Piperidinecarboxamide azaindan derivatives, their preparation and use

Abstract

The present application relates to substituted piperidinecarboxamide azaindan derivatives, their preparation methods, and pharmaceutical compositions containing said derivatives or deuterated derivatives for use in medicine. In particular, the present application relates to substituted piperidinecarboxamide azaindan derivatives represented by general formula (I), their preparation methods and pharma- ceutically acceptable salts, and their use as CGRP receptor antagonists in the prevention and / or treatment of CGRP-related diseases, particularly in the field of migraine. The definition of each substituent in general formula (I) is the same as that in the present specification. [Formula 1] TIFF2025514364000068.tif43166

Description

[Technical field]

[0001] The present application relates to piperidinecarboxamide azaindan derivatives, processes for their preparation, and pharmaceutical compositions containing the derivatives or deuterated derivatives thereof, as well as their use as therapeutic or prophylactic agents, in particular as calcitonin gene-related peptide (CGRP) receptor antagonists. [Background technology]

[0002] Migraine is a common trigeminovascular headache that can last from 4 to 72 hours and is characterized by repeated attacks of moderate or severe throbbing pain on one or both sides of the head, nausea and vomiting, and hypersensitivity to light, sound, smell, or touch, significantly impacting the patient's life (Sreiner TJ et al., J Neurol Neurosurg Psychiatry 2004,75:808-811). The World Health Organization (WHO) lists migraine as one of the 10 most disabling diseases. People with migraine are more likely than others to experience depression, anxiety, sleep disorders, other pain, and fatigue. Statistics show that migraine affects 1.3 billion patients worldwide (about 11% of adults), with the proportion of women being three times that of men, about 40 million in the United States, about 8 million in Japan, and 13 million in China. In the United States, migraine results in an estimated $80 billion in medical costs and lost productivity annually, representing a huge waste of resources. Currently, the etiology of migraine is still not very clear internationally. The more recognized theory is the trigeminovascular theory, which effectively combines nerves, blood vessels, and neurotransmitters, which better explains the pathogenesis of migraine and is now widely accepted.

[0003] Currently, migraine is clinically divided into symptomatic and preventive treatments, and the first-line treatment for symptomatic treatment is still the use of nonsteroidal anti-inflammatory drugs, ergotamines or triptans, and opioids may be used in combination with other drugs for severe patients. Currently, triptans are the first-line treatment for migraine, but some patients are not sensitive to triptans and the therapeutic effect is not significant. In addition, triptans have side effects that cause cardiovascular risks, and these problems also limit the use of triptans. The prescriptions commonly used for preventive treatment are antiepileptics, tricyclic antidepressants, and beta-receptor blockers, but only some of them can prevent migraine. These preventive drugs were originally used to treat other diseases, are not specific for migraine prevention, and have obvious side effects, so they are not the first-line treatment for migraine prevention. In the field of migraine, it is believed that continued exploration is necessary in the future to find drugs with better therapeutic effects.

[0004] Calcitonin gene-related peptide (CGRP) is a neuropeptide containing 37 amino acid residues discovered by Amara et al. in 1982. It is widely present in the central and peripheral nervous systems, especially in the cell bodies and cell terminals of sensory neurons (Amara SG et al., Science 1982,298:240-244). Peripheral CGRP is found in the dorsal root ganglion, while central CGRP is found in the trigeminal ganglion. Both are synthesized in the cell bodies of sensory neurons and then rapidly transported to the central and peripheral terminals. The central terminals function as afferent fibers of sensory neurons and are mainly responsible for transmitting the sensations of pain and temperature. In the periphery, sensory nerve fibers containing CGRP are widely distributed in various tissues and organs, where they are released through axon reflexes in response to various stimuli.

[0005] CGRP is currently the most powerful endogenous vasodilator, and has become the focus and hotspot of research in the field of pain, especially migraine. Multiple clinical studies have confirmed that plasma CGRP levels increase during migraine attacks, and the intensity and duration of migraine are positively correlated with plasma CGRP levels (Han TH et al., Arch Drug Inf 2010,3:55-62). In addition, Goadsby et al. found that the CGRP content of the external jugular vein increases during migraine attacks, but not in the cubital vein, indicating that CGRP is released intracranially during migraine (Goadsby PJ et al., Ann Neurol 1990,28:183-187). Animal studies have also shown that CGRP released by trigeminal nerve activation can cause cerebral and meningeal blood vessel dilation, release of inflammatory mediators from mast cells, and transmission of harmful biological information released from intracranial blood vessels to the central nervous system (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 content of CGRP.

[0006] CGRP has a molecular weight of approximately 3800 Da and consists of 2800 base pairs. In its 37 amino acid sequence, the N-terminus at positions 2 and 7 is linked by a disulfide bond, and the C-terminus is a phenylalanine residue. These two structures are essential for CGRP to have biological activity. Two types of human CGRP are currently known: α-CGRP and β-CGRP. α-CGRP is expressed mainly in the nervous system, such as the hypothalamus, cerebellum, brainstem, and trigeminal nervous system, and β-CGRP is expressed mainly in the intestinal sensory system. α-CGRP is formed by splicing of the calcitonin (CT) gene, while β-CGRP is encoded by an isolated gene. The two forms of CGRP differ by three amino acids, but have similar biological effects in the circulatory system (Edvinsson L, Expert Opinion on Therapeutic Targets 2007,11:1179-1188).

[0007] The CGRP receptor is a G protein-coupled receptor, and is composed of seven transmembrane protein complexes (calcitonin receptor like receptor, CLR), one transmembrane protein receptor activity modifying protein 1 (RAMP1), and one intracellular protein (receptor component protein, RCP) (Evans BN et al., J Biology Chem 2000,275:38-43). RAMP1 is a type of small transmembrane protein that mediates the membrane translocation of CLR in the form of a molecular chaperone. RCP is a type of small polypeptide that mediates the transmission of downstream signals of CLR. At present, the mechanism by which CGRP is involved in migraine is unclear. Most scholars believe that CGRP, as a multifunctional neuropeptide, is involved in the processes of neurogenic inflammation, peripheral and central sensitization, and cortical spreading inhibition, thereby inducing migraine.

[0008] As research on CGRP and its receptors progresses, our understanding of CGRP is deepening day by day. It took 35 years from the isolation of the first CGR in 1983 until three CGRP monoclonal antibody drugs were approved in the United States in 2018. Currently, four CGRP monoclonal antibody drugs are on the market, but in addition to CGRP monoclonal antibodies, research and development of CGRP receptor antagonists is also attracting attention. Small molecule compounds have obvious advantages in terms of ease of drug administration, so to date, three small molecule CGRP receptor antagonists are on the market.

[0009] In the development process of CGRP receptor antagonists, there are surprises and setbacks. Take Olcegepant, Telcagepant, and MK-3207 as examples. Although the effectiveness of this class of drugs has been confirmed in multiple clinical trials, these compounds could only be discontinued due to the occurrence of severe side effects such as hepatotoxicity in many patients during clinical application. Through continuous optimization and screening to find more suitable compounds, fortunately, in December 2019, the FDA approved the sale of Ubrogepant, a drug developed by Abbvie for the treatment of acute migraine. In February of the following year, Rimegepant, developed by Biohaven, was also approved as a treatment for acute migraine, and in May 2021, Rimegepant was approved for the expanded indication of preventive treatment of paroxysmal migraine. In September 2021, Atogepant, developed by Abbvie, was approved by the FDA for the preventive treatment of paroxysmal migraine. The successful launch of these three small molecule drugs has brought hope to migraine sufferers worldwide, but they are also associated with side effects such as constipation, nausea and drowsiness, necessitating the need to find safer and more effective CGRP small molecule drugs. Summary of the Invention

[0010] In response to the above technical problem, the present application provides a substituted piperidinecarboxamide azaindan derivative represented by general formula (I) or a stereoisomer, tautomer, deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof:

[0011] [ka]

[0012] During the ceremony, R1 is selected from a hydrogen atom, a formyl group, an alkyl group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are R a and optionally substituted with one or more substituents of Each R aare the same or different and each independently selected from deuterium, tritium, halogen, amino, hydroxyl, cyano, alkoxy, alkyl, cycloalkyl, heterocycloalkyl, wherein said amino, hydroxyl, cyano, alkoxy, alkyl, cycloalkyl, heterocycloalkyl are optionally substituted by one or more substituents selected from alkyl, haloalkyl, halogen, amino, hydroxyl, cyano, or alkoxy; R2 is selected from an alkyl group, a deuterated alkyl group, an aminoalkyl group, a haloalkyl group, and a hydroxyalkyl group; each R3 is the same or different and is independently selected from halogen, amino, hydroxyl, cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; X or Y are the same or different and are each independently selected from =CR4-, =N-, -NR5-, -O-, -S-, -S(O)- or -S(O)2-; R4 or R5 are the same or different and are each independently selected from a hydrogen atom or an alkyl group; W is selected from -CH2- or a single bond; Z is selected from =CH- or =N-; n is 0, 1, 2, 3, 4, or 5.

[0013] In one particular embodiment, R2 is an alkyl group and the remaining R1, R3, X, Y, W and Z are as defined above for general formula (I).

[0014] In one particular embodiment, R2 is C 1~6 is an alkyl group and the remainder of R1, R3, X, Y, W and Z are as defined above for general formula (I).

[0015] In one particular embodiment, R2 is a methyl group and the remaining R1, R3, X, Y, W and Z are as defined above for general formula (I).

[0016] In one particular embodiment, R is an alkyl group or R a wherein R2, R3, X, Y, W and Z are selected from alkyl groups substituted with substituents, and the remaining R2, R3, X, Y, W and Z are as defined above for general formula (I).

[0017] In one particular embodiment, R is C 1~6 Alkyl group or R a C substituted with a substituent 1~6 alkyl groups, and the remainder of R2, R3, X, Y, W and Z are as defined above for general formula (I).

[0018] In one particular embodiment, R1 is selected from isopropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-methylpropyl, 3,3,3-trifluoropropyl and 3,3,3-trifluoro-2-hydroxypropyl, and the remaining R2, R3, X, Y, W and Z are as defined above for general formula (I).

[0019] In one particular embodiment, R1 is 2,2,2-trifluoroethyl and the remaining R2, R3, X, Y, W and Z are as defined above for general formula (I).

[0020] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, and the remaining R1, R2, R3, Y, W and Z are as defined above for general formula (I).

[0021] In one particular embodiment, Y is selected from =CR4-, -O-, -NR5-, =N-, -S-, and the remaining R1, R2, R3, X, W and Z are as defined above for general formula (I).

[0022] In one particular embodiment, R4 or R5 is a hydrogen atom.

[0023] In one particular embodiment, R3 are the same and are all halogen, and the remaining R1, R2, X, Y, W and Z are as defined above for general formula (I).

[0024] In one particular embodiment, R3 is fluorine, n is 3 and the remaining R1, R2, X, Y, W and Z are as defined above for general formula (I).

[0025] In one particular embodiment, W is a single bond and the remaining R1, R2, R3, X, Y, and Z are as defined above for general formula (I).

[0026] In one particular embodiment, Z is =CH and the remaining R1, R2, R3, X, Y, and W are as defined above for general formula (I).

[0027] In one particular embodiment, n is 0 and the remaining R1, R2, R3, X, Y, W and Z are as defined above for general formula (I).

[0028] In a preferred embodiment of the present application, the present application provides a compound represented by general formula (I) or a stereoisomer, tautomer, deuterated derivative or a pharma- ceutically acceptable salt thereof, which is a compound represented by general formula (II) or a stereoisomer, tautomer, deuterated derivative or a pharma- ceutically acceptable salt thereof,

[0029] [ka]

[0030] In the formula, R1, R2, R3, X, Y, W and Z are as defined for general formula (I).

[0031] In a preferred embodiment of the present application, the present application provides a compound represented by general formula (II) or a stereoisomer, tautomer, deuterated derivative or a pharma- ceutically acceptable salt thereof, which is a compound represented by general formula (III) or a stereoisomer, tautomer, deuterated derivative or a pharma- ceutically acceptable salt thereof,

[0032] [ka]

[0033] In the formula, R1, R3, X, Y, and W are as defined for general formula (I).

[0034] In a preferred embodiment of the present application, the present application provides a compound represented by general formula (III) or a stereoisomer, tautomer, deuterated derivative thereof or a pharma- ceutically acceptable salt thereof, which is a compound represented by general formula (IV) or a stereoisomer, tautomer, deuterated derivative thereof or a pharma- ceutically acceptable salt thereof,

[0035] [ka]

[0036] In the formula, R1, R3, X, and Y are as defined for general formula (I).

[0037] In a preferred embodiment of the present application, the present application provides a compound represented by general formula (III) or a stereoisomer, tautomer, deuterated derivative or a pharma- ceutically acceptable salt thereof, which is a compound represented by general formula (V) or a stereoisomer, tautomer, deuterated derivative or a pharma- ceutically acceptable salt thereof,

[0038] [ka]

[0039] In the formula, R1, R3, X, and Y are as defined for general formula (I).

[0040] In a preferred aspect of the present application, the present application provides a compound represented by general formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer, deuterated derivative thereof or a pharma- ceutically acceptable salt thereof, wherein R1 is selected from isopropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-methylpropyl, 3,3,3-trifluoropropyl and 3,3,3-trifluoro-2-hydroxypropyl.

[0041] In a preferred aspect of the present application, the present application provides a compound represented by general formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer, deuterated derivative thereof or a pharma- ceutically acceptable salt thereof, wherein R1 is selected from 2,2,2-trifluoroethyl.

[0042] In a preferred aspect of the present application, the present application provides a compound represented by general formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer, deuterated derivative thereof or a pharma- ceutically acceptable salt thereof, wherein R3 is selected from fluorine and n is selected from 3.

[0043] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, -O-, -NR5-, =N-, -S-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0044] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -O-, -NR5-, =N-, -S-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0045] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, -O-, -NR5-, =N-, -S-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0046] In one particular embodiment, X is -S-, Y is selected from =CR4-, -O-, -NR5-, =N-, -S-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0047] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0048] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0049] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0050] In one particular embodiment, X is -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0051] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0052] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0053] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0054] In one particular embodiment, X is -S-, Y is selected from =CR4-, =N-, -S-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0055] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, -S-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0056] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -S-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0057] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, -S-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0058] In one particular embodiment, X is -S-, Y is selected from =CR4-, -S-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0059] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0060] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is =CR4-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0061] In one particular embodiment, X is selected from -O-, -S-, Y is =CR4-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0062] In one particular embodiment, X is -S-, Y is =CR4-, W is selected from -CH2- or a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0063] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0064] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0065] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0066] In one particular embodiment, X is -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0067] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0068] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0069] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0070] In one particular embodiment, X is -S-, Y is selected from =CR4-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0071] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0072] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0073] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0074] In one particular embodiment, X is -S-, Y is selected from =CR4-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0075] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0076] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is =CR4-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0077] In one particular embodiment, X is selected from -O-, -S-, Y is =CR4-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0078] In one particular embodiment, X is -S-, Y is =CR4-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0079] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0080] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0081] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0082] In one particular embodiment, X is -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0083] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0084] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0085] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0086] In one particular embodiment, X is -S-, Y is selected from =CR4-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0087] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0088] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0089] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0090] In one particular embodiment, X is -S-, Y is selected from =CR4-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0091] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0092] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is =CR4-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0093] In one particular embodiment, X is selected from -O-, -S-, Y is =CR4-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0094] In one particular embodiment, X is -S-, Y is =CR4-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I).

[0095] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0096] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0097] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0098] In one particular embodiment, X is -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0099] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0100] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0101] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0102] In one particular embodiment, X is -S-, Y is selected from =CR4-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0103] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0104] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0105] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0106] In one particular embodiment, X is -S-, Y is selected from =CR4-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0107] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0108] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is =CR4-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0109] In one particular embodiment, X is selected from -O-, -S-, Y is =CR4-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0110] In one particular embodiment, X is -S-, Y is =CR4-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0111] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0112] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0113] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0114] In one particular embodiment, X is -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0115] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0116] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0117] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0118] In one particular embodiment, X is -S-, Y is selected from =CR4-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0119] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0120] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0121] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0122] In one particular embodiment, X is -S-, Y is selected from =CR4-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0123] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0124] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0125] In one particular embodiment, X is selected from -O-, -S-, Y is =CR4-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0126] In one particular embodiment, X is -S-, Y is =CR4-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 6.

[0127] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0128] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0129] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0130] In one particular embodiment, X is -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0131] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0132] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0133] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0134] In one particular embodiment, X is -S-, Y is selected from =CR4-, =N-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0135] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0136] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0137] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0138] In one particular embodiment, X is selected from -S-, Y is selected from =CR4-, -S-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0139] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0140] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is =CR4-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0141] In one particular embodiment, X is selected from -O-, -S-, Y is =CR4-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0142] In one particular embodiment, X is -S-, Y is =CR4-, W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0143] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0144] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0145] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0146] In one particular embodiment, X is -S-, Y is selected from =CR4-, -NR5-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0147] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0148] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0149] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0150] In one particular embodiment, X is -S-, Y is selected from =CR4-, =N-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0151] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0152] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0153] In one particular embodiment, X is selected from -O-, -S-, Y is selected from =CR4-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0154] In one particular embodiment, X is selected from -S-, Y is selected from =CR4-, -S-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0155] In one particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0156] In one particular embodiment, X is selected from -NR5-, -O-, -S-, Y is =CR4-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0157] In one particular embodiment, X is selected from -O-, -S-, Y is =CR4-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0158] In one particular embodiment, X is -S-, Y is =CR4-, W is a single bond, and the remaining R1, R2, R3, and Z are as defined above for general formula (I), and the substitution positions of R3 are 2, 3, and 5.

[0159] In one particular embodiment, R2 is an alkyl group and R1 is an alkyl group or R a The substituent is selected from alkyl groups substituted with a substituent.

[0160] In one particular embodiment, R2 is a methyl group and R1 is an alkyl group or R a The substituent is selected from alkyl groups substituted with a substituent.

[0161] In one particular embodiment, R2 is a methyl group and R1 is C 1~6 Alkyl group or R a C substituted with a substituent 1~6 The alkyl group is selected from the group consisting of aryl, ... and alkyl groups.

[0162] In one particular embodiment, R2 is a methyl group and R1 is one or more R a C substituted with a substituent 1~6 It is an alkyl group.

[0163] In one particular embodiment, R2 is a methyl group and R1 is one or more R a C substituted with a substituent 1~6 is an alkyl group, and each R a is independently selected from halogen.

[0164] In one particular embodiment, R2 is a methyl group and R1 is one or more R a C substituted with a substituent 1~6is an alkyl group, and each R a is independently selected from fluorine, chlorine, and bromine.

[0165] In one particular embodiment, R2 is a methyl group and R1 is one or more R a C substituted with a substituent 1~6 is an alkyl group, R a is fluorine.

[0166] In one particular embodiment, R2 is a methyl group and R1 is selected from isopropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-methylpropyl, 3,3,3-trifluoropropyl and 3,3,3-trifluoro-2-hydroxypropyl.

[0167] In one particular embodiment, R2 is a methyl group and R1 is 2,2,2-trifluoroethyl.

[0168] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, and R3 is the same or different and is independently selected from halogen, amino, hydroxyl, cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0169] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, and R3 are the same and are all halogen.

[0170] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, and R3 is fluorine.

[0171] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, and n is 3.

[0172] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, and n is 0.

[0173] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, and Z is selected from =CH- or =N-.

[0174] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, and Z is selected from =CH- or =N-.

[0175] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, and Z is =CH.

[0176] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, and Z is =CH.

[0177] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH and W is -CH2-.

[0178] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, and W is -CH2-.

[0179] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, and W is a single bond.

[0180] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, and W is a single bond.

[0181] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, and X is selected from =N-, -NR5-, -O-, and -S-.

[0182] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, and X is selected from =N-, -NR5-, -O-, -S-.

[0183] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, and X is selected from =N-, -NR5-, -O-, -S-.

[0184] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, and X is selected from =N-, -NR5-, -O-, -S-.

[0185] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, and X is selected from -NR5-, -O-, and -S-.

[0186] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, and X is selected from -NR5-, -O-, -S-.

[0187] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, and X is selected from -NR5-, -O-, and -S-.

[0188] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, and X is selected from -NR5-, -O-, -S-.

[0189] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, and X is selected from -O-, -S-.

[0190] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, and X is selected from -O-, -S-.

[0191] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, and X is selected from -O-, -S-.

[0192] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, and X is selected from -O-, -S-.

[0193] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, and X is -S-.

[0194] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, and X is selected from -S-.

[0195] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, and X is -S-.

[0196] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, and X is -S-.

[0197] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, and X is -O-.

[0198] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, and X is selected from -O-.

[0199] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, and X is -O-.

[0200] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, and X is -O-.

[0201] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0202] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0203] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0204] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0205] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0206] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0207] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0208] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0209] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0210] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0211] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is selected from -O-, -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0212] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from -O-, -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0213] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0214] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0215] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-, and -S-.

[0216] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-, and -S-.

[0217] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is -O-, and Y is selected from =CR4-, -O-, -NR5-, =N-, and -S-.

[0218] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0219] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is -O-, and Y is selected from =CR4-, -O-, -NR5-, =N-, and -S-.

[0220] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -O-, and Y is selected from =CR4-, -O-, -NR5-, =N-, and -S-.

[0221] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, and Y is selected from =CR4-, =N-, -S-.

[0222] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, and Y is selected from =CR4-, =N-, -S-.

[0223] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, and Y is selected from =CR4-, =N-, -S-.

[0224] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, and Y is selected from =CR4-, =N-, -S-.

[0225] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, and Y is selected from =CR4-, =N-, -S-.

[0226] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, and Y is selected from =CR4-, =N-, -S-.

[0227] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0228] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, and Y is selected from =CR4-, =N-, -S-.

[0229] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is selected from =CR4-, =N-, -S-.

[0230] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is selected from =CR4-, =N-, -S-.

[0231] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is selected from -O-, -S-, and Y is selected from =CR4-, =N-, -S-.

[0232] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from -O-, -S-, and Y is selected from =CR4-, =N-, -S-.

[0233] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is -S-, and Y is selected from =CR4-, =N-, -S-.

[0234] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -S-, and Y is selected from =CR4-, =N-, -S-.

[0235] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is -S-, and Y is selected from =CR4-, =N-, -S-.

[0236] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -S-, and Y is selected from =CR4-, =N-, -S-.

[0237] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is -O-, and Y is selected from =CR4-, =N-, -S-.

[0238] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, and Y is selected from =CR4-, =N-, -S-.

[0239] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is -O-, and Y is selected from =CR4-, =N-, -S-.

[0240] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -O-, and Y is selected from =CR4-, =N-, -S-.

[0241] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, and Y is selected from =CR4-, =N-.

[0242] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, and Y is selected from =CR4-, =N-.

[0243] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, and Y is selected from =CR4-, =N-.

[0244] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, and Y is selected from =CR4-, =N-.

[0245] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, and Y is selected from =CR4-, =N-.

[0246] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, and Y is selected from =CR4-, =N-.

[0247] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-.

[0248] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, and Y is selected from =CR4-, =N-.

[0249] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is selected from =CR4-, =N-.

[0250] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is selected from =CR4-, =N-.

[0251] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is selected from -O-, -S-, and Y is selected from =CR4-, =N-.

[0252] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from -O-, -S-, and Y is selected from =CR4-, =N-.

[0253] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is -S-, and Y is selected from =CR4-, =N-.

[0254] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -S-, and Y is selected from =CR4-, =N-.

[0255] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is -S-, and Y is selected from =CR4-, =N-.

[0256] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -S-, and Y is selected from =CR4-, =N-.

[0257] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is -O-, and Y is selected from =CR4-, =N-.

[0258] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, and Y is selected from =CR4-, =N-.

[0259] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is -O-, and Y is selected from =CR4-, =N-.

[0260] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -O-, and Y is selected from =CR4-, =N-.

[0261] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, and Y is =N-.

[0262] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, and Y is =N-.

[0263] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, and Y is =N-.

[0264] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, and Y is =N-.

[0265] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, and Y is =N-.

[0266] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, and Y is =N-.

[0267] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, and Y is =N-.

[0268] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, and Y is =N-.

[0269] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is =N-.

[0270] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is =N-.

[0271] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is selected from -O-, -S-, and Y is =N-.

[0272] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from -O-, -S-, and Y is =N-.

[0273] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is -S- and Y is =N-.

[0274] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -S-, and Y is =N-.

[0275] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is -S-, and Y is =N-.

[0276] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -S-, and Y is =N-.

[0277] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is -O- and Y is =N-.

[0278] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, and Y is =N-.

[0279] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is -O-, and Y is =N-.

[0280] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -O-, and Y is =N-.

[0281] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, and Y is =CR4-.

[0282] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, and Y is =CR4-.

[0283] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, and Y is =CR4-.

[0284] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, and Y is =CR4-.

[0285] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, and Y is =CR4-.

[0286] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, and Y is =CR4-.

[0287] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, and Y is =CR4-.

[0288] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, and Y is =CR4-.

[0289] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is =CR4-.

[0290] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is =CR4-.

[0291] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is selected from -O-, -S-, and Y is =CR4-.

[0292] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from -O-, -S-, and Y is =CR4-.

[0293] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is -S-, and Y is =CR4-.

[0294] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -S-, and Y is =CR4-.

[0295] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is -S-, and Y is =CR4-.

[0296] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -S-, and Y is =CR4-.

[0297] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is -O-, and Y is =CR4-.

[0298] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, and Y is =CR4-.

[0299] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is -O-, and Y is =CR4-.

[0300] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -O-, and Y is =CR4-.

[0301] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0302] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0303] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0304] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0305] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0306] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0307] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0308] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0309] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is selected from -O-, -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0310] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0311] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is selected from -O-, -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0312] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from -O-, -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0313] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0314] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0315] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0316] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0317] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is -CH2-, X is -O-, Y is =CR4-, and R4 is a hydrogen atom.

[0318] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, Y is =CR4- and R4 is a hydrogen atom.

[0319] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, Z is =CH, W is a single bond, X is -O-, Y is =CR4-, and R4 is a hydrogen atom.

[0320] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -O-, Y is =CR4-, and R4 is a hydrogen atom.

[0321] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, 6 or 2, 3, 5, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0322] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, 6 or 2, 3, 5, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0323] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, 6 or 2, 3, 5, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0324] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, 6 or 2, 3, 5, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0325] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, 6 or 2, 3, 5, Z is =CH, W is -CH2-, X is selected from -O-, -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0326] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, 6 or 2, 3, 5, Z is =CH, W is a single bond, X is selected from -O-, -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0327] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, 6 or 2, 3, 5, Z is =CH, W is -CH2-, X is -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0328] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, 6 or 2, 3, 5, Z is =CH, W is a single bond, X is -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0329] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, 6 or 2, 3, 5, Z is =CH, W is -CH2-, X is -O-, Y is =CR4-, and R4 is a hydrogen atom.

[0330] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, 6 or 2, 3, 5, Z is =CH, W is a single bond, X is -O-, Y is =CR4-, and R4 is a hydrogen atom.

[0331] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 6, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, and -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0332] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 6, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, and -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0333] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 6, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, and -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0334] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 6, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, and -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0335] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 6, Z is =CH, W is -CH2-, X is selected from -O- and -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0336] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 6, Z is =CH, W is a single bond, X is selected from -O- and -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0337] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, 6 or 2, 3, 5, Z is =CH, W is -CH2-, X is -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0338] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 6, Z is =CH, W is a single bond, X is -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0339] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 6, Z is =CH, W is -CH2-, X is -O-, Y is =CR4-, and R4 is a hydrogen atom.

[0340] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 6, Z is =CH, W is a single bond, X is -O-, Y is =CR4-, and R4 is a hydrogen atom.

[0341] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 5, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, and -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0342] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 5, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, and -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0343] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 5, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, and -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0344] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 5, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, and -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0345] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 5, Z is =CH, W is -CH2-, X is selected from -O- and -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0346] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 5, Z is =CH, W is a single bond, X is selected from -O- and -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0347] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 5, Z is =CH, W is -CH2-, X is -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0348] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 5, Z is =CH, W is a single bond, X is -S-, Y is =CR4-, and R4 is a hydrogen atom.

[0349] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 5, Z is =CH, W is -CH2-, X is -O-, Y is =CR4-, and R4 is a hydrogen atom.

[0350] In one particular embodiment, R2 is a methyl group, R1 is 2,2,2-trifluoroethyl, R3 is fluorine, n is 3, the substitution positions of the three fluorines are 2, 3, and 5, Z is =CH, W is a single bond, X is -O-, Y is =CR4-, and R4 is a hydrogen atom.

[0351] In the above specific embodiments, the definitions of R1, R2, R3, X, Y, W and Z not mentioned are as described for general formula (I).

[0352] In a preferred embodiment of the present application, the compound described by general formula (I) is the following compound:

[0353] [Table 1]

[0354] [Table 2]

[0355] [Table 3]

[0356] [Table 4]

[0357] [Table 5]

[0358] [Table 6]

[0359] [Table 7]

[0360] [Table 8]

[0361] [Table 9]

[0362] or a stereoisomer, tautomer, deuterated derivative, or a pharma- ceutically acceptable salt thereof. Note: If there is a difference between a drawn structure and the name given to that structure, the drawn structure takes precedence.

[0363] Further, the present application provides a pharmaceutical composition comprising an effective amount of a compound described by general formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer, deuterated derivative thereof or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, excipient, or combination thereof.

[0364] The present application provides the use of a compound described in general formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer, deuterated derivative thereof or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a CGRP receptor antagonist.

[0365] The present application also provides the use of a compound according to general formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer, deuterated derivative or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing and / or treating a disease mediated by CGRP, wherein said disease mediated by CGRP is preferably a cerebrovascular or vasculopathy disease, and said cerebrovascular or vasculopathy disease mediated by CGRP is selected from the group consisting of episodic migraine, migraine without aura, chronic migraine, pure menstrual migraine, menstrual-related migraine, migraine with aura, childhood / adolescent migraine, hemiplegic migraine, sporadic hemiplegic migraine, basilar migraine, cyclic vomiting, abdominal migraine, benign paroxysmal vertigo of childhood, retinal migraine, cluster headache, dialysis headache, chronic headache of unknown etiology, tension / stress-induced headache, allergy, -induced headaches, osteoarthritis and associated osteoporotic fracture pain, hot flashes associated with menopause or medically induced menopause due to surgery or medication, cyclic vomiting syndrome, opioid withdrawal, psoriasis, asthma, obesity, morphine tolerance, neurodegenerative diseases, epilepsy, allergic rhinitis, rosacea, toothache, earache, otitis media, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, gout, trigeminal neuralgia, nasal polyps pain due to pain in the anus, chronic sinusitis, temporomandibular joint disorder, back pain, lower back pain, cough, dystonic pain, inflammatory pain, postoperative incision pain, sciatica, complex regional pain syndrome, Behçet's disease, endometriosis, phantom limb syndrome, dysmenorrhea, pain associated with childbirth, pain due to skin burns, or chronic secondary visceral pain such as inflammatory bowel disease (including Crohn's disease, ileitis, ulcerative colitis), gastroesophageal reflux disease, dyspepsia, irritable bowel syndrome, renal colic, cystitis, pancreatitis, prostatitis.

[0366] The present application further provides the use of a compound described by general formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer, deuterated derivative thereof or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing and / or treating a cerebrovascular or vascular disorder.

[0367] The present application relates to episodic migraine, migraine without aura, chronic migraine, pure menstrual migraine, menstrual related migraine, migraine with aura, child / adolescent migraine, hemiplegic migraine, sporadic hemiplegic migraine, basilar migraine, cyclic vomiting, abdominal migraine, benign paroxysmal vertigo of childhood, retinal migraine, cluster headache, dialysis headache, chronic headache of unknown cause, tension / stress induced headache, allergy induced headache, osteoarthritis and associated osteoporotic fracture pain, hot flashes associated with menopause or medically induced menopause due to surgery or medication, cyclic vomiting syndrome, opioid withdrawal, psoriasis, asthma, obesity, morphine tolerance, neurodegenerative diseases, epilepsy, allergic rhinitis, rosacea, toothache, earache, otitis media, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia. and / or a pharmaceutical composition thereof, in the preparation of a medicament for the prevention and / or treatment of chronic secondary visceral pain such as chronic inflammatory bowel disease (including Crohn's disease, ileitis, ulcerative colitis), gastroesophageal reflux disease, dyspepsia, irritable bowel syndrome, renal colic, cystitis, pancreatitis, prostatitis, or the like.

[0368] The present application further provides a method for preventing and / or treating a disease mediated by CGRP, comprising administering to a subject a compound described in general formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer, deuterated derivative thereof or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the disease mediated by CGRP is a cerebrovascular or vasculopathy disease.

[0369] Further, the cerebrovascular or vascular disorder mediated by CGRP is selected from the group consisting of episodic migraine, migraine without aura, chronic migraine, pure menstrual migraine, menstrual-related migraine, migraine with aura, childhood / adolescent migraine, hemiplegic migraine, sporadic hemiplegic migraine, basilar migraine, cyclic vomiting, abdominal migraine, benign paroxysmal vertigo of childhood, retinal migraine, cluster headache, dialysis headache, chronic headache of unknown etiology, tension / stress-induced headache, allergy-induced headache, osteoarthritis and associated osteoporotic fracture pain, hot flashes associated with menopause or medically induced menopause due to surgery or drug treatment, cyclic vomiting syndrome, opioid withdrawal, psoriasis, asthma, obesity, morphine, rheumatoid arthritis ... The pain is selected from chronic secondary visceral pain such as inflammatory bowel disease (including Crohn's disease, ileitis, ulcerative colitis), gastroesophageal reflux disease, dyspepsia, irritable bowel syndrome, renal colic, cystitis, pancreatitis, prostatitis, and the like.

[0370] The present application further provides the use of a compound described in general formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer, deuterated derivative thereof or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prophylaxis and / or treatment of cerebrovascular or vascular disorders.

[0371] The present application relates to the treatment of episodic migraine, migraine without aura, chronic migraine, pure menstrual migraine, menstrual related migraine, migraine with aura, child / adolescent migraine, hemiplegic migraine, sporadic hemiplegic migraine, basilar migraine, cyclic vomiting, abdominal migraine, benign paroxysmal vertigo of childhood, retinal migraine, cluster headache, dialysis headache, chronic headache of unknown cause, tension / stress induced headache, allergy induced headache, osteoarthritis and associated osteoporotic fracture pain, hot flashes associated with menopause or medically induced menopause due to surgery or medication, cyclic vomiting syndrome, opioid withdrawal, psoriasis, asthma, obesity, morphine tolerance, neurodegenerative diseases, epilepsy, allergic rhinitis, rosacea, toothache, earache, otitis media, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain The present invention provides use of a compound represented by general formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer, deuterated derivative thereof or a pharmacologic acceptable salt thereof, or a pharmaceutical composition thereof, in the prophylaxis and / or treatment of chronic secondary visceral pain such as chronic inflammatory bowel disease (including Crohn's disease, ileitis, ulcerative colitis), gastroesophageal reflux disease, dyspepsia, irritable bowel syndrome, renal colic, cystitis, pancreatitis, prostatitis, or the like.

[0372] The compounds of the present application are optionally in the form of single optical isomers, single enantiomers or racemic mixtures, tautomeric forms and in the form of free bases or corresponding acid addition salts formed with pharmacologically acceptable acids.

[0373] The compounds of the present application can exist as tautomers. All tautomers of the compounds of the present application are considered to be within the scope of the present application. [Brief description of the drawings]

[0374] [Figure 1]FIG. 1 is a graph showing the blood flow rate change versus time curve (%). [Diagram 2] Figure 2 shows the area under the blood flow rate change versus time curve (%·min).

[0375] Disclosure of the Invention Unless otherwise stated, several terms used in the specification and claims of this application are defined as follows.

[0376] "Alkyl" when used as a group or part of a group means C1-C 20 It refers to a straight or branched chain aliphatic hydrocarbon group of C1 to C 10 It is preferably an alkyl group, more preferably a C1-C6 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, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted.

[0377] "Cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocycles. C3-C 12Cycloalkyl groups are preferred, C3-C8 cycloalkyl groups are more preferred, and C3-C6 cycloalkyl groups are most preferred. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., and are preferably cyclopropyl and cyclohexenyl. The cycloalkyl group may be substituted or unsubstituted as necessary.

[0378] "Heterocyclyl", "heterocycloalkyl", "heterocycle" or "heterocyclic" are used interchangeably in this application and all refer to non-aromatic heterocyclyl groups in which one or more ring-forming atoms is a heteroatom, such as oxygen, nitrogen, or sulfur atom, including monocyclic, polycyclic, fused, bridged, and spirocyclic rings, preferably 5-7 membered monocyclic rings, or 7-10 membered bicyclic or tricyclic rings, which may contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuryl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, and hexahydropyrimidine. Heterocyclyl groups can be substituted or unsubstituted.

[0379] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, which may be linked together in a fused fashion. The term "aryl" includes monocyclic or bicyclic aryl groups, such as the aromatic groups phenyl, naphthyl, and tetrahydronaphthyl. Preferred aryl groups are C6-C 10 The aryl group is preferably an aryl group, more preferably a phenyl group and a naphthyl group, and most preferably a naphthyl group. The aryl group may be substituted or unsubstituted.

[0380] "Heteroaryl" refers to an aromatic 5-6 membered monocyclic ring or 8-10 membered bicyclic ring, which may contain 1-4 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxy-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, quinolyl, indazolyl, benzoisothiazolyl, benzoxazolyl, and benzisoxazolyl. Heteroaryl may be substituted or unsubstituted.

[0381] "Alkoxy" refers to an (alkyl-O-) group. Here, the alkyl group is as defined herein. C1 to C6 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

[0382] "Hydroxy" refers to the group --OH.

[0383] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0384] "Amino" refers to -NH2.

[0385] "Cyano" refers to -CN.

[0386] "Nitro" refers to -NO2.

[0387] "Carboxy" refers to -C(O)OH.

[0388] "DMSO" refers to dimethyl sulfoxide.

[0389] "BOC" refers to tert-butoxycarbonyl.

[0390] "TFA" refers to trifluoroacetic acid.

[0391] "PMB" refers to p-methoxybenzyl.

[0392] "SEM" refers to (trimethylsilyl)ethoxymethyl.

[0393] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl.

[0394] "Aminoalkyl" refers to an alkyl group substituted with an amino.

[0395] "Leaving group" is an atom or functional group that is separated from a larger molecule in a chemical reaction, a term used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant that is attacked by the nucleophile is called the substrate, and the atom or group of atoms that leaves the substrate molecule with a pair of electrons is called the leaving group. Groups that are easy to accept electrons and have a strong negative charge are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to leave another molecule. The reason is that the smaller the pKa of the conjugate acid, the less the corresponding leaving group needs to bond with another atom, and the more likely it is to exist in the form of an anion (or an electrically neutral leaving group). Common leaving groups include, but are not limited to, halogens, methanesulfonyl, -OTs, -OTf, or -OH.

[0396] "Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently replaced with the corresponding number of substituents. Needless to say, the substituents are present only at possible chemical positions, and the skilled person can determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

[0397] As referred to herein, unless otherwise specified, "substituted" or "substituted" means that the group can be substituted by one or more substituents selected from alkyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, and hydroxyalkyl.

[0398] "Pharmaceutically acceptable salt" refers to a specific salt of the above compound that can maintain the original biological activity and is suitable for medical use. The pharmaceutically acceptable salt of the compound represented by general formula (I) may be a metal salt or an amine salt formed with a suitable acid.

[0399] It will be appreciated by those skilled in the art that salts (including pharma- ceutically acceptable salts) of compounds of general formula (I), (II), (III), (IV) or (V) can be prepared. These salts can be prepared in situ during the final isolation and purification of the compounds, or by independently reacting the purified compounds in their free acid or free base form with a suitable base or acid, respectively. Bases commonly used to form pharma-ceutically acceptable salts include organic or inorganic bases, and acids used to form pharma-ceutically acceptable salts include organic or inorganic acids.

[0400] The pharma- ceutically 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 form of these compounds with a stoichiometric amount of a suitable base, or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. These reactions are usually carried out in water, an organic solvent, or a mixture of both. Non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are usually used, as appropriate. Lists of other suitable salts can be found in "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0401] "Deuterated derivative" refers to a compound that contains carbon-bonded deuterium at at least one site on the compound, and in which the carbon-bonded deuterium content exceeds the natural content.

[0402] "Pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or physiologically pharmaceutical acceptable salts or prodrugs thereof, and other chemical components, together with other components, such as physiologically pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living body and promote absorption of the active ingredient to exert its biological activity.

[0403] The pharmaceutical compositions of the present application can be formulated for a particular route of administration, such as oral administration, parenteral administration, or rectal administration. Furthermore, the pharmaceutical compositions of the present application can be prepared in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including, but not limited to, solutions, suspensions, or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations (e.g., sterilization) and / or can contain conventional inert diluents, lubricants, or buffers, as well as auxiliary materials such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[0404] Typically, a pharmaceutical composition comprises an active ingredient and a) diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine; b) lubricants, such as silicon dioxide, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; in the case of tablets, c) binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, d) disintegrants such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) Absorbents, colourants, flavourings and sweeteners; A tablet or capsule comprising:

[0405] Tablets may be film coated or enteric coated according to methods known in the art.

[0406] Compositions suitable for oral administration include an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the form of a tablet, tablet, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule, or syrup or elixir. Compositions for oral use may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and in order to provide an elegant and palatable preparation, the composition may contain one or more selected from sweeteners, flavoring agents, coloring agents, and preservatives. Tablets may contain the active ingredient mixed with non-toxic pharma- ceutically acceptable excipients suitable for the manufacture of tablets. These excipients include, for example, inert diluents (such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents (such as corn starch, alginic acid), binding agents (such as starch, gelatin, gum arabic), and lubricants (such as magnesium stearate, stearic acid, or talc). Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over an extended period of time. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral administration are provided in hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (such as calcium carbonate, calcium phosphate, or kaolin), or in soft gelatin capsules in which the active ingredient is mixed with water or an oil vehicle (such as peanut oil, liquid paraffin, or olive oil).

[0407] Certain injectable compositions are isotonic aqueous solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may be sterilized and / or contain auxiliary substances such as preservatives, stabilizing agents, wetting agents or emulsifying agents, dissolution promoters, salts for adjusting osmotic pressure and / or buffers. In addition, other therapeutically valuable substances may also be included. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75% or about 1-50% of the active ingredient.

[0408] Because water may facilitate the 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.

[0409] The anhydrous pharmaceutical compositions and dosage forms of the present application can be prepared using anhydrous or low moisture ingredients and low moisture or low humidity conditions. The anhydrous pharmaceutical composition can be prepared and stored to maintain its anhydrous properties. Thus, the anhydrous composition is packaged using materials known to prevent contact with water so that it can be included in a suitable formulation kit. Examples of suitable packaging include, but are not limited to, airtight foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0410] The present application further provides pharmaceutical compositions and dosage forms that contain one or more agents that reduce the rate of decomposition of the active ingredient, the compound of the present application. Such agents (herein referred to as "stabilizers") include, but are not limited to, antioxidants (e.g., ascorbic acid), pH buffers, or salt buffers, etc.

[0411] For an individual of about 50-70 kg, the pharmaceutical composition or combination product of the present application may be a unit dose of about 1-1000 mg of active ingredient, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredient. The therapeutically effective amount of the compound, pharmaceutical composition or combination product thereof depends on the species, weight, age and individual condition of the individual, the condition or disease being treated, or its severity. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the progression of the condition or disease.

[0412] "Stereoisomer" of a compound having a given stereochemical configuration refers to the opposite enantiomer of the compound, and all diastereomers, including the geometric isomer (Z / E) of the compound. For example, if a compound has an S,R,Z stereochemical configuration, then the stereoisomers include the opposite enantiomer of the R,S,Z configuration, and diastereomers of the S,S,Z configuration, the R,R,Z configuration, the S,R,E configuration, the R,S,E configuration, the S,S,E configuration, and the R,R,E configuration. If the stereochemical configuration of the compound is not specified, "stereoisomer" refers to any of the possible stereochemical configurations of the compound.

[0413] The compounds of general formula (I), (II), (III), (IV) or (V), their stereoisomers, or tautomers of the compounds of general formula (I), (II), (III), (IV) or (V) or complexes of their stereoisomers can be administered alone or in combination with one or more pharma- ceutically active compounds. In general, one or more of these compounds are administered in the form of a pharmaceutical composition (formulation) in combination with one or more pharma- ceutically acceptable excipients. The choice of excipient depends, among other things, on the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Useful pharmaceutical compositions and methods for their preparation can be found, for example, in A. R. Gennaro (Ed.), Remington: Pharmaceutical Science and Practice (20th ed., 2000).

[0414] The compounds of the present application may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present application are contemplated within the scope of the present invention, including, but not limited to, diastereoisomers, enantiomers, and atropisomers and geometric (conformational) isomers, as well as mixtures thereof, such as racemic mixtures.

[0415] Unless otherwise indicated, structures depicted herein include all isomers of the structure (e.g., diastereomeric, enantiomeric, atropisomers, and geometric (conformational) isomeric forms; e.g., R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) structural isomers, etc.). Thus, all individual stereoisomers and enantiomeric mixtures, diastereomeric mixtures, and geometric (conformational) isomeric mixtures of the compounds of the present application are within the scope of the present application.

[0416] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, which can be divided into two types: cis-trans isomers and enantiomers, or into two types: enantiomers and diastereomers. A stereoisomer is a type of isomer. Isomers in a molecule in which the atoms or groups of atoms are connected in the same order, but in a different spatial arrangement, are called stereoisomers.

[0417] The term "substantially enantiomerically pure" refers to an enantiomeric purity of greater than 90% at a given stereocenter. Thus, the term "substantially enantiomerically pure" refers to greater than 80% ee (enantiomeric excess). In the case of compounds that exist as stereoisomers, such stereoisomers may be substantially enantiomerically pure at the stereocenter, or preferably have an enantiomeric purity of greater than 97%, more preferably an enantiomeric purity of greater than 99%.

[0418] Method for synthesizing the compounds of the present application In order to achieve the objectives of this application, this application adopts the following technical solutions:

[0419] The present application provides a process for preparing a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative, or a pharma- ceutically acceptable salt thereof, the process comprising:

[0420] [ka]

[0421] Includes.

[0422] A compound represented by general formula (Ib) is obtained by electrophilic addition and rearrangement of a compound represented by general formula (Ia), a compound represented by general formula (Ib) is obtained by chlorination reaction of a compound represented by general formula (Ic), a compound represented by general formula (Ie) is obtained by cyclization reaction of a compound represented by general formula (Ic) with a compound represented by general formula (Id), a compound represented by general formula (Ie) is obtained by deprotection of the compound represented by general formula (Ie) and a compound represented by general formula (If) is obtained by condensation reaction of a compound represented by general formula (If) with a compound represented by general formula (Ig); Where: PG is an amino protecting group, X or Y are the same or different and each independently

[0423] [ka]

[0424] is selected from The definitions of R1, R2, R3, W, Z and n are as described for general formula (I). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0425] The present application will now be further described by way of examples, which are not intended to limit the scope of the present application.

[0426] Working Example The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. It should be noted that the following examples are used to illustrate the present application, but are not intended to limit the present application. 1 H NMR spectra were recorded on a Bruker instrument (400 MHz) and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadening, dd = doublet of doublets, dt = doublet of triplets. Coupling constants, if given, are in Hz.

[0427] Mass spectra were measured on an LC / MS instrument, and ESI or APCI ionization methods can be used.

[0428] Silica gel plates for thin layer chromatography use Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates, the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.2mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm.

[0429] In column chromatography, Yantai Yellow Sea silica gel 200-300 mesh silica gel is usually used as the carrier.

[0430] In the following examples, all temperatures are in degrees Celsius unless otherwise noted, and various starting materials and reagents were either commercially available or synthesized according to known methods unless otherwise noted, and commercially available materials and reagents were used directly without further purification unless otherwise specified. Commercially available manufacturers include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co.KG, Acros Organics, Guangzhan Chemical Technology Co., Ltd., and Jingyan Chemical Technology Co., Ltd. CD3OD: deuterated methanol. CDCl3: deuterated chloroform. DMSO-d6: deuterated dimethyl sulfoxide. D2O: Heavy water.

[0431] In the examples, unless otherwise specified, the solution in the reaction refers to an aqueous solution.

[0432] The compounds are purified using C18 reverse phase column preparative or semi-preparative purification, silica gel column chromatography eluent system and thin layer chromatography, where the eluent system is selected from A: petroleum ether and tetrahydrofuran system, B: acetonitrile and water system, C: petroleum ether and ethyl acetate system, the volume ratio of the solvents varies according to the polarity of the compounds, and can also be adjusted by adding a small amount of acidic or alkaline reagents such as trifluoroacetic acid, acetic acid, triethylamine, etc.

[0433] Example 1 N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0434] [ka]

[0435] [ka]

[0436] Step 1 Diethyl 3,3'-(2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-3,3-diyl)dipropionate 1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one 1a (2 g, 7.56 mmol) was dissolved in dimethyl sulfoxide (13 mL), potassium tert-butoxide solution (1 M, 378.22 μL) was added, and the mixture was stirred at 25° C. for 10 minutes. Ethyl acrylate 1b (1.59 g, 15.89 mmol) was slowly added dropwise at 45° C., and the mixture was stirred for 1 hour. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (40 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (eluent: System A) to obtain diethyl 3,3'-(2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-3,3-diyl)dipropionate 1c (2.4 g). Yield: 61.46%. MS m / z(ESI): 465.3 [M+1]

[0437] Step 2 Diethyl 3,3'-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-3,3-diyl)dipropionate Diethyl 3,3'-(2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-3,3-diyl)dipropionate 1c (2.4 g, 5.17 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (20 mL) was added, and the mixture was stirred at 25°C for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, tetrahydrofuran (20 mL), triethylamine (10 mL), and aqueous ammonia (20 mL) were added, and the mixture was stirred at 25° C. for 1 hour. The mixture was then concentrated under reduced pressure, the pH was adjusted to 6 with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain diethyl 3,3'-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-3,3-diyl)dipropionate 1d (1.6 g), which was used directly in the next reaction without purification. MS m / z(ESI): 335.2 [M+1]

[0438] Step 3 Ethyl 2',4-dioxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-3-carboxylate Diethyl 3,3'-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-3,3-diyl)dipropionate 1d (1.5 g, 4.49 mmol) was dissolved in tetrahydrofuran (30 mL), potassium tert-butoxide solution (1 M, 13.46 mL) was slowly added dropwise at low temperature, and stirred for 20 minutes. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain ethyl 2',4-dioxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-3-carboxylate 1e (1.2 g), which was directly used in the next reaction without purification. MS m / z(ESI): 289.3 [M+1]

[0439] Step 4 Spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione Ethyl 2',4-dioxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-3-carboxylate 1e (1.1 g, 3.82 mmol) was dissolved in 3M hydrochloric acid (50 mL), methanol (5 mL) and dioxane (10 mL) were added, and the reaction solution was stirred at 100°C for 2 hours, then concentrated under reduced pressure and adjusted to pH 8 with saturated sodium bicarbonate solution. Extracted three times with a mixed solution of ethyl acetate and tetrahydrofuran, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine-2',4(1'H)-dione 1f (700 mg). Yield: 84.8%. MS m / z(ESI): 217.1 [M+1] 1H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.20 (dd, J = 5.6, 1.6 Hz,1H),7.51 (dd, J = 7.2, 1.6 Hz,1H), 7.01 (dd, J = 7.2, 5.2 Hz,1H), 3.18-3.10 (m, 2H), 2.48-2.310 (m, 2H), 2.26-2.13 (m, 4H).

[0440] Step 5 1'-(4-Methoxybenzyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione Spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine-2',4(1'H)-dione 1f (0.54g, 2.5mmol) and cesium carbonate (1.22g, 3.75mmol) were added to N,N-dimethylformamide (3mL), p-methoxybenzyl chloride (470mg, 3.0mmol) was slowly added dropwise, and the mixture was reacted at 10°C for 16 hours. The reaction was monitored by LC-MS, and after the reaction was completed, the reaction solution was poured into water (20mL), extracted with ethyl acetate (30mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: system A) to obtain 1'-(4-methoxybenzyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 1g (670mg). Yield: 79.7%. MS m / z(ESI): 337.2 [M+1]

[0441] Step 6 3-((Dimethylamino)methylene)-1'-(4-methoxybenzyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 1'-(4-Methoxybenzyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 1g (0.75 g, 2.23 mmol) was dissolved in dichloromethane (10 mL), and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (700 mg, 4.01 mmol) was added and reacted at 60°C for 16 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was poured into water (30 mL), extracted with ethyl acetate (40 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-((dimethylamino)methylene)-1'-(4-methoxybenzyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 1h (1.2 g), which was directly used in the next reaction without purification. MS m / z(ESI): 391.9 [M+1]

[0442] Step 7 4-Chloro-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-3-ene-3-carbaldehyde 3-((dimethylamino)methylene)-1'-(4-methoxybenzyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 1h (1.2 g) was dissolved in dichloromethane (10 mL), phosphorus oxychloride (1.14 g, 9.88 mmol) was slowly added, and the mixture was reacted at 10°C for 3 hours. The reaction was monitored by LC-MS, and after completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (eluent: system A) to obtain 4-chloro-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-3-ene-3-carbaldehyde 1i (350 mg). Yield: 27.76%. MS m / z(ESI): 383.2 [M+1]

[0443] Step 8 1'-(4-Methoxybenzyl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 4-Chloro-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-3-ene-3-carbaldehyde 1i (0.1 g, 261.3 μmol) and ethyl 2-hydroxyacetate 1j (119.65 mg, 1.15 mmol) were dissolved in tetrahydrofuran (2 mL), cooled to 0 degrees Celsius, sodium hydride (39.7 mg, 992.58 μmol, purity 60%) was added, and the temperature was raised to 90°C under nitrogen protection and stirred for 4 hours. The reaction was monitored by LC-MS, and after completion of the reaction, the reaction solution was poured into saturated ammonium chloride solution (5 mL), extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (eluent: system A) to obtain 1'-(4-methoxybenzyl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 1k (42 mg). Yield: 37%. MS m / z(ESI): 433.3 [M+1]

[0444] Step 9 2'-Oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 1'-(4-Methoxybenzyl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 1k (62 mg, 138.23 μmol) and aluminum trichloride (41.74 mg, 276.46 μmol) were added to anisole (1 mL), heated to 130 °C, reacted for 4 hours, and the reaction was monitored by LC-MS. After the reaction was completed, the reaction solution was poured into water (5 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified and separated by thin layer plate to obtain 2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 1l (35 mg). Yield: 77%. MS m / z(ESI): 312.9 [M+1]

[0445] Step 10 2'-Oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 2'-Oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 1l (30 mg, 96.06 μmol) was added to 1.6 mL of a mixed solution (tetrahydrofuran:methanol:water = 10:3:3), sodium hydroxide (11.53 mg, 288.17 μmol) was added, and the mixture was stirred at 10 ° C for 16 hours. The reaction was monitored by LC-MS, and after the reaction was completed, it was concentrated under reduced pressure, 2 mL of water was added to the residue, the pH was adjusted to 5 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL × 3). Concentration under reduced pressure gave 2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m (25 mg), which was used directly in the next reaction without purification. MS m / z(ESI): 285.2 [M+1]

[0446] Step 11 3-Amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 9mL of 1,4-dioxane solution was added to (6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl) tert-butyl carbamate 1n (885mg, 2.01mmol, prepared according to the method described in patent application WO2012064910) and 4M hydrochloric acid, and the reaction was carried out at 25°C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p (753mg). Yield: 89%. MS m / z(ESI): 341.1 [M+1]

[0447] Step 12 N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 2'-Oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m (25 mg, 87.95 μmol) was added to N,N-dimethylformamide (0.5 mL), followed by 3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p (26.51 mg, 70.36 μmol), N,N-diisopropylethylamine (56.72 mg, 439.73 μmol), and 1-hydroxybenzotriazole (23.77 mg, 175.89 μmol). Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33.6 mg, 175.89 μmol) was added and stirred at 25° C. for 4 hours. The reaction was monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, and the resulting residue was separated on a C18 reverse phase column (eluent: B system) to obtain N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 1 (17 mg). Yield: 31.87%. MS m / z(ESI): 606.8 [M+1] 1 H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 5.2 Hz, 1H), 7.20-7.07 (m, 2H), 7.00-6.83 (m, 3H), 4.94-4.88 (m, 1H), 4.58-4.47 (dd, J = 12.0, 6.8 Hz, 1H), 4.01-3.93 (m, 2H),3.35-3.25 (m, 1H), 3.14 (d, J = 16 Hz, 1H), 3.03-2.95 (m, 1H), 2.87-2.71 (m, 3H), 2.53 (d, J = 16 Hz, 1H), 2.43-2.35 (m, 1H), 1.95-1.90 (m, 1H), 1.26-1.22 (m, 3H).

[0448] Example 1A (R)-N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 1A

[0449] Example 1B (R)-N-((3R,5R,6S)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 1B

[0450] Example 1C (S)-N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 1C

[0451] Example 1D (S)-N-((3R,5R,6S)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 1D

[0452] [ka]

[0453] [ka]

[0454] [ka]

[0455] Step 1 1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione Cesium carbonate (12.3 g, 37.87 mmol) and 1,5-dichloropentan-3-one (2.2 g, 14.19 mmol) were added in sequence to a solution of 1-((2-(trimethylsilyl)ethoxy))methyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one 1a (2.5 g, 9.46 mmol) in tetrahydrofuran (100 mL), and the mixture was stirred at 70 ° C for 48 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, the solid was washed with dichloromethane, the organic phase was concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (eluent: C system) to obtain 1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 1q (0.5 g). Yield: 15.2%. MS m / z(ESI): 347.2 [M+1] 1 H NMR (400 MHz, CDCl3) δ 8.26 (dd, J = 1.3, 5.2 Hz, 1H), 7.51 (dd, J = 1.4, 7.4 Hz, 1H), 7.02 (dd, J = 5.3, 7.3 Hz, 1H), 5.29 (s, 2H), 3.79-3.60 (m, 2H), 3.23-3.05 (m, 2H), 2.50 (td, J = 5.3, 15.3 Hz, 2H), 2.30-2.04 (m, 4H), 1.06-0.85 (m, 2H), 0.02 (s, 9H).

[0456] Step 2 3-((Dimethylamino)methylene)-1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 1q (2.14g, 6.18mmol) was dissolved in dichloromethane (40mL), 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (2.37g, 13.6mmol) was added, and the mixture was heated to 60°C and reacted for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (eluent: system A) to obtain 3-((dimethylamino)methylene)-1'-((2-(trismethylsilyl)ethoxy)methyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 1r (2.46g). Yield: 99%. MS m / z(ESI): 402.3 [M+1]

[0457] Step 3 4-Chloro-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-3-ene-3-carbaldehyde 3-((dimethylamino)methylene)-1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 1r (2.0 g, 4.98 mmol) was dissolved in dichloromethane (50 mL) and phosphorus oxychloride (2.37 g, 15.44 mmol) was added at 0° C. and stirring was continued at 0° C. for 1.5 h. After the reaction was completed, saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane (120mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (eluent: System A) to obtain 4-chloro-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-3-ene-3-carbaldehyde 1s (1.47g). Yield: 67.60%. MS m / z(ESI): 393.3 [M+1]

[0458] Step 4 2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl Under nitrogen protection, 4-chloro-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-3-ene-3-carbaldehyde 1s (1.37 g, 3.49 mmol) and ethyl 2-hydroxyacetate 1j (1.63 g, 15.69 mmol) were dissolved in tetrahydrofuran (35 mL), sodium hydride (557.83 mg, 13.95 mmol, purity 60%) was added at 20 ° C., and the reaction was carried out at 85 ° C. for 3 hours. After the reaction was completed, the reaction solution was slowly poured into an ice-cooled saturated aqueous ammonium chloride solution, extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: system A) to obtain ethyl 2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 1t (560 mg). Yield: 32.66%. MS m / z(ESI): 443.3 [M+1]

[0459] Step 5 (S)-2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl ester 1t-A (R)-2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl ester 1t-B Ethyl 2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 1t (500 mg, 1.13 mmol) was purified by chiral separation using SFC (column model: Waters SFC-150, Dnicel IG, 20 × 250 mm, 10 μm; mobile phase: A for CO2, B for ethanol; detection wavelength: 214 nm, column temperature: 40 °C) to obtain a single configuration compound (shorter retention time) and a single configuration compound (longer retention time). Single configuration compounds (short retention time): 180 mg, yield: 32.4%, retention time 1.128 min, chiral purity 100% ee. MS m / z(ESI):443.3 [M+1] Single configuration compounds (long retention time): 186 mg, yield: 33.4%, retention time 1.522 min, chiral purity 100% ee. MS m / z(ESI):443.2 [M+1]

[0460] Step 6 (S)-Ethyl 2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 1l-A (R)-Ethyl 2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 1l-B The chiral resolved (S)-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 1t-A (180 mg, 406.32 μmol) or (R)-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 1t-B (180 mg, 406.32 μmol) was dissolved in tetrahydrofuran (3 mL) and stirred at 25°C for 3 hours to complete the reaction. After that, the mixture was concentrated under reduced pressure, tetrahydrofuran (3 mL) and ammonia (0.5 mL) were added, and the mixture was stirred at 25°C for 0.5 hours. The residue obtained by concentrating the mixture under reduced pressure was separated and purified by column chromatography (eluent: system A) to obtain (S)-ethyl 2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 1l-A (114 mg) (yield: 85%) and (R)-ethyl 2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 1l-B (126 mg) (yield: 99%), respectively. MS m / z(ESI):313.2 [M+1] MS m / z(ESI):313.2 [M+1]

[0461] Step 7 (S)-2'-Oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m-A (R)-2'-Oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m-B (S)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 1l-A (114 mg, 365.01 μmol) or (R)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 1l-B (126 mg, 403.43 μmol) was dissolved in 4.5 mL of a mixed solution (methanol: tetrahydrofuran: water = 3: 1: 0.5), sodium hydroxide (43.80 mg, 1.10 mmol) was added, and the mixture was stirred at 40 ° C. for 1 hour. After the reaction was completed, the pH was adjusted to 6 with 1M dilute hydrochloric acid and concentrated under reduced pressure to obtain (S)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m-A (150 mg) and (R)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m-B (180 mg), which were directly used in the next reaction without purification. MS m / z(ESI):285.1[M+1] MS m / z(ESI):285.2[M+1]

[0462] Step 8 ((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl) tert-butylcarbamate 1n-A ((3R,5R,6S)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl) tert-butylcarbamate 1n-B After purification of tert-butyl (6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)carbamate 1n (2.6 g, 5.90 mmol) by chiral separation using SFC (column model: Waters SFC-150, Dnicel IG, 20 × 250 mm, 10 μm; mobile phase: A for CO2, B for ethanol; detection wavelength: 214 nm, column temperature: 40 °C), a single configuration compound (shorter retention time) and a single configuration compound (longer retention time) were obtained. Single configuration compounds (short retention time): 1.3g, yield: 50%, retention time 0.900 min, chiral purity 100% ee. MS m / z(ESI):462.8 [M+1] Single configuration compounds (long retention time): 1.2g, yield: 46%, retention time 1.239 min, chiral purity 99.8% ee. MS m / z(ESI):462.8 [M+1]

[0463] Step 9 (3S,5S,6R)-3-Amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p-A (3R,5R,6S)-3-Amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p-B ((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)tert-butylcarbamate 1n-A (500 mg, 1.14 mmol) or ((3R,5R,6S)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)tert-butylcarbamate 1n-B (500 mg, 1.14 mmol) was dissolved in 6 mL of dioxane hydrochloride solution and reacted at 25° C. for 2 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain (3S,5S,6R)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p-A and (3R,5R,6S)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p-B, which were directly used in the next reaction without purification. MS m / z(ESI):314.2[M+1] MS m / z(ESI):314.2[M+1]

[0464] Step 10 (R)-N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 1A (S)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m-A (7 mg, 24.62 μmol), (3S,5S,6R)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p-A (10.20 mg, 2 7.09 μmol), 1-hydroxybenzotriazole (6.65 mg, 49.25 μmol) and N,N-diisopropylethylamine (15.91 mg, 123.12 μmol) were dissolved in N,N-dimethylformamide (0.5 mL), and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.44 mg, 49.25 μmol) was added and the mixture was stirred at 25° C. for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was separated using a C18 reverse phase column (eluent: B system) to obtain (R)-N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 1A (7 mg). Yield: 46.8%. MS m / z(ESI):607.3[M+1] 1 H NMR (400 MHz, CDCl3) δ 8.14 (dd, J = 5.2, 1.2 Hz, 1H), 7.14-7.06 (m, 2H), 6.99 (s, 1H), 6.90-6.83 (m, 2H), 4.94-4.82 (m, 1H), 4.60-4.55 (m, 1H), 3.99-3.92 (m, 2H), 3.37-3.27 (m, 1H), 3.11 (d, J = 16.0 Hz, 1H), 2.99-2.71 (m, 4H), 2.52 (d, J = 8.0 Hz, 1H), 2.41-2.33 (m, 1H), 1.94-1.89 (m, 1H), 1.23 (t, J = 6.4 Hz, 3H).

[0465] Step 11 (R)-N-((3R,5R,6S)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 1B (S)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m-A (7 mg, 24.62 μmol), (3R,5R,6S)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p-B (10.20 mg, 2 7.09 μmol), 1-hydroxybenzotriazole (6.65 mg, 49.25 μmol) and N,N-diisopropylethylamine (15.91 mg, 123.12 μmol) were dissolved in N,N-dimethylformamide (0.5 mL), and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.44 mg, 49.25 μmol) was added and the mixture was stirred at 25° C. for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain (R)-N-((3R,5R,6S)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 1B (3.8 mg). Yield: 25.4%. MS m / z(ESI):607.4[M+1] 1H NMR (400 MHz, CDCl3) δ 8.13-8.12 (m, 1H), 7.14-7.08 (m, 2H), 6.99 (s, 1H), 6.89-6.83 (m, 2H), 4.94-4.79 (m, 1H), 4.50-4.45 (m, 1H), 3.99-3.92 (m, 2H), 3.35-3.25 (m, 1H), 3.13 (d, J = 16.0 Hz, 1H), 3.01-2.76 (m, 4H), 2.52 (d, J = 16.0 Hz, 1H), 2.41-2.34 (m, 1H), 1.92 (dd, J = 13.2, 5.6 Hz, 1H), 1.25 (t, J = 6.4 Hz, 3H).

[0466] Step 12 (S)-N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 1C (R)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m-B (7 mg, 24.62 μmol), (3S,5S,6R)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p-A (10.20 mg, 2 7.09 μmol), 1-hydroxybenzotriazole (6.65 mg, 49.25 μmol) and N,N-diisopropylethylamine (15.91 mg, 123.12 μmol) were dissolved in N,N-dimethylformamide (0.5 mL), and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.44 mg, 49.25 μmol) was added and the mixture was stirred at 25° C. for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was separated using a C18 reverse phase column (eluent: B system) to obtain (S)-N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 1C (10 mg). Yield: 66.9%. MS m / z(ESI):607.4[M+1] 1 H NMR (400 MHz, CDCl3) δ 8.14-8.12 (m, 1H), 7.13-7.09 (m, 2H), 6.99 (s, 1H), 6.89-6.84 (m, 2H), 4.92-4.86 (m, 1H), 4.50-4.45 (m, 1H), 3.99-3.92 (m, 2H), 3.32-3.27 (m, 1H), 3.13 (d, J = 16.0 Hz, 1H), 3.01-2.73 (m, 4H), 2.52 (d, J = 16.0 Hz, 1H), 2.42-2.34 (m, 1H), 1.93-1.89 (m, 1H), 1.25 (t, J = 6.4 Hz, 3H).

[0467] Step 13 (S)-N-((3R,5R,6S)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 1D (R)-2'-Oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m-B (7 mg, 24.62 μmol), (3R,5R,6S)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p-B (10.20 mg, 2 7.09 μmol), 1-hydroxybenzotriazole (6.65 mg, 49.25 μmol) and N,N-diisopropylethylamine (15.91 mg, 123.12 μmol) were dissolved in N,N-dimethylformamide (0.5 mL), and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.44 mg, 49.25 μmol) was added and the mixture was stirred at 25° C. for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain (S)-N-((3R,5R,6S)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 1D (5 mg). Yield: 33.5%. MS m / z(ESI):607.4[M+1] 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 5.2 Hz, 1H), 7.14-7.07 (m, 2H), 6.99 (s, 1H), 6.91-6.84 (m, 2H), 4.94-4.79 (m, 1H), 4.60-4.55 (m, 1H), 3.99-3.94 (m, 2H), 3.38-3.27 (m, 1H), 3.12 (d, J = 16.0 Hz, 1H), 3.00-2.71 (m, 4H), 2.52 (d, J = 16.0 Hz, 1H), 2.41-2.33 (m, 1H), 1.94-1.90 (m, 1H), 1.23 (t, J = 6.0 Hz, 3H).

[0468] Example 2 N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzo[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0469] [ka]

[0470] [ka]

[0471] Step 1 1'-(4-Methoxybenzyl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzo[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 4-Chloro-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-3-ene-3-carbaldehyde 1i (150 mg, 391.81 μmol) and ethyl 2-mercaptoacetate 2a (306.51 mg, 2.55 mmol) were dissolved in N,N-dimethylformamide (4 mL), sodium hydride (101.87 mg, 2.55 mmol, purity 60%) was added at 0 degrees Celsius, and the mixture was stirred under nitrogen protection for 1 hour and at 25°C for 30 minutes. After the reaction was completed by monitoring with LC-MS, the reaction solution was poured into saturated ammonium chloride solution (5 mL), extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified and separated by thin-layer plate to obtain ethyl 1'-(4-methoxybenzyl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzo[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 2b (130 mg). Yield: 66.58%. MS m / z(ESI): 449.4 [M+1] 1 H NMR (400 MHz, CDCl3) δ 8.16 (dd, J = 5.6, 1.6 Hz, 1H), 7.47 (s, 1H), 7.43 - 7.40 (m, 2H), 6.97 (dd, J = 5.6, 1.6 Hz, 1H), 6.84-6.78 (m, 3H), 4.96 (dd, J = 14.0, 4.4 Hz, 2H), 4.33 (q, J = 7.2 Hz, 2H), 3.76 (s, 3H), 3.24-3.11 (m, 2H), 2.99-2.90 (m, 1H),2.61 (d, J = 16.0 Hz, 1H), 2.39-2.31 (m, 1H), 1.82 1.77 (m, 1H), 1.36 (t, J = 7.2 Hz, 3H).

[0472] Step 2 1'-(4-Methoxybenzyl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzo[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid Ethyl 1'-(4-methoxybenzyl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzo[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 2b (20 mg, 44.59 μmol) was dissolved in trifluoroacetic acid (0.3 mL) and trifluoromethanesulfonic acid (1 mL), stirred at 130°C for 3 hours, and monitored by LC-MS. After completion of the reaction, the reaction solution was diluted with water ( The mixture was added with 15 mL of ethyl acetate, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated using a C18 reverse phase column (eluent: B system) to obtain 1'-(4-methoxybenzyl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzo[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 2c (10 mg). Yield: 67.21%. MS m / z(ESI): 301.1 [M+1]

[0473] Step 3 N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzo[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 1'-(4-Methoxybenzyl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzo[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 2c (10 mg, 33.30 μmol), 3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p (12.54 mg , 33.30 μmol), 1-hydroxybenzotriazole (9.00 mg, 66.59 μmol), and N,N-diisopropylethylamine (21.52 mg, 166.48 μmol) were dissolved in N,N-dimethylformamide (0.5 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.77 mg, 66.59 μmol) was added, and the mixture was stirred at 25° C. for 18 hours. After the reaction was completed, it was monitored by LC-MS and concentrated under reduced pressure, water (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated using a C18 reverse phase column (eluent: B system) to obtain N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzo[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 2 (6 mg). Yield: 27.50%. MS m / z(ESI): 622.9 [M+1] 1H NMR (400 MHz, CDCl3) δ 8.32-8.23 (m, 1H), 8.14-8.13 (m, 1H), 7.24-7.23 (m, 1H), 7.14-7.00 (m, 3H), 6.90-6.82 (m, 2H), 4.95-4.83 (m, 1H), 4.53-4.47 (m, 1H), 3.99-3.94 (m, 2H), 3.35-3.14 (m, 3H), 3.03-2.93 (m, 1H), 2.83-2.80 (m, 2H), 2.66-2.60 (m, 1H), 2.41-2.33 (m, 1H), 1.95-1.90 (m, 1H), 1.25 (d, J = 6.0 Hz, 3H).

[0474] Example 3 N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0475] [ka]

[0476] [ka]

[0477] Step 1 1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridin]-3-en-2'(1'H)-one 1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one 1a (770 mg, 2.91 mmol) was dissolved in N,N-dimethylformamide (12 mL), and cesium carbonate (2.37 g, 7.28 mmol) and (Z)-1,4-dichlorobutan-2-ene 3a (364.03 mg, 2.91 mmol) were added at 0° C., followed by stirring at 25° C. for 18 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (eluent: C system) to obtain 1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridin]-3-en-2'(1'H)-one 3b (780 mg). Yield: 84.63%. MS m / z(ESI): 317.0 [M+1] 1 H NMR (400 MHz, DMSO-d6) δ 8.14-8.10 (m, 1H), 7.56-7.44 (m, 1H), 7.04-7.00 (m, 1H), 5.90-5.82 (m, 1H), 5.36-5.05 (m, 3H), 3.59-3.51 (m, 2H), 2.83-2.70 (m, 1H), 2.57-2.51 (m, 1H), 2.18-2.15 (m, 1H), 2.01-1.83 (m, 1H), 0.83-0.77 (m, 2H), 0.13-0.11 (m, 9H).

[0478] Step 2 1'-((2-(trimethylsilyl)ethoxy)methyl)-6-oxaspiro[bicyclo[3.1.0]hexane-3,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one 1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridin]-3-en-2'(1'H)-one 3b (23 g, 72.7 mmol) was dissolved in dichloromethane (400 mL), m-chloroperoxybenzoic acid (25.1 g, 14.5 mmol) was added at low temperature, and the mixture was reacted at room temperature for 24 hours under nitrogen protection. After the reaction was completed, dichloromethane (100 mL) was added to the reaction solution, which was then vacuum filtered. The filtrate was washed with sodium thiosulfate solution (200 mL x 2) and saturated sodium bicarbonate solution (200 mL), respectively. The organic phase was washed with water (300 mL) and saturated saline (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (eluent: C system) to obtain 1'-((2-(trimethylsilyl)ethoxy)methyl)-6-oxaspiro[bicyclo[3.1.0]hexane-3,3'-pyrrolo[2,3-b]pyridine]-2'(1'H)-one 3c (4.9 g). Yield: 20.3%. MS m / z(ESI): 333.1 [M+1]

[0479] Step 3 3-Hydroxy-1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one 1'-((2-(trimethylsilyl)ethoxy)methyl)-6-oxaspiro[bicyclo[3.1.0]hexane-3,3'-pyrrolo[2,3-b]pyridine]-2'(1'H)-one 3c (1.2 g, 3.61 mmol) was dissolved in ethanol (45 mL), 10% palladium carbon (1.20 g, 988.06 μmol) was added, and the mixture was stirred at 90°C for 24 hours under nitrogen protection. After the reaction was completed, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (eluent: C system) to obtain 3-hydroxy-1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridine]-2'(1'H)-one 3d (460 mg). Yield: 34.29%. MS m / z(ESI): 335.3 [M+1] 1 H NMR (400 MHz, CDCl3) δ 8.17 (dd, J = 5.6, 1.6 Hz, 1H), 7.76 (dd, J = 7.6, 1.6 Hz, 1H), 6.98 (dd, J = 7.2, 1.2 Hz, 1H), 5.23 (s, 2H), 4.75-4.72 (m, 1H), 3.67-3.63 (m, 2H), 2.45 (dd, J = 14.4, 5.2 Hz, 1H), 2.29-2.14 (m, 3H), 2.02-1.95 (m, 1H), 1.89 (dt, J = 14.0, 2.4 Hz, 1H), 0.98-0.94 (m, 2H), 0.05 (s, 9H).

[0480] Step 4 1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridine]-2',3(1'H)-dione 3-Hydroxy-1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridine]-2'(1'H)-one 3d (740 mg, 2.21 mmol) was dissolved in dichloromethane (20 mL), Dess-Martin oxidant (1.97 g, 4.65 mmol) was added, and the mixture was stirred at 30°C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The resulting residue was purified and separated using a thin layer plate to obtain 1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridine]-2',3(1'H)-dione 3e (640 mg). Yield: 78.31%. MS m / z(ESI): 332.9 [M+1] 1H NMR (400 MHz, CDCl3) δ 8.25 (dd, J = 5.2, 1.6 Hz, 1H), 7.43 (dd, J = 7.6, 1.6 Hz, 1H), 7.00 (dd, J =5.2, 2.0 Hz, 1H), 5.25 (s, 2H), 3.68-3.64 (m, 2H), 2.89-2.76 (m, 2H), 2.61-2.42 (m, 3H), 2.24-2.16 (m, 1H), 0.98-0.93 (m, 2H), 0.05 (s, 9H).

[0481] Step 5 3-((Dimethylamino)methylene)-1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridine]-2',3(1'H)-dione 3e (640 mg, 1.92 mmol) was dissolved in dichloromethane (35 mL), 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (960 mg, 5.51 mmol) was added, and the mixture was stirred at 60°C for 3 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 3-((dimethylamino)methylene)-1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 3f (750 mg), which was directly used in the next reaction without purification. MS m / z(ESI): 388.0 [M+1]

[0482] Step 6 3-Chloro-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridine]-3-ene-4-carbaldehyde 3-((dimethylamino)methylene)-1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 3f (750 mg, 1.94 mmol) was dissolved in dichloromethane (20 mL), and phosphorus oxychloride (592.19 mg, 3.87 mmol) was added at 0°C. The mixture was stirred at 10°C for 20 minutes under nitrogen protection. After the reaction was completed, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (eluent: C system) to obtain 3-chloro-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridine]-3-ene-4-carbaldehyde 3g (200 mg). Yield: 21.82%. MS m / z(ESI): 379.3 [M+1] 1 H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.25 (dd, J = 5.2, 1.6 Hz, 1H), 7.47 (dd, J = 7.6, 7.2 Hz, 1H), 7.00 (dd, J =5.2, 2.0 Hz, 1H), 5.25 (s, 2H), 3.69-3.65 (m, 2H), 3.49 (dt, J = 18.8, 2.4 Hz, 1H), 3.19 (dt, J = 16.4, 2.0 Hz, 1H), 2.99-2.83 (m, 2H), 0.98-0.94 (m, 2H), 0.03 (s, 9H).

[0483] Step 7 2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 3-Chloro-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridine]-3-ene-4-carbaldehyde 3g (50 mg, 131.95 μmol) and ethyl 2-mercaptoacetate 2a (103.07 mg, 857.69 μmol) were dissolved in N,N-dimethylformamide (2.5 mL), sodium hydride (34.31 mg, 857.69 μmol, purity 60%) was added at 0 degrees Celsius, and the mixture was stirred for 1 hour under nitrogen protection and at 20°C for 1.5 hours. After the reaction was completed, the reaction was quenched by adding saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (40 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified and separated using a thin-layer plate to give ethyl 2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 3h (36 mg). Yield: 58.29%. MS m / z(ESI): 445.3 [M+1] 1 H NMR (400 MHz, CDCl3) δ 8.23 ​​(dd, J = 5.6, 1.6 Hz, 1H), 7.57(s, 1H), 7.27 (dd, J = 7.6,1.6 Hz, 1H), 6.91 (dd, J =7.2, 5.2 Hz, 1H), 5.28 (s, 2H), 4.34 (q, J = 6.8 Hz, 2H), 3.71-3.67 (m, 2H), 3.62-3.57 (m, 1H), 3.46-3.42 (m, 1H), 3.07 (d, J = 16.4 Hz, 1H), 2.92 (d, J = 15.2 Hz, 1H), 1.37 (t, J = 6.8 Hz, 3H), 1.00-0.96 (m, 2H), 0.03 (s, 9H).

[0484] Step 8 2'-Oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 3h (46 mg, 103.46 μmol) was dissolved in trifluoroacetic acid (1 mL) and stirred at 15°C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and tetrahydrofuran (1 mL) and ammonium hydroxide (0.5 mL) were added, followed by stirring at 15°C for 2 hours. The residue obtained by concentrating under reduced pressure was purified and separated using a thin layer plate to obtain 2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 3i (20 mg). Yield: 55.34%. MS m / z(ESI): 315.2 [M+1]

[0485] Step 9 2'-Oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid Ethyl 2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 3i (20 mg, 63.62 μmol) was dissolved in 1 mL of a mixed solution (methanol:water:tetrahydrofuran = 5:2:3), sodium hydroxide (7.63 mg, 190.86 μmol) was added, and the mixture was stirred at 40 ° C for 5 hours. After the reaction was completed, the pH was adjusted to 5 with 1 M hydrochloric acid and concentrated under reduced pressure to obtain 2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j (20 mg), which was directly subjected to the next reaction without purification.

[0486] Step 10 N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 2'-Oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j (9.00 mg, 31.43 μmol), 3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p (11.84 mg, 31.43 μmol), 1-hydroxybenzotriazole (8.50 mg, 62.87 μmol) and N,N-diisopropylethylamine (20.31 mg, 157.17 μmol) were dissolved in N,N-dimethylformamide. The mixture was dissolved in hexane (0.5 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.05 mg, 62.87 μmol) was added, and the mixture was stirred at 20° C. for 18 hours and concentrated under reduced pressure. The resulting residue was separated using a C18 reverse phase column (eluent: B system) to obtain N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 3 (12 mg). Yield: 59.59%. MS m / z(ESI): 608.7 [M+1] 1H NMR (400 MHz, CDCl3) δ 8.14-8.13 (m, 1H), 7.36-7.34 (s, 1H), 7.30-7.28 (m, 1H),7.13-7.07 (m, 1H), 6.93-6.83 (m, 2H), 4.91-4.75 (m, 1H), 4.50-4.44 (m, 1H), 3.97-3.94 (m, 2H), 3.61 (d, J = 16.0 Hz, 1H), 3.47-3.42 (m, 1H), 3.34-3.26 (m, 1H), 3.09 (d, J = 16.4 Hz, 1H), 2.93 (d, J = 15.2 Hz, 1H), 2.81-2.76 (m, 2H), 1.24 (d, J = 6.0 Hz, 3H).

[0487] Example 3A (S)-N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 3A

[0488] Example 3B (S)-N-((3R,5R,6S)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 3B

[0489] Example 3C (R)-N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 3C

[0490] Example 3D (R)-N-((3R,5R,6S)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 3D

[0491] [ka]

[0492] [ka]

[0493] Step 1 (S)-2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl ester 3h-A (R)-2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 3h-B Ethyl 2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 3h (410 mg, 0.92 mmol) was purified by chiral separation using SFC (column model: Waters SFC-150, Denisel IG, 20 × 250 mm, 10 μm; mobile phase: A for CO2, B for ethanol; detection wavelength: 214 nm, column temperature: 40 °C) to give a single configuration compound (shorter retention time) and a single configuration compound (longer retention time). Single configuration compounds (short retention time): 188 mg, yield: 45.9%, retention time 2.126 min, chiral purity 100% ee. MS m / z(ESI): 445.3 [M+1] Single component compounds (long retention time): 184 mg, yield: 44.9%, retention time 2.845 min, chiral purity 100% ee. MS m / z(ESI): 445.3[M+1]

[0494] Step 2 (S)-Ethyl 2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 3i-A (R)-Ethyl 2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 3i-B (S)-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 3h-A (188 mg, 0.92 mmol) or (R)-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 3h-B (184 mg, 0.92 mmol) was dissolved in trifluoroacetic acid (3 mL), stirred at 25°C for 3 hours, and after completion of the reaction, concentrated under reduced pressure, tetrahydrofuran (3 mL) and aqueous ammonia (0.5 mL) were added, and stirring was continued for 0.5 minutes. The mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (eluent: system A) to give (S)-ethyl 2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 3i-A (130 mg, yield: 93.24%) and (R)-ethyl 2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 3i-B (120 mg, yield: 86.07%). MS m / z(ESI): 314.9[M+1] MS m / z(ESI): 315.1[M+1]

[0495] Step 3 (S)-2'-Oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j-A (R)-2'-Oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j-B (S)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 3i-A (130 mg, 413.54 μmol) or (R)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 3i-B (120 mg, 382.17 μmol) was dissolved in 2 mL of a mixed solution (methanol:tetrahydrofuran:water = 3:1:1), and the solution was diluted with sodium hydroxide. The mixture was stirred at 40° C. for 5 hours, adjusted to pH 5 with 1 M dilute hydrochloric acid, and concentrated under reduced pressure to give (S)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j-A (220 mg, yield: 100%) and (R)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j-B (210 mg, yield: 100%). MS m / z(ESI): 287.1[M+1] MS m / z(ESI): 287.1[M+1]

[0496] Step 4 (S)-N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 3A (S)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j-A (10 mg, 34.93 μmol), (3S,5S,6R)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p-A (13.16 mg , 34.93 μmol), 1-hydroxybenzotriazole (9.44 mg, 69.86 μmol) and N,N-diisopropylethylamine (22.57 mg, 174.64 μmol) were dissolved in N,N-dimethylformamide (0.7 mL), and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.39 mg, 69.86 μmol) was added and the mixture was stirred at 25° C. for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was separated using a C18 reverse phase column (eluent: B system) to obtain (S)-N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 3A (3.59 mg). Yield: 16.9%. MS m / z(ESI): 609.0 [M+1] 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 5.2 Hz, 1H),7.36 (d, J = 3.6Hz, 1H), 7.30-7.27 (m, 1H), 7.14-7.06 (m, 1H), 6.93-6.82 (m, 2H), 4.94-4.85 (m, 1H), 4.45 (dd, J = 10.8, 6.8 Hz, 1H), 3.98-3.90 (m, 2H), 3.61 (d, J = 16.0 Hz, 1H), 3.45 (d, J = 15.2 Hz, 1H), 3.34-3.25 (m,1H), 3.09 (d, J = 16.0 Hz, 1H), 2.93 (d, J = 15.2 Hz, 1H), 2.81-2.74 (m, 2H), 1.24 (d, J = 4.8 Hz, 3H).

[0497] Step 5 (S)-N-((3R,5R,6S)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 3B (S)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j-A (10 mg, 34.93 μmol), (3R,5R,6S)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p-B (13.16 mg) , 34.93 μmol), 1-hydroxybenzotriazole (9.44 mg, 69.86 μmol) and N,N-diisopropylethylamine (22.57 mg, 174.64 μmol) were dissolved in N,N-dimethylformamide (0.7 mL), and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.39 mg, 69.86 μmol) was added and the mixture was stirred at 25° C. for 18 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reverse phase column (eluent: system B) to obtain (S)-N-((3R,5R,6S)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 3B (2.83 mg. Yield: 13.3%). MS m / z(ESI): 609.3 [M+1] 1H NMR (400 MHz, CDCl3) δ 8.11 (dd, J = 5.6, 1.6 Hz, 1H), 7.32-7.28 (m, 2H), 7.14-7.06 (m, 1H), 6.91 (dd, J = 7.6, 5.6 Hz, 1H), 6.88-6.82 (m,1H), 4.93-4.87(m, 1H), 4.43 (dd, J = 10.8, 7.6Hz, 1H), 3.98-3.91 (m,2H), 3.62 (d, J =16 Hz, 1H), 3.43 (d, J =15.2 Hz, 1H), 3.36-3.26 (m, 1H), 3.09 (d, J = 16.4Hz, 1H), 2.92 (d, J = 15.2 Hz, 1H), 2.83-2.74 (m, 2H), 1.25 (d, J = 6.4 Hz, 3H).

[0498] Step 6 (R)-N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 3C (R)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j-B (10 mg, 34.93 μmol), (3S,5S,6R)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p-A (13.16 mg , 34.93 μmol), 1-hydroxybenzotriazole (9.44 mg, 69.86 μmol) and N,N-diisopropylethylamine (22.57 mg, 174.64 μmol) were dissolved in N,N-dimethylformamide (0.7 mL), and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.39 mg, 69.86 μmol) was added and the mixture was stirred at 25° C. for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain (R)-N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 3C (4.23 mg). Yield: 19.9%. MS m / z(ESI): 609.3 [M+1] 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 5.2 Hz, 1H), 7.30-7.27 (m, 2H), 7.13-7.05 (m, 1H), 6.92-6.83 (m, 2H), 4.93-4.85 (m, 1H), 4.45 (t, J = 10.8 Hz, 1H), 3.98-3.89 (m, 2H), 3.61 (dd, J = 19.6, 4.4 Hz, 1H), 3.43 (dd, J = 14.8, 2.8 Hz, 1H), 3.35-3.24 (m,1H), 3.08 (dd, J = 16.4, 4.0 Hz, 1H), 2.92 (dd, J = 15.2, 4.0 Hz, 1H), 2.80-2.75 (m, 2H), 1.24 (d, J = 6.0 Hz, 3H).

[0499] Step 7 (R)-N-((3R,5R,6S)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 3D (R)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j-B (10 mg, 34.93 μmol), (3R,5R,6S)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p-B (13.16 mg) , 34.93 μmol), 1-hydroxybenzotriazole (9.44 mg, 69.86 μmol) and N,N-diisopropylethylamine (22.57 mg, 174.64 μmol) were dissolved in N,N-dimethylformamide (0.7 mL), and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.39 mg, 69.86 μmol) was added and the mixture was stirred at 25° C. for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was separated using a C18 reverse phase column (eluent: B system) to obtain (R)-N-((3R,5R,6S)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 3D (8.29 mg). Yield: 39.3%. MS m / z(ESI): 609.3 [M+1] 1H NMR (400 MHz, CDCl3)δ 8.11 (dd, J = 5.6, 1.2 Hz, 1H), 7.36-7.32(m, 2H), 7.14-7.06 (m, 1H), 6.98-6.92 (m, 1H), 6.88-6.83 (m, 1H), 4.97-4.87 (m, 1H), 4.43 (dd, J = 11.2, 6.8 Hz, 1H), 3.96-3.93 (m, 2H), 3.60 (d, J = 16 Hz, 1H), 3.44 (d, J = 15.2 Hz, 1H), 3.35-3.25 (m, 1H), 3.08 (d, J = 16.4 Hz, 1H), 2.92 (d, J = 15.2 Hz, 1H), 2.87-2.72 (m, 2H), 1.25 (d, J = 5.6 Hz, 3H).

[0500] Example 4 N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0501] [ka]

[0502] [ka]

[0503] Step 1 2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'-pyrrolo[2,3-b]]pyridine]-2-carboxylate ethyl 3-Chloro-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridine]-3-ene-4-carboxaldehyde 3g (120 mg, 316.69 μmol) and ethyl 2-hydroxyacetate 1j (148 mg, 1.43 mmol) were dissolved in tetrahydrofuran (3 mL), sodium hydride (50.66 mg, 1.27 mmol, 60% purity) was added slowly at room temperature, and the mixture was stirred at 85 °C for 2.5 hours under nitrogen protection. After the reaction was completed, it was quenched by adding saturated ammonium chloride solution (20 mL), and the mixture was extracted with ethyl acetate (40 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified and separated using a thin-layer plate to obtain ethyl 2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'-pyrrolo[2,3-b]]pyridine]-2-carboxylate 4a (43 mg). Yield: 31.68%. MS m / z(ESI): 429.3 [M+1]

[0504] Step 2 2'-Oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 4a (20 mg, 46.67 μmol) was dissolved in trifluoroacetic acid (1 mL) and stirred at 15°C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and tetrahydrofuran (1 mL) and ammonium hydroxide (0.5 mL) were added, stirred at 15°C for 2 hours, and concentrated under reduced pressure. The resulting residue was purified and separated using a thin layer plate to obtain 2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 4b (13.6 mg). Yield: 97.69%. MS m / z(ESI): 299.2 [M+1]

[0505] Step 3 2'-Oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 2'-Oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl 4b (20 mg, 67.05 μmol) was dissolved in 1 mL of a mixed solution (methanol:water:tetrahydrofuran = 5:2:3), sodium hydroxide (8.05 mg, 201.14 μmol) was added, and the mixture was stirred at 40 ° C for 5 hours. After the reaction was completed, the pH was adjusted to 5 with 1 M hydrochloric acid, and after concentration, 2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 4c (18 mg) was obtained, which was directly subjected to the next reaction without purification. MS m / z(ESI): 271.1 [M+1]

[0506] Step 4 N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 2'-Oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 4c (10 mg, 37.00 μmol), 3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p (13.94 mg, 37.00 μmol), 1-hydroxybenzotriazole (5.00 mg, 37.00 μmol) and N,N-diisopropylethylamine (4.78 mg, 37.00 μmol) were dissolved in N,N-dimethylformamide (0.5 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.09 mg, 37.00 μmol) was further added, and the mixture was stirred at 20 ° C. for 18 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 4 (6 mg). Yield: 26%. MS m / z(ESI): 592.7 [M+1] 1 H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 5.2 Hz, 1H), 7.43-7.40 (m, 1H), 7.13-7.04 (m, 2H), 6.98-6.83 (m, 2H), 4.93-4.87 (m, 1H), 4.60-4.42 (m, 1H), 3.99-3.91 (m, 2H), 3.44-3.21 (m, 3H), 2.95-2.70 (m, 4H), 1.26-1.22 (m, 3H).

[0507] Example 5A (5R)-N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-formamide 5A

[0508] Example 5B (5S)-N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-formamide 5B

[0509] [ka]

[0510] [ka]

[0511] Step 1 6-Methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)pyridin-2(1H)-one Under nitrogen protection, 5-bromo-6-methyl-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one 5a (1.0 g, 3.07 mmol), (2,3,5-trifluorophenyl)boronic acid 5b (1.11 g, 6.30 mmol) and potassium phosphate (2.36 g, 11.11 mmol) were dissolved in tetrahydrofuran (30 mL), bis(tri-tert-butylphosphine)palladium (284.99 mg, 555.46 μmol) was added, and the mixture was heated to 40° C. and stirred for 4 hours. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, extracted with ethyl acetate (50mL x 3), the organic phases were combined, concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (eluent: system A) to obtain 6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)pyridin-2(1H)-one 5c (1.2g). Yield: 89.35%. MS m / z(ESI): 322.1 [M+1]

[0512] Step 2 6-Methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one Under hydrogen protection, 6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)pyridin-2(1H)-one 5c (3.2 g, 9.96 mmol) was dissolved in acetic acid (200 mL), and then platinum dioxide (3.21 g, 14.15 mmol) was added to the reaction solution, which was heated to 80° C. and reacted under high pressure for 48 hours. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, extracted with ethyl acetate (50 mL×3), and the organic phase was combined and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (eluent: system A) to obtain 6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one 5d (2.8 g). Yield: 86%. MS m / z(ESI): 326.2 [M+1]

[0513] Step 3 3-Azido-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one 6-Methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one 5d (1.7 g, 5.23 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to -78 ° C, lithium bistrimethylsilylamide (1 M, 8.15 mL) was added dropwise, stirred for 1 hour, 15 mL of a solution of 2,4,6-triisopropylbenzenesulfonyl azide 5e (2.26 g, 7.32 mmol) in tetrahydrofuran was slowly added dropwise, stirred at -78 ° C for 2 hours, then acetic acid (8 mL) was added dropwise, stirred at -78 ° C for 30 minutes, heated to 25 ° C, and stirred for 18 hours. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate water (20 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined and concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (eluent: system A) to obtain 3-azido-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one 5f (2.1 g). Yield: 100%. MS m / z(ESI): 366.8 [M+1]

[0514] Step 4 tert-Butyl (6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)carbamate Under hydrogen protection, 3-azido-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one 5f (590 mg, 1.61 mmol) was dissolved in ethanol (15 mL), di-tert-butyl dicarbonate (526.76 mg, 2.42 mmol) and 10% palladium carbon (190 mg, 156.44 μmol) were added, and the mixture was stirred at 25 ° C. for 18 hours. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, extracted with ethyl acetate (50 mL × 3), the organic phase was combined, concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (eluent: system A) to obtain (6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)carbamic acid tert-butyl 5g (500 mg). Yield: 70%. MS m / z(ESI): 462.9 [M+23]

[0515] Step 5 3-Amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one hydrochloride (6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl) tert-butyl carbamate 5g (100 mg, 227.08 μmol) was dissolved in 4M hydrochloric acid dioxane solution (5 mL) and stirred at 25 ° C. for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one hydrochloride 5h (77 mg, yield: 99.7%), which was directly used in the next reaction without purification. MS m / z(ESI): 341.2 [M+1]

[0516] Step 6 (5R)-N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 5A 3-Amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one hydrochloride 5h (10.20 mg, 27.09 μmol), (S)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m-A (7.00 mg, 24.62

[0123] μmol), 1-hydroxybenzotriazole (6.65 mg, 49.25 μmol) and N,N-diisopropylethylamine (15.91 mg, 123.12 μmol) were dissolved in N,N-dimethylformamide (0.5 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.44 mg, 49.25 μmol) was added, and the mixture was stirred at 20° C. for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain (5R)-N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 5A (3.89 mg). Yield: 21.78%. MS m / z(ESI):607.4 [M+1] 1H NMR (400 MHz, CDCl3) δ 8.14 (dd, J = 5.2, 1.2 Hz, 1H), 7.10-7.08 (m, 1H), 7.00-6.99 (m, 1H), 6.91-6.85 (m, 2H), 6.69-6.65 (m, 1H), 4.94-4.88 (m, 1H), 4.56-4.38 (m, 1H), 4.07-3.88 (m, 2H), 3.32-3.25 (m, 1H), 3.13 (d, J = 16.0Hz, 1H), 3.01-2.94 (m, 1H), 2.85-2.33 (m, 5H), 1.95-1.90 (m, 1H), 1.13-1.08 (m, 3H).

[0517] Step 7 (5S)-N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 5B 3-Amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one hydrochloride 5h (10.20 mg, 27.09 μmol), (R)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m-B (7 mg, 24.62 μmol) mol), 1-hydroxybenzotriazole (6.65 mg, 49.25 μmol), and N,N-diisopropylethylamine (15.91 mg, 123.12 μmol) were dissolved in N,N-dimethylformamide (0.5 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.44 mg, 49.25 μmol) was added, and the mixture was stirred at 20° C. for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain (5S)-N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 5B (6.86 mg). Yield: 38.18%. MS m / z(ESI):607.3 [M+1] 1 H NMR (400 MHz, CDCl3) δ 8.13 (dd, J = 5.2, 1.2 Hz, 1H), 7.11-7.08 (m, 1H), 7.01-6.99 (m, 1H), 6.92-6.85 (m, 2H), 6.69-6.65 (m, 1H), 4.96-4.86 (m, 1H), 4.56-4.38 (m, 1H), 4.06-3.88 (m, 2H), 3.33-3.24 (m, 1H), 3.14 (d,J = 16.0Hz, 1H), 3.02-2.93 (m, 1H), 2.84-2.33 (m, 5H), 1.95-1.90 (m, 1H), 1.13-1.08 (m, 3H).

[0518] Example 6A (R)-N-((3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6A

[0519] Example 6B (S)-N-((3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6B

[0520] Example 6C (R)-N-((3R,5R,6S)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6C

[0521] Example 6D (S)-N-((3R,5R,6S)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6D

[0522] [ka]

[0523] [ka]

[0524] Step 1 (2R)-2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)-5-oxohexanoic acid methyl ester (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionic acid methyl ester 6b (6.34 g, 19.27 mmol) and cesium carbonate (12.59 g, 38.55 mmol) were added to N,N-dimethylformamide (80 mL) and stirred at 25° C. for 1 hour, and then 1-(3-chlorophenyl)propan-2-one 6a (3.9 g, 23.13 mmol) was added and stirred at 25° C. for 2.5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water (200 mL) was added, extracted with ethyl acetate (200 mL × 2), washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain methyl (2R)-2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)-5-oxohexanoate 6c (5.9 g, yield: 82.8%), which was directly used in the next reaction without purification. MS m / z(ESI): 392.1 [M+23]

[0525] Step 2 (2R)-2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)-5-((2,2,2-trifluoroethyl)amino)hexanoic acid methyl ester (2R)-2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)-5-oxohexanoic acid methyl ester 6c (5.0 g, 13.51 mmol), 2,2,2-trifluoroethane-1-amine 6d (5.36 g, 54.08 mmol), acetic acid (4.87 g, 81.12 mmol) and sodium triacetoxyborohydride (11.46 g, 54.08 mmol) were added to dichloroethane (130 mL) and reacted at 25° C. for 16 hours. After completion of the reaction, dichloromethane (100 mL) was added to the reaction solution, which was washed with water (200 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain methyl (2R)-2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)-5-((2,2,2-trifluoroethyl)amino)hexanoate 6e (6.15 g, yield: 100%), which was directly used in the next reaction without purification. MS m / z(ESI): 453.1 [M+1]

[0526] Step 3 tert-Butyl (5-(3-chlorophenyl)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl)carbamate (2R)-2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)-5-((2,2,2-trifluoroethyl)amino)methyl hexanoate 6e (6.15 g, 13.58 mmol) was dissolved in ethanol (100 mL), potassium carbonate (5.63 g, 40.74 mmol) was added, and the mixture was reacted at 20° C. for 24 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 ml×2). The organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and the residue obtained by concentrating under reduced pressure was separated using a C18 reverse phase column (eluent: B system) to obtain tert-butyl (5-(3-chlorophenyl)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl)carbamate 6f (1.03 g). Yield: 18.02%. MS m / z(ESI): 365.1 [M-55]

[0527] Step 4 tert-Butyl (6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)carbamate Under hydrogen protection, (5-(3-chlorophenyl)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl) tert-butyl carbamate 6f (1.03 g, 2.45 mmol) was dissolved in methanol (20 mL), 10% palladium carbon (0.2 g) was added, and the mixture was reacted at 25 ° C. for 20 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with methanol, and the filtrate was combined and concentrated under reduced pressure to obtain (6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl) tert-butyl carbamate 6g (960 mg, yield: 100%), which was directly used in the next reaction without purification. MS m / z(ESI): 409.3 [M+23] 1 H NMR (400 MHz,CDCl3) δ 7.35-7.31 (m, 2H), 7.27-7.25 (m, 1H), 7.18-7.17 (m, 2H), 5.37 (s, 1H), 4.95-4.84 (m, 1H), 4.18-4.14 (m, 1H), 3.87-3.81 (m, 1H), 3.55-3.50 (m, 1H), 3.26-3.15 (m, 1H), 2.63-2.58 (m, 1H), 2.44-2.35 (m, 1H), 1.45 (s, 9H), 0.95 (t, J = 6.8Hz, 3H).

[0528] Step 5 ((3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)carbamic acid tert-butyl ester 6h-A ((3R,5R,6S)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)carbamic acid tert-butyl ester 6h-B After purification of tert-butyl (6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)carbamate 6g (400 mg, 1.04 mmol) by chiral separation using SFC (column model: Waters SFC-150, Dnicel IG, 20×250 mm, 10 μm; mobile phase: A for CO2, B for ethanol; detection wavelength: 214 nm, column temperature: 40° C.), a single configuration compound (shorter retention time) and a single configuration compound (longer retention time) were obtained. Single configuration compounds (short retention time): 200 mg, yield: 45%, retention time 0.761 min, chiral purity 100% ee. MS m / z(ESI): 409.3 [M+23] Single configuration compounds (long retention time): 195 mg, yield: 43.9%, retention time 2.526 min, chiral purity 100% ee. MS m / z(ESI): 409.3 [M+23]

[0529] Step 6 (3S,5S,6R)-3-Amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-A (3R,5R,6S)-3-Amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-B ((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl) tert-butyl carbamate 6h-A (195 mg, 504.65 μmol) or ((3R,5R,6S)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl) tert-butyl carbamate 6h-B (195 mg, 504.65 μmol) was dissolved in 4 M dioxane hydrochloride solution (6 mL) ), stirred at 25° C. for 2 h, and concentrated under reduced pressure to give (3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-A (150 mg, yield: 100%); (3R,5R,6S)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-B (150 mg, yield: 100%), which were directly used in the next reaction without purification. MS m / z(ESI): 287.2 [M+1] MS m / z(ESI): 287.2 [M+1]

[0530] Step 7 (R)-N-((3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6A (S)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m-A (10 mg, 34.93 μmol), (3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-A (11.15 mg, 35.18 μmol) ol), 1-hydroxybenzotriazole (9.44 mg, 69.86 μmol), and N,N-diisopropylethylamine (22.57 mg, 174.64 μmol) were dissolved in N,N-dimethylformamide (0.7 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.39 mg, 69.86 μmol) was added, and the mixture was stirred at 25° C. for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain (R)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6A (8.27 mg). Yield: 42.55%. MS m / z(ESI): 553.4[M+1] 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 6.0Hz, 1H), 7.34 (t, J = 7.2 Hz, 2H), 7.29 (s, 1H), 7.18 (d, J = 6.4 Hz, 2H), 7.09 (d, J = 8.4Hz, 1H), 6.99 (s, 1H), 6.87 (t, J = 8.0 Hz, 1H), 4.98-4.87 (m, 1H), 4.58-4.54(m, 1H), 3.92-3.87 (m, 1H), 3.63 (d, J = 12.8 Hz, 1H), 3.29-3.21 (m, 1H), 3.13 (d, J = 14.0 Hz, 1H), 3.00-2.93 (m, 1H), 2.84-2.74 (m, 2H), 2.55-2.44 (m, 2H), 2.40-2.33 (m, 1H), 1.95-1.89 (m, 1H), 1.01 (d, J = 6.8Hz, 3H).

[0531] Example 6B (S)-N-((3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6B (R)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m-B (10 mg, 34.93 μmol), (3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-A (11.15 mg, 35.18 μmol) ol), 1-hydroxybenzotriazole (9.44 mg, 69.86 μmol), and N,N-diisopropylethylamine (22.57 mg, 174.64 μmol) were dissolved in N,N-dimethylformamide (0.7 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.39 mg, 69.86 μmol) was added, and the mixture was stirred at 25° C. for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain (S)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6B (7.14 mg). Yield: 36.73%. MS m / z(ESI): 553.4[M+1] 1H NMR (400 MHz, CDCl3) δ 8.11 (dd, J = 5.6, 1.6 Hz, 1H), 7.36-7.32 (m, 2H), 7.29-7.27 (m, 1H), 7.20-7.18 (m, 2H), 7.10 (dd, J = 7.2, 1.6 Hz, 1H), 6.98 (d, J = 1.2 Hz, 1H), 6.87 (dd, J = 7.6, 5.6 Hz, 1H), 4.98-4.90 (m, 1H), 4.25 (t, J = 9.6 Hz, 1H), 3.92-3.86 (m, 1H), 3.62-3.57 (m, 1H), 3.31-3.23 (m, 1H), 3.13 (d, J = 14.8 Hz, 1H), 3.01-2.95 (m, 1H), 2.84-2.74 (m, 1H), 2.68-2.63 (m, 2H), 2.53 (d, J = 16.0 Hz, 1H), 2.41-2.33 (m, 1H), 1.94-1.89 (m,1H), 1.04 (d, J = 6.4 Hz, 3H).

[0532] Example 6C (R)-N-((3R,5R,6S)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6C (S)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m-A (10 mg, 34.93 μmol), (3R,5R,6S)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-B (11.15 mg, 35.18 μmol) ol), 1-hydroxybenzotriazole (9.44 mg, 69.86 μmol), and N,N-diisopropylethylamine (22.57 mg, 174.64 μmol) were dissolved in N,N-dimethylformamide (0.7 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.39 mg, 69.86 μmol) was added, and the mixture was stirred at 25° C. for 18 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reverse phase column (eluent: system B) to obtain (R)-N-((3R,5R,6S)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6C (6.52 mg), yield: 33.54%. MS m / z(ESI): 553.3[M+1] 1H NMR (400 MHz, CDCl3) δ 8.12 (dd, J = 5.2, 1.6 Hz, 1H), 7.36-7.32 (m, 2H), 7.29-7.27 (m, 1H), 7.21-7.17(m, 2H), 7.09 (dd, J = 7.2, 1.2 Hz, 1H), 6.98 (d, J = 1.6 Hz, 1H), 6.87 (dd, J =7.6, 5.2 Hz, 1H), 4.98-4.90 (m, 1H), 4.45-4.40 (m, 1H), 3.92-3.86 (m, 1H), 3.62-3.57 (m, 1H), 3.30-3.20 (m, 1H), 3.13 (d, J = 16.8 Hz, 1H), 2.98 (dd, J = 17.2, 6.0 Hz, 1H), 2.84-2.75 (m, 1H), 2.68-2.63 (m, 2H), 2.53 (d, J = 16.0 Hz, 1H), 2.41-2.33 (m, 1H), 1.94-1.89 (m, 1H), 1.05 (d, J = 6.0 Hz, 3H).

[0533] Example 6D (S)-N-((3R,5R,6S)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6D (R)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m-B (10 mg, 34.93 μmol), (3R,5R,6S)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-B (11.15 mg, 35.18 μmol) ol), 1-hydroxybenzotriazole (9.44 mg, 69.86 μmol), and N,N-diisopropylethylamine (22.57 mg, 174.64 μmol) were dissolved in N,N-dimethylformamide (0.7 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.39 mg, 69.86 μmol) was added, and the mixture was stirred at 25° C. for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain (S)-N-((3R,5R,6S)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6D (6.68 mg). Yield: 34.37%. MS m / z(ESI): 553.4[M+1] 1H NMR (400 MHz, CDCl3) δ 8.12 (dd, J = 5.2, 1.6 Hz, 1H), 7.34 (t, J = 6.8 Hz, 2H), 7.28-7.27 (m,1H), 7.19-7.17 (m, 2H), 7.10 (dd, J = 7.6, 1.6 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 6.88 (dd, J = 7.6, 5.2 Hz, 1H), 4.98-4.87 (m, 1H), 4.56 (q, J = 6.8 Hz, 1H), 3.93-3.87 (m, 1H), 3.65-3.61 (m, 1H), 3.32-3.22 (m, 1H), 3.13 (d, J = 14.0 Hz, 1H), 3.00-2.94 (m, 1H), 2.85-2.74 (m, 2H), 2.55-2.47 (m, 2H), 2.41-2.33 (m, 1H), 1.94-1.89 (m, 1H), 1.01 (d, J = 6.4 Hz, 3H).

[0534] Example 7A (5S)-N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 7A

[0535] Example 7B (5R)-N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 7B

[0536] [ka]

[0537] [ka]

[0538] Step 1 (5S)-N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 7A (S)-2'-Oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j-A (10 mg, 34.93 μmol), 3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one hydrochloride 5h (13.16 mg, 34.93 μmol),

[0222] N,N-Dimethylformamide (0.7 mL) was dissolved in 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.39 mg, 69.86 μmol), 1-hydroxybenzotriazole (9.44 mg, 69.86 μmol), and N,N-diisopropylethylamine (22.57 mg, 174.64 μmol), and the solution was stirred at 20° C. for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain (5S)-N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 7A (2.33 mg). Yield: 10.96%. MS m / z(ESI): 609.4 [M+1] 1H NMR (400 MHz, CDCl3) δ 8.13-8.12 (m, 1H), 7.36-7.33 (m, 2H), 6.99-6.89 (m, 2H), 6.71-6.68 (m, 1H), 5.07-5.03 (m, 1H), 4.42-4.33 (m, 1H), 4.08-3.89 (m, 2H), 3.67-3.61 (m, 1H), 3.49-3.42 (m, 1H), 3.34-3.25 (m, 1H), 3.13-3.10 (m, 1H), 2.97-2.90 (m, 1H), 2.70-2.58 (m, 2H), 1.13-1.12 (m, 3H).

[0539] Step 2 (5R)-N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 7B (R)-2'-Oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j-B (10 mg, 34.93 μmol), 3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one hydrochloride 5h (13.16 mg, 34.93 μmol),

[0222] N,N-Dimethylformamide (0.7 mL) was dissolved in 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.39 mg, 69.86 μmol), 1-hydroxybenzotriazole (9.44 mg, 69.86 μmol), and N,N-diisopropylethylamine (22.57 mg, 174.64 μmol), and the solution was stirred at 20° C. for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain (5R)-N-(6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 7B (10.17 mg). Yield: 47.85%. MS m / z(ESI): 609.3 [M+1] 1 H NMR (400 MHz, CDCl3) δ 8.13 (dd, J = 5.2, 1.6 Hz, 1H), 7.34 (d, J = 6.8 Hz, 1H), 7.29-7.27 (m, 1H), 6.90 (dd, J = 7.6, 5.6 Hz, 2H), 6.70 - 6.66 (m, 1H), 4.95-4.93 (m, 1H), 4.44-4.36 (m, 1H), 4.07-4.00 (m, 1H), 3.93-3.88 (m, 1H), 3.64-3.95 (m, 1H), 3.47-3.42 (m, 1H), 3.30-3.24 (m, 1H), 3.10 (d, J = 16.0 Hz, 1H), 2.96-2.92 (m, 1H), 2.70-2.52 (m, 2H), 1.11-1.09 (m, 3H).

[0540] Example 8A (S)-N-((3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 8A

[0541] Example 8B (R)-N-((3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 8B

[0542] Example 8C (S)-N-((3R,5R,6S)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 8C

[0543] Example 8D (R)-N-((3R,5R,6S)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 8D

[0544] [ka]

[0545] [ka]

[0546] Step 1 (S)-N-((3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 8A (S)-2'-Oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j-A (10 mg, 34.93 μmol), (3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-A (10.15 mg, 31.43

[0222] N,N-Diisopropylethylamine (22.57 mg, 174.64 μmol), 1-hydroxybenzotriazole (9.44 mg, 69.86 μmol), and N,N-diisopropylethylamine (22.57 mg, 174.64 μmol) were dissolved in N,N-dimethylformamide (0.7 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.39 mg, 69.86 μmol) was added, and the mixture was stirred at 25° C. for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain (S)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 8A (5.77 mg). Yield: 29.79%. MS m / z(ESI): 555.3 [M+1] 1H NMR (400 MHz, CDCl3) δ 8.13 (dd, J = 5.2, 1.6 Hz, 1H), 7.36-7.33 (m, 3H), 7.28-7.26 (m, 2H), 7.25-7.18 (m, 2H), 6.90 (dd, J = 7.6, 5.6 Hz, 1H), 4.97-4.87 (m, 1H), 4.40 (dd, J = 11.6, 7.2 Hz, 1H), 3.92-3.86 (m, 1H), 3.65-3.58 (m, 2H), 3.43(d, J = 15.2 Hz, 1H), 3.31-3.21 (m, 1H), 3.09 (d, J = 16.8 Hz, 1H), 2.92 (d, J = 15.2 Hz, 1H), 2.75-2.70 (m, 1H), 2.58 (dd, J = 25.2, 12.4 Hz, 1H), 1.04(d, J = 6.8 Hz, 3H).

[0547] Step 2 (R)-N-((3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 8B (R)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j-B (10 mg, 34.93 μmol), (3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-A (10.15 mg, 31.43

[0222] N,N-Diisopropylethylamine (22.57 mg, 174.64 μmol), 1-hydroxybenzotriazole (9.44 mg, 69.86 μmol), and N,N-diisopropylethylamine (22.57 mg, 174.64 μmol) were dissolved in N,N-dimethylformamide (0.7 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.39 mg, 69.86 μmol) was added, and the mixture was stirred at 25° C. for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain (R)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 8B (4.88 mg). Yield: 25.19%. MS m / z(ESI): 555.3 [M+1] 1H NMR (400 MHz, CDCl3) δ 8.14-8.12 (m, 1H), 7.36-7.32 (m, 3H), 7.29-7.24 (m, 2H), 7.20-7.18 (m, 2H), 6.92-6.89 (m, 1H), 4.95-4.89 (m, 1H), 6.80 (dd, J = 11.6, 6.8 Hz, 1H), 3.91-3.86 (m, 1H), 3.61 (d, J = 15.6 Hz, 2H), 3.45 (d, J = 15.6 Hz, 1H), 3.28-3.23 (m,1H), 3.10 (d, J = 15.6 Hz, 1H), 2.94 (d, J = 15.2 Hz, 1H), 2.75-2.71 (m, 1H), 2.60 (dd, J =24.4, 12.4 Hz, 1H), 1.04 (d, J = 6.8 Hz, 3H).

[0548] Step 3 (S)-N-((3R,5R,6S)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 8C (S)-2'-Oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j-A (10 mg, 34.93 μmol), (3R,5R,6S)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-B (10.15 mg, 31.43

[0222] N,N-Diisopropylethylamine (22.57 mg, 174.64 μmol), 1-hydroxybenzotriazole (9.44 mg, 69.86 μmol), and N,N-diisopropylethylamine (22.57 mg, 174.64 μmol) were dissolved in N,N-dimethylformamide (0.7 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.39 mg, 69.86 μmol) was added, and the mixture was stirred at 25° C. for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain (S)-N-((3R,5R,6S)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 8C (5.25 mg). Yield: 27.1%. MS m / z(ESI): 555.3 [M+1] 1 H NMR (400 MHz, CDCl3) δ 8.15-8.13 (m, 1H), 7.36-7.32 (m, 3H), 7.29-7.26 (m, 2H), 7.21-7.18 (m, 2H), 6.93-6.89 (m, 1H), 4.98-4.86 (m, 1H), 4.43-4.38 (m, 1H), 3.92-3.86 (m, 1H), 3.60 (d, J = 15.6 Hz, 2H), 3.45 (d, J = 15.2 Hz, 1H), 3.31-3.20(m, 1H), 3.09 (d, J = 16.4 Hz, 1H), 2.94 (d, J = 15.2 Hz, 1H), 2.74-2.70 (m, 1H), 2.66-2.56 (m,1H), 1.04 (d, J = 6.4 Hz, 3H).

[0549] Step 4 (R)-N-((3R,5R,6S)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 8D (R)-2'-Oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j-B (10 mg, 34.93 μmol), (3R,5R,6S)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-B (10.15 mg, 31.43

[0222] N,N-Diisopropylethylamine (22.57 mg, 174.64 μmol), 1-hydroxybenzotriazole (9.44 mg, 69.86 μmol), and N,N-diisopropylethylamine (22.57 mg, 174.64 μmol) were dissolved in N,N-dimethylformamide (0.7 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.39 mg, 69.86 μmol) was added, and the mixture was stirred at 25° C. for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain (R)-N-((3R,5R,6S)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 8D (5.6 mg). Yield: 28.9%. MS m / z(ESI): 555.3 [M+1] 1H NMR (400 MHz, CDCl3) δ 8.13 (dd, J = 5.2, 1.2 Hz, 1H), 7.36-7.32 (m, 3H), 7.28-7.26 (m, 2H), 7.20-7.18 (m, 2H), 6.90 (dd, J = 7.2, 5.2 Hz, 1H), 4.98-4.87 (m, 1H), 4.38-4.34 (m, 1H), 3.92-3.86 (m, 1H), 3.66-3.57 (m, 2H), 3.41 (d, J= 15.2 Hz, 1H), 3.21-3.21 (m, 1H), 3.08 (d, J= 16.8 Hz, 1H), 2.91 (d, J= 15.2 Hz, 1H), 2.71-2.59 (m, 2H), 1.05 (d, J= 6.8 Hz, 3H).

[0550] Example 9 N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0551] [ka]

[0552] [ka]

[0553] Step 1 3-Bromo-1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 1q (1.5 g, 4.33 mmol) was dissolved in tetrahydrofuran (30 mL), phenyltrimethylammonium tribromide (1.79 g, 4.76 mmol) was added in batches at 0 ° C., and the mixture was stirred at 25 ° C. for 16 hours. After the reaction was completed, the mixture was diluted with 100 mL of water, extracted with ethyl acetate (50 mL × 3), the organic phase was combined and concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (eluent: C system) to obtain 3-bromo-1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 9a (1.1 g). Yield: 59.7%. MS m / z(ESI): 425.0 [M+1]

[0554] Step 2 2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 3-Bromo-1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 9a (290 mg, 0.6817 mmol) and ethyl 2-amino-2-thioacetate 9b (99.86 mg, 0.7499 mmol) were added to anhydrous toluene (6 mL), stirred, and heated to reflux for 16 h. After the reaction was completed, the temperature was lowered to room temperature, 10 mL of saturated sodium bicarbonate water was added to the reaction solution, the mixture was stirred for 10 minutes, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified and separated using a thin-layer plate to obtain ethyl 2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 9c (100 mg). Yield: 31.9%. MS m / z(ESI): 460.2 [M+1]

[0555] Step 3 2'-Oxo-1',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 9c (100 mg, 217.57 μmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at 30° C. for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL), stirred at 30° C. for 1 hour, and then concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (eluent: system A) to obtain 2'-oxo-1',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 9d (60 mg). Yield: 44.38%. MS m / z(ESI): 330.1 [M+1]

[0556] Step 4 2'-Oxo-1',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 2'-Oxo-1',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 9d (30 mg, 48.75 μmol) was dissolved in 2 mL of a mixed solution (water:methanol:tetrahydrofuran = 2:1:1), sodium hydroxide (10.9 mg, 273 μmol) was added, and the mixture was stirred at 45 ° C for 1 hour. After the reaction was completed, the reaction solution was adjusted to pH 4 with 1 M dilute hydrochloric acid and concentrated under reduced pressure to obtain 2'-oxo-1',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 9e (30 mg), which was directly subjected to the next reaction without purification. MS m / z(ESI): 302.1 [M+1]

[0557] Step 5 N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 2'-Oxo-1',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 9e (30 mg, 99.3 μmol), (3S,5S,6R)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p-A (28.80 mg, 69.69 μmol), N,N-diisopropylethylamine (128.43 mg, 995.62 μmol), and 1-hydroxybenzotriazole (26.91 mg, 199.12 μmol) were dissolved in N,N-dimethylformamide ( 2mL), then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38.03mg, 199.12μmol) was added, stirred at 30℃ for 16 hours, concentrated under reduced pressure, and the resulting residue was separated on a C18 reverse phase column (eluent: B system) to obtain N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 9 (10.97mg). Yield: 14.19%. MS m / z(ESI): 624.4 [M+1] 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.24 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 4.0 Hz, 1H), 7.53-7.44 (m, 1H), 7.19-7.14 (m, 2H), 6.92-6.89 (m, 1H), 4.72-4.57 (m, 2H), 3.98-3.93 (m, 1H), 3.85-3.74 (m, 2H), 3.23-3.06 (m, 4H), 2.95-2.88 (m, 1H), 2.18-2.14 (m, 2H), 2.01-1.96 (m, 1H), 1.22 (d, J = 6.4 Hz, 3H).

[0558] Example 10 N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydro-1H-spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0559] [ka]

[0560] [ka]

[0561] Step 1 Ethyl 3-(3-chloro-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridin]-3-en-4-yl)acrylate 3g (160mg, 422.25μmol) of 3-chloro-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridine]-3-ene-4-carbaldehyde and 2-(triphenyl-λ 5 -phosphiteethylidene)ethyl acetate 10a (147.10 mg, 422.25 μmol) was dissolved in dichloromethane (4 mL), stirred at 25 ° C for 3 hours, and concentrated under reduced pressure. The residue obtained was separated and purified by column chromatography (eluent: system A) to obtain 3-(3-chloro-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridin]-3-en-4-yl)ethyl acrylate 10b (190 mg). Yield: 99%. MS m / z(ESI): 449.1 [M+1]

[0562] Step 2 2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydro-1H-spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl Ethyl 3-(3-chloro-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridin]-3-en-4-yl)acrylate 10b (200 mg, 445.42 μmol) was dissolved in dimethyl sulfoxide (5 mL), sodium azide (52.11 mg, 801.76 μmol) was added, and the mixture was incubated at 70°C for 18 hours under nitrogen protection. Stir, add 30 mL of ethyl acetate and 20 mL of water, extract with ethyl acetate (30 mL x 3), combine the organic phases and concentrate under reduced pressure, and the resulting residue is purified and separated on a thin-layer plate to obtain ethyl 2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydro-1H-spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 10c (62 mg). Yield: 28.65%. MS m / z(ESI): 427.9 [M+1]

[0563] Step 3 2'-Oxo-1',2',4,6-tetrahydro-1H-spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydro-1H-spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 10c (62 mg, 145.01 μmol) was dissolved in trifluoroacetic acid (1 mL) and stirred at 25°C for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, 1 mL of tetrahydrofuran was added, and the mixture was stirred at 25°C for 0.5 hours. The residue obtained by concentrating under reduced pressure was purified and separated on a thin layer plate to obtain 2'-oxo-1',2',4,6-tetrahydro-1H-spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 10d (23 mg). Yield: 48.55%. MS m / z(ESI): 298.0 [M+1]

[0564] Step 4 2'-Oxo-1',2',4,6-tetrahydro-1H-spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 2'-Oxo-1',2',4,6-tetrahydro-1H-spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl 10d (23 mg, 80.30 μmol) was dissolved in 2 mL of a mixed solution (water:methanol:tetrahydrofuran = 2:1:1), sodium hydroxide (9.64 mg, 240.90 μmol) was added, and the mixture was stirred at 40 ° C for 2 hours. After the reaction was completed, the reaction solution was adjusted to pH 3 with 1 M dilute hydrochloric acid and concentrated under reduced pressure to obtain 2'-oxo-1',2',4,6-tetrahydro-1H-spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 10e (20 mg), which was directly subjected to the next reaction without purification. MS m / z(ESI): 269.9 [M+1]

[0565] Step 5 N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydro-1H-spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 2'-Oxo-1',2',4,6-tetrahydro-1H-spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 10e (20 mg, 74.28 μmol), (3S,5S,6R)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p-A (50.37 m g, 133.70 μmol), 1-hydroxybenzotriazole (20.07 mg, 148.56 μmol) and N,N-diisopropylethylamine (96 mg, 742.79 μmol) were dissolved in N,N-dimethylformamide (1 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.39 mg, 148.56 μmol) was added, and the mixture was stirred at 25° C. for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydro-1H-spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 10 (6.57 mg). Yield: 11.91%. MS m / z(ESI): 591.8 [M+1] 1H-NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 11.05 (s, 1H), 8.43-8.40 (m, 1H), 8.07-8.06 (m, 1H), 7.51-7.39 (m, 2H), 7.20-7.15 (m, 1H), 6.93-6.90 (m, 1H), 6.59 (s, 1H), 4.70-4.62 (m, 1H), 4.36-4.28 (m, 1H), 3.96-3.92 (m, 1H), 3.79-3.76 (m, 2H), 3.11-2.99 (m, 3H), 2.82 (d, J = 16.0 Hz, 1H), 2.71 (d, J = 14.4 Hz, 1H), 2.16-2.10 (m, 1H), 1.26-1.23 (m, 3H).

[0566] Example 11 N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0567] [ka]

[0568] [ka]

[0569] Step 1 4,5-Dimethylthiazole-2-carboxylate methyl 4,5-Dimethylthiazole-2-carboxylic acid 11a (900 mg, 5.73 mmol) and N,N-dimethylformamide (83.70 mg, 1.15 mmol) were dissolved in methanol (20 mL), and oxalyl chloride (1.02 g, 8.02 mmol) was slowly added dropwise at 0 degrees Celsius, followed by stirring at 0 degrees Celsius for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (eluent: system A) to obtain methyl 4,5-dimethylthiazole-2-carboxylate 11b (618 mg). Yield: 56.74%. MS m / z(ESI): 172.1 [M+1]

[0570] Step 2 4,5-Bis(bromomethyl)thiazole-2-carboxylate methyl ester Methyl 4,5-dimethylthiazole-2-carboxylate 11b (618 mg, 3.61 mmol) and azobisisobutyronitrile (355.62 mg, 2.17 mmol) were dissolved in dichloroethane (36 mL), N-bromosuccinimide (1.28 g, 7.22 mmol) was added, and the mixture was stirred at 70° C. for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified and separated on a thin layer plate to obtain methyl 4,5-bis(bromomethyl)thiazole-2-carboxylate 11c (360 mg). Yield: 27.28%. MS m / z(ESI): 327.9 [M+1]

[0571] Step 3 2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl Methyl 4,5-bis(bromomethyl)thiazole-2-carboxylate 11c (150 mg, 437.27 μmol) and 1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one 1a (109.83 mg, 415.41 μmol) were dissolved in ethanol (7.5 mL), and cesium carbonate (283.38 mg, 869.25 μmol) was added and stirred at 25° C. for 16 hours. After the reaction was completed, the mixture was extracted with water (20 mL x 3) and ethyl acetate (30 mL x 3), the organic phases were combined and concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (eluent: System A) to obtain ethyl 2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 11d (50 mg). Yield: 20.53%. MS m / z(ESI): 445.9 [M+1]

[0572] Step 4 2'-Oxo-1',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 11d (50 mg, 112.21 μmol) and 1 mL of trifluoroacetic acid were dissolved in tetrahydrofuran (1 mL) and stirred at 25°C for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, tetrahydrofuran (1 mL) and aqueous ammonia (0.2 mL) were added, and the mixture was stirred at 25°C for 0.5 hours. The residue obtained by concentrating under reduced pressure was purified and separated on a thin layer plate to obtain 2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 11e (33 mg). Yield: 68.08%. MS m / z(ESI): 316.1 [M+1]

[0573] Step 5 2'-Oxo-1',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 2'-Oxo-1',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl 11e (33 mg, 104.65 μmol) was added to 1 mL of a mixed solution (water:methanol:tetrahydrofuran = 3:1:1), sodium hydroxide (12.56 mg, 313.94 μmol) was added, and the mixture was stirred at 40 ° C for 1 hour. After the reaction was completed, the reaction solution was adjusted to pH 5 with 1 M dilute hydrochloric acid and concentrated under reduced pressure to obtain 2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 11f (41 mg, yield: 98.59%), which was directly subjected to the next reaction without purification. MS m / z(ESI): 288.1 [M+1]

[0574] Step 6 N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 2'-Oxo-1',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 11f (20 mg, 57.85 μmol), (3S,5S,6R)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p-A (34.8

[0223] To a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20.56 mg, 115.70 μmol), 1-hydroxybenzotriazole (15.63 mg, 115.70 μmol) and triethylamine (74.76 mg, 578.48 μmol) in N,N-dimethylformamide (1 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20.56 mg, 115.70 μmol) was added, and the mixture was stirred at 25°C for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 11 (8.47 mg). Yield: 19.28%. MS m / z(ESI): 609.8 [M+1] 1 H NMR (400 MHz, CDCl3) δ 11.14 (s, 1H), 9.27-9.24 (m, 1H), 8.07 (dd, J = 5.2, 1.6 Hz, 1H), 7.60-7.57 (m, 1H), 7.49-7.40 (m, 1H), 7.16-7.10 (m, 1H), 6.94 (dd, J = 7.6, 5.6 Hz, 1H), 4.69-4.52 (m, 2H), 3.95-3.94 (m, 1H), 3.82-3.70 (m, 2H), 3.24-3.05 (m, 5H), 2.15-2.10 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H).

[0575] Example 12 N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0576] [ka]

[0577] [ka]

[0578] Step 1 (E)-2-Styryl-1'-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one 3-Bromo-1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 9a (400 mg, 940.31 μmol) and phenylacrylamide 12a (138.39 mg, 940.31 μmol) were dissolved in toluene (4 mL) and stirred at 100 ° C. for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (eluent: system A) to obtain (E)-2-styryl-1'-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2'(1'H)-one 12b (170 mg). Yield: 34.35%. MS m / z(ESI): 474.1 [M+1]

[0579] Step 2 2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate methyl (E)-2-Styryl-1'-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2'(1'H)-one 12b (150 mg, 316.70 μmol) was dissolved in a mixture (tetrahydrofuran:acetone:water=6:3:1), N-methylmorpholine N-oxide (278.26 mg, 2.37 mmol) and potassium osmate (492.47 mg, 1.58 mmol) were added, and the mixture was stirred at 30°C for 4 hours, and potassium carbonate (87.41 mg, 633.40 μmol) and methyl iodide (224.76 mg, 1.58 mmol) were added, and the mixture was stirred for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (eluent: C system) to obtain 2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate methyl 12c (42 mg). Yield: 29.24%. MS m / z(ESI): 430.3 [M+1]

[0580] Step 3 2'-Oxo-1',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate methyl 2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-methyl carboxylate 12c (42 mg, 97.78 μmol) was added to trifluoroacetic acid (2 mL) and stirred at 25 ° C. for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (2 mL), ammonia water (0.3 mL) was added, and the mixture was stirred at 25 ° C. for 0.5 hours, and then concentrated under reduced pressure. The resulting residue was purified and separated by a thin layer plate to obtain 2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-methyl carboxylate 12d (20 mg). Yield: 61.51%. MS m / z(ESI): 299.9 [M+1]

[0581] Step 4 2'-Oxo-1',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 2'-Oxo-1',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid methyl 12d (20 mg, 66.83 μmol) was dissolved in 1.6 mL of a mixed solution (water:methanol:tetrahydrofuran = 1:2:4), sodium hydroxide (8.02 mg, 66.83 μmol) was added, and the mixture was stirred at 25 ° C for 2 hours. After the reaction was completed, the reaction solution was adjusted to pH 5 with 1 M dilute hydrochloric acid and concentrated under reduced pressure to obtain 2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 12e (25 mg), which was directly subjected to the next reaction without purification. MS m / z(ESI): 286.0 [M+1]

[0582] Step 5 N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 2'-Oxo-1',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 12e (20 mg, 65.10 μmol), (3S,5S,6R)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p-A (22.15 mg, 65.10 μmol), 1-hydroxybenzotriazole (17.59 mg, 130.19 μmol) and N,N-diisopropylethylamine (42.07 mg, 325.48 μmol) were dissolved in N,N-dimethylformamide (0.5 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24.96 mg, 130.19 μmol) was added, and the mixture was stirred at 45° C. for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 12 (2.29 mg). Yield: 4.86%. MS m / z(ESI): 608.2 [M+1] 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 4.8 Hz, 1H), 7.13-7.07 (m, 2H), 6.92-6.83 (m, 2H), 4.93-4.88 (m, 1H), 4.63-4.51 (m, 1H), 4.00-3.91 (m, 2H), 3.36-3.27 (m, 2H), 2.95-2.71 (m, 5H), 2.35-2.27 (m, 1H), 1.93-1.88 (m, 1H), 1.25-1.22 (m, 3H).

[0583] Example 13 N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0584] [ka]

[0585] [ka]

[0586] Step 1 Ethyl 3-(4-chloro-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[2,3-b]]pyridin]-3-en-3-yl)acrylate 4-Chloro-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-3-ene-3-carbaldehyde 1s (374 mg, 951.77 μmol) and 2-(triphenyl-λ 5-phosphiteethylidene)ethyl acetate 10a (397.89 mg, 1.14 mmol) was dissolved in dichloromethane (6.67 mL) and stirred at 25 ° C for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (eluent: system A) to obtain 3- (4-chloro-2'-oxo-1'- ((2- (trimethylsilyl) ethoxy) methyl) -1',2'-dihydrospiro [cyclohexane-1,3'-pyrrolo [2,3-b]] pyridin] -3-en-3-yl) ethyl acrylate 13a (310 mg). Yield: 69.64%. MS m / z(ESI): 463.2 [M+1]

[0587] Step 2 2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 3-(4-chloro-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydrospiro[cyclohexane-1,3'-pyrrolo[2,3-b]]pyridin]-3-en-3-yl)ethyl acrylate 13a (260 mg, 561.51 μmol) was dissolved in dimethyl sulfoxide (7.8 mL), sodium azide (65.71 mg, 1.01 mmol) was added, and the mixture was stirred at 70°C for 18 hours under nitrogen protection. 40 mL of ethyl acetate and 40 mL of water were added, and the mixture was extracted with ethyl acetate (40 mL x 3), and the organic phases were combined. Concentration under reduced pressure, the obtained residue was separated and purified by column chromatography (eluent: system A) to obtain ethyl 2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 13b (120 mg). Yield: 35.49%. MS m / z(ESI): 442.2 [M+1]

[0588] Step 3 2'-Oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 13b (120 mg, 271.74 μmol) was dissolved in trifluoroacetic acid (2 mL) and stirred at 25 ° C. for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, tetrahydrofuran (2 mL) and aqueous ammonia (0.3 mL) were added, and the mixture was stirred at 25 ° C. for 0.5 hours and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (eluent: system A) to obtain 2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 13c (80 mg). Yield: 86.99%. MS m / z(ESI): 312.1 [M+1]

[0589] Step 4 2'-Oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 2'-Oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl 13c (80 mg, 256.96 μmol) was dissolved in 2.5 mL of a mixed solution (water:methanol:tetrahydrofuran = 1:3:1), sodium hydroxide (30.83 mg, 770.88 μmol) was added, and the mixture was stirred at 40 ° C for 2 hours. After the reaction was completed, the reaction solution was adjusted to pH 5 with 1 M dilute hydrochloric acid and concentrated under reduced pressure to obtain 2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 13d (80 mg), which was directly subjected to the next reaction without purification. MS m / z(ESI): 284.1 [M+1]

[0590] Step 5 N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 2'-Oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 13d (30 mg, 87.79 μmol), (3S,5S,6R)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p-A (59.53 mg, 158.0 2 μmol), 1-hydroxybenzotriazole (23.72 mg, 178.58 μmol), and N,N-diisopropylethylamine (113.46 mg, 877.90 μmol) were dissolved in N,N-dimethylformamide (1 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.20 mg, 175.58 μmol) was added, and the mixture was stirred at 25° C. for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reversed-phase column (eluent: B system) to obtain N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 13 (4.05 mg). Yield: 5.37%. MS m / z(ESI): 605.8 [M+1] 1H-NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 11.08 (s, 1H), 8.38 (t, J = 8.0 Hz, 1H), 8.05 (dd, J = 5.2, 1.6 Hz, 1H), 7.52-7.45 (m, 1H), 7.19-7.14 (m, 1H), 6.96-6.93 (m, 1H), 6.87-6.83 (m, 1H), 6.56-6.55 (m, 1H), 4.71-4.60 (m, 1H), 4.42-4.32 (m, 1H), 3.95-3.92 (m, 1H), 3.83-3.76 (m, 2H), 3.11-3.02 (m, 1H), 2.91-2.81 (m, 2H), 2.63-2.58 (m, 1H), 2.46-2.42 (m, 1H), 2.15-2.03 (m, 2H), 1.76-7.71 (m, 1H), 1.24 (d, J = 6.0 Hz, 3H).

[0591] Example 13A (S)-N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 13A

[0592] Example 13B (R)-N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 13B

[0593] [ka]

[0594] [ka]

[0595] Step 1 (S)-2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl ester 13b-A (R)-2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 13b-B Ethyl 2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 13b (796 mg, 1.80 mmol) was purified by chiral separation using SFC (column model: Waters SFC-150, Denisel IG, 20 × 250 mm, 10 μm; mobile phase: A for CO2, B for ethanol; detection wavelength: 214 nm, column temperature: 40 °C) to give a single configuration compound (shorter retention time) and a single configuration compound (longer retention time). Single configuration compounds (short retention time): 322 mg, yield: 40.5%, retention time 1.964 min, chiral purity 100% ee. MS m / z(ESI):442.2 [M+1] Single configuration compounds (long retention time): 317 mg, yield: 39.8%, retention time 2.242 min, chiral purity 99% ee. MS m / z(ESI): 442.2 [M+1]

[0596] Step 2 (S)-Ethyl 2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 13c-A (R)-Ethyl 2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 13c-B The chiral resolved (S)-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 13b-A (316.00 mg, 715.59 μmol) or (R)-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 13b-B (311.00 mg, 704.27 μmol) was dissolved in trifluoroacetic acid (1.5 mL) and stirred at 25 °C for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, 1.5 mL of tetrahydrofuran and 0.3 mL of aqueous ammonia were added, and the mixture was stirred at 25° C. for 0.5 hours. The mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (eluent: A system) to obtain (S)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 13c-A (190 mg, yield: 85.1%) and (R)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-ethyl carboxylate 13c-B (195 mg, yield: 88.8%), respectively. MS m / z(ESI): 312.1 [M+1] MS m / z(ESI): 312.1 [M+1]

[0597] Step 3 (S)-2'-Oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 13d-A (R)-2'-Oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 13d-B (S)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 13c-A (190 mg, 610.28 μmol) or (R)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate ethyl 13c-B (195 mg, 626.34 μmol) was dissolved in 5.5 mL of a mixed solution (methanol: tetrahydrofuran: water = 1: 3: 1), sodium hydroxide (73.23 mg, 1.83 mmol) was added, and the mixture was stirred at 50 ° C. for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, the reaction solution was adjusted to pH 5 with 1M diluted hydrochloric acid, extracted with ethyl acetate (20mL x 5) and methanol (2mL x 5), and the organic phases were combined and concentrated under reduced pressure to obtain (S)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 13d-A (157mg, yield: 84.37%) and (R)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 13d-B (158mg, yield: 80.14%), which were directly used in the next reaction without purification. MS m / z(ESI): 284.1 [M+1] MS m / z(ESI): 284.1 [M+1]

[0598] Step 4 (S)-N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 13A (R)-N-((3S,5S,6R)-6-Methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 13B (S)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 13d-A (20 mg, 70.60 μmol) or (R)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 13d-B (20 mg, 70.60 μmol), (3S,5S,6R)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl) )-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride 1p-A (23.94 mg, 63.54 μmol), 1-hydroxybenzotriazole (19.08 mg, 141.20 μmol) and N,N-diisopropylethylamine (91.25 mg, 706.01 μmol) were added to N,N-dimethylformamide (1 mL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25.09 mg, 141.20 μmol), and the mixture was stirred at 25 ° C. for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was separated using a C18 reverse phase column (eluent: B system) to obtain (S)-N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 13. A (35.88 mg, yield: 69.22%), (R)-N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 13B (34.65 mg, yield: 67.52%) was obtained. MS m / z(ESI): 606.2 [M+1] MS m / z(ESI): 606.5 [M+1] 1H-NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 11.08 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.03(dd, J = 5.2, 1.6 Hz, 1H), 7.49-7.45 (m, 1H), 7.19-7.13 (m, 1H), 6.93 (dd, J = 7.2, 1.6 Hz, 1H), 6.84 (dd, J = 7.2, 5.2 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 4.68-4.58 (m, 1H), 4.39-4.32 (m, 1H), 3.94-3.90 (m, 1H), 3.80-3.72 (m, 2H), 3.08-2.99 (m, 1H), 2.89-2.79 (m, 2H), 2.66-2.57 (m, 1H), 2.42 (d, J = 14.8 HZ, 1H), 2.13-2.02 (m, 2H), 1.74-1.69 (m, 1H), 1.22 (d, J = 6.4 Hz, 3H). 1 HNMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 11.02 (s, 1H), 8.32 (d, J = 8.0 HZ, 1H), 7.97 (dd, J = 5.2, 1.6 Hz, 1H), 7.44-7.36 (m, 1H), 7.13-7.06 (m, 1H), 6.85 (dd, J = 7.2, 1.6 Hz, 1H), 6.77 (dd, J = 7.2, 5.2 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 4.62-4.51 (m, 1H), 4.29-4.22 (m, 1H), 3.87-3.82 (m, 1H), 3.77-3.62 (m, 2H), 3.03-2.93 (m, 1H), 2.83-2.73 (m, 2H), 2.59-2.50 (m, 1H), 2.35 (d, J = 15.6 HZ, 1H), 2.06-1.94 (m, 2H), 1.67-1.63 (m, 1H), 1.16 (d, J = 6.4 Hz, 3H).

[0599] Biological evaluation Test Example 1: Measurement of the inhibitory effect of the present compound on the CGRP signaling pathway in CHO-K1 cells expressing human CGRP receptors The inhibitory effect of CGRP signaling pathway in vitro is evaluated by measuring cAMP level. The principle is that after CGRP binds to CGRP receptor, it activates CGRP signaling pathway and induces increase in cAMP level, so that decrease in cAMP level indicates inhibition of CGRP signaling pathway. The specific experimental method is as follows: CHO-K1 cells expressing human CGRP receptor (CGRPR / CHO-K1, PerkinElmer, ES-420-C) were cultured in F12K + 10% FBS + 400 μg / mL G418 + 10 μg / mL Blasticidin medium and harvested during logarithmic growth phase. Following the kit instructions, cells were resuspended in Stimulation Buffer containing 0.5 mM IBMX and 5 μL of cell suspension was added to each well of a 96-well microplate (Cisbio, 66PL96025), resulting in a cell density of 15,000 cells / well. 2.5 μL of gradient diluted compound solution was added to each well and incubated at 37 °C for 30 min, after which 2.5 μL of 40 ng / mL human α-CGRP (Bachem, H-1470.0500) diluted in Stimulation Buffer containing 0.5 mM IBMX was added to give a final concentration of 10 ng / mL. After incubation at 37 °C for 30 min, 5 μL of Anti-cAMP-Cryptate solution and 5 μL of cAMP-d2 solution were added to each well. After incubation at room temperature for 60 min, the HTRF signal was read using a microplate reader (Molecular Devices). The IC of the inhibitory effect of the compound on the increase in cAMP levels was calculated based on the compound concentration and HTRF signal using Graphpad Prism. 50 values ​​were calculated.

[0600] The biological activity of the compounds of the present application was measured through the above test, and the IC 50 The values ​​are shown in Table 1 below.

[0601] [Table 10]

[0602] Conclusion: The compounds of this application have significant inhibitory effects on the CGRP signaling pathway in CHO-K1 cells expressing human CGRP receptors. Among them, the positive control compound Atogepant was prepared according to the protocol described in patent application WO2012064910, and its structure is as follows:

[0603] [ka]

[0604] Test Example 2: Measurement of the inhibitory effect of the compound of the present application on the CGRP signaling pathway in SK-N-MC cells The inhibitory effect of CGRP signaling pathway in vitro is evaluated by measuring cAMP level. The principle is that after CGRP binds to CGRP receptor, it activates CGRP signaling pathway and induces increase in cAMP level, so that decrease in cAMP level indicates inhibition of CGRP signaling pathway. The specific experimental method is as follows: cAMP was measured using the CAMP-GS DYNAMIC KIT detection kit (Cisbio, 62AM4PEB).

[0605] SK-N-MC (ATCC, HTB-10) cells that endogenously express CGRP receptors were cultured in EMEM+10% FBS medium, and cells were harvested during logarithmic growth phase. According to the kit's instruction manual, cells were resuspended in Stimulation Buffer containing 0.5 mM IBMX, and 5 μL of cell suspension was added to each well of a 96-well microplate (Cisbio, 66PL96025), with a cell density of 15,000 cells / well. 2.5 μL of gradient diluted compound solution was added to each well and incubated at 37°C for 30 minutes, after which 2.5 μL of 40 ng / mL human α-CGRP (Bachem, H-1470.0500) diluted in Stimulation Buffer containing 0.5 mM IBMX was added, with a final concentration of 10 ng / mL. After incubation at 37°C for 30 minutes, 5 μL of Anti-cAMP-Cryptate solution and 5 μL of cAMP-d2 solution were added to each well. After incubation at room temperature for 60 min, the HTRF signal was read using a microplate reader (Molecular Devices). Graphpad Prism was used to calculate the IC of the inhibitory effect of the compounds on the increase in cAMP levels based on the compound concentration and HTRF signal. 50 values ​​were calculated.

[0606] The biological activity of the compounds of the present application was measured through the above test, and the IC 50 The values ​​are shown in Table 2 below.

[0607] [Table 11]

[0608] Conclusion: The compounds of the present application have significant inhibitory effects on the CGRP signaling pathway in SK-N-MC cells.

[0609] Test Example 3: Measurement of affinity of the present compound for human CGRP receptor Cell membrane homogenates (containing 16 μg of protein) from CHO cells expressing human CGRP receptors were diluted with 0.03 nM 125[I]h-CGRPα and gradient diluted test samples were incubated in buffer (50 mM Hepes-NaOH (pH 7.4), 10 mM MgCl2, 4 mM KCl, 10 mM NaCl, 1 mM EDTA, 1 μM phosphorylamide, 0.3% BSA, and 0.04% bacitracin) at 22 °C for 90 min. A control group without test samples was set up to obtain the highest binding signal of the experiment, and nonspecific binding of the experiment was determined by a control group with addition of 1 μM nonisotopically labeled h-CGRPα. After incubation, glass fiber filters (GF / B, Packard) soaked in 0.3% PEI were placed in a 96-well cell collector (Unfilter, Packard), and the samples were quickly filtered under vacuum conditions and washed several times with pre-cooled buffer containing 50 mM Tris-HCl and 150 mM NaCl. After drying the filters, scintillation fluid (Microscint 0, Packard) was added and the radioactive signal value was measured using a scintillation counter (Topcount, Packard). The results were expressed as the percentage inhibition of specific binding of the radioactive ligand. Nonisotopically labeled h-CGRPα was used as a standard sample as a control, and the test samples and standard samples were tested at multiple concentrations. 125 A competition curve with [I]h-CGRPα was generated and the IC50 of each sample was calculated. The inhibition constant Ki was further calculated using the Cheng Prusoff equation, Ki = IC50 / (1 + L / K D ), where L is the [ 125 I] represents the concentration of h-CGRPα (0.03 nM), and K D is in the system 125 I] The dissociation constant (0.06 nM) of h-CGRPα and the human CGRP receptor.

[0610] The affinity of the compound of the present invention was measured through the above test, and the measured Ki values ​​are shown in Table 3 below.

[0611] [Table 12]

[0612] Conclusion: The compound of the present application has strong affinity for human CGRP receptor. The positive control compound Ubrogepant was prepared according to the protocol described in patent application WO2012064910, and its structure is as follows:

[0613] [ka]

[0614] Test Example 4: Study on oral pharmacokinetics of the compound of the present invention in SD rats 1. Purpose of the experiment SD rats were used as test animals, and LC / MS / MS method was used to measure the forced oral administration and intravenous injection of the compounds of the present application, and to measure the drug concentrations in plasma at different time points, to study the pharmacokinetic characteristics of the compounds of the present application in rats.

[0615] 2. Experimental Design 2.1 Experimental drugs and animals The positive control compound Atogepant, Example 1A and Example 3A of the present application; Eighteen healthy adult Sprague Dawley (SD) male rats were purchased from Zhaoyan (Suzhou) New Drug Research Center Co., Ltd. 2.2 Drug preparation and administration Oral gavage group: An appropriate amount of the test compound was weighed out, 100% polyethylene glycol 400 was added, and the compound was dissolved by vortexing. Upon completion of the preparation, all solutions were colorless and transparent, and the concentration of the formulation was 2 mg / mL. Intravenous injection group: An appropriate amount of the test compound was weighed out, 90% polyethylene glycol 400 and 10% ethanol were added, and the compound was dissolved by vortexing. Upon completion of the preparation, all solutions were colorless and transparent, and the concentration of the formulation was 1 mg / mL. Eighteen healthy adult SD male rats were fasted overnight and fed 4 hours after dosing. 2.3 Sample collection Approximately 0.2 mL of blood was collected from the jugular vein before administration and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 10 and 24 hours after administration and anticoagulated with EDTA-K2. After blood samples were collected, they were transferred to labeled ice-water bath centrifuge tubes and quickly centrifuged to separate plasma. Centrifugation conditions: 4000 rpm, 10 min, 4°C. The collected plasma was stored below -40°C for testing. LC-MS / MS method was used to measure the content of test compounds in the plasma of SD rats after gavage and intravenous administration of various compounds.

[0616] 3. Pharmacokinetic parameters The pharmacokinetic parameters of the compounds in the examples of this application and the positive control compound Atogepant are shown in Table 4 below.

[0617] [Table 13]

[0618] Conclusion: Compared with Atogepant, Examples 1A and 3A of the present application have better pharmacokinetic properties, with better drug absorption, extended half-life, significantly improved blood drug concentration, area under the curve, and bioavailability in SD rats.

[0619] Test Example 5. Oral pharmacokinetics of the compound of the present invention in cynomolgus monkeys 1. Purpose of the experiment Cynomolgus monkeys were used as test animals, and the compound of the present application was administered orally by force. The drug concentration in plasma at different time points was measured using LC / MS / MS method to study the pharmacokinetic characteristics of the compound of the present application in rats.

[0620] 2. Experimental Design 2.1 Experimental drugs and animals The positive control compound Atogepant, Example 1A and Example 3A of the present application; Six healthy adult male cynomolgus monkeys, Kangshun Biotechnology Co., Ltd. 2.2 Drug preparation and administration Oral gavage group: An appropriate amount of the test compound was weighed out, 100% polyethylene glycol 400 was added, and the compound was dissolved by vortexing. Upon completion of the preparation, all solutions were colorless and transparent, and the concentration of the formulation was 1 mg / mL. Six healthy adult male cynomolgus monkeys were fasted overnight and fed 4 hours after dosing. 2.3 Sample collection Approximately 0.2 mL of blood was collected from the jugular vein before administration and 0.25, 0.5, 1, 2, 4, 6, 8, 10 and 24 hours after administration and anticoagulated with EDTA-K2. After blood samples were collected, they were transferred to labeled ice-water bath centrifuge tubes and quickly centrifuged to separate plasma. Centrifugation conditions: 4000 rpm, 10 min, 4°C. The collected plasma was stored below -40°C for testing. An LC-MS / MS method was used to measure the content of test compounds in the plasma of cynomolgus monkeys after gavage and intravenous administration of various compounds.

[0621] 3. Pharmacokinetic parameters The pharmacokinetic parameters of the compounds in the examples of this application and the positive control compound Atogepant are shown in Table 5 below.

[0622] [Table 14]

[0623] Conclusion: Compared with Atogepant, Example 1A and Example 3A of the present application have better pharmacokinetic properties, with better drug absorption, extended half-life, significantly improved blood drug concentration and area under the curve in cynomolgus monkeys.

[0624] Test Example 6. In vivo efficacy test 1. Purpose of the experiment The inhibitory effect of the compounds of the present invention on blood flow in cynomolgus monkeys was evaluated in a capsaicin-induced blood flow model in cynomolgus monkeys.

[0625] 2. Experimental Drugs In Examples 1A and 3A, 100% polyethylene glycol 400 was used as the solvent.

[0626] 3. Experimental Method and Materials 3.1 Experimental animals and breeding conditions Experimental animals: male cynomolgus monkeys, weighing 3.2 kg to 5.80 kg at the time of administration, purchased from Guangxi Xiongsen Primate Experimental Animal Breeding Development Co., Ltd., production license: SCXK(Kui)2016-0003; experimental animal quality certificate number: NO.0002942. Breeding conditions: Animals were kept in stainless steel cages using a single-cage breeding method. The cage specifications were length x width x height = 1 m x 1 m x 0.8 m. Before Stein anesthesia, animals needed to fast (no water deprivation). For the rest of the time, animals were fed approximately 100 g of food once each morning and afternoon, supplemented with fresh fruit. The set temperature of the animal room was 18-26°C, humidity was 40-70%, and lighting was 12 hours alternating between light and dark. 3.2 Animal Grouping After adaptive breeding of cynomolgus monkeys, 10 cynomolgus monkeys were randomly selected and basal values ​​were recorded using a moorFLPI-2 laser speckle blood flow meter before capsaicin stimulation. After capsaicin stimulation, blood flow was measured again, and animals with area under the time-to-blood flow rate change curve (AUC) ≥ 1000 (min %) and small individual variation were selected for this experiment. 3.3 Experimental Method: The blank solvent control group was given 100% polyethylene glycol 400, and the treatment groups were given high and low doses of Example 1A and Example 3A, respectively, dissolved in 100% polyethylene glycol 400. Specific dosing information is shown in Table 6.

[0627] [Table 15]

[0628] Blood flow detection: Capsaicin was administered once to all animals on the day of administration, and blood flow was measured at 0 minutes (before capsaicin administration), 5 minutes, 10 minutes, 15 minutes, 20 minutes, and 30 minutes after capsaicin administration, and changes in blood flow during this period were monitored. After the experiment was completed on the same day, a washout was performed at intervals of 7 to 10 days, during which the experimental animals were rotated in order, and such experiments were repeated three times to calculate the average data for each group. 3.4 Data Statistics All data were graphed and statistically analyzed using Excel and GraphPad Prism 8 software. The blood flow rate change, AUC (area under the blood flow rate change-time curve), and blood flow inhibition rate were calculated using Excel. Blood flow rate change (%) = (blood flow rate at each time point - basal blood flow rate) / basal blood flow rate × 100%; Trapezoidal rule calculates the blood flow rate change-time area under the curve (AUC): AUC = 1 / 2 (5 min blood flow rate change + 10 min blood flow rate change) × 5 min + 1 / 2 (10 min blood flow rate change + 15 min blood flow rate change) × 5 min + 1 / 2 (15 min blood flow rate change + 20 min blood flow rate change) × 5 min + 1 / 2 (20 min blood flow rate change + 30 min blood flow rate change) × 10 min; Blood flow inhibition rate (%) = (AUC blank vehicle control group - AUC treatment group) / AUC blank vehicle control group × 100%.

[0629] 4.Results The effects of Examples 1A and 3A on blood flow in cynomolgus monkeys stimulated with capsaicin are shown in Table 7, Figures 1 and 2.

[0630] [Table 16]

[0631] 5. Conclusion Under the conditions of this test, compared with the blank solvent control group, low and high doses of Example 1A and high dose of Example 3A could significantly inhibit the increase in skin blood flow induced by capsaicin, with the blood flow inhibition rate reaching more than 70%, while low dose of Example 3A showed no inhibitory effect on the increase in skin blood flow induced by capsaicin.

Claims

1. A compound represented by general formula (I): 【Chemistry 1】 During the ceremony, R １ is selected from a hydrogen atom, a formyl group, an alkyl group, a cycloalkyl group, and a heterocyclyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are selected from R ａ and R １ is preferably an alkyl group or R ａ R is preferably selected from alkyl groups substituted with a substituent. １ is C １～６ Alkyl group or R ａ C substituted with a substituent １～６ alkyl groups, Each R ａ are the same or different and each independently selected from deuterium, tritium, halogen, amino, hydroxyl, cyano, alkoxy, alkyl, cycloalkyl, heterocycloalkyl, wherein said amino, hydroxyl, cyano, alkoxy, alkyl, cycloalkyl, heterocycloalkyl are optionally substituted by one or more substituents selected from alkyl, haloalkyl, halogen, amino, hydroxyl, cyano, or alkoxy; R ２ is selected from an alkyl group, a deuterated alkyl group, an aminoalkyl group, a haloalkyl group, and a hydroxyalkyl group; R ２ is preferably an alkyl group, more preferably C １～６ an alkyl group, more preferably a methyl group; Each R ３ are the same or different and are each independently selected from halogen, amino, hydroxyl, cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, preferably R ３ are the same and are both halogens, X and Y are the same or different and each independently represents ═CR ４ -, =N-, -NR ５ -, -O-, -S-, -S(O)- or -S(O) ２ -, preferably X is ═N—, —NR ５ -, -O-, -S-, preferably Y is ═CR ４ -, -O-, -NR ５ -, =N-, -S-, R ４ Or R ５ are the same or different and are each independently selected from a hydrogen atom or an alkyl group; W is -CH ２ - or a single bond; Z is selected from ═CH— or ═N—; n is 0, 1, 2, 3, 4, or 5, or a stereoisomer, tautomer, deuterated derivative, or a pharma- ceutically acceptable salt thereof.

2. A compound represented by general formula (II) or a stereoisomer, tautomer, deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, 【Chemistry 2】 In the formula, R １ , R ２ , R ３ 2. The compound of claim 1, wherein X, Y, W and Z are as defined in claim 1, or a stereoisomer, tautomer, deuterated derivative thereof or a pharma- ceutically acceptable salt thereof.

3. A compound represented by general formula (III) or a stereoisomer, tautomer, deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, 【Chemistry 3】 In the formula, R １ , R ３ 3. The compound of claim 2, wherein X, Y, and W are as defined in claim 1, or a stereoisomer, tautomer, deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

4. A compound represented by general formula (IV) or a stereoisomer, tautomer, deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, 【Chemistry 4】 In the formula, R １ , R ３ 4. The compound of claim 3, wherein X, and Y are as defined in claim 1, or a stereoisomer, tautomer, deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

5. A compound represented by general formula (V) or a stereoisomer, tautomer, deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, 【Chemistry 5】 In the formula, R １ , R ３ 4. The compound of claim 3, wherein X, and Y are as defined in claim 1, or a stereoisomer, tautomer, deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

6. R １ is selected from isopropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-methylpropyl, 3,3,3-trifluoropropyl and 3,3,3-trifluoro-2-hydroxypropyl, or a stereoisomer, tautomer, deuterated derivative or a pharma- ceutically acceptable salt thereof according to claim 1 or 2.

7. R １ is 2,2,2-trifluoroethyl, or a stereoisomer, tautomer, deuterated derivative, or a pharma- ceutically acceptable salt thereof according to claim 1 or 2.

8. R ３ 3. The compound of claim 1 or 2, wherein n is selected from fluorine and n is selected from 3, or a stereoisomer, tautomer, deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof.

9. The compound is 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 3. The compound of claim 1 or 2, wherein:

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a stereoisomer, tautomer, deuterated derivative thereof, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, excipient, or composition thereof.

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

12. 11. Use of a compound according to any one of claims 1 to 9 or a stereoisomer, tautomer, deuterated derivative or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, in the preparation 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 vasculovascular disease.

13. The cerebrovascular or vascular disease mediated by CGRP is selected from the group consisting of episodic migraine, migraine without aura, chronic migraine, pure menstrual migraine, menstrual-related migraine, migraine with aura, childhood / adolescent migraine, hemiplegic migraine, sporadic hemiplegic migraine, basilar migraine, cyclic vomiting, abdominal migraine, benign paroxysmal vertigo of childhood, retinal migraine, cluster headache, dialysis headache, chronic headache of unknown etiology, tension / stress-induced headache, allergy-induced headache, osteoarthritis and associated osteoporotic fracture pain, hot flashes associated with menopause or medically induced menopause due to surgery or drug treatment, cyclic vomiting syndrome, opioid withdrawal, psoriasis, asthma, obesity, morphine tolerance, neurodegenerative disorders, 13. The use according to claim 12, wherein the pain is selected from chronic secondary visceral pain such as inflammatory bowel disease (including Crohn's disease, ileitis, ulcerative colitis), gastroesophageal reflux disease, dyspepsia, irritable bowel syndrome, renal colic, cystitis, pancreatitis, prostatitis, and the like.

14. A compound according to any one of claims 1 to 9, or a stereoisomer, tautomer, deuterated derivative or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for use in the prophylaxis and / or treatment of a disease mediated by CGRP.

15. The cerebrovascular or vascular disease mediated by CGRP is selected from the group consisting of episodic migraine, migraine without aura, chronic migraine, pure menstrual migraine, menstrual-related migraine, migraine with aura, childhood / adolescent migraine, hemiplegic migraine, sporadic hemiplegic migraine, basilar migraine, cyclic vomiting, abdominal migraine, benign paroxysmal vertigo of childhood, retinal migraine, cluster headache, dialysis headache, chronic headache of unknown etiology, tension / stress-induced headache, allergy-induced headache, osteoarthritis and associated osteoporotic fracture pain, hot flashes associated with menopause or medically induced menopause due to surgery or drug treatment, cyclic vomiting syndrome, opioid withdrawal, psoriasis, asthma, obesity, morphine tolerance, neurodegenerative diseases, epilepsy, allergic rhinitis, rosacea, toothache, earache, nausea, vomiting ...

15. The compound according to claim 14, or a stereoisomer, tautomer, deuterated derivative or a pharmacologic acceptable salt thereof, or a pharmaceutical composition thereof, wherein the pain is selected from chronic secondary visceral pain such as inflammatory bowel disease (including Crohn's disease, ileitis, ulcerative colitis), gastroesophageal reflux disease, dyspepsia, irritable bowel syndrome, renal colic, cystitis, pancreatitis, prostatitis, or the like.

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