Nitrogen-containing condensed ring 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 a nitrogen-containing condensed ring compound represented by formula (A-I) or a pharmacologically acceptable salt thereof. The present invention relates to a nitrogen-containing condensed ring compound represented by formula (A-I) or a pharmacologically acceptable salt thereof. The compound or the pharmacologically acceptable salt thereof according to the present invention has an antagonistic activity against thyroid-stimulating hormone receptors and is therefore useful as a therapeutic agent for thyroid-related diseases (e.g., hyperthyroidism, Graves' disease, thyroid eye disease, and thyroid cancer) and others.

Description

Nitrogen-containing fused ring compound

[0001] The present invention relates to a nitrogen-containing fused ring compound useful as a pharmaceutical. More specifically, the present invention relates to a nitrogen-containing fused ring compound or a pharmacologically acceptable salt thereof that has antagonist activity against 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 nitrogen-containing fused ring 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-6] and [1] to [9].

[0014] [A-1] A compound represented by formula (A-I): [Wherein, ring Z is C 6-10 Aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl; V 1 is CR V1 R V1’ , C.R. V1 , N.R. V1 , N, O, or S; V 2 is CR V2 R V2’ , C.R. V2 , N.R. V2 , N, O, or S; V 3 is CR V3 R V3’ , C.R. V3 , N.R. V3 , N, O, or S; V 4 is a single bond, CR T1 R T2 , C.R. T1 , O, N.R. T3 or N; V 5 is CR 3 , C, or N; V 6 is NR 1 X is CR X0 R X0’ , O, N.R. X3 , CO, -C(=CR X1 R X2 )-, -(CR X1 R X2 )2-, OCR X1 R X2 , C.R. X1 R X2 O, NR X3 CR X1 R X2 , C.R. X1 R X2 NR X3 , or -CR X1 =CR X2 - and R X0 , R X0’ , R X1 , and R X2 are each independently a hydrogen atom, a halogen atom, a hydroxyl, or C 1-6Alkyl or haloC 1-6 alkyl; R X3 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; R X0 is R X0’ may be taken together with R to form a 3- to 8-membered saturated carbocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; X1 is R X2 may be taken together with R to form a 3- to 8-membered saturated carbocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; X1 is R X3 may be taken together with R to form a 3- to 8-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; 1 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; R 1 is R X0 , R X1 , or R X3 and may be taken together to form a 5- to 8-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B, or a 5- to 8-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; the substituent group B may be selected from a halogen atom, a hydroxyl, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 R is a group consisting of alkoxy and oxo; when two or more groups selected from the substituent group B are present, each group may be the same or different; 2 is a halogen atom, cyano, hydroxy, amino, C 1-6 Alkyl, HaloC 1-6 Alkyl, halohydroxy C 1-6 Alkyl, SF5, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkyl or C 6-10 Aryl C 1-6 alkoxy; R X0 is R2 may be taken together with R to form a 5- to 8-membered ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; X1 is R 2 may be taken together with R to form a 5- to 8-membered ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; X3 is R 2 may be taken together with R to form a 5- to 8-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B, or a 5- to 8-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; q is 0 or 1; R V1 , R V1’ , R V2 , R V2’ , R V3 , and R V3’ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or a C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl, HaloC 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkoxy, NR V4 COR V5 , N.R. V4 COOR V6 , or NR V4 CONR V7 R V8 and R V4 is a hydrogen atom or C 1-6 alkyl; R V5 , R V6 , R V7 , and R V8 are each independently a hydrogen atom or a group selected from the group consisting of the following (i) to (ix): (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 A3-8 (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 (v) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 6-10 Aryl C 1-6 (vi) a 3- to 8-membered heterocycloalkyl that is unsubstituted or substituted with 1 to 6 groups selected from the substituent group A; (vii) a 3- to 8-membered heterocycloalkyl C that is unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 1-6 alkyl, (viii) a 5- to 10-membered heteroaryl that is unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, and (ix) a 5- to 10-membered heteroaryl C that is unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 1-6 Alkyl; Substituent group A is a halogen atom, cyano, hydroxy, N(C 1-6 Alkyl)2, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkoxy, and C 3-8 cycloalkyl; when two or more groups selected from the substituent group A are present, each group may be the same or different; R T1 and R T2 are each independently a hydrogen atom, a halogen atom, a hydroxyl, or C 1-6 Alkyl or haloC 1-6 alkyl; R T3 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; R 3 is a hydrogen atom, a halogen atom, or C 1-6 alkyl; R 4 is C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6Alkoxy C 1-6 Alkyl, OR 5 , N.R. 5 R 5' , C 3-8 cycloalkyl, unsubstituted or 3- to 8-membered heterocycloalkyl substituted with 1 to 6 groups selected from the substituent group C, C 6-10 aryl, or a 5- or 6-membered heteroaryl unsubstituted or substituted with 1 to 4 groups selected from the substituent group C; the substituent group C is a halogen atom, cyano, hydroxy, C 1-6 Alkyl, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, oxo, CONH2, CONH-(C 1-6 alkyl), and CONH-(C 3-8 When two or more groups selected from the substituent group C are present, each group may be the same or different; 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 5 is R 5' may be taken together with R to form a 3- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B, or a 3- to 10-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; R 3 is R T1 , R T2 , or R T3 may be taken together with R to form a 3- to 10-membered ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; 3 is R 5 may be taken together with R to form a 3- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B, or a 3- to 10-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; R 4 is R T1 , RT2 , or R T3 may be taken together with R to form a 3- to 10-membered ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; 5 is R T1 , R T2 , or R T3 may be taken together with R to form a 3- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B, or a 3- to 10-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; R V7 is R V8 may be taken together with W to form a 3- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B, or a 3- to 10-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; 1 is CR W1 R W2 , O, N.R. W3 or a single bond; W 2 is CR W1 R W2 , O, N.R. W3 or a single bond; R W1 and R W2 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R W3 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; W 3 CO, CNR W4 , SO, SO2, or a single bond; R W4 is a hydrogen atom, C 1-6 Alkyl, cyano, hydroxy, C 1-6 Alkoxy, CO-(C 1-6 alkyl), or SO2-(C 1-6 alkyl); n is an integer from 0 to 3; when n is 2 or 3, each R 2 may be the same or different; R 4 and R 5 is R W1 or R W3and may be taken together to form a 5- to 8-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B, or a 5- to 8-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; Y is O, S, or NR Y and R Y is a hydrogen atom or C 1-6 alkyl; R Y is R 1 may be taken together with and form a 5- to 8-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from substituent group B, or a 5- to 8-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from substituent group B; represents a single bond or a double bond] or a pharmacologically acceptable salt thereof; (provided that in formula (AI), W 1 is a single bond; and W 2 is CH2 or NH; and W 3 is CO; and R 4 But C 1-6 Alkyl, HaloC 1-6 Alkyl, NR 5 R 5' , or C 3-8 When R is cycloalkyl, it is any one of the following (a) to (f): (a) R T1 and R T2 is not a hydrogen atom (b) X is not O and X is CHR X0 When R X0 is a hydrogen atom and C 1-6 (c) R 1 is Haro C 1-6 (d) V is alkyl 2 is CR V2 and R V2 is Haro C 1-6 Alkoxy, NR V4 COR V5 , N.R. V4 COOR V6 , or NR V4 CONR V7 R V8 (e) Y is not O (f) q is 0).

[0015] [A-2-1] The compound according to [A-1] above, which is represented by formula (A-II): [Wherein, ring Z is C 6-10 Aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl; V 1 is CR V1 R V1’ , C.R. V1 , N.R. V1 , N, O, or S; V 2 is CR V2 R V2’ , C.R. V2 , N.R. V2 , N, O, or S; R V1 , R V1’ , R V2 , and R V2’ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or a C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkoxy, NR V4 COR V5 , N.R. V4 COOR V6 , or NR V4 CONR V7 R V8 and R V4 is a hydrogen atom or C 1-6 alkyl; R V5 , R V6 , R V7 , and R V8 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, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, and C 3-8 cycloalkyl; when two or more groups selected from the substituent group A are present, each group may be the same or different; X is CR X0 R X0’ , O, N.R. X3 , CO, -C(=CR X1 R X2 )-, -(CR X1 R X2 )2-, OCR X1 R X2 , C.R. X1 R X2 O, NR X3 CR X1 R X2 , C.R. X1 R X2 NR X3 , or -CR X1 =CR X2 - and R X0 , R X0’ , R X1 , and R X2 are each independently a hydrogen atom, a halogen atom, a hydroxyl, or C 1-6 Alkyl or haloC 1-6 alkyl; R X3 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; R X0 is R X0’ may be taken together with R to form a 3- to 8-membered saturated carbocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B;X1 is R X2 may be taken together with R to form a 3- to 8-membered saturated carbocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; X1 is R X3 may be taken together with R to form a 3- to 8-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; 1 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; R 1 is R X0 , R X1 , or R X3 and may be taken together to form a 5- to 8-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B, or a 5- to 8-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; the substituent group B may be selected from a halogen atom, a hydroxyl, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 R is a group consisting of alkoxy and oxo; when two or more groups selected from the substituent group B are present, each group may be the same or different; 2 is a halogen atom, cyano, hydroxy, amino, C 1-6 Alkyl, HaloC 1-6 Alkyl, halohydroxy C 1-6 Alkyl, SF5, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkyl or C 6-10 Aryl C 1-6 alkoxy; R T1 is a hydrogen atom, halogen atom, hydroxy, C 1-6 Alkyl or haloC 1-6 alkyl; R 4 is C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, OR 5 , N.R. 5 R5' , C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl; 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 5 is R 5' may be taken together with W to form a 3- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B, or a 3- to 10-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; 1 is CR W1 R W2 , O, N.R. W3 or a single bond; R W1 and R W2 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R W3 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; n is an integer from 0 to 3; when n is 2 or 3, each R 2 may be the same or different; Y is O or S; represents a single bond or a double bond] or a pharmacologically acceptable salt thereof. [A-2-2] The compound according to [A-1] or [A-2-1] above, wherein R T1 [A-2-3] A compound according to any one of [A-1] to [A-2-2] above, wherein R 1 is a hydrogen atom or C 1-6 [A-2-4] A compound according to any one of [A-1] to [A-2-3] above, wherein ring Z is C or a pharmacologically acceptable salt thereof. 6-10 [A-2-5] A compound according to any one of [A-1] to [A-2-4], wherein X is CRX0 R X0’ , O, CO, or -(CR X1 R X2 )2-; R X0 , and R X0’ are each independently a hydrogen atom, C 1-6 Alkyl or haloC 1-6 [A-2-6] A compound according to any one of [A-1] to [A-2-5] above, wherein R is alkyl, or a pharmacologically acceptable salt thereof. V1 , R V1’ , R V2 , and R V2’ are each independently a hydrogen atom, a halogen atom, a cyano, or a C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 [A-2-7] A compound according to any one of [A-1] to [A-2-6] above, wherein Y is O, or a pharmacologically acceptable salt thereof. [A-2-8] A compound according to any one of [A-1] to [A-2-7] above, wherein R 4 NR 5 R 5' and R 5 and R 5' is the same as in the above [A-1] or a pharmacologically acceptable salt thereof. [A-2-9] A compound according to any one of the above [A-1] to [A-2-8], wherein W 1 NR W3 and R W3 [A-2-10] A compound according to any one of [A-1] to [A-2-9] above, wherein R 5 and R 5' is a hydrogen atom, or a pharmacologically acceptable salt thereof. [A-2-11] The compound according to the above [A-2-1], wherein ring Z is C 6-10 is aryl; V 1 But, CR V1, N, or S; V 2 But, CR V2 , or S; R V1 and R V2 are each independently a hydrogen atom, a halogen atom, a cyano, or a hydroxy C 1-6 alkyl; X is CHR X0 or CO; R X0 is a hydrogen atom or C 1-6 alkyl; R 1 But C 1-6 alkyl; R 2 is a halogen atom; R T1 is a hydrogen atom; R 4 is NH2; W 1 is NH; n is 2; and Y is O, or a pharmacologically acceptable salt thereof. [A-2-12] A compound according to any one of [A-1] to [A-2-11] above, which is selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof. [A-3-1] The compound according to the above [A-1], which is represented by formula (A-III): [Wherein, ring Z is C 6-10 Aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl; V 1 is CR V1 R V1’ , C.R. V1 , N.R. V1 , N, O, or S; V 3 is CR V3 R V3’ , C.R. V3 , N.R. V3 , N, O, or S; R V1 , R V1’ , R V3 , and R V3’ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or a C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, hydroxy C 1-6Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkoxy, NR V4 COR V5 , N.R. V4 COOR V6 , or NR V4 CONR V7 R V8 and R V2 is Haro C 1-6 Alkoxy, NR V4 COR V5 , N.R. V4 COOR V6 , or NR V4 CONR V7 R V8 and R V4 is a hydrogen atom or C 1-6 alkyl; R V5 , R V6 , R V7 , and R V8 are each independently a hydrogen atom or a group selected from the group consisting of the following (i) to (ix): (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 (v) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 6-10 Aryl C 1-6 (vi) a 3- to 8-membered heterocycloalkyl that is unsubstituted or substituted with 1 to 6 groups selected from the substituent group A; (vii) a 3- to 8-membered heterocycloalkyl C that is unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 1-6alkyl, (viii) a 5- to 10-membered heteroaryl that is unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, and (ix) a 5- to 10-membered heteroaryl C that is unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 1-6 Alkyl; Substituent group A is a halogen atom, cyano, hydroxy, N(C 1-6 Alkyl)2, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkoxy, and C 3-8 cycloalkyl; when two or more groups selected from the substituent group A are present, each group may be the same or different; X is CR X0 R X0’ , O, N.R. X3 , CO, -C(=CR X1 R X2 )-, -(CR X1 R X2 )2-, OCR X1 R X2 , C.R. X1 R X2 O, NR X3 CR X1 R X2 , C.R. X1 R X2 NR X3 , or -CR X1 =CR X2 - and R X0 , R X0’ , R X1 , and R X2 are each independently a hydrogen atom, a halogen atom, a hydroxyl, or C 1-6 Alkyl or haloC 1-6 alkyl; R X3 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; R X0 is R X0’ may be taken together with R to form a 3- to 8-membered saturated carbocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; X1 is RX2 may be taken together with R to form a 3- to 8-membered saturated carbocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; X1 is R X3 may be taken together with R to form a 3- to 8-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; 1 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; R 1 is R X0 , R X1 , or R X3 and may be taken together to form a 5- to 8-membered ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; the substituent group B may be selected from a halogen atom, hydroxy, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 R is a group consisting of alkoxy and oxo; when two or more groups selected from the substituent group B are present, each group may be the same or different; 2 is a halogen atom, cyano, hydroxy, amino, C 1-6 Alkyl, HaloC 1-6 Alkyl, halohydroxy C 1-6 Alkyl, SF5, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkyl or C 6-10 Aryl C 1-6 alkoxy; R T1 is a hydrogen atom, halogen atom, hydroxy, C 1-6 Alkyl or haloC 1-6 alkyl; R 4 is C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, OR 5 , N.R. 5 R 5' , C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl; R 5and R 5' are each independently a hydrogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl or C 3-8 cycloalkyl; R 5 is R 5' may be taken together with W to form a 3- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B, or a 3- to 10-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; 1 is CR W1 R W2 , O, N.R. W3 or a single bond; R W1 and R W2 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R W3 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; n is an integer from 0 to 3; when n is 2 or 3, each R 2 may be the same or different; q is 0 or 1; Y is O or S; represents a single bond or a double bond] or a pharmacologically acceptable salt thereof. [A-3-2] The compound according to [A-1] or [A-3-1] above, wherein R T1 [A-3-3] A compound according to the above [A-1], [A-3-1], or [A-3-2], wherein R 1 is a hydrogen atom or C 1-6 [A-3-4] The compound according to any one of [A-1] and [A-3-1] to [A-3-3], wherein ring Z is C 6-10 [A-3-5] A compound according to any one of [A-1] to [A-3-4], wherein X is CR X0 R X0’, O, CO, or -(CR X1 R X2 [A-3-6] The compound according to any one of [A-1] and [A-3-1] to [A-3-5], wherein R V1 , R V1’ , R V3 , and R V3’ are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, HaloC 1-6 Alkyl or hydroxy C 1-6 [A-3-7] A compound according to any one of [A-1] or [A-3-1] to [A-3-6], wherein Y is O, or a pharmacologically acceptable salt thereof. [A-3-8] A compound according to any one of [A-1] or [A-3-1] to [A-3-7], wherein R 4 NR 5 R 5' and R 5 and R 5' is the same as defined in [A-1] above, or a pharmacologically acceptable salt thereof. [A-3-9] A compound according to any one of [A-1] above or [A-3-1] to [A-3-8] above, wherein q is 1, or a pharmacologically acceptable salt thereof. [A-3-10] A compound according to any one of [A-1] above or [A-3-1] to [A-3-9] above, wherein W 1 [A-3-11] A compound or a pharmacologically acceptable salt thereof, wherein R is CH2, NH, or a single bond. [A-3-12] A compound according to any one of [A-1] or [A-3-1] to [A-3-10], wherein R 5 and R 5' is a hydrogen atom, or a pharmacologically acceptable salt thereof. [A-3-12] The compound according to the above [A-3-1], wherein ring Z is C 6-10 aryl, or 5- or 6-membered heteroaryl; V 1 is CH; V 3 is CH; R V2 But NHCOOR V6 and RV6 is a group selected from the group consisting of the following (i) to (iii): (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 cycloalkyl, and (iii) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 3-8 Cycloalkyl C 1-6 Alkyl; Substituent group A is a halogen atom and C 1-6 alkyl; when two or more groups selected from the substituent group A are present, each group may be the same or different; X is O; R 1 But C 1-6 alkyl; R 2 Cyano or haloC 1-6 alkyl; R T1 is a hydrogen atom; R 4 is NH2; W 1 is CH2, NH, or a single bond; n is 1; q is 1; and Y is O, or a pharmacologically acceptable salt thereof.

[0016] [A-4] A pharmaceutical composition comprising the compound according to any one of [A-1] to [A-3-12] or a pharmacologically acceptable salt thereof, and a pharmaceutical additive. [A-5] The pharmaceutical composition according to [A-4], which is a pharmaceutical composition for treating a thyroid-related disease. [A-6] The pharmaceutical composition according to [A-5], wherein the thyroid-related disease is hyperthyroidism, Graves' disease, or thyroid ophthalmopathy.

[0017] 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-4] above.

[0018] In one embodiment, the present invention relates to use of a compound described in any of [A-1] to [A-3-12] or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition for treating a thyroid-related disease.

[0019] [1] A compound represented by formula (I): [Wherein, ring Z is C 6-10 Aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl; V 1 is CR V1 R V1’ , C.R. V1 , N.R. V1 , N, O, or S; V 2 is CR V2 R V2’ , C.R. V2 , N.R. V2 , N, O, or S; V 3 is CR V3 R V3’ , C.R. V3 , N.R. V3 , N, O, or S; V 4 is a single bond, CR T1 R T2 , C.R. T1 , O, N.R. T3 or N; V 5 is CR 3 , C, or N; V 6 is CR 1 , C.R. 1 R 1’ , N, or NR 1 X is CR X0 R X0’ , O, N.R. X3 , CO, -C(=CR X1 R X2 )-, -(CR X1 R X2 )2-, OCR X1 R X2 , C.R. X1 R X2 O, NR X3 CR X1 R X2 , C.R. X1 R X2 NR X3 , or -CR X1 =CR X2 - and R X0 , R X0’ , R X1 , and R X2are each independently a hydrogen atom, a halogen atom, a hydroxyl, or C 1-6 Alkyl or haloC 1-6 alkyl; R X3 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; R X0 is R X0’ may be taken together with R to form a 3- to 8-membered saturated carbocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; X1 is R X2 may be taken together with R to form a 3- to 8-membered saturated carbocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; X1 is R X3 may be taken together with R to form a 3- to 8-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; 1 and R 1’ are each independently a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; R X0 is R 1 may be taken together with R to form a 5- to 8-membered ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; X1 is R 1 may be taken together with R to form a 5- to 8-membered ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; X3 is R 1 and may be taken together to form a 5- to 8-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B, or a 5- to 8-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; the substituent group B may be selected from a halogen atom, a hydroxyl, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 R is a group consisting of alkoxy and oxo; when two or more groups selected from the substituent group B are present, each group may be the same or different; 2 is a halogen atom, cyano, hydroxy, amino, C 1-6Alkyl, HaloC 1-6 Alkyl, halohydroxy C 1-6 Alkyl, SF5, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkyl or C 6-10 Aryl C 1-6 alkoxy; R X0 is R 2 may be taken together with R to form a 5- to 8-membered ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; X1 is R 2 may be taken together with R to form a 5- to 8-membered ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; X3 is R 2 may be taken together with R to form a 5- to 8-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B, or a 5- to 8-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; q is 0 or 1; R V1 , R V1’ , R V2 , R V2’ , R V3 , and R V3’ are each independently a hydrogen atom, a halogen atom, a hydroxyl, or C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl, HaloC 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkoxy, NR V4 COR V5 , N.R. V4 COOR V6 , or NR V4 CONR V7 R V8 and R V4 is a hydrogen atom or C 1-6 alkyl; R V5 , R V6 , R V7 , and RV8 are each independently a hydrogen atom or a group selected from the group consisting of the following (i) to (ix): (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 (v) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 6-10 Aryl C 1-6 (vi) a 3- to 8-membered heterocycloalkyl that is unsubstituted or substituted with 1 to 6 groups selected from the substituent group A; (vii) a 3- to 8-membered heterocycloalkyl C that is unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 1-6 alkyl, (viii) a 5- to 10-membered heteroaryl that is unsubstituted or substituted with 1 to 5 groups selected from the substituent group A, and (ix) a 5- to 10-membered heteroaryl C that is unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 1-6 Alkyl; Substituent group A is a halogen atom, cyano, hydroxy, N(C 1-6 Alkyl)2, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkoxy, and C 3-8 cycloalkyl; when two or more groups selected from the substituent group A are present, each group may be the same or different; R T1 and R T2 are each independently a hydrogen atom, a halogen atom, a hydroxyl, or C 1-6 Alkyl or haloC 1-6 alkyl; R T3 is a hydrogen atom, C 1-6Alkyl or haloC 1-6 alkyl; R 3 is a hydrogen atom, a halogen atom, or C 1-6 alkyl; R 4 is C 1-6 Alkyl, HaloC 1-6 Alkyl, OR 5 , N.R. 5 R 5' , C 3-8 cycloalkyl, unsubstituted or 3- to 8-membered heterocycloalkyl substituted with 1 to 6 groups selected from the substituent group C, C 6-10 aryl, or a 5- or 6-membered heteroaryl unsubstituted or substituted with 1 to 4 groups selected from the substituent group C; the substituent group C is a halogen atom, cyano, hydroxy, C 1-6 Alkyl, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, oxo, CONH2, CONH-(C 1-6 alkyl), or CONH-(C 3-8 When two or more groups selected from the substituent group C are present, each group may be the same or different; 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 is R 4 , R T1 , R T2 , or R T3 may be taken together with R to form a 3- to 10-membered ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; 3 is R 5 may be taken together with R to form a 3- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B, or a 3- to 10-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; R 4 is R T1 , RT2 , or R T3 may be taken together with R to form a 3- to 10-membered ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; 5 is R T1 , R T2 , or R T3 may be taken together with R to form a 3- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B, or a 3- to 10-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; R V7 is R V8 may be taken together with W to form a 3- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B, or a 3- to 10-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; 1 is CR W1 R W2 , O, N.R. W3 or a single bond; W 2 is CR W1 R W2 , O, N.R. W3 or a single bond; R W1 and R W2 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R W3 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; W 3 CO, CNR W4 , SO, SO2, or a single bond; R W4 is a hydrogen atom, C 1-6 Alkyl, cyano, hydroxy, C 1-6 Alkoxy, CO-(C 1-6 alkyl), or SO2-(C 1-6 alkyl); n is an integer from 0 to 3; when n is 2 or 3, each R 2 may be the same or different; R 4 and R 5 is R W1 or R W3and may be taken together to form a 5- to 8-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B, or a 5- to 8-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from the substituent group B; Y is O, OR Y , S, S.R. Y , N.R. Y , or NR Y R Y' and R Y and R Y' is a hydrogen atom or C 1-6 alkyl; R Y is R 1 may be taken together with and form a 5- to 8-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from substituent group B, or a 5- to 8-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from substituent group B; represents a single bond or a double bond] or a pharmacologically acceptable salt thereof; (provided that in formula (I), W 1 is a single bond; and W 2 is CH2 or NH; and W 3 is CO; and R 4 But C 1-6 Alkyl, HaloC 1-6 Alkyl, NR 5 R 5 ', or C 3-8 When R is cycloalkyl, it is any one of the following (a) to (f): (a) R T1 and R T2 is not a hydrogen atom (b) X is not O and X is CHR X0 When R X0 is a hydrogen atom and C 1-6 (c) V 6 But NR 1 If R 1 is Haro C 1-6 (d) V is alkyl 2 is CR V2 and R V2 is Haro C 1-6 Alkoxy, NR V4 COR V5 , N.R.V4 COOR V6 , or NR V4 CONR V7 R V8 (e) Y is not O (f) q is 0).

[0020] [2-A1] The compound according to [1] above, which is represented by formula (I-A1): [In the formula, rings Z, X, V 1 , V 3 , V 4 , V 5 , V 6 , W 1 , W 2 , W 3 , R 2 , R 4 , n, Y, and q have the same meanings as in [1] above; R V2 is Haro C 1-6 Alkoxy, NR V4 COR V5 , N.R. V4 COOR V6 , or NR V4 CONR V7 R V8 and represents a single or double bond; R V4 , R V5 , R V6 , R V7 , and R V8 has the same meaning as in the above [1], or a pharmacologically acceptable salt thereof.

[0021] [2-A2] The compound according to [1] or [2-A1] above, which is represented by formula (I-A2): [In the formula, rings Z, X, W 1 , W 2 , W 3 , R 1 , R 2 , R 3 , R 4 and n have the same meaning as in [1] above; R V2 has the same meaning as in [2-A1] above; V 1 is CR V1 or N; V 3 is CR V3or N; V 4 is a single bond, CR T1 R T2 , O, or NR T3 and Y is O, S, or NR Y and R V1 , R V3 , R T1 , R T2 , R T3 , and R Y has the same meaning as in the above [1]] or a pharmacologically acceptable salt thereof. [2-A3] A compound according to any one of the above [1] to [2-A2], which is represented by formula (I-A3): [In the formula, rings Z, R 1 , R 2 , R 3 , R 4 and n have the same meaning as in [1] above; X is CR X0 R X0’ , O, N.R. X3 , CO, or -C(=CH2)-; Y is O or S; R V2 has the same meaning as in [2-A1] above; V 1 , V 3 , and V 4 has the same meaning as in [2-A2] above; W is a single bond, CH, or NH; R X0 , R X0’ , and R X3 has the same meaning as in the above [1]] or a pharmacologically acceptable salt thereof. [2-A4] A compound according to any one of the above [1] to [2-A3], wherein: R V2 But NR V4 COOR V6 [2-A5] A compound according to any one of [1] to [2-A4] above, wherein R V6 is a group selected from the group consisting of the following (i) to (iii): (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 a compound or a pharmacologically acceptable salt thereof, wherein when two or more groups selected from Substituent Group A are present, the respective groups may be the same or different. [2-A6] A compound according to any one of [1] to [2-A5] above, wherein: Substituent Group A is a halogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl, and C 3-8 A compound of the group consisting of cycloalkyl or a pharmacologically acceptable salt thereof.

[0022] [2-B1] The compound according to [1] above, which is represented by formula (I-B1): [In the formula, rings Z, X, V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , R 2 , n, Y, and q are as defined in [1] above; W 0 is a group represented by the following formula (w-1): (In the formula, W 1 , W 2 , W 3 , and R 4 has the same meaning as in [1] above; provided that W 1 is a single bond, it is any one of the following (g) to (i); (g) W 2 is CR W1 R W2 If R W1 and R W2 is not a hydrogen atom at the same time, but a W 2 NR W3 If R W3 is not a hydrogen atom (h) R 4 But C 1-6 Alkyl, HaloC 1-6 Alkyl, NR 5 R 5 ', or C 3-8 Not cycloalkyl (i) W 3 is not CO W2 is a single bond, it is any one of the following (j) to (l); (j) W 1 is CR W1 R W2 If R W1 and R W2 is not a hydrogen atom at the same time, but a W 1 NR W3 If R W3 is not a hydrogen atom (k) R 4 But C 1-6 Alkyl, HaloC 1-6 Alkyl, NR 5 R 5' , or C 3-8 Not cycloalkyl (l) W 3 is not CO); represents a single or double bond; R W1 , R W2 , R W3 , R 5 , and R 5' has the same meaning as in the above [1]. [2-B2] A compound according to the above [1] or [2-B1], which is represented by formula (I-B2): [In the formula, rings Z, X, R 1 , R 2 , R 3 and n have the same meaning as in [1] above; W 0 has the same meaning as in [2-B1] above; V 1 is CR V1 or N; V 2 is CR V2 or N; V 3 is CR V3 or N; V 4 is a single bond, CR T1 R T2 , O, or NR T3 and Y is O, S, or NR Y and R V1 , R V2 , R V3 , R T1 , R T2 , R T3 , and R Yhas the same meaning as in the above [1]] or a pharmacologically acceptable salt thereof.

[0023] [2-B3] A compound according to any one of [1], [2-B1], and [2-B2] above, which is represented by formula (I-B3): [In the formula, rings Z, R 1 , R 2 , R 3 and n have the same meaning as in [1] above; W 0 has the same meaning as in [2-B1] above; V 1 , V 2 , V 3 , and V 4 has the same meaning as in [2-B2] above; X is CR X0 R X0’ , O, N.R. X3 , CO, or -C(=CH2)-; Y is O or S; R X0 , R X0’ , and R X3 has the same meaning as in the above [1]] or a pharmacologically acceptable salt thereof. [2-B4] A compound according to any one of the above [2-B1] to [2-B3], wherein: W 0 is the following group: or In the formula, R W But C 1-6 Alkoxy, 3- to 8-membered heterocycloalkyl, or C 6-10 aryl or a pharmacologically acceptable salt thereof.

[0024] [2-C1] The compound according to [1] above, which is represented by formula (I-C1): [In the formula, rings Z, V 1 , V 2 , V 3 , V 4 , V 5 , W 1 , W 2 , W 3 , R 2 , R 4 , n, and q have the same meanings as in [1] above; X' is CR X0 or N; V 6’ is CR 1or N; Y is O or S; R 6 is a halogen atom, hydroxy, C 1-6 Alkyl, HaloC 1-6 alkyl, or oxo; m is an integer from 0 to 4; represents a single or double bond; R X0 , and R 1 has the same meaning as in the above [1]] or a pharmacologically acceptable salt thereof. [2-C2] A compound according to the above [1] or [2-C1], which is represented by the formula (I-C2): [In the formula, rings Z, W 1 , W 2 , W 3 , R 2 , R 3 , R 4 and n have the same meaning as in [1] above; V 1 is CR V1 or N; V 2 is CR V2 or N; V 3 is CR V3 or N; V 4 is a single bond, CR T1 R T2 , O, or NR T3 and R V1 , R V2 , R V3 , R T1 , R T2 , and R T3 has the same meaning as in [1] above; Y, R 6 and m has the same meaning as in the above [2-C1], or a pharmacologically acceptable salt thereof. [2-C3] A compound according to the above [1], [2-C1], or [2-C2], which is represented by formula (I-C3): [In the formula, rings Z, R 2 , R 3 , R 4 and n have the same meaning as in [1] above; Y, R 6 and m have the same meaning as in [2-C1] above; V 1 , V 2 , V 3 , and V 4has the same meaning as in the above [2-C2]; W is CH2 or NH] or a pharmacologically acceptable salt thereof. [2-C4] A compound according to any one of the above [1] or [2-C1] to [2-C3], wherein: R 6 But C 1-6 A compound or a pharmacologically acceptable salt thereof, wherein the compound is alkyl, or oxo.

[0025] [2-D1] The compound according to [1] above, which is represented by formula (I-D1): [In the formula, rings Z, X, V 1 , V 2 , V 3 , V 4 , V 5 , W 1 , W 2 , W 3 , R 2 , R 4 , n, and q have the same meanings as in [1] above; V 6’ is C, CR 1 or N; R 7 is a halogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; r is an integer from 1 to 4; p is an integer from 0 to 3; represents a single or double bond; R 1 has the same meaning as in the above [1]] or a pharmacologically acceptable salt thereof. [2-D2] A compound according to the above [1] or [2-D1], which is represented by the formula (I-D2): [In the formula, rings Z, X, W 1 , W 2 , W 3 , R 2 , R 3 , R 4 and n have the same meaning as in [1] above; R 7 and p have the same meaning as in [2-D1] above; V 1 is CR V1 or N; V 2 is CR V2 or N; V 3 is CR V3 or N; V 4is a single bond, CR T1 R T2 , O, or NR T3 and R V1 , R V2 , R V3 , R T1 , R T2 , and R T3 has the same meaning as in the above [1]] or a pharmacologically acceptable salt thereof. [2-D3] A compound according to the above [1], [2-D1], or [2-D2], which is represented by the formula (I-D3): [In the formula, rings Z, R 2 , R 3 , R 4 and n have the same meaning as in [1] above; R 7 and p have the same meaning as in [2-D1] above; V 1 , V 2 , V 3 , and V 4 has the same meaning as in [2-D2] above; X is CR X0 R X0’ , O, N.R. X3 , CO, or -C(=CH2)-; W is CH2 or NH; R X0 , R X0’ , and R X3 has the same meaning as in the above [1]] or a pharmacologically acceptable salt thereof. [2-D4] A compound according to any one of the above [1] or [2-D1] to [2-D3], wherein: R 7 But C 1-6 [2-E1] A compound according to any one of [1] to [2-D4] above, wherein: V is an alkyl group or a pharmacologically acceptable salt thereof. 4 But, CR T1 R T2 If R T1 and R T2 [2-E2] A compound according to any one of [1] to [2-E1] above, wherein: V 4 But, CR T1 R T2[2-E3] A compound according to any one of [1] to [2-E2] above, wherein R T1 and R T2 are each independently a hydrogen atom or a hydroxyl, or a pharmacologically acceptable salt thereof.

[0026] [2-F1] The compound according to any one of [1] to [2-E3] above, wherein X is CR X0 R X0’ , N.R. X3 , CO, -C(=CH2)-, -(CR X1 R X2 )2-, OCR X1 R X2 , C.R. X1 R X2 O, NR X3 CR X1 R X2 , C.R. X1 R X2 NR X3 , or -CR X1 =CR X2 - and R X0 and R X0’ are each independently a hydrogen atom, a halogen atom, a hydroxyl, or C 1-6 Alkyl or haloC 1-6 alkyl; provided that X is CHR X0 When R X0 is a hydrogen atom and C 1-6 [2-F2] A compound according to any one of [1] to [2-F1] above, wherein X is CR or a pharmaceutically acceptable salt thereof. X0 R X0’ , CO, -C(=CH2)-, or OCR X1 R X2 [2-F3] A compound according to any one of [1] to [2-F2] above, wherein R X0 and R X0’ are each independently a hydrogen atom, a halogen atom, a hydroxyl, or C 1-6 Alkyl or haloC 1-6[2-F4] A compound according to any one of [1] to [2-F3], wherein R is alkyl, or a pharmacologically acceptable salt thereof. X1 and R X2 are each independently a hydrogen atom, a hydroxyl, or C 1-6 or a pharmacologically acceptable salt thereof.

[0027] [2-G] The compound according to any one of [1] to [2-F4] above, wherein: V 6 But NR 1 If R 1 But, Haro C 1-6 [2-H1] A compound according to any one of [1] to [2-G] above, wherein Y is S, or NR Y and R Y is a hydrogen atom or C 1-6 alkyl; R Y But R 1 and optionally together with each other to form a 5- to 8-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from substituent group B, or a 5- to 8-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from substituent group B; when two or more groups selected from substituent group B are present, the respective groups may be the same or different, or a pharmacologically acceptable salt thereof. [2-H2] A compound according to any of the above [1] to [2-H1], wherein: Y is S, or a pharmacologically acceptable salt thereof.

[0028] [3] The compound according to any one of [1] to [2-H2] above, wherein ring Z is C 6-10 [4] A compound according to any one of [1] to [3], wherein: R is an aryl, or a 5- or 6-membered heteroaryl; or a pharmacologically acceptable salt thereof. 3 [5] A compound according to any one of [1] to [4] above, wherein: R 2 is a halogen atom, cyano, or haloC 1-6 or a pharmacologically acceptable salt thereof.

[0029] [6-A1] The compound according to any one of [1] to [5] above, wherein: R V1 , R V1’ , R V2 , R V2’ , R V3 , and R V3’ are each independently a hydrogen atom, a halogen atom, a hydroxyl, or C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl or C 6-10 Aryl C 1-6 [6-A2] A compound according to any one of [1] to [6-A1] above, wherein: V is an alkoxy group or a pharmacologically acceptable salt thereof. 1 But, CR V1 and V 2 is CH; V 3 is CH; R V1 However, hydrogen atoms, halogen atoms, C 1-6 Alkyl, HaloC 1-6 Alkyl or hydroxy C 1-6 [6-A3] A compound according to any one of [1] to [6-A2], wherein: V is an alkyl group or a pharmacologically acceptable salt thereof. 6 But NR 1 If R V1 is a hydrogen atom or C 1-6 or a pharmacologically acceptable salt thereof.

[0030] [6-B1] The compound according to any one of [1] to [6-A3] above, wherein: W 1 is a single bond; W 2 is CH2, NH, or a single bond; W 3 [6-B2] A compound according to any one of [1] to [6-B1] above, wherein: R 4 But C 1-6 Alkyl, HaloC 1-6 Alkyl, -NR 5 R5' , or C 3-8 [6-B3] A compound according to any one of [1] to [6-B2], wherein: R 4 [6-B4] A compound according to any one of [1] to [6-B3], wherein: W is -NH2, or a pharmacologically acceptable salt thereof. 2 is NH or a pharmacologically acceptable salt thereof.

[0031] [6-C] The compound according to any one of [1] to [6-B4] above, wherein: V 4 [6-D1] A compound according to any one of [1] to [6-C] above, wherein X is O, or CHR X0 [6-D2] The compound according to any one of [1] to [6-D1] above, wherein: X is O, or a pharmacologically acceptable salt thereof. [6-E] The compound according to any one of [1] to [6-D2] above, wherein: R 1 But C 1-6 [6-F] The compound according to any one of [1] to [6-E], wherein Y is O, or a pharmacologically acceptable salt thereof.

[0032] [7] A pharmaceutical composition comprising the compound according to any one of [1] to [6-F] or a pharmacologically acceptable salt thereof, and a pharmaceutical additive. [8] The pharmaceutical composition according to [7], which is a pharmaceutical composition for treating a thyroid-related disease. [9] The pharmaceutical composition according to [8], wherein the thyroid-related disease is hyperthyroidism, Graves' disease, or thyroid ophthalmopathy.

[0033] In one embodiment, the present invention relates to a method for treating a thyroid-related disease, comprising administering to a patient a required amount of the pharmaceutical composition described in [7] above.

[0034] In one embodiment, the present invention relates to use of a compound described in any of [1] to [6-F] or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition for treating a thyroid-related disease.

[0035] 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.

[0036] Hereinafter, embodiments of the present invention will be described in more detail.

[0037] In the present invention, each term has the following meaning unless otherwise specified.

[0038] "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, etc.

[0039] "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 "Alkyl" refers to an alkyl group. Examples include carboxymethyl and carboxyethyl. "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.

[0040] "C 6-10"Aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group having 6 to 10 carbon atoms, and a portion of the ring may be partially saturated. Examples include phenyl, naphthyl, and indanyl. "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. "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.

[0041] "C 3-8"Cycloalkyl" refers to 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, bicyclo[2.2.2]octyl, etc. "3 to 8-membered heterocycloalkyl" refers to a 3 to 8-membered cycloalkyl group in which carbon atoms in the ring are replaced with one or two heteroatoms selected from oxygen, nitrogen, and sulfur atoms, including 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, octahydrocyclopenta[c]pyrrole, and the like.

[0042] "3- to 10-membered saturated carbocyclic ring" means a monocyclic or polycyclic saturated hydrocarbon ring having 3 to 10 carbon atoms. "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.

[0043] "3- to 10-membered unsaturated carbocyclic ring" means a monocyclic or polycyclic, fully or partially unsaturated hydrocarbon ring having 3 to 10 carbon atoms. "5- to 8-membered unsaturated carbocyclic ring" means a monocyclic or polycyclic, fully or partially unsaturated hydrocarbon ring having 5 to 8 carbon atoms.

[0044] "3- to 10-membered saturated heterocycle" means a monocyclic or polycyclic 3- to 10-membered saturated heterocycle having 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur atoms in the ring. "3- to 8-membered saturated heterocycle" means a monocyclic or polycyclic 3- to 8-membered saturated heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms in the ring. "5- to 8-membered saturated heterocycle" means a monocyclic or polycyclic 5- to 8-membered saturated heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms in the ring.

[0045] 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.

[0046] The term "3- to 10-membered ring" refers to a 3- to 10-membered saturated carbocyclic ring, a 3- to 10-membered saturated heterocyclic ring, a 3- to 10-membered unsaturated carbocyclic ring, or a 3- to 10-membered unsaturated heterocyclic ring. The term "5- to 8-membered ring" refers to 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.

[0047] "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.

[0048] "C 6-10 Aryl C 1-6 "Alkyl" means one C 6-10 Aryl-substituted C 1-6 It means alkyl. For example, benzyl.6-10 Aryl C 2-6 "Alkynyl" means one C 6-10 Aryl-substituted C 2-6 It means alkynyl, for example, phenylethynyl.

[0049] "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 and pyridin-3-ylethynyl are mentioned. "5- to 10-membered heteroaryl C 1-6 "Alkyl" refers to a C substituted with one 5- to 10-membered heteroaryl. 1-6 It means alkyl.

[0050] "C 3-8 Cycloalkyl C 1-6 "Alkyl" means one C 3-8 Cycloalkyl-substituted C 1-6 It means alkyl. For example, cyclopropylethyl. 3-8 Cycloalkyl C 2-6 "Alkynyl" means one C 3-8 Cycloalkyl-substituted C 2-6 It means alkynyl, for example, cyclopropylethynyl.

[0051] 3-8 membered heterocycloalkyl C 1-6 "Alkyl" refers to a C substituted with one 3- to 8-membered heterocycloalkyl. 1-6 It means alkyl, for example, morpholinoethyl.

[0052] The following abbreviations in the text, figures, and tables have the following meanings: BF3-Et2O: boron trifluoride-diethyl ether complex BH3-THF: borane-tetrahydrofuran complex Boc: tert-butoxycarbonyl Boc2O: di-tert-butyl dicarbonate Cbz: benzyloxycarbonyl CDI: carbonyldiimidazole DBU: diazabicycloundecene DCE: 1,2-dichloroethane DCM: dichloromethane DIBAL-H: diisobutylaluminum hydride DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMP: Dess-Martin periodinane DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride DPPA: diphenylphosphoryl azide Et2O: diethyl ether 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 NCS: N-Chlorosuccinimide NMP: N-Methylpyrrolidone TBAF: Tetrabutylammonium fluoride TBS: tert-butyldimethylsilyl TBSCl: tert-butyldimethylsilyl chloride TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran TMS: Trimethylsilyl TMSCl: Trimethylsilyl chloride T3P: Propylphosphonic anhydride (cyclic trimer) Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Xphos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl 10% Pd / C: 10% Palladium carbon (approximately 55% wet with water) Lawesson's reagent: 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide 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 a dihydroxypropylated 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 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

[0053] When one or more asymmetric carbon atoms are present in the compounds represented by formulae (A-I) to (AIII) or (I) to (I-D3), 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.

[0054] In the compounds represented by formulae (AI) to (AIII) or (I) to (I-D3), when cis-trans isomers exist, the present invention encompasses both of the cis-trans isomers.

[0055] When tautomers exist in the compounds represented by formulae (AI) to (AIII) or (I) to (I-D3), the present invention includes all of the tautomers.

[0056] In the present invention, the determination of stereochemistry can also be carried out by methods well known in the art.

[0057] The compounds represented by formulae (AI) to (AIII) or (I) to (I-D3) can be converted into pharmacologically acceptable salts thereof, if necessary, in accordance with a conventional method. Such salts include acid addition salts and salts with bases.

[0058] Examples of acid addition salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and acid addition salts with organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, benzoic acid, glutamic acid, and aspartic acid.

[0059] 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.

[0060] 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.

[0061] When the compounds represented by Formulae (A-I) to (AIII) or Formulae (I) to (I-D3) 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.

[0062] In the compounds represented by formulas (AI) to (AIII) or formulas (I) to (I-D3), 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 (AIII) or (I) to (I-D3) are 2 Examples include compounds in which hydrogen is replaced by H (D: deuterium atom).

[0063] Compounds represented by formulae (A-I) to (AIII) or (I) to (I-D3) in which some atoms are replaced with isotopes can be produced by methods similar to those 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).

[0064] The compounds of the present invention represented by formulae (A-I) to (AIII) or (I) to (I-D3) can be produced, for example, by the methods shown in Schemes 1 to 30 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 (AIII) or (I) to (I-D3) correspond to the compounds of formulae (I-1) to (I-25).

[0065] The compounds of the present invention represented by formulae (AI) to (AIII) or formulae (I) to (I-D3) 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.

[0066] In the reactions of each step, when raw materials and reagents are commercially available, commercially available products can be used.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] A microwave reactor such as Biotage Initiator may be used in the reactions of each step. When a microwave reactor is used, the conditions vary depending on the raw materials, solvent, and model used, but can be varied 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.

[0071] Unless otherwise specified, the reaction in each step is carried out without solvent or using an appropriate solvent. Examples of the appropriate solvent include solvents inert to the reaction. Specific examples of the solvent used include the solvents described in the Reference Examples or Examples corresponding to each step, or the following solvents. Two or more of the following solvents may be mixed in an appropriate ratio and used. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-propanol, etc.; Ethers: diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane, cyclopentyl methyl ether, 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, DCE, 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.

[0072] 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 hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc.; organic magnesiums: isopropylmagnesium chloride, etc.; organic lithiums: methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, etc.

[0073] When an acid is used in the reaction of each step, the reaction is carried out using an acid suitable for the reaction. Specific examples of the acid used include the acids described in the Reference Examples and Examples corresponding to each step, or the following acids: inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; organic acids: acetic acid, TFA, citric acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, trifluoromethanesulfonic acid, etc.; Lewis acids: BF3-Et2O, zinc iodide, aluminum chloride, zinc chloride, titanium(IV) chloride, bismuth(III) trifluoromethanesulfonate, etc.

[0074] 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: CDI, etc.; Uronium salts, phosphonium salts: HATU, 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, etc.; Triazines: DMT-MM, etc.; Others: T3P, etc.

[0075] 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.

[0076] When an oxidizing agent is used in the reaction of each step, the reaction is carried out using an oxidizing agent suitable for the reaction. Specific examples of the oxidizing agent used include the oxidizing agents described in the Reference Examples or Examples corresponding to each step, or the following oxidizing agents: peracids: m-chloroperbenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, etc.; chlorates: sodium hypochlorite, sodium chlorite, etc.; iodates: sodium periodate, etc.; hypervalent iodine reagents: iodobenzene diacetate, DMP, etc.; chromium-containing reagents: pyridinium dichromate, Jones reagent, etc.; manganese-containing reagents: manganese dioxide, potassium permanganate, etc.

[0077] 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: CDI, etc.

[0078] 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.

[0079] When hydrolysis is carried out in each step, the reaction can be carried out in the presence of an acid or a base. Examples of the acid and base that can be used include those mentioned above.

[0080] When catalytic reduction is carried out in each step, the reaction can be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst that can be used include palladium carbon powder, Pearlman's catalyst, platinum carbon powder, Raney nickel, (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)iridium(I) hexafluorophosphate, etc. If necessary, an acid may be used in the reaction.

[0081] When reduction is carried out in each step, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent that can be used include the examples mentioned above.

[0082] When metal reduction 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.

[0083] When oxidation is carried out in each step, the reaction can be carried out in the presence of an oxidizing agent. Examples of the oxidizing agent that can be used include those mentioned above. When a nitroxy radical oxidation catalyst is used, the reaction can be carried out in the presence of a reoxidizing agent. Examples of the nitroxy radical oxidation catalyst that can be used include 2,2,6,6-tetramethylpiperidine 1-oxyl and 2-azaadamantane-N-oxyl. Examples of the reoxidizing agent that can be used include sodium hypochlorite and iodobenzene diacetate. If necessary, the reaction can be carried out by adding an additive such as tetrabutylammonium hydrogen sulfate or potassium bromide.

[0084] 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.

[0085] In each step, when an aromatic nucleophilic substitution reaction is carried out, the reaction can be carried out in the presence of a base. Examples of the base include those mentioned above.

[0086] 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.

[0087] 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). 、Examples of the base include bis(triphenylphosphine)palladium(II) chloride, tetrakis(triphenylphosphine)palladium(0), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride dichloromethane adduct, etc. Examples of the base to be used include the examples mentioned above.

[0088] When a Mizoroki-Heck cross-coupling reaction is carried out in each step, the reaction can be carried out in the presence of a palladium catalyst, a ligand, and a base. Examples of the palladium catalyst include palladium(II) acetate. Examples of the ligand include tris(2-methylphenyl)phosphine. Examples of the base used include the above-mentioned examples.

[0089] When a Buchwald-Hardwig cross-coupling reaction is carried out in each step, the reaction can be carried out in the presence of a palladium catalyst, a ligand, and a base. Examples of the palladium catalyst that can be used include tris(dibenzylideneacetone)dipalladium(0). Examples of the ligand that can be used include Xantphos. Examples of the base that can be used include the examples mentioned above.

[0090] When bromination is carried out in each step, the reaction can be carried out in the presence of a brominating reagent, such as NBS.

[0091] When chlorination is carried out in each step, the reaction can be carried out in the presence of a chlorinating reagent, such as NCS.

[0092] When a Wittig reaction is carried out in each step, the reaction can be carried out in the presence of a base. Examples of the base to be used include those mentioned above.

[0093] When the Horner-Wadsworth-Emmons reaction is carried out in each step, the reaction can be carried out in the presence of a base. Examples of the base that can be used include those mentioned above.

[0094] When Brown hydroboration is carried out in each step, the reaction can be carried out in the presence of a boronating agent, such as BH3-THF.

[0095] 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.

[0096] 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.

[0097] When asymmetric alkylation is carried out in each step, the reaction can be carried out in the presence of a base and an optically active phase transfer catalyst. Examples of the base to be used include those mentioned above. Examples of the optically active phase transfer catalyst to be used include (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepinium bromide and (11bS,11'bS)-2,6-bis(3,4,5-trifluorophenyl)-3,3',5,5'-tetrahydro-4,4'-spirobi[dinaphtho[2,1-c:1',2'-e]azepin]-4-ium. bromide, 6,10-dibenzyl-N,N'-dimethyl-N,N,N',N'-tetrakis(4-methylbenzyl)-1,4-dioxaspiro[4.5]decane-(2S,3S)diylbis(methylammonium) bis(tetrafluoroborate) salt, N-benzylcinchoninium chloride, N-benzylcinchoninium bromide, N-anthranylcinchoninium chloride, N-anthranylcinchoninium bromide, and the like.

[0098] When oxidative cleavage is carried out in each step, the reaction can be carried out in the presence of an oxidative cleavage agent, such as a combination of osmium(VIII) tetroxide and sodium periodate.

[0099] The compound represented by formula (I-1) can be produced, for example, according to the method described in Scheme 1.

[0100] The symbols in the formula have the same meanings as above. 1 is a protecting group, W 1P is CR W1 R W2 , or a single bond.

[0101] Process 1-1 The compound (1-2) can also be produced by removing the protecting group of the compound (1-1).

[0102] Process 1-2 Compound (I-1) can also be produced by amidation of compound (1-2) and compound (1-3).

[0103] The compound represented by formula (I-2) can be produced, for example, according to the method described in Scheme 2.

[0104] The symbols in the formula have the same meanings as above. 2 is a protecting group, and R P2 is C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-8 cycloalkyl, unsubstituted or 3- to 8-membered heterocycloalkyl substituted with 1 to 6 groups selected from the substituent group C, C 6-10 aryl, or a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 4 groups selected from the substituent group C;

[0105] Process 2-1 The compound (2-2) can also be produced by removing the protecting group of the compound (2-1).

[0106] Process 2-2 Compound (I-2a) can also be produced by reacting compound (2-2) with trimethylsilyl isocyanate. Alternatively, compound (I-2a) can be produced by reacting compound (2-2) with potassium cyanate or sodium cyanate in the presence of an acid.

[0107] Process 2-3 Compound (I-2b) can also be produced by ureation of compound (2-2) and compound (1-3).

[0108] Process 2-4 Compound (I-2c) can also be produced by carbamating compound (2-2) with compound (2-3).

[0109] Process 2-5 Compound (I-2d) can also be produced by amidation of compound (2-2) and compound (2-4).

[0110] Process 2-6 Compound (I-2e) can also be produced by reacting compound (2-2) with tert-butyl N-(chlorosulfonyl)carbamate, followed by reaction with an acid.

[0111] The compound represented by formula (1-1) can be produced, for example, according to the method described in Scheme 3.

[0112] The symbols in the formula have the same meanings as above.

[0113] Process 3-1 The compound (1-1a) can also be produced by amidation of the compound (3-1) and the compound (3-2).

[0114] Process 3-2 The compound (1-1b) can also be produced by carbamate reaction of the compound (3-1) and the compound (3-3).

[0115] Process 3-3 The compound (1-1c) can also be produced by ureation of the compound (3-1) and the compound (3-4).

[0116] The compound represented by formula (2-1) can be produced, for example, according to the method described in Scheme 4.

[0117] The symbols in the formula have the same meanings as above.

[0118] Process 4-1 The compound (2-1a) can also be produced by amidation of the compound (4-1) and the compound (3-2).

[0119] Process 4-2 The compound (2-1b) can also be produced by carbamating the compound (4-1) with the compound (3-3).

[0120] Process 4-3 The compound (2-1c) can also be produced by ureation of the compound (4-1) and the compound (3-4).

[0121] The compound represented by formula (3-1) can be produced, for example, according to the method described in Scheme 5.

[0122] The symbols in the formula have the same meanings as above. 5 is a chlorine atom, a bromine atom, an iodine atom, OCO-(C 1-6 alkyl), or methanesulfonyloxy group, V 4P is a single bond, CR T1 R T2 , O, or NR T3 is.

[0123] Process 5-1 The compound (5-3) can also be produced by reacting the compound (5-1) with the compound (5-2) in the presence of a base.

[0124] Process 5-2 The compound (3-1a) can also be produced by reacting the compound (5-3) with an acid and hydroxylamine.

[0125] Process 5-3 The compound (5-5) can also be produced by reacting the compound (5-4) with the compound (5-2) in the presence of a base.

[0126] Process 5-4 The compound (3-1a) can also be produced by reacting the compound (5-5) with an acid and hydroxylamine.

[0127] The compound represented by formula (4-1) can be produced, for example, according to the method described in Scheme 6.

[0128] The symbols in the formula have the same meanings as above.

[0129] Process 6-1 The compound (6-1) can also be produced by reacting the compound (5-1) with DPPA and Boc2O in the presence of a base.

[0130] Process 6-2 The compound (4-1a) can also be produced by reacting the compound (6-1) with an acid and hydroxylamine, followed by reaction with Boc2O.

[0131] Process 6-3 The compound (6-2) can also be produced by reacting the compound (5-4) with DPPA and Boc2O in the presence of a base.

[0132] Process 6-4 The compound (4-1a) can also be produced by reacting the compound (6-2) with an acid and hydroxylamine, followed by reaction with Boc2O.

[0133] The compounds represented by formula (1-1), formula (2-1), and formula (2-2) can be produced, for example, according to the method described in Scheme 7.

[0134] The symbols in the formula have the same meanings as above. 7 is a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonyloxy group, and R 1P is C 1-6 Alkyl or haloC 1-6 It is alkyl.

[0135] Process 7-1 The compound (7-3) can also be produced by reacting the compound (7-1) with the compound (7-2) in the presence of a base.

[0136] Process 7-2 Compound (2-1d) can also be produced by reacting compound (7-3) with DPPA and Boc2O in the presence of a base.

[0137] Process 7-3 The compound (1-1d) can also be produced by reacting the compound (7-3) with the compound (5-2a) in the presence of a base.

[0138] Process 7-4 The compound (1-1e) can also be produced by reacting the compound (7-3) with the compound (5-2b) in the presence of a base.

[0139] Process 7-5 The compound (7-4) can also be produced by reducing the compound (1-1e).

[0140] Process 7-6 The compound (7-5) can also be produced by reacting the compound (7-4) with methanesulfonyl chloride.

[0141] Process 7-7 The compound (7-6) can also be produced by reacting the compound (7-5) with sodium azide.

[0142] Process 7-8 The compound (2-2a) can also be produced by catalytic reduction of the compound (7-6).

[0143] The compound represented by formula (5-1) can be produced, for example, according to the method described in Scheme 8.

[0144] The symbols in the formula have the same meanings as above.

[0145] Process 8-1 The compound (8-1) can also be produced by brominating the compound (7-1a).

[0146] Process 8-2 The compound (8-2) can also be produced by reacting the compound (8-1) with the compound (7-2) in the presence of a base.

[0147] Process 8-3 The compound (5-1a) can also be produced by the Buchwald-Hardwig cross-coupling reaction of the compound (8-2) with benzophenone imine.

[0148] The compound represented by formula (7-1) can be produced, for example, according to the method described in Scheme 9.

[0149] The symbols in the formula have the same meanings as above. X 9 is a single bond or C 1-6 alkylene, and PG 9 is a protecting group.

[0150] Process 9-1 The compound (9-3) can also be produced by subjecting the compound (9-1) and the compound (9-2) to a nucleophilic aromatic substitution reaction.

[0151] Process 9-2 The compound (9-4) can also be produced by metal reduction of the compound (9-3).

[0152] Process 9-3 The compound (9-6) can also be produced by the Mizoroki-Heck cross-coupling reaction of the compound (9-4) and the compound (9-5).

[0153] Process 9-4 The compound (9-7) can also be produced by catalytic reduction of the compound (9-6).

[0154] Process 9-5 The compound (7-1b) can also be produced by reacting the compound (9-7) with a base.

[0155] The compound of formula (5-4) can be produced, for example, according to the method described in Scheme 10.

[0156] The symbols in the formula have the same meanings as above. 10 is a protecting group, and LG 10 is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonyloxy group, and X 10 is a single bond or C 1-6 It is alkylene.

[0157] Process 10-1 The compound (10-2) can also be produced by reacting the compound (10-1) with acetic anhydride in the presence of an acid.

[0158] Process 10-2 The compound (10-3) can also be produced by reacting the compound (10-2) with concentrated nitric acid in the presence of an acid.

[0159] Process 10-3 The compound (10-4) can also be produced by hydrolysis of the compound (10-3).

[0160] Process 10-4 The compound (10-5) can also be produced by protecting the hydroxyl group of the compound (10-4).

[0161] Process 10-5 The compound (10-6) can also be produced by reacting the compound (10-5) with the compound (7-2) in the presence of a base.

[0162] Process 10-6 The compound (10-7) can also be prepared by removing the protecting group of the compound (10-6).

[0163] Process 10-7 The compound (10-8) can also be produced by reducing the compound (10-7).

[0164] Process 10-8 The compound (10-9) can also be produced by reacting the compound (10-8) with acetonylacetone in the presence of an acid.

[0165] Process 10-9 The compound (5-4a) can also be produced by reacting the compound (10-9) with the compound (10-10) in the presence of a base.

[0166] The compounds represented by formula (2-1) and formula (2-2) can be produced, for example, according to the method described in Scheme 11.

[0167] The symbols in the formula have the same meanings as above. 11 is a protecting group, and LG 11is a bromine atom or an iodine atom.

[0168] Process 11-1 The compound (11-3) can also be produced by the Negishi coupling reaction of the compound (11-1) and the compound (11-2).

[0169] Process 11-2 The compound (2-2b) can also be produced by reacting the compound (11-3) with an acid.

[0170] Process 11-3 The compound (11-4) can also be produced by hydrolysis of the compound (11-3).

[0171] Process 11-4 The compound (2-1e) can also be produced by amidation of the compound (11-4).

[0172] The compound of formula (11-1) can be produced, for example, according to the method described in Scheme 12.

[0173] The symbols in the formula have the same meanings as above. 12 is a chlorine atom, a bromine atom, or an iodine atom, and R X0P is C 2-6 alkenyl, PG 12 , and P.G. 12’ are each independently a protecting group.

[0174] Process 12-1 The compound (11-1a) can also be produced by reacting the compound (9-4) with the compound (7-2) in the presence of a base.

[0175] Process 12-2 The compound (12-3) can also be produced by reacting the compound (12-1) with the compound (12-2).

[0176] Process 12-3 The compound (12-4) can also be produced by metal reduction of the compound (12-3).

[0177] Process 12-4 The compound (12-5) can also be produced by oxidation of the compound (12-4).

[0178] Process 12-5 The compound (11-1b) can also be produced by reacting the compound (12-5) with the compound (7-2) in the presence of a base.

[0179] Process 12-6 The compound (12-7) can also be produced by reacting the compound (12-5) with the compound (12-6).

[0180] Process 12-7 The compound (12-8) can also be produced by reacting the compound (12-7) with triethylsilane in the presence of an acid.

[0181] Process 12-8 The compound (11-1c) can also be produced by reacting the compound (12-8) with the compound (7-2) in the presence of a base.

[0182] Process 12-9 The compound (12-10) can also be produced by reacting the compound (12-9) with the compound (12-2).

[0183] Process 12-10 The compound (12-11) can also be produced by reacting the compound (12-10) with triethylsilane in the presence of an acid.

[0184] Process 12-11 The compound (12-12) can also be produced by removing the protecting group of the compound (12-11).

[0185] Process 12-12 The compound (11-1d) can also be produced by reacting the compound (12-12) with the compound (7-2) in the presence of a base.

[0186] The compound of formula (7-3) can be produced, for example, according to the method described in Scheme 13.

[0187] The symbols in the formula have the same meanings as above.

[0188] Process 13-1 The compound (13-3) can also be produced by reacting the compound (13-1) with the compound (13-2) in the presence of an acid.

[0189] Process 13-2 The compound (13-4) can also be produced by brominating the compound (13-3).

[0190] Process 13-3 The compound (13-5) can also be produced by reacting the compound (13-4) with the compound (7-2) in the presence of a base.

[0191] Process 13-4 The compound (13-7) can also be produced by the Mizoroki-Heck cross-coupling reaction of the compound (13-5) and the compound (13-6).

[0192] Process 13-5 The compound (13-8) can also be produced by catalytic reduction of the compound (13-7).

[0193] Process 13-6 The compound (7-3a) can also be produced by amidation of the compound (13-8).

[0194] The compound represented by formula (I-14) can be produced, for example, according to the method described in Scheme 14.

[0195] The symbols in the formula have the same meanings as above. P is C 6-10 It is aryl, or a 5- or 6-membered heteroaryl.

[0196] Process 14-1 The compound (14-2) can also be produced by reacting the compound (14-1) with acetone in the presence of an acid.

[0197] Process 14-2 The compound (14-4) can also be produced by reacting the compound (14-2) with the compound (14-3) in the presence of an acid.

[0198] Process 14-3 The compound (14-5) can also be produced by brominating the compound (14-4).

[0199] Process 14-4 The compound (14-6) can also be produced by the Negishi coupling reaction of the compound (14-5) and the compound (11-2).

[0200] Process 14-5 The compound (14-7) can also be produced by hydrolysis of the compound (14-6).

[0201] Process 14-6 The compound (14-8) can also be produced by amidation of the compound (14-7).

[0202] Process 14-7 The compound (14-9) can also be produced by removing the Boc group of the compound (14-8).

[0203] Process 14-8 Compound (I-14a) can also be produced by reacting compound (14-9) with trimethylsilyl isocyanate. Alternatively, compound (I-14a) can be produced by reacting compound (14-9) with potassium cyanate or sodium cyanate in the presence of an acid.

[0204] Process 14-9 Compound (I-14b) can also be produced by catalytic reduction of compound (I-14a).

[0205] The compound represented by formula (I-15) can be produced, for example, according to the method described in Scheme 15.

[0206] The symbols in the formula have the same meanings as above. P15 is a hydrogen atom, halogen atom, hydroxy, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy or haloC 1-6 It is an alkoxy.

[0207] Process 15-1 The compound (15-3) can also be produced by amidation of the compound (15-1) and the compound (15-2).

[0208] Process 15-2 The compound (15-4) can also be produced by reacting the compound (15-3) with an acid.

[0209] Process 15-3 The compound (15-5) can also be produced by reducing the compound (15-4).

[0210] Process 15-4 The compound (15-6) can also be produced by chlorinating the compound (15-5).

[0211] Process 15-5 Compound (15-7) can also be produced by brominating compound (15-6).

[0212] Process 15-6 The compound (15-8) can also be produced by the Negishi coupling reaction of the compound (15-7) and the compound (11-2).

[0213] Process 15-7 The compound (15-9) can also be produced by reacting the compound (15-8) with an acid.

[0214] Process 15-8 Compound (I-15a) can also be produced by reacting compound (15-9) with trimethylsilyl isocyanate. Alternatively, compound (I-15a) can be produced by reacting compound (15-9) with potassium cyanate or sodium cyanate in the presence of an acid.

[0215] Process 15-9 Compound (I-15b) can also be produced by catalytic reduction of compound (I-15a).

[0216] The compound represented by formula (I-16) can be produced, for example, according to the method described in Scheme 16.

[0217] The symbols in the formula have the same meanings as above. P16 , R P16' , and R X0'P are each independently 1-6 Alkyl or haloC 1-6 alkyl, LG 16 is a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonyloxy group, and PG 16 is a protecting group.

[0218] Process 16-1 The compound (16-2) can also be produced by the Wittig reaction of the compound (16-1) with methyltriphenylphosphonium bromide.

[0219] Process 16-2 The compound (16-4) can also be produced by reacting the compound (16-2) with the compound (16-3) in the presence of an acid.

[0220] Process 16-3 The compound (16-5) can also be prepared by protecting the amino group of the compound (16-4).

[0221] Process 16-4 Compound (16-6) can also be produced by Brown hydroboration of compound (16-5), followed by reaction with aqueous sodium hydroxide and aqueous hydrogen peroxide.

[0222] Process 16-5 The compound (16-7) can also be produced by oxidation of the compound (16-6).

[0223] Process 16-6 The compound (16-9) can also be produced by reacting the compound (16-7) with the compound (16-8) in the presence of a base.

[0224] Process 16-7 The compound (16-10) can also be prepared by removing the protecting group of the compound (16-9).

[0225] Process 16-8 Compound (16-11) can also be produced by brominating compound (16-10).

[0226] Process 16-9 The compound (16-12) can also be produced by the Negishi coupling reaction of the compound (16-11) and the compound (11-2).

[0227] Process 16-10 Compound (16-13) can also be produced by hydrolysis of compound (16-12).

[0228] Process 16-11 The compound (16-14) can also be produced by amidation of the compound (16-13).

[0229] Process 16-12 The compound (16-15) can also be prepared by removing the protecting group of the compound (16-14).

[0230] Process 16-13 Compound (I-16a) can also be produced by reacting compound (16-15) with trimethylsilyl isocyanate. Alternatively, compound (I-16a) can be produced by reacting compound (16-15) with potassium cyanate or sodium cyanate in the presence of an acid.

[0231] Process 16-14 Compound (I-16b) can also be produced by catalytic reduction of compound (I-16a).

[0232] The compound represented by formula (2-1) can be produced, for example, according to the method described in Scheme 17.

[0233] The symbols in the formula have the same meanings as above. 17 is a protecting group.

[0234] Process 17-1 The compound (17-1) can also be produced by reacting the compound (11-1) with DMF in the presence of a base.

[0235] Process 17-2 The compound (17-3) can also be produced by reacting the compound (17-1) with the compound (17-2) in the presence of a base.

[0236] Process 17-3 The compound (2-1f) can also be produced by reacting the compound (17-3) with an acid.

[0237] The compound represented by formula (I-18) can be produced, for example, according to the method described in Scheme 18.

[0238] The symbols in the formula have the same meanings as above. 18 is a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonyloxy group, and k is an integer of 1 to 4.

[0239] Process 18-1 The compound (I-18a) can also be produced by reacting the compound (2-2c) with the compound (18-1).

[0240] Process 18-2 Compound (I-18b) can also be produced by reacting compound (I-18a) with a base.

[0241] Process 18-3 The compound (I-18c) can also be produced by reacting the compound (2-2c) with the compound (18-2).

[0242] Process 18-4 Compound (I-18d) can also be produced by reacting compound (I-18c) with a base.

[0243] The compound represented by formula (I-19) can be produced, for example, according to the method described in Scheme 19.

[0244] The symbols in the formula have the same meanings as above. 19 is a protecting group.

[0245] Process 19-1 The compound (19-2) can also be prepared by removing the protecting group of the compound (19-1).

[0246] Process 19-2 Compound (I-19) can also be produced by carbamating compound (19-2) with compound (1-3).

[0247] The compound of formula (19-1) can be produced, for example, according to the method described in Scheme 20.

[0248] The symbols in the formula have the same meanings as above. 20 is a protecting group.

[0249] Process 20-1 The compound (20-2) can also be produced by reacting the compound (20-1) with the compound (9-2) in the presence of a base.

[0250] Process 20-2 The compound (20-4) can also be produced by reacting the compound (20-2) with the compound (20-3) in the presence of a base.

[0251] Process 20-3 The compound (20-5) can also be produced by reducing the compound (20-4).

[0252] Process 20-4 The compound (20-6) can also be produced by metal reduction of the compound (20-5).

[0253] Process 20-5 The compound (20-7) can also be prepared by protecting the hydroxyl group of the compound (20-6).

[0254] Process 20-6 The compound (19-1a) can also be produced by reacting the compound (20-7) with the compound (7-2) in the presence of a base.

[0255] The compound represented by formula (2-2) can be produced, for example, according to the method described in Scheme 21.

[0256] The symbols in the formula have the same meanings as above.

[0257] Process 21-1 The compound (2-2e) can also be produced by reacting the compound (2-2d) with Lawesson's reagent.

[0258] The compound represented by formula (2-1) can be produced, for example, according to the method described in Scheme 22. The symbols in the formula have the same meanings as above. P22 is a hydrogen atom or C 1-5 It is alkyl.

[0259] Process 22-1 The compound (2-1h) can also be produced by reacting the compound (2-1g) with Lawesson's reagent.

[0260] Process 22-2 The compound (2-1i) can also be produced by reacting the compound (2-1h) with aminoacetaldehyde diethyl acetal, followed by reaction with an acid.

[0261] Process 22-3 The compound (2-1j) can also be produced by reacting the compound (2-1h) with the compound (22-1).

[0262] The compound represented by formula (I-23) can be produced, for example, according to the method described in Scheme 23. The symbols in the formula have the same meanings as above. 23 is a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonyloxy group.

[0263] Process 23-1 The compound (23-3) can also be produced by subjecting the compound (23-1) and the compound (23-2) to a nucleophilic aromatic substitution reaction.

[0264] Process 23-2 The compound (23-4) can also be produced by reducing the compound (23-3).

[0265] Process 23-3 The compound (23-5) can also be produced by ureation of the compound (23-4).

[0266] Process 23-4 The compound (23-7) can also be produced by subjecting the compound (23-5) and the compound (23-6) to Suzuki-Miyaura cross-coupling reaction.

[0267] Process 23-5 The compound (23-8) can also be produced by catalytic reduction of the compound (23-7).

[0268] Process 23-6 The compound (I-23) can also be produced by reacting the compound (23-8) with the compound (23-9).

[0269] The compound represented by formula (2-1) can be produced, for example, according to the method described in Scheme 24.

[0270] The symbols in the formula have the same meanings as above. 24 is a protecting group.

[0271] Process 24-1 The compound (24-2) can also be produced by reacting the compound (17-1) with the compound (24-1) in the presence of a base.

[0272] Process 24-2 The compound (2-1k) can also be produced by subjecting the compound (24-2) to Curtius rearrangement reaction.

[0273] The compound of formula (I-25) can be produced, for example, according to the method described in Scheme 25.

[0274] The symbols in the formula have the same meanings as above. 25 , and R 25’ are each independently a halogen atom, cyano, hydroxy, C 1-6 Alkyl, HaloC 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, oxo, CONH2, CONH-(C 1-6 alkyl), or CONH-(C 3-8 cycloalkyl).

[0275] Process 25-1 The compound (I-25a) can also be produced by reacting the compound (2-2f) with the compound (25-1).

[0276] Process 25-2 The compound (25-2) can also be produced by reacting the compound (2-2f) with benzoyl isothiocyanate, followed by reaction with a base.

[0277] Process 25-3 Compound (I-25b) can also be produced by reacting compound (25-2) with methyl iodide and then with 2,2-diethoxyethan-1-amine, followed by reaction with an acid.

[0278] The compound represented by formula (2-1) can be produced, for example, according to the method described in Scheme 26.

[0279] The symbols in the formula have the same meanings as above. 26 is a chlorine atom, a bromine atom, or an iodine atom.

[0280] Process 26-1 The compound (26-2) can also be produced by reacting the compound (26-1) with the compound (7-2) in the presence of a base.

[0281] Process 26-2 The compound (26-3) can also be produced by subjecting the compound (26-2) to a Negishi coupling reaction with the compound (11-2).

[0282] Process 26-3 The compound (26-4) can also be produced by hydrolysis of the compound (26-3).

[0283] Process 26-4 The compound (26-5) can also be produced by amidation of the compound (26-4).

[0284] Process 26-5 The compound (26-6) can also be produced by catalytic reduction of the compound (26-5).

[0285] Process 26-6 The compound (2-1l) can also be produced by the Mizoroki-Heck cross-coupling reaction of the compound (26-6) and the compound (26-7).

[0286] Process 26-7 The compound (2-1m) can also be produced by catalytic reduction of the compound (2-1l).

[0287] The compounds represented by formula (2-2) and formula (11-3) can be produced, for example, according to the method described in Scheme 27.

[0288] The symbols in the formula have the same meanings as above. 27 , and P.G. 27’ are each independently a protecting group.

[0289] Process 27-1 Compound (27-2) can also be produced by removing one Boc group of compound (27-1).

[0290] Process 27-2 The compound (27-3) can also be produced by reacting the compound (27-2) with the compound (7-2) in the presence of a base.

[0291] Process 27-3 The compound (27-4) can also be produced by reducing the compound (27-3).

[0292] Process 27-4 The compound (27-5) can also be produced by reacting the compound (27-4) with methanesulfonyl chloride, followed by reaction with lithium bromide.

[0293] Process 27-5 Compound (27-7) can also be produced by asymmetric alkylation of compound (27-5) and compound (27-6).

[0294] Process 27-6 The compound (2-2g) can also be produced by reacting the compound (27-7) with an acid.

[0295] Process 27-7 The compound (27-8) can also be produced by reacting the compound (27-7) with an acid.

[0296] Process 27-8 The compound (11-3a) can also be produced by converting the amino group of the compound (27-8) to a -NHBoc group.

[0297] The compound of formula (27-1) can be produced, for example, according to the method described in Scheme 28.

[0298] The symbols in the formula have the same meanings as above. 28 is a chlorine atom, a bromine atom, or an iodine atom.

[0299] Process 28-1 The compound (28-3) can also be produced by subjecting the compound (28-1) and the compound (28-2) to a Negishi coupling reaction.

[0300] Process 28-2 The compound (27-1a) can also be produced by converting the amino group of the compound (28-3) to a -N(boc)2 group.

[0301] Process 28-3 The compound (27-1a) can also be produced by subjecting the compound (28-4) and the compound (28-5) to Suzuki-Miyaura cross-coupling reaction.

[0302] The compound represented by formula (2-1) can be produced, for example, according to the method described in Scheme 29.

[0303] The symbols in the formula have the same meanings as above. 29 is a protecting group.

[0304] Process 29-1 The compound (29-3) can also be produced by subjecting the compound (29-1) and the compound (29-2) to a Horner-Wadsworth-Emmons reaction.

[0305] Process 29-2 The compound (29-4) can also be produced by catalytic reduction of the compound (29-3).

[0306] Process 29-3 The compound (29-5) can also be produced by reacting the compound (29-4) with an acid.

[0307] Process 29-4 The compound (2-1n) can also be produced by reacting the compound (29-5) with the compound (7-2) in the presence of a base.

[0308] The compound of formula (29-1) can be produced, for example, according to the method described in Scheme 30.

[0309] The symbols in the formula have the same meanings as above. 30 is a protecting group.

[0310] Process 30-1 The compound (30-2) can also be produced by reacting the compound (30-1) with the compound (12-2).

[0311] Process 30-2 The compound (30-3) can also be produced by oxidation of the compound (30-2).

[0312] Process 30-3 The compound (29-1a) can also be produced by reacting the compound (30-3) with DMF in the presence of a base.

[0313] Process 30-4 The compound (30-5) can also be produced by subjecting the compound (30-4) and the compound (28-5) to Suzuki-Miyaura cross-coupling reaction.

[0314] Process 30-5 The compound (30-6) can also be produced by hydrolysis of the compound (30-5).

[0315] Process 30-6 The compound (30-7) can also be produced by subjecting the compound (30-6) to Curtius rearrangement reaction.

[0316] Process 30-7 The compound (30-8) can also be produced by removing the Boc group of the compound (30-7).

[0317] Process 30-8 Compound (30-9) can also be produced by bromination of compound (30-8).

[0318] Process 30-9 The compound (30-10) can also be produced by Suzuki-Miyaura cross-coupling reaction of the compound (30-9) with potassium vinyltrifluoroborate.

[0319] Process 30-10 The compound (30-11) can also be produced by converting the amino group of the compound (30-10) to a -NHBoc group.

[0320] Process 30-11 The compound (29-1b) can also be prepared by oxidative cleavage of the compound (30-11).

[0321] The compounds represented by Formulae (AI) to (AIII) or Formulae (I) to (I-D3) 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.

[0322] 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.

[0323] 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.

[0324] 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.

[0325] 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 one embodiment, the compounds of the present invention can be used to prevent the onset of thyroid eye disease in patients with Graves' disease.

[0326] 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)."

[0327] 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.

[0328] 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.

[0329] The pharmaceutical composition of the present invention comprises a compound represented by formula (AI) to (AIII) or formula (I) to (I-D3) or a pharmacologically acceptable salt thereof as an active ingredient.

[0330] The pharmaceutical compositions of the present invention are prepared using a compound represented by Formula (A-I) to (AIII) or Formula (I) to (I-D3) 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.

[0331] When the pharmaceutical composition of the present invention is used for treatment, the dosage of the compound represented by Formula (A-I) to (AIII) or Formula (I) to (I-D3) or a pharmacologically acceptable salt thereof is determined appropriately depending on the patient's age, sex, weight, disease, and degree of treatment. The daily dosage may be administered once, twice, three times, or four times. When administered orally, 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.

[0332] 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.

[0333] When a compound represented by Formulae (A-I) to (AIII), or Formulae (I) to (I-D3), 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 formulated separately, these preparations can be administered separately or simultaneously. In addition, the dosage of a compound represented by Formulae (A-I) to (AIII), or Formulae (I) to (I-D3), or a pharmacologically acceptable salt thereof, may be appropriately reduced depending on the dosage of the other drug used in combination.

[0334] The compounds represented by formulae (A-I) to (AIII) or (I) to (I-D3) may be appropriately converted into prodrugs for use. For example, prodrugs of the compounds represented by formulae (A-I) to (AIII) or (I) to (I-D3) 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.

[0335] 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.

[0336] 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.

[0337] Reference Example 1 1-Bromo-2-nitro-3-phenoxybenzene To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (4.01 g), phenol (1.89 g), and DMF (40 mL), potassium carbonate (10.1 g) was added at room temperature and stirred at 80°C for 6 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to give the title compound (5.58 g).

[0338] Reference Example 2 2-Bromo-6-phenoxyaniline To a mixture of Reference Example 1 (5.58 g), acetic acid (43 mL), and ethanol (43 mL), iron powder (3.05 g) was added at room temperature, and the mixture was stirred at 91°C for 11 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 94 / 6) to give the title compound (4.68 g).

[0339] Reference Example 3: Ethyl (E)-3-(2-amino-3-phenoxyphenyl)acrylate. A mixture of Reference Example 2 (1.11 g), ethyl acrylate (1.25 g), palladium(II) acetate (0.093 g), tris(2-methylphenyl)phosphine (0.255 g), TEA (2.11 g), and MeCN (21 mL) was stirred at 130°C for 1 hour under microwave irradiation. 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 86 / 14) to give the title compound (1.08 g). 1 H-NMR (CDCl3) δ ppm: 1.35 (3H, t, J=7.2 Hz), 4.21 (2H, br), 4.28 (2H, q, J=7.2 Hz), 6.40 (1H, d, J=16.0 Hz), 6.66-6.76 (1H, m), 6.86 (1H, dd, J=1.3, 7.8 Hz), 6.96-7.02 (2H, m), 7.06-7.13 (1H, m), 7.21 (1H, dd, J=1.3, 8.0 Hz), 7.29-7.37 (2H, m), 7.85 (1H, d, J=16.0 Hz)

[0340] Reference Example 4 8-phenoxy-3,4-dihydroquinolin-2(1H)-one Under an argon atmosphere, 10% Pd / C (0.199 g) was added to a mixture of Reference Example 3 (1.07 g) and methanol (15 mL) at room temperature, and the mixture was stirred at the same temperature under a hydrogen atmosphere for 7.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. A mixture of the residue and ethanol (15 mL) was stirred at 83°C for 15 hours. Lithium hydroxide monohydrate (0.159 g) was added to the reaction mixture, and the mixture was stirred at 83°C for 40 minutes. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and water were added to the residue, and the aqueous layer was separated. 2 mol / L hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The combined organic layers were 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 55 / 45) to obtain the title compound (0.803 g).

[0341] Reference Example 5 6-Bromo-1-methyl-8-phenoxy-3,4-dihydroquinolin-2(1H)-one To a mixture of Reference Example 4 (0.108 g) and DMF (3.0 mL), NBS (0.096 g) was added at 50°C and stirred at the same temperature for 1 hour. The reaction mixture was allowed to cool to room temperature, and then saturated aqueous sodium sulfite solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a mixture of the residue and DMF (3.0 mL), methyl iodide (0.128 g) and sodium hydride (approximately 60%) (0.023 g) were added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Ice was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=74 / 26 to 45 / 55) to obtain the title compound (0.147 g). 1 H-NMR (CDCl3) δ ppm: 2.55-2.67 (2H, m), 2.82-2.93 (2H, m), 3.36 (3H, s), 6.85-7.04 (3H, m), 7.05-7.19 (2H, m), 7.28-7.41 (2H, m)

[0342] Reference Example 6 6-((diphenylmethylene)amino)-1-methyl-8-phenoxy-3,4-dihydroquinolin-2(1H)-one Under an argon atmosphere, a mixture of Reference Example 5 (0.104 g), benzophenone imine (0.085 g), tris(dibenzylideneacetone)dipalladium(0) (0.029 g), Xantphos (0.036 g), sodium tert-butoxide (0.060 g), and toluene (3.0 mL) was stirred at 90°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and 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 = 65 / 35 to 26 / 74) to give the title compound (0.122 g).

[0343] Reference Example 7: tert-Butyl 6-((diphenylmethylene)amino)-1-methyl-2-oxo-8-phenoxy-1,2,3,4-tetrahydroquinoline-3-carboxylate. To a mixture of Reference Example 6 (0.054 g) and THF (1.0 mL), LDA (1.09 mol / L in THF / n-hexane) (0.171 mL) was added at -78°C, and the mixture was stirred at the same temperature for 30 minutes. A mixture of BocO (0.054 g) and THF (0.3 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 30 minutes. A saturated aqueous ammonium chloride solution 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 silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 51 / 49) to give the title compound (0.039 g).

[0344] Reference Example 8: tert-Butyl 6-amino-1-methyl-2-oxo-8-phenoxy-1,2,3,4-tetrahydroquinoline-3-carboxylate. Hydroxylammonium chloride (0.015 g) and sodium acetate (0.015 g) were added to a mixture of Reference Example 7 (0.039 g) and methanol (1.0 mL) at room temperature, followed by stirring at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was 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 the title compound (0.027 g).

[0345] Reference Example 9 tert-butyl 2-(6-((diphenylmethylene)amino)-1-methyl-2-oxo-8-phenoxy-1,2,3,4-tetrahydroquinolin-3-yl)acetate Reference Example 9 was synthesized in the same manner as in Reference Example 7, except that tert-butyl bromoacetate was used instead of Boc2O.

[0346] Reference Example 10 tert-butyl 2-(6-amino-1-methyl-2-oxo-8-phenoxy-1,2,3,4-tetrahydroquinolin-3-yl)acetate Reference Example 10 was synthesized in the same manner as in Reference Example 8, using Reference Example 9 instead of Reference Example 7.

[0347] Reference Example 11: 6-nitro-2-oxo-1,2,3,4-tetrahydroquinolin-8-yl acetate. A mixture of 8-hydroxy-3,4-dihydroquinolin-2(1H)-one (2.98 g), acetic anhydride (15 mL), and concentrated sulfuric acid (0.090 g) was stirred at 80° C. for 2 hours. To the reaction mixture, acetic acid (15 mL) and concentrated nitric acid (1.5 mL) were added under ice-cooling, and the mixture was stirred under ice-cooling for 10 minutes and at room temperature for 1 hour. Water was added to the reaction mixture under ice-cooling, and the mixture was stirred under ice-cooling for 10 minutes. The insoluble matter was collected by filtration, and the resulting solid was washed with water and then dried under reduced pressure to give the title compound (4.57 g).

[0348] Reference Example 12 8-Hydroxy-6-nitro-3,4-dihydroquinolin-2(1H)-one Potassium carbonate (3.03 g) was added to a mixture of Reference Example 11 (4.57 g), methanol (48 mL), and water (9.0 mL) at room temperature, followed by stirring at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Water, 1 mol / L hydrochloric acid (36.5 mL), and methanol (3.0 mL) were added to the residue, followed by stirring at room temperature for 30 minutes. Insoluble matter was collected by filtration, and the resulting solid was washed with water and then dried under reduced pressure to give the title compound (3.40 g).

[0349] Reference Example 13 8-((tert-butyldimethylsilyl)oxy)-6-nitro-3,4-dihydroquinolin-2(1H)-one Imidazole (1.31 g) and TBSCl (1.74 g) were added to a mixture of Reference Example 12 (2.0 g) and DMF (20 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. TBSCl (0.724 g) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 1 hour and at 40° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, and then saturated aqueous ammonium chloride solution and water were added, 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 n-hexane and then dried under reduced pressure to obtain the title compound (2.10 g).

[0350] Reference Example 14: 8-Hydroxy-1-methyl-6-nitro-3,4-dihydroquinolin-2(1H)-one. To a mixture of Reference Example 13 (2.88 g), methyl iodide (1.90 g), and DMF (30 mL), sodium hydride (approximately 60%) (0.714 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was suspended in n-hexane / ethyl acetate (3 / 1), and insoluble matter was collected by filtration. The resulting solid was dried under reduced pressure to give the title compound (1.28 g).

[0351] Reference Example 15: 6-Amino-8-hydroxy-1-methyl-3,4-dihydroquinolin-2(1H)-one. Nickel(II) bromide (0.126 g) and sodium borohydride (0.654 g) were added to a mixture of Reference Example 14 (1.28 g), THF (25 mL), and methanol (25 mL) under ice-cooling, and the mixture was stirred for 1 hour under ice-cooling. Saturated aqueous ammonium chloride solution, water, and ethyl acetate were added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 48.5 / 48.5 / 3 to 0 / 97 / 3) to give the title compound (0.950 g).

[0352] Reference Example 16: 6-(2,5-Dimethyl-1H-pyrrol-1-yl)-8-hydroxy-1-methyl-3,4-dihydroquinolin-2(1H)-one. Using an apparatus equipped with a Dean-Stark tube, a mixture of Reference Example 15 (0.950 g), acetonylacetone (0.733 g), p-toluenesulfonic acid monohydrate (0.470 g), and toluene (50 mL) was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100) to give the title compound (0.610 g).

[0353] Reference Example 17 2-((6-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-8-yl)oxy)benzonitrile To a mixture of Reference Example 16 (0.300 g), 2-fluorobenzonitrile (0.202 g), and NMP (3.0 mL), potassium carbonate (0.460 g) was added at room temperature, and the mixture was stirred at 100° C. for 10 hours. The reaction mixture was allowed to cool to room temperature, and water and ethyl acetate were added, and the mixture was extracted with n-hexane / ethyl acetate (1 / 3). 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 = 80 / 20 to 30 / 70) to give the title compound (0.300 g).

[0354] Reference Example 18 tert-butyl 2-(8-(2-cyanophenoxy)-6-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate Reference Example 18 was synthesized in the same manner as in Reference Example 7, using Reference Example 17 instead of Reference Example 6 and tert-butyl bromoacetate instead of BocO.

[0355] Reference Example 19: Ethyl 2-(6-amino-8-(2-cyanophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate A mixture of Reference Example 18 (0.140 g), concentrated hydrochloric acid (0.481 mL), and ethanol (3.0 mL) was refluxed for 1 hour. Hydroxylamine hydrochloride (0.200 g) was added to the reaction mixture, and the mixture was refluxed for 1 hour. Under ice-cooling, 2 mol / L aqueous sodium hydroxide solution (4.5 mL) 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 by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 20 / 80) to obtain the title compound (0.060 g).

[0356] Reference Example 20: tert-Butyl (8-(2-cyanophenoxy)-6-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate. To a mixture of Reference Example 17 (0.250 g) and THF (2.0 mL), LDA (1.08 mol / L in THF / n-hexane) (1.56 mL) was added at -78°C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, a mixture of DPPA (0.463 g) and THF (1.0 mL) was added at -78°C, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, a mixture of BocO (0.294 g) and THF (1.0 mL) was added at -78°C, and the mixture was stirred at the same temperature for 30 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 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 Method A (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 50 / 50) to obtain the title compound (0.130 g).

[0357] Reference Example 21: tert-Butyl (6-amino-8-(2-cyanophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate. A mixture of Reference Example 20 (0.120 g), hydroxylamine hydrochloride (0.171 g), ethanol (1.0 mL), and water (0.5 mL) was stirred at 100°C for 4 hours. Hydroxylamine hydrochloride (0.514 g) and water (0.5 mL) were added to the reaction mixture, and the mixture was stirred at 100°C for 8 hours. Under ice-cooling, 2 mol / L aqueous sodium hydroxide solution (5.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue and THF (2.0 mL), BocO (0.081 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Methanol was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 20 / 80) to give the title compound (0.070 g).

[0358] Reference Example 22 6-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-8-((6-(trifluoromethyl)pyridin-2-yl)oxy)-3,4-dihydroquinolin-2(1H)-one Reference Example 22 was synthesized in the same manner as in Reference Example 17, using 2-chloro-6-(trifluoromethyl)pyridine instead of 2-fluorobenzonitrile.

[0359] Reference Example 23 tert-butyl (6-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-2-oxo-8-((6-(trifluoromethyl)pyridin-2-yl)oxy)-1,2,3,4-tetrahydroquinolin-3-yl)carbamate Reference Example 23 was synthesized in the same manner as in Reference Example 20 using Reference Example 22 instead of Reference Example 17.

[0360] Reference Example 24 tert-butyl (6-amino-1-methyl-2-oxo-8-((6-(trifluoromethyl)pyridin-2-yl)oxy)-1,2,3,4-tetrahydroquinolin-3-yl)carbamate Reference Example 24 was synthesized in the same manner as in Reference Example 21 using Reference Example 23 instead of Reference Example 20.

[0361] Reference Example 25: 1-methyl-8-phenoxy-3,4-dihydroquinolin-2(1H)-one. To a mixture of Reference Example 4 (0.170 g), methyl iodide (0.202 g), and THF (2.0 mL), sodium hydride (approximately 60%) (0.037 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Ice 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 silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 74 / 26 to 57 / 43) to give the title compound (0.178 g).

[0362] Reference Example 26 tert-Butyl 1-methyl-2-oxo-8-phenoxy-1,2,3,4-tetrahydroquinoline-3-carboxylate Reference Example 26 was synthesized in the same manner as in Reference Example 7, except for using Reference Example 25 instead of Reference Example 6.

[0363] Reference Example 27 1-methyl-2-oxo-8-phenoxy-1,2,3,4-tetrahydroquinoline-3-carboxylic acid A mixture of Reference Example 26 (0.237 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (2.0 mL) was stirred at room temperature for 30 minutes and then at 50° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure to obtain the title compound (0.216 g).

[0364] Reference Example 28: 3-(hydroxymethyl)-1-methyl-8-phenoxy-3,4-dihydroquinolin-2(1H)-one. To a mixture of Reference Example 27 (0.050 g), N-methylmorpholine (0.020 g), and THF (1.0 mL), isobutyl chloroformate (0.025 g) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, and sodium borohydride (0.013 g) was added to the filtrate under ice-cooling, and the mixture was stirred at room temperature for 1 hour. 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 by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give the title compound (0.025 g).

[0365] Reference Example 29: (1-methyl-2-oxo-8-phenoxy-1,2,3,4-tetrahydroquinolin-3-yl)methyl methanesulfonate. To a mixture of Reference Example 28 (0.025 g), TEA (0.012 g), and THF (1.0 mL), methanesulfonyl chloride (0.012 g) was added under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with MTBE. The extract was washed with water, 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 0 / 100) to give the title compound (0.008 g).

[0366] Reference Example 30: 3-(aminomethyl)-1-methyl-8-phenoxy-3,4-dihydroquinolin-2(1H)-one. A mixture of Reference Example 29 (0.008 g), sodium azide (0.007 g), and DMF (1.0 mL) was stirred at 50° C. for 3 hours. After the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with MTBE. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3-(azidomethyl)-1-methyl-8-phenoxy-3,4-dihydroquinolin-2(1H)-one (0.008 g). A mixture of the obtained compound (0.006 g), 10% Pd / C (0.010 g), and methanol (1.0 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 to give the title compound (0.006 g).

[0367] Reference Example 31 (2-Amino-3-bromophenyl)(2-chlorophenyl)methanol To a mixture of 1-chloro-2-iodobenzene (0.680 g) and THF (3.0 mL), isopropylmagnesium chloride (2 mol / L in THF) (1.43 mL) was added at -40°C and stirred for 30 minutes under ice-cooling. To the reaction mixture, a mixture of 3-bromo-2-nitrobenzaldehyde (0.328 g) and THF (3.0 mL) was added at -40°C and stirred at the same temperature for 10 minutes and then under ice-cooling for 1 hour. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a mixture of the residue, ethanol (3.0 mL), and water (1.0 mL), iron powder (0.399 g) and ammonium chloride (1.91 g) were added and stirred at 80°C for 1.5 hours. The reaction mixture was allowed to cool to room temperature and then filtered through Celite. 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. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 65 / 35) to give the title compound (0.375 g).

[0368] Reference Example 32 (2-Amino-3-bromophenyl)(2-chlorophenyl)methanone Manganese dioxide (IV) (0.278 g) was added to a mixture of Reference Example 31 (0.200 g) and DCM (5.0 mL) at room temperature, and the mixture was stirred at 50°C for 2 hours and at room temperature for 10 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 75 / 25) to give the title compound (0.171 g).

[0369] Reference Example 33: (3-Bromo-2-(methylamino)phenyl)(2-chlorophenyl)methanone. To a mixture of Reference Example 32 (0.171 g) and ethyl acetate (2.0 mL), pyridine (0.057 g) and trifluoroacetic anhydride (0.150 g) were added under ice-cooling, followed by stirring at room temperature for 30 minutes. Pyridine (0.057 g) and trifluoroacetic anhydride (0.150 g) were added to the reaction mixture, followed by stirring at room temperature for 30 minutes. Pyridine (0.057 g) and trifluoroacetic anhydride (0.150 g) were added to the reaction mixture, followed by stirring 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 saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a mixture of the residue and DMF (1.5 mL), methyl iodide (0.117 g) and potassium carbonate (0.152 g) were added at room temperature, followed by stirring at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a mixture of the residue, methanol (1.5 mL), and THF (1.5 mL), 5 mol / L aqueous sodium hydroxide solution (0.220 mL) was 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 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 = 100 / 0 to 85 / 15) to give the title compound (0.148 g).

[0370] Reference Example 34: (R)-3-Amino-8-(2-chlorobenzoyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one. To a mixture of zinc powder (0.066 g) and DMF (0.6 mL), a mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.225 g) and THF (0.3 mL) was added under water cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, a mixture of Reference Example 33 (0.148 g) and THF (0.6 mL), palladium(II) acetate (0.005 g), and Xphos (0.022 g) were added, and the mixture was stirred under an argon atmosphere at 40°C for 2 hours and then at room temperature overnight. 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 (0.45 mL), and toluene (0.7 mL), methanesulfonic acid (0.131 g) was added at room temperature, and the mixture was stirred at 70°C for 3 hours. The reaction mixture was allowed to cool to room temperature, and then ethyl acetate and water were added, 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 saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.050 g).

[0371] Reference Example 35: 1-(2-Amino-3-bromophenyl)-1-(2-chlorophenyl)ethan-1-ol. Under an argon atmosphere, methylmagnesium bromide (3 mol / L in EtO) (0.521 mL) was added to a mixture of Reference Example 32 (0.231 g) and EtO (2.5 mL) under ice-cooling, and the mixture was stirred for 15 minutes under ice-cooling and then at room temperature for 1 hour. Saturated aqueous ammonium chloride and water were 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 (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to give the title compound (0.247 g).

[0372] Reference Example 36: 2-Bromo-6-(1-(2-chlorophenyl)vinyl)aniline To a mixture of Reference Example 35 (0.195 g) and DCE (3.0 mL), BF3-Et2O (0.127 g) and triethylsilane (0.174 g) were added at room temperature, and the mixture was stirred at 70°C for 2 hours and at 50°C for 15 hours. A 5 mol / L aqueous sodium hydroxide solution (0.180 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 silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to give the title compound (0.171 g).

[0373] Reference Example 37: 2-Bromo-6-(1-(2-chlorophenyl)vinyl)-N-methylaniline. To a mixture of Reference Example 36 (0.171 g) and THF (1.7 mL), methyllithium (1.04 mol / L in EtO) (0.585 mL) was added at -78°C, and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (0.094 g) 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 1.5 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to give the title compound (0.168 g).

[0374] Reference Example 38: (R)-3-Amino-8-(1-(2-chlorophenyl)vinyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one. Under an argon atmosphere, a mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.257 g) and DMF (0.35 mL) was added to a mixture of zinc powder (0.075 g) and DMF (0.7 mL), and the mixture was stirred at room temperature for 1 hour. A mixture of Reference Example 37 (0.168 g) and DMF (0.7 mL), palladium(II) acetate (0.006 g), and Xphos (0.025 g) were added to the reaction mixture at room temperature, and the mixture was stirred at 40° C. for 2 hours and then at room temperature for 15 hours. A saturated aqueous ammonium chloride solution, water, 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. Methanesulfonic acid (0.104 g) was added to a mixture of the residue, ethanol (0.6 mL), and toluene (0.8 mL) at room temperature, and the mixture was stirred at 80°C for 30 minutes. A 5 mol / L aqueous sodium hydroxide solution (0.217 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 using Method A (elution solvent: ethyl acetate / methanol = 98 / 2 to 80 / 20) to obtain the title compound (0.024 g).

[0375] Reference Example 39: 4-chloro-2-(2-phenylpropan-2-yl)aniline. Trifluoromethanesulfonic acid (0.151 g) was added to a mixture of 4-chloroaniline (0.640 g) and prop-1-en-2-ylbenzene (0.593 g), and the mixture was stirred at 160°C for 8 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with DCM. The extract was 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 (0.750 g).

[0376] Reference Example 40: 2-Bromo-4-chloro-6-(2-phenylpropan-2-yl)aniline. To a mixture of Reference Example 39 (0.750 g) and DMF (7.0 mL), NBS (0.652 g) was added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. Saturated aqueous sodium bicarbonate, 1 mol / L aqueous sodium thiosulfate, and n-hexane were 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 by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 98 / 2 to 90 / 10) to give the title compound (0.640 g).

[0377] Reference Example 41 2-Bromo-4-chloro-N-methyl-6-(2-phenylpropan-2-yl)aniline Reference Example 41 was synthesized in the same manner as in Reference Example 37, using Reference Example 40 instead of Reference Example 36.

[0378] Reference Example 42: (E)-3-(5-chloro-2-(methylamino)-3-(2-phenylpropan-2-yl)phenyl)benzyl acrylate. Palladium(II) acetate (0.023 g) was added to a mixture of Reference Example 41 (0.340 g), tris(2-methylphenyl)phosphine (0.061 g), TEA (0.406 g), benzyl acrylate (0.326 g), and MeCN (3.0 mL), and the mixture was stirred at 130°C for 1 hour under microwave irradiation. 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 90 / 10) to give the title compound (0.240 g). 1 H-NMR (CDCl3) δ ppm: 1.64 (6H, s), 2.19 (3H, d, J=5.6 Hz), 3.01 (1H, q, J=5.6 Hz), 5.21 (2H, s), 6.33 (1H, d, J=16.0 Hz), 7.17-7.51 (12H, m), 7.79 (1H, d, J=16.0 Hz)

[0379] Reference Example 43: 1-methyl-8-(2-phenylpropan-2-yl)-3,4-dihydroquinolin-2(1H)-one. To a mixture of Reference Example 42 (0.240 g), THF (3.0 mL), and methanol (5.0 mL), 10% Pd / C (0.100 g) was added and stirred at 50°C under a hydrogen atmosphere for 2 hours. The reaction mixture was allowed to cool to room temperature and then filtered through Celite. The filtrate was concentrated under reduced pressure. To a mixture of the residue, HATU (0.326 g), and DMF (3.0 mL), DIPEA (0.222 g) was added at room temperature and stirred at the same temperature for 12 hours. Saturated aqueous ammonium chloride and n-hexane were 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=95 / 5 to 70 / 30) to obtain the title compound (0.110 g).

[0380] Reference Example 44: 6-chloro-2,2,4-trimethyl-1,2-dihydroquinoline. To a mixture of 4-chloroaniline (2.00 g) and acetone (20 mL), bismuth(III) trifluoromethanesulfonate (1.20 g) was added and refluxed overnight. 1 mol / L hydrochloric acid and ethyl acetate were added to the reaction mixture, and the mixture was filtered through Celite. Saturated brine was added to the filtrate, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 95 / 5) to obtain the title compound (1.02 g).

[0381] Reference Example 45: 6-chloro-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinoline. To a mixture of Reference Example 44 (1.02 g) and benzene (15 mL), aluminum chloride (III) (1.96 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour and at 60°C overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to give the title compound (0.419 g).

[0382] Reference Example 46 8-Bromo-6-chloro-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinoline Reference Example 46 was synthesized in the same manner as in Reference Example 40, except for using Reference Example 45 instead of Reference Example 39.

[0383] Reference Example 47 Methyl (2R)-2-amino-3-(6-chloro-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-8-yl)propanoate Reference Example 47 was synthesized in the same manner as in Reference Example 38 using Reference Example 46 instead of Reference Example 37.

[0384] Reference Example 48: Methyl (2R)-2-((tert-butoxycarbonyl)amino)-3-(6-chloro-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-8-yl)propanoate. To a mixture of Reference Example 47 (0.070 g) and DCM (1.0 mL), BocO (0.059 g) was added at room temperature, followed by stirring at the same temperature for 2 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 by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to obtain the title compound (0.122 g).

[0385] Reference Example 49 (2R)-2-((tert-butoxycarbonyl)amino)-3-(6-chloro-2,2,4-trimethyl-4-phenyl-1,2,3,4-tetrahydroquinolin-8-yl)propanoic acid To a mixture of Reference Example 48 (0.114 g), methanol (0.3 mL), and THF (0.3 mL), 4 mol / L aqueous lithium hydroxide solution (0.125 mL) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. 2 mol / L hydrochloric acid (0.251 mL) 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 = 70 / 30 to 0 / 100) to obtain the title compound (0.080 g).

[0386] Reference Example 50 (E)-N,3-Diphenylbut-2-enamide A mixture of (E)-3-phenylbut-2-enoic acid (1.15 g), aniline (0.759 g), HATU (3.24 g), DIPEA (0.916 g), and DCM (40 mL) was stirred at room temperature overnight. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate, water, and saturated brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 75 / 25) to give the title compound (1.42 g).

[0387] Reference Example 51: 4-Methyl-4-phenyl-1,2,3,4-tetrahydroquinoline. A mixture of Reference Example 50 (1.42 g) and concentrated sulfuric acid (13.5 mL) was stirred at room temperature for 30 minutes. Ice and water were added to the reaction mixture, and the mixture was stirred for 30 minutes. The insoluble matter was filtered off, and the resulting solid was washed with water and then dissolved in ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4-methyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one (1.08 g). Under an argon atmosphere, BH3-THF (0.89 mol / L in THF) (4.67 mL) was added to a mixture of the resulting compound (0.329 g) and THF (5.5 mL) at room temperature, and the mixture was stirred at the same temperature for 20 minutes and at 65°C for 3 hours. To the reaction mixture, 2 mol / L hydrochloric acid (1.90 mL) was added under ice cooling and stirred at room temperature for 30 minutes. To the reaction mixture, 2 mol / L aqueous sodium hydroxide solution (1.90 mL) 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 APS column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain the title compound (0.115 g).

[0388] Reference Example 52 6-chloro-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinoline Reference Example 52 was synthesized in the same manner as in Reference Example 40, except for using Reference Example 51 instead of Reference Example 39 and NCS instead of NBS. 1 H-NMR (CDCl3) δ ppm: 1.72 (3H, s), 1.90-2.03 (1H, m), 2.08-2.23 (1H, m), 2.93-3.09 (1H, m), 3.15-3.31 (1H, m), 3.95 (1H, br), 6.46 (1H, d, J=8.4 Hz), 6.86-7.03 (2H, m), 7.08-7.22 (3H, m), 7.23-7.36 (2H, m)

[0389] Reference Example 53 8-Bromo-6-chloro-4-methyl-4-phenyl-1,2,3,4-tetrahydroquinoline Reference Example 53 was synthesized in the same manner as in Reference Example 40, except for using Reference Example 52 instead of Reference Example 39.

[0390] Reference Example 54 (6R)-6-amino-9-chloro-1-methyl-1-phenyl-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one Reference Example 54 was synthesized in the same manner as in Reference Example 38 using Reference Example 53 instead of Reference Example 37.

[0391] Reference Example 55: 4-Chloro-2-(1-phenylvinyl)aniline. Under an argon atmosphere, potassium hexamethyldisilazide (1 mol / L in THF) (16.5 mL) was added to a mixture of methyltriphenylphosphonium bromide (6.20 g) and THF (20 mL) at room temperature, and the mixture was stirred at the same temperature for 45 minutes. A mixture of (2-amino-5-chlorophenyl)(phenyl)methanone (2.01 g) and THF (6.9 mL) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 45 minutes. Saturated aqueous ammonium chloride and water were added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 70 / 30) to give the title compound (2.06 g).

[0392] Reference Example 56: 6-chloro-2,2-dimethyl-4-phenyl-1,2-dihydroquinoline. A mixture of Reference Example 55 (2.06 g), BF-EtO (0.122 g), acetone (6.3 mL), and toluene (18 mL) was stirred at 140°C for 10 hours under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to give the title compound (2.19 g).

[0393] Reference Example 57: tert-Butyl 6-chloro-2,2-dimethyl-4-phenylquinoline-1(2H)-carboxylate. To a mixture of Reference Example 56 (1.37 g) and THF (13 mL), n-butyllithium (1.57 mol / L in n-hexane) (3.87 mL) was added at -78°C and stirred at the same temperature for 30 minutes. To the reaction mixture, a mixture of BocO (1.66 g) and THF (2.6 mL) was added at -78°C and 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 n-hexane. 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 = 95 / 5) to give the title compound (1.65 g).

[0394] Reference Example 58: tert-Butyl 6-chloro-3-hydroxy-2,2-dimethyl-4-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate. To a mixture of Reference Example 57 (1.65 g) and THF (23 mL), BH3-THF (0.89 mol / L in THF) (15.0 mL) was added under ice-cooling under an argon atmosphere. The mixture was stirred for 45 minutes under ice-cooling, 45 minutes at room temperature, and 5 hours at 35°C. THF (7.7 mL), water (7.7 mL), 5 mol / L aqueous sodium hydroxide solution (6.24 mL), and 30% aqueous hydrogen peroxide (1.37 mL) were added under ice-cooling, and the mixture was stirred for 16 hours at room temperature. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=98 / 2 to 85 / 15) to obtain the title compound (0.856 g).

[0395] Reference Example 59: tert-Butyl 6-chloro-2,2-dimethyl-3-oxo-4-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate. Under an argon atmosphere, DMP (1.12 g) was added to a mixture of Reference Example 58 (0.856 g) and DCM (9.0 mL) under ice-cooling, and the mixture was stirred for 40 minutes under ice-cooling. A 1 mol / L aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution, 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 85 / 15) to give the title compound (0.581 g).

[0396] Reference Example 60: tert-Butyl 6-chloro-2,2,4-trimethyl-3-oxo-4-phenyl-3,4-dihydroquinoline-1(2H)-carboxylate. Under an argon atmosphere, sodium hydride (approximately 60%) (0.090 g) was added to a mixture of Reference Example 59 (0.580 g), methyl iodide (1.07 g), and DMF (7.3 mL) under ice-cooling, and the mixture was stirred for 30 minutes 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 silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to give the title compound (0.522 g).

[0397] Reference Example 61: 6-chloro-2,2,4-trimethyl-4-phenyl-1,4-dihydroquinolin-3(2H)-one. To a mixture of Reference Example 60 (0.521 g) and DCM (7.0 mL), TFA (5.18 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture under ice-cooling, 2 mol / L aqueous sodium hydroxide solution (25 mL) 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: n-hexane / ethyl acetate = 98 / 2 to 90 / 10) to obtain the title compound (0.369 g).

[0398] Reference Example 62 8-bromo-6-chloro-2,2,4-trimethyl-4-phenyl-1,4-dihydroquinolin-3(2H)-one Reference Example 62 was synthesized in the same manner as in Reference Example 40, using Reference Example 61 instead of Reference Example 39.

[0399] Reference Example 63: Methyl (2R)-2-((tert-butoxycarbonyl)amino)-3-(6-chloro-2,2,4-trimethyl-3-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-8-yl)propanoate. Under an argon atmosphere, a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.261 g) and DMF (0.35 mL) was added to a mixture of zinc powder (0.076 g) and DMF (0.7 mL), and the mixture was stirred at room temperature for 1 hour. A mixture of Reference Example 62 (0.200 g) and DMF (0.7 mL), palladium(II) acetate (0.006 g), and Xphos (0.025 g) was added to the reaction mixture at room temperature, and the mixture was stirred at 40° C. for 2 hours and then allowed to stand at the same temperature for 13 hours. To the reaction mixture, saturated aqueous ammonium chloride solution, water, and n-hexane / ethyl acetate (1 / 1) were added 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. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 98 / 2 to 70 / 30) to give the title compound (0.103 g).

[0400] Reference Example 64 (2R)-2-((tert-butoxycarbonyl)amino)-3-(6-chloro-2,2,4-trimethyl-3-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-8-yl)propanoic acid Reference Example 64 was synthesized in the same manner as in Reference Example 49 using Reference Example 63 instead of Reference Example 48.

[0401] Reference Example 65: 2-(benzyloxy)-6-bromoaniline To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.500 g), benzyl alcohol (0.258 g), and DMF (3.0 mL), potassium carbonate (0.628 g) was added at room temperature, and the mixture was stirred at 110°C for 4 hours, at room temperature for 12 hours, and at 110°C for 10 hours. After the reaction mixture was allowed to cool to room temperature, water and n-hexane were added, 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. A mixture of the residue, iron powder (0.635 g), ammonium chloride (3.04 g), water (2.0 mL), and ethanol (6.0 mL) was stirred at 80°C for 2 hours. After the reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer 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=98 / 2 to 80 / 20) to obtain the title compound (0.365 g).

[0402] Reference Example 66 2-(benzyloxy)-6-bromo-N-methylaniline Reference Example 66 was synthesized in the same manner as in Reference Example 33, except for using Reference Example 65 instead of Reference Example 32.

[0403] Reference Example 67 (R)-3-amino-8-(benzyloxy)-1-methyl-3,4-dihydroquinolin-2(1H)-one Reference Example 67 was synthesized in the same manner as in Reference Example 38, using Reference Example 66 instead of Reference Example 37.

[0404] Reference Example 68: 6-Bromo-2-(2-chloro-5-fluorophenoxy)-3-methylaniline To a mixture of 1-bromo-3-fluoro-4-methyl-2-nitrobenzene (0.305 g), 2-chloro-5-fluorophenol (0.200 g), and DMF (10 mL), potassium carbonate (0.360 g) was added and stirred at 100°C for 2 hours. The reaction mixture was allowed to cool to room temperature, and then water, ethyl acetate, and toluene were added, and the organic layer was separated. The organic layer 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 = 100 / 0 to 55 / 45) to give 1-bromo-3-(2-chloro-5-fluorophenoxy)-4-methyl-2-nitrobenzene (0.439 g). To a mixture of the obtained compound (0.439 g), ethanol (4.5 mL), and water (1.5 mL), ammonium chloride (1.74 g) and iron powder (0.362 g) were added and stirred at 80°C for 1.5 hours. The reaction mixture was allowed to cool to room temperature and then filtered through Celite. Water was added to the filtrate, 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 = 100 / 0 to 70 / 30) to obtain the title compound (0.355 g).

[0405] Reference Example 69: 6-Bromo-2-(2-chloro-5-fluorophenoxy)-N,3-dimethylaniline. To a mixture of Reference Example 68 (0.355 g) and THF (3.0 mL), methyllithium (1.04 mol / L in EtO) (1.3 mL) was added at -78°C, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, a mixture of methyl iodide (0.214 g) and THF (1.5 mL) was added at -78°C, and the mixture was stirred under ice-cooling for 2 hours. Saturated aqueous ammonium chloride and water were added to the reaction mixture under water-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain the title compound (0.349 g).

[0406] Reference Example 70: (3R)-3-Amino-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-1,2,3,4-tetrahydroquinolin-2-one. Under an argon atmosphere, zinc powder (0.141 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.393 g) and DMF (3.0 mL), and the mixture was stirred at room temperature for 1.5 hours. A mixture of Reference Example 69 (0.338 g) and DMF (1.0 mL), palladium(II) acetate (0.012 g), and Xphos (0.047 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 13 hours. A saturated aqueous ammonium chloride solution, water, and ethyl acetate were added to the reaction mixture. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and then concentrated under reduced pressure. To a mixture of the residue and DCM (4.0 mL), TFA (2.24 g) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture, 5 mol / L aqueous sodium hydroxide solution (3.9 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 = 50 / 50 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to obtain the title compound (0.135 g).

[0407] Reference Example 71: 3-(2-chloro-5-fluorophenoxy)-4-methyl-2-(methylamino)benzaldehyde. Under an argon atmosphere, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride dichloromethane adduct (0.474 g) was added to a mixture of Reference Example 69 (2.00 g), sodium carbonate (0.923 g), triethylsilane (1.35 g), and NMP (10 mL). The mixture was stirred at 100°C for 3 hours under a carbon monoxide atmosphere. The reaction mixture was allowed to cool to room temperature, and water and n-hexane were added. The mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to give the title compound (1.40 g).

[0408] Reference example 72 (2R* ,3S * )-2-(((benzyloxy)carbonyl)amino)-3-(3-(2-chloro-5-fluorophenoxy)-4-methyl-2-(methylamino)phenyl)-3-hydroxypropanoate To a mixture of ethyl((benzyloxy)carbonyl)glycine (0.363 g) and THF (3.0 mL), LDA (1.07 mol / L in THF / n-hexane) (2.50 mL) was added at -78°C, and the reaction mixture was stirred at the same temperature for 1 hour. A mixture of Reference Example 71 (0.750 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 30 minutes and then under ice-cooling for 1 hour. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=95 / 5 to 60 / 40) to obtain the title compound (0.090 g).

[0409] Reference Example 73: 2-Bromo-6-(2-chloro-5-fluorophenoxy)aniline To a mixture of 1-bromo-3-fluoro-2-nitrobenzene (0.300 g), 2-chloro-5-fluorophenol (0.220 g), and DMF (10 mL), potassium carbonate (0.377 g) was added and stirred at 100°C for 1 hour. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with EtO. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a mixture of the residue, ethanol (9.0 mL), and water (3.0 mL), ammonium chloride (1.46 g) and iron powder (0.777 g) were added and stirred at 90°C for 1 hour. The reaction mixture was allowed to cool to room temperature and then filtered through Celite. The filtrate was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=100 / 0 to 75 / 25) to obtain the title compound (0.417 g).

[0410] Reference Example 74: 2-Bromo-6-(2-chloro-5-fluorophenoxy)-N-methylaniline. To a mixture of Reference Example 73 (0.417 g) and THF (7.0 mL), methyllithium (1.06 mol / L in EtO) (1.37 mL) was added at -78°C, and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (0.224 g) 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 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. 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 = 100 / 0 to 77 / 23) to give the title compound (0.436 g).

[0411] Reference Example 75: (3R)-3-Amino-8-(2-chloro-5-fluorophenoxy)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one. Under an argon atmosphere, zinc powder (0.215 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.650 g) and DMF (7.0 mL), and the mixture was stirred at room temperature for 2 hours. A mixture of Reference Example 74 (0.435 g) and DMF (1.0 mL), palladium(II) acetate (0.015 g), and Xphos (0.063 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (4.0 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the residue, and the organic layer was separated. The organic layer was washed with water and then concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 71 / 29) to give the title compound (0.198 g).

[0412] Reference Example 76: 1-(2-chloro-5-fluorophenoxy)-3-methyl-2-nitrobenzene. To a mixture of 1-fluoro-3-methyl-2-nitrobenzene (0.730 g), 2-chloro-5-fluorophenol (0.724 g), and DMF (4.7 mL), potassium carbonate (0.976 g) was added at room temperature, and the mixture was stirred at 60°C for 1 hour and at 100°C for 68 hours. After the reaction mixture was allowed to cool to room temperature, 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 85 / 15) to give the title compound (1.26 g).

[0413] Reference Example 77: 8-(2-chloro-5-fluorophenoxy)-3-hydroxy-3,4-dihydroquinolin-2(1H)-one. To a mixture of Reference Example 76 (1.26 g), dimethyl oxalate (2.63 g), and DMF (13 mL), sodium hydride (approximately 60%) (0.891 g) was added under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes and at room temperature for 20 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 suspended in n-hexane, and the insoluble matter was collected by filtration. The resulting solid was washed with n-hexane and then dried under reduced pressure. Sodium borohydride (0.054 g) was added to a mixture of the resulting compound and MeCN (5.3 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 15 minutes. Acetic acid (16.3 mL) was added to the reaction mixture, and the temperature was raised to 50°C. Iron powder (0.594 g) was added to the reaction mixture, and the mixture was stirred at 50°C for 30 minutes, at 65°C for 45 minutes, and at 80°C for 11 hours. The reaction mixture was allowed to cool to room temperature, and water was added. Insoluble matter was removed by filtration, and the filtrate was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium bicarbonate, and saturated brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 85 / 15 to 20 / 80). The resulting product was suspended in n-hexane / DCM (4 / 1), and the insoluble matter was collected by filtration. The resulting solid was washed with n-hexane and dried under reduced pressure to give the title compound (0.528 g).

[0414] Reference Example 78 (3-((tert-Butyldimethylsilyl)oxy)-8-(2-chloro-5-fluorophenoxy)-3,4-dihydroquinolin-2(1H)-one To a mixture of Reference Example 77 (0.300 g), imidazole (0.100 g), and THF (3.0 mL), TBSCl (0.220 g) was added at room temperature, and the mixture was stirred at the same temperature for 20 minutes. DMF (1.5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours, at 50°C for 3 hours, and at 65°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and water 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 (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 60 / 40) to give the title compound (0.361 g).

[0415] Reference Example 79: 8-(2-chloro-5-fluorophenoxy)-3-hydroxy-1-methyl-3,4-dihydroquinolin-2(1H)-one. To a mixture of Reference Example 78 (0.361 g) and DMF (1.8 mL), methyl iodide (0.134 g) and potassium carbonate (0.177 g) were added, followed by stirring at room temperature for 1 hour, at 60°C for 1 hour, and at 80°C for 2 hours. Methyl iodide (0.109 g) was added to the reaction mixture at room temperature, followed by stirring at 80°C for 17 hours. After allowing the reaction mixture to cool to room temperature, water 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. To a mixture of the residue and THF (1.8 mL), TBAF (1 mol / L in THF) (1.03 mL) was added under ice-cooling, followed by stirring for 45 minutes under ice-cooling. 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 0 / 100) to obtain the title compound (0.230 g).

[0416] Reference Example 80: 8-Bromo-1-methyl-3,4-dihydroquinazolin-2(1H)-one. To a mixture of 3-bromo-2-fluorobenzonitrile (0.500 g), potassium carbonate (0.691 g), and 1,4-dioxane (2.5 mL), 40% aqueous methylamine solution (0.417 mL) was added and stirred at 40°C for 14 hours. The reaction mixture was allowed to cool to room temperature, and water was added, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Under an argon atmosphere, BH3-THF (1 mol / L in THF) (7.08 mL) was added to a mixture of the residue and THF (2.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours and at 40°C for 2 hours. Methanol (3.0 mL) and 6 mol / L hydrochloric acid (2.75 mL) were added to the reaction mixture under ice cooling, and the mixture was stirred at 60°C for 1 hour and at room temperature for 13 hours. 2 mol / L aqueous sodium hydroxide solution (9.44 mL) was added to the reaction mixture under ice cooling, and the mixture was extracted twice with DCM. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. CDI (0.402 g) was added to a mixture of the residue, pyridine (0.280 g), and DCE (15 mL), and the mixture was stirred at room temperature for 6 hours. 1 mol / L hydrochloric acid (11.8 mL) was added to the reaction mixture, and the mixture was extracted with DCM. The extract was washed with saturated aqueous sodium bicarbonate and saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. MTBE was added to the residue, and the mixture was stirred at room temperature for 30 minutes. Insoluble matter was collected by filtration, and the resulting solid was washed with MTBE and dried under reduced pressure to give the title compound (0.404 g).

[0417] Reference Example 81: 1-methyl-8-(1-phenylvinyl)-3,4-dihydroquinazolin-2(1H)-one. A mixture of Reference Example 80 (0.100 g), (1-phenylvinyl)boronic acid (0.092 g), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.015 g), potassium carbonate (0.172 g), water (0.4 mL), and 1,4-dioxane (1.6 mL) was stirred at 120°C for 2 hours under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give the title compound (0.096 g).

[0418] Reference Example 82 1-methyl-8-(1-phenylethyl)-3,4-dihydroquinazolin-2(1H)-one To a mixture of Reference Example 81 (0.095 g), THF (1.0 mL), and ethanol (1.0 mL), 10% Pd / C (0.029 g) was added under ice-cooling, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (0.096 g).

[0419] Reference Example 83: 8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid. Dimethyl malonate (0.621 g) and 28% sodium methoxide methanol solution (1.21 g) were added to a mixture of Reference Example 71 (0.460 g) and methanol (5.0 mL), and the mixture was stirred at room temperature for 14 hours. Dimethyl malonate (0.621 g) and 28% sodium methoxide methanol solution (1.81 g) were added to the reaction mixture, and the mixture was stirred at 50°C for 2 hours. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 30 minutes. 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 the title compound (0.170 g).

[0420] Reference Example 84: 2-Bromo-6-ethynylaniline. Under an argon atmosphere, dimethyl (1-diazo-2-oxopropyl)phosphonate (0.501 g) was added to a mixture of 3-bromo-2-nitrobenzaldehyde (0.500 g), potassium carbonate (0.601 g), and methanol (20 mL) at room temperature, followed by stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with EtO. The extract was washed with saturated aqueous sodium bicarbonate and saturated brine, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. Under an argon atmosphere, 4,4'-bipyridyl (0.003 g) was added to a mixture of the residue, tetrahydroxydiboron (0.584 g), and DMF (10 mL) at room temperature, followed by stirring at the same temperature for 10 minutes. Water was added to the reaction mixture, 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, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain the title compound (0.271 g).

[0421] Reference Example 85: 2-Bromo-6-ethynyl-N-methylaniline. To a mixture of Reference Example 84 (0.271 g) and ethyl acetate (5.0 mL) under an argon atmosphere, trifluoroacetic anhydride (0.377 g) was added in an ice-salt bath, and the mixture was stirred for 40 minutes in an ice-salt bath. Methanol (0.056 mL) 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 a mixture of the residue, methyl iodide (0.294 g), and DMF (4.0 mL) under an argon atmosphere, potassium carbonate (0.382 g) was 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 n-hexane / ethyl acetate (1 / 1). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Under an argon atmosphere, a mixture of 48% aqueous potassium hydroxide (0.155 g) and methanol (0.8 mL) was added to a mixture of the residue and THF (4.0 mL) at room temperature, and the mixture was stirred at the same temperature for 13 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified sequentially by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) and silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5) to give the title compound (0.178 g).

[0422] Reference Example 86: Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(3-ethynyl-2-(methylamino)phenyl)propanoate. Under an argon atmosphere, TMSCl (0.018 g) was added to a mixture of zinc powder (0.122 g) and DMF (2.0 mL) 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 (0.558 g) and THF (1.0 mL) under water cooling, followed by stirring for 30 minutes under water cooling. Palladium(II) acetate (0.010 g) and Xphos (0.040 g), followed by a mixture of Reference Example 85 (0.178 g) and THF (2.0 mL) under water cooling, followed by stirring at 40° C. for 2 hours. 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 (0.258 g).

[0423] Reference Example 87: tert-Butyl (R)-(8-ethynyl-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate. To a mixture of Reference Example 86 (0.258 g), methanol (1.0 mL), and THF (1.0 mL) was added 5 mol / L aqueous sodium hydroxide solution (0.466 mL) at room temperature under an argon atmosphere, followed by stirring at the same temperature for 30 minutes. 2 mol / L hydrochloric acid (1.36 mL) was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a mixture of the residue, DIPEA (0.201 g), and MeCN (4.0 mL) was added HATU (0.310 g) at room temperature under an argon atmosphere, followed by stirring at the same temperature for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=100 / 0 to 50 / 50) to obtain the title compound (0.080 g).

[0424] Reference Example 88: tert-Butyl (4-bromo-2-formylthiophen-3-yl)(tert-butoxycarbonyl)carbamate. Under an argon atmosphere, a mixture of methyl 3-amino-4-bromothiophene-2-carboxylate (0.502 g) and THF (2.0 mL) was added to a mixture of lithium aluminum hydride (0.323 g) and THF (8.0 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Sodium sulfate decahydrate (4.11 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred for 10 minutes under ice-cooling and then for 30 minutes at room temperature. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Under an argon atmosphere, manganese dioxide (IV) (0.923 g) was added to a mixture of the residue and ethyl acetate (10 mL) at room temperature, and the mixture was stirred at the same temperature for 18 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Under an argon atmosphere, a mixture of BocO (0.927 g) and THF (1.0 mL) was added to a mixture of the residue, TEA (0.430 g), DMAP (0.052 g), and THF (5.0 mL) 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 dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to give the title compound (0.265 g).

[0425] Reference Example 89: 4-Bromo-2-(2-chloro-5-fluorobenzyl)thiophen-3-amine. Under an argon atmosphere, isopropylmagnesium chloride (2 mol / L in THF) (0.326 mL) was added to a mixture of 1-chloro-4-fluoro-2-iodobenzene (0.167 g) and THF (1.5 mL) at −78°C, followed by stirring on ice for 30 minutes. A mixture of Reference Example 88 (0.265 g) and THF (1.5 mL) was added to the reaction mixture at −78°C, followed by stirring at the same temperature for 10 minutes and then on ice for 1 hour. Saturated aqueous ammonium chloride 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. Under an argon atmosphere, TFA (0.743 g) and triethylsilane (0.152 g) were added to a mixture of the residue and DCM (3.0 mL) at room temperature, followed by stirring at the same temperature for 62 hours. 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 dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to give the title compound (0.104 g).

[0426] Reference Example 90 4-bromo-2-(2-chloro-5-fluorobenzyl)-N-methylthiophen-3-amine Reference Example 90 was synthesized in the same manner as in Reference Example 85, using Reference Example 89 instead of Reference Example 84.

[0427] Reference Example 91 (R)-2-((tert-butoxycarbonyl)amino)-3-(5-(2-chloro-5-fluorobenzyl)-4-(methylamino)thiophen-3-yl)propanoic acid methyl ester Reference Example 91 was synthesized in the same manner as in Reference Example 86 using Reference Example 90 instead of Reference Example 85.

[0428] Reference Example 92: Methyl 3-amino-4-(2-chloro-5-fluorobenzyl)thiophene-2-carboxylate. Under an argon atmosphere, a mixture of 2-(bromomethyl)-1-chloro-4-fluorobenzene (0.243 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 methyl 3-amino-4-bromothiophene-2-carboxylate (0.171 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 2 hours. After allowing the reaction mixture to cool to room temperature, saturated aqueous ammonium chloride, water, and n-hexane / ethyl acetate (1 / 1) were added, 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. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to give the title compound (0.176 g).

[0429] Reference Example 93: Methyl 3-(bis(tert-butoxycarbonyl)amino)-4-(2-chloro-5-fluorobenzyl)thiophene-2-carboxylate. To a mixture of Reference Example 92 (0.166 g) and THF (1.1 mL), a mixture of BocO (0.363 g) and THF (1.1 mL), TEA (0.062 g), and DMAP (0.007 g) were added at room temperature, and the mixture was stirred at the same temperature for 45 minutes, at 50°C for 2 hours, and at room temperature for 60 hours. A saturated aqueous solution of 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 (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to give the title compound (0.228 g).

[0430] Reference Example 94: Methyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-(2-chloro-5-fluorobenzyl)thiophene-2-carboxylate To a mixture of Reference Example 93 (0.228 g) and DCM (1.5 mL), TFA (0.078 g) was added and stirred at room temperature for 4 hours. To the reaction mixture, 5 mol / L aqueous sodium hydroxide solution (0.140 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, methyl iodide (0.097 g) and DMF (1.5 mL), potassium carbonate (0.094 g) was added at room temperature, and the mixture was stirred at 60°C for 17 hours. To the reaction mixture, methyl iodide (0.097 g) and potassium carbonate (0.094 g) were added at room temperature, and the mixture was stirred at 80°C for 2 hours. After the reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride and water were 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 = 95 / 5 to 80 / 20) to give the title compound (0.172 g).

[0431] Reference Example 95: tert-Butyl (4-(2-chloro-5-fluorobenzyl)-2-(hydroxymethyl)thiophen-3-yl)(methyl)carbamate. To a mixture of Reference Example 94 (0.200 g) and DCM (2.0 mL), DIBAL-H (1.03 mol / L in n-hexane) (1.41 mL) was added at -78°C under an argon atmosphere, and the mixture was stirred at the same temperature for 20 minutes. Methanol and a 30% aqueous solution of Rochelle's salt were added to the reaction mixture, and the mixture was stirred at room temperature for a while. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 60 / 40) to give the title compound (0.169 g).

[0432] Reference Example 96: tert-Butyl (R)-3-(3-((tert-butoxycarbonyl)(methyl)amino)-4-(2-chloro-5-fluorobenzyl)thiophen-2-yl)-2-((diphenylmethylene)amino)propanoate. Methanesulfonyl chloride (0.058 g) was added to a mixture of Reference Example 95 (0.163 g), TEA (0.068 g), and ethyl acetate (2.1 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. The reaction mixture was filtered, and the insoluble matter was washed with ethyl acetate (2.1 mL). Lithium bromide monohydrate (0.133 g) was added to the filtrate under ice-cooling, and the mixture was stirred at room temperature for 45 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 magnesium sulfate, and concentrated under reduced pressure. To a mixture of the residue, tert-butyl 2-((diphenylmethylene)amino)acetate (0.172 g), (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepinium bromide (0.029 g), and toluene (2.0 mL), a mixture of potassium hydroxide (0.773 g) and water (1.0 mL) was added under ice-cooling, and the mixture was stirred for 45 minutes under ice-cooling. 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 sequentially by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) and Method A (eluent: n-hexane / ethyl acetate = 95 / 5 to 85 / 15) to give the title compound (0.249 g).

[0433] Reference Example 97: (R)-6-amino-3-(2-chloro-5-fluorobenzyl)-4-methyl-6,7-dihydrothieno[3,2-b]pyridin-5(4H)-one. To a mixture of Reference Example 96 (0.169 g), ethanol (2.0 mL), and toluene (1.0 mL), methanesulfonic acid (0.491 g) was added and the mixture was stirred at 80°C for 4.5 hours. Under ice-cooling, 5 mol / L aqueous sodium hydroxide solution (1.02 mL) and water were 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 / methanol = 70 / 30 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to obtain the title compound (0.055 g).

[0434] Reference Example 98: Methyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-(2-chloro-5-fluorobenzyl)-5-methylthiophene-2-carboxylate To a mixture of Reference Example 94 (0.303 g) and THF (3.7 mL), LDA (1.07 mol / L in THF / n-hexane) (1.03 mL) was added at −78° C., and the mixture was stirred at the same temperature for 15 minutes. Methyl iodide (0.520 g) was added to the reaction mixture, and the mixture was stirred at −78° C. 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 by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate=100 / 0 to 80 / 20) to obtain the title compound (0.306 g).

[0435] Reference Example 99 tert-butyl (4-(2-chloro-5-fluorobenzyl)-2-(hydroxymethyl)-5-methylthiophen-3-yl)(methyl)carbamate Reference Example 99 was synthesized in the same manner as in Reference Example 95 using Reference Example 98 instead of Reference Example 94.

[0436] Reference Example 100: (R)-tert-butyl 3-(3-((tert-butoxycarbonyl)(methyl)amino)-4-(2-chloro-5-fluorobenzyl)-5-methylthiophen-2-yl)-2-((diphenylmethylene)amino)propanoate. Reference Example 100 was synthesized in the same manner as in Reference Example 96 using Reference Example 99 instead of Reference Example 95.

[0437] Reference Example 101 (R)-6-amino-3-(2-chloro-5-fluorobenzyl)-2,4-dimethyl-6,7-dihydrothieno[3,2-b]pyridin-5(4H)-one Reference Example 101 was synthesized in the same manner as in Reference Example 97, using Reference Example 100 instead of Reference Example 96.

[0438] Reference Example 102 Methyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-(2-chloro-5-fluorobenzyl)-5-formylthiophene-2-carboxylate Reference Example 102 was synthesized in the same manner as in Reference Example 98, except for using DMF instead of methyl iodide.

[0439] Reference Example 103: Methyl 3-((tert-butoxycarbonyl)(methyl)amino)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-(2-chloro-5-fluorobenzyl)thiophene-2-carboxylate. To a mixture of Reference Example 102 (0.100 g), THF (1.0 mL), and methanol (1.0 mL), sodium borohydride (0.004 g) was added under ice-cooling, and the mixture was stirred under ice-cooling 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. Imidazole (0.023 g) was added to a mixture of the residue, TBSCl (0.051 g), and DMF (1.0 mL), and the mixture was stirred at room temperature for 19 hours. TBSCl (0.017 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. Imidazole (0.023 g) was added to the reaction mixture and stirred at room temperature for 30 minutes. Water was 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 silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 85 / 15) to give the title compound (0.090 g).

[0440] Reference Example 104 tert-butyl (5-(((tert-butyldimethylsilyl)oxy)methyl)-4-(2-chloro-5-fluorobenzyl)-2-(hydroxymethyl)thiophen-3-yl)(methyl)carbamate Reference Example 104 was synthesized in the same manner as in Reference Example 95 using Reference Example 103 instead of Reference Example 94.

[0441] Reference Example 105 tert-butyl (R)-3-(3-((tert-butoxycarbonyl)(methyl)amino)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-(2-chloro-5-fluorobenzyl)thiophen-2-yl)-2-((diphenylmethylene)amino)propanoate Reference Example 105 was synthesized in the same manner as in Reference Example 96 using Reference Example 104 instead of Reference Example 95.

[0442] Reference Example 106: (R)-6-amino-3-(2-chloro-5-fluorobenzyl)-2-(ethoxymethyl)-4-methyl-6,7-dihydrothieno[3,2-b]pyridin-5(4H)-one. To a mixture of Reference Example 105 (0.082 g), ethanol (1.0 mL), and toluene (0.5 mL), methanesulfonic acid (0.195 g) was added and stirred at 80°C for 3 hours. Under ice-cooling, 5 mol / L aqueous sodium hydroxide solution (0.406 mL) 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 APS column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100) to obtain the title compound (0.025 g).

[0443] Reference Example 107 tert-Butyl (4-formylthiophen-3-yl)carbamate To a mixture of methyl 4-((tert-butoxycarbonyl)amino)thiophene-3-carboxylate (0.800 g) and DCM (8.0 mL), DIBAL-H (1.02 mol / L in n-hexane) (7.01 mL) was added at −78° C., and the mixture was stirred under ice-cooling for 30 minutes. DIBAL-H (1.02 mol / L in n-hexane) (7.01 mL) was added to the reaction mixture at −78° C., and the mixture was stirred under ice-cooling for 15 minutes. 30% aqueous Rochelle salt solution was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. The mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a mixture of the residue and DCM (10 mL), DMP (2.15 g) was added under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. To the reaction mixture was added 1 mol / L aqueous sodium thiosulfate solution under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. 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 80 / 20) to obtain the title compound (0.523 g).

[0444] Reference Example 108 tert-Butyl (4-((2-chloro-5-fluorophenyl)(hydroxy)methyl)thiophen-3-yl)carbamate To a mixture of 1-chloro-4-fluoro-2-iodobenzene (0.846 g) and THF (3.0 mL), isopropylmagnesium chloride (2 mol / L in THF) (1.65 mL) was added at -78°C, and the mixture was stirred under ice-cooling for 30 minutes. A mixture of Reference Example 107 (0.250 g) and THF (3.0 mL) was added at -78°C, and the mixture was stirred under ice-cooling 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 silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 80 / 20) to give the title compound (0.393 g).

[0445] Reference Example 109 tert-Butyl (4-(2-chloro-5-fluorobenzoyl)thiophen-3-yl)carbamate To a mixture of Reference Example 108 (0.393 g) and DCM (12 mL), DMP (0.699 g) was added under ice-cooling, and the mixture was stirred under ice-cooling for 4 hours. 1 mol / L aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred under ice-cooling for 30 minutes. 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 = 95 / 5 to 80 / 20) to obtain the title compound (0.355 g).

[0446] Reference Example 110 tert-Butyl (4-(2-chloro-5-fluorobenzoyl)-2-formylthiophen-3-yl)carbamate To a mixture of Reference Example 109 (0.157 g) and THF (5.0 mL), LDA (1.07 mol / L in THF / n-hexane) (0.742 mL) was added at −78° C., and the mixture was stirred at the same temperature for 10 minutes. DMF (0.097 g) was added to the reaction mixture, and the mixture was stirred at −78° C. for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was 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 (0.065 g).

[0447] Reference Example 111: (Z)-2-(((benzyloxy)carbonyl)amino)-3-(3-((tert-butoxycarbonyl)amino)-4-(2-chloro-5-fluorobenzoyl)thiophen-2-yl)acrylate Methyl N-benzyloxycarbonyl-2-phosphonoglycine trimethyl ester (0.067 g) and DCM (1.0 mL) were added to a mixture of DBU (0.031 g) at room temperature, followed by stirring at the same temperature for 15 minutes. A mixture of Reference Example 110 (0.065 g) and DCM (1.0 mL) was added to the reaction mixture, followed by stirring 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 = 95 / 5 to 50 / 50) to give the title compound (0.060 g).

[0448] Reference Example 112: Methyl 2-(((benzyloxy)carbonyl)amino)-3-(3-((tert-butoxycarbonyl)amino)-4-(2-chloro-5-fluorobenzoyl)thiophen-2-yl)propanoate. To a mixture of Reference Example 111 (0.030 g) and DCM (1.0 mL), (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)iridium(I) hexafluorophosphate (0.004 g) was added, and the mixture was stirred under hydrogen pressure (0.4 MPa) at room temperature for 9 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 50 / 50) to obtain the title compound (0.030 g).

[0449] Reference Example 113: Methyl 3-(bromomethyl)isothiazole-4-carboxylate A mixture of 3-methylisothiazole-4-carboxylic acid (1.00 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (5.0 mL), and methanol (6.0 mL) was stirred at 80°C for 1 hour under microwave irradiation. The reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. A mixture of the residue, NBS (0.905 g), benzoyl peroxide (0.410 g), and carbon tetrachloride (18 mL) was stirred at 70°C for 5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain the title compound (0.864 g).

[0450] Reference Example 114: Methyl 3-(2-chloro-5-fluorobenzyl)isothiazole-4-carboxylate. A mixture of Reference Example 113 (0.614 g), 2-chloro-5-fluorophenylboronic acid (0.382 g), bis(triphenylphosphine)palladium(II) chloride (0.059 g), sodium carbonate (0.268 g), water (2.5 mL), ethanol (5.0 mL), and toluene (5.0 mL) was stirred at 100°C for 1 hour under microwave irradiation. 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 by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to give the title compound (0.273 g).

[0451] Reference Example 115: tert-Butyl (tert-butoxycarbonyl)(3-(2-chloro-5-fluorobenzyl)isothiazol-4-yl)carbamate. A mixture of Reference Example 114 (0.250 g), 4 mol / L aqueous lithium hydroxide solution (0.875 mL), methanol (1.0 mL), and THF (1.0 mL) was stirred at 60° C. for 30 minutes. The reaction mixture was allowed to cool to room temperature, and 2 mol / L hydrochloric acid was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure to give 3-(2-chloro-5-fluorobenzyl)isothiazole-4-carboxylic acid (0.240 g). A mixture of the obtained compound (0.125 g), DPPA (0.317 g), TEA (0.140 g), toluene (2.0 mL), and 1,4-dioxane (1.0 mL) was refluxed for 3 hours. The reaction mixture was allowed to cool to room temperature, then water was added, 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, BocO (1.00 g), DMAP (0.056 g), and THF (2.0 mL) was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to give the title compound (0.094 g).

[0452] Reference Example 116: tert-Butyl (tert-butoxycarbonyl)(3-(1-(2-chloro-5-fluorophenyl)ethyl)-5-methylisothiazol-4-yl)carbamate. To a mixture of Reference Example 115 (0.070 g) and THF (3.0 mL), LDA (1.01 mol / L in THF / n-hexane) (0.313 mL) was added at −78° C., and the mixture was stirred at the same temperature for 15 minutes. Methyl iodide (0.067 g) was added to the reaction mixture at −78° C., and the mixture was stirred at room temperature for 15 minutes. LDA (1.01 mol / L in THF / n-hexane) (0.156 mL) was added to the reaction mixture at −78° C., and the mixture was stirred at the same temperature 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 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 80 / 20) to obtain the title compound (0.055 g).

[0453] Reference Example 117 tert-Butyl (3-(1-(2-chloro-5-fluorophenyl)ethyl)-5-methylisothiazol-4-yl)carbamate A mixture of Reference Example 116 (0.055 g), TFA (0.054 g), and DCM (2.0 mL) was stirred at room temperature for 5 hours. A saturated aqueous carbonate 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 by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 70 / 30) to obtain the title compound (0.030 g).

[0454] Reference Example 118 tert-Butyl (3-(1-(2-chloro-5-fluorophenyl)ethyl)-5-methylisothiazol-4-yl)(methyl)carbamate A mixture of Reference Example 117 (0.030 g), methyl iodide (0.115 g), potassium carbonate (0.034 g), and DMF (1.0 mL) was stirred at room temperature for 63 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 80 / 20) to obtain the title compound (0.028 g).

[0455] Reference Example 119 tert-Butyl (5-(bromomethyl)-3-(1-(2-chloro-5-fluorophenyl)ethyl)isothiazol-4-yl)(methyl)carbamate A mixture of Reference Example 118 (0.028 g), NBS (0.013 g), benzoyl peroxide (0.006 g), and carbon tetrachloride (1.0 mL) was stirred at 70°C for 30 minutes. To the reaction mixture was added benzoyl peroxide (0.023 g) at room temperature, and the mixture was stirred at 70°C for 1 hour. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain the title compound (0.015 g).

[0456] Reference Example 120 tert-butyl (2R)-3-(4-((tert-butoxycarbonyl)(methyl)amino)-3-(1-(2-chloro-5-fluorophenyl)ethyl)isothiazol-5-yl)-2-((diphenylmethylene)amino)propanoate Reference Example 119 (0.015 g), tert-butyl 2-((diphenylmethylene)amino)acetate (0.014 g), (S)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1′,2′-e]azepinium bromide (0.002 g) and toluene (1.0 mL), a mixture of potassium hydroxide (0.120 g) and water (0.5 mL) was added under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes and at room temperature for 1 hour. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to give the title compound (0.012 g).

[0457] The structural formulas of the reference examples are shown in the table below.

[0458] The stereochemistry of Reference Example 72 in the table indicates the relative configuration.

[0459] Example 1: Cyclopentyl (3-carbamoyl-1-methyl-2-oxo-8-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl)carbamate. To a mixture of cyclopentanol (0.013 g), TEA (0.015 g), and THF (1.0 mL), triphosgene (0.014 g) was added under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was added to a mixture of Reference Example 8 (0.027 g), TEA (0.015 g), and THF (1.0 mL) under 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 = 84 / 16 to 35 / 65) to give tert-butyl 6-(((cyclopentyloxy)carbonyl)amino)-1-methyl-2-oxo-8-phenoxy-1,2,3,4-tetrahydroquinoline-3-carboxylate (0.030 g). A mixture of the obtained compound (0.030 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (0.500 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To a mixture of the residue and THF (1.0 mL), TEA (0.032 g), HATU (0.036 g), and ammonia (2 mol / L in methanol) (0.062 mL) were 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 ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=40 / 60 / 0-0 / 100 / 0-0 / 53 / 47) to obtain the title compound (0.023 g).

[0460] Example 2 Cyclopentyl (3-(2-amino-2-oxoethyl)-1-methyl-2-oxo-8-phenoxy-1,2,3,4-tetrahydroquinolin-6-yl)carbamate Example 2 was synthesized in the same manner as in Example 1, except that Reference Example 10 was used instead of Reference Example 8.

[0461] Example 3 Cyclopentyl (3-(2-amino-2-oxoethyl)-8-(2-cyanophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)carbamate To a mixture of Reference Example 19 (0.060 g) and DCM (1.0 mL), N-methylmorpholine (0.040 g) and cyclopentyl chloroformate (0.035 g) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, cyclopentyl chloroformate (0.035 g) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, N-methylmorpholine (0.064 g) and cyclopentyl chloroformate (0.070 g) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified using Method A (eluent: n-hexane / ethyl acetate = 90 / 10 to 50 / 50) to give ethyl 2-(8-(2-cyanophenoxy)-6-(((cyclopentyloxy)carbonyl)amino)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate (0.062 g). To a mixture of the obtained compound (0.062 g), THF (0.5 mL), and methanol (0.5 mL), 4 mol / L aqueous lithium hydroxide solution (0.095 mL) was added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. Water and 1 mol / L hydrochloric acid (1.0 mL) were 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 and MeCN (1.0 mL), DMT-MM (0.052 g) and 28% aqueous ammonia (0.013 mL) were added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. 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 / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) to give the title compound (0.052 g).

[0462] Example 4: Cyclopentyl (8-(2-cyanophenoxy)-1-methyl-2-oxo-3-ureido-1,2,3,4-tetrahydroquinolin-6-yl)carbamate. To a mixture of Reference Example 21 (0.070 g) and DCM (1.0 mL), N-methylmorpholine (0.043 g) and cyclopentyl chloroformate (0.038 g) were added under ice-cooling, followed by stirring at room temperature for 1 hour. To the reaction mixture, cyclopentyl chloroformate (0.038 g) was added at room temperature, followed by stirring at the same temperature for 30 minutes. To the reaction mixture, N-methylmorpholine (0.069 g) and cyclopentyl chloroformate (0.076 g) were added under ice-cooling, followed by stirring at room temperature for 30 minutes. To the reaction mixture, saturated aqueous sodium bicarbonate and water were added, 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 = 90 / 10 to 60 / 40) to give cyclopentyl tert-butyl (8-(2-cyanophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-3,6-diyl)dicarbamate (0.080 g). To a mixture of the resulting compound (0.080 g) and DCM (1.0 mL), TFA (0.350 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, 2 mol / L aqueous sodium hydroxide solution (2.0 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 (0.028 mL), and THF (1.0 mL), potassium cyanate (0.016 g) and methanesulfonic acid (0.016 g) were added at room temperature, and the mixture was stirred at the same temperature for 5 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 THF / water (1 / 2) and then dried under reduced pressure to give the title compound (0.048 g).

[0463] Example 5 Cyclopentyl (1-methyl-2-oxo-8-((6-(trifluoromethyl)pyridin-2-yl)oxy)-3-ureido-1,2,3,4-tetrahydroquinolin-6-yl)carbamate Example 5 was synthesized in the same manner as in Example 4, using Reference Example 24 instead of Reference Example 21.

[0464] Example 6 (S)-1,1,1-trifluoropropan-2-yl (1-methyl-2-oxo-8-((6-(trifluoromethyl)pyridin-2-yl)oxy)-3-ureido-1,2,3,4-tetrahydroquinolin-6-yl)carbamate Pyridine (0.010 g) and 4-nitrophenyl chloroformate (0.027 g) were added to a mixture of Reference Example 24 (0.030 g) and DCM (1.0 mL) under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. (S)-1,1,1-trifluoropropan-2-ol (0.023 g) and DMAP (0.024 g) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified using Method A (eluent: n-hexane / ethyl acetate = 80 / 20 to 40 / 60) to give ((S)-1,1,1-trifluoropropan-2-yl)tert-butyl (1-methyl-2-oxo-8-((6-(trifluoromethyl)pyridin-2-yl)oxy)-1,2,3,4-tetrahydroquinoline-3,6-diyl)dicarbamate (0.034 g). To a mixture of the obtained compound (0.034 g) and DCM (1.0 mL), TFA (0.131 g) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, 1 mol / L aqueous sodium hydroxide solution (2.0 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 (0.010 mL), and THF (0.5 mL), potassium cyanate (0.006 g) and methanesulfonic acid (0.006 g) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: ethyl acetate / methanol = 98 / 2 to 88 / 12) to give the title compound (0.021 g).

[0465] Example 7 Cyclopropylmethyl (1-methyl-2-oxo-8-((6-(trifluoromethyl)pyridin-2-yl)oxy)-3-ureido-1,2,3,4-tetrahydroquinolin-6-yl)carbamate Example 7 was synthesized in the same manner as in Example 6, except that cyclopropylmethanol was used instead of (S)-1,1,1-trifluoropropan-2-ol.

[0466] Example 8 1-methylcyclopropyl (1-methyl-2-oxo-8-((6-(trifluoromethyl)pyridin-2-yl)oxy)-3-ureido-1,2,3,4-tetrahydroquinolin-6-yl)carbamate Example 8 was synthesized in the same manner as in Example 6, except that 1-methylcyclopropan-1-ol was used instead of (S)-1,1,1-trifluoropropan-2-ol.

[0467] Example 9 (1-methyl-2-oxo-8-((6-(trifluoromethyl)pyridin-2-yl)oxy)-3-ureido-1,2,3,4-tetrahydroquinolin-6-yl)carbamate isopropyl Example 9 was synthesized in the same manner as in Example 6, except that propan-2-ol was used instead of (S)-1,1,1-trifluoropropan-2-ol.

[0468] Example 10 1-((1-methyl-2-oxo-8-phenoxy-1,2,3,4-tetrahydroquinolin-3-yl)methyl)urea To a mixture of Reference Example 30 (0.005 g) and THF (0.5 mL), a mixture of potassium cyanate (0.002 g) and water (0.100 mL) and methanesulfonic acid (0.002 g) were added at room temperature, followed by stirring at the same temperature for 3 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. APS was added to a mixture of the residue and methanol. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water / MeCN=70 / 30 to 10 / 90) to obtain the title compound (0.002 g).

[0469] Example 11 (R)-1-(8-(2-chlorobenzoyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example 34 (0.050 g), water (0.029 mL), and THF (1.0 mL), potassium cyanate (0.017 g) and methanesulfonic acid (0.016 g) were added at room temperature, and the mixture was stirred at the same temperature for 10 hours. 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 purified by APS column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 90 / 10) to give the title compound (0.047 g).

[0470] Example 12 1-((3R)-8-((2-chlorophenyl)(hydroxy)methyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Example 11 (0.030 g) and methanol (1.0 mL), sodium borohydride (0.006 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 90 / 10) to give the title compound (0.025 g).

[0471] Example 13 (R)-1-(8-(1-(2-chlorophenyl)vinyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example 38 (0.024 g), methanol (0.2 mL), and THF (0.3 mL), potassium cyanate (0.009 g), water (0.027 mL), and acetic acid (0.006 g) were added at room temperature, followed by stirring 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 ODS column chromatography (elution solvent: water / MeCN=70 / 30 to 10 / 90) to obtain the title compound (0.015 g).

[0472] Example 14 1-(1-methyl-2-oxo-8-(2-phenylpropan-2-yl)-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example 43 (0.110 g) and THF (2.0 mL), LDA (1.09 mol / L in THF / n-hexane) (0.550 mL) was added at -78°C, and the mixture was stirred at the same temperature for 30 minutes. DPPA (0.163 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 1 hour. A mixture of BocO (0.103 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 Method A (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 70 / 30) to give tert-butyl (1-methyl-2-oxo-8-(2-phenylpropan-2-yl)-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (0.110 g). To a mixture of the resulting compound (0.110 g) and DCM (1.0 mL), TFA (0.636 g) was added under ice-cooling and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) to give 3-amino-1-methyl-8-(2-phenylpropan-2-yl)-3,4-dihydroquinolin-2(1H)-one (0.079 g). To a mixture of the obtained compound (0.079 g), water (0.050 mL), and THF (1.0 mL), potassium cyanate (0.029 g) and methanesulfonic acid (0.028 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 obtained solid was washed with water and MTBE and then dried under reduced pressure to give the title compound (0.063 g).

[0473] Example 15 1-((2R)-5,5,7-trimethyl-3-oxo-7-phenyl-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-2-yl)urea DIPEA (0.024 g) was added to a mixture of Reference Example 49 (0.030 g) and MeCN (3.1 mL), and the mixture was stirred at room temperature for 5 minutes. T3P (1.7 mol / L in ethyl acetate) (0.073 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes and at 60°C for 3.5 hours. DIPEA (0.024 g) and T3P (1.7 mol / L in ethyl acetate) (0.073 mL) were added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 15 minutes and at 60°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then saturated aqueous ammonium chloride solution and water 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 = 100 / 0 to 70 / 30) to give tert-butyl ((2R)-9-chloro-5,5,7-trimethyl-3-oxo-7-phenyl-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-2-yl)carbamate (0.013 g). To a mixture of the obtained compound (0.012 g) and DCM (0.5 mL), TFA (0.060 g) was added under ice-cooling and the mixture was stirred at room temperature for 2.5 hours. To the reaction mixture under ice-cooling, 1 mol / L aqueous sodium hydroxide solution (0.530 mL) was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, water (0.010 mL), methanol (0.2 mL), and THF (0.3 mL), potassium cyanate (0.004 g) and acetic acid (0.003 g) were added at room temperature, and the mixture was stirred at the same 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 APS column chromatography (eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0 to 0 / 100 / 0 to 0 / 90 / 10) to give 1-((2R)-9-chloro-5,5,7-trimethyl-3-oxo-7-phenyl-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-2-yl)urea (0.007 g).A mixture of the obtained compound (0.006 g), 10% Pd / C (0.003 g), THF (0.5 mL), and methanol (1.0 mL) was stirred under a hydrogen atmosphere at room temperature for 4.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to give the title compound (0.005 g).

[0474] Example 16 1-((2R)-7-methyl-3-oxo-7-phenyl-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-2-yl)urea Potassium cyanate (0.002 g) and acetic acid (0.002 g) were added to a mixture of Reference Example 54 (0.005 g), water (0.005 mL), methanol (0.2 mL), and THF (0.3 mL) at room temperature, followed by stirring at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0 = 0 / 100 / 0 to 0 / 85 / 15) to give 1-((2R)-9-chloro-7-methyl-3-oxo-7-phenyl-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-2-yl)urea (0.003 g). A mixture of the obtained compound (0.003 g), 10% Pd / C (0.002 g), and methanol (1.0 mL) was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to give the title compound (0.003 g).

[0475] Example 17 1-((2R)-5,5,7-trimethyl-3,6-dioxo-7-phenyl-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-2-yl)urea Example 17 was synthesized in the same manner as in Example 15 using Reference Example 64 instead of Reference Example 49.

[0476] Example 18 (R)-1-(8-(benzyloxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Potassium cyanate (0.037 g) and acetic acid (0.023 g) were added to a mixture of Reference Example 67 (0.100 g), water (0.128 mL), methanol (0.5 mL), and THF (1.0 mL) at room temperature, followed by stirring at the same temperature for 4 hours. Water was 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 obtain the title compound (0.098 g).

[0477] Example 19 (R)—N-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)morpholine-4-carboxamide To a mixture of Reference Example 70 (0.036 g), DIPEA (0.069 g), and DCM (1.0 mL), triphosgene (0.016 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Morpholine (0.028 g) was added to the reaction mixture, 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 sequentially by silica gel column chromatography (eluent: n-hexane / ethyl acetate=40 / 60 to 0 / 100) and APS column chromatography (eluent: n-hexane / ethyl acetate=40 / 60 to 0 / 100). The resulting product was suspended in n-hexane / ethyl acetate (5 / 1), and the insoluble matter was collected by filtration. The resulting solid was dried under reduced pressure to give the title compound (0.020 g).

[0478] Example 20 (R)—N-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)benzamide To a mixture of Reference Example 70 (0.115 g), DIPEA (0.089 g), and DCM (1.0 mL), benzoyl chloride (0.063 g) was added under water-cooling, and the mixture was stirred under water-cooling 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 APS column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 50 / 50) to obtain the title compound (0.066 g).

[0479] Example 21 1-((3R * ,4S * )-8-(2-chloro-5-fluorophenoxy)-4-hydroxy-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example 72 (0.090 g), ethanol (0.5 mL), and toluene (1.0 mL), methanesulfonic acid (0.049 g) was added and the mixture was stirred at 70°C for 1.5 hours. After the reaction mixture was allowed to cool to room temperature, saturated aqueous sodium bicarbonate 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 = 80 / 20 to 40 / 60) to give ((3R * ,4S * Benzyl 8-(2-chloro-5-fluorophenoxy)-4-hydroxy-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (0.070 g) was obtained. Platinum(IV) oxide (0.010 g) was added to a mixture of the obtained compound (0.070 g) and ethanol (2.0 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 13 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Water (0.037 mL), potassium cyanate (0.022 g), and acetic acid (0.014 g) were added to a mixture of the residue and THF (0.5 mL), 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 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 (0.028 g).

[0480] Example 22 (R)-(8-(2-chloro-5-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate Methyl chloroformate (0.022 g) was added to a mixture of Reference Example 75 (0.050 g), DIPEA (0.040 g), and DCM (0.5 mL) at room temperature, followed by stirring at the same temperature for 50 minutes. 1 mol / L hydrochloric acid 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 = 50 / 50 to 0 / 100) to give the title compound (0.037 g).

[0481] Example 23 N-((3R)-8-(2-chloro-5-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)aminosulfonamide To a mixture of chlorosulfonyl isocyanate (0.033 g) and DCM (0.5 mL), tert-butanol (0.017 g) was added at room temperature, followed by stirring at the same temperature for 30 minutes. To the reaction mixture, a mixture of Reference Example 75 (0.050 g) and DCM (0.5 mL) was added, followed by TEA (0.032 g) at room temperature, followed by stirring at the same temperature for 1 hour. To the reaction mixture, 1 mol / L hydrochloric acid was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue and DCM (0.5 mL), TFA (0.178 g) was added at room temperature, followed by stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=50 / 50 to 0 / 100) to obtain the title compound (0.036 g).

[0482] Example 24 (R)-8-(2-chloro-5-fluorophenoxy)-1-methyl-3-(2-oxoimidazolidin-1-yl)-3,4-dihydroquinolin-2(1H)-one To a mixture of Reference Example 75 (0.050 g) and THF (1.0 mL), 2-chloroethyl isocyanate (0.020 g) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. TEA (0.024 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. 2-Chloroethyl isocyanate (0.063 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue and THF (1.0 mL), sodium hydride (approximately 60%) (0.012 g) was added under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes and at room temperature for 1 hour. To the reaction mixture was added saturated aqueous ammonium chloride, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To the residue were added DCM, a small amount of methanol, and MTBE, and the insoluble matter was removed by filtration. 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 give the title compound (0.025 g).

[0483] Example 25 (R)-3-(8-(2-chloro-5-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)oxazolidin-2-one To a mixture of Reference Example 75 (0.063 g), TEA (0.040 g), and THF (0.63 mL), 2-chloroethyl chloroformate (0.042 g) was added under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. Insoluble matter was removed by filtration and washed with THF (0.63 mL). To the filtrate was added 28% sodium methoxide in methanol (0.075 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 20 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 silica gel column chromatography (eluent: n-hexane / ethyl acetate=70 / 30 to 0 / 100) to obtain the title compound (0.056 g).

[0484] Example 26: 8-(2-chloro-5-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl carbamate. 4-Nitrophenyl chloroformate (0.018 g) was added to a mixture of Reference Example 79 (0.023 g), TEA (0.011 g), DMAP (0.002 g), and DCM (0.5 mL) at room temperature, followed by stirring at the same temperature for 3 hours. 28% aqueous ammonia (0.241 mL) was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, 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 using Method A (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100) to give the title compound (0.019 g).

[0485] Example 27 1-(8-(2-chloro-5-fluorophenoxy)-1-methyl-2-thioxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example 75 (0.020 g) and toluene (1.0 mL), Lawesson's reagent (0.126 g) was added at room temperature, followed by stirring at 110°C for 14 hours. The reaction mixture was allowed to cool to room temperature, and water was added, followed by extraction with DCM. The extract was concentrated under reduced pressure. The residue was purified sequentially by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 50 / 50) and APS column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 50 / 50) to give 3-amino-8-(2-chloro-5-fluorophenoxy)-1-methyl-3,4-dihydroquinoline-2(1H)-thione (0.022 g). To a mixture of the obtained compound (0.022 g), water (0.012 mL), and THF (1.0 mL), potassium cyanate (0.007 g) and methanesulfonic acid (0.007 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 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 90 / 10) to give the title compound (0.005 g).

[0486] Example 28 1-(9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[1,2-a]quinolin-4-yl)urea Under an argon atmosphere, zinc powder (1.52 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (5.21 g) and DMF (19 mL) under water cooling, and the mixture was stirred at room temperature for 45 minutes. A mixture of Reference Example 73 (3.34 g) and DMF (9.5 mL), palladium(II) acetate (0.118 g), and Xphos (0.503 g) were added to the reaction mixture at room temperature, and the mixture was stirred at 40° C. for 30 minutes and then at room temperature for 15 hours. Acetic acid (1.90 g) was added to the reaction mixture, and the mixture was stirred at 70° C. for 1.5 hours. 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. Insoluble matter was removed by filtration, 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. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 70 / 30) to give tert-butyl (R)-(8-(2-chloro-5-fluorophenoxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (4.03 g). To a mixture of the obtained compound (4.03 g) and toluene (99 mL), Lawesson's reagent (4.20 g) was added at room temperature, and the mixture was stirred at 70°C for 30 minutes and then at 90°C for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was suspended in n-hexane / DCM (2 / 1), and insoluble matter was removed by filtration. 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 tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-thioxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (3.05 g). To a mixture of the obtained compound (0.555 g), TEA (0.266 g), and ethanol (5.0 mL), aminoacetaldehyde diethyl acetal (0.350 g) was added at room temperature, and the mixture was stirred at 70 °C for 2 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure.A mixture of the residue and acetic acid (5.0 mL) was stirred at 100°C for 1.5 hours and at 120°C for 4 hours. To the reaction mixture, 5 mol / L aqueous sodium hydroxide solution (17.4 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 = 90 / 10 to 50 / 50) to give tert-butyl (9-(2-chloro-5-fluorophenoxy)-4,5-dihydroimidazo[1,2-a]quinolin-4-yl)carbamate (0.078 g). To a mixture of the resulting compound (0.078 g) and DCM (0.78 mL), TFA (0.414 g) was added at room temperature, and the mixture was stirred at the same temperature for 45 minutes. To the reaction mixture, 5 mol / L aqueous sodium hydroxide solution (0.726 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 (0.078 mL), and THF (0.78 mL), potassium cyanate (0.019 g) and acetic acid (0.011 g) were added under ice-cooling, and the mixture was stirred for 2.5 hours under ice-cooling. Water and MTBE 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 the title compound (0.042 g).

[0487] Example 29 1-(9-(2-chloro-5-fluorophenoxy)-1-methyl-4,5-dihydroimidazo[1,2-a]quinolin-4-yl)urea Under an argon atmosphere, zinc powder (1.52 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (5.21 g) and DMF (19 mL) under water cooling, and the mixture was stirred at room temperature for 45 minutes. A mixture of Reference Example 73 (3.34 g) and DMF (9.5 mL), palladium(II) acetate (0.118 g), and Xphos (0.503 g) were added to the reaction mixture at room temperature, and the mixture was stirred at 40° C. for 30 minutes and then at room temperature for 15 hours. Acetic acid (1.90 g) was added to the reaction mixture, and the mixture was stirred at 70° C. for 1.5 hours. 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. Insoluble matter 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 purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 70 / 30) to give tert-butyl (R)-(8-(2-chloro-5-fluorophenoxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (4.03 g). To a mixture of the obtained compound (4.03 g) and toluene (99 mL), Lawesson's reagent (4.20 g) was added at room temperature, and the mixture was stirred at 70°C for 30 minutes and at 90°C for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was suspended in n-hexane / DCM (2 / 1), and the insoluble matter was removed by filtration. 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 tert-butyl (8-(2-chloro-5-fluorophenoxy)-2-thioxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (3.05 g). To a mixture of the obtained compound (0.418 g) and 1-butanol (7.3 mL), propargylamine (1.63 g) was added and stirred at 100 °C for 15 minutes. After allowing the reaction mixture 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 = 90 / 10 to 55 / 45) to give tert-butyl (9-(2-chloro-5-fluorophenoxy)-1-methyl-4,5-dihydroimidazo[1,2-a]quinolin-4-yl)carbamate (0.412 g). To a mixture of the obtained compound (0.100 g) and DCM (1.0 mL), TFA (0.514 g) was added at room temperature and stirred at the same temperature for 20 minutes. A 5 mol / L aqueous sodium hydroxide solution (0.902 mL) was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, water (0.100 mL), and THF (1.0 mL), potassium cyanate (0.024 g) and acetic acid (0.014 g) were added at room temperature and stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100) to obtain the title compound (0.049 g).

[0488] Example 30 2-(1-methyl-2-oxo-8-(1-phenylethyl)-1,4-dihydroquinazolin-3(2H)-yl)acetamide A mixture of Reference Example 82 (0.030 g) and DMF (0.5 mL) was added to a mixture of sodium hydride (approximately 60%) (0.005 g) and DMF (0.5 mL) under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. 2-Bromoacetamide (0.016 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. 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 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: ethyl acetate / methanol = 100 / 0 to 90 / 10) to give the title compound (0.010 g).

[0489] Example 31 1-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)urea To a mixture of Reference Example 83 (0.100 g), DMF (0.5 mL), and tert-butanol (1.0 mL), TEA (0.056 g) and DPPA (0.114 g) were added and stirred at 60°C for 3 hours. The reaction mixture was allowed to cool to room temperature, and then saturated aqueous sodium bicarbonate 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 using Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 80 / 20) to give tert-butyl (8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)carbamate (0.040 g). To a mixture of the resulting compound (0.040 g) and DCM (1.0 mL), TFA (0.211 g) was added and stirred at room temperature for 13 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue and DCM (1.0 mL), triphosgene (0.027 g) and TEA (0.028 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. Ammonium chloride (0.049 g) and DIEPA (0.119 g) were 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 stirred at room temperature for 10 minutes. Insoluble matter was collected by filtration, and the resulting solid was washed with water and MTBE and then dried under reduced pressure to give the title compound (0.014 g).

[0490] Example 32 1-(4-(2-chloro-5-fluorophenoxy)-3,5-dimethyl-2-oxo-1,2,3,7b-tetrahydro-1aH-cyclopropa[c]quinolin-1a-yl)urea Under an argon atmosphere, to a mixture of diethylzinc (1 mol / L in n-hexane) (0.158 mL) and DCM (0.5 mL) was added methyl iodide (0.084 g) under ice-cooling, and the mixture was stirred under ice-cooling for 10 minutes. To the reaction mixture was added a mixture of Example 31 (0.024 g) and DCM (0.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added saturated aqueous ammonium chloride under ice-cooling, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=30 / 70 / 0-0 / 100 / 0-0 / 95 / 5) to obtain the title compound (0.001 g).

[0491] Example 33 (R)-8-(2-chloro-5-fluorophenoxy)-1-methyl-3-((4-oxo-4,5-dihydro-1H-imidazol-2-yl)amino)-3,4-dihydroquinolin-2(1H)-one DMAP (0.053 g) was added to a mixture of 2-thioxoimidazolidin-4-one (0.500 g), methyl iodide (2.44 g), DIPEA (1.11 g), and DCM (1.5 mL) at room temperature, and the mixture was stirred at the same temperature for 14 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 give 2-(methylthio)-1,5-dihydro-4H-imidazol-4-one (0.354 g). A mixture of the obtained compound (0.041 g), Reference Example 75 (0.100 g), and ethanol (3.0 mL) was stirred at 140 °C for 1 hour under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified sequentially by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 65 / 35) and ODS column chromatography (eluent: water / MeCN = 70 / 30 to 10 / 90) to give the title compound (0.025 g).

[0492] Example 34 (R)-3-((1H-imidazol-2-yl)amino)-8-(2-chloro-5-fluorophenoxy)-1-methyl-3,4-dihydroquinolin-2(1H)-one A mixture of Reference Example 75 (0.150 g), benzoyl isothiocyanate (0.114 g), TEA (0.095 g), and DCM (5.0 mL) was stirred at room temperature for 30 minutes. 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. A mixture of the residue, 2 mol / L aqueous sodium hydroxide solution (1.17 mL), and THF (5.0 mL) was stirred at room temperature for 3 hours. The reaction mixture was poured into saturated aqueous ammonium chloride 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 = 100 / 0 to 20 / 80) to give (R)-1-(8-(2-chloro-5-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)thiourea (0.050 g). A mixture of the obtained compound (0.050 g), methyl iodide (0.021 g), and acetone (1.3 mL) was stirred at 55 °C for 1 hour under microwave irradiation. The reaction mixture was filtered. The insoluble matter was washed with EtO and then dried under reduced pressure to give methyl (R)-(8-(2-chloro-5-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamimidothioate (0.043 g). A mixture of the obtained compound (0.021 g), 2,2-diethoxyethan-1-amine (0.007 g), and MeCN (0.5 mL) was stirred at 90°C for 10 hours under microwave irradiation. The reaction mixture was concentrated under reduced pressure. A mixture of the residue, 6 mol / L hydrochloric acid (0.087 mL), and THF (0.5 mL) was stirred at room temperature for 30 minutes. Water and saturated aqueous sodium bicarbonate solution were 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 sequentially by silica gel column chromatography (eluent: n-hexane / ethyl acetate=100 / 0 to 0 / 100) and ODS column chromatography (eluent: water / MeCN=70 / 30 to 10 / 90) to obtain the title compound (0.006 g).

[0493] Example 35 (R)-1-(1-methyl-2-oxo-8-phenethyl-1,2,3,4-tetrahydroquinolin-3-yl)urea Under an argon atmosphere, 10% Pd / C (0.016 g) was added to a mixture of Reference Example 87 (0.080 g), ethanol (1.5 mL), and THF (1.5 mL) at room temperature, and the mixture was stirred at the same temperature for 5 minutes under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give tert-butyl (R)-(1-methyl-2-oxo-8-vinyl-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (0.081 g). A mixture of the obtained compound (0.041 g), bromobenzene (0.042 g), palladium(II) acetate (0.003 g), tris(2-methylphenyl)phosphine (0.008 g), TEA (0.054 g), and MeCN (1.0 mL) was stirred at 140 °C for 10 minutes under microwave irradiation. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified sequentially by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 85 / 15) and ODS column chromatography (eluent: water / MeCN = 70 / 30 to 10 / 90) to give tert-butyl (R,E)-(1-methyl-2-oxo-8-styryl-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (0.007 g). Under an argon atmosphere, 10% Pd / C (0.001 g) was added to a mixture of the obtained compound (0.007 g), methanol (0.5 mL), and THF (0.5 mL) at room temperature, and the mixture was stirred under a hydrogen atmosphere at the same temperature for 2.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Under an argon atmosphere, TFA (0.042 g) was added to a mixture of the residue and DCM (0.5 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. 2 mol / L aqueous sodium hydroxide was added to the reaction mixture under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. Under an argon atmosphere, potassium cyanate (0.002 g) and acetic acid (0.001 g) were added to a mixture of the residue, water (0.007 mL), and THF (0.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 22 hours.Potassium cyanate (0.002 g) and acetic acid (0.001 g) were added to the reaction mixture, which was then stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 95 / 5) to give the title compound (0.004 g).

[0494] Example 36 (R)-1-(7-(2-chloro-5-fluorobenzyl)-1-methyl-2-oxo-1,2,3,4-tetrahydrothieno[3,4-b]pyridin-3-yl)urea Under an argon atmosphere, methanesulfonic acid (0.021 g) was added to a mixture of Reference Example 91 (0.034 g), ethanol (0.3 mL), and toluene (0.5 mL) at room temperature, and the mixture was stirred at 80° C. for 5 hours and then at room temperature for 15 hours. Methanesulfonic acid (0.036 g) was added to the reaction mixture at room temperature, and the mixture was stirred at 80° C. for 3 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 dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 20 / 80) to give (R)-3-amino-7-(2-chloro-5-fluorobenzyl)-1-methyl-3,4-dihydrothieno[3,4-b]pyridin-2(1H)-one (0.024 g). Under an argon atmosphere, potassium cyanate (0.008 g) and acetic acid (0.005 g) were added to a mixture of the resulting compound (0.024 g), water (0.027 mL), and THF (0.5 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=30 / 70 / 0-0 / 100 / 0-0 / 95 / 5) to obtain the title compound (0.010 g).

[0495] Example 37 (R)-1-(3-(2-chloro-5-fluorobenzyl)-4-methyl-5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-6-yl)urea To a mixture of Reference Example 97 (0.054 g), water (0.060 mL), and THF (0.54 mL), potassium cyanate (0.018 g) and acetic acid (0.011 g) were added at room temperature, and the mixture was stirred at the same temperature for 16 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 Method A (elution solvent: n-hexane / ethyl acetate / methanol = 70 / 30 / 0 to 0 / 100 / 0 to 0 / 85 / 15). The resulting product was suspended in MTBE, and the insoluble matter was collected by filtration. The resulting solid was washed with MTBE and then dried under reduced pressure to give the title compound (0.030 g).

[0496] Example 38 (R)-1-(3-(2-chloro-5-fluorobenzyl)-2,4-dimethyl-5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-6-yl)urea Example 38 was synthesized in the same manner as in Example 37 using Reference Example 101 instead of Reference Example 97.

[0497] Example 39 (R)-1-(2-Bromo-3-(2-chloro-5-fluorobenzyl)-4-methyl-5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-6-yl)urea To a mixture of Example 37 (0.010 g) and DCM (1.0 mL), NBS (0.006 g) was added under ice-cooling, and the mixture was stirred under ice-cooling for 45 minutes. Aqueous sodium thiosulfate 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 by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 70 / 30 / 0 to 0 / 100 / 0 to 0 / 90 / 10) to give the title compound (0.011 g).

[0498] Example 40 (R)-1-(3-(2-chloro-5-fluorobenzyl)-2-cyano-4-methyl-5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-6-yl)urea. To a mixture of Example 39 (0.009 g), zinc(II) cyanide (0.005 g), zinc powder (0.0004 g), and DMF (1.0 mL) was added bis(tri-t-butylphosphine)palladium(0) (0.001 g) under an argon atmosphere, followed by stirring at 80°C for 2 hours. The reaction mixture was allowed to cool to room temperature, and then saturated aqueous sodium bicarbonate and water were added. The mixture was extracted twice with n-hexane / ethyl acetate (1 / 1) and twice with n-hexane / ethyl acetate (1 / 2). The combined extracts were 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 / methanol = 70 / 30 / 0 to 0 / 100 / 0 to 0 / 80 / 20), Method A (eluent: ethyl acetate / methanol = 100 / 0 to 95 / 5), Method B (eluent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100), and PLC (developing solvent: ethyl acetate) to obtain the title compound (0.002 g).

[0499] Example 41 (R)-1-(3-(2-chloro-5-fluorobenzyl)-2-(hydroxymethyl)-4-methyl-5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-6-yl)urea A mixture of BocO (0.021 g) and DCM (0.5 mL) was added to a mixture of Reference Example 106 (0.024 g) and DCM (0.5 mL), and the mixture was stirred at room temperature for 2 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 70 / 30) to give tert-butyl (R)-(3-(2-chloro-5-fluorobenzyl)-2-(ethoxymethyl)-4-methyl-5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-6-yl)carbamate (0.032 g). To a mixture of the obtained compound (0.023 g) and DCM (0.5 mL), TFA (0.109 g) was added at room temperature and stirred at the same temperature for 8 hours. To the reaction mixture was added 5 mol / L aqueous sodium hydroxide solution (0.190 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 (0.005 g) and acetic acid (0.003 g) were added under ice-cooling, and the mixture was stirred at room temperature for 22 hours. Potassium cyanate (0.005 g) and acetic acid (0.003 g) were added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 30 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 = 50 / 50 / 0 to 0 / 100 / 0 to 0 / 80 / 20) and PLC (developing solvent: ethyl acetate / methanol = 95 / 5) to give the title compound (0.002 g).

[0500] Example 42 1-(3-(2-chloro-5-fluorobenzoyl)-4-methyl-5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-6-yl)urea A mixture of Reference Example 112 (0.030 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (1.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. A mixture of the residue and DMF (1.0 mL) was stirred at 70°C for 1 hour. Potassium carbonate (0.011 g) and methyl iodide (0.014 g) were added to the reaction mixture 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 ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 98 / 2 to 50 / 50) to give benzyl (3-(2-chloro-5-fluorobenzoyl)-4-methyl-5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-6-yl)carbamate (0.016 g). To a mixture of sodium iodide (0.016 g) and MeCN (0.5 mL), TMSCl (0.011 g) was added at room temperature and stirred at the same temperature for 15 minutes. To the reaction mixture, a mixture of the above (3-(2-chloro-5-fluorobenzoyl)-4-methyl-5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-6-yl)carbamate (0.010 g) and MeCN (0.5 mL) was added at room temperature and stirred at 50 °C for 2 hours. To the reaction mixture, 1 mol / L aqueous sodium thiosulfate solution was added under ice-cooling, 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, water (0.008 g), potassium cyanate (0.003 g), acetic acid (0.003 g), and THF (1.0 mL) was stirred at room temperature for 63 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (0.003 g).

[0501] Example 43 1-((6R)-3-(1-(2-chloro-5-fluorophenyl)ethyl)-4-methyl-5-oxo-4,5,6,7-tetrahydroisothiazolo[4,5-b]pyridin-6-yl)urea A mixture of Reference Example 120 (0.012 g), methanesulfonic acid (0.124 g), ethanol (0.4 mL), and toluene (0.2 mL) was stirred at room temperature for 30 minutes and at 70° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, and water and ethyl acetate were added, 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 DCM. The extract was concentrated under reduced pressure. A mixture of the residue, water (0.005 g), potassium cyanate (0.002 g), acetic acid (0.002 g), and THF (1.0 mL) was stirred at room 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, and the residue was purified by ODS column chromatography (eluent: 0.2% NH in water / 0.2% NH in MeCN = 68.3 / 31.7 to 5 / 95) to obtain the title compound (0.001 g).

[0502] The structural formulas, physical properties, and TSHR antagonist activity (see Test Example 1) of the examples are shown in the table below.

[0503] The stereochemistry designation for Example 21 in the table indicates the relative configuration.

[0504] Test Example 1: Measurement of antagonist activity using TSH-induced cAMP production as an index in human TSHR stably expressing CHO cells

[0505] The human TSHR gene sequence (reference number NM_000369.2) was inserted into the multicloning site of pcDNA3.1(+). The constructed plasmid vector was introduced into CHO cells using the lipofection method to establish CHO cells stably expressing human TSHR. The resulting cells were plated at 5 x 10 in a 96-well poly-D-lysine-coated plate. 4Cells were seeded at 100 μL / well and cultured in F12 medium containing 10% FBS, 400 μg / mL G418, 50 U / mL penicillin, and 50 μg / mL streptomycin at 37°C and 5% CO2 for 1 day. After removing the medium, the cells were washed twice with 100 μL of assay buffer (Hanks' Balanced Salt Solution containing 20 mM HEPES and 1 mM IBMX) per well. 30 μL of assay buffer containing the test compound was added to the well and incubated for 15 minutes at room temperature. Next, 30 μL of assay buffer containing human TSH (R&D Systems, Inc., final concentration 50 ng / mL) was added and incubated for 1 hour at 37°C. The supernatant was removed, and cell lysates were prepared by adding Lysis and Detection Buffer 2 (Cisbio) and incubating at room temperature for 1 hour. According to the instructions for the cAMP Gs HiRange Kit (Cisbio), cell lysates were reacted with d2-labeled cAMP and anti-cAMP Europium Cryptate-labeled antibodies (Cisbio) in a 384-well white microplate. The fluorescence intensity ratio (measurement wavelength: 665 nm / 620 nm) was then measured using a multiplate reader (PHERAstar FSX, BMG LABTECH Japan). The fluorescence intensity ratio for each sample was converted to cAMP content using a standard curve. The cAMP content was converted as a percentage of the control value to calculate the cAMP production rate. The cAMP production rate was plotted against the test compound concentration using Prism (Graph Pad Software Inc.), and the IC 50 The IC values ​​were calculated for each test compound. 50 are shown in the table above. In the table, IC 50 <3.0 μM: A, 3.0 μM ≤ IC 50 <30 μM: Denoted as B. IC 50 If the value could not be calculated, it was expressed as C.

[0506] As shown in the above table, the compounds of the present invention were found to have human TSHR antagonist activity.

[0507] The compound of the present invention or a pharmacologically acceptable salt thereof has TSHR antagonist activity and is therefore useful as a therapeutic agent for thyroid-related diseases.

Claims

1. A compound represented by formula (A-I): [In the formula, ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; V 1 is CR V1 R V1’ , CR V1 , NR V1 , N, O, or S; V 2 is CR V2 R V2’ , CR V2 , NR V2 , N, O, or S; V 3 is CR V3 R V3’ , CR V3 , NR V3 , N, O, or S; V 4 is a single bond, CR T1 R T2 , CR T1 , O, NR T3 , or N; V 5 is CR 3 , C, or N; V 6 is NR 1 ; X is CR X0 R X0’ , O, NR X3 , CO, -C(=CR X1 R X2 )-, -(CR X1 R X2 )2-, OCR X1 R X2 , CR X1 R X2 O, NR X3 CR X1 R X2 , CR X1 R X2 NR X3 , or -CR X1 =CR X2 -; R X0 , R X0’ , R X1 , and R X2 are each independently a hydrogen atom, a halogen atom, hydroxy, C 1-6 alkyl, or halo C 1-6 is alkyl; R X3 is a hydrogen atom, C 1-6 alkyl, or haloC 1-6 alkyl; R X0 is R X0’ together with R may form a 3- to 8-membered saturated carbon ring substituted with 1 to 6 groups selected from unsubstituted or substituent group B; R X1 is R X2 together with R may form a 3- to 8-membered saturated carbon ring substituted with 1 to 6 groups selected from unsubstituted or substituent group B; R X1 is R X3 together with R may form a 3- to 8-membered saturated heterocyclic ring substituted with 1 to 6 groups selected from unsubstituted or substituent group B; R 1 is a hydrogen atom, C 1-6 alkyl, or haloC 1-6 alkyl; R 1 is R X0 , R X1 , or R X3 together with may form an unsubstituted or 5- to 8-membered saturated heterocyclic ring substituted with 1 to 6 groups selected from substituent group B, or an unsubstituted or 5- to 8-membered unsaturated heterocyclic ring substituted with 1 to 6 groups selected from substituent group B; substituent group B consists of a halogen atom, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, and oxo; when two or more groups are present that are selected from substituent group B, each group may be the same or different; R 2 is a halogen atom, cyano, hydroxy, amino, C 1-6 alkyl, haloC 1-6 alkyl, halohydroxyC 1-6 alkyl, SF5, C 1-6 alkoxy, haloC 1-6 alkoxy, C 6-10 arylC 1-6 alkyl, or C 6-10 arylC 1-6 alkoxy; R X0 is R 2 may form, together with, a 5- to 8-membered ring which is unsubstituted or substituted with 1 to 6 groups selected from substituent group B; R X1 is, R 2 may form, together with, a 5- to 8-membered ring which is unsubstituted or substituted with 1 to 6 groups selected from substituent group B; R X3 is, R 2 may form, together with, a 5- to 8-membered saturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from substituent group B, or a 5- to 8-membered unsaturated heterocyclic ring which is unsubstituted or substituted with 1 to 6 groups selected from substituent group B; q is 0 or 1; R V1 , R V1’ , R V2 , R V2’ , R V3 , and R V3’ are each independently a hydrogen atom, a halogen atom, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, C 6-10 arylC 1-6 alkyl, haloC 1-6 alkoxy, C 6-10 arylC 1-6 alkoxy, NR V4 COR V5 , NR V4 COOR V6 , or NR V4 CONR V7 R V8 ; R V4 is a hydrogen atom, or C 1-6 alkyl; R V5 , R V6 , R V7 , and R V8 are each independently a hydrogen atom, or a group selected from the group consisting of the following (i) to (ix): (i) C 1-6 alkyl which is unsubstituted or substituted with 1 to 6 groups selected from substituent group A, (ii) C 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, (v) C substituted with 1 to 6 groups selected from unsubstituted or substituent group A 6-10 Aryl C 1-6 Alkyl, (vi) 3- to 8-membered heterocycloalkyl substituted with 1 to 6 groups selected from unsubstituted or substituent group A, (vii) 3- to 8-membered heterocycloalkyl C substituted with 1 to 6 groups selected from unsubstituted or substituent group A 1-6 Alkyl, (viii) 5- to 10-membered heteroaryl substituted with 1 to 6 groups selected from unsubstituted or substituent group A, and (ix) 5- to 10-membered heteroaryl C substituted with 1 to 6 groups selected from unsubstituted or substituent group A 1-6 Alkyl; substituent group A consists of a halogen atom, cyano, hydroxy, N(C 1-6 Alkyl)2, C 1-6 Alkyl, halo C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkoxy, and C 3-8 Cycloalkyl; when there are two or more groups selected from substituent group A, each group may be the same or different; R T1 And R T2 Are each independently a hydrogen atom, a halogen atom, hydroxy, C 1-6 Alkyl, or halo C 1-6 Alkyl; R T3 Is a hydrogen atom, C 1-6 Alkyl, or halo C 1-6 Alkyl; R 3 Is a hydrogen atom, a halogen atom, or C 1-6 Alkyl; R 4 Is C 1-6 Alkyl, halo C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 alkyl, OR 5 , NR 5 R 5' , C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl substituted with 1 to 6 groups selected from the group C, C 6-10 aryl, or 5- or 6-membered heteroaryl substituted with 1 to 4 groups selected from the group C; the group C is a halogen atom, cyano, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, oxo, CONH2, CONH-(C 1-6 alkyl), and CONH-(C 3-8 cycloalkyl); when two or more groups selected from the group C are present, each group may be the same or different; 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 5 is, together with R 5' a 3- to 10-membered saturated heterocyclic ring substituted with 1 to 6 groups selected from the group B or an unsubstituted or 3- to 10-membered unsaturated heterocyclic ring substituted with 1 to 6 groups selected from the group B; R 3 is, R T1 , R T2 , or together with R T3 a 3- to 10-membered ring substituted with 1 to 6 groups selected from the group B; R 3 is, together with R 5 a 3- to 10-membered saturated heterocyclic ring substituted with 1 to 6 groups selected from the group B or an unsubstituted or 3- to 10-membered unsaturated heterocyclic ring substituted with 1 to 6 groups selected from the group B; R 4 is, R T1 , R T2 、 or R T3 may together form a 3- to 10-membered ring substituted with 1 to 6 groups selected from unsubstituted or substituted group B; R 5 is R T1 、 R T2 、 or R T3 may together form an unsubstituted or substituted 3- to 10-membered saturated heterocyclic ring substituted with 1 to 6 groups selected from substituted group B, or an unsubstituted or substituted 3- to 10-membered unsaturated heterocyclic ring substituted with 1 to 6 groups selected from substituted group B; R V7 is R V8 may together form an unsubstituted or substituted 3- to 10-membered saturated heterocyclic ring substituted with 1 to 6 groups selected from substituted group B, or an unsubstituted or substituted 3- to 10-membered unsaturated heterocyclic ring substituted with 1 to 6 groups selected from substituted group B; W 1 is CR W1 R W2 、 O、 NR W3 、 or a single bond; W 2 is CR W1 R W2 、 O、 NR W3 、 or a single bond; R W1 and R W2 are each independently a hydrogen atom, a halogen atom, C 1-6 alkyl, or haloC 1-6 alkyl; R W3 is a hydrogen atom, C 1-6 alkyl, or haloC 1-6 alkyl; W 3 is CO, CNR W4 、 SO、 SO2, or a single bond; R W4 is a hydrogen atom, C 1-6 alkyl, cyano, hydroxy, C 1-6 alkoxy, CO-(C 1-6 alkyl), or SO2-(C 1-6 alkyl); n is an integer from 0 to 3; when n is 2 or 3, each R 2 may be the same as or different from each other; R 4 and R 5 are R W1 or R W3 may form a 5- to 8-membered saturated heterocyclic ring unsubstituted or substituted with 1 to 6 groups selected from the group B, or a 5- to 8-membered unsaturated heterocyclic ring unsubstituted or substituted with 1 to 6 groups selected from the group B; Y is O, S, or NR Y wherein; R Y is a hydrogen atom or C 1-6 alkyl; R Y together with R 1 may form a 5- to 8-membered saturated heterocyclic ring unsubstituted or substituted with 1 to 6 groups selected from the group B, or a 5- to 8-membered unsaturated heterocyclic ring unsubstituted or substituted with 1 to 6 groups selected from the group B; ( represents a single bond or a double bond) or a pharmaceutically acceptable salt thereof; provided that in formula (A-I), W 1 is a single bond; and W 2 is CH2 or NH; and W 3 is CO; and R 4 is C 1-6 alkyl, halo C 1-6 alkyl, NR 5 R 5' or C 3-8 cycloalkyl, then it is any of the following (a) to (f); (a) R T1 and R T2 are not hydrogen atoms simultaneously (b) X is not O, and when X is CHR X0 R X0 is neither a hydrogen atom nor C 1-6 alkyl (c) R 1 is halo C 1-6 alkyl (d) V 2 is CR V2 and R V2 is halo C 1-6 alkoxy, NR V4 COR V5 NR V4 COOR V6 or NR V4 CONR V7 R V8 (e) Y is not O (f) q is 0).

2. The compound according to claim 1, which is a compound represented by formula (A-II): [In the formula, ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; V 1 is CR V1 R V1’ 、CR V1 、NR V1 、N、O, or S; V 2 is CR V2 R V2’ 、CR V2 、NR V2 、N、O, or S; R V1 、R V1’ 、R V2 、and R V2’ are each independently a hydrogen atom, a halogen atom, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, halo C 1-6 alkoxy, NR V4 COR V5 、NR V4 COOR V6 、or NR V4 CONR V7 R V8 ; R V4 is a hydrogen atom or C 1-6 alkyl; R V5 、R V6 、R V7 、and R V8 are each independently a hydrogen atom or a group selected from the group consisting of the following (i) to (v): (i) C 1-6 alkyl unsubstituted or substituted with 1 to 6 groups selected from substituent group A, (ii) C 3-8 cycloalkyl unsubstituted or substituted with 1 to 6 groups selected from substituent group A, (iii) C 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; the substituent group A consists of a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, and C 3-8 cycloalkyl; when two or more groups are present that are selected from the substituent group A, each group may be the same or different; X is CR X0 R X0’ , O, NR X3 , CO, -C(=CR X1 R X2 )-, -(CR X1 R X2 )2-, OCR X1 R X2 , CR X1 R X2 O, NR X3 CR X1 R X2 , CR X1 R X2 NR X3 , or -CR X1 =CR X2 -; R X0 , R X0’ , R X1 , and R X2 are each independently a hydrogen atom, a halogen atom, hydroxy, C 1-6 alkyl, or halo C 1-6 alkyl; R X3 is a hydrogen atom, C 1-6 alkyl, or halo C 1-6 alkyl; R X0 is R X0’ and together with R X1 may form a 3- to 8-membered saturated carbon ring substituted with 1 to 6 groups selected from unsubstituted or substituent group B; R X2 may combine together to form a 3- to 8-membered saturated carbon ring unsubstituted or substituted with 1 to 6 groups selected from substituent group B; R X1 is R X3 may combine together to form a 3- to 8-membered saturated heterocyclic ring unsubstituted or substituted with 1 to 6 groups selected from substituent group B; R 1 is a hydrogen atom, C 1-6 alkyl, or halo C 1-6 alkyl; R 1 is R X0 , R X1 , or R X3 may combine together to form a 5- to 8-membered saturated heterocyclic ring unsubstituted or substituted with 1 to 6 groups selected from substituent group B, or a 5- to 8-membered unsaturated heterocyclic ring unsubstituted or substituted with 1 to 6 groups selected from substituent group B; substituent group B consists of a halogen atom, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, and oxo; when two or more groups are present that are selected from substituent group B, the respective groups may be the same or different; R 2 is a halogen atom, cyano, hydroxy, amino, C 1-6 alkyl, halo C 1-6 alkyl, halohydroxy C 1-6 alkyl, SF5, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl C 1-6 alkyl, or C 6-10 aryl C 1-6 alkoxy; R T1 is a hydrogen atom, a halogen atom, hydroxy, C 1-6 alkyl, or halo C 1-6 alkyl; R 4 is C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, OR 5 , NR 5 R 5' alkyl, C 3-8 Cycloalkyl, 3- to 8-membered heterocycloalkyl; R 5 and R 5' are each independently a hydrogen atom, C 1-6 alkyl, halo C 1-6 alkyl, or C 3-8 cycloalkyl; R 5 is, together with R 5' a 3- to 10-membered saturated heterocycle substituted with 1 to 6 groups selected from unsubstituted or substituent group B, or a 3- to 10-membered unsaturated heterocycle substituted with 1 to 6 groups selected from unsubstituted or substituent group B, or may form; W 1 is CR W1 R W2 O, NR W3 or a single bond; R W1 and R W2 are each independently a hydrogen atom, a halogen atom, C 1-6 alkyl, or halo C 1-6 alkyl; R W3 is a hydrogen atom, C 1-6 alkyl, or halo C 1-6 alkyl; n is an integer from 0 to 3; when n is 2 or 3, each R 2 may be the same as or different from each other; Y is O or S; represents a single bond or a double bond) or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, wherein; R T1 is a compound in which R is a hydrogen atom or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, wherein; R 1 is a hydrogen atom, or C 1-6 alkyl, or a pharmacologically acceptable salt thereof.

5. The compound according to claim 4, wherein ring Z is C 6-10 a compound which is aryl, or 5- or 6-membered heteroaryl, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5, wherein X is CR X0 R X0’ , O, CO, or -(CR X1 R X2 )2-; R X0 , and R X0’ are each independently a hydrogen atom, C 1-6 alkyl, or halo C 1-6 alkyl, or a pharmacologically acceptable salt thereof.

7. The compound according to claim 6, wherein; R V1 , R V1’ , R V2 , and R V2’ are each independently a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, or C 1-6 alkoxy C 1-6 alkyl, or a pharmacologically acceptable salt thereof.

8. The compound according to claim 7, wherein Y is O; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8, wherein R 4 is NR 5 R 5' ; and R 5 and R 5' have the same meaning as in claim 1, or a pharmacologically acceptable salt thereof.

10. The compound according to claim 9, wherein W 1 is NR W3 ; and R W3 has the same meaning as in claim 1, or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 10, wherein; R 5 and R 5' are hydrogen atoms, or a pharmacologically acceptable salt thereof.

12. The compound according to claim 1, which is a compound represented by formula (A-III): [In the formula, ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; V 1 is CR V1 R V1’ 、CR V1 、NR V1 、N、O, or S; V 3 is CR V3 R V3’ 、CR V3 、NR V3 、N、O, or S; R V1 、R V1’ 、R V3 、and R V3’ are each independently a hydrogen atom, a halogen atom, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, halo C 1-6 alkoxy, NR V4 COR V5 、NR V4 COOR V6 、or NR V4 CONR V7 R V8 ; R V2 is halo C 1-6 alkoxy, NR V4 COR V5 、NR V4 COOR V6 、or NR V4 CONR V7 R V8 ; R V4 is a hydrogen atom or C 1-6 alkyl; R V5 、R V6 、R V7 、and R V8 is, independently, a hydrogen atom or a group selected from the group consisting of the following (i) to (ix): (i) C 1-6 alkyl, (ii) C 3-8 cycloalkyl substituted with 1 to 6 groups selected from the substituent group A, (iii) C 3-8 cycloalkyl C 1-6 alkyl, (iv) C 6-10 aryl, (v) C 6-10 aryl C 1-6 alkyl, (vi) 3- to 8-membered heterocycloalkyl substituted with 1 to 6 groups selected from the substituent group A, (vii) 3- to 8-membered heterocycloalkyl C 1-6 alkyl substituted with 1 to 6 groups selected from the substituent group A, (viii) 5- to 10-membered heteroaryl substituted with 1 to 6 groups selected from the substituent group A, and (ix) 5- to 10-membered heteroaryl C 1-6 alkyl substituted with 1 to 6 groups selected from the substituent group A; the substituent group A is a group consisting of a halogen atom, cyano, hydroxy, N(C 1-6 alkyl)2, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl C 1-6 alkoxy, and C 3-8 cycloalkyl; when two or more groups are present that are selected from the substituent group A, each group may be the same or different; X is CR X0 R X0’ , O, NR X3 , CO, -C(=CR X1 R X2 )-, -(CR X1 R X2 )2-, OCR X1 R X2 , CR X1 R X2 O, NR X3 CR X1 R X2 , CR X1 R X2 NR X3 , or -CR X1 =CR X2 -; R X0 R X0’ R X1 , and R X2 are each independently a hydrogen atom, a halogen atom, hydroxy, C 1-6 alkyl, or haloC 1-6 alkyl; R X3 is a hydrogen atom, C 1-6 alkyl, or haloC 1-6 alkyl; R X0 is R X0’ and together may form a 3- to 8-membered saturated carbon ring substituted with 1 to 6 groups selected from unsubstituted or substituent group B; R X1 is R X2 and together may form a 3- to 8-membered saturated carbon ring substituted with 1 to 6 groups selected from unsubstituted or substituent group B; R X1 is R X3 and together may form a 3- to 8-membered saturated heterocyclic ring substituted with 1 to 6 groups selected from unsubstituted or substituent group B; R 1 is a hydrogen atom, C 1-6 alkyl, or haloC 1-6 alkyl; R 1 is R X0 R X1 , or R X3 and together may form a 5- to 8-membered ring substituted with 1 to 6 groups selected from unsubstituted or substituent group B; Substituent group B consists of a halogen atom, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, and oxo; When two or more groups are selected from substituent group B, each group may be the same or different; R 2 is a halogen atom, cyano, hydroxy, amino, C 1-6 alkyl, halo C 1-6 alkyl, halohydroxy C 1-6 alkyl, SF5, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl C 1-6 alkyl, or C 6-10 aryl C 1-6 alkoxy; R T1 is a hydrogen atom, halogen atom, hydroxy, C 1-6 alkyl, or halo C 1-6 alkyl; R 4 is C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, OR 5 、NR 5 R 5' 、C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl; R 5 and R 5' are each independently a hydrogen atom, C 1-6 alkyl, halo C 1-6 alkyl, or C 3-8 cycloalkyl; R 5 is R 5' together with may form a 3- to 10-membered saturated heterocyclic ring substituted with 1 to 6 groups selected from unsubstituted or substituent group B, or a 3- to 10-membered unsaturated heterocyclic ring substituted with 1 to 6 groups selected from unsubstituted or substituent group B; W 1 is CR W1 R W2 、O、NR W3 、or a single bond; R W1 and R W2 are each independently a hydrogen atom, halogen atom, C 1-6 alkyl, or halo C 1-6 alkyl; R W3 is a hydrogen atom, C 1-6 alkyl, or halo C 1-6 alkyl; n is an integer from 0 to 3; when n is 2 or 3, each R 2 may be the same as or different from each other; q is 0 or 1; Y is O or S; represents a single bond or a double bond) or a pharmaceutically acceptable salt thereof.

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

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

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

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