CN114907358A

CN114907358A - Pyridine-containing polycyclic derivative regulator, and preparation method and application thereof

Info

Publication number: CN114907358A
Application number: CN202210120799.2A
Authority: CN
Inventors: 高鹏; 岑诚; 孙广俊; 王少宝; 修文华; 谭松良
Original assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansoh Biomedical Co Ltd
Current assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansoh Biomedical Co Ltd
Priority date: 2021-02-09
Filing date: 2022-02-09
Publication date: 2022-08-16

Abstract

The invention relates to a regulator containing pyridine polycyclic derivatives, a preparation method and application thereof. In particular, the invention relates to a compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound as a regulator in preparing medicaments related to treating Parkinson's disease, wherein each substituent in the general formula (I) is defined as the same as that in the specification.

Description

Pyridine-containing polycyclic derivative regulator, and preparation method and application thereof

Technical Field

The invention belongs to the field of biological medicines, and particularly relates to a pyridine-containing polycyclic derivative regulator, and a preparation method and application thereof.

Background

Leucine-rich repeat kinase 2(LRRK2) is encoded by 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 that belongs to the Rho subgroup of one of the Ras superfamily, and plays a switching role in cell signaling. The abnormal pathways of LRRK2 and ROCK lead to a variety of diseases, including Parkinson's Disease (PD), glaucoma, and the like.

PD is a neurodegenerative disease associated with dyskinesias, including bradykinesia, rigidity, tremor, and postural instability. Pathological features of PD include intracellular inclusion bodies containing aggregates of alpha-synuclein, and loss of Dopamine (DA) neurons in the substantia nigra. Currently marketed drug treatments can slow the progression of the disease. However, the goal of current treatments is to alleviate symptoms and there is still a great need to develop more effective therapeutic agents. The most common mutation in PD is the LRRK2 mutation, observed in patients with autosomal dominant hereditary PD and sporadic PD. LRRK2 is highly expressed in neurons, microglia, immune cells and macrophages. LRRK2 mutation or activation can affect lysosomal function, leading to apoptosis of neuronal cells. Small molecule LRRK2 kinase inhibitors have neuroprotective effects in preclinical models of PD, making LRRK2 inhibitors a therapeutic hotspot for PD. Recent studies have also shown that LRRK2 is also over-activated in idiopathic PD, and therefore LRRK2 treatment may be beneficial for this common subset of PD. Currently, 2 LRRK2 inhibitors are in phase I clinic for the treatment of PD. In addition, numerous preclinical studies have shown that ROCK also plays an important role in PD.

Glaucoma is a multifactorial disease, the number of glaucoma patients exceeds 2000 million in China, the blindness causing number exceeds 1/4, and the intraocular pressure reduction is the only target for glaucoma treatment at present. ROCK inhibitors act directly on Trabecular Meshwork (TM), the main pathogenic site of glaucoma, are effective in treating glaucoma from multiple angles, have effects of lowering ocular pressure, reducing scars, and protecting optic nerves, and have been used for the treatment of glaucoma. LRRK2 is widely distributed in TM cells, and inhibitors of LRRK2 modulate LRRK2 in TM cells and may cause relaxation of TM by inhibiting contractile tension of actin cytoskeleton, thereby lowering intraocular pressure. Currently 1 LRRK2 inhibitor is in phase I clinic for the treatment of glaucoma.

Meanwhile, the inhibition of LRRK2 and ROCK1/2 has the potential of treating PD and glaucoma, has great clinical requirements, and no similar double-target inhibitor enters the clinic at present. The LRRK2/ROCK dual inhibitor has good application prospect in the pharmaceutical industry as a medicine, the invention provides a selective LRRK2/ROCK dual inhibitor with a novel structure, and the compound with the structure shows good intracerebral exposure and excellent effect and action.

Disclosure of Invention

The invention aims to provide a compound shown as a general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

wherein:

ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be monocyclic, bicyclic or tricyclic;

ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

R ¹ each independently of the otherOptionally further substituted, selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or, any two R ¹ (ii) linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, said cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally being further substituted;

R ² each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, alkyl, deuterated alkoxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) ₂ ) _n1 NR _A1 R _B1 、-CR _A1 R _B1 (CH ₂ ) _n1 NR _C1 R _D1 、-(CH ₂ ) _n1 R _A1 、-CR _A1 R _B1 R _C1 、-(CH ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 C(O)OR _A1 、-(CH ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 SR _A1 、-(CH ₂ ) _n1 NR _A1 C(O)(CH ₂ ) _n2 R _B1 、-(CH ₂ ) _n1 NR _A1 C(O)OR _B1 、-(CH ₂ ) _n1 NR _A1 C(O)NR _B1 R _C1 or-NR _A1 (CH ₂ ) _n1 R _B1 Said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;

or, R ¹ And R ² Linked to form a heterocyclic group, which may optionally be further definedIs substituted;

R _A1 、R _B1 、R _C1 and R _D1 Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;

or, R _A1 、R _B1 、R _C1 And R _D1 Any two of which, together with the nitrogen or carbon atom to which they are attached, are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which may optionally be further substituted;

R ³ selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;

or, R ² And R ³ (ii) linked to form a heterocyclyl, which heterocyclyl may optionally be further substituted;

R ⁴ each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;

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

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

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

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

z is selected from 0, 1,2, 3 or 4.

In a further preferred embodiment of the invention, ring A is selected from C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl;

preferably 5-6 membered monocyclic heteroaryl or 7-14 membered bicyclic heteroaryl;

more preferably

In a further preferred embodiment of the invention, ring B is selected from C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl;

preferably C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-10 membered heteroaryl;

more preferably phenyl or 5-7 membered nitrogen containing heteroaryl;

further preferred is phenyl, pyridyl or pyrazolyl.

In a further preferred embodiment of the invention, R ¹ Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said amino, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro,Hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl;

preferably hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-10 membered heteroaryl;

more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, cyano, vinyl, ethynyl, cyclopropyl or trifluoromethyl, said methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl and cyclopropyl being optionally further substituted by one or more substituents of deuterium, fluorine, chlorine, bromine, amino, cyano, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, vinyl, ethynyl, cyclopropyl or trifluoromethyl;

more preferably hydrogen, cyano, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-3 Alkyl radical, C _1-3 Hydroxyalkyl or C _1-3 Substituted with one or more substituents of alkoxy;

or, any two R ¹ Link formation C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl;

preferably C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-10 membered heteroaryl;

more preferably C _3-6 Cycloalkyl radicalsOptionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl, C _1-3 Alkoxy or C _1-3 Substituted with one or more substituents of haloalkoxy;

further preferably, any two R ¹ The linkage forms a cyclopropyl, cyclobutyl or cyclopentyl group.

In a further preferred embodiment of the invention, R ² Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Deuterated alkoxy, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, - (CH) ₂ ) _n1 NR _A1 R _B1 、-CR _A1 R _B1 (CH ₂ ) _n1 NR _C1 R _D1 、-(CH ₂ ) _n1 R _A1 、-CR _A1 R _B1 R _C1 、-(CH ₂ ) _n1 C(O)OR _A1 、-(CH ₂ ) _n1 C(O)R _A1 、-(CH ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 SR _A1 、-(CH ₂ ) _n1 NR _A1 C(O)(CH ₂ ) _n2 R _B1 、-(CH ₂ ) _n1 NR _A1 C(O)OR _B1 、-(CH ₂ ) _n1 NR _A1 C(O)NR _B1 R _C1 or-NR _A1 (CH ₂ ) _n1 R _B1 Said amino group, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-to 10-membered heteroaryl, - (CH) ₂ ) _n1 NR _A2 R _B2 、-CR _A2 R _B2 (CH ₂ ) _n1 NR _C2 R _D2 、-(CH ₂ ) _n1 R _A2 、-CR _A2 R _B2 R _C2 、-(CH ₂ ) _n1 OR _A2 、-(CH ₂ ) _n1 C(O)OR _A2 、-(CH ₂ ) _n1 OR _A2 、-(CH ₂ ) _n1 SR _A2 、-(CH ₂ ) _n1 NR _A2 C(O)(CH ₂ ) _n2 R _B2 、-(CH ₂ ) _n1 NR _A2 C(O)OR _B2 、-(CH ₂ ) _n1 NR _A2 (CH ₂ ) _n2 NR _B2 R _C2 、-(CH ₂ ) _n1 O(CH ₂ ) _n2 NR _B2 R _C2 、-(CH ₂ ) _n1 NR _A2 C(O)NR _B2 R _C2 and-NR _A2 (CH ₂ ) _n1 R _B2 Is substituted with one or more substituents of (1);

preferably hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Deuterated alkoxy, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-to 10-membered heteroaryl, - (CH) ₂ ) _n1 NR _A1 R _B1 、-CR _A1 R _B1 (CH ₂ ) _n1 NR _C1 R _D1 、-(CH ₂ ) _n1 R _A1 、-CR _A1 R _B1 R _C1 、-(CH ₂ ) _n1 C(O)R _A1 、-(CH ₂ ) _n1 C(O)OR _A1 、-(CH ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 SR _A1 、-(CH ₂ ) _n1 NR _A1 C(O)(CH ₂ ) _n2 R _B1 、-(CH ₂ ) _n1 NR _A1 C(O)OR _B1 、-(CH ₂ ) _n1 NR _A1 C(O)NR _B1 R _C1 or-NR _A1 (CH ₂ ) _n1 R _B1 Said amino group, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl;

more preferably hydrogen, deuterium, halogen, amino, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Deuterated alkoxy, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered nitrogen-containing heteroaryl, 5-6 membered sulfur-containing heteroaryl, 7-10 membered bicyclic nitrogen-containing heteroaryl, -C (O) R _A1 Or- (CH) ₂ ) _n1 NR _C1 R _D1 The amino group, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Deuterated alkoxy, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy radical、C _1-3 Haloalkoxy, C _3-6 Cycloalkyl and 5-6 membered nitrogen containing heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-10 Aryl, 5-to 10-membered heteroaryl, - (CH) ₂ ) _n1 NR _A2 R _B2 、-NR _A2 (CH ₂ ) _n2 NR _B2 R _C2 and-O (CH) ₂ ) _n2 NR _B2 R _C2 Is substituted with one or more substituents of (a);

further preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, cyano, methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, thienyl, piperidinyl, tetrahydropyranyl, pyridinyl, trifluoromethyl, or the like,

Pyrazinyl, pyrazolyl, -C (O) CH ₃ 、-N(CH ₃ ) ₂ 、-CH ₂ N(CH ₃ ) ₂ Or- (CH) ₂ ) ₂ N(CH ₃ ) ₂ Said amino, methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, pyridyl, pyrazinyl and pyrazolyl, optionally further deuterium, fluoro, chloro, bromo, amino, cyano, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, oxetanyl, morpholinyl, piperazinyl, -CH ₂ N(CH ₃ ) ₂ 、-O(CH ₂ ) ₂ N(CH ₃ ) ₂ 、-N(CH ₃ )(CH ₂ ) ₂ N(CH ₃ ) ₂ Trifluoromethyl and- (CH) ₂ ) ₂ N(CH ₃ ) ₂ Is substituted with one or more substituents of (1);

or, R ¹ And R ² Link formation 7-20-membered heterocyclyl, said 7-20-membered heterocyclyl being further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl;

preferably 10-20 membered heterocyclyl, said 10-20 membered heterocyclyl being further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-10 membered heteroaryl;

R _A1 、R _B1 、R _C1 and R _D1 Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said amino, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-10 membered heteroaryl;

preferably hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-10 membered heteroaryl;

more preferably hydrogen, deuterium, halogen, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, cyclopropyl, cyclobutyl or cyclopentyl;

or, R _A1 、R _B1 、R _C1 And R _D1 Any two of which are linked to form C with the nitrogen or carbon atom to which they are attached _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl;

preferably C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-10 membered heteroaryl;

R _A2 、R _B2 、R _C2 and R _D2 Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said amino, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-10 membered heteroaryl; and is

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

In a further preferred embodiment of the invention, R ³ Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said amino, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl;

or, R ² And R ³ Linked to form a 3-12 membered heterocyclic group, said 3-12 membered heterocyclic group being further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl;

preferably 3-8 membered heterocyclyl, said 3-8 membered heterocyclyl being further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-10 membered heteroaryl;

more preferably 5-6 membered heterocyclyl;

further preferred is a pyrrolidonyl group, a piperidin-2-onyl group, a 3, 4-dihydropyridin-2 (1H) -onyl group or a 4, 5-dihydropyridazin-3 (2H) -onyl group.

In a further preferred embodiment of the invention, R ⁴ Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said amino, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl;

preferably hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Halogenated alkoxy、C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-10 membered heteroaryl;

more preferably hydrogen, deuterium, halogen, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, cyclopropyl, cyclobutyl or cyclopentyl.

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (II-A):

in a further preferred embodiment of the invention, y is 0, 1 or 2,

when the compound is of the formula (II-A) and ring A is

When R is ¹ Is not hydrogen.

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (II-B):

in a further preferred embodiment of the invention, ring a is selected from a bis-heteroaromatic ring or a mono-heteroaromatic ring; preferably a 5-membered heteroarylheterocyclo, 6-membered heteroarylheterocyclo or 5-membered monoheteroaryl; more preferably a 5-membered heteroarylo 5-membered heterocyclic group, a 5-membered heteroarylo 6-membered heterocyclic group, a 6-membered heteroarylo 5-membered heterocyclic group, a 6-membered heteroarylo 6-membered heterocyclic group, a 5-membered heteroaryl group containing 3 nitrogen atoms or a 5-membered heteroaryl group containing 4 nitrogen atoms;

most preferred are the following groups:

in a further preferred embodiment of the present invention, the ring A of the formula (II-A) and of the formula (II-B) is selected from

R ¹ Each independently selected from hydrogen, cyano, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl or C _3-6 Cycloalkyl radical, said C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl and C _3-6 Cycloalkyl optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-3 Alkyl radical, C _1-3 Hydroxyalkyl and C _1-3 Substituted with one or more substituents of alkoxy;

or, any two R ¹ Link formation C _3-6 Cycloalkyl radical, said C _3-6 Cycloalkyl optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy and C _1-3 Substituted with one or more substituents of haloalkoxy;

R ² each independently selected from hydrogen, deuterium, halogen, amino, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Deuterated alkanesOxy radical, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _3-6 Cycloalkyl or 5-6 membered nitrogen-containing heteroaryl, said amino, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Deuterated alkoxy, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _3-6 Cycloalkyl and 5-6 membered nitrogen containing heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-3 Alkyl radical, C _1-3 Hydroxyalkyl and C _1-3 Substituted with one or more substituents of alkoxy;

or, R ¹ And R ² Linked to form a 10-20 membered heterocyclic group, said 10-20 membered heterocyclic group being further deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-10 membered heteroaryl;

R ³ selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-to 10-membered heteroaryl, optionally further substituted by deuterium, halogenPlain, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl;

or, R ² And R ³ Linked to form a 5-6 membered heterocyclyl;

R ⁴ each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl;

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

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (II-C), the general formula (II-C-A) or the general formula (II-C-B):

wherein:

ring C is selected from 3-12 membered heterocyclyl or 5-14 membered heteroaryl;

preferably 3-8 membered heterocyclyl or 5-10 membered heteroaryl;

R ⁵ each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said amino, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl;

preferably hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroarylA group, the amino group and C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl;

more preferably hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyano, vinyl, ethynyl, cyclopropyl or trifluoromethyl, said methyl, ethyl, propyl, methoxy, ethoxy, vinyl, ethynyl and cyclopropyl being optionally further substituted by one or more substituents of deuterium, halogen, amino, cyano, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, dimethylamino, vinyl, ethynyl, cyclopropyl or trifluoromethyl;

or, any two R ⁵ Link formation C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl;

more preferably cyclopropyl, cyclobutyl or cyclopentyl; and is

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

when formula (II-C) and ring B is phenyl, R ² Is not imidazole or substituted imidazole; and when the compound is of the formula (II-C), ring B is

When R is ² Not pyridine or substituted pyridine.

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (II-D):

wherein:

x is selected from-NH-, -O-or-S-;

l is selected from- (CH) ₂ ) _m -；

Ring C is selected from 3-12 membered heterocyclyl or 5-14 membered heteroaryl;

preferably 3-8 membered heterocyclyl or 5-10 membered heteroaryl;

R ⁵ each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said amino, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl;

preferably hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl;

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

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

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

In a further preferred embodiment of the present invention, the compound is further represented by formula (III), formula (III-A) or formula (III-B):

wherein: n is selected from 0, 1,2, 3 or 4.

In a further preferred embodiment of the present invention, the compound is further represented by general formula (IV):

wherein: m ₁ 、M ₂ Each independently is N or CH;

R ⁵ independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said amino, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further deuterium,Halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl;

preferably hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl, C1-6 deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1- 6 haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl.

In a more preferred embodiment of the present invention, the compound is further represented by the general formula (IV-1), the general formula (IV-2) or the general formula (IV-3):

in a preferred embodiment of the present invention,the R is ² Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Deuterated alkoxy, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-to 10-membered heteroaryl, - (CH) ₂ ) _n1 NR _A1 R _B1 、-CR _A1 R _B1 (CH ₂ ) _n1 NR _C1 R _D1 、-(CH ₂ ) _n1 R _A1 、-CR _A1 R _B1 R _C1 、-(CH ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 C(O)R _A1 、-(CH ₂ ) _n1 C(O)OR _A1 、-(CH ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 SR _A1 、-(CH ₂ ) _n1 NR _A1 C(O)(CH ₂ ) _n2 R _B1 、-(CH ₂ ) _n1 NR _A1 C(O)OR _B1 、-(CH ₂ ) _n1 NR _A1 C(O)NR _B1 R _C1 or-NR _A1 (CH ₂ ) _n1 R _B1 The amino group, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-to 10-membered heteroaryl, - (CH) ₂ ) _n1 NR _A2 R _B2 、-CR _A2 R _B2 (CH ₂ ) _n1 NR _C2 R _D2 、-(CH ₂ ) _n1 R _A2 、-CR _A2 R _B2 R _C2 、-(CH ₂ ) _n1 OR _A2 、-(CH ₂ ) _n1 C(O)OR _A2 、-(CH ₂ ) _n1 OR _A2 、-(CH ₂ ) _n1 SR _A2 、-(CH ₂ ) _n1 NR _A2 C(O)(CH ₂ ) _n2 R _B2 、-(CH ₂ ) _n1 NR _A2 C(O)OR _B2 、-(CH ₂ ) _n1 NR _A2 (CH ₂ ) _n2 NR _B2 R _C2 、-(CH ₂ ) _n1 O(CH ₂ ) _n2 NR _B2 R _C2 、-(CH ₂ ) _n1 NR _A2 C(O)NR _B2 R _C2 and-NR _A2 (CH ₂ ) _n1 R _B2 Is substituted with one or more substituents of (1);

R _A1 、R _B1 、R _C1 and R _D1 Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 A halogenated alkoxy group,C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl;

or, R _A1 、R _B1 、R _C1 And R _D1 Any two of which are linked to form C with the nitrogen or carbon atom to which they are attached _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl;

R _A2 、R _B2 、R _C2 and R _D2 Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl; and is provided with

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

In a further preferred embodiment of the invention, R ² Each independently selected from amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Deuterated alkoxy, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered oxygen-or nitrogen-containing heterocyclic group, C _6-10 Aryl, 5-10 membered oxygen-containing or nitrogen heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Deuterated alkoxy, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered oxygen-or nitrogen-containing heterocyclic group, C _6-10 Aryl and 5-10 membered oxygen-containing or nitrogen-containing heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 And one or more substituents in the alkynyl group.

In a further preferred embodiment of the invention, R ² Each independently selected from amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Deuterated alkoxy, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-to 10-membered heteroaryl, - (CH) ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 C(O)R _A1 、-(CH ₂ ) _n1 NR _A2 R _B2 Or- (CH) ₂ ) _n1 O(CH ₂ ) _n2 NR _B2 R _C2 Said amino group, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Deuterated alkoxy, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-to 10-membered heteroaryl, - (CH) ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 C(O)R _A1 、-(CH ₂ ) _n1 NR _A2 R _B2 And- (CH) ₂ ) _n1 O(CH ₂ ) _n2 NR _B2 R _C2 Is substituted with one or more substituents of (1);

preferably, R ² Each independently selected from hydrogen, deuterium, halogen, amino, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Deuterated alkoxy, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _3-6 Cycloalkyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, - (CH) ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 C(O)R _A1 、-(CH ₂ ) _n1 NR _A2 R _B2 Or- (CH) ₂ ) _n1 O(CH ₂ ) _n2 NR _B2 R _C2 Said amino group, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Deuterated alkoxy, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _3-6 Cycloalkyl, 3-8 membered heterocyclyl and 5-6 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-3 Alkyl radical, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy- (CH) ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 C(O)R _A1 、-(CH ₂ ) _n1 NR _A2 R _B2 And- (CH) ₂ ) _n1 O(CH ₂ ) _n2 NR _B2 R _C2 Is substituted with one or more substituents of (a),

R _A1 、R _A2 、R _B2 and R _C2 Each independently selected from hydrogen, deuterium, halogen, amino, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Deuterated alkoxy, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _3-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-2 members selected from N or O, 5-6 membered heteroaryl group containing 1-2 members selected from N or O,

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

more preferably, R ² Each independently selected from fluorine, chlorine, bromine, methyl, ethyl, methoxy, cyclopropyl, methyl, ethyl, methyl, propyl, isopropyl, isobutyl, substituted or substituted aryl,

The invention further relates to a medical intermediate which is a compound shown as a general formula (A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

wherein:

X ₁ is halogen, borate, -Sn (R) ₆ R ₇ R ₈ ) Sulfonate or borate groups, preferably fluorine, chlorine, bromine, iodine, -B (OH) ₂ or-OTf;

R ₆ 、R ₇ and R ₈ Each independently selected from C _1-6 An alkyl group; preferably C _1-3 An alkyl group;

R ² selected from amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Deuterated alkoxy, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-to 10-membered heteroaryl, - (CH) ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 C(O)R _A1 、-(CH ₂ ) _n1 NR _A2 R _B2 Or- (CH) ₂ ) _n1 O(CH ₂ ) _n2 NR _B2 R _C2 Said amino group, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Deuterated alkoxy, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical、C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, - (CH) ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 C(O)R _A1 、-(CH ₂ ) _n1 NR _A2 R _B2 、-(CH ₂ ) _n1 O(CH ₂ ) _n2 NR _B2 R _C2 Is substituted with one or more substituents of (a);

preferably, R ² Each independently selected from hydrogen, deuterium, halogen, amino, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Deuterated alkoxy, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _3-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-2 members selected from N or O, 5-6 membered heteroaryl group containing 1-2 members selected from N or O, - (CH) ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 C(O)R _A1 、-(CH ₂ ) _n1 NR _A2 R _B2 Or- (CH) ₂ ) _n1 O(CH ₂ ) _n2 NR _B2 R _C2 Said amino group, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Deuterated alkoxy, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _3-6 Cycloalkyl, 4-6 membered heterocyclyl containing 1-2 members selected from N or O and 5-6 membered heteroaryl containing 1-2 members selected from N or O, optionally further deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-3 Alkyl radical, C _1-3 Hydroxyalkyl, C _1-3 Alkoxy, - (CH) ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 C(O)R _A1 、-(CH ₂ ) _n1 NR _A2 R _B2 And- (CH) ₂ ) _n1 O(CH ₂ ) _n2 NR _B2 R _C2 Is substituted with one or more substituents of (a),

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

The invention further relates to a method for preparing the compound shown in the general formula (IV), the stereoisomer or the pharmaceutically acceptable salt thereof, which comprises the following steps:

wherein:

M ₁ 、M ₂ each independently is N or CH;

X ₂ is halogen, borate, -Sn (R) ₆ R ₇ R ₈ ) Sulfonate or borate groups, preferably fluorine, chlorine, bromine, iodine, -B (OH) ₂ or-OTf;

R ⁵ independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said amino, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-to 12-memberedHeterocyclic group, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl;

preferably hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl;

X ₁ and R ₂ As described above.

The invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of any one of the compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.

The invention further relates to an application of any compound with the general formula, a stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparing LRRK2 or ROCK inhibitor medicines. The invention further relates to an application of the compound with the general formula, a stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparing a selective LRRK2 and ROCK dual inhibitor drug.

The invention further relates to the application of the compound shown in the general formula, the stereoisomer or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof in preparing medicaments for treating nervous system diseases, cardiovascular diseases, cancers, inflammations, autoimmune diseases, metabolic diseases and related diseases; the nervous system disease is preferably Parkinson's disease, glaucoma, Alzheimer's disease or epilepsy and the application in the drugs for the related diseases.

The invention also relates to a method for treating and/or preventing cancer and related diseases, which comprises the step of administering a therapeutically effective dose of the compound shown as the general formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a patient.

The invention also provides methods of using the compounds or pharmaceutical compositions of the invention to treat disease conditions, including but not limited to conditions associated with dual inhibitors of LRRK2 or ROCK inhibitors, or combinations thereof.

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

Detailed description of the invention

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 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-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.

The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means-CH ₂ -, "ethylene" means- (CH) ₂ ) ₂ -, "propylene" means- (CH) ₂ ) ₃ -, "butylene" means- (CH) ₂ ) ₄ -and the like. 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, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon substituent, and the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and further preferably 3 to 6 carbon atoms. Non-limiting examples of cycloalkyl groups include monocyclic cycloalkyl, spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:

spirocycloalkyl groups also containing a single spirocycloalkyl group with a heterocycloalkyl group sharing a spiro atom, non-limiting examples include:

the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic 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 of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 5 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) _m (wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 10 ring atoms; further preferably from 3 to 8 ring atoms. Non-limiting examples of heterocyclic groups include monocyclic heterocyclic groups, spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, pyrrolidinonyl, piperidin-2-onyl, 3, 4-dihydropyridin-2 (1H) -onyl, 4, 5-dihydropyridazin-3 (2H) -onyl, azetidinyl, oxetanyl, oxacyclohexyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, piperidinyl, piperazinyl, pyridazinyl, thienyl, and the like,

Etc.; preferably pyrrolidinyl, pyrrolidinonyl, piperidin-2-onyl, 3, 4-dihydropyridin-2 (1H) -onyl, 4, 5-dihydropyridazin-3 (2H) -onyl, azetidinyl, oxetanyl, dihydropyrrolyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, etc,

Piperazinyl and pyranyl; more preferably dihydropyrrolyl, pyrrolidinyl, pyrrolidinonyl, piperidin-2-onyl, 3, 4-dihydropyridin-2 (1H) -onyl, 4, 5-dihydropyridazin-3 (2H) -onyl, azetidinyl, oxetanyl, oxolanyl, morpholinyl, piperidinyl, piperazinyl, and piperazinyl,

A pyranyl group. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring.

The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, or S (O) _m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocycleThe group "means 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 of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O) _m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O) _m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:

the heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, more preferably 6 to 8 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl groups include monocyclic heteroaryl, bicyclic heteroaryl or polycyclic heteroaryl; monocyclic heteroaryl is preferably 5 to 10 membered, more preferably 5 to 8 membered, most preferably 5 or 6 membered, for example pyrazinyl, pyridazinyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably pyridyl, pyrazinyl, pyridazinyl, triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferred are triazolyl, pyrrolyl, thienyl, thiazolyl, pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl.

Bicyclic heteroaryl is preferably 5-membered heteroarylheterocyclo or 6-membered heteroarylheterocyclo; more preferred is a 5-membered heteroarylo 5-membered heterocyclyl group, a 5-membered heteroarylo 6-membered heterocyclyl group, a 6-membered heteroarylo 5-membered heterocyclyl group or a 6-membered heteroarylo 6-membered heterocyclyl group. Non-limiting examples of bicyclic heteroaryls include the following:

the heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more 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 carboxylate groups.

The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is defined as above, preferably alkyl having 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.

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

"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

"alkenyl" means alkenyl, also known as alkenyl, preferably 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. Non-limiting examples of alkenyl groups include: vinyl and propenyl. Wherein said alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"alkynyl" refers to alkenyl, also known as alkynyl, and to unsaturated hydrocarbyl containing-C.ident.C-; the alkynyl group having 2 to 8 carbon atoms is preferable, the alkynyl group having 2 to 6 carbon atoms is more preferable, the alkynyl group having 2 to 4 carbon atoms is further preferable, and the alkynyl group having 2 to 3 carbon atoms is most preferable. Wherein said alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"fused ring group" means a polycyclic group formed by two or more carbocyclic or heterocyclic rings sharing a ring edge, the fused ring group including fused ring alkyl groups, fused ring heteroaryl groups, fused ring aryl groups, and fused ring heteroaryl groups, wherein the fused ring alkyl groups mean cycloalkyl groups and heterocyclic, aryl, and heteroaryl groups sharing a ring edge; the fused ring heterocyclic group refers to a polycyclic group formed by a heterocyclic group and cycloalkyl, aryl and heteroaryl which share a ring edge; the fused ring aryl refers to polycyclic groups formed by sharing ring edges of aryl, cycloalkyl, heterocyclic group and heteroaryl; the fused ring heteroaryl refers to heteroaryl and polycyclic radicals formed by cycloalkyl, heterocyclic radical and hetero radical in a way of sharing a ring edge; for example:

"deuterated alkyl" refers to an alkyl group substituted with one or more deuterium, wherein alkyl is as defined above.

"deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium, wherein the alkoxy group is as defined above.

"hydroxy" refers to an-OH group.

"halogen" means fluorine, chlorine, bromine or iodine.

"amino" means-NH ₂ 。

"cyano" means-CN.

"nitro" means-NO ₂ 。

"carboxy" refers to-C (O) OH.

"THF" refers to tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N, N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"MeCN" refers to acetonitrile.

"DMA" refers to N, N-dimethylacetamide.

“Et ₂ O "means diethyl ether.

"DCE" refers to 1, 2-dichloroethane.

"DIPEA" refers to N, N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

“Pd ₂ (dba) ₃ "refers to tris (dibenzylideneacetone) dipalladium.

"Dppf" refers to 1, 1' -bisdiphenylphosphinoferrocene.

"HATU" refers to 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bistrimethylsilyl amide.

"MeLi" refers to methyllithium.

"n-BuLi" refers to n-butyllithium.

“NaBH(OAc) ₃ "refers to sodium triacetoxyborohydride.

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", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B, C.

All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to the present invention can also be replaced by a deuterium atom.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.

Detailed Description

The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.

Examples

The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated methanol (CD) ₃ OD) and deuterated chloroform (CDCl) ₃ ) Internal standard is Tetramethylsilane (TMS).

LC-MS was measured using an Agilent 1200Infinity Series Mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).

The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.

All reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees celsius.

The eluent system of silica gel column chromatography and the developing agent system of thin layer chromatography used for purifying the intermediate and the compound in the example comprise: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1-1

(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

First step synthesis of (S) -5-methoxy-2-methyl-3, 4-dihydro-2H-pyrrole

To a solution of (S) -5-methylpyrrolidin-2-one (1.7g,17.2mmol) in dichloromethane (40mL) was added trimethyloxonium tetrafluoroborate (3.55g,24.0mmol) in portions under an ice bath. The reaction was slowly warmed to room temperature, stirred at this temperature for 5 hours, and then saturated NaHCO was added ₃ Aqueous solution (5mL), dichloromethane (50 mL. times.2) and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, added with glacial acetic acid (5mL) and concentrated under reduced pressure to give the crude product which was used directly in the next reaction.

MS m/z(ESI):114.1[M+H] ⁺ .

Second step Synthesis of (S) -6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine

6-Aminomethylpyridinohydrazide (2.35g,15.4mmol) was dissolved in 2-pentanol (15mL) and acetic acid (2mL) at room temperature, and (S) -5-methoxy-2-methyl-3, 4-dihydro-2H-pyrrole (1.93g,17.1mmol) was added. The reaction was heated to 125 ℃ and stirred at this temperature for 12 hours, cooled to room temperature and concentrated under reduced pressure. Then saturated NaHCO was added ₃ Aqueous solution (5mL), dichloromethane (50 mL. times.2) extraction, organic phase washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and column chromatographed to give the title compound (S) -6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2, 1-c)][1,2,4]Triazol-3-yl) pyridin-2-amine (1.62g, 49% yield over two steps).

MS m/z(ESI):216.1[M+H] ⁺ .

Step three, synthesizing ethyl 3-methoxy-1- (pyrazine-2-yl) -1H-pyrazole-4-carboxylate

2-chloropyrazine (2.02g,17.6mmol), ethyl 3-methoxy-1H-pyrazole-4-carboxylate (2.5g,14.7mmol), CuI (280mg,1.5mmol), L-proline (338.4mg,2.9mmol) and potassium carbonate (5.08g,36.7mmol) were mixed in DMF (60mL), N ₂ The reaction was heated to 100 ℃ under ambient atmosphere overnight. Cooled to room temperature, filtered to remove solids, 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-carboxylate (2.5g, 68%).

MS m/z(ESI):249.1[M+H] ⁺ .

The fourth step of synthesis of 3-methoxy-1- (pyrazin-2-yl) -1H-pyrazole-4-carboxylic acid

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

MS m/z(ESI):221.1[M+H] ⁺ .

Fifth step Synthesis of 3-methoxy-1- (pyrazin-2-yl) -1H-pyrazole-4-Carbonylchloride

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

The sixth step (S) -Synthesis of 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

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

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):418.2[M+H] ⁺ .

Examples 1 to 2

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):418.2[M+H] ⁺ .

Example 2-1

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):436.2[M+H] ⁺ .

Examples 2 to 2

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):436.2[M+H] ⁺ .

Example 3-1

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):436.2[M+H] ⁺ .

Examples 3 to 2

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):436.2[M+H] ⁺ .

Example 4-1

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):436.2[M+H] ⁺ .

Example 4 to 2

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):436.2[M+H] ⁺ .

Example 5-1

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):448.2[M+H] ⁺ .

Example 5-2

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):448.2[M+H] ⁺ .

Example 6-1

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):448.2[M+H] ⁺ .

Example 6 to 2

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):448.2[M+H] ⁺ .

Example 7-1

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):448.2[M+H] ⁺ .

Example 7-2

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):448.2[M+H] ⁺ .

Example 8-1

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):443.2[M+H] ⁺ .

Example 8 to 2

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):443.2[M+H] ⁺ .

Example 9-1

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):443.2[M+H] ⁺ .

Example 9-2

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):443.2[M+H] ⁺ .

Example 10-1

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):443.2[M+H] ⁺ .

Example 10-2

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):443.2[M+H] ⁺ .

Example 11

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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):420.2[M+H] ⁺ .

Example 12

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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):432.2[M+H] ⁺ .

Example 13

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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):430.2[M+H] ⁺ .

Example 14-1

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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),5.12-5.21(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).

MS m/z(ESI):448.2[M+H] ⁺ .

Example 14-2

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):448.2[M+H] ⁺ .

Example 15

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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):432.2[M+H] ⁺ .

Example 16

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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):430.2[M+H] ⁺ .

Example 17-1

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):430.2[M+H] ⁺ .

Example 17-2

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):430.2[M+H] ⁺ .

Example 18-1

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):428.2[M+H] ⁺ .

Example 18-2

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):428.2[M+H] ⁺ .

Example 19-1

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):472.2[M+H] ⁺ .

Example 19-2

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):472.2[M+H] ⁺ .

Example 20-1

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):436.2[M+H] ⁺ .

Example 20-2

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):436.2[M+H] ⁺ .

Example 21-1

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):443.2[M+H] ⁺ .

Example 21-2

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):443.2[M+H] ⁺ .

Example 22-1

(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

Preparation 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 ] pyrazol-4 (2H) -one reference is made to example 1-1.

MS m/z(ESI):400.2[M+H] ⁺ .

Example 22-2

(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

Preparation 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 ] pyrazol-4 (2H) -one was carried out as described in example 1-1.

MS m/z(ESI):400.2[M+H] ⁺ .

Example 23-1

(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

Preparation 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 referred to example 1-1.

MS m/z(ESI):414.2[M+H] ⁺ .

Example 23-2

(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

Preparation 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 was as in example 1-1.

MS m/z(ESI):414.2[M+H] ⁺ .

Example 24-1

(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

Preparation 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 described in example 1-1.

MS m/z(ESI):412.2[M+H] ⁺ .

Example 24-2

(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

Preparation 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 described in example 1-1.

MS m/z(ESI):412.2[M+H] ⁺ .

Example 25-1

(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

Preparation 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 was carried out according to example 1-1.

MS m/z(ESI):413.2[M+H] ⁺ .

Example 25-2

(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

Preparation 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 was carried out according to example 1-1.

MS m/z(ESI):413.2[M+H] ⁺ .

Example 26

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

Preparation 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 reference was made to example 1-1.

MS m/z(ESI):420.2[M+H] ⁺ .

Example 27

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

Preparation 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 reference was made to example 1-1.

MS m/z(ESI):418.2[M+H] ⁺ .

Example 28

(S) -3-methoxy-N- (6- (5-methyl-4- (1,1, 1-trifluoropropan-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1- (pyrazin-2-yl) -1H-pyrazole-4-carboxamide

Preparation of (S) -3-methoxy-N- (6- (5-methyl-4- (1,1, 1-trifluoropropan-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1- (pyrazin-2-yl) -1H-pyrazole-4-carboxamide reference is made to example 1-1.

MS m/z(ESI):474.2[M+H] ⁺ .

Example 29

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

Preparation 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 reference example 1-1.

MS m/z(ESI):432.2[M+H] ⁺ .

Example 30

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

Preparation of N- (6- (1-isopropyl-1H-tetrazol-5-yl) pyridin-2-yl) -3-methoxy-1- (pyrazin-2-yl) -1H-pyrazole-4-carboxamide reference was made to example 1-1.

MS m/z(ESI):407.2[M+H] ⁺ .

Example 31

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

Preparation of N- (6- (1-cyclopropyl-1H-tetrazol-5-yl) pyridin-2-yl) -3-methoxy-1- (pyrazin-2-yl) -1H-pyrazole-4-carboxamide reference was made to example 1-1.

MS m/z(ESI):405.2[M+H] ⁺ .

Example 32-1

(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

Preparation 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 reference is made to example 1-1.

1H NMR(400MHz,CDCl ₃ )δ1.61(d,J＝6.5Hz,3H),2.40-2.46(m,1H),2.98-3.13(m,3H),3.81(s,3H),4.11(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)；

MS m/z(ESI):354.2[M+H] ⁺ .

Example 32-2

(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

Preparation 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 reference is made to example 1-1.

1H NMR(400MHz,CDCl ₃ )δ1.61(d,J＝6.5Hz,3H),2.42-2.47(m,1H),2.99-3.13(m,3H),3.81(s,3H),4.11(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)；

MS m/z(ESI):354.2[M+H] ⁺ .

Example 33-1

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):380.2[M+H] ⁺ .

Example 33-2

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):380.2[M+H] ⁺ .

Example 34-1

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):411.2[M+H] ⁺ .

Example 34-2

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):411.2[M+H] ⁺ .

Example 35-1

(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

Preparation 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 the procedure was as in example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):351.2[M+H] ⁺ .

Example 35-2

(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

Preparation 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 the procedure was as in example 1-1.

MS m/z(ESI):351.2[M+H] ⁺ .

Example 36-1

(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

Preparation 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 the procedure was as in example 1-1.

MS m/z(ESI):405.2[M+H] ⁺ .

Example 36-2

(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

Preparation 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 the procedure was as in example 1-1.

MS m/z(ESI):405.2[M+H] ⁺ .

Example 37-1

(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

Preparation 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 the procedure is as in example 1-1.

MS m/z(ESI):423.2[M+H] ⁺ .

Example 37-2

(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

Preparation 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 the procedure is as in example 1-1.

MS m/z(ESI):423.2[M+H] ⁺ .

Example 38

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

Preparation of N- (6- (6',7' -dihydrospiro [ cyclopropane-1, 5 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-yl) -2-methoxynicotinamide the procedure was as in example 1-1.

MS m/z(ESI):363.2[M+H] ⁺ .

Example 39

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

Preparation 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 the procedure was as in example 1-1.

MS m/z(ESI):381.2[M+H] ⁺ .

Example 40

(S) -2-methoxy-N- (6- (5-methyl-4- (1,1, 1-trifluoropropan-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) nicotinamide

Preparation of (S) -2-methoxy-N- (6- (5-methyl-4- (1,1, 1-trifluoropropan-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) nicotinamide the procedure was as in example 1-1.

MS m/z(ESI):407.2[M+H] ⁺ .

EXAMPLE 41

(S) -2-methoxy-N- (6- (1- (1,1, 1-trifluoropropan-2-yl) -1H-tetrazol-5-yl) pyridin-2-yl) nicotinamide

Preparation of (S) -2-methoxy-N- (6- (1- (1,1, 1-trifluoropropan-2-yl) -1H-tetrazol-5-yl) pyridin-2-yl) nicotinamide was carried out according to example 1-1.

MS m/z(ESI):394.2[M+H] ⁺ .

Example 42-1

(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] triazazole-2 (2,6) -pyridin-5 (1,2) -benzocyclononan-4-one

Preparation 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] triazazol-2 (2,6) -pyridin-5 (1,2) -benzocyclononan-4-one is described in example 1-1.

MS m/z(ESI):499.2[M+H] ⁺ .

Example 42-2

(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] triazazole-2 (2,6) -pyridin-5 (1,2) -benzocyclononan-4-one

Preparation 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] triazazol-2 (2,6) -pyridin-5 (1,2) -benzocyclononan-4-one is carried out as described in example 1-1.

MS m/z(ESI):499.2[M+H] ⁺ .

Example 43

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):461.2[M+H] ⁺ .

Example 44

(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

Preparation of (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 reference is made to example 1-1.

MS m/z(ESI):460.2[M+H] ⁺ .

Example 45

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):459.2[M+H] ⁺ .

Example 46

(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

Preparation of (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 reference is made to example 1-1.

MS m/z(ESI):462.2[M+H] ⁺ .

Example 47

(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

Preparation of (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 reference is made to example 1-1.

MS m/z(ESI):461.2[M+H] ⁺ .

Example 48

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):417.2[M+H] ⁺ .

Example 49

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):495.2[M+H] ⁺ .

Example 50

(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

Preparation 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 reference was made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):447.2[M+H] ⁺ .

Example 51

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):442.2[M+H] ⁺ .

Example 52

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):485.2[M+H] ⁺ .

Example 53

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):431.2[M+H] ⁺ .

Example 54

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):485.2[M+H] ⁺ .

Example 55

(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

Preparation 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 reference was made to example 1-1.

MS m/z(ESI):442.2[M+H] ⁺ .

Example 56

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):451.2[M+H] ⁺ .

Example 57

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):495.2[M+H] ⁺ .

Example 58

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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):418.2[M+H] ⁺ .

Example 59

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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):432.2[M+H] ⁺ .

Example 60

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):485.2[M+H] ⁺ .

Example 61

(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- (oxoalk-3-ylmethyl) pyridin-2-yl) -1H-pyrazole-4-carboxamide

Preparation 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- (oxoalk-3-ylmethyl) pyridin-2-yl) -1H-pyrazole-4-carboxamide reference was made to example 1-1.

MS m/z(ESI):487.2[M+H] ⁺ .

¹ H NMR(400MHz,CDCl ₃ )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)。

Example 62

(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- (Oxetan-3-yl) pyridin-2-yl) -1H-pyrazole-4-carboxamide

Preparation 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- (oxetan-3-yl) pyridin-2-yl) -1H-pyrazole-4-carboxamide reference was made to example 1-1.

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)；

MS m/z(ESI):473.2[M+H] ⁺ .

Example 63

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):474.2[M+H] ⁺ .

Example 64

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):474.2[M+H] ⁺ .

Example 65

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):474.2[M+H] ⁺ .

Example 66

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):488.2[M+H] ⁺ .

Example 67

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):504.2[M+H] ⁺ .

Example 68

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):517.2[M+H] ⁺ .

Example 69

1- ((R) -7- (dimethylamino) -6, 7-dihydro-5H-cyclopentyl [ b ] pyridin-2-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

Preparation 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-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1H-pyrazole-4-carboxamide reference is made to example 1-1.

MS m/z(ESI):500.2[M+H] ⁺ .

Example 70

1- ((S) -7- (dimethylamino) -6, 7-dihydro-5H-cyclopentyl [ b ] pyridin-2-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

Preparation 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-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1H-pyrazole-4-carboxamide reference is made to example 1-1.

MS m/z(ESI):500.2[M+H] ⁺ .

Example 71

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):472.2[M+H] ⁺ .

Example 72

(S) -1- (5-fluorothien-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

Preparation of (S) -1- (5-fluorothien-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 reference is made to example 1-1.

MS m/z(ESI):440.2[M+H] ⁺ .

Example 73

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):497.2[M+H] ⁺ .

Example 74

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):417.2[M+H] ⁺ .

Example 75

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )δ1.65(d,J＝6.8Hz,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)；

MS m/z(ESI):477.2[M+H] ⁺ .

Example 76

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):485.2[M+H] ⁺ .

Example 77

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):485.2[M+H] ⁺ .

Example 78

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):442.2[M+H] ⁺ .

Example 79

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):484.2[M+H] ⁺ .

Example 80

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):445.2[M+H] ⁺ .

Example 81

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):424.2[M+H] ⁺ .

Example 82

(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- (Oxiran-3-yl) -1H-pyrazole-4-carboxamide

Preparation 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- (oxetan-3-yl) -1H-pyrazole-4-carboxamide reference is made to example 1-1.

MS m/z(ESI):396.2[M+H] ⁺ .

Example 83

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):382.2[M+H] ⁺ .

Example 84

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):453.2[M+H] ⁺ .

Example 87

(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

Preparation 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 the procedure was referenced to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )δ1.61(d,J＝6.6Hz,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).

MS m/z(ESI):466.2[M+H] ⁺ .

Example 86

(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

Preparation 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 reference was made to example 1-1.

MS m/z(ESI):437.2[M+H] ⁺ .

Example 87

(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-methylazetidin-3-yl) -1H-pyrazole-4-carboxamide

Preparation 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-methylazetidin-3-yl) -1H-pyrazole-4-carboxamide reference is made to example 1-1.

MS m/z(ESI):409.2[M+H] ⁺ .

Example 88

1- ((2R,4S,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

Preparation of 1- ((2R,4S,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 reference is made to example 1-1.

MS m/z(ESI):452.2[M+H] ⁺ .

Example 89

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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):452.2[M+H] ⁺ .

Example 90

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):353.2[M+H] ⁺ .

Example 91

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):408.2[M+H] ⁺ .

Example 92

Methyl (R) -3- (6- (3-methoxy-1- (pyrazin-2-yl) -1H-pyrazol-4-carbanilido < oxalylamino >) pyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole-5-carboxylate

Preparation of methyl (R) -3- (6- (3-methoxy-1- (pyrazin-2-yl) -1H-pyrazol-4-carbanilido < oxalylamino >) pyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole-5-carboxylate the procedure is as in example 1-1.

MS m/z(ESI):462.2[M+H] ⁺ .

Example 93

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):475.2[M+H] ⁺ .

Example 94

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):475.2[M+H] ⁺ .

Example 95

(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

Preparation of (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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):475.2[M+H] ⁺ .

Example 96

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):485.2[M+H] ⁺ .

Example 97

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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,2H),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)；

MS m/z(ESI):474.2[M+H] ⁺ .

Example 98

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):485.2[M+H] ⁺ .

Example 99

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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),5.00-5.05(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).

MS m/z(ESI):502.2[M+H] ⁺ .

Example 100

(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

Preparation 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 reference was made to example 1-1.

MS m/z(ESI):515.2[M+H] ⁺ .

Example 101

(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

Preparation 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 refers to example 1-1.

MS m/z(ESI):503.2[M+H] ⁺ .

Example 102

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):447.2[M+H] ⁺ .

Example 103

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):420.2[M+H] ⁺ .

Example 104

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):420.2[M+H] ⁺ .

Example 105

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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),4.11(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)；

MS m/z(ESI):406.2[M+H] ⁺ .

Example 106

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):493.2[M+H] ⁺ .

Example 107

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):447.2[M+H] ⁺ .

Example 108

(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

Preparation 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 reference was made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):461.2[M+H] ⁺ .

Example 109

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

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

Preparation 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 reference is made to example 1-1.

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)；

MS m/z(ESI):447.2[M+H] ⁺ .

Example 110

(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

Preparation 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 reference is made to example 1-1.

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),3.43-3.54(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)；

MS m/z(ESI):380.2[M+H] ⁺ .

Example 111

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] octan-3-yl) -1H-pyrazole-4-carboxamide

Preparation 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] octan-3-yl) -1H-pyrazole-4-carboxamide reference is made to example 1-1.

MS m/z(ESI):463.2[M+H] ⁺ .

Example 112

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] octan-3-yl) -1H-pyrazole-4-carboxamide

Preparation 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] octan-3-yl) -1H-pyrazole-4-carboxamide reference is made to example 1-1.

MS m/z(ESI):463.2[M+H] ⁺ .

Example 113

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):460.2[M+H] ⁺ .

Example 114

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):419.2[M+H] ⁺ .

Example 115

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):424.2[M+H] ⁺ .

Example 116

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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),7.24(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).

MS m/z(ESI):455.2[M+H] ⁺ .

Example 117

(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

Preparation 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 reference was made to example 1-1.

MS m/z(ESI):474.2[M+H] ⁺ .

Example 118

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):379.2[M+H] ⁺ .

Example 119

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):432.2[M+H] ⁺ .

Example 120

(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-methyloxetan-3-yl) methyl) -1H-pyrazole-4-carboxamide

Preparation 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-methyloxetan-3-yl) methyl) -1H-pyrazole-4-carboxamide the procedure was referenced to example 1-1.

MS m/z(ESI):424.2[M+H] ⁺ .

Example 121

(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] heptan-6-yl) -1H-pyrazole-4-carboxamide

Preparation 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] heptan-6-yl) -1H-pyrazole-4-carboxamide reference was made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):436.2[M+H] ⁺ .

Example 122

1- ((1, 4-dioxan-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

Preparation of 1- ((1, 4-dioxan-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 the procedure was followed in example 1-1.

¹ H NMR(400MHz,CDCl ₃ )δ1.62(d,J＝5.3Hz,3H),2.39-2.51(m,1H),2.94-3.18(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),7.79-7.86(m,1H),7.94(s,1H),7.99-8.06(m,1H),8.28-8.34(m,1H),9.15(s,1H)；

MS m/z(ESI):440.2[M+H] ⁺ .

Example 123

(S) -1- (2, 2-dimethyl-1, 3-dioxan-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

Preparation of (S) -1- (2, 2-dimethyl-1, 3-dioxan-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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):454.2[M+H] ⁺ .

Example 124

MS m/z(ESI):503.2[M+H] ⁺ .

Example 125

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- (oxetan-2-ylmethyl) -1H-pyrazole-4-carboxamide

Preparation 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- (oxetan-2-ylmethyl) -1H-pyrazole-4-carboxamide reference is made to example 1-1.

MS m/z(ESI):410.2[M+H] ⁺ .

Example 126

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):368.2[M+H] ⁺ .

Example 127

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-hydroxypropan-2-yl) -1H-pyrazole-4-carboxamide

Preparation 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-hydroxypropan-2-yl) -1H-pyrazole-4-carboxamide reference is made to example 1-1.

¹ H NMR(400MHz,DMSO-d ₆ )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)；

MS m/z(ESI):452.2[M+H] ⁺ .

Example 128

(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- (oxetan-3-ylmethyl) -1H-pyrazole-4-carboxamide

Preparation 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- (oxetan-3-ylmethyl) -1H-pyrazole-4-carboxamide reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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).

MS m/z(ESI):410.2[M+H] ⁺ .

Example 129

1H-pyrazole-4-carboxamides

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):340.2[M+H] ⁺ .

Example 130

(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

Preparation 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 was carried out according to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):381.2[M+H] ⁺ .

Example 131

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):407.2[M+H] ⁺ .

Example 132

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):371.2[M+H] ⁺ .

Example 133

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):354.2[M+H] ⁺ .

Example 134

(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

Preparation 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 the procedure was as in example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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),6.97-7.06(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)；

MS m/z(ESI):351.2[M+H] ⁺ .

Example 135

(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

Preparation 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 method of preparation reference example 1-1.

MS m/z(ESI):351.2[M+H] ⁺ .

Example 136

(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

Preparation 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 the procedure was as in example 1-1.

MS m/z(ESI):423.2[M+H] ⁺ .

Example 137

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):407.2[M+H] ⁺ .

Example 138

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

Preparation 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) picolinamide reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):351.2[M+H] ⁺ .

Example 139

(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

Preparation 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 the procedure was as in example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):376.2[M+H] ⁺ .

Example 140

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

Preparation 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) picolinamide reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):351.2[M+H] ⁺ .

Example 141

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):352.2[M+H] ⁺ .

Example 142

(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

Preparation 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 example 1-1 was referenced.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):352.2[M+H] ⁺ .

Example 143

(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

Preparation 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 the procedure was as in example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):419.2[M+H] ⁺ .

Example 144

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):460.2[M+H] ⁺ .

Example 145

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):460.2[M+H] ⁺ .

Example 146

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):425.2[M+H] ⁺ .

Example 147

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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),5.10-5.16(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)；

MS m/z(ESI):447.2[M+H] ⁺ .

Example 148

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):406.2[M+H] ⁺ .

Example 149

(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

Preparation 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 reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):420.2[M+H] ⁺ .

Example 150

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-methylpyrrolidin-3-yl) -1H-pyrazole-4-carboxamide

Preparation 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-methylpyrrolidin-3-yl) -1H-pyrazole-4-carboxamide reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):423.2[M+H] ⁺ .

Example 151

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-methylpyrrolidin-3-yl) -1H-pyrazole-4-carboxamide

Preparation 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-methylpyrrolidin-3-yl) -1H-pyrazole-4-carboxamide reference is made to example 1-1.

¹ H NMR(400MHz,CDCl ₃ )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,1H),8.02(d,J＝7.7Hz,1H),8.04(s,1H),8.29(d,J＝8.2Hz,1H),9.10(s,1H)；

MS m/z(ESI):423.2[M+H] ⁺ .

Example 152

(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

Preparation 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 reference is made to example 1-1.

MS m/z(ESI):474.2[M+H] ⁺ .

Example 153

(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- (oxetan-3-yl) pyridin-3-yl) -1H-pyrazole-4-carboxamide

Preparation 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- (oxetan-3-yl) pyridin-3-yl) -1H-pyrazole-4-carboxamide reference was made to example 1-1.

MS m/z(ESI):473.2[M+H] ⁺ .

Example 154-1

(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

First step synthesis of (S) -5-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazole

(S) -5-methoxy-2-methyl at room temperature-3, 4-dihydro-2H-pyrrole (2g,17.67mmol), 2, 2-dimethoxyethane-1-amine (2.04g,19.44mmol) were dissolved in MeOH (16mL), dichloromethane (4mL) was added, the reaction was heated to 80 deg.C and stirred for 5H, after cooling, the organic solvent was concentrated under reduced pressure, the crude product was dissolved in formic acid (10mL), and the tube was sealed and heated to 130 deg.C and reacted for 12H. LCMS detects reaction completion, after cooling to room temperature, the organic solvent is concentrated under reduced pressure, ethyl acetate is added to dissolve the residue, NaHCO is added ₃ The saturated aqueous solution was extracted with ethyl acetate (300 m.times.3), the combined organic phases were separated and the organic solvent was concentrated under reduced pressure to give (S) -5-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ]]1.6g of crude imidazole was used directly in the next step.

MS m/z(ESI):123.1[M+H] ⁺ .

Second step Synthesis of (S) - (5-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-3-yl) boronic acid

At room temperature, crude product (S) -5-methyl-6, 7-dihydro-5H-pyrrolo [1, 2-a) in the last step is added]Imidazole (1.6g,13.10mmol), 4,4 '-di-tert-butyl-2, 2' -bipyridine (373mg,1.39mmol),biboric acid pinacol ester(4.99g,19.65mmol) was dissolved in n-hexane (7.5mL) and THF (7.5mL), the nitrogen was deoxygenated for 5 minutes, 1, 5-cyclooctadiene iridium chloride dimer (461mg, 686. mu. mol) was added, and the mixture was stirred at room temperature for 12 hours. LCMS detects that the reaction is finished, the organic solvent is decompressed and concentrated, and then the (S) - (5-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] is obtained by preparative separation of reversed phase column]Imidazol-3-yl) boronic acid (1.15g, 39% yield over two steps).

MS m/z(ESI):167.2[M+H] ⁺ .

Step three, synthesizing 3-methoxy-1-methyl-1H-pyrazole-4-carbonyl chloride

3-methoxy-1-methyl-pyrazole-4-carboxylic acid (0.5g,3.52mmol) was dissolved in dichloromethane (15mL) under ice-bath, oxalyl chloride (4.39g,34.6mmol) was added, and the reaction mixture was stirred for 5 minutes under ice-bath, DMF (0.5mL) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction, the organic solvent was concentrated under reduced pressure to obtain 600mg of crude 3-methoxy-1-methyl-1H-pyrazole-4-carbonyl chloride, which was used directly in the next reaction.

The fourth step of synthesis of N- (6-bromopyridin-2-yl) -3-methoxy-1-methyl-1H-pyrazole-4-carboxamide

Crude 3-methoxy-1-methyl-1H-pyrazole-4-carbonyl chloride (600mg,3.44mmol) was dissolved in pyridine (6mL) at room temperature, 6-bromopyridin-2-amine (595mg,3.44mmol) was added, and the reaction was stirred at room temperature for 10 hours. LCMS detection showed the reaction was complete and after concentration of the organic solvent under reduced pressure, normal phase column chromatography gave N- (6-bromopyridin-2-yl) -3-methoxy-1-methyl-1H-pyrazole-4-carboxamide (302mg, 28% yield over two steps).

MS m/z(ESI):310.8[M+H] ⁺ .

Fifth step Synthesis of preparation 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

N- (6-bromo-2-pyridinyl) -3-methoxy-1-methyl-pyrazole-4-carboxamide (0.24g, 771.37. mu. mol), potassium phosphate (327mg,1.54mmol) dissolved in 1,4-Dioxane (10mL), H, at room temperature ₂ To O (2mL), Pd (PPh) was added ₃ ) ₄ (267mg, 231.41. mu. mol), (S) - (5-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ]]Imidazole-3-yl) boric acid (256mg,1.54mmol), deoxidizing with nitrogen for three times, heating the reaction to 100 ℃, stirring for 12 hours, concentrating the organic solvent under reduced pressure, and separating by reverse phase column preparation to obtain (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 (96mg, 35%).

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):353.2[M+H] ⁺ .

Example 154-2

(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

Preparation 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 reference example 154-1.

MS m/z(ESI):353.2[M+H] ⁺ .

Example 155-1

(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

Preparation 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 reference example 154-1.

MS m/z(ESI):417.2[M+H] ⁺ .

Example 155-2

(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

Preparation 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 reference example 154-1.

MS m/z(ESI):417.2[M+H] ⁺ .

Example 155

(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

Preparation 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 reference was made to example 154-1.

MS m/z(ESI):473.2[M+H] ⁺ .

Example 157

(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

Preparation 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 reference was made to example 154-1.

MS m/z(ESI):430.2[M+H] ⁺ .

Example 158

(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

The method comprises the following steps: preparation 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 reference example 154-1.

The method 2 comprises the following steps: first step synthesis of 1- (tert-butyl) 4-ethyl 3-methoxy-1H-pyrazole-1, 4-dicarboxylate

To a mixed solution of 1- (tert-butyl) 4-ethyl 3-hydroxy-1H-pyrazole-1, 4-dicarboxylate (20.1g,78.4mmol) in THF (150mL) and DMF (150mL) was added NaH (4.71g,118mmol,60 wt%) in portions under an ice-water bath, after which stirring was continued for 1 hour under an ice-water bath, iodomethane (11.1g,78.4mmol) was then added slowly dropwise, the ice-water bath was removed, and the mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride, concentrated under reduced pressure to remove THF, water and ethyl acetate were added to the residue, the organic phase was separated by extraction, washed with saturated brine several times, the organic phases were combined and dried, and the filtrate was concentrated under reduced pressure after filtration to give the title compound 1- (tert-butyl) 4-ethyl 3-methoxy-1H-pyrazole-1, 4-dicarboxylate (18.8g, 89%) as a crude product which was used directly in the next reaction.

Second step synthesis of ethyl 3-methoxy-1H-pyrazole-4-carboxylate

Add TFA (79.3g,696mmol) to a solution of 1- (tert-butyl) 4-ethyl 3-methoxy-1H-pyrazole-1, 4-dicarboxylate (18.8g,69.6mmol) in DCM (200mL) and stir at RT overnight. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate, then washed successively with a saturated aqueous sodium bicarbonate solution and a saturated brine, the organic phase was separated and dried, and after filtration, the filtrate was concentrated under reduced pressure to give a crude title compound ethyl 3-methoxy-1H-pyrazole-4-carboxylate (7.70g, 65%) which was used in the next reaction.

MS m/z(ESI):171.1[M+H] ⁺ .

Step three, synthesizing ethyl 3-methoxy-1- (4-methoxybenzyl) -1H-pyrazole-4-carboxylic ester

To a solution of ethyl 3-methoxy-1H-pyrazole-4-carboxylate (7.70g,45.3mmol) in THF (100mL) in an ice-water bath was added NaH (2.71g) in portions, followed by stirring at that temperature for 1 hour, PMB-Cl (7.09g,45.3mmol) was slowly added dropwise, and then stirring was carried out at room temperature overnight. The reaction solution was quenched with a saturated aqueous ammonium chloride solution, the organic solvent was concentrated under reduced pressure, and then a liquid was separated with ethyl acetate and a saturated saline solution, the organic phase was separated and dried, the filtrate was concentrated under reduced pressure after filtration, and column chromatography was performed to obtain the title compound ethyl 3-methoxy-1- (4-methoxybenzyl) -1H-pyrazole-4-carboxylate (8.80g, 67%).

MS m/z(ESI):291.1[M+H] ⁺ .

Fourthly, synthesizing 3-methoxy-1- (4-methoxybenzyl) -1H-pyrazole-4-carboxylic acid

To a mixed solution of ethyl 3-methoxy-1- (4-methoxybenzyl) -1H-pyrazole-4-carboxylate (11.0g,37.9mmol) in methanol (50mL) and water (50mL) was added lithium hydroxide monohydrate (4.54g), followed by stirring at room temperature overnight. The organic solvent was removed by concentration under reduced pressure, the pH was adjusted to weak acidity with dilute hydrochloric acid, and a solid was precipitated, filtered and dried to give the title compound, 3-methoxy-1- (4-methoxybenzyl) -1H-pyrazole-4-carboxylic acid (6.97g, 70%).

MS m/z(ESI):263.1[M+H] ⁺ .

Fifth step synthesis of 3-methoxy-1- (4-methoxybenzyl) -1H-pyrazole-4-carbonyl chloride

3-methoxy-1- (4-methoxybenzyl) -1H-pyrazole-4-carboxylic acid (200mg,0.76mmol) was dissolved in dichloromethane (8mL) under ice-bath conditions, oxalyl chloride (960mg,7.6mmol) was added, and the reaction mixture was stirred for 5 minutes under ice-bath conditions, one drop of DMF was added dropwise, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain 214mg of crude 3-methoxy-1- (4-methoxybenzyl) -1H-pyrazole-4-carbonyl chloride, which was used directly in the next reaction.

Sixthly, synthesizing N- (6-bromopyridine-2-yl) -3-methoxy-1- (4-methoxybenzyl) -1H-pyrazole-4-formamide

Crude 3-methoxy-1- (4-methoxybenzyl) -1H-pyrazole-4-carbonyl chloride (214mg) was dissolved in pyridine (6mL) at room temperature, 6-bromopyridin-2-amine (132mg,0.76mmol) was added, and the mixture was stirred at room temperature for 2 hours. The organic solvent was concentrated under reduced pressure and then subjected to normal phase column chromatography to give N- (6-bromopyridin-2-yl) -3-methoxy-1- (4-methoxybenzyl) -1H-pyrazole-4-carboxamide (170mg, 53%).

MS m/z(ESI):417.2[M+H] ⁺ .

Seventh step 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

N- (6-Bromopyridin-2-yl) -3-methoxy-1- (4-methoxybenzyl) -1H-pyrazole-4-carboxamide (380mg,0.91mmol) and potassium phosphate (386mg,1.82mmol) were mixed at room temperature in 1,4-Dioxane (10mL) and H ₂ To O (2mL), Pd (PPh) was added ₃ ) ₄ (316mg,0.27mmol) and (S) - (5-methyl-6, 7-dihydro-5H-pyrrolo [1, 2-a)]Imidazol-3-yl) boronic acid (181mg,1.09mmol), reacted at 110 ℃ under nitrogen atmosphere overnight. Cooling the reaction solution to room temperature, concentrating under reduced pressure, and separating 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 (325mg, 77%).

MS m/z(ESI):459.2[M+H] ⁺

Eighth step 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

(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 (150mg,0.33mmol) was dissolved in trifluoroacetic acid (6mL) at room temperature and allowed to warm to 90 ℃ for reaction overnight. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to give 105mg 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 used directly in the next reaction.

Ninth step 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-pyrazole-4-carboxamide

(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 (30mg,0.088mmol), 4-bromotetrahydro-2H-pyran (29mg,0.18mmol), cesium carbonate (58mg,0.18mmol) and potassium iodide (15mg,0.088mmol) were mixed in DMF (1mL) at room temperature and stirred at 120 ℃ for 2H. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and subjected to normal phase column chromatography to give (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 (7mg, 18%).

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):423.2[M+H] ⁺ .

Example 159

(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

Preparation 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 reference example 154-1.

MS m/z(ESI):379.2[M+H] ⁺ .

Example 160

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

Preparation of (S) -3-methoxy-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-3-yl) pyridin-2-yl) -1- (oxolane-3-yl) -1H-pyrazole-4-carboxamide reference was made to example 158.

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):395.2[M+H] ⁺ .

Example 161

(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

Preparation 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 reference example 154-1.

MS m/z(ESI):381.2[M+H] ⁺ .

Example 162

(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

Preparation 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 reference example 158.

MS m/z(ESI):452.2[M+H] ⁺ .

Example 163

(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

Preparation 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 reference example 158.

MS m/z(ESI):436.2[M+H] ⁺ .

Example 164

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

Preparation of (S) -3-methoxy-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-3-yl) pyridin-2-yl) -1- (1-methylazetidin-3-yl) -1H-pyrazole-4-carboxamide reference example 158.

MS m/z(ESI):408.2[M+H] ⁺ .

Example 165

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

Preparation 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 reference is made to example 158.

MS m/z(ESI):451.2[M+H] ⁺ .

Example 166

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

Preparation 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 reference is made to example 158.

MS m/z(ESI):451.2[M+H] ⁺ .

Example 167

(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

The method comprises the following steps: preparation 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 reference is made to example 154-1.

The method 2 comprises the following steps:

(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 (30mg,0.088mmol), 1-bromo-2-methylpropan-2-ol (27mg,0.18mmol), cesium carbonate (58mg,0.18mmol) and potassium iodide (15mg,0.088mmol) were mixed in DMF (1mL) at room temperature, warmed to 120 ℃ and stirred for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and subjected to normal-phase column chromatography to give (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 (8mg, 20%).

¹ H NMR(400MHz,CDCl ₃ )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)；

MS m/z(ESI):411.2[M+H] ⁺ .

Example 168

(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

Preparation 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 reference is made to example 154-1.

¹ H NMR(400MHz,CDCl ₃ )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)

MS m/z(ESI):405.2[M+H] ⁺ .

Example 169

(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

Preparation 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 reference is made to example 154-1.

MS m/z(ESI):405.2[M+H] ⁺ .

Example 170

(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

Preparation 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 reference is made to example 158.

MS m/z(ESI):409.2[M+H] ⁺ .

Example 171

(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

Preparation 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 reference is made to example 158.

MS m/z(ESI):435.2[M+H] ⁺ .

Example 172

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

Preparation 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 reference example 158.

MS m/z(ESI):409.2[M+H] ⁺ .

Example 173

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

Preparation 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 reference example 158.

MS m/z(ESI):409.2[M+H] ⁺ .

Example 174

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] octan-7-yl) -1H-pyrazole-4-carboxamide

Preparation 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] octan-7-yl) -1H-pyrazole-4-carboxamide reference is made to example 158.

MS m/z(ESI):449.2[M+H] ⁺ .

Example 175

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

Preparation 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 reference is made to example 158.

MS m/z(ESI):451.2[M+H] ⁺ .

Example 176

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

Preparation of 3-methoxy-N- (6- ((S) -5-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-3-yl) pyridin-2-yl) -1- (((S) -oxetan-2-yl) methyl) -1H-pyrazole-4-carboxamide reference example 158.

MS m/z(ESI):409.2[M+H] ⁺ .

Example 177

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

Preparation of 3-methoxy-N- (6- ((S) -5-methyl-6, 7-dihydro-5H-pyrrolo [1,2-a ] imidazol-3-yl) pyridin-2-yl) -1- (((R) -oxetan-2-yl) methyl) -1H-pyrazole-4-carboxamide reference example 158.

MS m/z(ESI):409.2[M+H] ⁺ .

Example 178

MS m/z(ESI):451.2[M+H] ⁺ .

Example 179

MS m/z(ESI):451.2[M+H] ⁺ .

Example 180

1- ((1R,3R,5S) -8-oxabicyclo [3.2.1] octan-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

Preparation of 1- ((1R,3R,5S) -8-oxabicyclo [3.2.1] octan-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 reference is made to example 158.

MS m/z(ESI):449.2[M+H] ⁺ .

Example 181

1- ((1R,3S,5S) -8-oxabicyclo [3.2.1] octan-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

Preparation of 1- ((1R,3S,5S) -8-oxabicyclo [3.2.1] octan-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 reference is made to example 158.

MS m/z(ESI):449.2[M+H] ⁺ .

Example 182

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

Preparation 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 reference is made to example 158.

MS m/z(ESI):418.2[M+H] ⁺ .

Example 183

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

Preparation 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 reference is made to example 158.

MS m/z(ESI):418.2[M+H] ⁺ .

Example 184

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

Preparation 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 reference example 158.

MS m/z(ESI):423.2[M+H] ⁺ .

Example 185

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

Preparation 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 reference is made to example 158.

MS m/z(ESI):423.2[M+H] ⁺ .

Biological test evaluation

The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.

Test example 1 determination of LRRK2 kinase inhibitory Activity of Compounds of the invention

1. Purpose of the experiment:

compounds of the invention were tested for their inhibitory activity against LRRK2 kinase.

2. Experimental reagents and instrumentation:

2.1 Experimental apparatus:

centrifuge (5810R) was purchased from Eppendorf corporation;

pipettes were purchased from Eppendorf or Rainin;

the microplate reader is purchased from BioTek company of America, and is a SynergyH1 full-function microplate reader.

2.2 Experimental reagents:

LRRK2(G2019S) was purchased from SignalChem, cat # L10-12 GG-05;

LRRK2, active (WT) available from SignalChem under Cat number L10-11G-05;

LRRKtide is available from SignalChem under item number L10-58;

ADP-Glo kit purchased from Promega, cat # V9102;

384 well plates were purchased from Perkin Elmer, cat # 6007299;

BSA was purchased from Sigma, cat # B2064-100 g;

Tris-HCl, cat # 15567027 from therofisher;

MgCl ₂ purchased from Sigma, cat # M1028-100 ml.

3. The experimental method comprises the following steps:

the experiment adopts an ADP-Glo kinase measuring method of Promega company, kinase LRRK2 carries out catalytic reaction in the presence of substrates LRRKtide and ATP, ATP generates ADP, and ADP is obtained by measuringDetermining the content of ADP in the reaction to characterize the activity of the kinase and obtaining the half inhibition concentration IC of the compound on the inhibition of the activity of LRRK2 WT/G2019S kinase ₅₀ . The specific experimental operations were as follows:

the kinase reaction was carried out in a white 384-well plate, and 2. mu.L of a reaction solution for kinase (40mmol/L Tris-HCl,10mmol/L MgCl) was added to each well ₂ And 0.1. mu.g/. mu.L BSA), then 2. mu.L of 0.1-2nM LRRK2 kinase solution diluted with the kinase reaction solution is added to each well, 4. mu.L of 0.1-2. mu.g/. mu.L substrate LRRKtide prepared with the kinase reaction solution is added to all wells, finally 2. mu.L of 10-100. mu.M ATP solution diluted with the reaction solution is added to start the reaction, after 60-120 minutes of room temperature reaction, 10. mu.L ADP-Glo reagent is added to each well for room temperature reaction for 30-60 minutes to remove the excess ATP in the reaction, 20. mu.L of kinase detection reagent is added to each well, and after 10-30 minutes of room temperature reaction in the dark, the chemiluminescence value is detected by a BioTek Synergy H1 microplate reader.

4. The experimental treatment method comprises the following steps:

percent inhibition data {% inhibition 100- [ (test compound value-negative control value) for wells treated with compound was calculated by plating positive control wells (vehicle control wells) and negative control wells (no kinase added) on the plate]V (positive control value-negative control value) × 100 }. IC was calculated using GraphPad prism to fit different concentrations and corresponding percent inhibition data to a 4-parameter nonlinear logistic formula ₅₀ The value is obtained.

5. The experimental results are as follows:

it was concluded from the above protocol that the compounds of the present invention showed approximately 0.1nM to 1000nM (IC) in the LRRK2 kinase activity assay ₅₀ ) The biological activity of (1). The specific experimental results are shown in table 1:

TABLE 1 LRRK2 kinase Activity of Compounds of the examples of the invention

6. And (4) experimental conclusion:

the data show that the compounds of the embodiment of the invention have stronger inhibitory activity on LRRK2 kinase.

Test example 2 determination of the inhibitory Activity of the Compounds of the present invention against ROCK1 and ROCK2 kinases

1. Purpose of the experiment:

the purpose of this test example was to test the inhibitory activity of compounds against ROCK1 and ROCK2 kinase.

2. Experimental reagents and instrumentation:

2.1 Experimental apparatus:

centrifuge (Avanti J-15R) was purchased from BECKMAN COULTRE;

biochemical incubator (SPX-100B-Z) purchased from Shanghai Boxun;

automatic micropore pipettor purchased (PRC384U) from BioTek;

envision microplate Reader (2104Multilabel Reader) from Perkin Elmer;

the ultrasonic nanoliter liquid handling system (Echo550) was purchased from Labcyte.

2.2 Experimental reagents:

ROCK1(Carna, cat # 01-109);

ROCK2(Carna, cat # 01-110);

FAM-labeled polypeptide (Peptide10) (Invitrogen, cat # XP 116583);

ATP (Sigma, cat # A7699-1G);

DMSO (Sigma, cat # D2650);

EDTA (Sigma, cat # E5134);

96-well plates (Corning, cat # 3365);

384 well plates (PE, cat # 6008289);

ADP-Glo kit (Promega, cat # v 9102/3);

staurosporine (Staurosporine) (selelck, cat # S1421);

Tris-HCl, Ph7.5(Sigma, cat # T2319-1L);

MgCl ₂ (Sigma, cat # M2670-500 g).

3. The experimental method comprises the following steps:

the experiment adopts ADP-Glo kinase measuring method of Promega company, kinases ROCK1 and ROCK2 carry out catalytic reaction under the condition that polypeptide marked by substrate FAM and ATP exist, ATP generates ADP, the activity of the kinase is represented by measuring the content of the ADP in the reaction, and the half inhibition concentration IC of the compound on the inhibition of ROCK1 and ROCK2 kinase activity is obtained ₅₀ . The specific experimental operations were as follows:

the kinase reaction was carried out in 384 well plates using 40mmol/L TrisHCl and 20mmol/L MgCl as the kinase reaction solution ₂ 0.1% BSA, and 1mM DTT. 50nL of compounds with different concentrations diluted by DMSO are added into each well, 2.5 muL of 2x ROCK1 or ROCK2 kinase solution diluted by kinase reaction solution is added into each well, 2.5 muL of a mixture of 2x substrate FAM labeled polypeptide and ATP prepared by the kinase reaction solution is added into all the wells, 5 muL of ADP-Glo reagent is added into each well after reaction for 60 minutes at room temperature to remove excessive ATP in the reaction at room temperature for 180 minutes, 10 muL of kinase detection reagent is added into each well, and chemiluminescence values are detected by an Envision microplate reader after reaction for 30 minutes at room temperature in a dark place.

4. The experimental treatment method comprises the following steps:

percent inhibition data {% inhibition 100- [ (test compound value-negative control value) for wells treated with compound was calculated by plating positive control wells (vehicle control wells) and negative control wells (no kinase added) on the plate]V (positive control value-negative control value) × 100 }. Calculating IC by 4-parameter fitting method of concentration and inhibition rate in XLFit ₅₀ The value is obtained.

5. The experimental results are as follows:

it was concluded from the above protocol that the compounds of the present invention showed approximately 0.1nM to 1000nM (IC) in ROCK1 and ROCK2 kinase activity assays ₅₀ ) The biological activity of (1). The specific experimental results are shown in tables 2 and 3:

TABLE 2 ROCK1 kinase Activity of the compounds of the examples of the present invention

TABLE 3 ROCK2 kinase Activity of the compounds of the examples of the present invention

6. And (4) experimental conclusion:

the data show that the compounds of the embodiment of the invention have stronger inhibitory activity on ROCK1 and ROCK2 kinase.

Test example 3 Effect of the Compounds of the invention on the level of LRRK2 phosphorylation in MC38 cells

1. Purpose of the experiment: the purpose of this test example was to test the inhibitory activity of compounds on the phosphorylation level of LRRK2 in MC38 cells.

2. Experimental reagents and instruments

2.1 Experimental instruments

Pipettes were purchased from Eppendorf or Rainin;

centrifuge is available from Eppendorf;

the tissue grinding instrument is purchased from Shanghai Jingxin experiment equipment science and technology department;

protein electrophoresis equipment was purchased from Biorad;

the semi-dry membrane converter was purchased from Biorad;

protein imaging System, model ChemiDoc, available from Biorad ^TM MP；

The dry thermostat was purchased from Hangzhou Australian Kangsheng instruments, Inc.

2.2 Experimental cells

MC38 cells were purchased from Biotech, Inc. of Jani, Guangzhou.

2.3 Experimental reagents

3. Experimental methods

Selecting MC38 cells with high expression of pLRRK2, culturing in 1640 culture medium containing 10% FBS until the fusion degree is about 80%, collecting MC38 cells, and preparing the cells into 1x10 ⁶ Cell suspension/mL, seeded in 24-well plates, 1mL per well. After the cells are cultured in the adherent mode overnight, compound solutions with different concentrations are added, the initial concentration of the compound is 1uM, 3 times of dilution is carried out, 6 doses are added, the mixture is placed at 37 ℃ and 5% CO ₂ After incubation in the incubator for 2 hours, the culture medium was removed, PBS was added and washed once, and 80. mu.L of protein lysate (NuPAGE) was added to each well of the cell plate ^TM LDS Sample Buffer(4×)，

Sample Reducing Agent (10 ×)) and prepared as a protein load. The protein loading solution was placed in a dry thermostat and incubated at 100 ℃ for 10 minutes to denature the protein. Gel electrophoresis is carried out on the denatured protein by 120V voltage, membrane transfer is carried out by a semi-dry membrane transfer instrument after the gel electrophoresis is finished, a PVDF membrane is blocked by a confining liquid for 1 hour, and is incubated at 4 ℃ for one-time overnight (Anti-LRRK2(phospho S935) antibody 1: 1000 dilution, Anti-LRRK2 antibody 1: 1000 dilution and GAPDH antibody 1:5000 dilution, and a secondary antibody is incubated for 1 hour at room temperature after washing by TBST (after the washing by TBST, the secondary antibody is incubated for 1 hour at room temperature) (the

680RD coat anti-Rabbit IgG (H + L)1:3000, the water-soluble organic acid is diluted by 3000 degrees,

800CW Goat anti-Mouse IgG (H + L)1:3000 dilution), washed with TBST, the membrane was placed on Bio rFluorescence imaging was performed in the ad imager at 680nm and 800nm channels.

4. The experimental treatment method comprises the following steps:

the inhibition ratio of each concentration was calculated using the gray value by performing gray analysis of the western blot band using ImageJ software. IC was calculated using GraphPad prism to fit different concentrations and corresponding percent inhibition data to a four parameter nonlinear logistic formula ₅₀ The value is obtained.

5. The experimental results are as follows:

the above protocol led to the cytological activity of the compounds of the invention in the MC38pLRRK2 assay, as shown in Table 4.

TABLE 4 cytological Activity of Compounds exemplified in the invention

6. And (4) experimental conclusion:

the data show that the compounds of the embodiment of the invention have stronger inhibitory activity on the phosphorylation level of LRRK2 in MC38 cells.

Test example 4 determination of mouse pharmacokinetics of the Compound of the present invention

1. The research purpose is as follows:

balb/c mice were used as test animals to study the plasma and brain pharmacokinetic behavior of the compounds of the invention orally administered at 5mg/kg dose in mice.

2. Test protocol

2.1 test drugs:

the compound is prepared by self.

2.2 test animals:

balb/c Mouse, male.

2.3 administration:

balb/c mice, male; p.o. after fasting overnight, the dose was 5mg/kg and the administration volume was 10 mL/kg.

2.4, preparing the medicine:

preparing oral administration medicines: 0.5% CMC-Na (1% Tween 80).

5g of hydroxyethyl cellulose (HEC, CMC-Na, viscosity: 800-1200Cps) is weighed, dissolved in 1000mL of purified water, 10g of Tween80 is added, and the mixture is mixed and stirred uniformly to obtain a clear solution.

The compound of the invention is weighed and added into a 4-mL glass bottle, 2.4mL of the solution is added, and ultrasonic treatment is carried out for 10 minutes to obtain a colorless clear solution with the concentration of 0.5 mg/mL.

2.5 sample collection:

laboratory animal CO ₂ After euthanasia, collecting heart blood and brain tissue 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h after administration, placing the blood in an EDTA-2K test tube, centrifuging at 6000rpm at 4 ℃ for 6min to separate blood plasma, washing the brain tissue with precooled PBS, wiping, weighing, and storing at-80 ℃; food was consumed 4h after dosing.

2.6 sample treatment:

1) adding 160uL acetonitrile into 40uL of the plasma sample for precipitation, mixing, centrifuging for 5-20 minutes at 3500 Xg, diluting brain tissue, homogenizing and centrifuging.

2) Taking 100uL of the treated supernatant solution for LC/MS/MS analysis to analyze the concentration of the compound to be detected.

2.7 liquid phase analysis

Liquid phase conditions: a Shimadzu LC-20AD pump;

mass Spectrometry conditions AB Sciex API 4000 Mass Spectroscopy;

a chromatographic column: phenomenex Gemiu 5um C1850 × 4.6 mm;

the mobile phase: the solution A is 0.1% formic acid water solution, and the solution B is acetonitrile;

flow rate: 0.8 mL/min;

elution time: 0-4.0 min, eluent as follows:

3. test results and analysis

The main pharmacokinetic parameters were calculated using WinNonlin 8.1, and the results of the mouse pharmacokinetic experiments are shown in table 5:

TABLE 5 mouse pharmacokinetic experiment results

4. And (4) test conclusion:

the mouse pharmacokinetic experiment results of the embodiment of the invention show that the compound of the embodiment of the invention has good intracerebral exposure.

Test example 5 Effect of the Compounds of the present invention on the phosphorylation level of mouse cerebral cortex LRRK2

1. Purpose of the experiment: the purpose of this test example was to test the effect of a single oral dose of the compound on the level of phosphorylation of mouse cerebral cortex LRRK 2.

2. Experimental reagents and instruments

2.1 Experimental instruments

Pipettes were purchased from Eppendorf or Rainin;

centrifuge is available from Eppendorf;

protein electrophoresis equipment was purchased from Biorad;

the semi-dry membrane converter was purchased from Biorad;

the microplate reader is purchased from Biotek corporation, and is of the Synergy H1 type;

protein imaging System, model ChemiDoc, available from Biorad ^TM MP；

2.2 Experimental reagents

3. Experimental methods

The compounds were formulated as suspension solutions using 0.5% CMC-Na (1% Tween 80) and administered at 10mL/kg volumes. Mice were given different doses of compound solutions (1, 10, 100mg/kg) by oral gavage and controlled with a drug-free unit (blank). Mice were euthanized 2 hours after dosing with excess carbon dioxide. Immediately after euthanasia, the mouse brains were dissected and cerebral cortex sections were removed, placed in EP tubes and frozen in dry ice. The phosphorylation level of LRRK2 Ser935 in cerebral cortex was analyzed by Western Blot method, 1mL of precooled tissue lysate (50mM Tris, 150mM NaCl, 1mM EDTA, 1.25% CHAPS, 1% Triton X-100, PhosSTOP, EDTA-free Protease Inhibitor) was added to each cortical tube, and after being ground in a steel ball using a tissue grinder, the ground mixture was incubated on ice for 30 minutes, and then centrifuged in a precooled centrifuge at 12000rpm for 20 minutes at 4 ℃. Taking the protein supernatant, quantifying by using a BCA kit, and then using 10x

Sample Reducing Agent、4xNuPAGE ^TM LDS Sample Buffer and 1x tissue lysate are prepared into protein Sample solution with the same concentration, and the protein Sample solution is put into a dry thermostat and incubated for 10 minutes at 100 ℃ to denature protein. Gel electrophoresis is carried out on the denatured protein by 120V voltage, membrane transfer is carried out by a semi-dry membrane transfer instrument after the gel electrophoresis is finished, a PVDF membrane is blocked by a confining liquid for 1 hour, a primary Anti-overnight (Anti-LRRK2(phospho S935) antibody 1: 1000 dilution, Anti-LRRK2 antibody 1: 1000 dilution and GAPDH antibody 1:5000 dilution) are incubated at 4 ℃, a secondary antibody is incubated for 1 hour at room temperature after washing by TBST (the secondary antibody is incubated for 1 hour at room temperature after washing by TBST), (the primary antibody is a peptide, a peptide and a peptide

680RD coat anti-Rabbit IgG (H + L)1: the diluted solution is diluted by 3000 degrees of concentration,

800CW Goat anti-Mouse IgG (H + L)1:3000 dilution), washed with TBST, and the membrane was fluorescence imaged in a Biorad imager at 680nm and 800nm channels.

4. Results of the experiment

5. Conclusion of the experiment

The compound can reduce the phosphorylation level of mouse cerebral cortex LRRK2 at 1mpk, and has good dose correlation, and the maximum inhibition degree is reached at 10 mpk.

Test example 6 study on ocular hypotensive effect of the compound of the present invention on New Zealand white rabbits

1. Purpose of the experiment:

the purpose of this experiment was to evaluate the ocular hypotensive effect of eye drop administration of the compound of the present invention on normal tension rabbits.

2. Experimental animals:

new Zealand white rabbits (Oryctolagus cuniculus), male 3-4 months old, 2.1-3.3 kg body weight, normal grade, 10/group.

3. Experimental apparatus and experimental reagent:

name (R)	Supplier/manufacturer	Model number
			Electronic balance	METLER TOLEDO	XP205
PH test paper	Sigma	010B164786
			Tonometer	icare	TonoVet
Micro-pipette	Aibende	Research

Name (R)	Supplier/manufacturer	Batch number
			Sulfobutyl-beta-cyclodextrin (SBE-beta-CD)	Kunshire Rick chemical materials Co Ltd	20210102
Sterilized water for injection	Suzhou Jiuzhuntang pharmacy Co., Ltd	2001030105
			Sodium chloride injection	Suzhou Jiuzhuntang pharmacy Co., Ltd	2006150110

The experimental method comprises the following steps:

experiment design: male new zealand white rabbits were randomly grouped by weight, 10 rabbits/group. Each group of animals was administered the vehicle or the compound of the present invention to the left eye and was administered by eye drop at 50. mu.L/eye for 1 time without administration to the right eye; intraocular pressure was measured 1 time per group of animals in both eyes before and 1,2,4, 6, 8, 10 hours after the administration. The experimental designs are shown in the following tables:

the administration route is as follows: the test sample is administrated by local eye drop; the eye drop administration is intended to be a clinical administration route.

The administration method comprises the following steps: a micropipette is used for sucking 50 mu L of solvent and the compound of the invention, and the liquid is dripped into the conjunctival sac, and the upper eyelid and the lower eyelid are slightly closed for several times.

Intraocular pressure measurement: the animals were fixed, the tonometer probe of the TonoVet tonometer was placed perpendicular to the eye, and the tonometer was measured at least 3 times until the tonometer of the animals was stabilized (fluctuation range ≤ 3mm Hg), and the mean value of the tonometers of the last three measurements was used as the final tonometer value.

4. Data collection and analysis:

for intraocular pressure data collected in this trial, the following statistical methods will be used:

unless otherwise indicated below, all reported numerical data (except data directly received and analyzed by proventis and/or LIMS) were calculated using Microsoft Excel software for group mean and standard deviation. The above-mentioned descriptive statistics will be made for the data collected at each time point/segment and further subdivision of the descriptive statistics will be decided according to the variables to be analyzed and the classification variables of the data (such as gender, measurement period, and other relevant variables), groups with an instance number less than 3 do not need to be statistically analyzed.

When the number of groups is greater than 2, analysis of homogeneity of variance between groups is carried out using the Levene's test method at a significance level of 0.05. Single-factor analysis of variance (ANOVA) was used if differences between groups were not significant (p > 0.05). If the differences were significant (p.ltoreq.0.05), pairwise comparisons between the different dose groups and the control group were made using the Dunnett's test method.

When the Leven's test method indicates a significant difference (p.ltoreq.0.05) and only positive values in the group, log conversion is performed. When the transformed data has significant differences in the analysis of variance and homogeneity (p is less than or equal to 0.05) or zero and/or negative numbers in the data, a nonparametric Kruskal-Wallis test is used for comparison between groups. When the Kruskal-Wallis test results in significant differences (p.ltoreq.0.05), pairwise comparisons between groups were performed using Dunnett's test on ranks.

When only 2 groups were compared, the Leven's test described above was used, but the two-sample T-test was used instead of ANOVA, the Wilcoxon rank-sum test instead of Kruskal-Wallis, and the Dunnett's test or the Dunnett's test on ranks test was not required.

At the 0.05 significance level, the intraocular pressure of the right and left eyes of all groups of animals was compared by paired t-test, and significance results (p ≦ 0.001, p ≦ 0.01, or p ≦ 0.05) were reported.

At the 0.05 significance level, pairwise comparisons between groups were performed by bilateral testing, with significance results reported as p ≦ 0.001, p ≦ 0.01, or p ≦ 0.05, p representing the observed probability.

5. The experimental results are as follows:

during this trial, the animals were first subjected to tonometric adaptation training prior to dosing, and no abnormal tonus was observed.

The experimental results are shown in tables 6 and 7 below:

TABLE 6 Effect of Compounds of the invention on intraocular pressure in the left eye of various groups of animals

Note: left eye intraocular pressure between groups was analyzed by bilateral T-test with p < 0.05, p < 0.01, p < 0.001, p Value (compare to Vehicle group).

The experimental result shows that the compound has a more remarkable intraocular pressure reducing effect.

TABLE 7 comparison of left and right eye pressure of each group of experimental animals

Table 7 comparison of left and right eyes of each group of experimental animals

Compared with the non-administration eye (right eye), the solvent control group has no statistical difference in intraocular pressure after administration for 1,2,4, 6, 8 and 10 hours by the left eye, which shows that the test system is reliable without interfering with the intraocular pressure test; and the duration of the ocular hypotensive effect of the compound of the invention is longer.

Claims

1. A compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

wherein:

ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

R ¹ each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;

or, any two R ¹ Linked to form a cycloalkyl group,Heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally being further substituted;

R ² each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, alkyl, deuterated alkoxy, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) ₂ ) _n1 NR _A1 R _B1 、-CR _A1 R _B1 (CH ₂ ) _n1 NR _C1 R _D1 、-(CH ₂ ) _n1 R _A1 、-CR _A1 R _B1 R _C1 、-(CH ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 C(O)OR _A1 、-(CH ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 SR _A1 、-(CH ₂ ) _n1 NR _A1 C(O)(CH ₂ ) _n2 R _B1 、-(CH ₂ ) _n1 NR _A1 C(O)OR _B1 、-(CH ₂ ) _n1 NR _A1 C(O)NR _B1 R _C1 or-NR _A1 (CH ₂ ) _n1 R _B1 Said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;

or, R ¹ And R ² (ii) linked to form a heterocyclyl, which heterocyclyl may optionally be further substituted;

R _A1 、R _B1 、R _C1 and R _D1 Each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted;

R ³ selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;

R ⁴ each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;

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

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

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

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

z is selected from 0, 1,2, 3 or 4.

2. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 1,

ring A is selected from C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl;

more preferably

Or, ring B is selected from C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl;

more preferably phenyl or 5-7 membered nitrogen containing heteroaryl;

further preferably phenyl, pyridyl or pyrazolyl;

or, R ¹ Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said amino, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl;

preferably hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyanoRadical, carboxyl, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl;

more preferably hydrogen, cyano, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-3 Alkyl radical, C _1-3 Hydroxyalkyl and C _1-3 Substituted with one or more substituents of alkoxy;

or, any two R ¹ Link formation C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl;

preferably C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl;

more preferably C _3-6 Cycloalkyl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy and C _1-3 Substituted with one or more substituents of haloalkoxy;

or, R ² Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Deuterated alkoxy, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, - (CH) ₂ ) _n1 NR _A1 R _B1 、-CR _A1 R _B1 (CH ₂ ) _n1 NR _C1 R _D1 、-(CH ₂ ) _n1 R _A1 、-CR _A1 R _B1 R _C1 、-(CH ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 C(O)OR _A1 、-(CH ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 SR _A1 、-(CH ₂ ) _n1 NR _A1 C(O)(CH ₂ ) _n2 R _B1 、-(CH ₂ ) _n1 NR _A1 C(O)OR _B1 、-(CH ₂ ) _n1 NR _A1 C(O)NR _B1 R _C1 or-NR _A1 (CH ₂ ) _n1 R _B1 Said amino group, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-to 10-membered heteroaryl, - (CH) ₂ ) _n1 NR _A2 R _B2 、-CR _A2 R _B2 (CH ₂ ) _n1 NR _C2 R _D2 、-(CH ₂ ) _n1 R _A2 、-CR _A2 R _B2 R _C2 、-(CH ₂ ) _n1 OR _A2 、-(CH ₂ ) _n1 C(O)OR _A2 、-(CH ₂ ) _n1 OR _A2 、-(CH ₂ ) _n1 SR _A2 、-(CH ₂ ) _n1 NR _A2 C(O)(CH ₂ ) _n2 R _B2 、-(CH ₂ ) _n1 NR _A2 C(O)OR _B2 、-(CH ₂ ) _n1 NR _A2 C(O)NR _B2 R _C2 and-NR _A2 (CH ₂ ) _n1 R _B2 Is substituted with one or more substituents of (1);

preferably hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Deuterated alkoxy, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-to 10-membered heteroaryl, - (CH) ₂ ) _n1 NR _A1 R _B1 、-CR _A1 R _B1 (CH ₂ ) _n1 NR _C1 R _D1 、-(CH ₂ ) _n1 R _A1 、-CR _A1 R _B1 R _C1 、-(CH ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 C(O)OR _A1 、-(CH ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 SR _A1 、-(CH ₂ ) _n1 NR _A1 C(O)(CH ₂ ) _n2 R _B1 、-(CH ₂ ) _n1 NR _A1 C(O)OR _B1 、-(CH ₂ ) _n1 NR _A1 C(O)NR _B1 R _C1 or-NR _A1 (CH ₂ ) _n1 R _B1 Said amino group, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl;

more preferably hydrogen, deuterium, halogen, amino group, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Deuterated alkoxy, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _3-6 Cycloalkyl or 5-6 membered nitrogen containing heteroaryl;

or, R ¹ And R ² Linked to form a 7-20 membered heterocyclic group, said 7-20 membered heterocyclic group being further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl;

R _A1 、R _B1 、R _C1 and R _D1 Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said amino, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl;

preferably hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl;

R _A2 、R _B2 、R _C2 and R _D2 Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said amino, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro,Hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl; and is

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

or, R ³ Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said amino, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl;

preferably hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl;

or, R ² And R ³ Linked to form a 3-12 membered heterocyclic group, said 3-12 membered heterocyclic group being further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl;

preferably 3-8 membered heterocyclyl, said 3-8 membered heterocyclyl being further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl;

more preferably 5-6 membered heterocyclyl;

or, R ⁴ Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said amino, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl;

preferably hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen,Amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl.

3. The compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 2, wherein the compound is further represented by formula (II-a) or formula (II-B):

when the compound is of the formula (II-A) and ring A is

When R is ¹ Is not hydrogen.

4. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 3, characterized in that ring a is selected from bicyclic heteroaryl or monocyclic heteroaryl; preferably a 5-membered heteroarylheterocyclo, 6-membered heteroarylheterocyclo or 5-membered monoheteroaryl; more preferably a 5-membered heteroarylo 5-membered heterocyclic group, a 5-membered heteroarylo 6-membered heterocyclic group, a 6-membered heteroarylo 5-membered heterocyclic group, a 6-membered heteroarylo 6-membered heterocyclic group, a 5-membered heteroaryl group containing 3 nitrogen atoms or a 5-membered heteroaryl group containing 4 nitrogen atoms;

further preferred are the following groups:

or, any two R ¹ Link formation C _3-6 Cycloalkyl, said C _3-6 Cycloalkyl is optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy and C _1-3 Substituted with one or more substituents of haloalkoxy;

R ² each independently selected from hydrogen, deuterium, halogen, amino, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Deuterated alkoxy, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _3-6 Cycloalkyl or 5-6 membered nitrogen-containing heteroaryl, said amino, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Deuterated alkoxy, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _3-6 Cycloalkyl and 5-6 membered nitrogen containing heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-3 Alkyl radical, C _1-3 Hydroxyalkyl and C _1-3 Substituted with one or more substituents of alkoxy;

or, R ¹ And R ² Linked to form a 10-20 membered heterocyclic group, said 10-20 membered heterocyclic group being further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl;

R ³ selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl;

or, R ² And R ³ Linked to form a 5-6 membered heterocyclyl;

R ⁴ each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl,C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said amino, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl; and is

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

5. The compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 2, wherein the compound is further represented by formula (II-C), formula (II-C-a), or formula (II-C-B):

wherein:

ring C is selected from 3-12 membered heterocyclyl or 5-14 membered heteroaryl;

preferably 3-8 membered heterocyclyl or 5-10 membered heteroaryl;

R ⁵ each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said amino, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl;

or, any two R ⁵ Link formation C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl; and is

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

when the compound is of the formula (II-C) and ring B is phenyl, R ² Is not imidazole or substituted imidazole; and when the compound is of the formula (II-C), ring B is

When R is ² Not pyridine or substituted pyridine.

6. The compound, a stereoisomer, or a pharmaceutically-acceptable salt thereof according to claim 5, wherein the compound is further represented by formula (III), formula (III-a), or formula (III-B):

wherein: n is selected from 0, 1,2, 3 or 4.

7. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 3,5, or 6, which is further represented by formula (IV):

wherein: m ₁ 、M ₂ Each independently is N or CH;

R ⁵ independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said amino, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-8 Alkyl radical, C _1-8 Deuterated alkyl, C _1-8 Haloalkyl, C _1-8 Hydroxyalkyl radical, C _1-8 Alkoxy radical, C _1-8 Haloalkoxy, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl;

preferably hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said ammoniaBase, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl.

8. The compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 7, wherein the compound is further represented by formula (IV-1), formula (IV-2), or formula (IV-3):

9. the compound, its stereoisomers, or its pharmaceutically acceptable salts according to any one of claims 5 to 8, wherein R is ² Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Deuterated alkoxy, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-to 10-membered heteroaryl, - (CH) ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 C(O)R _A1 、-(CH ₂ ) _n1 NR _A2 R _B2 Or- (CH) ₂ ) _n1 O(CH ₂ ) _n2 NR _B2 R _C2 The amino group, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Deuterated alkoxy, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C _1-6 Alkyl radical, C _1-6 Deuterated alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-to 10-membered heteroaryl, - (CH) ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 C(O)R _A1 、-(CH ₂ ) _n1 NR _A2 R _B2 、-(CH ₂ ) _n1 O(CH ₂ ) _n2 NR _B2 R _C2 Is substituted with one or more substituents of (1);

preferably, R ² Each independently selected from hydrogen, deuterium, halogen, amino, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Deuterated alkoxy, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _3-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-2 members selected from N or O, 5-6 membered heteroaryl group containing 1-2 members selected from N or O, - (CH) ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 C(O)R _A1 、-(CH ₂ ) _n1 NR _A2 R _B2 Or- (CH) ₂ ) _n1 O(CH ₂ ) _n2 NR _B2 R _C2 The amino group, C _1-3 Alkyl radical, C _1-3 Deuterated alkyl, C _1-3 Deuterated alkoxy, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy radical, C _1-3 Haloalkoxy, C _3-6 Cycloalkyl, 4-6 membered heterocyclyl containing 1-2 members selected from N or O and 5-6 membered heteroaryl containing 1-2 members selected from N or O, optionally further deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C _1-3 Alkyl radical, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy, - (CH) ₂ ) _n1 OR _A1 、-(CH ₂ ) _n1 C(O)R _A1 、-(CH ₂ ) _n1 NR _A2 R _B2 And- (CH) ₂ ) _n1 O(CH ₂ ) _n2 NR _B2 R _C2 Is substituted with one or more substituents of (a),

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

10. A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9, wherein the compound has the following specific structure:

11. a compound represented by the general formula (A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

wherein:

R ² as claimed in claim 9.

12. A process for preparing a compound of formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of:

wherein:

M ₁ 、M ₂ each independently is N or CH;

R ⁵ as claimed in claim 7;

X ₁ and R ₂ As claimed inThe method is obtained in 11.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

14. Use of a compound according to any one of claims 1 to 10, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, in the manufacture of a dual inhibitor medicament of an LRRK2 or ROCK inhibitor, or a combination thereof.

15. Use of a compound according to any one of claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for the treatment of neurological, cardiovascular, cancer, inflammation, autoimmune and metabolic disorders and related diseases; the nervous system disease is preferably parkinson's disease, glaucoma, alzheimer's disease or epilepsy.