.86 (m, 2H), 1.85-1.80 (m, 2H), 1.77-1.69 (m, 2H), 1.62-1.56 (d, J = 9.1 Hz, 2H).

[0702] Example 33:

[0703] 1-(6-(4-aminopyrimidin-2-yl)-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile

[0704] Procedure:

[0705] Starting from 2-chloropyrimidin-4-amine and 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile, the preparation method refers to INT-2 and Example 3 to obtain 8.55 mg of target molecule 1-(6-(4-aminopyrimidin-2-yl)-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile.

[0706] MS (ESI) M / Z: 450.7 [M+H] + .

[0707] 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.18 (d, J = 5.9 Hz, 1H), 7.31-7.21 (m, 2H), 7.11 (s, 2H), 7.01-6.94 (m, 1H), 6.42 (d, J = 5.9 Hz, 1H), 4.51-4.42 (m, 1H), 3.54-3.45 (m, 2H), 3.12-3.01 (m, 2H), 1.90-1.80 (m, 2H), 1.74-1.67 (m, 2H), 1.58-1.48 (m, 4H).

[0708] Example 34:

[0709] 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1-methoxy-6-oxo-1,6-dihydropyridin-3-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile

[0710] Procedure

[0711] Step A: 5-bromo-2-chloropyridine (1 g, 5.23 mmol) was dissolved in dichloromethane (15 mL) at room temperature, and meta-chloroperoxybenzoic acid (2.71 g, 15.71 mmol) was added slowly. The reaction was heated to 50 °C for 16 hours. After the reaction was cooled to room temperature, calcium hydroxide (1.6 g, 21.62 mmol) was added, and stirred at room temperature for 0.5 hours. The reaction was filtered through celite, and the filtrate was dried under nitrogen to give 1 g of the target molecule 5-bromo-2-chloropyridine 1-oxide.

[0712] MS (ESI) M / Z: 208.0 [M+H] + .

[0713] Step B: 5-bromo-2-chloropyridine 1-oxide (900 mg, 4.35 mmol) was dissolved in chloroform (25 mL) at room temperature, and trifluoroacetic anhydride (5 mL) was added slowly. The reaction was heated to 60 °C for 16 hours. After the reaction was cooled to room temperature, sodium bicarbonate solid (1 g) and methanol (5 mL) were added, and stirred at room temperature for 0.5 hours. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give 900 mg of the target molecule 5-bromo-1-hydroxypyridin-2(1H)-one.

[0714] MS (ESI) M / Z: 190.1 [M+H] + .

[0715] Step C: 5-Bromo-l-hydroxypyridin-2(lH)-one (900 mg, 4.76 mmol), potassium carbonate (1.97 g, 14.28 mmol) and iodomethane (2.02 g, 14.28 mmol) were dissolved in acetonitrile (8 mL) and the reaction was heated to 60 °C for 16 h. The reaction was allowed to cool to room temperature, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford 600 mg of 5-bromo-l-methoxypyridin-2(lH)-one.

[0716] MS (ESI) M / Z: 204.0 [M+H] + .

[0717] 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 2.7 Hz, 1H), 7.55 (dd, J = 9.8, 2.7 Hz, 1H), 6.53 (d, J = 9.8 Hz, 1H), 3.95 (s, 3H).

[0718] Step D: 5-Bromo-l-methoxypyridin-2(lH)-one (300 mg, 1.48 mmol), bis(pinacolato)diboron (563.05 mg, 2.21 mmol) and potassium acetate (435.12 mg, 4.44 mmol) were added to 1,4-dioxane (2.5 mL) under nitrogen at room temperature. Pd(dppf)Cl2(241.53 mg, 0.29 mmol) was added and the reaction was heated to 80 °C for 2 h. The reaction was allowed to cool to room temperature and l-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropane-l- carbonitrile (30 mg, 0.077 mmol), cesium carbonate (50.03 mg, 0.15 mmol) and Pd(dtbpf)Cl2(6.28 mg, 0.0077 mmol) were added. The reaction was heated to 100 °C for 1.5 h. The reaction was quenched by the addition of water (5 mL) and extracted with ethyl acetate (3x). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative high performance liquid chromatography to afford 11.37 mg of l-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-methoxy-6-oxo-l,6- dihydropyridin-3-yl)pyrazin-2-yl)cyclopropane-l-carbonitrile.

[0719] MS (ESI) M / Z: 480.2 [M+H] + .

[0720] 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 2.5 Hz, 1H), 8.28 (s, 1H), 8.09 (dd, J = 9.6, 2.5 Hz, 1H), 7.36 - 7.22 (m, 2H), 7.07 - 6.95 (m, 1H), 6.68 (d, J = 9.6 Hz, 1H), 4.59 - 4.44 (m, 1H), 4.03 (s, 3H), 3.45 - 3.41 (m, 2H), 3.06 - 2.99 (m, 2H), 1.99 (s, 2H), 1.80 - 1.69 (m, 6H).

[0721] Example 35:

[0722] 5-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1-(methoxymethyl)cyclopropyl)pyrazin-2-yl)-1- methylpyridin-2(1H)-one

[0723] Procedure:

[0724] Step A: 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carboxylic acid ethyl ester (220 mg, 0.55 mmol) was dissolved in tetrahydrofuran (4 mL) under ice water bath, then lithium aluminum hydride tetrahydrofuran solution (0.44 mL, 2.5 mol / L tetrahydrofuran solution) was added dropwise, the reaction solution was reacted under ice water bath for 1 hour. Quench with water, add 1N dilute hydrochloric acid until the system becomes clear, extract with ethyl acetate (30 mL x 3 times), wash the combined organic phase with saturated sodium chloride (20 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, then purify the residue obtained with silica gel column chromatography to obtain 150 mg of the target molecule (1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropyl)methanol.

[0725] MS (ESI) M / Z: 362.2 [M+H] + .

[0726] Step C: To a solution of (l-(5-(4-(2,4-difluorophenoxy)piperidin-l- yl)pyrazin-2-yl)cyclopropyl)methanol (130 mg, 0.36 mmol) in dimethyl sulfoxide (3 mL) was added sodium hydride (44.5 mg, 1.11 mmol) and iodomethane (102.2 mg, 0.72 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 86.7 mg of 2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(l- (methoxymethyl)cyclopropyl)pyrazine.

[0727] MS (ESI) M / Z: 376.2 [M+H] + .

[0728] Step C: To a solution of 2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(l- (methoxymethyl)cyclopropyl)pyrazine (50 mg, 0.13 mmol) in acetic acid / N,N- dimethylformamide (0.1 mL / 2 mL) was added NCS (22.6 mg, 0.17 mmol) at room temperature. The reaction mixture was heated to 40 °C for 1 h. The reaction mixture was cooled to room temperature and quenched with water. The reaction mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 55 mg of 3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-5-(l- (methoxymethyl)cyclopropyl)pyrazine.

[0729] MS (ESI) M / Z: 410.2 [M+H] + .

[0730] Step D: Into a reaction vial was added 3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-l- yl)-5-(l-(methoxymethyl)cyclopropyl)pyrazine (55 mg, 0.13 mmol), (6-methylpyridin-2- yl)boronic acid (45.8 mg, 0.2 mmol), Pd(dtbpf)Cl2(8.5 mg, 0.013 mmol) and cesium carbonate (127.1 mg, 0.39 mmol) followed by 1,4-dioxane / water (2 mL / 0.2 mL), which was heated to 100 °C for 3 h under nitrogen protection. The reaction was allowed to cool to room temperature, quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and the crude was purified by preparative high performance liquid chromatography to give 12.09 mg of 5-(3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l- (methoxymethyl)cyclopropyl)pyrazin-2-yl)-l-methylpyridin-2(lH)-one.

[0731] MS (ESI) M / Z: 483.2 [M+H] + ;

[0732] 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 2.6 Hz, 1H), 8.19 (s, 1H), 8.11 (dd, J = 9.5, 2.6 Hz, 1H), 7.35 - 7.24 (m, 2H), 7.05 - 6.97 (m, 1H), 6.51 (d, J = 9.4 Hz, 1H), 4.55 - 4.44 (m, 1H), 3.68 (s, 2H), 3.54 (s, 3H), 3.43 - 3.36 (m, 2H), 3.32 (s, 3H), 3.03 - 2.93 (m, 2H), 2.06 - 1.96 (m, 2H), 1.80 - 1.68 (m, 2H), 1.22 - 1.16 (m, 2H), 0.95 - 0.95 (m, 2H).

[0733] Example 36:

[0734] 1-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-3-methyl-6-(l-methyl-6-oxo-l,6- dihydropyridazin-3-yl)pyrazin-2-yl)cyclopropane-l-carbonitrile

[0735] Preparation Method:

[0736] With 6-chloro-2-methylpyridazine-3(2H)-one and 3,5-dichloropicolinic acid methyl ester as raw materials, the preparation method refers to Example 28 and Example 30, and 23.76 mg of the target molecule 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-methyl-6-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile is obtained.

[0737] MS (ESI) M / Z: 478.9 [M+H] + .

[0738] 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 9.7 Hz, 1H), 7.33-7.24 (m, 2H), 7.05 (d, J = 9.7 Hz, 1H), 7.03-6.97 (m, 1H), 4.56-4.48 (m, 1H), 3.70 (s, 3H), 3.62-3.50 (m, 2H), 3.22-3.09 (m, 2H), 2.61 (s, 3H), 2.02-1.90 (m, 2H), 1.76-1.71 (m, 2H), 1.70-1.61 (m, 2H), 1.59-1.50 (m, 2H).

[0739] Example 37:

[0740] 6-(6-(1-(Difluoromethyl)cyclopropyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)-2-methylpyridazin-3(2H)-one

[0741] Preparation method:

[0742] With 6-chloro-2-methylpyridazine-3(2H)-one and 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile as raw materials, the preparation method refers to Example 24 and Example 30 to obtain 6.77 mg of the target molecule 6-(6-(1-(difluoromethyl)cyclopropyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)-2-methylpyridazin-3(2H)-one.

[0743] MS (ESI) M / Z: 490.1 [M+H] + .

[0744] 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.93 (d, J = 9.7 Hz, 1H), 7.34 - 7.25 (m, 2H), 7.08 (d, J = 9.7 Hz, 1H), 7.04 - 6.97 (m, 1H), 4.59 - 4.48 (m, 1H), 3.72 (s, 3H), 3.62 - 3.51 (m, 2H), 3.21 - 3.11 (m, 2H), 2.01 - 1.92 (m, 2H), 1.72 - 1.61 (m, 2H), 1.43 - 1.37 (m, 2H), 1.36 - 1.30 (m, 2H).

[0745] Example 38:

[0746] 6-(3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-(trifluoromethyl)cyclopropyl)pyrazin-2-yl)-2-methylpyridazin-3(2H)-one

[0747] Preparation method:

[0748] Starting from 6-chloro-2-methylpyridazin-3(2H)-one and 2-chloro-5-(4-(2,4- difluorophenoxy)piperidin-l-yl)pyrazine, 6.85 mg of 6-(3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-(trifluoromethyl)cyclopropyl)pyrazin-2-yl)-2-methylpyridazin-3(2H)-one was obtained by referring to the preparation methods in Example 27 and Example 30.

[0749] MS (ESI) M / Z: 508.6 [M+H] + .

[0750] 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.93 (d, J = 9.7 Hz, 1H), 7.34 - 7.25 (m, 2H), 7.08 (d, J = 9.7 Hz, 1H), 7.04 - 6.97 (m, 1H), 4.59 - 4.48 (m, 1H), 3.72 (s, 3H), 3.62 - 3.51 (m, 2H), 3.21 - 3.11 (m, 2H), 2.01 - 1.92 (m, 2H), 1.72 - 1.61 (m, 2H), 1.43 - 1.37 (m, 2H), 1.36 - 1.30 (m, 2H).

[0751] Example 39:

[0752] 5-(3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-(2-oxopyrrolidin-l- yl)cyclopropyl)pyrazin-2-yl)-l-methylpyridin-2(lH)-one

[0753] Preparation method:

[0754] Using l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one and l-(l-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropyl)pyrrolidin-2-one as the raw materials, the preparation method of which is described in reference to Example 13 and Example 16, 27.01 mg of the target molecule 5-(3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-(2-oxopyrrolidin-l-yl)cyclopropyl)pyrazin-2-yl)-l-methylpyridin-2(lH)-one was obtained.

[0755] MS (ESI) M / Z: 522.7 [M+H] + .

[0756] 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 2.5 Hz, 1H), 8.08 (dd, J = 9.5, 2.6 Hz, 1H), 7.98 (s, 1H) 7.33 - 7.23 (m, 2H), 7.02 - 6.97 (m, 1H), 6.50 (d, J = 9.5 Hz, 1H), 4.50 - 4.46 (m, 1H), 3.53 (s, 3H), 3.51-

[0757] 3.46 (m, 2H), 3.41 - 3.33 (m, 2H), 3.02 - 2.94 (m, 2H), 2.38 - 2.32 (m, 2H), 2.07 - 1.96 (m, 4H), 1.76 - 1.72 (m, 2H), 1.50 - 1.46 (m, 2H), 1.30 - 1.26 (m, 2H).

[0758] Example 40:

[0759] 5-(3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-methoxycyclopropyl)pyrazin-2-yl)-l- methylpyridin-2(lH)-one

[0760] Operation steps:

[0761] Step A: 5-chloropyrazine-2-carboxylic acid methyl ester (2 g, 11.59 mmol) was dissolved in DMF (20 mL) at room temperature, then 4-(2,4-difluorophenoxy)piperidine (2.47 g, 11.59 mmol) and DIPEA (4.49 g, 34.77 mmol) were added successively, and the reaction was heated to 80 °C for 1 h. After the reaction was returned to room temperature, it was slowly added to water (200 mL), and a large amount of solid was precipitated, which was filtered, washed with water (20 mL x 3 times), and dried to give 3.8 g of 5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazine-2-carboxylic acid methyl ester.

[0762] MS (ESI) M / Z: 350.2 [M+H] + .

[0763] Step B: Ethyl magnesium bromide (4.29 mL, 1 M / L in THF) was added to anhydrous THF (2 mL) at -20 °C, then tetraisopropyl titanate (609.65 mg, 2.15 mmol) was slowly added dropwise, and the reaction was kept at -20 °C for 1 h. Then 5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazine-2-carboxylic acid methyl ester (500 mg, 1.43 mmol) was dissolved in anhydrous THF (2 mL) and slowly added dropwise to the reaction system, and the reaction was raised to room temperature overnight. Water (20 mL) was added to quench the reaction, and ethyl acetate (30 mL x 2 times) was used for extraction, and the organic phase was combined and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 143 mg of 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropan-1-ol.

[0764] MS (ESI) M / Z: 348.2 [M+H] + .

[0765] Step C: 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropan-1-ol (146 mg, 0.21 mmol) was dissolved in anhydrous DMF (5 mL) under ice water bath, and sodium hydride (25.2 mg, 0.63 mmol) was added to the reaction system, and the reaction was continued for 0.5 h under ice water bath. Then iodomethane (60 mg, 0.42 mmol) was added, and the reaction was continued at room temperature for 2 h. Ethyl acetate (50 mL) was added to the reaction, and water (10 mL x 5 times) was used for washing, and the organic phase was combined and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 18 mg of 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(1-methoxycyclopropyl)pyrazine.

[0766] MS (ESI) M / Z: 362.2 [M+H]+ .

[0767] Step D and E: Starting from 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2- yl)cyclopropan-1-ol and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin- 2(1H)-one, the procedure described in Example 12 and Example 13 to give 1.53 mg of the target molecule 5-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1-methoxycyclopropyl)pyrazin- 2-yl)-1-methylpyridin-2(1H)-one.

[0768] MS (ESI) M / Z: 469.2 [M+H] + .

[0769] 1 H NMR (400 MHz, DMSO-d6) d 8.35 (d, J = 2.5 Hz, 1H), 8.27 (s, 1H), 8.08 (dd, J = 9.5, 2.5 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.01 (t, J = 8.6 Hz, 1H), 6.50 (d, J = 9.4 Hz, 1H), 4.53 - 4.42 (m, 1H), 3.53 (s, 3H), 3.42 - 3.39 (m, 2H), 3.34 (s, 3H), 3.03 - 2.98 (m, 2H), 2.03 - 1.97 (m, 2H), 1.77 - 1.70 (m, 2H), 1.26 - 1.18 (m, 4H).

[0770] Example 41:

[0771] 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(6-methoxypyridin-2-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile

[0772] Procedure

[0773] Step A: 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1- carbonitrile (50 mg, 0.13 mmol), 2-methoxy-6-(tributylstannyl)pyridine (99.7 mg, 0.26 mmol), Pd(Ph3)2Cl2(9 mg, 0.13 mmol) and anhydrous lithium chloride (16.3 mg, 0.385 mmol) were dissolved in anhydrous toluene (1 mL) at room temperature under nitrogen protection. The reaction solution was heated to 110 °C in a sealed tube for 6 hours under nitrogen protection.

[0774] The reaction solution was concentrated under reduced pressure after it reached room temperature, and the obtained residue was subjected to silica gel column chromatography to obtain 56 mg of a crude product. The crude product was slurried with anhydrous methanol (4 mL), filtered, and the filter cake was washed with methanol (3 mL x 4 times). After the obtained filter cake was dried, 40.98 mg of the target molecule 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(6-methoxypyridin-2-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile was obtained.

[0775] MS (ESI) M / Z: 464.1 [M+H] + .

[0776] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.86 (dd, J = 8.2, 7.4 Hz, 1H), 7.45 (dd, J = 0.8, 7.6 Hz, 1H), 7.35 - 7.20 (m, 2H), 7.06 - 6.92 (m, 1H), 6.85 (dd, J = 0.8, 8.8 Hz, 1H), 4.53 - 4.47 (m, 1H), 3.88 (s, 3H), 3.50 - 3.44 (m, 2H), 3.16 - 2.99 (m, 2H), 1.92 - 1.83 (m, 2H), 1.77 - 1.73 (m, 2H), 1.65 - 1.62 (m, 2H), 1.61 - 1.52 (m, 2H).

[0777] Example 42:

[0778] 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-vinylpyrazin-2-yl)cyclopropane-1-carbonitrile

[0779] Operation steps:

[0780] Step A: (3-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)methanol (5 g, 14.05 mmol) was dissolved in dichloromethane (50 mL), and then sulfurous dichloride (5.02 g, 42.16 mmol) was slowly added. After the addition was completed, the reaction solution was returned to room temperature and reacted for 2 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate was slurried to obtain 3.6 g of the target molecule 3-chloro-2-(chloromethyl)-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazine.

[0781] 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.40-7.24 (m, 2H), 7.11-6.82 (m, 1H), 4.78 (s, 2H), 4.66-4.51 (m, 1H), 4.02-3.91 (m, 2H), 3.59-3.44 (m, 2H), 2.07-1.95 (m, 2H), 1.79-1.54 (m, 2H).

[0782] Step B: 3-chloro-2-(chloromethyl)-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazine (3.6 g, 9.62 mmol) was dissolved in acetonitrile (72 mL) under ice bath, then trimethylsilyl cyanide (1909 mg, 19.24 mmol) and tetrabutylammonium fluoride (19.2 mL, 19.24 mmol) were added, after the addition was completed, the reaction liquid was returned to room temperature and stirred for 16 hours. Quench with water (50 mL), extract with ethyl acetate (50 mL x 3 times), wash the combined organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, then purify the residue obtained by silica gel column chromatography to obtain 2.4 g of the target molecule 2-(3-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)acetonitrile.

[0783] MS (ESI) M / Z: 365.2 [M+H] + .

[0784] 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.43-7.27 (m, 2H), 7.15-6.86 (m, 1H), 4.69-4.52 (m, 1H), 4.13 (s, 2H), 3.98-3.92 (m, 2H), 3.60-3.42 (m, 2H), 2.11-1.79 (m, 2H), 1.78-1.50 (m, 2H).

[0785] Step C: 2-(3-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)acetonitrile (2.4 g, 6.58 mmol) was dissolved in dimethyl sulfoxide (50 mL) under ice bath, then diphenyl(vinyl)sulfonium trifluoromethanesulfonate (3577 mg, 9.87 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3005 mg, 19.74 mmol) were added, after the addition was completed, the reaction liquid was stirred at 30 °C for 16 hours. Quench with water (100 mL). The mixture was extracted with ethyl acetate (50 mL x 3 times), the organic phase was washed with saturated brine (100 mL), then dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 2.15 g of the target molecule 1-(3-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropane-l- carbonitrile.

[0786] MS (ESI) M / Z: 391.1 [M+H] + .

[0787] 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.38 - 7.24 (m, 2H), 7.13 - 6.83 (m, 1H), 4.66 - 4.53 (m, 1H), 4.09 - 3.84 (m, 2H), 3.55 - 3.43 (m, 2H), 2.06 - 1.94 (m, 2H), 1.74 - 1.62 (m, 4H), 1.52 - 1.44 (m, 2H).

[0788] Step D: 3'-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6'-isopropylspiro[cyclopropane-l,7'- pyrrolo[2,3-b]pyrazine] (120 mg, 0.308 mmol) was dissolved in N,N-dimethylformamide (2 mL) and acetic acid (1 mL) at room temperature, then NBS (65.7 mg, 0.369 mmol) was added, and the reaction liquid was reacted at 25 °C for 16 hours. Quench with water (50 mL), extract with ethyl acetate (30 mL x 3 times), wash the organic phase with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the residue was purified by silica gel column chromatography to give 94 mg of the target molecule 1-(6-bromo-3-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropane-l- carbonitrile

[0789] MS (ESI) M / Z: 468.9 [M+H] + .

[0790] Step E: 1-(6-bromo-3-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropane-l-carbonitrile (90 mg, 0.181 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (55.3 mg, 0.235 mmol), cesium carbonate (118 mg, 0.362 mmol) and Pd(dtbpf)Cl2(11.8 mg, 0.018 mmol) were all dissolved in anhydrous dioxane (1 mL) and pure water (0.1 mL), the reaction was heated to 80 °C for 1 hour. After the reaction was returned to room temperature, it was filtered, the filter cake was washed with ethyl acetate (3 mL x 4 times), and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography to obtain 52 mg of the target molecule 1-(3-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)pyrazin-2-yl)cyclopropane-l-carbonitrile.

[0791] MS (ESI) M / Z: 498.1 [M+H] + .

[0792] 1 H NMR (400 MHz, DMSO-d6) d 8.29 (d, J = 2.5 Hz, 1H), 7.95 (dd, J = 9.5, 2.6 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.08 - 6.93 (m, 1H), 6.51 (d, J = 9.5 Hz, 1H), 4.53 - 4.48 (m, 1H), 3.54 (s, 3H), 3.53 - 3.45 (m, 2H), 3.16 - 3.04 (m, 2H), 1.99 - 1.94 (m, 2H), 1.79 - 1.75 (m, 2H), 1.75 - 1.67 (m, 2H), 1.66 - 1.62 (m, 2H).

[0793] Step F: To a solution of 1-(3-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l- methyl-6-oxo-l,6-dihydropyridin-3-yl)pyrazin-2-yl)cyclopropane-l-carbonitrile (40 mg, 0.08 mmol) and potassium vinyltrifluoroborate (32.3 mg, 0.24 mmol) in 1,4-dioxane / water (1 mL / 0.1 mL) was added Pd-XPhos-G2 (6.3 mg, 0.008 mmol) and cesium carbonate (52.4 mg, 0.161 mmol) under nitrogen at room temperature. The reaction was heated to 100 °C and stirred for 3 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by thin layer chromatography and preparative high performance liquid chromatography to give 17.26 mg of the desired molecule 1-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)-3-vinylpyrazin-2-yl)cyclopropane-l-carbonitrile.

[0794] MS (ESI) M / Z: 490.2 [M+H] + .

[0795] 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 2.5 Hz, 1H), 8.05 (dd, J = 9.5, 2.6 Hz, 1H), 7.34 - 7.19 (m, 3H), 7.07 - 6.91 (m, 1H), 6.51 (d, J = 9.5 Hz, 1H), 6.45 (dd, J = 16.8, 2.2 Hz, 1H), 5.72 (dd, J = 10.6, 2.2 Hz, 1H), 4.55 - 1.49 (m, 1H), 3.55 (s, 3H), 3.53 - 3.51 (m, 2H), 3.17 - 3.06 (m, 2H), 2.06 - 1.96 (m, 2H), 1.81 - 1.76 (m, 2H), 1.76 - 1.68 (m, 2H), 1.64 - 1.59 (m, 2H).

[0796] Example 43:

[0797] 1-(6-(6-aminopyridazin-3-yl)-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)cyclopropane-l- carbonitrile

[0798] Procedure:

[0799] Step A: 6-Chloropyridazin-3-amine (5 g, 38.6 mmol) and 4-dimethylaminopyridine (471.6 mg, 3.86 mmol) were dissolved in dichloromethane (80 mL) under ice bath, then triethylamine (19.5 g, 193 mmol) and di-tert-butyl dicarbonate (23.6 g, 108.1 mmol) were added, the reaction was stirred at room temperature for 48 hours. Water (200 mL) was added to quench the reaction, the mixture was extracted with dichloromethane (80 mL x 3 times), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, then the residue was purified by silica gel column chromatography to give 7.4 g of tert-butyl (6-chloropyridazin-3-yl)carbamate.

[0800] MS (ESI) M / Z: 330.1 [M+H] + .

[0801] 1 H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 9.0 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 1.40 (s, 18H).

[0802] Step B: tert-Butyl (6-chloropyridazin-3-yl)carbamate (200 mg, 0.61 mmol), hexylditin (707.7 mg, 1.22 mmol), Pd2(dba)3 (55.9 mg, 0.061 mmol) and tricyclohexylphosphine (34.2 mg, 0.122 mmol) were dissolved in anhydrous toluene (3 mL) under nitrogen protection at room temperature, the reaction was heated to 110 °C under nitrogen protection for 16 hours. The reaction was cooled to room temperature and concentrated under reduced pressure, then the residue was purified by silica gel column chromatography to give 80 mg of tert-butyl (6-(tributylstannyl)pyridazin-3-yl)carbamate.

[0803] MS (ESI) M / Z: 584.1 [M+H] + .

[0804] 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 1.56-1.47 (m, 6H), 1.37 (s, 18H), 1.30-1.24 (m, 8H), 1.19-1.15 (m, 4H), 0.83 (t, J = 7.3 Hz, 9H).

[0805] Step C: To a solution of (1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1- yl)pyrazin-2-yl)cyclopropane-1-carbonitrile (45 mg, 0.11 mmol) and tert-butyl (6- (tributylstannyl)pyridazin-3-yl)carbamate (80 mg, 0.14 mmol) in 1,4-dioxane (1 mL) was added Pd(dtbpf)Cl2 (7.2 mg, 0.011 mmol) and cesium carbonate (71.7 mg, 0.22 mmol) under nitrogen atmosphere. The reaction mixture was heated to 90 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 36 mg of tert-butyl (6-(6-(1-cyanocyclopropyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2- yl)pyridazin-3-yl)carbamate.

[0806] MS (ESI) M / Z: 650.9 [M+H] + .

[0807] 1 H NMR (400 MHz, DMSO-d6) d 8.39 (s, 1H), 8.25 (d, J = 8.9 Hz, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.31 - 7.21 (m, 2H), 7.05 - 6.92 (m, 1H), 4.63 - 4.41 (m, 1H), 3.46 - 3.42 (m, 2H), 3.12 - 3.05 (m, 2H), 2.03 - 1.99 (m, 2H), 1.90 - 1.84 (m, 2H), 1.80 - 1.75 (m, 2H), 1.70 - 1.65 (m, 2H), 1.38 (s, 18H).

[0808] Step D: To a solution of tert-butyl (6-(6-(1-cyanocyclopropyl)-3-(4-(2,4- difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)pyridazin-3-yl)carbamate (36 mg, 0.055 mmol) in 1,4-dioxane (0.5 mL) was added hydrochloric acid in dioxane (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The mixture was made basic with aqueous sodium bicarbonate solution and extracted with ethyl acetate (5 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give 10.59 mg of 1-(6-(6-aminopyridazin-3-yl)-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2- yl)cyclopropane-1-carbonitrile.

[0809] MS (ESI) M / Z: 450.1 [M+H] + .

[0810] 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.71 (d, J = 9.2 Hz, 1H), 7.31 - 7.22 (m, 2H), 7.02 - 6.94 (m, 1H), 6.88 (d, J = 9.2 Hz, 1H), 6.65 (s, 2H), 4.54 - 4.41 (m, 1H), 3.52 - 3.41 (m, 2H), 3.08 - 2.99 (m, 2H), 1.94 - 1.85 (m, 2H), 1.78 - 1.71 (m, 2H), 1.66 - 1.56 (m, 4H).

[0811] Example 44:

[0812] 2-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)pyrazin-2-yl)-2-methylpropan

[0813] Procedure:

[0814] Step A: 2-(5-chloropyrazin-2-yl)acetonitrile (500 mg, 3.26 mmol) was dissolved in DMF (10 mL) and NaH (312.96 mg, 13.04 mmol) was added slowly under ice bath. The reaction was kept under ice bath for 0.5 h. Then iodomethane (0.69 g, 4.89 mmol) was added dropwise to the reaction system and the reaction was allowed to warm to room temperature for 2 h. Ethyl acetate (100 mL) was added to the system and then washed with water (10 mL x 5 times). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography to obtain 586 mg of the target molecule 2-(5-chloropyrazin-2-yl)-2-methylpropanenitrile.

[0815] MS (ESI) M / Z: 234.0 [M+H] + .

[0816] Step B: 2-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)-2- methylpropanenitrile (836.8 mg, 2.33 mmol) was dissolved in DMF (5 mL) and AcOH (0.5 mL) at room temperature, and NCS (373.35 mg, 2.80 mmol) was added. The reaction was heated to 40 °C for 3 h. Ethyl acetate (100 mL) was added to the system, and the mixture was washed with water (10 mL x 5 times). The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 716.1 mg of the target molecule 2-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)-2- methylpropanenitrile.

[0817] MS (ESI) M / Z: 359.2 [M+H] + .

[0818] Step B: 2-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)-2- methylpropanenitrile (836.8 mg, 2.33 mmol) was dissolved in DMF (5 mL) and AcOH (0.5 mL) at room temperature, and NCS (373.35 mg, 2.80 mmol) was added. The reaction was heated to 40 °C for 3 h. Ethyl acetate (100 mL) was added to the system, and the mixture was washed with water (10 mL x 5 times). The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 716.1 mg of the target molecule 2-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)-2- methylpropanenitrile.

[0819] MS (ESI) M / Z: 393.2 [M+H] + .

[0820] Step D: 2-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)-2- methylpropanenitrile (100 mg, 0.25 mmol) was dissolved in 1,4-dioxane (4 mL) and water (0.4 mL) under nitrogen protection at room temperature, then 1-methyl-5-(tetramethyl- 1,3,2-dioxaborolan-2-yl)-l,2-dihydropyridin-2-one (58.77 mg, 0.25 mmol), Pd(dtbpf)Cl2 (162.94 mg, 0.25 mmol) and cesium carbonate (81.45 mg, 0.25 mmol) were added successively, and the reaction solution was heated to 100 °C under nitrogen protection for 5 h. After the reaction solution was cooled to room temperature, water (10 mL) was added to the system, and ethyl acetate (20 mL x 3 times) was extracted, and the combined organic phase was concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to obtain 52.2 mg of the target molecule 2-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)pyrazin-2-yl)-2-methylpropanenitrile.

[0821] MS (ESI) M / Z: 466.2 [M+H] + .

[0822] 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 2.6 Hz, 1H), 8.31 (s, 1H), 8.09 (dd, J = 9.5, 2.6 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.03 - 6.97 (m, 1H), 6.54 (d, J = 9.5 Hz, 1H), 4.52 - 4.48 (m, 1H), 3.55 (s, 3H), 3.52 - 3.41 (m, 2H), 3.09 - 3.02 (m, 2H), 2.03 - 1.98 (m, 2H), 1.77 - 1.69 (m, 8H).

[0823] Example 45:

[0824] 1-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(6-methoxypyridin-2-yl)pyrazin-2-yl)- cyclopropane-l-carbonitrile

[0825] Procedure

[0826] Step A: l-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl) cyclopropane-l-carbonitrile (50 mg, 0.13 mmol), 2-methoxy-6-(tributylstannyl)pyridine (99.7 mg, 0.26 mmol), bis(triphenylphosphine)palladium dichloride (9 mg, 0.13 mmol) and anhydrous lithium chloride (16.3 mg, 0.385 mmol) were dissolved in anhydrous toluene (1 mL) under nitrogen protection at room temperature, and the reaction was heated to 110 °C in a sealed tube for 6 hours. After the reaction was cooled to room temperature, the reaction was concentrated under reduced pressure, and the obtained residue was purified by normal phase column to obtain 40.98 mg of the target molecule l-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(6-methoxypyridin-2-yl)pyrazin-2-yl)cyclopropane-l- carbonitrile.

[0827] MS (ESI) M / Z: 464.1 [M+H] + .

[0828] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.86 (dd, J = 8.2, 7.4 Hz, 1H), 7.45 (dd, J = 0.8, 7.6 Hz, 1H), 7.35 - 7.20 (m, 2H), 7.06 - 6.92 (m, 1H), 6.85 (dd, J = 0.8, 8.8 Hz, 1H), 4.53 - 4.47 (m, 1H), 3.88 (s, 3H), 3.50 - 3.44 (m, 2H), 3.16 - 2.99 (m, 2H), 1.92 - 1.83 (m, 2H), 1.77 - 1.73 (m, 2H), 1.65 - 1.62 (m, 2H), 1.61 - 1.52 (m, 2H).

[0829] Example 46:

[0830] 5-(3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(l-ethynylcyclopropyl)pyrazin-2-yl)-l- methylpyridin-2(lH)-one

[0831] Procedure:

[0832] Step: 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1-methyl-6-oxo-1,6- dihydropyridin-3-yl)pyrazin-2-yl)cyclopropane-1-carbaldehyde (30 mg, 0.064 mmol) was dissolved in methanol (1 mL), after the addition of potassium carbonate (26.54 mg, 0.19 mmol), (1-diazo-2-oxopropyl)dimethylphosphonate (24.59 mg, 0.13 mmol) was added slowly dropwise, after the addition was completed, stirring was continued for 2 hours. Water (10 mL) was added to the system, extracted with ethyl acetate (10 mL x 3 times), the combined organic phase was dried and concentrated under reduced pressure, the residue was purified by preparative high performance liquid chromatography to obtain 4.86 mg of the target molecule 5-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1- ethynylcyclopropyl)pyrazin-2-yl)-1-methylpyridin-2(1H)-one.

[0833] MS (ESI) M / Z: 467.2 [M+H] + .

[0834] Step B: 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1-methyl-6-oxo-1,6- dihydropyridin-3-yl)pyrazin-2-yl)cyclopropane-1-carbaldehyde (30 mg, 0.064 mmol) was dissolved in methanol (1 mL), after the addition of potassium carbonate (26.54 mg, 0.19 mmol), (1-diazo-2-oxopropyl)dimethylphosphonate (24.59 mg, 0.13 mmol) was added slowly dropwise, after the addition was completed, stirring was continued for 2 hours. Water (10 mL) was added to the system, extracted with ethyl acetate (10 mL x 3 times), the combined organic phase was dried and concentrated under reduced pressure, the residue was purified by preparative high performance liquid chromatography to obtain 4.86 mg of the target molecule 5-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(1- ethynylcyclopropyl)pyrazin-2-yl)-1-methylpyridin-2(1H)-one.

[0835] MS (ESI) M / Z: 463.2 [M+H] + .

[0836] 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.36 (d, J = 2.6 Hz, 1H), 8.08-8.07 (dd, J = 9.5, 2.6 Hz, 1H), 7.31-7.25 (m, 2H), 7.01-6.97 (m, 1H), 6.05-6.47 (m, 1H), 4.48-4.47 (m, 1H), 3.52 (s, 3H), 3.40-3.36 (m, 2H), 3.19 (s, 1H), 3.00-2.95 (m, 2H), 2.00-1.97 (m, 2H), 1.75-1.69 (m, 2H), 1.56-1.54 (m, 2H), 1.37-1.35 (m, 2H).

[0837] Example 47:

[0838] 1-(6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(4-(2,4,5-trifluorophenoxy)piperidin-1- yl)pyrazin-2-yl)cyclopropane-1-carbonitrile

[0839] Procedure:

[0840] The starting material was 2,4,5-trifluorophenol, and the preparation method referred to INT-1 and Example 13 to obtain 13.92 mg of the target molecule 1-(6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(4-(2,4,5-trifluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile.

[0841] MS (ESI) M / Z: 482.3 [M+H]+.

[0842] 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 2.5 Hz, 1H), 8.26 (s, 1H), 8.07 (dd, J = 9.5, 2.6 Hz, 1H), 7.64-7.49 (m, 2H), 6.51 (d, J = 9.5 Hz, 1H), 4.61-4.52 (m, 1H), 3.53 (s, 3H), 3.46-3.38 (m, 2H), 3.09-2.98 (m, 2H), 2.03-1.96 (m, 2H), 1.80-1.67 (m, 6H).

[0843] Example 48:

[0844] 5-(6-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)-1-methylpyridin-2(1H)-one

[0845] Procedure:

[0846] Step A: 2-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazine (50 mg, 0.153 mmol), cyclopropylboronic acid (30.3 mg, 0.353 mmol), Pd(dppf)Cl2(12.5 mg, 0.0153 mmol) and potassium carbonate (42.3 mg, 0.306 mmol) were dissolved in 1,4-dioxane (1.0 mL) under nitrogen protection, the reaction solution was heated to 90 °C in a sealed tube for 16 h. After the reaction solution returned to room temperature, it was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 20 mg of the target molecule 2-cyclopropyl-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazine.

[0847] MS (ESI) M / Z: 332.2 [M+H] + .

[0848] 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 1.4 Hz, 1H), 8.06 (d, J = 1.4 Hz, 1H), 7.35 - 7.25 (m, 2H), 7.05 - 6.97 (m, 1H), 4.61 - 4.52 (m, 1H), 3.97 - 3.85 (m, 2H), 3.36 - 3.32 (m, 1H), 3.32 - 3.28 (m, 1H), 2.05 - 1.92 (m, 3H), 1.69 - 1.57 (m, 2H), 0.90 - 0.83 (m, 2H), 0.79 - 0.72 (m, 2H).

[0849] Step B: 2-cyclopropyl-5-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazine (130 mg, 0.39 mmol) was dissolved in DMF (2.5 mL) and acetic acid (2.5 mL) at room temperature, NCS (67.7 mg, 0.51 mmol) was added, and the reaction solution was heated to 50 °C for 16 h. After the reaction solution returned to room temperature, it was quenched with water (30 mL), the pH was adjusted to 7 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (30 mL x 3 times), washed with water (90 mL) and saturated brine (60 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 100 mg of the target molecule 3-chloro-5-cyclopropyl-2-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazine.

[0850] MS (ESI) M / Z: 366.1 [M+H] + .

[0851] 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.36-7.25 (m, 2H), 7.07-6.96 (m, 1H), 4.60-4.49 (m, 1H), 3.61-3.49 (m, 2H), 3.20-3.08 (m, 2H), 2.13-2.00 (m, 3H), 1.82-1.71 (m, 2H), 1.01-0.93 (m, 2H), 0.85-0.78 (m, 2H).

[0852] Step C: 3-chloro-5-cyclopropyl-2-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazine (50 mg, 0.137 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (64.3 mg, 0.273 mmol), Pd(dtbpf)Cl2(8.9 mg, 0.0137 mmol) and cesium carbonate (89.3 mg, 0.274 mmol) were dissolved in 1,4-dioxane (1 mL) and water (0.1 mL) at room temperature, the reaction was heated to 90 °C under nitrogen protection for 1 h. After the reaction was returned to room temperature, the reaction was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography and preparative high performance liquid chromatography to obtain 23.56 mg of the target molecule 5-(6-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)-l-methylpyridin-2(lH)-one.

[0853] MS (ESI) M / Z: 439.3 [M+H] + .

[0854] 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 2.5 Hz, 1H), 8.13-8.07 (m, 2H), 7.32-7.24 (m, 2H), 7.03-6.96 (m, 1H), 6.49 (d, J = 9.5 Hz, 1H), 4.51-4.42 (m, 1H), 3.53 (s, 3H), 3.40-3.32 (m, 2H), 2.99-2.87 (m, 2H), 2.15-2.08 (m, 1H), 2.04-1.95 (m, 2H), 1.78-1.67 (m, 2H), 0.97-0.87 (m, 4H).

[0855] Example 49:

[0856] 5-(6-(2,2-difluorocyclopropyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)-1-methylpyridin-2(1H)-one

[0857] Procedure:

[0858] Step A: 2-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazine (500 mg, 1.53 mmol) was dissolved in 1,4-dioxane (4 mL) and water (0.4 mL) at room temperature, and vinylboronic acid pinacol ester (0.47 g, 3.06 mmol), Pd(dtbpf)Cl2(0.10 g, 0.15 mmol) and cesium carbonate (1.0 g, 3.06 mmol) were added successively. The reaction was heated to 100 °C under nitrogen protection for 4 h. After the reaction was cooled to room temperature, water (50 mL) was added to the system, and the organic phase was extracted with ethyl acetate (50 mL x 3 times). The organic phase was combined and dried, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 495.4 mg of the target molecule 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-vinylpyrazine.

[0859] MS (ESI) M / Z: 318.2 [M+H] + .

[0860] Step B: 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-vinylpyrazine (445.4 mg, 1.40 mmol) was dissolved in THF (10 mL) at room temperature, and NaI (104.92 mg, 0.70 mmol) and TMSCF3(796.26 mg, 5.6 mmol) were added successively. The reaction was heated to 60 °C for 2 h. After the reaction was cooled to room temperature, water (20 mL) was added to the system, and the organic phase was extracted with ethyl acetate (20 mL x 3 times). The organic phase was combined and dried, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 315.2 mg of the target molecule 2-(2,2-difluorocyclopropyl)-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazine.

[0861] MS (ESI) M / Z: 368.2 [M+H] + .

[0862] Step C: 2-(2,2-difluorocyclopropyl)-5-(4-(2,4-difluorophenoxy)piperidin-l- yl)pyrazine (150 mg, 0.41 mmol) was dissolved in DMF (3 mL) and AcOH (0.3 mL) at room temperature, and NCS (65.70 mg, 0.49 mmol) was added. The reaction was heated to 40 °C for 2 h. After the reaction was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was combined and dried, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give 108.8 mg of the target molecule 3-chloro-5-(2,2-difluorocyclopropyl)-2-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazine.

[0863] MS (ESI) M / Z: 402.0 [M+H] + .

[0864] Step D: 3-chloro-5-(2,2-difluorocyclopropyl)-2-(4-(2,4-difluorophenoxy)piperidin-l- yl)pyrazine (108 mg, 0.27 mmol) was dissolved in 1,4-dioxane (5 mL) and water (0.5 mL) at room temperature, and 1-methyl-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2- dihydropyridin-2-one (76.17 mg, 0.32 mmol), Pd(dtbpf)Cl2(17.60 mg, 0.027 mmol), and cesium carbonate (175.94 mg, 0.54 mmol) were added sequentially. The reaction was heated to 100 °C under nitrogen for 5 h. After the reaction was cooled to room temperature, water (10 mL) was added to the system, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was combined and dried, and the solvent was removed under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to give 47.35 mg of the target molecule 5-(6-(2,2-difluorocyclopropyl)-3-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)-l-methyl-l,2-dihydropyridin-2-one.

[0865] MS (ESI) M / Z: 475.2 [M+H] + .

[0866] 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 2.6 Hz, 1H), 8.20 (s, 1H), 8.09 (dd, J = 9.5, 2.6 Hz, 1H), 7.33 - 7.24 (m, 2H), 7.04 - 6.97 (m, 1H), 6.51 (d, J = 9.5 Hz, 1H), 4.52 - 4.47 (m, 1H), 3.55 (s, 3H), 3.44 - 3.40 (m, 2H), 3.22 - 3.13 (m, 1H), 3.05 - 2.98 (m, 2H), 2.35 - 2.24 (m, 1H), 2.08 - 1.97 (m, 3H), 1.73 (d, J = 10.5 Hz, 2H).

[0867] Example 50:

[0868] 1-(6-(1-(diifluoromethyl)-6-oxo-1,6-dihydropyridazin-3-yl)-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile

[0869] Procedure:

[0870] Step A: 6-chloro-2-(difluoromethyl)pyridazin-3(2H)-one (75 mg, 0.4 mmol) was dissolved in DMF (1 mL), then sodium difluorochloroacetate (200 mg, 1.3 mmol) and potassium carbonate (174 mg, 1.3 mmol) were added successively, and the reaction was heated to 60 °C for 16 hours. After the reaction was cooled to room temperature, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3 times). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 6-chloro-2-(difluoromethyl)pyridazin-3(2H)-one (75 mg, 0.4 mmol).

[0871] MS (ESI) M / Z: 181.0 [M+H] + .

[0872] 1 H NMR (400 MHz, DMSO-d6) δ 7.87 (t, J = 57.8 Hz, 1H), 7.67 (d, J = 9.9 Hz, 1H), 7.18 (d, J = 9.9 Hz, 1H).

[0873] Step B: 6-Chloro-2-(difluoromethyl)pyridazin-3(2H)-one (500 mg, 2.77 mmol), bis(pinacolato)diboron (844 mg, 3.32 mmol), palladium acetate (62.2 mg, 0.277 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl (264.1 mg, 0.554 mmol) and potassium acetate (815.5 mg, 8.31 mmol) were dissolved in anhydrous 1,4-dioxane (7 mL) at room temperature. The reaction was heated to 100 °C under nitrogen protection for 3 h. After the reaction was cooled to room temperature, water (20 mL) was added to quench the reaction, and the aqueous phase was lyophilized to obtain the crude product 1-(difluoromethyl)-6-oxo-1,6-dihydropyridazin-3-yl)boronic acid (1.5 g, brown solid).

[0874] MS (ESI) M / Z: 191.1 [M+H] + .

[0875] Step C: (1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1- carbonitrile (50 mg, 0.128 mmol) and 1-(difluoromethyl)-6-oxo-1,6-dihydropyridazin-3-yl)boronic acid (174 mg, 0.91 mmol) were dissolved in 1,4-dioxane / water (2 mL / 0.2 mL) at room temperature. Then, 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (8.3 mg, 0.0128 mmol) and cesium carbonate (83.4 mg, 0.256 mmol) were added to the above reaction solution. The reaction was heated to 90 °C under nitrogen protection for 2 h. After the reaction was cooled to room temperature, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography and preparative high performance liquid chromatography. 19.64 mg of the target molecule 1-(6-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridazin-3-yl)-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carbonitrile was obtained.

[0876] MS (ESI) M / Z: 501.1 [M+H]+.

[0877] 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 8.05 (d, J = 9.9 Hz, 1H), 7.97 (t, J = 58.2 Hz, 1H), 7.32 - 7.24 (m, 2H), 7.22 (d, J = 9.9 Hz, 1H), 7.02 - 6.95 (m, 1H), 4.61 - 4.48 (m, 1H), 3.64 - 3.53 (m, 2H), 3.24 - 3.09 (m, 2H), 1.99 - 1.89 (m, 2H), 1.80 - 1.77 (m, 2H), 1.71 - 1.61 (m, 4H).

[0878] Example 51:

[0879] 6-(6-(2,2-difluorocyclopropyl)-3-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)-2- methylpyridazin-3(2H)-one

[0880] Procedure:

[0881] Starting from 3-chloro-5-(2,2-difluorocyclopropyl)-2-(4-(2,4-difluorophenoxy)piperidin-l- yl)pyrazine and 2-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one, 12.62 mg of the target molecule 6-(6-(2,2-difluorocyclopropyl)-3-(4-(2,4-difluorophenoxy)piperidin-l- yl)pyrazin-2-yl)-2-methylpyridazin-3(2H)-one was obtained by referring to the procedures of Example 30 and Example 48.

[0882] MS (ESI) M / Z: 476.3 [M+H] + .

[0883] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.94 (d, J = 9.7 Hz, 1H), 7.32 - 7.26 (m, 2H), 7.07 (d, J = 9.7 Hz, 1H), 7.08 - 6.98 (m, 1H), 4.53 - 4.50 (m, 1H), 3.72 (s, 3H), 3.54 - 3.50 (m, 2H), 3.23 - 3.09 (m, 3H), 2.24 - 2.16 (m, 1H), 2.08 - 1.93 (m, 3H), 1.72 - 1.59 (m, 2H).

[0884] Example 52:

[0885] 6-(6-(2,2-difluorocyclopropyl)-3-(4-(2,4-difluorophenoxy)piperidin-l-yl)pyrazin-2-yl)-2- (difluoromethyl)pyridazin-3(2H)-one

[0886] Procedure:

[0887] Starting from 3-chloro-5-(2,2-difluorocyclopropyl)-2-(4-(2,4-difluorophenoxy)piperidin-l- yl)pyrazine and 2-(difluoromethyl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridazin- 3(2H)-one, the procedure as described in Reference Example 48 and Example 49 gave 6.82 mg of the target molecule 6-(6-(2,2-difluorocyclopropyl)-3-(4-(2,4-difluorophenoxy)piperidin-l- yl)pyrazin-2-yl)-2-(difluoromethyl)pyridazin-3(2H)-one.

[0888] MS (ESI) M / Z: 512.2 [M+H]+.

[0889] 1 H NMR (400 MHz, DMS-d6) δ 8.36 (s, 1H), 8.05 (d, J = 9.9 Hz, 1H), 8.03 (t, J = 58.2 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.21 (d, J = 9.9 Hz, 1H), 7.00 (t, J = 8.6 Hz, 1H), 4.60 - 4.45 (m, 1H), 3.66 - 3.49 (m, 2H), 3.25 - 3.14 (m, 3H), 2.23 - 2.19 (m, 1H), 2.10 - 1.91 (m, 3H), 1.75 - 1.60 (m, 2H).

[0890] Example 53:

[0891] 1-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl-4-d)-6-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)pyrazin-2-yl)cyclopropane-l-carbonitrile

[0892] Procedure:

[0893] Step A: tert-Butyl 4-oxopiperidine-l-carboxylate (1 g, 4.96 mmol) was dissolved in deuterated methanol, and sodium borodeuteride (270 mg, 6.45 mmol) was added portionwise under ice bath. The reaction was kept at 0 °C for 1 h. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 990 mg of tert-butyl 4-hydroxypiperidine-l-carboxylate-4-d as a crude product.

[0894] MS (ESI) M / Z: 147.2 [M-56+H] + .

[0895] Step B: tert-Butyl 4-hydroxypiperidine-l-carboxylate-4-d (800 mg, 3.96 mmol), 2,4-difluorophenol (567 mg, 4.36 mmol), and triphenylphosphine (1.25 g, 4.75 mmol) were dissolved in tetrahydrofuran (16 mL) under nitrogen protection with ice bath. Diisopropyl azodicarboxylate (960.5 mg, 4.75 mmol) was added dropwise. The reaction was heated to 60 °C for 16 h. The reaction was quenched with water (30 mL) after it was cooled to room temperature. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 630 mg of tert-butyl 4-(2,4-difluorophenoxy)piperidine-l-carboxylate-4-d.

[0896] MS (ESI) M / Z: 215 [M-100+H] +

[0897] 1 H NMR (400 MHz, DMSO-d6) δ 7.33 - 7.22 (m, 2H), 7.04 - 6.97 (m, 1H), 3.67 - 3.61 (m, 2H), 3.23 - 3.04 (m, 2H), 1.89 - 1.84 (m, 2H), 1.55 - 1.48 (m, 2H), 1.40 (s, 9H).

[0898] Step C: tert-Butyl 4-(2,4-difluorophenoxy)piperidine-l-carboxylate-4-d (630 mg, 2 mmol) was dissolved in ethyl acetate (3 mL) at room temperature, and hydrochloric acid-1,4-dioxane solution (3 mL) was added. The reaction was stirred at room temperature for 2 h. The crude product was concentrated under reduced pressure to give 457 mg of 4-(2,4-difluorophenoxy)piperidine-4-d as a crude product.

[0899] MS (ESI) M / Z: 215.1 [M+H]+ .

[0900] Step D: 4-(2,4-difluorophenoxy)piperidin-4-yl (100 mg, 0.47 mmol), 1-(5- chloropyrazin-2-yl)cyclopropane-1-carbonitrile (86 mg, 0.47 mmol) and cesium fluoride (213 mg, 1.4 mmol) were dissolved in dimethyl sulfoxide (2 mL) under nitrogen protection at room temperature, and the reaction was heated to 120 °C for 3 hours. After the reaction was cooled to room temperature, water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3 times). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 76 mg of the target molecule 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl-4-d)pyrazin-2-yl)cyclopropane-1- carbonitrile.

[0901] MS (ESI) M / Z: 358.2 [M+H] + .

[0902] 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 1.5 Hz, 1H), 8.20 (d, J = 1.5 Hz, 1H), 7.35-7.26 (m, 2H), 7.07-6.98 (m, 1H), 4.00-3.94 (m, 2H), 3.48-3.37 (m, 2H), 2.00-1.95 (m, 2H), 1.74-1.67 (m, 2H), 1.66-1.59 (m, 2H), 1.57-1.51 (m, 2H).

[0903] Step E: 1-(5-(4-(2,4-difluorophenoxy)piperidin-1-yl-4-d)pyrazin-2-yl)cyclopropane-1- carbonitrile (76 mg, 0.212 mmol) was dissolved in DMF (2 mL) and acetic acid (0.5 mL) at room temperature, followed by the addition of NBS (37 mg, 0.276 mmol), and the reaction was heated to 50 °C for 16 hours. After the reaction was cooled to room temperature, water (30 mL) was added to quench the reaction, and the mixture was adjusted to basic with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (20 mL x 3 times), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 56 mg of the target molecule 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl-4-d)pyrazin-2- yl)cyclopropane-1-carbonitrile.

[0904] MS (ESI) M / Z: 392.2 [M+H] + .

[0905] 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.35-7.26 (m, 2H), 7.06-6.98 (m, 1H), 3.72-3.60 (m, 2H), 3.30-3.19 (m, 2H), 2.07-1.99 (m, 2H), 1.85-1.71 (m, 4H), 1.66-1.58 (m, 2H).

[0906] Step F: 1-(6-chloro-5-(4-(2,4-difluorophenoxy)piperidin-l-yl-4-d)pyrazin-2-yl)cyclopropane-l- carbonitrile (56 mg, 0.143 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin- 2(lH)-one (33.6 mg, 0.17 mmol), l,l'-bis(diphenylphosphino)ferrocene palladium dichloride (9.32 mg, 0.0143 mmol) and cesium carbonate (93.2 mg, 0.286 mmol) were all dissolved in dioxane (1 mL) and pure water (0.1 mL), the reaction was heated at 75 °C in a sealed tube for 1 hour.

[0907] After the reaction was cooled to room temperature, it was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography, the obtained crude product was purified by preparative high performance liquid chromatography, the product was collected and freeze-dried under reduced pressure. 40 mg of target molecule 1-(5-(4-(2,4-difluorophenoxy)piperidin-l-yl-4-d)-6-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)pyrazin-2-yl)cyclopropane-l-carbonitrile was obtained.

[0908] MS (ESI) M / Z: 465.3 [M+H]+.

[0909] 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 2.5 Hz, 1H), 8.25 (s, 1H), 8.07 (dd, J = 9.5, 2.6 Hz, 1H), 7.35-7.22 (m, 2H), 7.05-6.95 (m, 1H), 6.51 (d, J = 9.5 Hz, 1H), 3.53 (s, 3H), 3.47-3.38 (m, 2H), 3.05-3.00 (m, 2H), 2.03-1.93 (m, 2H), 1.80-1.67 (m, 6H).

[0910] Biological activity examples

[0911] The agonistic effect of the compounds of the present disclosure on the GPR6 signaling pathway and other in vitro and in vivo effects are further illustrated by the following specific embodiments to show that the compounds of the present disclosure are effective for the treatment of diseases related to the GPR6 target. The beneficial effects of the compounds of the present disclosure include, but are not limited to, the following specific embodiments.

[0912] Experimental Example 1, Detection of the human GPR3, GPR6 and GPR12 reverse agonistic activity of the compounds of the present disclosure

[0913] The reverse agonistic activity of the compounds of the examples on human GPR3, GPR6 and GPR12 was tested using the HTRF cAMP detection method

[0914] Experimental materials:

[0915] Flp-In-TREx-293 cells were purchased from Invitrogen (Cat. No. R78007); DMEM was purchased from Gibco (Cat. No. 10566-016); fetal bovine serum was purchased from Biosum (Cat. No. BS-0006); Hygromycin B was purchased from Invivogen (Cat. No. ant-hg-5); Blasticidin S was purchased from Gibco (Cat. No. A1113903); Penicillin-Streptomycin was purchased from Gibco (Cat. No. 15140122); HBSS was purchased from Gibco (Cat. No. 14025076); BSA was purchased from Perkin Elmer (Cat. No. CR84-100); cAMP kit was purchased from Perkin Elmer (Cat. No. TRF0263); IBMX was purchased from Sigma (Cat. No. I5879); HEPES was purchased from Gibco (Cat. No. 15630080); 384-well compound dilution plate was purchased from Labcyte (Cat. No. PP-0200); 384-well assay plate was purchased from Perkin Elmer (Cat. No. 6007680); Envision was purchased from Perkin Elmer (Model No. 2105).

[0916] Experimental method:

[0917] The gene expression of Flp-In-TREx-293-human GPR6, GPR3 and GPR12 cell lines is regulated by tetracycline-inducible elements. The cell lines are cultured in DMEM high glucose, 10% fetal bovine serum, 1% penicillin / streptomycin, 200 μg / mL hygromycin B and 15 μg / mL blasticidin S complete medium, and incubated in a 37 °C, 5% CO2 cell incubator. On the day of the experiment, the test compounds are gradient diluted with DMSO, and then 50 nL is transferred to a 384-well experimental plate. After the cells are induced for 4 hours with complete medium containing 1 μg / mL tetracycline, the receptor expression is digested, resuspended in experimental buffer containing HBSS + 20 mM HEPES + 0.1% fatty acid-free BSA + 500 μM IBMX, and seeded into a 384-well experimental plate at a volume of 20 μL per well containing 500-1000 cells, and incubated at 37 °C for 30 minutes. Subsequently, 5 μL of Eu-cAMP tracer and Ulight-anti-cAMP detection reagent working solution are added to the 384-well experimental plate, and incubated at room temperature for 1 hour, and then the data is collected using the HTRF module of Envision.

[0918] Data processing: The data is processed and fitted using the XFit four-parameter equation to calculate the IC 50 values of the compounds:

[0919] Calculation formula: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope))

[0920] Y: % activity; X: logarithmic value of compound concentration;

[0921] Top / bottom: curve upper and lower platforms; Hill Slope: curve slope.

[0922] Experimental results:

[0923] Table 1 Reverse agonistic activity of the compounds of the present application on human GPR3, GPR6 and GPR12

[0924] The compounds of the present disclosure have good reverse agonistic activity on GPR6, and good selectivity relative to GPR3, GPR12.

[0925] Experimental Example 2 Liver microsomal stability of the compounds of the present disclosure

[0926] 1. Purpose of the experiment

[0927] The purpose of this experiment is to study the in vitro metabolic stability of the test substance in different species of liver microsomes. The concentration of the test compound in the incubation system is detected by LC-MS / MS, and the intrinsic clearance of the test compound in the microsomal system is calculated to evaluate its stability.

[0928] 2. Experimental materials

[0929] Human, monkey, dog, rat and mouse liver microsomes were purchased from BD Gentest at a concentration of 20 mg / mL; potassium phosphate buffer, 100 mM; NADPH (nicotinamide adenine dinucleotide phosphate); stop solution, acetonitrile (containing internal standards 100 nM alprazolam, 200 nM caffeine and 100 nM tolbutamide).

[0930] 3. Experimental method

[0931] 1) Preparation of reaction system: 20 mg / mL microsomes were diluted with 100 mM phosphate buffer solution, a certain amount of NADPH was added to the microsomal solution, pre-incubated at 37°C for 10 min, and the reaction was started by adding the test compound; the final concentrations of liver microsomes, NADPH and test compound in the incubation system were 0.5 mg / mL, 1 mM and 1 μM, respectively.

[0932] 2) Take 30 μL of incubation sample at 0.5, 5, 15, 30 and 60 min, respectively. Add 150 μL of acetonitrile containing internal standard to terminate the reaction, vortex for 10 min, and then centrifuge at 3220 g for 40 min to precipitate the protein.

[0933] 3) Transfer 100 μL of supernatant to the injection plate, add 100 μL of pure water and mix well, and use for LC-MS / MS analysis.

[0934] 4) Perform data analysis to calculate the in vitro half-life (t 1 / 2 ) and in vitro clearance of the test compound.

[0935] The experimental results show that the compounds of the embodiments of the present application have good liver microsomal stability, especially compounds 12, 13, 14, 19, 20, 21, 25, 27, 30, 34, 49 and 53.

[0936] Experimental Example 3 Effect of the compound of the present application on hERG potassium channel

[0937] This experiment uses the electrophysiological whole-cell manual voltage clamp method to test the effect of the compound on the hERG potassium channel (human Ether-a-go-go Related Gene potassium channel) current.

[0938] 1. Experimental materials

[0939] Cisapride, NaCl, KCl, MgCl2, CaCl2, glucose, HEPES, EGTA and DMSO were purchased from Sigma. CHO-hERG cell line (Chinese Hamster Ovary, stably expressing hERG channel) was constructed by Ion Channel Research Platform, Shanghai Institute of Materia Medica, Chinese Academy of Sciences.

[0940] 2. Experimental Methods

[0941] 1) Cell culture and treatment: CHO cells stably expressing hERG were cultured in 35 mm cell culture dishes in a 37 °C, 5% CO2 incubator, and passaged every 48 hours at a ratio of 1:5. The culture medium was composed of 90% F12 (Invitrogen), 10% fetal bovine serum (Gibco), 100 μg / mL G418 (Invitrogen) and 100 μg / mL Hygromycin B (Invitrogen). On the day of experiment, the cell culture medium was removed and the cells were rinsed once with extracellular solution. Then 0.25% Trypsin-EDTA (Invitrogen) solution was added and the cells were incubated at room temperature for 3-5 minutes. The trypsin solution was removed and the cells were resuspended in extracellular solution and transferred to experimental dishes for electrophysiological recording.

[0942] 2) Compound preparation: On the day of experiment, the compounds were prepared as 10 mM stock solutions in DMSO, which were then serially diluted 3-fold in DMSO and finally in extracellular solution to the final concentrations to be tested. The positive control compound cisapride was prepared by taking 10 μL of 150 μM cisapride stock solution in DMSO and adding it to 4990 μL of extracellular solution to give a final concentration of 300 nM to be tested. The final concentration of DMSO in the test solutions was no more than 0.2%, which has no effect on the hERG potassium channel.

[0943] 3) Electrophysiological recording procedure: CHO cells stably expressing hERG potassium channels were used to record hERG potassium currents using the whole-cell voltage-clamp technique at room temperature. Glass microelectrodes were pulled from glass electrode canes (BF150-86-10, Sutter) using a micropipette puller and had a tip resistance of 2-5 MΩ after being filled with internal solution. The glass microelectrode was inserted into the amplifier probe to be connected to the patch-clamp amplifier. The clamping voltage and data recording were controlled and recorded by a computer through pClamp software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -100 mV, and the step voltage to induce hERG potassium current (IhERG) was given from -100 mV to +20 mV for 2 s, and then repolarized to -50 mV for 1 s, and then returned to -100 mV. This voltage stimulation was given every 5 s, and after the hERG potassium current was determined to be stable (1 min), the drug administration process was started. Each test concentration of the compound was given for at least 1 min to reach a steady effect or at most 3 min, and at least 2 cells were tested for each concentration (n≥2).

[0944] 4) Data analysis and processing were performed using pClamp and GraphPad Prism 8 software. The degree of inhibition of hERG potassium current (peak value of hERG tail current induced at -50 mV) by different concentrations of compounds was calculated using the following formula: Inhibition% = [1-(I / Io)]x100%. Where Inhibition% represents the inhibition percentage of hERG potassium current by the compound, I and Io represent the amplitude of hERG potassium current after and before drug administration, respectively. The IC 50 The IC50value was calculated using GraphPad Prism 8 software by fitting the following equation: Y = Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)). Where X is the Log value of the test concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0945] The experimental results show that the compounds of the embodiments of the present disclosure have a lower risk of hERG, especially compounds 12, 13 and 30.

[0946] Experimental Example 4: In vivo pharmacokinetic determination of the compounds of the present disclosure in mice and rats

[0947] Mice and rats were used as test animals to study the in vivo PK of the compounds of the present disclosure after intravenous and oral administration. Plasma samples were collected at specific time points, and the compound concentration in the plasma was detected by LC-MS / MS to calculate the PK parameters, reflecting the pharmacokinetic behavior of the compounds of the present disclosure in the plasma of mice and rats.

[0948] 1. Test protocol

[0949] 1.1 Test drug:

[0950] Some of the compounds of the present invention.

[0951] 1.2 Test animals

[0952] Mice, C57BL6J, male, supplied by Zhejiang Vantolliva Experimental Animal Technology Co., Ltd.

[0953] Rats, SD, male, supplied by Zhejiang Vantolliva Experimental Animal Technology Co., Ltd.

[0954] 1.3 Dosing

[0955] Example 13 Dosing information for mice: IV (intravenous bolus) and PO (oral) groups are 3 mice each. The IV dose for mice is 1 mg / kg with a 2 mL / kg volume. The PO dose for mice is 3 mg / kg with a 10 mL / kg volume, and the dosing vehicle is 10 vol% DMSO / 20 vol% Solutol / 70 vol% Saline.

[0956] Example 13 Dosing information for rats: The IV dose is 1 mg / kg with a 2 mL / kg volume. The PO dose is 5 mg / kg with a 10 mL / kg volume, and the dosing vehicle is 10 vol% DMSO / 20 vol% Solutol / 70 vol% Saline.

[0957] 1.4 Experimental equipment

[0958] Centrifuge purchased from Eppendorf, pipette purchased from Eppendorf.

[0959] 1.5 Sample collection

[0960] After dosing, mice and rats were taken blood at 0.0833 (IV), 0.25, 0.5, 1, 2, 4, 8 and 24 hours. The blood was collected into EDTA-K2 tubes and centrifuged at 4°C, 4000g for 5 min to separate plasma, which was stored at -80°C.

[0961] 1.6 Sample processing

[0962] Mouse plasma sample processing:

[0963] 1) 10 μL of plasma sample was added to 200 μL of acetonitrile containing mixed internal standards, vortex mixed and centrifuged for 15 min.

[0964] 2) The supernatant after processing was diluted with water and mixed well, and then used for LC-MS / MS analysis of the concentration of the test compound.

[0965] Rat plasma sample processing:

[0966] 1) 30 μL plasma sample was added to 200 μL acetonitrile containing internal standard, vortex mixed and centrifuged for 15 minutes.

[0967] 2) The supernatant after processing was diluted with water, mixed and analyzed by LC-MS / MS to determine the concentration of the test compound.

[0968] 2. Experimental results

[0969] The pharmacokinetic parameters were calculated using WinNonlin 6.1, and the pharmacokinetic parameters are shown in Tables 2 and 3. Among them, Cmax represents the maximum plasma concentration, CL represents the clearance, AUC represents the area under the curve, and F represents the bioavailability. max

[0970] Table 2 Pharmacokinetic parameters of the compound of the present application in mice after intravenous injection and oral administration

[0971] Table 3 Pharmacokinetic parameters of the compound of the present application in rats after intravenous injection and oral administration

[0972] Results: As can be seen from Tables 2 and 3, the compound of the present application has good pharmacokinetic properties in mice and rats.​

Claims

1. The compound of formula (I), its pharmaceutically acceptable salt or isomer thereof, characterized in that, X 1 selected from N and CR X1 ; X 2 selected from N and CR X2 ; X 3 selected from N and CR X3 ; X 4 selected from N and CR X4 ; Ring B is selected from C 3-6 cycloalkyl and 3-6 membered heterocyclyl; Ring C is selected from phenyl and 5-6 membered heteroaryl; R X1 R X2 R X3 and R X4 Each group is independently selected from hydrogen, hydroxyl, cyano, carboxyl, oxo, amino, and C. 1-6 Alkyl, Halogenated C 1- 6-alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, (R a (R) b N-, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R a (R) b )NC(O)-、C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -L 3 -R 5 6-8 fused heterocyclic groups, C 2-6 alkenyl and C 2-6 alkynyl group; wherein, the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, (R a (R) b N-, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R a (R) b )NC(O)-、C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, 6-8 membered fused heterocyclic, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally surrounded by one or more R groups. 1A The R that was replaced 1A Independently selected from halogens, hydroxyl groups, cyano groups, (R a (R) b N-, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, (R a (R) b )NC(O)-、C 1-6 Alkyl-C(O)-, Oxygenated, C 2-6 alkenyl and C 2-6 alkynyl group; L 3 selected from -C(R L3a )(R L3b )-, -N(R L3c )- and -O-; R L3a and R L3b are each independently selected from hydrogen, hydroxyl, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy and haloC 1-6 alkoxy, or R L3a and R L3b together with the carbon atom to which they are attached form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl or C 5-9 spirocycloalkyl group; said C 3-6 cycloalkyl, 3-6 membered heterocyclyl and C 5-9 spirocycloalkyl group is optionally substituted with one or more groups selected from hydroxyl, hydroxyl, cyano, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy and haloC 1-6 alkoxy; R L3c selected from hydrogen and C 1-6 alkyl; R 5 Selected from hydrogen, hydroxyl, cyano, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, (R a (R) b )NC(O)-、(R a (R) b N-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, C 3-6 Cycloalkyl-S(O)2-, C 2-6 alkenyl and C 2-6 alkynyl group; the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-S(O)2-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, C 3-6 Cycloalkyl-S(O)2-, C 2-6 alkenyl and C 2- 6-Alynyl group optionally coupled with one or more R 5A Replaced by, R 5A Independently selected from hydroxyl, cyano, halogen, =NR c C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, oxo and (R d (R) e )N-; R a , R b , R c , R d and R e are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl and C 1-6 alkyl-C(O)-, or R a , R b and the nitrogen atom to which they are attached together form a 3-6 membered heterocyclyl; R 2 selected from hydrogen, deuterium, hydroxyl, cyano, amino, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy and halogenated C 1-6 alkoxy; R 3 selected from hydrogen, hydroxy, cyano, amino, halogen, C 1-6 alkyl, halogen-C 1-6 alkyl, C 1-6 alkoxy and halogen-C 1-6 alkoxy; L 1 selected from -0-, -N(R L1a )-, -N=, -(CR L1a R L1b )q-, -C(R L1a )=, -C(O)-, -S-, -S(0)2-, and -S(O)-; R L1a and R L1b are each independently selected from the group consisting of hydrogen, halogen and C 1-6 alkyl; L 2 is selected from a chemical bond, -0-, -N(R L2a )-, -C(O)-, -C(O)-N(R L2a )-, -C(R L2a R L2b )-, -C(R L2a R L2b )-N(R L2a )-, -N=C(R L2a )-, and -N(R L2a )-0-; R L2a and R L2b are each independently selected from the group consisting of hydrogen, hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy; R 4 is selected from the group consisting of hydroxyl, C 4A alkyl, haloC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl-C(O)-, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 6-8 membered bridged heterocyclyl, 7-11 membered spirocyclyl, 6-10 membered fused heterocyclyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, and phenyl; R 4A is independently selected from the group consisting of hydroxyl, cyano, amino, halo, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 3-6 alkyl, C t alkyl, C t alkyl, C a alkyl, C b alkyl, C 1-6 alkyl; n, p, q and t are each independently selected from 0, 1, 2, 3 and 4.

2. The compound, pharmaceutically acceptable salt, or isomer thereof according to claim 1, wherein one or more of the following conditions are met: (1) the heteroatoms in the "heteroaryl", "heterocyclyl", "fused heterocyclyl", "bridged heterocyclyl" and "spirocyclyl" are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; (2) the "isomers" are stereoisomers; (3) in ring B, said C 3-6 Cycloalkyl is a 5-6 membered saturated monocyclic carbocyclic ring, for example (4) in ring B, the 3-6 membered heterocyclyl is a 5-6 membered saturated monocyclic ring having 1 or 2 heteroatoms selected from N and O, for example, is (5) each said 5-6 membered heteroaryl is independently a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms selected from N and O, for example (6) each of the C 1-6 alkyl is independently methyl, ethyl, n-propyl or i-propyl, preferably methyl; (7) each C 1-4 alkyl is independently methyl, ethyl, n-propyl or i-propyl, preferably methyl; (8) each said halo-substituted C 1-6 alkyl is independently C 1-6 alkyl, said halo is F, Cl or Br, said C 1-6 alkyl is C 1-4 alkyl; for example, -CF3or -CHF2; (9) each of said C 1-6 alkoxy is independently methoxy, ethoxy, n-propoxy or i-propoxy, preferably methoxy; (10) each said halo-substituted C 1-6 alkoxy is independently C 1-6 alkoxy, said halo is F, Cl or Br, said C 1-6 alkoxy is C 1-4 alkoxy; for example, -OCF3or -OCHF2; (11) each said C 3-6 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl; (12) each of the 6-8 membered fused heterocyclyl groups is independently a heteroatom selected from N, a 6-8 membered fused heterocyclyl group having 1 heteroatom, for example (13) each of the 3-6 membered heterocyclyl groups is independently a saturated or partially saturated 4-6 membered monocyclic heterocyclyl group having 1 or 2 heteroatoms selected from N and O, for example (14) each occurrence of C 2-6 alkenyl is independently C 2-4 alkenyl, for example ethenyl; (15) each said C 2-6 alkynyl is independently C 2-4 alkynyl, such as ethynyl or propynyl; (16) each of the halogens is independently F, Cl, Br or I, preferably F; (17) L 3 When R L3a , R L3b together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group, said C 3-6 cycloalkyl group is Preferably (18) L 3 When R L3a , R L3b and the carbon atom to which they are attached form a 3-6 membered heterocyclyl group, the 3-6 membered heterocyclyl group is saturated, the heteroatoms are selected from N and O, and the number of heteroatoms is 1 or 2, for example (19) L 3 When R L3a , R L3b and the carbon atom to which they are attached together form a C 5-9 spirocycloalkyl group, the C 5-9 spirocycloalkyl group is a saturated 3-membered spiro 3-membered carbocyclic ring, for example (20) each of the 6-10 membered fused heterocyclyl groups is independently a 5-membered fused 6-membered heterocyclyl group having 1 or 2 heteroatoms selected from N and O, for example and (21) when R a , R b and the nitrogen atom to which they are attached together form a 3-6 membered heterocyclyl group, the 3-6 membered heterocyclyl group is saturated or partially saturated, the heteroatoms are selected from N and O, and the number of heteroatoms is 1 or 2 members of the 3-6 membered heterocycle.

3. The compound, pharmaceutically acceptable salt, or isomer thereof according to claim 1 or 2, characterized in that, one or more of the following conditions are met: (1) structural unit selected from the group consisting of the "*" indicates the connection to ring B; (2)R X1 R X2 R X3 and R X4 Each group is independently selected from hydrogen, hydroxyl, cyano, carboxyl, amino, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -L 3 -R 5 、(R a (R) b )NC(O)-, 6-8 fused heterocyclic group, C 2-4 alkenyl and C 2-4 alkynyl group; wherein, the C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, (R a (R) b )NC(O)-, 6-8 fused heterocyclic group, C 2-4 alkenyl, C 2-4 The alkynyl group is optionally surrounded by one or more R groups. 1A The R that was replaced 1A Independently selected from halogen, hydroxyl, cyano, amino, C 1- 4-alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, (R a (R) b )NC(O)-、C 1-4 Alkyl-C(O)-, Oxygenated, C 2-4 alkenyl and C 2-4 alkynyl group; L 3 selected from -C(R L3a )(R L3b )-, -N(R L3c )- and -O-; R L3a and R L3b are each independently selected from hydrogen, halogen, or R L3a , R L3b together with the carbon atom to which they are attached form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl, or C 5-7 spiro cycloalkyl; said C 3-6 cycloalkyl, 3-6 membered heterocyclyl, and C 5-7 spiro cycloalkyl is optionally substituted with one or more groups selected from hydroxy, hydroxy, cyano, halogen, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, and halo C 1-4 alkoxy; R L3c selected from hydrogen and C 1-4 alkyl; R 5 Selected from hydrogen, hydroxyl, cyano, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-C(O)-, C 1-4 Alkyl-S(O)2-, (R a (R) b )NC(O)-、(R a (R) b N-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, C 3-6 Cycloalkyl-S(O)2-, C 2-4 alkenyl and C 2-4 alkynyl group, the C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkyl-S(O)2-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, C 3-6 Cycloalkyl-S(O)2-, C 2-4 alkenyl and C 2-4 The alkynyl group is optionally surrounded by one or more R groups. 5A Replaced by, R 5A Independently selected from hydroxyl, cyano, halogen, =NR c C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1- 4-alkoxy, halogenated C 1-4 Alkoxy, oxo and (R d (R) e )N-; R a , R b , R c , R d and R e are each independently selected from hydrogen, C 1-4 alkyl, haloC 1-4 alkyl and C 1-4 alkyl-C(O)-, or R a , R b and the nitrogen atom to which they are attached together form a 3-6 membered heterocyclyl; (3) Ring B is selected from 5-6 membered heterocyclyl and C 4-6 cycloalkyl; (4)L 1 Selected from -O-, -N(R) L1a )-、-C(R L1a R L1b )- and *-C(R L1a = ; R L1a and R L1b Selected independently from H, halogens and C 1-4 Alkyl group; the asterisk (*) indicates that it is attached to a ring carbon. (5) ring C is selected from phenyl; (6) R 3 selected from halogen, C 1-4 alkyl and haloC 1-4 alkyl; (7) L 2 is selected from a chemical bond, -N(R L2a )-, -C(O)-, *-C(O)-N(R L2a )-, *-C(R L2a R L2b )-N(R L2a )-, *-N=C(R L2a )- and *-N(R L2a )-O-; R L2a , R L2b are each independently selected from H, OH, halogen, C 1-4 alkyl and C 1-4 alkoxy; the "*" end indicates attachment to R 4 ; and (8) R 4 selected from the group consisting of optionally substituted C 4A substituted with one or more R 1-4 alkyl, haloC 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 fused heterocyclyl, and phenyl; R 4A selected from hydrogen, hydroxy, cyano, amino, halogen, C 1-4 alkyl, halogen-C 1-4 alkyl, C 1-4 alkoxy, halogen-C 1-4 alkoxy, (R a )(R b )N-, oxo and deuterated C 1-4 alkyl; R a and R b are each independently selected from hydrogen, C 1-4 alkyl, haloC 1-4 alkyl and C 1-4 alkyl-C(O)-.

4. The compound, pharmaceutically acceptable salt, or isomer thereof according to any one of claims 1-3, wherein, one or more of the following conditions are met: (1) structural unit selected from the group consisting of the "*" indicates the connection to ring B; (2)R X2 Selected from hydrogen, cyano, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, (R a (R) b )NC(O)-、C 3-6 cycloalkyl, 3-6 membered heterocyclic groups, -L 3 -R 5 C 2-6 alkenyl and C 2-6 Alkyne group; wherein the 3-6 membered heterocyclic group is optionally surrounded by one or more R groups. 1A The R that was replaced 1A Selected from halogens; L 3 -C(R L3a )(R L3b )-; R L3a , R L3b together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 5-9 spirocycloalkyl; R 5 selected from cyano, (R a )(R b )N-C(O)- and 5-6 membered heteroaryl; said 5-6 membered heteroaryl is optionally substituted with one or more C 1-6 alkyl; R a and R b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; (3)R X3 Selected from hydrogen, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, -L 3 -R 5 and 6-8 fused heterocyclic groups; wherein, the C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, or 6-8 membered fused heterocyclic groups may be optionally surrounded by one or more R 1A The R that was replaced 1A Selected from halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, (R) a (R) b )NC(O)-、C 1-6 Alkyl-C(O)- and oxo-; L 3 selected from -C(R L3a )(R L3b )-; R L3a , R L3b are each independently selected from hydrogen, halogen, and C 1-6 alkyl, or R L3a , R L3b together with the carbon atom to which they are attached form a C 3- 6 cycloalkyl, 3-6 membered heterocyclyl, C 5-9 spirocycloalkyl; said C 3-6 6 cycloalkyl, 3-6 membered heterocyclyl, C 5-9 spirocycloalkyl is optionally substituted with one or more groups selected from halogen and C 1-6 alkyl; R 5 Selected from hydroxyl, cyano, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, (R a (R) b )NC(O)-、(R a (R) b N-, 3-6 membered heterocyclic groups, 5-6 membered heteroaryl groups, C 3-6 cycloalkyl-S(O)2- and C 2-6 alkynyl group; the C 1-6 Alkyl, C 1-6 Alkyl-S(O)2-, 3-6-membered heterocyclic or 5-6-membered heteroaryl, optionally with one or more R 5A Replaced by, R 5A Selected from cyano, halogen, =NR c C 1-6 Alkyl, C 1-6 Alkoxy, oxo and (R d (R) e )N-; R a , R b , R c , R d , R e are each independently selected from the group consisting of hydrogen, C 1-6 alkyl and C 1-6 alkyl-C(O)-; (4) R X1 is H; (5) R X4 is H; (6) ring B is 5-6 membered heterocyclyl; (7) L 1 is selected from -0-, -NH-, -CHF-, -CF2-, -CH2-, *-CH= and *-CF=, preferably -0-, -CH2- or *-CH=; the "*" end indicates the attachment to ring C; (8) L 2 is selected from a chemical bond, -NH-, *-CH2-NH-, *-C(O)-NH-, -C(O)-, *-N=C(CH3)-, and *-NH-O-; the "*" end indicates attachment to R 4 group; (9) R 3 selected from halogen and C 1-6 alkyl; (10) R 2 is deuterium; (11) R 4 is selected from the group consisting of optionally substituted C 4A 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered fused heterocyclyl, 5-6 membered heteroaryl, and phenyl; R 4A is independently selected from the group consisting of hydroxyl, cyano, amino, halo, C 1-6 alkyl, haloC 1- 6alkyl, C 1-6 alkoxy, (R a )(R b )N-, oxo, and deuterated C 1-6 alkyl;​ (12) n is 0 or 1; and (13) p is 2 or 3.

5. The compound, pharmaceutically acceptable salt, or isomer thereof according to any one of claims 1-4, wherein one or more of the following conditions are met: (1) structural unit selected from the group consisting of (2) R X2 selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl and -L 3 -R 5 ; L 3 -C(R L3a )(R L3b )-; R L3a , R L3b together with the carbon atom to which they are attached form C 3-6 cycloalkyl; R 5 selected from cyano, (R a )(R b )N-C(O)- and 5-6 membered heteroaryl; said 5-6 membered heteroaryl is optionally substituted with one or more C 1-6 alkyl; R a and R b are each independently selected from C 1-6 alkyl; (3) R X3 selected from hydrogen, C 3-6 cycloalkyl and -L 3 -R 5 ; said C 3-6 cycloalkyl is optionally substituted with one or more halogen; L 3 selected from -C(R L3a )(R L3b )-; R L3a , R L3b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl, or R L3a , R L3b together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; R 5 Selected from cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-S(O)2-, (R a (R) b )NC(O)-, 3-6 membered heterocyclic groups, 5-6 membered heteroaryl groups and C 2-6 alkynyl group; the C 1-6 Alkyl, 3-6 membered heterocyclic or 5-6 membered heteroaryl, optionally enclosed by one or more R 5A Replaced by, R 5A Selected from C 1-6 Alkyl, C 1-6 Alkyl and oxo; R a and R b are each independently selected from C 1-6 alkyl; (4) ring B is 6 membered heterocyclyl with one N heteroatom; (5) L 1 is -O-; (6) L 2 is selected from a chemical bond, -NH-, and *-C(O)-NH-; the "*" end indicates attachment to R 4 group; (7) R 3 halogen; and (8) R 4 is selected from the group consisting of 3-6 membered heterocyclyl and 5-6 membered heteroaryl optionally substituted with one or more R 4A ; R 4A is independently selected from the group consisting of amino, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, oxo, and deuterated C 1-6 alkyl.

6. The compound, pharmaceutically acceptable salt, or isomer thereof according to any one of claims 1-5, wherein one or more of the following conditions are met: (1) structural unit For (2) R X3 selected from C 3-6 cycloalkyl and -L 3 -R 5 ; said C 3-6 cycloalkyl is optionally substituted with one or more halogen; L 3 selected from -C(R L3a )(R L3b )-; R L3a , R L3b together with the carbon atom to which they are attached form C 3-6 cycloalkyl; R 5 Selected from cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-S(O)2-, (R a (R) b )NC(O)-, 3-6 membered heterocyclic groups, 5-6 membered heteroaryl groups and C 2-6 alkynyl group; the C 1-6 Alkyl, 3-6 membered heterocyclic or 5-6 membered heteroaryl, optionally enclosed by one or more R 5A Replaced by, R 5A Selected from C 1-6 Alkyl, C 1-6 Alkyl and oxo; R a and R b are each independently selected from C 1-6 alkyl; More preferably, R X3 selected from C 3-6 cycloalkyl and -L 3 -R 5 ; said C 3-6 cycloalkyl is optionally substituted with one or more halogen; L 3 selected from -C(R L3a )(R L3b )-; R L3a , R L3b together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; R 5 selected from cyano and haloC 1-6 alkyl; (3) L 2 is selected from a chemical bond and -NH-, preferably a chemical bond; and (4) R 4 selected from optionally substituted 3-6 membered heterocyclyl; R 4A substituted 3-6 membered heterocyclyl; R 4A independently selected from C 1-6 alkyl, haloC 1-6 alkyl, oxo, and deuterated C 1-6 alkyl.

7. The compound, pharmaceutically acceptable salt, or isomer thereof of any one of claims 1-6, having any one of the following structures: wherein, X 1 , X 2 , X 4 , R x2 , R 2 , R 3 , R 4 , R 4A , L 1 , L 2 , L 3 , R L3a , R L3b , R 5 , ring B, ring C, n, p are as defined in any one of claims 1 to 6; R 4-1 Same as R 4 Defined; Preferably R 4-1 Selected from one or more R 4A The following groups are substituted: 3-6 membered heterocyclic groups and 5-6 membered heteroaryl groups.

8. The compound, pharmaceutically acceptable salt, or isomer thereof of any one of claims 1-6, having a structure shown below: wherein R X2 selected from H, C 1-4 alkyl; R X3 Selected from C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups and -L 3 -R 5 The C mentioned above 3-6 Cycloalkyl and 3-6 membered heterocyclic groups are optionally separated by one or more R 1A The R that was replaced 1A Selected from cyano, halogen, C 1-4 Alkyl and Halogenated C 1-4 alkyl; L 3 selected from -C(R L3a )(R L3b )-; R L3a , R L3b are each independently selected from the group consisting of hydrogen, halogen and C 1-4 alkyl, or R L3a , R L3b together with the atoms to which they are attached form a C 3-6 cycloalkyl; R 5 selected from cyano, halogen, C 1-4 alkyl and halogenated C 1-4 alkyl; R 4-1 selected from 5-6 membered heterocyclyl optionally substituted with one or more R 4A substituents; R 4A selected from hydrogen, oxo, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy and deuterated C 1-4 alkyl; R 3 selected from halogen, C 1-4 alkyl and haloC 1-4 alkyl; p is selected from 1, 2 and 3.

9. The compound, pharmaceutically acceptable salt, or isomer thereof of any one of claims 1-6, having a structure shown below: wherein R 2 is H or deuterium; R 3 is H or F; R X2 and R X3 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl and -L 3 -R 5 ; said C 3-6 cycloalkyl is optionally substituted with one or more halogens; Preferably, R X3 Selected from C 3-6 cycloalkyl and -L 3 -R 5 The C mentioned above 3-6 The cycloalkyl group may be optionally replaced by one or more halogens; L 3 -C(R L3a )(R L3b )-; R L3a , R L3b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl, or R L3a , R L3b together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; R 5 Selected from cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-S(O)2-, (R a (R) b )NC(O)-, 3-6 membered heterocyclic groups, 5-6 membered heteroaryl groups and C 2-6 alkynyl group; the C 1-6 Alkyl, 3-6 membered heterocyclic or 5-6 membered heteroaryl, optionally enclosed by one or more R 5A Replaced by, R 5A Selected from C 1-6 Alkyl, C 1-6 Alkyl and oxo; R a and R b are each independently selected from C 1-6 alkyl; L 2 is selected from a single bond, -NH-, and -C(O)-NH-; R 4 Selected from one or more R 4A Substituted groups include: 3-6 membered heterocyclic groups and 5-6 membered heteroaryl groups; R 4A Independently selected from amino, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, oxo, and deuterated C 1-6 alkyl.

10. The compound, pharmaceutically acceptable salt, or isomer thereof of any one of claims 1-6, having a structure shown below: wherein, R X2 selected from hydrogen and C 1-6 alkyl, preferably hydrogen; R X3 selected from C 3-6 cycloalkyl and -L 3 -R 5 ; said C 3-6 cycloalkyl is optionally substituted with one or more halogen; L 3 selected from -C(R L3a )(R L3b )-; R L3a , R L3b together with the carbon atom to which they are attached form C 3-6 cycloalkyl; R 5 selected from cyano and haloC 1-6 alkyl; R 4 selected from the group consisting of 3-6 membered heterocyclyl; and 4A substituted with one or more R R 4A independently selected from C 1-6 alkyl, haloC 1-6 alkyl, oxo, and deuterated C 1-6 alkyl.

11. The compound, pharmaceutically acceptable salt, or isomer thereof according to any one of claims 1-10, wherein, one or more of the following conditions are met: (1) R X1 (2) R X2 (3) R X3 (4) R X4 are each independently selected from H, -NH2, -CHF2, -CN, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -CH=CH2, -CºCH, -CºCCH3, -OCH3, (2) Ring B is selected from * indicates attachment to L 1 the end (3) R 2 is selected from H, D, OH, F, Cl, -CH3, and -CH2CH3; n is selected from 0 and 1 ; (4) R 3 selected from F, CI, -CH3, and -CF3; (5) L 2 is selected from a chemical bond, -NH-, *-CH2-NH-, *-C(O)-NH-, -C(O)-, *-N=C(CH3)-, and *-NH-O-; the "*" end indicates attachment to R 4 groups; and (6) R 4 selected from -CH3, -CH2CH3, -CH(CH3)2, 12. The compound, pharmaceutically acceptable salt, or isomer thereof according to any one of claims 1-11, wherein, one or more of the following conditions are met: (1) R X2 selected from H, -NH2, -OCH3, -CN, -CHF2, -CH2CH3, -CH(CH3)2, -CF3, -CH=CH2, -CH3, -CºCH, -CºCCH3, (2) R X3 selected from H, -CN, -CF3, (3) Ring B is selected from * indicates attachment to L 1 the end (4) n is 0; (5) structural unit selected from the group consisting of and (6) R 4 selected from 13. The compound, pharmaceutically acceptable salt, or isomer thereof of any one of claims 1-12, wherein, one or more of the following conditions are met: (1) R X2 is H, -CH3, or -CH=CH2; preferably H or -CH3; (2) R X3 is H, Preferably (3) structural unit For and (4) R 4 To 14. A compound, a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein the compound is selected from any one of the following:

15. A pharmaceutical composition comprising a compound, a pharmaceutically acceptable salt thereof or an isomer thereof according to any one of claims 1-14 and one or more pharmaceutically acceptable carriers.

16. Use of a compound, a pharmaceutically acceptable salt thereof or an isomer thereof according to any one of claims 1-14, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for the prevention and / or treatment of a GPR6-mediated disease.

17. The use according to claim 16, wherein the GPR6-mediated disease comprises Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorder, epilepsy, Alzheimer's disease, anxiety and depression.

18. Use of a compound, a pharmaceutically acceptable salt thereof or an isomer thereof according to any one of claims 1-14, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for the prevention and / or treatment of Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorder, epilepsy, Alzheimer's disease, anxiety or depression.

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