Substituted sulfonamide compound

Abstract

The present invention addresses the problem of providing a novel compound that has an OX2R agonist activity.　The present invention relates to a substituted sulfonamide compound which is represented by formula (I) or a pharmacologically acceptable salt thereof. A compound according to the present invention, or a pharmacologically acceptable salt thereof, has an agonist activity against OX2R, and is useful as, for example, a therapeutic agent for sleep disorders associated with OX2R (for example, narcolepsy, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia associated with a physical disease, hypersomnia associated with a mental disease, hypersomnia associated with a drug or a substance, circadian rhythm sleep-wake disorders, insufficient sleep syndrome, and extended sleep).

Description

Substituted Sulfonamide Compounds

[0001] The present invention relates to a substituted sulfonamide compound useful as a pharmaceutical. More specifically, the present invention relates to a substituted sulfonamide compound or a pharmacologically acceptable salt thereof that has agonist activity against orexin type 2 receptor (OX2R) and is useful as a therapeutic agent for sleep disorders associated with OX2R.

[0002] Orexin is a neuropeptide produced and secreted by orexin neurons in the hypothalamus, and there are two subtypes: orexin A and orexin B. Orexin neurons project throughout the central nervous system, excluding the cerebellum, with prominent projections to areas involved in the wakefulness and sleep mechanisms, such as monoaminergic neurons and cholinergic neurons in the brainstem and the paraventricular nucleus of the thalamus. Orexin receptors are expressed in the projection sites, and two subtypes, orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R), are present in different tissue distributions. The orexin nervous system plays an important role in maintaining wakefulness, and its dysfunction is thought to be a cause of narcolepsy.

[0003] Narcolepsy is a chronic neurological sleep disorder characterized by excessive daytime sleepiness and sleep attacks. Narcolepsy is classified into two types: Type 1 (NT1), which is accompanied by cataplexy (a sudden episode of physical weakness due to strong emotions), and Type 2 (NT2), which is not. Currently, central nervous system stimulants such as modafinil, methylphenidate, and pemoline are used to treat hypersomnia. However, all of these drugs can cause paradoxical reactions, and methylphenidate and pemoline have strong side effects, including dependence. On the other hand, antidepressants are used to treat cataplexy because the aforementioned drugs are ineffective. However, these drugs are difficult to use due to their strong side effects, and discontinuing the medication can worsen the condition due to the rebound phenomenon characteristic of antidepressants. Thus, the current treatment for narcolepsy is limited to symptomatic treatment, and therapeutic options based on the etiology of narcolepsy are needed.

[0004] A study using postmortem brains of narcolepsy patients reported that orexin neurons in the hypothalamus were reduced compared to healthy controls (Non-Patent Document 1). Furthermore, in dogs, a model of hereditary narcolepsy, it has been reported that the causative gene for narcolepsy is the gene encoding OX2R (Non-Patent Document 2). OX1R-deficient mice do not develop narcoleptic symptoms, whereas OX2R-deficient mice do (Non-Patent Document 3). These findings strongly suggest that OX2R signaling is important for maintaining wakefulness and that its attenuation is involved in the development of narcolepsy. Therefore, OX2R agonists are expected to be therapeutic agents for narcolepsy and other sleep disorders.

[0005] TAK-925 is a known OX2R agonist, and subcutaneous administration of TAK-925 has been shown to prolong wakefulness in wild-type mice (Non-Patent Document 4). Furthermore, clinical trials have shown that TAK-925 maintains wakefulness and reduces daytime sleepiness in NT1 patients (Patent Document 1).

[0006] Compounds having OX2R agonist activity are described in Patent Documents 1 to 14 and Non-Patent Document 4. However, the substituted sulfonamide compound of the present invention is not described in any of these documents.

[0007] International Publication No. 2021 / 048822 International Publication No. 2021 / 166934 International Publication No. 2021 / 142083 International Publication No. 2021 / 048821 U.S. Patent Application Publication No. 2020 / 0247747 U.S. Patent Application Publication No. 2019 / 0040010 U.S. Patent Application Publication No. 2020 / 0385346 U.S. Patent Application Publication No. 2017 / 0226137 International Publication No. 2022 / 109117 U.S. Patent Application Publication No. 2022 / 0056017 International Publication No. 2022 / 040058 International Publication No. 2021 / 026047 U.S. Patent Application Publication No. 2020 / 0255403 U.S. Patent Application Publication No. 2022 / 0144771

[0008] Thomas C. Thannickal et al., Neuron, 2000, Vol. 27, No. 3, pp. 469-474; Ling Lin et al., Cell, 1999, Vol. 98, No. 3, pp. 365-376; Michihiro Mieda et al., Proceedings of the National Academy of Sciences of the United States of America, 2004, Vol. 101, No. 13, pp. 4649-4654; Hiroshi Yukitake et al., Pharmacology, Biochemistry and Behavior, 2019, Vol. 187, pp. 172-794

[0009] An objective of the present invention is to provide a novel compound having OX2R agonist activity.

[0010] The present invention relates to a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof:

[0011] That is, the present invention relates to the following [1] to

[16] , etc. [1] A compound represented by formula (I): [Wherein, ring W is C 3-8 Cycloalkyl, C 5-10 Bicycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl; ring Z is a ring represented by formula (1), (2), or (3): Y 1 is a single bond, CR a1 R a2 , C.R. a1 , O, or NR b1 and Y 2 is CR 5 R 6 , or CR 5 and Y 3 is CR a1 or N; Y 4 is a single bond, CR a1 R a2 , O, or NR b2 and Y 5 is C or N; Y 6 , Y7 , and Y 8 are each independently a1 ,O,S,NR b3 or N; represents a single or double bond; R 5 and R 6 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, HaloC 1-6 Alkyl or C 1-6 alkoxy, or may be taken together to form a 3- to 8-membered saturated ring; R 7 and R 8 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; R 7 and R 8 When there are two or more of each, each R 7 and R 8 may be the same or different; p, q, s, and t are each independently 1 or 2; r is an integer from 0 to 2; R a1 , R a2 , R a3 and R a4 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R a1 and R a2 When there are two or more of each, each R a1 and R a2 may be the same or different; R b1 , R b2 , and R b3 are each independently a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; R b3 When there are two or more R b3 may be the same or different; L 1 is a single bond, CR a5 R a6 , or NR c and R a5 and R a6are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R c is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; L 2 is a single bond or O; R 1 is COR d , a 5- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A, or a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A; 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 R is a group consisting of alkyl, and oxo; when two or more groups selected from the substituent group A are present, each group may be the same or different; R d is C 1-6 Alkyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted C 3-8 Cycloalkyl, HaloC 1-6 Alkyl, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl or NR e R e’ and R e and R e’ are each independently a hydrogen atom, a hydroxyl, or C 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkyl or C 3-8 They may be cycloalkyl or may be joined together to form a 3- to 8-membered saturated heterocyclic ring unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; the substituent group B may be a halogen atom, C 1-6Alkyl, C 1-6 Alkoxy and HaloC 1-6 alkyl; when two or more groups selected from the substituent group B are present, each group may be the same or different; R 2 is C 1-6 Alkyl, C 2-6 Alkenyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted C 3-8 Cycloalkyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted 3- to 8-membered heterocycloalkyl, haloC 1-6 Alkyl or C 1-6 alkylamino; R 3 is a halogen atom, hydroxy, amino, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 alkylamino; n is an integer from 0 to 2; when n is 2, each R 3 may be the same or different; R 4 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, C 2-6 Alkenyl, HaloC 1-6 Alkyl, unsubstituted or C substituted with 1 to 3 groups selected from the substituent group C 3-8 Cycloalkyl, 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group C, C unsubstituted or substituted with 1 to 3 groups selected from the substituent group C 6-10 aryl, a 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group C, or a 9- or 10-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group C; the substituent group C is a halogen atom, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, C 1-6When two or more groups selected from the substituent group C are present, the groups may be the same or different (provided that the ring Z is a ring represented by formula (1); and p is 1; and Y 1 is CR a1 R a2 and Y 2 is CR 5 R 6 If so, it is one of the following (a) to (f): (a) L 1 is CR a5 R a6 , or NR c (b) L 2 is O. (c) The ring W is C 3-8 Cycloalkyl, C 5-10 (d) R is a bicycloalkyl, a 3- to 8-membered heterocycloalkyl, a naphthalene, a 5- or 6-membered heteroaryl, or a 9- or 10-membered heteroaryl. 4 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, C 2-6 Alkenyl, HaloC 1-6 Alkyl, unsubstituted or C substituted with 1 or 2 groups selected from the substituent group C 3-8 (e) R is a cycloalkyl or a 3- to 8-membered heterocycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group C. 1 (f) R is a 5- to 8-membered heterocycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A, or a 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A. 5 is Haro C 1-6 alkyl or R 6 [2] The compound according to [1] above, which is represented by formula (I-I): [Wherein, ring W is C 3-8 Cycloalkyl, C 5-10 Bicycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10aryl, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl; Y 1 is a single bond, CR a1 R a2 , C.R. a1 , O, or NR b1 and Y 2 is CR 5 R 6 , or CR 5 and represents a single or double bond; R 5 and R 6 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, HaloC 1-6 Alkyl or C 1-6 alkoxy, or may be taken together to form a 3- to 8-membered saturated ring; R 7 and R 8 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; R 7 and R 8 When there are two or more of each, each R 7 and R 8 may be the same or different; p is 1 or 2; R a1 and R a2 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R b1 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; L 1 is a single bond, CR a5 R a6 , or NR c and R a5 and R a6 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R c is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; L 2 is a single bond or O; R1 is COR d , a 5- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A, or a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A; 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 R is a group consisting of alkyl, and oxo; when two or more groups selected from the substituent group A are present, each group may be the same or different; d is C 1-6 Alkyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted C 3-8 Cycloalkyl, HaloC 1-6 Alkyl, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl or NR e R e’ and R e and R e’ are each independently a hydrogen atom, a hydroxyl, or C 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkyl or C 3-8 They may be cycloalkyl or may be joined together to form a 3- to 8-membered saturated heterocyclic ring unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; the substituent group B may be a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy and HaloC 1-6 alkyl; when two or more groups selected from the substituent group B are present, each group may be the same or different; R 2 is C 1-6 Alkyl, C 2-6Alkenyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted C 3-8 Cycloalkyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted 3- to 8-membered heterocycloalkyl, haloC 1-6 Alkyl or C 1-6 alkylamino; R 3 is a halogen atom, hydroxy, amino, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 alkylamino; n is an integer from 0 to 2; when n is 2, each R 3 may be the same or different; R 4 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, C 2-6 Alkenyl, HaloC 1-6 Alkyl, unsubstituted or C substituted with 1 to 3 groups selected from the substituent group C 3-8 Cycloalkyl, 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group C, C unsubstituted or substituted with 1 to 3 groups selected from the substituent group C 6-10 aryl, a 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group C, or a 9- or 10-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group C; the substituent group C is a halogen atom, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, C 1-6 alkylamino, and oxo; when two or more groups selected from the substituent group C are present, each group may be the same or different; (provided that p is 1; and Y 1 is CR a1 R a2 and Y 2 is CR 5 R 6 If so, it is one of the following (a) to (f): (a) L1 is CR a5 R a6 , or NR c (b) L 2 is O. (c) The ring W is C 3-8 Cycloalkyl, C 5-10 (d) R is a bicycloalkyl, a 3- to 8-membered heterocycloalkyl, a naphthalene, a 5- or 6-membered heteroaryl, or a 9- or 10-membered heteroaryl. 4 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, C 2-6 Alkenyl, HaloC 1-6 Alkyl, unsubstituted or C substituted with 1 or 2 groups selected from the substituent group C 3-8 (e) R is a cycloalkyl or a 3- to 8-membered heterocycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group C. 1 (f) R is a 5- to 8-membered heterocycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A, or a 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A. 5 is Haro C 1-6 alkyl or R 6 [3] The compound according to [1] above, represented by formula (I-II): [Wherein, ring W is C 3-8 Cycloalkyl, C 5-10 Bicycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl; Y 3 is CR a1 or N; Y 4 is a single bond, CR a1 R a2 , O, or NR b2 and R 6 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl or C 1-6 alkoxy; R7 and R 8 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; R 7 and R 8 When there are two or more of each, each R 7 and R 8 may be the same or different; q is 1 or 2; r is an integer from 0 to 2; R a1 , R a2 , R a3 and R a4 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R a1 and R a2 When there are two or more of each, each R a1 and R a2 may be the same or different; R b2 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; L 1 is a single bond, CR a5 R a6 , or NR c and R a5 and R a6 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R c is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; L 2 is a single bond or O; R 1 is COR d , a 5- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A, or a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A; 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C1-6 Alkoxy C 1-6 R is a group consisting of alkyl, and oxo; when two or more groups selected from the substituent group A are present, each group may be the same or different; d is C 1-6 Alkyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted C 3-8 Cycloalkyl, HaloC 1-6 Alkyl, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl or NR e R e’ and R e and R e’ are each independently a hydrogen atom, a hydroxyl, or C 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkyl or C 3-8 They may be cycloalkyl or may be joined together to form a 3- to 8-membered saturated heterocyclic ring unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; the substituent group B may be a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy and HaloC 1-6 alkyl; when two or more groups selected from the substituent group B are present, each group may be the same or different; R 2 is C 1-6 Alkyl, C 2-6 Alkenyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted C 3-8 Cycloalkyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted 3- to 8-membered heterocycloalkyl, haloC 1-6 Alkyl or C 1-6 alkylamino; R 3 is a halogen atom, hydroxy, amino, C 1-6 Alkyl, HaloC 1-6 Alkyl, C1-6 Alkoxy or C 1-6 alkylamino; n is an integer from 0 to 2; when n is 2, each R 3 may be the same or different; R 4 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, C 2-6 Alkenyl, HaloC 1-6 Alkyl, unsubstituted or C substituted with 1 to 3 groups selected from the substituent group C 3-8 Cycloalkyl, 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group C, C unsubstituted or substituted with 1 to 3 groups selected from the substituent group C 6-10 aryl, a 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group C, or a 9- or 10-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group C; the substituent group C is a halogen atom, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, C 1-6 and when two or more groups selected from Substituent Group C are present, each group may be the same or different] or a pharmacologically acceptable salt thereof. [4] The compound according to [1] above, represented by formula (I-III): [Wherein, ring W is C 3-8 Cycloalkyl, C 5-10 Bicycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl; Y 5 is C or N; Y 6 , Y 7 , and Y 8 are each independently a1 ,O,S,NR b3 or N; R 7 and R 8 are each independently a hydrogen atom, a halogen atom, or C 1-6alkyl; R 7 and R 8 When there are two or more of each, each R 7 and R 8 may be the same or different; s and t are each independently 1 or 2; R a1 is a hydrogen atom, a halogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; R a1 When there are two or more R a1 may be the same or different; R b3 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; R b3 When there are two or more R b3 may be the same or different; L 1 is a single bond, CR a5 R a6 , or NR c and R a5 and R a6 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R c is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; L 2 is a single bond or O; R 1 is COR d , a 5- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A, or a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A; 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 R is a group consisting of alkyl, and oxo; when two or more groups selected from the substituent group A are present, each group may be the same or different;d is C 1-6 Alkyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted C 3-8 Cycloalkyl, HaloC 1-6 Alkyl, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl or NR e R e’ and R e and R e’ are each independently a hydrogen atom, a hydroxyl, or C 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkyl or C 3-8 They may be cycloalkyl or may be joined together to form a 3- to 8-membered saturated heterocyclic ring unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; the substituent group B may be a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy and HaloC 1-6 alkyl; when two or more groups selected from the substituent group B are present, each group may be the same or different; R 2 is C 1-6 Alkyl, C 2-6 Alkenyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted C 3-8 Cycloalkyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted 3- to 8-membered heterocycloalkyl, haloC 1-6 Alkyl or C 1-6 alkylamino; R 3 is a halogen atom, hydroxy, amino, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 alkylamino; n is an integer from 0 to 2; when n is 2, each R 3may be the same or different; R 4 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, C 2-6 Alkenyl, HaloC 1-6 Alkyl, unsubstituted or C substituted with 1 to 3 groups selected from the substituent group C 3-8 Cycloalkyl, 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group C, C unsubstituted or substituted with 1 to 3 groups selected from the substituent group C 6-10 aryl, a 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group C, or a 9- or 10-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group C; the substituent group C is a halogen atom, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, C 1-6 [5] The compound according to any one of [1] to [4] above, wherein ring W is selected from the group consisting of C 3-8 Cycloalkyl, C 5-10 Bicycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10 aryl, or 5- or 6-membered heteroaryl; Y 3 is N; Y 5 is C; Y 6 , Y 7 , and Y 8 But, CR a1 q and s are 1; t is 2; R d But C 1-6 Alkyl or NR e R e’ and R e and R e’ are each independently a hydrogen atom, a hydroxyl, or a C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl or C3-8 cycloalkyl, or together unsubstituted or 1 to 3 C 1-6 R may form a 3- to 8-membered saturated heterocyclic ring substituted with alkyl; 4 is a hydrogen atom, C 2-6 Alkenyl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group C 6-10 [6] A compound according to any one of [1] to [5] above, wherein Y is aryl, or a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group C, or a pharmacologically acceptable salt thereof. 4 But, CR a1 R a2 , O, or NR b2 and R 5 is a hydrogen atom or C 1-6 alkyl; R 6 is a hydrogen atom; R 7 and R 8 is a hydrogen atom; r is 1 or 2; R a1 , R a2 , R a3 and R a4 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; R b1 is a hydrogen atom or C 1-6 alkyl; L 1 is a single bond or NR c and R c is a hydrogen atom or C 1-6 alkyl; 1-6 Alkyl, C 1-6 R is the group consisting of alkoxy and oxo; 2 But C 1-6 Alkyl, C 3-8 Cycloalkyl or haloC 1-6 alkyl; R 3 is a halogen atom or C 1-6 alkyl; n is 0 or 1; the substituent group C is a halogen atom, C 1-6 Alkyl, and C 1-6[7] A compound according to any one of [1], [2], [5], and [6], wherein Y is a group consisting of alkoxy, or a pharmacologically acceptable salt thereof. 1 is CR a1 , O, or NR b1 [8] The compound according to any one of [1] to [7] above, wherein L 1 is a single bond; R 1 But, COR d and R d But NR e R e’ [9] The compound according to any one of [1] to [8], wherein ring W is C 6-10 aryl, or 5- or 6-membered heteroaryl; L 2 is a single bond; R e and R e’ are each independently a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl or C 3-8 cycloalkyl, or together unsubstituted or 1 to 3 C 1-6 R may form a 3- to 8-membered saturated heterocyclic ring substituted with alkyl; 4 is unsubstituted or substituted with one group selected from the substituent group C 6-10 A compound or a pharmacologically acceptable salt thereof, which is an aryl, or a 5- or 6-membered heteroaryl that is unsubstituted or substituted with one group selected from the substituent group C.

[10] The compound according to any one of [1] or [5] to [9] above, wherein ring Z is a ring represented by formula (1) or (2):

[11] A compound according to any one of [1], [2], [5], [6], or [8] to

[10] above, selected from the group consisting of the following compounds: and

[12] The compound according to any one of [1], [2], or [5] to

[10] above, selected from the group consisting of the following compounds: and

[13] The compound according to any one of [1], [3], and [5] to

[10] above, which is selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

[14] A pharmaceutical composition comprising the compound according to any one of [1] to

[13] above or a pharmacologically acceptable salt thereof, and a pharmaceutical additive.

[15] The pharmaceutical composition according to

[14] above, which is a pharmaceutical composition for treating a sleep disorder involving OX2R.

[16] The pharmaceutical composition according to

[15] above, wherein the sleep disorder involving OX2R is narcolepsy.

[0012] In one embodiment, the present invention relates to a method for treating a sleep disorder associated with OX2R, comprising administering to a patient a required amount of the pharmaceutical composition according to

[14] above.

[0013] In one embodiment, the present invention relates to use of the compound according to any one of [1] to

[13] or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating a sleep disorder involving OX2R.

[0014] The compound of the present invention has excellent OX2R agonist activity, and therefore the compound of the present invention or a pharmacologically acceptable salt thereof is useful as a therapeutic agent for sleep disorders involving OX2R.

[0015] Hereinafter, embodiments of the present invention will be described in more detail.

[0016] In the present invention, each term has the following meaning unless otherwise specified.

[0017] "Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. 1-6"Alkyl" means a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. 2-6 "Alkenyl" means a straight-chain or branched alkenyl group having 2 to 6 carbon atoms. Examples include ethenyl, 1-propenyl, and 2-propenyl. 1-6 The term "alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like.

[0018] "Hydroxy C 1-6 "Alkyl" refers to a C substituted with 1 or 2 hydroxy groups. 1-6 "HaloC" refers to alkyl. Examples include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, etc. 1-6 "Alkyl" means a C alkyl group substituted with 1 to 5 halogen atoms of the same or different types. 1-6 Examples of the alkyl include monofluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and pentafluoroethyl. 1-6 Alkoxy C 1-6 "Alkyl" means one C 1-6 Alkoxy-substituted C 1-6 It means alkyl, and examples thereof include methoxymethyl, methoxyethyl, ethoxymethyl, and ethoxyethyl.

[0019] "C 6-10"Aryl" means a phenyl group or a naphthyl group. "5- or 6-membered heteroaryl" means a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. Examples include pyridyl, pyrimidyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl. "9- or 10-membered heteroaryl" means a 9- or 10-membered bicyclic aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. Examples include indolyl, isoindolyl, benzofuryl, benzothiophenyl, benzimidazolyl, purinyl, benzotriazolyl, quinolyl, isoquinolyl, quinazolyl, cinnolyl, pteridinyl, chromenyl, and isochromenyl.

[0020] "C 3-8 "Cycloalkyl" means a 3- to 8-membered monocyclic saturated hydrocarbon group. Examples include cyclopropyl, cyclobutyl, cyclopentyl, etc. 5-10"Bicycloalkyl" means a 5- to 10-membered bicyclic saturated hydrocarbon group. Examples include bicyclo[1.1.1]pentyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, spiro[3.3]heptyl, etc. "3- to 8-membered heterocycloalkyl" means a 3- to 8-membered cycloalkyl group in which carbon atoms in the ring are replaced with one or two heteroatoms selected from oxygen, nitrogen, and sulfur atoms, and also includes partially bridged structures. For example, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, azabicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[2.2.1]heptanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, pyrrolidonyl, piperidonyl, oxiranyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, octahydrocyclopenta[c]pyrrole, and the like. "5- to 8-membered heterocycloalkyl" refers to a 5- to 8-membered cycloalkyl group in which a carbon atom in the ring is replaced by one or two heteroatoms selected from oxygen, nitrogen, and sulfur atoms, and includes partially bridged structures. Examples include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, azabicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[2.2.1]heptanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 2-azaspiro[3.3]heptanyl, cc, pyrrolidonyl, piperidonyl, tetrahydrofuranyl, tetrahydropyranyl, and octahydrocyclopenta[c]pyrrole.

[0021] The term "3- to 8-membered saturated carbocyclic ring" refers to a monocyclic or polycyclic saturated hydrocarbon ring having 3 to 8 carbon atoms. The term "3- to 8-membered saturated heterocyclic ring" refers to a monocyclic or polycyclic 3- to 8-membered saturated ring having 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms in the ring.

[0022] The term "3- to 8-membered saturated ring" means a 3- to 8-membered saturated carbocyclic ring or a 3- to 8-membered saturated heterocyclic ring.

[0023] "C 1-6 "Alkylamino" means (C 1-6 alkyl)-NH-, or (C 1-6 alkyl)N-, (C 1-6 The two Cs of the group represented by alkyl)2N- 1-6 The alkyls may be the same or different, and examples thereof include methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, methylethylamino, and diethylamino.

[0024] The following abbreviations used in the text, figures, and tables have the following meanings: AZADOL®: 2-hydroxy-2-azaadamantane Boc2O: di-tert-butyl dicarbonate Boc: tert-butoxycarbonyl DCM: dichloromethane DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate LDA: lithium diisopropylamide MeCN: acetonitrile NMP: N-methylpyrrolidone 5% Pd / C: 5% palladium on carbon (approximately 59% water-wet) 10% Pd / C: 10% palladium on carbon (approximately 55% water-wet) Pd(Amphos)2Cl2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(PPh3)4: tetrakis(triphenylphosphine)palladium(0); TBME: t-butyl methyl ether; TEA: triethylamine; THF: tetrahydrofuran; Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; Xphos Pd G3: (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; APS: aminopropylated silica gel; ODS: octadecylsilylated silica gel. Chiral preparative column chromatography: Chiral preparative column chromatography using YMC CHIRALART Cellulose-SB. Ref. No.: Reference example number Str.: Structural formula Ex. No.: Example number Phys. data: Physical properties 1H-NMR: Proton nuclear magnetic resonance spectrum CDCl3: Chloroform-d1 MS: Mass spectrometry (The values ​​in the table were measured by electrospray ionization or electrospray ionization-atmospheric pressure chemical ionization multi-ionization method.) Act.: Activation rate of the test substance at a compound concentration of 10 μM, where the fluorescence intensity when 1 μM human orexin A peptide was added was taken as 100%, and the fluorescence intensity when only the vehicle was added was taken as 0%. CHO: Chinese hamster ovary HEPES: 2-(4-(2-hydroxyethyl)-1-piperazinyl)ethanesulfonic acid

[0025] When one or more asymmetric carbon atoms are present in the compound of formula (I), the present invention encompasses compounds in which each asymmetric carbon atom is in the R configuration, compounds in the S configuration, and any combination thereof. Furthermore, their racemates, racemic mixtures, single enantiomers, and diastereomeric mixtures are also included within the scope of the present invention.

[0026] In the case where the compound represented by formula (I) has cis-trans isomers, the present invention encompasses both of the cis-trans isomers.

[0027] When tautomers exist in the compound represented by formula (I), the present invention includes all of the tautomers.

[0028] In the present invention, the determination of stereochemistry can also be carried out by methods well known in the art.

[0029] The compound represented by formula (I) can be converted into a pharmacologically acceptable salt thereof according to a conventional method, if necessary. Such salts include acid addition salts and salts with bases.

[0030] Examples of acid addition salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and acid addition salts with organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, benzoic acid, glutamic acid, and aspartic acid.

[0031] Examples of salts with bases include salts with inorganic bases such as lithium salts, sodium salts, potassium salts, calcium salts, and magnesium salts, and salts with organic bases such as N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, triethylamine, piperidine, morpholine, pyrrolidine, arginine, lysine, and choline.

[0032] Unless otherwise specified, a suffix to a chemical name or structural formula referring to a salt, such as "hydrochloride" or "HCl," does not denote a stoichiometric description but simply refers to the salt form.

[0033] When the compound represented by formula (I) or a pharmacologically acceptable salt thereof exists, for example, as a crystal, the present invention includes any crystalline form. For example, pharmacologically acceptable salts also include solvates with pharmaceutically acceptable solvents such as water or ethanol, co-crystals with a suitable co-crystal former, etc.

[0034] In the compound represented by formula (I), some of the atoms may be replaced with the corresponding isotopes. The present invention also includes compounds replaced with these isotopes. Examples of isotopes include: 2 H, 3 H, 11 C. 13 C. 14 C. 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O. 17 O. 18 O, and 35 In one embodiment, some of the hydrogen atoms of the compound represented by formula (I) are isotopes of the hydrogen atom, carbon atom, chlorine atom, fluorine atom, iodine atom, nitrogen atom, oxygen atom, and sulfur atom represented by S. 2 Examples include compounds in which hydrogen is replaced by H (D: deuterium atom).

[0035] A compound represented by formula (I) in which some atoms are replaced with isotopes can be produced by a method similar to the production method described below using a commercially available reagent containing an isotope. Alternatively, the compound can be produced by a method described in the literature (see, for example, Journal of Organic Synthesis, Vol. 65, No. 12, pp. 1179-1190, 2007, and RADIOISOTOPES, Vol. 56, No. 11, pp. 741-750, 2007).

[0036] The compound of the present invention represented by formula (I) can be produced, for example, by the methods shown in Schemes 1 to 7 or methods similar thereto, or by methods described in the literature or methods similar thereto. In the schemes, the compound of formula (I) corresponds to the compounds of formulae (I-1) to (I-3).

[0037] The compound of the present invention represented by formula (I) can be produced by the following method, but the following production method is an example of a general production method and is not intended to limit the production method.

[0038] In the reactions of each step, when raw materials and reagents are commercially available, commercially available products can be used.

[0039] In the reaction of each step, the reaction time varies depending on the starting materials used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days unless otherwise specified.

[0040] In the reactions of each step, the reaction temperature varies depending on the starting materials and solvents used, but is usually −78° C. to reflux temperature unless otherwise specified.

[0041] In the reaction of each step, the pressure varies depending on the starting materials, solvent, reaction temperature, etc. used, but is usually 1 to 20 atmospheres unless otherwise specified.

[0042] A microwave reactor such as Biotage Initiator may be used in the reactions of each step. When a microwave reactor is used, the conditions vary depending on the raw materials, solvent, and model used, but the reaction can be carried out under the following conditions: pressure range: 1 to 30 bar, power range: 1 to 400 W, reaction temperature: room temperature to 300°C, and reaction time: 1 minute to 1 day.

[0043] Unless otherwise specified, the reaction in each step is carried out without solvent or using an appropriate solvent. Examples of the appropriate solvent include solvents inert to the reaction. Specific examples of the solvent used include the solvents described in the Reference Examples or Examples corresponding to each step, or the following solvents. Two or more of the following solvents may be mixed in an appropriate ratio and used. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-propanol, etc.; Ethers: diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane, cyclopentyl methyl ether, TBME, etc.; Aromatic hydrocarbons: benzene, chlorobenzene, 1,2-dichlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, n-hexane, n-pentane, etc.; Amides: DMF, N,N-dimethylacetamide, NMP, etc.; Halogenated hydrocarbons: DCM, 1,2-dichloroethane, chloroform, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Sulfoxides: DMSO, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, etc.; Esters: ethyl acetate, methyl acetate, isopropyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; Water.

[0044] When a base is used in the reaction of each step, the reaction is carried out using a base suitable for the reaction. Specific examples of the base to be used include the bases described in the Reference Examples or Examples corresponding to each step, and the following bases. Inorganic bases: sodium hydroxide, lithium hydroxide, potassium hydroxide, etc.; basic salts: sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, etc.; organic bases: TEA, DIPEA, diethylamine, pyridine, DMAP, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; metal alkoxides: sodium ethoxide, sodium methoxide, potassium tert-butoxide, etc.; alkali metal hydrides: sodium hydride, etc.; metal amides: sodium amide, LDA, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, etc.; organic magnesiums: isopropyl magnesium chloride, etc.; organic lithiums: methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, etc.

[0045] When an acid is used in the reaction of each step, the reaction is carried out using an acid suitable for the reaction. Specific examples of the acid used include the acids described in the Reference Examples and Examples corresponding to each step or the following acids: inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; organic acids: acetic acid, trifluoroacetic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, aluminum chloride, zinc chloride, titanium(IV) chloride, etc.

[0046] When a condensing agent is used in the reaction of each step, the reaction is carried out using a condensing agent suitable for the reaction. Specific examples of the condensing agent used include the condensing agents described in the Reference Examples or Examples corresponding to each step, or the following condensing agents. Carbodiimides: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, etc.; Imidazoles: carbonyldiimidazole, etc.; Uronium salts, phosphonium salts: HATU, 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, etc.; Triazines: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, etc.; Others: propylphosphonic anhydride (cyclic trimer), etc.

[0047] When a reducing agent is used in the reaction of each step, the reaction is carried out using a reducing agent suitable for the reaction. Specific examples of the reducing agent to be used include the reducing agents described in the Reference Examples or Examples corresponding to each step, or the following reducing agents. Metal hydrides: lithium aluminum hydride, lithium borohydride, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride, etc.; Boranes: borane-THF complex, picoline borane complex, decaborane, etc.

[0048] In each step, when a protecting group is required depending on the type of functional group, the protective group may be introduced and removed in a suitable combination according to a conventional method. Regarding the type of protective group, protection, and deprotection, for example, the method described in "Greene's Protective Groups in Organic Synthesis," edited by Peter GM Wuts, fifth edition, Wiley-Interscience, 2014 can be mentioned.

[0049] When hydrolysis is carried out in each step, the reaction can be carried out in the presence of an acid or a base. Examples of the acid and base that can be used include those mentioned above.

[0050] When catalytic reduction is carried out in each step, the reaction can be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst that can be used include palladium carbon powder, Pearlman's catalyst, platinum carbon powder, Raney nickel, etc. If necessary, an acid may be used in the reaction.

[0051] When oxidation is carried out in each step, the reaction can be carried out in the presence of an oxidizing agent. Examples of the oxidizing agent include metachloroperbenzoic acid and iodobenzene diacetate. If necessary, an oxidation catalyst such as AZADOL may be used in the reaction.

[0052] When reduction is carried out in each step, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent that can be used include the examples mentioned above.

[0053] When amidation is carried out in each step, the reaction can be carried out using a condensing agent in the presence or absence of a base. Examples of the condensing agent and base used include those mentioned above. When a carbodiimide is used as the condensing agent, the reaction may be carried out by adding an additive such as 1-hydroxybenzotriazole or DMAP, as necessary. The reaction can also be carried out using a halogenating agent in the presence or absence of a base. Examples of the halogenating agent include thionyl chloride, oxalyl chloride, phosphoryl chloride, sulfuryl chloride, phosphorus trichloride, and phosphorus pentachloride.

[0054] When reductive amination is performed in each step, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent that can be used include those mentioned above. The reaction can also be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst that can be used include palladium carbon powder, Pearlman's catalyst, platinum carbon powder, Raney nickel, etc.

[0055] In each step, when an aromatic nucleophilic substitution reaction is carried out, the reaction can be carried out in the presence of a base. Examples of the base include those mentioned above.

[0056] When a Suzuki-Miyaura cross-coupling reaction is carried out in each step, the reaction can be carried out in the presence of a palladium catalyst and a base. Examples of the palladium catalyst include bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) and Pd(PPh3)4. Examples of the base used include those mentioned above.

[0057] When a Mitsunobu reaction is carried out in each step, the reaction can be carried out using an azodicarboxylic acid ester and triphenylphosphine. Examples of the azodicarboxylic acid ester to be used include diethyl azodicarboxylate and diisopropyl azodicarboxylate.

[0058] When sulfonylation is carried out in each step, the reaction can be carried out using a sulfonylating reagent in the presence of a base. Examples of the sulfonylating reagent that can be used include methanesulfonyl chloride, ethanesulfonyl chloride, etc. Examples of the base that can be used include the examples mentioned above.

[0059] When sulfamoylation is carried out in each step, the reaction can be carried out using a sulfamoylating reagent in the presence of a base. Examples of the sulfamoylating reagent that can be used include N-methylsulfamoyl chloride, dimethylsulfamoyl chloride, etc. Examples of the base that can be used include the examples mentioned above.

[0060] When the Staudinger reaction is carried out in each step, the reaction can be carried out using a phosphorus reagent, such as triphenylphosphine.

[0061] When a Curtius rearrangement reaction is carried out in each step, the reaction can be carried out by treating with an acid using an azide reagent. Examples of the azide reagent that can be used include diphenylphosphoryl azide. Examples of the acid that can be used include the above-mentioned examples.

[0062] When hydroboration is carried out in each step, the reaction can be carried out using a borane reagent, such as borane-THF complex.

[0063] The compound represented by formula (I) can be produced, for example, according to the method described in Scheme 1.

[0064] The symbols in the formula have the same meanings as above. 1 represents a protecting group. X 1 represents a chlorine atom or a bromine atom.

[0065] Compound (1-2) can also be produced by reacting compound (1-1) with compound (1-4) in the presence of a base.

[0066] Compound (1-3) can also be prepared by removing the protecting group of compound (1-2), reacting the compound with methanesulfonyl chloride in the presence of a base, and then reacting the compound with sodium azide.

[0067] The compound of formula (I) can also be prepared by subjecting compound (1-3) to Staudinger reaction or catalytic reduction, followed by sulfonylation or sulfamoylation.

[0068] Compound (1-4) can be produced, for example, according to the method described in Scheme 2.

[0069] The symbols in the formula have the same meanings as above. X 2 and X 3 represents a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfonyloxy group.

[0070] Compound (2-5) can also be produced by Suzuki-Miyaura cross-coupling reaction between compound (2-1) and compound (2-2), or between compound (2-3) and compound (2-4).

[0071] The compound (1-4) can also be prepared by converting the hydroxy group of the compound (2-5) to a chlorine atom or a bromine atom.

[0072] The compound represented by formula (I-1) can be produced, for example, according to the method described in Scheme 3.

[0073] The symbols in the formula have the same meanings as above. 2indicates a protecting group.

[0074] Compound (3-2) can also be produced by reacting compound (3-1) with compound (1-4) in the presence of a base.

[0075] Compound (3-3) can also be prepared by hydrolyzing compound (3-2) and then amidating it.

[0076] Compound (3-4) can also be prepared by removing the protecting group of compound (3-3), reacting the compound with methanesulfonyl chloride in the presence of a base, and then reacting the compound with sodium azide.

[0077] Compound (3-5) can also be prepared by removing the protecting group of compound (3-2), reacting the compound with methanesulfonyl chloride in the presence of a base, and then reacting the compound with sodium azide.

[0078] Compound (3-6) can also be prepared by Staudinger reaction or catalytic reduction of compound (3-5), followed by sulfonylation or sulfamoylation.

[0079] Compound (3-7) can also be produced by reacting compound (3-1) with compound (3-11) in the presence of a base.

[0080] Compound (3-8) can also be prepared by removing the protecting group from compound (3-7), reacting the compound with methanesulfonyl chloride in the presence of a base, and then reacting the compound with sodium azide.

[0081] Compound (3-9) can also be prepared by Staudinger reaction or catalytic reduction of compound (3-8), followed by sulfonylation or sulfamoylation.

[0082] Compound (3-10) can also be prepared by hydrolyzing compound (3-9) followed by amidation.

[0083] The compound of formula (I-1) can also be prepared by subjecting the compound (3-4) to Staudinger reaction or catalytic reduction, followed by sulfonylation or sulfamoylation.

[0084] The compound of formula (I-1) can also be prepared by hydrolyzing the compound (3-6) and then amidating it.

[0085] The compound represented by formula (I-1) can also be produced by Suzuki-Miyaura cross-coupling reaction of compound (3-10) and compound (2-2).

[0086] The compound represented by formula (I-2) can be produced, for example, according to the method described in Scheme 4.

[0087] The symbols in the formula have the same meanings as above.

[0088] Compound (4-1) can also be prepared by hydrolyzing compound (3-6) followed by Curtius rearrangement reaction.

[0089] The compound of formula (I-2) can also be prepared by reductively aminating the compound (4-1), if necessary, and then reacting the compound with the compound (4-2) in the presence of a base.

[0090] The compound represented by formula (I-3) can be produced, for example, according to the method described in Scheme 5.

[0091] The symbols in the formula have the same meanings as defined above. Ring A represents a 5- or 6-membered heteroaryl.

[0092] Compound (5-1) can also be prepared by reducing compound (3-6).

[0093] Compound (5-2) can also be prepared by hydrolysis of compound (3-6).

[0094] The compound represented by formula (I-3) can also be produced by a heterocycle-forming reaction from compound (5-1) or compound (5-2). The heterocycle-forming reaction can be carried out by a known method or a method equivalent thereto. For example, the imidazole-forming reaction can be carried out using compound (5-1), glyoxal, and aqueous ammonia by a known method or a method equivalent thereto. For example, the oxazole-forming reaction can be carried out using compound (5-2), a propargylamine derivative, and a gold catalyst by a known method or a method equivalent thereto.

[0095] Compound (6-4) can be prepared, for example, according to the method described in Scheme 6.

[0096] The symbols in the formula have the same meanings as above. 3 and PG 4 represents a protecting group. u is an integer of 1 or 2.

[0097] Compound (6-2) can also be prepared by reacting compound (6-1) with compound (1-4) in the presence of a base.

[0098] Compound (6-3) can also be prepared by removing the acetal protecting group of compound (6-2).

[0099] Compound (6-4) is a PG of compound (6-3). 4 and then reductive amination.

[0100] The compound represented by compound (7-6) can be prepared, for example, according to the method described in Scheme 7.

[0101] The symbols in the formula have the same meanings as above. 5 and PG 6 indicates a protecting group.

[0102] Compound (7-2) can also be prepared by hydroboration of compound (7-1), followed by treatment with aqueous sodium hydroxide and aqueous hydrogen peroxide.

[0103] Compound (7-3) is a PG of compound (7-2).6 and reacting with compound (7-7) in the presence of a base.

[0104] Compound (7-4) can also be prepared by reacting compound (7-3) with a base.

[0105] Compound (7-5) can also be prepared by reacting compound (7-4) with compound (1-4) in the presence of a base.

[0106] Compound (7-6) can also be prepared by reducing the cyclic amide of compound (7-5).

[0107] The scheme shown above is an example of a method for producing a compound represented by formula (I) or a production intermediate thereof. The scheme can be modified in various ways that can be easily understood by those skilled in the art.

[0108] The compound represented by formula (I) and its production intermediates can also be isolated and purified, if necessary, by isolation and purification means well known to those skilled in the art, such as solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography, etc.

[0109] The compound of the present invention has excellent OX2R agonist activity and can therefore be used as a therapeutic agent for sleep disorders involving OX2R. In the present invention, examples of sleep disorders involving OX2R include narcolepsy, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to physical diseases (e.g., sleep apnea syndrome, periodic leg movements, Parkinson's disease, trauma, Niemann-Pick disease type C, Norrie disease, Prader-Willi syndrome, myotonic dystrophy, Moebius syndrome, fragile X syndrome, brain tumor, cerebral infarction, cerebral contusion, infection, hypothyroidism, hepatic encephalopathy, renal failure, adrenal insufficiency, pancreatic insufficiency, exposure to toxic substances, pediatric congenital metabolic disorders, progressive supranuclear palsy, hypoventilation syndrome, multiple sclerosis, Examples of hypersomnia include hypersomnia due to rheumatoid arthritis, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen's encephalitis, Wernicke's encephalitis, limbic encephalitis, Hashimoto's encephalopathy, dementia with Lewy bodies, Alzheimer's disease, migraine, headache, or neuropathic pain), hypersomnia due to psychiatric disorders (e.g., hypersomnia associated with depression, anxiety disorder, panic disorder, addiction, obsessive-compulsive disorder, eating disorder, bipolar disorder, epilepsy, schizophrenia, personality disorder, developmental disorder, or post-traumatic stress disorder), drug- or substance-induced hypersomnia, circadian rhythm sleep-wake disorder, insufficient sleep syndrome, and prolonged sleep. Preferably, the compound of the present invention can be used as a therapeutic agent for narcolepsy, idiopathic hypersomnia, Kleine-Levin syndrome, or sleep apnea syndrome. More preferably, the compound of the present invention can be used as a therapeutic agent for narcolepsy (see Patent Document 1).

[0110] In the present invention, "treatment" includes the meaning of "prevention."

[0111] In the present invention, the term "agonist" refers to a drug that activates the function of a target protein regardless of its binding site. For example, the term "agonist" includes the meanings of "allosteric agonist" and "positive allosteric modulator (PAM)."

[0112] While OX2R is involved in maintaining wakefulness, signaling via OX1R is thought to be involved in the formation of drug addiction through the reward system (see, for example, PLoS One, 2022, Vol. 27, No. 7, e0271901). In one embodiment, the compounds of the present invention have selective agonist activity against OX2R among orexin receptors. Agonist activity against OX1R can be measured by methods well known in the art or methods equivalent thereto (see, for example, Non-Patent Document 4).

[0113] The therapeutic effect of the compound of the present invention on sleep disorders involving OX2R can be confirmed by methods well known in the art. For example, a method for confirming the effect in an animal model of narcolepsy includes the method described in Neuron, 2001, Vol. 30, No. 2, pp. 345-354, or a method similar thereto.

[0114] The pharmaceutical composition of the present invention may be used in various dosage forms depending on the intended use, including, for example, powders, granules, fine granules, dry syrup, tablets, capsules, injections, liquids, ointments, suppositories, patches, eye drops, and enemas.

[0115] The pharmaceutical composition of the present invention comprises a compound represented by formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.

[0116] The pharmaceutical compositions of the present invention are prepared using the compound represented by formula (I) or a pharmacologically acceptable salt thereof and at least one pharmaceutical additive. These pharmaceutical compositions can also be prepared by appropriately mixing, diluting, or dissolving the compound with pharmaceutical additives such as suitable excipients, disintegrants, binders, lubricants, diluents, buffers, isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizers, according to the dosage form, using methods known in pharmaceutical science.

[0117] When the pharmaceutical composition of the present invention is used for treatment, the dosage of the compound represented by formula (I) or a pharmacologically acceptable salt thereof is determined appropriately depending on the patient's age, sex, weight, disease, and degree of treatment. The daily dosage may be administered once, twice, three times, or four times. When administered orally or parenterally, the dosage for an adult can be set, for example, in the range of 0.01 to 1000 mg / day. In one embodiment, the oral dosage can be set in the range of 0.01 to 500 mg / day, preferably 0.01 to 100 mg / day.

[0118] In one embodiment, the pharmaceutical composition of the present invention can be used in combination with drugs other than OX2R agonists. Examples of other drugs that can be used in combination to treat sleep disorders involving OX2R include drugs for treating narcolepsy (e.g., modafinil, methylphenidate, pemoline, amphetamine, sodium oxybate, pitolisant, solriamfetol, etc.), antidepressants (e.g., clomipramine, imipramine, paroxetine, fluvoxamine, milnacipran, etc.), caffeine, etc.

[0119] When the compound represented by formula (I) or its pharmacologically acceptable salt is used in combination with other drugs, these active ingredients can be administered as a preparation containing them together, or as a preparation in which each of these active ingredients is separately formulated. When formulated separately, these preparations can be administered separately or simultaneously. In addition, the dosage of the compound represented by formula (I) or its pharmacologically acceptable salt may be appropriately reduced depending on the dosage of the other drug used in combination.

[0120] The compound represented by formula (I) may be appropriately converted into a prodrug for use. For example, a prodrug of the compound represented by formula (I) can be produced by introducing a group constituting the prodrug using a corresponding halide or the like, followed by purification. Examples of the group constituting the prodrug include the groups described in "Development of Pharmaceuticals" (Hirokawa Shoten, 1990), Vol. 7, pp. 163-198.

[0121] The present invention will be explained in more detail below based on Reference Examples, Examples and Test Examples, but the present invention is not limited to the contents thereof.

[0122] The names of compounds described in the following examples, excluding commercially available reagents, were named using ChemDraw Professional (PerkinElmer), MarvinSketch (ChemAxon), etc. The configuration of an asymmetric center marked with "*" in the compound name means that it is the relative configuration.

[0123] Reference Example A-1 (cis-4-(chloromethoxy)cyclohexyl)benzene To a mixture of cis-4-phenylcyclohexanol (1.20 g) and DCM (12 mL), paraformaldehyde (0.225 g) and then chlorotrimethylsilane (2.22 g) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours and diluted with DCM (24 mL). Anhydrous sodium sulfate was added to the reaction mixture. The mixture was stirred at room temperature for 15 minutes and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.44 g).

[0124] Reference Example A-2 Reference Example A-2 was synthesized in the same manner as in Reference Example A-1, except that benzyl 4-hydroxypiperidine-1-carboxylate was used instead of cis-4-phenylcyclohexanol.

[0125] Reference Example A-3 6-(5-Fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-one A mixture of potassium tert-butoxide (0.788 g), trimethylsulfoxonium iodide (1.55 g), and DMSO (12 mL) was stirred at room temperature for 30 minutes. A mixture of 2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5-fluoropyrimidine (0.415 g) and DMSO (1.6 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred at 50°C for 2 hours and then at 70°C for 5 hours. Trimethylsulfoxonium iodide (1.55 g) and potassium tert-butoxide (0.788 g) were added to the reaction mixture at 70°C, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 30 / 70) to give 5-fluoro-2-(spiro[bicyclo[4.1.0]heptane-3,2'-[1,3]dioxolan]-6-yl)pyrimidine (0.200 g). A mixture of the obtained compound (0.200 g), 2 mol / L hydrochloric acid (5 mL), and THF (3 mL) was stirred at room temperature for 15 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.163 g).

[0126] Reference Example A-4 4-(5-Fluoropyrimidin-2-yl)cyclohexan-1-one A mixture of 2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5-fluoropyrimidine (0.109 g), methanol (3 mL), and 5% Pd / C (0.022 g) was stirred at room temperature under a hydrogen atmosphere for 45 minutes. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Methanol and DCM were added to the residue, and the mixture was passed through a short silica gel column and concentrated under reduced pressure. A mixture of the residue, 2 mol / L hydrochloric acid (0.542 mL), and THF (2 mL) was stirred at 50°C for 1.5 hours and allowed to cool to room temperature. A 2 mol / L aqueous sodium hydroxide solution (0.597 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.041 g).

[0127] Reference Example A-5 2-(3-(bromomethyl)phenyl)-5-fluoropyrimidine To a mixture of (3-(5-fluoropyrimidin-2-yl)phenyl)methanol (3.41 g), TEA (3.38 g), and ethyl acetate (50 mL) was added methanesulfonyl chloride (2.87 g) under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a mixture of the residue and ethyl acetate (80 mL), lithium bromide monohydrate (5.25 g) was added at room temperature, and the mixture was stirred at 60°C for 1 hour and allowed to cool to room temperature. The reaction mixture was added to water, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (4.08 g).

[0128] Reference Example A-6 2-(5-(bromomethyl)-2-fluorophenyl)-5-fluoropyrimidine A mixture of (2-fluoro-5-(hydroxymethyl)phenyl)boronic acid (3.07 g), 2-chloro-5-fluoropyrimidine (3.17 g), cesium carbonate (8.83 g), Pd(PPh3)4 (0.418 g), DMF (45 mL), and water (34 mL) was stirred at 100°C for 2 hours and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 50 / 50 to 20 / 80) to give (4-fluoro-3-(5-fluoropyrimidin-2-yl)phenyl)methanol (2.17 g). To a mixture of the obtained compound (2.17 g), TEA (1.98 g), and ethyl acetate (30 mL), methanesulfonyl chloride (1.68 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a mixture of the residue and ethyl acetate (30 mL), lithium bromide monohydrate (3.07 g) was added at room temperature, and the mixture was stirred at 60°C for 1 hour and allowed to cool to room temperature. The reaction mixture was added to water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (2.58 g).

[0129] Reference Example A-7 5-Bromo-2-(3-(bromomethyl)phenyl)pyrimidine To a mixture of (3-(5-bromopyrimidin-2-yl)phenyl)methanol (1.07 g), TEA (0.531 g), and ethyl acetate (30 mL) was added methanesulfonyl chloride (0.509 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered. To the filtrate was added lithium bromide monohydrate (1.27 g) at room temperature, and the mixture was stirred at 60°C for 1 hour and allowed to cool to room temperature. The reaction mixture was filtered. The filtrate was added to water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (1.13 g).

[0130] Reference Example A-8 2-(5-(bromomethyl)-2-methylphenyl)-5-fluoropyrimidine A mixture of (4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (0.308 g), 2-chloro-5-fluoropyrimidine (0.329 g), sodium carbonate (0.395 g), Pd(dppf)Cl DCM adduct (0.101 g), 1,4-dioxane (5 mL), ethanol (2.5 mL), and water (2.5 mL) was stirred at 90°C for 1 hour under microwave irradiation. The reaction mixture was added to saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 55 / 45) to give (3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)methanol (0.240 g). To a mixture of the obtained compound (0.215 g), TEA (0.199 g), and ethyl acetate (5 mL), methanesulfonyl chloride (0.169 g) was added under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a mixture of the residue and ethyl acetate (5 mL), lithium bromide monohydrate (0.310 g) was added at room temperature, and the mixture was stirred at 60 °C for 30 minutes and allowed to cool to room temperature. The reaction mixture was added to water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.232 g).

[0131] Reference Example A-9 Reference Example A-9 was synthesized in the same manner as in Reference Example A-8, except that (2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol was used instead of (4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol.

[0132] Reference Example B-1: (1R*,3S*)-3-Azido-1-(3-chlorobenzyl)cyclopentane-1-methyl carboxylate. Under an argon atmosphere, LDA (1.09 mol / L in THF / n-hexane) (16 mL) was added to a mixture of ethyl 3-cyclopentene-1-carboxylate (2.00 g) and THF (32 mL) at −78°C, and the mixture was stirred at the same temperature for 30 minutes. A mixture of 3-chlorobenzyl bromide (3.22 g) and THF (16 mL) was added to the reaction mixture at −78°C, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride and water were added to the reaction mixture under ice-cooling. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 95 / 5) to give ethyl 1-(3-chlorobenzyl)cyclopent-3-ene-1-carboxylate (3.50 g). A mixture of the obtained compound (3.50 g), 2 mol / L aqueous sodium hydroxide (33 mL), methanol (66 mL), and THF (33 mL) was stirred at 70 °C for 3.5 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid was added to the reaction mixture. The mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-(3-chlorobenzyl)cyclopent-3-ene-1-carboxylic acid (3.06 g). To a mixture of DMSO (1.31 g) and chloroform (25 mL), bromotrimethylsilane (2.57 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 2 hours. A mixture of 1-(3-chlorobenzyl)cyclopent-3-ene-1-carboxylic acid (3.06 g) and chloroform (18 mL) was added to the reaction mixture under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. DIPEA (2.17 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at 70°C for 2 hours and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to give (1S*,4R*,6S*)-6-bromo-4-(3-chlorobenzyl)-2-oxabicyclo[2.2.1]heptan-3-one (2.20 g). To a mixture of the obtained compound (2.20 g), 2,2'-azobisisobutyronitrile (0.115 g), and toluene (35 mL) was added tris(trimethylsilyl)silane (2.60 g) at room temperature. The mixture was stirred at 80 °C for 1 hour and allowed to cool to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5 to 80 / 20) to give (1R*,4R*)-4-(3-chlorobenzyl)-2-oxabicyclo[2.2.1]heptan-3-one (1.52 g). A mixture of the obtained compound (1.52 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (16 mL), and methanol (13 mL) was stirred at 70 °C for 1 hour. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 40 / 60) to give (1R*,3R*)-1-(3-chlorobenzyl)-3-hydroxycyclopentane-1-carboxylate (1.29 g). To a mixture of the obtained compound (1.29 g), TEA (0.968 g), and DCM (16 mL), methanesulfonyl chloride (0.822 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 50 minutes. The reaction mixture was added to water and extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue and DMSO (16 mL), sodium azide (0.933 g) was added at room temperature, and the mixture was stirred at 60°C for 30 minutes and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=98 / 2 to 90 / 10) to obtain the title compound (1.24 g).

[0133] Reference Examples B-2 to B-4 Reference Examples B-2 to B-4 were synthesized in the same manner as in Reference Example B-1, except that the compounds of the corresponding Reference Examples were used instead of 3-chlorobenzyl bromide.

[0134] Reference Example B-5: (1R*,3S*)-1-(3-chlorobenzyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate. Triphenylphosphine (1.34 g) was added to a mixture of Reference Example B-1 (1.00 g), methanol (8 mL), and water (0.123 mL) at room temperature. The mixture was stirred at the same temperature for 7 hours and concentrated under reduced pressure. Methanesulfonyl chloride (0.585 g) was added to a mixture of the residue, TEA (1.03 g), and DCM (8 mL) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 50 / 50) to obtain the title compound (1.00 g).

[0135] Reference Example B-6: Methyl (1S*,3S*)-3-(methylsulfonamido)-1-((((cis)-4-phenylcyclohexyl)oxy)methyl)cyclopentane-1-carboxylate. To a mixture of Reference Example B-2 (0.380 g), BocO (0.348 g), and ethyl acetate (5 mL) was added 10% Pd / C (0.076 g) under ice-cooling, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to give methyl (1S*,3S*)-3-((tert-butoxycarbonyl)amino)-1-((((cis)-4-phenylcyclohexyl)oxy)methyl)cyclopentane-1-carboxylate (0.340 g). A mixture of the obtained compound (0.230 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (2 mL) was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. To a mixture of the residue, TEA (0.162 g), and DCM (3 mL), methanesulfonyl chloride (0.092 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 60 / 40 to 40 / 60) to obtain the title compound (0.181 g).

[0136] Reference Examples B-7 to B-8 Reference Examples B-7 to B-8 were synthesized in the same manner as in Reference Example B-5, except that the compounds of the corresponding Reference Examples were used instead of Reference Example B-1.

[0137] Reference Examples B-9 to B-10 Reference Examples B-9 to B-10 were synthesized in the same manner as in Reference Example B-1, except that the corresponding reagents were used instead of 3-chlorobenzyl bromide.

[0138] Reference Example B-11: (1R*,3S*)-1-([1,1'-biphenyl]-3-ylmethyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate. A mixture of Reference Example B-5 (0.249 g), phenylboronic acid (0.176 g), tripotassium phosphate (0.458 g), Xphos Pd G3 (0.030 g), 1,2-dimethoxyethane (3 mL), and water (1.5 mL) was stirred at 80°C for 30 minutes under microwave irradiation. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 50 / 50) to obtain the title compound (0.280 g).

[0139] Reference Example B-12 (1R*,3S*)-1-([1,1'-biphenyl]-3-ylmethyl)-3-(methylsulfonamido)cyclopentane-1-carboxylic acid. A mixture of Reference Example B-11 (0.180 g), 4 mol / L aqueous lithium hydroxide solution (0.581 mL), methanol (0.8 mL), THF (0.8 mL), and water (0.2 mL) was stirred at 150°C for 15 minutes under microwave irradiation. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (0.173 g).

[0140] Reference Example B-13 N-((1S*,3R*)-3-([1,1'-biphenyl]-3-ylmethyl)-3-aminocyclopentyl)methanesulfonamide A mixture of Reference Example B-12 (0.096 g), diphenylphosphoryl azide (0.078 g), TEA (0.039 g), and 1,4-dioxane (2 mL) was stirred at 100°C for 1 hour and allowed to cool to room temperature. 2 mol / L hydrochloric acid (2 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 3 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 98 / 2) to obtain the title compound (0.074 g).

[0141] Reference Example B-14: (1R*,3S*)-1-([1,1'-biphenyl]-3-ylmethyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)cyclopentane-1-carboxylate. To a mixture of Reference Example B-11 (0.148 g), potassium carbonate (0.158 g), tetrabutylammonium iodide (0.028 g), and DMF (2 mL), 4-methoxybenzyl chloride (0.090 g) was added at room temperature. The mixture was stirred at 80°C for 1 hour and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 50 / 50) to obtain the title compound (0.190 g).

[0142] Reference Example B-15 Reference Example B-15 was synthesized in the same manner as in Reference Example B-12, except that Reference Example B-14 was used instead of Reference Example B-11.

[0143] Reference Example B-16 Reference Example B-16 was synthesized in the same manner as in Reference Example B-13, except that Reference Example B-15 was used instead of Reference Example B-12.

[0144] Reference Example B-17 ((1R*,3S*)-1-([1,1'-biphenyl]-3-ylmethyl)-3-(methylsulfonamido)cyclopentyl)carbamate Methyl chloroformate (0.012 g) was added to a mixture of Reference Example B-13 (0.006 g), DIPEA (0.030 g) and DCM (1 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 30 / 70 to 0 / 100) to obtain the title compound (0.006 g).

[0145] Reference Example C-1 Methyl (1S,4R)-4-((diphenylmethylene)amino)cyclopent-2-ene-1-carboxylate A mixture of methyl (1S,4R)-4-((tert-butoxycarbonyl)amino)cyclopent-2-ene-1-carboxylate (3.00 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (31 mL), and methanol (30 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. A mixture of the residue, diphenylmethanimine (2.20 g), and DCM (24 mL) was stirred at room temperature for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue, and the mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound (3.74 g).

[0146] Reference Example C-2: Methyl (1S,3S)-3-(methylsulfonamido)-1-(((triethylsilyl)oxy)methyl)cyclopentane-1-carboxylate. Under an argon atmosphere, to a mixture of Reference Example C-1 (1.00 g), ((chloromethoxy)methyl)benzene (0.615 g), and THF (15 mL) was added lithium bis(trimethylsilyl)amide (1.0 mol / L in THF) (6.6 mL) at −78° C., and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to give methyl (1R,4R)-1-((benzyloxy)methyl)-4-((diphenylmethylene)amino)cyclopent-2-ene-1-carboxylate (1.14 g). A mixture of the obtained compound (1.14 g), 2 mol / L hydrochloric acid (10 mL), and THF (10 mL) was stirred at room temperature for 30 minutes. 2 mol / L aqueous sodium hydroxide solution (11 mL) was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a mixture of the residue and DCM (10 mL), TEA (0.542 g) and methanesulfonyl chloride (0.460 g) were added under ice-cooling, and the mixture was stirred at room temperature for 5 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 40 / 60) to give methyl (1R,4R)-1-((benzyloxy)methyl)-4-(methylsulfonamido)cyclopent-2-ene-1-carboxylate (0.730 g). A mixture of the obtained compound (0.730 g), 10% Pd / C (0.350 g), and THF (10 mL) was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue, imidazole (0.167 g), and DCM (7 mL) was added chlorotriethylsilane (0.338 g) at room temperature, and the mixture was stirred at the same temperature for 30 minutes.Imidazole (0.167 g) and then chlorotriethylsilane (0.338 g) were added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 50 / 50) to obtain the title compound (0.689 g).

[0147] Reference Example D-1 (1r,4r)-4-Azido-1-(3-(5-fluoropyrimidin-2-yl)benzyl)cyclohexane-1-methyl carboxylate A mixture of methyl 4-hydroxycyclohexane-1-carboxylate (0.260 g), tert-butyldimethylchlorosilane (0.297 g), imidazole (0.135 g), and DMF (2 mL) was stirred at room temperature for 16 hours. The reaction mixture was added to water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20) to give methyl 4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carboxylate (0.249 g). Under an argon atmosphere, to a mixture of the obtained compound (0.206 g), Reference Example A-5 (0.196 g), and THF (3 mL) was added lithium bis(trimethylsilyl)amide (1.0 mol / L in THF) (0.881 mL) in an ice-salt bath, and the mixture was stirred at the same temperature for 1.5 hours. Saturated aqueous ammonium chloride solution, saturated brine, and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to give methyl (1s,4s)-4-((tert-butyldimethylsilyl)oxy)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)cyclohexane-1-carboxylate (0.241 g). A mixture of the obtained compound (0.241 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (2.6 mL), and methanol (5 mL) was stirred at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 25 / 75) to give methyl (1s,4s)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-hydroxycyclohexane-1-carboxylate (0.094 g).To a mixture of the obtained compound (0.078 g), TEA (0.115 g), and DCM (5 mL) was added methanesulfonyl chloride (0.065 g) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a mixture of the residue and DMSO (5 mL), sodium azide (0.181 g) was added at room temperature. The mixture was stirred at 70°C for 11 hours and allowed to cool to room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain the title compound (0.070 g).

[0148] Reference Example D-2 Reference Example D-2 was synthesized in the same manner as in Reference Example B-5, except that Reference Example D-1 was used instead of Reference Example B-1.

[0149] Reference Example D-3 (1r,4r)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-(methylsulfonamido)cyclohexane-1-carboxylic acid A mixture of Reference Example D-2 (0.045 g), 2 mol / L aqueous sodium hydroxide solution (0.267 mL), 1,4-dioxane (1.5 mL), and water (0.75 mL) was stirred at 100°C for 75 minutes under microwave irradiation. 2 mol / L aqueous sodium hydroxide solution (0.160 mL) was added to the reaction mixture, and the mixture was stirred at 100°C for 15 minutes under microwave irradiation. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.030 g).

[0150] Reference Example D-4 1-tert-butyl 2-methyl 5-hydroxypiperidine-1,2-dicarboxylate To a mixture of methyl 5-hydroxypicolinate (1.02 g), hydrogen chloride (5-10% in methanol) (0.301 mL), and ethanol (10 mL) was added 5% rhodium on carbon (0.198 g) at room temperature, and the mixture was stirred at the same temperature for 17.5 hours under hydrogen pressure (0.4 MPa). The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue, TEA (1.32 g), and THF (35 mL), BocO (1.73 g) was added at room temperature, and the mixture was stirred at the same temperature for 18 hours. The reaction mixture was added to water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to give the title compound (0.528 g).

[0151] Reference Example D-5 Reference Example D-5 was synthesized in the same manner as in Reference Example D-1, except that Reference Example D-4 was used instead of methyl 4-hydroxycyclohexane-1-carboxylate.

[0152] Reference Example D-6 Reference Example D-6 was synthesized in the same manner as in Reference Example B-5, except that Reference Example D-5 was used instead of Reference Example B-1.

[0153] Reference Example E-1: Methyl 4-((triisopropylsilyl)oxy)tetrahydrofuran-2-carboxylate. To a mixture of methyl 4-hydroxytetrahydrofuran-2-carboxylate (0.280 g), imidazole (0.261 g), and DCM (6 mL) was added triisopropylsilyl trifluoromethanesulfonate (0.646 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Imidazole (0.130 g) and then triisopropylsilyl trifluoromethanesulfonate (0.587 g) were added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 2 hours. Water and saturated aqueous sodium bicarbonate were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to obtain the title compound (0.373 g).

[0154] Reference Example E-2: Methyl (2S,4R)-2-([1,1'-biphenyl]-3-ylmethyl)-4-azidotetrahydrofuran-2-carboxylate. Under an argon atmosphere, to a mixture of Reference Example E-1 (0.370 g) and THF (6 mL) was added LDA (1.11 mol / L in THF / n-hexane) (1.3 mL) at −78°C, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a mixture of 1-(bromomethyl)-3-phenylbenzene (0.333 g) and THF (3 mL) at −78°C, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10) to give methyl (2S*,4S*)-2-([1,1'-biphenyl]-3-ylmethyl)-4-((triisopropylsilyl)oxy)tetrahydrofuran-2-carboxylate (0.194 g). To a mixture of the obtained compound (0.190 g) and THF (2 mL), tetrabutylammonium fluoride (1 mol / L in THF) (0.486 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give methyl (2S*,4S*)-2-([1,1'-biphenyl]-3-ylmethyl)-4-hydroxytetrahydrofuran-2-carboxylate (0.099 g). To a mixture of the obtained compound (0.097 g), TEA (0.063 g), and DCM (2 mL), methanesulfonyl chloride (0.053 g) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. Sodium azide (0.061 g) was added to a mixture of the residue and DMSO (2 mL) at room temperature, and the mixture was stirred at 60°C for 5 hours and allowed to cool to room temperature. Water and saturated brine were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=80 / 20 to 60 / 40) to obtain the title compound (0.085 g).

[0155] Reference Example E-3 Reference Example E-3 was synthesized in the same manner as in Reference Example E-2, except that Reference Example A-7 was used instead of 1-(bromomethyl)-3-phenylbenzene.

[0156] Reference Example E-4 (2S*,4R*)-2-([1,1'-biphenyl]-3-ylmethyl)-4-(methylsulfonamido)tetrahydrofuran-2-carboxylic acid To a mixture of Reference Example E-2 (0.067 g), ethanol (2 mL), and THF (2 mL), 10% Pd / C (0.013 g) was added under ice-cooling. The mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue, TEA (0.040 g), and DCM (2 mL), methanesulfonyl chloride (0.034 g) was added under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 20 / 80) to give methyl (2S*,4R*)-2-([1,1'-biphenyl]-3-ylmethyl)-4-(methylsulfonamido)tetrahydrofuran-2-carboxylate (0.065 g). A mixture of the obtained compound (0.075 g), 2 mol / L aqueous sodium hydroxide solution (0.481 mL), THF (0.5 mL), and ethanol (2 mL) was stirred at 90 °C for 2 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (0.069 g).

[0157] Reference Example E-5 Reference Example E-5 was synthesized in the same manner as in Reference Example E-4, except that Reference Example E-3 was used instead of Reference Example E-2.

[0158] Reference Example F-1 Reference Example F-1 was synthesized in the same manner as in Reference Example E-1, except that N-Boc-cis-4-hydroxy-L-proline methyl ester was used instead of methyl 4-hydroxytetrahydrofuran-2-carboxylate.

[0159] Reference Example F-2: 1-tert-butyl 2-methyl (2S,4R)-2-([1,1'-biphenyl]-3-ylmethyl)-4-azidopyrrolidine-1,2-dicarboxylate. Under an argon atmosphere, to a mixture of Reference Example F-1 (0.430 g) and THF (5 mL) was added LDA (1.08 mol / L in THF / n-hexane) (1.2 mL) at −78°C, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a mixture of 1-(bromomethyl)-3-phenylbenzene (0.291 g) and THF (2 mL) at −78°C, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5) to give 1-tert-butyl 2-methyl (2S,4S)-2-([1,1'-biphenyl]-3-ylmethyl)-4-((triisopropylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (0.446 g) as a mixture with the (2R,4S)-isomer. To a mixture of the obtained compound (0.340 g) and THF (6 mL), tetrabutylammonium fluoride (1 mol / L in THF) (0.719 mL) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 60 / 40 to 40 / 60) followed by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 50 / 50) to give 1-tert-butyl 2-methyl (2S,4S)-2-([1,1'-biphenyl]-3-ylmethyl)-4-hydroxypyrrolidine-1,2-dicarboxylate (0.179 g). To a mixture of the resulting compound (0.157 g), TEA (0.077 g), and DCM (2 mL), methanesulfonyl chloride (0.066 g) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue and DMSO (2 mL), sodium azide (0.074 g) was added at room temperature.The mixture was stirred at 60°C for 4 hours and at 100°C for 2.5 hours, and then allowed to cool to room temperature. Water and saturated brine were added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate and n-hexane (4 / 1). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to obtain the title compound (0.151 g).

[0160] Reference Examples F-3 to F-4 Reference Examples F-3 to F-4 were synthesized in the same manner as in Reference Example F-2, except that the compounds of the corresponding Reference Examples were used instead of 1-(bromomethyl)-3-phenylbenzene.

[0161] Reference Example F-5 (2S,4R)-2-([1,1'-biphenyl]-3-ylmethyl)-1-(tert-butoxycarbonyl)-4-(methylsulfonamido)pyrrolidine-2-carboxylic acid To a mixture of Reference Example F-2 (0.115 g), ethanol (1 mL), and THF (1 mL), 10% Pd / C (0.023 g) was added under ice-cooling. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue, TEA (0.053 g), and DCM (2 mL) was added methanesulfonyl chloride (0.045 g) under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 60 / 40 to 30 / 70) to give 1-tert-butyl 2-methyl (2S,4R)-2-([1,1'-biphenyl]-3-ylmethyl)-4-(methylsulfonamido)pyrrolidine-1,2-dicarboxylate (0.106 g). A mixture of the obtained compound (0.070 g), 2 mol / L aqueous sodium hydroxide solution (0.358 mL), and methanol (2 mL) was stirred at 60 °C for 90 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.071 g).

[0162] Reference Example F-6 (2S,4R)-2-(3-(5-bromopyrimidin-2-yl)benzyl)-1-(tert-butoxycarbonyl)-4-(methylsulfonamido)pyrrolidine-2-carboxylic acid To a mixture of Reference Example F-3 (0.382 g), methanol (10 mL), and water (0.027 mL), triphenylphosphine (0.290 g) was added at room temperature. The mixture was stirred at the same temperature for 13 hours and concentrated under reduced pressure. To a mixture of the residue, TEA (0.224 g), and DCM (10 mL), methanesulfonyl chloride (0.127 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to give 1-tert-butyl 2-methyl (2S,4R)-2-(3-(5-bromopyrimidin-2-yl)benzyl)-4-(methylsulfonamido)pyrrolidine-1,2-dicarboxylate (0.305 g). A mixture of the obtained compound (0.305 g), 4 mol / L aqueous lithium hydroxide solution (1.3 mL), methanol (2 mL), and THF (2 mL) was stirred at 150 °C for 15 minutes under microwave irradiation. The reaction mixture was added to 2 mol / L hydrochloric acid and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.280 g).

[0163] Reference Example F-7 (2S,4R)-1-(tert-butoxycarbonyl)-2-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-(methylsulfonamido)pyrrolidine-2-carboxylic acid A mixture of Reference Example F-4 (1.39 g), triphenylphosphine (1.20 g), methanol (28 mL), and water (0.110 mL) was stirred at room temperature for 10 hours and concentrated under reduced pressure. To a mixture of the residue, TEA (0.923 g), and DCM (28 mL), methanesulfonyl chloride (0.522 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added to water and extracted with DCM. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 30 / 70) to give 1-tert-butyl 2-methyl (2S,4R)-2-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-(methylsulfonamido)pyrrolidine-1,2-dicarboxylate (1.21 g). A mixture of the obtained compound (0.600 g), 2 mol / L aqueous sodium hydroxide solution (2.7 mL), and 2-propanol (6 mL) was stirred at 60 °C for 11 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (0.583 g).

[0164] Reference Example F-8 Reference Example F-8 was synthesized in the same manner as in Reference Example B-5, except that Reference Example F-4 was used instead of Reference Example B-1 and ethanesulfonyl chloride was used instead of methanesulfonyl chloride.

[0165] Reference Example F-9: 1-tert-butyl 2-methyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-5-oxopyrrolidine-1,2-dicarboxylate. A mixture of N-Boc-cis-4-hydroxy-L-proline methyl ester (3.00 g), imidazole (0.999 g), tert-butyldimethylsilyl chloride (2.21 g), and DMF (15 mL) was stirred at room temperature for 15 hours. The reaction mixture was added to water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 85 / 15) to give 1-tert-butyl 2-methyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (4.15 g). To a mixture of the resulting compound (4.15 g), sodium periodate (7.41 g), and ethyl acetate (20 mL), a mixture of ruthenium(III) chloride hydrate (0.520 g) and water (20 mL) was added at room temperature, and the mixture was stirred at the same temperature for 14 hours. 1 mol / L aqueous sodium thiosulfate solution and 2-propanol were added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 10 minutes and filtered through Celite. The filtrate was extracted with ethyl acetate, and the extract was washed with 1 mol / L aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 85 / 15) to give the title compound (2.49 g).

[0166] Reference Example F-10: 1-tert-butyl 2-methyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-5-methylenepyrrolidine-1,2-dicarboxylate. To a mixture of Reference Example F-9 (2.49 g), pyridine (1.06 g), and THF (6 mL) was added bis(cyclopentadienyl)dimethyltitanium (5% in toluene) (94 mL) at room temperature under an argon atmosphere. The mixture was stirred at 70°C for 9 hours and allowed to cool to room temperature. Diethyl ether was added to the reaction mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain the title compound (2.46 g).

[0167] Reference Example F-11: 1-tert-butyl 2-methyl (2S,4R,5S)-4-azido-2-(3-(5-fluoropyrimidin-2-yl)benzyl)-5-methylpyrrolidine-1,2-dicarboxylate. A mixture of Reference Example F-10 (2.46 g), 10% Pd / C (0.738 g), and methanol (5 mL) was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to give 1-tert-butyl 2-methyl (2S,4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-methylpyrrolidine-1,2-dicarboxylate (2.00 g). A mixture of the obtained compound (2.00 g), tetrabutylammonium fluoride (1 mol / L in THF) (8 mL), and THF (2 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 60 / 40) to give 1-tert-butyl 2-methyl (2S,4S,5S)-4-hydroxy-5-methylpyrrolidine-1,2-dicarboxylate (0.959 g). Methanesulfonyl chloride (0.635 g) was added to a mixture of the obtained compound (0.959 g), TEA (0.749 g), and DCM (10 mL) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into water and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue, sodium azide (0.721 g), and DMSO (10 mL) was stirred at 100°C for 3 hours under microwave irradiation. The reaction mixture was added to water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to give 1-tert-butyl 2-methyl (2S,4R,5S)-4-azido-5-methylpyrrolidine-1,2-dicarboxylate (0.677 g).Under an argon atmosphere, to a mixture of the resulting compound (0.230 g) and THF (4 mL) was added LDA (1.07 mol / L in THF / n-hexane) (0.907 mL) at -78°C, and the mixture was stirred at the same temperature for 25 minutes. To the reaction mixture was added a mixture of Reference Example A-5 (0.238 g) and THF (1 mL) at -78°C, and the mixture was stirred at the same temperature for 15 minutes, then at room temperature for 1.5 hours. Saturated aqueous ammonium chloride and water were added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 85 / 15) to obtain the title compound (0.070 g).

[0168] Reference Example F-12 (2S,4R,5S)-1-(tert-butoxycarbonyl)-2-(3-(5-fluoropyrimidin-2-yl)benzyl)-5-methyl-4-(methylsulfonamido)pyrrolidine-2-carboxylic acid Reference Example F-11 (0.070 g), triphenylphosphine (0.058 g), methanol (1 mL) and water (0.027 mL) were stirred at 100 ° C. for 4 hours under microwave irradiation and concentrated under reduced pressure. Methanesulfonyl chloride (0.025 g) was added to a mixture of the residue, TEA (0.030 g) and DCM (1 mL) under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. TEA (0.030 g) and methanesulfonyl chloride (0.025 g) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into water and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 60 / 40) to give 1-tert-butyl 2-methyl (2S,4R,5S)-2-(3-(5-fluoropyrimidin-2-yl)benzyl)-5-methyl-4-(methylsulfonamido)pyrrolidine-1,2-dicarboxylate (0.047 g). A mixture of the obtained compound (0.047 g), 2 mol / L aqueous sodium hydroxide solution (0.226 mL), and 2-propanol (0.750 mL) was stirred at 90 °C for 2 hours under microwave irradiation. 2 mol / L hydrochloric acid (0.249 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.041 g).

[0169] Reference Example G-1 1-tert-butyl 2-methyl (2S,4S,5S)-5-allyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate Under an argon atmosphere, to a mixture of Reference Example F-9 (4.75 g) and THF (40 mL) was added lithium triethylborohydride (1.0 mol / L in THF) (14 mL) at −78° C., and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added saturated aqueous sodium bicarbonate and 30% aqueous hydrogen peroxide at −78° C. The mixture was stirred at room temperature for 30 minutes and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20) to give 1-tert-butyl 2-methyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-5-hydroxypyrrolidine-1,2-dicarboxylate (4.65 g). A mixture of the obtained compound (4.65 g), acetic anhydride (1.64 g), TEA (1.88 g), DMAP (0.151 g), and DCM (20 mL) was stirred at room temperature for 1.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10) to give 1-tert-butyl 2-methyl (2S,4S)-5-acetoxy-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (3.58 g). Under an argon atmosphere, to a mixture of the obtained compound (3.58 g) and diethyl ether (35 mL), boron trifluoride diethyl ether complex (1.46 g) and allyltrimethylsilane (4.41 g) were added at -78 °C, and the mixture was stirred at the same temperature for 20 minutes and at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to give the title compound (2.42 g).

[0170] Reference Example G-2: 1-tert-butyl 2-methyl (2S,4S,5S)-5-(2-(1,3-dioxolan-2-yl)ethyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate. Under an argon atmosphere, to a mixture of Reference Example G-1 (2.99 g) and THF (45 mL) was added borane-THF complex (0.9 mol / L in THF) (17 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes and at room temperature for 40 minutes. To the reaction mixture were added 2 mol / L aqueous sodium hydroxide solution (19 mL) and 30% aqueous hydrogen peroxide (15 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 65 / 35) to give 1-tert-butyl 2-methyl (2S,4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylate (2.59 g). Under an argon atmosphere, to a mixture of the resulting compound (2.59 g) and DCM (30 mL), Dess-Martin periodinane (5.52 g), DCM (1 mL), and water (0.123 mL) were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Diethyl ether, saturated aqueous sodium bicarbonate, and 1 mol / L aqueous sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10) to give 1-tert-butyl 2-methyl (2S,4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-(3-oxopropyl)pyrrolidine-1,2-dicarboxylate (1.73 g). A mixture of the obtained compound (1.73 g), ethylene glycol (1.29 g), pyridinium p-toluenesulfonate (0.105 g), and toluene (40 mL) was stirred using a Dean-Stark apparatus at 105 °C for 2 hours and at 120 °C for 1 hour, and then allowed to cool to room temperature.To the reaction mixture was added 2 mol / L aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 80 / 20) to obtain the title compound (1.46 g).

[0171] Reference Example G-3: (1R,3S,7aS)-3-(3-Bromobenzyl)-1-(methylsulfonamido)hexahydro-1H-pyrrolidine-3-carboxylate. Under an argon atmosphere, to a mixture of Reference Example G-1 (1.00 g), 1-bromo-3-(bromomethyl)benzene (0.657 g), and THF (10 mL) was added lithium bis(trimethylsilyl)amide (1.0 mol / L in THF) (3 mL) at -20°C, and the mixture was stirred at the same temperature for 1 hour. Water and saturated aqueous ammonium chloride were added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to give 1-tert-butyl 2-methyl (2S,4S,5S)-5-allyl-2-(3-bromobenzyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (1.32 g). Under an argon atmosphere, to a mixture of the resulting compound (1.32 g) and THF (20 mL), borane-THF complex (0.9 mol / L in THF) (3.9 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 1 hour. To the reaction mixture, 2 mol / L aqueous sodium hydroxide solution (5.8 mL) and 35% aqueous hydrogen peroxide (1.4 mL) were added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 50 / 50) to give 1-tert-butyl 2-methyl (2S,4S,5S)-2-(3-bromobenzyl)-4-((tert-butyldimethylsilyl)oxy)-5-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylate (1.03 g). To a mixture of the obtained compound (1.03 g), TEA (0.533 g), and DCM (10 mL) was added methanesulfonyl chloride (0.241 g) at room temperature, and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was added to water, extracted with DCM, and the extract was concentrated under reduced pressure.To a mixture of the residue and DCM (10 mL), trifluoroacetic acid (6.01 g) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour and concentrated under reduced pressure. To a mixture of the residue and DCM (10 mL), DIPEA (0.681 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into water, extracted with DCM, and the extract was concentrated under reduced pressure. A mixture of the residue, hydrogen chloride (4 mol / L in 1,4-dioxane) (2.2 mL), and methanol (20 mL) was stirred at room temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give methyl (1S,3S,7aS)-3-(3-bromobenzyl)-1-hydroxyhexahydro-1H-pyrrolidine-3-carboxylate (0.440 g). To a mixture of the resulting compound (0.440 g), TEA (0.377 g), and DCM (4 mL) was added methanesulfonyl chloride (0.171 g) under ice-cooling under an argon atmosphere, and the mixture was stirred at room temperature for 15 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue, sodium azide (0.242 g), and DMSO (4 mL) was stirred at 80 °C for 3 hours and then allowed to cool to room temperature. The reaction mixture was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 20 / 80) to give methyl (1R,3S,7aS)-1-azido-3-(3-bromobenzyl)hexahydro-1H-pyrrolidine-3-carboxylate (0.305 g). A mixture of the resulting compound (0.250 g), triphenylphosphine (0.259 g), methanol (2 mL), and water (0.024 mL) was stirred at room temperature for 64 hours and then concentrated under reduced pressure. Methanesulfonyl chloride (0.113 g) was added to a mixture of the residue, TEA (0.133 g), and DCM (2 mL) under ice cooling, and the mixture was stirred at room temperature for 15 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM.The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 60 / 40 to 30 / 70) to obtain the title compound (0.220 g).

[0172] Reference Example G-4: (1S,3S,7aS)-1-((tert-butyldimethylsilyl)oxy)-3-(3-(5-fluoropyrimidin-2-yl)benzyl)hexahydro-1H-pyrrolidine-3-carboxylate. Under an argon atmosphere, to a mixture of Reference Example G-2 (0.540 g), Reference Example A-5 (0.345 g), and THF (10 mL) was added lithium bis(trimethylsilyl)amide (1.0 mol / L in THF) (2.4 mL) in an ice-salt bath, and the mixture was stirred at the same temperature for 20 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5 to 80 / 20) to give 1-tert-butyl 2-methyl (2S,4S,5S)-5-(2-(1,3-dioxolan-2-yl)ethyl)-4-((tert-butyldimethylsilyl)oxy)-2-(3-(5-fluoropyrimidin-2-yl)benzyl)pyrrolidine-1,2-dicarboxylate (0.659 g). To a mixture of the resulting compound (0.659 g) and DCM (5 mL), trifluoroacetic acid (3.49 g) was added under ice-cooling, and the mixture was stirred at room temperature for 13 hours and concentrated under reduced pressure. To a mixture of the residue and 1,2-dichloroethane (10 mL), sodium triacetoxyborohydride (0.433 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate solution under ice-cooling, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 40 / 60) to give the title compound (0.346 g).

[0173] Reference Example G-5: (1R,3S,7aS)-1-azido-3-(3-(5-fluoropyrimidin-2-yl)benzyl)hexahydro-1H-pyrrolidine-3-carboxylate. To a mixture of Reference Example G-4 (0.346 g) and methanol (5 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (3.6 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 40 / 60 to 0 / 100) to give methyl (1S,3S,7aS)-3-(3-(5-fluoropyrimidin-2-yl)benzyl)-1-hydroxyhexahydro-1H-pyrrolidine-3-carboxylate (0.218 g). To a mixture of the resulting compound (0.218 g), TEA (0.119 g), and DCM (3 mL), methanesulfonyl chloride (0.101 g) was added under ice cooling, and the mixture was stirred at room temperature for 25 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a mixture of the residue and DMSO (4 mL), sodium azide (0.115 g) was added at room temperature. The mixture was stirred at 100°C for 2 hours, at room temperature for 13 hours, and at 100°C for 2 hours, and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 75 / 25) to obtain the title compound (0.142 g).

[0174] Reference Example G-6 (1R,3S,7aS)-3-(3-(5-fluoropyrimidin-2-yl)benzyl)-1-(methylsulfonamido)hexahydro-1H-pyrrolidine-3-carboxylate A mixture of Reference Example G-5 (0.065 g), triphenylphosphine (0.065 g), methanol (1 mL), and water (0.006 mL) was stirred at room temperature for 12 hours and at 60 ° C. for 1 hour, allowed to cool to room temperature, and then concentrated under reduced pressure. Methanesulfonyl chloride (0.028 g) was added to a mixture of the residue, TEA (0.033 g), and DCM (1 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. TEA (0.033 g) and methanesulfonyl chloride (0.028 g) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added saturated aqueous sodium bicarbonate, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 60 / 40 to 30 / 70) to give the title compound (0.040 g).

[0175] Reference Example G-7: (1S,3S,7aS)-1-((tert-butyldimethylsilyl)oxy)-3-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)hexahydro-1H-pyrrolidine-3-carboxylate Methyl ester. Under an argon atmosphere, to a mixture of Reference Example G-1 (0.542 g) and THF (3 mL), borane-THF complex (0.9 mol / L in THF) (2.3 mL) was added under ice-cooling. The mixture was stirred at the same temperature for 10 minutes and then at room temperature for 1 hour. To the reaction mixture, 2 mol / L aqueous sodium hydroxide solution (3.4 mL) and 35% aqueous hydrogen peroxide (2.4 mL) were added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 20 / 80) to give 1-tert-butyl 2-methyl (2S,4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylate (0.461 g). To a mixture of the obtained compound (0.461 g), TEA (0.335 g), and DCM (3 mL), methanesulfonyl chloride (0.152 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. A mixture of the residue, trifluoroacetic acid (2.6 mL), and DCM (3 mL) was stirred at room temperature for 30 minutes and concentrated under reduced pressure. A mixture of the residue, DIPEA (0.713 g), and DCM (3 mL) was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give methyl (1S,3S,7aS)-1-((tert-butyldimethylsilyl)oxy)hexahydro-1H-pyrrolidine-3-carboxylate (0.300 g). To a mixture of the resulting compound (0.025 g) and THF (0.5 mL) was added sodium bis(trimethylsilyl)amide (1.0 mol / L in THF) (0.1 mL) at -78 °C. The mixture was stirred at the same temperature for 30 minutes.To the reaction mixture was added a mixture of Reference Example A-6 (0.025 g) and THF (0.5 mL) at -78°C. The mixture was stirred at the same temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 80 / 20) to obtain the title compound (0.012 g).

[0176] Reference Examples G-8 to G-9 Reference Examples G-8 to G-9 were synthesized in the same manner as in Reference Example G-4, except that the compounds of the corresponding Reference Examples were used instead of Reference Example A-5.

[0177] Reference Examples G-10 to G-12 Reference Examples G-10 to G-12 were synthesized in the same manner as in Reference Example G-5, except that the compounds of the corresponding Reference Examples were used instead of Reference Example G-4.

[0178] Reference Examples G-13 to G-15 Reference Examples G-13 to G-15 were synthesized in the same manner as in Reference Example G-6, except that the compounds of the corresponding Reference Examples were used instead of Reference Example G-5.

[0179] Reference Example G-16 (1R,3S,7aS)-1-((tert-butoxycarbonyl)amino)-3-(3-(5-fluoropyrimidin-2-yl)benzyl)hexahydro-1H-pyrrolidine-3-carboxylate A mixture of Reference Example G-5 (2.74 g), triphenylphosphine (2.72 g), methanol (100 mL), and water (0.249 mL) was stirred at room temperature for 58 hours. The reaction mixture (70 mL) was concentrated under reduced pressure. A mixture of the residue, BocO (1.51 g), and DCM (70 mL) was stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate=100 / 0 to 80 / 20) to obtain the title compound (2.00 g).

[0180] Reference Example G-17 (1R,3S,7aS)-1-((tert-butoxycarbonyl)amino)-3-(3-(5-fluoropyrimidin-2-yl)benzyl)hexahydro-1H-pyrrolidine-3-carboxylic acid A mixture of Reference Example G-16 (0.080 g), 2 mol / L aqueous sodium hydroxide solution (0.425 mL), 1,4-dioxane (3 mL), and water (1.4 mL) was stirred at 100°C for 20 minutes under microwave irradiation. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (0.086 g).

[0181] Reference Example G-18 ((1R,3S,7aS)-3-(dimethylcarbamoyl)-3-(3-(5-fluoropyrimidin-2-yl)benzyl)hexahydro-1H-pyrrolidin-1-yl)carbamate tert-Butyl Reference Example G-17 (0.022 g), dimethylamine hydrochloride (0.039 g), DIPEA (0.093 g), and DMF (2 mL) were mixed and stirred at room temperature for 30 minutes. The reaction mixture was added to water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 50 / 50 to 20 / 80) to give the title compound (0.015 g).

[0182] Reference Example H-1 Methyl 3-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-indene-1-carboxylate A mixture of 3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid (1.00 g), concentrated sulfuric acid (0.046 g), and methanol (2 mL) was stirred under reflux for 2 hours and allowed to cool to room temperature. The reaction mixture was added to saturated aqueous sodium bicarbonate and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to give methyl 3-oxo-2,3-dihydro-1H-indene-1-carboxylate (1.01 g). To a mixture of the obtained compound (0.961 g) and methanol (24 mL), sodium borohydride (0.201 g) was added at room temperature, and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was added to 2 mol / L hydrochloric acid and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue, tert-butyldimethylchlorosilane (1.09 g), imidazole (0.494 g), THF (14 mL), and DMF (7 mL) was stirred at room temperature for 14 hours. Ethyl acetate and saturated brine were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to obtain the title compound (1.28 g).

[0183] Reference Example H-2: Methyl (1R*,3S*)-3-((tert-butyldimethylsilyl)oxy)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-2,3-dihydro-1H-indene-1-carboxylate. Under an argon atmosphere, to a mixture of Reference Example H-1 (1.16 g), Reference Example A-5 (1.11 g), and THF (37 mL) was added lithium bis(trimethylsilyl)amide (1.0 mol / L in THF) (4.5 mL) at -78°C, and the mixture was stirred at the same temperature for 30 minutes. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to give the title compound (2.24 g).

[0184] Reference Example H-3: (1R*,3R*)-3-azido-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-2,3-dihydro-1H-indene-1-carboxylate. A mixture of Reference Example H-2 (1.86 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (9.4 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to give (1R*,3S*)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-3-hydroxy-2,3-dihydro-1H-indene-1-carboxylate (1.13 g). To a mixture of the obtained compound (0.400 g), TEA (0.214 g), and DCM (10 mL), methanesulfonyl chloride (0.182 g) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue, sodium azide (0.206 g), and DMSO (10 mL) was stirred at 100°C under microwave irradiation for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 75 / 25) to give the title compound (0.285 g).

[0185] Reference Example H-4: Methyl (1S,3S,8aS)-1-((tert-butyldimethylsilyl)oxy)-3-(3-(5-fluoropyrimidin-2-yl)benzyl)octahydroindolizine-3-carboxylate. Under an argon atmosphere, to a mixture of Reference Example G-1 (2.99 g) and THF (45 mL) was added borane-THF complex (0.9 mol / L in THF) (17 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes and at room temperature for 40 minutes. To the reaction mixture were added 2 mol / L aqueous sodium hydroxide solution (19 mL) and 30% aqueous hydrogen peroxide (15 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 65 / 35) to give 1-tert-butyl 2-methyl (2S,4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylate (2.59 g). Under an argon atmosphere, to a mixture of the resulting compound (2.59 g) and DCM (30 mL), Dess-Martin periodinane (5.52 g), DCM (1 mL), and water (0.123 mL) were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Diethyl ether, saturated aqueous sodium bicarbonate, and 1 mol / L aqueous sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10) to give 1-tert-butyl 2-methyl (2S,4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-(3-oxopropyl)pyrrolidine-1,2-dicarboxylate (1.73 g). To a mixture of (methoxymethyl)triphenylphosphonium chloride (0.238 g) and THF (1 mL), potassium tert-butoxide (0.058 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 1 minute.To the reaction mixture was added a mixture of 1-tert-butyl 2-methyl (2S,4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-(3-oxopropyl)pyrrolidine-1,2-dicarboxylate (0.144 g) and THF (1 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hours and then at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to give 1-tert-butyl 2-methyl (2S,4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-(4-methoxybut-3-en-1-yl)pyrrolidine-1,2-dicarboxylate (0.093 g). To a mixture of the obtained compound (0.093 g), Reference Example A-5 (0.062 g), and THF (1.5 mL), lithium bis(trimethylsilyl)amide (1.0 mol / L in THF) (0.420 mL) was added in an ice-salt bath, and the mixture was stirred at the same temperature for 15 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to give 1-tert-butyl 2-methyl (2S,4S,5S)-4-((tert-butyldimethylsilyl)oxy)-2-(3-(5-fluoropyrimidin-2-yl)benzyl)-5-(4-methoxybut-3-en-1-yl)pyrrolidine-1,2-dicarboxylate (0.056 g). To a mixture of the obtained compound (0.056 g) and DCM (1 mL), trifluoroacetic acid (0.303 g) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. To a mixture of the residue and 1,2-dichloroethane (1 mL), sodium triacetoxyborohydride (0.038 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 35 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=100 / 0 to 80 / 20) to obtain the title compound (0.018 g).

[0186] Reference Example H-5: (6S,8S,8aS)-6-(3-Bromobenzyl)-8-((tert-butyldimethylsilyl)oxy)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylate. Under an argon atmosphere, to a mixture of Reference Example F-10 (1.10 g) and THF (30 mL) was added borane-THF complex (0.9 mol / L in THF) (4.9 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 30 minutes. To the reaction mixture were added 2 mol / L aqueous sodium hydroxide solution (7.4 mL) and 35% aqueous hydrogen peroxide (5.2 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to give 1-tert-butyl 2-methyl (2S,4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (0.806 g). A mixture of the obtained compound (0.600 g), trifluoroacetic acid (3 mL), and DCM (5 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. To a mixture of the residue, 2 mol / L aqueous sodium hydroxide solution (3.1 mL), and DCM (5 mL) was added chloroacetyl chloride (0.261 g) at room temperature, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to give methyl (2S,4S,5S)-4-((tert-butyldimethylsilyl)oxy)-1-(2-chloroacetyl)-5-(hydroxymethyl)pyrrolidine-2-carboxylate (0.461 g). To a mixture of the obtained compound (0.461 g) and tert-butanol (5 mL), potassium tert-butoxide (1 mol / L in THF) (1.5 mL) was added at room temperature, and the mixture was stirred at the same temperature for 15 minutes. Water and 2 mol / L hydrochloric acid were added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.To a mixture of the residue and methanol (10 mL), trimethylsilyldiazomethane (0.6 mol / L in n-hexane) (15 mL) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 50 / 50) to give methyl (6S,8S,8aS)-8-((tert-butyldimethylsilyl)oxy)-4-oxohexahydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylate (0.179 g). To a mixture of the resulting compound (0.176 g), 1-bromo-3-(bromomethyl)benzene (0.134 g), and THF (5 mL) was added lithium bis(trimethylsilyl)amide (1.0 mol / L in THF) (0.534 mL) at -78 °C, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 30 minutes. Saturated aqueous ammonium chloride and water were added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to give methyl (6S,8S,8aS)-6-(3-bromobenzyl)-8-((tert-butyldimethylsilyl)oxy)-4-oxohexahydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylate (0.070 g). To a mixture of methyl (6S,8S,8aS)-6-(3-bromobenzyl)-8-((tert-butyldimethylsilyl)oxy)-4-oxohexahydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylate (0.300 g) and THF (6 mL) was added borane-THF complex (0.93 mol / L in THF) (6.5 mL) at 60°C. The mixture was stirred at the same temperature for 40 minutes and allowed to cool to room temperature. Saturated aqueous ammonium chloride and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.262 g).

[0187] Reference Example H-6 Reference Example H-6 was synthesized in the same manner as in Reference Example G-5, except that Reference Example H-4 was used instead of Reference Example G-4.

[0188] Reference Example H-7: (6S,8R,8aR)-8-Azido-6-(3-bromobenzyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylate. To a mixture of Reference Example H-5 (0.262 g) and methanol (6 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (4.1 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give (6S,8S,8aS)-6-(3-bromobenzyl)-8-hydroxyhexahydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylate (0.200 g). To a mixture of (6S,8S,8aS)-6-(3-bromobenzyl)-8-hydroxyhexahydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylate (0.285 g), TEA (0.467 g), and DCM (15 mL) was added methanesulfonyl chloride (0.265 g) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. Saturated aqueous sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. A mixture of the residue, sodium azide (0.152 g), and DMSO (25 mL) was stirred at 100°C for 40 minutes. Sodium azide (0.149 g) was added to the reaction mixture, and the mixture was stirred at 100°C for 25 minutes. Sodium azide (0.149 g) was added to the reaction mixture, and the mixture was stirred at 100°C for 35 minutes and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100) to give the title compound (0.152 g).

[0189] Reference Examples H-8 to H-9 Reference Examples H-8 to H-9 were synthesized in the same manner as in Reference Example B-5, except that the compounds of the corresponding Reference Examples were used instead of Reference Example B-1.

[0190] The structural formulas of the reference examples are shown in the table below.

[0191] The stereochemistry notations in the table for Reference Examples B-1 to B-17, Reference Examples D-5 to D-6, Reference Examples E-2 to E-5, Reference Examples H-2 to H-3 and Reference Examples H-8 indicate the relative configuration.

[0192] Example 1 (1R*,3S*)-N-Methoxy-N-methyl-3-(methylsulfonamido)-1-(3-(prop-1-en-2-yl)benzyl)cyclopentane-1-carboxamide To a mixture of Reference Example B-5 (1.29 g) and methanol (15 mL), 2 mol / L aqueous sodium hydroxide solution (10 mL) was added at room temperature, and the mixture was stirred at 60°C for 2 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. HATU (1.56 g) was added to a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (1.45 g), DIPEA (2.41 g), and DMF (19 mL) at room temperature. The mixture was stirred at 70°C for 2 hours and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give (1R*,3S*)-1-(3-chlorobenzyl)-N-methoxy-N-methyl-3-(methylsulfonamido)cyclopentane-1-carboxamide (0.98 g). A mixture of the obtained compound (0.023 g), isopropenylboronic acid pinacol ester (0.021 g), Pd(Amphos)2Cl2 (4.4 mg), sodium carbonate (0.020 g), toluene (1 mL), and water (0.5 mL) was stirred at 110 °C for 1.5 hours under microwave irradiation. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. A mixture of the residue, isopropenylboronic acid pinacol ester (0.021 g), Pd(Amphos)Cl (4.4 mg), sodium carbonate (0.020 g), toluene (1 mL), and water (0.5 mL) was stirred under microwave irradiation at 110° C. for 1.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=60 / 40 to 0 / 100) and then APS column chromatography (eluent: n-hexane / ethyl acetate=60 / 40 to 0 / 100) to obtain the title compound (0.019 g).

[0193] Example 2 (1S*,3S*)-N-methoxy-N-methyl-3-(methylsulfonamido)-1-(((cis-4-phenylcyclohexyl)oxy)methyl)cyclopentane-1-carboxamide A mixture of Reference Example B-6 (0.180 g), 2 mol / L aqueous sodium hydroxide solution (1.1 mL), and methanol (3.0 mL) was stirred at 60°C for 19 hours and allowed to cool to room temperature. To the reaction mixture was added 2 mol / L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A mixture of the residue (0.020 g), N,O-dimethylhydroxylamine hydrochloride (0.025 g), DIPEA (0.033 g), 1-hydroxybenzotriazole (0.012 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.015 g), and DMF (0.5 mL) was stirred at 70 °C for 5 hours and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give the title compound (0.006 g).

[0194] Example 3 (1R*,3S*)-N-Methoxy-N-methyl-3-(methylsulfonamido)-1-(naphthalen-1-ylmethyl)cyclopentane-1-carboxamide To a mixture of Reference Example B-7 (0.038 g) and methanol (1.1 mL), 2 mol / L aqueous sodium hydroxide solution (0.523 mL) was added at room temperature, and the mixture was stirred at 60°C for 3 hours. 2 mol / L aqueous sodium hydroxide solution (0.523 mL) was added to the reaction mixture at 60°C, and the mixture was stirred at 70°C for 1.5 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (0.029 g), DIPEA (0.048 g), and DMF (1 mL) was added HATU (0.031 g) at room temperature. The mixture was stirred at 70°C for 2 hours and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give the title compound (0.024 g).

[0195] Example 4 (1S*,3S*)-1-(((1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)oxy)methyl)-N-methoxy-N-methyl-3-(methylsulfonamido)cyclopentane-1-carboxamide To a mixture of Reference Example B-8 (0.045 g) and methanol (1.0 mL), 2 mol / L aqueous sodium hydroxide solution (0.858 mL) was added at room temperature, and the mixture was stirred at 60° C. for 1 hour and allowed to cool to room temperature. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. HATU (0.036 g) was added to a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (0.033 g), DIPEA (0.055 g), and DMF (1 mL) at room temperature. The mixture was stirred at 70°C for 2 hours and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give benzyl 4-(((1S*,3S*)-1-(methoxy(methyl)carbamoyl)-3-(methylsulfonamido)cyclopentyl)methoxy)piperidine-1-carboxylate (0.037 g). A mixture of the obtained compound (0.037 g), methanol (1.0 mL), THF (1.0 mL), and 10% Pd / C (0.011 g) was stirred at room temperature under a hydrogen atmosphere for 8 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. A mixture of the residue, 2-chloro-5-fluoropyrimidine (0.007 g), DIPEA (0.015 g), and acetonitrile (0.5 mL) was stirred at 90°C under an argon atmosphere for 1 hour and then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 60 / 40 to 0 / 100) to give the title compound (0.006 g).

[0196] Example 5 (1S,3S)-1-(((6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-N-methoxy-N-methyl-3-(methylsulfonamido)cyclopentane-1-carboxamide To a mixture of Reference Example C-2 (0.050 g), Reference Example A-3 (0.034 g), triethylsilane (0.032 g), and acetonitrile (0.8 mL) was added trimethylsilyl trifluoromethanesulfonate (0.036 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added trimethylsilyl trifluoromethanesulfonate (0.036 g) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 30 / 70) to give methyl (1S,3S)-1-(((6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-yl)oxy)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate (0.049 g). A mixture of the obtained compound (0.049 g), 6 mol / L hydrochloric acid (1 mL), and 1,4-dioxane (1 mL) was stirred at 100 °C for 1 hour and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. HATU (0.046 g) was added to a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (0.032 g), DIPEA (0.072 g), and DMF (1 mL) at room temperature. The mixture was stirred at 70°C for 15 minutes and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by chiral preparative column chromatography (elution solvent: n-hexane / ethanol = 85 / 15) to give the title compound (0.014 g).

[0197] Example 6 Example 6 was synthesized in the same manner as in Example 5, except that Reference Example A-4 was used instead of Reference Example A-3.

[0198] Example 7 (1S*,3S*)-N-Methoxy-N-methyl-3-(methylsulfonamido)-1-((6-phenylpyridin-2-yl)methyl)cyclopentane-1-carboxamide To a mixture of Reference Example B-9 (0.010 g), methanol (0.5 mL), and water (0.001 mL), triphenylphosphine (0.013 g) was added at room temperature. The mixture was stirred at the same temperature for 14.5 hours and concentrated under reduced pressure. To a mixture of the residue, TEA (0.006 g), and DCM (1 mL), methanesulfonyl chloride (0.006 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to water and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give methyl (1S*,3S*)-1-((6-chloropyridin-2-yl)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate (0.009 g). A mixture of the obtained compound (0.009 g), phenylboronic acid (0.006 g), potassium phosphate tribasic (0.016 g), Xphos Pd G3 (2.1 mg), 1,2-dimethoxyethane (0.25 mL), and water (0.25 mL) was stirred at 80 °C for 1 hour under microwave irradiation. The reaction mixture was added to saturated aqueous ammonium chloride and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give (1S*,3S*)-3-(methylsulfonamido)-1-((6-phenylpyridin-2-yl)methyl)cyclopentane-1-carboxylate (0.007 g). A mixture of the obtained compound (0.007 g), 4 mol / L aqueous lithium hydroxide solution (0.023 mL), methanol (0.25 mL), and THF (0.25 mL) was stirred at 150 °C for 20 minutes under microwave irradiation. The reaction mixture was added to 2 mol / L hydrochloric acid and washed with ethyl acetate.The aqueous layer was concentrated under reduced pressure, and the residue was purified by ODS column chromatography (eluent: water / MeCN = 90 / 10 to 10 / 90) to give (1S*,3S*)-3-(methylsulfonamido)-1-((6-phenylpyridin-2-yl)methyl)cyclopentane-1-carboxylic acid (3.0 mg). HATU (3.4 mg) was added to a mixture of the obtained compound (3.0 mg), N,O-dimethylhydroxylamine hydrochloride (1.6 mg), DIPEA (0.005 g), and DMF (0.5 mL) at room temperature. The mixture was stirred at 70°C for 1.5 hours and allowed to cool to room temperature. The reaction mixture was poured into water and extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give the title compound (1.6 mg).

[0199] Example 8 (1R*,3S*)-N-Methoxy-N-methyl-3-(methylsulfonamido)-1-((5-(pyrimidin-2-yl)thiophen-3-yl)methyl)cyclopentane-1-carboxamide To a mixture of Reference Example B-10 (0.020 g), methanol (1 mL), and water (0.002 mL), triphenylphosphine (0.026 g) was added at room temperature. The mixture was stirred at the same temperature for 14 hours and concentrated under reduced pressure. To a mixture of the residue, TEA (0.014 g), and DCM (1 mL), methanesulfonyl chloride (0.012 g) was added under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was added to a saturated aqueous solution of sodium bicarbonate and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 60 / 40) to give methyl (1R*,3S*)-1-((5-chlorothiophen-3-yl)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate (0.019 g). A mixture of the obtained compound (0.019 g), 4 mol / L aqueous lithium hydroxide solution (0.067 mL), methanol (0.25 mL), and THF (0.25 mL) was stirred at 150 °C for 20 minutes under microwave irradiation. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. HATU (0.020 g) was added to a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (0.009 g), DIPEA (0.030 g), and DMF (0.5 mL) at room temperature. The mixture was stirred at 70°C for 1.5 hours and allowed to cool to room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give (1R*,3S*)-1-((5-chlorothiophen-3-yl)methyl)-N-methoxy-N-methyl-3-(methylsulfonamido)cyclopentane-1-carboxamide (0.014 g).A mixture of the obtained compound (0.014 g), bis(pinacolato)diboron (0.027 g), potassium carbonate (0.015 g), Pd2(dba)3 (3.3 mg), Xphos (3.4 mg), and 1,4-dioxane (0.5 mL) was stirred at 110 °C for 1 hour under microwave irradiation. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give (1R*,3S*)-N-methoxy-N-methyl-3-(methylsulfonamido)-1-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl)methyl)cyclopentane-1-carboxamide (0.008 g). A mixture of the obtained compound (0.008 g), 2-bromopyrimidine (0.005 g), sodium carbonate (0.005 g), Pd(dppf)Cl DCM adduct (1.3 mg), 1,4-dioxane (0.25 mL), ethanol (0.125 mL), and water (0.125 mL) was stirred at 90 °C for 1 hour under microwave irradiation. The reaction mixture was added to saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to obtain the title compound (1.6 mg).

[0200] Example 9 N-((1S*,3R*)-3-([1,1'-biphenyl]-3-ylmethyl)-3-(5-methyloxazol-2-yl)cyclopentyl)methanesulfonamide To a mixture of Reference Example B-12 (0.024 g) and DCM (1 mL), oxalyl chloride (0.015 g) and DMF (4.7 mg) were added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, propargylamine (0.036 g) and then DIPEA (0.074 g) were added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added to water and extracted with DCM. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give (1R*,3S*)-1-([1,1'-biphenyl]-3-ylmethyl)-3-(methylsulfonamido)-N-(prop-2-yn-1-yl)cyclopentane-1-carboxamide (0.025 g). Tetrachloroauric acid tetrahydrate (0.005 g) was added to a mixture of the obtained compound (0.025 g) and DCM (2 mL) at room temperature. The mixture was stirred at the same temperature for 3 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 0 / 100) and then APS column chromatography (eluent: n-hexane / ethyl acetate = 30 / 70 to 0 / 100) to give the title compound (0.008 g).

[0201] Example 10 N-((1S*,3R*)-3-([1,1'-biphenyl]-3-ylmethyl)-3-(3-methoxypyridin-2-yl)cyclopentyl)methanesulfonamide To a mixture of Reference Example B-11 (0.394 g), potassium carbonate (0.422 g), tetrabutylammonium iodide (0.075 g), and DMF (2 mL), 4-methoxybenzyl chloride (0.239 g) was added at room temperature. The mixture was stirred at 80°C for 1 hour and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Lithium aluminum hydride (0.077 g) was added to a mixture of the residue and THF (2 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Sodium sulfate decahydrate was added to the reaction mixture at room temperature. The mixture was stirred at the same temperature for 15 minutes, then filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give N-((1S*,3R*)-3-([1,1'-biphenyl]-3-ylmethyl)-3-(hydroxymethyl)cyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide (0.384 g). To a mixture of the obtained compound (0.360 g) and DCM (4 mL), Dess-Martin periodinane (0.382 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, 1 mol / L aqueous sodium thiosulfate solution and DCM were added under ice-cooling, and the mixture was stirred at room temperature for 14 hours. Saturated aqueous sodium bicarbonate solution was added to the mixture, and the mixture was stirred at room temperature for 30 minutes and filtered through Celite. The filtrate was extracted with DCM, and the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to give N-((1S*,3R*)-3-([1,1'-biphenyl]-3-ylmethyl)-3-formylcyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide (0.285 g). 1,2-Dibromoethane (0.480 g) was added to a mixture of magnesium (0.407 g) and THF (7 mL).The mixture was heated to an internal temperature of 63°C with stirring and then allowed to cool to an internal temperature of 40°C. Mercury(II) chloride (0.025 g) was added to the reaction mixture at an internal temperature of 40°C, and the mixture was stirred at room temperature for 30 minutes. A mixture of chloro(methoxy)methane (1.31 g) and toluene (5 mL) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred at the same temperature for 1 hour. A mixture of N-((1S*,3R*)-3-([1,1'-biphenyl]-3-ylmethyl)-3-formylcyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide (0.183 g) and THF (5 mL) was added to the reaction mixture at -23°C, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a mixture of the residue and DCM (5 mL) was added Dess-Martin periodinane (0.195 g) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 1 mol / L aqueous sodium thiosulfate solution under ice-cooling. The mixture was stirred at room temperature for 30 minutes and then extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 50 / 50) to give N-((1S*,3R*)-3-([1,1'-biphenyl]-3-ylmethyl)-3-(2-methoxyacetyl)cyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide (0.172 g). A mixture of the obtained compound (0.020 g), propargylamine (0.043 g), sodium tetrachloroaurate(III) dihydrate (0.008 g), and ethanol (2 mL) was stirred at 180°C for 30 minutes under microwave irradiation. Propargylamine (0.043 g) was added to the reaction mixture, and the mixture was stirred at 180°C for 3 hours under microwave irradiation. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to give N-((1S*,3R*)-3-([1,1'-biphenyl]-3-ylmethyl)-3-(3-methoxypyridin-2-yl)cyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide (0.006 g). A mixture of the obtained compound (0.006 g), trifluoroacetic acid (1 mL), and triethylsilane (0.007 g) was stirred at 70 °C for 1 hour and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 60 / 40 to 0 / 100) to give the title compound (0.003 g).

[0202] Example 11 N-((1S*,3R*)-3-(1-ethyl-1H-imidazol-2-yl)-3-(3-(pyrimidin-2-yl)benzyl)cyclopentyl)methanesulfonamide To a mixture of Reference Example B-5 (0.188 g), potassium carbonate (0.225 g), tetrabutylammonium iodide (0.040 g), and DMF (2 mL), 4-methoxybenzyl chloride (0.128 g) was added at room temperature. The mixture was stirred at 80°C for 1 hour and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 50 / 50) to give methyl (1R*,3S*)-1-(3-chlorobenzyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)cyclopentane-1-carboxylate (0.223 g). To a mixture of the resulting compound (0.055 g) and THF (2 mL), lithium aluminum hydride (0.009 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Sodium sulfate decahydrate was added to the reaction mixture under ice-cooling. The mixture was stirred at the same temperature for 30 minutes, then filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue and DCM (2 mL), Dess-Martin periodinane (0.055 g) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 1 mol / L aqueous sodium thiosulfate solution was added to the reaction mixture under ice-cooling. The mixture was stirred at room temperature for 30 minutes and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A mixture of the residue, glyoxal (8.8 mol / L aqueous solution) (0.027 mL), methanol (1 mL), and 28% aqueous ammonia (1 mL) was stirred at room temperature for 13 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Sodium hydride (approximately 60% in mineral oil) (0.014 g) was added to a mixture of the residue and THF (2 mL) at room temperature, and the mixture was stirred at the same temperature for 15 minutes.To the reaction mixture, bromoethane (0.090 g) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous ammonium chloride and water were added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 70 / 30) to give N-((1S*,3R*)-3-(3-chlorobenzyl)-3-(1-ethyl-1H-imidazol-2-yl)cyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide (0.027 g). A mixture of the resulting compound (0.015 g), bis(pinacolato)diboron (0.023 g), potassium acetate (0.009 g), Pd(dppf)Cl (2.0 mg), Xphos (3.0 mg), and 1,4-dioxane (2 mL) was stirred at 110 °C under microwave irradiation for 1 h and then concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to give N-((1S*,3R*)-3-(1-ethyl-1H-imidazol-2-yl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)cyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide (0.012 g). A mixture of the obtained compound (0.012 g), 2-bromopyrimidine (0.013 g), sodium carbonate (0.013 g), Pd(dppf)Cl DCM adduct (2.0 mg), 1,4-dioxane (1 mL), ethanol (0.5 mL), and water (0.5 mL) was stirred at 90 °C for 1 hour under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give N-((1S*,3R*)-3-(1-ethyl-1H-imidazol-2-yl)-3-(3-(pyrimidin-2-yl)benzyl)cyclopentyl)-N-(4-methoxybenzyl)methanesulfonamide (0.006 g).A mixture of the obtained compound (0.006 g) and trifluoroacetic acid (1 mL) was stirred for 1 hour at 70° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by APS column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 70 / 30) to obtain the title compound (0.004 g).

[0203] Example 12 N-((1R*,3S*)-1-([1,1'-biphenyl]-3-ylmethyl)-3-(methylsulfonamido)cyclopentyl)butyramide To a mixture of Reference Example B-13 (4.0 mg), DIPEA (0.017 g), butyric acid (4.8 mg), and DMF (1 mL), HATU (0.005 g) was added at room temperature. The mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 30 / 70 to 0 / 100) to obtain the title compound (4.0 mg).

[0204] Example 13 N-((1R*,3S*)-1-([1,1'-biphenyl]-3-ylmethyl)-3-(methylsulfonamido)cyclopentyl)-N-methylisobutyramide To a mixture of Reference Example B-13 (0.020 g) and methanol (1 mL), 37% aqueous formaldehyde solution (0.010 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added sodium borohydride (3.0 mg) at room temperature. The mixture was stirred at the same temperature for 30 minutes and concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give N-((1S*,3R*)-3-([1,1'-biphenyl]-3-ylmethyl)-3-(methylamino)cyclopentyl)methanesulfonamide (0.014 g). To a mixture of the obtained compound (0.005 g), DIPEA (0.017 g), and DCM (2 mL), isobutyryl chloride (0.005 g) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give the title compound (4.0 mg).

[0205] Example 14 Example 14 was synthesized in the same manner as in Example 13, except that propionaldehyde was used instead of the aqueous formaldehyde solution and acetyl chloride was used instead of isobutyryl chloride.

[0206] Example 15 N-((1S*,3R*)-3-([1,1'-biphenyl]-3-ylmethyl)-3-(2-oxopyrrolidin-1-yl)cyclopentyl)methanesulfonamide To a mixture of Reference Example B-16 (0.025 g), TEA (0.011 g), and DCM (1 mL), 4-chlorobutyryl chloride (0.013 g) was added at room temperature, and the mixture was stirred at the same temperature for 15 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue and THF (2 mL), potassium tert-butoxide (0.018 g) was added at room temperature, and the mixture was stirred at the same temperature for 10.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A mixture of the residue, trifluoroacetic acid (1 mL), triethylsilane (0.020 g), and DCM (1 mL) was stirred at room temperature for 6 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 30 / 70 to 0 / 100) to give the title compound (0.018 g).

[0207] Example 16 (1R,4R)-1-(4-Fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methyl-4-(methylsulfonamido)cyclopent-2-ene-1-carboxamide Under an argon atmosphere, to a mixture of Reference Example C-1 (2.26 g), Reference Example A-6 (2.22 g), and THF (23 mL), lithium bis(trimethylsilyl)amide (1.11 mol / L in THF) (8 mL) was added in an ice-salt bath, and the mixture was stirred at the same temperature for 30 minutes. To the mixture, lithium bis(trimethylsilyl)amide (1.11 mol / L in THF) (2 mL) was added in an ice-salt bath, and the mixture was stirred at the same temperature for 15 minutes. Saturated aqueous ammonium chloride, saturated brine, and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to give methyl (1R,4R)-4-((diphenylmethylene)amino)-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)cyclopent-2-ene-1-carboxylate (2.13 g). To a mixture of the resulting compound (0.210 g) and THF (3 mL), 2 mol / L hydrochloric acid (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 4 hours. TBME and water were added to the reaction mixture, and the mixture was stirred, and the aqueous layer was separated. Ethyl acetate and 1 mol / L aqueous sodium hydroxide solution (10 mL) were added to the aqueous layer, and the mixture was stirred, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of the residue and ethyl acetate (3 mL), TEA (0.063 g) and then methanesulfonyl chloride (0.057 g) were added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 2 mol / L aqueous sodium hydroxide solution (3 mL) was added to a mixture of the residue and THF (4 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate.The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a mixture of the residue and DCM (3 mL), DMF (3.8 mg) and then oxalyl chloride (0.078 g) were added at room temperature. The mixture was stirred at the same temperature for 1 hour and then concentrated under reduced pressure. A mixture of the residue and DCM (2 mL) was added to a mixture of N,O-dimethylhydroxylamine hydrochloride (0.060 g), DIPEA (0.160 g), and DCM (4 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium bicarbonate, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 40 / 60 to 10 / 90) to obtain the title compound (0.128 g).

[0208] Example 17 (1r,4r)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-N,N-dimethyl-4-(methylsulfonamido)cyclohexane-1-carboxamide To a mixture of Reference Example D-3 (0.010 g), dimethylamine hydrochloride (0.015 g), DIPEA (0.044 g), and DMF (1 mL), HATU (0.012 g) was added at room temperature, and the mixture was stirred at the same temperature for 25 minutes. The reaction mixture was added to water and extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 25 / 75) to give the title compound (1.1 mg).

[0209] Example 18 (1r,4r)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methyl-4-(methylsulfonamido)cyclohexane-1-carboxamide To a mixture of Reference Example D-3 (0.009 g), N,O-dimethylhydroxylamine hydrochloride (0.038 g), DIPEA (0.088 g), and DMF (1 mL), HATU (0.012 g) was added at room temperature, and the mixture was stirred at 70 ° C. for 80 minutes and allowed to cool to room temperature. To the reaction mixture, N,O-dimethylhydroxylamine hydrochloride (0.010 g) and DIPEA (0.022 g) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, DMAP (0.007 g) was added at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was poured into water and extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 60 / 40) to obtain the title compound (1.2 mg).

[0210] Example 19 (2R*,5R*)-2-(3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methyl-5-(methylsulfonamido)piperidine-2-carboxamide A mixture of Reference Example D-6 (0.055 g), 6 mol / L hydrochloric acid (2 mL), and 1,4-dioxane (1 mL) was stirred at 100°C for 1 hour and allowed to cool to room temperature. 6 mol / L hydrochloric acid (9 mL) and 1,4-dioxane (2 mL) were added to the reaction mixture at room temperature, and the mixture was stirred at 100°C for 5.5 hours under microwave irradiation. The reaction mixture was partitioned between DCM and water. The aqueous layer was separated and concentrated under reduced pressure. To a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (0.154 g), DIPEA (0.408 g), and DMF (5 mL) was added HATU (0.055 g) at room temperature, and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was added to water and extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 25 / 75) followed by ODS column chromatography (eluent: water / MeCN = 10 / 90) to give the title compound (1.6 mg).

[0211] Example 20 (2S*,4R*)-2-([1,1'-biphenyl]-3-ylmethyl)-N-methoxy-N-methyl-4-(methylsulfonamido)tetrahydrofuran-2-carboxamide A mixture of Reference Example E-4 (0.020 g), N,O-dimethylhydroxylamine hydrochloride (0.021 g), DIPEA (0.034 g), HATU (0.026 g), and DMF (1 mL) was stirred at 70°C for 1 hour and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 70 / 30 / 0 to 0 / 100 / 0 to 0 / 90 / 10) to obtain the title compound (0.015 g).

[0212] Examples 21 to 22 Examples 21 to 22 were synthesized in the same manner as in Example 20, except that the corresponding reagents were used instead of N,O-dimethylhydroxylamine hydrochloride.

[0213] Example 23 (2S*,4R*)-N-Methoxy-N-methyl-4-(methylsulfonamido)-2-(3-(pyrimidin-2-yl)benzyl)tetrahydrofuran-2-carboxamide. To a mixture of Reference Example E-5 (0.012 g), oxalyl chloride (0.016 g), and DCM (0.5 mL) was added DMF (0.9 mg) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was added to a mixture of N,O-dimethylhydroxylamine hydrochloride (0.016 g), TEA (0.032 g), and DCM (1 mL) under ice cooling, and the mixture was stirred at the same temperature for 14 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 100 / 0 / 0 to 0 / 100 / 0 to 0 / 95 / 5) to obtain the title compound (0.010 g).

[0214] Examples 24 to 25 Examples 24 to 25 were synthesized in the same manner as in Example 23, except that the corresponding reagents were used instead of N,O-dimethylhydroxylamine hydrochloride.

[0215] Example 26 (2S,4R)-2-([1,1'-biphenyl]-3-ylmethyl)-N-ethyl-N-methyl-4-(methylsulfonamido)pyrrolidine-2-carboxamide A mixture of Reference Example F-5 (0.063 g), N-ethylmethylamine (0.031 g), DIPEA (0.086 g), HATU (0.101 g), and NMP (3 mL) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was added to 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give (2S,4R)-2-([1,1'-biphenyl]-3-ylmethyl)-2-(ethyl(methyl)carbamoyl)-4-(methylsulfonamido)pyrrolidine-1-carboxylate tert-butyl ester (0.045 g). A mixture of the obtained compound (0.045 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL), and methanol (1 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 100 / 0 / 0 to 0 / 100 / 0 to 0 / 90 / 10) to give the title compound (0.024 g).

[0216] Example 27 Example 27 was synthesized in the same manner as in Example 26, except that N,O-dimethylhydroxylamine hydrochloride was used instead of N-ethylmethylamine.

[0217] Example 28 (2S,4R)-2-([1,1'-biphenyl]-3-ylmethyl)-N-ethyl-N,1-dimethyl-4-(methylsulfonamido)pyrrolidine-2-carboxamide A mixture of Example 26 (0.014 g), 37% aqueous formaldehyde solution (0.011 g), and methanol (0.5 mL) was stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (0.014 g) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added to saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 30 / 70) to give the title compound (0.012 g).

[0218] Example 29 (2S,4R)-2-([1,1'-biphenyl]-3-ylmethyl)-N,1-diethyl-N-methyl-4-(methylsulfonamido)pyrrolidine-2-carboxamide. A mixture of Example 26 (0.027 g), acetaldehyde (5 mol / L in THF) (0.051 g), and 1,2-dichloroethane (1 mL) was stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (0.027 g) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give the title compound (0.019 g).

[0219] Example 30 Example 30 was synthesized in the same manner as in Example 28, except that Example 27 was used instead of Example 26.

[0220] Example 31 Example 31 was synthesized in the same manner as in Example 26, except that Reference Example F-7 was used instead of Reference Example F-5.

[0221] Example 32 Example 32 was synthesized in the same manner as in Example 26, except that Reference Example F-7 was used instead of Reference Example F-5 and N,O-dimethylhydroxylamine hydrochloride was used instead of N-ethylmethylamine.

[0222] Example 33 (2S,4R)-4-(ethylsulfonamido)-2-(3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methylpyrrolidine-2-carboxamide A mixture of Reference Example F-8 (0.029 g), 2 mol / L aqueous sodium hydroxide solution (0.18 mL), and 2-propanol (0.6 mL) was stirred at 60°C for 22 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (0.016 g), DIPEA (0.029 g), HATU (0.027 g), and NMP (0.6 mL) was stirred at 90°C for 2 hours under microwave irradiation. The reaction mixture was added to water and extracted with ethyl acetate. The extract was washed with 1 mol / L hydrochloric acid and saturated brine, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 20 / 80) to give tert-butyl (2S,4R)-4-(ethylsulfonamido)-2-(3-(5-fluoropyrimidin-2-yl)benzyl)-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (0.010 g). A mixture of the obtained compound (0.010 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (0.091 mL), and methanol (0.5 mL) was stirred at room temperature for 11 hours and concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate=60 / 40 to 0 / 100) to obtain the title compound (0.006 g).

[0223] Example 34 (2S,4R)-N-Methoxy-N-methyl-4-(methylsulfonamido)-2-(3-(pyrimidin-2-yl)benzyl)pyrrolidine-2-carboxamide A mixture of Reference Example F-6 (0.100 g), N,O-dimethylhydroxylamine hydrochloride (0.070 g), DIPEA (0.116 g), HATU (0.089 g), and NMP (0.6 mL) was stirred at 90°C for 2 hours under microwave irradiation. The reaction mixture was added to 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give tert-butyl (2S,4R)-2-(3-(5-bromopyrimidin-2-yl)benzyl)-2-(methoxy(methyl)carbamoyl)-4-(methylsulfonamido)pyrrolidine-1-carboxylate (0.054 g). To a mixture of the resulting compound (0.054 g), TEA (0.009 g), ethanol (1 mL), and THF (1 mL), 10% Pd / C (0.011 g) was added at room temperature. The mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. A mixture of the residue, hydrogen chloride (4 mol / L in 1,4-dioxane) (0.225 mL), and methanol (1 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate / methanol=100 / 0 / 0 to 0 / 100 / 0 to 0 / 90 / 10) to obtain the title compound (0.028 g).

[0224] Example 35 Example 35 was synthesized in the same manner as in Example 26, except that Reference Example F-12 was used instead of Reference Example F-5, and N,O-dimethylhydroxylamine hydrochloride was used instead of N-ethylmethylamine.

[0225] Example 36 Example 36 was synthesized in the same manner as in Example 28, except that Example 31 was used instead of Example 26.

[0226] Example 37 Example 37 was synthesized in the same manner as in Example 28, except that Example 32 was used instead of Example 26 and acetaldehyde was used instead of formaldehyde.

[0227] Example 38 (2S,4R,5S)-2-(3-(5-fluoropyrimidin-2-yl)benzyl)-N,N,1,5-tetramethyl-4-(methylsulfonamido)pyrrolidine-2-carboxamide A mixture of Reference Example F-12 (0.019 g), dimethylamine hydrochloride (0.012 g), DIPEA (0.025 g), HATU (0.016 g), and DMF (0.5 mL) was stirred at 70°C for 1 hour and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate and n-hexane (1 / 1). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 20 / 80) followed by ODS column chromatography (eluent: water / MeCN = 70 / 30 to 10 / 90) to give tert-butyl (2S,4R,5S)-2-(dimethylcarbamoyl)-2-(3-(5-fluoropyrimidin-2-yl)benzyl)-5-methyl-4-(methylsulfonamido)pyrrolidine-1-carboxylate (0.010 g). A mixture of the resulting compound (0.010 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (0.093 mL), and methanol (0.5 mL) was stirred at room temperature for 3 hours. To the reaction mixture, hydrogen chloride (4 mol / L in 1,4-dioxane) (0.093 mL) was added at room temperature, and the mixture was stirred at the same temperature for 19 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue, 37% aqueous formaldehyde solution (1.5 mg), and methanol (0.5 mL) was stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (0.005 g) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 40 / 60 to 20 / 80) to obtain the title compound (3.9 mg).

[0228] Example 39 (1R,3S,7aS)-3-([1,1'-biphenyl]-3-ylmethyl)-N,N-dimethyl-1-(methylsulfonamido)hexahydro-1H-pyrrolidine-3-carboxamide A mixture of Reference Example G-3 (0.200 g), 2 mol / L aqueous sodium hydroxide solution (1.2 mL), and methanol (2 mL) was stirred at 100°C for 15 minutes under microwave irradiation. 2 mol / L hydrochloric acid was added to the reaction mixture at room temperature. The mixture was extracted with DCM. The aqueous layer was adjusted to pH 7 with the addition of 0.5 mol / L phosphate buffer (pH 6.9) and 2 mol / L aqueous sodium hydroxide solution. The mixture was extracted with DCM. The aqueous layer was extracted with ethyl acetate. All organic layers were combined and concentrated under reduced pressure. To a mixture of the residue, dimethylamine hydrochloride (0.113 g), DIPEA (0.599 g), and DMF (2 mL) was added HATU (0.176 g) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 70 / 30) to give (1R,3S,7aS)-3-(3-bromobenzyl)-N,N-dimethyl-1-(methylsulfonamido)hexahydro-1H-pyrrolidine-3-carboxamide (0.131 g). A mixture of the obtained compound (0.005 g), phenylboronic acid (2.7 mg), tripotassium phosphate (0.007 g), Xphos Pd G3 (1.0 mg), 1,2-dimethoxyethane (1.5 mL), and water (0.5 mL) was stirred at 80°C for 30 minutes under an argon atmosphere and then allowed to cool to room temperature. The reaction mixture was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give the title compound (0.005 g).

[0229] Example 40 Example 40 was synthesized in the same manner as in Example 39, except that 2-fluorophenylboronic acid was used instead of phenylboronic acid.

[0230] Example 41 (1R,3S,7aS)-N,N-Dimethyl-1-(methylsulfonamido)-3-(3-(pyridin-2-yl)benzyl)hexahydro-1H-pyrrolidine-3-carboxamide A mixture of Reference Example G-3 (0.200 g), 2 mol / L aqueous sodium hydroxide solution (1.2 mL), and methanol (2 mL) was stirred at 100°C for 15 minutes under microwave irradiation. 2 mol / L hydrochloric acid was added to the reaction mixture at room temperature, and the mixture was extracted with DCM. The aqueous layer was adjusted to pH 7 by adding 0.5 mol / L phosphate buffer (pH 6.9) and 2 mol / L aqueous sodium hydroxide solution. The mixture was extracted with DCM. The aqueous layer was extracted with ethyl acetate. All organic layers were combined and concentrated under reduced pressure. To a mixture of the residue, dimethylamine hydrochloride (0.113 g), DIPEA (0.599 g), and DMF (2 mL) was added HATU (0.176 g) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 30 / 70 to 0 / 100) to give (1R,3S,7aS)-3-(3-bromobenzyl)-N,N-dimethyl-1-(methylsulfonamido)hexahydro-1H-pyrrolidine-3-carboxamide (0.131 g). A mixture of the obtained compound (0.010 g), tributyl(2-pyridyl)tin (0.011 g), Pd(PPh3)4 (1.2 mg), silver oxide (2.3 mg), and DMF (1 mL) was stirred at 120 °C for 30 minutes under microwave irradiation. A 10% aqueous potassium fluoride solution was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 0 / 100) and then ODS column chromatography (eluent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (2.0 mg).

[0231] Examples 42 to 43 (1R,3S,7aS)-3-(3-(5-fluoropyrimidin-2-yl)benzyl)-N,N-dimethyl-1-(methylsulfonamido)hexahydro-1H-pyrrolidine-3-carboxamide (Example 42) (1R,3S,7aS)-3-(3-(5-isopropoxypyrimidin-2-yl)benzyl)-N,N-dimethyl-1-(methylsulfonamido)hexahydro-1H-pyrrolidine-3-carboxamide (Example 43) A mixture of Reference Example G-6 (0.035 g), 2 mol / L aqueous sodium hydroxide solution (0.195 mL), and 2-propanol (1 mL) was stirred at 95° C. for 8 hours and then allowed to cool to room temperature. To the reaction mixture, 2 mol / L aqueous sodium hydroxide solution (0.195 mL), water (0.2 mL), and 2-propanol (0.5 mL) were added at room temperature and stirred at 120 °C for 15 minutes under microwave irradiation. Ethyl acetate was added to the reaction mixture, and the aqueous layer was separated. 2 mol / L hydrochloric acid (0.234 mL) was added to the aqueous layer, and the mixture was concentrated under reduced pressure. HATU (0.033 g) was added to a mixture of the residue, dimethylamine hydrochloride (0.026 g), DIPEA (0.061 g), and DMF (1 mL) at room temperature. The mixture was stirred at 60 °C for 3 hours and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate and n-hexane (1 / 1). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 50 / 50 to 20 / 80) to give a mixture of Example 42 and Example 43. This mixture was purified by ODS column chromatography (elution solvent: water / MeCN = 70 / 30 to 10 / 90) to give Example 42 (0.005 g) and Example 43 (2.3 mg). In ODS column chromatography, the compound eluted first was Example 42, and the compound eluted next was Example 43.

[0232] Example 44 (1R,3S,7aS)-3-(3-(5-fluoropyrimidin-2-yl)-4-methylbenzyl)-N,N-dimethyl-1-(methylsulfonamido)hexahydro-1H-pyrrolidine-3-carboxamide. A mixture of Reference Example G-13 (0.010 g), 2 mol / L aqueous sodium hydroxide solution (0.054 mL), water (0.2 mL), and 2-propanol (0.6 mL) was stirred at 120 °C for 1 hour under microwave irradiation. 2 mol / L hydrochloric acid (0.059 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. HATU (0.009 g) was added to a mixture of the residue, dimethylamine hydrochloride (0.007 g), DIPEA (0.042 g), and DMF (0.5 mL) at room temperature, and the mixture was stirred at the same temperature for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate and n-hexane (1 / 1). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (1.3 mg).

[0233] Examples 45 to 46 Examples 45 to 46 were synthesized in the same manner as in Example 44, except that the compounds of the corresponding Reference Examples were used instead of Reference Example G-13.

[0234] Example 47 (1R,3S,7aS)-3-(3-(5-fluoropyrimidin-2-yl)benzyl)-N-methyl-1-(methylsulfonamido)hexahydro-1H-pyrrolidine-3-carboxamide. A mixture of Reference Example G-6 (0.011 g), 2 mol / L aqueous sodium hydroxide solution (0.059 mL), water (0.4 mL), and 2-propanol (0.8 mL) was stirred at 120 °C for 1 hour under microwave irradiation. 2 mol / L hydrochloric acid (0.064 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. HATU (0.010 g) was added to a mixture of the residue, methylamine hydrochloride (0.017 g), DIPEA (0.045 g), and DMF (1 mL) at room temperature. The mixture was stirred at 70 °C for 15 minutes and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate and n-hexane (1 / 1). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (1.5 mg).

[0235] Example 48 Example 48 was synthesized in the same manner as in Example 47, except that pyrrolidine was used instead of methylamine hydrochloride.

[0236] Example 49 (1R,3S,7aS)-N-ethyl-3-(3-(5-fluoropyrimidin-2-yl)benzyl)-N-methyl-1-(methylsulfonamido)hexahydro-1H-pyrrolidine-3-carboxamide. To a mixture of Reference Example G-17 (0.010 g), N-ethylmethylamine (0.006 g), DIPEA (0.008 g), and DMF (2 mL), HATU (0.009 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give tert-butyl ((1R,3S,7aS)-3-(ethyl(methyl)carbamoyl)-3-(3-(5-fluoropyrimidin-2-yl)benzyl)hexahydro-1H-pyrrolidin-1-yl)carbamate. A mixture of the obtained compound and hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL) was stirred at room temperature for 30 minutes and concentrated under reduced pressure. Methanesulfonyl chloride (2.9 mg) was added to a mixture of the residue, TEA (0.007 g), and DCM (2 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added to water and extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=30 / 70 to 0 / 100) to obtain the title compound (2.0 mg).

[0237] Example 50 Example 50 was synthesized in the same manner as in Example 49, except that N-methylcyclopropanamine hydrochloride was used instead of N-ethylmethylamine.

[0238] Example 51 (1R,3S,7aS)-3-(3-(5-fluoropyrimidin-2-yl)benzyl)-N-methyl-1-(methylsulfonamido)-N-(2,2,2-trifluoroethyl)hexahydro-1H-pyrrolidine-3-carboxamide. To a mixture of Reference Example G-17 (0.034 g), 2,2,2-trifluoroethylamine (0.075 g), DIPEA (0.030 g), and DMF (2 mL), HATU (0.031 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue and DMF (2 mL), sodium hydride (approximately 60% in mineral oil) (0.015 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture, methyl iodide (0.011 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, dimethyl sulfate (0.007 g) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, saturated aqueous ammonium chloride solution was added under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give tert-butyl ((1R,3S,7aS)-3-(3-(5-fluoropyrimidin-2-yl)benzyl)-3-(methyl(2,2,2-trifluoroethyl)carbamoyl)hexahydro-1H-pyrrolidin-1-yl)carbamate (3.0 mg). A mixture of the obtained compound (3.0 mg) and hydrogen chloride (4 mol / L in 1,4-dioxane) (2 mL) was stirred at room temperature for 30 minutes and concentrated under reduced pressure. Methanesulfonyl chloride (0.007 g) was added to a mixture of the residue, TEA (2.3 mg), and DCM (2 mL) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=50 / 50 to 0 / 100) to obtain the title compound (3.0 mg).

[0239] Example 52 (1R,3S,7aS)-1-(ethylsulfonamido)-3-(3-(5-fluoropyrimidin-2-yl)benzyl)-N,N-dimethylhexahydro-1H-pyrrolidine-3-carboxamide A mixture of Reference Example G-18 (0.075 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (2 mL) was stirred at room temperature for 30 minutes and concentrated under reduced pressure. To a mixture of the residue, DIPEA (0.158 g), and DCM (2 mL), ethanesulfonyl chloride (0.063 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=30 / 70 to 0 / 100) and then by ODS column chromatography (eluent: water / MeCN=70 / 30 to 10 / 90) to obtain the title compound (0.038 g).

[0240] Example 53 Example 53 was synthesized in the same manner as in Example 52, except that fluoromethanesulfonyl chloride was used instead of ethanesulfonyl chloride.

[0241] Example 54 (1R,3S,7aS)-1-(cyclopropanesulfonamido)-3-(3-(5-fluoropyrimidin-2-yl)benzyl)-N,N-dimethylhexahydro-1H-pyrrolidine-3-carboxamide. A mixture of Reference Example G-18 (0.018 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL) was stirred at room temperature for 15 minutes and concentrated under reduced pressure. To a mixture of the residue, 1,8-diazabicyclo[5.4.0]-7-undecene (0.068 g), and DCM (2 mL), cyclopropanesulfonyl chloride (0.031 g) was added at room temperature, and the mixture was stirred at the same temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate=100 / 0 to 0 / 100) and then by ODS column chromatography (eluent: water / MeCN=70 / 30 to 10 / 90) to obtain the title compound (2.0 mg).

[0242] Example 55 Example 55 was synthesized in the same manner as in Example 54, except that isopropylsulfonyl chloride was used instead of cyclopropanesulfonyl chloride.

[0243] Example 56 (1R*,3R*)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-N,N-dimethyl-3-(methylsulfonamido)-2,3-dihydro-1H-indene-1-carboxamide A mixture of Reference Example H-8 (0.322 g), 6 mol / L hydrochloric acid (4.4 mL), and 1,4-dioxane (10 mL) was stirred at 100° C. for 24 hours and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. HATU (0.049 g) was added to a mixture of the residue (0.038 g), DIPEA (0.056 g), and DMF (1 mL) at room temperature, and the mixture was stirred at the same temperature for 10 minutes. Dimethylamine hydrochloride (0.011 g) was added to the reaction mixture at room temperature, and the mixture was stirred at 70°C for 1 hour and allowed to cool to room temperature. The reaction mixture was added to 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water / MeCN = 90 / 10 to 10 / 90) to give the title compound (2.8 mg).

[0244] Example 57 (1R,3S,8aS)-3-(3-(5-fluoropyrimidin-2-yl)benzyl)-N,N-dimethyl-1-(methylsulfonamido)octahydroindolizine-3-carboxamide. A mixture of Reference Example H-9 (0.019 g), 4 mol / L aqueous lithium hydroxide solution (0.031 mL), and THF (0.5 mL) was stirred at room temperature for 1 hour and at 100°C for 4.5 hours under microwave irradiation. 2 mol / L hydrochloric acid (0.073 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. HATU (0.017 g) was added to a mixture of the residue, dimethylamine hydrochloride (0.014 g), DIPEA (0.032 g), and DMF (1 mL) at room temperature, and the mixture was stirred at the same temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate and n-hexane (1 / 1). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 50 / 50) to obtain the title compound (0.013 g).

[0245] Example 58 (6S,8R,8aR)-6-(3-(5-fluoropyrimidin-2-yl)benzyl)-N,N-dimethyl-8-(methylsulfonamido)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxamide. A mixture of Reference Example H-7 (0.023 g), triphenylphosphine (0.023 g), methanol (2 mL), and water (0.002 mL) was stirred at room temperature for 14 hours and at 80°C under microwave irradiation for 1 hour, and then concentrated under reduced pressure. To a mixture of the residue, TEA (0.018 g), and DCM (2 mL), methanesulfonyl chloride (0.013 g) was added under ice cooling, and the mixture was stirred at room temperature for 15 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue, 2 mol / L aqueous sodium hydroxide solution (0.145 mL), and methanol (1 mL) was stirred at 100°C for 10 minutes under microwave irradiation. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. HATU (0.024 g) was added to a mixture of the residue, dimethylamine hydrochloride (0.047 g), DIPEA (0.113 g), and DMF (2 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 20 / 80 to 0 / 100) to give (6S,8R,8aR)-6-(3-bromobenzyl)-N,N-dimethyl-8-(methylsulfonamido)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxamide (0.017 g). A mixture of the obtained compound (0.017 g), bis(pinacolato)diboron (0.028 g), potassium acetate (0.011 g), Pd(dppf)Cl2 (2.7 mg), Xphos (3.5 mg), and 1,4-dioxane (1 mL) was stirred at 120 °C for 15 min under microwave irradiation.A mixture of 2-chloro-5-fluoropyrimidine (0.024 g), Xphos (3.5 mg), tripotassium phosphate (0.039 g), palladium(II) acetate (0.8 mg), 1,4-dioxane (0.5 mL), and water (0.5 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at 110°C under microwave irradiation for 1 hour and then concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100) and then ODS column chromatography (eluent: water / MeCN = 70 / 30 to 10 / 90) to give the title compound (0.005 g).

[0246] Example 59 Example 59 was synthesized in the same manner as in Example 58, except that ethanesulfonyl chloride was used instead of methanesulfonyl chloride.

[0247] The structural formulas, physical properties, and OX2R agonist activity (see Test Example 1) of the examples are shown in the table below.

[0248] The stereochemistry notation of Examples 1 to 4, 7 to 15, 19 to 25 and 56 in the table indicates the relative configuration.

[0249] Test Example 1

[0250] 1) Obtaining Human OX2R-Expressing Cells. The human OX2R sequence (Accession No. NM_001526.4) was inserted into the multicloning site of pcDNA3.4 (Life Technologies Japan, Inc.) to clone a human OX2R expression plasmid vector. This plasmid was then introduced into CHO-K1 cells using Lipofectamine 2000 (Life Technologies Japan, Inc.). After two days, the transfected CHO-K1 cells were passaged into 175T flasks and selectively cultured for six days. The selective medium used was Ham's F-12 Nutrient Mix (Life Technologies Japan, Inc.) containing Geneticin® (Life Technologies Japan, Inc.) at a final concentration of 1 mg / mL and heat-inactivated fetal bovine serum (Biowest) at a final concentration of 10%. After selective culture, the cells were replated onto 96-well plates, and human OX2R-expressing cell lines were obtained by limiting dilution.

[0251] 2) Measurement of OX2R agonist activity The agonist activity of the test substance on human OX2R was evaluated using the change in intracellular calcium concentration upon stimulation as an index. On the day before measuring the intracellular calcium concentration, 5 × 10 human OX2R-expressing cells suspended in medium were cultured. 3Cells were seeded into a 384-well plate at 50 μL / well and cultured overnight in an incubator set at 37°C and 5% CO2. After incubation, the medium was removed and replaced with 20 μL of loading buffer. The loading buffer used was an assay buffer containing Fluo4-AM (Dojindo Laboratories, Inc.) at a final concentration of 1.14 μM, Cremophor® EL (Nacalai Tesque, Inc.) at a final concentration of 0.02%, probenecid (Life Technologies Japan, Inc.) at a final concentration of 1.5 mM, and amaranth (Sigma-Aldrich Japan, LLC) at a final concentration of 0.5 mg / mL. The assay buffer used was Hank's balanced salt solution containing 20 mM HEPES, 1.5 mM CaCl2, 0.5 mM MgCl2, and 0.4 mM MgSO4, adjusted to pH 7.4. After incubating the cells at 37°C for 45 minutes, fluorescence intensity was measured over time using an FDSS® 7000 (Hamamatsu Photonics) (excitation wavelength: 480 nm, emission wavelength: 540 nm). Twenty seconds after the start of the measurement, a vehicle containing the test substance (final concentration: 10 μM) or vehicle alone was added, and the measurement was continued for 2 minutes. The vehicle was a solution prepared by diluting dimethyl sulfoxide to a final concentration of 0.1% in assay buffer containing a final concentration of 0.1% bovine serum albumin (Fujifilm Wako Pure Chemical Corporation). The fluorescence intensity upon addition of a final concentration of 1 μM human orexin A peptide (Peptide Institute, Inc.) was set as 100%, and the fluorescence intensity upon addition of vehicle alone was set as 0%. The agonist activity of the test substance against human OX2R was calculated by setting the fluorescence intensity upon addition of a final concentration of 1 μM human orexin A peptide (Peptide Institute, Inc.) as 100% and that upon addition of vehicle alone as 0%. The table above shows the activation rate of each test substance at a compound concentration of 10 μM. In the table, Act. ≧ 75%: A, 75% > Act. ≧ 50%: B, 50% > Act. ≧ 30%: C. These results demonstrated that the compounds of the present invention have agonistic activity against human OX2R.

[0252] The compound of the present invention or a pharmacologically acceptable salt thereof has OX2R agonist activity and is therefore useful as a therapeutic agent for sleep disorders involving OX2R.

Claims

1. A compound represented by formula (I): [Wherein, ring W is C 3-8 Cycloalkyl, C 5-10 Bicycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl; ring Z is a ring represented by formula (1), (2), or (3): Y 1 is a single bond, CR a1 R a2 , C.R. a1 , O, or NR b1 and Y 2 is CR 5 R 6 , or CR 5 and Y 3 is CR a1 or N; Y 4 is a single bond, CR a1 R a2 , O, or NR b2 and Y 5 is C or N; Y 6 , Y 7 , and Y 8 are each independently a1 ,O,S,NR b3 or N; represents a single or double bond; R 5 and R 6 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, HaloC 1-6 Alkyl or C 1-6 alkoxy, or may be taken together to form a 3- to 8-membered saturated ring; R 7 and R 8 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; R 7 and R 8 When there are two or more of each, each R 7 and R 8 may be the same or different; p, q, s, and t are each independently 1 or 2; r is an integer from 0 to 2; R a1 , R a2 , R a3 and R a4 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R a1 and R a2 When there are two or more of each, each R a1 and R a2 may be the same or different; R b1 , R b2 , and R b3 are each independently a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; R b3 When there are two or more R b3 may be the same or different; L 1 is a single bond, CR a5 R a6 , or NR c and R a5 and R a6 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R c is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; L 2 is a single bond or O; R 1 is COR d , a 5- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A, or a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A; 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 R is a group consisting of alkyl, and oxo; when two or more groups selected from the substituent group A are present, each group may be the same or different; R d is C 1-6 Alkyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted C 3-8 Cycloalkyl, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl or NR e R e’ and R e and R e’ are each independently a hydrogen atom, a hydroxyl, or C 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkyl or C 3-8 They may be cycloalkyl or may be joined together to form a 3- to 8-membered saturated heterocyclic ring unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; the substituent group B may be a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy and HaloC 1-6 alkyl; when two or more groups selected from the substituent group B are present, each group may be the same or different; R 2 is C 1-6 Alkyl, C 2-6 Alkenyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted C 3-8 Cycloalkyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted 3- to 8-membered heterocycloalkyl, haloC 1-6 Alkyl or C 1-6 alkylamino; R 3 is a halogen atom, hydroxy, amino, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 alkylamino; n is an integer from 0 to 2; when n is 2, each R 3 may be the same or different; R 4 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, C 2-6 Alkenyl, HaloC 1-6 Alkyl, unsubstituted or C substituted with 1 to 3 groups selected from the substituent group C 3-8 Cycloalkyl, 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group C, C unsubstituted or substituted with 1 to 3 groups selected from the substituent group C 6-10 aryl, a 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group C, or a 9- or 10-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group C; the substituent group C is a halogen atom, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, C 1-6 When two or more groups selected from the substituent group C are present, the groups may be the same or different (provided that the ring Z is a ring represented by formula (1); and p is 1; and Y 1 is CR a1 R a2 and Y 2 is CR 5 R 6 If so, it is one of the following (a) to (f): (a) L 1 is CR a5 R a6 , or NR c (b) L 2 is O. (c) The ring W is C 3-8 Cycloalkyl, C 5-10 (d) R is a bicycloalkyl, a 3- to 8-membered heterocycloalkyl, a naphthalene, a 5- or 6-membered heteroaryl, or a 9- or 10-membered heteroaryl. 4 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, C 2-6 Alkenyl, HaloC 1-6 Alkyl, unsubstituted or C substituted with 1 or 2 groups selected from the substituent group C 3-8 (e) R is a cycloalkyl or a 3- to 8-membered heterocycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group C. 1 (f) R is a 5- to 8-membered heterocycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A, or a 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A. 5 is Haro C 1-6 alkyl or R 6 (which together with the formula (I) form a 3- to 8-membered saturated ring) or a pharmacologically acceptable salt thereof.

2. The compound according to claim 1, wherein ring W is C 3-8 Cycloalkyl, C 5-10 Bicycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10 aryl, or 5- or 6-membered heteroaryl; Y 3 is N; Y 5 is C; Y 6 , Y 7 , and Y 8 But, CR a1 q and s are 1; t is 2; R d But C 1-6 Alkyl or NR e R e’ and R e and R e’ are each independently a hydrogen atom, a hydroxyl, or a C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl or C 3-8 cycloalkyl, or together unsubstituted or 1 to 3 C 1-6 R may form a 3- to 8-membered saturated heterocyclic ring substituted with alkyl; 4 is a hydrogen atom, C 2-6 Alkenyl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group C 6-10 A compound which is aryl, or a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, or a pharmacologically acceptable salt thereof.

3. The compound of claim 2, comprising: Y 4 But, CR a1 R a2 , O, or NR b2 and R 5 is a hydrogen atom or C 1-6 alkyl; R 6 is a hydrogen atom; R 7 and R 8 is a hydrogen atom; r is 1 or 2; R a1 , R a2 , R a3 and R a4 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; R b1 is a hydrogen atom or C 1-6 alkyl; L 1 is a single bond or NR c and R c is a hydrogen atom or C 1-6 alkyl; 1-6 Alkyl, C 1-6 R is the group consisting of alkoxy and oxo; 2 But C 1-6 Alkyl, C 3-8 Cycloalkyl or haloC 1-6 alkyl; R 3 is a halogen atom or C 1-6 alkyl; n is 0 or 1; the substituent group C is a halogen atom, C 1-6 Alkyl, and C 1-6 A compound of the group consisting of alkoxy or a pharmacologically acceptable salt thereof.

4. The compound of claim 3, comprising: Y 1 is CR a1 , O, or NR b1 or a pharmacologically acceptable salt thereof.

5. The compound of claim 4, comprising: L 1 is a single bond; R 1 But, COR d and R d But NR e R e’ or a pharmacologically acceptable salt thereof.

6. The compound according to claim 5, wherein ring W is C 6-10 aryl, or 5- or 6-membered heteroaryl; L 2 is a single bond; R e and R e’ are each independently a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl or C 3-8 cycloalkyl, or together unsubstituted or 1 to 3 C 1-6 R may form a 3- to 8-membered saturated heterocyclic ring substituted with alkyl; 4 is unsubstituted or substituted with one group selected from the substituent group C 6-10 A compound which is aryl, or a 5- or 6-membered heteroaryl which is unsubstituted or substituted with one group selected from substituent group C, or a pharmacologically acceptable salt thereof.

7. A compound selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

8. A compound selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

9. A compound selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmacologically acceptable salt thereof, and pharmaceutical additives.

11. The pharmaceutical composition according to claim 10, which is a pharmaceutical composition for treating a sleep disorder involving OX2R.

12. The pharmaceutical composition according to claim 11, wherein the sleep disorder involving OX2R is narcolepsy.

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