WO2025211415A1 - Substituted sulfonamide compound - Google Patents

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

The present invention relates to substituted sulfonamide compounds useful as pharmaceuticals. More specifically, the present invention relates to substituted sulfonamide compounds or pharmacologically acceptable salts thereof that have agonist activity against the orexin type 2 receptor (OX2R) and are useful as therapeutic agents for sleep disorders involving OX2R.

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 except for 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 receptor 1 (OX1R) and orexin receptor 2 (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 the cause of narcolepsy.

Narcolepsy is a chronic neurological disorder characterized by excessive daytime sleepiness and sleep attacks as its main symptoms. Narcolepsy is classified into two types based on its symptoms: Type 1 (NT1) when cataplexy (attacks of sudden physical weakness caused by strong emotions) is present, and Type 2 (NT2) when it is not.
Currently, in the treatment of narcolepsy, the central nervous system stimulants modafinil, methylphenidate, and pemoline are used for hypersomnia symptoms, but all of them can cause paradoxical reactions, and methylphenidate and pemoline have strong side effects such as dependency.On the other hand, for cataplexy, since the aforementioned drugs have no therapeutic effect, antidepressants are used, but they are difficult to use due to their strong side effects, and discontinuing the medication can cause exacerbation due to the rebound phenomenon characteristic of antidepressants.
Thus, the current state of narcolepsy treatment is that only symptomatic treatment is available for all symptoms, and there is a need for therapeutic agents that address the etiology of narcolepsy.

Studies using postmortem brains from narcolepsy patients have 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 gene responsible for narcolepsy is the gene encoding OX2R (Non-Patent Document 2), and that 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 in maintaining wakefulness, and that its attenuation is involved in the onset of narcolepsy. OX2R agonists are therefore expected to be therapeutic agents for narcolepsy and other sleep disorders.

One example of an OX2R agonist known is TAK-925, and subcutaneous administration of TAK-925 has been shown to extend wakefulness in wild-type mice (Non-Patent Document 4). Clinical trials have also shown that TAK-925 maintains wakefulness and reduces daytime sleepiness in NT1 patients (Patent Document 1).

Compounds with OX2R agonist activity are described in Patent Documents 1 to 14 and Non-Patent Document 4. However, the substituted sulfonamide compounds of the present invention are not described in any of these documents.

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

Thomas C. Thannickal et al., Neuron, 2000, Vol. 27, No. 3, pp. 469-474 Ling Lin et al., “Cell” 1999, Vol. 98, No. 3, p. 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, p. 172794

The objective of the present invention is to provide novel compounds with OX2R agonist activity.

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

That is, the present invention relates to the following [1] to [16], etc.
[1]
Compounds of formula (I):
[During the ceremony,
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 , CR ^a1 , O, or NR ^b1 ;
^Y2 is ^CR5R6 or ^{CR5 ;
Y3} is CR ^a1 or N;
^Y4 is a single bond, CR ^a1 R ^a2 , O, or NR ^b2 ;
^Y5 is C or N;
Y ⁶ , Y ⁷ , and Y ⁸ are each independently CR ^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, C _1-6 alkyl, haloC _1-6 alkyl, or C _1-6 alkoxy, or may be joined 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 a C _1-6 alkyl;
When there are two or more R ^7s and two or more R ^8s , 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, C _1-6 alkyl, or haloC _1-6 alkyl;
When there are two or more R ^a1 and two or more R ^a2 , 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;
When two or more R ^b3 are present, each R ^b3 may be the same or different;
L ¹ is a single bond, CR ^a5 R ^a6 or NR ^c ;
R ^a5 and R ^a6 are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, or haloC _1-6 alkyl;
R ^c is a hydrogen atom, C _1-6 alkyl, or haloC _1-6 alkyl;
^L2 is a single bond or O;
R ¹ is COR ^d , 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;
Substituent group A is the group consisting of halogen atoms, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, and oxo;
When two or more groups selected from Substituent group A are present, each group may be the same or different;
R ^d is C _1-6 alkyl, C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 C _1-6 alkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, or NR ^e R ^e′ ;
R ^e and R ^e′ are each independently a hydrogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, haloC _1-6 alkyl, or C _3-8 cycloalkyl, or may be joined together to form a 3- to 8-membered saturated heterocycle unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
Substituent group B is the group consisting of halogen atoms, C _1-6 alkyl, C _1-6 alkoxy, and haloC _1-6 alkyl;
When two or more groups selected from Substituent group B are present, each group may be the same or different;
R ² is C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 C _1-6 alkyl, 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 C _1-6 alkyl, haloC _1-6 alkyl, or C _1-6 alkylamino;
^R3 is a halogen atom, hydroxy, amino, _C1-6 alkyl, _haloC1-6 alkyl, _C1-6 alkoxy, or _C1-6 alkylamino;
n is an integer from 0 to 2;
When n is 2, each ^R3 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, C _3-8 cycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, 3 to 8-membered heterocycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, C _6-10 aryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, or 9- or 10-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C;
The substituent group C is the group consisting of 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 substituent group C are present, the groups may be the same or different from each other (provided that when 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 , any of the following (a) to (f) is true: (a) L ¹ is CR ^a5 R ^a6 or NR ^c ; (b) L ² is O; (c) ring W is C _3-8 cycloalkyl, C _5-10 bicycloalkyl, 3- to 8-membered heterocycloalkyl, naphthalene, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl; (d) R ⁴ is a hydrogen atom, a halogen atom, C _1-6 alkyl, C _2-6 alkenyl, haloC _1-6 alkyl, unsubstituted or substituted with 1 or 2 groups selected from substituent group C). (e) R ¹ is a _5- to 8-membered heterocycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group A, or a 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group A. (f) R ⁵ is haloC _1-6 alkyl, or forms a 3- to 8-membered saturated ring together with R ⁶ ) or a pharmacologically acceptable salt thereof.
[2]
The compound according to the above [1], represented by formula (II):
[During the ceremony,
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 ¹ is a single bond, CR ^a1 R ^a2 , CR ^a1 , O, or NR ^b1 ;
^Y2 is ^CR5R6 or ^{CR5 ;}
represents a single or double bond;
R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, haloC _1-6 alkyl, or C _1-6 alkoxy, or may be joined 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 a C _1-6 alkyl;
When there are two or more R ^7s and two or more R ^8s , 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, 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 ;
R ^a5 and R ^a6 are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, or haloC _1-6 alkyl;
R ^c is a hydrogen atom, C _1-6 alkyl, or haloC _1-6 alkyl;
^L2 is a single bond or O;
R ¹ is COR ^d , 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;
Substituent group A is the group consisting of halogen atoms, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, and oxo;
When two or more groups selected from Substituent group A are present, each group may be the same or different;
R ^d is C _1-6 alkyl, C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 C _1-6 alkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, or NR ^e R ^e′ ;
R ^e and R ^e′ are each independently a hydrogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, haloC _1-6 alkyl, or C _3-8 cycloalkyl, or may be joined together to form a 3- to 8-membered saturated heterocycle unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
Substituent group B is the group consisting of halogen atoms, C _1-6 alkyl, C _1-6 alkoxy, and haloC _1-6 alkyl;
When two or more groups selected from Substituent group B are present, each group may be the same or different;
R ² is C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 C _1-6 alkyl, 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 C _1-6 alkyl, haloC _1-6 alkyl, or C _1-6 alkylamino;
^R3 is a halogen atom, hydroxy, amino, _C1-6 alkyl, _haloC1-6 alkyl, _C1-6 alkoxy, or _C1-6 alkylamino;
n is an integer from 0 to 2;
When n is 2, each ^R3 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, C _3-8 cycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, 3 to 8-membered heterocycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, C _6-10 aryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, or 9- or 10-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C;
The substituent group C is the group consisting of 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;
(However, when p is 1, Y ¹ is CR ^a1 R ^a2 , and Y ² is CR ⁵ R ⁶ , any one of the following (a) to (f) is satisfied:
(a) L ¹ is CR ^a5 R ^a6 or NR ^c
(b) ^L2 is O
(c) Ring W is C _3-8 cycloalkyl, C _5-10 bicycloalkyl, 3- to 8-membered heterocycloalkyl, naphthalene, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl.
(d) R ⁴ is a hydrogen atom, a halogen atom, C _1-6 alkyl, C _2-6 alkenyl, haloC _1-6 alkyl, C _3-8 cycloalkyl unsubstituted or substituted with 1 or 2 groups selected from the substituent group C, or a 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group C.
(e) R ¹ 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.
(f) ^R5 is _haloC1-6 alkyl or together with ^R6 forms a 3- to 8-membered saturated ring.
or a pharmacologically acceptable salt thereof.
[3]
The compound according to [1] above, represented by formula (I-II):
[During the ceremony,
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;
^Y3 is CR ^a1 or N;
^Y4 is a single bond, CR ^a1 R ^a2 , O, or NR ^b2 ;
^R6 is a hydrogen atom, a halogen atom, _C1-6 alkyl, _haloC1-6 alkyl, or _C1-6 alkoxy;
R ⁷ and R ⁸ are each independently a hydrogen atom, a halogen atom, or a C _1-6 alkyl;
When there are two or more R ^7s and two or more R ^8s , 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, C _1-6 alkyl, or haloC _1-6 alkyl;
When there are two or more R ^a1 and two or more R ^a2 , 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 ;
R ^a5 and R ^a6 are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, or haloC _1-6 alkyl;
R ^c is a hydrogen atom, C _1-6 alkyl, or haloC _1-6 alkyl;
^L2 is a single bond or O;
R ¹ is COR ^d , 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;
Substituent group A is the group consisting of halogen atoms, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, and oxo;
When two or more groups selected from Substituent group A are present, each group may be the same or different;
R ^d is C _1-6 alkyl, C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 C _1-6 alkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, or NR ^e R ^e′ ;
R ^e and R ^e′ are each independently a hydrogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, haloC _1-6 alkyl, or C _3-8 cycloalkyl, or may be joined together to form a 3- to 8-membered saturated heterocycle unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
Substituent group B is the group consisting of halogen atoms, C _1-6 alkyl, C _1-6 alkoxy, and haloC _1-6 alkyl;
When two or more groups selected from Substituent group B are present, each group may be the same or different;
R ² is C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 C _1-6 alkyl, 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 C _1-6 alkyl, haloC _1-6 alkyl, or C _1-6 alkylamino;
^R3 is a halogen atom, hydroxy, amino, _C1-6 alkyl, _haloC1-6 alkyl, _C1-6 alkoxy, or _C1-6 alkylamino;
n is an integer from 0 to 2;
When n is 2, each ^R3 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, C _3-8 cycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, 3 to 8-membered heterocycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, C _6-10 aryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, or 9- or 10-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C;
The substituent group C is the group consisting of 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 Substituent group C are present, the respective groups may be the same or different] or a pharmacologically acceptable salt thereof.
[4]
The compound according to the above [1], represented by formula (I-III):
[During the ceremony,
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;
^Y5 is C or N;
Y ⁶ , Y ⁷ , and Y ⁸ are each independently CR ^a1 , O, S, NR ^b3 , or N;
R ⁷ and R ⁸ are each independently a hydrogen atom, a halogen atom, or a C _1-6 alkyl;
When there are two or more R ^7s and two or more R ^8s , 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;
When two or more R ^a1 are present, each R ^a1 may be the same or different;
R ^b3 is a hydrogen atom, C _1-6 alkyl, or haloC _1-6 alkyl;
When two or more R ^b3 are present, each R ^b3 may be the same or different;
L ¹ is a single bond, CR ^a5 R ^a6 or NR ^c ;
R ^a5 and R ^a6 are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, or haloC _1-6 alkyl;
R ^c is a hydrogen atom, C _1-6 alkyl, or haloC _1-6 alkyl;
^L2 is a single bond or O;
R ¹ is COR ^d , 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;
Substituent group A is the group consisting of halogen atoms, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, and oxo;
When two or more groups selected from Substituent group A are present, each group may be the same or different;
R ^d is C _1-6 alkyl, C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 C _1-6 alkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, or NR ^e R ^e′ ;
R ^e and R ^e′ are each independently a hydrogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, haloC _1-6 alkyl, or C _3-8 cycloalkyl, or may be joined together to form a 3- to 8-membered saturated heterocycle unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
Substituent group B is the group consisting of halogen atoms, C _1-6 alkyl, C _1-6 alkoxy, and haloC _1-6 alkyl;
When two or more groups selected from Substituent group B are present, each group may be the same or different;
R ² is C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 C _1-6 alkyl, 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 C _1-6 alkyl, haloC _1-6 alkyl, or C _1-6 alkylamino;
^R3 is a halogen atom, hydroxy, amino, _C1-6 alkyl, _haloC1-6 alkyl, _C1-6 alkoxy, or _C1-6 alkylamino;
n is an integer from 0 to 2;
When n is 2, each ^R3 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, C _3-8 cycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, 3 to 8-membered heterocycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, C _6-10 aryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, or 9- or 10-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C;
The substituent group C is the group consisting of 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 Substituent group C are present, the respective groups may be the same or different] or a pharmacologically acceptable salt thereof.
[5]
The compound according to any one of [1] to [4] above;
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;
^Y3 is N;
^Y5 is C;
Y ⁶ , Y ⁷ , and Y ⁸ are CR ^al ;
q and s are 1;
t is 2;
R ^d is C _1-6 alkyl or NR ^e R ^e′ ;
R ^e and R ^e′ are each independently a hydrogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkyl, or C _3-8 cycloalkyl, or may be joined together to form a 3- to 8-membered saturated heterocycle unsubstituted or substituted with 1 to 3 C _1-6 alkyl;
A compound or a pharmacologically acceptable salt thereof, wherein ^R4 is a hydrogen atom, a _C2-6 alkenyl, a _C6-10 aryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, or a 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C.
[6]
The compound according to any one of [1] to [5] above;
^Y4 is CR ^a1 R ^a2 , O, or NR ^b2 ;
R ⁵ is a hydrogen atom or C _1-6 alkyl;
^R6 is a hydrogen atom;
^R7 and ^R8 are hydrogen atoms;
r is 1 or 2;
R ^a1 , R ^a2 , R ^a3 and R ^a4 are each independently a hydrogen atom, a halogen atom or a C _1-6 alkyl;
R ^b1 is a hydrogen atom or C _1-6 alkyl;
L ¹ is a single bond or NR ^c ;
R ^c is a hydrogen atom or a C _1-6 alkyl;
Substituent group A is the group consisting of C _1-6 alkyl, C _1-6 alkoxy, and oxo;
^R2 is _C1-6 alkyl, _C3-8 cycloalkyl, or _haloC1-6 alkyl;
^R3 is a halogen atom or _C1-6 alkyl;
n is 0 or 1;
A compound or a pharmacologically acceptable salt thereof, wherein the substituent group C is the group consisting of a halogen atom, a C _1-6 alkyl, and a C _1-6 alkoxy.
[7]
The compound according to any one of [1], [2], [5], and [6] above;
A compound or a pharmacologically acceptable salt thereof, wherein Y ¹ is CR ^a1 , O, or NR ^b1 .
[8]
The compound according to any one of [1] to [7] above;
^L1 is a single bond;
^R1 is COR ^d ;
A compound wherein R ^d is NR ^e R ^e′ or a pharmacologically acceptable salt thereof.
[9]
The compound according to any one of [1] to [8] above;
Ring W is C _6-10 aryl or 5- or 6-membered heteroaryl;
^L2 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 may be joined together to form a 3- to 8-membered saturated heterocycle unsubstituted or substituted with 1 to 3 C _1-6 alkyl;
A compound, or a pharmacologically acceptable salt thereof, wherein ^R4 is a _C6-10 aryl that is unsubstituted or substituted with one group selected from substituent group C, or a 5- or 6-membered heteroaryl that is unsubstituted or substituted with one group selected from substituent group C.
[10]
The compound according to any one of [1] or [5] to [9] above,
Ring Z is a ring represented by formula (1) or (2):
A compound or a pharmacologically acceptable salt thereof.
[11]
The 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
or a pharmacologically acceptable salt thereof.
[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
or a pharmacologically acceptable salt thereof.
[13]
The compound according to any one of [1], [3], or [5] to [10] above, 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.

In one embodiment, the present invention relates to a method for treating a sleep disorder involving OX2R, comprising administering to a patient a required amount of the pharmaceutical composition described in [14] above.

In one embodiment, the present invention relates to the use of a compound described in any of [1] to [13] above or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of a sleep disorder involving OX2R.

The compounds of the present invention have excellent OX2R agonist activity. Therefore, the compounds of the present invention or pharmacologically acceptable salts thereof are useful as therapeutic agents for sleep disorders involving OX2R.

Embodiments of the present invention are described in more detail below.

In this invention, each term has the following meaning unless otherwise specified.

"Halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom.
"C _1-6 alkyl" means a straight or branched alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
"C _2-6 alkenyl" means a straight or branched alkenyl group having 2 to 6 carbon atoms. Examples include ethenyl, 1-propenyl, and 2-propenyl.
"C _1-6 alkoxy" means a straight or branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like.

"Hydroxy C _1-6 alkyl" means C _1-6 alkyl substituted with 1 or 2 hydroxy groups. Examples include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, etc.
The term "haloC _1-6 alkyl" refers to a C _1-6 alkyl substituted with 1 to 5 of the same or different halogen atoms. Examples include monofluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, pentafluoroethyl, etc.
"C _1-6 alkoxy C _1-6 alkyl" means a C _1-6 alkyl substituted with one C _1-6 alkoxy, for example, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl and the like.

"C _6-10 aryl" means a phenyl group or a naphthyl group.
The term "5- or 6-membered heteroaryl" refers to 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.
The term "9- or 10-membered heteroaryl" refers to 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.

"C _3-8 cycloalkyl" means a 3- to 8-membered monocyclic saturated hydrocarbon group, such as cyclopropyl, cyclobutyl, and cyclopentyl.
"C _5-10 bicycloalkyl" means a 5- to 10-membered bicyclic saturated hydrocarbon group, such as 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.
The term "3- to 8-membered heterocycloalkyl" refers to a 3- to 8-membered cycloalkyl group in which carbon atoms in the ring are replaced by 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.

The term "3- to 8-membered saturated carbocyclic ring" refers to a monocyclic or polycyclic saturated hydrocarbon ring having from 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 a nitrogen atom, an oxygen atom, and a sulfur atom in the ring.

"3- to 8-membered saturated ring" means a 3- to 8-membered saturated carbocyclic ring or a 3- to 8-membered saturated heterocyclic ring.

"C _1-6 alkylamino" means a group represented by (C _1-6 alkyl)-NH- or a group represented by (C _1-6 alkyl) ₂ N-, where the two C _1-6 alkyls in the group represented by (C _1-6 alkyl) ₂ N- may be the same or different. Examples include methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, etc.

The following abbreviations used in the text, figures, and tables have the following meanings:
AZADOL®: 2-hydroxy-2-azaadamantane
Boc ₂ O: 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% wet with water)
Pd(Amphos) ₂ Cl ₂ : bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
Pd ₂ (dba) ₃ : Tris(dibenzylideneacetone)dipalladium(0)
Pd(dppf)Cl ₂ : 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
Pd(PPh ₃ ) 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 100% and the fluorescence intensity when only the vehicle was added was 0%.
CHO: Chinese hamster ovary
HEPES: 2-(4-(2-hydroxyethyl)-1-piperazinyl)ethanesulfonic acid

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

When cis-trans isomers exist in the compound represented by formula (I), the present invention encompasses both of these cis-trans isomers.

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

In the present invention, stereochemistry can also be determined by methods known in the art.

The compound represented by formula (I) can also be converted into a pharmacologically acceptable salt thereof, if necessary, in accordance with conventional methods. Such salts include acid addition salts and salts with bases.

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.

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.

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

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, and co-crystals with an appropriate co-crystal former.

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 isotopes of hydrogen, carbon, chlorine, fluorine, iodine, nitrogen, oxygen, and sulfur atoms, represented by ^2H , ^3H , ^11C , ^13C , ^14C , ^36Cl , ^18F , ^123I , ^125I , ^13N , ^15N , ^15O , ^17O , 18O, and ^35S , respectively. One embodiment includes a compound represented by formula ⁽ I) in which some of the hydrogen atoms are replaced with ^2H (D: deuterium atom).

Compounds represented by formula (I) in which some atoms are replaced with isotopes can be produced using commercially available reagents containing isotopes, in a similar manner to the production method described below. They can also be produced using methods 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).

The compounds 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 compounds of formula (I) correspond to the compounds of formulas (I-1) to (I-3).

The compounds of the present invention represented by formula (I) can be produced by the methods shown below. However, the following production methods are examples of general production methods and are not intended to limit the production methods.

For the reactions in each step, if the raw materials and reagents are commercially available, commercially available products can be used.

The reaction time for each step varies depending on the raw materials, solvent, reaction temperature, etc. used, but is usually between 30 minutes and 3 days unless otherwise specified.

In each step, the reaction temperature varies depending on the raw materials and solvents used, but unless otherwise specified, it is usually between -78°C and reflux temperature.

In the reactions of each step, the pressure varies depending on the raw materials, solvent, reaction temperature, etc. used, but unless otherwise specified, it is usually 1 to 20 atmospheres.

In the reactions of each step, a microwave reactor such as the Biotage Initiator may be used. When using a microwave reactor, the conditions vary depending on the raw materials, solvent, and model used, but can be adjusted as follows: pressure range: 1 to 30 bar, power range: 1 to 400 W, reaction temperature: room temperature to 300°C, reaction time: 1 minute to 1 day.

Unless otherwise specified, the reaction in each step is carried out without solvent or using an appropriate solvent. Examples of appropriate solvents include solvents inert to the reaction. Specific examples of the solvent to be 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 for use. 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.

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 magnesium compounds: isopropyl magnesium chloride, etc.;
Organolithium compounds: methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, etc.

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 to be used include the acids described in the Reference Examples and Examples corresponding to each step and 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.

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 to be used include the condensing agents described in the Reference Examples or Examples corresponding to each step, and 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.

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, and 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.

In each step, if a protecting group is required depending on the type of functional group, it is possible to carry out the steps by appropriately combining the introduction and removal procedures according to conventional methods. For details on the types of protecting groups, protection, and deprotection, see, for example, the methods described in "Greene's Protective Groups in Organic Synthesis," edited by Peter G. M. Wuts, fifth edition, Wiley-Interscience, 2014.

When hydrolysis is performed in each step, the reaction can be carried out in the presence of an acid or a base. Examples of acids and bases that can be used include those listed above.

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

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

When reduction is performed in each step, the reaction can be carried out in the presence of a reducing agent. Examples of reducing agents that can be used include those listed above.

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 condensing agents and bases that can be used include those listed above. When using carbodiimides as condensing agents, the reaction can be carried out by adding additives such as 1-hydroxybenzotriazole or DMAP, as needed. The reaction can also be carried out using a halogenating agent in the presence or absence of a base. Examples of halogenating agents that can be used include thionyl chloride, oxalyl chloride, phosphoryl chloride, sulfuryl chloride, phosphorus trichloride, and phosphorus pentachloride.

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

When an aromatic nucleophilic substitution reaction is carried out in each step, the reaction can be carried out in the presence of a base. Examples of bases include those listed above.

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 that can be used include those mentioned above.

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

When sulfonylation is performed in each step, the reaction can be carried out using a sulfonylating reagent in the presence of a base. Examples of sulfonylating reagents that can be used include methanesulfonyl chloride and ethanesulfonyl chloride. Examples of bases that can be used include those listed above.

When sulfamoylation is performed in each step, the reaction can be carried out using a sulfamoylating reagent in the presence of a base. Examples of sulfamoylating reagents that can be used include N-methylsulfamoyl chloride and dimethylsulfamoyl chloride. Examples of bases that can be used include those listed above.

When the Staudinger reaction is performed in each step, the reaction can be carried out using a phosphorus reagent. Examples of phosphorus reagents that can be used include triphenylphosphine.

When a Curtius rearrangement reaction is performed in each step, the reaction can be carried out by treating with an acid using an azide reagent. Examples of azide reagents that can be used include diphenylphosphoryl azide. Examples of acids that can be used include those listed above.

When hydroboration is performed in each step, the reaction can be carried out using a borane reagent. Examples of borane reagents that can be used include borane-THF complex.

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

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

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

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

The compound represented by formula (I) can also be produced by Staudinger reaction or catalytic reduction of compound (1-3), followed by sulfonylation or sulfamoylation.

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

The symbols in the formula have the same meanings as above, and ^X2 and ^X3 represent a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfonyloxy group.

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

Compound (1-4) can also be produced by converting the hydroxy group of compound (2-5) to a chlorine atom or bromine atom.

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

The symbols in the formula have the same meanings as above, and ^PG2 represents a protecting group.

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

Compound (3-3) can also be produced by hydrolyzing compound (3-2) and then amidating it.

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

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

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

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

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

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

Compound (3-10) can also be produced by hydrolyzing compound (3-9) followed by amidation.

The compound represented by formula (I-1) can also be produced by Staudinger reaction or catalytic reduction of compound (3-4), followed by sulfonylation or sulfamoylation.

The compound represented by formula (I-1) can also be produced by hydrolyzing compound (3-6) and then amidating it.

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

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

The symbols in the formula have the same meanings as above.

Compound (4-1) can also be produced by hydrolyzing compound (3-6) followed by a Curtius rearrangement reaction.

The compound represented by formula (I-2) can also be produced by reductively aminating compound (4-1), if necessary, followed by reaction with compound (4-2) in the presence of a base.

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

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

Compound (5-1) can also be produced by reducing compound (3-6).

Compound (5-2) can also be produced by hydrolysis of compound (3-6).

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.

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

The symbols in the formula have the same meanings as above. ^PG3 and ^PG4 represent protecting groups. u is an integer of 1 or 2.

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

Compound (6-3) can also be produced by removing the acetal protecting group from compound (6-2).

Compound (6-4) can also be prepared by removing PG ⁴ from compound (6-3) and subjecting it to reductive amination.

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

The symbols in the formula have the same meanings as above, and ^PG5 and ^PG6 represent protecting groups.

Compound (7-2) can also be produced by hydroborating compound (7-1) followed by treatment with aqueous sodium hydroxide and hydrogen peroxide.

Compound (7-3) can also be prepared by removing PG ⁶ from compound (7-2) and reacting it with compound (7-7) in the presence of a base.

Compound (7-4) can also be produced by reacting compound (7-3) with a base.

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

Compound (7-6) can also be produced by reducing the cyclic amide of compound (7-5).

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

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

The compounds of the present invention have excellent OX2R agonist activity and can therefore be used as therapeutic agents for sleep disorders involving OX2R. In the present invention, sleep disorders involving OX2R include, for example, narcolepsy, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to physical illness (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, and multiple myeloma. Examples of hypersomnia include hypersomnia due to sclerosis, 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 compounds of the present invention can be used as therapeutic agents for narcolepsy, idiopathic hypersomnia, Kleine-Levin syndrome, and sleep apnea syndrome. More preferably, the compounds of the present invention can be used as therapeutic agents for narcolepsy (see Patent Document 1).

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

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

While OX2R is involved in maintaining wakefulness, signaling through 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 agonistic activity against OX2R among orexin receptors. The agonistic activity against OX1R can be measured by a method well known in the art or a method equivalent thereto (see, for example, Non-Patent Document 4).

The therapeutic effect of the compounds of the present invention on sleep disorders involving OX2R can be confirmed using 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.

The pharmaceutical composition of the present invention may be used in a variety of dosage forms depending on the intended use. Examples of such dosage forms include powders, granules, fine granules, dry syrup, tablets, capsules, injections, liquids, ointments, suppositories, patches, eye drops, and enemas.

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

The pharmaceutical compositions of the present invention are prepared using a 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, using methods known in pharmaceutical sciences depending on the dosage form.

When the pharmaceutical composition of the present invention is used for treatment, the dose of the compound represented by formula (I) or a pharmacologically acceptable salt thereof is appropriately determined depending on the patient's age, sex, weight, disease, degree of treatment, etc. The daily dose may be administered in one, two, three, or four divided doses.
For oral or parenteral administration, 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.

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.

When a compound represented by formula (I) or a pharmacologically acceptable salt thereof is used in combination with another drug, these active ingredients can be administered as a formulation containing them together, or as a formulation in which each of these active ingredients is formulated separately. When formulated separately, these formulations can be administered separately or simultaneously. Furthermore, the dosage of a compound represented by formula (I) or a pharmacologically acceptable salt thereof may be reduced appropriately depending on the dosage of the other drug used in combination.

The compound represented by formula (I) may be converted into a prodrug as appropriate for use. For example, a prodrug of the compound represented by formula (I) can be produced by introducing a group constituting the prodrug using the corresponding halide, etc., and purifying it. Examples of groups constituting the prodrug include those described in "Development of Pharmaceuticals" (Hirokawa Shoten, 1990), Vol. 7, pp. 163-198.

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.

The names of the compounds described in the examples below, excluding commercially available reagents, were named using ChemDraw Professional (PerkinElmer), MarvinSketch (ChemAxon), etc. The configuration of asymmetric centers marked with an "*" in the compound names indicates that they are relative configurations.

Reference example A-1
(cis-4-(Chloromethoxy)cyclohexyl)benzene To a mixture of cis-4-phenylcyclohexanol (1.20 g) and DCM (12 mL) was added paraformaldehyde (0.225 g) and then chlorotrimethylsilane (2.22 g) at room temperature. 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).

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.

Reference example A-3
A mixture of 6-(5-fluoropyrimidin-2-yl)bicyclo[4.1.0]heptan-3-one 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 obtain 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).

Reference example A-4
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 silica gel short 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. 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).

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 give the title compound (4.08 g).

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(PPh ₃ ) 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 (eluent: 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).

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 give the title compound (1.13 g).

Reference example A-8
A mixture of 2-(5-(bromomethyl)-2-methylphenyl)-5-fluoropyrimidine (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 ₂ 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).

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.

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 solution (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. To the reaction mixture, a mixture of 1-(3-chlorobenzyl)cyclopent-3-ene-1-carboxylic acid (3.06 g) and chloroform (18 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture, DIPEA (2.17 g) was added 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 methyl (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 give the title compound (1.24 g).

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

Reference example B-5
To a mixture of (1R*,3S*)-1-(3-chlorobenzyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate (Reference Example B-1) (1.00 g), methanol (8 mL), and water (0.123 mL), triphenylphosphine (1.34 g) was added at room temperature. The mixture was stirred at the same temperature for 7 hours and concentrated under reduced pressure.
To a mixture of the residue, TEA (1.03 g), and DCM (8 mL) was added methanesulfonyl chloride (0.585 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 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 the title compound (1.00 g).

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), Boc ₂ O (0.348 g), and ethyl acetate (5 mL), 10% Pd/C (0.076 g) was added 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) was added methanesulfonyl chloride (0.092 g) 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 give the title compound (0.181 g).

Reference example B-7 to reference example 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.

Reference example B-9 to reference example 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.

Reference example B-11
A mixture of (1R*,3S*)-1-([1,1'-biphenyl]-3-ylmethyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate (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 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 silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 90/10 to 50/50) to obtain the title compound (0.280 g).

Reference example B-12
A mixture of (1R*,3S*)-1-([1,1'-biphenyl]-3-ylmethyl)-3-(methylsulfonamido)cyclopentane-1-carboxylic acid (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).

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 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 APS column chromatography (elution solvent:
The mixture was purified with ethyl acetate/methanol (100/0 to 98/2) to give the title compound (0.074 g).

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).

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.

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.

Reference example B-17
Methyl ((1R*,3S*)-1-([1,1'-biphenyl]-3-ylmethyl)-3-(methylsulfonamido)cyclopentyl)carbamate. To a mixture of Reference Example B-13 (0.006 g), DIPEA (0.030 g), and DCM (1 mL), methyl chloroformate (0.012 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 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).

Reference example C-1
A mixture of methyl (1S,4R)-4-((diphenylmethylene)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).

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. 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 under a hydrogen atmosphere at room temperature for 2 hours, and 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. 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 (elution solvent: n-hexane/ethyl acetate = 90/10 to 50/50) to obtain the title compound (0.689 g).

Reference example D-1
(1r,4r)-4-Azido-1-(3-(5-fluoropyrimidin-2-yl)benzyl)cyclohexane-1-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 (eluent: 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) was added sodium azide (0.181 g) at room temperature. The mixture was stirred at 70°C for 11 hours 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. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 50/50) to obtain the title compound (0.070 g).

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.

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).

Reference example D-4
To a mixture of methyl 5-hydroxypicolinate (1.02 g), hydrogen chloride (5-10% in methanol) (0.301 mL), and ethanol (10 mL), 5% rhodium on carbon (0.198 g) was added at room temperature, and the mixture was stirred under hydrogen pressure (0.4 MPa) at the same temperature for 17.5 hours. 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) was added Boc ₂ O (1.73 g) 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 (eluent: n-hexane/ethyl acetate = 100/0 to 50/50) to give the title compound (0.528 g).

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 in place of methyl 4-hydroxycyclohexane-1-carboxylate.

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.

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 (eluent: n-hexane/ethyl acetate = 100/0 to 70/30) to give the title compound (0.373 g).

Reference example E-2
Methyl (2S*,4R*)-2-([1,1'-biphenyl]-3-ylmethyl)-4-azidotetrahydrofuran-2-carboxylate. Under an argon atmosphere, LDA (1.11 mol/L in THF/n-hexane) (1.3 mL) was added to a mixture of Reference Example E-1 (0.370 g) and THF (6 mL) at −78°C, and the mixture was stirred at the same temperature for 30 minutes. A mixture of 1-(bromomethyl)-3-phenylbenzene (0.333 g) and THF (3 mL) was added to the reaction mixture 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 (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 then 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 (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) was added methanesulfonyl chloride (0.053 g) 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) was added sodium azide (0.061 g) 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 give the title compound (0.085 g).

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.

Reference example E-4
To a mixture of (2S*,4R*)-2-([1,1'-biphenyl]-3-ylmethyl)-4-(methylsulfonamido)tetrahydrofuran-2-carboxylic acid 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) was added methanesulfonyl chloride (0.034 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 = 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 obtain the title compound (0.069 g).

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.

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.

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 resulting 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 then concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane/ethyl acetate = 60/40 to 40/60) and then 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 obtained compound (0.157 g), TEA (0.077 g), and DCM (2 mL) was added methanesulfonyl chloride (0.066 g) 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) was added sodium azide (0.074 g) 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).

Reference example F-3 to reference example 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.

Reference example F-5
(2S,4R)-2-([1,1'-biphenyl]-3-ylmethyl)-1-(tert-butoxycarbonyl)-4-(methylsulfonamido)pyrrolidine-2-carboxylic acid Reference Example F-2 (0.115 g), ethanol (1 mL), and THF (1 mL) were mixed and cooled with ice to add 10% Pd/C (0.023 g). 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).

Reference example F-6
(2S,4R)-2-(3-(5-bromopyrimidin-2-yl)benzyl)-1-(tert-butoxycarbonyl)-4-(methylsulfonamido)pyrrolidine-2-carboxylic acid Reference Example F-3 (0.382 g), methanol (10 mL), and water (0.027 mL) were added to a mixture of triphenylphosphine (0.290 g) 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) was added methanesulfonyl chloride (0.127 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 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).

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) was added methanesulfonyl chloride (0.522 g) 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 obtain the title compound (0.583 g).

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.

Reference example F-9
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 (eluent: 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).

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).

Reference example F-11
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).
To a mixture of the obtained compound (0.959 g), TEA (0.749 g), and DCM (10 mL), methanesulfonyl chloride (0.635 g) was added 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).

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 under microwave irradiation at 100° C. for 4 hours and then concentrated under reduced pressure.
To a mixture of the residue, TEA (0.030 g), and DCM (1 mL) was added methanesulfonyl chloride (0.025 g) under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture, TEA (0.030 g) and methanesulfonyl chloride (0.025 g) were added 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).

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. Saturated aqueous sodium bicarbonate and 30% aqueous hydrogen peroxide were added to the reaction mixture 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 (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-5-hydroxypyrrolidine-1,2-dicarboxylate 1-tert-butyl 2-methyl ester (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. 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. 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) was added boron trifluoride diethyl ether complex (1.46 g) and allyltrimethylsilane (4.41 g) at -78°C, and the mixture was stirred at the same temperature for 20 minutes and at room 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 (eluent: n-hexane/ethyl acetate = 100/0 to 80/20) to obtain the title compound (2.42 g).

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. 2 mol/L aqueous sodium hydroxide solution (19 mL) and 30% aqueous hydrogen peroxide (15 mL) were added to the reaction mixture 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 (2S,4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylate 1-tert-butyl 2-methyl (2.59 g).
Under an argon atmosphere, Dess-Martin periodinane (5.52 g), DCM (1 mL), and water (0.123 mL) were added to a mixture of the resulting compound (2.59 g) and DCM (30 mL) 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. A 2 mol/L aqueous solution of sodium hydroxide 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 80/20) to obtain the title compound (1.46 g).

Reference example G-3
(1R,3S,7aS)-3-(3-Bromobenzyl)-1-(methylsulfonamido)hexahydro-1H-pyrrolidine-3-carboxylate Methyl ester. Under an argon atmosphere, lithium bis(trimethylsilyl)amide (1.0 mol/L in THF) (3 mL) was added to a mixture of Reference Example G-1 (1.00 g), 1-bromo-3-(bromomethyl)benzene (0.657 g), and THF (10 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 (2S,4S,5S)-5-allyl-2-(3-bromobenzyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate 1-tert-butyl 2-methyl (1.32 g).
Under an argon atmosphere, to a mixture of the obtained compound (1.32 g) and THF (20 mL) was added borane-THF complex (0.9 mol/L in THF) (3.9 mL) 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 (2S,4S,5S)-2-(3-bromobenzyl)-4-((tert-butyldimethylsilyl)oxy)-5-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylate 1-tert-butyl 2-methyl (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 poured into 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 added to 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. 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. 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 obtained 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 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, 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 obtained 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 concentrated under reduced pressure.
To a mixture of the residue, TEA (0.133 g), and DCM (2 mL) was added methanesulfonyl chloride (0.113 g) under ice-cooling, and the mixture was stirred at room temperature for 15 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 = 60/40 to 30/70) to give the title compound (0.220 g).

Reference example G-4
Methyl (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 (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-dicarboxylic acid 1-tert-butyl 2-methyl (0.659 g).
To a mixture of the obtained compound (0.659 g) and DCM (5 mL) was added trifluoroacetic acid (3.49 g) 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. Saturated aqueous sodium bicarbonate solution 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 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 100/0 to 40/60) to obtain the title compound (0.346 g).

Reference example G-5
Methyl (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. 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 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 obtained 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) was added sodium azide (0.115 g) 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).

Reference example G-6
A mixture of (1R,3S,7aS)-3-(3-(5-fluoropyrimidin-2-yl)benzyl)-1-(methylsulfonamido)hexahydro-1H-pyrrolidine-3-carboxylate 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.
To a mixture of the residue, TEA (0.033 g), and DCM (1 mL) was added methanesulfonyl chloride (0.028 g) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, TEA (0.033 g) and methanesulfonyl chloride (0.028 g) were added under ice-cooling, and the mixture was stirred at room temperature for 5 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 (elution solvent: n-hexane/ethyl acetate = 60/40 to 30/70) to obtain the title compound (0.040 g).

Reference example G-7
Methyl (1S,3S,7aS)-1-((tert-butyldimethylsilyl)oxy)-3-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)hexahydro-1H-pyrrolidine-3-carboxylate. Under an argon atmosphere, to a mixture of Reference Example G-1 (0.542 g) and THF (3 mL) was added borane-THF complex (0.9 mol/L in THF) (2.3 mL) 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 were added 2 mol/L aqueous sodium hydroxide solution (3.4 mL) and 35% aqueous hydrogen peroxide (2.4 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 = 50/50 to 20/80) to give (2S,4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylate 1-tert-butyl 2-methyl ester (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 obtained compound (0.025 g) and THF (0.5 mL), sodium bis(trimethylsilyl)amide (1.0 mol/L in THF) (0.1 mL) was added at -78°C. The mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, a mixture of Reference Example A-6 (0.025 g) and THF (0.5 mL) was added 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 (elution solvent: n-hexane/ethyl acetate = 90/10 to 80/20) to obtain the title compound (0.012 g).

Reference example G-8 to reference example 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.

Reference example G-10 to reference example 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.

Reference example G-13 to reference example 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.

Reference example G-16
A mixture of (1R,3S,7aS)-1-((tert-butoxycarbonyl)amino)-3-(3-(5-fluoropyrimidin-2-yl)benzyl)hexahydro-1H-pyrrolidine-3-carboxylate 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, Boc ₂ O (1.51 g), and DCM (70 mL) was stirred at room temperature for 30 minutes. Saturated aqueous 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 give the title compound (2.00 g).

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).

Reference example G-18
tert-Butyl ((1R,3S,7aS)-3-(dimethylcarbamoyl)-3-(3-(5-fluoropyrimidin-2-yl)benzyl)hexahydro-1H-pyrrolidin-1-yl)carbamate. To a mixture of Reference Example G-17 (0.022 g), dimethylamine hydrochloride (0.039 g), DIPEA (0.093 g), and DMF (2 mL), HATU (0.020 g) was 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 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 obtain the title compound (0.015 g).

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).

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).

Reference example H-3
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 added to 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 for 1 hour under microwave irradiation. The reaction mixture was added to 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 (eluent: n-hexane/ethyl acetate = 100/0 to 75/25) to obtain the title compound (0.285 g).

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 (2S,4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylate 1-tert-butyl 2-methyl (2.59 g).
Under an argon atmosphere, Dess-Martin periodinane (5.52 g), DCM (1 mL), and water (0.123 mL) were added to a mixture of the resulting compound (2.59 g) and DCM (30 mL) 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, 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) was added under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hours and 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 (2S,4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-(4-methoxybut-3-en-1-yl)pyrrolidine-1,2-dicarboxylate 1-tert-butyl 2-methyl (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 (elution solvent: n-hexane/ethyl acetate = 100/0 to 80/20) to obtain the title compound (0.018 g).

Reference example H-5
Methyl (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 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 (2S,4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate 1-tert-butyl 2-methyl ester (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 (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).

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.

Reference example H-7
Methyl (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 concentrated under reduced pressure to give methyl (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 obtain the title compound (0.152 g).

Reference example H-8 to reference example 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.

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

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.

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.
To a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (1.45 g), DIPEA (2.41 g), and DMF (19 mL) was added HATU (1.56 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 (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 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.
A mixture of the residue, isopropenylboronic acid pinacol ester (0.021 g), Pd(Amphos) ₂ Cl ₂ (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. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 60/40 to 0/100) followed by APS column chromatography (eluent: n-hexane/ethyl acetate = 60/40 to 0/100) to give the title compound (0.019 g).

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).

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).

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.
To a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (0.033 g), DIPEA (0.055 g), and DMF (1 mL) was added HATU (0.036 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 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 under a hydrogen atmosphere at room temperature 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).

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 (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.
To a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (0.032 g), DIPEA (0.072 g), and DMF (1 mL) was added HATU (0.046 g) 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).

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.

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) was added methanesulfonyl chloride (0.006 g) 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 (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), tripotassium phosphate (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 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 give methyl (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).
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) was added HATU (3.4 mg) 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 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 0/100) to obtain the title compound (1.6 mg).

Example 8
(1R*,3S*)-N-Methoxy-N-methyl-3-(methylsulfonamido)-1-((5-(pyrimidin-2-yl)thiophen-3-yl)methyl)cyclopentane-1-carboxamide Reference Example B-10 (0.020 g), methanol (1 mL), and water (0.002 mL) were added to a mixture of triphenylphosphine (0.026 g) 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) was added methanesulfonyl chloride (0.012 g) under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. 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 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.
To a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (0.009 g), DIPEA (0.030 g), and DMF (0.5 mL) was added HATU (0.020 g) 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), Pd ₂ (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 ₂ 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 give the title compound (1.6 mg).

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 poured into 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).
To a mixture of the obtained compound (0.025 g) and DCM (2 mL), tetrachloroauric acid tetrahydrate (0.005 g) was added 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 obtain the title compound (0.008 g).

Example 10
N-((1S*,3R*)-3-([1,1'-biphenyl]-3-ylmethyl)-3-(3-methoxypyridin-2-yl)cyclopentyl)methanesulfonamide Reference Example B-11 (0.394 g), potassium carbonate (0.422 g), tetrabutylammonium iodide (0.075 g), and DMF (2 mL) were mixed and added with 4-methoxybenzyl chloride (0.239 g) 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.
To a mixture of the residue and THF (2 mL) was added lithium aluminum hydride (0.077 g) 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 resulting 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).
To a mixture of magnesium (0.407 g) and THF (7 mL) was added 1,2-dibromoethane (0.480 g). 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. To the reaction mixture was added a mixture of chloro(methoxy)methane (1.31 g) and toluene (5 mL) under ice cooling. The reaction mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added 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) at -23°C, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added saturated aqueous ammonium chloride solution and water under ice-cooling, and the mixture was extracted with ethyl acetate, 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 obtain the title compound (0.003 g).

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 (1R*,3S*)-1-(3-chlorobenzyl)-3-(N-(4-methoxybenzyl)methylsulfonamido)cyclopentane-1-carboxylate (0.223 g).
To a mixture of the obtained 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. To the reaction mixture, 1 mol/L aqueous sodium thiosulfate solution was added 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.
To a mixture of the residue and THF (2 mL), sodium hydride (approximately 60% in mineral oil) (0.014 g) was added at room temperature, and the mixture was stirred at the same temperature for 15 minutes. Bromoethane (0.090 g) was added to the reaction mixture 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 obtained 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 ₂ 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).

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).

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. Sodium borohydride (3.0 mg) was added to the reaction mixture 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) was added isobutyryl chloride (0.005 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 = 50/50 to 0/100) to obtain the title compound (4.0 mg).

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

Example 15
N-((1S*,3R*)-3-([1,1'-biphenyl]-3-ylmethyl)-3-(2-oxopyrrolidin-1-yl)cyclopentyl)methanesulfonamide Reference Example B-16 (0.025 g), TEA (0.011 g), and DCM (1 mL) were mixed at room temperature, and 4-chlorobutyryl chloride (0.013 g) was added. 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 solution of ammonium chloride 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).

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, a mixture of Reference Example C-1 (2.26 g), Reference Example A-6 (2.22 g), and THF (23 mL) was added with lithium bis(trimethylsilyl)amide (1.11 mol/L in THF) (8 mL) in an ice-salt bath, and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added lithium bis(trimethylsilyl)amide (1.11 mol/L in THF) (2 mL) 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 (1R,4R)-4-((diphenylmethylene)amino)-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)cyclopent-2-ene-1-carboxylate methyl ester (2.13 g).
To a mixture of the obtained 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 a 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), triethanolamine (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.
To a mixture of the residue and THF (4 mL), 2 mol/L aqueous sodium hydroxide solution (3 mL) was added 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) were added DMF (3.8 mg) and then oxalyl chloride (0.078 g) at room temperature, and 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, 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 = 40/60 to 10/90) to give the title compound (0.128 g).

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).

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. N,O-dimethylhydroxylamine hydrochloride (0.010 g) and DIPEA (0.022 g) were added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 1 hour. DMAP (0.007 g) was added to the reaction mixture 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).

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).

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).

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

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).

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

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 then 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).

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.

Example 28
A mixture of (2S,4R)-2-([1,1'-biphenyl]-3-ylmethyl)-N-ethyl-N,1-dimethyl-4-(methylsulfonamido)pyrrolidine-2-carboxamide (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).

Example 29
A mixture of (2S,4R)-2-([1,1'-biphenyl]-3-ylmethyl)-N,1-diethyl-N-methyl-4-(methylsulfonamido)pyrrolidine-2-carboxamide (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).

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

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.

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.

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 then 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, 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).

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 (2S,4R)-2-(3-(5-bromopyrimidin-2-yl)benzyl)-2-(methoxy(methyl)carbamoyl)-4-(methylsulfonamido)pyrrolidine-1-carboxylate tert-butyl ester (0.054 g).
To a mixture of the obtained compound (0.054 g), TEA (0.009 g), ethanol (1 mL), and THF (1 mL) was added 10% Pd/C (0.011 g) 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 give the title compound (0.028 g).

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.

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

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.

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 (2S, 4R, 5S)-2- (dimethylcarbamoyl) -2- (3- (5-fluoropyrimidin-2-yl) benzyl) -5-methyl-4- (methylsulfonamido) pyrrolidine-1-carboxylate tert-butyl ester (0.010 g).
A mixture of the obtained 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. 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, 37% aqueous formaldehyde (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 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 20/80) to obtain the title compound (3.9 mg).

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 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/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).

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.

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 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 = 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(PPh ₃ ) 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).

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 allowed to cool to room temperature. 2 mol/L aqueous sodium hydroxide solution (0.195 mL), water (0.2 mL), and 2-propanol (0.5 mL) were added to the reaction mixture at room temperature, and the mixture was 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.
To a mixture of the residue, dimethylamine hydrochloride (0.026 g), DIPEA (0.061 g), and DMF (1 mL) was added HATU (0.033 g) at room temperature, and 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 Examples 42 and 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 second was Example 43.

Example 44
(1R,3S,7aS)-3-(3-(5-fluoropyrimidin-2-yl)-4-methylbenzyl)-N,N-dimethyl-1-(methylsulfonamido)hexahydro-1H-pyrrolidine-3-carboxamide 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) were 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.
To a mixture of the residue, dimethylamine hydrochloride (0.007 g), DIPEA (0.042 g), and DMF (0.5 mL) was added HATU (0.009 g) 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).

Examples 45 to 46
Examples 45 and 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.

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.
To a mixture of the residue, methylamine hydrochloride (0.017 g), DIPEA (0.045 g), and DMF (1 mL) was added HATU (0.010 g) at room temperature, and 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).

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

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.
To a mixture of the residue, TEA (0.007 g), and DCM (2 mL) was added methanesulfonyl chloride (2.9 mg) 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 give the title compound (2.0 mg).

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.

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.
To a mixture of the residue, TEA (2.3 mg), and DCM (2 mL) was added methanesulfonyl chloride (0.007 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 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 (3.0 mg).

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) was added ethanesulfonyl chloride (0.063 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 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) followed by ODS column chromatography (eluent: water/MeCN = 70/30 to 10/90) to give the title compound (0.038 g).

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

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) followed by ODS column chromatography (eluent: water/MeCN = 70/30 to 10/90) to obtain the title compound (2.0 mg).

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

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.
To a mixture of the residue (0.038 g), DIPEA (0.056 g), and DMF (1 mL) was added HATU (0.049 g) 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).

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 then at 100° C. under microwave irradiation for 4.5 hours. 2 mol/L hydrochloric acid (0.073 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure.
To a mixture of the residue, dimethylamine hydrochloride (0.014 g), DIPEA (0.032 g), and DMF (1 mL) was added HATU (0.017 g) 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. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 70/30 to 50/50) to give the title compound (0.013 g).

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) was added methanesulfonyl chloride (0.013 g) under ice-cooling, and the mixture was stirred at room temperature for 15 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.
A mixture of the residue, 2 mol/L aqueous sodium hydroxide solution (0.145 mL), and methanol (1 mL) was stirred under microwave irradiation at 100° C. for 10 minutes. To the reaction mixture was added 2 mol/L hydrochloric acid, and the mixture was concentrated under reduced pressure.
To a mixture of the residue, dimethylamine hydrochloride (0.047 g), DIPEA (0.113 g), and DMF (2 mL) was added HATU (0.024 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 = 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)Cl ₂ (2.7 mg), Xphos (3.5 mg), and 1,4-dioxane (1 mL) was stirred under microwave irradiation at 120° C. for 15 minutes. 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 under microwave irradiation at 110° C. for 1 hour and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane/ethyl acetate=70/30 to 0/100) and then by ODS column chromatography (eluent: water/MeCN=70/30 to 10/90) to obtain the title compound (0.005 g).

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

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

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

Test Example 1

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.

2) Measurement of OX2R Agonist Activity. The agonistic effect of test substances on human OX2R was assessed using stimulation-induced changes in intracellular calcium concentration as an index. On the day before intracellular calcium concentration measurements, human OX2R-expressing cells suspended in medium were seeded into a 384-well plate at 5 x ¹⁰ cells/50 μL/well and cultured overnight in an incubator set at 37°C and 5% _CO2 . After culture, 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) at an excitation wavelength of 480 nm and an emission wavelength of 540 nm. Twenty seconds after the start of 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 used was a solution prepared by diluting dimethyl sulfoxide to a final concentration of 0.1% in assay buffer containing 0.1% bovine serum albumin (Fujifilm Wako Pure Chemical Corporation). The fluorescence intensity upon addition of human orexin A peptide (Peptide Institute, Inc.) at a final concentration of 1 μM was defined as 100%, and the fluorescence intensity upon addition of vehicle alone was defined as 0%. The agonist activity of the test substance against human OX2R was calculated based on this. The activation rate of each test substance at a compound concentration of 10 μM is shown in the table above. In the table, the activation rate is expressed as follows: Act. ≥ 75%: A, 75% > Act. ≥ 50%: B, 50% > Act. ≥ 30%: C. These results demonstrate that the compounds of the present invention have agonist activity against human OX2R.

The compounds of the present invention or pharmacologically acceptable salts thereof have OX2R agonist activity and are therefore useful as therapeutic agents for sleep disorders involving OX2R.

Claims (12)

Compounds of formula (I):
[During the ceremony,
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 , CR ^a1 , O, or NR ^b1 ;
^Y2 is ^CR5R6 or ^{CR5 ;
Y3} is CR ^a1 or N;
^Y4 is a single bond, CR ^a1 R ^a2 , O, or NR ^b2 ;
^Y5 is C or N;
Y ⁶ , Y ⁷ , and Y ⁸ are each independently CR ^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, C _1-6 alkyl, haloC _1-6 alkyl, or C _1-6 alkoxy, or may be joined 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 a C _1-6 alkyl;
When there are two or more R ^7s and two or more R ^8s , 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, C _1-6 alkyl, or haloC _1-6 alkyl;
When there are two or more R ^a1 and two or more R ^a2 , 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;
When two or more R ^b3 are present, each R ^b3 may be the same or different;
L ¹ is a single bond, CR ^a5 R ^a6 or NR ^c ;
R ^a5 and R ^a6 are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, or haloC _1-6 alkyl;
R ^c is a hydrogen atom, C _1-6 alkyl, or haloC _1-6 alkyl;
^L2 is a single bond or O;
R ¹ is COR ^d , 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;
Substituent group A is the group consisting of halogen atoms, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, and oxo;
When two or more groups selected from Substituent group A are present, each group may be the same or different;
R ^d is C _1-6 alkyl, C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 C _1-6 alkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, or NR ^e R ^e′ ;
R ^e and R ^e′ are each independently a hydrogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkoxyC _1-6 alkyl, haloC _1-6 alkyl, or C _3-8 cycloalkyl, or may be joined together to form a 3- to 8-membered saturated heterocycle unsubstituted or substituted with 1 to 3 groups selected from the substituent group B;
Substituent group B is the group consisting of halogen atoms, C _1-6 alkyl, C _1-6 alkoxy, and haloC _1-6 alkyl;
When two or more groups selected from Substituent group B are present, each group may be the same or different;
R ² is C _1-6 alkyl, C _2-6 alkenyl, C _3-8 cycloalkyl unsubstituted or substituted with 1 to 3 C _1-6 alkyl, 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 C _1-6 alkyl, haloC _1-6 alkyl, or C _1-6 alkylamino;
^R3 is a halogen atom, hydroxy, amino, _C1-6 alkyl, _haloC1-6 alkyl, _C1-6 alkoxy, or _C1-6 alkylamino;
n is an integer from 0 to 2;
When n is 2, each ^R3 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, C _3-8 cycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, 3 to 8-membered heterocycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, C _6-10 aryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, or 9- or 10-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C;
The substituent group C is the group consisting of 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, the groups may be the same or different from each other (provided that when 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 , any one of the following (a) to (f) is selected):
(a) L ¹ is CR ^a5 R ^a6 or NR ^c
(b) ^L2 is O
(c) Ring W is C _3-8 cycloalkyl, C _5-10 bicycloalkyl, 3- to 8-membered heterocycloalkyl, naphthalene, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl.
(d) R ⁴ is a hydrogen atom, a halogen atom, C _1-6 alkyl, C _2-6 alkenyl, haloC _1-6 alkyl, C _3-8 cycloalkyl unsubstituted or substituted with 1 or 2 groups selected from the substituent group C, or a 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group C.
(e) R ¹ 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.
(f) ^R5 is _haloC1-6 alkyl or together with ^R6 forms a 3- to 8-membered saturated ring.
or a pharmacologically acceptable salt thereof. 10. The compound of claim 1 ,
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;
^Y3 is N;
^Y5 is C;
Y ⁶ , Y ⁷ , and Y ⁸ are CR ^al ;
q and s are 1;
t is 2;
R ^d is C _1-6 alkyl or NR ^e R ^e′ ;
R ^e and R ^e′ are each independently a hydrogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, haloC _1-6 alkyl, or C _3-8 cycloalkyl, or may be joined together to form a 3- to 8-membered saturated heterocycle unsubstituted or substituted with 1 to 3 C _1-6 alkyl;
A compound, or a pharmacologically acceptable salt thereof, wherein ^R4 is a hydrogen atom, a _C2-6 alkenyl, a _C6-10 aryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C, or a 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from substituent group C. 3. The compound of claim 2 ;
^Y4 is CR ^a1 R ^a2 , O, or NR ^b2 ;
R ⁵ is a hydrogen atom or C _1-6 alkyl;
^R6 is a hydrogen atom;
^R7 and ^R8 are hydrogen atoms;
r is 1 or 2;
R ^a1 , R ^a2 , R ^a3 and R ^a4 are each independently a hydrogen atom, a halogen atom or a C _1-6 alkyl;
R ^b1 is a hydrogen atom or C _1-6 alkyl;
L ¹ is a single bond or NR ^c ;
R ^c is a hydrogen atom or a C _1-6 alkyl;
Substituent group A is the group consisting of C _1-6 alkyl, C _1-6 alkoxy, and oxo;
^R2 is _C1-6 alkyl, _C3-8 cycloalkyl, or _haloC1-6 alkyl;
^R3 is a halogen atom or _C1-6 alkyl;
n is 0 or 1;
A compound or a pharmacologically acceptable salt thereof, wherein the substituent group C is the group consisting of a halogen atom, a C _1-6 alkyl, and a C _1-6 alkoxy. 4. The compound of claim 3 ,
A compound or a pharmacologically acceptable salt thereof, wherein Y ¹ is CR ^a1 , O, or NR ^b1 . 5. The compound of claim 4,
^L1 is a single bond;
^R1 is COR ^d ;
A compound wherein R ^d is NR ^e R ^e′ or a pharmacologically acceptable salt thereof. 6. The compound of claim 5 ,
Ring W is C _6-10 aryl or 5- or 6-membered heteroaryl;
^L2 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 may be joined together to form a 3- to 8-membered saturated heterocycle unsubstituted or substituted with 1 to 3 C _1-6 alkyl;
A compound, or a pharmacologically acceptable salt thereof, wherein ^R4 is a _C6-10 aryl that is unsubstituted or substituted with one group selected from substituent group C, or a 5- or 6-membered heteroaryl that is unsubstituted or substituted with one group selected from substituent group C. A compound selected from the group consisting of the following compounds:
and
or a pharmacologically acceptable salt thereof. A compound selected from the group consisting of the following compounds:
and
or a pharmacologically acceptable salt thereof. A compound selected from the group consisting of the following compounds:
and
or a pharmacologically acceptable salt thereof. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmacologically acceptable salt thereof, and a pharmaceutical excipient. The pharmaceutical composition according to claim 10, which is a pharmaceutical composition for treating a sleep disorder involving OX2R. The pharmaceutical composition according to claim 11, wherein the sleep disorder involving OX2R is narcolepsy.