N-substituted cyclic amide compound

Abstract

The present invention addresses the problem of providing a novel compound that has a thyroid-stimulating hormone receptor antagonistic activity and is useful for the treatment of thyroid-related diseases. The present invention relates to an N-substituted cyclic amide compound represented by the formula or a pharmacologically acceptable salt thereof. The compound or the pharmacologically acceptable salt thereof according to the present invention has a thyroid-stimulating hormone receptor antagonistic activity and is useful as a therapeutic agent for thyroid-related diseases (e.g., hyperthyroidism, Graves' disease, thyroid eye disease, and thyroid cancer) and others.

Description

N-substituted cyclic amide compounds

[0001] The present invention relates to an N-substituted cyclic amide compound useful as a pharmaceutical. More specifically, the present invention relates to an N-substituted cyclic amide compound or a pharmacologically acceptable salt thereof that has antagonist activity against the thyroid-stimulating hormone receptor (TSHR) and is useful as a therapeutic agent for thyroid-related diseases.

[0002] The thyroid hormones triiodothyronine (T3) and thyroxine (T4) play important roles in development, growth, and metabolism, and their synthesis and secretion are strictly regulated by thyroid-stimulating hormone (TSH) secreted from the pituitary gland.

[0003] In hyperthyroidism, these thyroid hormones are secreted in excess for some reason, and the hormonal effects of this excess can cause a variety of undesirable physical and mental effects, including goiter, tachycardia, high blood pressure, fatigue, weight loss, palpitations, sleep disorders, and menstrual irregularities.

[0004] There are various causes of hyperthyroidism, but the most common is Graves' disease. In Graves' disease, an autoimmune mechanism causes the thyroid gland to be recognized as a foreign body, resulting in the production of autoantibodies against the TSHR present on thyroid follicular cells, known as TSHR antibodies (TRAb). It is thought that these TRAb act as TSHR agonists, overstimulating the TSHR and resulting in the secretion of more thyroid hormones than necessary, resulting in hyperthyroidism.

[0005] Thyroid eye disease is also known to be associated with Graves' disease. Thyroid eye disease is an autoimmune inflammatory disease that presents with a variety of ocular symptoms and is thought to be primarily caused by the agonistic action of TRAb on TSHR in the orbital tissue. It often develops around the same time as hyperthyroidism, but may not be accompanied by thyroid dysfunction.

[0006] Currently, Graves' disease is treated with antithyroid drugs such as thiamazole and propylthiouracil, which inhibit the biosynthesis of thyroid hormones. However, these drugs have problems such as a low remission rate, a long treatment period until remission is achieved, and a high incidence of side effects. Therefore, there is a need for drugs with a new mechanism of action for the treatment of Graves' disease.

[0007] Blocking TSHR or inhibiting signal transduction induced through TSHR inhibits thyroid hormone production, secretion, and thyroid cell proliferation. Therefore, TSHR antagonists are thought to be effective in treating Graves' disease and thyroid eye disease, which are caused by the agonistic action of TRAb on TSHR (Patent Documents 1 and 2). NCGC00242364 is a known TSHR antagonist, and has been shown to reduce blood T4 levels in mice administered with TSH-releasing hormone (TRH) and the thyroid-stimulating antibody M22 (Non-Patent Document 1).

[0008] Compounds having TSHR antagonist activity are described in Patent Documents 1 to 3 and Non-Patent Document 1. However, the N-substituted cyclic amide compound of the present invention is not described in any of Patent Documents 1 to 3 or Non-Patent Document 1.

[0009] US Patent Application Publication No. 2011 / 0172267 US Patent Application Publication No. 2012 / 0315217 US Patent Application Publication No. 2019 / 0134024

[0010] Susanne Neumann et al., Endocrinology 2014, Vol. 155, No. 1, pp. 310-314

[0011] An objective of the present invention is to provide novel compounds that have TSHR antagonist activity and are useful for treating thyroid-related diseases.

[0012] The present invention relates to a compound represented by the following formula (AI) or a pharmacologically acceptable salt thereof:

[0013] That is, the present invention relates to the following [A-1] to [A-51] and [B-1] to [B-51], etc. [A-1] A compound represented by formula (A-I): [wherein ring A is a group represented by the following formula (1), (2) or (3): W, X and Y each independently represent -CR 1b = or -N=; Q is -CR Q1 =, -CR Q1 R Q1’ -, -O-, -N= or -NR Q2 - and R Q1 and R Q1’ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, or C 1-6 Alkyl or haloC 1-6 alkyl; R Q2 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 Ring B is a 5- or 6-membered heteroaryl or benzene; R 1a and R 1c are each independently a halogen atom, hydroxy, carboxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, Hydroxy C 1-6 Alkyl, carboxy C 1-6 Alkyl, Amino C 1-6 Alkyl, Cyano C 1-6 Alkyl, -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , unsubstituted or substituted with 1 to 6 groups selected from the substituent group A -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), -(C1-6 (Alkylene)-NR 7 COR 8 , -(C 1-6 (Alkylene)-NR 7 COOR 9 , -(C 1-6 (Alkylene)-NR 7 CONR 10 R 11 Or -(C 1-6 (Alkylene)-CONR 12 R 13 and R 1b is a hydrogen atom, halogen atom, hydroxy, carboxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, Hydroxy C 1-6 Alkyl, carboxy C 1-6 Alkyl, Amino C 1-6 Alkyl, Cyano C 1-6 Alkyl, -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , unsubstituted or substituted with 1 to 6 groups selected from the substituent group A -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), -(C 1-6 (Alkylene)-NR 7 COR 8 , -(C 1-6 (Alkylene)-NR 7 COOR 9 , -(C 1-6 (Alkylene)-NR 7 CONR 10 R 11 Or -(C 1-6 (Alkylene)-CONR 12 R13 and R 7 is a hydrogen atom or C 1-6 alkyl; R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently a hydrogen atom or a group selected from the group consisting of the following (i) to (v): (i) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 1-6 (ii) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 3-8 (iii) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 3-8 Cycloalkyl C 1-6 (iv) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 6-10 aryl, and (v) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 6-10 Aryl C 1-6 Alkyl, Substituent group A is a halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-8 Cycloalkyl C 1-6 Alkyl, and C 3-8 Cycloalkyl C 1-6 alkoxy; when substituted with two or more groups selected from the substituent group A, each group may be the same or different; R 10 and R 11 may be joined together to form a 3- to 10-membered saturated heterocyclic ring or a 3- to 10-membered unsaturated heterocyclic ring; R 12 and R 13 may be joined together to form a 3- to 10-membered saturated heterocyclic ring or a 3- to 10-membered unsaturated heterocyclic ring; n is an integer from 1 to 3; when n is 2 or 3, each R 1a may be the same or different; R1b If there are two or more R 1b may be the same or different; k is an integer from 0 to 3; when k is 2 or 3, each R 1c may be the same or different; two R 1a may be taken together to form a 3- to 8-membered saturated carbocyclic ring or a 3- to 8-membered saturated heterocyclic ring; represents a single bond or a double bond; Ring Z is C 6-10 Aryl, 5- to 10-membered heteroaryl, or C 3-8 cycloalkyl; R 2 is C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3- to 8-membered heterocycloalkyl or -NR 5 R 5’ provided that when ring A is a group represented by formula (2) or formula (3), R 2 Halo C 1-6 Alkyl, 3- to 8-membered heterocycloalkyl, or -NHR 5 and R 5 and R 5' are each independently a hydrogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl or C 3-8 cycloalkyl; R 3 and R 3' are each independently a hydrogen atom, a halogen atom, a cyano, or C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl or cyano C 1-6 alkyl; R 4 is a halogen atom, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-8 Cycloalkyl C 1-6 Alkyl, C 3-8 Cycloalkyl C 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl C 1-6 Alkyl, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-8 Cycloalkyl C 2-6 Alkynyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, Cyano C 1-6 Alkyl, halohydroxy C 1-6 alkyl or -SF5; R 1a , R 1b or R 1c is R 3 may be taken together with L to form a 5- to 8-membered saturated heterocyclic ring or a 5- to 8-membered unsaturated heterocyclic ring; 1 -CR 6 R 6' -, -O-, or -NR 6 - and R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 0 to 3; when m is 2 or 3, each R 4 may be the same or different from each other; provided that when ring A is a group represented by formula (2), m is an integer of 1 to 3; p is an integer of 0 to 3; when p is 2 or 3, each R 3 and R 3'may be the same or different] or a pharmacologically acceptable salt thereof.

[0014] [A-2] The compound according to [A-1] above, which is represented by formula (A-II): [wherein ring A is a group represented by the following formula (1), (2) or (3): W, X and Y each independently represent -CR 1b = or -N=; Q is -CR Q1 =, -CR Q1 R Q1’ -, -O-, -N= or -NR Q2 - and R Q1 and R Q1’ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, or C 1-6 Alkyl or haloC 1-6 alkyl; R Q2 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 Ring B is a 5- or 6-membered heteroaryl or benzene; R 1a and R 1c are each independently a halogen atom, hydroxy, carboxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, carboxy C 1-6 Alkyl, -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , unsubstituted or substituted with 1 to 6 groups selected from the substituent group A -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), -(C 1-6 (Alkylene)-NR 7 COR 8 , -(C1-6 (Alkylene)-NR 7 COOR 9 , -(C 1-6 (Alkylene)-NR 7 CONR 10 R 11 Or -(C 1-6 (Alkylene)-CONR 12 R 13 and R 1b is a hydrogen atom, halogen atom, hydroxy, carboxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, carboxy C 1-6 Alkyl, Amino C 1-6 Alkyl, -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , unsubstituted or substituted with 1 to 6 groups selected from the substituent group A -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), -(C 1-6 (Alkylene)-NR 7 COR 8 , -(C 1-6 (Alkylene)-NR 7 COOR 9 , -(C 1-6 (Alkylene)-NR 7 CONR 10 R 11 Or -(C 1-6 (Alkylene)-CONR 12 R 13 and R 7 is a hydrogen atom or C 1-6 alkyl; R 8 , R 9 , R 10 , R 11 , R 12 and R 13are each independently a hydrogen atom or a group selected from the group consisting of the following (i) to (v): (i) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 1-6 (ii) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 3-8 (iii) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 3-8 Cycloalkyl C 1-6 (iv) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 6-10 aryl, and (v) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 6-10 Aryl C 1-6 Alkyl, Substituent group A is a halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-8 Cycloalkyl C 1-6 Alkyl, and C 3-8 Cycloalkyl C 1-6 alkoxy; when substituted with two or more groups selected from the substituent group A, each group may be the same or different; R 10 and R 11 may be joined together to form a 3- to 10-membered saturated heterocyclic ring or a 3- to 10-membered unsaturated heterocyclic ring; R 12 and R 13 may be joined together to form a 3- to 10-membered saturated heterocyclic ring or a 3- to 10-membered unsaturated heterocyclic ring; n is an integer from 1 to 3; when n is 2 or 3, each R 1a may be the same or different; R 1b If there are two or more R 1b may be the same or different; k is an integer from 0 to 3; when k is 2 or 3, each R 1c may be the same or different; two R 1amay be taken together to form a 3- to 8-membered saturated carbocyclic ring or a 3- to 8-membered saturated heterocyclic ring; represents a single bond or a double bond; Ring Z is C 6-10 Aryl, 5- to 10-membered heteroaryl or C 3-8 cycloalkyl; R 2 is C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-8 Cycloalkyl, 3- to 8-membered heterocycloalkyl, or -NR 5 R 5’ provided that when ring A is a group represented by formula (2) or formula (3), R 2 Halo C 1-6 Alkyl, 3- to 8-membered heterocycloalkyl, or -NHR 5 and R 5 and R 5' are each independently a hydrogen atom, C 1-6 Alkyl or C 3-8 cycloalkyl; R 3 and R 3' are each independently a hydrogen atom or C 1-6 alkyl; R 4 is a halogen atom, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-6 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl C 1-6 Alkyl, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-8Cycloalkyl C 2-6 Alkynyl, halohydroxy C 1-6 alkyl or -SF5; R 1a , R 1b or R 1c is R 3 may be taken together with L to form a 5- to 8-membered saturated heterocyclic ring or a 5- to 8-membered unsaturated heterocyclic ring; 1 -CR 6 R 6' -, -O-, or -NR 6 - and R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 0 to 3; when m is 2 or 3, each R 4 may be the same or different from each other; provided that when ring A is a group represented by formula (2), m is an integer of 1 to 3; p is an integer of 0 to 3; when p is 2 or 3, each R 3 and R 3' may be the same or different] or a pharmacologically acceptable salt thereof.

[0015] [A-3] The compound according to [A-1] or [A-2] above, which is represented by formula (A-III): [wherein ring A is a group represented by the following formula (1), (2) or (3): Q is -CH=, -CH2-, -O-, or -N=; R 1a is a halogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 alkyl, unsubstituted or substituted with 1 to 6 groups selected from the substituent group A -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl), -(C 1-6 alkylene)-NH-CO-(C 1-6 alkyl), or -(C1-6 alkylene)-CO-N(C 1-6 alkyl)2; Substituent group A is a halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-8 Cycloalkyl C 1-6 Alkyl, and C 3-8 Cycloalkyl C 1-6 alkoxy; when substituted with two or more groups selected from the substituent group A, each group may be the same or different; R 1c is a halogen atom, hydroxy, carboxy, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy, -CONH2, -NH-COO-(C 1-6 alkyl), or -NH-CO-NH-(C 1-6 alkyl); n is an integer from 1 to 3; when n is 2 or 3, each R 1a may be the same or different; two R 1a may be joined together to form a 3- to 8-membered saturated carbocyclic ring or a 3- to 8-membered saturated heterocyclic ring; R 1a is R 3 and may be taken together with each other to form a 5- to 8-membered saturated heterocyclic ring or a 5- to 8-membered unsaturated heterocyclic ring; W, X and Y each independently represent -CR 1b = or -N=; R 1b is a hydrogen atom, a halogen atom, a cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxy C 1-6 Alkyl, carboxy C 1-6 Alkyl, Amino C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6Alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl); at least one R 1b is other than a hydrogen atom; R 1b If there are two or more R 1b may be the same or different; R 1b is R 3 may be taken together with R to form a 5- to 8-membered saturated heterocyclic ring or a 5- to 8-membered unsaturated heterocyclic ring; k is an integer from 0 to 3; when k is 2 or 3, each R 1c may be the same or different; Ring B is a group represented by the following formula: S, T, U and V are each independently -CH=, -CR 1c = or -N=; represents a single bond or a double bond; Ring Z is C 6-10 Aryl, 5- or 6-membered heteroaryl, C 3-8 is a cycloalkyl or a ring represented by the formula: R 2 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl or -NR 5 R 5’ provided that when ring A is a group represented by formula (2) or formula (3), R 2 Ha-NHR 5 and R 5 and R 5' are each independently a hydrogen atom, C 1-6 Alkyl or C 3-8 cycloalkyl; R 3 and R 3' are each independently a hydrogen atom or C 1-6 alkyl; R 4 is a halogen atom, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, HaloC1-6 Alkyl, halohydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-8 Cycloalkyl C 2-6 alkynyl or -SF5; L 1 -CR 6 R 6' -, -O-, or -NR 6 - and R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 0 to 3; when m is 2 or 3, each R 4 may be the same or different from each other; provided that when ring A is a group represented by formula (2), m is an integer of 1 to 3; p is an integer of 1 to 3; when p is 2 or 3, each R 3 and R 3' may be the same or different from each other] or a pharmacologically acceptable salt thereof. [A-4] A compound according to any one of [A-1] to [A-3] above, which is a compound represented by formula (A-IV): [wherein ring A is a group represented by the following formula (1), (2) or (3): R 1a is a halogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, hydroxy C 1-6 Alkyl, Amino C 1-6 alkyl, unsubstituted or substituted with 1 to 6 groups selected from the substituent group A -(C 1-6alkylene)-(3- to 8-membered heterocycloalkyl), -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl), -(C 1-6 alkylene)-NH-CO-(C 1-6 alkyl), or -(C 1-6 alkylene)-CO-N(C 1-6 alkyl)2; Substituent group A is a halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-8 Cycloalkyl C 1-6 Alkyl, and C 3-8 Cycloalkyl C 1-6 alkoxy; when substituted with two or more groups selected from the substituent group A, each group may be the same or different; R 1c is a halogen atom, hydroxy, carboxy, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy, -CONH2, -NH-COO-(C 1-6 alkyl), or -NH-CO-NH-(C 1-6 alkyl); n is an integer from 1 to 3; when n is 2 or 3, each R 1a may be the same or different; two R 1a may be joined together to form a 3- to 8-membered saturated carbocyclic ring or a 3- to 8-membered saturated heterocyclic ring; R 1a is R 3 and may be taken together with each other to form a 5- to 8-membered saturated heterocyclic ring or a 5- to 8-membered unsaturated heterocyclic ring; W, X and Y each independently represent -CR 1b = or -N=; R 1b is a hydrogen atom, a halogen atom, a cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxy C1-6 Alkyl, carboxy C 1-6 Alkyl, Amino C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl); at least one R 1b is other than a hydrogen atom; R 1b If there are two or more R 1b may be the same or different; k is an integer from 0 to 3; when k is 2 or 3, each R 1c may be the same or different; Ring B is a group represented by the following formula: S, T, U and V are each independently -CH=, -CR 1c = or -N=; represents a single bond or a double bond; Ring Z is C 6-10 Aryl, 5- or 6-membered heteroaryl, C 3-8 is a cycloalkyl or a ring represented by the formula: R 5 is a hydrogen atom, C 1-6 Alkyl or C 3-8 cycloalkyl; R 3 and R 3' are each independently a hydrogen atom or C 1-6 alkyl; R 4 is a halogen atom, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, HaloC 1-6 Alkyl, halohydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-8 Cycloalkyl C 2-6 alkynyl or -SF5; L 1 -CR 6 R 6' -, -O-, or -NR 6 - and R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 0 to 3; when m is 2 or 3, each R 4 may be the same or different from each other; provided that when ring A is a group represented by formula (2), m is an integer of 1 to 3; p is an integer of 1 to 3; when p is 2 or 3, each R 3 and R 3' may be the same or different from each other] or a pharmacologically acceptable salt thereof. [A-5] A compound according to any one of [A-1] to [A-4] above, wherein R 5 [A-6] A compound according to any one of [A-1] to [A-5] above, wherein L 1 [A-7] A compound according to any one of [A-1] to [A-6] above, wherein W is -CR 1b = R 1b However, hydrogen atoms, halogen atoms, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxy C 1-6 Alkyl, carboxy C 1-6 Alkyl, Amino C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), or -(C 1-6 alkylene)-NH-COO-(C 1-6alkyl); S, U and V are each independently -CH= or -CR 1c = R 1c However, halogen atoms, carboxy, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy, -CONH2, -NH-COO-(C 1-6 alkyl), or -NH-CO-NH-(C 1-6 [A-8] The compound according to any one of [A-1] to [A-7], wherein X and Y are each independently -CR 1b =; T is -CH= or -CR 1c = and p is 1 or 2, or a pharmacologically acceptable salt thereof. [A-9] The compound according to any one of [A-1] to [A-8] above, wherein n is 1 or 2; and k is an integer of 0 to 2, or a pharmacologically acceptable salt thereof. [A-10] The compound according to any one of [A-1] to [A-9] above, wherein R 3 and R 3’ is a hydrogen atom; and p is 1. [A-11] A compound or a pharmacologically acceptable salt thereof, which is a compound according to any one of [A-1] to [A-10] above, wherein m is an integer of 1 to 3, or a pharmacologically acceptable salt thereof.

[0016] [A-12] A compound according to any one of [A-1] to [A-11] above, which is represented by formula (A-V): [In the formula, R 1a is a halogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, hydroxy C 1-6 Alkyl, Amino C 1-6 alkyl, unsubstituted or substituted with 1 to 6 groups selected from the substituent group A -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), -(C1-6 alkylene)-NH-COO-(C 1-6 alkyl), -(C 1-6 alkylene)-NH-CO-(C 1-6 alkyl), or -(C 1-6 alkylene)-CO-N(C 1-6 alkyl)2; Substituent group A is a halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-8 Cycloalkyl C 1-6 Alkyl, and C 3-8 Cycloalkyl C 1-6 alkoxy; when substituted with two or more groups selected from Substituent Group A, each group may be the same or different; n is an integer of 1 to 3; when n is 2 or 3, each R 1a may be the same or different; two R 1a may be joined together to form a 3- to 8-membered saturated carbocyclic ring or a 3- to 8-membered saturated heterocyclic ring; R 1a is R 3 and may be taken together to form a 5- to 8-membered saturated heterocyclic ring or a 5- to 8-membered unsaturated heterocyclic ring; 6-10 Aryl, 5- or 6-membered heteroaryl, C 3-8 is a cycloalkyl or a ring represented by the formula: R 2 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl or -NR 5 R 5’ and R 5 and R 5' are each independently a hydrogen atom, C 1-6 Alkyl or C 3-8 cycloalkyl; R 3 and R 3'are each independently a hydrogen atom or C 1-6 alkyl; R 4 is a halogen atom, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, HaloC 1-6 Alkyl, halohydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-8 Cycloalkyl C 2-6 alkynyl or -SF5; L 1 -CR 6 R 6' -, -O-, or -NR 6 - and R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 0 to 3; when m is 2 or 3, each R 4 may be the same or different; p is an integer from 1 to 3; when p is 2 or 3, each R 3 and R 3' may be the same or different] or a pharmacologically acceptable salt thereof.

[0017] [A-13] A compound according to any one of [A-1] to [A-12] above, which is represented by formula (A-VI): [In the formula, R 1a is a halogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, hydroxy C 1-6 Alkyl, Amino C 1-6alkyl, unsubstituted or substituted with 1 to 6 groups selected from the substituent group A -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl), -(C 1-6 alkylene)-NH-CO-(C 1-6 alkyl), or -(C 1-6 alkylene)-CO-N(C 1-6 alkyl)2; Substituent group A is a halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-8 Cycloalkyl C 1-6 Alkyl, and C 3-8 Cycloalkyl C 1-6 alkoxy; when substituted with two or more groups selected from Substituent Group A, each group may be the same or different; n is an integer of 1 to 3; when n is 2 or 3, each R 1a may be the same or different; two R 1a may be joined together to form a 3- to 8-membered saturated carbocyclic ring or a 3- to 8-membered saturated heterocyclic ring; R 1a is R 3 and may be taken together to form a 5- to 8-membered saturated heterocyclic ring or a 5- to 8-membered unsaturated heterocyclic ring; 6-10 Aryl, 5- or 6-membered heteroaryl, C 3-8 is a cycloalkyl or a ring represented by the formula: R 5 is a hydrogen atom, C 1-6 Alkyl or C 3-8 cycloalkyl; R 3 and R 3' are each independently a hydrogen atom or C 1-6 alkyl; R 4 is a halogen atom, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, HaloC1-6 Alkyl, halohydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-8 Cycloalkyl C 2-6 alkynyl or -SF5; L 1 -CR 6 R 6' -, -O-, or -NR 6 - and R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 0 to 3; when m is 2 or 3, each R 4 may be the same or different from each other; p is an integer from 1 to 3; when p is 2 or 3, each R 3 and R 3' may be the same or different; or a pharmacologically acceptable salt thereof.

[0018] [A-14] A compound according to any one of [A-1] to [A-11] above, which is represented by formula (A-VII): wherein W, X and Y each independently represent -CR 1b = or -N=; R 1b is a hydrogen atom, a halogen atom, a cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxy C 1-6 Alkyl, carboxy C 1-6 Alkyl, Amino C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6alkyl, unsubstituted or substituted with 1 to 6 groups selected from the substituent group A -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl); Substituent group A is a halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-8 Cycloalkyl C 1-6 Alkyl, and C 3-8 Cycloalkyl C 1-6 alkoxy; when substituted with two or more groups selected from the substituent group A, each group may be the same or different; at least one R 1b is other than a hydrogen atom; R 1b If there are two or more R 1b may be the same or different; ring Z is C 6-10 Aryl, 5- or 6-membered heteroaryl, C 3-8 is a cycloalkyl or a ring represented by the formula: R 5 is a hydrogen atom, C 1-6 Alkyl or C 3-8 cycloalkyl; R 3 and R 3' are each independently a hydrogen atom or C 1-6 alkyl; R 4 is a halogen atom, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, HaloC 1-6 Alkyl, halohydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-8 Cycloalkyl C 2-6 alkynyl or -SF5; L 1 -CR 6 R 6' -, -O-, or -NR 6 - and R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 1 to 3; when m is 2 or 3, each R 4 may be the same or different from each other; p is an integer from 1 to 3; when p is 2 or 3, each R 3 and R 3' may be the same or different] or a pharmacologically acceptable salt thereof.

[0019] [A-15] A compound according to any one of [A-1] to [A-11], which is represented by formula (A-VIII): [In the formula, R 1c is a halogen atom, hydroxy, carboxy, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy, -CONH2, -NH-COO-(C 1-6 alkyl), or -NH-CO-NH-(C 1-6 alkyl); k is an integer from 0 to 3; when k is 2 or 3, each R 1c may be the same or different; Ring B is a group represented by the following formula: S, T, U and V are each independently -CH=, -CR 1c = or -N=; represents a single bond or a double bond; Ring Z is C 6-10 Aryl, 5- or 6-membered heteroaryl, C3-8 is a cycloalkyl or a ring represented by the formula: R 5 is a hydrogen atom, C 1-6 Alkyl or C 3-8 cycloalkyl; R 3 and R 3' are each independently a hydrogen atom or C 1-6 alkyl; R 4 is a halogen atom, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, HaloC 1-6 Alkyl, halohydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-8 Cycloalkyl C 2-6 alkynyl or -SF5; L 1 -CR 6 R 6' -, -O-, or -NR 6 - and R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 0 to 3; when m is 2 or 3, each R 4 may be the same or different from each other; p is an integer from 1 to 3; when p is 2 or 3, each R 3 and R 3' may be the same or different] or a pharmacologically acceptable salt thereof.

[0020] [A-16] The compound according to any one of [A-1] to [A-11] above, wherein when ring A is a group represented by formula (2) or formula (3), R 5or a pharmacologically acceptable salt thereof, wherein is a hydrogen atom, methyl or cyclopropyl.

[0021] [A-17] A compound according to any one of [A-1] to [A-16], wherein: R 5 and R 5' are each independently a hydrogen atom, methyl or cyclopropyl, or a pharmacologically acceptable salt thereof.

[0022] [A-18] A compound according to any one of [A-1] to [A-17] above, wherein: R 2 Ga-NHR 5 or a pharmacologically acceptable salt thereof.

[0023] [A-19] The compound according to any one of [A-1] to [A-18], wherein R 5 is a hydrogen atom, or a pharmacologically acceptable salt thereof.

[0024] [A-20] The compound according to any one of [A-1] to [A-19], wherein L 1 is -NH- or a pharmacologically acceptable salt thereof.

[0025] [A-21] The compound according to any one of [A-1] to [A-20], wherein W is -CR 1b [A-22] A compound according to any one of [A-1] to [A-21], wherein X and Y are each independently -CR 1b = A compound or a pharmacologically acceptable salt thereof.

[0026] [A-23] A compound according to any one of [A-1] to [A-22] above, wherein: R 1b However, hydrogen atoms, halogen atoms, cyano, C 1-6 Alkyl, carboxy C 1-6 Alkyl, HaloC 1-6 Alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl) or a pharmacologically acceptable salt thereof.

[0027] [A-24] A compound according to any one of [A-1] to [A-23], wherein: R 1b However, hydrogen atoms, halogen atoms, C 1-6 Alkyl, HaloC 1-6 Alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl) or a pharmacologically acceptable salt thereof.

[0028] [A-25] The compound according to any one of [A-1] to [A-24], wherein: S, U, and V are each independently -CH= or -CR 1c = A compound or a pharmacologically acceptable salt thereof.

[0029] [A-26] The compound according to any one of [A-1] to [A-25], wherein T is -CH= or -CR 1c = A compound or a pharmacologically acceptable salt thereof.

[0030] [A-27] A compound according to any one of [A-1] to [A-26], wherein: R 1c However, halogen atoms, carboxy, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 A compound which is alkoxy or -CONH2, or a pharmacologically acceptable salt thereof.

[0031] [A-28] A compound according to any one of [A-1] to [A-27], wherein: R 1c But halogen atoms, C 1-6 Alkyl, HaloC 1-6 Alkyl or hydroxy C 1-6 or a pharmacologically acceptable salt thereof.

[0032] [A-29] A compound according to any one of [A-1] to [A-28], wherein: R 1a But halogen atoms, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy C 1-6alkyl, unsubstituted or substituted with 1 to 6 groups selected from the substituent group A -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), or -(C 1-6 alkylene)-NH-COO-(C 1-6 a compound in which the substituent group A is the same as that in the above [A-1], or a pharmacologically acceptable salt thereof;

[0033] [A-30] A compound according to any one of [A-1] to [A-29], wherein: R 1a But C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 alkyl, unsubstituted or substituted with 1 to 6 groups selected from the substituent group A -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), or -(C 1-6 alkylene)-NH-COO-(C 1-6 [A-31] A compound according to any one of [A-1] to [A-30] above, wherein n is 1 or 2, or a pharmacologically acceptable salt thereof. [A-32] A compound according to any one of [A-1] to [A-31] above, wherein k is an integer of 0 to 2, or a pharmacologically acceptable salt thereof. [A-33] A compound according to any one of [A-1] to [A-32] above, wherein k is 1 or 2, or a pharmacologically acceptable salt thereof.

[0034] [A-34] A compound according to any one of [A-1] to [A-33], wherein: R 3 and R 3’ is a hydrogen atom or C 1-6 A compound or a pharmacologically acceptable salt thereof, wherein: p is alkyl; and p is 1 or 2.

[0035] [A-35] A compound according to any one of [A-1] to [A-34], wherein: R 3 and R 3’ is a hydrogen atom; and p is 1 or 2, or a pharmacologically acceptable salt thereof.

[0036] [A-36] The compound according to any one of the above [A-1] to [A-35], wherein p is 1 or 2, or a pharmacologically acceptable salt thereof.

[0037] [A-37] The compound according to any one of the above [A-1] to [A-36], wherein p is 1, or a pharmacologically acceptable salt thereof.

[0038] [A-38] The compound according to any one of [A-1] to [A-37], wherein ring Z is C 6-10 aryl or a pharmacologically acceptable salt thereof.

[0039] [A-39] A compound according to any one of [A-1] to [A-38], wherein: R 4 But halogen atoms, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, halohydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-8 Cycloalkyl C 2-6 A compound which is alkynyl or -SF5, or a pharmacologically acceptable salt thereof.

[0040] [A-40] A compound according to any one of [A-1] to [A-39], wherein: R 4 But halogen atoms, C 1-6 Alkyl, HaloC 1-6 Alkyl, halohydroxy C 1-6 Alkyl, HaloC 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6Alkynyl, 5- or 6-membered heteroaryl C 2-6 A compound which is alkynyl or -SF5, or a pharmacologically acceptable salt thereof.

[0041] [A-41] The compound according to any one of the above [A-1] to [A-40], wherein m is an integer of 1 to 3, or a pharmacologically acceptable salt thereof.

[0042] [A-42] A compound according to any one of [A-1] to [A-41] above, selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

[0043] [A-43] A compound according to any one of [A-1] to [A-42] above, selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

[0044] [A-44] A compound according to any one of [A-1] to [A-42] above, selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

[0045] [A-45] A compound according to any one of [A-1] to [A-42] above, selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

[0046] [A-46] A compound according to any one of [A-1] to [A-41] above, selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

[0047] [A-47] A pharmaceutical composition comprising the compound according to any one of [A-1] to [A-46] above or a pharmacologically acceptable salt thereof, and a pharmaceutical additive.

[0048] [A-48] The pharmaceutical composition according to [A-47] above, which is a pharmaceutical composition for treating a thyroid-related disease.

[0049] [A-49] The pharmaceutical composition according to [A-48] above, wherein the thyroid-related disease is hyperthyroidism, Graves' disease, or thyroid eye disease.

[0050] [A-50] A TSHR inhibitor containing, as an active ingredient, any of the compounds described in [A-1] to [A-46] or a pharmacologically acceptable salt thereof. [A-51] A therapeutic agent for thyroid-related diseases containing, as an active ingredient, any of the compounds described in [A-1] to [A-46] or a pharmacologically acceptable salt thereof.

[0051] In one embodiment of the compounds represented by formulae (AI) to (A-VI), for example, two R 1a When these are taken together to form a 3- to 8-membered saturated carbocyclic ring, the ring is represented by the following formula (a) or (b): (wherein q is an integer from 1 to 4), (wherein r is an integer from 1 to 4);

[0052] In one embodiment, the present invention relates to a method for treating a thyroid-related disease, which comprises administering to a patient a required amount of the pharmaceutical composition described in [A-47] above.

[0053] In one embodiment, the present invention relates to use of any of the compounds described in [A-1] to [A-46] or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition for treating a thyroid-related disease.

[0054] [B-1] A compound represented by formula (I): [wherein ring A is a group represented by the following formula (1), (2) or (3): W, X and Y each independently represent -CR 1b = or -N=; Q is -CR Q1 =, -CR Q1 R Q1’ -, -O-, or -NR Q2 - and R Q1 and R Q1’ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, or C 1-6 Alkyl or haloC 1-6alkyl; R Q2 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 Ring B is a 5- or 6-membered heteroaryl or benzene; R 1a and R 1c are each independently a halogen atom, hydroxy, carboxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, Hydroxy C 1-6 Alkyl, carboxy C 1-6 Alkyl, Amino C 1-6 Alkyl, Cyano C 1-6 Alkyl, -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , -(C 1-6 (Alkylene)-NR 7 COR 8 , -(C 1-6 (Alkylene)-NR 7 COOR 9 , -(C 1-6 (Alkylene)-NR 7 CONR 10 R 11 Or -(C 1-6 (Alkylene)-CONR 12 R 13 and R 1b is a hydrogen atom, halogen atom, hydroxy, carboxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 3-8 Cycloalkyl, C3-8 Cycloalkoxy, Hydroxy C 1-6 Alkyl, carboxy C 1-6 Alkyl, Amino C 1-6 Alkyl, Cyano C 1-6 Alkyl, -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , -(C 1-6 (Alkylene)-NR 7 COR 8 , -(C 1-6 (Alkylene)-NR 7 COOR 9 , -(C 1-6 (Alkylene)-NR 7 CONR 10 R 11 Or -(C 1-6 (Alkylene)-CONR 12 R 13 and R 7 is a hydrogen atom or C 1-6 alkyl; R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently a hydrogen atom or a group selected from the group consisting of the following (i) to (v): (i) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 1-6 (ii) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 3-8 (iii) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 3-8 Cycloalkyl C 1-6 (iv) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 6-10 aryl, and (v) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 6-10 Aryl C 1-6Alkyl, Substituent group A is a halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-8 Cycloalkyl C 1-6 Alkyl, and C 3-8 Cycloalkyl C 1-6 alkoxy; when substituted with two or more groups selected from the substituent group A, each group may be the same or different; R 10 and R 11 may be joined together to form a 3- to 10-membered saturated heterocyclic ring or a 3- to 10-membered unsaturated heterocyclic ring; R 12 and R 13 may be joined together to form a 3- to 10-membered saturated heterocyclic ring or a 3- to 10-membered unsaturated heterocyclic ring; n is an integer from 1 to 3; when n is 2 or 3, each R 1a may be the same or different; R 1b If there are two or more R 1b may be the same or different; k is an integer from 0 to 3; when k is 2 or 3, each R 1c may be the same or different; two R 1a Let's get together and C 3-8 may form a cycloalkyl; represents a single bond or a double bond; Ring Z is C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl; R 2 is C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3- to 8-membered heterocycloalkyl or -NR5 R 5’ provided that when ring A is a group represented by formula (2) or formula (3), R 2 Ha-NHR 5 and R 5 and R 5' are each independently a hydrogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl or C 3-8 cycloalkyl; R 3 and R 3' are each independently a hydrogen atom, a halogen atom, a cyano, or C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, Cyano C 1-6 Alkyl, -NR 14 COR 15 , -NR 14 COOR 16 , -NR 14 CONR 17 R 18 , -CONR 19 R 20 , -(C 1-6 (Alkylene)-NR 14 COR 15 , -(C 1-6 (Alkylene)-NR 14 COOR 16 , -(C 1-6 (Alkylene)-NR 14 CONR 17 R 18 Or -(C 1-6 (Alkylene)-CONR 19 R 20 and R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 are each independently a hydrogen atom or C 1-6 alkyl; R 3 and R 3’ may be taken together to form an oxo group; R4 is a halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-8 Cycloalkyl C 1-6 Alkyl, C 3-8 Cycloalkyl C 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl C 1-6 Alkyl, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-8 Cycloalkyl C 2-6 Alkynyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, Cyano C 1-6 Alkyl, -NR 21 COR 22 , -NR 21 COOR 23 , -NR 21 CONR 24 R 25 , -CONR 26 R 27 , -(C 1-6 (Alkylene)-NR 21 COR 22 , -(C 1-6 (Alkylene)-NR 21 COOR 23 , -(C 1-6 (Alkylene)-NR 21 CONR 24 R 25 , -(C 1-6 (Alkylene)-CONR 26 R 27 , halohydroxy C1-6 alkyl or -SF5; R 21 , R 22 , R 23 , R 24 , R 25 , R 26 and R 27 are each independently a hydrogen atom or C 1-6 alkyl; R 1a , R 1b or R 1c is R 3 may be taken together with R to form a 5- to 8-membered saturated heterocyclic ring or a 5- to 8-membered unsaturated heterocyclic ring; 4 and R 3 may be joined together to form a 5- to 8-membered ring; L 1 -CR 6 R 6' -, -O-, or -NR 6 - and R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 0 to 3; when m is 2 or 3, each R 4 may be the same or different from each other; provided that when ring A is a group represented by formula (2), m is an integer of 1 to 3; p is an integer of 0 to 3; when p is 2 or 3, each R 3 and R 3' may be the same or different] or a pharmacologically acceptable salt thereof.

[0055] [B-2] The compound according to [B-1] above, which is represented by formula (II): [wherein ring A is a group represented by the following formula (1), (2) or (3): W, X and Y each independently represent -CR 1b = or -N=; Q is -CR Q1 =, -CR Q1 R Q1’ -, -O-, or -NR Q2 - and R Q1 and R Q1’ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, or C 1-6 Alkyl or haloC1-6 alkyl; R Q2 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 Ring B is a 5- or 6-membered heteroaryl or benzene; R 1a and R 1c are each independently a halogen atom, hydroxy, carboxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, Hydroxy C 1-6 Alkyl, carboxy C 1-6 Alkyl, -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , -(C 1-6 (Alkylene)-NR 7 COR 8 , -(C 1-6 (Alkylene)-NR 7 COOR 9 , -(C 1-6 (Alkylene)-NR 7 CONR 10 R 11 Or -(C 1-6 (Alkylene)-CONR 12 R 13 and R 1b is a hydrogen atom, halogen atom, hydroxy, carboxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, Hydroxy C 1-6 Alkyl, carboxy C 1-6 Alkyl, -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , -(C 1-6 (Alkylene)-NR7 COR 8 , -(C 1-6 (Alkylene)-NR 7 COOR 9 , -(C 1-6 (Alkylene)-NR 7 CONR 10 R 11 Or -(C 1-6 (Alkylene)-CONR 12 R 13 and R 7 is a hydrogen atom or C 1-6 alkyl; R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently a hydrogen atom or a group selected from the group consisting of the following (i) to (v): (i) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 1-6 (ii) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 3-8 (iii) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 3-8 Cycloalkyl C 1-6 (iv) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 6-10 aryl, and (v) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 6-10 Aryl C 1-6 Alkyl, Substituent group A is a halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-8 Cycloalkyl C 1-6 Alkyl, and C 3-8 Cycloalkyl C 1-6 alkoxy; when substituted with two or more groups selected from the substituent group A, each group may be the same or different; R10 and R 11 may be joined together to form a 3- to 10-membered saturated heterocyclic ring or a 3- to 10-membered unsaturated heterocyclic ring; R 12 and R 13 may be joined together to form a 3- to 10-membered saturated heterocyclic ring or a 3- to 10-membered unsaturated heterocyclic ring; n is an integer from 1 to 3; when n is 2 or 3, each R 1a may be the same or different; R 1b If there are two or more R 1b may be the same or different; k is an integer from 0 to 3; when k is 2 or 3, each R 1c may be the same or different; two R 1a Let's get together and C 3-8 may form a cycloalkyl; represents a single bond or a double bond; Ring Z is C 6-10 Aryl, 5- to 10-membered heteroaryl or C 3-8 cycloalkyl; R 2 is C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-8 Cycloalkyl or -NR 5 R 5’ provided that when ring A is a group represented by formula (2) or formula (3), R 2 Ha-NHR 5 and R 5 and R 5' are each independently a hydrogen atom, C 1-6 Alkyl or C 3-8 cycloalkyl; R 3 and R 3' are each independently a hydrogen atom or C 1-6 alkyl; R 4 is a halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C1-6 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl C 1-6 Alkyl, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-8 Cycloalkyl C 2-6 Alkynyl, halohydroxy C 1-6 alkyl or -SF5; R 1a , R 1b or R 1c is R 3 may be taken together with R to form a 5- to 8-membered saturated heterocyclic ring or a 5- to 8-membered unsaturated heterocyclic ring; 4 and R 3 may be joined together to form a 5- to 8-membered ring; L 1 -CR 6 R 6' -, -O-, or -NR 6 - and R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 0 to 3; when m is 2 or 3, each R 4 may be the same or different from each other; provided that when ring A is a group represented by formula (2), m is an integer of 1 to 3; p is an integer of 0 to 3; when p is 2 or 3, each R 3 and R 3' may be the same or different] or a pharmacologically acceptable salt thereof.

[0056] [B-3] The compound according to [B-1] or [B-2] above, which is represented by formula (III): [wherein ring A is a group represented by the following formula (1), (2) or (3): R 1a is a halogen atom, C 1-6 Alkyl, HaloC1-6 Alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl); R 1c is a halogen atom, hydroxy, carboxy, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 alkoxy or -CONH2; n is an integer from 1 to 3; when n is 2 or 3, each R 1a may be the same or different; two R 1a Let's get together and C 3-8 W, X, and Y may each independently form -CR 1b = or -N=; R 1b is a hydrogen atom, a halogen atom, a cyano, C 1-6 Alkyl, carboxy C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl); at least one R 1b is other than a hydrogen atom; R 1b If there are two or more R 1b may be the same or different; k is an integer from 0 to 3; when k is 2 or 3, each R 1c may be the same or different; Ring B is a group represented by the following formula: S, T, U and V are each independently -CH=, -CR 1c = or -N=; represents a single bond or a double bond; Ring Z is C 6-10 Aryl, 5- or 6-membered heteroaryl, C 3-8 is a cycloalkyl or a ring represented by the formula: R 2 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C1-6 Alkoxy C 1-6 Alkyl or -NR 5 R 5’ provided that when ring A is a group represented by formula (2) or formula (3), R 2 Ha-NHR 5 and R 5 and R 5' are each independently a hydrogen atom, C 1-6 Alkyl or C 3-8 cycloalkyl; R 3 and R 3' are each independently a hydrogen atom or C 1-6 alkyl; R 4 is a halogen atom, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, halohydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-8 Cycloalkyl C 2-6 alkynyl or -SF5; L 1 -CR 6 R 6' -, -O-, or -NR 6 - and R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 0 to 3; when m is 2 or 3, each R 4 may be the same or different from each other; provided that when ring A is a group represented by formula (2), m is an integer of 1 to 3; p is an integer of 1 to 3; when p is 2 or 3, each R 3 and R 3'may be the same or different from each other] or a pharmacologically acceptable salt thereof. [B-4] A compound according to any one of [B-1] to [B-3] above, which is a compound represented by formula (IV): [wherein ring A is a group represented by the following formula (1), (2) or (3): R 1a is a halogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl); R 1c is a halogen atom, hydroxy, carboxy, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, Hydroxy C 1-6 Alkyl, C 1-6 alkoxy or -CONH2; n is an integer from 1 to 3; when n is 2 or 3, each R 1a may be the same or different; two R 1a Let's get together and C 3-8 W, X, and Y may each independently form -CR 1b = or -N=; R 1b is a hydrogen atom, a halogen atom, a cyano, C 1-6 Alkyl, carboxy C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl); at least one R 1b is other than a hydrogen atom; R 1b If there are two or more R 1b may be the same or different; k is an integer from 0 to 3; when k is 2 or 3, each R 1c may be the same or different; Ring B is a group represented by the following formula: S, T, U and V are each independently -CH=, -CR 1c = or -N=; represents a single bond or a double bond; Ring Z is C 6-10 Aryl, 5- or 6-membered heteroaryl, C 3-8 is a cycloalkyl or a ring represented by the formula: R 5 is a hydrogen atom, C 1-6 Alkyl or C 3-8 cycloalkyl; R 3 and R 3' are each independently a hydrogen atom or C 1-6 alkyl; R 4 is a halogen atom, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, halohydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-8 Cycloalkyl C 2-6 alkynyl or -SF5; L 1 -CR 6 R 6' -, -O-, or -NR 6 - and R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 0 to 3; when m is 2 or 3, each R 4 may be the same or different from each other; provided that when ring A is a group represented by formula (2), m is an integer of 1 to 3; p is an integer of 1 to 3; when p is 2 or 3, each R 3 and R 3'may be the same or different from each other] or a pharmacologically acceptable salt thereof. [B-5] A compound according to any one of [B-1] to [B-4] above, wherein R 5 [B-6] A compound according to any one of [B-1] to [B-5], wherein L is a hydrogen atom, or a pharmacologically acceptable salt thereof. 1 [B-7] The compound according to any one of [B-1] to [B-6], wherein W is -CR 1b = R 1b However, hydrogen atoms, halogen atoms, cyano, C 1-6 Alkyl, carboxy C 1-6 Alkyl, HaloC 1-6 Alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl); S, U and V are each independently -CH= or -CR 1c = R 1c However, halogen atoms, carboxy, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, Hydroxy C 1-6 Alkyl, C 1-6 [B-8] A compound according to any one of [B-1] to [B-7], wherein X and Y are each independently -CR 1b =; T is -CH= or -CR 1c = and p is 1 or 2, or a pharmacologically acceptable salt thereof. [B-9] The compound according to any one of [B-1] to [B-8] above, wherein n is 1 or 2; and k is an integer of 0 to 2, or a pharmacologically acceptable salt thereof. [B-10] The compound according to any one of [B-1] to [B-9] above, wherein R 3 and R 3’ is a hydrogen atom; and p is 1. [B-11] A compound or a pharmacologically acceptable salt thereof, which is a compound according to any one of [B-1] to [B-10] above, wherein m is an integer of 1 to 3,

[0057] [B-12] A compound according to any one of [B-1] to [B-11] above, which is represented by formula (V): [In the formula, R 1a is a halogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl); n is an integer from 1 to 3; when n is 2 or 3, each R 1a may be the same or different; two R 1a Let's get together and C 3-8 Ring Z may form a cycloalkyl; 6-10 Aryl, 5- or 6-membered heteroaryl, C 3-8 is a cycloalkyl or a ring represented by the formula: R 2 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl or -NR 5 R 5’ and R 5 and R 5' are each independently a hydrogen atom, C 1-6 Alkyl or C 3-8 cycloalkyl; R 3 and R 3' are each independently a hydrogen atom or C 1-6 alkyl; R 4 is a halogen atom, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, halohydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C1-6 Alkoxy, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-8 Cycloalkyl C 2-6 alkynyl or -SF5; L 1 -CR 6 R 6' -, -O-, or -NR 6 - and R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 0 to 3; when m is 2 or 3, each R 4 may be the same or different from each other; p is an integer from 1 to 3; when p is 2 or 3, each R 3 and R 3' may be the same or different] or a pharmacologically acceptable salt thereof.

[0058] [B-13] A compound according to any one of [B-1] to [B-12] above, which is represented by formula (VI): [In the formula, R 1a is a halogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl); n is an integer from 1 to 3; when n is 2 or 3, each R 1a may be the same or different; two R 1a Let's get together and C 3-8 Ring Z may form a cycloalkyl; 6-10 Aryl, 5- or 6-membered heteroaryl, C 3-8 is a cycloalkyl or a ring represented by the formula: R 5 is a hydrogen atom, C 1-6 Alkyl or C 3-8 cycloalkyl; R 3 and R 3' are each independently a hydrogen atom or C 1-6 alkyl; R 4is a halogen atom, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, halohydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-8 Cycloalkyl C 2-6 alkynyl or -SF5; L 1 -CR 6 R 6' -, -O-, or -NR 6 - and R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 0 to 3; when m is 2 or 3, each R 4 may be the same or different from each other; p is an integer from 1 to 3; when p is 2 or 3, each R 3 and R 3' may be the same or different] or a pharmacologically acceptable salt thereof.

[0059] [B-14] A compound according to any one of [B-1] to [B-11] above, which is represented by formula (VII): wherein W, X and Y each independently represent -CR 1b = or -N=; R 1b is a hydrogen atom, a halogen atom, a cyano, C 1-6 Alkyl, carboxy C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl); at least one R1b is other than a hydrogen atom; R 1b If there are two or more R 1b may be the same or different; ring Z is C 6-10 Aryl, 5- or 6-membered heteroaryl, C 3-8 is a cycloalkyl or a ring represented by the formula: R 5 is a hydrogen atom, C 1-6 Alkyl or C 3-8 cycloalkyl; R 3 and R 3' are each independently a hydrogen atom or C 1-6 alkyl; R 4 is a halogen atom, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, halohydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-8 Cycloalkyl C 2-6 alkynyl or -SF5; L 1 -CR 6 R 6' -, -O-, or -NR 6 - and R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 1 to 3; when m is 2 or 3, each R 4 may be the same or different from each other; p is an integer from 1 to 3; when p is 2 or 3, each R 3 and R 3' may be the same or different] or a pharmacologically acceptable salt thereof.

[0060] [B-15] A compound according to any one of [B-1] to [B-11] above, which is a compound represented by formula (VIII): [In the formula, R 1c is a halogen atom, hydroxy, carboxy, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 alkoxy or -CONH2; k is an integer from 0 to 3; when k is 2 or 3, each R 1c may be the same or different; Ring B is a group represented by the following formula: S, T, U and V are each independently -CH=, -CR 1c = or -N=; represents a single bond or a double bond; Ring Z is C 6-10 Aryl, 5- or 6-membered heteroaryl, C 3-8 is a cycloalkyl or a ring represented by the formula: R 5 is a hydrogen atom, C 1-6 Alkyl or C 3-8 cycloalkyl; R 3 and R 3' are each independently a hydrogen atom or C 1-6 alkyl; R 4 is a halogen atom, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, halohydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-8 Cycloalkyl C2-6 alkynyl or -SF5; L 1 -CR 6 R 6' -, -O-, or -NR 6 - and R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 0 to 3; when m is 2 or 3, each R 4 may be the same or different from each other; p is an integer from 1 to 3; when p is 2 or 3, each R 3 and R 3' may be the same or different] or a pharmacologically acceptable salt thereof.

[0061] [B-16] The compound according to any one of [B-1] to [B-11] above, wherein when ring A is a group represented by formula (2) or formula (3), R 5 is a hydrogen atom, methyl or cyclopropyl, or a pharmacologically acceptable salt thereof.

[0062] [B-17] A compound according to any one of [B-1] to [B-16], wherein: R 5 and R 5' are each independently a hydrogen atom, methyl or cyclopropyl, or a pharmacologically acceptable salt thereof.

[0063] [B-18] A compound according to any one of [B-1] to [B-17], wherein: R 2 Ga-NHR 5 or a pharmacologically acceptable salt thereof.

[0064] [B-19] The compound according to any one of [B-1] to [B-18], wherein R 5 is a hydrogen atom, or a pharmacologically acceptable salt thereof.

[0065] [B-20] The compound according to any one of [B-1] to [B-19], wherein L 1 is -NH- or a pharmacologically acceptable salt thereof.

[0066] [B-21] The compound according to any one of [B-1] to [B-20], wherein W is -CR 1b [B-22] A compound according to any one of [B-1] to [B-21], wherein X and Y are each independently -CR 1b = A compound or a pharmacologically acceptable salt thereof.

[0067] [B-23] A compound according to any one of [B-1] to [B-22], wherein: R 1b However, hydrogen atoms, halogen atoms, cyano, C 1-6 Alkyl, carboxy C 1-6 Alkyl, HaloC 1-6 Alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl) or a pharmacologically acceptable salt thereof.

[0068] [B-24] The compound according to any one of [B-1] to [B-23], wherein: R 1b However, hydrogen atoms, halogen atoms, C 1-6 Alkyl, HaloC 1-6 Alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl) or a pharmacologically acceptable salt thereof.

[0069] [B-25] The compound according to any one of [B-1] to [B-24], wherein: S, U, and V are each independently -CH= or -CR 1c = A compound or a pharmacologically acceptable salt thereof.

[0070] [B-26] The compound according to any one of [B-1] to [B-25], wherein T is -CH= or -CR 1c = A compound or a pharmacologically acceptable salt thereof.

[0071] [B-27] A compound according to any one of [B-1] to [B-26], wherein: R 1c However, halogen atoms, carboxy, cyano, C 1-6 Alkyl, HaloC 1-6Alkyl, hydroxy C 1-6 Alkyl, C 1-6 A compound which is alkoxy or -CONH2, or a pharmacologically acceptable salt thereof.

[0072] [B-28] A compound according to any one of [B-1] to [B-27], wherein: R 1c But halogen atoms, C 1-6 Alkyl, HaloC 1-6 Alkyl or hydroxy C 1-6 or a pharmacologically acceptable salt thereof.

[0073] [B-29] A compound according to any one of [B-1] to [B-28], wherein: R 1a But halogen atoms, C 1-6 Alkyl, HaloC 1-6 Alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl) or a pharmacologically acceptable salt thereof.

[0074] [B-30] A compound according to any one of [B-1] to [B-29], wherein: R 1a But C 1-6 Alkyl, HaloC 1-6 Alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 [B-31] A compound according to any one of the above [B-1] to [B-30], wherein n is 1 or 2, or a pharmacologically acceptable salt thereof. [B-32] A compound according to any one of the above [B-1] to [B-31], wherein k is an integer of 0 to 2, or a pharmacologically acceptable salt thereof. [B-33] A compound according to any one of the above [B-1] to [B-32], wherein k is 1 or 2, or a pharmacologically acceptable salt thereof.

[0075] [B-34] The compound according to any one of [B-1] to [B-33], wherein: R 3 and R 3’ is a hydrogen atom or C 1-6A compound or a pharmacologically acceptable salt thereof, wherein: p is alkyl; and p is 1 or 2.

[0076] [B-35] A compound according to any one of [B-1] to [B-34], wherein: R 3 and R 3’ is a hydrogen atom; and p is 1 or 2, or a pharmacologically acceptable salt thereof.

[0077] [B-36] The compound according to any one of the above [B-1] to [B-35], wherein p is 1 or 2, or a pharmacologically acceptable salt thereof.

[0078] [B-37] The compound according to any one of the above [B-1] to [B-36], wherein p is 1, or a pharmacologically acceptable salt thereof.

[0079] [B-38] The compound according to any one of [B-1] to [B-37], wherein ring Z is C 6-10 aryl or a pharmacologically acceptable salt thereof.

[0080] [B-39] A compound according to any one of [B-1] to [B-38], wherein: R 4 But halogen atoms, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, halohydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-8 Cycloalkyl C 2-6 A compound which is alkynyl or -SF5, or a pharmacologically acceptable salt thereof.

[0081] [B-40] A compound according to any one of [B-1] to [B-39], wherein: R4 But halogen atoms, C 1-6 Alkyl, HaloC 1-6 Alkyl, halohydroxy C 1-6 Alkyl, HaloC 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, 5- or 6-membered heteroaryl C 2-6 A compound which is alkynyl or -SF5, or a pharmacologically acceptable salt thereof.

[0082] [B-41] The compound according to any one of [B-1] to [B-40] above, wherein m is an integer of 1 to 3, or a pharmacologically acceptable salt thereof.

[0083] [B-42] A compound according to any one of [B-1] to [B-41] above, selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

[0084] [B-43] A compound according to any one of [B-1] to [B-42] above, selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

[0085] [B-44] A compound according to any one of [B-1] to [B-42] above, selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

[0086] [B-45] A compound according to any one of [B-1] to [B-42] above, selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

[0087] [B-46] A compound according to any one of [B-1] to [B-41] above, selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

[0088] [B-47] A pharmaceutical composition comprising the compound according to any one of [B-1] to [B-46] above or a pharmacologically acceptable salt thereof, and a pharmaceutical additive.

[0089] [B-48] The pharmaceutical composition according to [B-47] above, which is a pharmaceutical composition for treating a thyroid-related disease.

[0090] [B-49] The pharmaceutical composition according to [B-48] above, wherein the thyroid-related disease is hyperthyroidism, Graves' disease, or thyroid eye disease.

[0091] [B-50] A TSHR inhibitor containing, as an active ingredient, the compound described in any one of [B-1] to [B-46] or a pharmacologically acceptable salt thereof. [B-51] A therapeutic agent for thyroid-related diseases containing, as an active ingredient, the compound described in any one of [B-1] to [B-46] or a pharmacologically acceptable salt thereof.

[0092] In one embodiment of the compounds represented by formulas (I) to (VI), for example, two R 1a Together they form C 3-8 When forming a cycloalkyl, the ring is represented by the following formula (a) or (b): (wherein q is an integer from 1 to 4), (wherein r is an integer from 1 to 4);

[0093] In one embodiment, the present invention relates to a method for treating a thyroid-related disease, which comprises administering to a patient a required amount of the pharmaceutical composition described in [B-47] above.

[0094] In one embodiment, the present invention relates to use of a compound described in any of [B-1] to [B-46] or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition for treating a thyroid-related disease.

[0095] The compound of the present invention has excellent TSHR antagonist activity, and therefore the compound of the present invention or a pharmacologically acceptable salt thereof is useful as a therapeutic agent for thyroid-related diseases.

[0096] Hereinafter, embodiments of the present invention will be described in more detail.

[0097] In the present invention, each term has the following meaning unless otherwise specified.

[0098] "Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. 1-6 "Alkyl" means a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. 1-6 "Alkylene" means a linear or branched alkylene group having 1 to 6 carbon atoms. Examples include methylene, ethylene, and 1-propylene. 2-6 "Alkenyl" means an alkenyl group having 2 to 6 carbon atoms and at least one double bond. Examples include ethenyl, 1-propenyl, and 2-propenyl. 2-6 "Alkynyl" means an alkynyl group having 2 to 6 carbon atoms and at least one triple bond. Examples include ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl. 1-6 The term "alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like.

[0099] "Hydroxy C 1-6 "Alkyl" refers to a C substituted with 1 or 2 hydroxy groups. 1-6 "HaloC" refers to alkyl. Examples include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, etc. 1-6 "Alkyl" means a C alkyl group substituted with 1 to 5 halogen atoms of the same or different types. 1-6 Examples of the halo group include monofluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and pentafluoroethyl. 1-6"Alkoxy" means a C substituted with 1 to 5 identical or different halogen atoms. 1-6 "C" means alkoxy. Examples thereof include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, etc. 1-6 Alkoxy C 1-6 "Alkyl" means one C 1-6 Alkoxy-substituted C 1-6 Examples include methoxymethyl, methoxyethyl, ethoxymethyl, and ethoxyethyl. "Carboxy C 1-6 "Alkyl" refers to a C substituted with one carboxyl 1-6 It means alkyl. For example, carboxymethyl, carboxyethyl, etc. 1-6 "Alkyl" means a group having one or two C 1-6 C substituted with one amino optionally substituted with alkyl 1-6 It means alkyl. Examples include aminomethyl, N-methylaminoethyl, N,N-dimethylaminoethyl, etc. "Cyano C 1-6 "Alkyl" refers to a C substituted with one cyano. 1-6 "Alkyl" refers to an alkyl group. Examples include cyanomethyl and cyanoethyl. "Halohydroxy C 1-6 "Alkyl" refers to a C alkyl group substituted with 1 to 6 halogen atoms of the same or different types and 1 or 2 hydroxyl groups. 1-6 It means alkyl, for example, 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl.

[0100] "C 6-10The term "aryl" refers to 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, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl. The term "5- to 10-membered heteroaryl" refers to a 5- to 10-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring, and a portion of the ring may be partially saturated. Examples thereof include pyridyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 2,3-dihydrobenzofuranyl, 1,2,3,4-tetrahydroquinolyl, and 1,2,3,4-tetrahydroisoquinolyl. 3-8 "Cycloalkyl" means a saturated hydrocarbon group having 3 to 8 ring members, including those with a partially bridged structure. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, and bicyclo[2.2.2]octyl. 3-8 "Cycloalkoxy" means (C 3-8The term "3- to 8-membered heterocycloalkyl" refers to a cycloalkyl group in which a carbon atom in the ring is substituted with one or two heteroatoms selected from oxygen, nitrogen, and sulfur atoms, and also includes those with a partially bridged structure. 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, and the like.

[0101] "C 6-10 "Aryloxy" means (C 6-10 "C" refers to a group represented by the formula (aryl)-O-. For example, phenoxy can be mentioned. 6-10 Aryl C 1-6 "Alkoxy" means one C 6-10 Aryl-substituted C 1-6 It means alkoxy, for example, benzyloxy.

[0102] "C 3-8 Cycloalkyl C 1-6 "Alkoxy" means one C 3-8 Cycloalkyl-substituted C 1-6 It means alkoxy, for example, cyclopropylmethyloxy.

[0103] "C 6-10 Aryl C 1-6 "Alkyl" means one C 6-10 Aryl-substituted C 1-6 It means alkyl, for example, benzyl.

[0104] "5- or 6-membered heteroaryl C 2-6"Alkyl" refers to a C substituted with one 5- or 6-membered heteroaryl. 2-6 It means alkyl, for example, pyridin-4-ylmethyl, thiophen-2-ylethyl, thiophen-3-ylethyl, etc.

[0105] "C 3-8 Cycloalkyl C 1-6 "Alkyl" means one C 3-8 Cycloalkyl-substituted C 1-6 It means alkyl, and examples thereof include cyclopropylmethyl, cyclopropylethan-1-yl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0106] "C 6-10 Aryl C 2-6 "Alkynyl" means one C 6-10 Aryl-substituted C 2-6 It means alkynyl, for example, phenylethynyl.

[0107] "5- or 6-membered heteroaryl C 1-6 "Alkyl" refers to a C substituted with one 5- or 6-membered heteroaryl. 1-6 "5- or 6-membered heteroaryl C 2-6 "Alkynyl" refers to a C alkynyl group substituted with one 5- or 6-membered heteroaryl. 2-6 It means alkynyl, for example, pyridin-4-ylethynyl, pyridin-3-ylethynyl, etc.

[0108] "C 3-8 Cycloalkyl C 2-6 "Alkynyl" means one C 3-8 Cycloalkyl-substituted C 2-6 It means alkynyl, for example, cyclopropylethynyl.

[0109] "3- to 8-membered saturated carbocyclic ring" means a monocyclic or polycyclic saturated hydrocarbon ring having 3 to 8 carbon atoms. "5- to 8-membered saturated carbocyclic ring" means a monocyclic or polycyclic saturated hydrocarbon ring having 5 to 8 carbon atoms.

[0110] The term "5- to 8-membered unsaturated carbocyclic ring" refers to a monocyclic or polycyclic, fully unsaturated or partially unsaturated cyclic hydrocarbon ring containing from 5 to 8 carbon atoms.

[0111] "3- to 8-membered saturated heterocyclic ring" means a monocyclic or polycyclic 3- to 8-membered saturated heterocyclic ring having 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur atoms in the ring. "3- to 10-membered saturated heterocyclic ring" means a monocyclic or polycyclic 3- to 10-membered saturated heterocyclic ring having 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur atoms in the ring. "5- to 8-membered saturated heterocyclic ring" means a monocyclic or polycyclic 5- to 8-membered saturated heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms in the ring.

[0112] The term "3- to 10-membered unsaturated heterocycle" refers to a monocyclic or polycyclic, fully unsaturated or partially unsaturated 3- to 10-membered heterocycle having 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur atoms in the ring. The term "5- to 8-membered unsaturated heterocycle" refers to a monocyclic or polycyclic, fully unsaturated or partially unsaturated 5- to 8-membered heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms in the ring.

[0113] The term "5- to 8-membered ring" means a 5- to 8-membered saturated carbocyclic ring, a 5- to 8-membered saturated heterocyclic ring, a 5- to 8-membered unsaturated carbocyclic ring, or a 5- to 8-membered unsaturated heterocyclic ring.

[0114] The following abbreviations used in the text, figures, and tables have the following meanings: AIBN: Azobisisobutyronitrile BH3-THF: Borane-tetrahydrofuran complex Boc: tert-butoxycarbonyl Boc2O: Di-tert-butyl dicarbonate DBU: Diazabicycloundecene DCM: Dichloromethane DEAD: Diethyl azodicarboxylate DIBAL-H: Diisobutylaluminum hydride DIPEA: N,N-Diisopropylethylamine DMAP: 4-Dimethylaminopyridine DME: 1,2-Dimethoxyethane DMF: N,N-Dimethylformamide DMP: Dess-Martin periodinane DPPA: Diphenylphosphoryl azide DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate LDA: Lithium diisopropylamide MeCN: Acetonitrile, MTBE: Methyl tert-butyl ether, NBS: N-Bromosuccinimide, NMP: N-Methylpyrrolidone, PdCl2(dppf)-DCM: [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride DCM adduct, TBAF: Tetrabutylammonium fluoride, TBAI: Tetrabutylammonium iodide, TBDPS: tert-butyldiphenylsilyl, TBDPSCl: tert-butyldiphenylsilyl chloride, TBS: tert-butyldimethylsilyl, TEA: Triethylamine, TFA: Trifluoroacetic acid, THF: Tetrahydrofuran, TMEDA: N,N,N',N'-Tetramethylethylenediamine, TMS: Trimethylsilyl, TMSCl: Trimethylsilyl chloride, Xphos: 2-Dicyclohexylphosphino-2',4',6'-Triisopropylbiphenyl 10% Pd / C: 10% palladium carbon (approximately 55% water-wet) APS: Aminopropylated silica gel Method A: Column chromatography using a silica gel column connected to the bottom of an aminopropylated silica gel column Method B: Column chromatography using an aminopropylated silica gel column connected to the bottom of a silica gel column ODS: Octadecylsilylated silica gel PLC: Preparative thin-layer chromatography Ref. No.: Reference example number Str.: Structural formula Ex. No.: Example number Phys. data: Physical properties IC, 50 : 50% inhibitory concentration 1 H-NMR: Proton nuclear magnetic resonance spectrum CD3OD: Methanol-d4 DMSO: Dimethyl sulfoxide DMSO-d6: Dimethyl sulfoxide-d6 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.) cAMP: Adenosine 3',5'-cyclic monophosphate CHO: Chinese hamster ovary FBS: Fetal bovine serum HEPES: 2-(4-(2-hydroxyethyl)-1-piperazinyl)ethanesulfonic acid IBMX: 3-isobutyl-1-methylxanthine

[0115] When one or more asymmetric carbon atoms are present in the compounds represented by formulae (A-I) to (A-VIII) or formulae (I) to (VIII), the present invention encompasses compounds in which each asymmetric carbon atom is in the R configuration, compounds in the S configuration, and any combination thereof. Furthermore, their racemates, racemic mixtures, single enantiomers, and diastereomeric mixtures are also included within the scope of the present invention.

[0116] In the compounds represented by formulae (AI) to (A-VIII) or formulae (I) to (VIII), when cis-trans isomers exist, the present invention encompasses all of the cis-trans isomers.

[0117] When tautomers exist in the compounds represented by formulae (AI) to (A-VIII) or formulae (I) to (VIII), the present invention includes all of the tautomers.

[0118] In the present invention, the determination of stereochemistry can also be carried out by methods well known in the art.

[0119] The compounds represented by formulas (AI) to (A-VIII) or (I) to (VIII) can be converted into their pharmacologically acceptable salts, if necessary, in a conventional manner. Such salts include acid addition salts and salts with bases.

[0120] 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, TFA, 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.

[0121] Examples of salts with bases include salts with inorganic bases such as lithium salts, sodium salts, potassium salts, calcium salts, and magnesium salts, and salts with organic bases such as N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, TEA, piperidine, morpholine, pyrrolidine, arginine, lysine, and choline.

[0122] Unless otherwise specified, a suffix to a chemical name or structural formula referring to a salt, such as "hydrochloride" or "HCl," does not denote a stoichiometric description but simply refers to the salt form.

[0123] When the compounds represented by Formulae (A-I) to (A-VIII) or Formulae (I) to (VIII) or pharmacologically acceptable salts thereof exist, for example, as crystals, the present invention encompasses any crystalline form. For example, pharmacologically acceptable salts also include solvates with pharmaceutically acceptable solvents such as water or ethanol, co-crystals with an appropriate co-crystal former, and the like.

[0124] In the compounds represented by formulas (AI) to (A-VIII) or formulas (I) to (VIII), some of the atoms may be replaced with the corresponding isotopes. The present invention also includes compounds replaced with these isotopes. Examples of isotopes include: 2 H, 3 H, 11 C. 13 C. 14 C. 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O. 17 O. 18 O, and 35 In one embodiment, some of the hydrogen atoms of the compounds represented by formulas (AI) to (A-VIII) or (I) to (VIII) are 2 Examples include compounds in which hydrogen is replaced by H (D: deuterium atom).

[0125] Compounds of formulae (A-I) to (A-VIII) or formulae (I) to (VIII) in which some atoms are replaced with isotopes can be produced by a method similar to the production method described below using commercially available building blocks containing isotopes. They can also be produced by 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).

[0126] The compounds of the present invention represented by formulae (A-I) to (A-VIII) or (I) to (VIII) 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 formulae (A-I) to (A-VIII) or (I) to (VIII) correspond to the compounds of formulae (I-1) to (I-5).

[0127] The compounds of the present invention represented by formulae (AI) to (A-VIII) or formulae (I) to (VIII) can be produced by the methods shown below. However, the production methods shown below are examples of general production methods and are not intended to limit the production methods.

[0128] In the reactions of each step, when raw materials and reagents are commercially available, commercially available products can be used.

[0129] In the reaction of each step, the reaction time varies depending on the starting materials used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days unless otherwise specified.

[0130] In the reactions of each step, the reaction temperature varies depending on the starting materials and solvents used, but is usually −78° C. to reflux temperature unless otherwise specified.

[0131] In the reaction of each step, the pressure varies depending on the starting materials, solvent, reaction temperature, etc. used, but is usually 1 to 20 atmospheres unless otherwise specified.

[0132] A microwave reactor such as Biotage's Initiator may be used in the reactions of each step. When a microwave reactor is used, the conditions vary depending on the raw materials, solvent, and model used, but the reaction can be carried out under the following conditions: pressure range: 1 to 30 bar, power range: 1 to 400 W, reaction temperature: room temperature to 300°C, and reaction time: 1 minute to 1 day.

[0133] Unless otherwise specified, the reaction in each step is carried out without solvent or using an appropriate solvent. Examples of the appropriate solvent include solvents inert to the reaction. Specific examples of the solvent used include the solvents described in the Reference Examples or Examples corresponding to each step, or the following solvents. Two or more of the following solvents may be mixed in an appropriate ratio and used. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-propanol, etc.; Ethers: diethyl ether, THF, DME, 1,4-dioxane, cyclopentyl methyl ether, MTBE, 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, carbon tetrachloride, etc.; Nitriles: MeCN, etc.; Sulfoxides: DMSO, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, TFA, methanesulfonic acid, etc.; Esters: ethyl acetate, methyl acetate, isopropyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; Water.

[0134] 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 used include bases described in the Reference Examples or Examples corresponding to each step, or 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, DBU, 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.; organomagnesiums: isopropylmagnesium chloride, etc.; organolithiums: methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, etc.

[0135] When an acid is used in the reaction of each step, the reaction is carried out using an acid suitable for the reaction. Specific examples of the acid used include the acids described in the Reference Examples and Examples corresponding to each step and the following acids: inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; organic acids: acetic acid, TFA, 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.

[0136] When a condensing agent is used in the reaction of each step, the reaction is carried out using a condensing agent suitable for the reaction. Specific examples of the condensing agent used include the condensing agents described in the Reference Examples or Examples corresponding to each step, or the following condensing agents. Carbodiimides: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, etc.; Imidazoles: carbonyldiimidazole, etc.; Uronium salts, phosphonium salts: HATU, 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, etc.; Triazines: DMT-MM, etc.; Others: propylphosphonic anhydride (cyclic trimer), etc.

[0137] 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, DIBAL-H, etc.; Boranes: BH3-THF, picoline borane complex, decaborane, etc.

[0138] When a carbonyl group-introducing reagent is used in the reaction of each step, the reaction is carried out using a carbonyl group-introducing reagent suitable for the reaction. Specific examples of the carbonyl group-introducing reagent to be used include the carbonyl group-introducing reagents described in the Reference Examples or Examples corresponding to each step, or the following carbonyl group-introducing reagents: phosgene, diphosgene, triphosgene, etc.; chloroformates: 4-nitrophenyl chloroformate, etc.; imidazoles: carbonyldiimidazole, etc.

[0139] In each step, when a protecting group is required depending on the type of functional group, the protective group may be introduced and removed in a suitable combination according to a conventional method. Regarding the type of protective group, protection, and deprotection, for example, the method described in "Greene's Protective Groups in Organic Synthesis," edited by Peter GM Wuts, fifth edition, Wiley-Interscience, 2014 can be mentioned.

[0140] When a hydrolysis reaction is carried out in each step, the reaction can be carried out in the presence of an acid or a base. Examples of the acid and base that can be used include those mentioned above.

[0141] In each step, when a catalytic reduction reaction is carried out, the reaction can be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst that can be used include palladium carbon powder, Pearlman's catalyst, platinum carbon powder, Raney nickel, etc. If necessary, an acid may be used in the reaction.

[0142] When a reduction reaction is carried out in each step, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent to be used include the above-mentioned examples.

[0143] When a metal reduction reaction is carried out in each step, the reaction can be carried out in the presence of a metal or the like. Examples of the metal or the like that can be used include iron powder, zinc powder, tin chloride, titanium trichloride, etc. If necessary, an acid may be used in the reaction.

[0144] When amidation is carried out in each step, the reaction can be carried out using a condensing agent in the presence or absence of a base. Examples of the condensing agent and base to be used include those mentioned above. When a carbodiimide is used as the condensing agent, the reaction may be carried out by adding an additive such as 1-hydroxybenzotriazole or DMAP, as necessary. The reaction can also be carried out using an acyl halide or an acid anhydride in the presence or absence of a base.

[0145] When reductive amination is performed in each step, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent that can be used include those mentioned above. The reaction can also be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst that can be used include palladium carbon powder, Pearlman's catalyst, platinum carbon powder, Raney nickel, etc.

[0146] When a Negishi coupling reaction is performed in each step, the reaction can be carried out in the presence of an organozinc compound, a palladium catalyst, and a ligand. Examples of the palladium catalyst include palladium(II) acetate and tris(dibenzylideneacetone)palladium(0). Examples of the ligand include Xphos, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and tris(2-methylphenyl)phosphine.

[0147] 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. The palladium catalyst used is bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II). 、 tetrakis(triphenylphosphine)palladium(0), etc. Examples of the base to be used include the examples mentioned above.

[0148] When Goldberg amination is performed in each step, the reaction can be carried out in the presence of a copper catalyst, a ligand, and a base. Examples of copper catalysts that can be used include copper(I) iodide, copper(I) bromide, copper(I) chloride, copper(II) chloride, copper(I) oxide, copper(II) oxide, copper(II) acetate, and copper(II) sulfate. Examples of ligands that can be used include 1,10-phenanthroline, TMEDA, and 2,2'-bipyridine. Examples of bases that can be used include those listed above.

[0149] When Sonogashira coupling reaction is carried out in each step, the reaction can be carried out in the presence of a palladium catalyst, a copper catalyst, and a base. Examples of the palladium catalyst include bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) and bis(acetonitrile)palladium(II) chloride. Examples of the copper catalyst include copper(I) iodide and copper(I) bromide. Examples of the base used include the above-mentioned examples.

[0150] When a Curtius rearrangement reaction is carried out in each step, the reaction can be carried out in the presence of an azide source, such as sodium azide or DPPA.

[0151] When carbamation or urea formation is carried out in each step, the reaction can be carried out using a carbonyl group-introducing reagent in the presence or absence of a base. Examples of the carbonyl group-introducing reagent and base to be used include those mentioned above.

[0152] The compounds represented by formulae (I-1a) to (I-1d) can be produced, for example, according to the method described in Scheme 1.

[0153] The symbols in the formula have the same meanings as above. 1P is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, or C 1-6 Alkoxy C 1-6 It is alkyl. R 1P’ is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-8 It is cycloalkyl.

[0154] Process 1-1 Compound (I-1a) can also be produced by reacting compound (1-1) with trimethylsilyl isocyanate. Alternatively, compound (I-1a) can be produced by reacting compound (1-1) with potassium cyanate or sodium cyanate in the presence of an acid.

[0155] Process 1-2 Compound (I-1b) can also be produced by ureation of compound (1-1) and compound (1-2).

[0156] Process 1-3 Compound (I-1c) can also be produced by amidation of compound (1-1) and compound (1-3).

[0157] Process 1-4 Compound (I-1d) can also be produced by carbamate reaction of compound (1-1) and compound (1-4).

[0158] The compound represented by formula (1-1a) can be produced, for example, according to the method described in Scheme 2.

[0159] The symbols in the formula have the same meanings as above.

[0160] Process 2-1 Compound (I-2) can also be produced by reacting compound (2-1) with DPPA and Boc2O in the presence of a base.

[0161] Process 2-2 The compound (1-1a) can also be prepared by removing the Boc group of the compound (I-2).

[0162] The compound represented by formula (2-1) can be produced, for example, according to the method described in Scheme 3.

[0163] The symbols in the formula have the same meanings as above. 1 is a chlorine atom, a bromine atom, or an iodine atom, and R 3P is C 1-6 Alkyl, C 6-10 Aryl, or C 6-10 Aryl C 1-6 alkyl, LG 2 is a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonyloxy group.

[0164] Process 3-1 Compound (3-3) can also be produced by Goldberg amination of compound (3-1) and compound (3-2).

[0165] Process 3-2 The compound (3-4) can also be produced by catalytic hydrogen reduction of the compound (3-3).

[0166] Process 3-3 The compound (2-1) can also be produced by reacting the compound (3-4) with the compound (3-5) in the presence of a base.

[0167] Process 3-4 Compound (3-8) can also be produced by reductive amination of compound (3-6) and compound (3-7).

[0168] Process 3-5 The compound (2-1) can also be produced by amidation of the compound (3-8).

[0169] The compound represented by formula (1-4b) can be produced, for example, according to the method described in Scheme 4.

[0170] The symbols in the formula have the same meanings as above. 4P is a hydrogen atom, a fluorine atom, C 1-6 Alkyl, HaloC 1-6 Alkyl, or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl).

[0171] Process 4-1 Compound (I-4b) can also be produced by catalytic hydrogen reduction of compound (I-4a).

[0172] The compound represented by formula (1-1b) can be produced, for example, according to the method described in Scheme 5.

[0173] The symbols in the formula have the same meanings as above.

[0174] Process 5-1 The compound (5-2) can also be produced by reacting the compound (5-1) with the compound (3-5) in the presence of a base.

[0175] Process 5-2 The compound (1-1b) can also be produced by reducing the nitro group of the compound (5-2).

[0176] Process 5-3 The compound (5-5) can also be produced by subjecting the compound (5-3) to Curtius rearrangement reaction.

[0177] Process 5-4 The compound (5-5) can also be produced by carbamate conversion of the compound (5-4).

[0178] Process 5-5 Compound (I-5) can also be produced by reacting compound (5-5) with compound (3-5) in the presence of a base.

[0179] Process 5-6 Compound (1-1b) can also be produced by removing the Boc group of compound (I-5).

[0180] The compound represented by formula (1-1c) can be produced, for example, according to the method described in Scheme 6.

[0181] The symbols in the formula have the same meanings as above. 6P is C 1-6 It is alkyl.

[0182] Process 6-1 Compound (6-3) can also be produced by the Negishi coupling reaction of compound (6-1) and compound (6-2).

[0183] Process 6-2 The compound (1-1c) can also be produced by reacting the compound (6-3) with an acid.

[0184] The compounds represented by formula (6-1) and formula (6-1a) can be produced, for example, according to the method described in Scheme 7.

[0185] The symbols in the formula have the same meanings as above. p' is an integer of 0 to 2.

[0186] Process 7-1 The compound (6-1) can also be produced by reacting the compound (7-1) with the compound (3-5) in the presence of a base.

[0187] Process 7-2 The compound (6-1a) can also be produced by reductive amination of the compound (7-1) and the compound (7-2).

[0188] The above-described schemes are examples of methods for producing compounds represented by formulas (AI) to (A-VIII) or formulas (I) to (VIII) or intermediates for producing them. The above-described schemes can be modified in various ways to be easily understood by those skilled in the art.

[0189] The compounds represented by formulae (AI) to (A-VIII) or formulae (I) to (VIII) and their production intermediates can also be isolated and purified, if necessary, by isolation and purification means well known to those skilled in the art, such as solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography, etc.

[0190] The compounds of the present invention have excellent TSHR antagonist activity and can be used as therapeutic agents for thyroid-related diseases. In the present invention, thyroid-related diseases include, for example, hyperthyroidism, Graves' disease, thyroid eye disease, and thyroid cancer. Preferably, the compounds of the present invention can be used as therapeutic agents for hyperthyroidism, Graves' disease, or thyroid eye disease (see Endocrinology, 2014, 155 (1), pp. 310-314). More preferably, the compounds of the present invention can be used as therapeutic agents for hyperthyroidism or Graves' disease.

[0191] In one embodiment, hyperthyroidism includes hyperthyroidism caused by, for example, Graves' disease, thyroiditis, Plummer's disease, toxic multinodular goiter, TSH-producing pituitary adenoma, hyperemesis gravidarum, ovarian goiter, gestational trophoblastic tumor, or germ cell tumor. Preferably, the compound of the present invention can be used as a therapeutic agent for hyperthyroidism caused by Graves' disease.

[0192] In one embodiment, the thyroid-related disease is a disease or condition associated with abnormal thyroid hormone levels. Diseases and conditions associated with abnormal thyroid hormone levels include, for example, diseases and conditions caused by TRAb.

[0193] In the present invention, "treatment" includes the meaning of "prevention." For example, treatment of hyperthyroidism, Graves' disease, or thyroid eye disease includes the meanings of "prevention of relapse / recurrence" and "maintenance of remission." In addition, in one embodiment, the compounds of the present invention can be used to prevent the onset of thyroid eye disease in patients with Graves' disease.

[0194] In the present invention, the term "antagonist" refers to a drug that inhibits or blocks the function of a target protein, regardless of its binding site. For example, the term "antagonist" includes the meanings of "allosteric antagonist" and "negative allosteric modulator (NAM)."

[0195] The therapeutic effect of the compound of the present invention on thyroid-related diseases can be confirmed by methods well known in the art. For example, the effect can be confirmed in an animal model of hyperthyroidism or Graves' disease by the method described in Endocrinology 2007, 148(5), pp. 2335-2344 or a method modified therefrom.

[0196] The pharmaceutical composition of the present invention may be used in various dosage forms depending on the intended use, including, for example, powders, granules, fine granules, dry syrup, tablets, capsules, injections, liquids, ointments, suppositories, patches, eye drops, and enemas.

[0197] The pharmaceutical composition of the present invention comprises a compound represented by formula (AI) to (A-VIII), or formula (I) to (VIII), or a pharmacologically acceptable salt thereof, as an active ingredient.

[0198] The pharmaceutical compositions of the present invention are prepared using a compound represented by Formula (A-I) to (A-VIII) or Formula (I) to (VIII) 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.

[0199] When the pharmaceutical composition of the present invention is used for treatment, the dosage of the compound represented by Formula (A-I) to (A-VIII) or Formula (I) to (VIII) or a pharmacologically acceptable salt thereof is appropriately determined depending on the patient's age, sex, body weight, disease, and degree of treatment. The daily dosage may be administered once, twice, three times, or four times. When administered orally, the dosage for an adult may be determined, for example, in the range of 0.1 to 5000 mg / day. In one embodiment, the oral dosage may be determined in the range of 1 to 1500 mg / day, preferably in the range of 1 to 500 mg / day. When administered parenterally, the dosage for an adult may be determined, for example, in the range of 0.01 to 5000 mg / day. In one embodiment, the parenteral dosage may be determined in the range of 0.1 to 1500 mg / day, preferably in the range of 0.1 to 500 mg / day.

[0200] In one embodiment, the pharmaceutical composition of the present invention can be used in combination with drugs other than TSHR antagonists. Examples of other drugs that can be used in combination for the treatment of thyroid-related diseases include antithyroid drugs (e.g., thiamazole, propylthiouracil, etc.), inorganic iodine, lithium carbonate, thyroid hormone preparations, etc.

[0201] When a compound represented by Formulae (A-I) to (A-VIII), or a compound represented by Formulae (I) to (VIII), or a pharmacologically acceptable salt thereof, is used in combination with another drug, these active ingredients can be administered as a preparation containing them together, or as a preparation in which each of these active ingredients is separately formulated. When these active ingredients are formulated separately, these preparations can be administered separately or simultaneously. In addition, the dosage of a compound represented by Formulae (A-I) to (A-VIII), or a compound represented by Formulae (I) to (VIII), or a pharmacologically acceptable salt thereof, may be appropriately reduced depending on the dosage of the other drug used in combination.

[0202] The compounds represented by formulas (A-I) to (A-VIII) or formulas (I) to (VIII) may be appropriately converted into prodrugs for use. For example, prodrugs of the compounds represented by formulas (A-I) to (A-VIII) or formulas (I) to (VIII) can be produced by introducing a prodrug-constituting group using a prodrug-converting reagent such as a corresponding halide, followed by purification. Examples of prodrug-constituting groups include those described in "Development of Pharmaceuticals" (Hirokawa Shoten, 1990), Vol. 7, pp. 163-198.

[0203] 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.

[0204] The names of compounds described in the following examples, excluding commercially available reagents, were named using ChemDraw Professional (PerkinElmer), MarvinSketch (ChemAxon), etc. The configuration of an asymmetric center marked with "*" in the compound name means that it is the relative configuration.

[0205] Reference Example A-1 5-(Difluoromethyl)-2-fluorobenzaldehyde To a mixture of 5-(difluoromethyl)-2-fluorobenzonitrile (2.30 g) and DCM (40 mL), DIBAL-H (1.02 mol / L in n-hexane) (27 mL) was added in an ice-salt bath, and the mixture was stirred for 1 hour in an ice-salt bath. 2 mol / L hydrochloric acid (40 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (1.62 g).

[0206] Reference Example A-2 5-(difluoromethyl)-2-fluorobenzyl methanesulfonate To a mixture of Reference Example A-1 (0.500 g) and methanol (9.6 mL), sodium borohydride (0.119 g) was added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. Water 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. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to obtain (5-(difluoromethyl)-2-fluorophenyl)methanol (0.375 g). To a mixture of the obtained compound (0.374 g), TEA (0.258 g), and DCM (7.1 mL), methanesulfonyl chloride (0.268 g) was added under ice-cooling, and the mixture was stirred under ice-cooling for 10 minutes and at room temperature for 30 minutes. Water was added to the reaction mixture under ice-cooling, 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 = 85 / 15 to 60 / 40) to give the title compound (0.383 g).

[0207] Reference Example A-3 3-chloro-2-fluoro-5-(trifluoromethyl)benzyl methanesulfonate Reference Example A-3 was synthesized in the same manner as in Reference Example A-2, except that 3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde was used instead of Reference Example A-1.

[0208] Reference Example A-4 4-(benzyloxy)-2-(bromomethyl)-1-fluorobenzene To a mixture of (5-(benzyloxy)-2-fluorophenyl)methanol (0.125 g) and toluene (1.3 mL), phosphorus tribromide (0.219 g) was added at room temperature, followed by stirring at 50° C. for 1 hour. To the reaction mixture, phosphorus tribromide (0.029 g) was added at room temperature, followed by stirring at 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.159 g).

[0209] Reference Example A-5 2-Fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzaldehyde To a mixture of 3-bromo-4-fluorophenol (1.15 g), 1-bromo-1,1,2,2-tetrafluoro-2-iodoethane (3.68 g), and DMSO (6.0 mL), cesium carbonate (2.93 g) was added at room temperature and stirred at 60°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and water was added. The mixture was extracted twice with n-hexane. The combined extracts were washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A mixture of the residue, zinc powder (1.18 g), and acetic acid (1.0 mL) was stirred at 50°C for 4 hours. The reaction mixture was allowed to cool to room temperature, and water was added, and the mixture was extracted with DCM. The extract was washed with saturated aqueous sodium bicarbonate and then 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 2-bromo-1-fluoro-4-(1,1,2,2-tetrafluoroethoxy)benzene (0.618 g). Under an argon atmosphere, n-butyllithium (1.57 mol / L in n-hexane) (1.35 mL) was added to a mixture of the resulting compound (0.617 g) and diethyl ether (7.1 mL) at -78°C and stirred at the same temperature for 20 minutes. DMF (0.197 mL) was added to the reaction mixture at -78°C and stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.559 g).

[0210] Reference Example A-6 2-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzyl methanesulfonate Reference Example A-6 was synthesized in the same manner as in Reference Example A-2, except that Reference Example A-5 was used instead of Reference Example A-1.

[0211] Reference Example A-7 2-fluoro-5-(trifluoromethyl)benzyl methanesulfonate Reference Example A-7 was synthesized in the same manner as in Reference Example A-2, except that 2-fluoro-5-(trifluoromethyl)benzaldehyde was used instead of Reference Example A-1.

[0212] Reference Example A-8 1-(Bromomethyl)-3-chloro-2-fluoro-5-(trifluoromethyl)benzene To a mixture of 3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde (1.00 g) and ethanol (10 mL), sodium borohydride (0.250 g) was added under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and then concentrated under reduced pressure. To a mixture of the residue and 1,2-dichloroethane (10 mL), phosphorus tribromide (1.79 g) was added at room temperature, and the mixture was stirred at the same temperature for 40 minutes. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and saturated aqueous sodium bicarbonate, 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 85 / 15) to obtain the title compound (0.484 g).

[0213] Reference Example A-9: Ethyl 2-amino-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzoate. A mixture of ethyl 2-aminobenzoate (2.00 g), hexafluoroacetone hydrate (2.93 g), and p-toluenesulfonic acid hydrate (0.115 g) was stirred at 140°C for 20 hours under microwave irradiation. The reaction mixture was poured into saturated aqueous sodium bicarbonate, 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 80 / 20). The resulting product was suspended in water, and the insoluble matter was collected by filtration. The resulting solid was dried under reduced pressure to give the title compound (2.30 g).

[0214] Reference Example A-10: Ethyl 2-fluoro-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzoate. To a mixture of Reference Example A-9 (0.579 g) and DME (15 mL), boron trifluoride diethyl ether complex (0.310 g) was added in an ice-salt bath, and the mixture was stirred for 15 minutes in an ice-salt bath. A mixture of tert-butyl nitrite (0.189 g) and DME (7.5 mL) was added to the reaction mixture in an ice-salt bath, and the mixture was stirred for 4 hours under ice-cooling. The reaction mixture was concentrated under reduced pressure. A mixture of the residue and chlorobenzene (15 mL) was refluxed for 2 hours. 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 = 98 / 2 to 85 / 15) to obtain the title compound (0.504 g).

[0215] Reference Example A-11: 2-Fluoro-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzaldehyde. To a mixture of Reference Example A-10 (0.855 g), THF (6.4 mL), and methanol (0.64 mL), lithium borohydride (4 mol / L in THF) (3.20 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 19 hours. Lithium borohydride (4 mol / L in THF) (1.28 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. Methanol (0.32 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 2.5 hours and at 60°C for 45 minutes. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture under ice-cooling, 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 = 90 / 10 to 70 / 30) to give 1,1,1,3,3,3-hexafluoro-2-(4-fluoro-3-(hydroxymethyl)phenyl)propan-2-ol (0.696 g). Manganese dioxide (IV) (1.61 g) was added to a mixture of the obtained compound (0.696 g) and DCM (6.2 mL) at room temperature, and the mixture was stirred at the same temperature for 65 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 = 98 / 2 to 70 / 30) to give the title compound (0.261 g).

[0216] Reference Example A-12 2-(1-bromoethyl)-1-fluoro-4-(trifluoromethyl)benzene 3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde was replaced with 1-(2-fluoro-5-(trifluoromethyl)phenyl)ethan-1-one, and Reference Example A-12 was synthesized in the same manner as in Reference Example A-8.

[0217] Reference Example B-1 (S)-6-(trifluoromethyl)piperidin-2-one Under an argon atmosphere, a mixture of 2-bromo-6-(trifluoromethyl)pyridine (4.00 g), (R)-4-benzyloxazolidin-2-one (3.76 g), potassium carbonate (4.89 g), copper(I) iodide (0.169 g), 1,10-phenanthroline (0.319 g), and toluene (30 mL) was stirred at 140 °C for 14 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 = 95 / 5 to 85 / 15) to give (R)-4-benzyl-3-(6-(trifluoromethyl)pyridin-2-yl)oxazolidin-2-one (5.80 g). To a mixture of the obtained compound (0.872 g), THF (4.4 mL), water (4.4 mL), and methanesulfonic acid (1.04 g), 10% Pd / C (0.548 g) was added at room temperature, and the mixture was stirred under a hydrogen atmosphere at 50°C for 35 hours. The reaction mixture was filtered through Celite, and saturated aqueous sodium bicarbonate solution was added to the filtrate. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. A mixture of the residue and toluene (9.0 mL) was stirred at 100°C for 2 hours. The reaction mixture was concentrated under reduced pressure. Ethyl acetate (2.7 mL), n-hexane (16 mL), and a small amount of (R)-4-benzyloxazolidin-2-one were added to the residue, and the mixture was stirred at room temperature for 15 minutes. The mixture was filtered, and the insoluble matter was washed with n-hexane / ethyl acetate (8 / 1), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=50 / 50 / 0 to 0 / 100 / 0 to 0 / 90 / 10) to obtain the title compound (0.321 g).

[0218] Reference Example B-2 (S)-6-(Difluoromethyl)piperidin-2-one A mixture of 2-bromo-6-(difluoromethyl)pyridine (3.14 g), (R)-4-benzyloxazolidin-2-one (3.21 g), potassium carbonate (4.17 g), copper(I) iodide (0.144 g), 1,10-phenanthroline (0.272 g), and toluene (25 mL) was stirred at 140 ° C. for 14 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 = 98 / 2 to 75 / 25) to give (R)-4-benzyl-3-(6-(difluoromethyl)pyridin-2-yl)oxazolidin-2-one (4.57 g). A mixture of the obtained compound (4.57 g), 10% Pd / C (1.29 g), THF (40 mL), water (40 mL), and concentrated hydrochloric acid (1.23 g) was stirred under hydrogen pressure (0.4 MPa) at 40°C for 90 hours. The reaction mixture was allowed to cool to room temperature and then filtered through Celite. Concentrated hydrochloric acid (1.23 g) was added to the filtrate, and the mixture was stirred at 70°C for 1.5 hours. The reaction mixture was allowed to cool to room temperature, and then sodium carbonate (8.95 g) was added. The mixture was filtered through Celite, and the filtrate 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 = 50 / 50 / 0 to 0 / 100 / 0 to 0 / 90 / 10) to give the title compound (0.880 g).

[0219] Reference Example B-3 (S)-5-fluoropiperidin-2-one Reference Example B-3 was synthesized in the same manner as in Reference Example B-2, except that 2-bromo-5-fluoropyridine was used instead of 2-bromo-6-(difluoromethyl)pyridine.

[0220] Reference example B-4 (4aS * ,8aR *) Octahydroquinolin-2(1H)-one To a mixture of 3,4,5,6,7,8-hexahydroquinolin-2(1H)-one (0.500 g) and formic acid (2.5 mL), sodium formate (1.40 g) was added at room temperature and refluxed for 40 hours. After the reaction mixture was allowed to cool to room temperature, 5 mol / L aqueous sodium hydroxide solution was added, 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 = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 90 / 10) to give the title compound (0.108 g).

[0221] Reference Example C-1 1-(5-Bromo-2-fluorobenzyl)-6-methylpiperidin-2-one Under an argon atmosphere, sodium hydride (approximately 60%) (0.170 g) was added to a mixture of 6-methylpiperidin-2-one (0.320 g) and DMF (6.9 mL) under ice-cooling, and the mixture was stirred for 10 minutes under ice-cooling. 4-Bromo-2-(bromomethyl)-1-fluorobenzene (0.833 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with n-hexane / ethyl acetate (1 / 1). 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 (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 20 / 80) to give the title compound (0.688 g).

[0222] Reference Example C-2 1-(5-(difluoromethyl)-2-fluorobenzyl)-6-methylpiperidin-2-one Reference Example C-2 was synthesized in the same manner as in Reference Example C-1, using Reference Example A-2 instead of 4-bromo-2-(bromomethyl)-1-fluorobenzene.

[0223] Reference Example C-3 1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methylpiperidin-2-one Reference Example C-3 was synthesized in the same manner as in Reference Example C-1, using Reference Example A-3 instead of 4-bromo-2-(bromomethyl)-1-fluorobenzene.

[0224] Reference Example C-4 1-((4-fluoro-(1,1'-biphenyl)-3-yl)methyl)-6-methylpiperidin-2-one To a mixture of Reference Example C-1 (0.210 g), phenylboronic acid (0.094 g), potassium carbonate (0.145 g), THF (1.1 mL) and water (1.1 mL), bis(triphenylphosphine)palladium(II) chloride (0.049 g) was added at room temperature and stirred at 70°C for 30 minutes. The reaction mixture was allowed to cool to room temperature, then poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine 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 / 88 / 12) to obtain the title compound (0.209 g).

[0225] Reference Example C-5: 1-(5-benzyl-2-fluorobenzyl)-6-methylpiperidin-2-one. A mixture of Reference Example C-1 (0.160 g), potassium benzyltrifluoroborate (0.211 g), cesium carbonate (0.347 g), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.038 g), 1,4-dioxane (1.6 mL), and water (0.16 mL) was stirred at 120°C for 1 hour under microwave irradiation. The reaction mixture was poured into saturated aqueous ammonium chloride at room temperature, 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 (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 60 / 40) to give the title compound (0.056 g).

[0226] Reference Example C-6 6-methyl-1-(3-phenoxybenzyl)piperidin-2-one Reference Example C-6 was synthesized in the same manner as in Reference Example C-1, except that 1-(bromomethyl)-3-phenoxybenzene was used instead of 4-bromo-2-(bromomethyl)-1-fluorobenzene.

[0227] Reference Example C-7 1-(5-(benzyloxy)-2-fluorobenzyl)-6-methylpiperidin-2-one Reference Example C-7 was synthesized in the same manner as in Reference Example C-1, using Reference Example A-4 instead of 4-bromo-2-(bromomethyl)-1-fluorobenzene.

[0228] Reference Example C-8 (R)-1-(2-Fluoro-5-(trifluoromethyl)benzyl)-6-methylpiperidin-2-one. To a mixture of (R)-6-methylpiperidin-2-one (0.150 g), 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (0.409 g), and DMF (2.0 mL), sodium hydride (approximately 60%) (0.064 g) was added under water-cooling, and the mixture was stirred at room temperature for 1 hour. Under water-cooling, saturated aqueous ammonium chloride and water were added to the reaction mixture, and the mixture was extracted with n-hexane / ethyl acetate (1 / 1). The extract was washed with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 15 / 85) to obtain the title compound (0.352 g).

[0229] Reference Example C-9: (S)-1-(2-Fluoro-5-(trifluoromethyl)benzyl)-6-(trifluoromethyl)piperidin-2-one. Under an argon atmosphere, sodium hydride (approximately 60%) (0.041 g) was added to a mixture of Reference Example B-1 (0.113 g) and DMF (1.8 mL) under ice-cooling, and the mixture was stirred for 10 minutes under ice-cooling. 2-(Bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (0.226 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice-cooling, and the mixture was extracted with n-hexane / ethyl acetate (1 / 1). 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 (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 20 / 80) to give the title compound (0.175 g).

[0230] Reference Example C-10 (S)-1-(5-(Difluoromethyl)-2-fluorobenzyl)-6-(trifluoromethyl)piperidin-2-one Under an argon atmosphere, sodium hydride (approximately 60%) (0.040 g) was added to a mixture of Reference Example B-1 (0.117 g) and DMF (1.8 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 10 minutes. Reference Example A-2 (0.204 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with n-hexane / ethyl acetate (1 / 1). 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 (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 20 / 80) to obtain the title compound (0.112 g).

[0231] Reference Example C-11 (S)-1-(2-Fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzyl)-6-(trifluoromethyl)piperidin-2-one. Under an argon atmosphere, sodium hydride (approximately 60%) (0.036 g) was added to a mixture of Reference Example B-1 (0.100 g) and DMF (1.6 mL) under ice-cooling, and the mixture was stirred for 15 minutes under ice-cooling. Reference Example A-6 (0.220 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 65 hours. Under ice-cooling, saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with n-hexane / ethyl acetate (1 / 1). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 85 / 15 to 50 / 50) to obtain the title compound (0.166 g).

[0232] Reference Example C-12 (S)-6-(Difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)piperidin-2-one. Under an argon atmosphere, sodium hydride (approximately 60%) (0.041 g) was added to a mixture of Reference Example B-2 (0.101 g) and DMF (1.8 mL) under ice-cooling, and the mixture was stirred for 10 minutes under ice-cooling. 2-(Bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (0.226 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice-cooling, and the mixture was extracted with n-hexane / ethyl acetate (1 / 1). 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 (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 20 / 80) to obtain the title compound (0.157 g).

[0233] Reference Example C-13 (S)-5-fluoro-1-(2-fluoro-5-(trifluoromethyl)benzyl)piperidin-2-one Reference Example C-13 was synthesized in the same manner as in Reference Example C-9, using Reference Example B-3 instead of Reference Example B-1.

[0234] Reference Example C-14 4- (3- (trifluoromethyl) benzyl) -4-azaspiro [2.5] octan-5-one 6-methylpiperidin-2-one instead of 4-azaspiro [2.5] octan-5-one, 4-bromo-2- (bromomethyl) -1-fluorobenzene instead of 1- (bromomethyl) -3- (trifluoromethyl) benzene was used, and Reference Example C-14 was synthesized in the same manner as in Reference Example C-1.

[0235] Reference Example C-15 2-(2-fluoro-5-(trifluoromethyl)benzyl)-2-azabicyclo[4.1.0]heptan-3-one 6-methylpiperidin-2-one instead of 2-azabicyclo[4.1.0]heptan-3-one, 4-bromo-2-(bromomethyl)-1-fluorobenzene instead of Reference Example A-7, Reference Example C-15 was synthesized in the same manner as in Reference Example C-1.

[0236] Reference Example C-16 (6S)-1-(1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)-6-(trifluoromethyl)piperidin-2-one Reference Example B-1 was used instead of 6-methylpiperidin-2-one, and Reference Example A-12 was used instead of 4-bromo-2-(bromomethyl)-1-fluorobenzene, and Reference Example C-16 was synthesized in the same manner as in Reference Example C-1.

[0237] Reference Example C-17 6-Methyl-1-(3-(trifluoromethyl)phenethyl)piperidin-2-one To a mixture of 5-oxohexanoic acid (0.200 g), 2-(3-(trifluoromethyl)phenyl)ethan-1-amine (0.291 g), and methanol (4.0 mL), decaborane (0.056 g) was added under water cooling, and the mixture was stirred at room temperature for 30 minutes. APS was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. A mixture of the residue, DIPEA (0.397 g), HATU (0.701 g), and MeCN (6.0 mL) was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate=90 / 10 to 0 / 100) to obtain the title compound (0.269 g).

[0238] Reference example C-18 (4aS * ,8aR * )-1-(3-(trifluoromethyl)benzyl)octahydroquinolin-2(1H)-one Reference Example B-4 was used instead of 6-methylpiperidin-2-one, and 1-(bromomethyl)-3-(trifluoromethyl)benzene was used instead of 4-bromo-2-(bromomethyl)-1-fluorobenzene, and Reference Example C-18 was synthesized in the same manner as in Reference Example C-1.

[0239] Reference Example D-1: tert-Butyl (6-bromo-2-hydroxypyridin-3-yl)carbamate. A mixture of 3-amino-6-bromopyridin-2-ol hydrobromide (1.00 g), BocO (0.970 g), TEA (1.13 g), DMAP (0.045 g), and DCM (10 mL) was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride 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 = 100 / 0 to 80 / 20) to give the title compound (0.402 g).

[0240] Reference Example D-2: tert-Butyl (4-hydroxy-2-methylpyrimidin-5-yl)carbamate. DPPA (0.695 g) was added to a mixture of 4-hydroxy-2-methylpyrimidine-5-carboxylic acid (0.354 g), TEA (0.465 g), tert-butyl alcohol (0.851 g), and toluene (10 mL) at room temperature, and the mixture was refluxed for 3.5 hours. After the reaction mixture was allowed to cool to room temperature, water and saturated aqueous ammonium chloride were added, 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 / methanol = 70 / 30 / 0 to 0 / 100 / 0 to 0 / 85 / 15) to give the title compound (0.068 g).

[0241] Reference Example D-3 tert-butyl (3-hydroxy-5-methylpyrazin-2-yl)carbamate Reference Example D-3 was synthesized in the same manner as in Reference Example D-2, except that 3-hydroxy-5-methylpyrazine-2-carboxylic acid was used instead of 4-hydroxy-2-methylpyrimidine-5-carboxylic acid.

[0242] Reference Example E-1 5-Bromo-1-(2-fluoro-5-(trifluoromethyl)benzyl)-3-nitropyridin-2(1H)-one To a mixture of 5-bromo-3-nitropyridin-2-ol (0.222 g) and DMF (4.0 mL), cesium carbonate (0.380 g) and 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (0.200 g) were added at room temperature, and the mixture was stirred at 70°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then water, n-hexane, and ethyl acetate were added, and the organic layer was separated. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 20 / 80) to obtain the title compound (0.180 g).

[0243] Reference Example E-2 3-amino-5-bromo-1-(2-fluoro-5-(trifluoromethyl)benzyl)pyridin-2(1H)-one To a mixture of Reference Example E-1 (0.180 g) and DMF (2.0 mL), tetrahydroxydiboron (0.123 g) and 4,4'-dipyridyl (0.0004 g) were added at room temperature, and the mixture was stirred at the same temperature for 10 minutes. Water, n-hexane, and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 60 / 40) to obtain the title compound (0.140 g).

[0244] Reference Example E-3 1-(2-Fluoro-5-(trifluoromethyl)benzyl)-6-methyl-3-nitropyridin-2(1H)-one To a mixture of 6-methyl-3-nitropyridin-2-ol (0.156 g) and DMF (2.0 mL), cesium carbonate (0.380 g) and 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (0.200 g) were added at room temperature, and the mixture was stirred at 70°C for 30 minutes. The reaction mixture was allowed to cool to room temperature, and then water, n-hexane, and ethyl acetate were added, and the organic layer was separated. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 20 / 80) to obtain the title compound (0.068 g).

[0245] Reference Example E-4 3-amino-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-methylpyridin-2(1H)-one A mixture of Reference Example E-3 (0.065 g), 10% Pd / C (0.050 g), THF (1.0 mL), and methanol (2.0 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 APS column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 20 / 80) to obtain the title compound (0.056 g).

[0246] Reference Example E-5 1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-3-nitropyridin-2(1H)-one To a mixture of 6-methyl-3-nitropyridin-2-ol (0.350 g) and DMF (5.0 mL), cesium carbonate (0.805 g) and Reference Example A-8 (0.480 g) were added at room temperature, and the mixture was stirred at 70 ° C. for 30 minutes. The reaction mixture was allowed to cool to room temperature, and then water, n-hexane, and ethyl acetate were added, and the organic layer was separated. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 30 / 70) to obtain the title compound (0.170 g).

[0247] Reference Example E-6 3-amino-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methylpyridin-2(1H)-one A mixture of Reference Example E-5 (0.170 g), 10% Pd / C (0.120 g), THF (1.0 mL), and methanol (5.0 mL) was stirred at room temperature under a hydrogen atmosphere for 2.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 20 / 80) to obtain the title compound (0.113 g).

[0248] Reference Example E-7 1-(2-fluoro-5-(trifluoromethyl)benzyl)-3-nitro-5-(trifluoromethyl)pyridin-2(1H)-one Instead of 5-bromo-3-nitropyridin-2-ol, 3-nitro-5-(trifluoromethyl)pyridin-2-ol was used, and Reference Example E-7 was synthesized in the same manner as in Reference Example E-1.

[0249] Reference Example E-8 3-amino-1-(2-fluoro-5-(trifluoromethyl)benzyl)-5-(trifluoromethyl)pyridin-2(1H)-one Reference Example E-7 (0.153 g), 10% Pd / C (0.120 g), THF (1.0 mL) and a mixture of methanol (5.0 mL) were 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 give the title compound (0.141 g).

[0250] Reference Example F-1 2-Bromo-5-(difluoromethyl)aniline To a mixture of 4-bromo-3-nitrobenzaldehyde (1.00 g) and toluene (10 mL), bis-(2-methoxyethyl)aminosulfur trifluoride (1.92 g) was added at room temperature and stirred at the same temperature for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate (20 mL) 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. To a mixture of the residue and DMF (10 mL), tetrahydroxydiboron (1.17 g) and 4,4'-dipyridyl (0.003 g) were added under water-cooling, and the mixture was stirred for 5 minutes under water-cooling. 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 Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to obtain the title compound (0.840 g).

[0251] Reference Example G-1 (R)-3-Amino-1-(3-methylbenzyl)-3,4-dihydroquinolin-2(1H)-one Decaborane (0.043 g) was added to a mixture of 2-bromoaniline (0.200 g), 3-methylbenzaldehyde (0.140 g), and methanol (1.0 mL) at room temperature, followed by stirring at the same temperature for 20 minutes. APS was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. The 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 = 98 / 2 to 85 / 15) to give 2-bromo-N-(3-methylbenzyl)aniline (0.294 g). Under an argon atmosphere, zinc powder (0.153 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.526 g) and DMF (1.2 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, the above mixture of 2-bromo-N-(3-methylbenzyl)aniline (0.294 g) and DMF (1.2 mL), palladium(II) acetate (0.012 g), and Xphos (0.051 g) were added at room temperature, and the mixture was stirred at 45°C for 1 hour. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride and ethyl acetate were added, and the mixture was stirred at the same temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue, ethanol (0.88 mL), and toluene (1.5 mL), methanesulfonic acid (0.614 g) was added at room temperature, and the mixture was stirred at 65°C for 1 hour and then at room temperature overnight. Ethyl acetate, toluene, and water were added to the reaction mixture, and the aqueous layer was separated. A saturated aqueous solution of sodium bicarbonate was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure to give the title compound (0.075 g).

[0252] Reference Example G-2 (R)-3-((3-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl)benzonitrile To a mixture of 2-bromoaniline (0.200 g), 3-formylbenzonitrile (0.198 g), and methanol (2.0 mL) was added decaborane (0.043 g) under water cooling, and the mixture was stirred at room temperature for 30 minutes. APS was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to give 3-(((2-bromophenyl)amino)methyl)benzonitrile (0.242 g). Under an argon atmosphere, zinc powder (0.120 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.413 g), THF (0.48 mL), and DMF (0.96 mL) under water-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, the above mixture of 3-(((2-bromophenyl)amino)methyl)benzonitrile (0.240 g) and THF (0.96 mL), palladium(II) acetate (0.009 g), and Xphos (0.040 g) were added at room temperature, and the mixture was stirred at 40°C for 2 hours. A saturated aqueous ammonium chloride solution, water, and n-hexane / ethyl acetate (1 / 1) were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and then concentrated under reduced pressure. To a mixture of the residue, ethanol (0.72 mL), and toluene (1.2 mL), methanesulfonic acid (0.241 g) was added at room temperature, and the mixture was stirred at 70°C for 30 minutes. The reaction mixture was concentrated under reduced pressure. Ethyl acetate, toluene, and water were added to the residue, and the aqueous layer was separated. A saturated aqueous solution of sodium bicarbonate was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and then concentrated under reduced pressure to give the title compound (0.043 g).

[0253] Reference Example G-3 (R)-3-amino-1-(3-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one Reference Example G-3 was synthesized in the same manner as in Reference Example G-1, except that 3-methoxybenzaldehyde was used instead of 3-methylbenzaldehyde.

[0254] Reference Example G-4 (R)-3-amino-1-(5-(difluoromethyl)-2-fluorobenzyl)-3,4-dihydroquinolin-2(1H)-one To a mixture of 2-bromoaniline (0.100 g), Reference Example A-1 (0.111 g), and methanol (2.0 mL), decaborane (0.021 g) was added under ice-cooling, and the mixture was stirred at room temperature for 13 hours. APS was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to give 2-bromo-N-(5-(difluoromethyl)-2-fluorobenzyl)aniline (0.188 g). Under an argon atmosphere, zinc powder (0.078 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.215 g) and DMF (2.0 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The above 2-bromo-N-(5-(difluoromethyl)-2-fluorobenzyl)aniline (0.180 g), palladium(II) acetate (0.006 g), and Xphos (0.026 g) were added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 8 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture, and the mixture was stirred at the same temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue and DCM (3.0 mL), TFA (1.24 g) was added under ice-cooling, and the mixture was stirred at room temperature for 37 hours. To the reaction mixture, 5 mol / L aqueous sodium hydroxide solution (2.2 mL) was added under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) to obtain the title compound (0.120 g).

[0255] Reference Example G-5 (R)-3-amino-1-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methyl)-3,4-dihydroquinolin-2(1H)-one 4-(bromomethyl)-2,2-difluorobenzo[d][1,3]dioxole (0.127 g) was added to a mixture of 2-bromoaniline (0.104 g), potassium carbonate (0.070 g), and DMF (1.5 mL) at room temperature, followed by stirring at 80°C for 17 hours. The reaction mixture was allowed to cool to room temperature, and then saturated aqueous ammonium chloride solution was added, and the mixture was extracted with n-hexane / ethyl acetate (1 / 1). 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 = 100 / 0 to 90 / 10) to give 2-bromo-N-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methyl)aniline (0.127 g). Under an argon atmosphere, a mixture of zinc powder (0.053 g) and DMF (0.48 mL) was added to a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.183 g) and DMF (0.24 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, a mixture of the above 2-bromo-N-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methyl)aniline (0.127 g) and DMF (0.48 mL), palladium(II) acetate (0.004 g), and Xphos (0.018 g) were added at room temperature, and the mixture was stirred at 80°C for 15 minutes and then at room temperature for 2 hours. Water, saturated aqueous ammonium chloride, and n-hexane / ethyl acetate (1 / 1) were added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a mixture of the residue, ethanol (0.37 mL), and toluene (0.55 mL), methanesulfonic acid (0.107 g) was added at room temperature, and the mixture was stirred at 80°C for 1 hour. To the reaction mixture was added 5 mol / L aqueous sodium hydroxide solution (0.223 mL) under ice-cooling, and the mixture was extracted with DCM, and the extract was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=50 / 50 / 0-0 / 100 / 0-0 / 80 / 20) to obtain the title compound (0.052 g).

[0256] Reference Example G-6 (R)-3-amino-7-methyl-1-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinolin-2(1H)-one Reference Example G-6 was synthesized in the same manner as in Reference Example G-2, except that 2-bromo-5-methylaniline was used instead of 2-bromoaniline and 3-(trifluoromethyl)benzaldehyde was used instead of 3-formylbenzonitrile.

[0257] Reference Example G-7 (R)-3-amino-7-methoxy-1-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinolin-2(1H)-one Reference Example G-7 was synthesized in the same manner as in Reference Example G-1, except that 2-bromo-5-methoxyaniline was used instead of 2-bromoaniline and 3-(trifluoromethyl)benzaldehyde was used instead of 3-methylbenzaldehyde.

[0258] Reference Example G-8 (R)-3-Amino-2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinoline-7-carbonitrile To a mixture of 3-amino-4-bromobenzonitrile (0.100 g), 3-(trifluoromethyl)benzaldehyde (0.088 g), and methanol (2.0 mL), decaborane (0.019 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. APS was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to give 4-bromo-3-((3-(trifluoromethyl)benzyl)amino)benzonitrile (0.200 g). Under an argon atmosphere, zinc powder (0.073 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.250 g) and DMF (1.0 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, the above mixture of 4-bromo-3-((3-(trifluoromethyl)benzyl)amino)benzonitrile (0.180 g) and DMF (1.5 mL), palladium(II) acetate (0.006 g), and Xphos (0.024 g) were added at room temperature, and the mixture was stirred at 40°C for 2 hours. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride and ethyl acetate were added, and the mixture was stirred at the same temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue, ethanol (0.5 mL), and toluene (1.0 mL), methanesulfonic acid (0.146 g) was added at room temperature, and the mixture was stirred at 70°C for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture under ice-cooling, 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 / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) to obtain the title compound (0.110 g).

[0259] Reference Example G-9 (R)-3-amino-5-fluoro-1-(2-fluoro-5-(trifluoromethyl)benzyl)-3,4-dihydroquinolin-2(1H)-one Reference Example G-9 was synthesized in the same manner as in Reference Example G-4, using 2-bromo-3-fluoroaniline instead of 2-bromoaniline and 2-fluoro-5-(trifluoromethyl)benzaldehyde instead of Reference Example A-1.

[0260] Reference Example G-10 (R)-3-amino-7-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-3,4-dihydroquinolin-2(1H)-one Reference Example G-10 was synthesized in the same manner as in Reference Example G-8, using Reference Example F-1 instead of 3-amino-4-bromobenzonitrile and 2-fluoro-5-(trifluoromethyl)benzaldehyde instead of 3-(trifluoromethyl)benzaldehyde.

[0261] Reference Example G-11 (R)-3-amino-1-(5-(difluoromethyl)-2-fluorobenzyl)-7-fluoro-3,4-dihydroquinolin-2(1H)-one Reference Example G-11 was synthesized in the same manner as in Reference Example G-4, except that 2-bromo-5-fluoroaniline was used instead of 2-bromoaniline.

[0262] Reference Example G-12 (R)-3-amino-7-chloro-1-(5-(difluoromethyl)-2-fluorobenzyl)-3,4-dihydroquinolin-2(1H)-one Reference Example G-12 was synthesized in the same manner as in Reference Example G-4, except that 2-bromo-5-chloroaniline was used instead of 2-bromoaniline.

[0263] Reference Example G-13 (R)-3-amino-1-(5-(difluoromethyl)-2-fluorobenzyl)-7-methyl-3,4-dihydroquinolin-2(1H)-one Reference Example G-13 was synthesized in the same manner as in Reference Example G-4, except that 2-bromo-5-methylaniline was used instead of 2-bromoaniline.

[0264] Reference Example G-14 (R)-3-amino-7-(difluoromethyl)-1-(5-(difluoromethyl)-2-fluorobenzyl)-3,4-dihydroquinolin-2(1H)-one To a mixture of Reference Example F-1 (0.100 g), Reference Example A-1 (0.086 g), and methanol (2.0 mL), decaborane (0.017 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. APS was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to give 2-bromo-5-(difluoromethyl)-N-(5-(difluoromethyl)-2-fluorobenzyl)aniline (0.210 g). Under an argon atmosphere, zinc powder (0.064 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.221 g) and DMF (2.0 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, the above mixture of 2-bromo-5-(difluoromethyl)-N-(5-(difluoromethyl)-2-fluorobenzyl)aniline (0.170 g) and DMF (2.0 mL), palladium(II) acetate (0.005 g), and Xphos (0.021 g) were added at room temperature, and the mixture was stirred at 40°C for 2 hours. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride and ethyl acetate were added, and the mixture was stirred at the same temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue, ethanol (1.0 mL), and toluene (2.0 mL), methanesulfonic acid (0.129 g) was added at room temperature, and the mixture was stirred at 70°C for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture under ice-cooling, 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 / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) to obtain the title compound (0.065 g).

[0265] Reference Example G-15 (R)-3-amino-1-(5-(difluoromethyl)-2-fluorobenzyl)-7-(trifluoromethyl)-3,4-dihydroquinolin-2(1H)-one Reference Example G-15 was synthesized in the same manner as in Reference Example G-14, except that 2-bromo-5-(trifluoromethyl)aniline was used instead of Reference Example F-1.

[0266] Reference Example G-16 (R)-3-amino-1-(5-(difluoromethyl)-2-fluorobenzyl)-7-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one To a mixture of methyl 3-amino-4-bromobenzoate (1.00 g), Reference Example A-1 (0.917 g), and methanol (2.0 mL), decaborane (0.159 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. APS was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to give methyl 4-bromo-3-((5-(difluoromethyl)-2-fluorobenzyl)amino)benzoate (1.36 g). To a mixture of the resulting compound (1.36 g) and THF (12 mL), lithium aluminum hydride (1 mol / L in THF) (4.19 mL) was added under ice-cooling, and the mixture was stirred for 2 hours under ice-cooling. Water (0.16 mL), 5 mol / L aqueous sodium hydroxide solution (0.16 mL), and water (0.48 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for a while. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give (4-bromo-3-((5-(difluoromethyl)-2-fluorobenzyl)amino)phenyl)methanol (1.28 g). Under an argon atmosphere, a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.548 g) and DMF (1.0 mL) was added to a mixture of zinc powder (0.160 g) and DMF (2.0 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, a mixture of the above (4-bromo-3-((5-(difluoromethyl)-2-fluorobenzyl)amino)phenyl)methanol (0.400 g) and DMF (2.0 mL), palladium(II) acetate (0.012 g), and Xphos (0.053 g) were added at room temperature, and the mixture was stirred at 40°C for 16 hours. The reaction mixture was allowed to cool to room temperature, and then water, a saturated aqueous ammonium chloride solution, and n-hexane / ethyl acetate (1 / 1) were added, followed by stirring at the same temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.To a mixture of the residue, ethanol (1.0 mL), and toluene (1.5 mL), methanesulfonic acid (0.320 g) was added at room temperature and stirred at 70°C for 1.5 hours. To the reaction mixture, 5 mol / L aqueous sodium hydroxide solution (0.666 mL) was added under ice-cooling, 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 / methanol = 50 / 50 / 0 to 0 / 100 / 0 to 0 / 65 / 35) to obtain the title compound (0.228 g).

[0267] Reference Example G-17 (R)-3-amino-1-(5-(difluoromethyl)-2-fluorobenzyl)-5,7-difluoro-3,4-dihydroquinolin-2(1H)-one Reference Example G-17 was synthesized in the same manner as in Reference Example G-4, except that 2-bromo-3,5-difluoroaniline was used instead of 2-bromoaniline.

[0268] Reference Example G-18: (R)-3-amino-7-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethoxy)benzyl)-3,4-dihydroquinolin-2(1H)-one. To a mixture of Reference Example F-1 (0.118 g), 2-fluoro-5-(trifluoromethoxy)benzaldehyde (0.116 g), and methanol (1.0 mL), decaborane (0.020 g) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. APS was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to give 2-bromo-5-(difluoromethyl)-N-(2-fluoro-5-(trifluoromethoxy)benzyl)aniline (0.209 g). Under an argon atmosphere, a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.249 g) and DMF (0.34 mL) was added to a mixture of zinc powder (0.073 g) and DMF (0.68 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, the above mixture of 2-bromo-5-(difluoromethyl)-N-(2-fluoro-5-(trifluoromethoxy)benzyl)aniline (0.209 g) and DMF (0.68 mL), palladium(II) acetate (0.006 g), and Xphos (0.024 g) were added at room temperature, and the mixture was stirred at 40°C for 2 hours and then at room temperature for 16 hours. Water, saturated aqueous ammonium chloride, and n-hexane / ethyl acetate (1 / 1) were added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of the residue, ethanol (0.52 mL), and toluene (0.77 mL), methanesulfonic acid (0.145 g) was added at room temperature and stirred at 80°C for 1 hour. To the reaction mixture was added 5 mol / L aqueous sodium hydroxide solution (0.300 mL) under ice-cooling, 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 / methanol = 50 / 50 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to obtain the title compound (0.077 g).

[0269] Reference Example G-19 (R)-3-amino-7-(difluoromethyl)-1-(2-fluoro-5-(pentafluorosulfur)benzyl)-3,4-dihydroquinolin-2(1H)-one Reference Example G-19 was synthesized in the same manner as in Reference Example G-18, using 2-fluoro-5-(pentafluorosulfur)benzaldehyde instead of 2-fluoro-5-(trifluoromethoxy)benzaldehyde.

[0270] Reference Example G-20 (R)-3-amino-7-(difluoromethyl)-1-(2-fluoro-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-3,4-dihydroquinolin-2(1H)-one Using Reference Example A-11 instead of 2-fluoro-5-(trifluoromethoxy)benzaldehyde, Reference Example G-20 was synthesized in the same manner as in Reference Example G-18.

[0271] Reference Example G-21 (R)-3-amino-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-7-fluoro-3,4-dihydroquinolin-2(1H)-one Reference Example G-21 was synthesized in the same manner as in Reference Example G-4, using 2-bromo-5-fluoroaniline instead of 2-bromoaniline and 3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde instead of Reference Example A-1.

[0272] Reference Example G-22 (R)-3-amino-1-(3-(trifluoromethyl)benzyl)-3,4-dihydrothieno[3,4-b]pyridin-2(1H)-one. To a mixture of tert-butyl (4-bromothiophen-3-yl)carbamate (0.300 g) and DMF (3.0 mL), sodium hydride (approximately 60%) (0.047 g) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (0.284 g) were added under ice-cooling, followed by stirring at room temperature for 1 hour. Saturated aqueous ammonium chloride solution, water, n-hexane, and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue and methanol (3.0 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (1.35 mL) was added at room temperature, followed by stirring at the same temperature for 4 hours. To the reaction mixture, 5 mol / L aqueous sodium hydroxide solution (1.2 mL) was added under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to give 4-bromo-N-(3-(trifluoromethyl)benzyl)thiophen-3-amine (0.360 g). Under an argon atmosphere, zinc powder (0.154 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.705 g) and DMF (2.0 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, a mixture of the above 4-bromo-N-(3-(trifluoromethyl)benzyl)thiophen-3-amine (0.360 g) and DMF (2.0 mL), palladium(II) acetate (0.012 g), and Xphos (0.051 g) were added at room temperature, and the mixture was stirred at 40°C for 2 hours. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride, n-hexane, and ethyl acetate were added, and the mixture was stirred at the same temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue, ethanol (1.0 mL), and toluene (2.0 mL), methanesulfonic acid (0.309 g) was added at room temperature, and the mixture was stirred at 70°C for 1 hour. The reaction mixture was concentrated under reduced pressure.To the residue was added saturated aqueous sodium bicarbonate, 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: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) to give the title compound (0.260 g).

[0273] Reference Example G-23 (R)-2-((tert-butoxycarbonyl)amino)-3-(3-((3-(trifluoromethyl)benzyl)amino)pyridin-4-yl)propanoate Methyl 4-bromopyridin-3-amine (0.300 g), 3-(trifluoromethyl)benzaldehyde (0.302 g), and methanol (3.0 mL) were added with decaborane (0.064 g) at room temperature, followed by stirring at the same temperature for 14 hours. APS was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 50 / 50) to give 4-bromo-N-(3-(trifluoromethyl)benzyl)pyridin-3-amine (0.180 g). Under an argon atmosphere, zinc powder (0.078 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.358 g) and DMF (1.0 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, the above mixture of 4-bromo-N-(3-(trifluoromethyl)benzyl)pyridin-3-amine (0.180 g) and DMF (1.0 mL), palladium(II) acetate (0.006 g), and Xphos (0.026 g) were added at room temperature, and the mixture was stirred at 40°C for 2 hours. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride and ethyl acetate were added, and the mixture was stirred at the same temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer 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=90 / 10 to 50 / 50) to obtain the title compound (0.049 g).

[0274] Reference Example G-24 (3R)-3-amino-7-fluoro-1-(1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)-3,4-dihydroquinolin-2(1H)-one Reference Example G-24 was synthesized in the same manner as in Reference Example G-4, using 2-bromo-5-fluoroaniline instead of 2-bromoaniline and 1-(2-fluoro-5-(trifluoromethyl)phenyl)ethan-1-one instead of Reference Example A-1.

[0275] Reference Example G-25 (R)-3-amino-1-phenethyl-3,4-dihydroquinolin-2(1H)-one Reference Example G-25 was synthesized in the same manner as in Reference Example G-4, except that 2-phenylacetaldehyde was used instead of Reference Example A-1.

[0276] Reference Example G-26 (R)-3-Amino-1-(3-phenylpropyl)-3,4-dihydroquinolin-2(1H)-one. To a mixture of 3-phenylpropan-1-ol (1.50 g) and DCM (20 mL), sodium bicarbonate (0.928 g) and DMP (5.57 g) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate and 1 mol / L aqueous sodium thiosulfate were added to the reaction mixture under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure to give 3-phenylpropanal (1.45 g). 2-Bromoaniline (0.200 g) and decaborane (0.043 g) were added to a mixture of the obtained compound (0.200 g) and methanol (1.0 mL) at room temperature, and the mixture was stirred at the same temperature for 20 minutes. APS was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The 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 = 98 / 2 to 85 / 15) to give 2-bromo-N-(3-phenylpropyl)aniline (0.337 g). Under an argon atmosphere, a mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.573 g) and THF (2.0 mL) was added to a mixture of zinc powder (0.167 g) and DMF (2.7 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The above mixture of 2-bromo-N-(3-phenylpropyl)aniline (0.337 g) and THF (1.0 mL), palladium(II) acetate (0.013 g), and Xphos (0.055 g) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Methanesulfonic acid (0.335 g) was added to a mixture of the residue, ethanol (1.0 mL), and toluene (1.7 mL) at room temperature, and the mixture was stirred at 40°C for 30 minutes, at 75°C for 1 hour, and at room temperature overnight. The reaction mixture was concentrated under reduced pressure. Ethyl acetate, toluene, and water were added to the residue, and the aqueous layer was separated. A saturated aqueous solution of sodium bicarbonate was added to the aqueous layer, and the mixture was extracted with ethyl acetate.The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (0.203 g).

[0277] Reference Example G-27 (R)-3-Amino-1-(cyclohexylmethyl)-3,4-dihydroquinolin-2(1H)-one To a mixture of 2-bromoaniline (0.150 g), cyclohexanecarbaldehyde (0.103 g), and methanol (1.7 mL), decaborane (0.032 g) was added under ice cooling and stirred at room temperature for 30 minutes. APS was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane) to give 2-bromo-N-(cyclohexylmethyl)aniline (0.196 g). Under an argon atmosphere, zinc powder (0.104 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.356 g) and DMF (1.2 mL) under water cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, the above mixture of 2-bromo-N-(cyclohexylmethyl)aniline (0.193 g) and DMF (0.77 mL), palladium(II) acetate (0.008 g), and Xphos (0.034 g) were added at room temperature, and the mixture was stirred at 40°C for 3 hours. A saturated aqueous ammonium chloride solution, water, and n-hexane / ethyl acetate (1 / 1) were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and then concentrated under reduced pressure. To a mixture of the residue, ethanol (0.58 mL), and toluene (0.97 mL), methanesulfonic acid (0.208 g) was added at room temperature, and the mixture was stirred at 70°C for 2 hours. The reaction mixture was 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 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 70 / 30) to give the title compound (0.120 g).

[0278] Reference Example H-1 Methyl 2-(3-(trifluoromethyl)phenyl)acetate A mixture of 2-(3-(trifluoromethyl)phenyl)acetic acid (2.02 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (9.89 mL), and methanol (10 mL) was stirred at 60° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogen carbonate was added to the residue, 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 (1.89 g).

[0279] Reference Example H-2 Methyl 2-(bromomethyl)-4-(trifluoromethyl)benzoate Under an argon atmosphere, NBS (0.575 g) and AIBN (0.013 g) were added to a mixture of methyl 2-methyl-4-(trifluoromethyl)benzoate (0.587 g) and carbon tetrachloride (11 mL) at room temperature, and the mixture was stirred at 70°C for 16 hours and at 100°C for 1.5 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was suspended in n-hexane, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 97 / 3) to give the title compound (0.674 g).

[0280] Reference Example H-3 (6-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate Methanesulfonyl chloride (0.039 g) was added to a mixture of (6-(trifluoromethyl)pyridin-2-yl)methanol (0.050 g), TEA (0.043 g), and DCM (2.8 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. The reaction mixture was poured into water at room temperature, 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 (0.065 g).

[0281] Reference Example I-1 (S)-6-(Hydroxymethyl)piperidin-2-one To a mixture of (S)-6-oxopiperidine-2-carboxylic acid (1.00 g) and methanol (4.0 mL), thionyl chloride (2.49 g) was added under ice-cooling and stirred at 60°C for 8 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Sodium borohydride (1.06 g) was added to a mixture of the residue and ethanol (20 mL) under ice-cooling and stirred at room temperature for 65 hours. A small amount of acetic acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was suspended in DCM, and insoluble material was removed by filtration. The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.783 g).

[0282] Reference Example I-2 (S)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)piperidin-2-one A mixture of Reference Example I-1 (0.783 g), imidazole (0.825 g), TBDPSCl (1.83 g), DMAP (0.074 g), and DCM (20 mL) was stirred at room temperature for 2 hours. The reaction mixture was poured into water, 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 0 / 100) to obtain the title compound (1.21 g).

[0283] Reference Example I-3: (2S,5S)-5-(2-ethoxy-2-oxoethyl)pyrrolidine-1,2-dicarboxylate 1-(tert-butyl)2-benzyl (S)-5-oxopyrrolidine-1,2-dicarboxylate 1-(tert-butyl)2-benzyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (1.00 g) and THF (20 mL) were added with lithium triethylborohydride (1 mol / L in THF) (4.70 mL) at -78°C and stirred at the same temperature for 30 minutes. Saturated aqueous sodium bicarbonate 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 to give (2S)-5-hydroxypyrrolidine-1,2-dicarboxylate 1-(tert-butyl)2-benzyl (1.20 g). To a mixture of ethyl diethylphosphonoacetate (0.439 g) and DMF (3.0 mL), sodium hydride (approximately 60%) (0.085 g) was added under ice-cooling and stirred at room temperature for 30 minutes. The above mixture of 1-(tert-butyl)2-benzyl (2S)-5-hydroxypyrrolidine-1,2-dicarboxylate (0.500 g) and DMF (2.0 mL) was added to the reaction mixture, and the mixture was stirred at room 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 = 95 / 5 to 70 / 30) to give the title compound (0.343 g).

[0284] Reference Example I-4: tert-Butyl (2S,5S)-2-(2-ethoxy-2-oxoethyl)-5-formylpyrrolidine-1-carboxylate. A mixture of Reference Example I-3 (0.343 g), 10% Pd / C (0.051 g), and ethanol (3.0 mL) was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue and THF (3.0 mL), BH3-THF (0.9 mol / L in THF) (3.89 mL) was added under ice-cooling, and the mixture was stirred under ice-cooling for 3 hours. Water 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. To a mixture of the residue and DCM (10 mL), DMP (1.12 g) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added 1 mol / L aqueous sodium thiosulfate solution, 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 = 95 / 5 to 70 / 30) to obtain the title compound (0.242 g).

[0285] Reference Example J-1 (S)-1-(5-bromo-2-fluorobenzyl)-6-(trifluoromethyl)piperidin-2-one Reference Example J-1 was synthesized in the same manner as in Reference Example C-9, using 4-bromo-2-(bromomethyl)-1-fluorobenzene instead of 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene.

[0286] Reference Example J-2 (S)-1-(5-Allyl-2-fluorobenzyl)-6-(trifluoromethyl)piperidin-2-one. Under an argon atmosphere, PdCl(dppf)-DCM (0.117 g) was added to a mixture of Reference Example J-1 (0.169 g), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.241 g), potassium carbonate (0.330 g), 1,4-dioxane (2.0 mL), and water (0.4 mL) at room temperature, followed by stirring at 80°C for 15 hours under microwave irradiation. 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 (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 40 / 60) to obtain the title compound (0.128 g).

[0287] Reference Example J-3 (S)-1-(5-(cyclopropylethynyl)-2-fluorobenzyl)-6-(trifluoromethyl)piperidin-2-one. Under an argon atmosphere, Xphos (0.034 g) and bis(acetonitrile)palladium(II) dichloride (0.006 g) were added to a mixture of Reference Example J-1 (0.169 g), ethynylcyclopropane (0.063 g), cesium carbonate (0.466 g), and MeCN (2.4 mL) at room temperature, and the mixture was stirred at 90°C for 15 hours under microwave irradiation. 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 (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 40 / 60) to obtain the title compound (0.138 g).

[0288] Reference Example J-4 (2S,5S)-2-(2-ethoxy-2-oxoethyl)-5-(hydroxy(2-(trifluoromethyl)phenyl)methyl)pyrrolidine-1-carboxylate tert-butyl 2-bromobenzotrifluoride (1.13 g), magnesium (0.134 g), iodine (0.063 g), and THF (9.3 mL) were stirred under microwave irradiation at 60 ° C. for 20 minutes to give (2-(trifluoromethyl)phenyl)magnesium bromide (0.5 mol / L in THF) (10 mL). Under an argon atmosphere, the above (2-(trifluoromethyl)phenyl)magnesium bromide (0.5 mol / L in THF) (8.5 mL) was added to a mixture of Reference Example I-4 (0.242 g) and THF (5.0 mL) at -78 ° C. and stirred at room temperature for 15 minutes. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 60 / 40) to obtain the title compound (0.119 g). 1 H-NMR (CDCl3) δ ppm: 1.24 (3H, t, J=7.2 Hz), 1.52 (9H, s), 1.73-2.52 (4H, m), 2.66-3.31 (1H, m), 3.77-5.14 (6H, m), 5.20-5.88 (1H, m), 7.33-8.09 (4H, m)

[0289] Reference Example J-5 tert-Butyl (2S,5S)-2-(2-ethoxy-2-oxoethyl)-5-(2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxylate A mixture of Reference Example J-4 (0.119 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (3.00 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To a mixture of the residue, TEA (0.140 g), and DCM (3.0 mL), triphosgene (0.033 g) was added 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 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 ethyl 2-((1S,5S,7aS)-3-oxo-1-(2-(trifluoromethyl)phenyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-5-yl)acetate (0.068 g). A mixture of the obtained compound (0.068 g), 10% Pd / C (0.036 g), and methanol (3.0 mL) was stirred at 50°C for 1 hour under a hydrogen atmosphere. After the reaction mixture was allowed to cool to room temperature, BocO (0.120 g) was added and stirred at the same temperature for 30 minutes. 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 = 95 / 5 to 70 / 30) to give the title compound (0.059 g).

[0290] Reference Example J-6: tert-Butyl (2S,5S)-2-((Z)-3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobut-2-en-1-yl)-5-(2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxylate. To a mixture of Reference Example J-5 (0.059 g) and DCM (3.0 mL), DIBAL-H (1.02 mol / L in n-hexane) (0.418 mL) was added at -78°C and stirred at the same temperature for 30 minutes. Methanol and 30% aqueous Rochelle salt solution were added to the reaction mixture, followed by stirring at room temperature for 1 hour, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tert-butyl (2S,5S)-2-(2-oxoethyl)-5-(2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxylate (0.053 g). To a mixture of N-benzyloxycarbonyl-2-phosphonoglycine trimethyl ester (0.071 g) and DCM (1.0 mL), DBU (0.032 g) was added at room temperature and stirred at the same temperature for 10 minutes. To the reaction mixture, a mixture of the above tert-butyl (2S,5S)-2-(2-oxoethyl)-5-(2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxylate (0.053 g) and DCM (1.0 mL) was added and 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. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=80 / 20 to 50 / 50) to obtain the title compound (0.072 g).

[0291] Reference Example J-7 (S)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)piperidin-2-one To a mixture of Reference Example I-2 (1.21 g) and DMF (24 mL), sodium hydride (approximately 60%) (0.145 g) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 2-(Bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (1.02 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, 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 (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to obtain the title compound (0.684 g).

[0292] Reference Example J-8: (S)-1-(2-Fluoro-5-(trifluoromethyl)benzyl)-6-oxopiperidine-2-carboxylic acid 2-fluoro-5-(trifluoromethyl)benzyl To a mixture of (S)-6-oxopiperidine-2-carboxylic acid (0.500 g) and DMF (3.0 mL), sodium hydride (approximately 60%) (0.385 g) was added under ice-cooling, and the mixture was stirred under ice-cooling for 20 minutes. 2-(Bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (1.84 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hours and at 60°C for 4 hours. After allowing the reaction mixture to cool to room temperature, saturated aqueous ammonium chloride solution was added, 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: n-hexane / ethyl acetate=100 / 0 to 60 / 40) to obtain the title compound (0.194 g).

[0293] Reference Example J-9 (S)-1-(2-Fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)piperidin-2-one To a mixture of Reference Example J-8 (0.194 g) and ethanol (1.0 mL), sodium borohydride (0.074 g) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. 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 (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 30 / 70) to obtain the title compound (0.097 g).

[0294] Reference Example J-10 (S)-1-(2-Fluoro-5-(trifluoromethyl)benzyl)-6-(((trimethylsilyl)oxy)methyl)piperidin-2-one To a mixture of Reference Example J-9 (0.097 g), TEA (0.096 g) and THF (1.0 mL), TMSCl (0.069 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure to obtain the title compound (0.097 g).

[0295] Reference Example J-11 tert-Butyl ((3R,6S)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate To a mixture of Reference Example J-7 (1.32 g) and THF (20 mL), LDA (1.01 mol / L in THF / n-hexane) (4.80 mL) was added at -78°C, and the mixture was stirred at the same temperature for 10 minutes. DPPA (1.33 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes. A mixture of BocO (0.741 g) and THF (10 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride was added, 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 70 / 30) to give the title compound (0.897 g).

[0296] Reference Example J-12 tert-Butyl ((3R,6S)-6-(azidomethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate Reference Example J-11 (0.897 g) and THF (15 mL) were mixed and stirred at room temperature for 20 minutes with TBAF (1 mol / L in THF) (4.85 mL). A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified sequentially by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5 to 60 / 40) and silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 30 / 70) to give tert-butyl ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidin-3-yl)carbamate (0.308 g). To a mixture of the resulting compound (0.020 g), TEA (0.019 g), and DCM (1.5 mL) was added methanesulfonyl chloride (0.012 g) under ice-cooling under an argon atmosphere, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A mixture of the residue, sodium azide (0.012 g), and DMSO (1.0 mL) was stirred at 80°C for 2 hours. After the reaction mixture was allowed to cool to room temperature, water was added, 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 = 80 / 20 to 0 / 100) to give the title compound (0.020 g).

[0297] Reference Example J-13 1-(2-Fluoro-5-(trifluoromethyl)benzyl)piperidine-2,6-dione A mixture of piperidine-2,6-dione (3.17 g), 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (7.92 g), potassium carbonate (4.65 g) and acetone (40 mL) was refluxed for 14 hours. The reaction mixture was allowed to cool to room temperature, filtered, 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 75 / 25) to obtain the title compound (7.73 g).

[0298] Reference Example J-14 2-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxopiperidin-2-yl)methyl acetate Under an argon atmosphere, to a mixture of Reference Example J-13 (7.73 g) and DCM (100 mL), DIBAL-H (1.03 mol / L in n-hexane) (34.5 mL) was added at -78°C, and the mixture was stirred at the same temperature for 1.5 hours. Methanol and saturated aqueous Rochelle salt solution were added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 30 minutes, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-hydroxypiperidin-2-one (7.39 g). Under an argon atmosphere, sodium hydride (approximately 60%) (2.03 g) was added to a mixture of triethyl phosphonoacetate (10.2 g) and THF (80 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 50 minutes. The above mixture of 1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-hydroxypiperidin-2-one (7.39 g) and THF (20 mL) was added to the reaction mixture under ice-cooling, 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 DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 20 / 80) to obtain the title compound (2.18 g).

[0299] Reference Example J-15 6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)piperidin-2-one Under an argon atmosphere, to a mixture of Reference Example J-14 (2.18 g), methanol (10 mL), and THF (10 mL), sodium borohydride (0.685 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Sodium borohydride (0.913 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. Under an argon atmosphere, TBDPSCl (1.99 g) was added to a mixture of the residue, imidazole (0.821 g), DMAP (0.074 g), and DCM (20 mL) at room temperature, and the mixture was stirred at the same temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 60 / 40) to obtain the title compound (2.58 g).

[0300] Reference example J-16 ((3R * ,6S *)-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate tert-Butyl ester. Under an argon atmosphere, to a mixture of Reference Example J-15 (1.50 g) and THF (20 mL), LDA (1.01 mol / L in THF / n-hexane) (2.93 mL) was added at -78°C, and the mixture was stirred at the same temperature for 25 minutes. DPPA (0.814 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 30 minutes. A mixture of BocO (0.822 g) and THF (5.0 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 40 minutes. Water was added to the reaction mixture under ice-cooling, and the mixture was stirred at 50°C for 30 minutes. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride was added, 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 60 / 40) to give the title compound (0.539 g).

[0301] Reference Example K-1 Methyl 5-bromo-6-((tert-butyldimethylsilyl)oxy)picolinate Under an argon atmosphere, tert-butyldimethylsilyl trifluoromethanesulfonate (10.4 g) was added to a mixture of methyl 5-bromo-6-oxo-1,6-dihydropyridine-2-carboxylate (3.04 g), TEA (5.30 g), and DCM (60 mL) 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 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 95 / 5) to obtain the title compound (1.49 g).

[0302] Reference Example L-1 Methyl 3-(5-bromo-6-((tert-butyldimethylsilyl)oxy)pyridin-2-yl)-3-oxo-2-(3-(trifluoromethyl)phenyl)propanoate Under an argon atmosphere, to a mixture of Reference Example K-1 (1.49 g) and THF (20 mL) was added lithium bis(trimethylsilyl)amide (1 mol / L in THF) (8.61 mL), followed by a mixture of Reference Example H-1 (1.31 g) and THF (10 mL) at -78°C, and the mixture was stirred under ice-cooling for 2 hours. Saturated aqueous ammonium chloride solution 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 silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 90 / 10) to give the title compound (0.469 g).

[0303] Reference Example L-2 3-Bromo-6-(1,3-dihydroxy-2-(3-(trifluoromethyl)phenyl)propyl)pyridin-2(1H)-one To a mixture of Reference Example L-1 (0.847 g) and methanol (10 mL), sodium borohydride (0.241 g) was added under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure. A saturated aqueous solution of ammonium chloride was added to the residue, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue and methanol (10 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (1.99 mL) was added at room temperature, and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to obtain the title compound (0.376 g).

[0304] Reference Example L-3 6-bromo-5-oxo-2-(3-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydroindolizin-1-yl acetate. Under an argon atmosphere, DEAD (2.2 mol / L in toluene) (0.654 mL) was added to a mixture of Reference Example L-2 (0.376 g), triphenylphosphine (0.503 g), and THF (6.0 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100) to give 6-bromo-1-hydroxy-2-(3-(trifluoromethyl)phenyl)-2,3-dihydroindolizin-5(1H)-one (0.359 g). A mixture of the obtained compound (0.359 g), acetic anhydride (0.147 g), TEA (0.194 g), DMAP (0.012 g), and DCM (5.0 mL) 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 dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified sequentially by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50), silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 60 / 40), and ODS column chromatography (eluent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (0.069 g).

[0305] Reference Example M-1: (R)-(7-(difluoromethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate tert-Butyl (R)-(7-(difluoromethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate. Under an argon atmosphere, TMSCl (0.049 g) was added to a mixture of zinc powder (0.324 g) and DMF (4.0 mL) at room temperature, and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture was added a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (1.48 g) and THF (2.0 mL) under water cooling, and the mixture was stirred for 30 minutes under water cooling. To the reaction mixture was added palladium(II) acetate (0.025 g) and Xphos (0.107 g), followed by a mixture of Reference Example F-1 (0.500 g) and THF (4.0 mL) under water cooling, and the mixture was stirred at 40°C for 2 hours. Acetic acid (0.811 g) was added to the reaction mixture, and the mixture was stirred at 60°C for 1 hour. After the reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with n-hexane / ethyl acetate (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 = 100 / 0 to 60 / 40) to obtain the title compound (0.452 g).

[0306] Reference Example M-2: tert-Butyl (3-bromothiophen-2-yl)carbamate. To a mixture of 3-bromothiophene-2-carboxylic acid (0.300 g) and tert-butanol (3.0 mL), TEA (0.293 g) and DPPA (0.598 g) were added and stirred at 60°C for 4 hours. The reaction mixture was allowed to cool to room temperature, and then 2 mol / L aqueous sodium hydroxide solution (2.5 mL) was added, 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 (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to give the title compound (0.275 g).

[0307] Reference Example M-3: (R)-5-Amino-4,7-dihydrothieno[2,3-b]pyridin-6(5H)-one. Under an argon atmosphere, zinc powder (0.026 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.089 g) and DMF (0.65 mL) at room temperature, followed by stirring at the same temperature for 1 hour. To the reaction mixture, a mixture of Reference Example M-2 (0.050 g) and DMF (1.3 mL), palladium(II) acetate (0.002 g), and Xphos (0.009 g) were added at room temperature, followed by stirring at 40°C for 30 minutes and then at room temperature for 15 hours. Water, saturated aqueous ammonium chloride, and n-hexane / ethyl acetate (1 / 1) were added to the reaction mixture, followed by stirring at room temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a mixture of the residue, ethanol (1.0 mL), and toluene (0.5 mL), methanesulfonic acid (0.052 g) was added at room temperature and stirred at 80°C for 45 minutes. Methanesulfonic acid (0.294 g) was added to the reaction mixture at room temperature and stirred at 80°C for 4.5 hours. 5 mol / L aqueous sodium hydroxide solution (0.720 mL) was added to the reaction mixture under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 100 / 0 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to obtain the title compound (0.008 g).

[0308] Reference Example M-4: (R)-tert-Butyl (6-oxo-4,5,6,7-tetrahydrothieno[2,3-b]pyridin-5-yl)carbamate. To a mixture of Reference Example M-3 (0.008 g) and DCM (0.5 mL), BocO (0.016 g) was added and stirred at room temperature for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to obtain the title compound (0.003 g).

[0309] Reference Example M-5 tert-Butyl (2-bromothiophen-3-yl)carbamate Reference Example M-5 was synthesized in the same manner as in Reference Example M-2, except that 2-bromothiophene-3-carboxylic acid was used instead of 3-bromothiophene-2-carboxylic acid.

[0310] Reference Example M-6 (R)-6-amino-6,7-dihydrothieno[3,2-b]pyridin-5(4H)-one Reference Example M-6 was synthesized in the same manner as in Reference Example M-3, except that Reference Example M-5 was used instead of Reference Example M-2.

[0311] Reference Example M-7 tert-butyl (R)-(5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-6-yl)carbamate Reference Example M-7 was synthesized in the same manner as in Reference Example M-4, using Reference Example M-6 instead of Reference Example M-3.

[0312] Reference Example M-8 tert-Butyl (2-methylthiazol-5-yl)carbamate Reference Example M-8 was synthesized in the same manner as in Reference Example M-2, except that 2-methylthiazole-5-carboxylic acid was used instead of 3-bromothiophene-2-carboxylic acid.

[0313] Reference Example M-9 tert-Butyl (4-bromo-2-methylthiazol-5-yl)carbamate A mixture of Reference Example M-8 (0.420 g), NBS (0.349 g), and DMF (20 mL) was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium bicarbonate, 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 60 / 40) to obtain the title compound (0.513 g).

[0314] Reference Example M-10: Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(5-((tert-butoxycarbonyl)amino)-2-methylthiazol-4-yl)propanoate. To a mixture of zinc powder (0.252 g) and DMF (4.0 mL) under an argon atmosphere, TMSCl (0.038 g) was added at room temperature, followed by stirring at the same temperature for 20 minutes. To the reaction mixture was added a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (1.15 g) and THF (2.0 mL) under water cooling, followed by stirring under water cooling for 30 minutes. Palladium(II) acetate (0.020 g) and Xphos (0.083 g) were added to the reaction mixture, followed by a mixture of Reference Example M-9 (0.513 g) and THF (4.0 mL) under water cooling, and the mixture was stirred at 40°C for 12 hours. After the reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with n-hexane / ethyl acetate (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 = 100 / 0 to 60 / 40) to give the title compound (0.651 g).

[0315] Reference Example M-11: (R)-tert-butyl (2-methyl-5-oxo-4,5,6,7-tetrahydrothiazolo[5,4-b]pyridin-6-yl)carbamate. A mixture of Reference Example M-10 (0.156 g), 4 mol / L aqueous lithium hydroxide solution (0.282 mL), and THF (3.6 mL) was stirred at room temperature for 2 hours. The reaction mixture was poured into 2 mol / L hydrochloric acid, 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, hydrogen chloride (4 mol / L in 1,4-dioxane) (0.470 mL), and 1,4-dioxane (3.0 mL) was stirred at 50° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure to yield (R)-2-amino-3-(5-amino-2-methylthiazol-4-yl)propanoic acid dihydrochloride (0.103 g). To a mixture of the resulting compound (0.030 g), TEA (0.055 g), 4-(dimethylamino)pyridine N-oxide hydrate (0.302 g), and MeCN (10 mL), BocO (0.060 g) was added under ice-cooling and stirred at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 25 / 75) to yield the title compound (0.017 g).

[0316] Reference Example M-12 (Z)-4-((2-hydroxyphenyl)amino)-4-oxobut-2-enoic acid A mixture of furan-2,5-dione (2.00 g), 2-aminophenol (2.23 g), and toluene (22 mL) was stirred at room temperature for 12 hours. The insoluble matter was collected by filtration, and the resulting solid was washed with toluene and then dried under reduced pressure to obtain the title compound (6.07 g).

[0317] Reference Example M-13: 2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl acetate. A mixture of Reference Example M-12 (1.00 g), TEA (0.910 g), and ethanol (30 mL) was refluxed for 3 hours. 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 = 100 / 0 to 50 / 50) to obtain the title compound (0.388 g).

[0318] Reference Example M-14 (Z)-4-((2-hydroxy-4-nitrophenyl)amino)-4-oxobut-2-enoic acid Reference Example M-14 was synthesized in the same manner as in Reference Example M-12, except that 2-amino-5-nitrophenol was used instead of 2-aminophenol.

[0319] Reference Example M-15 Ethyl 2-(7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate Reference Example M-15 was synthesized in the same manner as in Reference Example M-13, except that Reference Example M-14 was used instead of Reference Example M-12.

[0320] Reference Example N-1 (3-bromo-2-((2-fluoro-5-(trifluoromethyl)benzyl)amino)phenyl)methanol To a mixture of 2-amino-3-bromobenzoic acid (2.00 g), 2-fluoro-5-(trifluoromethyl)benzaldehyde (2.13 g), and methanol (19 mL), decaborane (0.339 g) was added under water cooling, and the mixture was stirred at room temperature for 20 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. n-Hexane / DCM (1 / 1) was added to the residue, and the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 70 / 30) to give 3-bromo-2-((2-fluoro-5-(trifluoromethyl)benzyl)amino)benzoic acid (1.70 g). To a mixture of the obtained compound (1.70 g) and THF (8.7 mL), BH3-THF (0.9 mol / L in THF) (14.4 mL) was added at room temperature, and the mixture was stirred at the same temperature for 18 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 washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (0.274 g).

[0321] Reference Example N-2 (R)-3-amino-1-(2-fluoro-5-(trifluoromethyl)benzyl)-8-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one Under an argon atmosphere, a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.358 g) and DMF (0.65 mL) was added to a mixture of zinc powder (0.104 g) and DMF (1.3 mL), and the mixture was stirred at room temperature for 1 hour. A mixture of Reference Example N-1 (0.274 g) and DMF (1.3 mL), palladium(II) acetate (0.008 g), and Xphos (0.035 g) were added to the reaction mixture at room temperature, and the mixture was stirred at 40 °C for 5 hours and then at room temperature for 14 hours. Water, saturated aqueous ammonium chloride solution, and n-hexane / ethyl acetate (1 / 1) were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Methanesulfonic acid (0.209 g) was added to a mixture of the residue, ethanol (0.65 mL), and toluene (1.0 mL) at room temperature, and the mixture was stirred at 70°C for 1.5 hours. A 5 mol / L aqueous sodium hydroxide solution (0.435 mL) was added to the reaction mixture under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0 to 0 / 100 / 0 to 0 / 70 / 30) to obtain the title compound (0.040 g).

[0322] Reference Example N-3 Ethyl 2-(4-(2-fluoro-5-(trifluoromethyl)benzyl)-7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate A mixture of Reference Example M-15 (0.357 g), potassium carbonate (0.264 g), 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (0.360 g) and DMF (13 mL) was stirred at 60°C for 1.5 hours under microwave irradiation. The reaction mixture was poured into water, 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 (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 60 / 40) to obtain the title compound (0.632 g).

[0323] Reference Example N-4: 2-(7-amino-4-(2-fluoro-5-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl acetate. Under an argon atmosphere, 10% Pd / C (0.077 g) was added to a mixture of Reference Example N-3 (0.316 g) and THF (5.6 mL), and the mixture was stirred at 50° C. under a hydrogen atmosphere for 1.5 hours. The reaction mixture was allowed to cool to room temperature and then filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate=100 / 0 to 40 / 60) to obtain the title compound (0.211 g).

[0324] Reference Example N-5 1-(2-Fluoro-5-(trifluoromethyl)benzyl)quinoxalin-2(1H)-one 2-(Bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (1.67 g) was added to a mixture of quinoxalin-2(1H)-one (0.731 g), potassium carbonate (1.38 g), and DMF (5.0 mL), and the mixture was stirred at room temperature for 1.5 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture. The insoluble matter was collected by filtration and washed with water. The resulting solid was dissolved in DCM, and the mixture was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to obtain the title compound (0.997 g). 1 H-NMR (CDCl3) δ ppm: 5.56 (2H, s), 7.19-7.44 (4H, m), 7.48-7.63 (2H, m), 7.94 (1H, dd, J=1.6, 8.0 Hz), 8.43 (1H, s)

[0325] Reference Example N-6 3-Amino-1-(2-fluoro-5-(trifluoromethyl)benzyl)quinoxalin-2(1H)-one Under an argon atmosphere, a mixture of Reference Example N-5 (0.258 g), ammonium cerium(IV) nitrate (0.658 g), trimethylsilyl azide (0.277 g), water (0.029 g), and ethyl acetate (8.0 mL) was stirred at room temperature for 16 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was suspended in a mixed solvent of n-hexane / DCM / methanol, and the insoluble matter was collected by filtration. The resulting solid was washed with n-hexane / DCM (1 / 1) and then dried under reduced pressure to give the title compound (0.114 g).

[0326] Reference Example N-7 1-(4-(2-Fluoro-5-(trifluoromethyl)benzyl)-7-nitro-3-oxo-3,4-dihydroquinoxalin-2-yl)urea To a mixture of Reference Example N-6 (0.051 g) and DCM (0.5 mL), triphosgene (0.044 g) and TEA (0.045 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 20 minutes. Ammonium chloride (0.080 g) and DIPEA (0.194 g) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. MeCN (0.5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride, MTBE, and n-hexane were added to the reaction mixture, and the insoluble matter was collected by filtration. The resulting solid was washed with water and MTBE and then dried under reduced pressure to give 1-(4-(2-fluoro-5-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydroquinoxalin-2-yl)urea (0.039 g). To a mixture of the resulting compound (0.027 g) and sulfuric acid (0.5 mL), nitric acid (0.005 g) was added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. Nitric acid (0.002 g) was added to the reaction mixture, and the mixture was stirred under ice-cooling for 1 hour. Water was added to the reaction mixture, and the insoluble matter was collected by filtration. The resulting solid was washed with water and then dried under reduced pressure to give the title compound (0.023 g). 1 H-NMR (DMSO-d6) δ ppm: 5.58 (2H, s), 7.40-7.84 (5H, m), 8.17 (1H, dd, J=2.8, 9.2 Hz), 8.60 (1H, br), 8.69 (1H, br), 8.75 (1H, d, J=2.8 Hz)

[0327] Reference Example N-8 1-(7-amino-4-(2-fluoro-5-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydroquinoxalin-2-yl)urea To a mixture of Reference Example N-7 (0.022 g), ammonium chloride (0.028 g), water (0.5 mL), and ethanol (2.0 mL), iron powder (0.029 g) was added at room temperature, and the mixture was stirred at 70° C. for 2.5 hours. The reaction mixture was allowed to cool to room temperature, and water was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to obtain the title compound (0.014 g).

[0328] The structural formulas of the reference examples are shown in the table below.

[0329] The stereochemistry notation of Reference Examples B-4, C-18 and J-16 in the table indicates the relative configuration.

[0330] Example A-1 1-((3R * ,6R * ​)-1-(5-bromo-2-fluorobenzyl)-6-methyl-2-oxopiperidin-3-yl)urea. To a mixture of Reference Example C-1 (0.687 g) and THF (11 mL), LDA (1.07 mol / L in THF / n-hexane) (3.21 mL) was added at -78°C and stirred at the same temperature for 15 minutes. DPPA (0.945 g) was added to the reaction mixture at -78°C and stirred at the same temperature for 1 hour. A mixture of BocO (0.599 g) and THF (5.5 mL) was added to the reaction mixture at -78°C and stirred at the same temperature for 10 minutes and then under ice-cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. After cooling to room temperature, saturated aqueous ammonium chloride was added, 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 Method A (eluent: n-hexane / ethyl acetate = 90 / 10 to 70 / 30) to give ((3R * ,6R * tert-Butyl 2-(5-bromo-2-fluorobenzyl)-6-methyl-2-oxopiperidin-3-yl)carbamate (0.446 g) was obtained. To a mixture of the obtained compound (0.214 g) and DCM (2.1 mL), TFA (1.17 g) was added at room temperature, and the mixture was stirred at the same temperature for 40 minutes. 5 mol / L aqueous sodium hydroxide solution (2.06 mL) was added to the reaction mixture under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, water (0.210 mL), and THF (2.1 mL), potassium cyanate (0.055 g) and acetic acid (0.032 g) were added under ice-cooling, and the mixture was stirred at room 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 / methanol=30 / 70 / 0-0 / 100 / 0-0 / 95 / 5) to obtain the title compound (0.113 g).

[0331] Example A-2 1-((3R * ,6R *)-1-(5-(difluoromethyl)-2-fluorobenzyl)-6-methyl-2-oxopiperidin-3-yl)urea. To a mixture of Reference Example C-2 (0.067 g) and THF (1.2 mL), LDA (1.07 mol / L in THF / n-hexane) (0.346 mL) was added at -78°C, and the mixture was stirred at the same temperature for 20 minutes. DPPA (0.102 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes. A mixture of BocO (0.065 g) and THF (0.6 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride solution was added, 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 Method A (eluent: n-hexane / ethyl acetate = 90 / 10 to 70 / 30) to give ((3R * ,6R * )-1-(5-(difluoromethyl)-2-fluorobenzyl)-6-methyl-2-oxopiperidin-3-yl)carbamate tert-butyl ester (0.032 g) was obtained. To a mixture of the obtained compound (0.031 g) and DCM (0.5 mL), TFA (0.183 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. 5 mol / L aqueous sodium hydroxide solution (0.320 mL) was added to the reaction mixture under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, water (0.050 mL), and THF (0.5 mL), potassium cyanate (0.009 g) and acetic acid (0.005 g) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.020 g).

[0332] Example A-3 1-((3R * ,6R *)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxopiperidin-3-yl)urea Example A-3 was synthesized in the same manner as in Example A-2, using Reference Example C-3 instead of Reference Example C-2.

[0333] Example A-4 1-((3R * ,6R * )-1-((4-fluoro-[1,1'-biphenyl]-3-yl)methyl)-6-methyl-2-oxopiperidin-3-yl)urea Example A-4 was synthesized in the same manner as in Example A-1, except that Reference Example C-4 was used instead of Reference Example C-1.

[0334] Example A-5 1-((3R * ,6R * )-1-(5-benzyl-2-fluorobenzyl)-6-methyl-2-oxopiperidin-3-yl)urea Example A-5 was synthesized in the same manner as in Example A-1, using Reference Example C-5 instead of Reference Example C-1.

[0335] Example A-6 1-((3R * ,6R * )-6-methyl-2-oxo-1-(3-phenoxybenzyl)piperidin-3-yl)urea Example A-6 was synthesized in the same manner as in Example A-2, except that Reference Example C-6 was used instead of Reference Example C-2.

[0336] Example A-7 1-((3R * ,6R *)-1-(2-fluoro-5-(phenylethynyl)benzyl)-6-methyl-2-oxopiperidin-3-yl)urea Under an argon atmosphere, to a mixture of Example A-1 (0.035 g), phenylacetylene (0.030 g), TEA (0.040 g), and DMF (1.0 mL), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.003 g) was added at room temperature and stirred at 80 ° C. for 17 hours. The reaction mixture was allowed to cool to room temperature, and then saturated aqueous ammonium chloride and water were added, and the mixture was extracted with diethyl ether. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified sequentially by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 95 / 5) and silica gel column chromatography (eluent: DCM / methanol = 100 / 0 to 90 / 10) to obtain the title compound (0.007 g).

[0337] Example A-8 1-((3R * ,6R * )-1-(2-fluoro-5-(pyridin-4-ylethynyl)benzyl)-6-methyl-2-oxopiperidin-3-yl)urea Example A-8 was synthesized in the same manner as in Example A-7, using 4-ethynylpyridine instead of phenylacetylene.

[0338] Example A-9 1-((3R * ,6R * )-1-(2-fluoro-5-(pyridin-3-ylethynyl)benzyl)-6-methyl-2-oxopiperidin-3-yl)urea Example A-9 was synthesized in the same manner as in Example A-7, using 3-ethynylpyridine instead of phenylacetylene.

[0339] Example A-10 1-((3R * ,6R *)-1-(5-(cyclopropylethynyl)-2-fluorobenzyl)-6-methyl-2-oxopiperidin-3-yl)urea. Under an argon atmosphere, Xphos (0.007 g) and bis(acetonitrile)palladium(II) chloride (0.001 g) were added to a mixture of Example A-1 (0.034 g), ethynylcyclopropane (0.012 g), cesium carbonate (0.091 g), and MeCN (0.7 mL) at room temperature, and the mixture was stirred at 90°C for 12 hours under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was collected by filtration. The resulting solid was purified by silica gel column chromatography (elution solvent: DCM / methanol = 100 / 0 to 90 / 10) to obtain the title compound (0.003 g).

[0340] Example A-11 1-((3R * ,6R * )-1-(5-(benzyloxy)-2-fluorobenzyl)-6-methyl-2-oxopiperidin-3-yl)urea Example A-11 was synthesized in the same manner as in Example A-1, using Reference Example C-7 instead of Reference Example C-1.

[0341] Example A-12 1-((3R * ,6R * )-1-(2-Fluoro-5-phenethylbenzyl)-6-methyl-2-oxopiperidin-3-yl)urea Example A-7 (0.007 g), 10% Pd / C (0.007 g), THF (0.5 mL), and methanol (0.5 mL) were stirred under a hydrogen atmosphere at room temperature 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: ethyl acetate / methanol = 100 / 0 to 80 / 20) to obtain the title compound (0.004 g).

[0342] Example A-13 1-((3R,6R)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxopiperidin-3-yl)urea To a mixture of Reference Example C-8 (0.350 g) and THF (6.0 mL), LDA (1.07 mol / L in THF / n-hexane) (1.47 mL) was added at -78°C, and the mixture was stirred at the same temperature for 30 minutes. DPPA (0.433 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 20 minutes. A mixture of BocO (0.396 g) and THF (3.0 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 15 minutes. Water was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution, water, and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 70 / 30) to give tert-butyl ((3R,6R)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxopiperidin-3-yl)carbamate (0.226 g). To a mixture of the obtained compound (0.123 g) and DCM (2.0 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (0.685 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate / methanol = 60 / 40 / 0 to 0 / 100 / 0 to 0 / 70 / 30) to give (3R,6R)-3-amino-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-methylpiperidin-2-one (0.050 g). To a mixture of the obtained compound (0.050 g), water (0.059 mL), methanol (0.5 mL), and THF (0.5 mL), potassium cyanate (0.017 g) and acetic acid (0.012 g) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure.The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate / methanol=70 / 30 / 0-0 / 100 / 0-0 / 32 / 68) to obtain the title compound (0.027 g).

[0343] Example A-14 1-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea To a mixture of Reference Example C-9 (0.174 g) and THF (2.5 mL), LDA (1.07 mol / L in THF / n-hexane) (0.711 mL) was added at -78 ° C., and the mixture was stirred at the same temperature for 20 minutes. DPPA (0.209 g) was added to the reaction mixture at -78 ° C., and the mixture was stirred at the same temperature for 45 minutes. A mixture of BocO (0.133 g) and THF (1.3 mL) was added to the reaction mixture at -78 ° C., and the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, and then saturated aqueous ammonium chloride solution was added, 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 using Method A (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 70 / 30) to give tert-butyl ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)carbamate (0.144 g). To a mixture of the obtained compound (0.050 g) and DCM (0.5 mL), TFA (0.249 g) was added at room temperature and stirred at the same temperature for 45 minutes. To the reaction mixture was added 5 mol / L aqueous sodium hydroxide solution (0.435 mL) under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, water (0.050 mL), and THF (0.5 mL), potassium cyanate (0.012 g) and acetic acid (0.007 g) were added at room temperature, and the mixture was stirred at the same temperature for 1.5 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 / methanol = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 95 / 5) to give the title compound (0.010 g).

[0344] Example A-15 1-((3R,6S)-1-(5-(difluoromethyl)-2-fluorobenzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea To a mixture of Reference Example C-10 (0.109 g) and THF (1.7 mL), LDA (1.07 mol / L in THF / n-hexane) (0.469 mL) was added at -78°C, and the mixture was stirred at the same temperature for 15 minutes. DPPA (0.138 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes. A mixture of BocO (0.088 g) and THF (0.85 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 50 minutes. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride was added, 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 using Method A (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 70 / 30) to give tert-butyl ((3R,6S)-1-(5-(difluoromethyl)-2-fluorobenzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)carbamate (0.086 g). To a mixture of the obtained compound (0.025 g) and DCM (0.5 mL), TFA (0.129 g) was added at room temperature, and the mixture was stirred at the same temperature for 40 minutes. To the reaction mixture, 5 mol / L aqueous sodium hydroxide solution (0.230 mL) was added under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, water (0.050 mL), and THF (0.5 mL), potassium cyanate (0.006 g) and acetic acid (0.004 g) were added under ice-cooling, and the mixture was stirred at room temperature for 2.5 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 / methanol = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 95 / 5) to give the title compound (0.017 g).

[0345] Example A-16 1-((3R,6S)-1-(2-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea To a mixture of Reference Example C-11 (0.165 g) and THF (1.4 mL), LDA (1.07 mol / L in THF / n-hexane) (0.591 mL) was added at -78°C, and the mixture was stirred at the same temperature for 20 minutes. DPPA (0.174 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 50 minutes. A mixture of BocO (0.110 g) and THF (0.7 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 15 minutes and then under ice-cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 2 hours. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride was added, 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 using Method A (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 70 / 30) to give tert-butyl ((3R,6S)-1-(2-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)carbamate (0.098 g). To a mixture of the obtained compound (0.097 g) and DCM (0.97 mL), TFA (0.437 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, 5 mol / L aqueous sodium hydroxide solution (0.765 mL) was added under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, water (0.097 mL), and THF (0.97 mL), potassium cyanate (0.021 g) and acetic acid (0.012 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 40 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: ethyl acetate / methanol = 100 / 0 to 95 / 5) to give the title compound (0.070 g).

[0346] Example A-17 1-((3R,6S)-6-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)urea To a mixture of Reference Example C-12 (0.152 g) and THF (2.3 mL), LDA (1.07 mol / L in THF / n-hexane) (0.656 mL) was added at -78°C, and the mixture was stirred at the same temperature for 20 minutes. DPPA (0.193 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes. A mixture of BocO (0.123 g) and THF (1.2 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride was added, 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 using Method A (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 70 / 30) to give tert-butyl ((3R,6S)-6-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate (0.085 g). To a mixture of the obtained compound (0.027 g) and DCM (0.5 mL), TFA (0.140 g) was added at room temperature, and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture, 5 mol / L aqueous sodium hydroxide solution (0.245 mL) was added under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, water (0.050 mL), and THF (0.5 mL), potassium cyanate (0.007 g) and acetic acid (0.004 g) were added at room temperature, and the mixture was stirred at the same temperature for 19 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 suspended in diethyl ether, and the insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (0.012 g).

[0347] Example A-18 1-((3R,5S)-5-fluoro-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)urea Example A-18 was synthesized in the same manner as in Example A-2, using Reference Example C-13 instead of Reference Example C-2.

[0348] Example A-19 (2-((3R * ,5S * )-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxo-5-ureidopiperidin-3-yl)ethyl)carbamate tert-butyl Example B-3 (0.010 g), platinum(IV) oxide (0.020 g), and methanol (2.0 mL) were stirred under a hydrogen atmosphere at room temperature for 1 hour and at 50°C for 2 hours. The reaction mixture was allowed to cool to room temperature, 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 / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) to give the title compound (0.004 g).

[0349] Example A-20 1-(5-oxo-4-(3-(trifluoromethyl)benzyl)-4-azaspiro[2.5]octan-6-yl)urea Example A-20 was synthesized in the same manner as in Example A-1, except that Reference Example C-14 was used instead of Reference Example C-1.

[0350] Example A-21 1-((1R * ,4R * ,6S * )-2-(2-fluoro-5-(trifluoromethyl)benzyl)-3-oxo-2-azabicyclo[4.1.0]heptan-4-yl)urea Example A-21 was synthesized in the same manner as in Example A-1, using Reference Example C-15 instead of Reference Example C-1.

[0351] Example A-22 1-((3R,6S)-1-(1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea Example A-22 was synthesized in the same manner as in Example A-1, using Reference Example C-16 instead of Reference Example C-1.

[0352] Example A-23 1-((3R * ,6S *) 6-methyl-2-oxo-1-(3-(trifluoromethyl)phenethyl)piperidin-3-yl)urea Example A-23 was synthesized in the same manner as in Example A-13, using Reference Example C-17 instead of Reference Example C-8.

[0353] Example A-24 1-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)-3-methylurea To a mixture of Reference Example C-9 (0.174 g) and THF (2.5 mL), LDA (1.07 mol / L in THF / n-hexane) (0.711 mL) was added at -78°C, and the mixture was stirred at the same temperature for 20 minutes. DPPA (0.209 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes. A mixture of BocO (0.133 g) and THF (1.3 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride was added, 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 using Method A (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 70 / 30) to give tert-butyl ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)carbamate (0.144 g). To a mixture of the obtained compound (0.046 g) and DCM (0.5 mL), TFA (0.229 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, 5 mol / L aqueous sodium hydroxide solution (0.400 mL) was added under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, TEA (0.030 g), and DCM (1.0 mL), triphosgene (0.030 g) was added under ice-cooling and stirred at room temperature for 30 minutes. Methylamine (2 mol / L in THF) (0.502 mL) was added to the reaction mixture at room temperature and stirred at the same temperature for 2 hours. Methylamine (2 mol / L in THF) (1.00 mL) was added to the reaction mixture at room temperature and 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 / methanol = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 95 / 5) to give the title compound (0.006 g).

[0354] Example A-25 (S)—N-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)-2-methoxypropanamide To a mixture of Reference Example C-9 (0.174 g) and THF (2.5 mL), LDA (1.07 mol / L in THF / n-hexane) (0.711 mL) was added at −78° C. and stirred at the same temperature for 20 minutes. DPPA (0.209 g) was added to the reaction mixture at −78° C. and stirred at the same temperature for 45 minutes. A mixture of BocO (0.133 g) and THF (1.3 mL) was added to the reaction mixture at −78° C. and stirred at the same temperature for 10 minutes and then under ice-cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50° C. for 1 hour. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride was added, 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 using Method A (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 70 / 30) to give tert-butyl ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)carbamate (0.144 g). To a mixture of the obtained compound (0.046 g) and DCM (0.5 mL), TFA (0.228 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 5 mol / L aqueous sodium hydroxide solution (0.400 mL) under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, (S)-2-methoxypropanoic acid (0.014 g), DIPEA (0.019 g), and MeCN (0.5 mL), HATU (0.046 g) was added at room temperature and stirred at the same temperature for 1 hour. 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 using Method A (eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0 to 0 / 100 / 0 to 0 / 95 / 5) to give the title compound (0.034 g).

[0355] Example A-26 1-cyclopropyl-3-((3R,6S)-6-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)urea Example A-26 was synthesized in the same manner as in Example A-24, using Reference Example C-12 instead of Reference Example C-9 and cyclopropylamine instead of methylamine.

[0356] Example A-27 N-((3R,6S)-6-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)acetamide To a mixture of Reference Example C-12 (0.152 g) and THF (2.3 mL), LDA (1.07 mol / L in THF / n-hexane) (0.656 mL) was added at -78°C, and the mixture was stirred at the same temperature for 20 minutes. DPPA (0.193 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes. A mixture of BocO (0.123 g) and THF (1.2 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then saturated aqueous ammonium chloride solution was added, 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 using Method A (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 70 / 30) to give tert-butyl ((3R,6S)-6-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate (0.085 g). To a mixture of the obtained compound (0.018 g) and DCM (0.5 mL), TFA (0.091 g) was added at room temperature and stirred at the same temperature for 1.5 hours. To the reaction mixture was added 5 mol / L aqueous sodium hydroxide solution (0.160 mL) under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, TEA (0.012 g), and DCM (0.5 mL), acetyl chloride (0.005 g) was added at room temperature and stirred at the same temperature for 45 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 / methanol = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 95 / 5) to give the title compound (0.011 g).

[0357] Example A-28 N-((3R,6S)-6-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)cyclopropanecarboxamide Example A-28 was synthesized in the same manner as in Example A-27, using cyclopropanecarbonyl chloride instead of acetyl chloride.

[0358] Example A-29 1-((3R * ,4aS * ,8aR * )-(2-oxo-1-(3-(trifluoromethyl)benzyl)decahydroquinolin-3-yl)urea Example A-29 was synthesized in the same manner as in Example A-14, using Reference Example C-18 instead of Reference Example C-9.

[0359] Example B-1 1-(5-bromo-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2-dihydropyridin-3-yl)urea To a mixture of Reference Example E-2 (0.140 g) and DCM (3.0 mL), triphosgene (0.114 g) and TEA (0.116 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. Ammonium chloride (0.205 g) and DIPEA (0.496 g) were added to the reaction mixture 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 stirred at room temperature for 10 minutes. The insoluble matter was collected by filtration, and the obtained solid was washed with water and MTBE and then dried under reduced pressure to obtain the title compound (0.130 g).

[0360] Example B-2 3-(1-(2-Fluoro-5-(trifluoromethyl)benzyl)-6-oxo-5-ureido-1,6-dihydropyridin-3-yl)propanoic acid To a mixture of Example B-1 (0.100 g), tri-o-tolylphosphine (0.015 g), TEA (0.099 g), benzyl acrylate (0.079 g), and MeCN (1.0 mL), palladium(II) acetate (0.006 g) was added at room temperature and stirred at 80°C for 1 hour, followed by stirring at 140°C under microwave irradiation for 10 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was suspended in MTBE, and insoluble matter was collected by filtration. The resulting solid was dried under reduced pressure to give benzyl (E)-3-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxo-5-ureido-1,6-dihydropyridin-3-yl)acrylate (0.067 g). A mixture of the resulting compound (0.065 g), 10% Pd / C (0.030 g), THF (2.0 mL), and methanol (2.0 mL) was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was suspended in MTBE, and insoluble matter was collected by filtration. The resulting solid was dried under reduced pressure to give the title compound (0.044 g).

[0361] Example B-3 tert-Butyl (2-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxo-5-ureido-1,6-dihydropyridin-3-yl)ethyl)carbamate To a mixture of Example B-2 (0.042 g), DMF (0.5 mL), and tert-butyl alcohol (1.0 mL), TEA (0.021 g) and DPPA (0.043 g) were added at room temperature, followed by stirring at 60°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then 1 mol / L aqueous sodium hydroxide solution was added, 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 (1.0 mL), BocO (0.046 g) was added at room temperature, followed by stirring at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by Method A (eluent: n-hexane / ethyl acetate / methanol=50 / 50 / 0-0 / 100 / 0-0 / 88 / 12) to obtain the title compound (0.015 g).

[0362] Example B-4 1-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)urea To a mixture of Reference Example E-4 (0.055 g) and DCM (1.0 mL), triphosgene (0.054 g) and TEA (0.056 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. Ammonium chloride (0.098 g) and DIPEA (0.237 g) were added to the reaction mixture 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 stirred at room temperature for 10 minutes. The insoluble matter was collected by filtration, and the obtained solid was washed with water and MTBE and then dried under reduced pressure to obtain the title compound (0.048 g).

[0363] Example B-5 1-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)urea To a mixture of Reference Example E-6 (0.040 g) and DCM (1.0 mL), triphosgene (0.035 g) and TEA (0.036 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. Ammonium chloride (0.064 g) and DIPEA (0.154 g) were added to the reaction mixture 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 stirred at room temperature for 10 minutes. The insoluble matter was collected by filtration, and the obtained solid was washed with water and MTBE and then dried under reduced pressure to obtain the title compound (0.026 g).

[0364] Example B-6 1-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)urea Example B-6 was synthesized in the same manner as in Example B-1, using Reference Example E-8 instead of Reference Example E-2.

[0365] Example B-7 1-(6-cyano-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2-dihydropyridin-3-yl)urea To a mixture of Reference Example D-1 (0.402 g) and MeCN (6.0 mL), potassium carbonate (0.330 g) and 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (0.460 g) were added at room temperature, and the mixture was stirred at the same temperature for 4.5 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. The residue was purified using Method B (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 85 / 15) to give tert-butyl (6-bromo-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate (0.035 g). Under an argon atmosphere, to a mixture of the obtained compound (0.034 g), zinc(II) cyanide (0.017 g), zinc powder (0.001 g), and DMF (1.0 mL), bis(tri-tert-butylphosphine)palladium(0) (0.004 g) was added at room temperature and stirred at 100 °C for 18 hours. The reaction mixture was allowed to cool to room temperature and then filtered through Celite. The filtrate was 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 tert-butyl (6-cyano-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate (0.014 g). To a mixture of the resulting compound (0.013 g) and DCM (0.5 mL), TFA (0.071 g) was added at room temperature and stirred at the same temperature for 1.5 hours. To the reaction mixture was added 5 mol / L aqueous sodium hydroxide solution (0.125 mL) under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, TEA (0.009 g), and DCM (0.5 mL), triphosgene (0.009 g) was added under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. To the reaction mixture were added ammonium chloride (0.017 g) and DIPEA (0.040 g) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water, and the mixture was stirred at room temperature for 10 minutes.The insoluble matter was collected by filtration, and the resulting solid was washed with water and MTBE and then dried under reduced pressure to obtain the title compound (0.005 g).

[0366] Example B-8 1-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)urea To a mixture of Reference Example D-2 (0.067 g) and DMF (1.3 mL), sodium hydride (approximately 60%) (0.018 g) was added under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. Reference Example A-3 (0.100 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 1 hour and at 50°C for 1.5 hours. Reference Example A-3 (0.046 g) was added to the reaction mixture at room temperature, and the mixture was stirred at 50°C for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with n-hexane / ethyl acetate (1 / 1). 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 = 90 / 10 to 30 / 70) to give tert-butyl (1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)carbamate (0.053 g). To a mixture of the obtained compound (0.050 g) and DCM (0.5 mL), TFA (0.261 g) was added at room temperature and stirred at the same temperature for 1 hour. To the reaction mixture was added 5 mol / L aqueous sodium hydroxide solution (0.460 mL) under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, TEA (0.035 g), and DCM (0.5 mL), triphosgene (0.034 g) was added under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. To the reaction mixture, ammonium chloride (0.061 g), DIPEA (0.148 g), and DCM (0.5 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 1.5 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 suspended in MTBE, and the insoluble matter was collected by filtration. The obtained solid was washed with MTBE and then dried under reduced pressure to give the title compound (0.005 g).

[0367] Example B-9 1-(4-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-5-methyl-3-oxo-3,4-dihydropyrazin-2-yl)urea Example B-9 was synthesized in the same manner as in Example B-8, using Reference Example D-3 instead of Reference Example D-2.

[0368] Example B-10 1-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)-3-methylurea To a mixture of Reference Example E-6 (0.033 g) and DCM (1.0 mL), triphosgene (0.032 g) and TEA (0.030 g) were added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Methylamine (2 mol / L in THF) (0.986 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 45 / 55) to obtain the title compound (0.008 g).

[0369] Example B-11 1-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)-3-cyclopropylurea Example B-11 was synthesized in the same manner as in Example B-10, except that cyclopropanamine was used instead of methylamine.

[0370] Example C-1 (R)-1-(1-(3-methylbenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea A mixture of potassium cyanate (0.018 g) and water (0.068 mL) was added to a mixture of Reference Example G-1 (0.050 g), acetic acid (0.012 g), and methanol (0.15 mL) at room temperature, followed by stirring at the same temperature for 1 hour. Water was added to the reaction mixture, followed by stirring at room temperature for 20 minutes. Insoluble matter was collected by filtration, and the resulting solid was washed with a mixed solvent of water / THF / methanol (10 / 1 / 1) and then dried under reduced pressure to obtain the title compound (0.010 g).

[0371] Example C-2 (R)-1-(1-(3-cyanobenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-2 (0.043 g), water (0.055 mL), potassium cyanate (0.016 g), methanol (0.256 mL), and THF (0.383 mL), acetic acid (0.011 g) was added under ice-cooling, and the mixture was stirred at room temperature for 13 hours. To the reaction mixture, THF (0.256 mL), methanol (0.192 mL), and water (1.92 mL) were added, and the mixture was stirred at room temperature for 40 minutes. The insoluble matter was collected by filtration, and the resulting solid was washed with ethanol / n-heptane (1 / 4) and then dried under reduced pressure to obtain the title compound (0.026 g).

[0372] Example C-3 (R)-1-(1-(3-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Example C-3 was synthesized in the same manner as in Example C-1, except that Reference Example G-3 was used instead of Reference Example G-1.

[0373] Example C-4 (R)-1-(1-(5-(difluoromethyl)-2-fluorobenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-4 (0.120 g), water (0.067 mL), and THF (1.0 mL), potassium cyanate (0.040 g) and methanesulfonic acid (0.038 g) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium hydrogen carbonate, methanol, and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (0.058 g).

[0374] Example C-5 (R)-1-(1-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-5 (0.052 g), water (0.071 mL), and THF (0.71 mL), potassium cyanate (0.023 g), acetic acid (0.016 g), and THF (0.5 mL) were added at room temperature, and the mixture was stirred at the same temperature for 17 hours. Water, a saturated aqueous solution of sodium bicarbonate, and MTBE were added to the reaction mixture, and the insoluble matter was collected by filtration. The obtained solid was washed with water and MTBE and then dried under reduced pressure to obtain the title compound (0.037 g).

[0375] Example C-6 (R)-1-(7-methyl-2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea Example C-6 was synthesized in the same manner as in Example C-2, except that Reference Example G-6 was used instead of Reference Example G-2.

[0376] Example C-7 (R)-1-(7-methoxy-2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea Example C-7 was synthesized in the same manner as in Example C-1, except that Reference Example G-7 was used instead of Reference Example G-1.

[0377] Example C-8 (R)-1-(7-cyano-2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea Example C-8 was synthesized in the same manner as in Example C-5, except that Reference Example G-8 was used instead of Reference Example G-5.

[0378] Example C-9 (R)-1-(5-fluoro-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-9 (0.085 g), water (0.043 mL) and THF (1.0 mL), potassium cyanate (0.025 g) and methanesulfonic acid (0.024 g) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The insoluble matter was filtered off, and the resulting solid was washed with water and ethyl acetate and then dried under reduced pressure to obtain the title compound (0.064 g).

[0379] Example C-10 (R)-1-(7-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-10 (0.079 g), water (0.037 mL) and THF (0.5 mL), potassium cyanate (0.021 g) and acetic acid (0.013 g) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The insoluble matter was filtered off, and the resulting solid was washed with water and MTBE and then dried under reduced pressure to obtain the title compound (0.052 g).

[0380] Example C-11 (R)-1-(1-(5-(difluoromethyl)-2-fluorobenzyl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-11 (0.110 g), water (0.059 mL) and THF (1.0 mL), potassium cyanate (0.034 g) and methanesulfonic acid (0.033 g) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The insoluble matter was collected by filtration, and the resulting solid was washed with water and MTBE and then dried under reduced pressure to obtain the title compound (0.100 g).

[0381] Example C-12 (R)-1-(7-chloro-1-(5-(difluoromethyl)-2-fluorobenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-12 (0.150 g), water (0.076 mL) and THF (1.5 mL), potassium cyanate (0.045 g) and methanesulfonic acid (0.043 g) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium hydrogen carbonate and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.090 g).

[0382] Example C-13 (R)-1-(1-(5-(difluoromethyl)-2-fluorobenzyl)-7-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-13 (0.099 g), water (0.053 mL), and THF (1.0 mL), potassium cyanate (0.031 g) and methanesulfonic acid (0.030 g) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The insoluble matter was collected by filtration, and the resulting solid was washed with water and MTBE and then dried under reduced pressure to obtain the title compound (0.083 g).

[0383] Example C-14 (R)-1-(7-(difluoromethyl)-1-(5-(difluoromethyl)-2-fluorobenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-14 (0.065 g), water (0.032 mL) and THF (0.5 mL), potassium cyanate (0.019 g) and acetic acid (0.011 g) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The insoluble matter was collected by filtration, and the resulting solid was washed with water and MTBE and then dried under reduced pressure to obtain the title compound (0.045 g).

[0384] Example C-15 (R)-1-(1-(5-(difluoromethyl)-2-fluorobenzyl)-2-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-15 (0.039 g), water (0.018 mL) and THF (0.5 mL), potassium cyanate (0.011 g) and acetic acid (0.006 g) were added at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The insoluble matter was collected by filtration, and the resulting solid was washed with water and MTBE and then dried under reduced pressure to obtain the title compound (0.033 g).

[0385] Example C-16 (R)-1-(1-(5-(difluoromethyl)-2-fluorobenzyl)-7-(hydroxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-16 (0.050 g), water (0.026 mL) and THF (0.5 mL), potassium cyanate (0.015 g) and acetic acid (0.009 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. Water and diethyl ether were added to the reaction mixture, and the insoluble matter was filtered off. The obtained solid was washed with water and diethyl ether and then dried under reduced pressure to obtain the title compound (0.035 g).

[0386] Example C-17 (R)-1-(1-(5-(difluoromethyl)-2-fluorobenzyl)-5,7-difluoro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-17 (0.150 g), water (0.076 mL) and THF (1.0 mL), potassium cyanate (0.044 g) and methanesulfonic acid (0.042 g) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The insoluble matter was collected by filtration, and the resulting solid was washed with water and MTBE and then dried under reduced pressure to obtain the title compound (0.040 g).

[0387] Example C-18 (R)-1-(7-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethoxy)benzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-18 (0.077 g), water (0.084 mL) and THF (0.84 mL), potassium cyanate (0.028 g) and acetic acid (0.019 g) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water and MTBE were added to the reaction mixture, and the insoluble matter was filtered off. The obtained solid was washed with water and MTBE and then dried under reduced pressure to obtain the title compound (0.030 g).

[0388] Example C-19 (R)-1-(7-(difluoromethyl)-1-(2-fluoro-5-(pentafluorosulfur)benzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-19 (0.063 g), water (0.070 mL) and THF (0.7 mL), potassium cyanate (0.023 g) and acetic acid (0.016 g) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the insoluble matter was filtered off. The obtained solid was washed with water and MTBE and then dried under reduced pressure to obtain the title compound (0.026 g).

[0389] Example C-20 (R)-1-(7-(difluoromethyl)-1-(2-fluoro-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Reference Example G-20 (0.036 g), water (0.050 mL) and a mixture of THF (0.5 mL) were added potassium cyanate (0.012 g) and acetic acid (0.008 g) at room temperature, and the mixture was stirred at the same temperature for 19 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 / methanol = 40 / 60 / 0 to 0 / 100 / 0 to 0 / 90 / 10) to obtain the title compound (0.032 g).

[0390] Example C-21 (R)-1-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Example C-21 was synthesized in the same manner as in Example C-12, using Reference Example G-21 instead of Reference Example G-12.

[0391] Example C-22 (R)-1-(2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydrothieno[3,4-b]pyridin-3-yl)urea Example C-22 was synthesized in the same manner as in Example C-14, using Reference Example G-22 instead of Reference Example G-14.

[0392] Example C-23 (R)-1-(2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydro-1,7-naphthyridin-3-yl)urea To a mixture of Reference Example G-23 (0.049 g), methanol (0.5 mL), and THF (0.5 mL), 4 mol / L aqueous lithium hydroxide solution (0.081 mL) was added under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. 1 mol / L hydrochloric acid (0.4 mL) was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. HATU (0.062 g) and TEA (0.022 g) were added to a mixture of the residue and THF (1.0 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100) to give tert-butyl (R)-(2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydro-1,7-naphthyridin-3-yl)carbamate (0.028 g). To a mixture of the obtained compound (0.028 g) and DCM (1.0 mL), TFA (0.152 g) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, water (0.012 mL), and THF (1.0 mL), potassium cyanate (0.007 g) and acetic acid (0.004 g) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was stirred at room temperature for 10 minutes after adding saturated aqueous sodium bicarbonate and water. The insoluble matter was filtered off, and the resulting solid was washed with water and MTBE and dried under reduced pressure to give the title compound (0.010 g).

[0393] Example C-24 1-((3R)-7-fluoro-1-(1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Example C-24 was synthesized in the same manner as in Example C-20, using Reference Example G-24 instead of Reference Example G-20.

[0394] Example C-25 (R)-1-(2-oxo-1-phenethyl-1,2,3,4-tetrahydroquinolin-3-yl)urea Example C-25 was synthesized in the same manner as in Example C-12, except that Reference Example G-25 was used instead of Reference Example G-12.

[0395] Example C-26 (R)-1-(2-oxo-1-(3-phenylpropyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea Example C-26 was synthesized in the same manner as in Example C-2, except that Reference Example G-26 was used instead of Reference Example G-2.

[0396] Example C-27 (R)-1-(1-(cyclohexylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Example C-27 was synthesized in the same manner as in Example C-2, except that Reference Example G-27 was used instead of Reference Example G-2.

[0397] Example C-28 (R)-1-(1-(5-(difluoromethyl)-2-fluorobenzyl)-2-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl)-3-methylurea To a mixture of Reference Example G-15 (0.030 g) and DCM (1.0 mL), triphosgene (0.023 g) and TEA (0.023 g) were added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Methylamine (2 mol / L in THF) (0.058 mL) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Methylamine (2 mol / L in THF) (0.773 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 10 minutes. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was collected by filtration. The resulting solid was washed with MTBE and dried under reduced pressure to give the title compound (0.025 g).

[0398] Example C-29 (R)-1-(2-Fluoro-5-(trifluoromethyl)benzyl)-2-oxo-3-ureido-1,2,3,4-tetrahydroquinoline-7-carboxylic acid. Under an argon atmosphere, zinc powder (0.625 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (2.15 g) and DMF (7.8 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. A mixture of methyl 3-amino-4-bromobenzoate (1.00 g) and DMF (3.9 mL), palladium(II) acetate (0.049 g), and Xphos (0.207 g) was added to the reaction mixture at room temperature, and the mixture was stirred at 40 ° C. for 5 hours. Acetic acid (0.783 g) was added to the reaction mixture, and the mixture was stirred at 70 ° C. for 1 hour. After the reaction mixture was allowed to cool to room temperature, water and n-hexane / ethyl acetate (1 / 1) were added and the mixture was stirred at room temperature for 10 minutes. The insoluble material was removed by filtration, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated brine and then concentrated under reduced pressure. The residue was suspended in n-hexane / ethyl acetate (2 / 1), and the insoluble material was removed by filtration. The resulting solid was washed with water and n-hexane and then dried under reduced pressure to give methyl (R)-3-((tert-butoxycarbonyl)amino)-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate (0.619 g). To a mixture of the resulting compound (0.300 g) and DMF (3.0 mL), 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (0.265 g) and potassium carbonate (0.194 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes and at room temperature for 6 hours. To the reaction mixture, saturated aqueous ammonium chloride and water were added under ice-cooling, and the mixture was extracted with n-hexane / ethyl acetate (1 / 1). The extract was washed with water and saturated brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was suspended in n-hexane, and the insoluble matter was collected by filtration. The resulting solid was washed with n-hexane and dried under reduced pressure to give methyl (R)-3-((tert-butoxycarbonyl)amino)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate (0.390 g).To a mixture of the obtained compound (0.206 g) and DCM (2.0 mL), TFA (0.946 g) was added at room temperature and stirred at the same temperature for 45 minutes. To the reaction mixture, 5 mol / L aqueous sodium hydroxide solution (1.66 mL) was added under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, water (0.2 mL), and THF (2.0 mL), potassium cyanate (0.037 g) and acetic acid (0.026 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 45 minutes. THF (2.0 mL) was added to the reaction mixture, and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 65 hours. Water was added to the reaction mixture, and the insoluble matter was collected by filtration. The resulting solid was washed with water and then dried under reduced pressure to give methyl (R)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-3-ureido-1,2,3,4-tetrahydroquinoline-7-carboxylate (0.173 g). To a mixture of the resulting compound (0.051 g), methanol (0.5 mL), and THF (0.5 mL), 4 mol / L aqueous lithium hydroxide solution (0.116 mL) was added under ice cooling, and the mixture was stirred at room temperature for 50 minutes and at 50 °C for 1 hour. After allowing the reaction mixture to cool to room temperature, 1 mol / L hydrochloric acid (0.465 mL) and water were added, and the insoluble matter was filtered off. The resulting solid was washed with water and then dried under reduced pressure to give the title compound (0.036 g).

[0399] Example C-30 (R)-1-(2-Fluoro-5-(trifluoromethyl)benzyl)-2-oxo-3-ureido-1,2,3,4-tetrahydroquinoline-7-carboxamide Example C-29 (0.030 g), ammonium chloride (0.038 g), HATU (0.032 g) and MeCN (2.0 mL) were added to a mixture, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution and MTBE were added to the reaction mixture, and the insoluble matter was filtered off. The resulting solid was washed with water and MTBE and then dried under reduced pressure to obtain the title compound (0.018 g).

[0400] Example D-1 1-((3R,6S)-1-(5-allyl-2-fluorobenzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea To a mixture of Reference Example J-2 (0.127 g) and THF (2.0 mL), LDA (1.07 mol / L in THF / n-hexane) (0.565 mL) was added at -78°C, and the mixture was stirred at the same temperature for 15 minutes. DPPA (0.166 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 75 minutes. A mixture of BocO (0.105 g) and THF (1.0 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride solution was added, 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 = 95 / 5 to 70 / 30) to give tert-butyl ((3R,6S)-1-(5-allyl-2-fluorobenzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)carbamate (0.129 g). To a mixture of the obtained compound (0.128 g) and DCM (1.3 mL), TFA (0.678 g) was added at room temperature and stirred at the same temperature for 1 hour. To the reaction mixture was added 5 mol / L aqueous sodium hydroxide solution (1.19 mL) under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, water (0.130 mL), and THF (1.3 mL), potassium cyanate (0.032 g) and acetic acid (0.019 g) were added under ice-cooling and stirred at room temperature for 21 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 / methanol = 40 / 60 / 0 to 0 / 100 / 0 to 0 / 95 / 5) to give the title compound (0.082 g).

[0401] Example D-2 1-((3R,6S)-1-(5-(2-cyclopropylethyl)-2-fluorobenzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea To a mixture of Reference Example J-3 (0.137 g) and THF (2.0 mL), LDA (1.07 mol / L in THF / n-hexane) (0.566 mL) was added at -78°C, and the mixture was stirred at the same temperature for 15 minutes. DPPA (0.167 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 75 minutes. A mixture of BocO (0.106 g) and THF (1.0 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride was added, 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 = 95 / 5 to 70 / 30) to give tert-butyl ((3R,6S)-1-(5-(cyclopropylethynyl)-2-fluorobenzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)carbamate (0.098 g). To a mixture of the obtained compound (0.097 g) and DCM (0.97 mL), TFA (0.487 g) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, 5 mol / L aqueous sodium hydroxide solution (0.854 mL) was added under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, water (0.097 mL), and THF (0.97 mL), potassium cyanate (0.023 g) and acetic acid (0.013 g) were added under ice-cooling, and the mixture was stirred at room temperature for 21 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 sequentially by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 40 / 60 / 0 to 0 / 100 / 0 to 0 / 95 / 5) and Method A (eluent: DCM / methanol = 100 / 0 to 90 / 10) to give 1-((3R,6S)-1-(5-(cyclopropylethynyl)-2-fluorobenzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea (0.008 g).A mixture of the obtained compound (0.007 g), 10% Pd / C (0.002 g), THF (0.5 mL), and methanol (0.5 mL) was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol = 100 / 0 to 90 / 10) to give the title compound (0.004 g).

[0402] Example D-3 1-((3S,6R,8aR)-5-oxo-3-(2-(trifluoromethyl)benzyl)octahydroindolizin-6-yl)urea A mixture of Reference Example J-6 (0.072 g), (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)iridium(I) hexafluorophosphate (0.007 g), and DCM (2.0 mL) was stirred under hydrogen pressure (0.4 MPa) at room temperature for 3 hours. The reaction mixture was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to give tert-butyl (2R,5S)-2-(3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)-5-(2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxylate (0.072 g). A mixture of the obtained compound (0.072 g), 4 mol / L aqueous lithium hydroxide solution (0.156 mL), water (0.156 mL), and methanol (2.0 mL) was stirred at room temperature for 1 hour. 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. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (2.00 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. HATU (0.052 g) was added to a mixture of the residue, DIEPA (0.065 g), and DMF (2.0 mL) at room temperature, and the mixture was stirred at the same temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with 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 = 80 / 20 to 60 / 40) to give benzyl ((3S,6R,8aR)-5-oxo-3-(2-(trifluoromethyl)benzyl)octahydroindolizin-6-yl)carbamate (0.020 g). A mixture of the obtained compound (0.020 g), 10% Pd / C (0.006 g), and THF (2.0 mL) was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure.Under an argon atmosphere, potassium cyanate (0.005 g) and acetic acid (0.005 g) were added to a mixture of the residue, water (0.016 g), and THF (1.0 mL) 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 DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2 to 80 / 20) to give the title compound (0.013 g).

[0403] Example D-4 1-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidin-3-yl)urea To a mixture of Reference Example J-7 (0.150 g) and THF (2.5 mL), LDA (1.07 mol / L in THF / n-hexane) (0.387 mL) was added at -78°C, and the mixture was stirred at the same temperature for 20 minutes. DPPA (0.114 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes. A mixture of BocO (0.072 g) and THF (1.3 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride solution was added, 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 tert-butyl ((3R,6S)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate (0.076 g). To a mixture of the obtained compound (0.074 g) and DCM (1.0 mL), TFA (0.256 g) was added at room temperature and stirred at the same temperature for 20 minutes. To the reaction mixture was added 5 mol / L aqueous sodium hydroxide solution under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, water (0.050 mL), and THF (0.5 mL), potassium cyanate (0.010 g) and acetic acid (0.007 g) were added at room temperature, and the mixture was stirred at the same temperature for 19 hours. 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, TBAF (1 mol / L in THF) (0.135 mL), and THF (1.0 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified sequentially by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 100 / 0 / 0 to 0 / 100 / 0 to 0 / 70 / 30) and PLC (developing solvent: ethyl acetate / methanol = 90 / 10) to give the title compound (0.001 g).

[0404] Example D-5 1-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(pyrrolidin-1-ylmethyl)piperidin-3-yl)urea To a mixture of Reference Example J-7 (0.189 g) and THF (1.5 mL), LDA (1.07 mol / L in THF / n-hexane) (0.650 mL) was added at -78 ° C. and stirred at the same temperature for 20 minutes. DPPA (0.191 g) was added to the reaction mixture at -78 ° C. and stirred at the same temperature for 45 minutes. A mixture of BocO (0.091 g) and THF (1.0 mL) was added to the reaction mixture at -78 ° C. and stirred at the same temperature for 10 minutes and under ice-cooling for 1 hour. Water was added to the reaction mixture and stirred at 50 ° C. for 1 hour. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride was added, 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 = 95 / 5 to 60 / 40) to give tert-butyl ((3R,6S)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate (0.184 g). To a mixture of the obtained compound (0.184 g) and THF (3.0 mL), TBAF (1 mol / L in THF) (0.559 mL) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water and saturated aqueous ammonium chloride 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 APS column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 50 / 50) to give tert-butyl ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidin-3-yl)carbamate (0.081 g). Methanesulfonyl chloride (0.018 g) was added to a mixture of the obtained compound (0.033 g), TEA (0.028 g), and DCM (1.0 mL) under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. 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.To a mixture of the residue, pyrrolidine (0.140 g), TBAI (0.029 g), and DMF (1.0 mL), potassium carbonate (0.054 g) was added and stirred at 75°C for 2.5 hours. After the reaction mixture was allowed to cool to room temperature, water and saturated aqueous ammonium chloride were added, and the mixture was extracted with n-hexane / ethyl acetate (1 / 1). 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 = 88 / 12 to 0 / 100) to give tert-butyl ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(pyrrolidin-1-ylmethyl)piperidin-3-yl)carbamate (0.012 g). To a mixture of the obtained compound (0.012 g) and DCM (1.0 mL), TFA (0.296 g) was added and stirred at room temperature for 20 minutes. 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. To a mixture of the residue, water (0.009 mL), and THF (1.0 mL), potassium cyanate (0.003 g) and acetic acid (0.002 g) were added, and the mixture was stirred at room temperature for 2 hours and at 40°C for 30 minutes. Potassium cyanate (0.001 g) was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. After the reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to give the title compound (0.003 g).

[0405] Example D-6 1-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(methoxymethyl)-2-oxopiperidin-3-yl)urea To a mixture of Reference Example J-10 (0.097 g) and THF (1.0 mL), LDA (1.07 mol / L in THF / n-hexane) (0.408 mL) was added at -78°C, and the mixture was stirred at the same temperature for 10 minutes. DPPA (0.120 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes. A mixture of BocO (0.067 g) and THF (0.5 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. Acetic acid (0.25 mL) and 2 mol / L hydrochloric acid (0.321 mL) were added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous sodium bicarbonate 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 = 18 / 82 to 0 / 100) to give tert-butyl ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidin-3-yl)carbamate (0.021 g). To a mixture of the obtained compound (0.021 g), methyl iodide (0.014 g), and DMF (0.5 mL), sodium hydride (approximately 60%) (0.003 g) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water and saturated aqueous ammonium chloride were added to the reaction mixture, and the mixture was extracted with n-hexane / ethyl acetate (1 / 1). 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 = 88 / 12 to 0 / 100) to give tert-butyl ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(methoxymethyl)-2-oxopiperidin-3-yl)carbamate (0.009 g). To a mixture of the obtained compound (0.009 g) and DCM (1.0 mL), TFA (0.296 g) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure.To a mixture of the residue, water (0.008 mL), and THF (1.0 mL), potassium cyanate (0.002 g) and acetic acid (0.003 g) were added and stirred at room temperature for 1.5 hours. Water and saturated aqueous sodium bicarbonate solution 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: ethyl acetate / methanol = 100 / 0 to 80 / 20) to give the title compound (0.001 g).

[0406] Example D-7 1-((3R,6S)-6-(ethoxymethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)urea To a mixture of Reference Example J-11 (0.897 g) and THF (15 mL), TBAF (1 mol / L in THF) (4.85 mL) was added and stirred at room temperature for 20 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified sequentially by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5 to 60 / 40) and silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 30 / 70) to give tert-butyl ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidin-3-yl)carbamate (0.308 g). To a mixture of the obtained compound (0.025 g), ethyl iodide (0.012 g), and DMF (0.5 mL), sodium hydride (approximately 60%) (0.003 g) was added at room temperature and stirred at the same temperature for 30 minutes. Ethyl iodide (0.005 g) was added to the reaction mixture and stirred at room temperature for 30 minutes. Sodium hydride (approximately 60%) (0.003 g) was added to the reaction mixture and stirred at room temperature for 30 minutes. Water and saturated aqueous ammonium chloride were added to the reaction mixture, and the mixture was extracted with n-hexane / ethyl acetate (1 / 1). 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 = 88 / 12 to 0 / 100) to give tert-butyl ((6S)-6-(ethoxymethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate (0.008 g). To a mixture of the obtained compound (0.008 g) and DCM (1.0 mL), TFA (0.296 g) was added and stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure.To a mixture of the residue, water (0.006 mL), and THF (1.0 mL), potassium cyanate (0.002 g) and acetic acid (0.002 g) were added, and the mixture was stirred at room temperature for 1.5 hours and at 50°C for 2 hours. After the reaction mixture was allowed to cool to room temperature, water and saturated aqueous sodium bicarbonate solution were added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to give the title compound (0.001 g).

[0407] Example D-8 N-(((2S,5R)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxo-5-ureidopiperidin-2-yl)methyl)acetamide A mixture of Reference Example J-12 (0.020 g), 10% Pd / C (0.020 g), and ethyl acetate (2.0 mL) was stirred under a hydrogen atmosphere with ice-cooling for 30 minutes and at room temperature for 2 hours. The reaction mixture was filtered through Celite, and the insoluble matter was washed with ethyl acetate (2.0 mL). DIPEA (0.035 g) and acetyl chloride (0.017 g) were added to the filtrate with ice-cooling, and the mixture was stirred at room 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 / methanol = 70 / 30 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to give tert-butyl ((3R,6S)-6-(acetamidomethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate (0.019 g). A mixture of the obtained compound (0.019 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (1.5 mL), and methanol (1.5 mL) was stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue, and the mixture was extracted with DCM. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of the residue, water (0.015 mL), and THF (1.0 mL), potassium cyanate (0.005 g) and acetic acid (0.005 g) were added 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 10 times with DCM. The combined extracts were concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water / MeCN = 90 / 10 to 10 / 90) to obtain the title compound (0.005 g).

[0408] Example D-9 1-((3R,6S)-6-((dimethylamino)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)urea To a mixture of Reference Example J-11 (0.897 g) and THF (15 mL), TBAF (1 mol / L in THF) (4.85 mL) was added and stirred at room temperature for 20 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified sequentially by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5 to 60 / 40) and silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 30 / 70) to give tert-butyl ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidin-3-yl)carbamate (0.308 g). DMSO (0.028 g) was added to a mixture of oxalyl chloride (0.023 g) and DCM (1.0 mL) under an argon atmosphere at -78 °C and stirred at the same temperature for 1 hour. A mixture of the above tert-butyl ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidin-3-yl)carbamate (0.050 g) and DCM (0.3 mL) was added to the reaction mixture at −78° C., and the mixture was stirred at the same temperature for 30 minutes. TEA (0.060 g) was added to the reaction mixture at −78° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Sodium triacetoxyborohydride (0.076 g) was added to a mixture of the residue, dimethylamine (2 mol / L in THF) (0.178 mL), and DCM (2.0 mL), and the mixture was stirred at room temperature for 1 hour. Water and saturated aqueous sodium bicarbonate solution 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 APS column chromatography (eluent: n-hexane / ethyl acetate = 88 / 12 to 0 / 100) to give tert-butyl ((3R,6S)-6-((dimethylamino)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate (0.024 g). To a mixture of the obtained compound (0.024 g) and DCM (1.0 mL), TFA (0.296 g) was added and stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure. To a mixture of the residue, water (0.019 mL), and THF (1.0 mL), potassium cyanate (0.009 g) and acetic acid (0.006 g) were added and stir...

Claims

1. A compound represented by formula (A-III): [wherein, ring A is a group represented by the following formula (1), (2) or (3): Q is -CH=, -CH2-, -O-, or -N=; R 1a is a halogen atom, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, unsubstituted or substituted with 1 to 6 groups selected from substituent group A of -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl), -(C 1-6 alkylene)-NH-CO-(C 1-6 alkyl), or -(C 1-6 alkylene)-CO-N(C 1-6 alkyl)2; substituent group A is a halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, C 3-8 cycloalkylC 1-6 alkyl, and C 3-8 cycloalkylC 1-6 alkoxy; when substituted with 2 or more groups selected from substituent group A, each group may be the same or different; R 1c is a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, C 1-6 alkoxy, -CONH2, -NH-COO-(C 1-6 alkyl), or -NH-CO-NH-(C 1-6 is (alkyl); n is an integer from 1 to 3; when n is 2 or 3, each R 1a may be the same as or different from each other; two Rs 1a may combine together to form a 3- to 8-membered saturated carbon ring or a 3- to 8-membered saturated heterocyclic ring; R 1a is R 3 and may combine together to form a 5- to 8-membered saturated heterocyclic ring or a 5- to 8-membered unsaturated heterocyclic ring; W, X and Y are each independently -CR 1b = or -N=; R 1b is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl); at least one R 1b is other than a hydrogen atom; when there are two or more Rs 1b , each R 1b may be the same as or different from each other; R 1b is R 3 and may combine together to form a 5- to 8-membered saturated heterocyclic ring or a 5- to 8-membered unsaturated heterocyclic ring; k is an integer from 0 to 3; when k is 2 or 3, each R 1c may be the same as or different from each other; ring B is a group represented by the following formula: is thiazole or thiophene; S, T, U and V are each independently -CH=, -CR 1c = or -N=; represents a single bond or a double bond; ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl or a ring represented by the following formula: R 2 is C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl or -NR 5 R 5’ ; provided that when ring A is a group represented by formula (2) or formula (3), R 2 is -NHR 5 ; R 5 and R 5' are each independently a hydrogen atom, C 1-6 alkyl or C 3-8 cycloalkyl; R 3 and R 3' are each independently a hydrogen atom or C 1-6 alkyl; R 4 is a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, halo C 1-6 alkyl, halohydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl or -SF5; L 1 is -CR 6 R 6' -, -O- or -NR 6 -; R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 0 to 3; when m is 2 or 3, each R 4 may be the same as or different from each other; provided that when ring A is a group represented by formula (2), m is an integer from 1 to 3; p is an integer from 1 to 3; when p is 2 or 3, each R 3 and R 3' may be the same as or different from each other〕 or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, which is a compound represented by formula (A-IV): [In the formula, ring A is a group represented by the following formula (1), (2), or (3): R 1a is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, or a 1-6 membered group selected from unsubstituted or substituted group A and substituted with -(C 1-6 alkylene)-(3-8 membered heterocycloalkyl), -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl), -(C 1-6 alkylene)-NH-CO-(C 1-6 alkyl), or -(C 1-6 alkylene)-CO-N(C 1-6 alkyl)2; Substituent group A is a halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, C 3-8 cycloalkyl C 1-6 alkyl, and C 3-8 cycloalkyl C 1-6 alkoxy; When substituted with 2 or more groups selected from substituent group A, each group may be the same or different; R 1c is a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, -CONH2, -NH-COO-(C 1-6 alkyl), or -NH-CO-NH-(C 1-6 is (alkyl); n is an integer from 1 to 3; when n is 2 or 3, each R 1a may be the same as or different from each other; two Rs 1a may combine together to form a 3- to 8-membered saturated carbon ring or a 3- to 8-membered saturated heterocyclic ring; R 1a is R 3 and may combine together to form a 5- to 8-membered saturated heterocyclic ring or a 5- to 8-membered unsaturated heterocyclic ring; W, X, and Y are each independently -CR 1b = or -N=; R 1b is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl); at least one R 1b is other than a hydrogen atom; when two or more Rs 1b are present, each R 1b may be the same as or different from each other; k is an integer from 0 to 3; when k is 2 or 3, each R 1c may be the same as or different from each other; ring B is a group represented by the following formula: thiazole or thiophene; S, T, U, and V are each independently -CH=, -CR 1c = or -N=; represents a single bond or a double bond; ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl or a ring represented by the following formula: R 5 is a hydrogen atom, C 1-6 alkyl or C 3-8 is cycloalkyl; R 3 and R 3' are each independently a hydrogen atom or C 1-6 alkyl; R 4 is a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, halo C 1-6 alkyl, halohydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl or -SF5; L 1 is -CR 6 R 6' -, -O- or -NR 6 -; R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 0 to 3; when m is 2 or 3, each R 4 may be the same as or different from each other; provided that when ring A is a group represented by formula (2), m is an integer from 1 to 3; p is an integer from 1 to 3; when p is 2 or 3, each R 3 and R 3' may be the same as or different from each other] or a pharmacologically acceptable salt thereof.

3. The compound according to claim 2, wherein R 5 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, wherein L 1 is —NH—, or a pharmacologically acceptable salt thereof.

5. The compound according to claim 4, wherein W is -CR 1b =; R 1b is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl); S, U, and V are each independently -CH= or -CR 1c =; R 1c is a halogen atom, carboxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, -CONH2, -NH-COO-(C 1-6 alkyl), or -NH-CO-NH-(C 1-6 alkyl); or a pharmacologically acceptable salt thereof.

6. The compound according to claim 5, wherein X and Y are each independently, -CR 1b =; T is, -CH= or -CR 1c =; p is 1 or 2; or a pharmacologically acceptable salt thereof.

7. The compound according to claim 6, wherein n is 1 or 2; k is an integer from 0 to 2, or a pharmacologically acceptable salt thereof.

8. The compound according to claim 7, wherein R 3 and R 3’ are hydrogen atoms; p is 1; or a pharmacologically acceptable salt thereof.

9. The compound according to claim 8, wherein m is an integer from 1 to 3, or a pharmacologically acceptable salt thereof.

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

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

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, or a pharmacologically acceptable salt thereof, and a pharmaceutical additive.

13. The pharmaceutical composition according to claim 12, which is a pharmaceutical composition for treating thyroid-related diseases.

14. The pharmaceutical composition according to claim 13, wherein the thyroid-related disease is hyperthyroidism, Graves' disease, or thyroid ophthalmopathy.

15. A compound represented by formula (A-II): [In the formula, ring A is a group represented by the following formula (1), (2), or (3): W, X, and Y are each independently -CR 1b = or -N=; Q is -CR Q1 =, -CR Q1 R Q1’ -, -O-, -N= or -NR Q2 -; R Q1 and R Q1’ are each independently a hydrogen atom, a halogen atom, hydroxy, C 1-6 alkyl or halo C 1-6 alkyl; R Q2 is a hydrogen atom, C 1-6 alkyl or halo C 1-6 alkyl; ring B is a 5- or 6-membered heteroaryl or benzene; R 1a and R 1c are each independently a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, -NR 7 COR 8 -, -NR 7 COOR 9 -, -NR 7 CONR 10 R 11 -, -CONR 12 R 13 、a 1- to 6-membered group selected from unsubstituted or substituent group A and substituted with -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), -(C 1-6 alkylene)-NR 7 COR 8 、-(C 1-6 alkylene)-NR 7 COOR 9 、-(C 1-6 alkylene)-NR 7 CONR 10 R 11 or -(C 1-6 alkylene)-CONR 12 R 13 ; R 1b is a hydrogen atom, a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl, -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , unsubstituted or substituted with 1 to 6 groups selected from substituent group A -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), -(C 1-6 alkylene)-NR 7 COR 8 , -(C 1-6 alkylene)-NR 7 COOR 9 , -(C 1-6 alkylene)-NR 7 CONR 10 R 11 or -(C 1-6 alkylene)-CONR 12 R 13 ; R 7 is a hydrogen atom or C 1-6 alkyl; R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently a hydrogen atom or a group selected from the group consisting of the following (i) to (v): (i) C substituted with 1 to 6 groups selected from unsubstituted or substituent group A 1-6 alkyl, (ii) C substituted with 1 to 6 groups selected from unsubstituted or substituent group A 3-8 cycloalkyl, (iii) C substituted with 1 to 6 groups selected from unsubstituted or substituent group A 3-8 cycloalkyl C 1-6 alkyl, (iv) C substituted with 1 to 6 groups selected from unsubstituted or substituent group A 6-10 aryl, and (v) C substituted with 1 to 6 groups selected from unsubstituted or substituent group A 6-10 aryl C 1-6 alkyl, substituent group A is a halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, C 3-8 cycloalkyl C 1-6 alkyl, and C 3-8 cycloalkyl C 1-6 alkoxy; when substituted with 2 or more groups selected from substituent group A, each group may be the same or different; R 10 and R 11 may together form a 3- to 10-membered saturated heterocyclic ring or a 3- to 10-membered unsaturated heterocyclic ring; R 12 and R 13 may together form a 3- to 10-membered saturated heterocyclic ring or a 3- to 10-membered unsaturated heterocyclic ring; n is an integer from 1 to 3; when n is 2 or 3, each R 1a may be the same as or different from each other; when there are two or more R 1b each R 1b may be the same as or different from each other; k is an integer from 0 to 3; when k is 2 or 3, each R 1c may be the same as or different from each other; two R 1a may together form a 3- to 8-membered saturated carbon ring or a 3- to 8-membered saturated heterocyclic ring; represents a single bond or a double bond; ring Z is C 6-10 Aryl, 5- to 10-membered heteroaryl or C 3-8 cycloalkyl; R 2 is C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, or -NR 5 R 5’ ; provided that when ring A is a group represented by formula (2) or formula (3), R 2 is haloC 1-6 alkyl, 3- to 8-membered heterocycloalkyl, or -NHR 5 ; R 5 and R 5' are each independently a hydrogen atom, C 1-6 alkyl or C 3-8 cycloalkyl; R 3 and R 3' are each independently a hydrogen atom or C 1-6 alkyl; R 4 is a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl, C 6-10 arylC 2-6 alkynyl, C 6-10 aryloxy, C 6-10 arylC 1-6 alkoxy, 5- or 6-membered heteroarylC 1-6 alkyl, 5- or 6-membered heteroarylC 2-6 alkynyl, C 3-8 cycloalkylC 2-6 alkynyl, halohydroxyC 1-6 alkyl or -SF5; R 1a 、R 1b or R 1c is R 3 may together form a 5- to 8-membered saturated heterocyclic ring or a 5- to 8-membered unsaturated heterocyclic ring; L 1 is -CR 6 R 6' -, -O- or -NR 6 -; R 6 and R 6' are each independently a hydrogen atom or C 1-6 alkyl; m is an integer from 0 to 3; when m is 2 or 3, each R 4 may be the same as or different from each other; provided that when ring A is a group represented by formula (2), m is an integer from 1 to 3; p is an integer from 0 to 3; when p is 2 or 3, each R 3 and R 3' may be the same as or different from each other〕 or a TSHR inhibitor containing, as an active ingredient, a pharmacologically acceptable salt thereof.

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