CN117624191A

CN117624191A - Indazole carboxamide derivatives, preparation method and application thereof

Info

Publication number: CN117624191A
Application number: CN202311084135.6A
Authority: CN
Inventors: 应永铖; 李国春; 原晓辉; 余尚海; 顾厉明; 娄万乔
Original assignee: Xiyuan Anjian Medicine Shanghai Co ltd
Current assignee: Xiyuan Anjian Medicine Shanghai Co ltd
Priority date: 2022-08-30
Filing date: 2023-08-25
Publication date: 2024-03-01
Also published as: WO2024046223A1

Abstract

The application relates to a substituted indazole carboxamide derivative, a preparation method thereof and application of a pharmaceutical composition containing the derivative or deuterated derivative in medicine. In particular, the present application relates to substituted indazole carboxamide derivatives of general formula (I), a process for their preparation and pharmaceutically acceptable salts thereof, and their use as CGRP receptor antagonists in the prevention and/or treatment of CGRP related diseases, in particular in the migraine field. Wherein each substituent in the general formula (I) is defined as the specification.

Description

Indazole carboxamide derivatives, preparation method and application thereof

Technical Field

The present application relates to indazole carboxamide derivatives, a process for their preparation and pharmaceutical compositions containing them or deuterated derivatives, and their use as therapeutic agents, in particular as calcitonin gene-related peptide (CGRP) receptor antagonists.

Background

Migraine is a common trigeminal vascular headache, and pain may last from 4 to 72 hours, manifested as moderate or severe jumping pain on one or both sides of the head and recurrent episodes, or with nausea, vomiting, symptoms sensitive to light, sound, smell or touch, severely affecting the patient's life (Steiner TJ et al, J Neurol Neurosurg Psychiatry 2004, 75:808-811). The world health organization WHO has classified migraine as one of the ten most disabling diseases, and migraine sufferers are more likely to develop depression, anxiety, sleep disorders, other pain and fatigue than others. Migraine has been shown to affect 13 million patients worldwide, about 11% of adults, with three times as many female patients as male patients, about 4000 tens of thousands of patients in the united states, about 800 tens of thousands in japan, and 1300 tens of thousands in china. Medical costs and productivity losses caused by migraine headaches annually are estimated at $800 billion in the united states, which is a huge resource drain. The pathogenesis of migraine is not completely defined internationally, and is known as trigeminal vasoreflex theory, the pathogenesis of migraine is well explained by effectively combining nerves, blood vessels and neurotransmitters, and the pathogenesis of migraine is widely accepted.

Currently, migraine is clinically divided into symptomatic and prophylactic treatments, wherein the first-line therapy of symptomatic treatment is still using non-steroidal anti-inflammatory drugs, ergotamines or triptans, and even using opioid and other drug combinations for severe patients. Triptans are the first-line therapy of current migraine treatments, but some patients are not sensitive to this type and the therapeutic effect is not obvious, and in addition, the problems of the triptans have side effects that cause cardiovascular risks, which limit the use of the triptans. The common prescription for preventing and treating is antiepileptic drugs, tricyclic antidepressants and beta-receptor blockers, wherein only part of the drugs have the effect of preventing migraine. Since these preventive drugs are originally used for the treatment of other diseases, they are not specific for the prevention of migraine and have remarkable side effects, they are not preferable for the preventive treatment of migraine. It is conceivable that in the migraine field, there is still a need to search for drugs with better therapeutic effects.

Calcitonin gene-related peptide (CGRP) is a neuropeptide containing 37 amino acid residues found by Amara et al in 1982 and is widely found in the central and peripheral nervous systems, particularly the cell bodies and endings of sensory neurons (Amara SG et al, science 1982, 298:240-244). Peripheral CGRP is synthesized in the dorsal root ganglion, central CGRP is synthesized in the trigeminal ganglion, both in the sensory neuron cell body, and then rapidly transported to the central and peripheral end tips. The central terminal is used as sensory neuron afferent fiber and is mainly responsible for the conduction of pain and temperature sensation. In the periphery, CGRP-containing sensory nerve fibers are widely distributed in various tissues and organs and are released by means of axonal reflex due to various stimuli.

CGRP is currently the most powerful endogenous vasodilating substance and has become an important and hot spot of research in the area of pain, especially migraine. Several clinical studies demonstrated that in the onset of migraine, the level of CGRP in the plasma increased and that the intensity and duration of migraine was positively correlated with plasma CGRP levels (Han TH et al, arch Drug Inf 2010, 3:55-62). In addition Goadsby et al found an increase in CGRP content in the external jugular vein but no increase in the elbow vein upon migraine attacks, indicating intracranial release of CGRP upon migraine (Goadsby PJ et al, ann Neurol1990, 28:183-187). Animal studies have also found that CGRP released by trigeminal activation can cause brain and meningeal vasodilation, mast cell release inflammatory mediators, and nociceptive biological information of intracranial vascular release to the center (Williamson D et al, microsc Res Tech 2001, 53:167-178). Various studies have shown that migraine is closely related to abnormal release and elevated levels of CGRP.

The molecular weight of CGRP is about 3800Da, and consists of 2800 base pairs, in 37 amino acid sequences of the CGRP, the 2 nd and 7 th positions of the N end are connected by disulfide bonds, the C end is phenylalanine residue, and the two structures are necessary groups for the biological activity of the CGRP. Human CGRP is currently known in both the α -CGRP and the β -CGRP types, where α -CGRP is mainly expressed in the nervous system, such as in the hypothalamus, cerebellum, brainstem and trigeminal system, and β -CGRP is mainly expressed in the intestinal sensory system. alpha-CGRP is formed by splicing of the Calcitonin (CT) gene, whereas beta-CGRP is encoded by an isolated gene, which has similar biological effects in the circulatory system despite the three amino acids difference between the two forms of CGRP (Edvinsson L Expert Opinion on Therapeutic Targets 2007, 11:1179-1188).

CGRP receptors belong to the G protein-coupled receptor and consist of 7 transmembrane protein complexes (calcitonin receptor-like receptor calcitonin receptor like receptor, CLR), 1 transmembrane protein receptor activity modifying protein (receptor activity modifying protein, RAMP 1) and 1 intracellular protein (receptor component protein receptor component protein, RCP) (Evans BN et al, J Biology Chem 2000, 275:38-43). RAMP1 is a class of small molecule transmembrane proteins that mediate membrane translocation of CLR in the form of chaperones, and RCP is a class of small molecule polypeptides that mediate downstream signaling of CLR. At present, the mechanism of the CGRP involved in migraine is not clear, and most students consider that the CGRP is involved in the processes of neurogenic inflammation, peripheral and central sensitization and cortical spreading inhibition as multifunctional neuropeptides, thereby inducing the migraine.

As CGRP and its receptors have been increasingly studied, our knowledge has increased, and CGR was first isolated from 1983 to 2018, three CGRP monoclonal drugs were approved for the us market for 35 years. At present, four CGRP monoclonal antibodies are marketed, besides CGRP monoclonal antibodies, research and development of CGRP receptor antagonists are also of great concern, after all, small molecular compounds have obvious advantages in terms of the friendliness of the administration mode, and three small molecular CGRP receptor antagonists are marketed up to the present.

In the development of CGRP receptor antagonists, there has been surprise and frustration, taking Olcegepant, telcagepant, MK-3207 as an example, although several clinical trials have proven the effectiveness of these drugs, these compounds can only be paused due to serious adverse reactions such as hepatotoxicity, etc. in a plurality of patients in clinical applications. Fortunately, the FDA approved Ubrogepant for the treatment of acute migraine in 2019 by constantly optimizing the screen for more suitable compounds, which was developed by Abbvie company. Rimegepant developed by Biohaven was also successfully approved for the treatment of acute migraine and for 5 months 2021 for the extension of indications for prophylactic treatment of episodic migraine. Atogepant developed by Abbvie corporation was approved by the FDA for prophylactic treatment of episodic migraine at month 9 of 2021. The successful marketing of the three small molecule drugs brings hopes for migraine patients worldwide, but has side effects such as constipation, nausea, somnolence and the like, so the search for safer and more effective CGRP small molecule drugs is very necessary.

Disclosure of Invention

In view of the above technical problems, the present application provides a substituted indazole carboxamide derivative represented by general formula (I):

Wherein:

ring a is selected from heterocyclyl or cycloalkyl;

ring B is selected from heterocyclyl or cycloalkyl;

R ₁ selected from = O, heteroaryl or fused ring, said heteroaryl or fused ring optionally being further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, deuterated alkyl, alkoxy, cycloalkyl, = O;

alternatively, two R ₁ Together with the atoms to which they are attached form a 5-to 7-membered cycloalkyl or fused ring, said 5-to 7-membered cycloalkyl or fused ring being further substituted with one or more R _a Is substituted by a substituent of (2);

each R _a The same or different, each independently selected from = O, hydroxy, halo, nitro, cyano, alkyl, deuterated alkyl, alkoxy, cycloalkyl, haloalkyl, hydroxyalkyl, or aminoalkyl;

R ₂ selected from heterocyclyl or cycloalkyl, said heterocyclyl or cycloalkyl optionally being further substitutedSubstituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, deuterated alkyl, alkoxy, cycloalkyl, =o;

m is 1,2 or 3;

n is 1 or 2;

p is 0,1 or 2.

In a specific embodiment, ring A is a cyclopentylalkyl group,

ring B is selected from heterocyclyl or cycloalkyl;

R ₂ selected from heterocyclyl or cycloalkyl optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, deuterated alkyl, alkoxy, cycloalkyl, =o;

m is 1,2 or 3;

n is 1 or 2;

p is 0,1 or 2.

In a specific embodiment, ring B is piperazinyl,

ring a is selected from heterocyclyl or cycloalkyl;

m is 1,2 or 3;

n is 1 or 2;

p is 0,1 or 2.

In a specific embodiment, two R' s ₁ Together with the atoms to which they are attached form a 5-to 7-membered cycloalkyl or fused ring, said fused ring being pyrrolopyridine,

ring a is selected from heterocyclyl or cycloalkyl;

ring B is selected from heterocyclyl or cycloalkyl;

m is 1,2 or 3;

n is 1 or 2;

p is 0,1 or 2.

In a specific embodiment, R ₂ Is a piperidine which is used as a main component,

ring a is selected from heterocyclyl or cycloalkyl;

Ring B is selected from heterocyclyl or cycloalkyl;

R ₁ selected from =o, heteroaryl or fused ring, said heteroaryl or fused ring optionally being further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, deuteroalkaneSubstituents for group, alkoxy, cycloalkyl, =o;

m is 1,2 or 3;

n is 1 or 2;

p is 0,1 or 2.

In a specific embodiment, n is 1,

ring a is selected from heterocyclyl or cycloalkyl;

ring B is selected from heterocyclyl or cycloalkyl;

m is 1,2 or 3;

p is 0,1 or 2.

In a specific embodiment, m is 2 and ring a is selected from heterocyclyl or cycloalkyl;

ring B is selected from heterocyclyl or cycloalkyl;

n is 1 or 2;

p is 0,1 or 2.

In a preferred embodiment of the present application, there is provided a compound of formula (I) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, which is a compound of formula (II) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof:

wherein:

ring a is selected from heterocyclyl or cycloalkyl;

R ₁ selected from =o, heteroaryl or fused ring, said heteroaryl or fused ring optionally being further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, deuterated alkylAlkoxy, cycloalkyl, =o;

m is 1,2 or 3.

In a specific embodiment, two R' s ₁ Together with the atoms to which they are attached, form a 5-to 7-membered cycloalkyl or fused ring, said fused ring being pyrrolopyridine, ring A being selected from heterocyclyl or cycloalkyl; m is 1,2 or 3.

In a specific embodiment, R ₁ Selected from = O, heteroaryl or fused ring, said heteroaryl or fused ring optionally being further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, deuterated alkyl, alkoxy, cycloalkyl, = O;

each R _a The same or different, each independently selected from = O, hydroxy, halo, nitro, cyano, alkyl, deuterated alkyl, alkoxy, cycloalkyl, haloalkyl, hydroxyalkyl, or aminoalkyl; ring a is selected from heterocyclyl or cycloalkyl;

m is 2.

In a specific embodiment, two R' s ₁ Together with the atoms to which they are attached, form a 5-to 7-membered cycloalkyl or fused ring, said fused ring being pyrrolopyridine, ring A being selected from heterocyclyl or cycloalkyl; m is 2. Preferred embodiments of the present application provide a compound of formula (II) or a stereoisomer, tautomer, deuterated derivative or a combination thereof A pharmaceutically acceptable salt which is a compound of formula (III) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof:

wherein:

m is 1,2 or 3.

each R _a Identical or different, each independently selected from =o, hydroxyHalogen, nitro, cyano, alkyl, deuterated alkyl, alkoxy, cycloalkyl, haloalkyl, hydroxyalkyl or aminoalkyl;

ring a is selected from heterocyclyl or cycloalkyl; m is 2.

In a specific embodiment, two R' s ₁ Together with the atoms to which they are attached, form a 5-to 7-membered cycloalkyl or fused ring, said fused ring being pyrrolopyridine, ring A being selected from heterocyclyl or cycloalkyl; m is 2.

In a preferred embodiment of the present application, there is provided a compound of formula (III) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, which is a compound of formula (IV) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof:

wherein:

m is 1,2 or 3;

in a specific embodiment, two R' s ₁ Together with the atoms to which they are attached, form a 5-to 7-membered cycloalkyl or fused ring, said fused ring being pyrrolopyridine and m being 1,2 or 3.

In a specific embodimentWherein R is ₁ Selected from = O, heteroaryl or fused ring, said heteroaryl or fused ring optionally being further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, deuterated alkyl, alkoxy, cycloalkyl, = O;

each R _a The same or different are each independently selected from = O, hydroxy, halo, nitro, cyano, alkyl, deuterated alkyl, alkoxy, cycloalkyl, haloalkyl, hydroxyalkyl or aminoalkyl, m is 2.

In a specific embodiment, two R' s ₁ Together with the atoms to which they are attached, form a 5-to 7-membered cycloalkyl or fused ring, said fused ring being pyrrolopyridine and m being 2. In a preferred embodiment of the present application, there is provided a compound of formula (III) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, which is a compound of formula (V) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof:

wherein:

each R _a Identical or different, each independently selected from =o, hydroxy, halogenNitro, cyano, alkyl, deuterated alkyl, alkoxy, cycloalkyl, haloalkyl, hydroxyalkyl, or aminoalkyl;

m is 1,2 or 3;

In a specific embodiment, two R' s ₁ Together with the atoms to which they are attached, form a 5-to 7-membered cycloalkyl or fused ring, said fused ring being pyrrolopyridine and m being 2.

The present application provides a substituted indazole carboxamide derivative represented by general formula (I-a) or stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof:

Wherein:

ring a is selected from heterocyclyl;

R ₁ selected from = O, hydroxy, halo, nitro, cyano, alkyl, deuterated alkyl, alkoxy, cycloalkyl, haloalkyl, hydroxyalkyl, or aminoalkyl;

m is 0 or 1;

p is 0,1 or 2.

In a specific embodiment, ring A is pyrrolyl, R ₁ Selected from = O, hydroxy, halo, nitro, cyano, alkyl, deuterated alkyl, alkoxy, cycloalkyl, haloalkyl, hydroxyalkyl, or aminoalkyl;

m is 0 or 1;

p is 0,1 or 2.

In a specific embodiment, ring A is oxazinyl, R ₁ Selected from = O, hydroxy, halo, nitro, cyano, alkyl, deuterated alkyl, alkoxy, cycloalkyl, haloalkyl, hydroxyalkyl, or aminoalkyl;

m is 0 or 1;

p is 0,1 or 2.

In a specific embodiment, R ₁ Is =o, ring a is selected from heterocyclyl;

m is 0 or 1;

p is 0,1 or 2.

In a specific embodiment, R ₁ Is =o, ring a is selected from pyrrolyl;

m is 0 or 1;

p is 0,1 or 2.

In a specific embodiment, R ₁ Is =o, ring a is selected from oxazinyl;

m is 0 or 1;

p is 0,1 or 2.

In a specific embodiment, m is 1 and ring a is selected from heterocyclyl;

p is 0,1 or 2.

In a specific embodiment, m is 1 and ring a is selected from pyrrolyl;

R ₁ selected from =o, hydroxy, halogen, nitro, cyano, alkyl, deuterated alkyl, alkoxy, cycloalkyl, haloalkylA hydroxyalkyl or aminoalkyl group;

p is 0,1 or 2.

In a specific embodiment, m is 1 and ring a is selected from oxazinyl;

p is 0,1 or 2.

In a specific embodiment, p is 1 and ring a is selected from heterocyclyl;

m is 0 or 1.

In a specific embodiment, p is 1 and ring a is selected from pyrrolyl;

m is 0 or 1.

In a specific embodiment, p is 1 and ring a is selected from oxazinyl;

m is 1.

In a specific embodiment, p is 1 and ring a is selected from heterocyclyl;

m is 1.

In a specific embodiment, p is 1 and ring a is selected from pyrrolyl;

R ₁ selected from =o, hydroxy, halogen, nitro, cyano, alkyl, deuterated alkyl, alkoxy, cycloalkyl, haloalkyl, halogen,Hydroxyalkyl or aminoalkyl;

m is 1.

In a specific embodiment, p is 1 and ring a is selected from oxazinyl;

m is 1.

In a specific embodiment, p is 2 and ring a is selected from heterocyclyl;

m is 0 or 1.

In a specific embodiment, p is 2 and ring a is selected from pyrrolyl;

m is 0 or 1.

In a specific embodiment, p is 2 and ring a is selected from oxazinyl;

m is 1.

In a specific embodiment, p is 2 and ring a is selected from heterocyclyl;

m is 1.

In a specific embodiment, p is 2 and ring a is selected from pyrrolyl;

R ₁ selected from =o, hydroxy, halogen, nitro, cyano, alkyl, deuterated alkyl, alkoxy, cycloalkyl, haloalkyl, hydroxyalkyl, or ammoniaA arylalkyl group;

m is 1.

In a specific embodiment, p is 2 and ring a is selected from oxazinyl;

m is 1.

The present application provides a substituted indazole carboxamide derivative represented by general formula (I-B) or stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof:

wherein:

ring a is selected from heterocyclyl;

x is selected from C or N;

provided that when X is selected from C, ring A is selected from tetrahydropyridine and p is 2;

m is 0 or 1;

p is 0,1 or 2.

In a specific embodiment, X is C and ring A is selected from tetrahydropyridinyl and p is 2;

m is 0 or 1.

In a specific embodiment, X is N and ring A is selected from heterocyclyl;

m is 0 or 1;

p is 0,1 or 2.

In a specific embodiment, ring a is tetrahydropyridinyl;

x is selected from C or N;

provided that when X is selected from C, ring A is selected from tetrahydropyridinyl and p is 2;

m is 0 or 1.

In a specific embodiment, ring a is imidazolidinyl;

x is selected from N;

m is 0 or 1;

p is 0,1 or 2.

In a specific embodiment, ring a is tetrahydropyridinyl;

x is selected from C;

p is 2;

m is 0 or 1. In a specific embodiment, R ₁ Is =o; ring a is selected from heterocyclyl;

x is selected from C or N;

m is 0 or 1.

In a specific embodiment, R ₁ Is =o; ring a is selected from tetrahydropyridinyl;

x is selected from C or N;

m is 0 or 1;

p is 0,1 or 2.

In a specific embodiment, R ₁ Is =o; ring a is selected from imidazolidinyl;

x is selected from N;

m is 0 or 1;

p is 0,1 or 2.

In a specific embodiment, m is 1 and ring a is selected from heterocyclyl;

x is selected from C or N;

p is 0,1 or 2.

In a specific embodiment, m is 1 and ring a is selected from heterocyclyl;

x is selected from C or N;

p is 0,1 or 2.

In a specific embodiment, m is 1 and ring a is selected from tetrahydropyridinyl;

x is selected from C or N;

p is 0,1 or 2.

In a specific embodiment, m is 1 and ring a is selected from imidazolidinyl;

X is selected from N;

R ₁ selected from =o, hydroxy, halogen, nitro, cyano, alkyl, deuterated alkyl, alkoxy, cycloalkyl, haloalkyl, hydroxyAlkyl or aminoalkyl;

p is 0,1 or 2.

In a specific embodiment, m is 1 and ring a is selected from heterocyclyl;

x is selected from C or N;

R ₁ is =o;

p is 0,1 or 2.

In a specific embodiment, m is 1 and ring a is selected from heterocyclyl;

x is selected from C or N;

R ₁ is =o;

p is 0,1 or 2.

x is selected from C or N;

R ₁ is =o;

p is 0,1 or 2.

In a specific embodiment, m is 1 and ring a is selected from imidazolidinyl;

x is selected from N;

R ₁ is =o;

p is 0,1 or 2.

In a specific embodiment, p is 1 and ring a is selected from heterocyclyl;

x is selected from N;

m is 0 or 1.

In a specific embodiment, p is 1 and ring a is selected from heterocyclyl;

x is selected from N;

R ₁ selected from =o, hydroxy, halogen,Nitro, cyano, alkyl, deuterated alkyl, alkoxy, cycloalkyl, haloalkyl, hydroxyalkyl, or aminoalkyl;

m is 0 or 1.

In a specific embodiment, p is 1 and ring a is selected from tetrahydropyridinyl;

x is selected from N;

m is 0 or 1.

In a specific embodiment, p is 1 and ring a is selected from imidazolidinyl;

x is selected from N;

m is 0 or 1.

In a specific embodiment, p is 1 and ring a is selected from heterocyclyl;

x is selected from N;

R ₁ is =o;

m is 0 or 1.

In a specific embodiment, p is 1 and ring a is selected from heterocyclyl;

x is selected from N;

R ₁ is =o;

m is 0 or 1.

x is selected from N;

R ₁ is =o;

m is 0 or 1.

In a specific embodiment, p is 1 and ring a is selected from imidazolidinyl;

x is selected from N;

R ₁ is =o;

m is 0 or 1.

In a specific embodiment, p is 1 and ring a is selected from heterocyclyl;

x is selected from N;

m is 1.

In a specific embodiment, p is 1 and ring a is selected from heterocyclyl;

x is selected from N;

m is 1.

x is selected from N;

m is 1.

In a specific embodiment, p is 1 and ring a is selected from imidazolidinyl;

x is selected from N;

m is 1.

In a specific embodiment, p is 1 and ring a is selected from heterocyclyl;

x is selected from N;

R ₁ is =o;

m is 1.

In a specific embodiment, p is 1 and ring a is selected from heterocyclyl;

x is selected from N;

R ₁ is =o;

m is 1.

x is selected from N;

R ₁ is =o;

m is 1.

In a specific embodiment, p is 1 and ring a is selected from imidazolidinyl;

x is selected from N;

R ₁ is =o;

m is 1.

In a specific embodiment, p is 2 and ring a is selected from heterocyclyl;

x is selected from C or N; provided that when X is selected from C, ring A is selected from tetrahydropyridinyl;

m is 0 or 1.

In a specific embodiment, p is 2 and ring a is selected from heterocyclyl;

m is 0 or 1.

In a specific embodiment, p is 2 and ring a is selected from tetrahydropyridinyl;

m is 0 or 1.

In a specific embodiment, p is 2 and ring a is selected from imidazolidinyl;

x is selected from N;

R ₁ selected from =o, hydroxy, halogen, nitro, cyano, alkylDeuterated alkyl, alkoxy, cycloalkyl, haloalkyl, hydroxyalkyl or aminoalkyl;

m is 0 or 1.

In a specific embodiment, p is 2 and ring a is selected from heterocyclyl;

R ₁ is =o;

m is 0 or 1.

In a specific embodiment, p is 2 and ring a is selected from heterocyclyl;

R ₁ is =o;

m is 0 or 1.

R ₁ is =o;

m is 0 or 1.

In a specific embodiment, p is 2 and ring a is selected from imidazolidinyl;

X is selected from N;

R ₁ is =o;

m is 0 or 1.

In a specific embodiment, p is 2 and ring a is selected from heterocyclyl;

m is 1.

In a specific embodiment, p is 2 and ring a is selected from heterocyclyl;

m is 1.

In a specific embodiment, p is 2 and ring a is selected from imidazolidinyl;

x is selected from N;

m is 1.

In a specific embodiment, p is 2 and ring a is selected from heterocyclyl;

R ₁ is =o;

m is 1.

In a specific embodiment, p is 2 and ring a is selected from heterocyclyl;

R ₁ is =o;

m is 1.

R ₁ is =o;

m is 1.

In a specific embodiment, p is 2 and ring a is selected from imidazolidinyl;

x is selected from N;

R ₁ is =o;

m is 1.

In a preferred embodiment of the present application, the compound of formula (I) is selected from:

/>

or a stereoisomer, tautomer, deuterated derivative thereof or a pharmaceutically acceptable salt thereof.

Note that: if there is a difference between the drawn structure and the name given to the structure, the drawn structure will be given greater weight.

Still further, the present application provides a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), (III), (IV), (V), (I-a) or (I-B), or a stereoisomer, tautomer, deuterated derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.

The application provides an application of a compound shown in a general formula (I), (II), (III), (IV), (V), (I-A) or (I-B) or a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a CGRP receptor antagonist.

The application also provides application of the compound shown in the general formula (I), (II), (III), (IV), (V), (I-A) or (I-B) or stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicines for preventing and/or treating diseases mediated by CGRP, wherein the diseases mediated by CGRP are preferably cerebrovascular diseases or vascular disorders; wherein the CGRP-mediated cerebrovascular or vascular disorders are selected from the group consisting of episodic migraine, non-premonitory migraine, chronic migraine, pure menstrual migraine, menstrual-related migraine, premonitory migraine, childhood/adolescent migraine, hemiplegic migraine, sporadic hemiplegic migraine, basal migraine, periodic vomiting, abdominal migraine, childhood benign paroxysmal vertigo, retinal migraine, cluster headache, dialysis headache, chronic headache of unknown cause, tension/pressure-induced headache, allergy-induced headache, osteoarthritis and associated osteoporotic fracture pain, hot flashes associated with menopause or with medical induced menopause caused by surgery or drug therapy, periodic vomiting syndrome, opioid withdrawal, psoriasis, asthma, obesity morphine tolerance, neurodegenerative diseases, epilepsy, allergic rhinitis, rosacea, toothache, ear pain, otitis media, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, gout, trigeminal neuralgia, nasal polyp, chronic sinusitis, temporomandibular syndrome, back pain, lower back pain, cough, dystonia pain, inflammatory pain, post-operative incision pain, sciatica, complex regional pain syndrome, behcet's disease, endometriosis, phantom limb syndrome, dysmenorrhea, pain associated with labor, pain caused by skin burns, or inflammatory bowel disease (including crohn's disease, ileitis and ulcerative colitis), gastroesophageal reflux disease, dyspepsia, irritable bowel syndrome, renal colic, cystitis, pain in the postoperative incision, sciatica, complex regional pain syndrome, behcet's disease, endometriosis, phantom limb syndrome, dysmenorrhea, pain associated with labor, pain caused by skin burns, or inflammatory bowel disease (including crohn's disease, ileitis and ulcerative colitis), chronic secondary visceral pain such as pancreatitis and prostatitis. The application further provides application of the compound shown in the general formula (I), (II), (III), (IV), (V), (I-A) or (I-B) or stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof or pharmaceutical composition thereof in preparing medicaments for preventing and/or treating cerebrovascular or vascular disorder diseases.

The present application provides a compound of formula (I), (II), (III), (IV), (V), (I-A) or (I-B) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, or pharmaceutical compositions thereof for the preparation of a medicament for the prophylaxis and/or treatment of narcolepsy, migraine without aura, chronic migraine, pure menstrual migraine, menstrual-related migraine, migraine with aura, childhood/adolescent migraine, hemiplegic migraine, sporadic hemiplegic migraine, basal migraine, periodic vomiting, abdominal migraine, benign paroxysmal vertigo in childhood, retinal migraine, cluster headache, dialysis headache, chronic headache of unknown origin, tension/pressure-induced headache, allergy-induced headache, osteoarthritis and related osteoporotic fracture pain, hectic fever associated with menopause or medical induced menopause caused by surgery or drug therapy periodic vomiting syndrome, opioid withdrawal, psoriasis, asthma, obesity, morphine tolerance, neurodegenerative diseases, epilepsy, allergic rhinitis, rosacea, dental pain, ear pain, otitis media, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, pain associated with rheumatoid arthritis, pain associated with pain associated pain diabetic neuropathy, gout, trigeminal neuralgia, nasal polyp, chronic sinusitis, temporomandibular syndrome, back pain, lower back pain, cough, dystonia pain, inflammatory pain, post-operative incision pain, sciatica, complex regional pain syndrome, behcet's disease, endometriosis, pain in the body of the patient, and pain in the body of the patient, use of a medicament for treating chronic secondary visceral pain such as phantom limb syndrome, dysmenorrhea, pain associated with labor, pain caused by skin burns, or inflammatory bowel disease (including crohn's disease, ileitis and ulcerative colitis), gastroesophageal reflux disease, dyspepsia, irritable bowel syndrome, renal colic, cystitis, pancreatitis and prostatitis.

The compounds of the present application are optionally in the form of individual optical isomers, individual enantiomers or mixtures of racemates, in the form of tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.

The compounds of the present application may exist as tautomers. All tautomeric forms of the compounds of the present application are contemplated to be within the scope of the present application.

Detailed description of the invention

Unless stated to the contrary, some of the terms used in the specification and claims of this application are defined as follows:

"alkyl" when taken as a group or part of a group is meant to include C ₁ -C ₂₀ Straight chain or branched aliphatic hydrocarbon groups. Preferably C ₁ -C ₁₀ Alkyl, more preferably C ₁ -C ₆ An alkyl group. Examples of alkyl groups include, but are not limited to, 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.

"cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocycles. Preferably C ₃ -C ₁₂ Cycloalkyl, more preferably C ₃ -C ₈ Cycloalkyl, most preferably C ₅ -C ₇ Cycloalkyl groups. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred. Cycloalkyl groups may be optionally substituted or unsubstituted.

"heterocyclyl", "heterocycloalkyl", "heterocycle" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more of the ring-forming atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, and the like, and include monocyclic, polycyclic, fused, bridged and spiro rings. Preferably having a 5 to 7 membered single ring or a 7 to 10 membered double or triple ring, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulphur. Examples of "heterocyclyl" include, but are not limited to, oxazinyl, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyridinyl, tetrahydrofuranyl, tetrahydropyranyl, 1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, imidazolidinyl, 2-oxo-imidazolidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl, piperazinyl, hexahydropyrimidine. The heterocyclic group may be substituted or unsubstituted.

"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 8-to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1, 2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl. Heteroaryl groups may be substituted or unsubstituted.

"fused ring" refers to a polycyclic group wherein two or more cyclic structures share a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but at least one of the rings does not have a fully conjugated pi-electron aromatic system, while at least one of the rings has a fully conjugated pi-electron aromatic system, wherein 0, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, or S, and the remaining ring atoms are carbon. The fused ring preferably includes a double-or triple-ring fused ring, wherein the double-ring fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably 7 to 14 membered, more preferably 8 to 10 membered. Examples of "fused rings" include, but are not limited to:

"alkoxy" refers to a group of (alkyl-O-). Wherein, the alkaneSee the relevant definitions herein. C (C) ₁ -C ₆ Is preferably selected. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.

"hydroxy" refers to an-OH group.

"halogen" refers to fluorine, chlorine, bromine and iodine.

"amino" means-NH ₂ 。

"cyano" refers to-CN.

"nitro" means-NO ₂ 。

"carboxy" means-C (O) OH.

"DMSO" refers to dimethyl sulfoxide.

"BOC" refers to t-butoxycarbonyl.

"TFA" refers to trifluoroacetic acid.

"PMB" refers to p-methoxybenzyl.

"SEM" refers to (trimethylsilyl) ethoxymethyl.

"hydroxyalkyl" refers to hydroxy-substituted alkyl.

"haloalkyl" refers to a halogen substituted alkyl.

"aminoalkyl" refers to an amino-substituted alkyl group.

"substituted" means that one or more hydrogen atoms, 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 substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

"substituted" or "substituted" as used herein, unless otherwise indicated, means that the group may be substituted with one or more groups selected from the group consisting of: alkyl, alkoxy, alkylthio, alkylamino, halogen, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl.

"deuterated" means that at least one hydrogen ("H") is replaced by deuterium ("D").

"deuterated alkyl" refers to an alkyl in which at least one hydrogen ("H") is replaced by deuterium ("D").

"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain the original biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds represented by the general formula (I) may be metal salts, amine salts with suitable acids.

It will be appreciated by those skilled in the art that salts of the compounds of formula (I), (II), (III), (IV), (V), (I-A) or (I-B), including pharmaceutically acceptable salts, may be prepared. These salts can be prepared in situ during the final isolation and purification of the compound or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.

Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids, for example, acetates, aspartates, benzoates, benzenesulfonates, bromides/hydrobromides, bicarbonates, bisulphates/sulphates, camphorsulfonates, chlorides/hydrochlorides, citrates, ethanedisulfonates, fumarates, glucoheptonates, gluconates, glucuronates, hippurates, hydroiodides, isethionates, lactates, lactobionates, lauryl sulfates, malates, maleates, malonates, mandelates, methanesulfonates, methylsulfates, naphthoates, naphthalenesulfonates, nicotinates, nitrates, stearates, oleates, oxalates, palmitoates, pamonates, phosphates/hydrogen phosphates/dihydrogen phosphates, polygalacturonates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.

Inorganic acids that can form salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts may be formed include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts may be formed with inorganic or organic bases.

Inorganic bases that may form salts include, for example, ammonium salts and metals of groups I to XII of the periodic Table of the elements. In certain embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases that can form salts include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include isopropylamine, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

Pharmaceutically acceptable salts of the present application can be synthesized from basic or acidic moieties by conventional chemical methods. In general, these salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (Na, ca, mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. These reactions are generally carried out in water or in an organic solvent, or in a mixture of both. Typically, a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is required where appropriate. Other suitable salts are listed in "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and Stahl and weruth, "Handbook of Pharmaceutical Salts: properties, selection, and Use "(Wiley-VCH, weinheim, germany, 2002).

"deuterated derivative" refers to a compound that contains deuterium bound to carbon in at least one position and has a deuterium content attached to carbon that exceeds its natural content.

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically acceptable salt or prodrug thereof, and other chemical components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

The pharmaceutical compositions according to the present application can be formulated for specific routes of administration, such as oral administration, parenteral administration, rectal administration, and the like. Furthermore, the pharmaceutical compositions of the present application can be made in solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories) or in liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical procedures (e.g., sterilization) and/or can contain conventional inert diluents, lubricants or buffers and adjuvants such as preserving agents, stabilizing agents, wetting agents, emulsifying agents, buffering agents and the like.

Typically, the pharmaceutical composition is a tablet or capsule comprising the active ingredient and

a) Diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine and the like;

b) Lubricants, for example, silica, talc, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; for tablets also contain

c) Binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired, and also

d) Disintegrants, for example starch, agar, alginic acid or a sodium salt thereof, or effervescent mixtures; and/or

e) Absorbents, colorants, flavors, and sweeteners.

The tablets may be film coated or enteric coated according to methods known in the art.

Suitable compositions for oral administration include an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the form of a tablet, lozenge, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule, or syrup or elixir. Compositions for oral use are prepared according to any method known in the art for preparing pharmaceutical compositions and can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a finished and palatable preparation. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate); granulating and disintegrating agents (e.g., corn starch, or alginic acid); binding agents (e.g. starch, gelatin or acacia); and a lubricant (e.g., magnesium stearate, stearic acid, or talc). The tablets are uncoated or they are coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented in hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Some injectable compositions are isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, dissolution enhancing agents, salts for regulating the osmotic pressure and/or buffers. In addition, it may contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75% or contain about 1-50% of the active ingredient.

Since water may promote degradation of certain compounds, the present application also provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present application as active ingredients.

Anhydrous pharmaceutical compositions and dosage forms of the present application can be prepared using anhydrous or low water content ingredients and low water content or low humidity conditions. Anhydrous pharmaceutical compositions can be prepared and stored in order to maintain their anhydrous nature. Thus, anhydrous compositions are packaged using materials known to prevent contact with water so that they can be contained in a suitable formulation kit. Examples of suitable packages include, without limitation, airtight foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

The present application further provides pharmaceutical compositions and dosage forms comprising 1 or more agents that reduce the rate of decomposition of the compounds of the present application as active ingredients. The agent (which is referred to herein as a "stabilizer") includes, without limitation, an antioxidant (e.g., ascorbic acid), a pH buffer, or a salt buffer, and the like.

For an individual of about 50-70kg, the pharmaceutical composition or combination product of the present application can be a unit dose of about 1-1000mg of the active ingredient, or about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg, or about 1-50mg of the active ingredient. The therapeutically effective dose of a compound, pharmaceutical composition or combination thereof will depend on the species, weight, age and condition of the individual, the condition or disease it is being treated for, or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients required to prevent, treat or inhibit the development of the condition or disorder.

"stereoisomers" of a compound having a given stereochemical configuration refers to the opposite enantiomer of the compound and to any diastereomer that includes the geometric isomer (Z/E) of the compound. For example, if a compound has an S, R, Z stereochemical configuration, then its stereoisomers would include its opposite enantiomer having an R, S, Z configuration, as well as its diastereomers having an S, Z configuration, R, Z configuration, S, R, E configuration, R, S, E configuration, S, E configuration, and R, E configuration. If the stereochemical configuration of a compound is not specified, "stereoisomer" refers to any of the possible stereochemical configurations of the compound.

The compounds of formula (I), (II), (III), (IV), (V), (I-A) or (I-B), stereoisomers thereof, or tautomers of the compounds of formula (I), (II), (III), (IV), (V), (I-A) or (I-B) or complexes of stereoisomers thereof may be administered alone or in combination with one or more pharmaceutically active compounds. Generally, one or more of these compounds is administered in the form of a pharmaceutical composition (formulation) in combination with one or more pharmaceutically acceptable excipients. The choice of excipient will depend on the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form, among other things. Useful pharmaceutical compositions and methods for their preparation can be found, for example, in a.r.gennaro (editions), ramington: pharmaceutical science and practice (20 th edition, 2000)

The compounds of the present application may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present application, including but not limited to diastereomers, enantiomers and atropisomers (attopiomers) and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present application.

Unless otherwise indicated, structures described herein also include all stereoisomers (e.g., diastereomers, enantiomers and atropisomers and geometric (conformational) isomeric forms of such structures, e.g., R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.

The term "stereoisomer" refers to an isomer produced by the spatial arrangement of atoms in a molecule, and can be classified into cis-trans isomers, enantiomers, and enantiomers. Stereoisomers belong to one of the isomers. Isomers that occur as a result of the same order of connection of atoms or groups of atoms in a molecule, but different spatial arrangements are called stereoisomers.

The term "substantially enantiomerically pure" refers to an enantiomeric purity of greater than 90% for a given stereocenter. Thus, the term "substantially enantiomerically pure" means greater than 80% ee (enantiomeric excess). For compounds that exist as stereoisomers, such stereoisomers may be substantially enantiomerically pure at the stereocenter, or preferably may have an enantiomeric purity of greater than 97%, or more preferably have an enantiomeric purity of greater than 99%.

Synthesis method of compound of the application

In order to complete the purpose of the application, the application adopts the following technical scheme:

the present application provides a process for the preparation of a compound of formula (I) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, said process comprising:

the method comprises the following steps:

carrying out nucleophilic substitution reaction on the compound shown in the general formula (Ia) and the N, N' -disuccinimidyl carbonate and the compound shown in the general formula (Ib) under alkaline conditions to obtain a compound shown in the formula (I);

wherein:

ring a, ring B, R ₁ 、R ₂ The definitions of p, m and n are as described in the general formula (I).

The second method is as follows:

carrying out nucleophilic substitution reaction on the compound shown in the general formula (Ic) and the compound shown in the general formula (Id) under alkaline conditions to obtain a compound shown in the formula (I-A);

wherein:

ring A, R ₁ The definition of m and p is as described in the general formula (I-A).

And a third method:

carrying out nucleophilic substitution reaction on the compound shown in the general formula (Ic) and the N, N' -disuccinimidyl carbonate and the compound shown in the general formula (Ie) under alkaline conditions to obtain a compound shown in the formula (I-B);

wherein:

ring A, R ₁ The definitions of X, m and p are as described in the general formula (I-B).

Detailed Description

The following examples are used to further describe the present application, but they are not intended to limit the scope of the present application.

Examples

The preparation of representative compounds represented by formula (I) and related structural identification data are presented in the examples. It must be noted that the following examples are given by way of illustration and not by way of limitation. ¹ The H NMR spectrum was determined with a Bruker instrument (400 MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. ¹ H NMR representation method: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.

The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm.

Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.

In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and, unless otherwise indicated, various starting materials and reagents are either commercially available or synthesized according to known methods, all of which are used without further purification and, unless otherwise indicated, commercially available manufacturers include, but are not limited to, aldrich Chemical Company, ABCR GmbH & co.kg, acros Organics, praise chemical technology limited, and vision chemical technology limited, etc.

CD ₃ OD: deuterated methanol.

CDCl ₃ : deuterated chloroform.

DMSO-d ₆ : deuterated dimethyl sulfoxide.

D ₂ O: heavy water.

The argon atmosphere means that the reaction flask is connected to an argon balloon of about 1L volume.

The examples are not particularly described, and the solution in the reaction is an aqueous solution.

Purifying the compound using a C18 reverse phase column or semi-preparative purification, a silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from the group consisting of: a: petroleum ether and tetrahydrofuran systems; b: acetonitrile and water systems; c: petroleum ether and ethyl acetate systems; d: methylene chloride and methanol systems; the volume ratio of the solvent is different according to the polarity of the compound, and can be adjusted by adding a small amount of acidic or alkaline reagent, such as trifluoroacetic acid, acetic acid or triethylamine.

Example 1

(R) -N- (3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) -2 '-oxo-1', 2 '-dihydrospiro [ piperidine-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxamide

First step

1-benzyl-5-bromo-7-methyl-1H-indazole

5-bromo-7-methyl-1H-indazole 1a (10 g,47.38 mmol) was added to tetrahydrofuran (50 mL), potassium t-butoxide (26.58 g,236.90 mmol) was added at zero degrees Celsius, stirring was maintained for 1 hour, then bromobenzyl (24.31 g,142.14 mmol) was added, heating to 75 degrees Celsius, stirring was continued for 16 hours, after the reaction was completed, vacuum concentration was performed, and the obtained residue was purified by column chromatography (eluent: A system) to give 1-benzyl-5-bromo-7-methyl-1H-indazole 1b (8.2 g), yield: 48.27%. MS m/z (ESI): 301.1[ M+1]

Second step

(R) -3- (1-benzyl-7-methyl-1H-indazol-5-yl) -2- ((tert-butoxycarbonyl) amino) propanoic acid methyl ester

1-benzyl-5-bromo-7-methyl-1H-indazole 1b (1 g,3.32 mmol) and methyl (S) -2- ((tert-butoxycarbonyl) amino) -3-iodopropionate 1c (6.56 g,19.92mmol, prepared according to the method described in patent application WO 2020074926) were dissolved in N, N-dimethylacetamide (11 mL), reduced to zero degrees Celsius, nickel dimethoxyethane (72.95 mg,332.03 μmol), manganese (912.04 mg,16.60 mmol) and 2-amidinopyridine hydrochloride (36.63 mg,232.42 μmol) were added, stirred at 40℃for 18 hours, ethyl acetate (100 mL) and water (30 mL) were added, the organic phases were combined, and the resulting residue was purified by column chromatography (eluent: A system) to give methyl (R) -3- (1-benzyl-7-methyl-1H-indazol-5-yl) -2) amino propionate- ((methyl) in 1.4 g) yield (1 g): 100% of the reaction mixture was directly subjected to the next reaction without purification.

MS m/z(ESI):424.3[M+1]

Third step

(R) -3- (7-methyl-1H-indazol-5-yl) -2- ((tert-butoxycarbonyl) amino) propanoic acid methyl ester

Methyl (R) -3- (1-benzyl-7-methyl-1H-indazol-5-yl) -2- ((tert-butoxycarbonyl) amino) propionate 1d (1.6 g,3.78 mmol) was added to methanol (5 mL) under nitrogen, 10% palladium on charcoal (48.00 g,39.52 mmol) and formic acid (3.63 g,75.56 mmol) were further added, heated to 75deg.C, stirred for 16 hours, after completion of the reaction, filtered, and the filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography (eluent: A system) to give methyl (R) -3- (7-methyl-1H-indazol-5-yl) -2- ((tert-butoxycarbonyl) amino) propionate 1e (937 mg), yield: 70.40%.

MS m/z(ESI):334.2[M+1]

Fourth step

(R) -3- (7-methyl-1H-indazol-5-yl) -2- ((tert-butoxycarbonyl) amino) propanoic acid

Methyl (R) -3- (7-methyl-1H-indazol-5-yl) -2- ((tert-butoxycarbonyl) amino) propionate 1e (1.23 g,3.69 mmol) was dissolved in 21.2mL of the mixed solution (tetrahydrofuran: methanol: water=2:1:1), lithium hydroxide (265.09 mg,11.07 mmol) was added, stirred at 25℃for 2 hours, after the reaction was completed, ethyl acetate (20 mL) and water (30 mL) were added, the pH of the aqueous layer was adjusted to 2 with dilute hydrochloric acid, extracted with ethyl acetate (40 mL. Times.3), the organic phases were combined, and concentrated under reduced pressure to give (R) -3- (7-methyl-1H-indazol-5-yl) -2- ((tert-butoxycarbonyl) amino) propionic acid 1f (883 mg), yield: 68.95%.

MS m/z(ESI):320.0[M+1]

Fifth step (R) - (3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) carbamic acid tert-butyl ester

(R) -3- (7-methyl-1H-indazol-5-yl) -2- ((tert-butoxycarbonyl) amino) propionic acid 1f (530 mg,1.66 mmol), 1- (1-methylpiperidin-4-yl) piperazine 1g (395.45 mg,2.16 mmol) N, N-diisopropylethylamine (857.96 mg,6.64 mmol) was dissolved in N, N-dimethylformamide (12 mL), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (945.97 mg,2.49 mmol) was added, stirred at 20℃for 18 hours, after the end of the reaction, the resulting residue was purified by column chromatography (eluent: D system) to give tert-butyl (R) - (3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) carbamate (mg), yield: 89.99%. MS m/z (ESI): 485.1[ M+1]

Sixth step

(R) -2-amino-3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) propan-1-one

Tert-butyl (R) - (3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) carbamate 1H (750 mg,1.55 mmol) was dissolved in 4M dioxane hydrochloride solution (11 mL), stirred at 25℃for 30 min, after the reaction was completed, concentrated under reduced pressure to give (R) -2-amino-3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) propan-1-one 1i (903 mg), yield: 93.52%, without purification, the next reaction was directly carried out.

MS m/z(ESI):385.4[M+1]

Seventh step

(R) -2-amino-3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) propan-1-one 1i (80 mg, 150.84. Mu. Mol) and triethylamine (152.63 mg,1.51 mmol) were dissolved in N, N-dimethylformamide (2.5 mL), N '-disuccinimidyl carbonate (50.23 mg, 196.09. Mu. Mol) was added and stirred at 25℃for 4 hours, spiro [ piperidin-4, 4' -pyrido [2,3-d ] [1,3] oxazin ] -2 '(1' H) -one 1j (30.86 mg, 120.67. Mu. Mol) was added, and after completion of the reaction, the reaction was stirred at 25℃for 18 hours, the resulting residue was concentrated under reduced pressure and the resulting residue was subjected to C18 reverse phase column preparation to separate (eluent: B system) to give (R) -N- (3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) -2 '-oxo-1', 2 '-dihydrospiro [ piperidine-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxamide 1 (28.6 mg), yield: 29.51%.

MS m/z(ESI):630.5[M+1]

¹ HNMR(400MHz,DMSO-d ₆ )δ13.02(s,1H),10.81(s,1H),8.19(dd,J＝4.8,1.6Hz,1H),7.96(d,J＝6.6Hz,1H),7.48(dd,J＝7.6,1.6Hz,1H),7.38(s,1H),7.05(dd,J＝7.6,4.8Hz,1H),7.01(s,1H),6.83(d,J＝8.0Hz,1H),4.81(q,J＝4.0Hz,1H),3.99(d,J＝14.4Hz,2H),3.59-3.56(m,1H),3.27-3.22(m,1H),3.13-2.86(m,5H),2.76-2.73(m,2H),2.47(s,3H),2.36-2.21(m,2H),2.13(s,3H),1.97-1.75(m,9H),1.55-1.50(m,1H),1.41-1.37(m,2H),1.25-1.14(m,2H).

Example 2

(R) -N- (3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) -2 '-oxo-1', 2 '-dihydrospiro [ piperidine-4, 3' -pyrrolo [2,3-b ] pyridine ] -1-carboxamide

First step

(R) -2-amino-3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) propan-1-one 1i (50 mg, 94.28. Mu. Mol) and triethylamine (198.12 mg,1.96 mmol) were dissolved in N, N-dimethylformamide (2 mL), N '-disuccinimidyl carbonate (31.40 mg, 122.56. Mu. Mol) was added, stirred at 20℃for 1 hour, spiro [ piperidin-4, 3' -pyrrolo [2,3-B ] pyridin ] -2 '(1' H) -one 2a (17.24 mg, 84.85. Mu. Mol) was added, stirred at 20℃for 15 hours, and after completion of the reaction, the resulting residue was concentrated under reduced pressure to give (eluent: B system) via C18 reverse phase column preparation of (R) -N- (3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) -piperazin-1-oxo-2 '(1' H) -2-yl) 2-a (17.24 mg, 84.85. Mu. Mol), and the resulting residue was prepared by separating (eluent: B system) via C18 reverse phase column to give (R) -N- (3- (1-methylpiperidin-4-yl) -1-2-oxo-1-2 '-2-oxo-2' -pyrrol-2 'yl) 1-2' yl) by following the reaction. 7.08%.

MS m/z(ESI):614.5[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ13.00(s,1H),11.01(s,1H),8.05-8.03(m,1H),7.94(s,1H),7.71(d,J＝7.2Hz,1H),7.35(s,1H),6.99(s,1H),6.92-6.89(m,1H),6.77(d,J＝8.0Hz,1H),4.81-4.76(m,1H),3.74-3.72(m,2H),3.56-3.50(m,4H),3.26-3.21(m,2H),3.11-3.07(m,1H),2.97-2.73(m,4H),2.44(s,3H),2.33-2.15(m,5H),1.95-1.83(m,4H),1.67-1.38(m,6H),1.25-1.16(m,2H).

Example 3

(R) -N- (3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) -4- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-1-yl) piperidine-1-carboxamide

First step

(R) -2-amino-3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) propan-1-one 1i (80 mg, 150.84. Mu. Mol) and triethylamine (152.63 mg,1.51 mmol) were dissolved in N, N-dimethylformamide (2.5 mL), N' -disuccinimidyl carbonate (46.37 mg, 181.01. Mu. Mol) was added, stirred at 20℃for 2 hours, 1- (piperidin-4-yl) -1, 3-dihydro-2H-imidazo [4,5-B ] pyridin-2-one 3a (34.58 mg, 135.76. Mu. Mol) was added, and after completion of the reaction, the resulting residue was concentrated under reduced pressure and separated by C18 reverse phase column preparation (eluent: B system) to give (R) -N- (3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) -4- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-B ] pyridin-1-yl) piperidine-1-carboxamide 3 (38.13 mg), yield: 38.43%.

MS m/z(ESI):629.5[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ12.99(s,1H),7.93(s,1H),7.85(dd,J＝5.2,0.08Hz,1H),7.36-7.34(m,2H),6.99(s,1H),6.90-6.87(m,1H),6.75(d,J＝8.0Hz,1H),4.75(q,J＝8.0Hz,1H),4.35-4.28(m,1H),4.13-4.10(m,2H),3.59-3.56(m,2H),3.23-3.06(m,2H),2.96-2.69(m,6H),2.43(s,3H),2.35-2.20(m,3H),2.09-1.85(m,7H),1.78-1.61(m,4H),1.51-1.45(m,1H),1.37-1.34(m,2H),1.19-1.10(m,2H).

Example 4A

(R) -N- ((R) -3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) -2 '-oxo-1', 2 '-dihydrospiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxamide 4A

Example 4B

(S) -N- ((R) -3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) -2 '-oxo-1', 2 '-dihydrospiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxamide 4B

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First step

(3-bromopyridin-2-yl) carbamic acid tert-butyl ester

1M sodium bis (trimethylsilyl) amide (127.9 mL,127.90 mmol) was dissolved in tetrahydrofuran (80 mL), the temperature was reduced to zero degrees Celsius, 3-bromopyridine-2-amine 4a (10 g,58.13 mmol) was added, the reaction was maintained at zero degrees Celsius for 0.5 hours, then di-tert-butyl dicarbonate (16.4 g,75.58 mmol) was dissolved in tetrahydrofuran (20 mL), and the reaction was carried out at zero degrees Celsius for 1 hour. After completion of the reaction, the reaction mixture was poured into an ice saturated aqueous ammonium chloride solution (200 mL), extracted with methylene chloride (200 mL. Times.3), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by column chromatography (eluent: C system) to give tert-butyl (3-bromopyridin-2-yl) carbamate 4b (13.59 g), yield: 71.4%.

MS m/z(ESI):273.0[M+1]

Second step

4- (2- ((tert-Butoxycarbonyl) amino) pyridin-3-yl) -4-hydroxyazepan-1-carboxylic acid tert-butyl ester

Under the protection of nitrogen, tert-butyl (3-bromopyridin-2-yl) carbamate 4b (3 g,11.02 mmol) was dissolved in tetrahydrofuran (20 mL), the temperature was lowered to-78 ℃, 2.5M of n-butyllithium (13.2 mL,33.08 mmol) was slowly added dropwise, the reaction was carried out at-78 ℃ for 0.5 hour, and then a solution of tert-butyl 4-oxo-azepane-1-carboxylate 4c (7.05 g,33.08 mmol) in tetrahydrofuran (10 mL) was added dropwise, and the reaction was carried out at 20 ℃ for 2 hours. After the reaction was completed, the reaction mixture was quenched with 50mL of saturated aqueous ammonium chloride solution of ice, and concentrated under reduced pressure to give tert-butyl 4d (4.48 g) of 4- (2- ((tert-butoxycarbonyl) amino) pyridin-3-yl) -4-hydroxyazepan-1-carboxylate, yield: 99.6% and the next reaction was carried out without purification.

MS m/z(ESI):408.2[M+1]

Third step

To a solution of tert-butyl 4- (2- ((tert-butoxycarbonyl) amino) pyridin-3-yl) -4-hydroxyazepan-1-carboxylate 4d (4.48 g,10.99 mmol) in tetrahydrofuran (30 mL) was added 1M potassium tert-butoxide solution (16.5 mL,16.48 mmol) and the mixture was reacted at 20℃for 16 hours. After the reaction, 100mL of methylene chloride and 100mL of water were added, the mixture was washed with a saturated sodium chloride solution and concentrated under reduced pressure, and the obtained residue was purified by column chromatography (eluent: C system) to give tert-butyl 2 '-oxo-1', 2 '-dihydrospiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylate 4e (807.2 mg), yield: 21.9%.

MS m/z(ESI):334.1[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ10.80(s,1H),8.19(d,J＝4.1Hz,1H),7.70(d,J＝7.5Hz,1H),7.09-7.05(m,7.6Hz,1H),3.80-3.59(m,1H),3.57-3.46(m,1H),3.43-3.33(m,1H),3.30-3.17(m,1H),2.19-1.89(m,5H),1.73-1.74(m,1H),1.42(s,9H)

Fourth step

(R) -2 '-oxo-1', 2 '-dihydro-spiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid tert-butyl ester 4e-A

(S) -2 '-oxo-1', 2 '-dihydro-spiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid tert-butyl ester 4e-B

Tert-butyl 2 '-oxo-1', 2 '-dihydrospiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylate 4e (0.918 mg,2.75 mmol) was purified by chiral resolution of SFC (column type: waters SFC-150, dnicel IG, 20X 250mm,10 μm; mobile phase: afor CO2 and B for Ethanol; detection wavelength: 214nm; column temperature: 40 ℃ C.) to give single configuration compounds (shorter retention time) and single configuration compounds (longer retention time).

Single configuration compounds (shorter retention time):

400mg, yield: 43.6%, retention time 1.612 min, chiral purity 100% ee.

MS m/z(ESI):334.2[M+1]

Single configuration compounds (longer retention time):

410mg, yield: 44.7%, retention time 2.030 minutes, chiral purity 99.1% ee.

MS m/z(ESI):334.2[M+1]

Fifth step

(R) -spiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazin ] -2' (1 ' H) -one 4f-A

(S) -spiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazin ] -2' (1 ' H) -one 4f-B

The chiral resolution of (R) -2' -oxo-1 ',2' -dihydrospiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid tert-butyl ester 4e-A (100 mg, 299.96. Mu. Mol) or (S) -2' -oxo-1 ',2' -dihydrospiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid tert-butyl ester 4e-B (100 mg, 299.96. Mu. Mol) was dissolved in 4M dioxane hydrochloride solution (2 mL), reacted at 30℃for 3 hours, after the reaction was completed, concentrated under reduced pressure to give (R) -spiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -2' (1 ' H) -ketone 4f-A (100 mg), yield: 100%, directly carrying out the next reaction without purification; (S) -spiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazin ] -2' (1 ' h) -one 4f-B (120 mg), yield: 100% of the reaction mixture was directly subjected to the next reaction without purification.

MS m/z(ESI):234.1[M+1]

Sixth step (R) -N- ((R) -3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) -2 '-oxo-1', 2 '-dihydrospiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxamide

(R) -2-amino-3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) propan-1-one 1i (47.08 mg, 88.77. Mu. Mol) was added to N, N-dimethylformamide (1 mL), triethylamine (99.80 mg, 986.28. Mu. Mol) and N, N '-disuccinimidyl carbonate (27.77 mg, 108.49. Mu. Mol) were added, stirred at 30℃for 1 hour, and (R) -spiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazin ] -2 '(1' H) -one 4f-A (0.03 g, 98.63. Mu. Mol) was further added, stirred at 30℃for 18 hours, and after the completion of the reaction, the resulting residue was concentrated under reduced pressure and the preparation of a C18 reverse phase column was separated (eluent: B system) to give (R) -N- ((R) -3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) -2 '-oxo-1', 2 '-dihydrospiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxamide 4A (27.87 mg), yield: 41.61%.

MS m/z(ESI):644.5[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ13.00(s,1H),10.75(s,1H),8.13(dd,J＝4.8,1.6Hz,1H),7.91(s,1H),7.35-7.30(m,2H),6.98(s,1H),6.93-6.90(m,1H),6.38(d,J＝8.4Hz,1H),4.80(q,J＝8.0Hz,1H),3.79-3.76(m,2H),3.56-3.49(m,5H),3.22-3.14(m,2H),2.96-2.81(m,3H),2.43-2.40(m,4H),2.25-2.17(m,4H),2.04-1.67(m,11H),1.46-1.32(m,2H),1.24-1.20(m,2H).

Seventh step (S) -N- ((R) -3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) -2 '-oxo-1', 2 '-dihydrospiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxamide

(R) -2-amino-3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) propan-1-one 1i (53.09 mg, 100.10. Mu. Mol) was added to N, N-dimethylformamide (2 mL), triethylamine (112.55 mg,1.11 mmol) and N, N '-disuccinimidyl carbonate (31.32 mg, 122.35. Mu. Mol) were added, stirred at 30℃for 1 hour, and (S) -spiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazin ] -2 '(1' H) -one 4f-B (0.03 g, 98.63. Mu. Mol) was further added, stirred at 30℃for 18 hours, and after completion of the reaction, the resulting residue was concentrated under reduced pressure and isolated by C18 reverse phase column preparation (eluent: B system) to give (S) -N- ((R) -3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) -2 '-oxo-1', 2 '-dihydrospiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxamide 4B (11 mg), yield: 13.52%.

MS m/z(ESI):644.6[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ10.78(s,1H),8.18(dd,J＝4.8,1.6Hz,1H),7.97(s,1H),7.40-7.33(m,2H),7.05-7.02(m,2H),6.41(d,J＝8.4Hz,1H),4.85(q,J＝8.0Hz,1H),3.76-3.72(m,1H),3.55-3.45(m,3H),3.23-3.10(m,4H),3.01-2.88(m,3H),2.65-2.56(m,5H),2.47-2.42(m,6H),2.38-2.35(m,1H),2.30-2.24(m,1H),2.17-1.95(m,6H),1.75-1.53(m,4H),1.40-1.23(m,1H).

Example 5A

(3 aR,5S,6 aS) -N- ((R) -3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) -2 '-oxo-1', 2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-b ] pyridine ] -2 (3H) -carboxamide

Example 5B

(3 aR,5R,6 aS) -N- ((R) -3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) -2 '-oxo-1', 2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-b ] pyridine ] -2 (3H) -carboxamide

First step

Dibenzyl maleate

Maleic acid 5a (4 g,34.46 mmol) and benzyl bromide (14.74 g,86.15 mmol) were dissolved in N, N-dimethylformamide (40 mL), potassium carbonate (19.02 g,137.85 mmol) was added, stirred at 25℃for 48 hours, water (40 mL) was added, extraction was performed with ethyl acetate (80 mL. Times.3), the organic phases were combined and concentrated under reduced pressure to give a crude product, and the resulting residue was purified by column chromatography (eluent: C system) to give dibenzyl maleate 5b (2.43 g), yield: 22.61%.

¹ H NMR(400MHz,CDCl ₃ )δ7.38-7.31(m,10H),6.29(s,2H),5.14(s,4H).

Second step

(3S, 4R) -pyrrolidine-1-carboxylic acid tert-butyl 3, 4-dicarboxylic acid dibenzyl ester

Dibenzyl maleate 5b (1.6 g,5.40 mmol), glycine (8.11 g,107.99 mmol) and paraformaldehyde (971.93 mg,32.40 mmol) were dissolved in toluene (100 mL), stirred for 4 hours at 130 ℃, after the reaction was completed, concentrated under reduced pressure, ethanol (30 mL) was added, di-tert-butyl dicarbonate (1.41 g,6.48 mmol) was added, stirred for 18 hours at 25 ℃, after the reaction was completed, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (eluent: A system) to give dibenzyl (3S, 4R) -pyrrolidine-1-carboxylate-3, 4-dicarboxylate 5c (1.40 g), yield: 47.19%.

MS m/z(ESI):462.4[M+23]

Third step

(3S, 4R) -3, 4-bis (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

The (3 s,4 r) -pyrrolidine-1-carboxylic acid tert-butyl ester-3, 4-dicarboxylic acid dibenzyl ester 5c (900 mg,2.05 mmol) was dissolved in tetrahydrofuran (30 mL), lithium aluminum hydride (466.89 mg,12.29 mmol) was added at zero degrees celsius and stirred for 30 minutes, 25% sodium hydroxide solution was added to quench the reaction, filtered and concentrated under reduced pressure to give (3 s,4 r) -3, 4-bis (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester 5d (473 mg), yield: 100% of the reaction mixture was directly subjected to the next reaction without purification. MS m/z (ESI) 254.0[ M+23]

Fourth step

(3S, 4R) -3, 4-bis (((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester

Tert-butyl (3 s,4 r) -3, 4-bis (hydroxymethyl) pyrrolidine-1-carboxylate 5d (473 mg,2.05 mmol) and triethylamine (2.07 g,20.45 mmol) were dissolved in dichloromethane (25 mL), methanesulfonyl chloride (1.41 g,12.27 mmol) was added at zero degrees celsius and stirred for 30 min, 1M diluted hydrochloric acid was added to adjust ph=5, extracted with dichloromethane (30 ml×3), the organic phases were combined, concentrated under reduced pressure and the resulting residue was purified by column chromatography (eluent: a system) to give tert-butyl (3 s,4 r) -3, 4-bis (((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylate 5e (790 mg), yield: 89.73%. ¹ H NMR(400MHz,CDCl ₃ )δ4.34-4.22(m,4H),3.59-3.51(m,2H),3.35-3.29(m,2H),3.05(s,6H),2.80-2.77(m,2H),1.45(s,9H).

Fifth step (3 aR,5S,6 aS) -2 '-oxo-1' - ((2- (trimethylsilyl) ethoxy) methyl) -1',2',3a,4,6 a-hexahydro-1H-spiro [ cyclopent ]

[c] Pyrrole-5, 3' -pyrrolo [2,3-b ] pyridine ] -2 (3H) -carboxylic acid tert-butyl ester 5g-A

(3 aR,5R,6 aS) -2 '-oxo-1' - ((2- (trimethylsilyl) ethoxy) methyl) -1',2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta ] e

[c] Pyrrole-5, 3' -pyrrolo [2,3-B ] pyridine ] -2 (3H) -carboxylic acid tert-butyl ester 5g-B

1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one 5f (850 mg,3.21 mmol) and tert-butyl (3S, 4R) -3, 4-bis (((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylate 5e (1.25 g,3.21 mmol) were dissolved in N, N-dimethylformamide (20 mL), cesium carbonate (3.67 g,11.25 mmol) was added, stirred at 80℃for 21 hours, water (20 mL) was added, extracted with ethyl acetate (40 mL. Times.3) and the organic phases were combined, the resulting residue was purified by column chromatography (eluent: A system) to give (3 aR,5S,6 aS) -2 '-oxo-1' - ((2- (trimethylsilyl) ethoxy) methyl) -1',2',3a,4,6 a-hexahydro-1H-spiro [ 3, 3-b ] pyrrolo [2,3 ] pyrrole ] -2H-carboxylic acid (38 mg,3 mg) respectively): 5.42% and (3 ar,5r,6 as) -2' -oxo-1 ' - ((2- (trimethylsilyl) ethoxy) methyl) -1',2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-B ] pyridine ] -2 (3H) -carboxylic acid tert-butyl ester 5g-B (126 mg), yield: 7.67%.

MS m/z(ESI):460.6[M+1]

MS m/z(ESI):460.5[M+1]

¹ H NMR(400MHz,CDCl ₃ )δ8.19(dd,J＝5.2,1.6Hz,1H),7.47(dd,J＝7.2,1.6Hz,1H),7.00(dd,J＝7.2,1.2Hz,1H),5.22(s,2H),3.68-3.52(m,4H),3.41-3.16(m,4H),2.40-2.31(m,2H),1.90-1.81(m,2H),1.49(s,9H),0.99-0.95(m,2H),0.08(s,9H).

¹ H NMR(400MHz,CDCl ₃ )δ8.21(dd,J＝5.2,1.2Hz,1H),7.48(dd,J＝7.6,1.6Hz,1H),6.96(d,J＝7.6,5.6Hz,1H),5.24(s,2H),3.67-3.55(m,4H),3.49-3.40(m,2H),3.06-3.01(m,2H),2.20-2.15(m,2H),2.06-2.01(m,2H),1.47(s,9H),0.97-0.93(m,2H),0.05(s,9H).

Sixth step (3 aR,5S,6 aS) -2, 3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3 '-pyrrolo [2,3-B ] pyridine ] -2' (1 'H) -one 5H-A (3 aR,5R,6 aS) -2, 3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-B ] pyridine ] -2 '(1' H) -one 5H-B

(3 aR,5S,6 aS) -2' -oxo-1 ' - ((2- (trimethylsilyl) ethoxy) methyl) -1',2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-B ] pyridine ] -2 (3H) -carboxylic acid tert-butyl ester 5g-A (89 mg, 193.62. Mu. Mol) and (3 aR,5R,6 aS) -2' -oxo-1 ' - ((2- (trimethylsilyl) ethoxy) methyl) -1',2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-B ] pyridine ] -2 (3H) -carboxylic acid tert-butyl ester 5g-B (90 mg, 195.80. Mu. Mol) was dissolved in trifluoroacetic acid (3 mL), stirred at 25℃for 3 hours, after completion of the reaction, concentrated under reduced pressure, tetrahydrofuran (2.00 mL) and aqueous ammonia (1 mL) were added, stirring was continued for 1 hour, and concentrated under reduced pressure to give (3 aR,5S,6 aS) -2, 3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-B ] pyridine ] -2' (1 ' H) -one 5H-A (44 mg), yield: 98.8% and (3 ar,5r,6 as) -2, 3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-B ] pyridin ] -2' (1 ' H) -one 5H-B (44 mg), yield: 97.7%, and the next reaction was directly carried out without purification.

MS m/z(ESI):230.2[M+1]

Seventh step (3 aR,5S,6 aS) -N- ((R) -3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) -2 '-oxo-1', 2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-b ] pyridine ] -2 (3H) -carboxamide

(R) -2-amino-3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) propan-1-one 1i (40 mg, 75.42. Mu. Mol) was added to N, N-dimethylformamide (1.2 mL), triethylamine (76.32 mg, 754.20. Mu. Mol) and N, N '-disuccinimidyl carbonate (25.12 mg, 98.05. Mu. Mol) were added, stirred at 25℃for 2 hours, and then (3 aR,5S,6 aS) -2, 3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ C ] pyrrole-5, 3-B ] pyridine ] -2' (1 'H) -one 5H-A (25.07 mg, 82.96. Mu. Mol) was added, stirred at 25℃for 15 hours, and after completion of the reaction, the resulting residue was concentrated under reduced pressure and subjected to a C18 reverse phase column to elution (eluent: B system), to give (3 aR,5S,6 aS) -N- ((R) -3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) -2' -oxo-1 ',2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-b ] pyridine ] -2 (3H) -carboxamide 5A (15 mg), yield: 29.50%.

MS m/z(ESI):640.6[M+1]

¹ HNMR(400MHz,DMSO-d ₆ )δ12.99(s,1H),10.85(s,1H),7.99(d,J＝6.4Hz,1H),7.92(s,1H),7.51(d,J＝8.4Hz,1H),7.33(s,1H),6.97(s,1H),6.92-6.89(m,1H),6.27(d,J＝8.0Hz,1H),4.78(q,J＝7.6Hz,1H),3.53-3.51(s,2H),3.25-2.77(m,12H),2.43(s,3H),2.32-2.14(m,7H),1.97-1.87(m,4H),1.72-1.65(m,2H),1.48-1.35(m,3H),1.21-1.15(m,1H),0.92(t,J＝7.2Hz,1H).

Eighth step (3 ar,5R,6 as) -N- ((R) -3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) -2 '-oxo-1', 2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-b ] pyridine ] -2 (3H) -carboxamide

(R) -2-amino-3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) propan-1-one 1i (47.39 mg, 89.35. Mu. Mol) was added to N, N-dimethylformamide (2 mL), triethylamine (100.45 mg, 992.72. Mu. Mol) and N, N ' -disuccinimidyl carbonate (31.32 mg, 122.35. Mu. Mol) were added, stirred at 30℃for 1 hour, and then (3 aR,5R,6 aS) -2, 3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ C ] pyrrole-5, 3-B ] pyridine ] -2' H) -one 5H-B (0.03 g, 99.27. Mu. Mol) was added, stirred at 30℃for 16 hours, and after completion of the reaction, the resulting residue was concentrated under reduced pressure and subjected to a C18 reverse phase eluent preparation (column separation: B system), to give (3 aR,5R,6 aS) -N- ((R) -3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) -2' -oxo-1 ',2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-B ] pyridine ] -2 (3H) -carboxamide 5B (11 mg), yield: 17.32%.

MS m/z(ESI):640.5[M+1]

¹ HNMR(400MHz,DMSO-d ₆ )δ11.01(s,1H),8.03(d,J＝5.2Hz,1H),7.94(s,1H),7.64(d,J＝7.2Hz,1H),7.33(s,1H),6.97-6.92(m,2H),6.36(d,J＝7.6Hz,1H),4.75(q,J＝7.2Hz,1H),3.59-3.48(m,1H),3.13-2.84(m,9H),2.64(s,5H),2.33-2.17(m,9H),1.97-1.91(m,5H),1.85-1.78(m,2H),1.48-1.40(m,2H),1.29-1.23(m,1H),0.92(t,J＝6.8Hz,1H).

Example 6

N- ((R) -3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2-yl) -4- (2-oxo-1, 2-dihydroquinolin-3-yl) azepane-1-carboxamide

First step

4- (2-methoxy-2-oxoethylene) azepane-1-carboxylic acid tert-butyl ester

Methyl 2- (dimethoxyphosphoryl) acetate 6a (1.87 g,10.32 mmol) was dissolved in tetrahydrofuran (15 mL), the temperature was reduced to zero degrees centigrade, sodium hydride (518.1 mg,12.95 mmol) was added in portions, the reaction was carried out at zero degrees centigrade for 0.5 hours, then a solution of t-butyl 4-oxo-azepane-1-carboxylate 4C (2.00 g,9.38 mmol) in tetrahydrofuran (5 mL) was added at zero degrees centigrade, the reaction was carried out at 25℃for 16 hours, after the completion of the reaction, the reaction solution was poured into an ice saturated aqueous ammonium chloride solution (100 mL), extracted with methylene chloride (100 mL. Times.3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the resulting residue was purified by column chromatography (eluent: C system) to give t-butyl 4- (2-methoxy-2-oxoethylene) azepane-1-carboxylate 6b (1.81 g), yield: 71.4%.

MS m/z(ESI):292.1[M+23]

Second step

4- (2-methoxy-2-oxoethyl) azepane-1-carboxylic acid tert-butyl ester

Under nitrogen protection, tert-butyl 4- (2-methoxy-2-oxoethylene) azepane-1-carboxylate 6b (1.89 g,7.02 mmol) was dissolved in methanol (20 mL), 10% palladium on carbon (189 mg) was added, the reaction was carried out at 25℃for 16 hours, after the completion of the reaction, filtration and three methanol rinses were carried out, and the filtrate was concentrated under reduced pressure to give tert-butyl 4- (2-methoxy-2-oxoethyl) azepane-1-carboxylate 6c (1.76 g), yield: 92.6% of the reaction mixture was directly subjected to the next reaction without purification.

MS m/z(ESI):294.1[M+23]

Third step

4- (1-hydroxy-3-methoxy-1- (2-nitrophenyl) -3-oxopropan-2-yl) azepan-1-carboxylic acid tert-butyl ester

Tert-butyl 4- (2-methoxy-2-oxoethyl) azepane-1-carboxylate 6c (1.76 g,6.49 mmol) was dissolved in tetrahydrofuran (17 mL), cooled to-78℃and 2M lithium diisopropylamide solution (4.2 mL,8.43 mmol) was added dropwise and reacted at-78℃for 0.5 h, and 2-nitrobenzaldehyde 6d (1.66 g,11.03 mmol) in tetrahydrofuran (5 mL) was added dropwise at-78 ℃. After the reaction was completed, the reaction mixture was quenched with ice saturated aqueous ammonium chloride (100 mL), extracted with methylene chloride (100 mL. Times.3), the combined organic phases were washed with saturated aqueous sodium chloride (100 mL), and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (eluent: C system) to give tert-butyl 4- (1-hydroxy-3-methoxy-1- (2-nitrophenyl) -3-oxopropan-2-yl) azepane-1-carboxylate 6e (2.38 g), yield: 85.0%.

MS m/z(ESI):445.3[M+23]

Fourth step

4- (4-hydroxy-2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) azepane-1-carboxylic acid tert-butyl ester

4- (1-hydroxy-3-methoxy-1- (2-nitrophenyl) -3-oxopropan-2-yl) azepan-1-carboxylic acid tert-butyl ester 6e (2.38 g,6.6 mmol) was dissolved in methanol (30 mL) under nitrogen protection, 10% palladium on carbon (189.5 mg) was added, the reaction was reacted at 25℃for 16 hours, after the completion of the reaction, the reaction solution was filtered, washed three times with methanol, concentrated under reduced pressure, acetic acid (25 mL) was added, reacted at 80℃for 2 hours, after the completion of the reaction, concentrated under reduced pressure to give 4- (4-hydroxy-2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) azepan-1-carboxylic acid tert-butyl ester 6f (3.22 g), yield: 100% of the reaction mixture was directly subjected to the next reaction without purification. MS m/z (ESI): 361.2[ M+1]

Fifth step

3- (azepan-4-yl) quinolin-2 (1H) -one

4- (4-hydroxy-2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) azepan-1-carboxylic acid tert-butyl ester 6f (3.22 g,8.94 mmol) was dissolved in methanol (30 mL), 4M diluted hydrochloric acid (22.3 mL,89.44 mmol) was added at zero degrees Celsius, stirred at 25 degrees Celsius for 16 hours, after completion of the reaction acetonitrile was added to slurry (15 mL), and filtered to give 3- (azepan-4-yl) quinolin-2 (1H) -one 6g (1.42 g), yield: 88%.

MS m/z(ESI):243.1[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ11.83(s,1H),9.14(m,1H),7.70-7.77(m,1H),7.64(d,J＝7.63Hz,1H),7.40-7.48(m,1H),7.30(d,J＝8.13Hz,1H),7.16-7.18(m,1H),3.19-3.36(m,2H),3.02-3.17(m,3H),1.67-1.92(m,2H),1.65-2.05(m,4H).

Sixth step

(R) -2-amino-3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) propan-1-one 1i (64 mg, 120.67. Mu. Mol) was added to N, N-dimethylformamide (3 mL), N' -disuccinimidyl carbonate (40.19 mg, 156.87. Mu. Mol) was added, stirring was carried out at 25℃for 2 hours, 3- (azepan-4-yl) quinolin-2 (1H) -one 6g (31.96 mg, 114.64. Mu. Mol) was added, stirring was carried out at 25℃for 18 hours, and after completion of the reaction, the resulting residue was isolated by C18 reverse phase column preparation (eluent: B system) to give N- ((R) -3- (7-methyl-1H-indazol-5-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -1-oxopropan-2- (2-oxo-1-dihydro-quinolin-1-yl) 2 (1H) -one 6g (31.96 mg), and the resulting residue was isolated by C18 reversed phase column preparation (eluent: B system): 66.47%.

MS m/z(ESI):653.6[M+1]

¹ H NMR(400MHz,DMSO-d ₆ )δ12.99(s,1H),11.71(s,1H),7.93(d,J＝5.2Hz,1H),7.60-7.54(m,2H),7.41-7.22(m,3H),7.13-7.08(m,1H),6.97(s,1H),6.30-6.24(m,1H),4.84-4.79(m,1H),3.65-3.45(m,3H),3.20-2.64(m,9H),2.43-2.42(m,3H),2.30-1.15(m,21H).

Biological evaluation

Test example 1 determination of the inhibitory Effect of Compounds of the present application on CGRP Signal pathway in CHO-K1 cells expressing the human CGRP receptor

The inhibition of in vitro CGRP signaling pathway is evaluated by indirect measurement of cAMP levels, the principle being that CGRP and CGRP receptor bind, and then activate CGRP signaling pathway, inducing an increase in cAMP levels, cAMP inducing expression of the reporter gene firefly luciferase regulated by CRE (cAMP response element), whereby a decrease in firefly luciferase activity level is indicative of inhibition of CGRP signaling pathway, and the specific experimental procedure is as follows:

CHO-K1 (CGRPR/CHO-K1, perkinelmer, ES-420-C) cells expressing the human CGRP receptor were transfected with pGL4.29[ luc2P/CRE/Hygro ] by Lipofectamine 2000 (Invitrogen, 11668019)]After (Promega, 9PIE 847) plasmid, cells were collected in the logarithmic growth phase after culturing in F12K+10% FBS+400. Mu.g/mL G418+10. Mu.g/mL Blastidin+350. Mu.g/mL Hygromycin B medium. 20. Mu.L of cell suspension liquid was added to each well of 384-well white microwell plates (Nest, 761601) at a cell density of 8000 cells/well. mu.L of a gradient diluted compound solution was added to each well, incubated at 37℃for 30 minutes, 5. Mu.L of 12ng/mL human. Alpha. -CGRP (Bachem, H-1470.0500) was added to each well, the final concentration was 2ng/mL, incubated at 37℃for 5 hours, and 15. Mu.L of a firefly luciferase reporter assay reagent was added to each well, incubated at room temperature for 15 minutes, and the luminescence signal was read using an enzyme-labeled instrument (Molecular Devices). IC of the inhibition of firefly luciferase activity level by the compound was calculated using Graphpad Prism based on the compound concentration and luminescence signal ₅₀ Values.

The biological activity of the compounds of the present application was determined by the above assay, measured in [ alpha-CGRP]IC at =2 ng/mL ₅₀ The values are shown in Table 1 below.

TABLE 1 IC of the inhibition of CGRP signaling pathway by compounds of the present application in CHO-K1 cells expressing the human CGRP receptor ₅₀

Conclusion: the compound has obvious inhibiting effect on CGRP signal path in CHO-K1 cell expressing human CGRP receptor.

Test example 2 determination of the inhibitory Effect of the Compounds of the present application on CGRP Signal pathway in SK-N-MC cells

The inhibition of CGRP signaling pathway in vitro is evaluated by measuring cAMP levels, the principle being that upon binding of CGRP to CGRP receptor, activation of CGRP signaling pathway induces an increase in cAMP levels, whereby a decrease in cAMP levels is indicative of inhibition of CGRP signaling pathway, as follows:

cAMP assay was performed using the CAMP-GSDYNAMIC KIT detection kit (Cisbio, 62AM4 PEB).

SK-N-MC (ATCC, HTB-10) cells endogenously expressing CGRP receptor were cultured in EMEM+10% FBS medium and cells were collected in log phase. Cells were resuspended in Stimulation Buffer containing 0.5mM IBMX and 5. Mu.L of cell suspension per well was added to a 96 well microplate (Cisbio, 66PL 96025) at a cell density of 15000 cells/well according to the instructions of the kit. 2.5. Mu.L of a gradient of diluted compound solution (highest concentration of 100nM, 3-fold dilution of compound solution, total 11 concentrations) was added to each well, and after incubation at 37℃for 30 minutes, 2.5. Mu.L of 40ng/mL human. Alpha. -CGRP (Bachem, H-1470.0500) diluted in Stimulation Buffer containing 0.5mM IBMX was added to each well, with a final concentration of 10ng/mL, and after incubation at 37℃for 30 minutes, 5. Mu.L of Anti-cAMP-Cryptate solution and 5. Mu.L of cAMP-d2 solution were added to each well. Incubation was performed at room temperature for 60 min, and HTRF signals were read using an enzyme label (Molecular Devices). IC of compounds for inhibition of cAMP level elevation was calculated using Graphpad Prism based on compound concentration and HTRF signal ₅₀ Values.

The biological activity of the compounds of the present application was determined by the above assay, measured in [ alpha-CGRP]IC at 10ng/mL ₅₀ The values are given in Table 2 below.

TABLE 2 IC for the inhibition of CGRP Signal pathway by Compounds of the present application in SK-N-MC cells ₅₀

Conclusion: the compound has obvious inhibition effect on CGRP signal paths in SK-N-MC cells.

Claims

1. A compound of formula (I) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof:

wherein:

ring a is selected from heterocyclyl or cycloalkyl;

ring B is selected from heterocyclyl or cycloalkyl;

m is 1,2 or 3;

n is 1 or 2;

p is 0,1 or 2.

2. The compound of claim 1, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein ring B is piperazinyl; or R is ₂ Is piperidine; or n is 1; or p is 0.

3. The compound according to claim 1 or 2, or a stereoisomer, tautomer, deuterated derivative, or a pharmaceutically acceptable salt thereof, which is a compound according to formula (II):

wherein: ring A, R ₁ And m is as defined in claim 1.

4. A compound according to claim 3, or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, which is a compound according to formula (III):

wherein: r is R ₁ And m is as defined in claim 1.

5. The compound of claim 4, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, which is a compound of formula (IV):

wherein: r is R ₁ And m is as defined in claim 1.

6. The compound of claim 4, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, which is a compound of formula (V):

wherein: r is R ₁ And m is as defined in claim 1.

7. A compound of the general formula (I-a) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof:

wherein:

ring a is selected from heterocyclyl;

m is 0 or 1;

p is 0,1 or 2.

8. A compound of the general formula (I-B) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof:

wherein:

Ring a is selected from heterocyclyl;

x is selected from C or N;

m is 0 or 1;

p is 0,1 or 2.

9. A compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, wherein said compound is:

10. a pharmaceutical composition comprising:

a compound according to any one of claims 1 to 9, or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

11. Use of a compound according to any one of claims 1 to 9, or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for the preparation of a CGRP receptor antagonist.

12. Use of a compound according to any one of claims 1 to 9, or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for the manufacture of a medicament for the prevention and/or treatment of a disease mediated by CGRP, wherein the disease mediated by CGRP is a cerebrovascular or vascular disorder.

13. The use according to claim 12, wherein the CGRP-mediated cerebrovascular or vascular disorders are selected from the group consisting of episodic migraine, non-premonitory migraine, chronic migraine, pure menstrual migraine, menstrual-related migraine, premonitory migraine, childhood/adolescent migraine, hemiplegic migraine, sporadic hemiplegic migraine, basal migraine, periodic vomiting, abdominal migraine, childhood benign paroxysmal vertigo, retinal migraine, cluster headache, dialysis headache, chronic headache of unknown cause, tension/pressure-induced headache, allergy-induced headache, neurogenic inflammation, postherpetic neuralgia, oophoralgia, climacteric migraine, ocular pain, diarrhea, osteoarthritis and associated osteoporotic fracture pain, hot flashes associated with menopause or medical induced menopause caused by surgery or drug therapy periodic vomiting syndrome, opioid withdrawal, psoriasis, asthma, obesity, morphine tolerance, neurodegenerative diseases, epilepsy, allergic rhinitis, rosacea, dental pain, ear pain, otitis media, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, gout, trigeminal neuralgia, nasal polyp, chronic sinusitis, temporomandibular syndrome, back pain, lower back pain, cough, dystonia pain, inflammatory pain, post-operative incision pain, sciatica, complex regional pain syndrome, behcet's disease, endometriosis, phantom limb syndrome, dysmenorrhoea, pain associated with labor, pain caused by skin burns, or inflammatory bowel disease (including Crohn's disease, ileitis and ulcerative colitis), chronic sinusitis, chronic secondary visceral pain such as gastroesophageal reflux disease, dyspepsia, irritable bowel syndrome, renal colic, cystitis, pancreatitis and prostatitis.