Pyridine-containing polycyclic derivative modulators, methods of making and using the same

Abstract

The present application relates to a kind of pyridine polycyclic derivative regulator, its preparation method and application, and the present application relates to a kind of pyridine polycyclic derivative regulator, its preparation method and application.Specifically, the present application relates to the compound shown in general formula (I), its preparation method and pharmaceutical composition containing the compound, and its application as regulator in the preparation of treating Parkinson's disease related drugs, wherein each substituent in general formula (I) is the same as defined in the specification.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to a regulator containing pyridine polycyclic derivatives, its preparation method, and its application. Background Technology

[0002] Leucine-rich repeat kinase 2 (LRRK2), encoded by the LRRK2 gene, is a large, multifunctional protein with serine-threonine kinase and GTPase activities. Rho kinase (ROCK), encoded by the Rho gene, is a serine / threonine kinase belonging to the Rho subgroup of the Ras superfamily, and plays a switching role in cell signaling. Abnormalities in the LRRK2 and ROCK pathways can lead to various diseases, including Parkinson's disease (PD) and glaucoma.

[0003] Parkinson's disease (PD) is a neurodegenerative disorder associated with movement disorders, including bradykinesia, rigidity, tremor, and postural instability. Pathological features of PD include intracellular inclusions containing α-synuclein aggregates and the loss of dopamine (DA) neurons in the substantia nigra. Currently available drug treatments can slow disease progression. However, the current goal of treatment is symptom relief, and there is still a pressing need to develop more effective therapeutic agents. The most common mutation in PD is the LRRK2 mutation, observed in patients with autosomal dominant PD and sporadic PD. LRRK2 is highly expressed in neurons, microglia, immune cells, and macrophages. LRRK2 mutations or activation affect lysosomal function, leading to neuronal apoptosis. Small molecule LRRK2 kinase inhibitors have shown neuroprotective effects in preclinical models of PD, making LRRK2 inhibitors a hot topic in PD treatment. Recent studies have also shown that LRRK2 is overactivated in idiopathic PD, suggesting that LRRK2 therapy may be beneficial for this common subgroup of PD. Currently, two LRRK2 inhibitors are in Phase I clinical trials for the treatment of PD. In addition, numerous preclinical studies have shown that ROCK plays an important role in PD.

[0004] Glaucoma is a multifactorial disease, affecting over 20 million people in China, and causing blindness in more than a quarter of them. Lowering intraocular pressure (IOP) is currently the sole goal of glaucoma treatment. ROCK inhibitors act directly on the trabecular meshwork (TM), the primary site of glaucoma, offering multi-faceted therapeutic benefits. They lower IOP, reduce scarring, and protect the optic nerve. ROCK inhibitors are currently used to treat glaucoma. LRRK2 is widely distributed in TM cells. LRRK2 inhibitors can regulate LRRK2 in TM cells and may lower IOP by inhibiting the contractile tension of the actin cytoskeleton, leading to TM relaxation. Currently, one LRRK2 inhibitor is in Phase I clinical trials for glaucoma treatment.

[0005] Simultaneous inhibition of LRRK2 and ROCK1 / 2 has the potential to treat PD and glaucoma, representing a significant clinical need. Currently, no similar dual-target inhibitors have entered clinical trials. LRRK2 / ROCK dual inhibitors have promising applications in the pharmaceutical industry. This invention provides a novel selective LRRK2 / ROCK dual inhibitor and discovers that compounds with this structure exhibit good brain exposure, excellent efficacy, and therapeutic effects. Summary of the Invention

[0006] The object of this invention is to provide a compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof:

[0007]

[0008] in:

[0009] Ring A is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, and ring A can be monocyclic, bicyclic, or tricyclic.

[0010] Ring B is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0011] R 1 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted;

[0012] Or, any two R 1 The links form cycloalkyl, heterocyclic, aryl, or heteroaryl groups, which may optionally be further substituted.

[0013] R 2 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, alkyl, deuterated alkyl, deuterated alkoxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(CH2). n1 NR A1 R B1 -CR A1 R B1 (CH2) n1 NR C1 R D1 -(CH2) n1 R A1 -CRA1 R B1 R C1 -(CH2) n1 OR A1 -(CH2) n1 C(O)OR A1 -(CH2) n1 OR A1 -(CH2) n1 SR A1 -(CH2) n1 NR A1 C(O)(CH2) n2 R B1 -(CH2) n1 NR A1 C(O)OR B1 -(CH2) n1 NR A1 C(O)NR B1 R C1 or -NR A1 (CH2) n1 R B1 The amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted.

[0014] Or, R 1 With R 2 The link forms a heterocyclic group, which may optionally be further replaced;

[0015] R A1 R B1 R C1 and R D1 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted;

[0016] Or, R A1 R B1 R C1 and R D1 Any two of the atoms and the nitrogen or carbon atoms attached to them are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further substituted.

[0017] R 3The group is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further substituted;

[0018] Or, R 2 With R 3 The link forms a heterocyclic group, which may optionally be further replaced;

[0019] R 4 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be further substituted;

[0020] n1 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0021] n2 is selected from 0, 1, 2, 3, 4, 5 or 6;

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

[0023] y is selected from 0, 1, 2, 3, or 4; and

[0024] z can be selected from 0, 1, 2, 3 or 4.

[0025] In a further preferred embodiment of the present invention, ring A is selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0026] Preferably, 5-6 member monocyclic heteroaryl or 7-14 member bicyclic heteroaryl;

[0027] More

[0028] In a further preferred embodiment of the present invention, ring B is selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0029] Preferred C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0030] More preferably, phenyl or 5-7 nitrogen-containing heteroaryl groups;

[0031] Further preferred groups are phenyl, pyridyl, or pyrazolyl.

[0032] In a further preferred embodiment of the present invention, R 1 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted;

[0033] Preferred groups include hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0034] More preferably, hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, cyano, vinyl, ethynyl, cyclopropyl, or trifluoromethyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, and cyclopropyl groups are optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, amino, cyano, hydroxyl, methyl, ethyl, propyl, methoxy, ethoxy, vinyl, ethynyl, cyclopropyl, or trifluoromethyl.

[0035] More preferably hydrogen, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, optionally further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, or C 1-3 Alkyl, C 1-3 Hydroxyalkyl or C 1-3 One or more substituents in the alkoxy group are substituted;

[0036] Or, any two R 1 Link formation C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted;

[0037] Preferred C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0038] More preferably C 3-6 Cycloalkyl groups, optionally further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, or C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 One or more substituents in the haloalkoxy group are substituted;

[0039] More preferably, any two R 1 The linkage forms cyclopropyl, cyclobutyl, or cyclopentyl groups.

[0040] In a further preferred embodiment of the present invention, R 2 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Deuterated alkoxy, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n1 NR A1 R B1 -CR A1 R B1 (CH2) n1 NR C1 R D1 -(CH2) n1 R A1 -CR A1 R B1 R C1 -(CH2) n1 C(O)OR A1 -(CH2) n1 C(O)R A1 -(CH2) n1 OR A1 -(CH2) n1 SR A1 -(CH2) n1 NR A1 C(O)(CH2) n2 R B1 -(CH2) n1 NR A1 C(O)OR B1 -(CH2) n1 NR A1 C(O)NR B1 R C1 or -NR A1 (CH2) n1 R B1 The amino group, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) n1 NR A2 R B2 -CR A2 R B2 (CH2) n1 NR C2 R D2 -(CH2) n1 R A2 -CR A2 R B2 R C2 -(CH2) n1 OR A2 -(CH2) n1 C(O)OR A2 -(CH2) n1 OR A2 -(CH2) n1 SR A2 -(CH2) n1 NR A2 C(O)(CH2) n2 R B2 -(CH2) n1 NR A2 C(O)OR B2 -(CH2) n1 NR A2 (CH2) n2 NR B2 R C2 -(CH2) n1 O(CH2) n2 NR B2 R C2-(CH2) n1 NR A2 C(O)NR B2 R C2 and -NR A2 (CH2) n1 R B2 One or more substituents in it are replaced;

[0041] Preferred groups include hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) n1 NR A1 R B1 -CR A1 R B1 (CH2) n1 NR C1 R D1 -(CH2) n1 R A1 -CR A1 R B1 R C1 -(CH2) n1 C(O)R A1 -(CH2) n1 C(O)OR A1 -(CH2) n1 OR A1 -(CH2) n1 SR A1 -(CH2) n1 NR A1 C(O)(CH2) n2 R B1 -(CH2) n1 NR A1 C(O)OR B1 -(CH2) n1 NR A1 C(O)NR B1 R C1 or -NR A1 (CH2) n1 R B1The amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0042] More preferably hydrogen, deuterium, halogen, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered nitrogen-containing heteroaryl, 5-6 membered sulfur-containing heteroaryl, 7-10 membered bicyclic nitrogen-containing heteroaryl, -C(O)R A1 Or -(CH2) n1 NR C1 R D1 The amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl and 5-6 nitrogen-containing heteroaryl groups, optionally further converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) n1 NR A2 R B2 -NR A2 (CH2) n2 NR B2 R C2 and -O(CH2) n2 NR B2 R C2 One or more substituents in it are replaced;

[0043] Further preferred groups include hydrogen, deuterium, fluorine, chlorine, bromine, amino, cyano, methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, aziridine, oxadiazine, thienyl, piperidinyl, tetrahydropyranyl, and pyridinyl. The amino, methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, pyridyl, pyrazinyl, or pyrazinyl groups may optionally be further substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, amino, cyano, hydroxyl, methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, oxacyclobutyl, morpholinyl, piperazinyl, -CH2N(CH3)2, -O(CH2)2N(CH3)2, -N(CH3)(CH2)2N(CH3)2, trifluoromethyl, and -(CH2)2N(CH3)2.

[0044] Or, R 1 With R 2 Linkage forms 7-20 membered heterocyclic groups, which are further converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted;

[0045] Preferably, the heterocyclic group is 10-20 membered, and the 10-20 membered heterocyclic group is further converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0046] R A1 R B1 R C1 and R D1 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0047] Preferred groups include hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0048] More preferably hydrogen, deuterium, halogen, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, cyclopropyl, cyclobutyl, or cyclopentyl;

[0049] Or, R A1 R B1 R C1 and R D1 Any two atoms in the carbon atom and the nitrogen or carbon atom bonded to them form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted;

[0050] Preferred C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0051] R A2 R B2 R C2 and R D2 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents of a 5-10 heteroaryl group are substituted; and

[0052] n1 and n2 are selected from 0, 1, 2, 3, 4, 5 or 6.

[0053] In a further preferred embodiment of the present invention, R 3 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted;

[0054] Preferred groups include hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0055] More preferably hydrogen, deuterium, halogen, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, cyclopropyl, cyclobutyl, or cyclopentyl;

[0056] Or, R 2 With R 3Linkage forms 3-12 membered heterocyclic groups, which are further converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted;

[0057] Preferably, the 3-8 membered heterocyclic group is used, and the 3-8 membered heterocyclic group is further converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0058] More preferably, 5-6 membered heterocyclic groups;

[0059] Further preferred groups are pyrrolidone, piperidine-2-keto, 3,4-dihydropyridine-2(1H)-keto, or 4,5-dihydropyridazine-3(2H)-keto.

[0060] In a further preferred embodiment of the present invention, R 4 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-8 Alkyl, C 1-8Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted;

[0061] Preferred groups include hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0062] More preferably hydrogen, deuterium, halogen, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0063] In a further preferred embodiment of the invention, the compound is further shown as in general formula (II-A):

[0064]

[0065] In a further preferred embodiment of the present invention, y is 0, 1, or 2.

[0066] When the compound is of the general formula (II-A), and ring A is At that time, R 1 It is not hydrogen.

[0067] In a further preferred embodiment of the invention, the compound is further shown as of general formula (II-B):

[0068]

[0069] In a further preferred embodiment of the present invention, ring A is selected from a di-heteroaromatic ring or a mono-heteroaromatic ring; preferably a 5-membered heteroaryl-heterocyclic group, a 6-membered heteroaryl-heterocyclic group, or a 5-membered mono-heterocyclic group; more preferably a 5-membered heteroaryl-5-membered heterocyclic group, a 5-membered heteroaryl-6-membered heterocyclic group, a 6-membered heteroaryl-5-membered heterocyclic group, a 6-membered heteroaryl-6-membered heterocyclic group, a 5-membered heteroaryl group containing 3 nitrogen atoms, or a 5-membered heteroaryl group containing 4 nitrogen atoms;

[0070] The following groups are preferred:

[0071]

[0072] In a further preferred embodiment of the invention, ring A in general formulas (II-A) and (II-B) is selected from...

[0073] R 1 Each is independently selected from hydrogen, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4alkenyl, C 2-4 alkynyl or C 3-6 cycloalkyl, the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group and C 3-6 Cycloalkyl groups, optionally further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, or C 1-3 Alkyl, C 1-3 Hydroxyalkyl and C 1-3 One or more substituents in the alkoxy group are substituted;

[0074] Or, any two R 1 Link formation C 3-6 cycloalkyl, the C 3-6 Cycloalkyl groups, optionally further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, or C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy and C 1-3 One or more substituents in the haloalkoxy group are substituted;

[0075] R 2 Each element is independently selected from hydrogen, deuterium, halogen, amino, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl or 5-6 nitrogen-containing heteroaryl groups, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl and 5-6 nitrogen-containing heteroaryl groups, optionally further converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-3 Alkyl, C 1-3Hydroxyalkyl and C 1-3 One or more substituents in the alkoxy group are substituted;

[0076] Or, R 1 With R 2 Linkage forms a 10-20 membered heterocyclic group, which is further converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 membered heteroaryl group are substituted;

[0077] R 3 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0078] Or, R 2 With R 3 Linkages form 5-6 membered heterocyclic groups;

[0079] R 4 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0080] And n1 and n2 are selected from 0, 1, 2, 3, 4, 5 or 6.

[0081] In a further preferred embodiment of the invention, the compound is further represented as shown in general formula (II-C), general formula (II-CA), or general formula (II-CB):

[0082]

[0083] in:

[0084] The ring C is selected from 3-12 membered heterocyclic groups or 5-14 membered heteroaryl groups;

[0085] Preferably, 3-8 membered heterocyclic groups or 5-10 membered heteroaryl groups are preferred;

[0086] R 5 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0087] Preferred groups include hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0088] More preferably, hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyano, vinyl, ethynyl, cyclopropyl, or trifluoromethyl, wherein the methyl, ethyl, propyl, methoxy, ethoxy, vinyl, ethynyl, and cyclopropyl groups are optionally further substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, methyl, ethyl, propyl, methoxy, ethoxy, dimethylamino, vinyl, ethynyl, cyclopropyl, or trifluoromethyl.

[0089] Or, any two R 5 Link formation C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14aryl and 5-14 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted;

[0090] More preferably, cyclopropyl, cyclobutyl, or cyclopentyl; and

[0091] i is selected from 0, 1, 2, 3 or 4;

[0092] When the general formula is (II-C) and ring B is phenyl, R 2 Not an imidazole or a substituted imidazole; and when the compound is of general formula (II-C), ring B is At that time, R 2 Not pyridine or substituted pyridine.

[0093] In a further preferred embodiment of the invention, the compound is further shown as in general formula (II-D):

[0094]

[0095] in:

[0096] X is selected from -NH-, -O-, or -S-;

[0097] L is selected from -(CH2) m -;

[0098] The ring C is selected from 3-12 membered heterocyclic groups or 5-14 membered heteroaryl groups;

[0099] Preferably, 3-8 membered heterocyclic groups or 5-10 membered heteroaryl groups are preferred;

[0100] R 5 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0101] Preferred groups include hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0102] Or, any two R 5 Link formation C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted;

[0103] m is selected from 1, 2, 3, 4, or 5;

[0104] y-1 is selected from 0, 1, 2, or 3;

[0105] i-1 is selected from 0, 1, 2 or 3.

[0106] In a further preferred embodiment of the invention, the compound is further shown as of general formula (III), general formula (III-A), or general formula (III-B):

[0107]

[0108] Where n is selected from 0, 1, 2, 3 or 4.

[0109] In a further preferred embodiment of the invention, the compound is further shown as in general formula (IV):

[0110]

[0111] Among them: M1 and M2 are each independently N or CH;

[0112] R 5 Independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0113] Preferred groups include hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C. 1-6 Alkyl, C1-6 deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 It is substituted by one or more substituents in aryl and 5-10 heteroaryl groups.

[0114] In a more preferred embodiment of the invention, the compound is further shown as in general formula (IV-1), general formula (IV-2), or general formula (IV-3):

[0115]

[0116] In a preferred embodiment of the present invention, the R 2 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) n1 NR A1 R B1 -CR A1 R B1 (CH2) n1 NR C1 RD1 -(CH2) n1 R A1 -CR A1 R B1 R C1 -(CH2) n1 OR A1 -(CH2) n1 C(O)R A1 -(CH2) n1 C(O)OR A1 -(CH2) n1 OR A1 -(CH2) n1 SR A1 -(CH2) n1 NR A1 C(O)(CH2) n2 R B1 -(CH2) n1 NR A1 C(O)OR B1 -(CH2) n1 NR A1 C(O)NR B1 R C1 or -NR A1 (CH2) n1 R B1 The amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) n1 NR A2 R B2 -CRA2 R B2 (CH2) n1 NR C2 R D2 -(CH2) n1 R A2 -CR A2 R B2 R C2 -(CH2) n1 OR A2 -(CH2) n1 C(O)OR A2 -(CH2) n1 OR A2 -(CH2) n1 SR A2 -(CH2) n1 NR A2 C(O)(CH2) n2 R B2 -(CH2) n1 NR A2 C(O)OR B2 -(CH2) n1 NR A2 (CH2) n2 NR B2 R C2 -(CH2) n1 O(CH2) n2 NR B2 R C2 -(CH2) n1 NR A2 C(O)NR B2 R C2 and -NR A2 (CH2) n1 R B2 One or more substituents in it are replaced;

[0117] R A1 R B1 R C1 and R D1 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0118] Or, R A1 R B1 R C1 and R D1 Any two atoms in the carbon atom and the nitrogen or carbon atom bonded to them form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0119] R A2 R B2 RC2 and R D2 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups; and

[0120] n1 and n2 are selected from 0, 1, 2, 3, 4, 5 or 6.

[0121] In a further preferred embodiment of the present invention, R 2 Each group is independently selected from amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C groups. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6alkynyl group, C 3-8 Cycloalkyl, 3-8 membered oxygen or nitrogen heterocyclic groups, C 6-10 Aryl, 5-10 hydroxyl or nitrogen-containing aryl, wherein the amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered oxygen or nitrogen heterocyclic groups, C 6-10 Aryl and 5-10 hydroxyl or nitrogen-containing aryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 One or more substituents in the alkynyl group are replaced.

[0122] In a further preferred embodiment of the present invention, R 2 Each group is independently selected from amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C groups. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) n1 OR A1 -(CH2) n1 C(O)R A1 -(CH2) n1 NR A2 R B2 Or -(CH2) n1 O(CH2) n2 NR B2 R C2 The amino group, C 1-6Alkyl, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) n1 OR A1 -(CH2) n1 C(O)R A1 -(CH2) n1 NR A2 R B2 and -(CH2) n1 O(CH2) n2 NR B2 R C2 One or more substituents in it are replaced;

[0123] Preferably, R 2 Each element is independently selected from hydrogen, deuterium, halogen, amino, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-8 membered heterocyclic, 5-6 membered heteroaryl, -(CH2) n1 OR A1 -(CH2) n1 C(O)R A1 -(CH2) n1 NR A2 R B2 Or -(CH2)n1 O(CH2) n2 NR B2 R C2 The amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-8 membered heterocyclic and 5-6 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkyl group (CH2) n1 OR A1 -(CH2) n1 C(O)R A1 -(CH2) n1 NR A2 R B2 and -(CH2) n1 O(CH2) n2 NR B2 R C2 One or more substituents in it are replaced.

[0124] R A1 R A2 R B2 and R C2 Each element is independently selected from hydrogen, deuterium, halogen, amino, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, containing 1-2 4-6 membered heterocyclic groups selected from N or O, containing 1-2 5-6 membered heteroaryl groups selected from N or O,

[0125] n1 and n2 are selected from 0, 1, 2, 3, 4, 5 or 6;

[0126] More preferably, R 2 Each is independently selected from fluorine, chlorine, bromine, methyl, ethyl, methoxy, cyclopropyl,

[0127]

[0128]

[0129]

[0130] The present invention further relates to a pharmaceutical intermediate, which is a compound of general formula (A), its stereoisomer, or a pharmaceutically acceptable salt thereof:

[0131]

[0132] in:

[0133] X1 is a halogen, borate group, -Sn(R6R7R8), sulfonate group or borate group, preferably fluorine, chlorine, bromine, iodine, -B(OH)2 or -OTf;

[0134] R6, R7, and R8 are each independently selected from C. 1-6 Alkyl; preferably C 1-3 alkyl;

[0135] R 2 Selected from amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) n1 OR A1 -(CH2) n1 C(O)R A1 -(CH2) n1 NR A2 R B2 Or -(CH2) n1 O(CH2) n2 NR B2 R C2 The amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) n1 OR A1 -(CH2) n1 C(O)R A1 -(CH2) n1 NR A2 R B2 -(CH2) n1 O(CH2) n2 NR B2 R C2 One or more substituents in it are replaced;

[0136] Preferably, R 2 Each element is independently selected from hydrogen, deuterium, halogen, amino, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, containing 1-2 4-6 membered heterocyclic groups selected from N or O, containing 1-2 5-6 membered heteroaryl groups selected from N or O, -(CH2) n1 OR A1 -(CH2) n1 C(O)R A1 -(CH2) n1 NR A2 R B2 Or -(CH2) n1 O(CH2) n2 NR B2 R C2 The amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, containing 1-2 4-6 membered heterocyclic groups selected from N or O and 1-2 5-6 membered heteroaryl groups selected from N or O, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkyl group, -(CH2) n1 OR A1 -(CH2) n1 C(O)R A1 -(CH2) n1 NR A2 R B2 and -(CH2) n1 O(CH2) n2 NR B2 R C2 One or more substituents in it are replaced.

[0137] R A1 R A2 R B2 and R C2 Each element is independently selected from hydrogen, deuterium, halogen, amino, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, containing 1-2 4-6 membered heterocyclic groups selected from N or O, containing 1-2 5-6 membered heteroaryl groups selected from N or O,

[0138] n1 and n2 are selected from 0, 1, 2, 3, 4, 5 or 6.

[0139] The present invention further relates to a method for preparing a compound of general formula (IV), its stereoisomers, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0140]

[0141] in:

[0142] M1 and M2 are each independently either N or CH;

[0143] X2 is a halogen, borate group, -Sn(R6R7R8), sulfonate group or borate group, preferably fluorine, chlorine, bromine, iodine, -B(OH)2 or -OTf;

[0144] R6, R7, and R8 are each independently selected from C. 1-6 Alkyl; preferably C 1-3 alkyl;

[0145] R 5 Independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0146] Preferred groups include hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups;

[0147] X1 and R2 are as described above.

[0148] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the compounds described herein, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0149] This invention further relates to the use of any of the general formula compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof in the preparation of LRRK2 or ROCK inhibitor drugs. This invention further relates to the use of any of the general formula compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof in the preparation of selective LRRK2 and ROCK dual inhibitor drugs.

[0150] The present invention further relates to the use of compounds of the general formula, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for treating nervous system diseases, cardiovascular diseases, cancer, inflammation, autoimmune diseases and metabolic diseases and related diseases; wherein the nervous system diseases are preferably Parkinson's disease, glaucoma, Alzheimer's disease or epilepsy and related diseases.

[0151] The present invention also relates to a method for treating, preventing and / or treating cancer and related diseases, comprising administering to a patient a therapeutically effective dose of a compound of the general formula, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0152] The present invention also provides a method for treating disease conditions using the compounds or pharmaceutical compositions of the present invention, including but not limited to conditions associated with dual inhibitors of LRRK2 or ROCK inhibitors, or combinations thereof.

[0153] The present invention also relates to methods for treating neurological diseases, cardiovascular diseases, cancer, inflammation, autoimmune diseases, metabolic diseases, and related diseases in mammals, comprising administering to said mammals a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.

[0154] Detailed description of the invention

[0155] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0156] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0157] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0158] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and even more preferably 3 to 6 carbon atoms. Non-limiting examples of cycloalkyl groups include monocyclic cycloalkyl, spirocyclic cycloalkyl, fused cycloalkyl, and bridged cycloalkyl. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenediyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-cyclic, and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0159] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintile rings sharing a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 4-quintile, 4-quintile, 4-quintile, 5-quintile, or 5-quintile / 6-quintile monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0160]

[0161] It also includes spirocyclic alkyl groups that share a spiro atom with a heterocyclic alkyl group, and non-limiting examples include:

[0162]

[0163] The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused-ring alkyl include:

[0164]

[0165] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 5- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0166]

[0167] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0168] The term "heterocyclic group" refers to a substituent in a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic hydrocarbon containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). mThe heterocyclic group comprises heteroatoms (where m is an integer from 0 to 2), but excludes ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 10 ring atoms; even more preferably, it contains 3 to 8 ring atoms. Non-limiting embodiments of the heterocyclic group include monocyclic heterocyclic groups, spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups. Non-limiting examples of monocyclic heterocyclic groups include pyrrolyl, pyrrolidone, piperidin-2-keto, 3,4-dihydropyridine-2(1H)-keto, 4,5-dihydropyridazin-3(2H)-keto, azacyclic butyl, oxacyclic butyl, oxacyclic hexyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl. etc.; preferably pyrrolidone, piperidin-2-keto, 3,4-dihydropyridine-2(1H)-keto, 4,5-dihydropyridazine-3(2H)-keto, aziridine, oxazine, dihydropyrrolidone, tetrahydrofuranyl, pyrazolyl, morpholinyl, etc. Piperazinyl and pyranyl; more preferably dihydropyrrolyl, pyrrolidone, piperidin-2-keto, 3,4-dihydropyridin-2(1H)-keto, 4,5-dihydropyridazin-3(2H)-keto, aziridine, oxetane, oxetane, morpholinyl, piperidinyl, piperazinyl Pyranyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0169] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 member monocyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m The heteroatom is a carbon atom (where m is an integer from 0 to 2). It may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6 to 14 fused, more preferably 7 to 10 fused. Spirocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups based on the number of shared spiro atoms between rings, preferably monospirocyclic and bispirocyclic groups. More preferably, they are 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic groups. Non-limiting examples of spirocyclic groups include:

[0170]

[0171] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0172]

[0173] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0174]

[0175] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0176]

[0177] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0178] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, more preferably 6- to 8-membered, such as phenyl and naphthyl. Phenyl is more preferred. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0179]

[0180] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0181] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl ring groups include monocyclic, bicyclic, or polycyclic heteroaryl groups; monocyclic heteroaryl groups are preferably 5 to 10-membered, more preferably 5 to 8-membered, and most preferably 5 or 6-membered, such as pyrazinyl, pyridazinyl, imidazolyl, furanyl, thiopheneyl, thiazolyl, pyrazolyl, oxazolyl, pyrroloyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably pyridinyl, pyrazinyl, pyridazinyl, triazolyl, thiopheneyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrroloyl, thiopheneyl, thiazolyl, pyridinyl, pyridazinyl, and pyrimidinyl.

[0182] Bicyclic heteroaryl groups are preferably 5-membered heteroaryl-heterocyclic or 6-membered heteroaryl-heterocyclic; more preferably 5-membered heteroaryl-5-membered heterocyclic, 5-membered heteroaryl-6-membered heterocyclic, 6-membered heteroaryl-5-membered heterocyclic, or 6-membered heteroaryl-6-membered heterocyclic. Non-limiting examples of bicyclic heteroaryl groups include the following groups:

[0183] The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0184]

[0185] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0186] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein alkyl is defined as described above, preferably alkyl containing 1 to 8 carbon atoms, more preferably alkyl containing 1 to 6 carbon atoms, and most preferably alkyl containing 1 to 3 carbon atoms. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0187] "Halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. Non-limiting examples of halogenated alkyl groups include: trifluoromethyl, trifluoroethyl.

[0188] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0189] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0190] "Alkenyl" refers to an alkenyl group, also known as an olefinic group, preferably an alkenyl group containing 2 to 8 carbon atoms, more preferably an alkenyl group containing 2 to 6 carbon atoms, even more preferably an alkenyl group containing 2 to 4 carbon atoms, and most preferably an alkenyl group containing 2 to 3 carbon atoms. Non-limiting examples of alkenyl groups include: vinyl and propenyl. The alkenyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0191] "Alkyne" refers to an alkenyl group, also known as an alkyne group, which is an unsaturated hydrocarbon group containing -C≡C-. Preferably, it is an alkyne group containing 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, even more preferably 2 to 4 carbon atoms, and most preferably 2 to 3 carbon atoms. The alkyne group can be further substituted with other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0192] "Fused ring group" refers to a polycyclic group formed by two or more carbon rings or heterocycles sharing a common ring edge. Fused ring groups include fused ring alkyl, fused ring heteroaryl, fused ring aryl, and fused ring heteroaryl. The fused ring alkyl refers to a polycyclic group formed by a cycloalkyl group and a heterocyclic group, aryl group, or heteroaryl group sharing a common ring edge; the fused ring heterocyclic group refers to a polycyclic group formed by a heterocyclic group and a cycloalkyl group, aryl group, or heteroaryl group sharing a common ring edge; the fused ring aryl group refers to a polycyclic group formed by an aryl group and a cycloalkyl group, heterocyclic group, or heteroaryl group sharing a common ring edge; the fused ring heteroaryl group refers to a polycyclic group formed by a heteroaryl group and a cycloalkyl group, heterocyclic group, or heterol group sharing a common ring edge. For example:

[0193]

[0194] "Deuterated alkyl" refers to an alkyl group that is substituted with one or more deuterium atoms, wherein the alkyl group is as defined above.

[0195] "Deuterated alkoxy" refers to an alkoxy group that is substituted with one or more deuterium groups, where the alkoxy group is as defined above.

[0196] "Hydroxy" refers to the -OH group.

[0197] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0198] "Amino" refers to -NH2.

[0199] “Cyano” refers to -CN.

[0200] "Nitro" refers to -NO2.

[0201] "Carboxyl group" refers to -C(O)OH.

[0202] "THF" refers to tetrahydrofuran.

[0203] “EtOAc” refers to ethyl acetate.

[0204] “MeOH” refers to methanol.

[0205] "DMF" refers to N,N-dimethylformamide.

[0206] "DIPEA" refers to diisopropylethylamine.

[0207] "TFA" refers to trifluoroacetic acid.

[0208] “MeCN” refers to Yi Qing.

[0209] “DMA” stands for N,N-dimethylacetamide.

[0210] “Et2O” refers to diethyl ether.

[0211] “DCE” refers to 1,2-dichloroethane.

[0212] "DIPEA" refers to N,N-diisopropylethylamine.

[0213] “NBS” refers to N-bromosuccinimide.

[0214] “NIS” refers to N-iodosuccinimide.

[0215] “Cbz-Cl” refers to benzyl chloroformate.

[0216] “Pd2(dba)3” refers to tris(dibenzylacetone)palladium.

[0217] “Dppf” refers to 1,1'-bis(diphenylphosphine)ferrocene.

[0218] “HATU” refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0219] "KHMDS" refers to potassium hexamethyldisilamide.

[0220] "LiHMDS" refers to lithium bis(trimethylsilyl)amine.

[0221] “MeLi” refers to methyl lithium.

[0222] “n-BuLi” refers to n-butyllithium.

[0223] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0224] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0225] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0226] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0227] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0228] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0229] "Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity. Detailed Implementation

[0230] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0231] Example

[0232] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0233] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6 mm column).

[0234] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0235] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0236] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0237] The eluent system for silica gel column chromatography and the developing solvent system for thin-layer chromatography used in the intermediates and the purification compounds in the examples include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and acetone system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and small amounts of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0238] Example 1-1

[0239] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[0240]

[0241] The first step: Synthesis of (S)-5-methoxy-2-methyl-3,4-dihydro-2H-pyrrole

[0242]

[0243] Under ice bath conditions, trimethyloxonium tetrafluoroboric acid (3.55 g, 24.0 mmol) was added in portions to a solution of (S)-5-methylpyrrolidone-2-one (1.7 g, 17.2 mmol) in dichloromethane (40 mL). The reaction was slowly brought to room temperature and stirred for 5 hours. Then, saturated NaHCO3 aqueous solution (5 mL) was added, followed by extraction with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure with glacial acetic acid (5 mL) to obtain the crude product, which was directly used in the next reaction.

[0244] MS m / z (ESI): 114.1 [M+H] + .

[0245] The second step involves the synthesis of (S)-6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridine-2-amine.

[0246]

[0247] At room temperature, 6-aminomethylpyridinyl hydrazide (2.35 g, 15.4 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (2 mL), and (S)-5-methoxy-2-methyl-3,4-dihydro-2H-pyrrole (1.93 g, 17.1 mmol) was added. The reaction was heated to 125 °C and stirred at this temperature for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. Then, saturated NaHCO3 aqueous solution (5 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography to give the title compound (S)-6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridine-2-amine (1.62 g, two-step yield 49%).

[0248] MS m / z(ESI): 216.1 [M+H] + .

[0249] The third step involves the synthesis of ethyl 3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid ester.

[0250]

[0251] 2-Chloropyrazine (2.02 g, 17.6 mmol), ethyl 3-methoxy-1H-pyrazole-4-carboxylic acid ester (2.5 g, 14.7 mmol), CuI (280 mg, 1.5 mmol), L-proline (338.4 mg, 2.9 mmol), and potassium carbonate (5.08 g, 36.7 mmol) were mixed in DMF (60 mL) and reacted overnight at 100 °C under a N2 atmosphere. After cooling to room temperature, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure and subjected to column chromatography to give the title compound ethyl 3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid ester (2.5 g, 68%).

[0252] MS m / z (ESI): 249.1 [M+H] + .

[0253] Step 4: Synthesis of 3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid

[0254]

[0255] Ethyl 3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid ester (2.5 g, 10 mmol) was dissolved in a mixed solution of MeOH (10 mL), THF (10 mL), and H2O (5 mL). NaOH (480 mg, 12 mmol) was added, and the reaction was carried out at 60 °C for 1 hour. After cooling to room temperature, the pH was adjusted to acidic with 1 N HCl aqueous solution. The mixture was then dissolved in ethyl acetate and water. The organic phase was washed with saturated brine, separated, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to give the title compound 3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid (1.0 g, 45%).

[0256] MS m / z(ESI): 221.1 [M+H] + .

[0257] Step 5: Synthesis of 3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carbonyl chloride

[0258]

[0259] 3-Methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid (220 mg, 1.0 mmol) was dissolved in thionyl chloride (3 mL), heated under reflux and stirred for 2 hours, cooled and concentrated under reduced pressure to obtain the crude product 3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carbonyl chloride, which was directly used in the next step of the reaction.

[0260] Step 6: Synthesis of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[0261]

[0262] At room temperature, (S)-6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridine-2-amine (86 mg, 0.4 mmol) was added to a solution of 3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carbonyl chloride (the crude product from the previous step) in THF (5 mL) and pyridine (5 mL), followed by the addition of 4-dimethylaminopyridine (24.4 mg, 0.2 mmol). The reaction was heated to 45°C and stirred at this temperature for 2 hours. Water (10 mL) was then added dropwise, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine, separated, and dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure, and column chromatography was used to separate the title compound (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide (83 mg, 50%).

[0263] 1 H NMR (400MHz, CDCl3) δ1.64 (d, J = 6.5Hz, 3H), 2.45-2.50 (m, 1H), 3.01-3.17 (m, 3H), 4.27 (s, 3H), 4.98-5.12 (m, 1H), 7.83- 7.89(m,1H),8.04-8.09(m,1H),8.33-8.37(m,1H),8.38-8.42(m,1H),8.52-8.54(m,1H),9.03(s,1H),9.17-9.25(m,2H);

[0264] MS m / z (ESI): 418.2 [M+H] + .

[0265] Examples 1-2

[0266] (R)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[0267]

[0268] The preparation method of (R)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0269] 1 H NMR (400MHz, CDCl3) δ1.64 (d, J = 6.5Hz, 3H), 2.44-2.48 (m, 1H), 3.02-3.15 (m, 3H), 4.27 (s, 3H), 5.01-5.09 (m, 1H), 7.83- 7.89(m,1H),8.04-8.09(m,1H),8.33-8.37(m,1H),8.38-8.42(m,1H),8.52-8.54(m,1H),9.03(s,1H),9.18-9.25(m,2H);

[0270] MS m / z (ESI): 418.2 [M+H] + .

[0271] Example 2-1

[0272] (S)-1-(6-Fluoropyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0273]

[0274] The preparation method of (S)-1-(6-fluoropyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0275] MS m / z (ESI): 436.2 [M+H] + .

[0276] Example 2-2

[0277] (R)-1-(6-Fluoropyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0278]

[0279] The preparation method of (R)-1-(6-fluoropyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0280] MS m / z (ESI): 436.2 [M+H] + .

[0281] Example 3-1

[0282] (S)-1-(5-Fluoropyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0283]

[0284] The preparation method of (S)-1-(5-fluoropyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0285] MS m / z (ESI): 436.2 [M+H] + .

[0286] Example 3-2

[0287] (R)-1-(5-Fluoropyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0288]

[0289] The preparation method of (R)-1-(5-fluoropyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0290] MS m / z (ESI): 436.2 [M+H] + .

[0291] Example 4-1

[0292] (S)-1-(3-Fluoropyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0293]

[0294] The preparation method of (S)-1-(3-fluoropyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0295] MS m / z (ESI): 436.2 [M+H] + .

[0296] Example 4-2

[0297] (R)-1-(3-Fluoropyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0298]

[0299] The preparation method of (R)-1-(3-fluoropyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0300] MS m / z (ESI): 436.2 [M+H] + .

[0301] Example 5-1

[0302] (S)-3-methoxy-1-(6-methoxypyrazin-2-yl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazol-4-carboxamide

[0303]

[0304] The preparation method of (S)-3-methoxy-1-(6-methoxypyrazin-2-yl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0305] MS m / z (ESI): 448.2 [M+H] + .

[0306] Example 5-2

[0307] (R)-3-methoxy-1-(6-methoxypyrazin-2-yl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazol-4-carboxamide

[0308]

[0309] The preparation method of (R)-3-methoxy-1-(6-methoxypyrazin-2-yl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0310] MS m / z (ESI): 448.2 [M+H] + .

[0311] Example 6-1

[0312] (S)-3-methoxy-1-(5-methoxypyrazin-2-yl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazol-4-carboxamide

[0313]

[0314] The preparation method of (S)-3-methoxy-1-(5-methoxypyrazin-2-yl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0315] MS m / z (ESI): 448.2 [M+H] + .

[0316] Example 6-2

[0317] (R)-3-methoxy-1-(5-methoxypyrazin-2-yl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazol-4-carboxamide

[0318]

[0319] The preparation method of (R)-3-methoxy-1-(5-methoxypyrazin-2-yl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0320] MS m / z (ESI): 448.2 [M+H] + .

[0321] Example 7-1

[0322] (S)-3-methoxy-1-(3-methoxypyrazin-2-yl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazol-4-carboxamide

[0323]

[0324] The preparation method of (S)-3-methoxy-1-(3-methoxypyrazin-2-yl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0325] MS m / z (ESI): 448.2 [M+H] + .

[0326] Example 7-2

[0327] (R)-3-methoxy-1-(3-methoxypyrazin-2-yl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazol-4-carboxamide

[0328]

[0329] The preparation method of (R)-3-methoxy-1-(3-methoxypyrazin-2-yl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0330] MS m / z (ESI): 448.2 [M+H] + .

[0331] Example 8-1

[0332] (S)-1-(6-cyanopyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0333]

[0334] The preparation method of (S)-1-(6-cyanopyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0335] MS m / z (ESI): 443.2 [M+H] + .

[0336] Example 8-2

[0337] (R)-1-(6-cyanopyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0338]

[0339] The preparation method of (R)-1-(6-cyanopyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0340] MS m / z (ESI): 443.2 [M+H] + .

[0341] Example 9-1

[0342] (S)-1-(5-cyanopyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0343]

[0344] The preparation method of (S)-1-(5-cyanopyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0345] MS m / z (ESI): 443.2 [M+H] + .

[0346] Example 9-2

[0347] (R)-1-(5-cyanopyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0348]

[0349] The preparation method of (R)-1-(5-cyanopyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0350] MS m / z (ESI): 443.2 [M+H] + .

[0351] Example 10-1

[0352] (S)-1-(3-cyanopyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0353]

[0354] The preparation method of (S)-1-(3-cyanopyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[0355] MS m / z (ESI): 443.2 [M+H] + .

[0356] Example 10-2

[0357] (R)-1-(3-cyanopyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0358]

[0359] The preparation method of (R)-1-(3-cyanopyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0360] MS m / z (ESI): 443.2 [M+H] + .

[0361] Example 11

[0362] N-(6-(5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[0363]

[0364] The preparation method of N-(6-(5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0365] MS m / z (ESI): 420.2 [M+H] + .

[0366] Example 12

[0367] N-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[0368]

[0369] The preparation method of N-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[0370] MS m / z(ESI): 432.2 [M+H] + .

[0371] Example 13

[0372] N-(6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazol]-3'-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide

[0373]

[0374] The preparation method of N-(6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazol]-3'-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0375] 1 H NMR (400MHz, CDCl3) δ0.88-0.92(m,2H),2.27-2.29(m,2H),2.85-2.88(m,2H),3.22-3.30(m,2H),4.28(s, 3H),7.83-7.90(m,1H),8.04-8.07(m,1H),8.35-8.43(m,2H),8.54(s,1H),9.03(s,1H),9.19-9.23(s,2H).

[0376] MS m / z (ESI): 430.2 [M+H] + .

[0377] Example 14-1

[0378] (R)-3-methoxy-N-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[0379]

[0380] The preparation method of (R)-3-methoxy-N-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0381] 1H NMR (400MHz, CDCl3) δ2.79-2.88(m,1H),2.99-3.17(m,2H),3.18-3.27(m,1H),3.32(s,3H),3.80-3.88(m,2H),4.29(s,3H),5.12-5.2 1(m,1H),7.86-7.94(m,1H),8.15(d,J=7.6Hz,1H),8.37-8.43(m,2H),8.52-8.57(m,1H),9.04(s,1H),9.18(s,1H),9.20-9.25(m,1H).

[0382] MS m / z (ESI): 448.2 [M+H] + .

[0383] Example 14-2

[0384] (S)-3-methoxy-N-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[0385]

[0386] The preparation method of (S)-3-methoxy-N-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0387] MS m / z (ESI): 448.2 [M+H] + .

[0388] Example 15

[0389] N-(6-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[0390]

[0391] The preparation method of N-(6-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[0392] MS m / z(ESI): 432.2 [M+H] + .

[0393] Example 16

[0394] N-(6-(5'H,7'H-spiro[cyclopropane-1,6'-pyrrolo[2,1-c][1,2,4]triazol]-3'-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[0395]

[0396] The preparation method of N-(6-(5'H,7'H-spiro[cyclopropane-1,6'-pyrrolo[2,1-c][1,2,4]triazol]-3'-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0397] MS m / z (ESI): 430.2 [M+H] + .

[0398] Example 17-1

[0399] (R)-3-methoxy-1-(pyrazin-2-yl)-N-(6-(5-vinyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazol-4-carboxamide

[0400]

[0401] The preparation method of (R)-3-methoxy-1-(pyrazin-2-yl)-N-(6-(5-vinyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0402] MS m / z (ESI): 430.2 [M+H] + .

[0403] Example 17-2

[0404] (S)-3-methoxy-1-(pyrazin-2-yl)-N-(6-(5-vinyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazol-4-carboxamide

[0405]

[0406] The preparation method of (S)-3-methoxy-1-(pyrazin-2-yl)-N-(6-(5-vinyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0407] MS m / z (ESI): 430.2 [M+H] + .

[0408] Example 18-1

[0409] (R)-N-(6-(5-ethynyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[0410]

[0411] The preparation method of (R)-N-(6-(5-ethynyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0412] MS m / z (ESI): 428.2 [M+H] + .

[0413] Example 18-2

[0414] (S)-N-(6-(5-ethynyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[0415]

[0416] The preparation method of (S)-N-(6-(5-ethynyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0417] MS m / z (ESI): 428.2 [M+H] + .

[0418] Example 19-1

[0419] (R)-3-methoxy-1-(pyrazin-2-yl)-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazol-4-carboxamide

[0420]

[0421] The preparation method of (R)-3-methoxy-1-(pyrazin-2-yl)-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0422] MS m / z (ESI): 472.2 [M+H] + .

[0423] Example 19-2

[0424] (S)-3-methoxy-1-(pyrazin-2-yl)-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazol-4-carboxamide

[0425]

[0426] The preparation method of (S)-3-methoxy-1-(pyrazin-2-yl)-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0427] MS m / z (ESI): 472.2 [M+H] + .

[0428] Example 20-1

[0429] (R)-N-(6-(5-(fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[0430]

[0431] The preparation method of (R)-N-(6-(5-(fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0432] 1 H NMR (400MHz, CDCl3) δ2.87-2.95(m,1H),3.08-3.19(m,2H),4.27(s,3H),4.79-4.85(m,1H),4.91-4.97(m,1H),5.01-5.08(m,1H),5.15-5 .24(m,1H),7.86-7.93(m,1H),8.14(d,J=7.6Hz,1H),8.35-8.42(m,2H),8.52-8.56(m,1H),9.04(s,1H),9.13(s,1H),9.21-9.25(m,1H).

[0433] MS m / z (ESI): 436.2 [M+H] + .

[0434] Example 20-2

[0435] (S)-N-(6-(5-(fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[0436]

[0437] The preparation method of (S)-N-(6-(5-(fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0438] MS m / z (ESI): 436.2 [M+H] + .

[0439] Example 21-1

[0440] (R)-N-(6-(5-(cyanomethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[0441]

[0442] The preparation method of (R)-N-(6-(5-(cyanomethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0443] MS m / z (ESI): 443.2 [M+H] + .

[0444] Example 21-2

[0445] (S)-N-(6-(5-(cyanomethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[0446]

[0447] The preparation method of (S)-N-(6-(5-(cyanomethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0448] MS m / z (ESI): 443.2 [M+H] + .

[0449] Example 22-1

[0450] (S)-5-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(pyrazin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one

[0451]

[0452] The preparation method of (S)-5-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(pyrazin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyrazole-4(2H)-one is as described in Examples 1-1.

[0453] MS m / z (ESI): 400.2 [M+H] + .

[0454] Example 22-2

[0455] (R)-5-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(pyrazin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one

[0456]

[0457] The preparation method of (R)-5-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(pyrazin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyrazole-4(2H)-one is as described in Examples 1-1.

[0458] MS m / z (ESI): 400.2 [M+H] + .

[0459] Example 23-1

[0460] (S)-5-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(pyrazin-2-yl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0461]

[0462] The preparation method of (S)-5-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(pyrazin-2-yl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one is as described in Examples 1-1.

[0463] MS m / z (ESI): 414.2 [M+H] + .

[0464] Example 23-2

[0465] (R)-5-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(pyrazin-2-yl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0466]

[0467] The preparation method of (R)-5-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(pyrazin-2-yl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one is as described in Examples 1-1.

[0468] MS m / z (ESI): 414.2 [M+H] + .

[0469] Example 24-1

[0470] (S)-5-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(pyrazin-2-yl)-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0471]

[0472] The preparation method of (S)-5-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(pyrazin-2-yl)-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one is as described in Examples 1-1.

[0473] MS m / z(ESI): 412.2 [M+H] + .

[0474] Example 24-2

[0475] (R)-5-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(pyrazin-2-yl)-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

[0476]

[0477] The preparation method of (R)-5-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(pyrazin-2-yl)-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one is as described in Examples 1-1.

[0478] MS m / z(ESI): 412.2 [M+H] + .

[0479] Example 25-1

[0480] (S)-5-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(pyrazin-2-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrazin-4-one

[0481]

[0482] The preparation method of (S)-5-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(pyrazin-2-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one is described in Example 1-1.

[0483] MS m / z (ESI): 413.2 [M+H] + .

[0484] Example 25-2

[0485] (R)-5-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(pyrazin-2-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrazin-4-one

[0486]

[0487] The preparation method of (R)-5-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2-(pyrazin-2-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one is as described in Examples 1-1.

[0488] MS m / z (ESI): 413.2 [M+H] + .

[0489] Example 26

[0490] N-(6-(4-isopropyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide

[0491]

[0492] The preparation method of N-(6-(4-isopropyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[0493] MS m / z (ESI): 420.2 [M+H] + .

[0494] Example 27

[0495] N-(6-(4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide

[0496]

[0497] The preparation method of N-(6-(4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[0498] MS m / z (ESI): 418.2 [M+H] + .

[0499] Example 28

[0500] (S)-3-methoxy-N-(6-(5-methyl-4-(1,1,1-trifluoropropane-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[0501]

[0502] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-4-(1,1,1-trifluoropropane-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[0503] MS m / z(ESI): 474.2 [M+H] + .

[0504] Example 29

[0505] 3-Methoxy-N-(6-(5-methyl-4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide

[0506]

[0507] The preparation method of 3-methoxy-N-(6-(5-methyl-4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[0508] MS m / z(ESI): 432.2 [M+H] + .

[0509] Example 30

[0510] N-(6-(1-isopropyl-1H-tetrazol-5-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide

[0511]

[0512] The preparation method of N-(6-(1-isopropyl-1H-tetrazole-5-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[0513] MS m / z (ESI): 407.2 [M+H] + .

[0514] Example 31

[0515] N-(6-(1-cyclopropyl-1H-tetrazol-5-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide

[0516]

[0517] The preparation method of N-(6-(1-cyclopropyl-1H-tetrazole-5-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[0518] MS m / z (ESI): 405.2 [M+H] + .

[0519] Example 32-1

[0520] (S)-3-methoxy-1-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0521]

[0522] The preparation method of (S)-3-methoxy-1-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[0523] 1H NMR (400MHz, CDCl3) δ1.61 (d, J = 6.5Hz, 3H), 2.40-2.46 (m, 1H), 2.98-3.13 (m, 3H), 3.81 (s, 3H), 4.1 1(s,3H),4.96-5.07(m,1H),7.78-7.86(m,2H),7.98-8.03(m,1H),8.27-8.31(m,1H),9.13(s,1H);

[0524] MS m / z (ESI): 354.2 [M+H] + .

[0525] Example 32-2

[0526] (R)-3-methoxy-1-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0527]

[0528] The preparation method of (R)-3-methoxy-1-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0529] 1H NMR (400MHz, CDCl3) δ1.61 (d, J = 6.5Hz, 3H), 2.42-2.47 (m, 1H), 2.99-3.13 (m, 3H), 3.81 (s, 3H), 4.1 1(s,3H),4.97-5.09(m,1H),7.79-7.87(m,2H),7.99-8.05(m,1H),8.28-8.32(m,1H),9.14(s,1H);

[0530] MS m / z (ESI): 354.2 [M+H] + .

[0531] Example 33-1

[0532] (S)-1-Cyclopropyl-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0533]

[0534] The preparation method of (S)-1-cyclopropyl-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0535] MS m / z (ESI): 380.2 [M+H] + .

[0536] Example 33-2

[0537] (R)-1-Cyclopropyl-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0538]

[0539] The preparation method of (R)-1-cyclopropyl-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0540] MS m / z (ESI): 380.2 [M+H] + .

[0541] Example 34-1

[0542] (S)-1-(2-(dimethylamino)ethyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0543]

[0544] The preparation method of (S)-1-(2-(dimethylamino)ethyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0545] MS m / z(ESI): 411.2 [M+H] + .

[0546] Example 34-2

[0547] (R)-1-(2-(dimethylamino)ethyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0548]

[0549] The preparation method of (R)-1-(2-(dimethylamino)ethyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0550] MS m / z(ESI): 411.2 [M+H] + .

[0551] Example 35-1

[0552] (S)-2-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)nicotinamide

[0553]

[0554] The preparation method of (S)-2-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)nicotinamide is as described in Examples 1-1.

[0555] 1 H NMR (400MHz, CDCl3) δ1.65 (d, J = 6.6Hz, 3H), 2.43-2.53 (m, 1H), 3.03-3.21 (m, 3H), 4.22 (s, 3H), 5.03-6.15 (m, 1H), 7.14-7.20 (m,1H),7.85-7.93(m,1H),8.11(d,J=7.6Hz,1H),8.34-8.39(m,1H),8.43(d,J=8.2Hz,1H),8.59-8.66(m,1H),10.43(s,1H);

[0556] MS m / z (ESI): 351.2 [M+H] + .

[0557] Example 35-2

[0558] (R)-2-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)nicotinamide

[0559]

[0560] The preparation method of (R)-2-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)nicotinamide is as described in Examples 1-1.

[0561] MS m / z (ESI): 351.2 [M+H] + .

[0562] Example 36-1

[0563] (R)-2-methoxy-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)nicotinamide

[0564]

[0565] The preparation method of (R)-2-methoxy-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)nicotinamide is as described in Examples 1-1.

[0566] MS m / z (ESI): 405.2 [M+H] + .

[0567] Example 36-2

[0568] (S)-2-methoxy-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)nicotinamide

[0569]

[0570] The preparation method of (S)-2-methoxy-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)nicotinamide is as described in Examples 1-1.

[0571] MS m / z (ESI): 405.2 [M+H]+ .

[0572] Example 37-1

[0573] (R)-5-fluoro-2-methoxy-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)nicotinamide

[0574]

[0575] The preparation method of (R)-5-fluoro-2-methoxy-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)nicotinamide is as described in Examples 1-1.

[0576] MS m / z(ESI): 423.2 [M+H] + .

[0577] Example 37-2

[0578] (S)-5-fluoro-2-methoxy-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)nicotinamide

[0579]

[0580] The preparation method of (S)-5-fluoro-2-methoxy-N-(6-(5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)nicotinamide is as described in Examples 1-1.

[0581] MS m / z(ESI): 423.2 [M+H] + .

[0582] Example 38

[0583] N-(6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazol]-3'-yl)pyridin-2-yl)-2-methoxynicotinamide

[0584]

[0585] The preparation method of N-(6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazol]-3'-yl)pyridin-2-yl)-2-methoxynicotinamide is as described in Examples 1-1.

[0586] MS m / z(ESI): 363.2 [M+H] + .

[0587] Example 39

[0588] N-(6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazol]-3'-yl)pyridin-2-yl)-5-fluoro-2-methoxynicotinamide

[0589]

[0590] The preparation method of N-(6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazol]-3'-yl)pyridin-2-yl)-5-fluoro-2-methoxynicotinamide is as described in Examples 1-1.

[0591] MS m / z(ESI): 381.2 [M+H] + .

[0592] Example 40

[0593] (S)-2-methoxy-N-(6-(5-methyl-4-(1,1,1-trifluoropropane-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)nicotinamide

[0594]

[0595] The preparation method of (S)-2-methoxy-N-(6-(5-methyl-4-(1,1,1-trifluoropropane-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)nicotinamide is as described in Example 1-1.

[0596] MS m / z (ESI): 407.2 [M+H] + .

[0597] Example 41

[0598] (S)-2-methoxy-N-(6-(1-(1,1,1-trifluoropropane-2-yl)-1H-tetrazol-5-yl)pyridin-2-yl)nicotinamide

[0599]

[0600] The preparation method of (S)-2-methoxy-N-(6-(1-(1,1,1-trifluoropropane-2-yl)-1H-tetrazol-5-yl)pyridin-2-yl)nicotinamide is as described in Example 1-1.

[0601] MS m / z(ESI): 394.2 [M+H] + .

[0602] Example 42-1

[0603] (R)-55-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-16,17-dihydro-15H-6-oxa-3-aza-1(3,5)-pyrrolo[2,1-c][1,2,4]triazol-2(2,6)-pyridine-5(1,2)-benzocyclononane-4-one

[0604]

[0605] The preparation method of (R)-55-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-16,17-dihydro-15H-6-oxa-3-aza-1(3,5)-pyrrolo[2,1-c][1,2,4]triazol-2(2,6)-pyridine-5(1,2)-benzocyclononane-4-one is described in Example 1-1.

[0606] MS m / z (ESI): 499.2 [M+H] + .

[0607] Example 42-2

[0608] (S)-55-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-16,17-dihydro-15H-6-oxa-3-aza-1(3,5)-pyrrolo[2,1-c][1,2,4]triazol-2(2,6)-pyridine-5(1,2)-benzocyclononane-4-one

[0609]

[0610] The preparation method of (S)-55-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-16,17-dihydro-15H-6-oxa-3-aza-1(3,5)-pyrrolo[2,1-c][1,2,4]triazol-2(2,6)-pyridine-5(1,2)-benzocyclononane-4-one is described in Example 1-1.

[0611] MS m / z (ESI): 499.2 [M+H] + .

[0612] Example 43

[0613] (R)-N-(6-(5-((dimethylamino)methyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[0614]

[0615] The preparation method of (R)-N-(6-(5-((dimethylamino)methyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0616] MS m / z (ESI): 461.2 [M+H] + .

[0617] Example 44

[0618] (R)-N-(6-(5-(1-hydroxycyclopropyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide

[0619]

[0620] The preparation method of (R)-N-(6-(5-(1-hydroxycyclopropyl)-6,7-dihydro-5H-pyrrole[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0621] MS m / z (ESI): 460.2 [M+H] + .

[0622] Example 45

[0623] (R)-N-(6-(5-(1-aminocyclopropyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide

[0624]

[0625] The preparation method of (R)-N-(6-(5-(1-aminocyclopropyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0626] MS m / z (ESI): 459.2 [M+H] + .

[0627] Example 46

[0628] (R)-N-(6-(5-(2-hydroxypropan-2-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide

[0629]

[0630] The preparation method of (R)-N-(6-(5-(2-hydroxypropane-2-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0631] MS m / z(ESI): 462.2 [M+H] + .

[0632] Example 47

[0633] (R)-N-(6-(5-(2-aminopropan-2-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide

[0634]

[0635] The preparation method of (R)-N-(6-(5-(2-aminopropane-2-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0636] MS m / z (ESI): 461.2 [M+H] + .

[0637] Example 48

[0638] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(pyridin-2-yl)-1H-pyrazol-4-carboxamide

[0639]

[0640] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[0641] 1 H NMR (400MHz, CDCl3) δ1.64 (d, J = 6.4Hz, 3H), 2.41-2.54 (m, 1H), 2.97-3.18 (m, 3H), 4.24 (s, 3H), 5.02-5.13 (m, 1H), 7.22-7.28(m,1H),7.83-7.90(m,3H),7.99(d,J=7.6Hz,1H),8.35(d,J=8.2Hz,1H),8.42-8.47(m,1H),9.06(s,1H).

[0642] MS m / z (ESI): 417.2 [M+H] + .

[0643] Example 49

[0644] (S)-1-(4-bromopyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0645]

[0646] The preparation method of (S)-1-(4-bromopyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0647] 1H NMR (400MHz, CDCl3) δ1.66 (d, J = 6.5Hz, 3H), 2.46-253 (m, 1H), 3.04-3.19 (m, 3H), 4.26 (s, 3H), 5.04-5.14 (m, 1H), 7.40 (d, J=5.2,1H),7.85-7.92(m,1H),7.98-8.04(m,1H),8.06(s,1H),8.26(d,J=5.3Hz,1H),8.36(d,J=8.1Hz,1H),9.05(s,1H).

[0648] MS m / z (ESI): 495.2 [M+H] + .

[0649] Example 50

[0650] (S)-3-methoxy-1-(6-methoxypyridin-2-yl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0651]

[0652] The preparation method of (S)-3-methoxy-1-(6-methoxypyridin-2-yl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0653] 1 H NMR (400MHz, CDCl3) δ1.64(d,J=6.4Hz,3H),2.42-2.55(m,1H),3.05-3.16(m,3H),4.00(s,3H),4.24(s,3H),5.02-5.12(m,1H),6.68(d,J= 8.1Hz,1H),7.40(d,J=7.6Hz,1H),7.71(t,J=7.9Hz,1H),7.88(t,J=7.9Hz,1H),7.99(d,J=7.6Hz,1H),8.35(d,J=8.2Hz,1H),9.02(s,1H).

[0654] MS m / z (ESI): 447.2 [M+H] + .

[0655] Example 51

[0656] (S)-1-(4-cyanopyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0657]

[0658] The preparation method of (S)-1-(4-cyanopyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[0659] MS m / z(ESI): 442.2 [M+H] + .

[0660] Example 52

[0661] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0662]

[0663] The preparation method of ((S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0664] 1 H NMR (400MHz, CDCl3) δ1.64 (d, J = 6.5Hz, 3H), 2.41-2.50 (m, 1H), 3.10-3.20 (m, 3H), 4.25 (s, 3H), 5.00-5.12 (m,1H),7.58(d,J=8.0Hz,1H),7.83-7.89(m,1H),8.04-8.09(m,3H),8.33-8.37(m,1H),9.17-9.25(m,2H).

[0665] MS m / z (ESI): 485.2 [M+H] + .

[0666] Example 53

[0667] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide

[0668]

[0669] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0670] 1 H NMR (400MHz, CDCl3) δ1.65(d,J=6.4Hz,3H),2.45-2.52(m,1H),2.56(s,3H),3.02-3.20(m,3H),4.23(s,3H),5.04-5.14(m,1H),7.08(d,J= 7.4Hz,1H),7.64(d,J=8.0Hz,1H),7.71(t,J=7.7Hz,1H),7.87(t,J=8.0Hz,1H),8.01(d,J=7.6Hz,1H),8.37(d,J=8.1Hz,1H),9.10(s,1H).

[0671] MS m / z (ESI): 431.2 [M+H] + .

[0672] Example 54

[0673] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(4-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0674]

[0675] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(4-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0676] 1H NMR (400MHz, CDCl3) δ1.66(d,J=6.1Hz,3H),2.44-2.56(m,1H),3.03-3.19(m,3H),4.28(s,3H),5.02-5.16(m,1H),7.46(d,J=5 .1Hz,1H),7.89(t,J=7.9Hz,1H),8.00(d,J=7.7Hz,1H),8.10(s,1H),8.36(d,J=8.2Hz,1H),8.62(d,J=5.1Hz,1H),9.11(s,1H).

[0677] MS m / z (ESI): 485.2 [M+H] + .

[0678] Example 55

[0679] (S)-1-(6-cyanopyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0680]

[0681] The preparation method of (S)-1-(6-cyanopyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[0682] MS m / z(ESI): 442.2 [M+H] + .

[0683] Example 56

[0684] (S)-1-(6-chloropyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0685]

[0686] The preparation method of (S)-1-(6-chloropyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0687] MS m / z (ESI): 451.2 [M+H] + .

[0688] Example 57

[0689] (S)-1-(6-bromopyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0690]

[0691] The preparation method of (S)-1-(6-bromopyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0692] MS m / z (ESI): 495.2 [M+H] + .

[0693] Example 58

[0694] 3-Methoxy-1-(pyridin-2-yl)-N-(6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0695]

[0696] The preparation method of 3-methoxy-1-(pyridin-2-yl)-N-(6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[0697] 1 H NMR (400MHz, CDCl3) δ3.27-3.34(m,2H),4.22(s,3H),4.31-4.37(m,2H),4.52-4.57(m,2H),7.20-7.24(m, 1H),7.82-7.88(m,3H),7.99-8.02(m,1H),8.34-8.37(m,1H),8.42-8.45(m,1H),9.07(s,1H),9.17(s,1H).

[0698] MS m / z (ESI): 418.2 [M+H] + .

[0699] Example 59

[0700] 3-Methoxy-N-(6-(7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-yl)-1-(pyridin-2-yl)-1H-pyrazol-4-carboxamide

[0701]

[0702] The preparation method of 3-methoxy-N-(6-(7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-yl)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[0703] 1 H NMR(400MHz, CDCl3)δ2.57(s,3H),2.86-2.93(m,2H),3.90(s,2H),4.23(s,3H),4.57-4.65(m,2H),7.20-7.24 (m,1H),7.81-7.89(m,3H),8.00-8.03(m,1H),8.34-8.37(m,1H),8.42-8.45(m,1H),9.07(s,1H),9.18(s,1H).

[0704] MS m / z(ESI): 432.2 [M+H] + .

[0705] Example 60

[0706] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(4-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxamide

[0707]

[0708] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(4-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0709] 1H NMR (400MHz, CDCl3) δ1.64 (d, J = 6.5Hz, 3H), 2.41-2.50 (m, 1H), 3.00-3.20 (m, 3H), 4.20 (s, 3H), 5.00-5.10 (m, 1H), 7.73 (d,J=6.4Hz,1H),7.83-7.89(m,1H),8.04-8.09(m,1H),8.22(s,1H),8.33-8.37(m,1H),8.85-8.95(m,2H),9.21(s,1H).

[0710] MS m / z (ESI): 485.2 [M+H] + .

[0711] Example 61

[0712] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(6-(oxoalkyl-3-ylmethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0713]

[0714] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(6-(oxoalkyl-3-ylmethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0715] MS m / z (ESI): 487.2 [M+H] + .

[0716] 1 H NMR (400MHz, CDCl3) δ1.68 (d, J=6.4Hz, 3H), 2.48-2.57 (m, 2H), 3.05-3.16 (m, 1H ),3.21(d,J=7.8Hz,2H),3.52-3.58(m,2H),4.23(s,3H),4.53-4.60(m,2H),4.87 -4.93(m,2H),5.12-5.18(m,1H),7.05(d,J=7.0Hz,1H),7.72(d,J=6.4Hz,1H),7. 87-7.93(m,2H),8.11-8.16(m,1H),8.39-8.45(m,1H),9.02(s,1H),9.21(s,1H).

[0717] Example 62

[0718] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(6-(oxepane-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0719]

[0720] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(6-(oxacyclopentan-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0721] 1 H NMR (400MHz, DMSO) δ1.52 (d, J = 6.4Hz, 3H), 2.35-2.42 (m, 1H), 2.85-2.92 ( m,1H),2.97-3.10(m,2H),4.19(s,3H),4.45-4.53(m,1H),4.86-4.98(m,4H ),4.99-5.07(m,1H),7.34(d,J=7.6Hz,1H),7.75(d,J=8.2Hz,1H),7.85-7. 90(m,1H),7.97-8.05(m,2H),8.18-8.24(m,1H),9.09(s,1H),9.58(s,1H);

[0722] MS m / z(ESI): 473.2 [M+H] + .

[0723] Example 63

[0724] (S)-1-(6-((dimethylamino)methyl)pyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0725]

[0726] The preparation method of (S)-1-(6-((dimethylamino)methyl)pyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0727] 1 H NMR (400MHz, CDCl3) δ1.63 (d, J = 6.5Hz, 3H), 2.42-2.83 (m, 7H), 2.98-3.13 (m, 3H), 3.80 (s, 2H), 4.23 (s, 3H), 5.00-5.10 ( m,1H),7.49(d,J=7.4Hz,1H),7.77-7.88(m,3H),8.04(d,J=7.6Hz,1H),8.35(d,J=8.2Hz,1H),9.13(s,1H),9.21(s,1H);

[0728] MS m / z(ESI): 474.2 [M+H] + .

[0729] Example 64

[0730] (S)-1-(5-((dimethylamino)methyl)pyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0731]

[0732] The preparation method of (S)-1-(5-((dimethylamino)methyl)pyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0733] 1 H NMR (400MHz, CDCl3) δ1.64 (d, J = 6.5Hz, 3H), 2.41-2.70 (m, 7H), 3.00-3.20 (m, 3H), 3.75-3.90 (m, 2H), 4.24 (s, 3H), 5.00-5. 05(m,1H),7.84(t,J=8.0Hz,1H),7.89(d,J=8.0Hz,1H),8.04(d,J=8.0Hz,1H),8.33-8.37(m,2H),9.06(s,1H),9.21(s,1H);

[0734] MS m / z(ESI): 474.2 [M+H] + .

[0735] Example 65

[0736] (S)-1-(4-((dimethylamino)methyl)pyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0737]

[0738] The preparation method of (S)-1-(4-((dimethylamino)methyl)pyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0739] MS m / z(ESI): 474.2 [M+H] + .

[0740] Example 66

[0741] (S)-1-(6-(2-(dimethylamino)ethyl)pyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0742]

[0743] The preparation method of (S)-1-(6-(2-(dimethylamino)ethyl)pyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0744] MS m / z (ESI): 488.2 [M+H] + .

[0745] Example 67

[0746] (S)-1-(6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0747]

[0748] The preparation method of (S)-1-(6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0749] MS m / z (ESI): 504.2 [M+H] + .

[0750] Example 68

[0751] (S)-1-(6-((2-(dimethylamino)ethyl)(methyl)amino)pyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0752]

[0753] The preparation method of (S)-1-(6-((2-(dimethylamino)ethyl)(methyl)amino)pyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0754] MS m / z (ESI): 517.2 [M+H] + .

[0755] Example 69

[0756] 1-((R)-7-(dimethylamino)-6,7-dihydro-5H-cyclopentyl[b]pyridin-2-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrole[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0757]

[0758] The preparation method of 1-((R)-7-(dimethylamino)-6,7-dihydro-5H-cyclopentyl[b]pyridin-2-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrole[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0759] MS m / z (ESI): 500.2 [M+H]+ .

[0760] Example 70

[0761] 1-((S)-7-(dimethylamino)-6,7-dihydro-5H-cyclopentyl[b]pyridin-2-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrole[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0762]

[0763] The preparation method of 1-((S)-7-(dimethylamino)-6,7-dihydro-5H-cyclopentyl[b]pyridin-2-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrole[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0764] MS m / z (ESI): 500.2 [M+H] + .

[0765] Example 71

[0766] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0767]

[0768] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0769] MS m / z (ESI): 472.2 [M+H] + .

[0770] Example 72

[0771] (S)-1-(5-Fluorothiophene-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0772]

[0773] The preparation method of (S)-1-(5-fluorothiophene-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0774] MS m / z (ESI): 440.2 [M+H] + .

[0775] Example 73

[0776] (S)-1-(5-((dimethylamino)methyl)-4-fluorothiophene-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0777]

[0778] The preparation method of (S)-1-(5-((dimethylamino)methyl)-4-fluorothiophen-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0779] MS m / z (ESI): 497.2 [M+H] + .

[0780] Example 74

[0781] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(pyridin-3-yl)-1H-pyrazol-4-carboxamide

[0782]

[0783] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(pyridin-3-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0784] MS m / z (ESI): 417.2 [M+H] + .

[0785] Example 75

[0786] (S)-1-(2,6-dimethoxypyridin-3-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0787]

[0788] The preparation method of (S)-1-(2,6-dimethoxypyridin-3-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0789] 1 H NMR (400MHz, CDCl3) δ1.65 (d, J = 6.8 Hz, 3H), 2.43-2.51 (m, 1H), 3.04-3.20 (m, 3H), 3.97 (s, 3H), 4.07 (s, 3H), 4.19 (s, 3H), 5.05-5.14 (m, 1H) ,6.44(d,J=8.6Hz,1H),7.83-7.90(m,1H),7.98(d,J=8.8Hz,1H),8.05-8.10(m,1H),8.37(d,J=8.4Hz,1H),8.56(s,1H),9.19-9.25(m,1H);

[0790] MS m / z (ESI): 477.2 [M+H] + .

[0791] Example 76

[0792] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxamide

[0793]

[0794] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0795] 1 H NMR (400MHz, CDCl3) δ1.64 (d, J = 6.6Hz, 3H), 2.41-2.50 (m, 1H), 3.01-3.18 (m, 3H), 4.26 (s, 3H), 5.00-5.09 (m, 1H), 7.79-7.92(m,2H),8.09(d,J=7.6Hz,1H),8.14-8.20(m,1H),8.33(d,J=8.2Hz,1H),8.58(s,1H),9.09-9.21(m,2H).

[0796] MS m / z (ESI): 485.2 [M+H] + .

[0797] Example 77

[0798] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxamide

[0799]

[0800] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0801] 1 H NMR(400MHz, CDCl3)δ1.64(d,J=6.6Hz,3H),2.43-2.49(m,1H),3.01-3.17(m,3H),4.19(s,3H),4.99-5.11(m,1H),7.68-7.73(m,1H) ,7.83-7.89(m,1H),7.97-8.02(m,1H),8.04-8.09(m,1H),8.21(s,1H),8.33(d,J=8.0Hz,1H),8.80-8.85(m,1H),9.17-9.24(m,1H).

[0802] MS m / z (ESI): 485.2 [M+H] + .

[0803] Example 78

[0804] (S)-1-(4-cyanopyridin-3-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0805]

[0806] The preparation method of (S)-1-(4-cyanopyridin-3-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[0807] 1 H NMR (400MHz, CDCl3) δ1.64 (d, J=6.5Hz, 3H), 2.43-2.52 (m, 1H), 3.00-3.20 (m, 3H), 4.28 (s, 3H), 5.00-5.12 (m, 1H), 7.70 (d, J= 8.0Hz,1H),7.83-7.93(m,1H),8.10-8.13(m,1H),8.33(d,J=8.0Hz,1H),8.59(s,1H),8.76(m,1H),9.06(s,1H),9.17(s,1H).

[0808] MS m / z(ESI): 442.2 [M+H] + .

[0809] Example 79

[0810] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(4-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxamide

[0811]

[0812] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(4-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[0813] MS m / z (ESI): 484.2 [M+H] + .

[0814] Example 80

[0815] (S)-1-(2,6-dimethylpyridin-3-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0816]

[0817] The preparation method of (S)-1-(2,6-dimethylpyridin-3-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0818] 1 H NMR (400MHz, CDCl3) δ1.63 (d, J = 6.6Hz, 3H), 2.42-2.50 (m, 1H), 2.57 (s, 3H), 2.64 (s, 3H), 3.01-3.13 (m, 3H), 4.19 (s, 3H), 5.01-5.08 (m, 1H), 7.17(d,J=8.2Hz,1H),7.60(d,J=8.2Hz,1H),7.82-7.88(m,1H),8.05(d,J=7.6Hz,1H),8.10(s,1H),8.33(d,J=8.4Hz,1H),9.20-9.25(m,1H).

[0819] MS m / z (ESI): 445.2 [M+H] + .

[0820] Example 81

[0821] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-carboxamide

[0822]

[0823] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0824] MS m / z (ESI): 424.2 [M+H] + .

[0825] Example 82

[0826] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(oxecyclohexane-3-yl)-1H-pyrazol-4-carboxamide

[0827]

[0828] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(oxecyclohexane-3-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0829] MS m / z(ESI): 396.2 [M+H] + .

[0830] Example 83

[0831] (S)-1-Acetyl-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0832]

[0833] The preparation method of (S)-1-acetyl-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0834] MS m / z(ESI): 382.2 [M+H] + .

[0835] Example 84

[0836] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(2-morpholinoethyl)-1H-pyrazole-4-carboxamide

[0837]

[0838] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(2-morpholinoethyl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0839] 1 H NMR (400MHz, CDCl3) δ1.61 (d, J = 6.6Hz, 3H), 1.68-1.80 (m, 1H), 2.39-2.47 (m ,1H),2.50-2.61(m,3H),2.79-2.93(m,2H),2.98-3.15(m,3H),3.67-3.79(m ,4H),4.11(s,3H),4.12-4.21(m,2H),4.98-5.04(m,1H),7.78-7.86(m,1H), 7.96(s,1H),8.01(d,J=7.6Hz,1H),8.30(d,J=8.4Hz,1H),9.12-9.18(m,1H).

[0840] MS m / z (ESI): 453.2 [M+H] + .

[0841] Example 87

[0842] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazole-4-carboxamide

[0843]

[0844] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0845] 1H NMR (400MHz, CDCl3) δ1.61 (d, J = 6.6 Hz, 3H), 2.31-2.48 (m, 5H), 2.49-2.73 (m, 7H), 2.78-2.86 (m, 2H), 2.98-3.17 (m, 3H), 4.04-4 .17(m,5H),4.97-5.06(m,1H),7.78-7.86(m,1H),7.94(s,1H),8.01(d,J=7.6Hz,1H),8.30(d,J=8.4Hz,1H),9.14-9.19(m,1H).

[0846] MS m / z (ESI): 466.2 [M+H] + .

[0847] Example 86

[0848] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-carboxamide

[0849]

[0850] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0851] MS m / z (ESI): 437.2 [M+H] + .

[0852] Example 87

[0853] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(1-methylazacyclobutane-3-yl)-1H-pyrazole-4-carboxamide

[0854]

[0855] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(1-methylazacyclobutane-3-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0856] MS m / z (ESI): 409.2 [M+H] + .

[0857] Example 88

[0858] 1-((2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrole[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0859]

[0860] The preparation method of 1-((2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrole[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0861] MS m / z (ESI): 452.2 [M+H] + .

[0862] Example 89

[0863] 1-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrole[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0864]

[0865] The preparation method of 1-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0866] MS m / z (ESI): 452.2 [M+H] + .

[0867] Example 90

[0868] (S)-3-methoxy-1-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)pyridin-2-yl)-1H-pyrazol-4-carboxamide

[0869]

[0870] The preparation method of (S)-3-methoxy-1-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[0871] MS m / z (ESI): 353.2 [M+H] + .

[0872] Example 91

[0873] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(1,2,5-oxadiazol-3-yl)-1H-pyrazol-4-carboxamide

[0874]

[0875] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(1,2,5-oxadiazol-3-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0876] MS m / z (ESI): 408.2 [M+H] + .

[0877] Example 92

[0878] Methyl(R)-3-(6-(3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carbon oxaloylamino(oxiamylamino))pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylic acid ester

[0879]

[0880] The preparation method of methyl(R)-3-(6-(3-methoxy-1-(pyrazin-2-yl)-1H-pyrazole-4-carbon oxaloylamino(oxiamylamino)pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylic acid ester is as described in Examples 1-1.

[0881] MS m / z(ESI): 462.2 [M+H] + .

[0882] Example 93

[0883] (S)-1-(6-((dimethylamino)methyl)pyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazol-4-carboxamide

[0884]

[0885] The preparation method of (S)-1-(6-((dimethylamino)methyl)pyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0886] MS m / z (ESI): 475.2 [M+H] + .

[0887] Example 94

[0888] (S)-1-(5-((dimethylamino)methyl)pyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazol-4-carboxamide

[0889]

[0890] The preparation method of (S)-1-(5-((dimethylamino)methyl)pyrazin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0891] MS m / z (ESI): 475.2 [M+H] + .

[0892] Example 95

[0893] (S)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0894]

[0895] The preparation method of (S)-1-(6-(2-hydroxypropane-2-yl)pyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0896] 1 H NMR (400MHz, CDCl3) δ1.48-1.69(m,9H),2.40-2.43(m,1H),2.91-3.13(m,3H),4.17(s,3H),5.00-5.05(m,1H),7.32(d ,J=7.6Hz,1H),7.69(d,J=7.6Hz,1H),7.75-7.83(m,2H),8.01(s,1H),8.32(d,J=7.6Hz,1H),9.02(s,1H),9.14(s,1H).

[0897] MS m / z (ESI): 475.2 [M+H] + .

[0898] Example 96

[0899] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0900]

[0901] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0902] 1 H NMR (400MHz, CDCl3) δ1.68 (d, J = 6.4Hz, 3H), 2.51-2.53 (m, 1H), 3.03-3.29 (m, 3H), 4.26 (s, 3H), 5.08-5.11 (m, 1H), 7 .88(s,1H),7.98(d,J=8.6Hz,1H),8.06(d,J=7.6Hz,1H),8.10(s,1H),8.38(s,1H),8.71(s,1H),9.09-9.21(m,2H);

[0903] MS m / z (ESI): 485.2 [M+H] + .

[0904] Example 97

[0905] (S)-1-(6-((dimethylamino)methyl)pyridin-3-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0906]

[0907] The preparation method of (S)-1-(6-((dimethylamino)methyl)pyridin-3-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0908] 1 H NMR (400MHz, CDCl3) δ1.65(d,J=6.4Hz,3H),2.45-2.51(m,1H),2.87(s,6H),3.05-3.14(m,3H),4.25(s,3H),4.33(s,2 H),7.86-7.91(m,1H),8.08-8.14(m,2H),8.15-8.22(m,2H),8.32-8.37(m,1H),8.52(s,1H),8.99(s,1H),9.18(s,1H);

[0909] MS m / z(ESI): 474.2 [M+H] + .

[0910] Example 98

[0911] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxamide

[0912]

[0913] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0914] 1 H NMR (400MHz, CDCl3) δ1.69 (d, J = 6.2Hz, 3H), 2.51-2.58 (m, 1H), 3.19-3.30 (m, 3H), 4.27 (s, 3H), 5.16-5.19 ( m,1H),7.94(s,1H),8.21-8.26(m,2H),8.59(s,1H),8.44(d,J=7.6Hz,1H),8.85(s,1H),9.08-9.12(m,2H);

[0915] MS m / z (ESI): 485.2 [M+H] + .

[0916] Example 99

[0917] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(5-morpholinopyridin-3-yl)-1H-pyrazole-4-carboxamide

[0918]

[0919] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(5-morpholinopyridin-3-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0920] 1 H NMR (400MHz, CDCl3) δ1.63 (d, J = 7.2Hz, 3H), 2.42-2.48 (m, 1H), 2.90-3.10 (m, 3H), 3.31-3.36 (m, 4H), 3.90-3.97 (m, 4H), 4.24 (s, 3H), 5.0 0-5.05(m,1H),7.48(s,1H),7.84-7.90(m,1H),8.08(d,J=7.6Hz,1H),8.24(s,1H),8.34(d,J=7.6Hz,1H),8.45-8.51(m,2H),9.18(s,1H).

[0921] MS m / z (ESI): 502.2 [M+H] + .

[0922] Example 100

[0923] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazole-4-carboxamide

[0924]

[0925] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0926] MS m / z (ESI): 515.2 [M+H] + .

[0927] Example 101

[0928] (S)-3-(3-methoxy-4-((6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-1H-pyrazol-1-yl)pyridin-2,6-dicarboxamide

[0929]

[0930] The preparation method of (S)-3-(3-methoxy-4-((6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-1H-pyrazol-1-yl)pyridine-2,6-dicarboxamide is as described in Examples 1-1.

[0931] MS m / z (ESI): 503.2 [M+H] + .

[0932] Example 102

[0933] (S)-3-methoxy-1-(1-methyl-2-carbonyl-1,2-dihydropyridin-4-yl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0934]

[0935] The preparation method of (S)-3-methoxy-1-(1-methyl-2-carbonyl-1,2-dihydropyridin-4-yl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0936] MS m / z (ESI): 447.2 [M+H] + .

[0937] Example 103

[0938] (S)-3-methoxy-1'-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1'H-[1,4'-bipyrazole]-4-carboxamide

[0939]

[0940] The preparation method of (S)-3-methoxy-1'-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1'H-[1,4'-bipyrazole]-4-carboxamide is as described in Examples 1-1.

[0941] MS m / z (ESI): 420.2 [M+H] + .

[0942] Example 104

[0943] (S)-3-methoxy-1'-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1'H-[1,3'-bipyrazole]-4-carboxamide

[0944]

[0945] The preparation method of (S)-3-methoxy-1'-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1'H-[1,3'-bipyrazole]-4-carboxamide is as described in Examples 1-1.

[0946] MS m / z (ESI): 420.2 [M+H] + .

[0947] Example 105

[0948] (S)-1-(bicyclo[1.1.1]pentan-1-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0949]

[0950] The preparation method of (S)-1-(bicyclo[1.1.1]pentan-1-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0951] 1 H NMR (400MHz, CDCl3) δ1.55 (d, J = 6.4Hz, 3H), 2.41 (s, 6H), 2.45 (s, 1H), 2.67 (s, 1H), 3.00-3.13 (m, 3H), 4.1 1(s,3H),5.00-5.07(m,1H),7.84-7.87(m,2H),8.05(d,J=7.4Hz,1H),8.32(d,J=8.2Hz,1H),8.40(s,1H);

[0952] MS m / z (ESI): 406.2 [M+H] + .

[0953] Example 106

[0954] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(1,2,2,6,6-pentamethylpiperidin-4-yl)-1H-pyrazol-4-carboxamide

[0955]

[0956] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(1,2,2,6,6-pentamethylpiperidin-4-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0957] MS m / z(ESI): 493.2 [M+H] + .

[0958] Example 107

[0959] (S)-3-methoxy-1-(1-methyl-2-carbonyl-1,2-dihydropyridin-3-yl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0960]

[0961] The preparation method of (S)-3-methoxy-1-(1-methyl-2-carbonyl-1,2-dihydropyridin-3-yl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0962] MS m / z (ESI): 447.2 [M+H] + .

[0963] Example 108

[0964] (S)-1-(1,5-dimethyl-6-carbonyl-1,6-dihydropyridin-3-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0965]

[0966] The preparation method of (S)-1-(1,5-dimethyl-6-carbonyl-1,6-dihydropyridin-3-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0967] 1 H NMR (400MHz, CDCl3) δ1.56 (d, J = 6.2Hz, 3H), 2.26 (s, 3H), 2.49-2.51 (m, 1H), 3.05-3.21 (m, 3H), 3.64 (s, 3H), 4.19 (s, 3H), 5.05 -5.11(m,1H),7.52(s,1H),7.63(s,1H),7.87-7.89(m,1H),8.01-8.09(m,1H),8.18(s,1H),8.35(d,J=8.4Hz,1H),9.15(s,1H);

[0968] MS m / z (ESI): 461.2 [M+H] +.

[0969] Example 109

[0970] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridine-2-

[0971] 1-(1-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)-1H-pyrazole-4-carboxamide

[0972]

[0973] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(1-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0974] 1 H NMR (400MHz, DMSO) δ1.53 (d, J = 6.4Hz, 3H), 2.53-2.56 (m, 1H), 2.82-3.13 (m, 3H), 3.50 (s, 3H), 4.15 (s, 3H), 4.92-5.03 (m, 1H), 6. 54(d,J=8.8Hz,1H),7.87(d,J=7.6Hz,1H),7.92-7.99(m,2H),8.21(d,J=8.6Hz,1H),8.31-8.33(m,1H),8.78(s,1H),9.37(s,1H);

[0975] MS m / z (ESI): 447.2 [M+H] + .

[0976] Example 110

[0977] (S)-1-Cyclopropyl-5-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0978]

[0979] The preparation method of (S)-1-cyclopropyl-5-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0980] 1 H NMR (400MHz, CDCl3) δ1.07-1.18(m,2H),1.23-1.34(m,2H),1.57(d,J=5.8Hz,3H),2.39-2.48(m,1H),2.98-3.17(m,3H),3.4 3-3.54(m,1H),4.21(s,3H),4.97-5.08(s,1H),7.82-7.88(m,2H),8.04(d,J=7.6Hz,1H),8.32(d,J=8.2Hz,1H),8.60(s,1H);

[0981] MS m / z (ESI): 380.2 [M+H] + .

[0982] Example 111

[0983] 3-Methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazole-4-carboxamide

[0984]

[0985] The preparation method of 3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0986] MS m / z (ESI): 463.2 [M+H] + .

[0987] Example 112

[0988] 3-Methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazole-4-carboxamide

[0989]

[0990] The preparation method of 3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0991] MS m / z (ESI): 463.2 [M+H] + .

[0992] Example 113

[0993] (S)-3-methoxy-1-(4-methoxybenzyl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0994]

[0995] The preparation method of (S)-3-methoxy-1-(4-methoxybenzyl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[0996] MS m / z (ESI): 460.2 [M+H] + .

[0997] Example 114

[0998] (S)-1-(3-cyanocyclobutyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[0999]

[1000] The preparation method of (S)-1-(3-cyanocyclobutyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1001] MS m / z (ESI): 419.2 [M+H] + .

[1002] Example 115

[1003] (S)-3-methoxy-1-(3-methoxycyclobutyl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1004]

[1005] The preparation method of (S)-3-methoxy-1-(3-methoxycyclobutyl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1006] MS m / z (ESI): 424.2 [M+H] + .

[1007] Example 116

[1008] (S)-1-(4-cyanobenzyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1009]

[1010] The preparation method of (S)-1-(4-cyanophenylmethyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1011] 1 H NMR (400MHz, CDCl3) δ1.63 (d, J = 7.2Hz, 3H), 2.42-2.48 (m, 1H), 2.98-3.15 (m, 3H), 4.11 (s, 3H), 5.00-5.05 (m, 1H), 5.23 (s, 2H), 7.2 4(d,J=7.6Hz,2H),7.67(d,J=7.6Hz,2H),7.81-7.85(m,1H),7.98(s,1H),8.04(d,J=7.6Hz,1H),8.29(d,J=7.6Hz,1H),9.14(s,1H).

[1012] MS m / z (ESI): 455.2 [M+H] + .

[1013] Example 117

[1014] (S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1015]

[1016] The preparation method of (S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1017] MS m / z(ESI): 474.2 [M+H] + .

[1018] Example 118

[1019] (S)-1-(cyanomethyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1020]

[1021] The preparation method of (S)-1-(cyanomethyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1022] 1 H NMR (400MHz, CDCl3) δ1.63 (d, J = 7.2Hz, 3H), 2.42-2.48 (m, 1H), 2.90-3.10 (m, 3H), 4.15 (s, 3H), 4.95 (s,2H),5.00-5.05(m,1H),7.84-7.90(m,1H),8.00-8.12(m,2H),8.29(d,J=7.6Hz,1H),9.10(s,1H).

[1023] MS m / z(ESI): 379.2 [M+H] + .

[1024] Example 119

[1025] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-ylmethyl)-1H-pyrazol-4-carboxamide

[1026]

[1027] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-ylmethyl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[1028] 1 H NMR (400MHz, CDCl3) δ1.60 (d, J = 6.4Hz, 3H), 2.38-2.47 (m, 1H), 2.94-3.16 (m, 3H), 4.10 (s, 3H), 4.96-5.06 (m, 1H), 5.33(s,2H),7.77-7.85(m,1H),7.99-8.05(m,1H),8.07(s,1H),8.26-8.32(m,1H),8.50-8.61(m,3H),9.14(s,1H);

[1029] MS m / z(ESI): 432.2 [M+H] + .

[1030] Example 120

[1031] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-((3-methyloxobutylcyclo-3-yl)methyl)-1H-pyrazole-4-carboxamide

[1032]

[1033] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-((3-methyloxobutylcyclo-3-yl)methyl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1034] MS m / z (ESI): 424.2 [M+H] + .

[1035] Example 121

[1036] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(2-oxaspiro[3.3]heptane-6-yl)-1H-pyrazol-4-carboxamide

[1037]

[1038] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(2-oxaspiro[3.3]heptane-6-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1039] 1 H NMR (400MHz, CDCl3) δ1.62 (d, J = 6.4Hz, 3H), 2.42-2.49 (m, 1H), 2.68-2.76 (m, 2H), 2.79-2.86 (m, 2H), 3.03-3.18 (m, 3H), 4.11 (s, 3H), 4.42-4.50 (m,1H),4.76(s,2H),4.78(s,2H),5.03-5.10(m,1H),7.79-7.85(m,1H) ,7.86(s,1H),8.04(d,J=7.6Hz,1H),8.31(d,J=8.2Hz,1H),9.13(s,1H);

[1040] MS m / z (ESI): 436.2 [M+H] + .

[1041] Example 122

[1042] 1-((1,4-dioxane-2-yl)methyl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1043]

[1044] The preparation method of 1-((1,4-dioxane-2-yl)methyl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1045] 1H NMR (400MHz, CDCl3) δ1.62 (d, J = 5.3Hz, 3H), 2.39-2.51 (m, 1H), 2.94-3.1 8(m,3H),3.29-3.37(m,1H),3.54-3.63(m,1H),3.67-3.75(m,2H),3.76-3 .84(m,2H),3.93-4.02(m,3H),4.11(s,3H),4.96-5.12(m,1H),7.79-7.8 6(m,1H),7.94(s,1H),7.99-8.06(m,1H),8.28-8.34(m,1H),9.15(s,1H);

[1046] MS m / z (ESI): 440.2 [M+H] + .

[1047] Example 123

[1048] (S)-1-(2,2-dimethyl-1,3-dioxane-5-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1049]

[1050] The preparation method of (S)-1-(2,2-dimethyl-1,3-dioxane-5-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1051] 1 H NMR (400MHz, CDCl3) δ1.61 (d, J = 7.2Hz, 3H), 1.63 (s, 6H), 2.42-2.48 (m, 1H), 2.90-3.10 (m, 3H), 3.75-3.80 (m, 1H), 4.10-4.15 (m, 6H),4.40-4.46(m,1H),5.00-5.05(m,1H),7.84-7.90(m,1H),7.96(s,1H),8.00-8.12(m,1H),8.29(d,J=7.6Hz,1H),9.14(s,1H).

[1052] MS m / z (ESI): 454.2 [M+H] + .

[1053] Example 124

[1054] (S)-3-(3-methoxy-4-((6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-1H-pyrazol-1-yl)pyridin-2,6-dicarboxamide

[1055]

[1056] The preparation method of (S)-3-(3-methoxy-4-((6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)carbamoyl)-1H-pyrazol-1-yl)pyridine-2,6-dicarboxamide is as described in Examples 1-1.

[1057] MS m / z (ESI): 503.2 [M+H] + .

[1058] Example 125

[1059] 3-Methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(oxobutylcyclo-2-ylmethyl)-1H-pyrazole-4-carboxamide

[1060]

[1061] The preparation method of 3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(oxobutylcyclo-2-ylmethyl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1062] MS m / z (ESI): 410.2 [M+H] + .

[1063] Example 126

[1064] (S)-3-methoxy-1,5-dimethyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1065]

[1066] The preparation method of (S)-3-methoxy-1,5-dimethyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1067] MS m / z (ESI): 368.2 [M+H] + .

[1068] Example 127

[1069] 3-Methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(1,1,1-trifluoro-3-hydroxypropane-2-yl)-1H-pyrazole-4-carboxamide

[1070]

[1071] The preparation method of 3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(1,1,1-trifluoro-3-hydroxypropane-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1072] 1 H NMR (400MHz, DMSO-d6) δ1.52 (d, J = 6.4Hz, 3H), 2.32-2.40 (m, 1H), 2.47-2.50 (m, 1H), 2.90-3.09 (m, 3H), 4.07 (s, 3H), 4.17-4.25 (m, 1H), 4. 29-4.36(m,1H),4.40-4.48(m,1H),4.90-5.01(m,1H),7.84-7.89(m, 1H),7.94-8.01(m,1H),8.15-8.21(m,1H),8.31(s,1H),9.30(s,1H);

[1073] MS m / z (ESI): 452.2 [M+H] + .

[1074] Example 128

[1075] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(oxobutylcyclo-3-ylmethyl)-1H-pyrazole-4-carboxamide

[1076]

[1077] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(oxobutylcyclo-3-ylmethyl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1078] 1 H NMR (400MHz, CDCl3) δ1.61 (d, J = 7.2Hz, 3H), 2.42-2.48 (m, 1H), 2.90-3.10 (m, 3H), 3.48-3.53 (m, 1H), 4.09 (s, 3H), 4.31-4.35 (m, 2H), 4.48 -4.55(m,2H),4.84-4.88(m,2H),5.00-5.05(m,1H),7.81-7.85(m,1H),7.90(s,1H),8.00-8.12(m,1H),8.29(d,J=7.6Hz,1H),9.12(s,1H).

[1079] MS m / z (ESI): 410.2 [M+H] + .

[1080] Example 129

[1081] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridine-2-

[1082] 1H-pyrazole-4-carboxamide

[1083]

[1084] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[1085] MS m / z (ESI): 340.2 [M+H] + .

[1086] Example 130

[1087] (S)-2,6-Dimethoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)nicotinamide

[1088]

[1089] The preparation method of (S)-2,6-dimethoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)nicotinamide is as described in Examples 1-1.

[1090] 1 H NMR (400MHz, CDCl3) δ1.63 (d, J = 6.4Hz, 3H), 2.42-2.50 (m, 1H), 2.99-3.16 (m, 3H), 4.02 (s, 3H), 4.20 (s, 3H), 5.01-5.10 (m, 1H) ),6.53(d,J=8.4Hz,1H),7.81-7.89(m,1H),8.06(d,J=7.6Hz,1H),8.41(d,J=8.4Hz,1H),8.50(d,J=8.4Hz,1H),10.23(s,1H);

[1091] MS m / z(ESI): 381.2 [M+H] + .

[1092] Example 131

[1093] (S)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-morpholinopyrimidin-4-carboxamide

[1094]

[1095] The preparation method of (S)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-morpholinopyrimidine-4-carboxamide is as described in Example 1-1.

[1096] 1 H NMR (400MHz, CDCl3) δ1.56 (d, J = 6.4Hz, 3H), 2.41-2.49 (m, 1H), 2.99-3.14 (m, 3H), 3.77-3.83 (m, 8H), 5.13-5.21 (m,1H),7.46(s,1H),7.86-7.94(m,1H),8.12(d,J=7.6Hz,1H),8.39(d,J=8.4Hz,1H),8.67(s,1H),10.36(s,1H);

[1097] MS m / z (ESI): 407.2 [M+H] +.

[1098] Example 132

[1099] (S)-4-methoxy-2-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)thiazolyl-5-carboxamide

[1100]

[1101] The preparation method of (S)-4-methoxy-2-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)thiazole-5-carboxamide is as described in Example 1-1.

[1102] 1 H NMR (400MHz, CDCl3) δ1.63 (d, J = 6.4Hz, 3H), 2.42-2.49 (m, 1H), 2.68 (s, 3H), 3.01-3.21 (m, 3H), 4.25 (s, 3H),5.01-5.10(m,1H),7.84(t,J=8.0Hz,1H),8.06(d,J=7.6Hz,1H),8.29(d,J=8.4Hz,1H),9.44(s,1H);

[1103] MS m / z (ESI): 371.2 [M+H] + .

[1104] Example 133

[1105] (S)-5-methoxy-1-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1106]

[1107] The preparation method of (S)-5-methoxy-1-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 1-1.

[1108] 1H NMR (400MHz, CDCl3) δ1.55 (d, J = 6.4Hz, 3H), 2.39-2.47 (m, 1H), 2.97-3.14 (m, 3H), 3.79 (s, 3H), 4.14 (s, 3H), 4. 97-5.06(m,1H),7.84(d,J=8.0Hz,1H),7.87(s,1H),8.03(d,J=7.6Hz,1H),8.31(d,J=8.3Hz,1H),8.45(s,1H);

[1109] MS m / z (ESI): 354.2 [M+H] + .

[1110] Example 134

[1111] (S)-4-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)nicotinamide

[1112]

[1113] The preparation method of (S)-4-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)nicotinamide is as described in Examples 1-1.

[1114] 1 H NMR (400MHz, CDCl3) δ1.61 (d, J = 6.3Hz, 3H), 2.40-2.48 (m, 1H), 2.98-3.12 (m, 3H), 4.15 (s, 3H), 4.96-5.06 (m, 1H), 6.9 7-7.06(m,1H),7.84-7.92(m,1H),8.05-8.11(m,1H),8.38-8.44(m,1H),8.64-8.74(m,1H),9.35(s,1H),9.91(s,1H);

[1115] MS m / z (ESI): 351.2 [M+H] + .

[1116] Example 135

[1117] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)isonicotinamide

[1118]

[1119] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)isonicotinamide is as described in Examples 1-1.

[1120] MS m / z (ESI): 351.2 [M+H] + .

[1121] Example 136

[1122] (S)-2-chloro-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(trifluoromethyl)nicotinamide

[1123]

[1124] The preparation method of (S)-2-chloro-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(trifluoromethyl)nicotinamide is as described in Examples 1-1.

[1125] MS m / z(ESI): 423.2 [M+H] + .

[1126] Example 137

[1127] (S)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-morpholinopyrimidin-2-carboxamide

[1128]

[1129] The preparation method of (S)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-morpholinopyrimidine-2-carboxamide is as described in Example 1-1.

[1130] 1H NMR (400MHz, CDCl3) δ1.56 (d, J = 6.4Hz, 3H), 2.39-2.48 (m, 1H), 3.02-3.12 (m, 3H), 3.75-3.87 (m, 8H), 5.05-5.13 (m, 1H), 6 .64(d,J=6.2Hz,1H),7.90(t,J=8.0Hz,1H),8.07-8.12(m,1H),8.39(d,J=6.2Hz,1H),8.46(d,J=8.4Hz,1H),10.34(s,1H);

[1131] MS m / z (ESI): 407.2 [M+H] + .

[1132] Example 138

[1133] (S)-6-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)methylpyridineamide

[1134]

[1135] The preparation method of (S)-6-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)methylpyridine amide is as described in Examples 1-1.

[1136] 1 H NMR (400MHz, CDCl3) δ1.61 (d, J = 6.4Hz, 3H), 2.40-2.48 (m, 1H), 3.01-3.17 (m, 3H), 4.07 (s, 3H), 5.01-5.08 (m, 1H), 7. 01(d,J=8.4Hz,1H),7.79-7.86(m,1H),7.87-7.96(m,2H),8.11(d,J=7.8Hz,1H),8.43(d,J=8.2Hz,1H),10.27(s,1H);

[1137] MS m / z (ESI): 351.2 [M+H] + .

[1138] Example 139

[1139] (S)-6-cyano-2-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)nicotinamide

[1140]

[1141] The preparation method of (S)-6-cyano-2-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)nicotinamide is as described in Examples 1-1.

[1142] 1 H NMR (400MHz, CDCl3) δ1.63 (d, J = 6.4Hz, 3H), 2.44-2.51 (m, 1H), 3.00-3.19 (m, 3H), 4.27 (s, 3H), 4.99-5.07 (m, 1H), 7.57 (d,J=7.6Hz,1H),7.90(t,J=8.0Hz,1H),8.10-8.16(m,1H),8.39(d,J=8.4Hz,1H),8.75(d,J=7.8Hz,1H),10.26(s,1H);

[1143] MS m / z (ESI): 376.2 [M+H] + .

[1144] Example 140

[1145] (S)-5-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)methylpyridineamide

[1146]

[1147] The preparation method of (S)-5-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)methylpyridine amide is as described in Examples 1-1.

[1148] 1 H NMR (400MHz, CDCl3) δ1.56 (d, J = 6.4Hz, 3H), 2.42-2.52 (m, 1H), 3.01-3.16 (m, 3H), 3.96 (s, 3H), 5.14-5.19 (m, 1H), 7.34-7.39 (m, 1H) ),7.88(t,J=8.0Hz,1H),8.06-8.10(m,1H),8.28(d,J=8.6Hz,1H),8.33(d,J=2.8Hz,1H),8.43(d,J=0.9,8.4Hz,1H),10.27(s,1H);

[1149] MS m / z (ESI): 351.2 [M+H] + .

[1150] Example 141

[1151] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)pyrazin-2-carboxamide

[1152]

[1153] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)pyrazine-2-carboxamide is as described in Example 1-1.

[1154] 1 H NMR (400MHz, CDCl3) δ1.56 (d, J = 6.4Hz, 3H), 2.41-2.49 (m, 1H), 3.01-3.15 (m, 3H), 4.19 (s, 3H), 5.09-5.17 (m, 1H), 7. 89(t,J=8.0Hz,1H),8.09(d,J=7.6Hz,1H),8.26-8.30(m,1H),8.39-8.42(m,1H),8.46(d,J=8.4Hz,1H),10.12(s,1H);

[1155] MS m / z(ESI): 352.2 [M+H] + .

[1156] Example 142

[1157] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)pyridazin-4-carboxamide

[1158]

[1159] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)pyridazine-4-carboxamide is as described in Example 1-1.

[1160] 1H NMR (400MHz, CDCl3) δ1.65 (d, J = 6.4Hz, 3H), 2.44-2.53 (m, 1H), 3.01-3.17 (m, 3H), 4.46 (s, 3H), 5.01-5.09 (m, 1H), 7.92 ( t,J=8.0Hz,1H),8.16(d,J=7.6Hz,1H),8.29(d,J=4.8Hz,1H),8.39(d,J=8.2Hz,1H),9.20(d,J=4.7Hz,1H),10.24(s,1H);

[1161] MS m / z(ESI): 352.2 [M+H] + .

[1162] Example 143

[1163] (S)-2-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(trifluoromethyl)nicotinamide

[1164]

[1165] The preparation method of (S)-2-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(trifluoromethyl)nicotinamide is as described in Examples 1-1.

[1166] 1 H NMR (400MHz, CDCl3) δ1.63 (d, J = 6.4Hz, 3H), 2.43-2.50 (m, 1H), 3.02-3.16 (m, 3H), 4.28 (s, 3H), 4.99-5.07 (m, 1H), 7.53 (d,J=7.6Hz,1H),7.89(t,J=8.0Hz,1H),8.12(d,J=7.8Hz,1H),8.40(d,J=8.2Hz,1H),8.76-8.81(m,1H),10.31(s,1H);

[1167] MS m / z (ESI): 419.2 [M+H] + .

[1168] Example 144

[1169] (S)-1-(3-(difluoromethyl)-3-hydroxycyclobutyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1170]

[1171] The preparation method of (S)-1-(3-(difluoromethyl)-3-hydroxycyclobutyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1172] MS m / z (ESI): 460.2 [M+H] + .

[1173] Example 145

[1174] (S)-1-(1-(difluoromethyl)-3-hydroxycyclobutyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1175]

[1176] The preparation method of (S)-1-(1-(difluoromethyl)-3-hydroxycyclobutyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1177] MS m / z (ESI): 460.2 [M+H] + .

[1178] Example 146

[1179] (S)-1-(2-(dimethylamino)-2-carbonylethyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1180]

[1181] The preparation method of (S)-1-(2-(dimethylamino)-2-carbonylethyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1182] MS m / z (ESI): 425.2 [M+H] + .

[1183] Example 147

[1184] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(1-methyl-6-carbonyl-1,6-dihydropyridin-2-yl)-1H-pyrazole-4-carboxamide

[1185]

[1186] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(1-methyl-6-carbonyl-1,6-dihydropyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1187] 1 H NMR (400MHz, CDCl3) δ1.69 (d, J = 6.2Hz, 3H), 2.51-2.55 (m, 1H), 3.04-3.27 (m, 3H), 3.43 (s, 3H), 4.21 (s, 3H), 5.10-5.1 6(m,1H),6.23(d,J=6.4Hz,1H),6.73(d,J=8.6Hz,1H),7.38-7.45(m,1H),8.10-8.21(m,2H),8.38(s,1H),9.17(s,1H);

[1188] MS m / z (ESI): 447.2 [M+H] + .

[1189] Example 148

[1190] (S)-1-(bicyclo[1.1.1]pentan-1-yl)-5-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1191]

[1192] The preparation method of (S)-1-(bicyclo[1.1.1]pentan-1-yl)-5-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1193] 1 H NMR (400MHz, CDCl3) δ1.55 (d, J = 6.4Hz, 3H), 2.41 (s, 6H), 2.45 (s, 1H), 2.67 (s, 1H), 3.00-3.13 (m, 3H), 4.1 1(s,3H),5.00-5.07(m,1H),7.84-7.87(m,2H),8.05(d,J=7.4Hz,1H),8.32(d,J=8.2Hz,1H),8.40(s,1H);

[1194] MS m / z (ESI): 406.2 [M+H] + .

[1195] Example 149

[1196] (S)-1-(bicyclo[1.1.1]pentan-1-ylmethyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1197]

[1198] The preparation method of (S)-1-(bicyclo[1.1.1]pentan-1-ylmethyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1199] 1 H NMR (400MHz, CDCl3) δ1.62(d,J=6.4Hz,3H),1.76(s,6H),2.40-2.48(m,1H),2.53(s,1H),2.99-3.13(m,3H),4.01(s ,2H),4.11(s,3H),4.99-5.07(m,1H),7.80-7.85(m,2H),8.02(d,J=7.6Hz,1H),8.31(d,J=8.4Hz,1H),9.17(s,1H);

[1200] MS m / z (ESI): 420.2 [M+H] + .

[1201] Example 150

[1202] 3-Methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-((R)-1-methylpyrrolidine-3-yl)-1H-pyrazole-4-carboxamide

[1203]

[1204] The preparation method of 3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-((R)-1-methylpyrrolidine-3-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1205] 1 H NMR (400MHz, CDCl3) δ1.60 (d, J = 6.4Hz, 3H), 2.19-2.32 (m, 1H), 2.39-2.48 (m, 1H), 2.51-2.72 (m, 4H), 2.98-3.15 (m, 4H), 3.16-3.29 (m, 3H), 4 .12(s,3H),4.80-4.89(m,1H),4.96-5.04(m,1H),7.77-7.85(m,1H),8 .02(d,J=7.6Hz,1H),8.05(s,1H),8.29(d,J=8.2Hz,1H),9.11(s,1H);

[1206] MS m / z(ESI): 423.2 [M+H] + .

[1207] Example 151

[1208] 3-Methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-((S)-1-methylpyrrolidine-3-yl)-1H-pyrazole-4-carboxamide

[1209]

[1210] The preparation method of 3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-((S)-1-methylpyrrolidine-3-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1211] 1 H NMR (400MHz, CDCl3) δ1.60 (d, J = 6.4Hz, 3H), 2.19-2.32 (m, 1H), 2.40-2.47 ( m,1H),2.58-2.67(m,1H),2.71-2.79(m,3H),2.98-3.15(m,4H),3.16-3.29 (m,3H),4.12(s,3H),4.80-4.89(m,1H),4.96-5.04(m,1H),7.77-7.85(m,1 H),8.02(d,J=7.7Hz,1H),8.04(s,1H),8.29(d,J=8.2Hz,1H),9.10(s,1H);

[1212] MS m / z(ESI): 423.2 [M+H] + .

[1213] Example 152

[1214] (S)-1-(2-((dimethylamino)methyl)pyridin-3-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1215]

[1216] The preparation method of (S)-1-(2-((dimethylamino)methyl)pyridin-3-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1217] MS m / z(ESI): 474.2 [M+H] + .

[1218] Example 153

[1219] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(6-(oxobutyl-3-yl)pyridin-3-yl)-1H-pyrazole-4-carboxamide

[1220]

[1221] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-(6-(oxobutylcyclo-3-yl)pyridin-3-yl)-1H-pyrazole-4-carboxamide is as described in Examples 1-1.

[1222] MS m / z(ESI): 473.2 [M+H] + .

[1223] Example 154-1

[1224] (S)-3-methoxy-1-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazol-4-carboxamide

[1225]

[1226] The first step: Synthesis of (S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

[1227]

[1228] At room temperature, (S)-5-methoxy-2-methyl-3,4-dihydro-2H-pyrrole (2 g, 17.67 mmol) and 2,2-dimethoxyethane-1-amine (2.04 g, 19.44 mmol) were dissolved in MeOH (16 mL), and dichloromethane (4 mL) was added. The reaction mixture was heated to 80 °C and stirred for 5 hours. After cooling, the organic solvent was concentrated under reduced pressure. The crude product was dissolved in formic acid (10 mL), sealed in a tube, and heated to 130 °C for 12 hours. The reaction was confirmed by LCMS. After cooling to room temperature, the organic solvent was concentrated under reduced pressure, and ethyl acetate was added to dissolve the residue. A saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with ethyl acetate (300 mL × 3). The organic phases were separated and combined, and the organic solvent was concentrated under reduced pressure to obtain 1.6 g of crude (S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, which was used directly in the next step.

[1229] MS m / z (ESI): 123.1 [M+H] + .

[1230] The second step involves the synthesis of (S)-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)boronic acid.

[1231]

[1232] At room temperature, the crude product from the previous step, (S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (1.6 g, 13.10 mmol), and 4,4'-di-tert-butyl-2,2'-dipyridine (373 mg, 1.39 mmol), were added. Pinaryl diboronate (4.99 g, 19.65 mmol) was dissolved in n-hexane (7.5 mL) and THF (7.5 mL), and the mixture was purged with nitrogen for 5 minutes. 1,5-cyclooctadiene iridium chloride dimer (461 mg, 686 μmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction was confirmed by LCMS. After concentrating the organic solvent under reduced pressure, the mixture was separated by reverse-phase column chromatography to obtain (S)-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)boronic acid (1.15 g, two-step yield 39%).

[1233] MS m / z (ESI): 167.2 [M+H] + .

[1234] Step 3: Synthesis of 3-methoxy-1-methyl-1H-pyrazole-4-carbonyl chloride

[1235]

[1236] Under ice bath conditions, 0.5 g (3.52 mmol) of 3-methoxy-1-methyl-pyrazole-4-carboxylic acid was dissolved in 15 mL of dichloromethane, and 4.39 g (34.6 mmol) of oxaloyl chloride was added. The reaction mixture was stirred under ice bath conditions for 5 minutes, and then 0.5 mL of DMF was added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the organic solvent was concentrated under reduced pressure to obtain 600 mg of crude 3-methoxy-1-methyl-1H-pyrazole-4-carbonyl chloride, which was used directly in the next reaction step.

[1237] Step 4: Synthesis of N-(6-bromopyridin-2-yl)-3-methoxy-1-methyl-1H-pyrazole-4-carboxamide

[1238]

[1239] At room temperature, crude 3-methoxy-1-methyl-1H-pyrazole-4-carbonyl chloride (600 mg, 3.44 mmol) was dissolved in pyridine (6 mL), and 6-bromopyridine-2-amine (595 mg, 3.44 mmol) was added. The reaction was stirred at room temperature for 10 hours. LCMS analysis showed that the reaction was complete. After concentrating the organic solvent under reduced pressure, normal-phase column chromatography was used to separate N-(6-bromopyridine-2-yl)-3-methoxy-1-methyl-1H-pyrazole-4-carboxamide (302 mg, two-step yield 28%).

[1240] MS m / z (ESI): 310.8 [M+H] + .

[1241] The fifth step was the synthesis of (S)-3-methoxy-1-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide.

[1242]

[1243] At room temperature, N-(6-bromo-2-pyridinyl)-3-methoxy-1-methylpyrazole-4-carboxamide (0.24 g, 771.37 μmol) and potassium phosphate (327 mg, 1.54 mmol) were dissolved in 1,4-Dioxane (10 mL) and H2O (2 mL), and Pd(PPh3)4 (267 mg, 231.41 μmol) and (S)-(5-methyl-6,7-dihydro-5H-pyrrolo) were added. [1,2-a]imidazol-3-yl)boronic acid (256 mg, 1.54 mmol) was deoxygenated three times with nitrogen, and the reaction was heated to 100 °C and stirred for 12 hours. The organic solvent was concentrated under reduced pressure, and (S)-3-methoxy-1-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide (96 mg, 35%) was prepared and isolated by reverse-phase column chromatography.

[1244] 1 H NMR (400MHz, CDCl3) δ1.50 (d, J = 6.2Hz, 3H), 2.28-2.33 (m, 1H), 2.79-2.91 (m, 2H), 3.01-3.09 (m, 1H), 3.81 (s, 3H), 4.11 (s ,3H),5.05-5.11(m,1H),7.35-7.44(m,1H),7.52(s,1H),7.63-7.69(m,1H),7.83(s,1H),8.07-8.10(m,1H),9.10(s,1H);

[1245] MS m / z (ESI): 353.2 [M+H] + .

[1246] Example 154-2

[1247] (R)-3-methoxy-1-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1248]

[1249] The preparation method of (R)-3-methoxy-1-methyl-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 154-1.

[1250] MS m / z (ESI): 353.2 [M+H] + .

[1251] Example 155-1

[1252] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[1253]

[1254] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 154-1.

[1255] MS m / z (ESI): 417.2 [M+H] + .

[1256] Example 155-2

[1257] (R)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-yl)-1H-pyrazol-4-carboxamide

[1258]

[1259] The preparation method of (R)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 154-1.

[1260] MS m / z (ESI): 417.2 [M+H] + .

[1261] Example 155

[1262] (S)-1-(6-((dimethylamino)methyl)pyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1263]

[1264] The preparation method of (S)-1-(6-((dimethylamino)methyl)pyridin-2-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 154-1.

[1265] MS m / z(ESI): 473.2 [M+H] + .

[1266] Example 157

[1267] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide

[1268]

[1269] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 154-1.

[1270] MS m / z (ESI): 430.2 [M+H] + .

[1271] Example 158

[1272] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-carboxamide

[1273]

[1274] Method 1: The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide is as described in Example 154-1.

[1275] Method 2: Step 1 Synthesis of 1-(tert-butyl)4-ethyl-3-methoxy-1H-pyrazole-1,4-dicarboxylic acid ester

[1276]

[1277] Under ice-water bath conditions, NaH (4.71 g, 118 mmol, 60 wt%) was added in portions to a mixed solution of 1-(tert-butyl)4-ethyl 3-hydroxy-1H-pyrazole-1,4-dicarboxylic acid ester (20.1 g, 78.4 mmol) in THF (150 mL) and DMF (150 mL). After the addition was complete, the mixture was stirred under ice-water bath conditions for 1 hour. Then, iodomethane (11.1 g, 78.4 mmol) was slowly added dropwise. The ice-water bath was removed, and the mixture was stirred overnight at room temperature. The reaction was quenched with saturated ammonium chloride aqueous solution, and THF was removed by concentration under reduced pressure. Water and ethyl acetate were added to the residue, and the organic phase was extracted and separated. The residue was washed several times with saturated brine, and the organic phases were combined, dried, filtered, and the filtrate was concentrated under reduced pressure to obtain crude 1-(tert-butyl)4-ethyl 3-methoxy-1H-pyrazole-1,4-dicarboxylic acid ester (18.8 g, 89%), which was used directly in the next reaction.

[1278] Step 2: Synthesis of ethyl 3-methoxy-1H-pyrazole-4-carboxylic acid ester

[1279]

[1280] TFA (79.3 g, 696 mmol) was added to a DCM solution (200 mL) of 1-(tert-butyl)-4-ethyl-3-methoxy-1H-pyrazole-1,4-dicarboxylic acid ester (18.8 g, 69.6 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate, then washed successively with saturated sodium bicarbonate aqueous solution and saturated brine. The organic phase was separated, dried, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound ethyl-3-methoxy-1H-pyrazole-4-carboxylic acid ester (7.70 g, 65%), which was used directly in the next reaction.

[1281] MS m / z (ESI): 171.1 [M+H] + .

[1282] Step 3: Synthesis of ethyl 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid ester

[1283]

[1284] In an ice-water bath, NaH (2.71 g) was added in portions to a 100 mL THF solution of ethyl 3-methoxy-1H-pyrazole-4-carboxylic acid ester (7.70 g, 45.3 mmol), and the mixture was stirred at this temperature for 1 hour. PMB-Cl (7.09 g, 45.3 mmol) was then slowly added dropwise, and the mixture was stirred overnight at room temperature. The reaction solution was quenched with a saturated ammonium chloride aqueous solution, the organic solvent was concentrated under reduced pressure, and the mixture was separated by ethyl acetate and saturated brine. The organic phase was dried, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography was used to obtain the title compound, ethyl 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid ester (8.80 g, 67%).

[1285] MS m / z(ESI): 291.1 [M+H] + .

[1286] Step 4: Synthesis of 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid

[1287]

[1288] To a mixed solution of ethyl 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid ester (11.0 g, 37.9 mmol) in methanol (50 mL) and water (50 mL), lithium hydroxide monohydrate (4.54 g) was added, and the mixture was stirred overnight at room temperature. The organic solvent was removed by concentration under reduced pressure, and the pH was adjusted to weakly acidic with dilute hydrochloric acid. A solid precipitated, which was filtered and dried to give the title compound 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid (6.97 g, 70%).

[1289] MS m / z(ESI): 263.1 [M+H] + .

[1290] Step 5: Synthesis of 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carbonyl chloride

[1291]

[1292] Under ice bath conditions, 200 mg (0.76 mmol) of 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid was dissolved in 8 mL of dichloromethane, and 960 mg (7.6 mmol) of oxaloyl chloride was added. The reaction mixture was stirred under ice bath conditions for 5 minutes, and one drop of DMF was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain 214 mg of crude 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carbonyl chloride, which was used directly in the next step of the reaction.

[1293] Step 6: Synthesis of N-(6-bromopyridin-2-yl)-3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamide

[1294]

[1295] At room temperature, crude 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carbonyl chloride (214 mg) was dissolved in pyridine (6 mL), and 6-bromopyridin-2-amine (132 mg, 0.76 mmol) was added. The mixture was stirred at room temperature for 2 hours. After concentrating the organic solvent under reduced pressure, normal-phase column chromatography was used to obtain N-(6-bromopyridin-2-yl)-3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamide (170 mg, 53%).

[1296] MS m / z (ESI): 417.2 [M+H] + .

[1297] Step 7: Synthesis of (S)-3-methoxy-1-(4-methoxybenzyl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1298]

[1299] At room temperature, N-(6-bromopyridin-2-yl)-3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamide (380 mg, 0.91 mmol) and potassium phosphate (386 mg, 1.82 mmol) were mixed in 1,4-Dioxane (10 mL) and H2O (2 mL), and Pd(PPh3)4 (316 mg, 0.27 mmol) and (S)-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)boronic acid (181 mg, 1.09 mmol) were added, and the reaction was carried out overnight at 110 °C under a nitrogen atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then separated by normal-phase column chromatography to obtain (S)-3-methoxy-1-(4-methoxybenzyl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide (325 mg, 77%).

[1300] MS m / z (ESI): 459.2 [M+H] +

[1301] Step 8: Synthesis of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1302]

[1303] At room temperature, (S)-3-methoxy-1-(4-methoxybenzyl)-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide (150 mg, 0.33 mmol) was dissolved in trifluoroacetic acid (6 mL), and the mixture was heated to 90 °C and reacted overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain 105 mg of crude (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, which was directly used in the next step of the reaction.

[1304] Step 9: Synthesis of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-carboxamide

[1305]

[1306] At room temperature, (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide (30 mg, 0.088 mmol), 4-bromotetrahydro-2H-pyran (29 mg, 0.18 mmol), cesium carbonate (58 mg, 0.18 mmol), and potassium iodide (15 mg, 0.088 mmol) were mixed in DMF (1 mL) and heated to 120 °C with stirring for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then separated by normal-phase column chromatography to obtain (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide (7 mg, 18%).

[1307] 1 H NMR (400MHz, CDCl3) δ1.50 (d, J = 6.4Hz, 3H), 1.96-2.07 (m, 2H), 2.07-2.14 (m, 3H), 2. 27-2.37(m,1H),2.80-3.03(m,2H),3.04-3.12(m,1H),3.50-3.58(m,2H),4.11(s,3H) ,4.12-4.16(m,1H),4.17-4.23(m,1H),5.05-5.15(m,1H),7.27-7.30(m,1H),7.50-7 .55(m,1H),7.65-7.71(m,1H),7.93(s,1H),8.10(d,J=8.2Hz,1H),9.09-9.13(m,1H);

[1308] MS m / z(ESI): 423.2 [M+H] + .

[1309] Example 159

[1310] (S)-1-Cyclopropyl-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1311]

[1312] The preparation method of (S)-1-cyclopropyl-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 154-1.

[1313] MS m / z(ESI): 379.2 [M+H] + .

[1314] Example 160

[1315] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(oxepane-3-yl)-1H-pyrazol-4-carboxamide

[1316]

[1317] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(oxacyclopentan-3-yl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1318] 1 H NMR (400MHz, CDCl3) δ1.52 (d, J = 6.4Hz, 3H), 2.32-2.39 (m, 1H), 2.94-3.11 (m, 3H), 4.17 (s, 3H), 4.99-5.05 (m, 2H), 5.08-5.18 (m, 3H) ,5.27-5.35(m,1H),7.28-7.32(m,1H),7.52-7.57(m,1H),7.68-7.74(m,1H),8.00(s,1H),8.13(d,J=8.2Hz,1H),9.10-9.15(m,1H);

[1319] MS m / z (ESI): 395.2 [M+H] + .

[1320] Example 161

[1321] (S)-1-Acetyl-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1322]

[1323] The preparation method of (S)-1-acetyl-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 154-1.

[1324] MS m / z(ESI): 381.2 [M+H]+ .

[1325] Example 162

[1326] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(2-morpholinoethyl)-1H-pyrazol-4-carboxamide

[1327]

[1328] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(2-morpholinoethyl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1329] MS m / z (ESI): 452.2 [M+H] + .

[1330] Example 163

[1331] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-carboxamide

[1332]

[1333] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1334] MS m / z (ESI): 436.2 [M+H] + .

[1335] Example 164

[1336] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(1-methylazacyclobutane-3-yl)-1H-pyrazole-4-carboxamide

[1337]

[1338] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(1-methylazacyclobutane-3-yl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1339] MS m / z (ESI): 408.2 [M+H] + .

[1340] Example 165

[1341] 1-((2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1342]

[1343] The preparation method of 1-((2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1344] MS m / z (ESI): 451.2 [M+H] + .

[1345] Example 166

[1346] 1-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1347]

[1348] The preparation method of 1-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1349] MS m / z (ESI): 451.2 [M+H] + .

[1350] Example 167

[1351] (S)-1-(2-hydroxy-2-methylpropyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1352]

[1353] Method 1: The preparation method of (S)-1-(2-hydroxy-2-methylpropyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 154-1.

[1354] Method 2:

[1355]

[1356] At room temperature, (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide (30 mg, 0.088 mmol), 1-bromo-2-methylpropane-2-ol (27 mg, 0.18 mmol), cesium carbonate (58 mg, 0.18 mmol), and potassium iodide (15 mg, 0.088 mmol) were mixed in DMF (1 mL) and heated to 120 °C with stirring for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then separated by normal-phase column chromatography to obtain (S)-1-(2-hydroxy-2-methylpropyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide (8 mg, 20%).

[1357] 1 H NMR (400MHz, CDCl3) δ1.21 (s, 6H), 1.52 (d, J = 6.6Hz, 3H), 2.32-2.40 (m, 1H), 2.87-3.18 (m, 3H), 3.96 (s, 2H), 4.12 (s, 3H),5.10-5.17(m,1H),7.29(s,1H),7.55(s,1H),7.69-7.74(m,1H),7.92(s,1H),8.13(d,J=8.2Hz,1H),9.09(s,1H);

[1358] MS m / z(ESI): 411.2 [M+H] + .

[1359] Example 168

[1360] (S)-1-(bicyclo[1.1.1]pentan-1-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1361]

[1362] The preparation method of (S)-1-(bicyclo[1.1.1]pentan-1-yl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 154-1.

[1363] 1 H NMR (400MHz, CDCl3) δ1.53 (d, J = 6.2Hz, 3H), 2.23-2.33 (m, 6H), 2.42-2.53 (m, 2H), 2.63-2.68 (m, 1H), 2.97-3.09 (m, 1H), 3.31-3. 39(m,2H),4.13(s,3H),7.30(s,1H),7.60-7.66(m,1H),7.76-7.83(m,1H),7.88(s,1H),8.28(d,J=8.4Hz,1H),9.10-9.16(m,1H)

[1364] MS m / z (ESI): 405.2 [M+H] + .

[1365] Example 169

[1366] (S)-1-(bicyclo[1.1.1]pentan-1-yl)-5-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1367]

[1368] The preparation method of (S)-1-(bicyclo[1.1.1]pentan-1-yl)-5-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 154-1.

[1369] MS m / z (ESI): 405.2 [M+H] + .

[1370] Example 170

[1371] (S)-1-((1-hydroxycyclopropyl)methyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1372]

[1373] The preparation method of (S)-1-((1-hydroxycyclopropyl)methyl)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1374] MS m / z (ESI): 409.2 [M+H] + .

[1375] Example 171

[1376] (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(4-carbonylcyclohexyl)-1H-pyrazole-4-carboxamide

[1377]

[1378] The preparation method of (S)-3-methoxy-N-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(4-carbonylcyclohexyl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1379] MS m / z (ESI): 435.2 [M+H] + .

[1380] Example 172

[1381] 3-Methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide

[1382]

[1383] The preparation method of 3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1384] MS m / z (ESI): 409.2 [M+H] + .

[1385] Example 173

[1386] 3-Methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide

[1387]

[1388] The preparation method of 3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1389] MS m / z (ESI): 409.2 [M+H] + .

[1390] Example 174

[1391] 3-Methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(4-oxaspiro[2,5]octane-7-yl)-1H-pyrazole-4-carboxamide

[1392]

[1393] The preparation method of 3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(4-oxaspiro[2.5]octane-7-yl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1394] MS m / z (ESI): 449.2 [M+H] + .

[1395] Example 175

[1396] 1-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1397]

[1398] The preparation method of 1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1399] MS m / z (ESI): 451.2 [M+H] + .

[1400] Example 176

[1401] 3-Methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(((S)-oxobutylcyclo-2-yl)methyl)-1H-pyrazole-4-carboxamide

[1402]

[1403] The preparation method of 3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(((S)-oxobutylcyclo-2-yl)methyl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1404] MS m / z (ESI): 409.2 [M+H] + .

[1405] Example 177

[1406] 3-Methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(((R)-oxobutylcyclo-2-yl)methyl)-1H-pyrazole-4-carboxamide

[1407]

[1408] The preparation method of 3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1-(((R)-oxobutylcyclo-2-yl)methyl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1409] MS m / z (ESI): 409.2 [M+H] + .

[1410] Example 178

[1411] 1-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1412]

[1413] The preparation method of 1-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1414] MS m / z (ESI): 451.2 [M+H] + .

[1415] Example 179

[1416] 1-((2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1417]

[1418] The preparation method of 1-((2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1419] MS m / z (ESI): 451.2 [M+H] + .

[1420] Example 180

[1421] 1-((1R,3r,5S)-8-oxabicyclo[3.2.1]octane-3-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1422]

[1423] The preparation method of 1-((1R,3r,5S)-8-oxabicyclo[3.2.1]octane-3-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1424] MS m / z (ESI): 449.2 [M+H] + .

[1425] Example 181

[1426] 1-((1R,3s,5S)-8-oxabicyclo[3.2.1]octane-3-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1427]

[1428] The preparation method of 1-((1R,3s,5S)-8-oxabicyclo[3.2.1]octane-3-yl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1429] MS m / z (ESI): 449.2 [M+H] + .

[1430] Example 182

[1431] 1-((1r,3S)-3-cyanocyclobutyl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1432]

[1433] The preparation method of 1-((1r,3S)-3-cyanocyclobutyl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1434] MS m / z (ESI): 418.2 [M+H] + .

[1435] Example 183

[1436] 1-((1s,3R)-3-cyanocyclobutyl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1437]

[1438] The preparation method of 1-((1s,3R)-3-cyanocyclobutyl)-3-methoxy-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1439] MS m / z (ESI): 418.2 [M+H] + .

[1440] Example 184

[1441] 3-Methoxy-1-((1r,3S)-3-methoxycyclobutyl)-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1442]

[1443] The preparation method of 3-methoxy-1-((1r,3S)-3-methoxycyclobutyl)-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1444] MS m / z(ESI): 423.2 [M+H] + .

[1445] Example 185

[1446] 3-Methoxy-1-((1s,3R)-3-methoxycyclobutyl)-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1447]

[1448] The preparation method of 3-methoxy-1-((1s,3R)-3-methoxycyclobutyl)-N-(6-((S)-5-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide is as described in Example 158.

[1449] MS m / z(ESI): 423.2 [M+H] + .

[1450] Biological testing evaluation

[1451] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[1452] Test Example 1: Determination of the inhibitory activity of the compound of the present invention against LRRK2 kinase.

[1453] 1. Experimental objective:

[1454] The inhibitory activity of the compounds of this invention against LRRK2 kinase was tested.

[1455] 2. Experimental reagents and instruments:

[1456] 2.1 Experimental Apparatus:

[1457] The centrifuge (5810R) was purchased from Eppendorf.

[1458] Pipettes were purchased from Eppendorf or Rainin.

[1459] The microplate reader was purchased from BioTek Inc. in the United States, model SynergyH1 full-function microplate reader.

[1460] 2.2 Experimental Reagents:

[1461] LRRK2 (G2019S) was purchased from SignalChem, item number L10-12GG-05;

[1462] LRRK2, Active(WT) was purchased from SignalChem, part number L10-11G-05;

[1463] LRRKtide was purchased from SignalChem, item number L10-58;

[1464] The ADP-Glo ​​kit was purchased from Promega, catalog number V9102.

[1465] The 384-well plate was purchased from Perkin Elmer, part number 6007299;

[1466] BSA was purchased from Sigma, product number B2064-100g;

[1467] Tris-HCl was purchased from Thermofisher, product number 15567027;

[1468] MgCl2 was purchased from Sigma, product number M1028-100ml.

[1469] 3. Experimental methods:

[1470] This experiment employed Promega's ADP-Glo ​​kinase assay. The kinase LRRK2 undergoes a catalytic reaction in the presence of the substrate LRRKtide and ATP, converting ATP into ADP. The kinase activity was characterized by measuring the ADP content in the reaction, and the half-maximal inhibitory concentration (IC50) of the compound inhibiting the activity of LRRK2 WT / G2019S kinase was determined. 50 The specific experimental procedure is as follows:

[1471] The kinase reaction was performed in a white 384-well plate. 2 μL of different concentrations of the compound (starting at 10000 nM, 3-fold dilution, 11 concentrations) diluted with kinase reaction solution (40 mmol / L Tris-HCl, 10 mmol / L MgCl2, and 0.1 μg / μL BSA) were added to each well. Then, 2 μL of 0.1–2 nM LRRK2 kinase solution diluted with kinase reaction solution was added to each well. 4 μL of 0.1–2 μg / μL substrate LRRKtide prepared with kinase reaction solution was added to all wells. Finally, 2 μL of 10–100 μM ATP solution diluted with reaction solution was added to initiate the reaction. After reacting at room temperature for 60–120 minutes, 10 μL of ADP-Glo ​​reagent was added to each well and reacted at room temperature for 30–60 minutes to remove excess ATP. Finally, 20 μL of kinase detection reagent was added to each well and reacted at room temperature in the dark for 10–30 minutes. The chemiluminescence value was then detected using a BioTek Synergy H1 microplate reader.

[1472] 4. Experimental treatment methods:

[1473] The percentage inhibition data for wells treated with the compound were calculated using positive control wells (solvent control wells) and negative control wells (no kinase added) on a plate: {% inhibition rate = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) × 100}. The IC50 was calculated using a GraphPad Prism approximation to fit different concentrations and corresponding percentage inhibition rate data to a 4-parameter nonlinear logic formula. 50 value.

[1474] 5. Experimental Results:

[1475] The above methods show that the compounds of this invention exhibit an activity level of approximately 0.1 nM to 1000 nM (IC50) in the LRRK2 kinase activity assay. 50 The biological activity of ) was observed. Specific experimental results are shown in Table 1:

[1476] Table 1. LRRK2 kinase activity of compounds from the embodiments of the present invention.

[1477]

[1478]

[1479]

[1480] 6. Experimental Conclusion:

[1481] The data above show that the compounds in the embodiments of the present invention have strong inhibitory activity against LRRK2 kinase.

[1482] Test Example 2: Determination of the inhibitory activity of the compounds of the present invention against ROCK1 and ROCK2 kinases.

[1483] 1. Experimental objective:

[1484] The purpose of this test case is to test the inhibitory activity of the compound against ROCK1 and ROCK2 kinases.

[1485] 2. Experimental reagents and instruments:

[1486] 2.1 Experimental Apparatus:

[1487] The centrifuge (Avanti J-15R) was purchased from BECKMAN COULTRE.

[1488] The biochemical incubator (SPX-100B-Z) was purchased from Shanghai Boxun.

[1489] The automated micropipette (PRC384U) was purchased from BioTek.

[1490] The Envision microplate reader (2104 Multilabel Reader) was purchased from Perkin Elmer.

[1491] The ultrasonic nanoliter liquid handling system (Echo550) was purchased from Labcyte.

[1492] 2.2 Experimental Reagents:

[1493] ROCK1 (Carna, item number 01-109);

[1494] ROCK2 (Carna, part number 01-110);

[1495] FAM-labeled peptide (Peptide10) (Invitrogen, catalog number XP116583);

[1496] ATP (Sigma, catalog number A7699-1G);

[1497] DMSO (Sigma, part number D2650);

[1498] EDTA (Sigma, part number E5134);

[1499] 96-well plate (Corning, part number 3365);

[1500] 384 perforated plate (PE, part number 6008289);

[1501] ADP-Glo ​​reagent kit (Promega, catalog number v9102 / 3);

[1502] Staurosporine (Selleck, catalog number S1421);

[1503] Tris-HCl, pH 7.5 (Sigma, catalog number T2319-1L);

[1504] MgCl2 (Sigma, product number M2670-500g).

[1505] 3. Experimental methods:

[1506] This experiment employed Promega's ADP-Glo ​​kinase assay. Kinases ROCK1 and ROCK2 undergo a catalytic reaction in the presence of a FAM-labeled peptide and ATP, converting ATP into ADP. The kinase activity was characterized by measuring the ADP concentration in the reaction, and the half-maximal inhibitory concentration (IC50) of the compounds inhibiting ROCK1 and ROCK2 kinase activity was determined. 50 The specific experimental procedure is as follows:

[1507] The kinase reaction was performed in 384-well plates using a kinase reaction solution of 40 mmol / L TrisHCl, 20 mmol / L MgCl2, 0.1% BSA, and 1 mM DTT. 50 nmol of different concentrations of the compound diluted with DMSO was added to each well. Then, 2.5 μL of 2x ROCK1 or ROCK2 kinase solution diluted with the kinase reaction solution was added to each well. Finally, 2.5 μL of a mixture of 2x substrate FAM-labeled peptide and ATP prepared with the kinase reaction solution was added to all wells. After reacting at room temperature for 60 minutes, 5 μL of ADP-Glo ​​reagent was added to each well, and the reaction was carried out at room temperature for 180 minutes to remove excess ATP. Finally, 10 μL of kinase assay reagent was added to each well, and the reaction was carried out at room temperature in the dark for 30 minutes. The chemiluminescence value was then detected using an Envision microplate reader.

[1508] 4. Experimental treatment methods:

[1509] The percentage inhibition data of the wells treated with the compound were calculated using positive control wells (solvent control wells) and negative control wells (no kinase added) on the plate {% inhibition rate = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) × 100}. The IC50 was calculated using a 4-parameter fitting method in XLFit based on the concentration and inhibition rate. 50 value.

[1510] 5. Experimental Results:

[1511] The above methods show that the compounds of this invention exhibit approximately 0.1 nM to 1000 nM (IC50) in ROCK1 and ROCK2 kinase activity assays. 50 The biological activity of ) was observed. Specific experimental results are shown in Tables 2 and 3:

[1512] Table 2. ROCK1 kinase activity of compounds in the embodiments of this invention.

[1513]

[1514]

[1515] Table 3. ROCK2 kinase activity of compounds in the embodiments of this invention.

[1516]

[1517]

[1518] 6. Experimental Conclusion:

[1519] The data above show that the compounds in the embodiments of the present invention have strong inhibitory activity against ROCK1 and ROCK2 kinases.

[1520] Test Example 3: Effect of the compound of the present invention on the phosphorylation level of LRRK2 in MC38 cells

[1521] 1. Experimental objective: The purpose of this test case is to test the inhibitory activity of the compound on LRRK2 phosphorylation levels in MC38 cells.

[1522] 2. Experimental reagents and instruments

[1523] 2.1 Experimental Apparatus

[1524] Pipettes were purchased from Eppendorf or Rainin.

[1525] The centrifuges were purchased from Eppendorf.

[1526] The tissue homogenizer was purchased from Shanghai Jingxin Laboratory Equipment Technology Department;

[1527] The protein electrophoresis equipment was purchased from Biorad.

[1528] The semi-dry transfer apparatus was purchased from Biorad.

[1529] The protein imaging system was purchased from Biorad, model ChemiDoc. TM MP;

[1530] The dry thermostat was purchased from Hangzhou Aokangsheng Instrument Co., Ltd.

[1531] 2.2 Experimental Cells

[1532] MC38 cells were purchased from Guangzhou Genio Biotechnology Co., Ltd.

[1533] 2.3 Experimental Reagents

[1534]

[1535]

[1536] 3. Experimental Methods

[1537] MC38 cells with high pLRRK2 expression were selected and cultured in 1640 medium containing 10% FBS until the confluence reached approximately 80%. The MC38 cells were then collected and prepared into 1x10⁻⁶ cells. 6 Cell suspension of 1 μL / mL was seeded into 24-well plates, 1 mL per well. After overnight cell adhesion culture, different concentrations of compound solutions were added, with an initial concentration of 1 μM, 3-fold dilution, 6 doses. The plates were incubated at 37°C, 5% CO2 for 2 hours. After incubation, the culture medium was removed, and the cells were washed once with PBS. Then, 80 μL of protein lysis buffer (NuPAGE) was added to each well of the cell plate. TMLDS Sample Buffer (4×), Sample Reducing Agent (10×) was prepared and a protein loading buffer was prepared. The protein loading buffer was placed in a dry thermostat and incubated at 100°C for 10 minutes to denature the protein. The denatured protein was subjected to gel electrophoresis at 120V. After completion, a semi-dry transfer membrane was used for transfer. The PVDF membrane was then blocked with blocking buffer for 1 hour and incubated with primary antibody overnight at 4°C (Anti-LRRK2 (phospho S935) antibody 1:1000 dilution, Anti-LRRK2 antibody 1:1000 dilution, GAPDH antibody 1:5000 dilution, washed with TBST and incubated with secondary antibody at room temperature for 1 hour). 680RD Goat anti-Rabbit IgG (H+L) diluted 1:3000 800CW Goat anti-Mouse IgG (H+L) diluted 1:3000 was washed with TBST and then placed in a Biorad imager for fluorescence imaging at 680nm and 800nm ​​channels.

[1538] 4. Experimental treatment methods:

[1539] The inhibition rate (ICP) of Western blot bands was calculated for each concentration using grayscale analysis with ImageJ software. GraphPad Prism was then used to fit data for different concentrations and corresponding percentage inhibition rates to a four-parameter nonlinear logic formula to calculate the IC. 50 value.

[1540] 5. Experimental Results:

[1541] The cellular activities of the compounds shown in this invention in the MC38pLRRK2 assay, obtained through the above methods, are shown in Table 4.

[1542] Table 4. Cellular activity of compounds in the embodiments of the present invention

[1543]

[1544]

[1545] 6. Experimental Conclusion:

[1546] The data above show that the compound in the embodiments of the present invention has a strong inhibitory activity on the phosphorylation level of LRRK2 in MC38 cells.

[1547] Test Example 4: Pharmacokinetic Determination of the Compounds of the Invention in Mice

[1548] 1. Research Objective:

[1549] Using Balb / c mice as test animals, the pharmacokinetic behavior of the compound of the present invention in plasma and brain in mice after oral administration at a dose of 5 mg / kg was studied.

[1550] 2. Test Plan

[1551] 2.1 Test Drugs:

[1552] The compound of this invention was prepared in-house.

[1553] 2.2 Experimental animals:

[1554] Balb / c Mouse, male.

[1555] 2.3 Administration:

[1556] Male Balb / c mice were administered oral medication (PO) at a dose of 5 mg / kg and a volume of 10 mL / kg after fasting overnight.

[1557] 2.4 Drug Preparation:

[1558] Oral administration preparation: 0.5% CMC-Na (1% Tween 80).

[1559] Weigh 5g of hydroxyethyl cellulose (HEC, CMC-Na, viscosity: 800-1200Cps), dissolve it in 1000mL of purified water, add 10g of Tween80, mix and stir until a clear solution is formed.

[1560] Weigh out the compound of the present invention and add it to a 4-mL glass bottle. Add 2.4mL of the solution and sonicate for 10 minutes to obtain a colorless and clear solution with a concentration of 0.5mg / mL.

[1561] 2.5 Sample Collection:

[1562] After CO2 euthanasia, cardiac blood and brain tissue were collected from experimental animals at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after drug administration. Blood was placed in EDTA-2K tubes and centrifuged at 6000rpm for 6min at 4℃ to separate plasma. Brain tissue was rinsed with pre-cooled PBS, dried, weighed, and stored at -80℃. Animals were fed 4h after drug administration.

[1563] 2.6 Sample preparation:

[1564] 1) Add 40uL of plasma sample to 160uL of acetonitrile for precipitation, mix, and centrifuge at 3500×g for 5-20 minutes. Dilute and homogenize brain tissue and centrifuge.

[1565] 2) Take 100 μL of the supernatant solution after treatment and analyze the concentration of the analyte by LC / MS / MS.

[1566] 2.7 Liquid Chromatography Analysis

[1567] • Liquid phase conditions: Shimadzu LC-20AD pump;

[1568] • Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer;

[1569] • Column: phenomenex Gemiu 5um C18 50×4.6mm;

[1570] • Mobile phase: Solution A is a 0.1% formic acid aqueous solution, and solution B is acetonitrile;

[1571] • Flow rate: 0.8 mL / min;

[1572] • Elution time: 0-4.0 minutes, eluent as follows:

[1573]

[1574] 3. Experimental Results and Analysis

[1575] The main pharmacokinetic parameters were calculated using WinNonlin 8.1. The results of the mouse pharmacokinetic experiment are shown in Table 5.

[1576] Table 5 Results of mouse pharmacokinetics experiments

[1577]

[1578] 4. Experimental Conclusion:

[1579] The results of the pharmacokinetic experiments in mice in this embodiment of the invention show that the compounds of this embodiment have good brain exposure.

[1580] Test Example 5: Effect of the compound of the present invention on the phosphorylation level of LRRK2 in the mouse cerebral cortex

[1581] 1. Experimental objective: The purpose of this test case is to test the effect of a single oral administration of the compound on the phosphorylation level of LRRK2 in the cerebral cortex of mice.

[1582] 2. Experimental reagents and instruments

[1583] 2.1 Experimental Apparatus

[1584] Pipettes were purchased from Eppendorf or Rainin.

[1585] The centrifuges were purchased from Eppendorf.

[1586] The tissue homogenizer was purchased from Shanghai Jingxin Laboratory Equipment Technology Department;

[1587] The protein electrophoresis equipment was purchased from Biorad.

[1588] The semi-dry transfer apparatus was purchased from Biorad.

[1589] The microplate reader was purchased from Biotek, model Synergy H1.

[1590] The protein imaging system was purchased from Biorad, model ChemiDoc. TM MP;

[1591] The dry thermostat was purchased from Hangzhou Aokangsheng Instrument Co., Ltd.

[1592] 2.2 Experimental Reagents

[1593]

[1594]

[1595] 3. Experimental Methods

[1596] The compound was prepared as a suspension using 0.5% CMC-Na (1% Tween 80) and administered at a volume of 10 mL / kg. Mice were orally orally or by gavage with different doses of the compound solution (1, 10, 100 mg / kg), with a blank control group. Two hours after administration, the mice were euthanized by carbon dioxide overdose. Immediately after euthanasia, the mice's brains were dissected, and the cerebral cortex was removed, placed in EP tubes, and frozen in dry ice. The phosphorylation level of LRRK2 Ser935 in the cerebral cortex was analyzed by Western blotting. 1 mL of pre-chilled tissue lysis buffer (50 mM Tris, 150 mM NaCl, 1 mM EDTA, 1.25% CHAPS, 1% Triton X-100, PhosSTOP, EDTA-free Protein Inhibitor) was added to each tube of cortical tissue. The tissue was then homogenized using a tissue homogenizer with steel balls, incubated on ice for 30 minutes, and then centrifuged at 12000 rpm for 20 minutes at 4°C using a pre-chilled centrifuge. The protein supernatant was collected, quantified using a BCA kit, and then analyzed with 10x... Sample Reducing Agent、4xNuPAGE TMLDS Sample Buffer and 1x tissue lysis buffer were mixed to prepare a protein loading buffer of equal concentration. The protein loading buffer was placed in a dry incubator and incubated at 100°C for 10 minutes to denature the protein. The denatured protein was subjected to gel electrophoresis at 120V. After gel electrophoresis, the protein was transferred to a membrane using a semi-dry transfer apparatus. The PVDF membrane was then blocked with blocking buffer for 1 hour and incubated overnight at 4°C with primary antibody (Anti-LRRK2 (phospho S935) antibody 1:1000 dilution, Anti-LRRK2 antibody 1:1000 dilution, GAPDH antibody 1:5000 dilution). After washing with TBST, the membrane was incubated with secondary antibody at room temperature for 1 hour. 680RD Goat anti-Rabbit IgG (H+L) diluted 1:3000 800CW Goat anti-Mouse IgG (H+L) diluted 1:3000 was washed with TBST and then placed in a Biorad imager for fluorescence imaging at 680nm and 800nm ​​channels.

[1597] 4. Experimental Results

[1598]

[1599] 5. Experimental Conclusions

[1600] The compound can reduce the phosphorylation level of LRRK2 in the mouse cerebral cortex starting from 1 mpk, with good dose-dependent effect, reaching the maximum inhibitory level at 10 mpk.

[1601] Test Example 6: Study on the efficacy of the compound of this invention in lowering intraocular pressure in New Zealand white rabbits

[1602] 1. Experimental objective:

[1603] The purpose of this experiment is to evaluate the intraocular pressure-lowering effect of the compound of the present invention administered as eye drops on rabbits with normal intraocular pressure.

[1604] 2. Laboratory animals:

[1605] New Zealand White Rabbit (Oryctolagus cuniculus), male, 3-4 months old, weighing 2.1-3.3 kg, standard grade, 10 rabbits / group.

[1606] 3. Experimental apparatus and reagents:

[1607] name Supplier / Manufacturer model Electronic balance METLER TOLEDO XP205 pH test strips Sigma 010B164786 Tonometer icare TonoVet micropipettes Eppendorf Research

[1608] name Supplier / Manufacturer batch number Sulfobutyl-β-cyclodextrin (SBE-β-CD) Kunshan Ruisike Chemical Raw Materials Co., Ltd. 20210102 Sterile water for injection Suzhou Jiushuntang Pharmacy Co., Ltd. 2001030105 Sodium chloride injection Suzhou Jiushuntang Pharmacy Co., Ltd. 2006150110

[1609] Experimental method and procedure:

[1610] Experimental Design: Male New Zealand white rabbits were randomly divided into groups of 10 each based on body weight. Each group received an ophthalmic instillation of the solvent or the compound of this invention into the left eye (50 μL / eye, once daily). The right eye was not treated. Intraocular pressure was measured in both eyes of each group before administration and at 1, 2, 4, 6, 8, and 10 hours after administration. The experimental design is shown in the table below:

[1611]

[1612]

[1613] Route of administration: The test sample was administered via topical eye drops; eye drops are the intended clinical route of administration.

[1614] Administration method: Using a micropipette, draw 50 μL of the solvent and the compound of this invention and drip the liquid into the conjunctival sac, then gently close the upper and lower eyelids several times.

[1615] Intraocular pressure measurement: Restrain the animal and place the probe of the TonoVet tonometer perpendicular to the eye being measured. Measure the intraocular pressure at least 3 times until the animal's intraocular pressure stabilizes (fluctuation range ≤3 mm Hg). The average of the last three measurements is taken as the final intraocular pressure value.

[1616] 4. Data collection and analysis:

[1617] The intraocular pressure data collected in this experiment will be analyzed using the following statistical methods:

[1618] Unless otherwise stated below, all reported numerical data (except for data collected and analyzed directly by Provantis and / or LIMS) were calculated using Microsoft Excel software for group means and standard deviations. The above descriptive statistics will be performed on data collected at each time point / segment, and further subdivisions of the descriptive statistics will be determined based on the variables to be analyzed and the categorical variables of the data (such as gender, measurement period, and other relevant variables). Groups with fewer than 3 cases do not require statistical analysis.

[1619] When the number of groups is greater than 2, Levene's test should be used at a significance level of 0.05 to perform homogeneity of variance analysis between groups. If the differences between groups are not significant (p>0.05), one-way ANOVA should be used. If the differences are significant (p≤0.05), Dunnett's test should be used to perform pairwise comparisons between different dosage groups and the control group.

[1620] If Levene's test indicates a significant difference (p≤0.05) and the group contains only positive values, a log transformation is performed. If the transformed data still show a significant difference (p≤0.05) after homogeneity of variance analysis, or if the data contains zero and / or negative numbers, a non-parametric Kruskal-Wallis test is used for inter-group comparisons. When the Kruskal-Wallis test result is significant (p≤0.05), Dunnett's test on ranks is used for pairwise comparisons between groups.

[1621] When there are only two groups to compare, use Levene's test as described above, but replace ANOVA with a two-sample T-test and Kruskal-Wallis with a Wilcoxon rank-sum test. There is no need to perform Dunnett's test or Dunnett's test on ranks.

[1622] At a significance level of 0.05, the intraocular pressure of the right and left eyes of all groups of animals were compared by paired t-tests, and the significance results (p≤0.001, p≤0.01, or p≤0.05) should be included in the report.

[1623] At a significance level of 0.05, pairwise comparisons between groups were performed using a two-sided test. The significance results were reported as p≤0.001, p≤0.01, or p≤0.05, where p represents the probability of observation.

[1624] 5. Experimental Results:

[1625] During this experiment, animals were first trained to adapt to intraocular pressure measurement before administration of the drug, and no abnormal intraocular pressure was observed.

[1626] The experimental results are shown in Tables 6 and 7 below:

[1627] Table 6. Effects of the compounds of the present invention on intraocular pressure in the left eye of each group of animals.

[1628]

[1629] Note: Left eye intraocular pressure was analyzed using a bilateral T-test between groups. *p<0.05, **p<0.01, ***p<0.001, pValue (compared to the Vehicle group).

[1630] Experimental results show that the compounds of this invention have a significant effect in lowering intraocular pressure.

[1631] Table 7 Comparison of intraocular pressure in the left and right eyes of experimental animals in each group.

[1632]

[1633] See Table 7 for comparison of the left and right eyes of the experimental animals in each group.

[1634]

[1635] Compared with the untreated eye (right eye), there were no statistically significant differences in intraocular pressure in the left eye of the solvent control group at 1, 2, 4, 6, 8, and 10 hours after administration, indicating that the testing system was reliable and there were no factors interfering with the intraocular pressure test; moreover, the intraocular pressure-lowering effect of the compound of this invention has a long duration.

Claims

1. Compounds of general formula (IV), their stereoisomers, or pharmaceutically acceptable salts thereof: in: M1 and M2 are each independently either N or CH; R 2 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Deuterated alkoxy, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n1 NR A1 R B1 -CR A1 R B1 (CH2) n1 NR C1 R D1 -(CH2) n1 R A1 -CR A1 R B1 R C1 -(CH2) n1 OR A1 -(CH2) n1 C(O)OR A1 -(CH2) n1 OR A1 -(CH2) n1 SR A1 -(CH2) n1 NR A1 C(O)(CH2) n2 R B1 -(CH2) n1 NR A1 C(O)OR B1 -(CH2) n1 NR A1 C(O)NR B1 R C1 or -NR A1 (CH2) n1 R B1 The amino group, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) n1 NR A2 R B2 -CR A2 R B2 (CH2) n1 NR C2 R D2 -(CH2) n1 R A2 -CR A2 R B2 R C2 -(CH2) n1 OR A2 -(CH2) n1 C(O)OR A2 -(CH2) n1 OR A2 -(CH2) n1 SR A2 -(CH2) n1 NR A2 C(O)(CH2) n2 R B2 -(CH2) n1 NR A2 C(O)OR B2 -(CH2) n1 NR A2 C(O)NR B2 R C2 and -NR A2 (CH2) n1 R B2 One or more substituents in it are replaced; R A1 R B1 R C1 and R D1 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups; Or, R A1 R B1 R C1 and R D1 Any two atoms in the carbon atom and the nitrogen or carbon atom bonded to them form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group or one or more substituents in the 5-14 membered heteroaryl group are substituted; R A2 R B2 R C2 and R D2 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups; n1 and n2 are selected from 0, 1, 2, 3, 4, 5 or 6; R 5 Independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 It is substituted by one or more substituents in the aryl group and the 5-14 heteroaryl group.

2. The compound according to claim 1, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, R 2 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) n1 NR A1 R B1 -CR A1 R B1 (CH2) n1 NR C1 R D1 -(CH2) n1 R A1 -CR A1 R B1 R C1 -(CH2) n1 OR A1 -(CH2) n1 C(O)OR A1 -(CH2) n1 OR A1 -(CH2) n1 SR A1 -(CH2) n1 NR A1 C(O)(CH2) n2 R B1 -(CH2) n1 NR A1 C(O)OR B1 -(CH2) n1 NR A1 C(O)NR B1 R C1 or -NR A1 (CH2) n1 R B1 The amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups; R A1 R B1 R C1 and R D1 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group is substituted with one or more substituents from 5-10 heteroaryl groups; Or, R A1 R B1 R C1 and R D1 Any two atoms in the carbon atom and the nitrogen or carbon atom bonded to them form a C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted; R 5 Independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 It is substituted by one or more substituents in aryl and 5-10 heteroaryl groups.

3. The compound according to claim 2, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, R 2 Each element is independently selected from hydrogen, deuterium, halogen, amino, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl or 5-6 nitrogen-containing heteroaryl groups, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl and 5-6 nitrogen-containing heteroaryl groups, optionally further converted by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-3 Alkyl, C 1-3 Hydroxyalkyl and C 1-3 It is replaced by one or more substituents in the alkoxy group.

4. The compound according to claim 3, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, R 2 Each element is independently selected from hydrogen, deuterium, halogen, amino, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl or 5-6 nitrogen-containing heteroaryl groups.

5. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that, The compounds are further shown as in general formula (IV-1), general formula (IV-2) or general formula (IV-3): Each group is defined as described in any one of claims 1-4.

6. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, characterized in that, R 2 Each element is independently selected from hydrogen, deuterium, halogen, amino, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, containing 1-2 4-6 membered heterocyclic groups selected from N or O, containing 1-2 5-6 membered heteroaryl groups selected from N or O, -(CH2) n1 OR A1 -(CH2) n1 C(O)R A1 -(CH2) n1 NR A2 R B2 Or -(CH2) n1 O(CH2) n2 NR B2 R C2 The amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, containing 1-2 4-6 membered heterocyclic groups selected from N or O and 1-2 5-6 membered heteroaryl groups selected from N or O, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkyl group, -(CH2) n1 OR A1 -(CH2) n1 C(O)R A1 -(CH2) n1 NR A2 R B2 and -(CH2) n1 O(CH2) n2 NR B2 R C2 One or more substituents in it are replaced. R A1 R A2 R B2 and R C2 Each element is independently selected from hydrogen, deuterium, halogen, amino, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, containing 1-2 4-6 membered heterocyclic groups selected from N or O, containing 1-2 5-6 membered heteroaryl groups selected from N or O, n1 and n2 are selected from 0, 1, 2, 3, 4, 5 or 6.

7. The compound according to claim 6, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, R 2 Each is independently selected from fluorine, chlorine, bromine, methyl, ethyl, methoxy, cyclopropyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

8. A compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, The specific structure of the compound is as follows: or .

9. Compounds of general formula (A), their stereoisomers, or pharmaceutically acceptable salts thereof: in: X1 is a halogen, borate group, -Sn(R6R7R8), sulfonate group or borate group; R6, R7, and R8 are each independently selected from C. 1-6 alkyl; R 2 As described in claim 6.

10. The compound according to claim 9, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, X1 is fluorine, chlorine, bromine, iodine, -B(OH)2, or -Otf; R6, R7, and R8 are each independently selected from C. 1-3 alkyl.

11. A method for preparing a compound of general formula (IV), its stereoisomers, or pharmaceutically acceptable salts thereof, comprising the following steps: in: M1 and M2 are each independently either N or CH; X2 can be a halogen, borate group, -Sn(R6R7R8), sulfonate group or borate group; R6, R7, and R8 are each independently selected from C. 1-6 alkyl; R 5 As described in claim 1; X1 and R2 are as described in claim 9 or 10; And X1 and X2 are not the same.

12. The method according to claim 11, characterized in that, X2 can be fluorine, chlorine, bromine, iodine, -B(OH)2, or -Otf; R6, R7, and R8 are each independently selected from C. 1-3 alkyl.

13. A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1 to 8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

14. The use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, or the pharmaceutical composition according to claim 13, in the preparation of a dual inhibitory drug of LRRK2 or ROCK inhibitors, or combinations thereof.

15. The use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, or the pharmaceutical composition according to claim 13, in the preparation of medicaments for treating nervous system diseases, cardiovascular diseases, cancer, inflammation, autoimmune diseases, and metabolic diseases.

16. The application according to claim 15, wherein the neurological disease is Parkinson's disease, glaucoma, Alzheimer's disease, or epilepsy.

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