Piperidinecarboxamide azaindane derivatives, processes for their preparation and uses thereof

Abstract

The application relates to a substituted piperidylcarboxamide azaindane derivative, a preparation method thereof and medical application of a pharmaceutical composition containing the derivative or a deuterated derivative. Specifically, the application relates to a substituted piperidylcarboxamide azaindane derivative shown in a general formula (I), a preparation method thereof and a pharmaceutically acceptable salt, and purposes of the substituted piperidylcarboxamide azaindane derivative as a CGRP receptor antagonist in prevention and / or treatment of CGRP related diseases, especially in the field of migraine. Wherein definitions of the substituents in the general formula (I) are the same as those in the specification.

Description

TECHNICAL FIELD

[0001] The present application relates to a piperidinecarboxamide azaindane derivative, a preparation method thereof, and a pharmaceutical composition containing the derivative or a deuterated derivative and the use thereof as a therapeutic or prophylactic agent, particularly as a calcitonin gene-related peptide (CGRP) receptor antagonist. BACKGROUND

[0002] Migraine is a common trigeminal-vascular headache, which can last for 4 to 72 hours, and is characterized by throbbing moderate or severe pain on one side or both sides of the head, and repeated attacks, or accompanied by symptoms such as nausea, vomiting, sensitivity to light, sound, odor or touch, which seriously affects the patient's life (Steiner TJ et al., J Neurol Neurosurg Psychiatry 2004, 75:808-811). Compared with other populations, migraine patients are more likely to have depression, anxiety, sleep disorders, other pain and fatigue. Statistics show that migraine affects 1.3 billion patients worldwide, about 11% of adults, of which female patients are three times more than male patients, with about 40 million patients in the United States, about 8 million in Japan, and however, there are 13 million patients in China. In the United States, the medical expenses and productivity loss caused by migraine are estimated to be $80 billion per year, which is a huge loss of resources. At present, the pathogenesis of migraine is still not very clear internationally, and the more recognized is the trigeminal-vascular reflex theory, which effectively combines nerves, blood vessels and neurotransmitters, and better explains the pathogenesis of migraine, which has been widely accepted and recognized.

[0003] At present, migraine is clinically divided into symptomatic treatment and preventive treatment, and the first-line therapy for symptomatic treatment is still the use of non-steroidal anti-inflammatory drugs, ergotamines or triptans, and even the combined use of opioid drugs and other drugs for severe patients. Triptans are the first-line therapy for migraine at present, but some patients are not sensitive to this kind of drug, and the treatment effect is not obvious. In addition, triptans have the side effect of causing cardiovascular risk, which also limits the use of triptans. The commonly prescribed preventive treatment is antiepileptic drugs, tricyclic antidepressants and beta blockers, only some of which have the effect of preventing migraine. Since these preventive drugs are originally used to treat other diseases, they are not specific for migraine prevention, and have obvious side effects, so they are not the preferred preventive treatment for migraine. It can be imagined that in the field of migraine, there is still a need to explore to seek drugs with better treatment effect.

[0004] Calcitonin gene-related peptide (CGRP) is a 37-amino acid residue neuropeptide discovered by Amara et al. in 1982, which is widely distributed in the central and peripheral nervous system, especially in the cell bodies and terminals of sensory neurons (Amara SG et al., Science 1982, 298: 240-244). Peripheral CGRP is synthesized in the cell bodies of sensory neurons in the dorsal root ganglion, and central CGRP is synthesized in the cell bodies of sensory neurons in the trigeminal ganglion, and then rapidly transported to the central and peripheral terminals. The central terminal acts as an afferent fiber of sensory neurons, mainly responsible for the transmission of pain and temperature sensation. In the periphery, CGRP-containing sensory nerve fibers are widely distributed in various tissues and organs, and are released by axon reflex in response to various stimuli.

[0005] CGRP is currently the most powerful endogenous vasodilator substance, and in the field of pain, especially migraine, CGRP has become a research focus and hotspot. A number of clinical studies have shown that the level of CGRP in plasma increases during the onset of migraine, and the intensity and duration of migraine are positively correlated with the level of plasma CGRP (Han TH et al., Arch Drug Inf 2010, 3: 55-62). In addition, Goadsby et al. found that the content of CGRP in the external jugular vein increased during the onset of migraine, but did not increase in the elbow vein, indicating that CGRP was released intracranially during migraine (Goadsby PJ et al., Ann Neurol 1990, 28: 183-187). Animal studies have also found that CGRP released by trigeminal nerve activation can cause dilation and hypertrophy of cerebral and meningeal blood vessels, release of inflammatory mediators by mast cells, and transmission of nociceptive biological information released by 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 the abnormal release and increased content of CGRP.

[0006] The molecular weight of CGRP is about 3800 Da, consisting of 2800 base pairs, among its 37 amino acid sequence, the 2nd and 7th positions at the N-terminal are connected by a disulfide bond, and the C-terminal is a phenylalanine residue, these two structures are essential for the biological activity of CGRP. There are currently two types of human CGRP, α-CGRP and β-CGRP, among which α-CGRP is mainly expressed in the nervous system, such as the hypothalamus, cerebellum, brainstem and trigeminal nerve system, and β-CGRP is mainly expressed in the intestinal sensory system. α-CGRP is formed by splicing of calcitonin (CT) gene, while β-CGRP is encoded by a separate gene, although 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] CGRP receptor belongs to G protein-coupled receptor, which is composed of 7 transmembrane protein complexes (calcitonin receptor like receptor, CLR), 1 transmembrane protein receptor activity modifying protein (receptor activity modifying protein 1, RAMP1) and 1 intracellular protein (receptor component protein, RCP) (Evans BN et al., J Biology Chem 2000, 275: 38-43). RAMP1 is a small molecule transmembrane protein that mediates the membrane translocation of CLR in the form of chaperone, and RCP is a small molecule polypeptide that mediates the transduction of downstream signals of CLR. At present, the mechanism of CGRP participating in migraine is not clear, most scholars believe that CGRP as a multifunctional neuropeptide is involved in neurogenic inflammation, peripheral and central sensitization and cortical diffuse inhibition, thereby inducing migraine.

[0008] With more and more research on CGRP and its receptor, our understanding of it has also increased day by day. From the first isolation of CGR in 1983 to the approval of three CGRP monoclonal antibody drugs in the United States in 2018, it has taken 35 years. There are currently four CGRP monoclonal antibody drugs on the market. In addition to CGRP monoclonal antibodies, the development of CGRP receptor antagonists has also attracted attention, after all, small molecule compounds have obvious advantages in terms of the friendliness of the administration method, and so far there have been three small molecule CGRP receptor antagonists on the market.

[0009] In the development of CGRP receptor antagonists, there are surprises and setbacks. For example, Olcegepant, Telcagepant, MK-3207, although a number of clinical trials have confirmed the effectiveness of these drugs, but due to the occurrence of liver toxicity and other serious adverse reactions in a number of patients in clinical application, these compounds can only be suspended. Through continuous optimization and screening, more suitable compounds are found. Fortunately, in December 2019, the FDA approved the listing of Ubrogepant developed by Abbvie Company, which is used for the treatment of acute migraine. In February of the following year, Rimegepant developed by Biohaven Company was also successfully approved for the treatment of acute migraine. In May 2021, Rimegepant was approved for the extension of indications for the preventive treatment of episodic migraine. In September 2021, Atogepant developed by Abbvie Company was approved by the FDA for the preventive treatment of episodic migraine. The successful listing of these three small molecule drugs brings hope to patients with migraine around the world, but there are also side effects such as constipation, nausea, and drowsiness, so it is necessary to seek more safe and effective CGRP small molecule drugs. SUMMARY

[0010] In view of the above technical problems, the present application provides a substituted piperidine carboxamide indolin derivative or its stereoisomer, tautomer, deuterium derivative or pharmaceutically acceptable salt thereof represented by general formula (I):

[0011]

[0012] Among them:

[0013] R1 is selected from a hydrogen atom, a formyl group, an alkyl group, a cycloalkyl group, a heterocyclic group; wherein the alkyl group, the cycloalkyl group, the heterocyclic group are optionally substituted by one or more R a substituents;

[0014] Each R a is the same or different, each independently selected from deuterium, tritium, halogen, amino, hydroxyl, cyano, alkoxy, alkyl, cycloalkyl, heterocycloalkyl, wherein the amino, hydroxyl, cyano, alkoxy, alkyl, cycloalkyl, heterocycloalkyl are optionally further substituted by one or more substituents selected from alkyl, haloalkyl, halogen, amino, hydroxyl, cyano or alkoxy;

[0015] R2 is selected from an alkyl group, a deuterated alkyl group, an aminoalkyl group, a haloalkyl group, a hydroxyalkyl group;

[0016] Each R3 is the same or different, each independently selected from halogen, amino, hydroxyl, cyano, alkoxy, alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl;

[0017] X or Y are the same or different, each independently selected from =CR4-, =N-, -NR5-, -O-, -S-, -S(O)- or -S(O)2-;

[0018] R4or R5are the same or different, each independently selected from a hydrogen atom or an alkyl group;

[0019] W is selected from -CH2- or a single bond;

[0020] Z is selected from =CH- or =N-;

[0021] n is 0, 1, 2, 3, 4 or 5.

[0022] In a particular embodiment, R2is an alkyl group, the remaining R1, R3, X, Y, W and Z being as defined above for the general formula (I).

[0023] In a particular embodiment, R2is C 1-6 an alkyl group, the remaining R1, R3, X, Y, W and Z being as defined above for the general formula (I).

[0024] In a particular embodiment, R2is a methyl group, the remaining R1, R3, X, Y, W and Z being as defined above for the general formula (I).

[0025] In a particular embodiment, R1is selected from an alkyl group or an alkyl group substituted with R a a substituent, the remaining R2, R3, X, Y, W and Z being as defined above for the general formula (I).

[0026] In a particular embodiment, R1is selected from a C 1-6 alkyl group or a C a alkyl group substituted with R 1-6 a substituent, the remaining R2, R3, X, Y, W and Z being as defined above for the general formula (I).

[0027] In a particular embodiment, R1is selected from isopropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-methylpropyl, 3,3,3-trifluoropropyl and 3,3,3-trifluoro-2-hydroxypropyl, the remaining R2, R3, X, Y, W and Z being as defined above for the general formula (I).

[0028] In a particular embodiment, R1is 2,2,2-trifluoroethyl, the remaining R2, R3, X, Y, W and Z being as defined above for the general formula (I).

[0029] In a particular embodiment, X is selected from =N-, -NR5-, -O-, -S-, the remaining R1, R2, R3, Y, W and Z being as defined above for the general formula (I).

[0030] In a particular embodiment, Y is selected from =CR4-, -O-, -NR5-, =N-, -S-, the remaining R1, R2, R3, X, W and Z being as defined above for the general formula (I).

[0031] In a particular embodiment, R4or R5is a hydrogen atom.

[0032] In a particular embodiment, R3is the same and is halogen, the remaining R1, R2, X, Y, W and Z being as defined above for the general formula (I).

[0033] In a particular embodiment, R3is fluorine and n is 3, the remaining R1, R2, X, Y, W and Z being as defined above for the general formula (I).

[0034] In a particular embodiment, W is a single bond, the remaining R1, R2, R3, X, Y and Z being as defined above for the general formula (I).

[0035] In a particular embodiment, Z is =CH, the remaining R1, R2, R3, X, Y and W being as defined above for the general formula (I).

[0036] In a particular embodiment, n is 0, the remaining R1, R2, R3, X, Y, W and Z being as defined above for the general formula (I).

[0037] According to a preferred embodiment of the present application, there is provided a compound according to general formula (I) or a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, which is a compound according to general formula (II) or a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof:

[0038]

[0039] wherein R1, R2, R3, X, Y, W and Z are as defined in general formula (I).

[0040] According to a preferred embodiment of the present application, there is provided a compound according to general formula (II) or a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, which is a compound according to general formula (III) or a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof:

[0041]

[0042] wherein: R1, R3, X, Y and W are defined as described in general formula (I).

[0043] In a preferred embodiment of the present application, there is provided a compound according to general formula (III) or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein the compound is according to general formula (IV) or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof:

[0044]

[0045] wherein: R1, R3, X and Y are defined as described in general formula (I).

[0046] In a preferred embodiment of the present application, there is provided a compound according to general formula (III) or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein the compound is according to general formula (V) or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof:

[0047]

[0048] wherein: R1, R3, X and Y are defined as described in general formula (I).

[0049] In a preferred embodiment of the present application, there is provided a compound according to general formula (I), (II), (III), (IV) or (V) or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein R1is selected from isopropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-methylpropyl, 3,3,3-trifluoropropyl and 3,3,3-trifluoro-2-hydroxypropyl.

[0050] In a preferred embodiment of the present application, there is provided a compound according to general formula (I), (II), (III), (IV) or (V) or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein R1is selected from 2,2,2-trifluoroethyl.

[0051] In a preferred embodiment of the present application, there is provided a compound according to general formula (I), (II), (III), (IV) or (V) or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein R3is selected from fluoro, and n is selected from 3.

[0052] In a 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, R3and Z are as defined above for general formula (I).

[0053] In one 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 Formula (I).

[0054] In one 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 Formula (I).

[0055] In one 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 Formula (I).

[0056] In one 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 Formula (I).

[0057] In one 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 Formula (I).

[0058] In one 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 Formula (I).

[0059] In one 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 Formula (I).

[0060] In one 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 Formula (I).

[0061] In a 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 Formula (I).

[0062] In a 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 Formula (I).

[0063] In a 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 Formula (I).

[0064] In a 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 Formula (I).

[0065] In a 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 Formula (I).

[0066] In a 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 Formula (I).

[0067] In a 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 Formula (I).

[0068] In a 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 Formula (I).

[0069] In a 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 Formula (I).

[0070] In a 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 Formula (I).

[0071] In a particular embodiment, X is -S-; Y is =CR4-; W is -CH2-, and the remaining R1, R2, R3, and Z are as defined above for Formula (I).

[0072] In a 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 Formula (I).

[0073] In a 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 Formula (I).

[0074] In a 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 Formula (I).

[0075] In a 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 Formula (I).

[0076] In a 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 Formula (I).

[0077] In a 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 Formula (I).

[0078] In a 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 Formula (I).

[0079] In a specific embodiment, X is -S-; Y is selected from =CR4-, =N-, -S-; W is -CH2-, and the remaining definitions of R1, R2, R3, and Z are as defined above for Formula (I).

[0080] In a specific embodiment, X is selected from =N-, -NR5-, -O-, -S-; Y is selected from =CR4-, -S-; W is -CH2-, and the remaining definitions of R1, R2, R3, and Z are as defined above for Formula (I).

[0081] In a specific embodiment, X is selected from =N-, -NR5-, -O-, -S-; Y is selected from =CR4-, -S-; W is -CH2-, and the remaining definitions of R1, R2, R3, and Z are as defined above for Formula (I).

[0082] In a specific embodiment, X is selected from =N-, -NR5-, -O-, -S-; Y is selected from =CR4-, -S-; W is -CH2-, and the remaining definitions of R1, R2, R3, and Z are as defined above for Formula (I).

[0083] In a specific embodiment, X is -S-; Y is selected from =CR4-, -S-; W is -CH2-, and the remaining definitions of R1, R2, R3, and Z are as defined above for Formula (I).

[0084] In a specific embodiment, X is selected from =N-, -NR5-, -O-, -S-; Y is =CR4-; W is -CH2-, and the remaining definitions of R1, R2, R3, and Z are as defined above for Formula (I).

[0085] In a specific embodiment, X is selected from =N-, -NR5-, -O-, -S-; Y is =CR4-; W is -CH2-, and the remaining definitions of R1, R2, R3, and Z are as defined above for Formula (I).

[0086] In a specific embodiment, X is selected from =N-, -NR5-, -O-, -S-; Y is =CR4-; W is -CH2-, and the remaining definitions of R1, R2, R3, and Z are as defined above for Formula (I).

[0087] In a specific embodiment, X is -S-; Y is =CR4-; W is -CH2-, and the remaining definitions of R1, R2, R3, and Z are as defined above for Formula (I).

[0088] In a specific 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 definitions of R1, R2, R3, and Z are as defined above for Formula (I).

[0089] In one 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 Formula (I).

[0090] In one 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 Formula (I).

[0091] In one 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 Formula (I).

[0092] In one 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 Formula (I).

[0093] In one 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 Formula (I).

[0094] In one 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 Formula (I).

[0095] In one 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 Formula (I).

[0096] In one 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 Formula (I).

[0097] In one 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 Formula (I).

[0098] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0099] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0100] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0101] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0102] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0103] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0104] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0105] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0106] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0107] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0108] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0109] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0110] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0111] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0112] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0113] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0114] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0115] In one 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 definitions of R1, R2, R3, and Z are as defined above for Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0116] In one embodiment, X is selected from =N-, -NR5-, -O-, -S-; Y is =CR4-; W is -CH2-; and the remaining definitions of R1, R2, R3, and Z are as defined above for Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0117] In one embodiment, X is selected from =N-, -NR5-, -O-, -S-; Y is =CR4-; W is -CH2-; and the remaining definitions of R1, R2, R3, and Z are as defined above for Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0118] In one embodiment, X is selected from =N-, -NR5-, -O-, -S-; Y is =CR4-; W is -CH2-; and the remaining definitions of R1, R2, R3, and Z are as defined above for Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0119] In one embodiment, X is selected from =N-, -NR5-, -O-, -S-; Y is =CR4-; W is -CH2-; and the remaining definitions of R1, R2, R3, and Z are as defined above for Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0120] In one 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 definitions of R1, R2, R3, and Z are as defined above for Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0121] In one 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 definitions of R1, R2, R3, and Z are as defined above for Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0122] In one 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 definitions of R1, R2, R3, and Z are as defined above for Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0123] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0124] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0125] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0126] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0127] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0128] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0129] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0130] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0131] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0132] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0133] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0134] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0135] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 6 positions.

[0136] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0137] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0138] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0139] In one embodiment, X is -S-; Y is selected from =CR4-, =N-, -NR5-, -O-, -S-; W is -CH2-; and the remaining R1, R2, R3, and Z are as defined above for Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0140] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0141] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0142] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0143] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0144] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0145] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0146] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0147] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0148] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0149] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0150] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0151] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0152] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0153] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0154] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0155] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0156] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0157] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0158] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0159] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0160] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0161] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0162] In one 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 Formula (I), wherein R3is substituted at the 2, 3, 5 positions.

[0163] In one specific implementation, X is -S-; Y is selected from =CR4-, -S-; W is a single bond, and the definitions of R1, R2, R3 and Z are as described above for the general formula (I), wherein the substitution positions of R3 are 2, 3, and 5.

[0164] In one specific implementation, X is selected from =N-, -NR5-, -O-, -S-; Y is =CR4-; W is a single bond, and the definitions of R1, R2, R3 and Z are as described above for the general formula (I), wherein the substitution positions of R3 are 2, 3, and 5.

[0165] In one specific implementation, X is selected from -NR5-, -O-, -S-; Y is =CR4-; W is a single bond, and the definitions of R1, R2, R3 and Z are as described above for the general formula (I), wherein the substitution positions of R3 are 2, 3, and 5.

[0166] In one specific implementation, X is selected from -O- and -S-; Y is =CR4-; W is a single bond, and the definitions of R1, R2, R3 and Z are as described above for the general formula (I), wherein the substitution positions of R3 are 2, 3, and 5.

[0167] In one specific implementation, X is -S-; Y is =CR4-; W is a single bond, and the definitions of R1, R2, R3 and Z are as described above for the general formula (I), wherein the substitution positions of R3 are 2, 3, and 5.

[0168] In one specific embodiment, R2 is an alkyl group, and R1 is selected from alkyl groups or alkyl groups treated with R. a The alkyl group that is replaced by the substituent.

[0169] In one specific embodiment, R2 is methyl, and R1 is selected from alkyl groups or alkyl groups. a The alkyl group that is replaced by the substituent.

[0170] In one specific embodiment, R2 is a methyl group, and R1 is selected from C1. 1-6 Alkyl or R a C replaced by substituent 1-6 alkyl.

[0171] In one specific embodiment, R2 is a methyl group, and R1 is a methyl group formed by one or more R groups. a C replaced by substituent 1-6 alkyl.

[0172] In one specific embodiment, R2 is a methyl group, and R1 is a methyl group formed by one or more R groups. a C replaced by substituent 1-6 Alkyl, each R a Each is independently selected from halogens.

[0173] In a particular embodiment, R2is methyl, R1is selected from isopropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-methylpropyl, 3,3,3-trifluoropropyl and 3,3,3-trifluoro-2-hydroxypropyl. a C substituted by one or more substituents independently selected from halogen, amino, hydroxyl, cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl. 1-6 alkyl, R a each independently selected from fluorine, chlorine, bromine.

[0174] In a particular embodiment, R2is methyl, R1is selected from isopropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-methylpropyl, 3,3,3-trifluoropropyl and 3,3,3-trifluoro-2-hydroxypropyl. a C substituted by one or more substituents independently selected from halogen, amino, hydroxyl, cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl. 1-6 alkyl, R a is fluorine.

[0175] In a particular embodiment, R2is methyl, R1is selected from isopropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-methylpropyl, 3,3,3-trifluoropropyl and 3,3,3-trifluoro-2-hydroxypropyl.

[0176] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl.

[0177] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3are identical or different, each independently selected from halogen, amino, hydroxyl, cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0178] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3are identical and are both halogen.

[0179] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluorine.

[0180] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluorine, n is 3.

[0181] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0.

[0182] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluorine, n is 3, Z is selected from =CH- or =N-.

[0183] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is selected from =CH- or =N-.

[0184] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluorine, n is 3, Z is =CH.

[0185] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, and Z is =CH.

[0186] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, and Z is =CH.

[0187] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, and Z is =CH.

[0188] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, and Z is =CH.

[0189] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, and Z is =CH.

[0190] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, and Z is =CH.

[0191] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, and Z is =CH.

[0192] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, and Z is =CH.

[0193] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, and Z is =CH.

[0194] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, and Z is =CH.

[0195] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, and Z is =CH.

[0196] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, and X is selected from -NR5-, -O-, -S-.

[0197] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, and X is selected from -NR5-, -O-, -S-.

[0198] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, and X is selected from -O-, -S-.

[0199] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, and X is selected from -O-, -S-.

[0200] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, and X is selected from -O-, -S-.

[0201] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, and X is selected from -O-, -S-.

[0202] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, and X is -S-.

[0203] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, and X is -S-.

[0204] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, and X is -S-.

[0205] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, and X is -S-.

[0206] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, and X is -O-.

[0207] In a particular embodiment, R2 is methyl, 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 selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0208] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is a single bond, X is -O-.

[0209] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -O-.

[0210] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0211] In a particular embodiment, R2 is methyl, 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 selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0212] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0213] In a particular embodiment, R2 is methyl, 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 selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0214] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0215] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0216] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0217] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0218] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, X is selected from -O-, -S-, Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0219] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, -S-, Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0220] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, X is selected from -O-, -S-, Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0221] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from -O-, -S-, Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0222] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, X is -S-, Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0223] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -S-, Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0224] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, X is -S-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0225] In a particular embodiment, R2is methyl, R1is 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-, -S-.

[0226] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, X is -O-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0227] In a particular embodiment, R2is methyl, R1is 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-.

[0228] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, X is -O-, and Y is selected from =CR4-, -O-, -NR5-, =N-, -S-.

[0229] In a particular embodiment, R2is methyl, R1is 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-, -S-.

[0230] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, 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-.

[0231] In a particular embodiment, R2is methyl, R1is 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-.

[0232] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, 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-.

[0233] In a particular embodiment, R2is methyl, R1is 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 selected from =CR4-, =N-, -S-.

[0234] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, X is selected from -O-, -S-, Y is selected from =CR4-, =N-, -S-.

[0235] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, -S-, Y is selected from =CR4-, =N-, -S-.

[0236] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, X is selected from -O-, -S-, Y is selected from =CR4-, =N-, -S-.

[0237] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from -O-, -S-, Y is selected from =CR4-, =N-, -S-.

[0238] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, X is selected from -O-, -S-, Y is selected from =CR4-, =N-, -S-.

[0239] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, -S-, Y is selected from =CR4-, =N-, -S-.

[0240] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, X is selected from -O-, -S-, Y is selected from =CR4-, =N-, -S-.

[0241] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is selected from -O-, -S-, Y is selected from =CR4-, =N-, -S-.

[0242] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, X is -S-, and Y is selected from =CR4-, =N-, -S-.

[0243] In a particular embodiment, R2is methyl, R1is 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-.

[0244] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, X is -S-, and Y is selected from =CR4-, =N-, -S-.

[0245] In a particular embodiment, R2is methyl, R1is 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-.

[0246] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, X is -O-, and Y is selected from =CR4-, =N-, -S-.

[0247] In a particular embodiment, R2is methyl, R1is 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-.

[0248] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, X is -O-, and Y is selected from =CR4-, =N-, -S-.

[0249] In a particular embodiment, R2is methyl, R1is 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-.

[0250] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, and Y is selected from =CR4-, =N-.

[0251] In a particular embodiment, R2 is methyl, 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-.

[0252] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, 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-.

[0253] In a particular embodiment, R2 is methyl, 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-.

[0254] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, and Y is selected from =CR4-, =N-.

[0255] In a particular embodiment, R2 is methyl, 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-.

[0256] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, 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-.

[0257] In a particular embodiment, R2 is methyl, 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-.

[0258] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is selected from =CR4-, =N-.

[0259] In a particular embodiment, R2 is methyl, 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-.

[0260] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is a single bond, X is selected from -O-, -S-, Y is selected from =CR4-, =N-.

[0261] In a particular embodiment, R2 is methyl, 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 selected from =CR4-, =N-.

[0262] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is -CH2-, X is -S-, Y is selected from =CR4-, =N-.

[0263] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, -S-, Y is selected from =CR4-, =N-.

[0264] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is a single bond, X is -S-, Y is selected from =CR4-, =N-.

[0265] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -S-, Y is selected from =CR4-, =N-.

[0266] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is -CH2-, X is -O-, Y is selected from =CR4-, =N-.

[0267] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, -S-, Y is selected from =CR4-, =N-.

[0268] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is a single bond, X is -O-, Y is selected from =CR4-, =N-.

[0269] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -O-, Y is selected from =CR4-, =N-.

[0270] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, and Y is =N-.

[0271] In a particular embodiment, R2is methyl, R1is 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-.

[0272] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, and Y is =N-.

[0273] In a particular embodiment, R2is methyl, R1is 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-.

[0274] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, and Y is =N-.

[0275] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, and Y is =N-.

[0276] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, and Y is =N-.

[0277] In a particular embodiment, R2is methyl, R1is 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-.

[0278] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is =N-.

[0279] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is =N-.

[0280] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, X is selected from -O-, -S-, and Y is =N-.

[0281] In a particular embodiment, R2is methyl, R1is 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-.

[0282] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, X is -S-, and Y is =N-.

[0283] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is =N-.

[0284] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, X is -S-, and Y is =N-.

[0285] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -S-, and Y is =N-.

[0286] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, X is -O-, and Y is =N-.

[0287] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is =N-.

[0288] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, X is -O-, and Y is =N-.

[0289] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -O-, and Y is =N-.

[0290] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, and Y is =CR4-.

[0291] In a particular embodiment, R2is methyl, R1is 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-.

[0292] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, and Y is =CR4-.

[0293] In a particular embodiment, R2is methyl, R1is 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-.

[0294] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, and Y is =CR4-.

[0295] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, and Y is =CR4-.

[0296] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, and Y is =CR4-.

[0297] In a particular embodiment, R2is methyl, R1is 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-.

[0298] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is =CR4-.

[0299] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is =CR4-.

[0300] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, X is selected from -O-, -S-, and Y is =CR4-.

[0301] In a particular embodiment, R2is methyl, R1is 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-.

[0302] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, X is -S-, and Y is =CR4-.

[0303] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is =CR4-.

[0304] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, X is -S-, and Y is =CR4-.

[0305] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -S-, and Y is =CR4-.

[0306] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is -CH2-, X is -O-, and Y is =CR4-.

[0307] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is =CR4-.

[0308] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, R3is fluoro, n is 3, Z is =CH, W is a single bond, X is -O-, and Y is =CR4-.

[0309] In a particular embodiment, R2is methyl, R1is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -O-, and Y is =CR4-.

[0310] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, R4 is a hydrogen atom.

[0311] In a particular embodiment, R2 is methyl, 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-, R4 is a hydrogen atom.

[0312] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, R4 is a hydrogen atom.

[0313] In a particular embodiment, R2 is methyl, 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-, R4 is a hydrogen atom.

[0314] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, Y is =CR4-, R4 is a hydrogen atom.

[0315] In a particular embodiment, R2 is methyl, 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-, R4 is a hydrogen atom.

[0316] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, Y is =CR4-, R4 is a hydrogen atom.

[0317] In a particular embodiment, R2 is methyl, 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-, R4 is a hydrogen atom.

[0318] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is -CH2-, X is selected from -O-, -S-, Y is =CR4-, R4 is a hydrogen atom.

[0319] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, -S-, Y is =CR4-, R4 is a hydrogen atom.

[0320] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is a single bond, X is -S-, Y is =CR4-, R4 is a hydrogen atom.

[0321] In a particular embodiment, R2 is methyl, 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-, R4 is a hydrogen atom.

[0322] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is -CH2-, X is -S-, Y is =CR4-, R4 is a hydrogen atom.

[0323] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -S-, Y is =CR4-, R4 is a hydrogen atom.

[0324] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is a single bond, X is -S-, Y is =CR4-, R4 is a hydrogen atom.

[0325] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is a single bond, X is -S-, Y is =CR4-, R4 is a hydrogen atom.

[0326] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is -CH2-, X is -O-, Y is =CR4-, R4 is a hydrogen atom.

[0327] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, n is 0, Z is =CH, W is -CH2-, X is selected from -O-, Y is =CR4-, R4 is a hydrogen atom.

[0328] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, Z is =CH, W is a single bond, X is -O-, Y is =CR4-, R4 is a hydrogen atom.

[0329] In a particular embodiment, R2 is methyl, 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.

[0330] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, n is 3, R3 is fluoro, and the three fluoro substituents are in positions 2,3,6 or 2,3,5; Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, and Y is =CR4-, R4 being a hydrogen atom.

[0331] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, n is 3, R3 is fluoro, and the three fluoro substituents are in positions 2,3,6 or 2,3,5; Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, and Y is =CR4-, R4 being a hydrogen atom.

[0332] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, n is 3, R3 is fluoro, and the three fluoro substituents are in positions 2,3,6 or 2,3,5; Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, and Y is =CR4-, R4 being a hydrogen atom.

[0333] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, n is 3, R3 is fluoro, and the three fluoro substituents are in positions 2,3,6 or 2,3,5; Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, and Y is =CR4-, R4 being a hydrogen atom.

[0334] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, n is 3, R3 is fluoro, and the three fluoro substituents are in positions 2,3,6 or 2,3,5; Z is =CH, W is -CH2-, X is selected from -O-, -S-, and Y is =CR4-, R4 being a hydrogen atom.

[0335] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, n is 3, R3 is fluoro, and the three fluoro substituents are in positions 2,3,6 or 2,3,5; Z is =CH, W is a single bond, X is selected from -O-, -S-, and Y is =CR4-, R4 being a hydrogen atom.

[0336] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, n is 3, R3 is fluoro, and the three fluoro substituents are in positions 2,3,6 or 2,3,5; Z is =CH, W is -CH2-, X is -S-, and Y is =CR4-, R4 being a hydrogen atom.

[0337] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 6 or 2, 3, 5; Z is =CH, W is a single bond, X is -S-, Y is =CR4-, R4 is a hydrogen atom.

[0338] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 6 or 2, 3, 5; Z is =CH, W is -CH2-, X is -O-, Y is =CR4-, R4 is a hydrogen atom.

[0339] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 6 or 2, 3, 5; Z is =CH, W is a single bond, X is -O-, Y is =CR4-, R4 is a hydrogen atom.

[0340] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 6; Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, R4 is a hydrogen atom.

[0341] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 6; Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, R4 is a hydrogen atom.

[0342] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 6; Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, Y is =CR4-, R4 is a hydrogen atom.

[0343] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 6; Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, Y =CR4-, R4 is a hydrogen atom.

[0344] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 6; Z is =CH, W is -CH2-, X is selected from -O-, -S-, Y is =CR4-, R4 is a hydrogen atom.

[0345] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 6; Z is =CH, W is a single bond, X is selected from -O-, -S-, Y is =CR4-, R4 is a hydrogen atom.

[0346] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 6 or 2, 3, 5; Z is =CH, W is -CH2-, X is -S-, Y is =CR4-, R4 is a hydrogen atom.

[0347] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 6; Z is =CH, W is a single bond, X is -S-, Y is =CR4-, R4 is a hydrogen atom.

[0348] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 6; Z is =CH, W is -CH2-, X is -O-, Y is =CR4-, R4 is a hydrogen atom.

[0349] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 6; Z is =CH, W is a single bond, X is -O-, Y is =CR4-, R4 is a hydrogen atom.

[0350] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 5; Z is =CH, W is -CH2-, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, R4 is a hydrogen atom.

[0351] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 5; Z is =CH, W is a single bond, X is selected from =N-, -NR5-, -O-, -S-, Y is =CR4-, R4 is a hydrogen atom.

[0352] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 5; Z is =CH, W is -CH2-, X is selected from -NR5-, -O-, -S-, Y is =CR4-, R4 is a hydrogen atom.

[0353] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 5; Z is =CH, W is a single bond, X is selected from -NR5-, -O-, -S-, Y is =CR4-, R4 is a hydrogen atom.

[0354] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 5; Z is =CH, W is -CH2-, X is selected from -O-, -S-, Y is =CR4-, R4 is a hydrogen atom.

[0355] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 5; Z is =CH, W is a single bond, X is selected from -O-, -S-, Y is =CR4-, R4 is a hydrogen atom.

[0356] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 5; Z is =CH, W is -CH2-, X is -S-, Y is =CR4-, R4 is a hydrogen atom.

[0357] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 5; Z is =CH, W is a single bond, X is -S-, Y is =CR4-, R4 is a hydrogen atom.

[0358] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 5; Z is =CH, W is -CH2-, X is -O-, Y is =CR4-, R4 is a hydrogen atom.

[0359] In a particular embodiment, R2 is methyl, R1 is 2,2,2-trifluoroethyl, R3 is fluoro, n is 3, the three fluoro substituents are in positions 2, 3, 5; Z is =CH, W is a single bond, X is -O-, Y is =CR4-, R4 is a hydrogen atom.

[0360] In the above detailed description, the definitions of R1, R2, R3, X, Y, W and Z not mentioned are as described in general formula (I).

[0361] In a preferred aspect of the present application, the compound of general formula (I) is selected from:

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370] or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof.

[0371] Note: If there is a discrepancy between the drawn structure and the name given for that structure, the drawn structure will control.

[0372] Further, the present application provides a pharmaceutical composition comprising an effective amount of a compound of general formula (I), (II), (III), (IV) or (V), or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0373] The present application provides use of a compound of general formula (I), (II), (III), (IV) or (V), or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a CGRP receptor antagonist.

[0374] The present application also provides the use of a compound of Formula (I), (II), (III), (IV) or (V), or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention and / or treatment of a CGRP-mediated disease, wherein the CGRP-mediated disease is preferably a cerebrovascular or vascular disorder; and wherein the CGRP-mediated cerebrovascular or vascular disorder is selected from the group consisting of an attack of migraine, migraine without aura, chronic migraine, pure menstrual migraine, menstrual-related migraine, migraine with aura, childhood / juvenile migraine, hemiplegic migraine, sporadic hemiplegic migraine, basilar-type migraine, periodic vomiting, abdominal migraine, benign paroxysmal positional vertigo in childhood, retinal migraine, cluster headache, dialysis headache, chronic headache of unknown origin, tension / stress-induced headache, allergy-induced headache, osteoarthritis and related osteoporotic bone fracture pain, hot flashes associated with menopause or medically induced menopause from surgery or drug therapy, cyclic vomiting syndrome, opioid withdrawal, psoriasis, asthma, obesity, morphine tolerance, neurodegenerative diseases, epilepsy, allergic rhinitis, rosacea, dental pain, ear pain, otitis media, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, gout, trigeminal neuralgia, nasal polyps, chronic rhinosinusitis, temporomandibular syndrome, back pain, lower back pain, cough, dystonic pain, inflammatory pain, postoperative incisional pain, sciatica, complex regional pain syndrome, Behcet's disease, endometriosis, phantom limb syndrome, dysmenorrhea, pain associated with childbirth, pain resulting from skin burns, or inflammatory bowel disease (including Crohn's disease, ileitis, and ulcerative colitis), gastro-esophageal reflux disease, dyspepsia, irritable bowel syndrome, renal colic, cystitis, pancreatitis, and prostatitis, and the like chronic secondary visceral pain.

[0375] The present application further provides the use of a compound of Formula (I), (II), (III), (IV) or (V), or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention and / or treatment of a cerebrovascular or vascular disorder.

[0376] The present application provides a use of a compound according to general formula (I), (II), (III), (IV) or (V), or a stereoisomer, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention and / or treatment of episodic migraine, migraine without aura, chronic migraine, pure menstrual migraine, menstrual-related migraine, migraine with aura, pediatric / adolescent migraine, hemiplegic migraine, sporadic hemiplegic migraine, basilar-type migraine, cyclical vomiting, abdominal migraine, benign paroxysmal positional vertigo in children, retinal migraine, cluster headache, dialysis headache, chronic headache of unknown origin, tension / stress-induced headache, allergy-induced headache, osteoarthritis and related osteoporotic bone fracture pain, hot flashes associated with menopause or medically induced menopause from surgery or drug treatment, cyclic vomiting syndrome, opioid withdrawal, psoriasis, asthma, obesity, morphine tolerance, neurodegenerative diseases, epilepsy, allergic rhinitis, rosacea, dental pain, ear pain, otitis media, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, gout, trigeminal neuralgia, nasal polyps, chronic rhinosinusitis, temporomandibular syndrome, back pain, lower back pain, cough, dystonic pain, inflammatory pain, postoperative incisional pain, sciatica, complex regional pain syndrome, Behcet's disease, endometriosis, phantom limb syndrome, dysmenorrhea, pain associated with childbirth, pain resulting from skin burns, or chronic secondary visceral pain in inflammatory bowel disease (including Crohn's disease, ileitis and ulcerative colitis), gastro-esophageal reflux disease, indigestion, irritable bowel syndrome, renal colic, cystitis, pancreatitis and prostatitis.

[0377] The compounds according to the application are optionally in the form of individual optical isomers, individual enantiomers or mixtures of racemates, in the form of tautomers and in the form of the free base or of the corresponding acid addition salts with pharmacologically acceptable acids.

[0378] The compounds according to the application can exist as tautomers. All tautomeric forms of the compounds according to the application are contemplated to be within the scope of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0379] Figure 1 is the rate of change of blood flow-time plot (%);

[0380] Figure 2 is the area under the rate of change of blood flow-time plot (%·min).

[0381] Detailed description of the invention

[0382] Unless otherwise stated, the following terms used in the specification and claims have the following definitions:

[0383] When "alkyl" is used as a group or part of a group, it refers to a group consisting of C1-C2. 20 Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C. 10 Alkyl groups, more preferably C1-C6 alkyl groups. 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.

[0384] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, bridged, or spirocyclic carbon ring. Preferably, it is C3-C. 12 Cycloalkyl groups, more preferably C3-C8 cycloalkyl groups, and most preferably C3-C6 cycloalkyl groups. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc., with cyclopropyl and cyclohexenyl being preferred. The cycloalkyl group may be optionally substituted or unsubstituted.

[0385] The terms “heterocyclic group,” “heterocyclic alkyl group,” “heterocyclic,” or “heterocyclic” are used interchangeably in this application and all refer to non-aromatic heterocyclic groups in which one or more cyclic atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, etc., including monocyclic, polycyclic, fused-ring, bridged-ring, and spirocyclic groups. Preferably, it has a 5- to 7-membered monocyclic or a 7- to 10-membered bicyclic or tricyclic group, which may contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of “heterocyclic group” include, but are not limited to, morpholino, oxobutyryl, thiomorpholino, tetrahydrofuran, tetrahydropyran, 1,1-dioxo-thiomorpholino, piperidinyl, 2-oxo-piperidinyl, pyrrolyl, 2-oxo-pyrrolyl, piperazine-2-one, 8-oxa-3-aza-bicyclic [3.2.1]octyl, piperazine, and hexahydropyrimidine. Heterocyclic groups may be substituted or unsubstituted.

[0386] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl group is C6-C. 10 Aryl, more preferably phenyl and naphthyl, most preferably naphthyl. The aryl group can be substituted or unsubstituted.

[0387] "Heteroaryl" means an aromatic 5- to 6-membered monocyclic ring or 8- to 10-membered bicyclic ring which can contain 1 to 4 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heteroaryl" groups include, but are not limited to, furanyl, pyridinyl, 2-oxo-l,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzoimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzoisothiazolyl, benzoxazolyl, and benzoisoxazolyl. The heteroaryl group can be substituted or unsubstituted.

[0388] "Alkoxy" means a group of the formula (alkyl-O-). Alkyl is as defined herein. C1-C6alkoxy is preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, and the like.

[0389] "Hydroxy" means the -OH group.

[0390] "Halo" means fluoro, chloro, bromo, and iodo.

[0391] "Amino" means -NH2.

[0392] "Cyano" means -CN.

[0393] "Nitro" means -NO2.

[0394] "Carboxy" means -C(O)OH.

[0395] "DMSO" means dimethyl sulfoxide.

[0396] "BOC" means tert-butoxycarbonyl.

[0397] "TFA" means trifluoroacetic acid.

[0398] "PMB" means p-methoxybenzyl.

[0399] "SEM" means (trimethylsilyl)ethoxymethyl.

[0400] "Hydroxyalkyl" means an alkyl group substituted with a hydroxy group.

[0401] "Aminoalkyl" means an alkyl group substituted with an amino group.

[0402] A "leaving group" or leaving group, in chemical reactions, is an atom or functional group that departs from a larger molecule, and is a term used in nucleophilic substitution and elimination reactions. In nucleophilic substitution reactions, the reactant that is attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called the leaving group. A good leaving group is one that can readily accept an electron and bear a negative charge. The smaller the pKa of the conjugate acid of the leaving group, the more likely it is to leave the molecule. This is because the smaller the pKa of the conjugate acid, the more the leaving group tends to exist as an anion (or neutral leaving group) rather than bond to another atom. Common leaving groups include, but are not limited to, halogen, mesyl, -OTs, -OTf, or -OH.

[0403] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of the group are independently of each other replaced by a corresponding number of substituents. It is understood that the substituents are only in their possible chemical positions, which can be determined (experimentally or theoretically) by a person skilled in the art without undue effort, as to whether a substitution is possible or not. For example, an amino group with a free hydrogen or a hydroxyl group can not be stable when bound to a carbon atom with an unsaturated (e.g. olefinic) bond.

[0404] "Substituted" or "substitution" as used herein, unless otherwise indicated, means that a group can be substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, alkylthio, alkylamino, halogen, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl;

[0405] "Pharmaceutically acceptable salt" means a salt of a compound that is suitable for medical use and that retains the biological activity of the parent compound. The pharmaceutically acceptable salts of the compounds of Formula (I) can be metal salts, amine salts with suitable acids.

[0406] It will be appreciated by those skilled in the art that salts of the compounds of Formula (I), (II), (III), (IV), or (V), including pharmaceutically acceptable salts, can be prepared. These salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. The bases commonly employed to form pharmaceutically acceptable salts include organic bases or inorganic bases, and the acids commonly employed to form pharmaceutically acceptable salts include inorganic acids or organic acids.

[0407] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are suitable for these purposes. Lists of additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0408] A "deuterated derivative" means a compound of the above that contains deuterium bound to carbon at least at one position, in an amount greater than its natural abundance.

[0409] A "pharmaceutical composition" means a mixture of one or more of the compounds described herein, or physiologically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to an organism and to facilitate absorption of the active ingredient.

[0410] The pharmaceutical compositions contemplated herein can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, among others. In addition, the pharmaceutical compositions of the present application can be made up in conventional forms, such as solutions, suspensions or emulsions, in solid form (including without limitation capsules, tablets, pills, granules or powders), or in liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and / or can contain conventional inert diluents, lubricating agents, or buffering agents, along with adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, among others.

[0411] Typically, the pharmaceutical composition is a tablet or capsule, which contains the active ingredient in admixture with

[0412] a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, and / or

[0413] b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium salt and / or polyethyleneglycol; for tablets also

[0414] c) Adhesives, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone; and if necessary.

[0415] d) Disintegrants, such as starch, agar, alginate or its sodium salt, or effervescent mixtures; and / or

[0416] e) Absorbents, colorants, flavorings and sweeteners.

[0417] According to methods known in the art, tablets can be film-coated or enteric-coated.

[0418] Suitable compositions for oral administration include an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the form of tablets, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions for oral use are prepared according to any method known in the art for preparing pharmaceutical compositions, and in order to provide a refined and palatable formulation, the composition may contain one or more agents selected from sweeteners, flavoring agents, coloring agents, and preservatives. Tablets may contain the active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for preparing tablets. These excipients are, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate); granulating and disintegrants (e.g., corn starch, or alginate); binders (e.g., starch, gelatin, or gum arabic); and lubricants (e.g., magnesium stearate, stearic acid, or talc). Tablets are either uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a prolonged effect over a longer period. For example, delaying materials such as glyceryl monostearate or glyceryl distearate can be used. Oral formulations can be presented in hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or in soft gelatin capsules, wherein the active ingredient is mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0419] Some injectable compositions are isotonic aqueous solutions or suspensions, and suppositories are advantageously prepared from fat emulsions or suspensions. The compositions may be sterilized and / or contain excipients such as preservatives, stabilizers, wetting or emulsifiers, dissolution promoters, salts and / or buffers for adjusting osmotic pressure. Furthermore, they may contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulation, or coating methods and contain approximately 0.1-75% or approximately 1-50% of the active ingredient.

[0420] Since water may promote the degradation of certain compounds, this application also provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of this application as active ingredients.

[0421] The anhydrous pharmaceutical compositions and dosage forms of the application can be prepared using anhydrous or low water containing ingredients and low water or low humidity conditions. The anhydrous pharmaceutical compositions can be prepared and stored such that they remain anhydrous. Thus, the anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable dosing packages. Examples of suitable packaging include, but are not limited to, air tight foils, plastics, unit dose containers such as tubular lamitabs, blister packs, and strip packs.

[0422] The application further provides pharmaceutical compositions and dosage forms that include one or more agents that reduce the rate of degradation of a compound of the application as an active ingredient. Such agents, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers or salt buffers, etc.

[0423] For a subject of about 50-70 kg, a pharmaceutical composition or combination of the application can be a unit dosage 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. A therapeutically effective dose of a compound, pharmaceutical composition, or combination thereof depends on the species of the subject, the body weight, age and individual condition of the subject, the disease or disorder of the subject being treated, or the severity of the disease or disorder. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat, or inhibit the progress of the disorder or disease.

[0424] A "stereoisomer" of a compound having a given stereochemical configuration refers to the opposite enantiomer of the compound and to any diastereomer including the geometric isomer (Z / E) of the compound. For example, if a compound has the S, R, Z stereochemical configuration, its stereoisomers will include its opposite enantiomer having the R, S, Z configuration, as well as its diastereomers having 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 a compound is not specified, "stereoisomers" refer to either enantiomer of the compound.

[0425] The compounds of general formula (I), (II), (III), (IV), or (V), stereoisomers thereof, or complexes of tautomers of the compounds of general formula (I), (II), (III), (IV), or (V) or stereoisomers thereof can be administered alone or in combination with one or more pharmaceutically active compounds. Generally, one or more of these compounds are administered in the form of a pharmaceutical composition (preparation) in combination with one or more pharmaceutically acceptable excipients. The choice of excipient depends on the particular mode of administration, the influence of the excipient on solubility and stability, the nature of the dosage form, and the like. Useful pharmaceutical compositions and methods of their preparation can be found, for example, in A.R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th edition, 2000)

[0426] The compounds of the present application can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present application, including but not limited to, diastereomeric, enantiomeric, and atropisomeric forms and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present application.

[0427] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (such as diastereomeric, enantiomeric, and atropisomeric forms and geometric (conformational) isomers) forms of the structure. For example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included within the scope of the present application. Thus, individual stereoisomers of the compounds of the present application are within the scope of the present application, as are enantiomeric, diastereomeric, and geometric (conformational) mixtures.

[0428] The term "stereoisomers" refers to isomers having the same molecular formula but differing in the arrangement of atoms in space. The stereoisomers belong to one of the following categories: enantiomeric, diastereomeric, and geometric (conformational) isomers. Enantiomeric and diastereomeric isomers differ in the configuration of one or more asymmetric centers and geometric isomers differ in the configuration of one or more double bonds.

[0429] The term "substantially enantiopure" refers to greater than 90% enantiomeric purity at a given stereocenter. Thus, the term "substantially enantiopure" refers to greater than 80% ee (enantiomeric excess). For compounds that exist as stereoisomers, the stereoisomer can be substantially enantiopure at the stereocenter, or preferably can have greater than 97% enantiomeric purity, or more preferably greater than 99% enantiomeric purity.

[0430] Synthetic methods for the compounds of the application

[0431] For the purposes of the present application, the following technical solutions are adopted:

[0432] The present application provides a preparation method of a compound of general formula (I) or a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, which comprises:

[0433]

[0434] The compound represented by general formula (Ia) is subjected to electrophilic addition and rearrangement to obtain a compound represented by general formula (Ib), the compound represented by general formula (Ib) is subjected to chlorination to obtain a compound represented by general formula (Ic), the compound represented by general formula (Ic) is subjected to ring formation reaction with a compound represented by general formula (Id) to obtain a compound represented by general formula (Ie), the compound represented by general formula (Ie) is subjected to deprotection to obtain a compound represented by general formula (If), and the compound represented by general formula (If) is subjected to condensation reaction with a compound represented by general formula (Ig) to obtain a compound represented by general formula (I);

[0435] wherein:

[0436] PG is an amino protecting group;

[0437] X or Y are the same or different, each independently selected from =CR4-, =N-, -NR5-, -O-, -S-, -S(O)-, -S(O)2-,

[0438]

[0439] R1, R2, R3, W, Z and n are as defined in general formula (I). DETAILED DESCRIPTION

[0440] The following examples are intended to further describe the present application but are not intended to limit the scope of the present application.

[0441] Examples

[0442] The examples below give the preparation of representative compounds of formula (I) and related structure identification data. It must be understood that the examples below are intended to illustrate the present application and not to limit it. 1 H NMR spectra were recorded on a Bruker instrument (400 MHz) and chemical shifts are expressed in ppm using tetramethylsilane as internal standard (0.00 ppm). 1 H NMR spectra were recorded on a Bruker instrument (400 MHz) and chemical shifts are expressed in ppm using tetramethylsilane as internal standard (0.00 ppm).

[0443] Mass spectra were determined using LC / MS instrument, and ionization mode can be ESI or APCI.

[0444] Thin layer chromatography silica gel plates were purchased from Huanghai HSG F254 or Qingdao GF254, and the silica gel plates used in thin layer chromatography (TLC) had a thickness of 0.15 mm to 0.2 mm, and the silica gel plates used in thin layer chromatography separation and purification of products had a thickness of 0.4 mm to 0.5 mm.

[0445] Column chromatography generally used silica gel with a mesh size of 200 to 300 as a carrier.

[0446] In the following examples, unless otherwise specified, all temperatures are in degrees Celsius, and unless otherwise specified, all starting materials and reagents were obtained from commercial sources and used without further purification, and unless otherwise specified, commercial suppliers 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.

[0447] CD3OD: deuterated methanol.

[0448] CDCl3: deuterated chloroform.

[0449] DMSO-d6: deuterated dimethyl sulfoxide.

[0450] D2O: heavy water.

[0451] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0452] The compounds were purified using C18 reverse phase column preparation or semi-preparation purification, silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from: A: petroleum ether and tetrahydrofuran system; B: acetonitrile and water system; C: petroleum ether and ethyl acetate system; wherein the volume ratio of the solvents is different according to the polarity of the compound, and a small amount of acidic or basic reagent can also be added for adjustment, such as trifluoroacetic acid, acetic acid or triethylamine, etc.

[0453] Example 1

[0454] 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[benfuran-5,3'-pyrrolo[2,3-b]pyridine]-2-formamide

[0455]

[0456] First step

[0457] 3,3'-(2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-3,3-diyl) diethyl dicarbonate

[0458] diethyl dicarbonate

[0459] Dissolve 1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one 1a (2 g, 7.56 mmol) in dimethyl sulfoxide (13 mL), add potassium tert-butoxide solution (1 M, 378.22 μL), stir at 25 °C for 10 min, slowly drop ethyl acrylate 1b (1.59 g, 15.89 mmol) at 45 °C, stir for 1 h. After the reaction is completed, add water (20 mL), extract with ethyl acetate (40 mL x 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the obtained residue is separated and purified by column chromatography (eluent: A system) to obtain 3,3'-(2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-3,3-diyl) diethyl dicarbonate 1c (2.4 g), yield: 61.46%. MS m / z (ESI): 465.3 [M+1]

[0460] Second step

[0461] 3,3'-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-3,3-diyl) diethyl dicarbonate

[0462] Dissolve 3,3'-(2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-3,3-diyl) diethyl dicarbonate 1c (2.4 g, 5.17 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (20 mL), stir at 25 °C for 18 h. After the reaction is completed, concentrate under reduced pressure, add tetrahydrofuran (20 mL), triethylamine (10 mL) and ammonia water (20 mL), stir at 25 °C for 1 h, concentrate under reduced pressure, adjust the pH to 6 with 1 M hydrochloric acid, extract with ethyl acetate (100 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain 3,3'-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-3,3-diyl) diethyl dicarbonate 1d (1.6 g), which is directly used in the next step without purification.

[0463] MS m / z (ESI): 335.2 [M+1]

[0464] Third step

[0465] 2',4-dioxo-l',2'-dihydrospiro[cyclohexane-l,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid ethyl ester

[0466] Diethyl 3,3'-(2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridine-3,3-diyl)dipropionate Id (1.5 g, 4.49 mmol) was dissolved in tetrahydrofuran (30 mL), and potassium tert-butoxide solution (1 M, 13.46 mL) was added dropwise slowly at low temperature and stirred for 20 minutes. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2',4-dioxo-l',2'-dihydrospiro[cyclohexane-l,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid ethyl ester le (1.2 g), which was used directly in the next step without purification.

[0467] MS m / z (ESI): 289.3 [M+1]

[0468] Fourth step

[0469] 2',4(1'H)-dioxospiro[cyclohexane-l,3'-pyrrolo[2,3-b]pyridine]

[0470] 2',4-dioxo-l',2'-dihydrospiro[cyclohexane-l,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid ethyl ester le (1.1 g, 3.82 mmol) was dissolved in 3 M hydrochloric acid (50 mL), and methanol (5 mL) and dioxane (10 mL) were added, and the reaction was stirred at 100 °C for 2 hours. After concentration under reduced pressure, the pH was adjusted to 8 with saturated sodium bicarbonate solution, and extracted with a mixed solution of ethyl acetate and tetrahydrofuran three times, the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2',4(1'H)-dioxospiro[cyclohexane-l,3'-pyrrolo[2,3-b]pyridine] If (700 mg), yield: 84.8%.

[0471] MS m / z (ESI): 217.1 [M+1]

[0472] 1 H 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).

[0473] Fifth step

[0474] 1'-(4-methoxybenzyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione

[0475] Spirro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 1f (0.54 g, 2.5 mmol) and cesium carbonate (1.22 g, 3.75 mmol) were added into N,N-dimethylformamide (3 mL), then p-methoxybenzyl chloride (470 mg, 3.0 mmol) was added dropwise slowly, and the reaction was carried out 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 (20 mL) and extracted with ethyl acetate (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: A system) to obtain 1'-(4-methoxybenzyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 1g (670 mg), with a yield of 79.7%.

[0476] MS m / z (ESI): 337.2 [M+1]

[0477] Sixth step

[0478] 3-((dimethylamino)methylene)-1'-(4-methoxybenzyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione

[0479] 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'-tetramethylmethane diamine (700 mg, 4.01 mmol) was added, and the reaction was carried out at 60 °C for 16 hours. The reaction was monitored by LC-MS, and after the reaction was completed, the reaction solution was poured into water (30 mL) and 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 used directly in the next step without purification.

[0480] MS m / z (ESI): 391.9 [M+1]

[0481] Seventh step

[0482] 4-chloro-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'- pyrrolo[2,3-b]pyridine]-3-en-3-formaldehyde

[0483] Dissolve 3-((dimethylamino)methylene)-1'-(4-methoxybenzyl)spiro[cyclohexane-1,3'- pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 1h (1.2 g) in dichloromethane (10 mL), slowly add phosphorus oxychloride (1.14 g, 9.88 mmol), react at 10 °C for 3 hours. Monitor the reaction by LC-MS, after the reaction is completed, concentrate under reduced pressure, the obtained residue is separated and purified by column chromatography (eluent: A system) to obtain 4-chloro-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'- pyrrolo[2,3-b]pyridine]-3-en-3-formaldehyde 1i (350 mg), yield: 27.76%.

[0484] MS m / z (ESI): 383.2 [M+1]

[0485] Eighth step

[0486] 1'-(4-methoxybenzyl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester

[0487] ester

[0488] Dissolve 4-chloro-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[cyclohexane-1,3'- pyrrolo[2,3-b]pyridine]-3-en-3-formaldehyde 1i (0.1 g, 261.3 μmol) and ethyl 2- hydroxyacetate 1j (119.65 mg, 1.15 mmol) in tetrahydrofuran (2 mL), cool to zero Celsius, add sodium hydride (39.7 mg, 992.58 μmol, 60% purity), under nitrogen protection, warm to 90 °C, stir for 4 hours. Monitor the reaction by LC-MS, after the reaction is completed, pour the reaction liquid into saturated ammonium chloride solution (5 mL), extract with ethyl acetate (20 mL x 3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, the obtained residue is separated and purified by column chromatography (eluent: A system) to obtain 1'-(4-methoxybenzyl)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 1k (42 mg), yield: 37%.

[0489] MS m / z (ESI): 433.3 [M+1]

[0490] Ninth step

[0491] 2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benfuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester

[0492] Ethyl 2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benfuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 1k (62 mg, 138.23 μmol) and aluminum trichloride (41.74 mg, 276.46 μmol) were added into anisole (1 mL), warmed to 130 °C, reacted for 4 hours, 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 x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by thin layer plate preparation to give ethyl 2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benfuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 1l (35 mg), yield: 77%. MS m / z (ESI): 312.9 [M+1]

[0493] Tenth step

[0494] 2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benfuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid

[0495] Ethyl 2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benfuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 1l (30 mg, 96.06 μmol) was added to a mixed solution of 1.6 mL (tetrahydrofuran:methanol:water = 10:3:3), sodium hydroxide (11.53 mg, 288.17 μmol) was added, stirred at 10 °C for 16 hours. The reaction was monitored by LC-MS, after the reaction was completed, concentrated under reduced pressure, the residue was added to 2 mL of water, 1M hydrochloric acid was used to adjust the pH to 5, extracted with ethyl acetate (10 mL x 3), concentrated under reduced pressure to give 2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benfuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m (25 mg), without purification, directly for the next reaction.

[0496] MS m / z (ESI): 285.2 [M+1]

[0497] Eleventh step

[0498] 3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride

[0499] tert-Butyl (6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3- yl)carbamate ln (885 mg, 2.01 mmol, prepared according to the method described in patent application WO2012064910) and 4M hydrochloric acid were added to 9 mL of 1,4-dioxane solution and reacted at 25 °C for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain 3-amino-6-methyl-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride lp (753 mg) in 89% yield. MS m / z (ESI): 341.1 [M+1]

[0500] Twelfth step

[0501] N-(6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'- oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0502] 2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid Im (25 mg, 87.95 umol) was added to N,N-dimethylformamide (0.5 mL), then 3-amino-6-methyl-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride Ip (26.51 mg, 70.36 umol), N,N-diisopropylethylamine (56.72 mg, 439.73 umol), 1-hydroxybenzotriazole (23.77 mg, 175.89 umol) were added, then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33.6 mg, 175.89 umol) was added, 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, the residue was prepared and separated by C18 reverse phase column (eluent: B system) to obtain N-(6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 1 (17 mg) in 31.87% yield.

[0503] MS m / z (ESI): 606.8 [M+1]

[0504] 1H NMR (400 MHz, CDC13) 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).

[0505] Example 1A

[0506] (R)-N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benfuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 1A

[0507] Example 1B

[0508] (R)-N-((3R,5R,6S)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benfuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide IB

[0509] Example 1C

[0510] (S)-N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benfuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 1C

[0511] Example 1D

[0512] (S)-N-((3R,5R,6S)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benfuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide ID

[0513]

[0514]

[0515] 1 '-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclohexane- 1,3'-pyrrolo[2,3- b]pyridine]-2',4(l'H)-dione

[0516] Cesium carbonate (12.3 g, 37.87 mmol) and 1,5-dichloropentan-3-one (2.2 g, 14.19 mmol) were added to a solution of l-((2-(trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one la (2.5 g, 9.46 mmol) in tetrahydrofuran (100 mL) successively and stirred at 70 °C for 48 h. After completion of the reaction, it was cooled to room temperature, filtered, the solid was washed with dichloromethane and the organic phase was concentrated under reduced pressure to get the residue which was purified by column chromatography (eluent: C system) to get l'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclohexane-l,3'-pyrrolo[2,3-b]pyridine]-2',4(l'H)-dione lq (0.5 g) in 15.2% yield.

[0517] MS m / z (ESI): 347.2 [M+1]

[0518] 1 H NMR (400 MHz, CDC13) 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).

[0519] Second step

[0520] 3-((dimethylamino)methylene)-l'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclohexane-l,3'-pyrrolo[2,3-b]pyridine]-2',4(l'H)-dione

[0521] Dissolve 1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclohexane-1,3'-pyrrolo[2,3- b]pyridine]-2',4(1'H)-dione 1q (2.14 g, 6.18 mmol) in dichloromethane (40 mL), add 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (2.37 g, 13.6 mmol), heat to 60 °C, and react for 16 hours. After the reaction is completed, concentrate under reduced pressure, and separate and purify the obtained residue by column chromatography (eluent: system A) to obtain 3-((dimethylamino)methylene)-1'-((2- (trimethylsilyl)ethoxy)methyl)spiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione 1r (2.46 g) at a rate of 99%. MS m / z (ESI): 402.3 [M+1]

[0522] Third step

[0523] 4-chloro-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydrospiro[cyclohexane-1,3'- pyrrolo[2,3-b]pyridine]-3-en-3-formaldehyde

[0524] Dissolve 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) in dichloromethane (50 mL), add phosphorus oxychloride (2.37 g, 15.44 mmol) at 0 °C, and continue stirring at 0 °C for 1.5 hours. After the reaction is completed, add a saturated sodium bicarbonate solution, extract with dichloromethane (120 mL x 3), dry the combined organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. Separate and purify the obtained residue 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-en-3- formaldehyde 1s (1.47 g) at a rate of 67.60%.

[0525] MS m / z (ESI): 393.3 [M+1]

[0526] Fourth step

[0527] 2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester

[0528] 2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester

[0529] Under nitrogen protection, 4-chloro-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)- 1',2'-dihydrospiro[cyclohexane-l,3'-pyrrolo[2,3-b]pyridine]-3-en-3-formal Is (1.37 g, 3.49 mmol) and ethyl 2-hydroxyacetate lj (1.63 g, 15.69 mmol) were dissolved in tetrahydrofuran (35 mL), sodium hydride (557.83 mg, 13.95 mmol, 60% purity) 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 saturated ammonium chloride solution, extracted with ethyl acetate (100 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was separated and purified by column chromatography (eluent: A system) to obtain ethyl 2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2',6,7-tetrahydro-4H- spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate It (560 mg) with a yield of 32.66%.

[0530] MS m / z (ESI): 443.3 [M+1]

[0531] Step 5 Ethyl (S)-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2',6,7-tetrahydro-4H- spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate It-A

[0532] [2,3-b]pyridine]-2-carboxylate It-A

[0533] (R)-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2',6,7-tetrahydro-4H- spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate It-B

[0534] [2,3-b]pyridine]-2-carboxylate It-B

[0535] Ethyl 2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2',6,7-tetrahydro-4H- spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate It (500 mg, 1.13 mmol) was purified by SFC chiral resolution (column type: Waters SFC-150, Dnicel IG, 20 x 250 mm, 10 pm; mobile phase: A for CO2 and 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).

[0536] Single configuration compound (short retention time):

[0537] 180 mg, yield: 32.4%, retention time 1.128 min, chiral purity 100% ee.

[0538] MS m / z (ESI): 443.3 [M+1]

[0539] Single configuration compound (long retention time):

[0540] 186 mg, yield: 33.4%, retention time 1.522 min, chiral purity 100% ee.

[0541] MS m / z (ESI): 443.2 [M+1]

[0542] Sixth step

[0543] (S)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 11-A

[0544] (R)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 11-B

[0545] Chiral resolution of (S)-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',6,7- tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 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-carboxylic acid ethyl ester 1t-B (180 mg, 406.32 μmol) was dissolved in tetrahydrofuran (3 mL), stirred at 25 °C for 3 hours, after the reaction was completed, tetrahydrofuran (3 mL) and ammonia (0.5 mL) were added respectively, stirred at 25 °C for 0.5 hours, concentrated under reduced pressure, the obtained residue was separated and purified by column chromatography (eluent: A system), to obtain (S)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 1l-A (114 mg), yield: 85%; (R)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 1l-B (126 mg), yield: 99%. MS m / z (ESI): 313.2 [M+1]

[0546] MS m / z (ESI): 313.2 [M+1]

[0547] Seventh step

[0548] (S)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxylic acid 1m-A

[0549] (R)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxylic acid 1m-B

[0550] (S)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 1l-A (114 mg, 365.01 pmol) or (R)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 1l-B (126 mg, 403.43 pmol) was dissolved in 4.5 mL of mixed solution (methanol: tetrahydrofuran: water = 3: 1: 0.5), sodium hydroxide (43.80 mg, 1.10 mmol) was added, stirred at 40 °C for 1 hour, after the reaction was completed, the pH was adjusted to 6 with 1M dilute hydrochloric acid, concentrated under reduced pressure, to obtain (S)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m-A (150 mg); (R)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m-B (180 mg), without purification, directly to the next step.

[0551] MS m / z (ESI): 285.1 [M+1]

[0552] MS m / z (ESI): 285.2 [M+1]

[0553] ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3- yl)carbamic acid tert-butyl ester

[0554] In-A

[0555] ((3R,5R,6S)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3- yl)carbamic acid tert-butyl ester In-B

[0556] ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3- yl)carbamic acid tert-butyl ester 1n (2.6 g, 5.90 mmol) was purified by SFC chiral resolution (column type: Waters SFC-150, Dnicel IG, 20 x 250 mm, 10 pm; mobile phase: A for CO2 and B for Ethanol; detection wavelength: 214 nm; column temperature: 40 °C) to obtain single configuration compound (shorter retention time) and single configuration compound (longer retention time).

[0557] Single configuration compound (short retention time):

[0558] 1.3 g, yield: 50%, retention time 0.900 min, chiral purity 100% ee.

[0559] MS m / z (ESI): 462.8 [M+1]

[0560] Single configuration compound (short retention time):

[0561] 1.2 g, yield: 46%, retention time 1.239 min, chiral purity 99.8% ee.

[0562] MS m / z (ESI): 462.8 [M+1]

[0563] Ninth step

[0564] (3S,5S,6R)-3-Amino-6-methyl-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride Ip-A

[0565] (3R,5R,6S)-3-Amino-6-methyl-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride Ip-B

[0566] ((3S,5S,6R)-6-Methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)carbamic acid tert-butyl ester In-A (500 mg, 1.14 mmol) or ((3R,5R,6S)-6-Methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)carbamic acid tert-butyl ester In-B (500 mg, 1.14 mmol) was dissolved in 6 mL of hydrochloric acid dioxane solution, reacted at 25 °C for 2 hours, after the reaction was completed, concentrated under reduced pressure to obtain (3S,5S,6R)-3-Amino-6-methyl-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride Ip-A; (3R,5R,6S)-3-Amino-6-methyl-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride Ip-B, respectively, without purification, directly for the next reaction.

[0567] MS m / z (ESI): 314.2 [M+1]

[0568] MS m / z (ESI): 314.2 [M+1]

[0569] Step 10 (R)-N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 1A

[0570] (S)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxylic acid lm-A (7 mg, 24.62 μmol), (3S,5S,6R)-3-amino-6-methyl-l-(2,2,2- trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride lp-A (10.20 mg, 27.09 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), then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.44 mg, 49.25 μmol) was added, stirred at 25 °C for 18 hours. After the reaction was completed, concentrated under reduced pressure, the obtained residue was separated by C18 reverse phase column preparation (eluent: B system) to obtain (R)-N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 1A (7 mg), yield: 46.8%.

[0571] MS m / z (ESI): 607.3 [M+1]

[0572] 1 H NMR (400 MHz, CDC13) 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).

[0573] Eleventh step (R)-N-((3R,5R,6S)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide IB

[0574] (S)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxylic acid lm-A (7 mg, 24.62 μmol), (3R,5R,6S)-3-amino-6-methyl-l-(2,2,2- trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride Ip-B (10.20 mg, 27.09 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), then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.44 mg, 49.25 μmol) was added, stirred at 25 °C for 18 hours. After the reaction was completed, concentrated under reduced pressure, the obtained residue was separated by C18 reverse phase column preparation (eluent: B system) to obtain (R)-N-((3R,5R,6S)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide IB (3.8 mg), yield: 25.4%.

[0575] MS m / z (ESI): 607.4 [M+1]

[0576] 1 H NMR (400 MHz, CDC13) 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).

[0577] Twelfth step (S)-N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 1C

[0578] (R)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxylic acid lm-B (7 mg, 24.62 μmol), (3S,5S,6R)-3-amino-6-methyl-l-(2,2,2- trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride lp-A (10.20 mg, 27.09 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), then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.44 mg, 49.25 μmol) was added, stirred at 25 °C for 18 hours. After the reaction was completed, concentrated under reduced pressure, the obtained residue was separated by C18 reverse phase column preparation (eluent: B system) to obtain (S)-N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 1C (10 mg), yield: 66.9%.

[0579] MS m / z (ESI): 607.4 [M+1]

[0580] 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).

[0581] Thirteenth step (S)-N-((3R,5R,6S)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 1D

[0582] (R)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxylic acid lm-B (7 mg, 24.62 μmol), (3R,5R,6S)-3-amino-6-methyl-l-(2,2,2- trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride lp-B (10.20 mg, 27.09 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), then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.44 mg, 49.25 μmol) was added, stirred at 25 °C for 18 hours. After the reaction was completed, concentrated under reduced pressure, the obtained residue was separated by C18 reverse phase column preparation (eluent: B system) to obtain (S)-N-((3R,5R,6S)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 1D (5 mg), yield: 33.5%.

[0583] MS m / z (ESI): 607.4 [M+1]

[0584] 1 H NMR (400 MHz, CDC13) 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).

[0585] Example 2

[0586] N-(6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'- oxo-l',2',6,7-tetrahydro-4H-spiro[benzo[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxamide

[0587]

[0588] First step

[0589] 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

[0590] Ethyl ester

[0591] Dissolve 4-chloro-l'-(4-methoxybenzyl)-2'-oxo-l',2'-dihydrospiro[cyclohexane-l,3'- pyrrolo[2,3-b]pyridine]-3-en-3-formal 1i (150 mg, 391.81 μmol) and ethyl 2-mercaptoacetate 2a (306.51 mg, 2.55 mmol) in N,N-dimethylformamide (4 mL), at zero degrees Celsius, add sodium hydride (101.87 mg, 2.55 mmol, 60% purity), stir for 1 hour under nitrogen protection, stir for 30 minutes at 25 degrees Celsius. After the reaction is completed, monitor by LC-MS, pour the reaction into saturated ammonium chloride solution (5 mL), extract with ethyl acetate (20 mL x 3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, purify by thin layer plate preparation to obtain ethyl l'-(4-methoxybenzyl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzo[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylate 2b (130 mg), yield: 66.58%.

[0592] MS m / z (ESI): 449.4 [M+1]

[0593] 1H NMR (400 MHz, CDC13) 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).

[0594] Second Step

[0595] 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

[0596] 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, LC-MS monitoring, after the reaction was completed, the reaction liquid was added to water (15 mL), extracted with ethyl acetate (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained residue was prepared and separated by 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 %.

[0597] MS m / z (ESI): 301.1 [M+1]

[0598] Third Step

[0599] 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

[0600] A mixture of 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) was dissolved in N,N-dimethylformamide (0.5 mL), and stirred at 25 °C for 18 h after adding 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.77 mg, 66.59 μmol). After the reaction was completed, the mixture was concentrated under reduced pressure, water (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated by C18 reverse phase column preparation (eluent: B system) to give 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) with a yield of 27.50%.

[0601] MS m / z (ESI): 622.9 [M+1]

[0602] 1 H 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).

[0603] Example 3

[0604] 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

[0605] [ cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0606]

[0607]

[0608] First step

[0609] 1 '-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridine]- 3-en-2'(1'H)-one

[0610] Dissolve 1 -((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2- one 1a (770 mg, 2.91 mmol) in N,N-dimethylformamide (12 mL), at zero degrees Celsius, add cesium carbonate (2.37 g, 7.28 mmol) and (Z)-1,4-dichlorobut-2-ene 3a (364.03 mg, 2.91 mmol), stir at 25 °C for 18 hours, add water (20 mL), extract with ethyl acetate (40 mL x 3), combine the organic phase, dry over anhydrous sodium sulfate, concentrate under reduced pressure, the obtained residue is separated and purified by column chromatography (eluent: C system), to obtain 1 '-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridine]-3-en-2'(1'H)-one 3b (780 mg), yield: 84.63%.

[0611] MS m / z (ESI): 317.0 [M+1]

[0612] 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).

[0613] Second step

[0614] 1 '-((2-(trimethylsilyl)ethoxy)methyl)-6-oxaspiro[bicyclo[3.1.0]hexane-3,3'- pyrrolo[2,3-b]pyridine]-

[0615] 2'(1'H)-ketone

[0616] Dissolve 1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopentane-1,3'-pyrrolo[2,3- b]pyridine]-3-en-2'(1'H)-ketone 3b (23 g, 72.7 mmol) in dichloromethane (400 mL), add m-chloroperoxybenzoic acid (25.1 g, 14.5 mmol) at low temperature, and stir at room temperature for 24 hours under nitrogen protection. After the reaction is completed, add dichloromethane (100 mL) to the reaction solution, and filter under vacuum. Wash the filtrate with sodium thiosulfate solution (200 mL x 2) and saturated sodium bicarbonate solution (200 mL), respectively, wash the organic phase with water (300 mL) and saturated brine (300 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The obtained residue is 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)-ketone 3c (4.9 g) at a yield of 20.3%.

[0617] MS m / z (ESI): 333.1 [M+1]

[0618] Third step

[0619] 3-hydroxy-1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopentane-1,3'-pyrrolo[2,3- b]pyridine]-2'(1'H)-ketone

[0620] Dissolve 1'-((2-(trimethylsilyl)ethoxy)methyl)-6-oxaspiro[bicyclo[3.1.0]hexane-3,3'- pyrrolo[2,3-b]pyridine]-2'(1'H)-ketone 3c (1.2 g, 3.61 mmol) in ethanol (45 mL), add 10% palladium-carbon (1.20 g, 988.06 μmol), and stir at 90°C for 24 hours under nitrogen protection. After the reaction is completed, filter through diatomite, and concentrate under reduced pressure. The obtained residue is 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)-ketone 3d (460 mg) at a yield of 34.29%.

[0621] MS m / z (ESI): 335.3 [M+1]

[0622] 1H NMR (400 MHz, CDC13) 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).

[0623] Fourth Step

[0624] 1 '-((2-(Trimethylsilyl)ethoxy)methyl)spiro[cyclopentane- 1,3'-pyrrolo[2,3- b]pyridine]-2',3(1'H)-dione

[0625] Dissolve 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) in dichloromethane (20 mL), after adding Dess-Martin oxidant (1.97 g, 4.65 mmol), stirring at 30 °C for 2 hours, after the reaction is completed, the obtained residue is prepared by thin layer plate purification 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%.

[0626] MS m / z (ESI): 332.9 [M+1]

[0627] 1 H NMR (400 MHz, CDC13) 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).

[0628] Fifth Step

[0629] 3-((dimethylamino)methylene)-1'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridine]-2',4(1'H)-dione

[0630] Dissolve 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) in dichloromethane (35 mL), add 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (960 mg, 5.51 mmol), stir for 3 hours at 60 ℃ under nitrogen protection. After the reaction is completed, concentrate 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 is directly used in the next step without purification.

[0631] MS m / z (ESI): 388.0 [M+1]

[0632] Sixth step

[0633] 3-chloro-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridine]-3-ene-4-carbaldehyde

[0634] Dissolve 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) in dichloromethane (20 mL), add phosphorus oxychloride (592.19 mg, 3.87 mmol) at 0 ℃, stir for 20 minutes at 10 ℃ under nitrogen protection. After the reaction is completed, add saturated sodium bicarbonate solution (20 mL), extract with dichloromethane (20 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The obtained residue is 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%.

[0635] MS m / z (ESI): 379.3 [M+1]

[0636] 1H NMR (400 MHz, CDC13) 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).

[0637] Seventh step

[0638] 2'-Oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester

[0639] b]pyridine]-2-carboxylic acid ethyl ester

[0640] Dissolve 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 (50 mg, 131.95 μmol) and 2-mercaptoacetic acid ethyl ester 2a (103.07 mg, 857.69 μmol) in N,N-dimethylformamide (2.5 mL), add sodium hydride (34.31 mg, 857.69 μmol, 60% purity) at 0 °C, stir for 1 hour under nitrogen protection, stir for 1.5 hours at 20 °C. After the reaction is completed, add saturated ammonium chloride solution (20 mL) to quench the reaction, extract with ethyl acetate (40 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the obtained residue by thin layer plate preparation to obtain 2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 3h (36 mg), yield: 58.29%.

[0641] MS m / z (ESI): 445.3 [M+1]

[0642] 1H NMR (400 MHz, CDC13) 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).

[0643] Eighth Step

[0644] Ethyl 2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylate

[0645] Ethyl 2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylate

[0646] MS m / z (ESI): 315.2 [M + 1]

[0647] Ninth Step

[0648] 2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid

[0649] 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 mixed solution (methanol: water: tetrahydrofuran = 5:2:3), after adding sodium hydroxide (7.63 mg, 190.86 μmol), stirring at 40 ℃ for 5 hours, after the reaction was completed, the pH was adjusted to 5 with 1M hydrochloric acid, 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), without purification, directly to the next step.

[0650] Tenth step

[0651] 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

[0652] [ cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0653] 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 mixed solution (methanol: water: tetrahydrofuran = 5:2:3), after adding sodium hydroxide (7.63 mg, 190.86 μmol), stirring at 40 ℃ for 5 hours, after the reaction was completed, the pH was adjusted to 5 with 1M hydrochloric acid, 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), without purification, directly to the next step.

[0654] MS m / z (ESI): 608.7 [M+1]

[0655] 1H NMR (400 MHz, CDC13) 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).

[0656] Example 3A

[0657] (S)-N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 3A

[0658] Example 3B

[0659] (S)-N-((3R,5R,6S)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 3B

[0660] Example 3C

[0661] (R)-N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 3C

[0662] Example 3D

[0663] (R)-N-((3R,5R,6S)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 3D

[0664]

[0665]

[0666] First Step

[0667] (S)-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 3h-A

[0668] [2,3-b]pyridine]-2-carboxylic acid ethyl ester 3h-B

[0669] (R)-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 3h-B

[0670] [2,3-b]pyridine]-2-carboxylic acid ethyl ester 3h-B

[0671] Ethyl 2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',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 SFC chiral resolution (column type: Waters SFC-150, Dnicel IG, 20 x 250 mm, 10 μm; mobile phase: A for CO2 and B for Ethanol; detection wavelength: 214 nm; column temperature: 40 °C) to give single configuration compound (shorter retention time) and single configuration compound (longer retention time).

[0672] Single configuration compound (shorter retention time):

[0673] 188 mg, yield: 45.9%, retention time 2.126 min, chiral purity 100% ee.

[0674] MS m / z (ESI): 445.3 [M+1]

[0675] Single configuration compound (longer retention time):

[0676] 184 mg, yield: 44.9%, retention time 2.845 min, chiral purity 100% ee.

[0677] MS m / z (ESI): 445.3 [M+1]

[0678] Second Step

[0679] (S)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 3i-A

[0680] (R)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 3i-B

[0681] (S)-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6- tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 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-carboxylic acid ethyl ester 3h-B (184 mg, 0.92 mmol) was dissolved in trifluoroacetic acid (3 mL), stirred at 25 °C for 3 hours, after the reaction was completed, concentrated under reduced pressure, added tetrahydrofuran (3 mL) and ammonia (0.5 mL) respectively, continued to stir for 0.5 hours, concentrated under reduced pressure, the obtained residue was separated and purified by column chromatography (eluent: A system), obtained (S)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 3i-A (130 mg), yield: 93.24%; (R)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 3i-B (120 mg), yield: 86.07%.

[0682] MS m / z (ESI): 314.9 [M+1]

[0683] MS m / z (ESI): 315.1 [M+1]

[0684] Third step

[0685] (S)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j-A

[0686] (R)-2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j-B

[0687] (S)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 3i-A (130 mg, 413.54 pmol) or (R)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 3i-B (120 mg, 382.17 pmol) was dissolved in 2 mL of mixed solution (methanol: tetrahydrofuran: water = 3: 1: 1), sodium hydroxide (49.62 mg, 1.24 mmol) was added, stirred at 40 °C for 5 hours, adjusted pH = 5 with 1M dilute hydrochloric acid, concentrated under reduced pressure to obtain (S)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j-A (220 mg), yield: 100%; (R)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid 3j-B (210 mg), yield: 100%;

[0688] MS m / z (ESI): 287.1 [M+1]

[0689] MS m / z (ESI): 287.1 [M+1]

[0690] Fourth step

[0691] (S)-N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 3A

[0692] (S)-2'-oxo-l',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-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride Ip-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 stirred at 25 °C for 18 hours. After the reaction, the obtained residue was concentrated under reduced pressure, and then prepared and separated by C18 reverse phase column (eluent: B system) to obtain (S)-N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 3A (3.59 mg), yield: 16.9%.

[0693] MS m / z (ESI): 609.0 [M+1]

[0694] 1 H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 5.2 Hz, 1H), 7.36 (d, J = 3.6 Hz, 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).

[0695] Step 5 (S)-N-((3R,5R,6S)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene- 5,3'-pyrrolo[2,3-b]pyrrole]-2-carboxamide 3B

[0696] (S)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyrrole]- 2-carboxylic acid 3j-A (10 mg, 34.93 μmol), (3R,5R,6S)-3-amino-6-methyl-l-(2,2,2- trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride Ip-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), then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.39 mg, 69.86 μmol) was added, stirred at 25 °C for 18 hours. After the reaction was completed, concentrated under reduced pressure, the obtained residue was separated by C18 reverse phase column preparation (eluent: B system) to obtain (S)-N-((3R,5R,6S)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyrrole]-2-carboxamide 3B (2.83 mg), yield: 13.3%.

[0697] MS m / z (ESI): 609.3 [M+1]

[0698] 1H NMR (400 MHz, CDC13) 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, 7.6 Hz, 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 = 16.4 Hz, 1H), 2.92 (d, J = 15.2 Hz, 1H), 2.83-2.74 (m, 2H), 1.25 (d, J = 6.4 Hz, 3H).

[0699] Step 6 (R)-N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 3C

[0700] (R)-2'-oxo-l',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-l-(2,2,2- trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride Ip-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. The mixture was stirred at 25 °C for 18 hours. After the reaction was completed, the resulting residue was separated by C18 reverse phase column preparation (eluent: B system) to give (R)-N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 3C (4.23 mg) in a yield of 19.9%.

[0701] MS m / z (ESI): 609.3 [M + 1]

[0702] 1 H NMR (400 MHz, CDC13) 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).

[0703] Step 7 (R)-N-((3R,5R,6S)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 3D

[0704] (R)-2'-oxo-l',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-l-(2,2,2- trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride lp-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 stirred at 25 °C for 18 hours. After the reaction, the obtained residue was concentrated under reduced pressure, and then separated by C18 reverse phase column preparation (eluent: B system) to obtain (R)-N-((3R,5R,6S)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 3D (8.29 mg), yield: 39.3%.

[0705] MS m / z (ESI): 609.3 [M+1]

[0706] 1 H NMR (400 MHz, CDC13) 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).

[0707] Example 4

[0708] N-(6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',4,6- tetrahydrospiro

[0709] [ cyclopenta[b]furan-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0710]

[0711]

[0712] First Step

[0713] 2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'-pyrrolo[2,3-

[0714] b]]pyridine]-2-carboxylic acid ethyl ester

[0715] To a solution of 3-chloro-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2'- dihydrospiro[cyclopentane-l,3'-pyrrolo[2,3-b]pyridine]-3-en-4-carbaldehyde 3g (120 mg, 316.69 pmol) and ethyl 2-hydroxyacetate lj (148 mg, 1.43 mmol) in tetrahydrofuran (3 mL) was added sodium hydride (50.66 mg, 1.27 mmol, 60% purity) slowly at room temperature. The reaction mixture was stirred at 85 °C for 2.5 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to afford ethyl 2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylate 4a (43 mg) in 31.68% yield.

[0716] MS m / z (ESI): 429.3 [M+1]

[0717] Second Step

[0718] Ethyl 2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'-pyrrolo[2,3-b]pyridine]- 2-carboxylate

[0719] To a solution of ethyl 2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'- pyrrolo[2,3-b]]pyridine]-2-carboxylate 4a (20 mg, 46.67 pmol) in trifluoroacetic acid (1 mL) was stirred at 15 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. Tetrahydrofuran (1 mL) and ammonium hydroxide (0.5 mL) were added to the reaction mixture and stirred at 15 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to afford ethyl 2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylate 4b (13.6 mg) in 97.69% yield.

[0720] MS m / z (ESI): 299.2 [M+1]

[0721] Third Step

[0722] 2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxylic acid

[0723] Ethyl 2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'-pyrrolo[2,3- b]pyridine]-2-carboxylate 4b (20 mg, 67.05 pmol) was dissolved in 1 mL of mixed solution (methanol: water: tetrahydrofuran = 5:2:3), sodium hydroxide (8.05 mg, 201.14 pmol) was added, 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 to obtain 2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid 4c (18 mg), which was used directly in the next step without purification.

[0724] MS m / z (ESI): 271.1 [M+1]

[0725] Fourth step

[0726] N-(6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'- oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxamide

[0727] [ cyclopenta[b]furan-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0728] Ethyl 2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'-pyrrolo[2,3- b]pyridine]-2-carboxylate 4b (20 mg, 67.05 pmol) was dissolved in 1 mL of mixed solution (methanol: water: tetrahydrofuran = 5:2:3), sodium hydroxide (8.05 mg, 201.14 pmol) was added, 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 to obtain 2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]furan-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid 4c (18 mg), which was used directly in the next step without purification.

[0729] MS m / z (ESI): 271.1 [M+1]

[0730] 1 H NMR (400 MHz, CDC13) 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).

[0731] Example 5A

[0732] (5R)-N-(6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)- 2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benfuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 5A

[0733] Example 5B

[0734] (5S)-N-(6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)- 2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benfuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 5B

[0735]

[0736]

[0737] First Step

[0738] 6-methyl-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)pyridin-2(lH)-one

[0739] Dissolve 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) in tetrahydrofuran (30 mL) under nitrogen protection, add bis(triphenylphosphine)palladium (284.99 mg, 555.46 μmol), heat to 40 °C, stir for 4 h. After the reaction is completed, filter, concentrate under reduced pressure, extract with ethyl acetate (50 mL x 3), combine the organic phases, concentrate under reduced pressure, and the obtained residue is separated and purified by column chromatography (eluent: A system) to obtain 6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)pyridin-2(1H)-one 5c (1.2 g), yield: 89.35%.

[0740] MS m / z (ESI): 322.1 [M+1]

[0741] Second step

[0742] 6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one

[0743] Dissolve 6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)pyridin-2(1H)-one 5c (3.2 g, 9.96 mmol) in acetic acid (200 mL) under hydrogen protection, then add platinum dioxide (3.21 g, 14.15 mmol) to the reaction solution, heat to 80 °C, and react under high pressure for 48 h. After the reaction is completed, filter, concentrate under reduced pressure, extract with ethyl acetate (50 mL x 3), combine the organic phases, concentrate under reduced pressure, and the obtained residue is separated and purified by column chromatography (eluent: A system) to obtain 6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one 5d (2.8 g), yield: 86%.

[0744] MS m / z (ESI): 326.2 [M+1]

[0745] Third step

[0746] 3-azido-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one

[0747] Dissolve 6-methyl-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one 5d (1.7 g, 5.23 mmol) in tetrahydrofuran (50 mL) and maintain at -78 °C, drop in lithium bis(trimethylsilyl)amide (1 M, 8.15 mL), stir for 1 h, drop in 15 mL of 2,4,6-triisopropylbenzenesulfonyl azide 5e (2.26 g, 7.32 mmol) in tetrahydrofuran solution, stir for 2 h at -78 °C, drop in acetic acid (8 mL), stir for 30 min at -78 °C, warm to 25 °C, stir for 18 h. After the reaction is completed, pour the reaction into saturated sodium bicarbonate solution (20 mL), extract with ethyl acetate (50 mL x 3), combine the organic phases, concentrate under reduced pressure, and the residue obtained is separated and purified by column chromatography (eluent: A system) to obtain 3-azido-6-methyl-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one 5f (2.1 g), yield: 100%.

[0748] MS m / z (ESI): 366.8 [M+1]

[0749] Fourth step

[0750] (6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)carbamic acid tert-butyl ester

[0751] Dissolve 3-azido-6-methyl-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one 5f (590 mg, 1.61 mmol) in ethanol (15 mL) under hydrogen protection, add di-tert-butyl dicarbonate (526.76 mg, 2.42 mmol) and 10% palladium on carbon (190 mg, 156.44 μmol), stir for 18 h at 25 °C, after the reaction is completed, filter, concentrate under reduced pressure, extract with ethyl acetate (50 mL x 3), combine the organic phases, concentrate under reduced pressure, and the residue obtained is separated and purified by column chromatography (eluent: A system) to obtain (6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)carbamic acid tert-butyl ester 5g (500 mg), yield: 70%.

[0752] MS m / z (ESI): 462.9 [M+23]

[0753] Fifth step

[0754] 3-amino-6-methyl-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one hydrochloride

[0755] tert-Butyl (6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3- yl)carbamate 5g (100 mg, 227.08 pmol) was dissolved in 4 M hydrochloric acid in dioxane (5 mL), stirred at 25 °C for 2 h, after the reaction was completed, concentrated under reduced pressure to give 3-amino-6-methyl-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one hydrochloride 5h (77 mg), yield: 99.7%, without purification, directly for the next step.

[0756] MS m / z (ESI): 341.2 [M+1]

[0757] Step 6 (5R)-N-(6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3- yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 5A

[0758] 3-amino-6-methyl-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one hydrochloride 5h (10.20 mg, 27.09 pmol), (S)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid lm-A (7.00 mg, 24.62 pmol), 1-hydroxybenzotriazole (6.65 mg, 49.25 pmol) and N,N-diisopropylethylamine (15.91 mg, 123.12 pmol) were dissolved in N,N-dimethylformamide (0.5 mL), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.44 mg, 49.25 pmol) was added, stirred at 20 °C for 18 h, after the reaction was completed, concentrated under reduced pressure, the residue was separated by C18 reverse phase column preparation (eluent: B system) to give (5R)-N-(6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 5A (3.89 mg), yield: 21.78%.

[0759] MS m / z (ESI): 607.4 [M+1]

[0760] 1H NMR (400 MHz, CDC13) 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 = 16.0 Hz, 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).

[0761] Step 7 (5S)-N-(6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 5B

[0762] (5S)-N-(6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 5B (6.86 mg) was obtained in 38.18% yield by stirring 3-amino-6-methyl-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one hydrochloride 5h (10.20 mg, 27.09 μmol), (R)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 1m-B (7 mg, 24.62 μmol), 1-hydroxybenzotriazole (6.65 mg, 49.25 μmol) and N,N-diisopropylethylamine (15.91 mg, 123.12 μmol) in N,N-dimethylformamide (0.5 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.44 mg, 49.25 μmol), stirring at 20 °C for 18 hours, after the reaction was completed, concentrated under reduced pressure, the obtained residue was separated by C18 reverse phase column preparation (eluent: B system), (5S)-N-(6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 5B (6.86 mg).

[0763] MS m / z (ESI): 607.3 [M+1]

[0764] 1H NMR (400 MHz, CDC13) 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 = 16.0 Hz, 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).

[0765] Example 6A

[0766] (R)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'- oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6A

[0767] -4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6A

[0768] Example 6B

[0769] (S)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'- oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6B

[0770] -4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6B

[0771] Example 6C

[0772] (R)-N-((3R,5R,6S)-6-methyl-2-oxo-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'- oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6C

[0773] Example 6D

[0774] (S)-N-((3R,5R,6S)-6-methyl-2-oxo-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'- oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6D

[0775]

[0776]

[0777] First step

[0778] (2R)-2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)-5-oxohexanoic acid methyl ester

[0779] Methyl (2R)-2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)-5-oxohexanoate 6c (5.0 g, 13.51 mmol), 2,2,2-trifluoroethan-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 into dichloroethane (130 mL), and the mixture was stirred at 25 °C for 16 h. After the reaction was completed, the reaction solution was added into dichloromethane (100 mL), washed with water (200 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl (2R)-2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)-5-((2,2,2-trifluoroethyl)amino)hexanoate 6e (6.15 g) in a yield of 100%, which was used in the next step without purification.

[0780] MS m / z (ESI): 392.1 [M+23]

[0781] Second step

[0782] (2R)-2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)-5-((2,2,2-trifluoroethyl)amino)hexanoic acid methyl ester

[0783] Methyl (2R)-2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)-5-oxohexanoate 6c (5.0 g, 13.51 mmol), 2,2,2-trifluoroethan-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 into dichloroethane (130 mL), and the mixture was stirred at 25 °C for 16 h. After the reaction was completed, the reaction solution was added into dichloromethane (100 mL), washed with water (200 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl (2R)-2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)-5-((2,2,2-trifluoroethyl)amino)hexanoate 6e (6.15 g) in a yield of 100%, which was used in the next step without purification.

[0784] MS m / z (ESI): 453.1 [M+1]

[0785] Third step

[0786] (5-(3-chlorophenyl)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)piperidin-3-yl)carbamic acid tert-butyl ester

[0787] Methyl (2R)-2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)-5-((2,2,2- trifluoroethyl)amino)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 reaction was carried out at 20 °C for 24 h. After the reaction was completed, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by C18 reverse phase column preparation (eluent: B system) to obtain (5-(3-chlorophenyl)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)piperidin-3-yl)carbamic acid tert-butyl ester 6f (1.03 g), yield: 18.02%.

[0788] MS m / z (ESI): 365.1 [M-55]

[0789] Fourth step

[0790] (5-(3-chlorophenyl)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)piperidin-3-yl)carbamic acid tert-butyl ester

[0791] (5-(3-chlorophenyl)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)piperidin-3-yl)carbamic acid tert-butyl ester 6f (1.03 g, 2.45 mmol) was dissolved in methanol (20 mL) under hydrogen protection, and 10% palladium-carbon (0.2 g) was added. The reaction was carried out at 25 °C for 20 h. After the reaction was completed, the reaction solution was filtered through diatomite, and the filter cake was washed with methanol. The filtrates were combined and concentrated under reduced pressure to obtain (6-methyl-2-oxo-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-3-yl)carbamic acid tert-butyl ester 6g (960 mg), yield: 100%. Without purification, the product was directly used in the next step.

[0792] MS m / z (ESI): 409.3 [M+23]

[0793] 1H NMR (400 MHz, CDC13) 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 = 6.8 Hz, 3H).

[0794] Fifth Step

[0795] ((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl) carbamic acid tert-butyl ester 6h-A

[0796] ((3R,5R,6S)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl) carbamic acid tert-butyl ester 6h-B

[0797] tert-Butyl (6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)carbamate 6g (400 mg, 1.04 mmol) was purified by SFC chiral resolution (column type: Waters SFC-150, Dnicel IG, 20 x 250 mm, 10 pm; mobile phase: A for CO2 and B for Ethanol; detection wavelength: 214 nm; column temperature: 40 °C) to give single configuration compound (shorter retention time) and single configuration compound (longer retention time).

[0798] Single configuration compound (shorter retention time):

[0799] 200 mg, yield: 45%, retention time 0.761 min, chiral purity 100% ee.

[0800] MS m / z (ESI): 409.3 [M+23]

[0801] Single configuration compound (longer retention time):

[0802] 195 mg, yield: 43.9%, retention time 2.526 min, chiral purity 100% ee.

[0803] MS m / z (ESI): 409.3 [M+23]

[0804] Sixth Step

[0805] (3S,5S,6R)-3-amino-6-methyl-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-A

[0806] (3R,5R,6S)-3-amino-6-methyl-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-B

[0807] ((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-3-yl)carbamic acid tert-butyl ester 6h-A (195 mg, 504.65 pmol) or ((3R,5R,6S)-6-methyl-2-oxo-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-3-yl)carbamic acid tert-butyl ester 6h-B (195 mg, 504.65 pmol) was dissolved in 4 M hydrochloric acid in dioxane (6 mL), stirred at 25 °C for 2 h, concentrated under reduced pressure to give (3S,5S,6R)-3-amino-6-methyl-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-A (150 mg), yield: 100%; (3R,5R,6S)-3-amino-6-methyl-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-B (150 mg), yield: 100%, without purification, directly to the next step.

[0808] MS m / z (ESI): 287.2 [M+1]

[0809] MS m / z (ESI): 287.2 [M+1]

[0810] Step 7 (R)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-l-(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

[0811] (R)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-l-(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

[0812] (S)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid lm-A (10 mg, 34.93 μmol), (3S,5S,6R)-3- amino-6-methyl-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-A (11.15 mg, 35.18 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, stirred at 25 °C for 18 h, after the reaction was completed, concentrated under reduced pressure, the obtained residue was separated by C18 reverse phase column preparation (eluent: B system) to obtain (R)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-l-(2,2,2- trifluoroethyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 6A (8.27 mg), yield: 42.55%.

[0813] MS m / z (ESI): 553.4 [M+1]

[0814] 1 H NMR (400 MHz, CDC13) δ 8.13 (d, J = 6.0 Hz, 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 = 8.4 Hz, 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 = 6.8 Hz, 3H).

[0815] Example 6B

[0816] (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[benfuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6B

[0817] -4H-spiro[benfuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6B

[0818] (R)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benfuran-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), 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, stirred at 25 °C for 18 hours, after the reaction was completed, concentrated under reduced pressure, the obtained residue was separated by C18 reverse phase column preparation (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[benfuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6B (7.14 mg), yield: 36.73 %.

[0819] MS m / z (ESI): 553.4 [M+1]

[0820] 1H NMR (400 MHz, CDC13) 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).

[0821] Example 6C

[0822] (R)-N-((3R,5R,6S)-6-methyl-2-oxo-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'- oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6C

[0823] (S)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid lm-A (10 mg, 34.93 pmol), (3R,5R,6S)-3-amino-6-methyl-5-phenyl-l-(2,2,2- trifluoroethyl)piperidin-2-one hydrochloride 6i-B (11.15 mg, 35.18 pmol), 1- hydroxybenzotriazole (9.44 mg, 69.86 pmol) and N,N-diisopropylethylamine (22.57 mg, 174.64 pmol) were dissolved in N,N-dimethylformamide (0.7 mL), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.39 mg, 69.86 pmol) was added, stirred at 25 °C for 18 h, after the reaction was completed, concentrated under reduced pressure, the obtained residue was separated by C18 reverse phase column preparation (eluent: B system) to obtain (R)-N-((3R,5R,6S)-6-methyl-2-oxo-5-phenyl-l-(2,2,2- trifluoroethyl)piperidin-3-yl)-2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzofuran-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 6C (6.52 mg), yield: 33.54%.

[0824] MS m / z (ESI): 553.3 [M+1]

[0825] 1 H NMR (400 MHz, CDC13) 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).

[0826] Example 6D

[0827] (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[benfuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6D

[0828] (R)-2'-oxo-1',2',6,7-tetrahydro-4H-spiro[benfuran-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), 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, stirred at 25 °C for 18 hours, after the reaction was completed, concentrated under reduced pressure, the obtained residue was separated by C18 reverse phase column preparation (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[benfuran-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 6D (6.68 mg), yield: 34.37 %.

[0829] MS m / z (ESI): 553.4 [M+1]

[0830] 1H NMR (400 MHz, CDC13) 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).

[0831] Example 7A

[0832] (5S)-N-(6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)- 2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxamide 7A

[0833] Example 7B

[0834] (5R)-N-(6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl)- 2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxamide 7B

[0835]

[0836] First Step (5S)-N-(6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin- 3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]- 2-carboxamide 7A

[0837] (S)-2'-oxo-l',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-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one hydrochloride 5h (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), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.39 mg, 69.86 μmol) was added, stirred at 20 °C for 18 hours, after the reaction was completed, concentrated under reduced pressure, the obtained residue was separated by C18 reverse phase column preparation (eluent: B system), to obtain (5S)-N-(6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,5- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 7A (2.33 mg), yield: 10.96%.

[0838] MS m / z (ESI): 609.4 [M+1]

[0839] 1 H NMR (400 MHz, CDC13) 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).

[0840] Second step (5R)-N-(6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,5- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 7B

[0841] (R)-2'-oxo-l',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-l-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one hydrochloride 5h (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), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.39 mg, 69.86 μmol) was added, stirred at 20 °C for 18 hours, after the reaction was completed, concentrated under reduced pressure, the obtained residue was separated by C18 reverse phase column preparation (eluent: B system), to obtain (5R)-N-(6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,5- trifluorophenyl)piperidin-3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 7B (10.17 mg), yield: 47.85%.

[0842] MS m / z (ESI): 609.3 [M+1]

[0843] 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).

[0844] Example 8A

[0845] (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

[0846] Example 8B

[0847] (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

[0848] Example 8C

[0849] (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

[0850] Example 8D

[0851] (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

[0852]

[0853]

[0854] First Step

[0855] (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

[0856] (S)-2'-oxo-l',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-l-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-A (10.15 mg, 31.43 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, stirred at 25 °C for 18 h, after the reaction was completed, concentrated under reduced pressure, the obtained residue was separated by C18 reverse phase column preparation (eluent: B system), to obtain (S)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-l-(2,2,2- trifluoroethyl)piperidin-3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 8A (5.77 mg), yield: 29.79%.

[0857] MS m / z (ESI): 555.3 [M+1]

[0858] 1 H 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).

[0859] 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

[0860] (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 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, stirred at 25 °C for 18 hours, after the reaction was completed, concentrated under reduced pressure, the obtained residue was separated by C18 reverse phase column preparation (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%.

[0861] MS m / z (ESI): 555.3 [M+1]

[0862] 1 H 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).

[0863] Step 3 (S)-N-((3R,5R,6S)-6-methyl-2-oxo-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-3-yl)- 2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxamide 8C

[0864] (S)-2'-oxo-l',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-l-(2,2,2- trifluoroethyl)piperidin-2-one hydrochloride 6i-B (10.15 mg, 31.43 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, stirred at 25 °C for 18 hours, after the reaction was completed, concentrated under reduced pressure, the obtained residue was separated by C18 reverse phase column preparation (eluent: B system), to obtain (S)-N-((3R,5R,6S)-6-methyl-2-oxo-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-3-yl)- 2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxamide 8C (5.25 mg), yield: 27.1%.

[0865] MS m / z (ESI): 555.3 [M+1]

[0866] 1 H NMR (400 MHz, CDC13) 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).

[0867] Fourth step (R)-N-((3R,5R,6S)-6-methyl-2-oxo-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 8D

[0868] (R)-2'-oxo-l',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-l-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride 6i-B (10.15 mg, 31.43 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, stirred at 25 °C for 18 hours, after the reaction was completed, concentrated under reduced pressure, the obtained residue was separated by C18 reverse phase column preparation (eluent: B system), to obtain (R)-N-((3R,5R,6S)-6-methyl-2-oxo-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-3-yl)-2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[b]thiophene-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 8D (5.6 mg), yield: 28.9%.

[0869] MS m / z (ESI): 555.3 [M+1]

[0870] 1 H 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).

[0871] Example 9

[0872] N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-

[0873] 1',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0874] First Step

[0875] 3-bromo-l'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclohexane-l,3'-pyrrolo[2,3-b]pyridine]- 2',4(l'H)-dione

[0876] l'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclohexane-l,3'-pyrrolo[2,3-b]pyridine]-2',4(l'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 portionwise at zero degrees Celsius, and stirring was performed at 25 °C for 16 hours. After the reaction was completed, 100 mL of water was added for dilution, extraction was performed with ethyl acetate (50 mL x 3), the organic phases were combined, and concentration was performed under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: C system) to obtain 3-bromo-l'-((2-(trimethylsilyl)ethoxy)methyl)spiro[cyclohexane-l,3'-pyrrolo[2,3-b]pyridine]-2',4(l'H)-dione 9a (1.1 g), at a yield of 59.7%.

[0877] MS m / z (ESI): 425.0 [M+1]

[0878] Second Step

[0879] 2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo

[0880] [2,3-b]pyridine]-2-carboxylic acid ethyl ester

[0881] To a solution of 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) in anhydrous toluene (6 mL) was stirred and heated to reflux for 16 h. After the reaction was completed, the temperature was reduced to room temperature, 10 mL of saturated sodium bicarbonate solution was added to the reaction, and stirred for 10 min, extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by thin layer plate preparative to give 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%.

[0882] MS m / z (ESI): 460.2 [M+1]

[0883] Third step

[0884] Ethyl 2'-oxo-1',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3-b]pyridine]- 2-carboxylate

[0885] 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, 217.57 pmol) was dissolved in trifluoroacetic acid (3 mL), stirred at 30 °C for 3 h, after the reaction was completed, concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (3 mL), stirred at 30 °C for 1 h, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give ethyl 2'-oxo-1',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'- pyrrolo[2,3-b]pyridine]-2-carboxylate 9d (60 mg), yield: 44.38%.

[0886] MS m / z (ESI): 330.1 [M+1]

[0887] Fourth step

[0888] 2'-oxo-1',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid

[0889] Ethyl 2'-oxo-l',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3- b]pyridine]-2-carboxylate 9d (30 mg, 48.75 pmol) was dissolved in 2 mL of mixed solution (water:methanol: tetrahydrofuran = 2: 1: 1), sodium hydroxide (10.9 mg, 273 pmol) was added, stirred at 45 °C for 1 hour, after the reaction was completed, the reaction solution was adjusted to pH 4 with 1M dilute hydrochloric acid, concentrated under reduced pressure, to obtain 2'-oxo-l',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid 9e (30 mg), without purification, directly to the next step.

[0890] MS m / z (ESI): 302.1 [M + 1]

[0891] Fifth step

[0892] N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'- oxo-l',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0893] 1',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0894] Ethyl 2'-oxo-l',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'-pyrrolo[2,3- b]pyridine]-2-carboxylate 9d (30 mg, 48.75 pmol) was dissolved in 2 mL of mixed solution (water:methanol: tetrahydrofuran = 2: 1: 1), sodium hydroxide (10.9 mg, 273 pmol) was added, stirred at 45 °C for 1 hour, after the reaction was completed, the reaction solution was adjusted to pH 4 with 1M dilute hydrochloric acid, concentrated under reduced pressure, to obtain 2'-oxo-l',2',4,7-tetrahydro-5H-spiro[benzo[d]thiazole-6,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid 9e (30 mg), without purification, directly to the next step.

[0895] MS m / z (ESI): 624.4 [M+1]

[0896] 1 H 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).

[0897] Example 10

[0898] N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-

[0899] 1',2',4,6-tetrahydro-1H-spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0900] First Step

[0901] 3-(3-chloro-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydrospiro[cyclopenta-1,3'- pyrrolo[2,3-b]pyridine]-3-en-4-yl)acrylic acid ethyl ester

[0902] pyridine]-3-en-4-yl)acrylic acid ethyl ester

[0903] 3-chloro-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2'-dihydrospiro[cyclopenta-1,3'- pyrrolo[2,3-b]pyridine]-3-en-4-carboxaldehyde 3g (160 mg, 422.25 pmol) and 2- (triphenyl-λ 5Ethyl 3-(3-chloro-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2'- dihydrospiro[cyclopentane-l,3'-pyrrolo[2,3-b]pyridin]-3-en-4-yl)acrylate 10b (190 mg) was obtained by dissolving ethyl (ethylenyl)phosphite 10a (147.10 mg, 422.25 μmol) in dichloromethane (4 mL), stirring at 25 °C for 3 h, and concentrating the residue under reduced pressure, which was separated and purified by column chromatography (eluent: system A) with a yield of 99%.

[0904] MS m / z (ESI): 449.1 [M+1]

[0905] Second step

[0906] Ethyl 2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2',4,6-tetrahydro-lH- spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate

[0907] [2,3-b]pyridine

[0908] Ethyl 3-(3-chloro-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2'- dihydrospiro[cyclopentane-l,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 stirring was performed under nitrogen protection at 70 °C for 18 h. After adding 30 mL of ethyl acetate and 20 mL of water, extraction was performed with ethyl acetate (30 mL x 3), the organic phases were combined, and concentrated under reduced pressure. The residue was separated and purified by thin layer plate prep to obtain ethyl 2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2',4,6-tetrahydro-lH- spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 10c (62 mg) with a yield of 28.65%.

[0909] MS m / z (ESI): 427.9 [M+1]

[0910] Third step

[0911] Ethyl 2'-oxo-l',2',4,6-tetrahydro-lH-spiro[cyclopenta[b]pyrrole-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylate

[0912] Ethyl 2'-oxo-1',2',4,6-tetrahydro-1H-spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3- b]pyridine]-2-carboxylate 10d (23 mg, 80.30 μmol) was dissolved in 2 mL of mixed solution (water:methanol: tetrahydrofuran = 2:1:1), then sodium hydroxide (9.64 mg, 240.90 μmol) was added, stirred at 40 °C for 2 hours, after the reaction was completed, the pH of the reaction solution was adjusted to 3 with 1M dilute hydrochloric acid, 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), without purification, directly to the next reaction.

[0913] MS m / z (ESI): 298.0 [M+1]

[0914] Fourth step

[0915] 2'-oxo-1',2',4,6-tetrahydro-1H-spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxylic acid

[0916] Ethyl 2'-oxo-1',2',4,6-tetrahydro-1H-spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3- b]pyridine]-2-carboxylate 10d (23 mg, 80.30 μmol) was dissolved in 2 mL of mixed solution (water:methanol: tetrahydrofuran = 2:1:1), then sodium hydroxide (9.64 mg, 240.90 μmol) was added, stirred at 40 °C for 2 hours, after the reaction was completed, the pH of the reaction solution was adjusted to 3 with 1M dilute hydrochloric acid, 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), without purification, directly to the next reaction.

[0917] MS m / z (ESI): 269.9 [M+1]

[0918] Fifth step

[0919] N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'- oxo-

[0920] 1',2',4,6-tetrahydro-1H-spiro[cyclopenta[b]pyrrole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0921] N,N-dimethylformamide (1 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.39 mg, 148.56 μmol) was added, stirred at 25 °C for 16 hours, after the reaction was completed, concentrated under reduced pressure, the obtained residue was prepared and separated by 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%.

[0922] MS m / z (ESI): 591.8 [M+1]

[0923] 1 H-NMR (400MHz, 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).

[0924] Example 11

[0925] N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-

[0926] 1',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0927] First step

[0928] methyl 4,5-dimethylthiazole-2-carboxylate

[0929] Methyl 4,5-dimethylthiazole-2-carboxylate 11b (618 mg) was obtained by dissolving 4,5-dimethylthiazole-2-carboxylic acid 11a (900 mg, 5.73 mmol) and N,N-dimethylformamide (83.70 mg, 1.15 mmol) in methanol (20 mL), slowly dropping oxalyl chloride (1.02 g, 8.02 mmol) at 0 °C, and continuing stirring at 0 °C for 2 hours. After the reaction was completed, the obtained residue was separated and purified by column chromatography (eluent: A system) under reduced pressure to obtain methyl 4,5-dimethylthiazole-2-carboxylate 11b (618 mg) at a yield of 56.74%.

[0930] MS m / z (ESI): 172.1 [M+1]

[0931] Second step

[0932] methyl 4,5-bis(bromomethyl)thiazole-2-carboxylate

[0933] Methyl 4,5-bis(bromomethyl)thiazole-2-carboxylate 11c (360 mg) was obtained by dissolving methyl 4,5-dimethylthiazole-2-carboxylate 11b (618 mg, 3.61 mmol) and azobisisobutyronitrile (355.62 mg, 2.17 mmol) in dichloroethane (36 mL), adding N-bromosuccinimide (1.28 g, 7.22 mmol), and stirring at 70 °C for 4 hours. After the reaction was completed, the obtained residue was purified by preparative thin layer chromatography under reduced pressure to obtain methyl 4,5-bis(bromomethyl)thiazole-2-carboxylate 11c (360 mg) at a yield of 27.28%.

[0934] MS m / z (ESI): 327.9 [M+1]

[0935] Third step

[0936] ethyl 2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-

[0937] b]pyridine]-2-carboxylate

[0938] Methyl 4,5-bis(bromomethyl)thiazole-2-carboxylate 11c (150 mg, 437.27 umol) and l-((2-(trimethylsilyl)ethoxy)methyl)-l,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one 1a (109.83 mg, 415.41 umol) were dissolved in ethanol (7.5 mL), cesium carbonate (283.38 mg, 869.25 umol) was added, stirred at 25 °C for 16 hours, after the reaction was completed, extracted with water (20 mL x 3) and ethyl acetate (30 mL x 3), the combined organic phase was concentrated under reduced pressure, the obtained residue was separated and purified by column chromatography (eluent: A system), to obtain ethyl 2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 11d (50 mg), yield: 20.53%.

[0939] MS m / z (ESI): 445.9 [M+1]

[0940] Fourth step

[0941] Ethyl 2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate

[0942] Ethyl 2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 11d (50 mg, 112.21 umol) and 1 mL of trifluoroacetic acid were dissolved in tetrahydrofuran (1 mL), stirred at 25 °C for 3 hours, after the reaction was completed, concentrated under reduced pressure, added tetrahydrofuran (1 mL) and ammonia water (0.2 mL), stirred at 25 °C for 0.5 hours, concentrated under reduced pressure, the obtained residue was purified by thin layer plate to obtain ethyl 2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 11e (33 mg), yield: 68.08%.

[0943] MS m / z (ESI): 316.1 [M+1]

[0944] Fifth step

[0945] 2'-oxo-l',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid

[0946] Ethyl 2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]- 2-carboxylate 11e (33 mg, 104.65 pmol) was dissolved in 1 mL of a mixed solution (water: methanol: tetrahydrofuran = 3: 1: 1), sodium hydroxide (12.56 mg, 313.94 pmol) was added, stirred at 40 °C for 1 hour, after the reaction was completed, the pH of the reaction solution was adjusted to 5 with 1M dilute hydrochloric acid, 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%, without purification, directly to the next step.

[0947] MS m / z (ESI): 288.1 [M+1]

[0948] Sixth step

[0949] 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

[0950] 1',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0951] Ethyl 2'-oxo-1',2',4,6-tetrahydrospiro[cyclopenta[d]thiazole-5,3'-pyrrolo[2,3-b]pyridine]- 2-carboxylate 11e (33 mg, 104.65 pmol) was dissolved in 1 mL of a mixed solution (water: methanol: tetrahydrofuran = 3: 1: 1), sodium hydroxide (12.56 mg, 313.94 pmol) was added, stirred at 40 °C for 1 hour, after the reaction was completed, the pH of the reaction solution was adjusted to 5 with 1M dilute hydrochloric acid, 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%, without purification, directly to the next step.

[0952] MS m / z (ESI): 609.8 [M+1]

[0953] 1 H NMR (400 MHz, CDC13) 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).

[0954] Example 12

[0955] N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'-oxo-

[0956] 1',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0957] First step (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

[0958] 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 phenylpropenamide 12a (138.39 mg, 940.31 μmol) were dissolved in toluene (4 mL), stirred at 100 °C for 18 hours, after the reaction was completed, concentrated under reduced pressure, the obtained residue was separated and purified by column chromatography (eluent: A system), to obtain (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 12b (170 mg), yield: 34.35%. MS m / z (ESI): 474.1 [M+1]

[0959] Second step

[0960] 2'-oxo- 1 '-((2-(trimethylsilyl)ethoxy)methyl)- 1 ',2',6,7-tetrahydro-4H- spiro[benzo [d] oxazole-5,3 '-pyrrolo

[0961] [2,3-b]pyridine]-2-carboxylate

[0962] (E)-2-styryl- 1 '-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-4H- spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2'(l'H)-one 12b (150 mg, 316.70 μmol) was dissolved in a mixed solution (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, stirred at 30°C for 4 hours, potassium carbonate (87.41 mg, 633.40 μmol) and iodomethane (224.76 mg, 1.58 mmol) were added, and stirring was continued for 18 hours. After the reaction was completed, the obtained residue was concentrated under reduced pressure, and column chromatography separation and purification (eluent: C system) were performed to obtain 2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 12c (42 mg), yield: 29.24%.

[0963] MS m / z (ESI): 430.3 [M+1]

[0964] Third step

[0965] 2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate

[0966] Methyl 2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3- b]pyridine]-2-carboxylate 12d (20 mg) was obtained by stirring methyl 2'-oxo-l',2',6,7- tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 12c (42 mg, 97.78 μmol) in trifluoroacetic acid (2 mL) at 25 °C for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (2 mL), and then ammonia water (0.3 mL) was added. The mixture was stirred at 25 °C for 0.5 h. The residue was purified by thin layer plate to give methyl 2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylate 12d (20 mg) in 61.51% yield. MS m / z (ESI): 299.9 [M+1]

[0967] Fourth Step

[0968] Methyl 2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3- b]pyridine]-2-carboxylate 12d (20 mg) was obtained by stirring methyl 2'-oxo-l',2',6,7- tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 12c (42 mg, 97.78 μmol) in trifluoroacetic acid (2 mL) at 25 °C for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (2 mL), and then ammonia water (0.3 mL) was added. The mixture was stirred at 25 °C for 0.5 h. The residue was purified by thin layer plate to give methyl 2'-oxo-l',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylate 12d (20 mg) in 61.51% yield. MS m / z (ESI): 299.9 [M+1]

[0969] MS m / z (ESI): 286.0 [M+1]

[0970] Fifth Step

[0971] N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2'- oxo-l',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0972] 1',2',6,7-tetrahydro-4H-spiro[benzo[d]oxazole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0973] 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% was obtained after the reaction was completed, concentrated under reduced pressure, and the obtained residue was separated by C18 reverse phase column preparation (eluent: B system).

[0974] MS m / z (ESI): 608.2 [M+1]

[0975] 1 H 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).

[0976] Example 13

[0977] N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-

[0978] 1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[0979]

[0980] First step

[0981] 3-(4-chloro-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2'-dihydrospiro[cyclohexane-l,3'- pyrrolo[2,3-b]pyridin]-3-en-3-yl)acrylic acid ethyl ester

[0982] b]]pyridin]-3-en-3-yl)acrylic acid ethyl ester

[0983] To a solution of 4-chloro-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2'-dihydrospiro[cyclohexane-l,3'- pyrrolo[2,3-b]pyridin]-3-en-3-formal 1s (374 mg, 951.77 μmol) and 2-(triphenyl-λ 5 Ethyl 3-(4-chloro-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2'-dihydrospiro[cyclohexane-l,3'- pyrrolo[2,3-b]]pyridin]-3-en-3-yl)acrylate 13a (310 mg) was obtained by dissolving ethyl 3-(4-chloro-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2'-dihydrospiro[cyclohexane-l,3'- pyrrolo[2,3-b]pyridin]-3-en-3-yl)acrylate 10a (397.89 mg, 1.14 mmol) in dichloromethane (6.67 mL), stirring at 25 °C for 16 hours, and purifying the residue obtained after the reaction was completed by column chromatography (eluent: A system).

[0984] MS m / z (ESI): 463.2 [M+1]

[0985] Second step

[0986] Ethyl 2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l,1',2',4,6,7-hexahydrospiro[indole-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylate

[0987] pyridine]-2-carboxylate

[0988] Ethyl 2'-oxo-l',2',4,6,7-hexahydrospiro[indoline-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxylate 13c (80 mg, 257.87 pmol) was dissolved in methanol (2 mL), and sodium borohydride (17.62 mg, 471.48 pmol) was added. The mixture was stirred at 25 °C for 3 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (2 mL) and stirred at 25 °C for 0.5 h. The residue was separated and purified by column chromatography (eluent: A system) to obtain ethyl 2'-oxo-l',2',4,6,7-hexahydrospiro[indoline-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxylate 13d (60 mg, 86.99% yield).

[0989] Third step

[0990] Ethyl 2'-oxo-l',2',4,6,7-hexahydrospiro[indoline-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxylate

[0991] Ethyl 2'-oxo-l',2',4,6,7-hexahydrospiro[indoline-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxylate 13c (80 mg, 257.87 pmol) was dissolved in methanol (2 mL), and sodium borohydride (17.62 mg, 471.48 pmol) was added. The mixture was stirred at 25 °C for 3 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (2 mL) and stirred at 25 °C for 0.5 h. The residue was separated and purified by column chromatography (eluent: A system) to obtain ethyl 2'-oxo-l',2',4,6,7-hexahydrospiro[indoline-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxylate 13d (60 mg, 86.99% yield).

[0992] MS m / z (ESI): 312.1 [M+1]

[0993] Fourth step

[0994] 2'-oxo-l',2',4,6,7-hexahydrospiro[indoline-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxylic acid

[0995] Ethyl 2'-oxo-1,1',2',4,6,7-hexahydrospiro[indoline-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxylate 13c (80 mg, 256.96 μmol) was dissolved in a mixed solution of 2.5 mL (water:methanol: tetrahydrofuran = 1:3:1), sodium hydroxide (30.83 mg, 770.88 μmol) was added, stirred at 40 °C for 2 hours, after the reaction was completed, the reaction solution was adjusted to pH 5 with 1M dilute hydrochloric acid, concentrated under reduced pressure, to obtain 2'-oxo-1,1',2',4,6,7-hexahydrospiro[indoline-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxylic acid 13d (80 mg), without purification, directly to the next step.

[0996] MS m / z (ESI): 284.1 [M+1]

[0997] Fifth step

[0998] 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[indoline-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide 13

[0999] 1,1',2',4,6,7-hexahydrospiro[indoline-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxamide

[1000] Ethyl 2'-oxo-1,1',2',4,6,7-hexahydrospiro[indoline-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxylate 13c (80 mg, 256.96 μmol) was dissolved in a mixed solution of 2.5 mL (water:methanol: tetrahydrofuran = 1:3:1), sodium hydroxide (30.83 mg, 770.88 μmol) was added, stirred at 40 °C for 2 hours, after the reaction was completed, the reaction solution was adjusted to pH 5 with 1M dilute hydrochloric acid, concentrated under reduced pressure, to obtain 2'-oxo-1,1',2',4,6,7-hexahydrospiro[indoline-5,3'-pyrrolo[2,3-b]pyridine]-2- carboxylic acid 13d (80 mg), without purification, directly to the next step.

[1001] MS m / z (ESI): 605.8 [M+1]

[1002] 1 H-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).

[1003] Example 13A

[1004] (S)-N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l,l',2',4,6,7-hexahydrospiro[indole-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 13A

[1005] Example 13B

[1006] (R)-N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l,l',2',4,6,7-hexahydrospiro[indole-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 13B

[1007]

[1008] First Step

[1009] (S)-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l,l',2',4,6,7- hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 13b-A

[1010] [2,3-b]pyridine]-2-carboxylic acid ethyl ester 13b-A [2,3-b]pyridine]-2-carboxylic acid ethyl ester 13b-A [2,3-b]pyridine]-2-carboxylic acid ethyl ester 13b-A [2,3-b]pyridine]-2-carboxylic acid ethyl ester 13b-A

[1011] (R)-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l, l',2',4,6,7- hexahydrospiro[cyclohexane-l,5'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 13a-B

[1012] [2,3-b]pyridine]-2-carboxylic acid ethyl ester 13b-B

[1013] Ethyl 2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l, l',2',4,6,7- hexahydrospiro[cyclohexane-l,5'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid ethyl ester 13b (796 mg, 1.80 mmol) was purified by SFC chiral resolution (column type: Waters SFC-150, Dnicel IG, 20 x 250 mm, 10 pm; mobile phase: A for CO2 and B for Ethanol; detection wavelength: 214 nm; column temperature: 40 °C) to give single configuration compound (shorter retention time) and single configuration compound (longer retention time).

[1014] Single configuration compound (shorter retention time):

[1015] 322 mg, yield: 40.5%, retention time 1.964 min, chiral purity 100% ee.

[1016] MS m / z (ESI): 442.2 [M+1]

[1017] Single configuration compound (longer retention time):

[1018] 317 mg, yield: 39.8%, retention time 2.242 min, chiral purity 99% ee.

[1019] MS m / z (ESI): 442.2 [M+1]

[1020] Second step

[1021] (S)-2'-oxo-l, l',2',4,6,7-hexahydrospiro[cyclohexane-l,5'-pyrrolo[2,3-b]pyridine]-2- carboxylic acid ethyl ester 13c-A

[1022] (R)-2'-oxo-l, l',2',4,6,7-hexahydrospiro[cyclohexane-l,5'-pyrrolo[2,3-b]pyridine]-2- carboxylic acid ethyl ester 13c-B

[1023] Chiral resolution of (S)-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1,1',2',4,6,7- hexahydrospiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 13b-A (316.00 mg, 715.59 μmol) or (R)-2'-oxo-1'-((2-(trimethylsilyl)ethoxy)methyl)-1,1',2',4,6,7- hexahydrospiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 13b-B (311.00 mg, 704.27 μmol) was dissolved in trifluoroacetic acid (1.5 mL), stirred at 25 °C for 3 hours, after the reaction was completed, concentrated under reduced pressure, 1.5 mL of tetrahydrofuran and 0.3 mL of ammonia were added, and stirred at 25 °C for 0.5 hours, concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (eluent: A system) to obtain (S)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[cyclohexane-1,3'- pyrrolo[2,3-b]pyridine]-2-carboxylate 13c-A (190 mg), yield: 85.1%; (R)-2'-oxo-1,1',2',4,6,7- hexahydrospiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2-carboxylate 13c-B (195 mg), yield: 88.8%.

[1024] MS m / z (ESI): 312.1 [M+1]

[1025] MS m / z (ESI): 312.1 [M+1]

[1026] Third step

[1027] (S)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2- carboxylic acid 13d-A

[1028] (R)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[cyclohexane-1,3'-pyrrolo[2,3-b]pyridine]-2- carboxylic acid 13d-B

[1029] (S)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyrrole]-2-carboxylic acid ethyl ester 13c-A (190 mg, 610.28 umol) or (R)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyrrole]-2-carboxylic acid ethyl ester 13c-B (195 mg, 626.34 umol) was dissolved in 5.5 mL of mixed solution (methanol: tetrahydrofuran: water = 1:3:1), sodium hydroxide (73.23 mg, 1.83 mmol) was added, 50 °C stirring for 16 hours, after the reaction was completed, concentrated under reduced pressure, adjusted the pH of the reaction solution to 5 with 1M dilute hydrochloric acid, extracted with ethyl acetate (20 mL x 5) and methanol (2 mL x 5), combined organic phase, concentrated under reduced pressure, respectively, (S)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyrrole]-2-carboxylic acid 13d-A (157 mg), yield: 84.37%; (R)-2'-oxo-1,1',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyrrole]-2-carboxylic acid 13d-B (158 mg), yield: 80.14% were obtained without purification, directly for the next step reaction. MS m / z (ESI): 284.1 [M+1]

[1030] MS m / z (ESI): 284.1 [M+1]

[1031] Fourth step

[1032] (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]pyrrole]-2-carboxamide 13A

[1033] (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]pyrrole]-2-carboxamide 13B

[1034] (S)-2'-oxo-l,l',2',4,6,7-hexahydrospiro[indole-5,3'-pyrrolo[2,3-b]pyridine]-2-carboxylic acid 13d-A (20 mg, 70.60 pmol) or (R)-2'-oxo-l,l',2',4,6,7-hexahydrospiro[indole-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxylic acid 13d-B (20 mg, 70.60 pmol), (3S,5S,6R)-3- amino-6-methyl-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride Ip-A (23.94 mg, 63.54 pmol), l-hydroxybenzotriazole (19.08 mg, 141.20 pmol) and N,N-diisopropylethylamine (91.25 mg, 706.01 pmol) were dissolved in N,N-dimethylformamide (1 mL), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25.09 mg, 141.20 pmol) was added, stirred at 25 °C for 16 h, after the reaction was completed, concentrated under reduced pressure, the obtained residue was separated by C18 reverse phase column preparation (eluent: B system), to give (S)-N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l,l',2',4,6,7-hexahydrospiro[indole-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 13A (35.88 mg), yield: 69.22 %; (R)-N-((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)-2'-oxo-l,l',2',4,6,7-hexahydrospiro[indole-5,3'- pyrrolo[2,3-b]pyridine]-2-carboxamide 13B (34.65 mg), yield: 67.52 %. MS m / z (ESI): 606.2 [M+1]

[1035] MS m / z (ESI): 606.5 [M+1]

[1036] 1H-NMR (400MHz, DMSO-d6) δ11.28(s,1H),11.08(s,1H),8.36(d,J=8.0Hz,1H),8.03(dd,J=5.2,1.6Hz,1H),7.4 9-7.45(m,1H),7.19-7.13(m,1H),6.93(dd,J=7.2,1.6Hz,1H),6.84(dd,J=7.2,5.2Hz,1H),6.54(d,J=2.4Hz,1 H),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=14.8HZ,1H),2.13-2.02(m,2H),1.74-1.69(m,1H),1.22(d,J=6.4Hz,3H).

[1037] 1 HNMR(400MHz,DMSO-d6)δ11.23(s,1H),11.02(s,1H),8.32(d,J=8.0H Z ,1H),7.97(dd,J=5.2,1.6Hz,1H),7.44-7.36(m,1H),7.13-7.06(m,1H),6. 85(dd,J=7.2,1.6Hz,1H),6.77(dd,J=7.2,5.2Hz,1H),6.47(d,J=2.4Hz,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=15.6H Z ,1H),2.06-1.94(m,2H),1.67-1.63(m,1H),1.16(d,J=6.4Hz,3H).

[1038] Biological evaluation

[1039] Test Example 1: Determination of the inhibitory effect of the compound of this application on the CGRP signaling pathway in CHO-K1 cells expressing the human CGRP receptor.

[1040] The inhibitory effect of CGRP signaling pathway in vitro was evaluated by measuring the level of cAMP. The principle is that after CGRP and CGRP receptor binding, CGRP signaling pathway is activated, and the level of cAMP is induced to increase, so the decrease of cAMP level represents that CGRP signaling pathway is inhibited. The specific experimental method is as follows:

[1041] CHO-K1 cells expressing human CGRP receptor (CGRPR / CHO-K1, PerkinElmer, ES-420-C) were cultured in F12K+10%FBS+400μg / mL G418+10μg / mL Blasticidin medium, and cells were collected in the logarithmic growth phase. According to the kit instructions, the cells were resuspended in Stimulation Buffer containing 0.5mM IBMX, and 5μL of cell suspension was added to each well of a 96-well microplate (Cisbio, 66PL96025) with a cell density of 15000 cells / well. 2.5μL of gradient-diluted compound solution was added to each well, and after incubation at 37℃ for 30 minutes, 2.5μL of 40ng / mL human α-CGRP (Bachem, H-1470.0500) diluted in Stimulation Buffer containing 0.5mM IBMX was added to each well, and the final concentration was 10ng / mL. After incubation at 37℃ for 30 minutes, 5μL of Anti-cAMP-Cryptate solution and 5μL of cAMP-d2 solution were added to each well. Incubate at room temperature for 60 minutes, and use an enzyme reader (Molecular Devices) to read the HTRF signal. According to the compound concentration and HTRF signal, the IC 50 value of the inhibitory effect of the compound on the increase of cAMP level was calculated using Graphpad Prism.

[1042] The biological activity of the compounds of the present application was determined by the above test, and the IC 50 value at [α-CGRP]=10ng / mL was measured and is shown in Table 1 below.

[1043] Table 1 IC 50

[1044]

[1045] Conclusion: The compounds of the present application have obvious inhibitory effect on CGRP signaling pathway in CHO-K1 cells expressing human CGRP receptor. Among them, the positive control compound Atogepant was prepared according to the scheme described in patent application WO2012064910, and the structure is as follows:

[1046]

[1047] Test 2, determination of the inhibitory effect of the compounds of the present application on the CGRP signaling pathway in SK-N-MC cells

[1048] The inhibitory effect on the CGRP signaling pathway in vitro was evaluated by measuring the cAMP level. The principle is that after CGRP and CGRP receptor binding, the CGRP signaling pathway is activated, and the cAMP level is induced to rise. Therefore, the decrease of cAMP level represents the inhibition of the CGRP signaling pathway. The specific experimental method is as follows:

[1049] The cAMP assay used CAMP-GS DYNAMIC KIT detection kit (Cisbio, 62AM4PEB).

[1050] SK-N-MC (ATCC, HTB-10) cells endogenously expressing CGRP receptor were cultured in EMEM + 10% FBS medium, and cells were collected in the logarithmic growth phase. According to the kit instructions, the 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 15000 cells / well. 2.5 μL of gradient-diluted compound solution was added to each well, and after incubation at 37°C for 30 minutes, 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 each well, and the final concentration was 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. Incubate at room temperature for 60 minutes, and use Enzyme Label (Molecular Devices) to read the HTRF signal. According to the compound concentration and HTRF signal, the IC 50 value of the inhibitory effect of the compound on the increase of cAMP level was calculated using Graphpad Prism.

[1051] The biological activity of the compounds of the present application was determined by the above test, and the IC 50 value at [α-CGRP] = 10 ng / mL is shown in Table 2 below.

[1052] Table 2 IC 50

[1053]

[1054] Conclusion: The compounds in this application have a significant inhibitory effect on the CGRP signaling pathway in SK-N-MC cells.

[1055] Test Example 3: Determination of the affinity of the compound of this application for the human CGRP receptor

[1056] Cell membrane homogenate of CHO cells expressing human CGRP receptor (containing 16 μg of protein) was mixed with 0.03 nM [ 125 [I]h-CGRPα and serially diluted test samples were incubated at 22°C for 90 minutes in buffer (50 mM Hepes-NaOH (pH 7.4), 10 mM MgCl2, 4 mM KCl, 10 mM NaCl, 1 mM EDTA, 1 μM phosphoramide, 0.3% BSA, and 0.04% bacitracin). A control group without test samples was set up to obtain the highest binding signal for this experiment. Non-specific binding was determined by adding 1 μM non-isotope-labeled h-CGRPα to the control group. After incubation, a glass fiber filter (GF / B, Packard) soaked in 0.3% PEI was placed in a 96-well cell collector (Unfilter, Packard). The sample was rapidly filtered under vacuum and washed multiple times with pre-cooled buffer containing 50 mM Tris-HCl and 150 mM NaCl. After the filter was dried, scintillation solution (Microscint O, Packard) was added, and the radiometric signal value was measured using a scintillation counter (Topcount, Packard). Results are expressed as the percentage of specific binding of radioligands inhibited. Non-isotopically labeled h-CGRPα was used as a standard sample for reference. Both the test sample and the standard sample were tested at multiple concentrations to obtain […]. 125 The competition curve of I]h-CGRPα was obtained, 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 represents the system [ 125 The concentration of I]h-CGRPα (0.03 nM), K D This indicates that in the system [ 125 The dissociation constant of I]h-CGRPα with human CGRP receptor (0.06 nM).

[1057] The affinity of the compound in this application was determined by the above experiments, and K was measured. i The values ​​are shown in Table 3 below.

[1058] Table 3. Kaffinity of the compound in this application with the human CGRP receptor. i

[1059] Compound No. Ki (pM) Example 1A 17 Example 3A 19 Atogepant 9.8 Ubrogepant 27

[1060] Conclusion: The compounds of the present application have strong affinity for human CGRP receptors. The positive control compound Ubrogepant, prepared according to the protocol described in patent application WO2012064910, has the following structure:

[1061]

[1062] Test Example 4, Oral pharmacokinetic study of the compounds of the present application in SD rats

[1063] 1. Purpose of the experiment

[1064] SD rats were used as test animals, and LC / MS / MS method was used to determine the drug concentration in the plasma at different times after intragastrically and intravenously administering the compounds of the present application, to study the pharmacokinetic characteristics of the compounds of the present application in rats.

[1065] 2. Experimental protocol

[1066] 2.1 Experimental drugs and animals

[1067] Positive control compound Atogepant, Example 1A and Example 3A of the present application;

[1068] 18 healthy adult Sprague Dawley (SD) male rats, Zhaoyan (Suzhou) New Drug Research Center Co., Ltd.

[1069] 2.2 Drug preparation and administration

[1070] Oral gavage group:

[1071] An appropriate amount of the test compound was weighed, 100% polyethylene glycol 400 was added, and the compound was dissolved by vortex oscillation. After preparation, all the solutions were colorless and transparent, and the preparation concentration was 2 mg / mL.

[1072] Intravenous injection group:

[1073] An appropriate amount of the test compound was weighed, 90% polyethylene glycol 400 and 10% ethanol were added, and the compound was dissolved by vortex oscillation. After preparation, all the solutions were colorless and transparent, and the preparation concentration was 1 mg / mL.

[1074] 18 healthy adult SD male rats were fasted overnight, and food was given 4 hours after administration.

[1075] 2.3 Sample collection

[1076] About 0.2 mL blood was collected from the jugular vein before administration and at 0.083 hour, 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 24 hours after administration, and was anticoagulated with EDTA-K2. After the blood sample was collected, it was placed in a labeled ice water bath centrifuge tube, and the plasma was quickly separated by centrifugation. The centrifugation conditions were 4000 rpm, 10 minutes, 4°C, and the collected plasma was stored at -40°C or below for testing. The content of the test compound in the plasma of SD rats after oral and intravenous administration of different compounds was determined by LC-MS / MS method.

[1077] 3. Pharmacokinetic parameter results

[1078] The pharmacokinetic parameters of the compound of the present application and the positive control compound Atogepant are shown in Table 4 below.

[1079] Table 4 Pharmacokinetic parameters of the compound of the present application and the positive control compound Atogepant

[1080]

[1081] Conclusion: Compared with Atogepant, the compounds of Example 1A and Example 3A of the present application have good pharmacokinetic absorption in SD rats, prolonged half-life, significantly increased blood drug concentration, area under the curve and bioavailability, and have good pharmacokinetic properties.

[1082] Test Example 5, Oral pharmacokinetic study of the compound of the present application in cynomolgus monkeys

[1083] 1. Purpose of the experiment

[1084] Cynomolgus monkeys were used as test animals, and the compound of the present application was administered by gavage. The drug concentration in the plasma at different times was determined by LC / MS / MS method to study the pharmacokinetic characteristics of the compound of the present application in rats.

[1085] 2. Experimental plan

[1086] 2.1 Experimental drugs and animals

[1087] Positive control compound Atogepant, Example 1A and Example 3A of the present application;

[1088] Six healthy adult male cynomolgus monkeys from Kangshun Biotechnology Co., Ltd.

[1089] 2.2 Drug preparation and administration

[1090] Oral gavage group:

[1091] An appropriate amount of the test compound was weighed, 100% polyethylene glycol 400 was added, and the compound was dissolved by vortexing. The preparation was a colorless transparent solution, and the concentration of the preparation was 1 mg / mL.

[1092] Six healthy adult male cynomolgus monkeys were fasted overnight and fed 4 hours after administration.

[1093] 2.3 Sample collection

[1094] About 0.2 mL of blood was collected from the jugular vein before administration and at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 24 hours after administration, and was anticoagulated with EDTA-K2. After the blood sample was collected, it was placed in a labeled ice water bath centrifuge tube, and the plasma was quickly separated by centrifugation. The centrifugation conditions were 4000 rpm for 10 minutes at 4°C. The collected plasma was stored at -40°C or below for testing. The content of the test compound in the cynomolgus monkey plasma after intragastrically administering different compounds was determined by LC-MS / MS method.

[1095] 3. Pharmacokinetic parameter results

[1096] The pharmacokinetic parameters of the compound of the present application and the positive control compound atogepant are shown in Table 5 below.

[1097] Table 5 Pharmacokinetic parameters of the compound of the present application and the positive control compound atogepant

[1098]

[1099] Conclusion: Compared with atogepant, the compounds of Example 1A and Example 3A in the present application have good pharmacokinetic absorption in cynomolgus monkeys, the half-life is prolonged, the blood drug concentration and the area under the curve are significantly improved, and have good pharmacokinetic properties.

[1100] Test Example 6, in vivo pharmacodynamic test

[1101] 1. Purpose of the experiment

[1102] In the capsaicin-induced cynomolgus monkey blood flow model, the inhibitory effect of the compound of the present application on the blood flow of cynomolgus monkeys was evaluated.

[1103] 2. Experimental drugs

[1104] Example 1A and Example 3A used 100% polyethylene glycol 400 as a solvent.

[1105] 3. Experimental methods and materials

[1106] 3.1 Experimental animals and feeding conditions

[1107] Experimental animals: male cynomolgus monkeys, body weight range 3.2-5.80 kg during the administration period, purchased from Guangxi Xiong Sen Primate Experimental Animal Breeding Development Co., Ltd., production license: SCXK(Gui)2016-0003; experimental animal quality certificate number: NO.0002942.

[1108] Feeding conditions: The animals were raised in stainless steel cages by single-cage feeding. The cage size is 1 m x 1 m x 0.8 m. Before Stesolid anesthesia, the animals were required to fast (not to restrict water), and the rest of the time the animals were given food twice a day in the morning and afternoon, about 100 g per time, supplemented with fresh fruits. The animal room was set at a temperature of 18-26℃, humidity of 40-70%, and light for 12 hours with light and dark alternation.

[1109] 3.2 Animal grouping

[1110] After adaptive feeding of cynomolgus monkeys, 10 cynomolgus monkeys were randomly selected. Before capsaicin stimulation, the moorFLPI-2 laser speckle blood flow instrument was used to record the baseline value, and after capsaicin stimulation, the blood flow was detected again. Animals with area under the curve (AUC) of time-blood flow change rate ≥1000 (min·%) and small individual differences were selected for this experiment.

[1111] 3.3 Experimental method:

[1112] The blank solvent control group was given 100% polyethylene glycol 400, and the drug groups were given high and low doses of Example 1A and Example 3A, which were dissolved in 100% polyethylene glycol 400. The specific administration information is shown in Table 6:

[1113] Table 6 Administration information table

[1114]

[1115] Note: Bolus is a large dose bolus; Infusion is a small dose continuous infusion.

[1116] Blood flow detection: All animals were given capsaicin on the day of administration, and blood flow was detected at 0 min (before capsaicin administration), 5 min, 10 min, 15 min, 20 min and 30 min after capsaicin administration. The blood flow changes during this period were monitored. After the experiment on the same day, elution was carried out at intervals of 7-10 days, and the experimental animals were rotated in turn. Such experiments were repeated three times to obtain the average value of the data of each group.

[1117] 3.4 Data statistics

[1118] All data were plotted and statistically analyzed using Excel and GraphPad Prism 8 software.

[1119] The blood flow rate change, AUC (area under the curve of blood flow rate-time) 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 x 100%; the area under the curve of blood flow rate-time (AUC) was calculated using the trapezoidal formula: AUC = 1 / 2 (blood flow rate change at 5 min + blood flow rate change at 10 min) x 5 min + 1 / 2 (blood flow rate change at 10 min + blood flow rate change at 15 min) x 5 min + 1 / 2 (blood flow rate change at 15 min + blood flow rate change at 20 min) x 5 min + 1 / 2 (blood flow rate change at 20 min + blood flow rate change at 30 min) x 10 min; blood flow inhibition rate (%) = (AUC of blank vehicle control group - AUC of drug group) / AUC of blank vehicle control group x 100%.

[1120] 4. Results

[1121] The effects of Example 1A and Example 3A on blood flow in cynomolgus monkeys after capsaicin stimulation are shown in Table 7, Figure 1 and Figure 2 Table 7 shows the results of blood flow rate change, area under the curve of blood flow rate-time and blood flow inhibition rate after drug administration in each group of animals

[1122]

[1123]

[1124] Note: *, **, *** represent p < 0.05, p < 0.01, p < 0.001, respectively, compared with the blank vehicle control group.

[1125] 5. Conclusion

[1126] Under the conditions of this experiment, compared with the blank vehicle control group, the low and high doses of Example 1A and the high dose of Example 3A can significantly inhibit the increase in capsaicin-induced skin blood flow, with a blood flow inhibition rate of more than 70%, while the low dose of Example 3A showed no inhibitory effect on capsaicin-induced skin blood flow.

Claims

1. A compound of general formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: in: R1is selected from C1-6alkyl substituted by one or more R a C substituted by one or more substituents selected from the group consisting of 1-6 alkyl; Each R a It is a halogen; R2is selected from C 1-6 alkyl; each R3is the same or different, each being independently selected from halogen or C 1-6 alkyl; X and Y are different, where X is selected from =N-, -NR5-, -O- or -S-, and Y is selected from =CR4- or =N-. R4or R5are the same or different, each independently selected from a hydrogen atom or C 1-6 alkyl; W is selected from -CH2- or a single bond; Z is =CH-; n can be 0, 1, 2, 3, 4, or 5.

2. The compound according to claim 1 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: wherein, R2 is a methyl group.

3. The compound according to claim 1 or its stereoisomers or its pharmaceutically acceptable salts: wherein, The R3 is selected from fluorine and methyl.

4. The compound according to claim 1 or its stereoisomers or its pharmaceutically acceptable salts: wherein, X is selected from =N-, -O-, or -S-, and Y is =CR4-.

5. The compound or its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 4, having the structure of general formula (II): 。 6. The compound according to claim 5, or its stereoisomer or pharmaceutically acceptable salt thereof, having the structure of general formula (III): 。 7. The compound according to claim 6, or its stereoisomer or pharmaceutically acceptable salt thereof, having the structure of general formula (IV): 。 8. The compound according to claim 6, or its stereoisomer or pharmaceutically acceptable salt thereof, having the structure of general formula (V): 。 9. The compound or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 4, 6 to 8, wherein R1 is selected from 2,2,2-trifluoroethyl, 2,2-difluoroethyl and 3,3,3-trifluoropropyl.

10. The compound of claim 1 or its stereoisomer or pharmaceutically acceptable salt thereof, wherein R1 is 2,2,2-trifluoroethyl.

11. The compound of claim 1 or its stereoisomer or its pharmaceutically acceptable salt, wherein R3 is selected from fluorine and n is selected from 3.

12. A compound or its stereoisomer or its pharmaceutically acceptable salt, wherein the compound is: 。 13. A compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the stereoisomer of the compound is: or .

14. A compound or its stereoisomer or its pharmaceutically acceptable salt, wherein the stereoisomer of the compound is: or .

15. A pharmaceutical composition comprising: The compound or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 14, and pharmaceutically acceptable carriers, excipients or combinations thereof.

16. Use of the compound or stereoisomer of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 15, in the preparation of a CGRP receptor antagonist.

17. Use of the compound or stereoisomer of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 15, in the preparation of a medicament for the prevention and / or treatment of CGRP-mediated diseases, wherein the CGRP-mediated diseases are cerebrovascular or vascular disorders.

18. Use of a compound according to any one of claims 1 to 14, or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for the prevention and / or treatment of a CGRP-mediated disease, wherein the CGRP-mediated disease is selected from the group consisting of episodic migraine, chronic migraine, pure menstrual migraine, menstrual-related migraine, paediatric / adolescent migraine, abdominal migraine, paediatric benign paroxysmal vertigo, cluster headache, dialysis headache, chronic headache of unknown origin, tension / stress-induced headache, allergy-induced headache, osteoarthritis and related osteoporotic bone fracture pain, hot flashes associated with menopause or medically induced menopause by surgery or drug treatment, cyclic vomiting syndrome, opioid withdrawal, psoriasis, asthma, obesity, morphine tolerance, epilepsy, allergic rhinitis, rosacea, dental pain, ear pain, otitis media, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, gout, trigeminal neuralgia, nasal polyps, chronic rhinosinusitis, temporomandibular syndrome, back pain, cough, dystonic pain, postoperative incisional pain, sciatica, complex regional pain syndrome, Behcet's disease, endometriosis, phantom limb syndrome, dysmenorrhea, pain associated with childbirth, pain resulting from skin burns, or chronic secondary visceral pain in inflammatory bowel disease, gastro-oesophageal reflux disease, dyspepsia, irritable bowel syndrome, renal colic, cystitis, pancreatitis and prostatitis.

19. Use according to claim 18, wherein the inflammatory bowel disease is selected from the group consisting of Crohn's disease, ileitis or ulcerative colitis.

20. Use according to claim 18, wherein the episodic migraine is selected from the group consisting of migraine without aura or migraine with aura; wherein the migraine with aura is selected from the group consisting of basilar-type migraine, retinal-type migraine or hemiplegic migraine.

21. The use according to claim 20, wherein, The hemiplegic migraine is selected from the group consisting of sporadic hemiplegic migraine.

22. Use of a compound according to any one of claims 1 to 14, or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for the prevention and / or treatment of a CGRP-mediated disease, wherein the CGRP-mediated disease is selected from the group consisting of cyclic vomiting, neurodegenerative disease, lower back pain or inflammatory pain.

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