GPR6 inverse agonist and application thereof

Abstract

The invention belongs to the field of medicines, and discloses a GPR6 inverse agonist as shown in the following formula (I), a preparation method, a pharmaceutical composition and application of the compound in preparation of medicines for treating GPR6-mediated related diseases.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a novel GPR6 inverse agonist, its pharmaceutically acceptable salts, its stereoisomers, its isotope-labeled substances, its solvates, its hydrates, its pharmaceutical preparations, compositions, pharmaceutical uses and treatment methods. Background Art

[0002] GPR6 (G-protein coupled receptors 6) is a highly active G-protein-coupled receptor (GPCR) belonging to the class A GPCR family, which also includes GPR3 ​​and GPR12. These three receptors share approximately 60% amino acid identity. Because GPR3, GPR6, and GPR12 lack identified endogenous ligands, they remain classified as orphan receptors. Receptors in this family have been shown to be constitutively active, capable of signaling through both Gs proteins and non-Gs protein mechanisms. Gs proteins can activate and stimulate cyclic adenosine monophosphate (cAMP) production. Initial cloning experiments in the mid-1990s revealed that GPR6 is primarily expressed in the central nervous system, with only trace amounts expressed in the periphery. Within central nervous system tissues, the striatum displays the highest GPR6 protein levels. Functionally, the striatum serves as a major input structure to the basal ganglia, regulating motor control systems, participating in reward pathways, and influencing learning and memory. GPR6 knockout mice show reduced cAMP levels in striatal tissue, consistent with GPR6-Gs protein coupling and cAMP signaling in vivo. Pharmacological targeting of GPR6 may prove useful for the treatment of striatal-associated neurological and neuropsychiatric disorders such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, autism spectrum disorder, schizophrenia, and drug addiction.

[0003] Parkinson's disease (PD) is a chronic, progressive movement disorder characterized by neurodegeneration and loss of dopamine-producing neurons in the substantia nigra pars compacta, leading to striatal dopamine (DA) depletion. Currently, dopaminergic therapies, including the DA prodrug levodopa (L-DOPA), catechol methyltransferase (COMT) inhibitors, monoamine oxidase B (MAO) inhibitors, and dopamine receptor agonists, are effective treatments for PD. However, long-term use can lead to severe movement disorders and multiple side effects. In addition, a variety of non-dopaminergic therapies are in clinical use, 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 significantly improves motor symptoms in PD. The development of a drug that selectively targets the indirect pathway in PD could avoid invasive deep brain stimulation (DBS) without increasing the risk of drug-induced movement disorders.

[0004] Developed by Cerevance, CVN424 is a non-dopaminergic, oral GPCR6 inverse agonist currently in Phase II clinical trials for Parkinson's disease. Unlike dopamine replacement therapy (L-DOPA), commonly used in Parkinson's disease, CVN424 selectively targets the indirect dopamine D2 receptor-dependent signaling pathway implicated in Parkinson's disease, resulting in the same positive outcomes as L-dopamine or deep brain stimulation without the side effects. In a Phase II study, CVN424 demonstrated safety and efficacy as an adjunct to L-dopamine in reducing the "off" period (the period during which patients experience Parkinson's symptoms despite treatment) in Parkinson's patients. Although GPR6 inverse agonist drugs are currently in clinical trials, the complexity, uncertainty, and high risk of drug development make it crucial to continue advancing the development of these targeted drugs and expand the pipeline of clinical candidates. Summary of the Invention

[0005] The present disclosure provides an inverse agonist targeting GPR6, which has higher selectivity than other subtypes, good in vitro and in vivo activity and pharmacokinetic properties, and can be used for GRP6-mediated related diseases.

[0006] The present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, and a hydrate thereof.

[0007]

[0008] X 1 、X 2 are independently selected from N, CR 5 ;

[0009] R 5 Selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy;

[0010] Ring A is selected from 5-6 membered heteroaryl, 5-10 membered heterocycloalkenyl, 6-10 membered bridged heterocycloalkenyl, C 3-6 cycloalkenyl;

[0011] Ring B is selected from C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 7-8 membered bridged heterocyclic group, 7-11 membered spiroheterocyclic group, 6-10 membered fused heterocyclic group;

[0012] Ring C is selected from phenyl, 5-6 membered heteroaryl;

[0013] R 1Independently selected from the following groups:

[0014] H, deuterium, oxo, CN, OH, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-6 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl-C 1-6 Alkylene, C 1-6 Alkoxy, 5-6 membered heteroaryl, COOH, =C(R 1c )(R 1d ), C 1-6 Alkyl-C(O)-C(O)-, C 2-6 Alkynyl-C(O)-, C 2-6 alkenyl-C(O)-,

[0015] Alternatively, two R 1 Connect to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 5-6 membered heteroaryl,

[0016] Alternatively, two R on adjacent ring atoms 1 Together with the atoms it is connected to form C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl;

[0017] Among them, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-6 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl-C 1-6 Alkylene, C 1-6 Alkoxy, 5-6 membered heteroaryl are optionally substituted with one or more R1A replaced by;

[0018] R 1A Selected from deuterium, halogen, OH, (R 1a )(R 1b )N-、COOH、C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, CN, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0019] R 1a 、R 1b 、R 1c 、R 1d are independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl-C(O)-, or R 1a 、R 1b The nitrogen atom to which it is connected forms a 3-6 membered heterocyclic group, or R 1c 、R 1d The atom to which it is connected forms a C 3-6 Cycloalkyl, 3-6 membered heterocyclic group;

[0020] R 2 Selected from H, OH, NH2, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, CN, C 2-6 Alkenyl, C 2-6 Alkynyl, or two R on adjacent ring atoms 2 Together with the ring atoms to which it is connected, it forms a C 3-6 Cycloalkyl, 3-6 membered heterocyclic group;

[0021] R 3 Selected from H, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 Alkynyl, C 2-6 alkenyl;

[0022] 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)-;

[0023] R L1a 、R L1b are independently selected from H, halogen, C 1-6 Alkyl, or R L1a and one of the R 3 Together with the atoms it is connected to form C 5-6 Cycloalkenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl;

[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 are independently selected from H, OH, halogen, C 1-6 Alkyl, C 1-6 alkoxy;

[0026] R 4 Selected from OH, or optionally one or more R 4a Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-C(O)-, 3-6 membered heterocyclic group, 6-8 membered bridged heterocyclic group, 7-11 membered spiro heterocyclic group, 6-10 membered fused heterocyclic group, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, phenyl;

[0027] R 4a Selected from CN, halogen, NH2, OH, 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 -, deuterated C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl;

[0028] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;

[0029] n, p, q, and t are independently selected from 0, 1, 2, 3, and 4.

[0030] In another embodiment of the present disclosure, the compound of formula (I), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate,

[0031]

[0032] X 1 、X 2 are independently selected from N, CR 5 ;

[0033] R 5 Selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy;

[0034] Ring A is selected from 5-6 membered heteroaryl, 5-10 membered heterocycloalkenyl, 6-10 membered bridged heterocycloalkenyl, C 3-6 cycloalkenyl;

[0035] Ring B is selected from C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 7-8 membered bridged heterocyclic group, 7-11 membered spiroheterocyclic group, 6-10 membered fused heterocyclic group;

[0036] Ring C is selected from phenyl, 5-6 membered heteroaryl;

[0037] R 1 Selected from H, deuterium, oxo, CN, OH, halogen, C 1-6 Alkyl, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-6 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl-C 1-6 Alkylene, C 1-6Alkoxy, 5-6 membered heteroaryl, COOH, =C(R 1c )(R 1d ), C 1-6 Alkyl-C(O)-C(O)-, C 2-6 Alkynyl-C(O)-, C 2-6 Alkenyl-C(O)-, or two R on the same carbon atom 1 Connect to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, or two R on adjacent ring atoms 1 Together with the atoms it is connected to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 5-6 membered heteroaryl; wherein, the C 1-6 Alkyl, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-6 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl-C 1-6 Alkylene, C 1-6 Alkoxy, 5-6 membered heteroaryl are optionally substituted with one or more R 1A substituted, the R 1A Selected from deuterium, halogen, OH, (R 1a )(R 1b )N-、COOH、C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, CN, halogenated C 1-6 alkyl;

[0038] R 1a 、R 1b 、R 1c 、R 1d are independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl-C(O)-, or R 1a 、R 1b The nitrogen atom to which it is connected forms a 3-6 membered heterocyclic group, or R 1c 、R 1d The atom to which it is connected forms a C 3-6 Cycloalkyl, 3-6 membered heterocyclic group;

[0039] R 2Selected from H, OH, NH2, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, CN, C 2-6 Alkynyl, or two R on adjacent ring atoms 2 Together with the ring atoms to which it is connected, it forms a C 3-6 Cycloalkyl, 3-6 membered heterocyclic group;

[0040] R 3 Selected from H, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 Alkynyl, C 2-6 alkenyl;

[0041] 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)-;

[0042] R L1a 、R L1b are independently selected from H, halogen, C 1-6 Alkyl, or R L1a and one of the R 3 Together with the atoms it is connected to form C 5-6 Cycloalkenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl;

[0043] 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-;

[0044] R L2a 、R L2b are independently selected from H, OH, halogen, C 1-6 Alkyl, C 1-6 alkoxy;

[0045] R 4 Selected from OH, or optionally one or more R 4a Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, 3-6 membered heterocyclic group, 6-8 membered bridged heterocyclic group, 7-11 membered spiro heterocyclic group, 6-10 membered fused heterocyclic group, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, phenyl;

[0046] R 4a Selected from CN, halogen, NH2, OH, 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 -, deuterated C 1-6 alkyl;

[0047] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;

[0048] n, p, q, and t are independently selected from 0, 1, 2, 3, and 4.

[0049] In another embodiment of the present disclosure, the compound represented by formula (I), its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, its hydrate,

[0050]

[0051] X 1 、X 2 are independently selected from N, CR 5 ;

[0052] R 5 Selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy;

[0053] Ring A is selected from 5-6 membered heteroaryl, 5-10 membered heterocycloalkenyl, 6-10 membered bridged heterocycloalkenyl;

[0054] Ring B is selected from C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 7-8 membered bridged heterocyclic group, 7-11 membered spiroheterocyclic group, 6-10 membered fused heterocyclic group;

[0055] Ring C is selected from phenyl, 5-6 membered heteroaryl;

[0056] R 1 Selected from H, oxo, CN, OH, halogen, C 1-6 Alkyl, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-6 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl-C 1-6 Alkylene, C 1-6 Alkoxy, 5-6 membered heteroaryl, COOH, or two R on the same carbon atom 1 Connect to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, or two adjacent R 1 Together with the atoms it is connected to form C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, , =C(R 1c )(R 1d ); wherein, the C 1-6 Alkyl, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-6 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl-C 1-6 Alkylene, C 1-6 Alkoxy, 5-6 membered heteroaryl are optionally substituted with one or more R 1A substituted, the R 1A Selected from halogen, OH, (R 1a )(R 1b )N-、COOH、C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, CN, halogenated C 1-6 alkyl;

[0057] R 1a、R 1b 、R 1c 、R 1d are independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl-C(O)-, or R 1a 、R 1b The nitrogen atom to which it is connected forms a 3-6 membered heterocyclic group, or R 1c 、R 1d The atom to which it is connected forms a C 3-6 Cycloalkyl, 3-6 membered heterocyclic group;

[0058] R 2 Selected from H, OH, NH2, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy;

[0059] R 3 Selected from H, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy;

[0060] 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)-;

[0061] R L1a 、R L1b are independently selected from H, halogen, C 1-6 alkyl;

[0062] 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-;

[0063] R L2a 、RL2b are independently selected from H, OH, halogen, C 1-6 Alkyl, C 1-6 alkoxy;

[0064] R 4 Selected from OH, or optionally one or more R 4a Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, 3-6 membered heterocyclic group, 6-8 membered bridged heterocyclic group, 7-11 membered spiro heterocyclic group, 6-10 membered fused heterocyclic group, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, phenyl;

[0065] R 4a Selected from CN, halogen, NH2, OH, 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 -;

[0066] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;

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

[0068] In another embodiment of the present disclosure, the compound of formula (I), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate,

[0069]

[0070] X 1 、X 2 are independently selected from N, CR 5 ;

[0071] R 5 Selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy;

[0072] Ring A is selected from 5-6 membered heteroaryl, 5-10 membered heterocycloalkenyl;

[0073] Ring B is selected from 5-6 membered heterocyclyl, 7-8 membered bridged heterocyclyl, 7-11 membered spiroheterocyclyl, 6-10 membered fused heterocyclyl;

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

[0075] R 1 Selected from H, oxo, CN, OH, halogen, C 1-6 Alkyl, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-6 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl-C 1-6 Alkylene, C 1-6 Alkoxy, or two R on the same carbon atom 1 Connect to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, or two adjacent R 1 Together with the atoms it is connected to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 5-6 membered heteroaryl; wherein, the C 1-6 Alkyl, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-6 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl-C 1-6 Alkylene, C 1-6 Alkoxy, 5-6 membered heteroaryl are optionally substituted with one or more R 1A substituted, the R 1A Selected from halogen, OH, (R 1a )(R 1b )N-、COOH、C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 alkyl;

[0076] R 1a 、R 1b are independently selected from H, C1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl-C(O)-, or R 1a 、R 1b It forms a 3-6 membered heterocyclic group with the nitrogen atom to which it is attached;

[0077] R 2 Selected from H, OH, NH2, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy;

[0078] R 3 Selected from H, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy;

[0079] 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)-;

[0080] R L1a 、R L1b are independently selected from H, halogen, C 1-6 alkyl;

[0081] 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-;

[0082] R L2a 、R L2b are independently selected from H, OH, halogen, C 1-6 Alkyl, C 1-6 alkoxy;

[0083] R 4 Selected from OH or optionally replaced by one or more R 4aSubstituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, 3-6 membered heterocyclic group, 6-8 membered bridged heterocyclic group, 7-11 membered spiro heterocyclic group, 6-10 membered fused heterocyclic group, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, phenyl;

[0084] R 4a Selected from CN, halogen, NH2, OH, 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 -;

[0085] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;

[0086] n, p, q, and t are independently selected from 0, 1, 2, 3, and 4.

[0087] In another embodiment of the present disclosure, the compound of formula (I), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate,

[0088]

[0089] X 1 、X 2 are independently selected from N, CR 5 ;

[0090] R 5 Selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy;

[0091] Ring A is selected from 5-6 membered heteroaryl, 6-10 membered heterocycloalkenyl;

[0092] Ring B is selected from 5-6 membered heterocyclyl, 7-8 membered bridged heterocyclyl, 7-11 membered spiroheterocyclyl, 6-10 membered fused heterocyclyl;

[0093] Ring C is selected from phenyl, 5-6 membered heteroaryl;

[0094] R 1 Selected from H, oxo, CN, C1-6 Alkyl, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-6 alkyl)2P(O)-、(R 1a )(R 1b )N-, or two R on the same carbon atom 1 Connect to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, or two adjacent R 1 Together with the atoms it is connected to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; wherein, the C 1-6 Alkyl, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-6 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 3-6 membered heterocyclic group are optionally substituted by one or more R 1A substituted, the R 1A Selected from halogen, hydroxy, (R 1a )(R 1b )N-;

[0095] R 1a 、R 1b are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl-C(O)-, or R 1a 、R 1b It forms a 3-6 membered heterocyclic group with the nitrogen atom to which it is attached;

[0096] R 2 Selected from H, OH, NH2, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy;

[0097] R 3 Selected from H, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C1-6 Alkoxy, halogenated C 1-6 alkoxy;

[0098] 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)-;

[0099] R L1a 、R L1b are independently selected from H, halogen, C 1-6 alkyl;

[0100] 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 )-;

[0101] R L2a 、R L2b are independently selected from H, OH, halogen, C 1-6 Alkyl, C 1-6 alkoxy;

[0102] R 4 Selected from optionally one or more R 4a Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, 3-6 membered heterocyclic group, 6-8 membered bridged heterocyclic group, 7-11 membered spiro heterocyclic group, 6-10 membered fused heterocyclic group, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, phenyl;

[0103] R 4a Selected from CN, 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 -;

[0104] m is selected from 0, 1, 2, 3, 4, 6, 7, 8;

[0105] n, p, q, and t are independently selected from 0, 1, 2, 3, and 4.

[0106] In another embodiment of the present disclosure, wherein X 1 、X 2 All are N.

[0107] In another embodiment of the present disclosure, wherein ring A is selected from 5-7 membered heterocycloalkenyl.

[0108] In another embodiment of the present disclosure, wherein ring A is selected from 6-7 membered heterocycloalkenyl.

[0109] In another embodiment of the present disclosure, wherein ring A is selected from 5-7 membered nitrogen-containing heterocycloalkenyl groups.

[0110] In another embodiment of the present disclosure, wherein ring A is selected from 6-7 membered nitrogen-containing heterocycloalkenyl groups.

[0111] In another embodiment of the present disclosure, the heteroatom in the 6-7 membered nitrogen-containing heterocycloalkenyl of ring A is 1 N and 0-1 atoms selected from O, S or N.

[0112] In another embodiment of the present disclosure, the ring A structure includes a -C(O)-NH- structure.

[0113] In another embodiment of the present disclosure, wherein ring A is selected from

[0114] In another embodiment of the present disclosure, wherein ring A is selected from

[0115] In another embodiment of the present disclosure, wherein ring A is selected from

[0116] In another embodiment of the present disclosure, wherein ring A is selected from

[0117] In another embodiment of the present disclosure, wherein ring A is selected from

[0118] In another embodiment of the present disclosure, wherein ring A is selected from

[0119] In another embodiment of the present disclosure, R 1Selected from H, deuterium, oxo, CN, OH, halogen, C 1-4 Alkyl, C 1-4 Alkyl-C(O)-, C 1-4 Alkyl-S(O)2-, C 1-4 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-4 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered heterocyclyl-C 1-4 Alkylene, C 1-4 Alkoxy, 5-6 membered heteroaryl, -COOH, =C(R 1c )(R 1d ), C 1-4 Alkyl-C(O)-C(O)-, C 2-4 Alkynyl-C(O)-, C 2-4 alkenyl-C(O)-,

[0120] Alternatively, two R 1 Connect to form C 3-6 Cycloalkyl, 4-6 membered heterocyclic group,

[0121] Alternatively, two R on adjacent ring atoms 1 Together with the atoms it is connected to form C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl;

[0122] Among them, the C 1-4 Alkyl, C 1-4 Alkyl-C(O)-, C 1-4 Alkyl-S(O)2-, C 1-4 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-4 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered heterocyclyl-C 1-4 Alkylene, C 1-4 Alkoxy, 5-6 membered heteroaryl are optionally substituted with one or more R 1A substituted, the R 1A Selected from deuterium, halogen, OH, (R 1a )(R 1b )N-、COOH、C 1-4 Alkyl, C 1-4Alkoxy, hydroxy C 1-4 Alkyl, CN, halogenated C 1-4 alkyl;

[0123] R 1a 、R 1b 、R 1c 、R 1d are independently selected from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkyl-C(O)-, or R 1a 、R 1b and the nitrogen atom to which it is connected form a 5-6 membered heterocyclic group; or R 1c 、R 1d The atom to which it is connected forms a C 3-6 Cycloalkyl, 4-6 membered heterocyclic group;

[0124] m is selected from 0, 1, 2, 3, 4, 5, 6;

[0125] Preferably, m is selected from 0, 1, 2, 3, 4.

[0126] In another embodiment of the present disclosure, R 1 Selected from H, oxo, CN, OH, halogen, C 1-4 Alkyl, C 1-4 Alkyl-C(O)-, C 1-4 Alkyl-S(O)2-, C 1-4 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-4 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered heterocyclyl-C 1-4 Alkylene, C 1-4 Alkoxy, 5-6 membered heteroaryl, COOH,

[0127] Alternatively, two R 1 Connect to form C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, =C(R 1c )(R 1d ),

[0128] Or, two adjacent R 1 Together with the atoms it is connected to form C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl;

[0129] Among them, the C 1-4 Alkyl, C1-4 Alkyl-C(O)-, C 1-4 Alkyl-S(O)2-, C 1-4 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-4 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered heterocyclyl-C 1-4 Alkylene, C 1-4 Alkoxy, 5-6 membered heteroaryl are optionally substituted with one or more R 1A substituted, the R 1A Selected from halogen, OH, (R 1a )(R 1b )N-、COOH、C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, CN, halogenated C 1-4 alkyl;

[0130] R 1a 、R 1b 、R 1c 、R 1d are independently selected from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkyl-C(O)-, or R 1a 、R 1b and the nitrogen atom to which it is connected form a 5-6 membered heterocyclic group; or R 1c 、R 1d The atom to which it is connected forms a C 3-6 Cycloalkyl, 4-6 membered heterocyclic group;

[0131] m is selected from 0, 1, 2, 3, 4, 5, 6;

[0132] Preferably, m is selected from 0, 1, 2, 3, 4.

[0133] In another embodiment of the present disclosure, wherein R 1 Selected from H, oxo, CN, OH, halogen, C 1-4 Alkyl, C 1-4 Alkyl-C(O)-, C 1-4 Alkyl-S(O)2-, C 1-4 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-4 alkyl)2P(O)-、(R1a )(R 1b )N-、C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered heterocyclyl-C 1-4 Alkylene, C 1-4 Alkoxy, or two R on the same carbon atom 1 Connect to form C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, or two adjacent R 1 Together with the atoms it is connected to form C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl; wherein, the C 1-4 Alkyl, C 1-4 Alkyl-C(O)-, C 1-4 Alkyl-S(O)2-, C 1-4 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-4 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered heterocyclyl-C 1-4 Alkylene, C 1-4 Alkoxy, 5-6 membered heteroaryl are optionally substituted with one or more R 1A substituted, the R 1A Selected from halogen, OH, (R 1a )(R 1b )N-、COOH、C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy C 1-4 alkyl;

[0134] R 1a 、R 1b are independently selected from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkyl-C(O)-, or R 1a 、R 1b It forms a 5-6 membered heterocyclic group with the nitrogen atom to which it is attached;

[0135] m is selected from 0, 1, 2, 3, 4, 5, 6;

[0136] Preferably, m is selected from 0, 1, 2, 3, 4.

[0137] In another embodiment of the present disclosure, wherein R 1 Selected from H, oxo, CN, C 1-4 Alkyl, C 1-4Alkyl-C(O)-, C 1-4 Alkyl-S(O)2-, C 1-4 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-4 alkyl)2P(O)-、(R 1a )(R 1b )N-, or two R on the same carbon atom 1 Connect to form C 3-6 Cycloalkyl, or two adjacent R 1 Together with the atoms it is connected to form C 3-6 Cycloalkyl, 5-6 membered heterocyclic group; wherein, the C 1-4 Alkyl, C 1-4 Alkyl-C(O)-, C 1-4 Alkyl-S(O)2-, C 1-4 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-4 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 5-6 membered heterocyclic group are optionally substituted by one or more R 1A substituted, the R 1A Selected from halogen, hydroxy, (R 1a )(R 1b )N-;

[0138] R 1a 、R 1b are independently selected from H, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkyl-C(O)-, or R 1a 、R 1b It forms a 5-6 membered heterocyclic group with the nitrogen atom to which it is attached;

[0139] m is selected from 0, 1, 2, 3, 4, 5, 6;

[0140] Preferably, m is selected from 0, 1, 2, 3, 4.

[0141] In another embodiment of the present disclosure, wherein R 1 Selected from H, oxo, CN, -CH 3、 CH3C(O)-, -OCH3, (CH3)2P(O)-, CH3S(O)2-, CH3O-C(O)-, CH3NH-C(O)-, CH3C(O)-NH-, OH, F, -CH2CH3, -CH2CH2OCH3, -CH2CN, -CH2CH3, -CH(CH3)2, cyclopropyl, -CH2CHF2, CH3-NH-, -COOH, -N(CH3)2, CF3CH2-、-CD3、-D、

[0142] Alternatively, two R 1 Connect to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, “*” indicates the connection position with ring A;

[0143] Alternatively, two R on adjacent ring atoms 1 Together with the atoms to which they are connected, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0144] In another embodiment of the present disclosure, wherein R 1 Selected from H, oxo, CN, -CH 3、 CH3C(O)-, -OCH3, (CH3)2P(O)-, CH3S(O)2-, CH3O-C(O)-, CH3NH-C(O)-, CH3C(O)-NH-, OH, F, -CH2CH3, -CH2CH2OCH3, -CH2CN, -CH2CH3, -CH(CH3)2, cyclopropyl, -CH2CHF2, CH3-NH-, -COOH, -N(CH3)2, CF3CH2-、-CD3、-D、

[0145] Alternatively, two R 1 Connect to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, “*” indicates the connection position with ring A;

[0146] Alternatively, two R on adjacent ring atoms 1 Together with the atoms to which they are connected, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0147] Preferably, two R on the same carbon atom1 Connect to form a cyclopropyl group;

[0148] Preferably, two R on adjacent ring atoms 1 Together with the atoms to which it is connected, it forms a cyclopropyl or cyclobutyl group.

[0149] In another embodiment of the present disclosure, two R 1 Together with the atoms to which they are connected,

[0150] In another embodiment of the present disclosure, wherein R 1 Selected from H, oxo, CN, -CH 3、 CH3C(O)-, -OCH3, (CH3)2P(O)-, CH3S(O)2-, CH3O-C(O)-, CH3NH-C(O)-, CH3C(O)-NH-, OH, F, -CH2CH3, -CH2CH2OCH3, -CH2CN, -CH2CH3, -CH(CH3)2, cyclopropyl, -CH2CHF2, CH3-NH-, -COOH, -N(CH3)2,

[0151] Alternatively, two R 1 Connect to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, “*” indicates the connection position with ring A;

[0152] Or, two adjacent R 1 Together with the atoms to which they are connected, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0153] Preferably, two R on the same carbon atom 1 Connect to form a cyclopropyl group;

[0154] Preferably, two adjacent R 1 Together with the atoms to which it is connected, it forms a cyclopropyl or cyclobutyl group.

[0155] In another embodiment of the present disclosure, wherein R 1 Selected from H, oxo, CN, -CH 3、 CH3C(O)-, -OCH3, (CH3)2P(O)-, CH3S(O)2-, CH3O-C(O)-, CH3NH-C(O)-, CH3C(O)-NH-, OH, F, -CH2CH3, -CH2CH2OCH3, Alternatively, two R 1 Connect to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, "*" indicates the connection position with ring A; or, two adjacent R 1 Together with the atoms to which they are connected, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0156] In another embodiment of the present disclosure, wherein R 1 Selected from H, oxo, CN, -CH 3、 CH3C(O)-, -OCH3, (CH3)2P(O)-, CH3S(O)2-, CH3O-C(O)-, CH3NH-C(O)-, CH3C(O)-NH-, Alternatively, two R 1 Connect to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; or, two adjacent R 1 Together with the atoms to which they are connected, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0157] Preferably, two R on the same carbon atom 1 Connect to form a cyclopropyl group;

[0158] Preferably, two adjacent R 1 Together with the atoms to which it is connected, it forms a cyclopropyl or cyclobutyl group.

[0159] In another embodiment of the present disclosure, R 1 Selected from H, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl; or, two R on adjacent ring atoms 1 Together with the ring atoms to which it is connected, it forms a C 3-6 cycloalkyl.

[0160] In another embodiment of the present disclosure, an R 1 Located on the nitrogen atom of ring A, R 1 As defined in any of the embodiments of the present disclosure.

[0161] In another embodiment of the present disclosure, for R 1 As defined in any embodiment of the present disclosure; ma is 0, 1, 2, 3, 4, 5, 6, or 7.

[0162] In another embodiment of the present disclosure, for R 1 As defined in any embodiment of the present disclosure; ma is 0, 1, 2, 3, 4, 5, 6, or 7.

[0163] In another embodiment of the present disclosure, for R 1 As defined in any embodiment of the present disclosure; ma is 0, 1, 2, 3, 4, 5, 6, or 7.

[0164] In another embodiment of the present disclosure, for R 1 As defined in any embodiment of the present disclosure; ma is 0, 1, 2, 3, or 4.

[0165] In another embodiment of the present disclosure, for R 1 As defined in any of the embodiments of the present disclosure.

[0166] In another embodiment of the present disclosure, ma is selected from 0, 1, 2, 3, 4, and 5.

[0167] In another embodiment of the present disclosure, ma is selected from 0, 1, 2, 3, and 4.

[0168] In another embodiment of the present disclosure, ma is selected from 0, 1, 2, and 3.

[0169] In another embodiment of the present disclosure, ma is selected from 0, 1, and 2.

[0170] In another embodiment of the present disclosure, the structural unit Selected from

[0171]

[0172]

[0173]

[0174]

[0175] In another embodiment of the present disclosure, the structural unit Selected from

[0176]

[0177] In another embodiment of the present disclosure, the structural unit Selected from

[0178]

[0179] In another embodiment of the present disclosure, the structural unit Selected from

[0180] In another embodiment of the present disclosure, the structural unit Selected from

[0181]

[0182] In another embodiment of the present disclosure, the structural unit Selected from

[0183] In another embodiment of the present disclosure, wherein ring B is selected from 5-6 membered heterocyclic group, C 4-6 Cycloalkyl.

[0184] In another embodiment of the present disclosure, wherein Ring B is selected from a 5-6 membered heterocyclic group.

[0185] In another embodiment of the present disclosure, wherein ring B is selected from “*” indicates the same as L 1 Ends are connected.

[0186] In another embodiment of the present disclosure, wherein ring B is selected from “*” indicates the same as L 1 Ends are connected.

[0187] In another embodiment of the present disclosure, wherein R 2 Selected from H, OH, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, or two R on adjacent ring atoms 2 Together with the ring atoms to which it is connected, it forms a C 3-6 Cycloalkyl.

[0188] In another embodiment of the present disclosure, wherein R 2 Selected from H, OH, F, Cl, -CH3, -CH2CH3; or, two R on adjacent ring atoms 2 Together with the ring atoms to which they are attached, they form a cyclopropyl, cyclobutyl, or cyclopentyl group; n is selected from 0, 1, or 2.

[0189] In another embodiment of the present disclosure, wherein R 2 Selected from H, OH, F, Cl, -CH3, -CH2CH3; n is selected from 0 or 1.

[0190] In another embodiment of the present disclosure, wherein L 1 Selected from -O-, -N(R L1a )-、-C(R L1a R L1b )-、-C(R L1a )=、-S(O)2-;R L1a 、R L1b are independently selected from H, halogen, C 1-4 alkyl.

[0191] In another embodiment of the present disclosure, wherein L 1 Selected from -O-, -N(R L1a )-、-C(R L1a R L1b )-、*-C(R L1a )=、-S(O)2-;R L1a 、R L1b are independently selected from H, halogen, C 1-4 Alkyl; the “*” end indicates connection to the ring C.

[0192] In another embodiment of the present disclosure, wherein L 1 Selected from -O-, -N(R L1a )-、-C(R L1a R L1b )-、-C(R L1a )=;R L1a 、R L1b are independently selected from H, halogen, C 1-4 alkyl.

[0193] In another embodiment of the present disclosure, wherein R L1a 、R L1b Each independently selected from H, F, Cl, -CH3.

[0194] In another embodiment of the present disclosure, L 1 Selected from -O-, -NH-, -CHF-, -CF2-, -CH2-, -CH=, -CF=, -S(O)2-, -CH(CH3)-.

[0195] In another embodiment of the present disclosure, L 1 Selected from -O-, -NH-, -CHF-, -CF2-, -CH2-, -CH=.

[0196] In another embodiment of the present disclosure, wherein L1 Selected from -O-.

[0197] In another embodiment of the present disclosure, wherein L 1 Selected from -CF=.

[0198] In another embodiment of the present disclosure, wherein, ring C is selected from phenyl and 5-6 membered heteroaryl.

[0199] In another embodiment of the present disclosure, wherein ring C is selected from phenyl and pyridine.

[0200] In another embodiment of the present disclosure, wherein ring C is selected from phenyl.

[0201] In another embodiment of the present disclosure, wherein R 3 Selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-4 Alkynyl, C 2-4 Alkenyl.

[0202] In another embodiment of the present disclosure, wherein R 3 Selected from F, Cl, -CH3, -CF3, HC≡C-, CH3C≡C-.

[0203] In another embodiment of the present disclosure, wherein R 3 Selected from F, Cl, -CH3, -CF3.

[0204] In another embodiment of the present disclosure, the structural unit for

[0205]

[0206] In another embodiment of the present disclosure, the structural unit for

[0207] In another embodiment of the present disclosure, wherein L 2 Selected from chemical bonds, -N(R L2a )-、-C(O)-、-C(O)-N(R L2a )-、-C(R L2a R L2b )-N(R L2a )-、-N=C(R L2a )-;R L2a 、R L2b are independently selected from H, OH, halogen, C 1-4 Alkyl, C 1-4 Alkoxy.

[0208] In another embodiment of the present disclosure, wherein L 2 Selected from chemical bonds, -N(R L2a )-、-C(O)-、*-C(O)-N(R L2a )-、*-C(R L2a R L2b )-N(R L2a )-、*-N=C(R L2a )-、-N(R L2a )-O-*;R L2a 、R L2b are independently selected from H, OH, halogen, C 1-4 Alkyl, C 1-4 Alkoxy; "*" indicates the end with R 4 Connected ends.

[0209] In another embodiment of the present disclosure, wherein L 2 Selected from -N(R L2a )-O-.

[0210] In another embodiment of the present disclosure, wherein L 2 Selected from chemical bonds, -NH-, -CH2-NH-, -C(O)-NH-, -C(O)-, -N=C(CH3)-.

[0211] In another embodiment of the present disclosure, wherein L 2 Selected from chemical bonds, -NH-, *-CH2-NH-, *-C(O)-NH-, -C(O)-, *-N=C(CH3)-, -NH-O-*; "*" indicates the end with R 4 Connected ends.

[0212] In another embodiment of the present disclosure, wherein L 2 Selected from -NH-O-.

[0213] In another embodiment of the present disclosure, wherein L 2 Selected from chemical bonds, -NH-.

[0214] In another embodiment of the present disclosure, wherein R 4 Selected from OH, or optionally replaced by one or more R 4a Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-C(O)-, 3-6 membered heterocyclic group, 6-8 membered bridged heterocyclic group, 6-8 membered fused heterocyclic group, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, phenyl;

[0215] R4a Selected from CN, NH2, OH, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkylene, C 3-6 Cycloalkyl-(CH2) t -, 3-6 membered heterocyclic group-(CH2) t -, deuterated C 1-4 Alkyl; t is selected from 0, 1, 2.

[0216] In another embodiment of the present disclosure, wherein R 4 Selected from OH, (CH3)2CH-, -OCH3, -OCH2CH3, optionally with one or more R 4a Substituted groups: R 4a Selected from CN, NH2, OH, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkylene, C 3-6 Cycloalkyl-(CH2) t -, 3-6 membered heterocyclic group-(CH2) t -, deuterated C 1-4 Alkyl; t is selected from 0, 1, 2.

[0217] In another embodiment of the present disclosure, wherein R 4 Selected from (CH3)2CH-, -OCH3, -OCH2CH3, optionally with one or more R 4a Substituted groups: R 4a Selected from CN, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkylene, C 3-6 Cycloalkyl-(CH2) t -, 3-6 membered heterocyclic group-(CH2) t -; t is selected from 0, 1, 2;

[0218] In another embodiment of the present disclosure, R 4aSelected from CN, -CH3, -CH2CH3, -CH2F, -OCH3, -CH2CH2OCH3, NH2, F, OH, -CHF2, -CD3.

[0219] In another embodiment of the present disclosure, wherein R 4a Selected from CN, -CH3, -CH2CH3, -CH2F, -OCH3, -CH2CH2OCH3, NH2, F, OH, -CHF2.

[0220] In another embodiment of the present disclosure, wherein R 4a Selected from CN, -CH3, -CH2CH3, -CH2F, -OCH3, -CH2CH2OCH3,

[0221] In another embodiment of the present disclosure, wherein R 4 Selected from OH, (CH3)2CH-, -OCH3, -OCH2CH3,

[0222] In another embodiment of the present disclosure, wherein R 4 Selected from

[0223] In another embodiment of the present disclosure, wherein R 4 Selected from OH, (CH3)2CH-, -OCH3, -OCH2CH3,

[0224] In another embodiment of the present disclosure, wherein R 4 Selected from

[0225] In another embodiment of the present disclosure, wherein R 4 Selected from

[0226] In another embodiment of the present disclosure, the compound, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate have a structure represented by the following general formula:

[0227]

[0228]

[0229] R 1 、R 4、R 3 , p is as defined in any of the above schemes;

[0230] X 3 Selected from O, S, CH2, N(R 1 );

[0231] Preferably, ma is selected from 0, 1, 2, 3, 4, 5, 6, 7;

[0232] Preferably, ma is selected from 0, 1, 2, 3, 4, 5;

[0233] Preferably, ma is selected from 0, 1, 2, 3, 4;

[0234] Preferably, ma is selected from 0, 1, 2, 3;

[0235] Preferably, ma is selected from 0, 1, and 2.

[0236] In another embodiment of the present disclosure, the compound, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate have a structure represented by the following general formula:

[0237]

[0238] R 1 、R 4 、R 3 , m, p are as defined in any of the above schemes;

[0239] X 3 Selected from O, S, CH2, N(R 1 ).

[0240] In another embodiment of the present disclosure, m is selected from 0, 1, 2, 3, and 4.

[0241] In another embodiment of the present disclosure, the compound, its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, and its hydrate are as follows:

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259] The present disclosure also provides a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I), its pharmaceutically acceptable salts, stereoisomers, isotope-labeled substances, solvates, hydrates thereof, and one or more pharmaceutically acceptable carriers.

[0260] In another embodiment of the present disclosure, the content of the compound, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate in the pharmaceutical composition is 1%-95%.

[0261] In another embodiment of the present disclosure, in the pharmaceutical composition, the pharmaceutically acceptable carrier includes one or more of a filler, a disintegrant, a binder, a glidant, and a lubricant.

[0262] The present disclosure also provides use of the compound of formula (I), its stereoisomers, its isotope-labeled substances, its solvates, its hydrates, or the pharmaceutical compositions thereof in the preparation of drugs for treating GPR6-mediated diseases.

[0263] In another embodiment of the present disclosure, the GPR6-mediated disease includes Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorder, epilepsy, Alzheimer's disease, anxiety disorders, and depression. Preferably, the GPR6-mediated disease is Parkinson's disease.

[0264] The present disclosure also provides a method for treating a GPR6-mediated disease, characterized by providing a subject with a therapeutically effective amount of the compound of formula (I), a pharmaceutically acceptable salt, a stereoisomer, an isotope-labeled substance, a solvate, or a hydrate thereof. Preferably, the GPR6-mediated disease is as described above.

[0265] Description and Definition

[0266] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear in the absence of a specific definition, but should be understood according to its ordinary meaning in the art.

[0267] The term "pharmaceutically acceptable" refers to 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 problems or complications, commensurate with a reasonable benefit / risk ratio.

[0268] The term "pharmaceutically acceptable salt" refers to a derivative of a compound of the present invention prepared with a relatively non-toxic acid or base. These salts can be prepared during compound synthesis, separation, and purification, or by reacting the purified free form of the compound with a suitable acid or base. When the compound contains a relatively acidic functional group (e.g., -COOH, -OH, -SO3H, etc.), it reacts with an appropriate inorganic or organic cation (base) to form a base addition salt, including salts formed with alkali metals or alkaline earth metals, ammonium salts formed with amines or their derivatives, and salts formed with amino acids. When the compound contains a relatively basic functional group (e.g., -NH2, etc.), it reacts with an appropriate inorganic or organic anion (acid) to form an acid addition salt, including salts formed with an inorganic acid or organic acid (e.g., carboxylic acid, etc.).

[0269] The term "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals, particularly mammals, and includes, for example, adjuvants, excipients, or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form. Pharmaceutically acceptable carriers are formulated within the purview of those skilled in the art based on a wide range of factors. These include, but are not limited to, the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the intended therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as a variety of solid and semisolid dosage forms. In addition to the active agent, such carriers include a variety of different ingredients and additives, and the inclusion of such additional ingredients in a formulation for various reasons (e.g., to stabilize the active agent, binders, etc.) is well known to those skilled in the art.

[0270] The term "effective prophylactic or therapeutic amount" refers to a sufficient amount of the compound of the present disclosure, its pharmaceutically acceptable salt, or its isomer to treat the disorder at a reasonable benefit / risk ratio applicable to any medical treatment and / or prevention. However, it should be recognized that the total daily dosage of the compound of Formula I or its pharmaceutically acceptable salt and composition of the present disclosure must be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dosage level must be determined based on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex, and diet; the administration time, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field.

[0271] The “isomers” described in the present disclosure include geometric isomers and stereoisomers, such as atropisomers, cis-trans isomers, enantiomers, diastereomers, tautomers, and racemic mixtures and other mixtures thereof, all of which fall within the scope of the present disclosure. The term “enantiomer” refers to stereoisomers that are mirror images of each other. The term “tautomer” refers to a type of functional group isomer that has different hydrogen attachment points due to one or more double bond displacements, for example, a ketone and its enol form are keto-enol tautomers. The term “diastereomer” refers to a stereoisomer whose molecule has two or more chiral centers and is not a mirror image of the molecule. The term “cis-trans isomer” refers to different spatial configurations in which double bonds or single bonds of ring carbon atoms in a molecule cannot rotate freely. The term "stereoisomer" primarily refers to isomers containing a chiral center, including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof. "Stereoisomers" include, but are not limited to, stereoisomers containing one chiral center in absolute configuration R and absolute configuration S, mixtures of R- and S-isomers containing one chiral center, and diastereomers containing two to four chiral centers. The term "atropisomer" refers to stereoisomers that can be separated due to hindered or very slow rotation about a single bond. Stereoisomers of the disclosed compounds can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. For example, one enantiomer of a compound disclosed herein can be prepared by asymmetric catalysis or chiral auxiliary derivatization. Alternatively, a single stereoisomer can be obtained from a mixture using chiral resolution techniques. Alternatively, the compound can be prepared directly using chiral starting materials. The separation of optically pure compounds disclosed herein is typically accomplished by preparative chromatography, employing chiral columns to separate chiral compounds.

[0272] The absolute stereo configuration of a compound can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction can be used. Alternatively, the absolute configuration of a compound can be confirmed based on the chiral structure of the starting material and the reaction mechanism of asymmetric synthesis. Alternatively, after resolution, the stereo configuration can be determined by comparison with a product with a confirmed absolute configuration. Compounds labeled "absolute configuration unknown / undetermined" herein are typically resolved from racemic compounds into individual isomers by chiral preparative SFC, followed by characterization and testing.

[0273] The present disclosure includes isotopically labeled compounds of all compounds herein. Isotopes are atoms having the same atomic number but a different number of neutrons. As a non-limiting general example, isotopes of hydrogen include protium (H, often represented by H), deuterium ( 2 H, often represented by D) and tritium ( 3 H, often represented by T); carbon isotopes include 11 C. 12C. 13 C and 14 Isotopes of C., such as 35 Cl, 36 Cl, 37 Cl; isotopes of fluorine, such as 18 F; isotopes of iodine, such as 123 I. 125 I. 127 I; isotopes of nitrogen, such as 13 N. 14 N and 15 N; isotopes of oxygen, such as 15 O. 16 O. 17 O and 18 O; isotopes of phosphorus, such as 31 P. 32 P; and sulfur isotopes such as 32 S. 35 S. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein using an appropriate isotopically labeled reagent in place of a non-labeled reagent.

[0274] This disclosure includes solvates and hydrates of all compounds herein. A solvate is a molecular complex formed by the mutual attraction between solvent molecules and compound molecules through intermolecular forces. When the solvent is water, it is generally referred to as a "hydrate." The solvent molecules may be stoichiometric or non-stoichiometric.

[0275] The term "optionally substituted" as used herein refers to two situations in which one or more hydrogen atoms of the substituted group may be "substituted" or "unsubstituted" by one or more substituents.

[0276] When the substituent structure appears A truncated bond indicates that the bond is the connecting bond of a substituent, e.g. Indicates that the pyrimidine ring is connected to a given group or a given structural formula through a C atom. A dash "-" appearing in a substituent structure indicates the point of attachment for the substituent, for example, -SCH3 is connected to a given group or a given structural formula through a sulfur atom.

[0277] and Indicates the absolute configuration of a stereocenter, i.e., R or S configuration. or It represents cis or trans configuration. Double real bonds or double imaginary bonds both represent cis configuration, and one real and one imaginary bond represent trans configuration.

[0278] When a substituent's bond can cross-link to a ring, it means that the substituent can be bonded to any atom on the ring. The substituent R can be substituted at any position on the benzene ring.

[0279] When a substituent is listed without indicating the atom via which the substituent is attached to a given group or a given formula, then the substituent may be attached via any bondable atom thereof.

[0280] When any variable (such as R d ) appears more than once in a compound's composition or structure, its definition is independent in each instance. For example, Indicates that the cyclopentyl group is surrounded by 3 R d is replaced, and each R d There are independent options.

[0281] Indicates that the chemical bond can be a double bond or a single bond.

[0282] Unless otherwise specified, the term "halogen" means a fluorine, chlorine, bromine or iodine atom.

[0283] Unless otherwise specified, the term "alkyl" refers to a group derived from a branched or straight chain saturated aliphatic alkane having the specified number of carbon atoms by removing one hydrogen. For example, "C 1-10 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 Alkyl, "C 1-6 Alkyl", "C 1-4 Alkyl", "C 1-3 "alkyl"; specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, etc.

[0284] Unless otherwise specified, the term "alkylene" refers to a group derived from a branched or straight chain saturated aliphatic alkane by removing two hydrogen atoms, and the removed hydrogen atoms may be derived from the same carbon atom or different carbon atoms; the "alkylene" described in the present disclosure is preferably a "straight chain alkylene"; the "alkylene" includes "C 1-6 Alkylene", "C 1-4 Alkylene", "C 1-2 "Alkylene"; specific examples include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH2)CH2-, -CH2CH2CH2CH2-, -CH(CH2)CH2CH2-, -CH(CH2CH2)CH2-, -C(CH2)(CH2)CH2-, -CH2CH2CH2CH2CH2-, etc.

[0285] Unless otherwise specified, the term "alkenyl" refers to a radical derived from a straight-chain or branched alkene (containing at least one carbon-carbon double bond) by removing a hydrogen atom, including "C 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, etc.

[0286] Unless otherwise specified, the term "alkynyl" refers to a radical derived from a straight-chain or branched alkyne (containing at least one carbon-carbon triple bond) by removing a hydrogen atom, including "C 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≡CC≡C-, etc.

[0287] Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen atom. 1-6 Alkyl, more preferably halogenated C 1-4 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 defined above.

[0288] Unless otherwise specified, the term "hydroxyalkyl" refers to a group derived from an alkyl group in which one or more hydrogen atoms are replaced by a hydroxy group. The "hydroxyalkyl" described in the present disclosure includes "hydroxy C 1-6 Alkyl", "Hydroxy C 1-4 alkyl"; specific examples include but are not limited to -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, wait.

[0289] Unless otherwise specified, the term "alkoxy" refers to an alkyl group as defined herein attached to another group through an oxygen atom, i.e., "alkyl-O-". 1-6 Alkoxy" (structure is C 1-6 Alkyl-O-), "C 1-4"alkoxy", specific examples include but are not limited to methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, etc.; preferably, the "alkoxy" described in the present disclosure is preferably C 1-4 Alkoxy, more preferably C 1-3 Alkoxy.

[0290] Unless otherwise specified, the term "ring" refers to saturated, partially saturated or unsaturated monocycles and polycycles, and "polycycles" include spirocycles, condensed rings or bridged rings. The group derived from the ring by removing hydrogen atoms is called a "cyclic group", which includes a monovalent ring, a divalent ring (commonly referred to as a subring), a trivalent ring, a tetravalent ring, etc., and the specific valence depends on the number of substituents connected to the ring. The description of "cyclic group" in this disclosure no longer specifically distinguishes the valence of the ring. Representative "cyclic groups" include substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. The term "hetero" refers to substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms (also known as heteroatoms). The heteroatoms are generally selected from N, O, S, P, and Se. Oxidized forms generally include NO, SO, S(O)2, and P(O). The nitrogen atom can be substituted, i.e., NR (R is H or other substituents defined herein). The number of atoms in the ring is generally defined as the number of ring members. For example, "3-6 membered heterocycloalkyl" refers to a ring of 3-6 atoms arranged around, each ring optionally containing 1 to 3 heteroatoms and / or heteroatoms, i.e., N, O, S, NO, SO, S(O)2, P(O), or NR, each ring optionally substituted by an R group, where R is a group defined herein.

[0291] Unless otherwise specified, the term "cycloalkyl" refers to a saturated cyclic group derived from a monocyclic cycloalkane by removing a hydrogen atom. The carbon atoms in the cycloalkyl group may be further oxidized to form C(O). The cycloalkyl group includes "C 3-8 Cycloalkyl", "C 3-6 Cycloalkyl", "C 3-5 Cycloalkyl", "C 4-6 Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0292] Unless otherwise specified, "cycloalkenyl" means a cycloalkyl group in which one or more of the ring bonds is a double bond and the cycloalkenyl group is not aromatic. The carbon atoms in the cycloalkenyl group may be further oxidized, i.e., to form C(O). The cycloalkenyl group includes "3-8 membered cycloalkenyl", "3-6 membered cycloalkenyl", "3-5 membered cycloalkenyl", and "5-6 membered cycloalkenyl". Specific examples include, but are not limited to,

[0293] Unless otherwise specified, the term "heterocyclyl" refers to a non-aromatic, saturated or partially saturated monocyclic group in which at least one ring atom is a heteroatom or heteroatom group, including heterocycloalkyl and heterocycloalkenyl groups. Ring carbon atoms in a heterocyclyl group may be optionally oxidized, forming -C(O). Preferably, the heteroatoms are independently selected from 1-3 nitrogen and / or oxygen atoms. Preferably, the heterocyclyl group is a nitrogen-containing heterocyclyl group, meaning that at least one ring atom is nitrogen and optionally contains one or more other heteroatoms; preferably, the nitrogen-containing heterocyclyl group contains 1 nitrogen atom and 0-2 atoms selected from nitrogen and / or oxygen and / or sulfur. Preferably, the nitrogen-containing heterocyclyl group contains 1 nitrogen atom and 0-1 atoms selected from oxygen and / or sulfur. Preferably, the heterocyclyl group is an oxygen-containing heterocyclyl group, meaning that at least one ring atom is oxygen and optionally contains one or more other heteroatoms; preferably, the oxygen-containing heterocyclyl group contains 1 oxygen atom and 0-2 atoms selected from nitrogen and / or oxygen. The heterocyclic groups disclosed herein include "5-10 membered heterocycloalkenyl", "6-10 membered heterocycloalkenyl", "5-6 membered heterocycloalkenyl", "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 the heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl,

[0294] Unless otherwise specified, the term "fused heterocyclic group" refers to a saturated or partially saturated non-aromatic cyclic group formed by two or more cyclic structures sharing two adjacent atoms, containing at least one ring atom as a heteroatom; the ring carbon atoms in the fused heterocyclic ring may be further oxo-substituted to form a C(O)-containing group. The fused heterocyclic group of the present invention includes "6-14 membered fused heterocyclic group", "6-10 membered fused heterocyclic group", "6-8 membered fused heterocyclic group", "8-9 membered fused heterocyclic group" and the fusion mode can be 5-6 membered heterocyclic group and 5-6 membered heterocyclic group, 5-6 membered heterocyclic group and 5-6 membered cycloalkyl group, benzo 5-6 membered heterocyclic group, benzo 5-6 membered saturated heterocyclic group, 5-6 membered heteroaryl and 5-6 membered heterocyclic group, 5-6 membered heteroaryl and 5-6 membered saturated heterocyclic group, benzo 5-6 membered heterocyclic group and 5-6 membered heterocyclic group, 5-6 membered heteroaryl and 5-6 membered heterocyclic group and 5-6 membered heterocyclic group, benzo 5-6 membered cycloalkyl and 5-6 membered heterocyclic group, 5-6 membered heteroaryl and 5-6 membered cycloalkyl and 5-6 membered heterocyclic group; specific examples of the fused heterocyclic group include but are not limited to:

[0295] wait.

[0296] Unless otherwise specified, the term "bridged heterocyclic group" refers to a saturated or partially saturated (i.e., bridged heterocyclic alkenyl) cyclic structure formed by two or more cyclic structures sharing two non-adjacent ring atoms, wherein at least one ring is a heterocycle. The ring carbon atoms in the bridged heterocyclic group are optionally oxoed, i.e., forming -C(O). "Bridged heterocyclic group" includes, for example, "5-11 membered bridged heterocyclic group," "6-11 membered bridged heterocyclic group," "5-10 membered bridged heterocyclic group," "7-10 membered bridged heterocyclic group," "6-9 membered bridged heterocyclic group," "7-8 membered bridged heterocyclic group," "9-10 membered heterobridged cyclic group," "6-10 membered bridged heterocyclic alkenyl," "6-8 membered bridged heterocyclic alkenyl," "7-8 membered nitrogen-containing bridged heterocyclic alkenyl," etc. Preferably, the heteroatoms are independently selected from 1-3 N and / or O. Preferably, the bridged heterocyclic group is a "nitrogen-containing bridged heterocyclic group", which means that at least one ring atom is N, and optionally contains one or more other heteroatoms; preferably, the "nitrogen-containing bridged heterocyclic group" contains 1 N atom and 0-2 atoms selected from N and / or O and / or S. Preferably, the "nitrogen-containing bridged heterocyclic group" contains 1 N atom and 0-1 atoms selected from O and / or S. Preferably, the bridged heterocyclic group is an "oxygen-containing bridged heterocyclic group", which means that at least one ring atom is O, and optionally contains one or more other heteroatoms; preferably, the "oxygen-containing heterocyclic group" contains 1 O atom and 0-2 atoms selected from N and / or O. Specific examples of the bridged heterocyclic group include, but are not limited to:

[0297] wait.

[0298] Unless otherwise specified, the term "spiroheterocyclyl" refers to a saturated or partially saturated cyclic structure formed by two or more cyclic structures sharing a carbon atom, and at least one of the rings is a heterocycle. The ring carbon atoms in the spiroheterocyclyl are optionally oxoed, i.e., forming -C(O). It includes, but is not limited to, the cyclic structure formed by heterocyclylspiroheterocyclyl and heterocyclylspiroheteroalkyl. 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 in which at least one ring atom 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: wait.

[0299] Unless otherwise specified, the term "heteroaryl" refers to a monocyclic group with aromatic properties in which at least one ring atom is a heteroatom and / or a heteroatom group, preferably, the heteroatoms are independently selected from 1-3 N and / or O. The heteroaryl group includes "5-6 membered heteroaryl"; specific examples include but are not limited to pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, and pyrimidinyl.

[0300] Combinations of substituents and / or variables described herein are permitted only if they result in stable compounds or useful synthetic intermediates. Persons skilled in the art will be able to exclude from this disclosure situations that are clearly beyond the ordinary knowledge of the art or unreasonable situations. A stable compound or stable structure is one that is sufficiently stable to withstand chemical reactions, be isolated to a useful degree of purity, and be formulated into an effective therapeutic agent. DETAILED DESCRIPTION

[0301] The compounds disclosed herein 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 combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples disclosed herein.

[0302] 1. Description of instruments, equipment and raw materials used

[0303] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS), or ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements are performed using a Bruker Neo 400M or Bruker Ascend 400 NMR instrument, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated chloroform (CDCl3), and heavy water (D2O) as the internal standard, with tetramethylsilane (TMS) as the internal standard.

[0304] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260-6125B single quadrupole massspectrometer (electrospray ionization as the ion source).

[0305] Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was performed using a Waters UPLC H-class SQD mass spectrometer (electrospray ionization as the ion source).

[0306] HPLC determination was performed using Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.

[0307] Waters 2555-2489 (10 μm, ODS 250 cm×5 cm) or GILSON C 281 was used for preparative HPLC.

[0308] Chiral HPLC was performed using Waters Acquity UPC2; the columns were Daicel Chiralpak AD-H (5 μm, 4.6*250 mm) and (3 μm, 4.6*100 mm).

[0309] Supercritical fluid chromatography (SFC) was performed using a Waters SFC 150MGM.

[0310] The starting materials and intermediates used in the present invention can be synthesized according to methods known in the art or purchased commercially. Experimental procedures in the examples where specific conditions are not specified were generally performed under conventional conditions or as recommended by the raw material or commercial manufacturer. Reagents where the specific sources are not specified were commercially available.

[0311] The reaction progress in the examples can be monitored by conventional methods such as thin layer chromatography (TLC) and LC-MS. The eluent system for column chromatography and the developing solvent system for thin layer chromatography used for purification can be composed of one or more of the following solvents: dichloromethane, methanol, n-hexane, ethyl acetate, petroleum ether, ethyl acetate, acetone, dichloromethane, etc. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine, acetic acid, trifluoroformic acid, etc. can also be added for adjustment.

[0312] In the examples of the present invention, when "M" appears, it means "mol / L", which is the concentration of the reagent.

[0313] The abbreviations used in the examples of the present invention and their corresponding chemical names are as follows:

[0314] abbreviation describe HCl Hydrogen chloride DIPEA / DIEA N,N-Diisopropylethylamine DCM dichloromethane DMF N,N-Dimethylformamide THF Tetrahydrofuran DEAD Diethyl azodicarboxylate HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate <![CDATA[POCl3]]> Phosphorus oxychloride NaOH Sodium hydroxide NCS N-chlorosuccinimide BINAP 1,1'-Binaphthyl-2,2'-diphenylphosphine Xphos 2-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl <![CDATA[Pd(OH)2 / C]]> Palladium hydroxide / carbon Pd / C Palladium on carbon <![CDATA[Pd(PPh3)4]]> Tetrakistriphenylphosphine palladium <![CDATA[Pd2(dba)3]]> Tris(dibenzylideneacetone)dipalladium

[0315] 2. Examples

[0316] Intermediate INT-1: 4-(2,4-difluorophenoxy)piperidine hydrochloride

[0317]

[0318] Steps:

[0319] Step A: Dissolve 2,4-difluorophenol (1.0 g, 7.69 mmol) in THF (20 mL) at room temperature, add tert-butyl 4-hydroxypiperidine-1-carboxylate (3.09 g, 15.37 mmol) and triphenylphosphine (3.0 g, 11.45 mmol), and cool to 0°C under nitrogen. Add DEAD (2.32 g, 13.32 mmol) dropwise. Heat the reaction mixture to 60°C and stir for 16 hours. Cool to room temperature, quench with water, and extract with ethyl acetate (10 mL x 3). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to yield 1.3 g of tert-butyl 4-(2,4-difluorophenoxy)piperidine-1-carboxylate.

[0320] MS (ESI) M / Z: 258.0 [M+H-56] + .

[0321] 1 H NMR(400MHz, CDCl3)δ6.92-6.86(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).

[0322] Step B: Dissolve tert-butyl 4-(2,4-difluorophenoxy)piperidine-1-carboxylate (2.06 g, 6.57 mmol) in ethyl acetate (40 mL) at room temperature. Add hydrochloric acid / dioxane (10 mL, 4 mol / L). Stir the mixture at 25°C for 4 hours. The reaction mixture is concentrated and filtered to yield 2.09 g of 4-(2,4-difluorophenoxy)piperidine hydrochloride.

[0323] MS (ESI) M / Z: 214.0 [M+H] + .

[0324] 1 H NMR(400MHz,DMSO-d6)δ9.03-8.93(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).

[0325] Intermediate INT-2: 1-(3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

[0326]

[0327]

[0328] Steps:

[0329] Step A: Dissolve pyridine-3,4-diamine (10.00 g, 91.70 mmol) in diethyl oxalate (50 mL) at room temperature, heat to 120°C, and stir for 16 hours. Cool to room temperature, filter, and wash the filter cake with methanol to obtain 14.9 g of pyrido[3,4-b]pyrazine-2,3-diol.

[0330] MS (ESI) M / Z: 164.0 [M+H] + .

[0331] 1 H NMR (400MHz, DMSO-d6) δ12.12(s,1H),12.03(s,1H),8.31(s,1H),8.17(d,J=5.3Hz,1H),7.06(d,J=5.3Hz,1H).

[0332] Step B: Pyrido[3,4-b]pyrazine-2,3-diol (14.9 g, 91.33 mmol) was dissolved in POCl3 (75 mL) at room temperature. The mixture was heated to 70°C and DMF (45 mL) was added dropwise. The reaction mixture was stirred at 70°C for 2 hours. After cooling to room temperature, the mixture was quenched with ice water and the pH was adjusted to 7-8 with 30% NaOH solution. The reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 4.5 g of 2,3-dichloropyrido[3,4-b]pyrazine.

[0333] MS (ESI) M / Z: 200.2 [M+H] + .

[0334] 1 H NMR (400MHz, DMSO-d6) δ9.50 (s, 1H), 8.93 (d, J = 5.7Hz, 1H), 8.05 (dd, J = 5.7, 0.8Hz, 1H).

[0335] Step C: Dissolve 2,3-dichloropyrido[3,4-b]pyrazine (300 mg, 1.50 mmol) in DMF (6 mL) at room temperature. Cool to 0°C, add INT-1 (355.76 mg, 1.42 mmol) and DIPEA (0.653 mL, 3.75 mmol), and stir at 0°C under nitrogen for 2 hours. The reaction mixture is quenched with ice-cold water and extracted with ethyl acetate (5 mL x 3). The combined organic phases are washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and filtered. The resulting residue is purified by silica gel column chromatography to yield 565 mg of 3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine.

[0336] MS (ESI) M / Z: 377.0 [M+H] + .

[0337] 1 H NMR (400MHz, DMSO-d6) δ9.14(d,J=0.8Hz,1H),8.65(d,J=5.8Hz,1H),7.68(dd,J=5.8,0.8Hz,1H),7.42-7.24(m,2H) ,7.08-6.99(m,1H),4.75-4.60(m,1H),4.00-3.89(m,2H),3.62-3.48(m,2H),2.18-2.08(m,2H),1.91-1.78(m,2H).

[0338] Step D: 3-Chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine (100 mg, 0.27 mmol) and benzyl bromide (47.9 mg, 0.28 mmol) were dissolved in acetonitrile (2 mL) at room temperature. The reaction mixture was heated to 70°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to yield 100 mg of 6-benzyl-3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-6-ium.

[0339] MS (ESI) M / Z: 467.2 [M+H] + .

[0340] Step E: Dissolve 6-benzyl-3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-6-ium (730 mg, 1.56 mmol) in acetonitrile (12 mL) at room temperature. Add sodium acetate borohydride (1.39 g, 6.55 mmol) to the solution under ice-cooling and allow to react at room temperature for 16 hours. The reaction mixture is quenched with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to afford 320 mg of 6-benzyl-3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine.

[0341] MS (ESI) M / Z: 471.3 [M+H] + .

[0342] 1 H NMR(400MHz,DMSO-d6)δ7.42-7.34(m,4H),7.34-7.25(m,3H),7.09-6.90(m,1H),4.63-4.47(m,1H),3.71(s,2H ),3.64-3.55(m,2H),3.52(s,2H),3.21-3.12(m,2H),2.88-2.73(m,4H),2.11-2.01(m,2H),1.83-1.68(m,2H).

[0343] Step F: 6-Benzyl-3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine (1 g, 2.12 mmol) was dissolved in DCM (20 mL) at room temperature, and 1-chloroethyl chloroformate (1.52 g, 10.6 mmol) was added. The mixture was heated to 80°C and reacted overnight. The reaction solution was cooled to room temperature, concentrated, and dissolved in methanol (20 mL). The reaction was then continued at 80°C for 0.5 hour, cooled to room temperature, and concentrated to afford 806.8 mg of the crude product 3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine.

[0344] MS (ESI) M / Z: 381.1 [M+H] + .

[0345] Step G: 3-Chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine (806.8 mg, 2.12 mmol) was dissolved in DCM (10 mL) on ice. TEA (256.9 mg, 2.544 mmol) and acetic anhydride (259.5 mg, 2.544 mmol) were then slowly added to the mixture. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to afford 900 mg of 1-(3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one.

[0346] MS (ESI) M / Z: 423.1 [M+H] + .

[0347] 1 H NMR (400 MHz, DMSO-d6) δ 7.35-7.22 (m, 2H), 7.04-6.96 (m, 1H), 4.60 (s, 1H), 4.58-4.49 (m, 2H), 3.76-3.73 (m, 2H), 3.61-3.58 (m, 2H), 3.19 (t, J = 10.3 Hz, 2H), 2.88 (t, J = 5.8 Hz, 1H), 2.75 (t, J = 5.8 Hz, 1H), 2.09 (d, J = 11.1 Hz, 3H), 2.06-1.99 (m, 2H), 1.81-1.68 (m, 2H). Intermediate INT-3: 3,5-dichloropyrazine-2-carboxaldehyde

[0348]

[0349] Steps:

[0350] Step A: Dissolve methyl 3,5-dichloropyrazine-2-carboxylate (1.0 g, 4.83 mmol) in anhydrous THF (48.6 mL) and methanol (5.5 mL) at room temperature, cool to 0°C in an ice-water bath, stir for 10 minutes, then add lithium borohydride THF solution (2.66 mL, 2 mol / L), continue stirring at 0°C for 10-15 minutes, add methanol (24 mL), return to room temperature and stir for 15 minutes. Slowly pour the reactant into 1M hydrochloric acid solution (20 mL) and ethyl acetate (40 mL) to quench, extract with ethyl acetate (20 mL × 3 times), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 670 mg of compound (3,5-dichloropyrazin-2-yl)methanol.

[0351] MS (ESI) M / Z: 179.0 [M+H] + .

[0352] 1 H NMR (400MHz, CDCl3) δ8.52 (s, 1H), 4.85 (s, 2H).

[0353] Step B: Dissolve (3,5-dichloropyrazin-2-yl)methanol (670 mg, 3.74 mmol) in DCM (20 mL) at room temperature. Add a solution of manganese dioxide (3.27 g, 37.6 mmol) in DCM (20 mL) and heat to 30°C with stirring for 16 hours. Cool to room temperature, filter through celite, and wash the filter cake with DCM. The organic phase is concentrated under reduced pressure to yield 540 mg of 3,5-dichloropyrazine-2-carbaldehyde.

[0354] MS (ESI) M / Z: 177.1 [M+H] + .

[0355] 1 H NMR (400MHz, CDCl3) δ10.29(s,1H),8.71(s,1H).

[0356] Intermediate INT-4: 2-methoxynicotinamide

[0357]

[0358] Steps:

[0359] Step A: Dissolve 2-methoxynicotinic acid (500 mg, 0.315 mmol), ammonium chloride (874.56 mg, 16.35 mmol), HATU (1.864 g, 4.9 mmol), and DIPEA (1.265 g, 9.81 mmol) in DMF (8 mL) at room temperature. After complete addition, the mixture was reacted at room temperature for 3 hours. The mixture was quenched with water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 268 mg of 2-methoxynicotinamide, which was purified by silica gel column chromatography.

[0360] MS (ESI) M / Z: 153.1 [M+H] + .

[0361] 1 H NMR (400MHz, DMSO-d6) δ8.30(dd,J=4.9,2.0Hz,1H),8.17(dd,J=7.5,2.0Hz,1H),7.69(s,2H),7.12(dd,J=7.5,4.9Hz,1H),3.97(s,3H).

[0362] Intermediate INT-5: 2-(tert-Butoxycarbonyl)-amino-6-tri-n-butyltin-pyridine

[0363]

[0364] Step A: 6-bromopyridin-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) at room temperature and heated to 50°C with stirring for 16 hours. The reaction solution was cooled to room temperature and diluted with DCM (100 mL) and water (100 mL). The mixture was extracted with DCM (100 mL x 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 3.01 g of N,N-bis-tert-butoxycarbonyl-6-bromopyridin-2-amine.

[0365] 1 H NMR (400MHz, CDCl3) δ7.58(t,J=7.8Hz,1H),7.38(d,J=7.8Hz,1H),7.26(d,J=7.8Hz,1H),1.46(s,18H).

[0366] Step B: Dissolve N,N-bis-tert-butoxycarbonyl-6-bromopyridin-2-amine (500 mg, 1.34 mmol), hexa-n-butylditin (777 mg, 1.34 mmol), and Pd(PPh3)4 (77 mg, 0.07 mmol) in 1,2-dichloroethane (5 mL) at room temperature. Heat the reaction mixture to 80°C and stir for 20 hours. Cool the reaction mixture to room temperature, dilute it with water (50 mL), and extract it with ethyl acetate (50 mL x 3). The organic phase is washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to afford 330 mg of 2-(tert-butoxycarbonyl)-amino-6-tri-n-butyltin-pyridine.

[0367] MS (ESI) M / Z: 585 [M+H] + .

[0368] Intermediate INT-6: 6-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrazino[2,3-c]azepine

[0369]

[0370]

[0371] Steps:

[0372] Step A: Methyl 3,5-dichloropyrazine-2-carboxylate (2.07 g, 10 mmol) and INT-1 (2.75 mg, 11 mmol) were dissolved in DMF (10 mL) at room temperature. DIPEA (5 mL, 30 mmol) was added under ice-cooling and the mixture was warmed to room temperature for 2 hours. The mixture was quenched with water and extracted with ethyl acetate (50 mL × 3 times). The organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2.9 g of methyl 3-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazine-2-carboxylate.

[0373] MS (ESI) M / Z: 384.1 [M+H] + .

[0374] Step B: 3-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazine-2-carboxylic acid methyl ester (2.7 g, 7.04 mmol), potassium ethylene trifluoroborate (1.1 g, 8.45 mmol), Pd(PPh3)4 (0.81 g, 0.7 mmol), and potassium carbonate (1.95 g, 14.08 mmol) were added to 1,4-dioxane / water (50 mL / 10 mL) at room temperature and reacted at 100°C under nitrogen for 2 hours. After cooling to room temperature, the mixture was quenched with water and extracted with ethyl acetate (100 mL × 3 times). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2.5 g of compound 5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-vinylpyrazine-2-carboxylic acid methyl ester.

[0375] MS (ESI) M / Z: 376.2 [M+H] + .

[0376] Step C: At room temperature, 5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-vinylpyrazine-2-carboxylic acid methyl ester (1.2 g, 3.2 mmol) was added, cooled to -78°C, and a THF solution of diisobutylaluminum hydride (6.4 mL, 1 mol / L) was added. The reaction was maintained at -78°C for 30 minutes. After returning to room temperature, the mixture was quenched with water and extracted with ethyl acetate (50 mL × 3 times). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 350 mg of compound 5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-vinylpyrazine-2-carboxaldehyde.

[0377] MS (ESI) M / Z: 346.2 [M+H]+ .

[0378] 1 H NMR (400MHz, DMSO-d6) δ9.89 (s, 1H), 8.48 (s, 1H), 7.74 (dd, J = 17.0, 10.5Hz, 1H), 7.41-7.27 (m,2H),7.09-7.00(m,1H),6.54(dd,J=17.1,2.4Hz,1H),5.71(dd,J=10.6,2.4Hz,1H),4.72

[0379] -4.60(m,1H),4.25-4.12(m,2H),3.79-3.64(m,2H),2.12-2.01(m,2H),1.81-1.67(m,2H).

[0380] Step D: 5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-vinylpyrazine-2-carbaldehyde (315 mg, 0.91 mmol) and benzyl(prop-2-en-1-yl)amine (201 mg, 1.36 mmol) were dissolved in THF (3 mL) at room temperature. Acetic acid (273 mL, 4.55 mmol) was then added. The mixture was stirred at room temperature for 30 minutes, followed by the addition of sodium triacetoxyborohydride (578.6 mg, 2.73 mmol). Stirring was continued at room temperature for 3 hours. The mixture was quenched with water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 380 mg of benzyl[(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-vinylpyrazin-2-yl)methyl](prop-2-en-1-yl)amine.

[0381] MS (ESI) M / Z: 477.3 [M+H] + .

[0382] Step E: Benzyl[(5-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-vinylpyrazin-2-yl)methyl](prop-2-en-1-yl)amine (360 mg, 0.76 mg) and Hoveyda-Grubbs second-generation catalyst (47.6 mg, 0.076 mmol) were added at room temperature, followed by the addition of DCM (3 mL). The mixture was refluxed at 60°C for 4 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 170 mg of the target molecule 6-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrazino[2,3-c]azepine.

[0383] MS (ESI) M / Z: 449.2 [M+H] + .

[0384] 1 H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.37-7.27(m,4H),7.27-7.22(m,3H), 7.04(tt,J=8.6,2.3Hz,1H),6.38(dt,J=12.7,2.2Hz,1H),6.10(dt,J=12.8, 3.7Hz,1H),4.65-4.54(m,1H),4.02-3.94(m,2H),3.89(s,2H),3.65(s,2H), 3.62-3.58(m,2H),3.42-3.34(m,2H),2.06-1.97(m,4H),1.75-1.61(m,2H).

[0385] Example 1: 1-(3-((2-oxabicyclo[2.1.1]hexan-4-yl)amino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyridin[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

[0386] Reaction route:

[0387]

[0388] Steps:

[0389] Step A: Dissolve 2,3-dichloropyrido[3,4-b]pyrazine (300 mg, 1.50 mmol) in DMF (6 mL) at room temperature. Cool to 0°C, add INT-1 (355.76 mg, 1.42 mmol) and DIPEA (0.653 mL, 3.75 mmol), and stir at 0°C under nitrogen for 2 hours. The reaction mixture is quenched with ice-cold water and extracted with ethyl acetate (5 mL x 3). The combined organic phases are washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and filtered. The resulting residue is purified by silica gel column chromatography to yield 565 mg of 3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine.

[0390] MS (ESI) M / Z: 377.0 [M+H] + .

[0391] 1H NMR (400MHz, DMSO-d6) δ9.14(d,J=0.8Hz,1H),8.65(d,J=5.8Hz,1H),7.68(dd,J=5.8,0.8Hz,1H),7.42-7.24(m,2H) ,7.08-6.99(m,1H),4.75-4.60(m,1H),4.00-3.89(m,2H),3.62-3.48(m,2H),2.18-2.08(m,2H),1.91-1.78(m,2H).

[0392] Step B: Dissolve 3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine (100 mg, 0.27 mmol) and benzyl bromide (47.9 mg, 0.28 mmol) in acetonitrile (2 mL) at room temperature. Heat the reaction mixture to 70°C for 16 hours. Cool the reaction mixture to room temperature and concentrate under reduced pressure to yield 100 mg of 6-benzyl-3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-6-ium.

[0393] MS (ESI) M / Z: 467.2 [M+H] + .

[0394] Step C: Dissolve 6-benzyl-3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazin-6-ium (730 mg, 1.56 mmol) in acetonitrile (12 mL) at room temperature. Add sodium acetate borohydride (1.39 g, 6.55 mmol) to the solution under ice-cooling and allow to react at room temperature for 16 hours. The reaction mixture is quenched with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to afford 320 mg of 6-benzyl-3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine.

[0395] MS (ESI) M / Z: 471.3 [M+H] + .

[0396] 1H NMR(400MHz,DMSO-d6)δ7.42-7.34(m,4H),7.34-7.25(m,3H),7.09-6.90(m,1H),4.63-4.47(m,1H),3.71(s,2H ),3.64-3.55(m,2H),3.52(s,2H),3.21-3.12(m,2H),2.88-2.73(m,4H),2.11-2.01(m,2H),1.83-1.68(m,2H).

[0397] Step D: 6-benzyl-3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine (115.5 mg, 0.25 mmol), 2-oxabicyclo[2.1.1]hexane-4-amine hydrochloride (50 mg, 0.37 mmol), Pd2dba3 (33.76 mg, 0.037 mmol), BINAP (22.96 mg, 0.037 mmol) and sodium tert-butoxide (70.86 mg, 0.74 mmol) were dissolved in anhydrous toluene (2 mL) at room temperature, sealed with a tube and heated to 90°C under nitrogen protection for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 50 mg of the compound 6-benzyl-N-(2-oxabicyclo[2.1.1]hexan-4-yl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyridin[3,4-b]pyrazin-3-amine.

[0398] MS (ESI) M / Z: 534.1 [M+H] + .

[0399] 1 H NMR (400MHz, DMSO-d6) δ7.35-7.31(m,4H),7.30-7.26(m,3H),7.04-6.97(m,1H),6.47(s,1H),4.45-4.55(m,1H),4.39(s,1H),3.67-3.66( m,4H),3.39(s,2H),2.87(t,J=9.5Hz,2H),2.72-2.63(m,4H),2.52-2.51(m,2H),2.05-2.04(m,4H),1.89-1.86(m,2H),1.81-1.82(m,2H).

[0400] Step E: 6-Benzyl-N-(2-oxabicyclo[2.1.1]hexan-4-yl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (50 mg, 0.09 mmol) was dissolved in methanol (6 mL) at room temperature. Palladium hydroxide (50 mg, 20% palladium hydroxide, 50% aqueous), Pd / C (50 mg, 10% Pd / C, 50% aqueous), and acetic acid (0.5 mL) were added. The reaction mixture was stirred at 30°C under hydrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, filtered through celite, and washed with methanol (5 mL x 3). The filtrate was concentrated under reduced pressure to obtain 39.5 mg of the compound N-(2-oxabicyclo[2.1.1]hexan-4-yl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyridin[3,4-b]pyrazin-3-amine.

[0401] MS (ESI) M / Z: 444.2 [M+H] + .

[0402] Step F: Dissolve N-(2-oxabicyclo[2.1.1]hexan-4-yl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (39.5 mg, 0.09 mmol) in DCM (3 mL) at room temperature. Slowly add triethylamine (45.4 mg, 0.45 mmol) and acetic anhydride (13.77 mg, 0.14 mmol) under ice-cooling. The reaction mixture is stirred at room temperature for 30 minutes. The mixture is quenched by adding water (20 mL). The mixed solution was extracted with DCM (10 mL × 3 times), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give 8.29 mg of compound 1-(3-((2-oxabicyclo[2.1.1]hexan-4-yl)amino)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one.

[0403] MS (ESI) M / Z: 486.1 [M+H] + .

[0404] 1H NMR (400MHz, DMSO-d6) δ7.35-7.24(m,2H),7.04-6.98(m,1H),6.62(d,J=10.5Hz,1H),4.57-4.47(m,1H),4.45(s,1H),4.42-4.41(m,2H),3.7 4-3.68(m,4H),3.28-3.29(m,2H),2.89(t,J=9.7Hz,2H),2.72(t,J=5.6Hz,1H),2.60(t,J=5.5Hz,1H),2.09-2.04(m,7H),1.93-1.82(m,4H).

[0405] Example 2: 1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(1-ethyl-1H-pyrazol-4-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

[0406]

[0407] Steps:

[0408] Step A: At room temperature, 3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine (150 mg, 0.4 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (133.2 mg, 0.6 mmol), Pd(dppf)Cl2 (29.2 mg, 0.04 mmol) and potassium carbonate (110.4 mg, 0.8 mmol) were dissolved in 1,4-dioxane / water (3.0 mL / 0.3 mL) and heated in a microwave oven under nitrogen protection at 100 ° C for 2 hours. The reaction solution was returned to room temperature and quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3 times), and the organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 140 mg of compound 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(1-ethyl-1H-pyrazol-4-yl)pyrido[3,4-b]pyrazine.

[0409] MS (ESI) M / Z: 437.2 [M+H] + .

[0410] 1H NMR(400MHz, DMSO-d6)δ9.12(s,1H),8.59-8.52(m,2H),8.17(s,1H),7.63(d,J=5.7Hz,1H),7.36-7.24(m,2H),7.07-6.97(m,1H),4.63-4 .53(m,1H),4.27(q,J=7.2Hz,2H),3.70-3.62(m,2H),3.30-3.22(m,2H),2.09(d,J=9.5Hz,2H),1.90-1.77(m,2H),1.44(t,J=7.3Hz,3H).

[0411] Step B: (2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(1-ethyl-1H-pyrazol-4-yl)pyrido[3,4-b]pyrazine (74 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2.5 mL) and acetic acid (2.5 mL) at room temperature, and palladium on carbon (50 mg, 10% The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere using a mixture of acetic anhydride (0.25 ml) and Pd / C (50% aqueous solution). The reaction mixture was filtered through celite and washed with tetrahydrofuran (5 mL x 3). The resulting residue was purified by silica gel column chromatography to yield 6.6 mg of the compound 1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(1-ethyl-1H-pyrazol-4-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one.

[0412] MS (ESI) M / Z: 483.3 [M+H] + .

[0413] 1 H NMR(400MHz,MeOD)δ8.31(d,J=1.9Hz,1H),8.15(d,J=2.1Hz,1H),7.19-7.13(m,1 H),7.01-6.92(m,1H),6.90-6.81(m,1H),4.71(s,2H),4.51-4.40(m,1H),4.30-4. 20(m,2H),3.95–3.84(m,2H),3.48-3.40(m,2H),3.10-2.94(m,3H),2.88(t,J=6.1 Hz,1H),2.21(d,J=8.2Hz,3H),2.13-2.06(m,2H),1.95-1.85(m,2H),1.49(t,3H).

[0414] Example 3: N-(6-acetyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)-2-methoxynicotinamide

[0415]

[0416] Steps:

[0417] 2,3-Dichloropyrido[3,4-b]pyrazine and 2-methoxynicotinic acid were used as raw materials. The preparation method was based on INT-4 and Example 1.

[0418] MS (ESI) M / Z: 539.1 [M+H] +

[0419] 1 HNMR(400MHz,DMSO-d6)δ10.31(s,1H),8.42-8.33(m,1H),8.21-8.18(m,1H),7.34-7.23( m,2H),7.23-7.15(m,1H),7.05-6.95(m,1H),4.57(s,1H),4.55-4.49(m,2H),4.02(d,J=5 .7Hz,3H),3.79(q,J=6.1Hz,2H),3.67-3.54(m,2H),3.17-3.09(m,2H),2.90(t,J=5.7Hz, 1H),2.77(t,J=5.6Hz,1H),2.11(d,J=10.2Hz,3H),2.02-1.99(m,2H),1.80-1.65(m,2H).

[0420] Example 4: 1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(1-methoxy-1H-pyrazol-4-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

[0421]

[0422] Steps:

[0423] With reference to the preparation process of other embodiments of the present invention, 11.8 mg of the target product 1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(1-methoxy-1H-pyrazol-4-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one was obtained.

[0424] MS (ESI) M / Z: 485.2 [M+H] + .

[0425] 1 H NMR (400 MHz, DMSO-d 6， mixture of rotamers)δ8.40(s,1H),7.90(d,J=3.9Hz,1H),7.33-7.26(m,2H),7.04-6.97(m,1H),4.63(d,J=15.7Hz,2H),4.58-4.47(m,1H),4.12(s,3H ),3.84-3.75(m,2H),3.30-3.26(m,2H),3.00-2.90(m,3H),2.79-2.76(m,1H),2.12(d,J=5.4Hz,3H),2.10-2.02(m,2H),1.88-1.77(m,2H).

[0426] Example 5: (R)-1-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-((tetrahydrofuran-3-yl)amino)-6,7-dihydropyrazino[2,3-f][1,4]oxazepin-8(9H)-yl)ethan-1-one

[0427]

[0428] Steps:

[0429] Step A: Dissolve INT-3 (540 mg, 3.05 mmol), 2-(benzylamino)ethan-1-ol (696 mg, 4.61 mmol), and acetic acid (1.08 mL) in THF (30 mL) at room temperature and stir overnight. Cool to 0°C, add sodium borohydride (466 mg, 12.31 mmol), and continue stirring at room temperature overnight. Quench with water and extract with ethyl acetate (20 mL x 3). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to yield 790 mg of 2-(benzyl((3,5-dichloropyrazin-2-yl)methyl)amino)ethan-1-ol as a yellow oil.

[0430] MS (ESI) M / Z: 312.3 [M+H] + .

[0431] Step B: Dissolve 2-(Benzyl((3,5-dichloropyrazin-2-yl)methyl)amino)ethan-1-ol (370 mg, 1.19 mmol) and potassium tert-butoxide (160 mg, 1.43 mmol) in THF (12 mL) at 0°C and continue stirring for 30 minutes. The mixture was quenched with water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 220 mg of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine.

[0432] MS (ESI) M / Z: 276.2 [M+H] + .

[0433] 1 H NMR (400MHz, CDCl3) δ8.24(s,1H),7.39-7.28(br,5H),4.31(s,2H),4.03(s,2H),3.77(s,2H),3.10(s,2H).

[0434] Step C: 8-Benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (220 mg, 0.80 mmol), 4-(2,4-difluorophenoxy)piperidine (204 mg, 0.96 mmol), Pd2dba3 (37 mg, 0.040 mmol), Xphos (38 mg, 0.080 mmol), and sodium tert-butoxide (230 mg, 2.40 mmol) were dissolved in anhydrous toluene (4 mL) at room temperature. The mixture was sealed and heated to 100°C under nitrogen for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 200 mg of the compound 8-benzyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine.

[0435] MS (ESI) M / Z: 453.4 [M+H] + .

[0436] 1H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.36-7.23(m,7H),7.06-6.99(m,1H),4.62-4.50(m,1H),4.18-4.11(m,2H),3.9 4-3.86(m,2H),3.74(s,2H),3.65(s,2H),3.31-3.29(m,2H),2.98-2.93(m,2H),1.99-1.94(m,2H),1.69-1.58(m,2H).

[0437] Step D: 8-Benzyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (50 mg, 0.11 mmol) was dissolved in methanol (5 mL) and acetic acid (0.5 mL) at room temperature. Pd(OH)2 (5 mg, 20% Pd(OH)2, 50% aqueous) and Pd / C (5 mg, 10% palladium on carbon, 50% aqueous) were added. The reaction mixture was stirred at 30°C under hydrogen atmosphere for 3 hours. The reaction solution was cooled to room temperature and filtered through celite, washed with methanol (5 mL × 3 times), and the filtrate was concentrated under reduced pressure to give 40 mg of the crude compound 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine, which was used directly in the next reaction.

[0438] MS (ESI) M / Z: 363.1 [M+H] + .

[0439] Step E: Dissolve 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (40 mg, 0.11 mmol) in DCM (3 mL) at room temperature. Slowly add triethylamine (13 mg, 0.13 mmol) and acetic anhydride (13 mg, 0.13 mmol) under ice-water bath. Stir at room temperature for 2 hours. Quench with water (20 mL) and extract with DCM (10 mL x 3). Combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 40 mg of the compound 1-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6,7-dihydropyrazino[2,3-f][1,4]oxazepin-8(9H)-yl)ethan-1-one.

[0440] MS (ESI) M / Z: 405.1 [M+H] + .

[0441] 1H NMR (400MHz, DMSO-d6) δ7.91(d,J=8.4Hz,1H),7.37-7.23(m,2H),7.02(t,J=8.4Hz,1H),4.71(s,1H),4.65(s,1H),4.60-4.50(m,1H ),4.45-4.37(m,1H),4.35-4.28(m,1H),3.94-3.86(m,2H),3.86-3.75(m,2H),3.40-3.33(m,2H),2.05-1.90(m,5H),1.61(br,2H).

[0442] Step F: 1-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6,7-dihydropyrazino[2,3-f][1,4]oxazepin-8(9H)-yl)ethan-1-one (40 mg, 0.099 mmol) and NCS (17 mg, 0.13 mmol) were dissolved in DMF (0.5 mL) and acetic acid (0.5 mL) at room temperature, heated to 40°C and stirred overnight. The mixture was cooled to room temperature, quenched with water, filtered, and the filter cake was dried to give 17 mg of 1-(2-chloro-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6,7-dihydropyrazino[2,3-f][1,4]oxazepin-8(9H)-yl)ethan-1-one.

[0443] MS (ESI) M / Z: 439.2 [M+H] + .

[0444] Step G: Dissolve 1-(2-chloro-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6,7-dihydropyrazino[2,3-f][1,4]oxazepin-8(9H)-yl)ethan-1-one (17 mg, 0.039 mmol), (R)-tetrahydrofuran-3-amine (4 mg, 0.047 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), BINAP (3 mg, 0.004 mmol), and sodium tert-butoxide (12 mg, 0.12 mmol) in anhydrous toluene (1.5 mL) at room temperature. Heat to 90°C under nitrogen for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 6.55 mg of (R)-1-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-((tetrahydrofuran-3-yl)amino)-6,7-dihydropyrazino[2,3-f][1,4]oxazepin-8(9H)-yl)ethan-1-one.

[0445] MS (ESI) M / Z: 490.1 [M+H] + .

[0446] 1 H NMR (400MHz, DMSO-d6) δ7.35-7.24(m,2H),7.01(t,J=8.7Hz,1H),5.75-5.57(dd,J=48Hz,6.0Hz,1H),4. 62(s,1H),4.54(s,1H),4.53-4.47(m,1H),4.38-4.30(m,1H),4.25-4.19(m,1H),4.04(t,J=4.7Hz,1H),3 .97-3.88(m,1H),3.88-3.82(m,1H),3.82-3.76(m,2H),3.75-3.67(m,1H),3.58-3.50(m,1H),3.41-3.3 2(m,2H),2.96-2.84(m,2H),2.23-2.13(m,1H),2.09-1.99(m,5H),1.98-1.91(m,1H),1.89-1.77(m,2H).

[0447] The following target compounds were prepared by referring to the synthesis methods of the above examples:

[0448]

[0449]

[0450]

[0451]

[0452] Example 17: 1-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(1-ethyl-1H-pyrazol-4-yl)-6,7-dihydropyrazino[2,3-f][1,4]oxazepin-8(9H)-yl)ethan-1-one

[0453]

[0454] Steps:

[0455] Step A: Dissolve 1-(2-chloro-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6,7-dihydropyrazino[2,3-f][1,4]oxazepin-8(9H)-yl)ethan-1-one (20 mg, 0.046 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (15 mg, 0.069 mmol), tetrakistriphenylphosphine palladium (6 mg, 0.005 mmol), and potassium carbonate (19 mg, 0.14 mmol) in a mixture of 1,4-dioxane (2 mL) and water (0.4 mL) at room temperature. Heat to 100°C under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 11.67 mg of compound 1-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-(1-ethyl-1H-pyrazol-4-yl)-6,7-dihydropyrazino[2,3-f][1,4]oxazepin-8(9H)-yl)ethan-1-one.

[0456] MS (ESI) M / Z: 499.1 [M+H] + .

[0457] 1 H NMR (400MHz, DMSO-d6) δ8.25 (s, 1H), 7.96 (d, J = 2.6Hz, 1H), 7.34-7.25 (m, 2H),7.05-6.95(m,1H),4.81(s,1H),4.74(s,1H),4.54-4.44(m,2H),4.40- 4.34(m,1H),4.25-4.16(m,2H),3.90-3.81(m,2H),3.31-3.26(m,2H),2.99 -2.88(m,2H),2.08-1.97(m,5H),1.86-1.74(m,2H),1.40(t,J=7.2Hz,3H).

[0458] The following target compounds were prepared by referring to the synthesis methods of the above examples:

[0459]

[0460] Example 21: (R)-2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-3'-((tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-7'-one

[0461]

[0462] Steps:

[0463] Step A: 3,5-Dichloropyrazine-2-carbonitrile (2 g, 11.49 mmol) was dissolved in DMF (20 mL) at room temperature, followed by the addition of DIPEA (2.96 g, 22.98 mmol) and 4-(2,4-difluorophenoxy)piperidine (2.45 g, 11.49 mmol), and the mixture was stirred at 0°C for 2 hours. The mixture was returned to room temperature and quenched with water. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 3.3 g of 3-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazine-2-carbonitrile.

[0464] MS (ESI) M / Z: 351.1 [M+H] + .

[0465] Step B: 3-Chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazine-2-carbonitrile (3.3 g, 9.43 mmol) was dissolved in DMSO (50 mL) at room temperature, and cesium carbonate (6.13 g, 18.86 mmol) and dimethyl malonate (1.86 g, 14.14 mmol) were added. The mixture was stirred at 70°C for 16 hours. After returning to room temperature, the mixture was quenched with water and extracted with ethyl acetate (80 mL × 3 times). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 3.5 g of dimethyl 2-(3-cyano-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)malonate.

[0466] MS (ESI) M / Z: 447.1 [M+H] + .

[0467] Step C: Dimethyl 2-(3-cyano-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)malonate (3.5 g, 7.84 mmol) was dissolved in a mixed solvent of DMSO (120 mL) and water (30 mL) at room temperature. Sodium chloride (4.58 g, 78.4 mmol) was then added and stirred at 130°C for 3 hours. After returning to room temperature, the reaction was quenched by adding water and extracted with ethyl acetate (200 mL × 3 times). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 2.4 g of the compound 2-(3-cyano-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl).

[0468] MS (ESI) M / Z: 389.1 [M+H] + .

[0469] Step D: Methyl 2-(3-cyano-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)acetate (500 mg, 1.29 mmol) was dissolved in DMSO (10 mL) at room temperature, followed by the addition of diphenyl(vinyl)sulfonium trifluoromethanesulfonate (559 mg, 1.55 mmol) and 1,8-diazacyclo[5,4,0]undecene-7 (587 mg, 3.86 mmol). The mixture was stirred at 30°C for 16 hours. After returning to room temperature, the reaction was quenched by addition of water and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford 435 mg of methyl 1-(3-cyano-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carboxylate.

[0470] MS (ESI) M / Z: 415.1 [M+H] + .

[0471] Step E: Methyl 1-(3-cyano-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carboxylate (710 mg, 1.71 mmol) was dissolved in methanol (25 mL) at room temperature. Sufficient Raney nickel was added, and the mixture was replaced with hydrogen. The mixture was stirred at 30°C for 2 days. After returning to room temperature, ammonia methanol solution (7 M, 25 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 680 mg of compound 2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazin]-7'-one.

[0472] MS (ESI) M / Z: 387.3 [M+H] + .

[0473] Step F: Dissolve 2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazin]-7'-one (250 mg, 0.65 mmol) in DMF (8 mL). Add NaH (60%, 74.48 mg, 1.94 mmol) in an ice bath. Stir the mixture at 0°C under nitrogen for 30 minutes. Then, add iodomethane (276 mg, 1.94 mmol) dropwise to the reaction mixture, return to room temperature, and continue the reaction for 2 hours. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3 times). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 120 mg of compound 2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-7'-one.

[0474] MS (ESI) M / Z: 401.4 [M+H] + .

[0475] Step G: At room temperature, 2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-7'-one (120 mg, 0.3 mmol) was dissolved in a mixed solvent (DMF / AcOH = 1 / 1, 8 mL), and then NCS (52 mg, 0.39 mmol) was added thereto, and the reaction solution was stirred at 40 ° C for 16 hours. After cooling to room temperature, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3 times). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 105 mg of compound 3'-chloro-2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-7'-one.

[0476] MS (ESI) M / Z: 435.0 [M+H] + .

[0477] Step H: At room temperature, 3′-chloro-2′-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6′-methyl-5′,6′-dihydro-7′H-spiro[cyclopropane-1,8′-pyrido[3,4-b]pyrazine]-7′-one (105 mg, 0.24 mmol) was dissolved in toluene (6 mL), and then (R)-tetrahydrofuran-3-amine (25 mg, 0.29 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), BINAP (15 mg, 0.024 mmol) and sodium tert-butoxide (69.67 mg, 0.72 mmol) were added thereto, and the mixture was stirred at 95°C for 3 hours under nitrogen protection. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (10 mL × 3 times). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain 33.82 mg of the target molecule (R)-2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-3'-((tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-7'-one.

[0478] MS (ESI) M / Z: 486.2 [M+H] + .

[0479] 1 HNMR (400MHz, DMSO-d6) δ7.35-7.24(m,2H),7.04-6.97(m,1H),5.97(d,J=6.1Hz,1H),4. 57-4.46(m,3H),4.41-4.33(m,1H),3.93-3.81(m,2H),3.75-3.67(m,1H),3.56(dd,J=8.8 ,4.7Hz,1H),3.40-3.33(m,2H),2.97(s,3H),2.95-2.86(m,2H),2.22-2.12(m,1H),2.08- 2.01(m,2H),2.01-1.91(m,1H),1.89-1.77(m,2H),1.40-1.33(m,2H),1.26-1.19(m,2H).

[0480] The following target compounds were prepared by referring to the synthesis methods of the above examples:

[0481]

[0482]

[0483]

[0484] Example 30: 3'-(6-aminopyridin-2-yl)-2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-5',6'-dihydro-7'-H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazin]-7'-one

[0485]

[0486] Steps

[0487] Step A: Dissolve 2-(tert-Butoxycarbonyl)-amino-6-tri-n-butyltin-pyridine (535 mg, 0.922 mmol), 3′-chloro-2′-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6′-methyl-5′,6′-dihydro-7′-H-pyrazolo[cyclopropane-1,8′-pyrido[3,4-b]pyrazin]-7′-one (100 mg, 0.23 mmol), lithium chloride (29.9 mg, 0.69 mmol), and bistriphenylphosphine palladium dichloride (32.25 mg, 0.046 mmol) in anhydrous toluene (2 mL) at room temperature. Stir the reaction mixture at 110°C for 4 hours under nitrogen. Return the reaction mixture to room temperature, filter, and concentrate under reduced pressure. The resulting residue was purified by silica gel column to give 155 mg of the target molecule tert-butyl(tert-butoxycarbonyl)(6-(2′-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-methyl-7′-oxo-6′,7′-dihydro-5′-H-spiro[cyclopropane-1,8′-pyrido[3,4-b]pyrazine]-3′-yl)pyridin-2-yl)carbamate.

[0488] MS (ESI) M / Z: 593.3 [M-100+H] + ,693.4[M+H] + .

[0489] Step B: At room temperature, tert-butyl(tert-butoxycarbonyl)(6-(2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-methyl-7'-oxo-6',7'-dihydro-5'-H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-3'-yl)pyridin-2-yl)carbamic acid (155 mg, 0.22 mmol) was dissolved in 1,4-dioxane (1 mL) and hydrochloric acid / 1,4-dioxane (4 M, 2 mL), and the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative high performance liquid chromatography to obtain 32.17 mg of the target molecule 3'-(6-aminopyridin-2-yl)-2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-5',6'-dihydro-7'-H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-7'-one formate.

[0490] MS (ESI) M / Z: 493.2 [M+H] + .

[0491] 1 H NMR(400MHz,DMSO-d6)δ8.15(s,0.2H),7.52-7.44(m,1H),7.31-7.20(m,2 H),7.02-6.93(m,1H),6.85(d,J=6.8Hz,1H),6.43(d,J=7.8Hz,1H),6.05( s,2H),4.62(s,2H),4.48-4.42(m,1H),3.51–3.37(m,2H),3.01(s,3H),3. 01–2.90(m,2H),1.96–1.79(m,2H),1.65–1.48(m,4H),1.45-1.43(m,2H).

[0492] Example 31: (R)-1-(2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3'-((tetrahydrofuran-3-yl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-6'(7'H)-yl)ethan-1-one

[0493]

[0494] Steps:

[0495] Step A: Dissolve 2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-7'-one (200 mg, 0.52 mmol) in THF (4 mL). Cool the mixture to 0°C and add borane-THF solution (1 M, 2.0 mL). After the addition is complete, heat to 65°C and stir for 4 hours. The reaction mixture is cooled to room temperature and quenched with methanol (5 mL). The mixture is then concentrated under reduced pressure to yield 200 mg of crude 2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6',7'-dihydro-5'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine].

[0496] MS (ESI) M / Z: 373.2 [M+H] + .

[0497] Step B: 2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6',7'-dihydro-5'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine] (200 mg, 0.53 mmol) was dissolved in DCM (5 mL), and triethylamine (325 mg, 3.22 mmol) and acetic anhydride (329 mg, 3.22 mmol) were added thereto and stirred at 30°C for 16 hours. Water was added to quench the reaction, and the mixture was extracted with DCM (20 mL × 3 times). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 35 mg of compound 1-(2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-6'(7'H)-yl)ethan-1-one.

[0498] MS (ESI) M / Z: 415.2 [M+H] + .

[0499] Step C: At room temperature, 1-(2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-6'(7'H)-yl)ethan-1-one (35 mg, 0.0845 mmol) was dissolved in a mixed solvent (DMF / AcOH = 1 / 1.2 mL), and then NCS (14.6 mg, 0.11 mmol) was added thereto, and the reaction solution was stirred at 40 ° C for 8 hours. The reaction solution was cooled to room temperature and water was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3 times). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 20 mg of compound 1-(3'-chloro-2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-6'(7'H)-yl)ethan-1-one.

[0500] MS (ESI) M / Z: 449.2 [M+H] + .

[0501] Step D: At room temperature, 1-(3'-chloro-2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-6'(7'H)-yl)ethan-1-one (20 mg, 0.0446 mmol) was dissolved in toluene (1 mL), and then (R)-tetrahydrofuran-3-amine (4.6 mg, 0.0536 mmol), Pd2(dba)3 (2 mg, 0.0022 mmol), BINAP (2.77 mg, 0.0044 mmol) and sodium tert-butoxide (12.8 mg, 0.134 mmol) were added thereto, and the mixture was stirred at 95 ° C for 3 hours under nitrogen protection. The reaction solution was cooled to room temperature and concentrated under vacuum. Water (10 mL) was added to the crude product, and the mixture was extracted with ethyl acetate (5 mL × 2 times). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained after concentration under reduced pressure was purified by silica gel column chromatography to give 6.35 mg of the target product (R)-1-(2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3'-((tetrahydrofuran-3-yl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-6'(7'H)-yl)ethan-1-one.

[0502] MS (ESI) M / Z: 500.2 [M+H] + .

[0503] 1H NMR (400MHz, DMSO-d6) δ7.35-7.24(m,2H),7.05-6.97(m,1H),5.87(dd,J=9.4,6.2Hz,1H),4.56-4. 46(m,3H),4.44-4.33(m,1H),3.94-3.80(m,2H),3.76-3.67(m,1H),3.63(d,J=6.7Hz,2H),3.59-3.5 2(m,1H),3.32-3.26(m,2H),2.93-2.81(m,2H),2.23-2.13(m,1H),2.09(d,J=16.9Hz,3H),2.05-1. 98(m,2H),1.97-1.89(m,1H),1.88-1.76(m,2H),1.23(s,1H),1.07-0.97(m,2H),0.89-0.86(m,1H).

[0504] The following target compounds were prepared by referring to the synthesis methods of the above examples:

[0505]

[0506]

[0507] Example 34: (R)-1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((tetrahydrofuran-3-yl)amino)-5,7,8,9-tetrahydro-6H-pyrazino[2,3-c]azepin-6-yl)ethan-1-one

[0508]

[0509] Steps:

[0510] Step A: 1-(6-Benzyl-5H,6H,7H-pyrazino[2,3-c]azepin-2-yl)-4-(2,4-difluorophenoxy)piperidine (170 mg, 0.38 mmol), 20% Pd(OH)2 / C (34 mg), and methanol (3 mL) were added at room temperature and reacted under a hydrogen atmosphere for 6 hours. After completion of the reaction, the solid was filtered off, and the crude product was concentrated under reduced pressure and used directly in the next step without purification.

[0511] MS (ESI) M / Z: 361.2 [M+H] + .

[0512] Step B: To a reaction flask containing crude 4-(2,4-difluorophenoxy)-1-(5H,6H,7H,8H,9Hpyrazino[2,3-c]azepin-2-yl)piperidine, add DCM (2 mL), triethylamine (0.16 mL, 1.14 mmol), and acetic anhydride (71 μL, 0.76 mmol) at room temperature for 1 hour. Purification by silica gel column chromatography afforded 150 mg of 1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5H,6H,7H,8H,9Hpyrazino[2,3-c]azepin-6-yl)ethan-1-one.

[0513] MS (ESI) M / Z: 403.2 [M+H] + .

[0514] 1 H NMR(400MHz, DMSO-d6)δ8.02(d,J=12.5Hz,1H),7.37-7.26(m,2H),7.07-6.99(m,1H),4.65-4.50(m,3H),4.02-3.92(m, 2H),3.78-3.66(m,2H),3.43-3.34(m,2H),3.00-2.89(m,2H),2.05-1.95(m,5H),1.93-1.81(m,1H),1.74-1.58(m,3H).

[0515] Step C: At room temperature, 1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5H,6H,7H,8H,9Hpyrazino[2,3-c]azepine-6-yl)ethan-1-one (120 mg, 0.3 mmol) and NCS (52.8 mg, 0.39 mmol) were added, followed by DMF (1 mL) and acetic acid (1 mL) for dissolution, and the mixture was reacted in an oil bath at 40 °C for 6 hours. The mixture was returned to room temperature and quenched with water, extracted with ethyl acetate (30 mL × 3 times), washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 96 mg of the product, compound 1-(3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5H,6H,7H,8H,9Hpyrazino[2,3-c]azepin-6-yl)ethan-1-one.

[0516] MS (ESI) M / Z: 437.2 [M+H] + .

[0517] 1H NMR(400MHz,DMSO-d6)δ7.37-7.24(m,2H),7.07-6.98(m,1H),4.71-4.54(m ,2H),3.80-3.55(m,3H),3.32-3.15(m,3H),2.89(s,1H),2.74(s,1H),2.09 -1.94(m,6H),1.92-1.71(m,4H).

[0518] Step D: At room temperature, 1-(3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5H,6H,7H,8H,9Hpyrazino[2,3-c]azepin-6-yl)ethan-1-one (96 mg, 0.22 mmol), (R)-3-aminotetrahydrofuran (28.8 mg, 0.33 mmol), Pd2dba3 (20.2 mg, 0.022 mmol), BINAP (27.4 mg, 0.33 mmol), sodium tert-butoxide (63.4 mg, 0.66 mmol) and toluene (3 mL) were added, and the mixture was reacted at 100°C for three hours under nitrogen protection. After returning to room temperature, the crude product was directly purified by preparative high performance liquid chromatography to obtain 18 mg of the target molecule (R)-1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((tetrahydrofuran-3-yl)amino)-5,7,8,9-tetrahydro-6H-pyrazino[2,3-c]azepin-6-yl)ethan-1-one.

[0519] MS (ESI) M / Z: 488.2 [M+H] + .

[0520] 1 H NMR(400MHz,DMSO-d6)δ7.36-7.24(m,2H),7.06-6.99(m,1H),5.87-5.63 (m,1H),4.62-4.45(m,3H),4.44-4.31(m,1H),3.99-3.91(m,1H),3.90-3 .82(m,1H),3.78-3.63(m,3H),3.60-3.51(m,1H),3.32-3.23(m,2H),3.0 3-2.76(m,4H),2.26-2.15(m,1H),2.11-1.81(m,9H),1.69-1.65(m,1H).

[0521] The following target compounds were prepared by referring to the synthesis methods of the above examples:

[0522]

[0523]

[0524]

[0525] Example 42: 1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(1-ethyl-1H-pyrazol-4-yl)-5,7,8,9-tetrahydro-6H-pyrazino[2,3-c]azepin-6-yl)ethan-1-one

[0526]

[0527] Steps:

[0528] Step A: At room temperature, 1-(3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5H,6H,7H,8H,9Hpyrazino[2,3-c]azepin-6-yl)ethan-1-one (45 mg, 0.1 mmol), 1-ethyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (33.3 mg, 0.15 mmol), Pd(PPh3)4 (11.6 mg, 0.01 mmol) and potassium carbonate (41.5 mg, 0.3 mmol) were added, followed by addition of 1,4-dioxane / water (1.5 mL / 0.3 mL), and the mixture was reacted in an oil bath at 100°C under nitrogen protection for 3 hours. After returning to room temperature, the crude product was directly purified by preparative high performance liquid chromatography to give 12 mg of compound 1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(1-ethyl-1H-pyrazol-4-yl)-5,7,8,9-tetrahydro-6H-pyrazino[2,3-c]azepin-6-yl)ethan-1-one.

[0529] MS (ESI) M / Z: 497.2 [M+H] + .

[0530] 1 H NMR (400MHz, DMSO-d6) δ8.32 (s, 1H), 8.04 (d, J = 3.4Hz, 1H), 7.35-7.24 (m, 2H) ,7.05-6.96(m,1H),4.65(d,J=3.5Hz,2H),4.56-4.45(m,1H),4.22(q,J=7.2H z,2H),3.73(dt,J=18.7,5.6Hz,2H),3.37-3.32(m,2H),3.06-2.89(m,4H),2. 11-1.89(m,6H),1.88-1.79(m,2H),1.77-1.71(m,1H),1.41(t,J=7.2Hz,3H).

[0531] Example 43:

[0532] 1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(((R)-tetrahydrofuran-3-yl)amino)pyrido[3,4-b]pyrazin-7-yl)-2-methylpropane-1,2-diol

[0533]

[0534] Steps:

[0535] Step A: Slowly dissolve 6-chloropyridine-3,4-diamine (2 g, 13.93 mmol) and oxalic acid (1.44 g, 16.02 mmol) in aqueous hydrochloric acid (21 mL, 4 mol / L) at room temperature. Heat to 120°C under nitrogen for 14 hours. After cooling to room temperature, the reaction mixture was quenched with water (20 mL) and filtered. The filter cake was washed with water (10 mL x 5). The filter cake was lyophilized to yield 2.3 g of 7-chloropyrido[3,4-b]pyrazine-2,3-diol hydrochloride.

[0536] MS (ESI) M / Z: 198.1 [M+H] + .

[0537] 1 H NMR (400MHz, DMSO-d6) δ12.28(s,1H),12.13(s,1H),8.10(s,1H),7.07(s,1H).

[0538] Step B: Dissolve 7-chloropyrido[3,4-b]pyrazine-2,3-diol hydrochloride (2 g, 10.15 mmol) in phosphorus oxychloride (10 mL) at room temperature. Heat to 75°C under nitrogen, stir for half an hour, and then slowly add dry DMF (6 mL). Stirring is continued for 3 hours. After cooling to room temperature, the reaction mixture is quenched by pouring into ice water (100 mL) and adjusting the pH to 8-9 with sodium hydroxide (1 mol / L). Extract with ethyl acetate (25 mL x 3), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography to yield 1.6 g of 2,3,7-trichloropyrido[3,4-b]pyrazine.

[0539] MS (ESI) M / Z: 234.2 [M+H] + .

[0540] 1 H NMR (400MHz, DMSO-d6) δ9.38 (d, J = 0.5 Hz, 3H), 8.29 (d, J = 0.6 Hz, 3H).

[0541] Step C: 2,3,7-Trichloropyrido[3,4-b]pyrazine (800 mg, 3.42 mmol) was dissolved in DMF (16 mL) at room temperature. 4-(2,4-difluorophenoxy)piperidine hydrochloride (810.3 mg, 3.25 mmol) and triethylamine (863 mg, 8.55 mmol) were then added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched by the addition of water (100 mL). The mixture was extracted with ethyl acetate (40 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 782 mg of 3,7-dichloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine.

[0542] MS (ESI) M / Z: 411.1 [M+H] + .

[0543] Step D: 3,7-Dichloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine (400 mg, 0.976 mmol) was dissolved in dry DMSO (8 mL) at room temperature. (R)-tetrahydrofuran-3-amine (102 mg, 0.976 mmol), potassium fluoride (73.56 mg, 1.268 mmol), and triethylamine (138 mg, 1.336 mmol) were then added to the solution. The mixture was stirred in a microwave oven at 60°C under nitrogen for 16 hours. After returning to room temperature, the mixture was quenched by adding water (500 mL). The mixture was extracted with ethyl acetate (25 mL × 3 times), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 410 mg of compound (R)-7-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine.

[0544] MS (ESI) M / Z: 462.2 [M+H] + .

[0545] 1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),7.50(s,1H),7.38-7.25(m,2H),7.12 (d,J=5.8Hz,1H),7.06-6.98(m,1H),4.70-4.52(m,2H),3.98(dd,J=8.9,6. 3Hz,1H),3.88(q,J=7.5Hz,1H),3.91-3.85(m,3H),3.67(dd,J=8.9,4.5Hz, 1H),3.34(m,2H),2.28-2.19(m,1H),2.12-1.99(m,3H),1.89-1.86(m,2H).

[0546] Step E: At room temperature, (R)-7-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine (330 mg, 0.716 mmol), 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane (261 mg, 1.432 mmol), Pd(dppf)Cl2 dichloromethane complex (52.4 mg, 0.0716 mmol) and potassium carbonate (296.3 mg, 2.147 mmol) were dissolved in dioxane (6 mL) and water (0.6 mL) and stirred at 110°C under nitrogen for 18 hours. The reaction solution was returned to room temperature and then filtered. The filter cake was extracted with ethyl acetate (10 mL × 3 times). The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 213 mg of compound (R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-(2-methylprop-1-en-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine.

[0547] MS (ESI) M / Z: 482.3 [M+H] + .

[0548] Step F: At room temperature, compound (R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-(2-methylprop-1-en-1-yl)-N-(tetrahydrofuran-3-yl)pyridine (80 mg, 0.16 mmol) and [3,4-b]pyrazin-3-amine were dissolved in isopropanol (80 mg, 0.166 mmol) and pure water (2 mL). Potassium osmate (24.5 mg, 0.0665 mmol) and N-methylmorpholine oxide (155.9 mg, 0.665 mmol) were added to the reaction solution in sequence, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched by adding water (15 mL). The reaction mixture was then extracted with ethyl acetate (10 mL x 3 times), washed with sodium bisulfite solution (15 mL x 2 times) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC. Purification conditions were as follows: preparative column Welch XBC18, 21.2 x 150 mm, 5 μm particle size; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile; flow rate: 20 mL / min; gradient: acetonitrile from 40% to 60% over 10 minutes; detection wavelength: 214 nm. The product was collected and lyophilized to obtain 4.19 mg of the compound 1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(((R)-tetrahydrofuran-3-yl)amino)pyrido[3,4-b]pyrazin-7-yl)-2-methylpropane-1,2-diol.

[0549] MS (ESI) M / Z: 516.2 [M+H] +

[0550] 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.16(s,0.45H),7.58(s,1H),7.37-7.26(m,2H),7.03(t,J= 8.7Hz,1H),6.89(d,J=5.9Hz,1H),5.34(d,J=5.1Hz,1H),4.62-4.57(m,2H),4.44(d,J=4.0Hz,1H) ,3.99(dd,J=8.3,6.5Hz,1H),3.89(dd,J=14.9,7.5Hz,1H),3.79-3.64(m,4H),3.37(m,1H),3.29 -3.21(m,2H),2.29-2.20(m,1H),2.14-2.01(m,3H),1.96-1.86(m,2H),1.08(s,3H),0.99(s,3H).

[0551] Example 44: (R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-methyl-3-((tetrahydrofuran-3-yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one

[0552]

[0553] Steps:

[0554] Step A: At room temperature, 3-chloro-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazine-2-carbonitrile (6 g, 17.14 mmol), triethylamine (1.73 g, 17.14 mmol), tetrabutylammonium chloride hydrate (4.76 g, 17.14 mmol) and 3,3-diethoxyprop-1-ene (3.34 g, 25.71 mmol) were dissolved in DMF (40 mL). Palladium acetate (192.4 mg, 0.05 mmol) was added under nitrogen protection. The mixture was sealed and reacted at 120°C for 48 h. After cooling to room temperature, the mixture was washed with 2N HCl (40 mL), extracted with ethyl acetate (80 mL × 3 times), washed with saturated brine (50 mL × 2 times), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4.28 g of the compound ethyl 3-(3-cyano-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)propanoate.

[0555] MS (ESI) M / Z: 417.2 [M+H] + .

[0556] Step B: Dissolve ethyl 3-(3-cyano-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)propanoate (2.4 g, 5.77 mmol) and Raney nickel (11.73 g, 57.70 mmol) in methanol (30 mL) at room temperature. The reaction mixture was reacted at room temperature for 16 h under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was collected and concentrated under reduced pressure to yield 2.1 g of crude 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one.

[0557] MS (ESI) M / Z: 375.2 [M+H] + .

[0558] Step C: Under ice-cooling, dissolve 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,8,9-tetrahydro-7H-pyranoazino[2,3-c]azepin-7-one (100 mg, 0.26 mmol) in DMF (2 mL). Add sodium hydride (32 mg, 0.80 mmol) and stir for 20 minutes. Then, add iodomethane (114 mg, 0.80 mmol) and continue stirring for 2 hours. Dilute with ice-water and extract with ethyl acetate. The organic phase is concentrated under reduced pressure and purified by silica gel column chromatography to obtain 90.5 mg of the desired product, 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-methyl-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one.

[0559] MS (ESI) M / Z: 389.0 [M+H] + .

[0560] Step D: 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-methyl-5,6,8,9-tetrahydro-7H-pyranoazino[2,3-c]azepin-7-one (90.5 mg, 0.23 mmol) was dissolved in DMF (2 mL) / acetic acid (2 mL) at room temperature. NCS (40 mg, 0.30 mmol) was added and the reaction was stirred at 40°C overnight. After returning to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 92 mg of the desired product, 3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-methyl-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one.

[0561] MS (ESI) M / Z: 423.2 [M+H] + .

[0562] Step E: 3-Chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-methyl-5,6,8,9-tetrahydro-7H-pyranazino[2,3-c]azepin-7-one (50 mg, 0.12 mmol) was dissolved in toluene (1 mL) at room temperature, and (R)-tetrahydrofuran-3-amine (36 mg, 0.39 mmol), Pd2(dba)3 (6 mg, 0.006 mmol), BINAP (8.17 mg, 0.013 mmol) and sodium tert-butoxide (37.8 mg, 0.39 mmol) were added. The mixture was heated to 90°C and stirred for 3 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give 17.6 mg of the target product, methyl (R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-methyl-3-((tetrahydrofuran-3-yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one.

[0563] MS (ESI) M / Z: 474.2 [M+H] + .

[0564] 1 H NMR (400MHz, DMSO-d6) δ7.35-7.23(m,2H),7.07-6.95(m,1H),5.89(d,J=6.1Hz,1H),4.61-4 .45(m,3H),4.44-4.36(m,1H),3.93(dd,J=8.7,6.3Hz,1H),3.88-3.79(m,1H),3.75–3.66(m, 1H),3.54(dd,J=8.8,4.9Hz,1H),3.38-3.27(m,2H),2.98-2.91(m,1H),2.90(s,3H),2.89-2 .83(m,3H),2.83-2.74(m,2H),2.23-2.14(m,1H),2.09-2.01(m,2H),1.99-1.91(m,1H),1.91

[0565] -1.81(m,2H).

[0566] The following target compounds were prepared by referring to the synthesis methods of the above examples:

[0567]

[0568] Example 46:

[0569] (R)-1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((tetrahydrofuran-3-yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-d]azepin-7-yl)ethan-1-one

[0570]

[0571] Steps:

[0572] Step A: Dissolve benzylamine (10 g, 93.32 mmol) and methyl acrylate (16.07 g, 186.64 mmol) in methanol (50 mL) at room temperature and heat to 75°C for 16 hours. Cool the reaction mixture to room temperature and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography to yield 22 g of dimethyl 3,3'-(benzylnitrodiyl)dipropionate.

[0573] MS (ESI) M / Z: 280.1 [M+H] + .

[0574] 1 H NMR (400MHz, DMSO-d6) δ7.36-7.17(m,5H),3.56(s,6H),3.54(s,2H),2.67(t,J=7.0Hz,4H),2.44(t,J=7.0Hz,4H).

[0575] Step B: Sodium (692 mg, 30.08 mmol) was dissolved in toluene (40 mL) at room temperature and heated to 110°C. Trimethylsilyl chloride (4.2 mL, 32.94 mmol) and dimethyl 3,3'-(benzylazinodiyl)dipropionate (2 g, 7.12 mmol) were slowly added to the reaction solution, and the reaction solution was reacted at 110°C for 3 hours. The reaction solution was returned to room temperature and concentrated under reduced pressure. The residue was extracted with DCM (10 mL × 3 times), washed with saturated sodium bicarbonate aqueous solution (20 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 470 mg of the compound 1-benzyl-4,5-bis(trimethylsilyl)oxy-2,3,6,7-tetrahydro-1H-azepine.

[0576] MS (ESI) M / Z: 364.2 [M+H] + .

[0577] 1 H NMR (400MHz, DMSO-d6) δ7.32-7.28(m,4H),7.26-7.20(m,1H),3.53(s,2H),2.53-2.51(m,4H),2.23-2.17(m,4H),0.11(s,18H).

[0578] Step C: Under ice-cooling, dissolve 1-benzyl-4,5-bis(trimethylsilyl)oxy-2,3,6,7-tetrahydro-1H-azepine (1.73 g, 4.76 mmol) in 1,4-dioxane (35 mL). Slowly add bromine (760 mg, 4.76 mmol) to the solution and stir for half an hour. Slowly add pyridine (1.51 g, 19.04 mmol) to the reaction solution, then add aminoacetamidine dihydrobromide (1.79 g, 7.62 mmol) in portions. Return to room temperature and stir for 16 hours. Add sodium hydroxide aqueous solution (2 mol / L) until the pH reaches 10. The mixture was extracted with DCM (30 mL × 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 660 mg of compound 7-benzyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine-2-amine.

[0579] MS (ESI) M / Z: 255.1 [M+H]+ .

[0580] 1 H NMR(400MHz,DMSO-d6)δ7.54(s,1H),7.36-7.31(m,4H),7.28-7.23(m,1H),6.0 1(s,2H),3.61(s,2H),2.88-2.84(m,2H),2.82-2.78(m,2H),2.58-2.53(m,4H).

[0581] Step D: Under ice-cooling, 7-benzyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine-2-amine (330 mg, 1.3 mmol) was dissolved in DCM (8 mL). Titanium tetrachloride (3.12 mL, 1 mol / L, 3.12 mmol) and tert-butyl nitrite (268 mg, 2.6 mmol) were slowly added dropwise to the solution. The mixture was slowly warmed to room temperature and stirred for 16 hours. Aqueous sodium hydroxide solution (2 mol / L) was slowly added to the reaction solution until pH = 8. The mixture was extracted with DCM (20 mL × 3 times). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 100 mg of the compound 7-benzyl-2-chloro-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine.

[0582] MS (ESI) M / Z: 274.0 [M+H] + .

[0583] 1 H NMR (400MHz, DMSO-d6) δ8.46(s,1H),7.39-7.31(m,4H),7.29-7.22(m,1H),3.66(s,2H),3.13-3.04(m,4H),2.69-2.62(m,4H).

[0584] Step E: 7-benzyl-2-chloro-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine (230 mg, 0.84 mmol), 4-(2,4-difluorophenoxy)piperidine (215 mg, 1.01 mmol), Pd2(dba)3 (76.9 mg, 0.084 mmol), XPhos (80 mg, 0.168 mmol) and sodium tert-butoxide (242 mg, 2.52 mmol) were dissolved in anhydrous toluene (3 mL) at room temperature. After nitrogen protection, the mixture was sealed and heated to 100°C for 3 hours. After returning to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 300 mg of the compound 7-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine.

[0585] MS (ESI) M / Z: 451.4 [M+H] + .

[0586] 1 H NMR(400MHz,DMSO-d6)δ8.02-7.95(s,1H),7.37-7.32(m,4H),7.31-7.22(m,3H),7.06-6.97(m,1H),4.60-4.52(m,1H),3.9 7-3.88(m,2H),3.63(s,2H),3.31-3.27(m,2H),2.96-2.86(m,4H),2.64-2.55(m,4H),2.03-1.93(m,2H),1.69-1.58(m,2H).

[0587] Step F: 7-Benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine (135 mg, 0.3 mmol) was dissolved in methanol (8 mL) at room temperature. Pd(OH)2 (80 mg, 20% Pd(OH)2, 50% aqueous), Pd / C (135 mg, 10% Pd / C, 50% aqueous), and acetic acid (0.67 mL) were then added. The mixture was stirred under a hydrogen atmosphere at 30°C for 1.5 hours. The mixture was returned to room temperature, filtered through celite, and washed with methanol (5 mL x 3). The filtrate was concentrated under reduced pressure to give 108 mg of 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine.

[0588] MS (ESI) M / Z: 361.4 [M+H] + .

[0589] Step G: Dissolve 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine (108 mg, 0.3 mmol) in DCM (5 mL) under ice-water bath. Triethylamine (91 mg, 0.9 mmol) and acetic anhydride (36.8 mg, 0.36 mmol) were then slowly added to the solution, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by the addition of water (15 mL) and extracted with DCM (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 resulting residue was purified by silica gel column chromatography to obtain 80 mg of the compound 1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-d]azepin-7-yl)ethan-1-one.

[0590] MS (ESI) M / Z: 403.3 [M+H] + .

[0591] 1 H NMR (400MHz, DMSO-d6) δ8.05 (d, J = 3.0Hz, 1H), 7.41-7.22 (m, 2H), 7.11-6.89 (m,

[0592] 1H),4.63-4.45(m,1H),3.98-3.90(m,2H),3.66-3.56(m,4H),3.39-3.33(m,2H),3.03-2.95

[0593] (m,2H),2.90-2.83(m,2H),2.08(d,J=1.1Hz,3H),2.02-1.95(m,2H),1.69-1.59(m,2H).

[0594] Step H: 1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-d]azepin-7-yl)ethan-1-one (80 mg, 0.2 mmol) was dissolved in DMF (2.5 mL) and acetic acid (2.5 mL) at room temperature. NCS (34.5 mg, 0.26 mmol) was then added, and the mixture was heated to 50°C and stirred for 16 hours. The reaction solution was returned to room temperature and quenched by adding water (30 mL), extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined, washed with saturated aqueous sodium bicarbonate solution (30 mL) and saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 50 mg of compound 1-(2-chloro-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-d]azepin-7-yl)ethan-1-one.

[0595] MS (ESI) M / Z: 437.2 [M+H] + .

[0596] 1 H NMR(400MHz,DMSO-d6)δ7.37-7.25(m,2H),7.07-6.96(m,1H),4.63-4.50(m,1H),3.72-3.52(m,6H),3.2 3-3.15(m,2H),3.07-3.00(m,2H),2.96-2.88(m,2H),2.09(s,3H),2.06-1.98(m,2H),1.83-1.71(m,2H).

[0597] Step I: 1-(2-chloro-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-d]azepin-7-yl)ethan-1-one (50 mg, 0.11 mmol), (R)-3-aminotetrahydrofuran (14.8 mg, 0.17 mmol), Pd2(dba)3 (10.1 mg, 0.011 mmol), BINAP (13.7 mg, 0.022 mmol) and sodium tert-butoxide (31.7 mg, 0.33 mmol) were dissolved in anhydrous toluene (2 mL) at room temperature. The mixture was sealed and heated to 90°C under nitrogen protection for 3 hours. After returning to room temperature, the mixture was concentrated under reduced pressure, and the resulting residue was purified by thin-layer chromatography and preparative high-performance liquid chromatography to give 22.72 mg of compound (R)-1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((tetrahydrofuran-3-yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-d]azepin-7-yl)ethan-1-one.

[0598] MS (ESI) M / Z: 488.3 [M+H] + .

[0599] 1 H NMR (400MHz, DMSO-d6) δ7.35-7.25(m,2H),7.05-6.97(m,1H),5.72(d,J=6.1Hz,1H ),4.56-4.47(m,1H),4.45-4.35(m,1H),3.94-3.88(m,1H),3.87-3.81(m,1H),3.74 -3.67(m,1H),3.63-3.56(m,4H),3.56-3.51(m,1H),3.30-3.23(m,2H),2.94-2.82( m,4H),2.81-2.74(m,2H),2.22-2.13(m,1H),2.11-2.02(m,5H),1.98-1.83(m,3H).

[0600] Example 47: (R)-3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-2'-((tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-7'-one

[0601]

[0602] Steps:

[0603] Step A: 3,6-Dichloropyrazine-2-carbonitrile (5 g, 28.7 mmol) was dissolved in DMSO (150 mL) at room temperature. Cesium carbonate (18.7 g, 57.5 mmol) and dimethyl malonate (5.7 g, 43.1 mmol) were added. The reaction mixture was heated to 70°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and quenched with water (1 L). The mixture was extracted with ethyl acetate (300 mL x 3). The organic phases were combined, washed with saturated brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2.8 g of the target molecule, dimethyl 2-(5-chloro-3-cyanopyrazin-2-yl)malonate.

[0604] MS (ESI) M / Z: 270.0 [M+H] + .

[0605] 1 H NMR (400MHz, DMSO-d6) δ9.16(s,1H),5.71(s,1H),3.76(s,6H).

[0606] Step B: Under ice-cooling, dimethyl 2-(5-chloro-3-cyanopyrazin-2-yl)malonate (3 g, 11.1 mmol) was dissolved in DMF (55 mL). 4-(2,4-difluorophenoxy)piperidine (2.37 g, 11.1 mmol) was added, followed by the slow dropwise addition of DIPEA (3.87 mL, 22.2 mmol). After completion of the addition, the reaction mixture was heated to 70°C for 16 hours. After cooling to room temperature, the mixture was quenched with water (200 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 3.1 g of the target molecule, dimethyl 2-(3-cyano-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)malonate.

[0607] MS (ESI) M / Z: 447.1 [M+H] + .

[0608] 1 H NMR (400MHz, DMSO-d6) δ8.64 (d, J = 3.2Hz, 1H), 7.40-7.25 (m, 2H), 7.08-6.99 (m, 1H), 5.29 (s, 1H), 4.65-4.55 (m,1H),4.06-3.95(m,2H),3.69(d,J=26.0Hz,6H),3.60-3.48(m,2H),2.09-1.96(m,2H),1.77-1.62(m,2H).

[0609] Step C: Dissolve dimethyl 2-(3-cyano-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)malonate (3.1 g, 6.94 mmol) in DMSO (100 mL) and water (25 mL) at room temperature. Add sodium chloride (4.06 g, 69.44 mmol). Heat the reaction at 130°C for 3 hours. Cool to room temperature and quench with water (300 mL). Extract the mixture with ethyl acetate (10 mL x 3). Combine the organic phases, wash with saturated brine (300 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography to yield 2.5 g of the target molecule, methyl 2-(3-cyano-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)acetate.

[0610] MS (ESI) M / Z: 389.2 [M+H] + .

[0611] 1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),7.37-7.26(m,2H),7.07-6.99(m,1H),4.67-4.55(m,1H),4.0 3-3.95(m,2H),3.91(s,2H),3.66(s,3H),3.56-3.45(m,2H),2.08-1.97(m,2H),1.74-1.62(m,2H).

[0612] Step D: Methyl 2-(3-cyano-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)acetate (1 g, 2.58 mmol) was dissolved in DMSO (20 mL) at room temperature. Diphenyl(vinyl)sulfonium trifluoromethanesulfonate (1.12 g, 3.1 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.18 g, 7.74 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched by addition of water (200 mL). The mixed solution was extracted with ethyl acetate (50 mL × 3 times), the organic phases were combined, washed with saturated brine (200 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 960 mg of the target molecule 1-(3-cyano-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carboxylic acid methyl ester.

[0613] MS (ESI) M / Z: 415.2 [M+H] + .

[0614] 1 H NMR(400MHz,DMSO-d6)δ8.58(s,1H),7.38-7.25(m,2H),7.07-6.99(m,1H),4.69-4.56(m,1H),4.03-3.96(m,2H ),3.62(s,3H),3.56-3.45(m,2H),2.06-1.98(m,2H),1.74-1.65(m,2H),1.64-1.60(m,2H),1.46-1.40(m,2H).

[0615] Step E: Methyl 1-(3-cyano-5-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)cyclopropane-1-carboxylate (960 mg, 2.42 mmol) was dissolved in methanol (25 mL) at room temperature. Sufficient Raney nickel was added and the mixture was heated to 30°C for 16 hours. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 470 mg of the target molecule, 3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazin]-7'-one.

[0616] MS (ESI) M / Z: 387.2 [M+H] + .

[0617] 1 H NMR (400MHz, DMSO-d6) δ8.22(s,1H),7.99(s,1H),7.36-7.24(m,2H),7.05-6.97(m,1H),4.63-4.54(m,1H),4.42(s,2 H),4.00-3.88(m,2H),3.40-3.33(m,2H),2.04-1.94(m,2H),1.69-1.59(m,2H),1.44-1.39(m,2H),1.28-1.23(m,2H).

[0618] Step F: Under ice-cooling, dissolve 3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazin]-7'-one (200 mg, 0.52 mmol) in DMF (5 mL). Add sodium hydride (31 mg, 0.78 mmol) and stir in an ice-cooling bath for 0.5 h. Then, slowly add iodomethane (88 mg, 0.62 mmol) dropwise and continue stirring at 0°C for 0.5 h. Quench the mixture with water (20 mL). The mixed solution was extracted with ethyl acetate (5 mL × 3 times), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 190 mg of 3′-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6′-methyl-5′,6′-dihydro-7′-spiro[cyclopropane-1,8′-pyrido[3,4-b]pyrazine]-7′-one.

[0619] MS (ESI) M / Z: 401.2 [M+H] + .

[0620] 1H NMR(400MHz,DMSO-d6)δ8.23(s,1H),7.35-7.25(m,2H),7.06-6.99(m,1H),4.61-4.53(m,3H),3.99-3.90(m,2H) ),3.43-3.34(m,2H),2.98(s,3H),2.04-1.95(m,2H),1.69-1.58(m,2H),1.48-1.43(m,2H),1.28-1.24(m,2H).

[0621] Step G: 3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-5',6'-dihydro-7'-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazin]-7'-one (190 mg, 0.47 mmol) was dissolved in DMF (5 mL) and acetic acid (5 mL) at room temperature. NCS (82 mg, 0.62 mmol) was added and the reaction mixture was heated to 50°C for 16 hours. After returning to room temperature, the mixture was quenched with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 160 mg of the target molecule 2′-chloro-3′-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6′-methyl-5′,6′-dihydro-7′H-pyrazolo[cyclopropane-1,8′-pyrido[3,4-b]pyrazin]-7′-one.

[0622] MS (ESI) M / Z: 435.2 [M+H] + .

[0623] 1 H NMR (400MHz, DMSO-d6) δ7.36-7.24(m,2H),7.08-6.98(m,1H),4.65(s,2H),4.61-4.52(m,1H),3.67-3.55(m,2H ),3.25-3.16(m,2H),2.99(s,3H),2.09-2.01(m,2H),1.84-1.73(m,2H),1.58-1.50(m,2H),1.32-1.27(m,2H).

[0624] Step H: 2′-chloro-3′-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6′-methyl-5′,6′-dihydro-7′-H-pyrazolo[cyclopropane-1,8′-pyrido[3,4-b]pyrazine]-7′-one (60 mg, 0.14 mmol), (R)-tetrahydrofuran-3-amine (18 mg, 0.21 mmol), Pd2(dba)3 (13 mg, 0.014 mmol), BINAP (17 mg, 0.03 mmol) and sodium tert-butoxide (40 mg, 0.4 mmol) were dissolved in toluene (1 mL) at room temperature. The reaction solution was heated to 90°C in a sealed tube and heated for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to afford 30.1 mg of the target molecule (R)-3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-2'-((tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazin]-7'-one.

[0625] MS (ESI) M / Z: 486.3 [M+H] + .

[0626] 1 H NMR(400MHz,DMSO-d6)δ7.36-7.25(m,2H),7.03-6.99(m,1H),6.06(d,J=5.7Hz,1H),4.57-4.5 0(m,1H),4.48(s,2H),4.33-4.23(m,1H),3.91-3.78(m,2H),3.74-3.66(m,1H),3.56-3.50(m, 1H),3.31-3.27(m,2H),2.97(s,3H),2.95-2.84(m,2H),2.20-2.12(m,1H),2.11-2.03(m,2H), 2.00-1.93(m,1H),1.92-1.82(m,2H),1.44-1.37(m,2H),1.36-1.30(m,1H),1.29-1.23(m,1H).

[0627] Example 48: 1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((1-methoxy-1H-pyrazol-4-yl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

[0628]

[0629] Steps:

[0630] With reference to the preparation process of other embodiments of the present invention, 1.01 mg of the target product 1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((1-methoxy-1H-pyrazol-4-yl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one was obtained.

[0631] MS (ESI) M / Z: 500.2 [M+H] + .

[0632] 1 H NMR(400MHz,MeOD)δ8.13(dd,J=8.9,1.6Hz,1H),7.44(d,J=3.7Hz,1H),7.22 -7.14(m,1H),7.02-6.95(m,1H),6.90-6.85(m,1H),4.64-4.60(m,2H),4.52 -4.44(m,1H),4.11(s,3H),3.90-3.82(m,2H),3.43-3.34(m,3H),3.08-3.0( m,2H),2.88-2.76(m,2H),2.22(s,3H),2.20-2.15(m,2H),2.06-1.99(m,2H).

[0633] Example 49: (R)-1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-8,8-dimethyl-3-((tetrahydrofuran-3-yl)oxy)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one

[0634]

[0635] Steps:

[0636] Step A: Methyl 2-(3-cyano-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)acetate (700 mg, 1.82 mmol) was dissolved in DMF (15 mL) under an ice bath. NaH (60%, 131 mg, 5.46 mmol) was then added. The mixture was stirred at 0°C under nitrogen for 30 minutes. Methyl iodide (1.29 g, 9.1 mmol) was then added dropwise to the reaction mixture. The reaction was allowed to react at room temperature for 2 hours. The reaction was quenched by the addition of water (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to yield 710 mg of the target molecule, methyl 2-(3-cyano-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)-2-methylpropanoate.

[0637] MS (ESI) M / Z: 417.3 [M+H] + .

[0638] 1 HNMR (400MHz, DMSO-d6): δ8.37(s,1H),7.37-7.27(m,2H),7.06-7.01(m,1H),4.64-4.61(m,1H),4. 10-4.06(m,2H),3.67(s,3H),3.65-3.61(m,2H),2.06-2.01(m,2H),1.74-1.68(m,2H),1.55(s,6H).

[0639] Step B: Methyl 2-(3-cyano-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)-2-methylpropanoate (710 mg, 1.71 mmol) was dissolved in methanol (25 mL) at room temperature. Sufficient Raney nickel was added, and the mixture was replaced with hydrogen. The mixture was stirred at 30°C for 16 hours. The reaction mixture was cooled to room temperature, and ammonia methanol solution (7 M, 25 mL) was added. The mixture was stirred at room temperature for half an hour. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 621 mg of the target molecule, 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-8,8-dimethyl-5,8-dihydropyrido[3,4-b]pyrazin-7(6H)-one.

[0640] MS (ESI) M / Z: 375.2 [M+H] + .

[0641] 1 H NMR (400MHz, DMSO-d6) δ8.23(s,1H),7.99(s,1H),7.39-7.23(m,2H),7.03(dd,J=11.9,5.5Hz,1H),4.60-4.57(m,1 H), 4.31 (d, J = 2.0Hz, 2H), 4.01-3.97 (m, 2H), 3.48-3.37 (m, 2H), 2.03-1.98 (m, 2H), 1.69-1.64 (m, 2H), 1.36 (s, 6H).

[0642] Step C: Under ice, 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-8,8-dimethyl-5,8-dihydropyrido[3,4-b]pyrazin-7(6H)-one (200 mg, 0.52 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL). Borane-dimethyl sulfide complex (2 M, 1 mL) was then added. After the addition was complete, the mixture was heated to 60°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and quenched with methanol (5 mL). The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain 57 mg of the target molecule, 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-8,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine.

[0643] MS (ESI) M / Z: 375.3 [M+H] + .

[0644] 1 H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.33-7.27(m,2H),7.05-6.99(m,1H),4.59-4.56(m,1H),4.00-3.94(m,2H),3 .92(s,2H),3.40–3.35(m,2H),3.04-3.00(m,1H),2.95(s,2H),2.02-1.97(m,2H),1.67-1.59(m,2H),1.24(s,6H).

[0645] Step D: 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-8,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine (57 mg, 0.17 mmol) was dissolved in DCM (3 mL) at room temperature. TEA (76 mg, 0.75 mmol) and acetic anhydride (23 mg, 0.225 mmol) were then added and stirred at room temperature for 16 hours. The reaction was quenched by the addition of water (10 mL) and extracted with DCM (10 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to afford 44 mg of the target molecule, 1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-8,8-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one.

[0646] MS (ESI) M / Z: 417.3 [M+H] + .

[0647] 1H NMR (400MHz, DMSO-d6) δ8.20 (d, J = 7.3Hz, 1H), 7.35-7.26 (m, 2H), 7.06-6.98 (m, 1H), 4.63-4.56 (m, 2H), 4.54 (s, 1H), 4.0 2-3.94(m,2H),3.57(s,2H),3.40-3.34(m,2H),2.12(d,J=8.0Hz,3H),2.01-1.97(m,2H),1.72-1.55(m,2H),1.23(s,6H).

[0648] Step E: At room temperature, 1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-8,8-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one (44 mg, 0.11 mmol) was dissolved in a mixed solvent (DMF / AcOH = 1 / 1.2 mL), and then NCS (18.7 mg, 0.14 mmol) was added thereto, and the mixture was heated to 50°C and stirred for 16 hours. The reaction solution was cooled to room temperature and water (20 mL) was added to quench the reaction. The product was extracted with ethyl acetate (10 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 36 mg of the target molecule 1-(3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-8,8-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one.

[0649] MS (ESI) M / Z: 451.2 [M+H] +.

[0650] 1 H NMR(400MHz,DMSO-d6)δ7.36-7.25(m,2H),7.06-6.98(m,1H),4.66(s,1H),4.58(s,2H),3.69-3.65(m,2H),3 .60(s,2H),3.28-3.22(m,2H),2.12(d,J=4.2Hz,3H),2.05(s,2H),1.82-1.71(m,2H),1.24(d,J=6.8Hz,6H).

[0651] Step F: 1-(3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-8,8-dimethyl-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one (36 mg, 0.08 mmol) was dissolved in toluene (1 mL) at room temperature, and then (R)-tetrahydrofuran-3-amine (14 mg, 0.16 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), BINAP (8 mg, 0.012 mmol) and sodium tert-butoxide (23 mg, 0.24 mmol) were added thereto, and the mixture was heated to 90°C under nitrogen protection and stirred for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 17.73 g of the target product (R)-1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-8,8-dimethyl-3-((tetrahydrofuran-3-yl)oxy)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one.

[0652] MS (ESI) M / Z: 502.2 [M+H] + .

[0653] 1 H NMR(400MHz,DMSO-d6)δ7.38-7.20(m,2H),7.05-6.97(m,1H),5.91(dd,J=9.9,6.0Hz,1H),4.59- 4.50(m,1H),4.46(d,J=14.5Hz,2H),4.41-4.32(m,1H),3.93-3.87(m,1H),3.87-3.80(m,1H),3.7 4-3.68(m,1H),3.58-3.54(m,1H),3.54-3.49(m,2H),3.38-3.33(m,2H),2.97-2.89(m,2H),2.22 -2.13(m,1H),2.12-2.01(m,5H),2.00-1.82(m,3H),1.19(d,J=2.5Hz,3H),1.13(d,J=1.2Hz,3H).

[0654] Example 50: 2′-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6′-methyl-3′-(((R)-tetrahydrofuran-3-yl)amino)-4,5,5′,6′-tetrahydro2H,7′H-spiro[furan-3,8′-pyrido[3,4-b]pyrazin]-7′-one

[0655]

[0656] Steps:

[0657] Step A: Under ice bath, methyl 2-(3-cyano-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)acetate (600 mg, 1.55 mmol) was dissolved in anhydrous DMF (18 mL). Sodium hydroxide (186 mg, 4.65 mmol, 60%) was added to the solution, and the mixture was returned to room temperature and stirred for 20 minutes. 1-Chloro-2-(chloromethoxy)ethane (239 mg, 1.85 mmol) was then added to the reaction mixture, and stirring was continued at room temperature for 3 hours. Water (100 mL) was added under ice bath to quench the mixture. The mixed solution was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 310 mg of the target molecule 3-(3-cyano-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)tetrahydrofuran-3-carboxylic acid methyl ester.

[0658] MS (ESI) M / Z: 445.3 [M+H] + .

[0659] Step B: Methyl 3-(3-cyano-6-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrazin-2-yl)tetrahydrofuran-3-carboxylate (310 mg, 0.698 mmol) was dissolved in methanol (6 mL) at room temperature. Raney nickel (412 mg, 6.98 mmol) was added to the reaction solution, and stirred at room temperature for 16 hours under hydrogen protection. The reaction solution was filtered, washed with methanol, and the organic phases were combined and concentrated under reduced pressure to obtain 336 mg of the target molecule 2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-4,5,5',6'-tetrahydro-2H,7'H-spiro[furan-3,8'-pyrido[3,4-b]pyrazin]-7'-one.

[0660] MS (ESI) M / Z: 417.3 [M+H] + .

[0661] Step C: Under ice bath, 2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-4,5,5',6'-tetrahydro-2H,7'H-spiro[furan-3,8'-pyrido[3,4-b]pyrazine]-7'-one (336 mg, 0.808 mmol) was dissolved in DMF (4 mL). To the above solution was added sodium hydroxide (97 mg, 2.423 mmol, 60%), and the mixture was stirred at room temperature for 20 minutes. Then, iodomethane (344 mg, 2.423 mmol) was added to the reaction solution, and stirred at room temperature for 3 hours. The reaction mixture was quenched by adding water (50 mL) under ice bath, extracted with ethyl acetate (20 mL × 3 times), and the organic phases were 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 obtain 220 mg of the target molecule 2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-4,5,5',6'-tetrahydro-2H,7'H-spiro[furan-3,8'-pyrido[3,4-b]pyrazine]-7'-one.

[0662] MS (ESI) M / Z: 431.2 [M+H] + .

[0663] Step D: 2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-4,5,5',6'-tetrahydro-2H,7'H-spiro[furan-3,8'-pyrido[3,4-b]pyrazine]-7'-one (110 mg, 0.256 mmol) was dissolved in a mixed solvent of DMF (1.0 mL) and acetic acid (1.0 mL) at room temperature. NCS (44 mg, 0.333 mmol) was added to the reaction solution, and the mixture was heated to 40°C and stirred for 16 h. The mixture was quenched by addition of aqueous sodium bicarbonate (20 mL) under ice bath, and the mixture was extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 80 mg of the target molecule 3'-chloro-2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-4,5,5',6'-tetrahydro-2H,7'H-spiro[furan-3,8'-pyrido[3,4-b]pyrazin]-7'-one.

[0664] MS (ESI) M / Z: 465.1 [M+H] + .

[0665] Step E: 3'-chloro-2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-4,5,5',6'-tetrahydro-2H,7'H-spiro[furan-3,8'-pyrido[3,4-b]pyrazine]-7'-one (80 mg, 0.172 mmol), (R)-tetrahydrofuran-3-amine (60 mg, 0.688 mmol), Pd2(dba)3 (16 mg, 0.017 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (21 mg, 0.034 mmol) and sodium tert-butoxide (50 mg, 0.516 mmol) were dissolved in anhydrous toluene (2 mL) at room temperature. The mixture was sealed and heated to 90°C under nitrogen protection for 3 hours. After cooling to room temperature, water (20 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography to give 40 mg of the target molecule 2′-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6′-methyl-3′-((R)-tetrahydrofuran-3-yl)amino)-4,5,5′,6′-tetrahydro-2H,7′H-spiro[furan-3,8′-pyrido[3,4-b]pyrazin]-7′-one.

[0666] MS (ESI) M / Z: 516.5 [M+H] + .

[0667] 1 H NMR (400MHz, DMSO-d6) δ7.37-7.24(m,2H),7.01(t,J=8.1Hz,1H),6.11(d,J=6.0Hz,1H) ,4.58-4.50(m,1H),4.47-4.31(m,3H),4.07-3.96(m,3H),3.93-3.69(m,4H),3.60-3.55

[0668] (m,1H),3.44-3.37(m,2H),2.99(s,3H),2.98-2.88(m,2H),2.42-2.35(m,1H),2.26-2.14(m,

[0669] 2H),2.11-2.03(m,2H),2.01-1.94(m,1H),1.93-1.79(m,2H).

[0670] Example 51: (R)-2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-3'-((tetrahydrofuran-3-yl)amino)-2,3,5,5',6,6'-hexahydro-7'H-pyran-4,8'-pyrido[3,4-b]pyrazin]-7'-one

[0671]

[0672] Steps:

[0673] With reference to the preparation process of other embodiments of the present invention, 24.38 mg of the target molecule (R)-2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-3'-((tetrahydrofuran-3-yl)amino)-2,3,5,5',6,6'-hexahydro-7'-pyran-4,8'-pyrido[3,4-b]pyrazin]-7'-one was obtained.

[0674] MS (ESI) M / Z: 530.6 [M+H] + .

[0675] 1 H NMR (400MHz, DMSO-d6) δ7.38-7.23(m,2H),7.03-6.98(m,1H),6.07(d,J=6 .0Hz,1H),4.57-4.53(m,1H),4.45-4.35(m,3H),3.95-3.80(m,5H),3.77-3 .67(m,1H),3.58(dd,J=8.8,4.8Hz,1H),3.42-3.35(m,2H),3.33-3.28(m, 2H),2.97(s,3H),2.94-2.90(m,1H),2.24-2.03(m,4H),2.04-1.83(m,6H).

[0676] Example 52: (R)-2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-3'-((tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'H-spiro[cyclobutane-1,8'-pyrido[3,4-b]pyrazine]-7'-one

[0677]

[0678] Steps:

[0679] With reference to the preparation process of other embodiments of the present invention, 44.13 mg of the target product (R)-2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-3'-((tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'H-spiro[cyclobutane-1,8'-pyrido[3,4-b]pyrazine]-7'-one was obtained.

[0680] MS (ESI) M / Z: 500.5 [M+H] + .

[0681] 1 HNMR(400MHz,DMSO-d6)δ7.38-7.25(m,2H),7.05-6.98(m,1H),6.09(d,J=6.0Hz,1H),4.62-4.54(m,1H),4.42-4.34(m,1H),4.32(s,2H),3.93 -3.82(m,2H),3.76-3.67(m,1H),3.61-3.55(m,1H),3.53-3.42(m,2H),3.10-3.00(m,2H) ,2.98(s,3H),2.57-2.52(m,2H),2.40-2.28(m,2H),2.22-2.03(m,5H),2.02-1.86(m,3H).

[0682] Example 53-1 and Example 53-2

[0683] (2S)-2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2,6'-dimethyl-3'-(((R)-tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'-spiro[cyclopropane-8'-pyridin[3,4-b]pyrazin]-7'-one (2R)-2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2,6'-dimethyl-3'-(((R)-tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'-spiro[cyclopropane-8'-pyridin[3,4-b]pyrazin]-7'-one

[0684]

[0685] Steps:

[0686] With reference to the preparation process of other embodiments of the present invention, 85 mg of the target molecule 2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2,6'-dimethyl-3'-(((R)-tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'-spiro[cyclopropane-8'-pyrido[3,4-b]pyrazine]-7'-one was obtained.

[0687] 29.67 mg of compound 53-P1 (t R =1.241 min) and 21.39 mg of compound 53-P2 (t R =1.651 min). Separation conditions (instrument: SFC-150 mg / m (waters); column: Daicel AS (25*250 mm, 10 um); temperature: 30°C; mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 85 / 15; flow rate: 100 mL / min; pressure: 100 bar, detection wavelength: 214 nm; cycle time: 6.64 min; sample concentration: 80 mg dissolved in 6.6 ml MeOH; injection volume: 1.4 mL).

[0688] Compound 53-1:

[0689] MS (ESI) M / Z: 500.4 [M+H] + .

[0690] 1 H NMR (400MHz, DMSO-d6) δ7.35-7.24(m,2H),7.04-6.97(m,1H),5.98(d,J=6.1Hz,1H),4.62(d,J=16.6Hz,1H),4.57-4. 49(m,1H),4.43-4.36(m,1H),4.32(d,J=16.6Hz,1H),3.92-3.81(m,2H),3.77-3.67(m,1H),3.57(dd,J=8.8,4.8Hz,1H ),3.34-3.32(m,1H),3.30–3.26(m,1H),2.95-2.92(m,4H),2.91-2.84(m,1H),2.24-2.14(m,1H),2.11-2.02(m,2H), 2.00-1.94(m,1H),1.91-1.81(m,2H),1.65-1.60(m,1H),1.59-1.52(m,1H),1.49-1.42(m,1H),1.06(d,J=6.1Hz,3H).

[0691] Compound 53-2:

[0692] MS (ESI) M / Z: 500.4 [M+H] + .

[0693] 1H NMR (400MHz, DMSO-d6) δ7.35-7.24(m,2H),7.04-6.98(m,1H),5.99(d,J=5.9Hz,1H),4.62(d,J=16.7Hz,1H),4.57-4.50(m,1 H),4.41-4.35(m,1H),4.32(d,J=16.6Hz,1H),3.92(dd,J=8.8,6.2Hz,1H),3.89-3.83(m,1H),3.75-3.68(m,1H),3.59(dd,J= 8.8,4.7Hz,1H),3.42-3.37(m,1H),3.31-3.24(m,1H),3.01-2.92(m,4H),2.90-2.81(m,1H),2.22-2.13(m,1H),2.11-2.00( m,2H),2.00-1.93(m,1H),1.91-1.79(m,2H),1.66-1.60(m,1H),1.58-1.51(m,1H),1.49-1.44(m,1H),1.05(d,J=6.1Hz,3H).

[0694] Example 54-1 and Example 54-2:

[0695] (2S)-3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2,6'-dimethyl-2'-(((R)-tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'-spiro[cyclopropane-8'-pyrido[3,4-b]pyrazin]-7'-one (2R)-3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2,6'-dimethyl-2'-(((R)-tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'-spiro[cyclopropane-8'-pyrido[3,4-b]pyrazin]-7'-one

[0696]

[0697] Steps:

[0698] Using 3,6-dichloropyrazine-2-carbonitrile as the starting material, referring to Example 47 and Example 53, the target molecule 3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2,6'-dimethyl-2'-(((R)-tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'-spiro[cyclopropane-8'-pyrido[3,4-b]pyrazine]-7'-one was obtained.

[0699] Compound 54-P1 (tR = 0.937 min) and compound 54-P2 (tR = 1.108 min) were separated by SFC. Separation conditions (instrument: SFC-150 mg / m (waters); column: Daicel IG (25*250 mm, 10 μm); temperature: 30°C; mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 60 / 40; flow rate: 100 mL / min; pressure: 100 bar; detection wavelength: 214 nm; cycle time: 3.24 min; sample concentration: 70 mg dissolved in 5.4 mL MeOH; injection volume: 1 mL) were used.

[0700] Compound 54-1:

[0701] MS (ESI) M / Z: 500.4 [M+H] + .

[0702] 1 H NMR (400MHz, DMSO-d6) δ7.36-7.26(m,2H),7.07-6.98(m,1H),5.99(d,J=5.6Hz,1H),4.60(d,J=16.1 Hz,1H),4.56-4.48(m,1H),4.36-4.26(m,2H),3.90-3.81(m,2H),3.74-3.67(m,1H),3.55(dd,J=8.8 ,4.5Hz,1H),3.38-3.34(m,2H),2.96(s,3H),2.94-2.86(m,2H),2.24-2.15(m,1H),2.12-2.02(m,2H ),2.01-1.94(m,1H),1.93-1.85(m,2H),1.68-1.63(m,1H),1.63-1.56(m,2H),1.08(d,J=5.5Hz,3H).

[0703] Compound 54-2:

[0704] MS (ESI) M / Z: 500.4 [M+H] + .

[0705] 1H NMR (400MHz, DMSO-d6) δ7.39-7.23(m,2H),7.09-6.96(m,1H),6.01(d,J=5.6Hz,1H),4.60(d,J=16.1Hz,1 H),4.57-4.49(m,1H),4.35-4.26(m,2H),3.92(dd,J=8.9,6.3Hz,1H),3.87-3.80(m,1H),3.75-3.67(m,1 H),3.57(dd,J=8.9,4.6Hz,1H),3.39-3.35(m,2H),2.96(s,3H),2.94-2.85(m,2H),2.22-2.12(m,1H),2. 11-2.03(m,2H),1.99-1.84(m,3H),1.69-1.57(m,2H),1.52(dd,J=7.0,2.0Hz,1H),1.12(d,J=6.0Hz,3H).

[0706] Example 55: (R)-2-(3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7'-oxo-2'-((tetrahydrofuran-3-yl)amino)-5'-H-spiro[cyclopropane-8'-pyrido[3,4-b]pyrazine]-6'-(7'H)-yl)acetonitrile

[0707]

[0708] Steps:

[0709] Using 3,6-dichloropyrazine-2-carbonitrile as the starting material, referring to Example 47 and Example 53, the target molecule (R)-2-(3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7'-oxo-2'-((tetrahydrofuran-3-yl)amino)-5'-H-spiro[cyclopropane-8'-pyrido[3,4-b]pyrazine]-6'-(7'H)-yl)acetonitrile was obtained.

[0710] MS (ESI) M / Z: 511.4 [M+H] + .

[0711] 1H NMR (400MHz, DMSO-d6) δ7.38-7.22(m,2H),7.09-6.96(m,1H),5.99(d,J=5.7,1H),4.59(s,2H),4.56 (s,1H),4.54-4.48(m,1H),4.33-4.24(m,1H),3.87(dd,J=8.8,6.31,1H),3.85-3.79(m,1H),3.73-3 .69(m,1H),3.55-3.52(m,1H),3.37-3.20(m,2H),2.98-2.87(m,2H),2.20-2.11(m,1H),2.10-2.02( m,2H),1.99-1.95(m,1H),1.91-1.85(m,2H)1.49-1.46(m,2H),1.45-1.42(m,1H),1.39-1.36(m,1H).

[0712] Example 56: (R)-8-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-methyl-N-(tetrahydrofuran-3-yl)-10,11-dihydro-5H-pyranoazino[2,3-e][1,2,4]triazolo[4,3-a]azepin-7-amine

[0713]

[0714] Steps:

[0715] Step A: Dissolve 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,8,9-tetrahydro-7H-pyrano-azino[2,3-c]azepin-7-one (350 mg, 0.93 mmol) in tetrahydrofuran (20 mL) at room temperature. Add Lawesson's reagent (756 mg, 1.87 mmol) and heat to 80°C with stirring for 3 hours. Dilute with saturated sodium thiosulfate solution, extract with ethyl acetate, and dry. The organic phase is concentrated under reduced pressure, and the residue is purified on a silica gel column to yield 176 mg of the target molecule, 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,8,9-tetrahydro-7H-pyrano-azino[2,3-c]azepin-7-thione.

[0716] MS (ESI) M / Z: 391.2 [M+H] + .

[0717] Step B: 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,8,9-tetrahydro-7H-pyrano-azino[2,3-c]azepine-7-thione (176 mg, 0.45 mmol) was dissolved in tert-butyl alcohol (20 mL) at room temperature. Acetylhydrazine (67 mg, 0.90 mmol) was added and the mixture was heated to 130°C and stirred overnight. The organic phase was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate and dried. The crude product was purified on a silica gel column to obtain 113 mg of the target molecule, 8-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-methyl-10,11-dihydro-5H-pyrano-azino[2,3-e][1,2,4]triazolo[4,3-a]azepine.

[0718] MS (ESI) M / Z: 413.2 [M+H] + .

[0719] Step C: 8-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-methyl-10,11-dihydro-5H-pyrano-azino[2,3-e][1,2,4]triazolo[4,3-a]azepine (113 mg, 0.274 mmol) was dissolved in acetic acid / DMF (2 mL / 2 mL) at room temperature. NCS (47.4 mg, 0.35 mmol) was added and the reaction mixture was heated to 40°C and stirred overnight. The mixture was quenched with water, extracted with ethyl acetate, and dried. The organic phase was concentrated under reduced pressure and the crude product was purified on a silica gel column to afford 50 mg of the target molecule, 7-chloro-8-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-methyl-10,11-dihydro-5H-pyrano-azino[2,3-e][1,2,4]triazolo[4,3-a]azepine.

[0720] MS (ESI) M / Z: 447.4 [M+H] + .

[0721] Step D: 7-Chloro-8-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-methyl-10,11-dihydro-5H-pyrano-azino[2,3-e][1,2,4]triazolo[4,3-a]azepine (50 mg, 0.11 mmol) was dissolved in toluene (3 mL) at room temperature, and (R)-tetrahydrofuran-3-amine (29 mg, 0.33 mmol), Pd2(dba)3 (10.25 mg, 0.011 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (13.9 mg, 0.022 mmol) and sodium tert-butoxide (32.28 mg, 0.33 mmol) were added. The reaction solution was heated to 90°C and stirred for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 8.42 mg of the target product (R)-8-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-methyl-N-(tetrahydrofuran-3-yl)-10,11-dihydro-5H-pyranazino[2,3-e][1,2,4]triazolo[4,3-a]azepin-7-amine.

[0722] MS (ESI) M / Z: 499.0 [M+H] + .

[0723] 1 H NMR (400MHz, DMSO-d6) δ7.34-7.25(m,2H),7.04-6.98(m,1H),6.03(d,J=6.1Hz,1H),5.05(s,2H),4.6 0-4.48(m,1H),4.47-4.35(m,1H),3.96(dd,J=8.8,6.3Hz,1H),3.85(dd,J=14.5,7.9Hz,1H),3.77-3.6 7(m,1H),3.54(dd,J=8.8,5.0Hz,1H),3.41-3.35(m,2H),3.20-3.14(m,2H),3.02-2.96(m,2H),2.93- 2.83(m,2H),2.36(s,3H),2.24-2.15(m,1H),2.08-2.01(m,2H),2.01-1.92(m,1H),1.89-1.80(m,2H).

[0724] Example 57: 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-2-{[(3R)-oxolan-3-yl]amino}-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one

[0725]

[0726] Steps:

[0727] Step A: 3-Bromo-6-chloropyrazin-2-amine (1 g, 4.80 mmol), palladium acetate (0.11 g, 0.48 mmol), and tri-o-tolylphosphine (0.18 g, 0.58 mmol) were added to toluene (20 mL) at room temperature. Methyl acrylate (0.83 g, 9.6 mol) and DIPEA (0.93 g, 7.20 mol) were then added. The mixture was heated to 100°C in a microwave oven for 12 hours. Ethyl acetate (100 mL) was added to the mixture, and the mixture was washed with water (10 mL x 5). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to yield 491 mg of (2E)-3-(3-amino-5-chloropyrazin-2-yl)prop-2-enoic acid methyl ester.

[0728] MS (ESI) M / Z: 214.1 [M+H] + .

[0729] Step B: Under ice-cooling, dissolve (2E)-3-(3-amino-5-chloropyrazin-2-yl)prop-2-enoic acid methyl ester (200 mg, 0.94 mmol) in a mixture of ethyl acetate (5 mL) and methanol (5 mL). Add sodium borohydride (82.82 mg, 0.94 mmol) and keep the mixture in an ice-cooling bath for 10 minutes. Add water (10 mL) and extract with ethyl acetate (20 mL x 3). The organic phase is concentrated under reduced pressure to obtain 182 mg of crude methyl 3-(3-amino-5-chloropyrazin-2-yl)propanoate, which is directly used in the next reaction.

[0730] MS (ESI) M / Z: 216.1 [M+H] + .

[0731] Step C: Dissolve the crude methyl 3-(3-amino-5-chloropyrazin-2-yl)propanoate (182 mg) obtained in the previous step in tetrahydrofuran (10 mL) at room temperature, add potassium tert-butoxide (96.87 mg, 1.01 mmol), and react at room temperature for 1 hour. Add water (10 mL) and extract with ethyl acetate (20 mL x 3). The organic phase is concentrated under reduced pressure to obtain 150 mg of crude 3-chloro-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one, which is used directly in the next step.

[0732] MS (ESI) M / Z: 184.1 [M+H] + .

[0733] Step D: Dissolve the crude 3-chloro-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one (150 mg) in DMSO (5 mL) at room temperature, and add cesium carbonate (320.61 mg, 0.98 mmol) and iodomethane (174.59 mg, 1.23 mmol) sequentially. The mixture is reacted at room temperature for 1 hour. Water (5 mL) is added to the system, and the mixture is extracted with ethyl acetate (20 mL × 3 times). The organic phases are combined and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to obtain 145 mg of the compound 3-chloro-5-methyl-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one.

[0734] MS (ESI) M / Z: 198.1 [M+H] + .

[0735] Step E: At room temperature, 3-chloro-5-methyl-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one (50 mg, 0.25 mmol), 4-(2,4-difluorophenoxy)piperidine (53.5 mg, 0.25 mmol), Pd2(dba)3 (22.89 mg, 0.025 mmol) and 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (14.30 mg, 0.030 mmol) were added to anhydrous toluene (52 mL), and sodium tert-butoxide (60.06 mg, 0.63 mmol) was added. The mixture was sealed and heated to 90°C for 2 hours. After cooling to room temperature, water (5 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3 times). The combined organic phases were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 41 mg of compound 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one.

[0736] MS (ESI) M / Z: 375.2 [M+H] + .

[0737] Step F: 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one (40 mg, 0.11 mmol) was dissolved in a mixture of DMF (1 mL) and acetic acid (1 mL) at room temperature. NBS (19.58 mg, 0.11 mmol) was added and the mixture was heated to 40°C for 1 hour. After returning to room temperature, the reaction was quenched by the addition of saturated sodium thiosulfate (2 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 26.3 mg of 2-bromo-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one.

[0738] MS (ESI) M / Z: 453.1 [M+H] + .

[0739] Step G: At room temperature, 2-bromo-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one (26.3 mg, 0.058 mmol), Pd2(dba)3 (5.3 mg, 0.0058 mmol) and 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (3.32 mg, 0.0070 mmol) were added to anhydrous toluene (2 mL), and then (3R)-oxolane-3-amine (7.58 mg, 0.087 mmol) and sodium tert-butoxide (13.93 mg, 0.15 mmol) were added. The mixture was sealed and heated to 90°C for 2 hours. After returning to room temperature, water (10 mL) was added to the system, and extraction was carried out with ethyl acetate (10 mL × 3 times). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by preparative high-performance liquid chromatography to obtain 5.4 mg of the target molecule 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-2-{[(3R)-oxolan-3-yl]amino}-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one.

[0740] MS (ESI) M / Z: 460.2 [M+H] + .

[0741] 1H NMR (400MHz, DMSO-d6) δ7.36-7.24(m,2H),7.07-6.97(m,1H),5.64(d,J=6.1Hz ,1H),4.58-4.50(m,1H),4.43-4.33(m,1H),3.95-3.81(m,2H),3.75-3.66(m,1H ),3.55(dd,J=8.8,4.7Hz,1H),3.22(s,3H),3.02-2.91(m,2H),2.86-2.77(m,2 H),2.70-2.59(m,2H),2.23-2.14(m,1H),2.12-2.03(m,2H),1.98-1.87(m,3H).

[0742] Example 58: (R)-3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-isopropyl-2'-((tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-7'-one

[0743]

[0744] Steps:

[0745] Using 3,6-dichloropyrazine-2-carbonitrile and 2-bromopropane as raw materials, referring to Example 47 and Example 53, the target molecule (R)-3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-isopropyl-2'-((tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-7'-one was obtained.

[0746] MS (ESI) M / Z: 514.4 [M+H] + .

[0747] 1H NMR (400MHz, DMSO-d6) δ7.36-7.25(m,2H),7.06-6.97(m,1H),6.06(d,J=5.7Hz,1H),4.85-4.75(m, 1H),4.58-4.49(m,1H),4.36(s,2H),4.31-4.24(m,1H),3.90-3.78(m,2H),3.75-3.66(m,1H),3.55 (dd,J=8.8,4.7Hz,1H),3.30-3.27(m,2H),2.94-2.90(m,2H),2.20-2.12(m,1H),2.10-2.02(m,2H) ,1.99-1.86(m,3H),1.44-1.39(m,2H),1.35-1.30(m,1H),1.28-1.25(m,1H),1.16(d,J=6.8Hz,6H).

[0748] Example 59: 3'-((3,3-difluorocyclobutyl)amino)-2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazin]-7'-one

[0749]

[0750] Using 3,5-dichloropyrazine-2-carbonitrile and 3,3-difluorocyclobutylamine as raw materials, referring to Example 21, the target molecule 3'-((3,3-difluorocyclobutyl)amino)-2'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-7'-one was obtained.

[0751] MS (ESI) M / Z: 506.2 [M+H] + .

[0752] 1 H NMR (400MHz, DMSO-d6) δ7.39-7.25(m,2H),7.07-6.98(m,1H),6.52(d,J=6.8Hz,1H),4.61-4.52(m,1H),4.50(s,2H),4.26-4.15(m, 1H),3.43-3.35(m,2H),2.98(s,3H),2.97-2.85(m,4H),2.12-2.00(m,2H),1.92-1.79(m,2H),1.43-1.34(m,2H),1.26-1.22(m,2H).

[0753] Example 60: (R)-3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-2'-((tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'H-spiro[cyclobutane-1,8'-pyrido[3,4-b]pyrazine]-7'-one

[0754]

[0755] Using 3,6-dichloropyrazine-2-carbonitrile and 1,3-dibromopropane as starting materials, referring to Example 52, the target molecule (R)-3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-2'-((tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'H-spiro[cyclobutane-1,8'-pyrido[3,4-b]pyrazine]-7'-one was obtained.

[0756] MS (ESI) M / Z: 500.5 [M+H] + .

[0757] 1 H NMR(400MHz,DMSO-d6)δ7.36-7.23(m,2H),7.06-6.98(m,1H),6.11(d,J=5.6Hz,1H),4 .59-4.43(m,2H),4.31(s,2H),4.01(dd,J=8.8,6.3Hz,1H),3.92-3.83(m,1H),3.77-3. 72(m,1H),3.65(dd,J=8.8,4.7Hz,1H),3.42-3.35(m,2H),3.01-2.90(m,5H),2.60-2. 52(m,2H),2.41-2.32(m,2H),2.28-2.23(m,1H),2.17-2.01(m,5H),1.95-1.84(m,2H).

[0758] Example 61: (R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(tetrahydrofuran-3-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine

[0759]

[0760] Steps:

[0761] Step A: Using 6-benzyl-3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine and (R)-tetrahydrofuran-3-amine as starting materials, refer to Example 1 to obtain (R)-6-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-3-amine.

[0762] MS (ESI) M / Z: 522.1 [M+H] + .

[0763] Step B: (R)-6-Benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (196.2 mg, 0.38 mmol) was dissolved in anhydrous methanol (3 mL) at room temperature. Pd / C (50 mg, 10% wt) was added, and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to yield 60 mg of the crude target molecule (R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine, which was used directly in the next step.

[0764] MS (ESI) M / Z: 432.2 [M+H] + .

[0765] Step C: At room temperature, (R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (60 mg, 0.14 mmol), Pd2(dba)3 (12.82 mg, 0.014 mmol) and 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (12.28 mg, 0.014 mmol) were added to 1,4-dioxane (3 mL), and then 2-bromo-5-methyl-1,3,4-oxadiazole (34.22 mg, 0.21 mmol) and cesium carbonate (136.84 mg, 0.42 mmol) were added. The mixture was sealed and heated to 100°C for 16 hours. Water (5 mL) was added to the system, extracted with ethyl acetate (10 mL × 3 times), and the organic phase was concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography, and the collected product was lyophilized under reduced pressure to give 1.28 mg of the target molecule (R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(tetrahydrofuran-3-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine.

[0766] MS (ESI) M / Z: 514.2 [M+H] + .

[0767] 1 H NMR (400MHz, DMSO-d6) δ7.34-7.23(m,2H),7.05-6.95(m,1H),5.91(d,J=6.1Hz,1H),4.53-4.49(m,1H),4.39(s,3H),3.94-3.82(m,2H),3.77-3 .66(m,3H),3.36-3.26(m,2H),2.95-2.87(m,2H),2.78(t,J=5.9Hz,2H) ,2.35(s,3H),2.26-2.16(m,1H),2.09-2.00(m,2H),2.00-1.81(m,4H).

[0768] Example 62: (R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-3-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one

[0769]

[0770] Steps:

[0771] Step A: 3-Bromo-6-chloropyrazin-2-amine (5.00 g, 23.99 mmol) was dissolved in DMF (80 mL) and acetic acid (20 mL) at room temperature, and NCS (3.84 g, 28.79 mmol) was added. The reaction system was heated to 40°C for 5 hours. After cooling to room temperature, the reaction solution was quenched by the addition of saturated sodium thiosulfate (30 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 4.9 g of the compound product, 3-bromo-5,6-dichloropyrazin-2-amine.

[0772] MS (ESI) M / Z: 242.0 [M+H] + .

[0773] Step B: 3-Bromo-5,6-dichloropyrazin-2-amine (2.00 g, 8.23 ​​mmol), Pd(OAc)2 (184.77 mg, 0.48 mmol), and tri-o-tolylphosphine (1.25 g, 0.82 mmol) were added sequentially to a 25 mL microwave tube at room temperature. Toluene (15 mL) was then added, followed by methyl acrylate (637.67 mg, 7.41 mmol) and DIPEA (2.13 g, 16.46 mmol). The reaction system was heated to 100°C for 3 hours. After cooling to room temperature, ethyl acetate (100 mL) was added and the mixture was washed with water (20 mL x 5). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 1.22 g of the desired product, methyl ((2E)-3-(3-amino-5,6-dichloropyrazin-2-yl)prop-2-enoate).

[0774] MS (ESI) M / Z: 248.0 [M+H] + .

[0775] Step C: Methyl ((2E)-3-(3-amino-5,6-dichloropyrazin-2-yl)prop-2-enoate (1.00 g, 4.03 mmol) was dissolved in a mixture of ethyl acetate (20 mL) and methanol (10 mL) under ice-cooling. Sodium borohydride (243.63 mg, 6.44 mmol) was added and the mixture was allowed to react in an ice-cooling bath for 10 minutes. Water (30 mL) was added to the mixture, and the mixture was washed with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 772 mg of the target molecule, crude methyl 3-(3-amino-5,6-dichloropyrazin-2-yl)propanoate.

[0776] MS (ESI) M / Z: 250.1 [M+H] + .

[0777] Step D: Methyl 3-(3-amino-5,6-dichloropyrazin-2-yl)propanoate (772 mg, 3.09 mmol) was dissolved in THF (20 mL) at room temperature, and potassium tert-butoxide (416.07 mg, 3.71 mmol) was added. The mixture was allowed to react at room temperature for 1 hour. Water (20 mL) was added to quench the reaction, followed by washing with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 680 mg of the target molecule, 2,3-dichloro-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one.

[0778] MS (ESI) M / Z: 218.1 [M+H] + .

[0779] Step E: Dissolve 2,3-dichloro-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one (200 mg, 0.92 mmol) in DMSO (5 mL) at room temperature, then add cesium carbonate (359.71 mg, 1.1 mmol) and iodomethane (195.88 mg, 1.38 mmol) in sequence. The reaction system is allowed to react at room temperature for 1 hour. Ethyl acetate (50 mL) is added to the system, and the mixture is extracted with water (10 mL x 3). The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to obtain 145 mg of the desired product, 2,3-dichloro-5-methyl-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one.

[0780] MS (ESI) M / Z: 232.0 [M+H] + .

[0781] Step F: 2,3-Dichloro-5-methyl-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one (144 mg, 0.62 mmol) was dissolved in DMSO (2 mL) at room temperature, and (R)-tetrahydrofuran-3-amine (59.42 mg, 0.68 mmol), potassium fluoride (72.04 mg, 1.24 mmol), and DIPEA (240.39 mg, 1.86 mmol) were added in sequence. The reaction system was heated to 120°C in a microwave oven for 6 hours. After the reaction solution was cooled to room temperature, water (50 mL) was added and the mixture was washed with ethyl acetate (10 mL × 5 times). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 83 mg of the target product, 2-chloro-5-methyl-3-{[(3R)-oxolan-3-yl]amino}-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one.

[0782] MS (ESI) M / Z: 283.1 [M+H]+ .

[0783] Step G: 2-chloro-5-methyl-3-{[(3R)-oxolan-3-yl]amino}-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one (40 mg, 0.14 mmol), 4-(2,4-difluorophenoxy)piperidine hydrochloride (42.0 mg, 1.07 mmol), Pd2(dba)3 (12.82 mg, 0.014 mmol) and XPhos (8.01 mg, 0.017 mmol) were added to anhydrous toluene (2 mL) at room temperature, and sodium tert-butoxide (33.63 mg, 0.35 mmol) was added. The reaction system was heated to 90 ° C in a microwave for 6 hours. The reaction solution was cooled to room temperature and quenched with water (5 mL), followed by extraction with ethyl acetate (20 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give 17.14 mg of the product 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-3-{[(3R)-oxolan-3-yl]amino}-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one.

[0784] MS (ESI) M / Z: 460.2 [M+H] + .

[0785] 1 H NMR (400MHz, DMSO-d6) δ7.34-7.25(m,2H),7.04-6.98(m,1H),5.98(d,J=5.8Hz,1H),4. 52-4.48(m,1H),4.42-4.34(m,1H),3.98-3.94(m,1H),3.89-3.83(m,1H),3.75-3.69(m ,1H),3.62-3.58(m,1H),3.23(s,3H),3.22-3.18(m,2H),2.86(t,J=9.2Hz,2H),2.82-2 .76(m,2H),2.69-2.64(m,2H),2.26-2.17(m,1H),2.10-1.95(m,3H),1.91-1.86(m,2H).

[0786] Example 63: (R)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrido[2,3-b]pyrazin-6(5H)-one

[0787]

[0788] Steps:

[0789] Step A: 2-Bromo-5-methyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one (70 mg, 0.17 mmol) was dissolved in DCM (2 mL) at room temperature. DDQ (77.18 mg, 0.34 mmol) was then added to the reaction system and stirred at room temperature overnight. The reaction was quenched by the addition of water (5 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 29 mg of the desired product, 2-bromo-5-methyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5H,6Hpyrido[2,3-b]pyrazin-6-one.

[0790] MS (ESI) M / Z: 407.1 [M+H] + .

[0791] Step B: 2-Bromo-5-methyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5H,6Hpyrido[2,3-b]pyrazin-6-one (29 mg, 0.071 mmol) was dissolved in DMSO (1 mL) at room temperature, and (R)-tetrahydrofuran-3-amine (18.56 mg, 0.21 mmol), potassium fluoride (12.38 mg, 0.21 mmol), and DIPEA (27.53 mg, 0.21 mmol) were added in sequence. The reaction system was heated to 120 ° C in a microwave oven for 6 hours. The reaction solution was cooled to room temperature, filtered, and purified by preparative high performance liquid chromatography to give 6.74 mg of the target product 5-cyclomethyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-{[(3R)-oxolan-3-yl]amino}-5H,6Hpyrido[2,3-b]pyrazin-6-one.

[0792] MS (ESI) M / Z: 458.2 [M+H] + .

[0793] 1H NMR(400MHz,DMSO-d6)δ7.66(d,J=9.5Hz,1H),7.37-7.22(m,2H),7.04-6.9 9(m,1H),6.51(d,J=9.6Hz,1H),6.11-6.10(m,1H),4.64-4.59(m,1H),4.46 -4.39(m,1H),3.99-3.95(m,1H),3.86(q,J=7.5Hz,1H),3.78-3.68(m,3H),3.61 -3.57(m,4H),2.26-2.17(m,1H),2.13-2.10(m,2H),2.02-1.94(m,1H),1.92-1.81(m,2H).

[0794] Example 64: 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-((R)-tetrahydrofuran-3-yl)amino)-5,6,10,10-tetrahydro-8H-oxazolo[3',4':1,2]pyrido[3,4-b]pyrazin-8-one

[0795]

[0796] Steps:

[0797] Step A: Dissolve 2-chloropyridine-3,4-diamine (500 mg, 3.48 mmol) in hydrochloric acid (5 mL, 4 mol / L) at room temperature. Add oxalic acid (360 mg, 4.0 mmol) to the reaction mixture, heat to 120°C, and stir for 16 hours. Cool the reaction mixture to room temperature, filter, and wash the solid with water to obtain 520 mg of the crude target molecule, 5-chloropyrido[3,4-b]pyrazine-2,3-diol.

[0798] MS (ESI) M / Z: 198.2 [M+H] + .

[0799] 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),11.55(s,1H),8.00(d,J=5.3Hz,1H),7.11(d,J=5.3Hz,1H).

[0800] Step B: 5-chloropyrido[3,4-b]pyrazine-2,3-diol (520 mg, 2.63 mmol) was dissolved in phosphorus oxychloride (2.6 mL) at room temperature. The reaction system was heated to 75°C and stirred for half an hour. N,N-dibutylformamide (1.56 mL) was then slowly added dropwise to the reaction mixture, and stirring was continued at 75°C for 3 hours. The reaction mixture was cooled to room temperature and slowly poured into ice water (50 mL) to quench the mixture. The pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 540 mg of the target molecule, 2,3,5-trichloropyrido[3,4-b]pyrazine.

[0801] MS (ESI) M / Z: 234.1 [M+H] + .

[0802] 1 H NMR (400MHz, DMSO-d6) δ8.71 (d, J = 5.7Hz, 1H), 8.07 (d, J = 5.7Hz, 1H).

[0803] Step C: 2,3,5-Trichloropyrido[3,4-b]pyrazine (540 mg, 2.3 mmol) and 4-(2,4-difluorophenoxy)piperidine (467 mg, 2.19 mmol) were dissolved in N,N-dimethylacetamide (10 mL) at room temperature. DIEA (594.5 mg, 4.6 mmol) was then slowly added dropwise to the solution under ice-water bath. The reaction mixture was stirred under ice-water bath for 2 hours. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 620 mg of the target molecule, 3,5-dichloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine.

[0804] MS (ESI) M / Z: 411.3 [M+H] + .

[0805] 1H NMR (400MHz, DMSO-d6) δ8.41(d,J=5.7Hz,1H),7.64(d,J=5.7Hz,1H),7.41-7.25(m,2H),7.14-6.94(m ,1H),4.77-4.53(m,1H),4.15-3.79(m,2H),3.75-3.56(m,2H),2.23-2.06(m,2H),1.94-1.78(m,2H).

[0806] Steps: 3,5-dichloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[3,4-b]pyrazine (200 mg, 0.49 mmol) and potassium fluoride (37 mg, 0.64 mmol) were dissolved in DMSO (5 mL) at room temperature. TEA (69.4 mg, 0.69 mmol) and (R)-3-aminotetrahydrofuran (85.4 mg, 0.98 mmol) were then added to the above solution, and the reaction solution was heated to 60°C for 16 hours. After the reaction solution was cooled to room temperature, water (30 mL) was added to quench it. The mixture was extracted with ethyl acetate (10 mL × 3 times), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 210 mg of the target molecule (R)-5-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine.

[0807] MS (ESI) M / Z: 462.3 [M+H] + .

[0808] 1 H NMR(400MHz,DMSO-d6)δ8.07(d,J=5.4Hz,1H),7.46(d,J=5.4Hz,1H),7.39-7.25( m,3H),7.09-6.97(m,1H),4.68-4.61(m,1H),4.59-4.52(m,1H),4.11-4.06(m,1H) ,3.92-3.85(m,1H),3.83-3.73(m,3H),3.68(dd,J=9.0,4.9Hz,1H),3.42-3.36(m ,1H),3.34-3.30(m,1H),2.34-2.25(m,1H),2.15-2.05(m,3H),1.93-1.84(m,2H).

[0809] Step E: At room temperature, (R)-5-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine (1.8 g, 3.89 mmol), palladium acetate (87.6 mg, 0.39 mmol), 1,3-bis(diphenylphosphino)propane (321.7 mg, 0.78 mmol) and triethylamine (2.36 g, 23.34 mmol) were dissolved in methanol (100 mL). The reaction solution was reacted at 100°C under 40 atmospheres in a carbon monoxide system for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.5 g of the target molecule, (R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((tetrahydrofuran-3-yl)amino)pyrido[3,4-b]pyrazine-5-carboxylic acid methyl ester.

[0810] MS (ESI) M / Z: 486.5 [M+H] + .

[0811] 1 H NMR(400MHz, DMSO-d6)δ8.27(d,J=5.4Hz,1H),7.56(d,J=5.4Hz,1H),7.38-7.26(m, 2H),7.23(d,J=4.8Hz,1H),7.06-6.98(m,1H),4.68-4.59(m,1H),4.45-4.34(m,1H) ,4.00-3.94(m,1H),3.90(s,3H),3.88-3.82(m,1H),3.81-3.71(m,3H),3.70-3.63( m,1H),3.45-3.39(m,2H),2.27-2.17(m,1H),2.14-2.03(m,3H),1.95-1.82(m,2H).

[0812] Step F: Dissolve (R)-methyl 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((tetrahydrofuran-3-yl)amino)pyrido[3,4-b]pyrazine-5-carboxylate (300 mg, 0.62 mmol) in tetrahydrofuran (10 mL) at room temperature. Then, under nitrogen, slowly add LiAlH4 tetrahydrofuran solution (0.3 mL, 0.74 mmol) dropwise to the reaction system while cooling to -20°C. Continue the reaction at -20°C for 1 hour. After returning to room temperature, add tetrahydrofuran (30 mL) to dilute the reaction solution. Slowly add sodium sulfate decahydrate to quench the reaction solution, and stir the mixture at room temperature for 1 hour. Filter, wash, and concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 110 mg of (R)-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((tetrahydrofuran-3-yl)amino)pyrido[3,4-b]pyrazin-5-yl)methanol.

[0813] MS (ESI) M / Z: 458.5 [M+H] + .

[0814] 1 H NMR(400MHz,DMSO-d6)δ8.27(d,J=5.5Hz,1H),7.42(d,J=5.5Hz,1H),7.39-7.2 4(m,2H),7.10-6.96(m,2H),5.02-4.96(m,2H),4.93-4.87(m,1H),4.65-4.59(m ,1H),4.58-4.50(m,1H),4.06-4.03(m,1H),3.93-3.84(m,1H),3.80-3.66(m,4 H),3.30-3.25(m,2H),2.31-2.21(m,1H),2.16-2.05(m,3H),1.95-1.84(m,2H).

[0815] Step G: (R)-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((tetrahydrofuran-3-yl)amino)pyrido[3,4-b]pyrazin-5-yl)methanol (280 mg, 0.61 mmol) was dissolved in acetonitrile (3 mL) at room temperature. Benzyl bromide (115 mg, 0.67 mmol) was then added to the solution, and the reaction mixture was heated to 70°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to yield 336 mg of crude (R)-6-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(hydroxymethyl)-3-(tetrahydrofuran-3-yl)amino)pyrido[3,4-b]pyrazin-6-ium.

[0816] MS (ESI) M / Z: 548.5 [M+H] + .

[0817] Step H: Under ice, (R)-6-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(hydroxymethyl)-3-(tetrahydrofuran-3-yl)amino)pyrido[3,4-b]pyrazin-6-ium (336 mg, 0.61 mmol) was dissolved in acetonitrile (10 mL). Sodium acetate borohydride (543 mg, 2.56 mmol) was then added to the solution. After addition, the mixture was allowed to react at room temperature for 16 hours. Saturated aqueous sodium bicarbonate (30 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 88 mg of the target molecule (6-benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((R)-tetrahydrofuran-3-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-5-yl)methanol.

[0818] MS (ESI) M / Z: 552.5 [M+H] + .

[0819] 1 H NMR(400MHz,DMSO-d6)δ7.46-7.37(m,2H),7.37-7.19(m,5H),7.08-6.94(m,1H),5 .84-5.72(m,1H),4.58-4.47(m,1H),4.39-4.27(m,2H),3.96-3.66(m,7H),3.61-3 .44(m,2H),3.39-3.34(m,1H),3.31-3.27(m,2H),3.18-3.08(m,1H),2.97-2.84(m ,2H),2.79-2.62(m,2H),2.23-2.12(m,1H),2.11-2.02(m,2H),1.95-1.82(m,3H).

[0820] Step I: (6-Benzyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((R)-tetrahydrofuran-3-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-5-yl)methanol (68 mg, 0.12 mmol) was dissolved in methanol (7 mL) at room temperature. Palladium hydroxide (41 mg, 20%), palladium on carbon (68 mg, 10%), and concentrated hydrochloric acid (3 drops) were then added to the solution. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through celite and washed with methanol (10 mL x 3). The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 45 mg of the target molecule (2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((R)-tetrahydrofuran-3-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-5-yl)methanol.

[0821] MS (ESI) M / Z: 462.5 [M+H] + .

[0822] 1 H NMR(400MHz,DMSO-d6)δ7.39-7.23(m,2H),7.12-6.95(m,1H),6.04-5.87(m,1H),5.12- 4.94(m,1H),4.58-4.47(m,1H),4.39-4.26(m,1H),4.08-3.77(m,4H),3.76-3.63(m,2H ),3.60-3.51(m,1H),3.29-3.15(m,4H),3.13-3.04(m,1H),2.98-2.86(m,2H),2.82-2. 73(m,1H),2.68-2.56(m,1H),2.21-2.15(m,1H),2.10-2.02(m,2H),2.00-1.83(m,3H).

[0823] Step J: Dissolve (2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((R)-tetrahydrofuran-3-yl)amino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-5-yl)methanol (35 mg, 0.076 mmol) in tetrahydrofuran (1.5 mL) at room temperature. Triethylamine (76.9 mg, 0.76 mmol) and N,N'-carbonyldiimidazole (61.5 mg, 0.38 mmol) were then added to the solution. The reaction mixture was sealed and heated to 80°C with stirring for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (8 mL x 5). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 16.88 mg of the target molecule 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-((R)-tetrahydrofuran-3-yl)amino)-5,6,10,10-tetrahydro-8H-oxazolo[3',4':1,2]pyrido[3,4-b]pyrazin-8-one.

[0824] MS (ESI) M / Z: 488.5 [M+H] + .

[0825] 1 H NMR (400MHz, DMSO-d6) δ7.33-7.23(m,2H),7.08-6.88(m,1H),6.07(dd,J=8.3,6.1Hz,1H),4.89-4.81(m,1H),4.67 (t,J=8.6Hz,1H),4.57-4.49(m,1H),4.39-4.26(m,2H),3.95-3.80(m,3H),3.74-3.67(m,1H),3.59-3.52(m,1H),3 .40-3.34 (m, 3H), 2.99-2.86 (m, 2H), 2.85-2.73 (m, 1H), 2.58-2.52 (m, 1H), 2.24-2.12 (m, 1H), 2.11-2.01 (m, 2H), 1.98-1.79 (m, 3H). Example 65: (R)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-ethyl-2-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one

[0826]

[0827] Steps:

[0828] Using 3-bromo-6-chloropyrazin-2-amine and iodoethane as starting materials, the preparation method was prepared with reference to Example 57 to obtain 37.55 mg of the target molecule (R)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-ethyl-2-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one.

[0829] MS (ESI) M / Z: 474.5 [M+H] +.

[0830] 1 H NMR (400MHz, DMSO-d6) δ7.37-7.23(m,2H),7.04-6.98(m,1H),5.64(d,J=6.0Hz,1H),4.61- 4.48(m,1H),4.43-4.33(m,1H),3.96-3.80(m,4H),3.75-3.66(m,1H),3.55(dd,J=8.7,4.7H z,1H),3.44-3.34(m,2H),3.02-2.88(m,2H),2.88-2.76(m,2H),2.66-2.56(m,2H),2.22-2 .13(m,1H),2.11-2.03(m,2H),1.98-1.92(m,1H),1.92-1.84(m,2H),1.10(t,J=6.9Hz,3H).

[0831] Example 66: (R)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(methyl-d3)-2-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one

[0832]

[0833] Steps

[0834] Using 3-bromo-6-chloropyrazin-2-amine and deuterated iodomethane as raw materials, the preparation method was referred to Example 57 to obtain 20.14 mg of the target molecule (R)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(methyl-d3)-2-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one.

[0835] MS (ESI) M / Z: 463.4 [M+H] + .

[0836] 1H NMR (400MHz, DMSO-d6) δ7.37-7.24(m,2H),7.06-6.97(m,1H),5.63(d,J=6.0Hz,1H ),4.58-4.49(m,1H),4.40-4.36(m,1H),3.93-3.88(m,1H),3.87-3.80(m,1H),3.74 -3.68(m,1H),3.57-3.53(m,1H),3.42-3.37(m,2H),2.99-2.93(m,2H),2.85-2.81( m,2H),2.65-2.61(m,2H),2.22-2.14(m,1H),2.10-2.06(m,2H),1.98-1.81(m,3H).

[0837] Example 67: 3-((3R,4R)-4-(2,4-difluorophenoxy)-3-fluoropiperidin-1-yl)-5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one

[0838]

[0839] Steps:

[0840] Using (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester as raw material, the preparation method was referred to INT-1 and Example 57 to obtain 4.48 mg of the target molecule 3-((3R,4R)-4-(2,4-difluorophenoxy)-3-fluoropiperidin-1-yl)-5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one.

[0841] MS (ESI) M / Z: 478.4 [M+H] + .

[0842] 1H NMR (400MHz, DMSO-d6) δ7.46-7.24(m,2H),7.07-6.99(m,1H),5.76(d,J=6.0Hz,1H),5.15-5.09(m,0.5H),5.02-4.96 (m,0.5H),4.67-4.54(m,1H),4.41-4.35(m,1H),3.93-3.84(m,2H),3.79-3.67(m,2H),3.57-3.54(m,1H),3.43-3.40 (m, 1H), 3.22 (s, 3H), 3.00-2.87 (m, 2H), 2.86-2.82 (m, 2H), 2.70-2.61 (m, 2H), 2.23-2.12 (m, 2H), 1.97-1.89 (m, 1H), 1.87-1.78 (m, 1H). Example 68: (R)-5-Cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one

[0843]

[0844] Steps:

[0845] With reference to the preparation process of other embodiments of the present invention, 3.1 mg of the target product (R)-5-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one was obtained.

[0846] MS (ESI) M / Z: 486.3 [M+H] + .

[0847] 1 H NMR (400MHz, DMSO-d6) δ7.34-7.24(m,2H),7.01(t,J=8.7Hz,1H),5.62(d,J=6.1Hz,1H), 4.55(s,1H),4.37(d,J=6.5Hz,1H),3.94-3.81(m,2H),3.71(q,J=7.5Hz,1H),3.56-3.53( m,1H),3.45(d,J=3.0Hz,2H),2.97(q,J=11.2Hz,2H),2.76(d,J=7.7Hz,2H),2.58(d,J=7 .5Hz,2H),2.22-1.98(m,4H),1.93(d,J=17.6Hz,3H),0.93(d,J=6.9Hz,2H),0.53(s,2H).

[0848] Example 69: (R)-5-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-((tetrahydrofuran-3-yl)amino)pyrido[2,3-b]pyrazin-6(5H)-one

[0849]

[0850] Steps:

[0851] Referring to the preparation process of other embodiments of the present invention, 2.07 mg of product (R)-5-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-((tetrahydrofuran-3-yl)amino)pyrido[2,3-b]pyrazin-6(5H)-one was obtained.

[0852] MS (ESI) M / Z: 484.2 [M+H] + .

[0853] 1 H NMR (400MHz, DMSO-d6) δ7.61 (d, J=9.6Hz, 1H), 7.38-7.26 (m, 2H), 7.05 -7.00(m,1H),6.43(d,J=9.6Hz,1H),6.11(d,J=5.7Hz,1H),4.66-4.59(m,1H),4 .43-4.38(m,1H),3.98-3.94(m,1H),3.88-3.83(m,1H),3.78-3.67(m,3H),3.60 -3.57(m,1H),3.27-3.21(m,2H),2.91-2.85(m,1H),2.24-2.16(m,1H),2.1 3-2.10(m,2H),2.01-1.83(m,3H),1.14(d,J=6.9Hz,2H),0.83-0.75(m,2H).

[0854] Example 70: (R)-5-methyl-2-((tetrahydrofuran-3-yl)amino)-3-(4-(2,4,5-trifluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one

[0855]

[0856] Steps:

[0857] Using 2,4,5-trifluorophenol and 3-bromo-6-chloropyrazin-2-amine as raw materials, the preparation method was referred to Example INT-1 and Example 57 to obtain 13.23 mg of the target molecule (R)-5-methyl-2-((tetrahydrofuran-3-yl)amino)-3-(4-(2,4,5-trifluorophenoxy)piperidin-1-yl)-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one.

[0858] MS (ESI) M / Z: 478.4 [M+H] +.

[0859] 1 H NMR(400MHz,DMSO-d6)δ7.67-7.48(m,2H),5.64(d,J=6.1Hz,1H),4.66-4.57(m ,1H),4.44-4.33(m,1H),3.95-3.80(m,2H),3.75-3.67(m,1H),3.55(dd,J=8.8, 4.7Hz,1H),3.42-3.36(m,2H),3.21(s,3H),3.04-2.92(m,2H),2.87-2.78(m,2 H),2.66-2.59(m,2H),2.23-2.13(m,1H),2.13-2.03(m,2H),1.98-1.82(m,3H).

[0860] Example 71: (R)-2-(4-(2,4-difluorophenoxy)-4-ethynylpiperidin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine

[0861]

[0862] Steps:

[0863] Step A: Dissolve 3-chloroperbenzoic acid (3.95 g, 22.91 mmol) in dichloromethane (25 mL) at room temperature. Add 2,4-difluoro-1-iodobenzene (5 g, 20.83 mmol) and boron trifluoride etherate (6.80 g, 47.91 mmol). Stir the reaction mixture under nitrogen for 30 minutes. Then, cool the mixture to 0°C and add (2,4-difluorophenyl)boric acid (3.62 g, 22.91 mmol). Stir for another 15 minutes. Purify the mixture directly by silica gel column chromatography to obtain 3 g of boron tetrafluoride bis(2,4-difluorophenyl)iodonium salt.

[0864] MS (ESI) M / Z: 353.0 [M+H] + .

[0865] Step B: Dissolve tert-butyl 4-ethynyl-4-hydroxypiperidine-1-carboxylate (0.41 g, 1.82 mmol) in toluene (18 mL) at room temperature. Cool the reaction mixture to 0°C under nitrogen. Add sodium bis(trimethylsilyl)amide (1.82 mL, 1 M in toluene) and continue stirring for 30 minutes. Then, add boron tetrafluoride bis(2,4-difluorophenyl)iodonium salt (0.8 g, 1.82 mmol). Heat the reaction mixture to 60°C under nitrogen and continue stirring for 5 hours. Cool the reaction mixture to room temperature and quench with ammonium chloride (10 mL). Extract the mixture with ethyl acetate (20 mL x 3). Combine the organic phases and wash with sodium chloride (10 mL x 2). Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.19 g of tert-butyl 4-(2,4-difluorophenoxy)-4-ethynylpiperidine-1-carboxylate.

[0866] MS (ESI) M / Z: 238.2 [M-99] + .

[0867] Step C: Dissolve tert-butyl 4-(2,4-difluorophenoxy)-4-ethynylpiperidine-1-carboxylate (0.18 g, 0.53 mmol) in 1,4-dioxane hydrochloric acid solution (4 mL, 4 M) at room temperature. Stir the reaction system under nitrogen for 4 hours. Concentrate the reaction mixture under reduced pressure to obtain 0.15 g of 4-(2,4-difluorophenoxy)-4-ethynylpiperidine hydrochloride.

[0868] MS (ESI) M / Z: 238.2 [M+H] + .

[0869] Step D: Dissolve 2,3-dichloropyrido[3,4-b]pyrazine hydrochloride (0.030 g, 0.13 mmol) and N,N-diisopropylethylamine (0.034 g, 0.26 mmol) in dimethyl sulfoxide (1 mL) at room temperature. The reaction system is then cooled to 0°C under nitrogen. Add 4-(2,4-difluorophenoxy)-4-ethynylpiperidine hydrochloride (0.031 g, 0.13 mmol), warm to room temperature, and continue stirring for 1 hour. Water (10 mL) is added to the reaction mixture to quench it. The mixture is extracted with ethyl acetate (10 mL x 3). The organic phases are combined and washed with aqueous sodium chloride (20 mL x 2). The mixture is then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.03 g of the compound 1-(3-chloropyrido[3,4-b]pyrazin-2-yl)-4-(2,4-difluorophenoxy)-4-ethynylpiperidine.

[0870] MS (ESI) M / Z: 401.1 [M+H]+ .

[0871] Step E: Dissolve 1-(3-chloropyrido[3,4-b]pyrazin-2-yl)-4-(2,4-difluorophenoxy)-4-ethynylpiperidine (0.03 g, 0.075 mmol), potassium fluoride (0.0052 g, 0.090 mmol), and DIEA (0.039 g, 0.30 mmol) in DMSO (1 mL) at room temperature. (R)-3-aminotetrahydrofuran (0.0065 g, 0.075 mmol) was then added to the reaction mixture. The reaction mixture was heated to 70°C under nitrogen and stirred for 1 hour. The reaction solution was purified by preparative high performance liquid chromatography to obtain 0.017 g of the compound 4-(2,4-difluorophenoxy)-1-(3-{[(3R)-oxolan-3-yl]amino}pyrido[3,4-b]pyrazin-2-yl)piperidine-4-carbonitrile.

[0872] MS (ESI) M / Z: 452.2 [M+H] + .

[0873] 1 H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.39-8.22(m,1H),7.56-7.44(m,2H),7.40-7.29(m,1H),7.13-7.00(m,2H),4.68-4.5 2(m,1H),4.05-3.96(m,1H),3.94-3.82(m,2H),3.80-3.61(m,4H),3.33-3.30(m,2H),2.34-2.13(m,5H),2.11-2.01(m,1H).

[0874] Example 72: (R)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methoxy-2-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one

[0875]

[0876] Steps:

[0877] With reference to the preparation process of other embodiments of the present invention, 3.6 mg of the target product (R)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methoxy-2-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one (3.6 mg, yellow solid) was obtained.

[0878] MS (ESI) M / Z: 476.5 [M+H] + .

[0879] 1 HNMR(400MHz,DMSO-d6)δ7.37-7.23(m,2H),7.06-6.97(m,1H),5.78(d,J=6.1Hz,1H ),4.61-4.51(m,1H),4.44-4.33(m,1H),3.94-3.84(m,2H),3.84(s,3H),3.75-3.68 (m,1H),3.59-3.52(m,1H),3.42-3.35(m,2H),3.02-2.91(m,2H),2.83(t,J=7.5Hz, 2H), 2.68 (t, J = 7.4Hz, 2H), 2.24-2.14 (m, 1H), 2.12-2.04 (m, 2H), 1.98-1.85 (m, 3H).

[0880] Example 73: (R)-1-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-((tetrahydrofuran-3-yl)amino)pyrido[2,3-b]pyrazin-6-yl)ethan-1-one

[0881]

[0882] Steps:

[0883] Step A: 6-chloropyridine-2,3-diamine (14.3 g, 100 mmol) and oxalic acid (13.5 g, 150 mmol) were added to water (160 mL) and concentrated hydrochloric acid (16 mL) at room temperature. The reaction mixture was heated to 100°C for 6 hours. After the reaction mixture cooled to room temperature, it was filtered to obtain 18 g of the target molecule, 6-chloropyrido[2,3-b]pyrazine-2,3-diol.

[0884] MS (ESI) M / Z: 198.1 [M+H] + .

[0885] Step B: 6-chloropyrido[2,3-b]pyrazine-2,3-diol (7.88 g, 40 mmol) was added to dichloromethane (50 mL) at room temperature, followed by thionyl chloride (5.81 mL, 80 mmol). DMF (0.5 mL) was slowly added under nitrogen, and the reaction system was heated to 45°C for 6 hours. The reaction solution was returned to room temperature and quenched with ice water. The mixture was extracted with dichloromethane, and the combined organic phases were washed with saturated brine, dried, filtered, and concentrated to obtain 8 g of the target product, 2,3,6-trichloropyrido[2,3-b]pyrazine.

[0886] MS (ESI) M / Z: 234.0 [M+H] + .

[0887] Step C: Dissolve 2,3,6-trichloropyrido[2,3-b]pyrazine (1.17 g, 5 mmol) in DMSO (15 mL) at room temperature, add 4-(2,4-difluorophenoxy)piperidine (1.07 g, 5 mmol) and DIEA (2.6 mL, 15 mmol), and continue stirring at room temperature for 2 hours. Water (100 mL) is added to the mixture to quench it. Extract with ethyl acetate (20 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to yield 1 g of the desired product, 2,6-dichloro-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[2,3-b]pyrazine.

[0888] MS (ESI) M / Z: 411.1 [M+H] + .

[0889] Step D: 2,6-Dichloro-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)pyrido[2,3-b]pyrazine (410 mg, 1 mmol) was dissolved in DMSO (5 mL) at room temperature. (R)-tetrahydrofuran-3-amine (87 mg, 1 mmol) and DIEA (0.52 mL, 3 mmol) were added at room temperature. The reaction system was heated to 60°C and stirred for 1 hour. The reaction system was cooled to room temperature and quenched with water (50 mL). The reaction was washed with ethyl acetate (10 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 300 mg of the desired product, (R)-6-chloro-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[2,3-b]pyrazin-2-amine.

[0890] MS (ESI) M / Z: 462.2 [M+H] + .

[0891] Step E: (R)-6-chloro-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[2,3-b]pyrazin-2-amine (46.1 mg, 0.1 mmol) was dissolved in toluene (1 mL), and tributyl(1-ethoxyethylene)tin (54.1 mg, 0.15 mmol) and tetrakistriphenylphosphine palladium (11.5 mg, 0.01 mmol) were added in sequence. The reaction system was heated to 110 ° C in a microwave under nitrogen protection for 1.5 hours. After the reaction system was cooled to room temperature, 2N dilute hydrochloric acid (3 mL) was added to the system and stirring was continued for 1 hour. The mixture was then extracted with ethyl acetate (1 mL × 3 times). The organic phases were combined and then added with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by high performance liquid chromatography to give 11.27 mg of the product (R)-1-(3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-((tetrahydrofuran-3-yl)amino)pyrido[2,3-b]pyrazin-6-yl)ethan-1-one.

[0892] MS (ESI) M / Z: 470.2 [M+H] + .

[0893] 1 H NMR(400MHz,DMSO-d6)δ7.98-7.93(m,2H),7..37-7.27(m,3H),7.06 -7.01(m,1H),4.68-4.60(m,2H),3.99(dd,J=8.8,6.4Hz,1H),3.92-3.87(m,1H),3.78-3.67(m ,4H),3.30-3.27(m,2H),2.68(s,3H),2.29-2.20(m,1H),2.11-2.05(m,3H),1.97-1.89(m,2H).

[0894] Example 74: (R)-1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((tetrahydrofuran-3-yl)amino)pyrido[2,3-b]pyrazin-6-yl)ethan-1-one

[0895]

[0896] Steps:

[0897] Step A: Dissolve 2,3,6-trichloropyrido[2,3-b]pyrazine (1.17 g, 5 mmol) in DMSO (15 mL) at room temperature, then add (R)-tetrahydrofuran-3-amine (435 mg, 5 mmol) and DIEA (2.6 mL, 15 mmol). Stir the reaction system at room temperature for 2 hours. Slowly add the reaction solution dropwise to water (100 mL) and continue stirring for 1 hour. A white solid precipitates, which is filtered to yield 1.3 g of the desired product, (R)-1-(2-chloro-3-((tetrahydrofuran-3-yl)amino)pyrido[2,3-b]pyrazin-6-yl)ethan-1-one.

[0898] MS (ESI) M / Z: 285.1 [M+H] + .

[0899] Step B: (R)-1-(2-chloro-3-((tetrahydrofuran-3-yl)amino)pyrido[2,3-b]pyrazin-6-yl)ethan-1-one (410 mg, 1 mmol) was dissolved in DMSO (5 mL) at room temperature, followed by the addition of 4-(2,4-difluorophenoxy)piperidine (213 mg, 1 mmol) and DIEA (0.52 mL, 3 mmol). The reaction system was heated to 65°C in a microwave oven and stirred for 1 hour. After cooling to room temperature, the reaction solution was slowly added dropwise to water (100 mL) and stirred for 1 hour. A light yellow solid gradually precipitated. After filtration, 300 mg of the desired product (R)-6-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[2,3-b]pyrazin-3-amine was obtained as a light yellow solid.

[0900] MS (ESI) M / Z: 462.2 [M+H] + .

[0901] Step C: At room temperature, (R)-6-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[2,3-b]pyrazin-3-amine (46.1 mg, 0.1 mmol) was dissolved in toluene (1 mL), and tributyl(1-ethoxyethylene)tin (54.1 mg, 0.15 mmol) and tetrakistriphenylphosphine palladium (11.5 mg, 0.01 mmol) were added in sequence. The reaction system was heated to 110 ° C in a microwave under nitrogen protection for 1.5 hours. After the reaction system was cooled to room temperature, 2N dilute hydrochloric acid (3 mL) was added and stirring was continued for 1 hour. The mixture was extracted with ethyl acetate (1 mL × 3 times). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance liquid chromatography to give 6.32 mg of the target product (R)-1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((tetrahydrofuran-3-yl)amino)pyrido[2,3-b]pyrazin-6-yl)ethan-1-one.

[0902] MS (ESI) M / Z: 470.2 [M+H] + .

[0903] 1 H NMR(400MHz, DMSO-d6)δ8.03(d,J=8.0Hz,1H),7.84(d,J=8.4Hz,1H),7.36-7.27( m,2H),7.22(d,J=6.4Hz,1H),7.05-7.00(m,1H),4.76-4.69(m,1H),4.65-4.59(m ,1H),3.98(dd,J=8.8,6.4Hz,1H),3.94-3.88(m,1H),3.80-3.69(m,4H),3.30-3. 25(m,2H),2.69(s,3H),2.29-2.24(m,1H),2.12-2.05(m,3H),1.94-1.86(m,2H).

[0904] Example 75-1 and Example 75-2:

[0905] (6aR,7aS)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)-5,6a,7,7a-tetrahydro-6H-cyclopropane[4,5]pyrido[2,3-b]pyrazin-6-one (6aS,7aR)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)-5,6a,7,7a-tetrahydro-6H-cyclopropane[4,5]pyrido[2,3-b]pyrazin-6-one

[0906]

[0907] Steps:

[0908] Step A: Under nitrogen protection at room temperature, sodium hydroxide (69.6 mg, 60% wt) and trimethyl sulfone iodide (389.52%, 1.77 mmol) were added to DMSO (3 mL). After reacting for 15 min, a DMSO (2 mL) solution of 2-chloro-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5H,6Hpyrido[2,3-b]pyrazin-6-one (240 mg, 0.59 mmol) was slowly added dropwise to the reaction system and reacted overnight under nitrogen atmosphere at room temperature. Ethyl acetate (100 mL) was added to the reaction system, and the mixture was extracted with water (10 mL × 5 times). The organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 182 mg of the target molecule 2-chloro-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5H,6Hpyrido[2,3-b]pyrazin-6-one.

[0909] MS (ESI) M / Z: 421.0 [M+H] + .

[0910] Step B: 2-chloro-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-5H,6Hpyrido[2,3-b]pyrazin-6-one (91 mg, 0.22 mmol), tris(dibenzylideneacetone)dipalladium (20.15 mg, 0.026 mmol) and 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (12.59 mg, 0.026 mmol) were added to a 25 mL microwave tube, anhydrous toluene (2 mL) was added, and ((R)-tetrahydrofuran-3-amine (28.75 mg, 0.33 mmol) and sodium tert-butoxide (46.51 mg, 0.48 mmol) was added and heated at 90°C for 6 hours. LCMS monitoring showed the disappearance of the starting material and the formation of the target product. Water (10 mL) was added to the system, followed by washing with ethyl acetate (10 mL × 3). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC. The mobile phase was water (containing 0.1% formic acid) and acetonitrile. The product was collected and lyophilized under reduced pressure to obtain 19.17 mg of the target molecule, 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)-5,6a,7,7a-tetrahydro-6H-cyclopropane[4,5]pyrido[2,3-b]pyrazin-6-one.

[0911] 5.33 mg of compound 75-1 (t R=1.241min) and 4.25mg of compound 75-2 (t R =1.651 min). Separation conditions (instrument: SFC-150 mg / m (waters); column: Daicel OJ (25*250 mm, 10 μm); temperature: 30°C; mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 60 / 40; flow rate: 100 mL / min; pressure: 100 bar, detection wavelength: 214 nm; cycle time: 7 min; sample concentration: 19.17 mg dissolved in 5.4 mL MeOH; injection volume: 2.7 mL).

[0912] Compound 75-1:

[0913] MS (ESI) M / Z: 472.2 [M+H] + .HPLC purity:100%;ee%:100%

[0914] 1 H NMR (400MHz, DMSO-d6) δ7.37-7.22(m,2H),7.04-6.97(m,1H),5.62(d,J=6.0Hz,1H),4.58-4.48(m,1H),4.46- 4.38(m,1H),3.98-3.91(m,1H),3.89-3.81(m,1H),3.77-3.68(m,1H),3.64-3.57(m,1H),3.49-3.39(m,1H),3 .36(s,1H),3.20(s,3H),3.11-2.99(m,1H),2.93-2.82(m,1H),2.47-2.44(m,1H),2.25-2.15(m,2H),2.13-2. 06(s,1H),2.05-1.97(m,1H),1.97-1.85(m,2H),1.84-1.74(m,1H),1.62-1.52(m,1H),0.58(q,J=4.8Hz,1H).

[0915] Compound 75-2:

[0916] MS (ESI) M / Z: 472.2 [M+H] + .HPLC purity:100%;ee%:100%

[0917] 1H NMR (400MHz, DMSO-d6) δ7.36-7.24(m,2H),7.06-6.95(m,1H),5.64(d,J=6.3Hz,1H),4.58-4 .47(m,1H),4.49-4.39(m,1H),3.96-3.91(m,1H),3.90-3.81(m,1H),3.75-3.65(m,1H),3.57 -3.49(m,1H),3.46-3.39(m,1H),3.38-3.32(s,1H),3.20(s,3H),3.07-2.98(m,1H),2.95-2 .85(m,1H),2.47-2.42(m,1H),2.26-2.16(m,2H),2.12-1.87(m,4H),1.86-1.75(m,1H),1.62

[0918] -1.52(m,1H),0.58(q,J=4.8Hz,1H).

[0919] Example 76: (R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-3-((tetrahydrofuran-3-yl)amino)pyrido[2,3-b]pyrazin-6(5H)-one

[0920]

[0921] Steps:

[0922] Step A: 2-chloro-5-methyl-3-{[(3R)-oxolan-3-yl]amino}-5H,6H,7H,8Hpyrido[2,3-b]pyrazin-6-one (40 mg, 0.14 mmol) was added to DCM (2 mL) at room temperature, followed by the addition of 2,3-dichloro-5,6-dicyanobenzoquinone (33.4 mg, 0.15 mmol) and stirred at room temperature for 3 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed by vortexing under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 32 mg of the target molecule, 2-chloro-5-methyl-3-{[(3R)-oxolan-3-yl]amino}-5H,6Hpyrido[2,3-b]pyrazin-6-one.

[0923] MS (ESI) M / Z: 281.2 [M+H] + ;

[0924] Step B: 2-chloro-5-methyl-3-{[(3R)-oxolan-3-yl]amino}-5H,6Hpyrido[2,3-b]pyrazin-6-one (32 mg, 0.11 mmol) was added to DMSO (1 mL) at room temperature, followed by the addition of DIEA (55 μL, 0.33 mmol), potassium fluoride (12.8 mg, 0.22 mmol) and 4-(2,4-difluorophenoxy)piperidine (35.2 mg, 0.17 mmol), and microwave heating to 160 ° C for 2 hours. The reaction mixture was cooled to room temperature and quenched with water. The mixture was extracted three times with ethyl acetate (30 mL x 3 times). The combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography to afford 4.5 mg of the target molecule (R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-3-((tetrahydrofuran-3-yl)amino)pyrido[2,3-b]pyrazin-6(5H)-one.

[0925] MS (ESI) M / Z: 458.2 [M+H] + ;

[0926] 1 H NMR(400MHz,DMSO-d6)δ7.68(d,J=9.5Hz,1H),7.36-7.27(m,2H),7.08-7.0 0(m,2H),6.39(d,J=9.5Hz,1H),4.63-4.52(m,2H),4.03(dd,J=8.9,6.4Hz, 1H),3.95-3.87(m,1H),3.81-3.69(m,2H),3.60(s,3H),3.39-3.34(m,2H), 3.03-2.91(m,2H),2.31-2.24(m,1H),2.15-2.07(m,3H),1.99-1.90(m,2H).

[0927] Example 77: (R)-3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-(methyl-d3)-2'-(tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-7'-one-5',5'-d2

[0928]

[0929] Steps:

[0930] Using sodium deuterated borohydride and deuterated iodomethane as raw materials, the preparation method was prepared according to Example 47 to obtain 20.78 mg of the target molecule (R)-3′-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6′-(methyl-d3)-2′-(tetrahydrofuran-3-yl)amino)-5′,6′-dihydro-7′H-spiro[cyclopropane-1,8′-pyrido[3,4-b]pyrazine]-7′-one-5′,5′-d2.

[0931] MS (ESI) M / Z: 491.4 [M+H] + .

[0932] 1 H NMR (400MHz, DMSO-d6) δ7.36-7.26(m,2H),7.06-6.98(m,1H),6.08(d,J=5.6Hz,1H ),4.59-4.47(m,1H),4.34-4.22(m,1H),3.92-3.78(m,2H),3.75-3.65(m,1H),3.58 -3.50(m,1H),3.33-3.26(m,2H),2.98-2.83(m,2H),2.21-2.10(m,1H),2.10-2.01( m,2H),2.00-1.82(m,3H),1.45-1.36(m,2H),1.36-1.29(m,1H),1.29-1.22(m,1H).

[0933] Example 78: (R)-3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2'-((tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-7'-one-5',5'-d2

[0934]

[0935] Steps:

[0936] Using sodium deuterated borohydride as the starting material, the preparation method was similar to that in Example 47 to give 15.42 mg of the target molecule (R)-3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2'-((tetrahydrofuran-3-yl)amino)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-7'-one-5',5'-d2.

[0937] MS (ESI) M / Z: 474.4 [M+H] + .

[0938] 1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.35-7.22(m,2H),7.05-6.98(m,1H),6.03( d,J=5.6Hz,1H),4.57-4.46(m,1H),4.34-4.22(m,1H),3.91-3.79(m,2H),3.74-3. 65(m,1H),3.57-3.49(m,1H),3.31-3.24(m,2H),2.96-2.83(m,2H),2.22-2.11(m ,1H),2.10-2.01(m,2H),2.00-1.82(m,3H),1.43-1.29(m,3H),1.28-1.22(m,1H).

[0939] Example 79: 2-((2-oxabicyclo[2.1.1]hexan-4-yl)amino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one

[0940]

[0941] Steps:

[0942] Using 2-oxabicyclo[2.1.1]hexan-4-amine as the starting material, the preparation method was similar to that in Example 57 to obtain 4.98 mg of the target molecule 2-((2-oxabicyclo[2.1.1]hexan-4-yl)amino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-methyl-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one.

[0943] MS (ESI) M / Z: 472.4 [M+H] + .

[0944] 1 H NMR (400MHz, DMSO-d6) δ7.37-7.23(m,2H),7.07-6.97(m,1H),6.35(s,1H),4.58-4.49(m,1H),4.42(s,1H),3.72(s,2H),3.4 2-3.37(m,2H),3.21(s,3H),3.01-2.92(m,2H),2.86-2.79(m,2H),2.68-2.60(m,2H),2.12-2.02(m,4H),1.94-1.83(m,4H).

[0945] Example 80: 2-((2-oxabicyclo[2.1.1]hexan-4-yl)amino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-ethyl-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one

[0946]

[0947] Steps

[0948] Using iodoethane and 2-oxabicyclo[2.1.1]hexan-4-amine as raw materials, the preparation method was similar to Example 57 to obtain 12.21 mg of the target molecule 2-((2-oxabicyclo[2.1.1]hexan-4-yl)amino)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-ethyl-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one.

[0949] MS (ESI) M / Z: 486.3 [M+H] +.

[0950] 1 H NMR (400MHz, DMSO-d6) δ7.37-7.25(m,2H),7.04-6.98(m,1H),6.38(s,1H),4.61-4.50(m,1H),4.42(s,1H),3.96-3.86(m,2H),3.72(s,2H) ,3.41-3.36(m,2H),2.99-2.89(m,2H),2.87-2.77(m,2H),2.66-2.60(m,2H),2.11-2.04(m,4H),1.93-1.84(m,4H),1.10(t,J=7.0Hz,3H).

[0951] Example 81: (R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-ethyl-3-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one

[0952]

[0953] Steps:

[0954] Using iodoethane as the starting material, the preparation method was similar to that in Example 62 to obtain 16.96 mg of the target molecule (R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-ethyl-3-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one.

[0955] MS (ESI) M / Z: 474.5 [M+H] + .

[0956] 1 H NMR (400MHz, DMSO-d6) δ7.35-7.23(m,2H),7.06-6.96(m,1H),5.98(d,J=5.6Hz,1H),4.5 7-4.45(m,1H),4.39-4.29(m,1H),4.00-3.89(m,3H),3.89-3.82(m,1H),3.76-3.68(m,1H ),3.65-3.60(m,1H),3.27-3.16(m,2H),2.91-2.81(m,2H),2.81-2.75(m,2H),2.68-2.6 2(m,2H),2.26-2.16(m,1H),2.11-1.96(m,3H),1.95-1.84(m,2H),1.12(t,J=6.9Hz,3H).

[0957] Example 82: 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,8-dimethyl-2-((R)-tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one

[0958]

[0959] Steps:

[0960] With reference to the preparation process of other embodiments of the present invention, 70 mg of the target molecule 2-chloro-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,8-dimethyl-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one was obtained.

[0961] MS (ESI) M / Z: 423.4 [M+H] + .

[0962] 1 H NMR (400MHz, DMSO-d6) δ7.39-7.25(m,2H),7.07-6.97(m,1H),4.63-4.53(m,1H),3.73-3.63(m,2H),3.27-3.23(m,5H),3.16 -3.10(m,1H),2.84(dd,J=16.0,6.1Hz,1H),2.58-2.52(m,1H),2.10-2.02(m,2H),1.82-1.73(m,2H),1.21(d,J=6.9Hz,3H).

[0963] Step H: Dissolve 2-chloro-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,8-dimethyl-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one (35 mg, 0.083 mmol), (R)-tetrahydrofuran-3-amine (8.7 mg, 0.1 mmol), tris(dibenzylideneacetone)palladium (7.6 mg, 0.0083 mmol), 1,1′-binaphthyl-2,2′-bisdiphenylphosphine (7.8 mg, 0.0124 mmol), and sodium tert-butoxide (15.95 mg, 0.166 mmol) in toluene (1 mL) at room temperature. Heat to 90°C under nitrogen in a sealed tube and stir for 2 hours. Cool the reaction mixture to room temperature, filter it, and concentrate the filtrate under reduced pressure. The resulting residue is purified by preparative HPLC. 13.9 mg of 3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,8-dimethyl-2-((R)-tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one was obtained.

[0964] MS (ESI) M / Z: 474.4 [M+H] + .

[0965] 1 H NMR(400MHz,DMSO-d6)δ7.39-7.23(m,2H),7.06-6.95(m,1H),5.72-5.55(m,1H),4.59-4.48 (m,1H),4.41-4.31(m,1H),3.97-3.90(m,1H),3.88-3.80(m,1H),3.74-3.68(m,1H),3.58-3. 52(m,1H),3.44-3.41(m,2H),3.22(s,3H),3.02-2.91(m,3H),2.78-2.70(m,1H),2.44-2.37( m,1H),2.24-2.14(m,1H),2.12-2.03(m,2H),1.99-1.83(m,3H),1.20(dd,J=6.9,1.2Hz,3H).

[0966] Example 83: 3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-2'-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazin]-7'-one

[0967] Steps

[0968] Step A: At room temperature, 2'-chloro-3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-5',6'-dihydro-7'-H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-7'-one (60 mg, 0.138 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (65 mg, 0.276 mmol), Pd(dtbpf)Cl2 (9 mg, 0.0138 mmol), and cesium carbonate (90 mg, 0.276 mmol) were dissolved in 1,4-dioxane / water (1 mL / 0.1 mL). The reaction solution was sealed and heated to 90°C for 2 hours.

[0969] The reaction solution was returned to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give 43.83 mg of the target molecule 3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-2'-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazin]-7'-one.

[0970] MS (ESI) M / Z: 508.4 [M+H] + .

[0971] 1 H NMR (400MHz, DMSO-d6) δ8.34(d,J=2.5Hz,1H),8.11-8.04(m,1H),7.33-7.24(m,2H),7.04-6.97(m,1H),6.49(d,J=9.5Hz,1H),4.65(s,2H),4.5 5-4.44(m,1H),3.53(s,3H),3.44-3.37(m,2H),3.03-2.94(m,5H),2.05 -1.95(m,2H),1.79-1.68(m,2H),1.55-1.48(m,2H),1.47-1.40(m,2H).

[0972] Example 84: 2'-(6-(Difluoromethyl)pyridin-2-yl)-3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazin]-7'-one

[0973]

[0974] Steps

[0975] Step A: At room temperature, 2'-chloro-3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-5',6'-dihydro-7'-H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazine]-7'-one (50 mg, 0.12 mmol), 2-(difluoromethyl)-6-(trimethyltinyl)pyridine (0.5 mL), Pd(dtbpf)Cl2 (8 mg, 0.012 mmol), and cesium carbonate (78 mg, 0.24 mmol) were dissolved in 1,4-dioxane (1 mL). The reaction solution was sealed and heated to 90°C for 4 hours.

[0976] The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give 8.35 mg of the target molecule 2'-(6-(difluoromethyl)pyridin-2-yl)-3'-(4-(2,4-difluorophenoxy)piperidin-1-yl)-6'-methyl-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[3,4-b]pyrazin]-7'-one.

[0977] MS (ESI) M / Z: 528.2 [M+H] + .

[0978] 1 H NMR (400MHz, DMSO-d6) δ8.14(t,J=7.8Hz,1H),8.00(d,J=7.9Hz,1H),7.72(d,J=7.5Hz,1H),7.3 1-7.20(m,2H),7.14-6.82(m,2H),4.69(s,2H),4.50-4.42(m,1H),3.41-3.34(m,2H),3.06-2.94 (m, 5H), 1.91-1.80 (m, 2H), 1.64-1.53 ​​(m, 2H), 1.53-1.46 (m, 2H), 1.39-1.32 (m, 2H). Example 85: (R)-4-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)furan-2(5H)-one

[0979]

[0980] Steps:

[0981] Step A: At room temperature, 2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-[(3R)-oxol-3-yl]-5H,6H,7H,8H-pyrido[3,4-b]pyrazine-3-amine (100 mg, 0.23 mmol) was added to isopropanol (1 mL), followed by the addition of oxolane-2,4-dione (50.64 mg, 0.51 mmol) and acetic acid (41.43 mg, 0.69 mmol), and the reaction solution was heated to 110 ° C for 1 hour in a microwave oven. The reaction mixture was returned to room temperature, and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL × 3 times). The organic phase was concentrated under reduced pressure, and the resulting residue was purified by preparative high-performance liquid chromatography to afford 20.21 mg of the target molecule (R)-4-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)furan-2(5H)-one.

[0982] MS (ESI) M / Z: 514.3 [M+H] + .

[0983] 1 H NMR (400MHz, DMSO-d6) δ7.33-7.25(m,2H),7.04-6.98(m,1H),5.97(d,J=6.4Hz ,1H),4.93(s,2H),4.86(s,1H),4.54-4.50(m,1H),4.42-4.37(m,1H),4.25(s, 2H),3.92-3.83(m,2H),3.74-3.69(m,1H),3.57-3.55(m,3H),3.30-3.28(m,1H ),2.94-2.73(m,5H),2.22-2.14(m,1H),2.07-2.05(m,2H),1.99-1.84(m,3H).

[0984] Biological activity examples

[0985] The following detailed embodiments further illustrate the agonistic effects of the compounds of the present invention on the GPR6 signaling pathway and other in vitro and in vivo effects, demonstrating that the compounds of the present invention are effective for treating GPR6-related diseases. The beneficial effects of the compounds of the present invention include, but are not limited to, the following specific implementation details.

[0986] Experimental Example 1: Detection of GPR6 inverse agonist activity of the disclosed compounds

[0987] The GRP6 inverse agonist activity of the example compounds was tested using the HTRF cAMP assay.

[0988] Experimental Materials:

[0989] 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); and a cAMP kit was purchased from Perkin Elmer (catalog number: TRF0263); IBMX was purchased from Sigma (catalog number: I5879); HEPES was purchased from Gibco (catalog number: 15630080); 384-well compound dilution plate was purchased from Labcyte (catalog number: PP-0200); 384-well experimental plate was purchased from PerkinElmer (catalog number: 6007680); Envision was purchased from Perkin Elmer (model: 2105).

[0990] Experimental methods:

[0991] The Flp-In-TREx-293-human GPR6 cell line, whose gene expression is regulated by a tetracycline-inducible element, was cultured in complete DMEM (DMEM-high glucose), 10% fetal bovine serum, 1% penicillin / streptomycin, 200 μg / mL hygromycin B, and 15 μg / mL blasticidin S at 37°C in a 5% CO2 incubator. On the day of the experiment, test compounds were serially diluted in DMSO, and 50 nL was transferred to a 384-well plate. After inducing receptor expression for 4 hours with complete medium containing 1 μg / mL tetracycline, cells were digested and resuspended in an assay buffer consisting of HBSS, 20 mM HEPES, 0.1% fatty acid-free BSA, and 500 μM IBMX. 500–1000 cells were seeded into 384-well plates at a volume of 20 μL per well and incubated at 37°C for 30 minutes. Subsequently, 5 μL of Eu-cAMP tracer and Ulight-anti-cAMP detection reagent working solution were added to the 384-well experimental plate, respectively. After incubation at room temperature for 1 hour, data were collected using the Envision HTRF module.

[0992] Data processing: XFit four-parameter equation was used to process and fit the data and calculate the IC of the compound. 50 value:

[0993] Calculation formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope))

[0994] Y: activity %; X: logarithmic value of compound concentration;

[0995] Top / bottom: upper and lower platforms of the curve; Hill Slope: slope of the curve.

[0996] Experimental results:

[0997]

[0998]

[0999] Experimental Example 2: Detection of the inverse agonist activity of the disclosed compounds on human GPR3, GPR6, and GPR12

[1000] The inverse agonist activity of the example compounds on human GPR3, GRP6 and GPR12 was tested using the HTRF cAMP assay.

[1001] Experimental Materials:

[1002] cAMP kit was purchased from Perkin Elmer (catalog number: TRF0263); 384-well assay plate was purchased from Perkin Elmer (catalog number: 6007680); and Envision was purchased from Perkin Elmer (model: 2105).

[1003] Experimental methods:

[1004] On the day of the experiment, the positive control and test compound were serially diluted in DMSO, and 50 nL was transferred to a 384-well assay plate. HEK293 human GPR3, GPR6, and GPR12 stable cell lines were conditioned and digested, then resuspended in an assay buffer consisting of HBSS, 20 mM HEPES, 0.1% fatty acid-free BSA, and 500 μM IBMX. 500-1000 cells were seeded into 384-well assay plates at a volume of 20 μL per well and incubated at 37°C for 30 minutes. Subsequently, 5 μL of the Eu-cAMP tracer and Ulight-anti-cAMP detection reagent working solutions were added to the 384-well assay plates, incubated at room temperature for 1 hour, and data were collected using the Envision HTRF module.

[1005] Data processing: XFit four-parameter equation was used to process and fit the data and calculate the IC of the compound. 50 value:

[1006] Calculation formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope))

[1007] Y: activity %; X: logarithmic value of compound concentration;

[1008] Top / bottom: upper and lower platforms of the curve; Hill Slope: slope of the curve.

[1009] Experimental results:

[1010]

[1011]

[1012]

[1013] The disclosed compounds have good inverse agonist activity against GPR6 and good selectivity relative to GPR3 ​​and GPR12.

[1014] Experimental Example 3 Whole-cell manual patch clamp assay

[1015] This experiment used the electrophysiological whole-cell manual voltage clamp method to test the effects of compounds on hERG potassium channel (human Ether-a-go-go Related Gene potassium channel) currents.

[1016] 1. Experimental Materials

[1017] Cisapride, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, glucose, HEPES, EGTA, and DMSO were purchased from Sigma. The CHO-hERG cell line (Chinese Hamster Ovary) (Chinese hamster ovary cells stably expressing hERG channels) was constructed in-house by the Ion Channel Research Platform of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences.

[1018] 2. Experimental Methods

[1019] 1) Cell Culture and Treatment: CHO cells stably expressing hERG were cultured in 35 mm diameter cell culture dishes in a 37°C, 5% CO2 incubator. The cells were passaged every 48 hours at a 1:5 ratio. The culture medium consisted of 90% F12 (Invitrogen), 10% fetal bovine serum (Gibco), 100 μg / mL G418 (Invitrogen), and 100 μg / mL Hygromycin B (Invitrogen). On the day of the experiment, the cell culture medium was aspirated, the cells were rinsed once with extracellular medium, and then digested with 0.25% Trypsin-EDTA (Invitrogen) solution at room temperature for 3-5 minutes. The digestion medium was aspirated, the cells were resuspended in extracellular medium, and then transferred to a dish for electrophysiological recording.

[1020] 2) Compound Preparation: On the day of testing, prepare the compound to a 20 mM stock solution in DMSO. Then, serially dilute the stock solution three-fold with DMSO and dilute it again with extracellular fluid to the desired final concentration. For the positive control compound, cisapride, prepare 10 μL of a 150 μM cisapride DMSO stock solution to 4990 μL of extracellular fluid and dilute 500-fold to a final concentration of 300 nM. The DMSO content in the final test concentration does not exceed 0.2%, as this concentration of DMSO has no effect on hERG potassium channels.

[1021] 3) Electrophysiological Recording Procedure: hERG potassium channel currents were recorded using the whole-cell voltage-clamp technique at room temperature in CHO cells stably expressing the hERG potassium channel. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. After perfusion with electrode solution, the tip resistance was approximately 2-5 MΩ. The microelectrodes were connected to the patch clamp amplifier by inserting them into the amplifier headstage. Clamp voltage and data recording were controlled and recorded by a computer using pClamp software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After whole-cell recordings were obtained, cells were clamped at -100 mV. To elicit hERG potassium currents (IhERG), a step voltage was applied from -100 mV to +20 mV for 2 s, followed by repolarization to -50 mV for 1 s before returning to -100 mV. This voltage stimulus was applied every 5 s, and drug administration was initiated after confirming the stability of the hERG potassium current (1 min). Compounds were administered for at least 1 minute to steady state of action or for a maximum of 3 minutes at each test concentration, and at least two cells (n≥2) were tested at each concentration.

[1022] 4) Data analysis and processing were performed using pClamp, GraphPad Prism 8, and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current evoked at -50 mV) by different compound concentrations was calculated using the following formula: Inhibition% = [1 – (I / Io)] × 100%, where Inhibition% represents the percentage of inhibition of the hERG potassium current by the compound, and I and Io represent the hERG potassium current amplitudes before and after drug addition, respectively.

[1023] Compound IC 50 Calculated using GraphPad Prism 8 software by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope))

[1024] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[1025] Test Example 2: Pharmacokinetics of the compounds of the present invention in mice and rats

[1026] Mice and rats were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in mouse plasma after intravenous injection and oral injection. Plasma samples were collected at specific time points, and the compound concentration in plasma was detected by LC-MS / MS. PK parameters were calculated.

[1027] 1. Experimental Plan

[1028] 1.1 Investigational Drugs:

[1029] Some compounds of the present invention.

[1030] 1.2 Experimental animals

[1031] Female balb / c nude mice were purchased from Sibeifu (Beijing) Biotechnology Co., Ltd.

[1032] Male SD rats were purchased from Spectrum Biotechnology Co., Ltd.

[1033] 1.3 Administration

[1034] Information on the dosing of the test compound in mice: Both the IV (intravenous injection) and PO (oral) experimental groups consisted of 3 mice. The IV dose for mice was 1 mg / kg, and the dosing volume was 2 mL / kg. The PO dose for mice was 3 mg / kg, and the dosing volume was 10 mL / kg. The dosing vehicle was 10 vol% DMSO / 20 vol% Solutol / 70 vol% Saline.

[1035] Dosing information for the test compound in rats: IV dose is 1 mg / kg, the dosing volume is 5 mL / kg; PO dose is 5 mg / kg, the dosing volume is 10 mL / kg, and the dosing solvent is 510 vol% DMSO / 20 vol% Solutol / 70 vol% Saline.

[1036] 1.4 Experimental Equipment

[1037] The centrifuge and pipette were purchased from Eppendorf.

[1038] 1.5 Sample collection

[1039] After administration to mice and rats, 0.025, 0.2, 0.5, 1, 2, 4, 8, and 24 hours, venous blood was collected, respectively, at 0.0833 (IV), 0.25, 0.5, and 0.6 mL, placed in EDTA-K2 tubes, centrifuged at 4°C, 2000g for 10 min to separate plasma, and stored at -80°C.

[1040] 1.6 Sample processing

[1041] Mouse plasma sample processing:

[1042] 1) 10 μL of plasma sample was added to 200 μL of acetonitrile for precipitation, vortexed and centrifuged for 15 minutes.

[1043] 2) The supernatant after treatment was diluted with water and analyzed by LC / MS / MS for the concentration of the test compound.

[1044] Rat plasma sample processing:

[1045] 1) 50 μL of plasma sample was added to 200 μL of acetonitrile for precipitation, vortexed and centrifuged for 15 minutes.

[1046] 2) The supernatant after treatment was diluted with water and analyzed by LC / MS / MS for the concentration of the test compound.

[1047] Pharmacokinetic parameters were calculated using WinNonlin 6.1. Here, Cmax represents the maximum plasma drug concentration, CL represents clearance, Vss represents the volume of distribution at steady state, T1 / 2 represents the terminal elimination half-life, MRTInf represents the mean residence time, AUC represents the area under the drug-dose curve, and F represents bioavailability.

Claims

1. A compound represented by general formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, or a hydrate thereof, characterized in that: X 1 、X 2 are independently selected from N, CR 5 ; R 5 Selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy; Ring A is selected from 5-6 membered heteroaryl, 5-10 membered heterocycloalkenyl, 6-10 membered bridged heterocycloalkenyl, C 3-6 cycloalkenyl; Ring B is selected from C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 7-8 membered bridged heterocyclic group, 7-11 membered spiroheterocyclic group, 6-10 membered fused heterocyclic group; Ring C is selected from phenyl, 5-6 membered heteroaryl; R 1 Independently selected from the following groups: H, deuterium, oxo, CN, OH, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-6 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl-C 1-6 Alkylene, C 1-6 Alkoxy, 5-6 membered heteroaryl, COOH, =C(R 1c )(R 1d ), C 1-6 Alkyl-C(O)-C(O)-, C 2-6 Alkynyl-C(O)-, C 2-6 alkenyl-C(O)-, Alternatively, two R 1 Connect to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 5-6 membered heteroaryl, Alternatively, two R on adjacent ring atoms 1 Together with the atoms it is connected to form C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl; Among them, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-6 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl-C 1-6 Alkylene, C 1-6 Alkoxy, 5-6 membered heteroaryl are optionally substituted with one or more R 1A replaced by; R 1A Selected from deuterium, halogen, OH, (R 1a )(R 1b )N-、COOH、C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, CN, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy; R 1a 、R 1b 、R 1c 、R 1d are independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl-C(O)-, or R 1a 、R 1b The nitrogen atom to which it is connected forms a 3-6 membered heterocyclic group, or R 1c 、R 1d The atom to which it is connected forms a C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; R 2 Selected from H, OH, NH2, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, CN, C 2-6 Alkenyl, C 2-6 Alkynyl, or two R on adjacent ring atoms 2 Together with the ring atoms to which it is connected, it forms a C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; R 3 Selected from H, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 Alkynyl, C 2-6 alkenyl; 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)-; R L1a 、R L1b are independently selected from H, halogen, C 1-6 Alkyl, or R L1a and one of the R 3 Together with the atoms it is connected to form C 5-6 Cycloalkenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl; L 2 Selected from a chemical 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-; R L2a 、R L2b are independently selected from H, OH, halogen, C 1-6 Alkyl, C 1-6 alkoxy; R 4 Selected from OH, or optionally one or more R 4a Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-C(O)-, 3-6 membered heterocyclic group, 6-8 membered bridged heterocyclic group, 7-11 membered spiro heterocyclic group, 6-10 membered fused heterocyclic group, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, phenyl; R 4a Selected from CN, halogen, NH2, OH, 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 -, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8; n, p, q, and t are independently selected from 0, 1, 2, 3, and 4.

2. The compound according to claim 1, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that: X 1 、X 2 All are N.

3. The compound according to claim 1 or 2, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that: Ring A is selected from 5-7 membered heterocycloalkenyl; Preferably, ring A is selected from 5-7 membered nitrogen-containing heterocycloalkenyl; Preferably, ring A is selected from 6-7 membered heterocycloalkenyl; Preferably, ring A is selected from 6-7 membered nitrogen-containing heterocycloalkenyl; Preferably, the heteroatom in the 6-7 membered nitrogen-containing heterocycloalkenyl group is 1 N and 0-1 atoms selected from O, S or N.

4. The compound according to claim 1 or 2, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that: Ring A is selected from 5. The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that: R 1 Independently selected from the following groups: H, deuterium, oxo, CN, OH, halogen, C 1-4 Alkyl, C 1-4 Alkyl-C(O)-, C 1-4 Alkyl-S(O)2-, C 1-4 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-4 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered heterocyclyl-C 1-4 Alkylene, C 1-4 Alkoxy, 5-6 membered heteroaryl, -COOH, =C(R 1c )(R 1d ), C 1-4 Alkyl-C(O)-C(O)-, C 2-4 Alkynyl-C(O)-, C 2-4 alkenyl-C(O)-; Alternatively, two R 1 Connect to form C 3-6 Cycloalkyl, 4-6 membered heterocyclic group; Alternatively, two R on adjacent ring atoms 1 Together with the atoms it is connected to form C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl; Among them, the C 1-4 Alkyl, C 1-4 Alkyl-C(O)-, C 1-4 Alkyl-S(O)2-, C 1-4 Alkoxy-C(O)-, (R 1a )(R 1b )NC(O)-、(C 1-4 alkyl)2P(O)-、(R 1a )(R 1b )N-、C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered heterocyclyl-C 1-4 Alkylene, C 1-4 Alkoxy, 5-6 membered heteroaryl are optionally substituted with one or more R 1A substituted, the R 1A Selected from deuterium, halogen, OH, (R 1a )(R 1b )N-、COOH、C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, CN, halogenated C 1-4 alkyl; R 1a 、R 1b 、R 1c 、R 1d are independently selected from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkyl-C(O)-, or R 1a 、R 1b and the nitrogen atom to which it is connected form a 5-6 membered heterocyclic group; or R 1c 、R 1d The atom to which it is connected forms a C 3-6 Cycloalkyl, 4-6 membered heterocyclic group; m is selected from 0, 1, 2, 3, 4, 5, 6; Preferably, m is selected from 0, 1, 2, 3, 4.

6. The compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that: R 1 Selected from H, oxo, CN, -CH 3、 CH3C(O)-, -OCH3, (CH3)2P(O)-, CH3S(O)2-, CH3O-C(O)-, CH3NH-C(O)-, CH3C(O)-NH-, OH, F, -CH2CH3, -CH2CH2OCH3, -CH2CN, -CH2CH3, -CH(CH3)2, cyclopropyl, -CH2CHF2, CH3-NH-, -COOH, -N(CH3)2, CF3CH2-、-CD3、-D、 Alternatively, two R 1 Connect to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, "*" indicates the connection position with ring A; Alternatively, two R on adjacent ring atoms 1 Together with the atoms to which they are connected, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Preferably, two R on the same carbon atom 1 Connect to form a cyclopropyl group; Preferably, two R on adjacent ring atoms 1 Together with the atoms to which it is connected, it forms a cyclopropyl or cyclobutyl group.

7. The compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that: Structural unit Selected from 8. The compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that: Ring B is selected from 5-6 membered heterocyclic group, C 4-6 Cycloalkyl; Preferably, ring B is selected from "*" indicates the same as L 1 Ends are connected.

9. The compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that: R 2 Selected from H, OH, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, or two R on adjacent ring atoms 2 Together with the ring atoms to which it is connected, it forms a C 3-6 Cycloalkyl; Preferably, R 2 Selected from H, OH, F, Cl, -CH3, -CH2CH3; or, two R on adjacent ring atoms 2 Together with the ring atoms to which they are attached, they form cyclopropyl, cyclobutyl, or cyclopentyl; n is selected from 0, 1 or 2.

10. The compound according to any one of claims 1 to 9, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that: L 1 Selected from -O-, -N(R L1a )-、-C(R L1a R L1b )-、-C(R L1a )=、-S(O)2-;R L1a 、R L1b are independently selected from H, halogen, C 1-4 alkyl; Preferably, R L1a 、R L1b Each independently selected from H, F, Cl, -CH3; Preferably, L 1 Selected from -O-, -NH-, -CHF-, -CF2-, -CH2-, -CH=, -CF=, -S(O)2-, -CH(CH3)-; Preferably, L 1 Selected from -O-.

11. The compound according to any one of claims 1 to 10, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that: Ring C is selected from phenyl, 5-6 membered heteroaryl; Preferably, ring C is selected from phenyl and pyridine.

12. The compound according to any one of claims 1 to 11, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that: R 3 Selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-4 Alkynyl, C 2-4 alkenyl; Preferably, R 3 Selected from F, Cl, -CH3, -CF3, HC≡C-, CH3C≡C-.

13. The compound according to any one of claims 1 to 12, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that: Structural unit for 14. The compound according to any one of claims 1 to 13, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that: L 2 Selected from chemical bonds, -N(R L2a )-、-C(O)-、-C(O)-N(R L2a )-、-C(R L2a R L2b )-N(R L2a )-、-N=C(R L2a )-、-N(R L2a )-O-;R L2a 、R L2b are independently selected from H, OH, halogen, C 1-4 Alkyl, C 1-4 alkoxy; Preferably, L 2 Selected from chemical bonds, -NH-, -CH2-NH-, -C(O)-NH-, -C(O)-, -N=C(CH3)-, -NH-O-; Preferably, L 2 Selected from chemical bonds, -NH-.

15. The compound according to any one of claims 1 to 14, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that: R 4 Selected from OH, or optionally replaced by one or more R 4a Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-C(O)-, 3-6 membered heterocyclic group, 6-8 membered bridged heterocyclic group, 6-8 membered fused heterocyclic group, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, phenyl; R 4a Selected from CN, NH2, OH, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkylene, C 3-6 Cycloalkyl-(CH2) t -, 3-6 membered heterocyclic group-(CH2) t -, deuterated C 1-4 Alkyl; t is selected from 0, 1, 2; Preferably, R 4 Selected from OH, (CH3)2CH-, -OCH3, -OCH2CH3, optionally with one or more R 4a Substituted groups: R 4a Selected from CN, NH2, OH, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkylene, C 3-6 Cycloalkyl-(CH2) t -, 3-6 membered heterocyclic group-(CH2) t -, deuterated C 1-4 Alkyl; t is selected from 0, 1, 2; Preferably, R 4a Selected from CN, -CH3, -CH2CH3, -CH2F, -OCH3, -CH2CH2OCH3, NH2, F, OH, -CHF2, -CD3.

16. The compound according to claim 15, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, characterized in that: R 4 Selected from OH, (CH3)2CH-, -OCH3, -OCH2CH3, 17. The compound according to any one of claims 1 to 16, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, or its hydrate, having a structure represented by the following general formula: R 1 、R 4 、R 3 , p as defined in any one of claims 1 to 16; X 3 Selected from O, S, CH2, N(R 1 ); Preferably, ma is selected from 0, 1, 2, 3, 4, 5, 6, 7; Preferably, ma is selected from 0, 1, 2, 3, 4, 5; Preferably, ma is selected from 0, 1, 2, 3, 4; Preferably, ma is selected from 0, 1, 2, 3; Preferably, ma is selected from 0, 1, and 2.

18. The following compounds, their pharmaceutically acceptable salts, stereoisomers, isotope-labeled substances, solvates, and hydrates:

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, its hydrate and one or more pharmaceutically acceptable carriers.

20. Use of the compound according to any one of claims 1 to 18, its pharmaceutically acceptable salt, stereoisomer, isotope-labeled substance, solvate, or hydrate thereof, or the pharmaceutical composition according to claim 19 in the preparation of a medicament for preventing and / or treating a disease mediated by GPR6.

21. The use according to claim 20, 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 disorders and depression.

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