Di-substituted bicyclo[1.1.1]pentane compound

Abstract

The present invention addresses the problem of providing a novel compound that has an antagonistic activity against thyroid-stimulating hormone receptors and is useful for the treatment of thyroid-related diseases.　The present invention relates to a di-substituted bicyclo[1.1.1]pentane compound represented by formula (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 useful as, for example, a therapeutic agent for thyroid-related diseases (e.g., hyperthyroidism, Graves' disease, thyroid eye disease, and thyroid cancer).

Description

Disubstituted bicyclo[1.1.1]pentane compounds

[0001] The present invention relates to a disubstituted bicyclo[1.1.1]pentane compound useful as a pharmaceutical. More specifically, the present invention relates to a disubstituted bicyclo[1.1.1]pentane compound or a pharmacologically acceptable salt thereof that has antagonist activity against the thyroid-stimulating hormone receptor (TSHR) and is useful as a therapeutic agent for thyroid-related diseases.

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

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

[0004] There are various causes of hyperthyroidism, but the most common is Graves' disease. In Graves' disease, an autoimmune mechanism causes the thyroid gland to be recognized as a foreign body, resulting in the production of autoantibodies against the TSHR present on thyroid follicular cells, known as TSHR antibodies (TRAb). It is thought that these TRAb act as TSHR agonists, overstimulating the TSHR and resulting in the excessive production of thyroid hormones, leading to the development of 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 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 T4 levels in mice treated 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. Patent Documents 4 to 6 describe or exemplify compounds containing disubstituted bicyclo[1.1.1]pentane. Patent Document 7 describes cycloalkyl compounds, Patent Document 8 describes carbamate compounds, and Patent Document 9 describes compounds having kinase inhibitory activity, all of which describe a wide range of general formulas. However, the disubstituted bicyclo[1.1.1]pentane compound of the present invention is not described in any of Patent Documents 1 to 9 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 International Publication No. 2019 / 032743 US Patent Application Publication No. 2014 / 0275245 US Patent Application Publication No. 2016 / 0075654 US Patent Application Publication No. 2019 / 0060257 US Patent Application Publication No. 2005 / 0203176 US Patent Application Publication No. 2007 / 0208166

[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 (I) or a pharmacologically acceptable salt thereof:

[0013] That is, the present invention relates to the following [1] to

[11] , etc. [1] Formula (I): wherein V is C 1-6 alkylene or a single bond; R 1 is a group selected from the group consisting of the following (a) to (h): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group A 1-6 (b) unsubstituted or substituted with 1 to 3 groups selected from the substituent group A 6-10 aryl, (c) a 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A, (d) a 9- or 10-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A, (e) C that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A 3-10 (f) 3- to 10-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A; (g) the following groups which are unsubstituted or substituted with 1 to 3 groups selected from the substituent group A: and (h) the following group unsubstituted or substituted with 1 to 3 groups selected from the substituent group A: Ring U and ring W each independently represent C 5-8 cycloalkyl, or 5- to 8-membered heterocycloalkyl; Substituent group A is a halogen atom, cyano, C 1-6 Alkyl, hydroxy, amino, -C(O)OR 12 , Haro C 1-6 Alkyl, Cyano C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl C 1-6 Alkyl, C 3-10 Cycloalkyl C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkoxy C 1-6 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl, 5- or 6-membered heteroarylC 1-6 Alkyl, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-10 Cycloalkyl C 2-6 Alkynyl, halohydroxy C 1-6 alkyl, and -SF5; when substituted with two or three groups selected from the substituent group A, each group may be the same or different; R 12 is a hydrogen atom or C 1-6 alkyl; R 2 , and R 2' are each independently a hydrogen atom or C 1-6 alkyl; R 2 is R 1 Together with C 5-8 cycloalkyl, or 5- to 8-membered heterocycloalkyl; R 3 is a group selected from the group consisting of the following (i) to (vii): and R 5 , and R 5' are each independently a hydrogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 3-10Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl or hydroxy C 1-6 alkyl; R 5 , and R 5' may be taken together to form a 3- to 10-membered heterocycloalkyl; R 6 is C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl or C 3-10 cycloalkyl; R 7 is C 1-6 Alkyl, HaloC 1-6 Alkyl, C 3-10 Cycloalkyl, or C 6-10 Aryl C 1-6 alkyl; R 8 , and R 8’ are each independently a hydrogen atom, C 1-6 alkyl, or hydroxy; R 4 is a halogen atom, cyano, C 1-6 Alkyl, hydroxy, -NR 9 R 9' , Haro C 1-6 Alkyl, Cyano C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, -NR 13 C(O)OR 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 11 R 11' , -OC(O)NR 11 R 11' , -(C 1-6 (Alkylene)-NR 13 C(O)OR 10 , -(C1-6 (Alkylene)-NR 13 C(O)R 11 , -(C 1-6 (Alkylene)-NR 13 C(O)NR 11 R 11' , or -(C 1-6 (alkylene)-OC(O)NR 11 R 11' and R 13 is a hydrogen atom or C 1-6 alkyl; R 9 , and R 9' are each independently a hydrogen atom or C 1-6 alkyl; R 10 is a group selected from the group consisting of the following (i) to (o): (i) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group B 1-6 (j) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group B 3-10 (k) unsubstituted or substituted with 1 to 6 groups selected from the substituent group B 3-10 Cycloalkyl C 1-6 (l) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl C 1-6 (m) a 3- to 10-membered heterocycloalkyl C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 1-6 alkyl, (n) a 5- or 6-membered heteroaryl C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 1-6 alkyl, and (o) a 9- or 10-membered heteroaryl unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; the substituent group B is a halogen atom, cyano, hydroxy, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryloxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl C 1-6Alkyl, and C 3-10 Cycloalkyl C 1-6 alkoxy; when substituted with two or more groups selected from the substituent group B, each group may be the same or different; R 11 , and R 11' are each independently a group selected from the group consisting of the following (p) to (x): (p) a hydrogen atom, (q) unsubstituted or C substituted with 1 to 6 groups selected from the substituent group C 1-6 alkyl, (r) unsubstituted or substituted with 1 to 6 groups selected from the substituent group C 3-10 cycloalkyl, (s) unsubstituted or substituted with 1 to 6 groups selected from the substituent group C 3-10 Cycloalkyl C 1-6 (t) unsubstituted or substituted with 1 to 3 groups selected from the substituent group C 6-10 Aryl C 1-6 alkyl, (u) 3- to 10-membered heterocycloalkyl C unsubstituted or substituted with 1 to 3 groups selected from the substituent group C 1-6 (v) a 5- or 6-membered heteroaryl C unsubstituted or substituted with 1 to 3 groups selected from the substituent group C 1-6 alkyl, (w) 9- or 10-membered heteroaryl unsubstituted or substituted with 1 to 3 groups selected from the substituent group C, and (x) the following groups unsubstituted or substituted with 1 to 3 groups selected from the substituent group C: Ring Z is C 5-8 cycloalkyl, or 5- to 8-membered heterocycloalkyl; the substituent group C is a halogen atom, cyano, hydroxy, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryloxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl C 1-6 Alkyl, and C 3-10 Cycloalkyl C 1-6alkoxy; when substituted with two or more groups selected from the substituent group C, each group may be the same or different; R 11 , and R 11' may be taken together to form a 3- to 10-membered heterocycloalkyl, or a pharmacologically acceptable salt thereof. [2] The compound according to [1] above, wherein: Substituent group A is a halogen atom, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkoxy C 1-6 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-6 R is the group consisting of alkoxy, 5- or 6-membered heteroaryl, and -SF5; 5 , and R 5' are each independently a hydrogen atom or C 1-6 alkyl; R 6 But C 1-6 alkyl; R 7 But C 1-6 Alkyl or C 6-10 Aryl C 1-6 alkyl; R 8 , and R 8’ are each independently a hydrogen atom or hydroxy; R 4 But halogen atoms, C 1-6 Alkyl, hydroxy, -NR 9 R 9' , hydroxy C 1-6 Alkyl, -NR 13 C(O)OR 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 11 R 11' , or -OC(O)NR 11 R 11' and R13 is a hydrogen atom; and the substituent group B is a halogen atom, a hydroxyl, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, and C 3-10 The substituent group C is a group consisting of a halogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryloxy, and C 3-10 [3] A compound according to [1] or [2], wherein V is -CH2- or a single bond; R is a compound selected from the group consisting of -cycloalkyl; or a pharmacologically acceptable salt thereof. 1 is a group selected from the group consisting of the following (a) to (d): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group A 6-10 (b) 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A; (c) the following groups which are unsubstituted or substituted with 1 to 3 groups selected from the substituent group A: and (d) the following group unsubstituted or substituted with 1 to 3 groups selected from Substituent Group A: [4] A compound according to any one of [1] to [3], wherein ring U and ring W have the same meaning as in [1] above; and substituent group A has the same meaning as in [2] above; or a pharmacologically acceptable salt thereof. 3 is a group selected from the group consisting of the following (i) to (iv): and R 5 , R 5' , and R 6 [5] A compound according to any one of [1] to [4], wherein: R 4 But -NHC(O)OR 10 , -NHC(O)R 11 , -NHC(O)NR 11 R 11' , or -OC(O)NR 11 R 11' and R10 is a group selected from the group consisting of the following (a) to (d): (a) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group B 1-6 (b) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group B 3-10 (c) unsubstituted or substituted with 1 to 6 groups selected from the substituent group B 3-10 Cycloalkyl C 1-6 alkyl, and (d) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl C 1-6 alkyl; the substituent group B has the same meaning as in [2] above; R 11 , and R 11' are each independently selected from the group consisting of the following (e) to (i): (e) a hydrogen atom, (f) unsubstituted or C substituted with 1 to 6 groups selected from the substituent group C 1-6 (g) unsubstituted or substituted with 1 to 6 groups selected from the substituent group C 3-10 (h) unsubstituted or substituted with 1 to 3 groups selected from the substituent group C 6-10 Aryl C 1-6 alkyl, and (i) the following groups unsubstituted or substituted with 1 to 3 groups selected from the substituent group C: Ring Z is a 5- to 8-membered heterocycloalkyl; and the substituent group C is a halogen atom, C 1-6 Alkyl, C 6-10 Aryloxy and haloC 1-6 [6] The compound according to any one of [1] to [5] above, wherein the substituent group A is a halogen atom, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, and C 3-10 cycloalkoxy; R 2 , and R 2' is a hydrogen atom; R 3 is the following group: R5 , and R 5' is a hydrogen atom; R 4 But -NHC(O)OR 10 and R 10 is a group selected from the group consisting of the following (a) to (d): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 1-6 (b) unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 3-10 (c) unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 3-10 Cycloalkyl C 1-6 alkyl, and (d) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl C 1-6 Alkyl; Substituent group B is a halogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl, and C 3-10 [7] A compound according to any one of [1] to [6] above, which is represented by formula (IA): [In the formula, V a is -CH2- or a single bond; R 1a is a group selected from the group consisting of the following (a) to (d): (a) unsubstituted or substituted group A a C substituted with 1 to 3 groups selected from 6-10 (b) unsubstituted or substituted group A a (c) a 5- or 6-membered heteroaryl substituted with 1 to 3 groups selected from group A a the following group substituted with 1 to 3 groups selected from: and (d) unsubstituted or substituted group A a the following group substituted with 1 to 3 groups selected from: Ring U a , and ring W a are each independently 5-8 cycloalkyl, or 5- to 8-membered heterocycloalkyl; Substituent Group A a is a halogen atom, cyano, C1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, and C 3-10 Substituent Group A is a group consisting of cycloalkoxy; a When substituted with two or three groups selected from the group consisting of 10a is a group selected from the group consisting of the following (e) to (h): (e) unsubstituted or substituted group B a C substituted with 1 to 3 groups selected from 1-6 Alkyl, (f) unsubstituted or substituted group B a C substituted with 1 to 3 groups selected from 3-10 cycloalkyl, (g) unsubstituted or substituted group B a C substituted with 1 to 3 groups selected from 3-10 Cycloalkyl C 1-6 alkyl, and (h) unsubstituted or substituted group B a C substituted with 1 to 3 groups selected from 6-10 Aryl C 1-6 Alkyl; Substituent Group B a is a halogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl, and C 3-10 Substituent group B is a group consisting of cycloalkyl; a [8] A compound according to any one of [1] to [7] above, which is selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof. [9] A pharmaceutical composition comprising the compound according to any one of [1] to [8] above or a pharmacologically acceptable salt thereof, and a pharmaceutical additive.

[10] The pharmaceutical composition according to [9] above, which is a pharmaceutical composition for treating a thyroid-related disease.

[11] The pharmaceutical composition according to

[10] above, wherein the thyroid-related disease is hyperthyroidism, Graves' disease, or thyroid ophthalmopathy.

[0014] 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 [9] above.

[0015] In one embodiment, the present invention relates to use of the compound according to any one of the above [1] to [8] or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition for treating a thyroid-related disease.

[0016] In one embodiment, the present invention provides a compound of formula (I): wherein V is C 1-6 alkylene or a single bond; R 1 is a group selected from the group consisting of the following (a) to (f): (a) a hydrogen atom, (b) a C unsubstituted or substituted with 1 to 3 groups selected from the substituent group A 6-10 aryl, (c) a 5- or 6-membered heteroaryl unsubstituted or substituted with 1 to 3 groups selected from the substituent group A, (d) a 5- or 6-membered heteroaryl unsubstituted or C 1-6 Alkyl-substituted C 3-10 (e) the following groups unsubstituted or substituted with 1 to 3 groups selected from the substituent group A: and (f) the following group unsubstituted or substituted with 1 to 3 groups selected from the substituent group A: Substituent group A is a halogen atom, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, and C 3-10 cycloalkoxy; when substituted with two or three groups selected from the substituent group A, each group may be the same or different; R 2, and R 2' are each independently a hydrogen atom or C 1-6 alkyl; R 3 is a group selected from the group consisting of the following (i) to (vii): and R 5 , and R 5' are each independently a hydrogen atom or C 1-6 alkyl; R 6 is C 1-6 alkyl; R 7 is C 1-6 Alkyl or C 6-10 Aryl C 1-6 alkyl; R 8 is a hydrogen atom or hydroxy; R 4 is a halogen atom, hydroxy, -NR 9 R 9' , C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, -NHC(O)OR 10 , -NHC(O)R 11 , -NHC(O)NR 11 R 11' , or -OC(O)NR 11 R 11' and R 9 , and R 9' are each independently a hydrogen atom or C 1-6 alkyl; R 10 is a group selected from the group consisting of the following (g) to (k): (g) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group B 1-6 (h) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group B 3-10 cycloalkyl, (i) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group B 3-10 Cycloalkyl C 1-6 (j) unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl C 1-6 alkyl, and (k) a 5- or 6-membered heteroaryl C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B1-6 Alkyl; Substituent group B is a halogen atom, hydroxy, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, and C 3-10 cycloalkyl; when substituted with two or more groups selected from the substituent group B, each group may be the same or different; R 11 , and R 11' are each independently a group selected from the group consisting of the following (l) to (q): (l) a hydrogen atom, (m) unsubstituted or C substituted with 1 to 6 groups selected from the substituent group C 1-6 alkyl, (n) unsubstituted or substituted with 1 to 6 groups selected from the substituent group C 3-10 (o) unsubstituted or substituted with 1 to 3 groups selected from the substituent group C 6-10 Aryl C 1-6 alkyl, (p) 3- to 10-membered heterocycloalkyl C unsubstituted or substituted with 1 to 3 groups selected from the substituent group C 1-6 alkyl, and (q) the following groups unsubstituted or substituted with 1 to 3 groups selected from the substituent group C: Substituent group C is a halogen atom, haloC 1-6 Alkyl, and C 6-10 and when substituted with two or more groups selected from Substituent group C, each group may be the same or different, or a pharmacologically acceptable salt thereof.

[0017] 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.

[0018] Hereinafter, embodiments of the present invention will be described in more detail.

[0019] In the present invention, each term has the following meaning unless otherwise specified.

[0020] "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, isopentyl, sec-butyl, tert-butyl, 3-methylbutan-2-yl, neopentyl, etc. 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 "Alkylene" means a straight-chain or branched alkylene group having 1 to 6 carbon atoms. Examples include methylene, ethylene, trimethylene, methylmethylene, ethylmethylene, dimethylmethylene, 1-methylethylene, and 2-methyltrimethylene. 1-6 The term "alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like.

[0021] "Haro C 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 hydroxy 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 "Alkyl" refers to a C substituted with 1 or 2 hydroxy groups. 1-6 It means alkyl. Examples include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, etc. "Amino C 1-6 "Alkyl" refers to a C substituted with 1 or 2 amino groups. 1-6 Examples include aminomethyl, aminoethyl, aminopropyl, 2-aminopropan-2-yl, etc. "Cyano C 1-6 "Alkyl" refers to a C substituted with one or two cyanos. 1-6It means alkyl. Examples include cyanomethyl, cyanoethyl, cyanopropyl, 2-cyanopropan-2-yl, etc. 1-6 Alkoxy C 1-6 "Alkyl" means one C 1-6 Alkoxy-substituted C 1-6 It means alkyl, and examples thereof include methoxymethyl, methoxyethyl, ethoxymethyl, and ethoxyethyl.

[0022] "Haro C 1-6 "Alkoxy" means a C substituted with 1 to 5 identical or different halogen atoms. 1-6 It means alkoxy, and examples thereof include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, and the like.

[0023] "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 "HaloC" refers to alkyl. For example, 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl is included. 1-6 Alkoxy C 1-6 "Alkyl" means one haloC 1-6 Alkoxy-substituted C 1-6 It means alkyl, for example, trifluoromethoxymethyl.

[0024] "C 6-10"Aryl" means a phenyl group or a naphthyl group. "5- or 6-membered heteroaryl" means a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. Examples include pyridyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl. "9- or 10-membered heteroaryl" means a bicyclic aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. Examples include indolyl, isoindolyl, benzofuryl, benzothiophenyl, benzimidazolyl, pryl, benzotriazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, cinnolyl, pteridinyl, chromenyl, and isochromenyl.

[0025] "C 3-10 "Cycloalkyl" means a 3- to 10-membered monocyclic or bicyclic hydrocarbon group. 5-8 "Cycloalkyl" means a 5- to 8-membered monocyclic or bicyclic hydrocarbon group. The monocyclic or bicyclic hydrocarbon group may be a saturated or partially unsaturated hydrocarbon group. The bicyclic hydrocarbon group may contain spiro rings, fused rings, and bridged rings. Examples of monocyclic hydrocarbon groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0026] "3- to 10-membered heterocycloalkyl" refers to a 3- to 10-membered monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. "5- to 8-membered heterocycloalkyl" refers to a 5- to 8-membered monocyclic or bicyclic heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. The monocyclic or bicyclic heterocyclic group may be saturated or partially unsaturated. The bicyclic heterocyclic group may contain spiro rings, fused rings, and bridged rings. Examples of monocyclic heterocyclic groups include aziridino, azetidino, morpholino, thiomorpholino, 1-pyrrolidinyl, piperidino, 4-piperidinyl, 1-piperazinyl, 1-pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.

[0027] "C 6-10 Aryl C 1-6 "Alkyl" means one C 6-10 Aryl-substituted C 1-6 It means alkyl. Examples include benzyl, phenethyl, 1-phenylethyl, etc. 6-10 Aryl C 2-6 "Alkynyl" means one C 6-10 Aryl-substituted C 2-6 It means alkynyl. For example, phenylethynyl. 6-10 Aryl C 1-6 "Alkoxy" means one C 6-10 Aryl-substituted C 1-6 "Alkoxy" refers to an alkoxy group. For example, benzyloxy is mentioned. "5- or 6-membered heteroaryl C 1-6 "Alkyl" refers to a C substituted with one 5- or 6-membered heteroaryl. 1-6 Examples include pyridin-4-ylmethyl, thiophen-2-ylethyl, and thiophen-3-ylethyl. "5- or 6-membered heteroaryl C 2-6 "Alkynyl" refers to a C alkynyl group substituted with one 5- or 6-membered heteroaryl. 2-6It means alkynyl. For example, pyridin-4-ylethynyl, pyridin-3-ylethynyl, etc. 3-10 Cycloalkyl C 1-6 "Alkyl" means one C 3-10 Cycloalkyl-substituted C 1-6 Examples of the alkyl include cyclopropylmethyl, cyclopropylethan-1-yl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl. 3-10 Cycloalkyl C 2-6 "Alkynyl" means one C 3-10 Cycloalkyl-substituted C 2-6 It means alkynyl. For example, cyclopropylethynyl is mentioned. 3-10 Cycloalkyl C 1-6 "Alkoxy" means one C 3-10 Cycloalkyl-substituted C 1-6 "Alkoxy" refers to alkoxy. For example, cyclopropylmethyloxy is mentioned. "3- to 10-membered heterocycloalkyl C 1-6 "Alkyl" refers to a C substituted with one 3- to 10-membered heterocycloalkyl. 1-6 It means alkyl, for example, tetrahydrofuranylmethyl.

[0028] "C 3-10 "Cycloalkoxy" means (C 3-10 cycloalkyl)-O-. For example, cyclopropyloxy.

[0029] "C 6-10 "Aryloxy" means (C 6-10 aryl)-O-. For example, phenoxy is mentioned.

[0030] When a group containing an acyclic structure and a cyclic structure is substituted with a group selected from Substituent Group A, Substituent Group B, or Substituent Group C, one or both of the acyclic structure and the cyclic structure may be substituted. For example, C substituted with 1 to 6 groups selected from Substituent Group B 3-10 Cycloalkyl C 1-6Examples of alkyl include (1-methylcyclopropyl)methyl, (2,2-difluorocyclopropyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, (1-(trifluoromethyl)cyclopropyl)methyl, (2,2-difluoro-1-methylcyclopropyl)methyl, (2,2-difluorocyclobutyl)methyl, (3-fluorocyclobutyl)methyl, (3,3-difluorocyclobutyl)methyl, 1-cyclopropyl-2,2,2-trifluoroethan-1-yl, and the like.

[0031] The following abbreviations used in the text, figures, and tables have the following meanings: Cbz-Cl: Benzyl chloroformate CDI: 1,1'-carbonyldiimidazole DCE: 1,2-dichloroethane DCM: Dichloromethane DIPEA: N,N-Diisopropylethylamine DMAP: 4-Dimethylaminopyridine DME: 1,2-Dimethoxyethane DMF: N,N-Dimethylformamide DMSO: Dimethyl sulfoxide DMT-MM: 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride EDC-HCl: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HOBt: 1-Hydroxybenzotriazole HOBt hydrate: HOBt monohydrate MeCN: Acetonitrile T3P (registered trademark): Propylphosphonic anhydride (cyclic trimer) TEA: Triethylamine THF: Tetrahydrofuran 10% Pd / C: 10% palladium carbon (approximately 55% water-wet) Aminosilicagel: Aminopropylated silica gel Method A: Column chromatography using a silica gel column connected to the bottom of an aminopropylated silica gel column Process: Process Scheme: Scheme Ref. No.: Reference Example Number Str.: Structural formula Ex. No.: Example Number Phys. data: Physical property values ​​IC 50 : 50% inhibitory concentration 1H-NMR: Proton nuclear magnetic resonance spectrum DMSO-d6: Dimethyl sulfoxide-d6 CDCl3: Chloroform-d1 MS: Mass spectrometry (The MS values ​​in the table were measured using the multi-ionization method of electrospray ionization-atmospheric pressure chemical ionization.) 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

[0032] When one or more asymmetric carbon atoms are present in the compound of formula (I), the present invention encompasses compounds in which each asymmetric carbon atom is in the R configuration, compounds in the S configuration, and any combination thereof. Furthermore, their racemates, racemic mixtures, single enantiomers, and diastereomeric mixtures are also included within the scope of the present invention.

[0033] In the case where the compound represented by formula (I) has cis-trans isomers, the present invention includes both of the cis-trans isomers.

[0034] When tautomers exist in the compound represented by formula (I), the present invention includes all of the tautomers.

[0035] In the present invention, the determination of stereochemistry can also be carried out by methods well known in the art.

[0036] The compound represented by formula (I) can be converted into a pharmacologically acceptable salt thereof according to a conventional method, if necessary. Such salts include acid addition salts and salts with bases.

[0037] 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.

[0038] 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.

[0039] Unless otherwise specified, a suffix to a chemical name or structural formula that refers to a salt, such as "hydrochloride" or "HCl," does not denote a stoichiometric description but simply denotes the salt form.

[0040] When the compound represented by formula (I) or a pharmacologically acceptable salt thereof exists, for example, as a crystal, the present invention includes any crystalline form. For example, pharmacologically acceptable salts also include solvates with pharmaceutically acceptable solvents such as water or ethanol, co-crystals with a suitable co-crystal former, etc.

[0041] In the compound represented by formula (I), some of the atoms may be replaced with the corresponding isotopes. The present invention also includes compounds replaced with these isotopes. Examples of isotopes include: 2 H, 3 H, 11 C. 13 C. 14 C. 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O. 17 O. 18 O, and 35 In one embodiment, some of the hydrogen atoms of the compound represented by formula (I) are isotopes of the hydrogen atom, carbon atom, chlorine atom, fluorine atom, iodine atom, nitrogen atom, oxygen atom, and sulfur atom represented by S. 2 Examples include compounds in which hydrogen is replaced by H (D: deuterium atom).

[0042] A compound represented by formula (I) in which some atoms are replaced with isotopes can be produced by a method similar to the production method described below, using a commercially available building block containing an isotope. For example, a compound represented by formula (I) in which some hydrogen atoms are replaced with deuterium atoms can also be produced by the above-mentioned method and methods described in the literature (see, for example, Journal of Organic Synthetic Chemistry, 2007, Vol. 65, No. 12, pp. 1179-1190). In addition, for example, a compound represented by formula (I) in which some carbon atoms are replaced with deuterium atoms can also be produced by the above-mentioned method and methods described in the literature (see, for example, Journal of Organic Synthetic Chemistry, 2007, Vol. 65, No. 12, pp. 1179-1190). 13 Compounds substituted at C can also be produced using the above method and methods described in the literature (see, for example, RADIOISOTOPES, 2007, Vol. 56, No. 11, pp. 741-750).

[0043] The compound of the present invention represented by formula (I) can be produced, for example, by the methods shown in Schemes 1 to 6 or methods similar thereto, or by methods described in the literature or methods similar thereto. In the schemes, the compound of formula (I) corresponds to the compounds represented by compounds (I-1) to (I-13) and compound (I').

[0044] The compound of the present invention represented by formula (I) can be produced by the following method, but the following production method is an example of a general production method and is not intended to limit the production method.

[0045] In the reactions of each step, when raw materials and reagents are commercially available, commercially available products can be used.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] A microwave reactor such as Biotage's Initiator may be used in the reactions of each step. When a microwave reactor is used, the conditions vary depending on the raw materials, solvent, and model used, but the reaction can be carried out under the following conditions: pressure range: 1 to 30 bar, power range: 1 to 400 W, reaction temperature: room temperature to 300°C, and reaction time: 1 minute to 1 day.

[0050] Unless otherwise specified, the reaction in each step is carried out without solvent or using an appropriate solvent. Examples of the appropriate solvent include solvents inert to the reaction. Specific examples of the solvent used include the solvents described in the Reference Examples or Examples corresponding to each step, or the following solvents. Two or more of the following solvents may be mixed in an appropriate ratio and used. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-propanol, etc.; Ethers: diethyl ether, THF, DME, 1,4-dioxane, cyclopentyl methyl ether, etc.; Aromatic hydrocarbons: benzene, chlorobenzene, 1,2-dichlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, n-hexane, etc.; Amides: DMF, N,N-dimethylacetamide, N-methylpyrrolidone, 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, trifluoroacetic acid, etc.; Esters: ethyl acetate, methyl acetate, isopropyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; Water.

[0051] When a base is used in the reaction of each step, the reaction is carried out using a base suitable for the reaction. Specific examples of the base to be used include the bases described in the Reference Examples or Examples corresponding to each step, and the following bases. Inorganic bases: sodium hydroxide, lithium hydroxide, potassium hydroxide, etc.; basic salts: sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, etc.; organic bases: TEA, DIPEA, diethylamine, pyridine, DMAP, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; metal alkoxides: sodium ethoxide, sodium methoxide, potassium tert-butoxide, etc.; alkali metal hydrides: sodium hydride, etc.; metal amides: sodium amide, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, etc.; organic magnesiums: isopropyl magnesium chloride, etc.; organic lithiums: n-butyllithium, sec-butyllithium, tert-butyllithium, etc.

[0052] When an acid or an acidic catalyst is used in the reaction of each step, the reaction is carried out using an acid or an acidic catalyst suitable for the reaction. Specific examples of the acid or acidic catalyst used include the acid or acidic catalysts described in the Reference Examples and Examples corresponding to each step, or the following acid or acidic catalysts: inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; organic acids: acetic acid, trifluoroacetic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, aluminum chloride, zinc chloride, titanium(IV) chloride, etc.

[0053] 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: EDC-HCl, 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.

[0054] When a reducing agent is used in the reaction of each step, the reaction is carried out using a reducing agent suitable for the reaction. Specific examples of the reducing agent to be used include the reducing agents described in the Reference Examples or Examples corresponding to each step, or the following reducing agents. Metal hydrides: lithium aluminum hydride, lithium borohydride, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride, etc.; Boranes: BH3-THF complex, picoline borane complex, decaborane, etc.

[0055] 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.

[0056] 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.

[0057] When a hydrolysis reaction is carried out in each step, the reaction can be carried out in the presence of an acid or a base. Examples of the acid and base that can be used include those mentioned above.

[0058] In each step, when a catalytic reduction reaction is carried out, the reaction can be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst that can be used include palladium carbon powder, Pearlman's catalyst, platinum carbon powder, Raney nickel, etc. If necessary, an acid may be used in the reaction.

[0059] When a reduction reaction is carried out in each step, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent to be used include the above-mentioned examples.

[0060] In each step, when an amidation reaction is carried out, 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 HOBt 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.

[0061] When a reductive amination reaction is carried out in each step, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent that can be used include those mentioned above. The reaction can also be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst that can be used include palladium carbon powder, Pearlman's catalyst, platinum carbon powder, Raney nickel, etc.

[0062] In each step, when a carbamate reaction or a urea reaction is carried out, 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.

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

[0064] The symbols in the formula have the same meanings as above. X is a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonyloxy group. Y is a hydroxyl or chlorine atom.

[0065] Process 1-1 Compound (1-6) can also be produced by reacting compound (1-1) with compound (1-2) in the presence of a base. Process 1-2 Compound (1-6) can be produced by reacting compound (1-1) with compound (1-2) in the presence of a base. 2' When is a hydrogen atom, it can also be produced by a reductive amination reaction of compound (1-1) with compound (1-3).

[0066] Process 1-3 The compound (1-5) can also be produced by an amidation reaction of the compound (1-1) and the compound (1-4).

[0067] Process 1-4 Compound (1-6) is R 2 , and R 2' When is a hydrogen atom, it can also be produced by a reduction reaction of compound (1-5).

[0068] Process 1-5 Compound (I) can also be produced by an amidation reaction of compound (1-6) and compound (1-7).

[0069] The compounds represented by formula (I-1), formula (I-2), formula (I-3), and formula (I-4) can be produced, for example, according to the method described in Scheme 2.

[0070] The symbols in the formula have the same meanings as above, and Z is a protected amino group.

[0071] Process 2-1 Compound (I-1) can also be prepared by removing the protecting group of compound (I').

[0072] Process 2-2 Compound (I-2) can also be produced by subjecting compound (2-1) and compound (I-1) to a carbamate reaction.

[0073] Process 2-3 Compound (I-3) can also be produced by an amidation reaction of compound (2-2) and compound (I-1).

[0074] Process 2-4 Compound (I-4) can also be produced by subjecting compound (2-3) and compound (I-1) to a urea reaction.

[0075] The compound represented by formula (I-5) can be produced, for example, according to the method described in Scheme 3.

[0076] The symbols in the formula have the same meanings as above. 4 is hydroxy. PG 1 is a protecting group.

[0077] Process 3-1 The compound (3-1) can also be produced by introducing a protecting group into the amino group of the compound (1-6).

[0078] Process 3-2 The compound (3-2) can also be produced by a carbamate reaction of the compound (3-1) and the compound (2-3).

[0079] Process 3-3 The compound (3-3) can also be prepared by removing the protecting group of the compound (3-2).

[0080] Process 3-4 Compound (I-5) can also be produced by an amidation reaction of compound (1-7) and compound (3-3).

[0081] The compounds represented by formula (I-6) and formula (I-7) can be produced, for example, according to the method described in Scheme 4.

[0082] The symbols in the formula have the same meanings as above. 2 , and P.G. 3 is a protecting group.

[0083] Process 4-1 The compound (4-2) can also be produced by an amidation reaction of the compound (1-6) and the compound (4-1).

[0084] Process 4-2 The compound (4-3) can also be prepared by removing the protecting group of the compound (4-2).

[0085] Process 4-3 Compound (I-6) can also be produced by an amidation reaction of compound (4-3) and compound (4-4).

[0086] Process 4-4 The compound (4-6) can also be produced by an amidation reaction of the compound (1-6) and the compound (4-5).

[0087] Process 4-5 The compound (4-7) can also be prepared by removing the protecting group of the compound (4-6).

[0088] Process 4-6 Compound (I-7) can also be produced by an amidation reaction of compound (4-7) and compound (4-4).

[0089] The compounds represented by formula (I-8), formula (I-9), formula (I-10), and formula (I-11) can be produced, for example, according to the method described in Scheme 5.

[0090] The symbols in the formula have the same meanings as above.

[0091] Process 5-1 The compound (5-2) can also be produced by an amidation reaction of the compound (1-6) and the compound (5-1).

[0092] Process 5-2 The compound (5-3) can also be prepared by removing the protecting group of the compound (5-2).

[0093] Process 5-3 Compound (I-8) can also be produced by reacting compound (5-3) with trimethylsilyl isocyanate or an alkali cyanate such as potassium cyanate or sodium cyanate.

[0094] Process 5-4 Compound (I-9) can also be produced by subjecting compound (5-3) and compound (4-4) to a urea reaction.

[0095] Process 5-5 Compound (I-10) can also be produced by an amidation reaction of compound (5-3) and compound (5-4).

[0096] Process 5-6 Compound (I-11) can also be produced by subjecting compound (5-3) and compound (5-5) to a carbamate reaction.

[0097] The compounds represented by formula (I-12) and formula (I-13) can be produced, for example, according to the method described in Scheme 6.

[0098] The symbols in the formula have the same meanings as above. 4 , and P.G. 5 is a protecting group.

[0099] Process 6-1 The compound (6-2) can also be produced by subjecting the compound (1-6) and the compound (6-1) to a urea reaction.

[0100] Process 6-2 The compound (6-3) can also be prepared by removing the protecting group of the compound (6-2).

[0101] Process 6-3 Compound (I-12) can also be produced by an amidation reaction of compound (6-3) and compound (4-4).

[0102] Process 6-4 The compound (6-5) can also be produced by an amidation reaction of the compound (1-6) and the compound (6-4).

[0103] Process 6-5 The compound (6-6) can also be prepared by removing the protecting group of the compound (6-5).

[0104] Process 6-6 Compound (I-13) can also be produced by subjecting compound (6-6) and compound (4-4) to a carbamate reaction.

[0105] The scheme shown above is an example of a method for producing a compound represented by formula (I) or a production intermediate thereof. The scheme can be modified in various ways that can be easily understood by those skilled in the art.

[0106] The compound represented by formula (I) and its production intermediates can also be isolated and purified, if necessary, by isolation and purification means well known to those skilled in the art, such as solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography, etc.

[0107] The compounds of the present invention have excellent TSHR antagonist activity and can therefore 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, Vol. 155, No. 1, pp. 310-314). More preferably, the compounds of the present invention can be used as therapeutic agents for hyperthyroidism or Graves' disease.

[0108] 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.

[0109] 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.

[0110] In the present invention, "treatment" includes the meaning of "prevention." For example, treatment of hyperthyroidism, Graves' disease, or thyroid eye disease includes the meanings of "prevention of relapse / recurrence" and "maintenance of remission." In addition, in one embodiment, the compounds of the present invention can be used to prevent the onset of thyroid eye disease in patients with Graves' disease.

[0111] 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)."

[0112] 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, a method for confirming the effect in an animal model of hyperthyroidism or Graves' disease includes the method described in "Endocrinology," 2007, Vol. 148, No. 5, pp. 2335-2344, or a method modified therefrom.

[0113] 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.

[0114] The pharmaceutical composition of the present invention comprises a compound represented by formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.

[0115] The pharmaceutical compositions of the present invention are prepared using the compound represented by formula (I) or a pharmacologically acceptable salt thereof and at least one pharmaceutical additive. These pharmaceutical compositions can also be prepared by appropriately mixing, diluting, or dissolving the compound with pharmaceutical additives such as suitable excipients, disintegrants, binders, lubricants, diluents, buffers, isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizers, according to the dosage form, using methods known in pharmaceutical science.

[0116] When the pharmaceutical composition of the present invention is used for treatment, the dosage of the compound represented by Formula (I) or a pharmacologically acceptable salt thereof is determined appropriately depending on the patient's age, sex, body weight, disease, and degree of treatment. The daily dosage may be administered once, twice, three times, or four times. When administered orally, the dosage for an adult may be determined, for example, in the range of 0.1 to 5000 mg / day. In one embodiment, the oral dosage may be determined in the range of 1 to 1500 mg / day, preferably 1 to 500 mg / day, and more preferably 10 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 0.1 to 500 mg / day, and more preferably 1 to 500 mg / day.

[0117] 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.

[0118] When the compound represented by formula (I) or its pharmacologically acceptable salt is used in combination with other drugs, these active ingredients can be administered as a preparation containing them together, or as a preparation in which each of these active ingredients is separately formulated. When formulated separately, these preparations can be administered separately or simultaneously. In addition, the dosage of the compound represented by formula (I) or its pharmacologically acceptable salt may be appropriately reduced depending on the dosage of the other drug used in combination.

[0119] The compound represented by formula (I) may be appropriately converted into a prodrug for use. For example, a prodrug of the compound represented by formula (I) can be produced by introducing a prodrug-constituting group using a prodrug-converting reagent such as a corresponding halide, followed by purification. Examples of the prodrug-constituting group include those described in "Drug Development," Hirokawa Shoten, 1990, Vol. 7, pp. 163-198.

[0120] 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.

[0121] The names of compounds described in the following Reference Examples and Examples were named using ChemDraw Professional (PerkinElmer), MarvinSketch (ChemAxon), etc., except for commercially available reagents.

[0122] Reference Example A-1: ​​Benzyl (3-hydroxybicyclo[1.1.1]pentan-1-yl)(3-(trifluoromethyl)benzyl)carbamate. To a mixture of 3-aminobicyclo[1.1.1]pentan-1-ol hydrochloride (0.050 g) and THF (1 mL), DIPEA (0.119 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 10 minutes. 3-(Trifluoromethyl)benzyl bromide (0.088 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Cbz-Cl (0.063 g) was added to the reaction mixture at room temperature. The reaction 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 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 74 / 26-49 / 51) to obtain the title compound (0.041 g).

[0123] Reference Example A-2 Benzyl (3-((tert-butylcarbamoyl)oxy)bicyclo[1.1.1]pentan-1-yl)(3-(trifluoromethyl)benzyl)carbamate To a mixture of Reference Example A-1 (0.041 g) and THF (1 mL), tert-butyl isocyanate (0.012 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. DIPEA (0.020 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Sodium hydride (approximately 60%) (0.005 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=100 / 0-50 / 50) to obtain the title compound (0.041 g).

[0124] Reference Example A-3 Methyl 3-((3-(trifluoromethyl)benzyl)amino)bicyclo[1.1.1]pentane-1-carboxylate To a mixture of 3-aminobicyclo[1.1.1]pentane-1-carboxylic acid hydrochloride (0.220 g) and methanol (2 mL), TEA (0.143 g) was added at room temperature. A solution of 3-(trifluoromethyl)benzaldehyde (0.246 g) in ethyl acetate (1 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. 10% Pd / C (0.019 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1.5 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. To a mixture of the residue, methanol (3 mL), and DCM (3 mL), trimethylsilyldiazomethane (0.6 mol / L in n-hexane) (3.36 mL) was slowly added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Acetic acid (0.1 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 10 minutes. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, 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 / 10-60 / 40) to give the title compound (0.284 g).

[0125] Reference Example A-4: Methyl 3-(N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentane-1-carboxylate. A mixture of Reference Example A-3 (0.284 g), N-carbamoylglycine (0.134 g), HOBt hydrate (0.189 g), EDC-HCl (0.255 g), and DMF (6 mL) was stirred at room temperature for 15 hours. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium bicarbonate, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 99 / 1 to 90 / 10) to give the title compound (0.196 g).

[0126] Reference Example B-1: Benzyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate Hydrochloride. Under an argon atmosphere, Cbz-Cl (0.336 g) was added to a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.300 g), DIPEA (0.293 g), and THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. n-Hexane was added to the residue, and the insoluble matter was collected by filtration. The resulting solid was dried under reduced pressure to obtain the dicarbamate. A mixture of the obtained dicarbamate, hydrogen chloride (4 mol / L in ethyl acetate) (3.8 mL), and ethyl acetate (7.6 mL) was stirred at room temperature for 2 hours, then at 40°C for 1 hour. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to obtain the title compound (0.402 g).

[0127] Reference Example B-2: tert-Butyl (3-(phenethylamino)bicyclo[1.1.1]pentan-1-yl)carbamate. To a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (2.00 g) and THF (20 mL), sodium triacetoxyborohydride (3.21 g) and phenylacetaldehyde (50% 2-propanol solution) (1.75 mL) were added sequentially at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. Aqueous sodium sulfite was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 0 / 100) to give the title compound (1.81 g).

[0128] Reference Example B-3 Methyl 4-((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)(phenethyl)amino)-4-oxobutanoate To a mixture of Reference Example B-2 (0.240 g), TEA (0.161 g) and DCM (4 mL), methyl 4-chloro-4-oxobutanoate (0.180 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture was purified by Method A (elution solvent: n-hexane / ethyl acetate = 90 / 10-40 / 60) to obtain the title compound (0.203 g).

[0129] Reference Example B-4: Ethyl (E)-4-((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)(phenethyl)amino)-4-oxobut-2-enoate. To a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.050 g) and THF (2 mL), sodium triacetoxyborohydride (0.080 g) and phenylacetaldehyde (50% solution in 2-propanol) (0.037 mL) were added sequentially at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. Aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a mixture of the residue, DIPEA (0.065 g), and DCM (2 mL), ethyl (E)-4-chloro-4-oxobut-2-enoate (0.041 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20-38 / 62) to give the title compound (0.063 g).

[0130] Reference Example B-5 tert-Butyl (3-(2-amino-N-phenethylacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate Under an argon atmosphere, 10% Pd / C (0.059 g) was added to a mixture of Example G-1 (0.132 g) and THF (1 mL) at room temperature. The reaction mixture was stirred at the same temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (0.101 g).

[0131] Reference Example B-6: tert-Butyl (3-(2-(2-chloro-3-fluorophenyl)acetamido)bicyclo[1.1.1]pentan-1-yl)carbamate. 2-(2-Chloro-3-fluorophenyl)acetic acid (0.228 g) was added to a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.200 g), DIPEA (0.391 g), and MeCN (5 mL) at room temperature. The reaction mixture was stirred at the same temperature for 5 minutes. T3P (1.7 mol / L in ethyl acetate) (0.890 mL) and DCM (5 mL) were added sequentially to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 45 minutes. DIPEA (0.130 g) and DMF (4 mL) were added to the reaction mixture at room temperature. The reaction mixture was stirred at 60° C. for 1 hour and then allowed to cool to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with n-hexane / ethyl acetate (2 / 1). The extract was washed with saturated aqueous sodium bicarbonate and saturated brine, and then concentrated under reduced pressure. Water was added to the residue, and the insoluble matter was filtered off. The resulting solid was washed with n-hexane and dried under reduced pressure to give the title compound (0.348 g).

[0132] Reference Example B-7 tert-Butyl (3-((2-chloro-3-fluorophenethyl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate Under an argon atmosphere, to a mixture of Reference Example B-6 (0.247 g) and THF (3.7 mL), BH3-THF complex (0.91 mol / L in THF) (2.72 mL) was slowly added at room temperature. The reaction mixture was stirred at the same temperature for 6 hours. Methanol (0.756 mL) and N,N'-dimethylethylenediamine (0.354 g) were added to the reaction mixture under ice-cooling. The reaction mixture was refluxed for 2.5 hours. The reaction mixture was allowed to cool to room temperature and poured into a saturated aqueous solution of sodium bicarbonate, 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 = 60 / 40-10 / 90) to obtain the title compound (0.148 g).

[0133] Reference Example B-8 tert-Butyl (3-(((2,3-dihydro-1H-inden-1-yl)methyl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate DIPEA (0.098 g) was added to a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.101 g), 1-(bromomethyl)-2,3-dihydro-1H-indene (0.128 g), and DMF (2.5 mL) at room temperature. The reaction mixture was stirred at 100° C. for 3 hours and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=65 / 35-43 / 57) to obtain the title compound (0.037 g).

[0134] Reference Example B-9: tert-Butyl (3-(2-amino-N-((2,3-dihydro-1H-inden-1-yl)methyl)acetamido)bicyclo[1.1.1]pentan-1-yl)carbamate. To a mixture of Reference Example B-8 (0.036 g), N-((benzyloxy)carbonyl)glycine (0.029 g), and MeCN (1 mL), TEA (0.033 g) and HATU (0.055 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20-60 / 40) to obtain an amide compound. Under an argon atmosphere, 10% Pd / C (0.009 g) was added to a mixture of the obtained amide, ethanol (1 mL), and THF (1 mL) at room temperature. The reaction mixture was stirred at the same temperature under a hydrogen atmosphere for 2.5 hours. Ethanol (1 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 53°C under a hydrogen atmosphere for 70 minutes. The reaction mixture was allowed to cool to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure to give the title compound (0.032 g).

[0135] Reference Example B-10 Methyl 4-((3-aminobicyclo[1.1.1]pentan-1-yl)(phenethyl)amino)-4-oxobutanoate hydrochloride A mixture of Reference Example B-3 (0.090 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (3 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the title compound (0.088 g).

[0136] Reference Example B-11 (R)-4-((3-(3-(6-fluoro-2,3-dihydrobenzofuran-3-yl)ureido)bicyclo[1.1.1]pentan-1-yl)(phenethyl)amino)-4-oxobutanoate Methyl (R)-4-((3-(3-(6-fluoro-2,3-dihydrobenzofuran-3-yl)ureido)bicyclo[1.1.1]pentan-1-yl)(phenethyl)amino)-4-oxobutanoate To a mixture of Reference Example B-10 (0.029 g), pyridine (0.010 g) and DCM (1 mL), 4-nitrophenyl chloroformate (0.025 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 45 minutes. To the reaction mixture, (R)-6-fluoro-2,3-dihydrobenzofuran-3-amine hydrochloride (0.047 g) and DIPEA (0.037 g) were added at room temperature. The reaction mixture was stirred at the same temperature overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, and the mixture was extracted with DCM. The extract was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=100 / 0 / 0-0 / 100 / 0-0 / 75 / 25) to obtain the title compound (0.018 g).

[0137] Reference Example C-1 tert-Butyl (3-((3-fluorobenzyl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate 3-Fluorobenzyl bromide (0.057 g) was added to a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.060 g), potassium carbonate (0.085 g), and DMF (0.61 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 60 / 40-37 / 63) to give the title compound (0.033 g).

[0138] Reference Example C-2 was synthesized in the same manner as in Reference Example C-1, except that 3-chlorobenzyl bromide was used instead of 3-fluorobenzyl bromide.

[0139] Reference Example C-3 tert-Butyl (3-((3-chloro-2-fluorobenzyl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate 3-Chloro-2-fluorobenzyl bromide (0.124 g) was added to a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.100 g), DIPEA (0.196 g), and MeCN (1 mL) at room temperature. The reaction mixture was stirred at the same temperature for 45 minutes. The reaction mixture was poured into 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 (elution solvent: n-hexane / ethyl acetate = 70 / 30-30 / 70) to obtain the title compound (0.103 g).

[0140] Reference Example C-4 was synthesized in the same manner as in Reference Example C-3, except that 3-chloro-5-fluorobenzyl bromide was used instead of 3-chloro-2-fluorobenzyl bromide.

[0141] Reference Example C-5: (R)-1,1,1-trifluoropropan-2-yl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate hydrochloride. To a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.150 g), TEA (0.230 g), MeCN (1 mL), and DCM (1 mL) was added HOBt hydrate (0.232 g) and (R) Reference Example E-14 (0.211 g) at room temperature. The reaction mixture was stirred at the same temperature for 12 hours. The reaction mixture was poured into 1 mol / L aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with 1 mol / L aqueous potassium carbonate solution and then concentrated under reduced pressure. n-Hexane was added to the residue, and the supernatant was removed by decantation. The resulting solid was dried under reduced pressure to obtain the dicarbamate derivative. To a mixture of the obtained dicarbamate and ethyl acetate (1 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (1.5 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 12 hours. n-Hexane and ethyl acetate were added to the reaction mixture, and the insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (0.168 g).

[0142] Reference Example C-6 was synthesized in the same manner as in Reference Example C-3, using Reference Example C-5 and 3-chloro-5-fluorobenzyl bromide instead of (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate tert-butyl and 3-chloro-2-fluorobenzyl bromide.

[0143] Reference Example C-7: tert-Butyl (3-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate. A mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.020 g), DIPEA (0.039 g), 1-(1-bromoethyl)-3-(trifluoromethyl)benzene (0.051 g), and THF (1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 94 / 6) to give the title compound (0.026 g).

[0144] Reference Example C-8 (3-(2-(1,3-dioxoisoindolin-2-yl)-N-(1-(3-(trifluoromethyl)phenyl)ethyl)acetamido)bicyclo[1.1.1]pentan-1-yl)carbamate tert-Butyl ester Reference Example C-7 (0.026 g), DIPEA (0.018 g), and THF (1 mL) were mixed and added with phthalylglycyl chloride (0.024 g) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. 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 = 50 / 50-0 / 100) to obtain the title compound (0.030 g).

[0145] Reference Example C-9: (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate cyclopropyl hydrochloride. To a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.172 g), Reference Example E-21 (0.203 g), and THF (3 mL), TEA (0.263 g) and HOBt hydrate (0.266 g) were added at room temperature. The reaction mixture was stirred at 60 °C for 1.5 hours. The reaction mixture was allowed to cool to room temperature and poured into 1 mol / L aqueous sodium hydroxide solution. The mixture was extracted with DCM. The extract was washed with 1 mol / L aqueous sodium hydroxide solution and then concentrated under reduced pressure. n-Hexane was added to the residue, and the insoluble matter was collected by filtration. The resulting solid was dried under reduced pressure to obtain the dicarbamate derivative. To a mixture of the obtained dicarbamate and ethyl acetate (2 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (5.09 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. n-Hexane was added to the reaction mixture at room temperature. The mixture was stirred under ice-cooling for 5 minutes, and the insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.176 g).

[0146] Reference Example C-10 (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate isopropyl hydrochloride To a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.200 g), DIPEA (0.196 g), and THF (5 mL), isopropyl chloroformate (0.161 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. To a mixture of the residue and ethyl acetate (2 mL), hydrogen chloride (4 mol / L in ethyl acetate) (2.48 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour and then concentrated under reduced pressure to give the title compound (0.222 g).

[0147] Reference Example D-1 (R)-4-((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)(phenethyl)amino)-2-hydroxy-4-oxobutanoate Methyl (R)-4-((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)(phenethyl)amino)-2-hydroxy-4-oxobutanoate To a mixture of Reference Example B-2 (0.050 g), (R)-3-hydroxy-4-methoxy-4-oxobutanoic acid (0.029 g), TEA (0.050 g) and MeCN (0.5 mL), HATU (0.082 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 2.5 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, 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 / 10-40 / 60) to obtain the title compound (0.052 g).

[0148] Reference Example D-2 Ethyl ((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)(phenethyl)carbamoyl)glycine To a mixture of Reference Example B-2 (0.040 g) and DCM (0.5 mL), 2-isocyanatoethyl acetate (0.019 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 3 hours. The reaction mixture was purified by Method A (elution solvent: n-hexane / ethyl acetate = 90 / 10-40 / 60) to obtain the title compound (0.041 g).

[0149] Reference Example D-3 tert-Butyl (3-((3-(trifluoromethyl)benzyl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate 3-(Trifluoromethyl)benzaldehyde (0.343 g) was added to a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.299 g), methanol (1.9 mL), and THF (1.9 mL) at room temperature. The reaction mixture was stirred at the same temperature for 2.5 hours. 10% Pd / C (0.030 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 3.5 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 85 / 15-40 / 60) to obtain the title compound (0.495 g).

[0150] Reference Example D-4 tert-Butyl (3-(2-(benzyloxy)-N-(3-(trifluoromethyl)benzyl)acetamido)bicyclo[1.1.1]pentan-1-yl)carbamate. To a mixture of Reference Example D-3 (0.041 g), DIPEA (0.044 g), and MeCN (1 mL), benzyloxyacetic acid (0.028 g) and T3P (1.7 mol / L in ethyl acetate) (0.132 mL) were added sequentially at room temperature. The reaction mixture was stirred at the same temperature for 13 hours. The reaction mixture was poured into a 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 (elution solvent: n-hexane / ethyl acetate = 80 / 20-57 / 43) to obtain the title compound (0.051 g).

[0151] Reference Example D-5 tert-Butyl (3-(2-hydroxy-N-(3-(trifluoromethyl)benzyl)acetamido)bicyclo[1.1.1]pentan-1-yl)carbamate Under a hydrogen atmosphere, a mixture of Reference Example D-4 (0.052 g), 10% Pd / C (0.011 g), and ethanol (1 mL) was stirred at 60° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure to obtain the title compound (0.039 g).

[0152] Reference Example E-1 (4-Nitrophenyl) 1-cyclopropyl-2,2,2-trifluoroethyl carbonate Pyridine (0.115 g) and 4-nitrophenyl chloroformate (0.161 g) were added to a mixture of 1-cyclopropyl-2,2,2-trifluoroethan-1-ol (0.102 g) and DCM (1.7 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 19 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure, and a small amount of ethyl acetate was added to the residue. n-Hexane was added to the mixture, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.194 g).

[0153] Reference Example E-2 was synthesized in the same manner as in Reference Example E-1, except that (1-(trifluoromethyl)cyclopropyl)methanol was used instead of 1-cyclopropyl-2,2,2-trifluoroethan-1-ol.

[0154] Reference Example E-3: 1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl (4-nitrophenyl)carbonate. Pyridine (0.087 g) and 4-nitrophenyl chloroformate (0.122 g) were added to a mixture of 1,1,1,3,3,3-hexafluoro-2-methylpropan-2-ol (0.100 g) and DCM (0.94 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 12 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure, and a small amount of ethyl acetate was added to the residue. n-Hexane was added to the mixture, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and a small amount of ethyl acetate was added to the residue. n-Hexane was added to the mixture, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.075 g).

[0155] Reference Example E-4 (4-Nitrophenyl) 3-hydroxy-3-methylbutyl carbonate Pyridine (0.046 g) and 4-nitrophenyl chloroformate (0.064 g) were added to a mixture of 3-methylbutane-1,3-diol (0.030 g) and DCM (0.5 mL) at room temperature. The reaction mixture was stirred at the same temperature for 45 minutes. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure, and a small amount of ethyl acetate was added to the residue. n-Hexane was added to the mixture, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.052 g).

[0156] Reference Example E-5 (4-nitrophenyl) 3-methoxy-3-methylbutyl carbonate 4-Nitrophenyl chloroformate (0.081 g) was added to a mixture of 3-methyl-3-methoxybutanol (0.050 g), TEA (0.051 g), and DCM (3 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. n-Hexane was added to the residue, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.136 g).

[0157] Reference Example E-6 was synthesized in the same manner as in Reference Example E-4, except that (2,2-difluoro-1-methylcyclopropyl)methanol was used instead of 3-methylbutane-1,3-diol.

[0158] Reference Example E-7 (4-Nitrophenyl)(3-fluorocyclobutyl)methyl carbonate Pyridine (0.076 g) and 4-nitrophenyl chloroformate (0.106 g) were added to a mixture of (3-fluorocyclobutyl)methanol (0.050 g) and DCM (1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 2.5 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure, and a small amount of ethyl acetate was added to the residue. n-Hexane was added to the mixture, and the mixture was stirred under ice-cooling. The supernatant was separated and concentrated under reduced pressure to give the title compound (0.132 g).

[0159] Reference Example E-8 (4-Nitrophenyl) 1-Cyclopropylethyl Carbonate 4-Nitrophenyl chloroformate (0.257 g) was added to a mixture of 1-cyclopropylethanol (0.100 g), pyridine (0.184 g), and DCM (2 mL) under ice-cooling. The reaction mixture was stirred overnight at room temperature. 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. n-Hexane was added to the residue, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.280 g).

[0160] Reference Examples E-9 and E-10 were synthesized in the same manner as in Reference Example E-4, except that the corresponding starting materials were used instead of 3-methylbutane-1,3-diol.

[0161] Reference Example E-11 (4-nitrophenyl) 2-fluorobenzyl carbonate 4-Nitrophenyl chloroformate (0.176 g) was added to a mixture of (2-fluorophenyl)methanol (0.100 g), pyridine (0.125 g), and DCM (3 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 2 hours. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. n-Hexane was added to the residue, and the insoluble matter was collected by filtration. The resulting solid was dried under reduced pressure to give the title compound (0.090 g).

[0162] Reference Example E-12 (R)-1-Cyclopropylethyl (4-nitrophenyl)carbonate Pyridine (0.367 g) and 4-nitrophenyl chloroformate (0.515 g) were added to a mixture of (R)-1-cyclopropylethan-1-ol (0.200 g) and DCM (4 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure, and a small amount of ethyl acetate was added to the residue. n-Hexane was added to the mixture, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and a small amount of ethyl acetate was added to the residue. n-Hexane was added to the mixture, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.432 g).

[0163] Reference Example E-13 was synthesized in the same manner as in Reference Example E-4, except that (1-methylcyclopropyl)methanol was used instead of 3-methylbutane-1,3-diol.

[0164] Reference Example E-14 (1,1,1-trifluoropropan-2-yl)(R)-4-nitrophenyl carbonate. 4-Nitrophenyl chloroformate (0.709 g) was added to a mixture of (R)-1,1,1-trifluoro-2-propanol (0.365 g), pyridine (0.506 g), and DCM (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. n-Hexane was added to the residue, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.430 g).

[0165] Reference Example E-15: 3,3-Difluorocyclobutyl (4-nitrophenyl)carbonate. Pyridine (0.029 g) and 4-nitrophenyl chloroformate (0.041 g) were added to a mixture of 3,3-difluorocyclobutan-1-ol (0.020 g) and DCM (1 mL) at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure, and a small amount of ethyl acetate was added to the residue. n-Hexane was added to the mixture, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.035 g).

[0166] Reference Examples E-16 and E-17 were synthesized in the same manner as in Reference Example E-4, except that corresponding starting materials were used instead of 3-methylbutane-1,3-diol.

[0167] Reference Example E-18 was synthesized in the same manner as in Reference Example E-8, except that 1,1,1-trifluoropropan-2-ol was used instead of 1-cyclopropylethanol.

[0168] Reference Example E-19 (4-Nitrophenyl) 1-methylcyclopropyl carbonate To a mixture of 1-methylcyclopropan-1-ol (0.100 g), pyridine (0.219 g), and DCM (3 mL), 4-nitrophenyl chloroformate (0.307 g) was added under ice-cooling. The reaction mixture 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. n-Hexane was added to the residue, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.312 g).

[0169] Reference Example E-20 was synthesized in the same manner as in Reference Example E-5, except that 2-hydroxymethylthiazole was used instead of 3-methyl-3-methoxybutanol.

[0170] Reference Example E-21 was synthesized in the same manner as in Reference Example E-3, except that cyclopropanol was used instead of 1,1,1,3,3,3-hexafluoro-2-methylpropan-2-ol.

[0171] The structural formulas of the reference examples are shown in the table below.

[0172]

[0173] Example A-1 N-(3-Fluorobicyclo[1.1.1]pentan-1-yl)-N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamide To a mixture of 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride (0.028 g), DIPEA (0.103 g), and MeCN (0.5 mL), 3-(trifluoromethyl)benzyl bromide (0.050 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. 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. To a mixture of the residue, DIPEA (0.078 g), and MeCN (1 mL), N-carbamoylglycine (0.035 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture, T3P (1.7 mol / L in ethyl acetate) (0.235 mL) was added at room temperature. The reaction 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 by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to give the title compound (0.020 g).

[0174] Example A-2 was synthesized in the same manner as in Example A-1, except that 3-methylbicyclo[1.1.1]pentan-1-amine hydrochloride was used instead of 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride.

[0175] Example A-3 N-(3-Hydroxybicyclo[1.1.1]pentan-1-yl)-N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamide A mixture of 3-aminobicyclo[1.1.1]pentan-1-ol hydrochloride (0.050 g), DIPEA (0.119 g), 3-(trifluoromethyl)benzyl bromide (0.093 g), and MeCN (1 mL) was stirred at room temperature for 1 hour. N-Carbamoylglycine (0.052 g) and T3P (1.7 mol / L in ethyl acetate) (0.282 mL) were added to the reaction mixture at room temperature. The reaction 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 washed with water and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: ethyl acetate / methanol=100 / 0 to 80 / 20) to obtain the title compound (0.033 g).

[0176] Example A-4 tert-Butylcarbamate 3-(N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl) tert-Butylcarbamate A mixture of Reference Example A-2 (0.040 g), 10% Pd / C (0.005 g), and ethanol (1 mL) was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. A mixture of the residue, N-carbamoylglycine (0.016 g), HOBt hydrate (0.023 g), EDC-HCl (0.026 g), and DMF (1 mL) was stirred at 50°C for 1 hour and then allowed to cool to room temperature. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: ethyl acetate / methanol=100 / 0-81 / 19) to obtain the title compound (0.023 g).

[0177] Example A-5 N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamide To a mixture of Reference Example A-4 (0.030 g) and methanol (1 mL), sodium borohydride (0.014 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined extracts were 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: ethyl acetate / methanol = 99 / 1-80 / 20) to obtain the title compound (0.021 g).

[0178] Example B-1 Benzyl (3-(N-isopentyl-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate A mixture of Reference Example B-1 (0.050 g), DIPEA (0.048 g), and methanol (1 mL) was stirred at room temperature for 10 minutes. Isovaleraldehyde (0.016 g) and decaborane (0.007 g) were added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture was purified by amino silica gel column chromatography (elution solvent: ethyl acetate) to obtain a secondary amine. A mixture of the obtained secondary amine, N-carbamoylglycine (0.029 g), DIPEA (0.048 g), HOBt hydrate (0.043 g), EDC-HCl (0.054 g), and DMF (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 80 / 20). 1 mol / L hydrochloric acid was added to the fraction containing the title compound, and the mixture was extracted with DCM. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (0.009 g).

[0179] Example B-2 tert-Butyl (3-(N-((1-methylcyclopropyl)methyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate Methanesulfonyl chloride (0.032 g) was added to a mixture of (1-methylcyclopropyl)methanol (0.022 g), TEA (0.077 g), and DCM (1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.050 g), potassium iodide (0.004 g), and potassium carbonate (0.070 g) at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, N-carbamoylglycine (0.030 g), DIPEA (0.130 g), and MeCN (1 mL), T3P (1.7 mol / L in ethyl acetate) (0.297 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution, 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 / 0-0 / 100 / 0-0 / 80 / 20) and amino silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0-80 / 20) to give the title compound (0.004 g).

[0180] Example B-3 tert-Butyl (3-(4-amino-4-oxo-N-phenethylbutanamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Reference Example B-3 (0.100 g), methanol (1 mL), and THF (1 mL), 4 mol / L aqueous lithium hydroxide solution (0.180 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours. Water and 1 mol / L hydrochloric acid (0.720 mL) were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, DMT-MM (0.100 g), and MeCN (2 mL), 15 mol / L aqueous ammonia (0.024 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate / methanol=50 / 50 / 0-0 / 100 / 0-0 / 85 / 15) to obtain the title compound (0.078 g).

[0181] Example B-4 tert-Butyl (E)-(3-(4-amino-4-oxo-N-phenethylbut-2-enamido)bicyclo[1.1.1]pentan-1-yl)carbamate A mixture of Reference Example B-4 (0.062 g), 2 mol / L aqueous sodium hydroxide solution (0.217 mL), methanol (0.5 mL), and THF (0.5 mL) was stirred at 50° C. for 1 hour and then allowed to cool to room temperature. 1 mol / L hydrochloric acid (0.5 mL) was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. 15 mol / L aqueous ammonia (0.029 mL) was added to a mixture of the residue, DMT-MM (0.060 g), and MeCN (1 mL) at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. 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 aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=50 / 50 / 0-0 / 100 / 0-0 / 83 / 17) to obtain the title compound (0.035 g).

[0182] Example B-5 tert-Butyl (3-(N-phenethyl-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Reference Example B-5 (0.040 g) and THF (1 mL), trimethylsilyl isocyanate (0.019 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into 1 mol / L hydrochloric acid, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-80 / 20) to obtain the title compound (0.018 g).

[0183] Example B-6 tert-Butyl (3-(N-(2-chloro-3-fluorophenethyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate N-Carbamoylglycine (0.081 g) was added to a mixture of Reference Example B-7 (0.162 g), DIPEA (0.207 g), and MeCN (3.2 mL) at room temperature. The reaction mixture was stirred at the same temperature for 40 minutes. T3P (1.7 mol / L in ethyl acetate) (0.457 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature 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 aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=30 / 70 / 0-0 / 100 / 0-0 / 80 / 20) to obtain the title compound (0.113 g).

[0184] Example B-7 (3-(N-((2,3-dihydro-1H-inden-1-yl)methyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate tert-Butyl Trimethylsilyl Isocyanate (0.050 g) was added to a mixture of Reference Example B-9 (0.028 g) and THF (1 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1.5 hours and then concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate / methanol = 15 / 85 / 0-0 / 100 / 0-0 / 90 / 10) to obtain the title compound (0.017 g).

[0185] Example C-1 tert-Butyl (3-(N-(3-fluorobenzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate. To a mixture of Reference Example C-1 (0.032 g), TEA (0.021 g), N-carbamoylglycine (0.018 g), HOBt hydrate (0.024 g), and MeCN (1 mL), EDC-HCl (0.030 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 17 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 15 / 85 / 0-0 / 100 / 0-0 / 87 / 13) to obtain the title compound (0.022 g).

[0186] Example C-2 tert-Butyl (3-(N-(3-chloro-2-fluorobenzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate. To a mixture of Reference Example C-3 (0.103 g), N-carbamoylglycine (0.054 g), TEA (0.061 g), HOBt hydrate (0.069 g), and DMF (1.5 mL) was added EDC-HCl (0.087 g) at room temperature. The reaction mixture was stirred at the same temperature for 3.5 hours. The reaction mixture was poured into 1 mol / L hydrochloric acid, and the mixture was extracted with diethyl ether / ethyl acetate (2 / 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 aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to obtain the title compound (0.022 g).

[0187] Example C-3 was synthesized in the same manner as in Example C-2, except that Reference Example C-4 was used instead of Reference Example C-3.

[0188] Example C-4: tert-Butyl (3-(N-(3-cyanobenzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate. A mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.030 g), 3-(bromomethyl)benzonitrile (0.030 g), DIPEA (0.020 g), and DMF (1 mL) was stirred at 80°C for 1 hour. N-Carbamoylglycine (0.027 g), HOBt hydrate (0.035 g), and EDC-HCl (0.044 g) were added to the reaction mixture at room temperature. The reaction mixture was stirred at 50°C for 1 hour and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and then 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 / 67 / 33) to obtain the title compound (0.022 g).

[0189] Example C-5 tert-Butyl (3-(N-(3-methylbenzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.030 g) and THF (2 mL), sodium triacetoxyborohydride (0.048 g) and 3-methylbenzaldehyde (0.018 g) were added sequentially at room temperature. The reaction mixture was stirred at the same temperature for 2 hours and then allowed to stand for 2 days. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of the residue, N-carbamoylglycine (0.027 g), HOBt hydrate (0.035 g), and DMF (1 mL) was added EDC-HCl (0.044 g) at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes, then at 50 °C for 30 minutes, and then allowed to cool to room temperature. Saturated aqueous sodium bicarbonate 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 (eluent: ethyl acetate / methanol = 100 / 0-46 / 54) to give the title compound (0.008 g).

[0190] Example C-6 tert-Butyl (3-(N-(3-cyclopropoxybenzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate Under an argon atmosphere, methanesulfonyl chloride (0.031 g) was added to a mixture of (3-cyclopropoxyphenyl)methanol (0.037 g), TEA (0.032 g), and DCM (1 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. A mixture of the residue, tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.057 g), DIPEA (0.043 g), and DMF (1 mL) was stirred at room temperature for 2 hours. To the reaction mixture, N-carbamoylglycine (0.047 g), DIPEA (0.057 g), HOBt hydrate (0.061 g), and EDC-HCl (0.077 g) were added at room temperature. The reaction mixture was stirred at the same temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to give the title compound (0.049 g).

[0191] Example C-7 was synthesized in the same manner as in Example C-4, except that 2-(bromomethyl)-6-(trifluoromethyl)pyridine was used instead of 3-(bromomethyl)benzonitrile.

[0192] Example C-8 tert-Butyl (3-(N-(thiophen-2-ylmethyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate Thiophene-2-carbaldehyde (0.027 g) was added to a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.040 g), sodium triacetoxyborohydride (0.064 g), and THF (1.4 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1.5 hours and then at 50°C for 1 hour. Sodium triacetoxyborohydride (0.171 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 17 hours. The reaction mixture was poured into 1 mol / L aqueous sodium hydroxide solution, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, DIPEA (0.078 g), and MeCN (1 mL) was added N-carbamoylglycine (0.036 g) at room temperature. The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added T3P (1.7 mol / L in ethyl acetate) (0.237 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to give the title compound (0.056 g).

[0193] Example C-9 was synthesized in the same manner as in Example C-8, except that thiophene-3-carbaldehyde was used instead of thiophene-2-carbaldehyde.

[0194] Example C-10 (3-(N-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate tert-Butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate tert-butyl (0.056 g) and MeCN (1.7 mL) were added to DIPEA (0.072 g) at room temperature. A solution of 4-(bromomethyl)-2,2-difluorobenzo[d][1,3]dioxole (0.073 g) in MeCN (0.1 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1.5 hours. To the reaction mixture, N-carbamoylglycine (0.049 g), DIPEA (0.143 g), and T3P (1.7 mol / L in ethyl acetate) (0.326 mL) were added sequentially at room temperature. The reaction mixture was stirred at the same temperature for 16 hours and then at 50 °C for 9 hours. The reaction mixture was allowed to cool to room temperature and 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: ethyl acetate / methanol = 100 / 0-91 / 9) to give the title compound (0.024 g).

[0195] Example C-11 tert-Butyl (3-(N-(1-(3-(trifluoromethyl)phenyl)ethyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate A mixture of Reference Example C-8 (0.030 g), hydrazine monohydrate (0.014 g), and ethanol (1 mL) was stirred at 70 ° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. To a mixture of the residue and THF (1 mL), trimethylsilyl isocyanate (0.031 g) was added at room temperature. The reaction mixture was stirred at the same temperature overnight and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-55 / 45) to obtain the title compound (0.020 g).

[0196] Example C-12 tert-Butyl (3-(N-(3-fluoro-5-(trifluoromethyl)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate A mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.100 g), DIPEA (0.130 g), 3-fluoro-5-(trifluoromethyl)benzyl bromide (0.143 g), and DMF (1 mL) was stirred at room temperature for 1 hour. N-Carbamoylglycine (0.089 g), HOBt hydrate (0.100 g), and EDC-HCl (0.126 g) were added to the reaction mixture at room temperature. The reaction mixture was stirred at 40 °C for 2 hours and then allowed to cool to room temperature. 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 sodium sulfate, and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol = 98 / 2 to 85 / 15) to give the title compound (0.080 g).

[0197] Example C-13 tert-Butyl (3-(N-(3-(trifluoromethoxy)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate 3-(Trifluoromethoxy)benzyl bromide (0.566 g) was added to a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.400 g), DIPEA (0.522 g), and DMF (2 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. N-Carbamoylglycine (0.357 g), HOBt hydrate (0.449 g), and EDC-HCl (0.503 g) were added to the reaction mixture at room temperature. The reaction mixture was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate and water, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol=100 / 0 to 80 / 20) to give the title compound (0.639 g).

[0198] Example C-14 tert-Butyl (3-(N-(3-(difluoromethoxy)-5-fluorobenzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.200 g) and THF (5 mL), sodium triacetoxyborohydride (0.321 g) and 3-(difluoromethoxy)-5-fluorobenzaldehyde (0.211 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour and then at 50 °C for 1 hour. Sodium triacetoxyborohydride (0.321 g) was added to the reaction mixture at 50 °C. The reaction mixture was stirred at the same temperature for 1 hour and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue, DIPEA (0.522 g), N-carbamoylglycine (0.179 g), and MeCN (5 mL), T3P (1.7 mol / L in ethyl acetate) (1.19 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to give the title compound (0.099 g).

[0199] Example C-15 was synthesized in the same manner as in Example C-14, except that 5-(difluoromethoxy)-2-fluorobenzaldehyde was used instead of 3-(difluoromethoxy)-5-fluorobenzaldehyde.

[0200] Example D-1 N1-(3-aminobicyclo[1.1.1]pentan-1-yl)-N1-phenethylsuccinamide hydrochloride Example B-3 (0.004 g) and ethyl acetate (1 mL) were added with hydrogen chloride (4 mol / L in 1,4-dioxane) (0.5 mL) at room temperature. The reaction mixture was stirred at the same temperature overnight and then concentrated under reduced pressure to give the title compound (0.003 g).

[0201] Example D-2 N-(3-aminobicyclo[1.1.1]pentan-1-yl)-N-benzyl-2-ureidoacetamide hydrochloride Under an argon atmosphere, benzaldehyde (0.259 g) was added to a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.420 g), sodium triacetoxyborohydride (0.673 g), and THF (15 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. N-carbamoylglycine (0.375 g) was added to a mixture of the residue, DIPEA (1.10 g), and MeCN (6 mL) at room temperature. The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture, T3P (1.7 mol / L in ethyl acetate) (2.49 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 17.5 hours. The reaction mixture was poured into saturated aqueous ammonium chloride, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified sequentially by amino silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 85 / 15), amino silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 80 / 20), and amino silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 85 / 15) to obtain the amide. To a mixture of the obtained amide and ethyl acetate (2 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (5.52 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 62 hours. n-Hexane was added to the reaction mixture, and the insoluble matter was collected by filtration. The obtained solid was dissolved in methanol, and the solvent was evaporated under reduced pressure to obtain the title compound (0.301 g).

[0202] Example D-3 N-(3-aminobicyclo[1.1.1]pentan-1-yl)-N-(2-fluorobenzyl)-2-ureidoacetamide hydrochloride To a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.100 g), DIPEA (0.098 g), and DMF (3 mL), 2-fluorobenzyl bromide (0.100 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. N-Carbamoylglycine (0.089 g), HOBt hydrate (0.129 g), and EDC-HCl (0.145 g) were added to the reaction mixture at room temperature. The reaction mixture was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 81 / 19) to obtain the amide compound. To a mixture of the obtained amide compound and ethyl acetate (1 mL), hydrogen chloride (4 mol / L in ethyl acetate) (0.818 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour and then concentrated under reduced pressure to obtain the title compound (0.118 g).

[0203] Example D-4 N-(3-aminobicyclo[1.1.1]pentan-1-yl)-N-(3-fluorobenzyl)-2-ureidoacetamide hydrochloride Example C-1 (0.477 g) and ethyl acetate (3 mL) were added to a mixture of hydrogen chloride (4 mol / L in ethyl acetate) (2.93 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour and then concentrated under reduced pressure to give the title compound (0.391 g).

[0204] Example D-5 N-(3-aminobicyclo[1.1.1]pentan-1-yl)-N-(3-chlorobenzyl)-2-ureidoacetamide hydrochloride To a mixture of Reference Example C-2 (0.243 g), DIPEA (0.340 g), and MeCN (5.9 mL), N-carbamoylglycine (0.133 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. T3P (1.7 mol / L in ethyl acetate) (0.752 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 2.5 hours. Saturated aqueous ammonium chloride 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 aminosilica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 85 / 15) to obtain the amide. To a mixture of the obtained amide compound and ethyl acetate (2.7 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (4.33 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 14 hours. n-Hexane / ethyl acetate (1 / 1) was added to the reaction mixture, and the insoluble matter was collected by filtration. The obtained solid was dissolved in methanol, and the solvent was evaporated under reduced pressure to give the title compound (0.250 g).

[0205] Example D-6 was synthesized in the same manner as Example D-1, except that Example C-2 was used instead of Example B-3.

[0206] Example D-7 was synthesized in the same manner as in Example D-1, except that Example C-3 was used instead of Example B-3.

[0207] Example D-8 N-(3-aminobicyclo[1.1.1]pentan-1-yl)-N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamide hydrochloride To a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.300 g), 3-(trifluoromethyl)benzaldehyde (0.316 g), and THF (6 mL) was added sodium triacetoxyborohydride (0.481 g) at room temperature. The reaction mixture was stirred at the same temperature overnight and then at 50 °C for 2 hours, and then allowed to cool to room temperature. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of the residue, N-carbamoylglycine (0.268 g), HOBt hydrate (0.348 g), and MeCN (6 mL) was added EDC-HCl (0.435 g) at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes, then at 50 °C for 30 minutes, and then allowed to cool to room temperature. Saturated aqueous 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: ethyl acetate / methanol = 100 / 0 to 46 / 54) to obtain the amide. To a mixture of the obtained amide and ethyl acetate (2 mL), hydrogen chloride (4 mol / L in ethyl acetate) (1.28 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour and then concentrated under reduced pressure to obtain the title compound (0.212 g).

[0208] Example D-9 N-(3-aminobicyclo[1.1.1]pentan-1-yl)-N-(3-fluoro-5-(trifluoromethyl)benzyl)-2-ureidoacetamide hydrochloride Example C-12 (0.060 g), hydrogen chloride (4 mol / L in ethyl acetate) (1 mL) and ethyl acetate (1 mL) were stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (0.044 g).

[0209] Example D-10 was synthesized in the same manner as in Example D-4, except that Example C-13 was used instead of Example C-1.

[0210] Example D-11 N-(3-aminobicyclo[1.1.1]pentan-1-yl)-N-(3-(difluoromethoxy)benzyl)-2-ureidoacetamide hydrochloride To a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.300 g), DIPEA (0.782 g), and MeCN (3 mL), 3-(difluoromethoxy)benzyl bromide (0.395 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, DIPEA (0.782 g), and MeCN (6 mL), N-carbamoylglycine (0.268 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 15 minutes. To the reaction mixture, T3P (1.7 mol / L in ethyl acetate) (1.78 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 3 hours. 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 amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to obtain the amide compound. To a mixture of the obtained amide compound and ethyl acetate (1.6 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (4.49 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 3.5 hours. n-Hexane was added to the reaction mixture. The mixture was stirred under ice-cooling for 15 minutes, and the insoluble matter was collected by filtration. The obtained solid was dissolved in methanol, and the solvent was evaporated under reduced pressure to obtain the title compound (0.264 g).

[0211] Example D-12 was synthesized in the same manner as in Example D-4, except that Example C-14 was used instead of Example C-1.

[0212] Example D-13 was synthesized in the same manner as in Example D-9, except that Example C-15 was used instead of Example C-12.

[0213] Example E-1 1-Cyclopropyl-2,2,2-trifluoroethyl (3-(N-benzyl-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Example D-2 (0.040 g), TEA (0.030 g), MeCN (0.5 mL), and DCM (0.5 mL), Reference Example E-1 (0.045 g) and HOBt hydrate (0.030 g) were added at room temperature. The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was allowed to cool to room temperature and poured into 1 mol / L aqueous potassium carbonate solution, and the mixture was extracted with DCM. The extract was washed with 1 mol / L aqueous potassium carbonate solution and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to obtain the title compound (0.033 g).

[0214] Example E-2 Benzyl (3-(N-benzyl-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Example D-2 (0.050 g), DIPEA (0.068 g), and DCM (0.5 mL), Cbz-Cl (0.034 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 40 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to obtain the title compound (0.046 g).

[0215] Example E-3 2-Fluorobenzyl (3-(N-benzyl-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Example D-2 (0.020 g), TEA (0.019 g), MeCN (0.5 mL), and DCM (0.5 mL), Reference Example E-11 (0.018 g) and HOBt hydrate (0.019 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 12 hours. The reaction mixture was poured into a 1 mol / L aqueous potassium carbonate solution, and the mixture was extracted with DCM. The extract was washed with a 1 mol / L aqueous potassium carbonate solution and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 70 / 30) to give the title compound (0.015 g).

[0216] Example E-4 (R)-1-Cyclopropylethyl (3-(N-(2-fluorobenzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate. To a mixture of Example D-3 (0.052 g), TEA (0.046 g), and MeCN (2 mL), Reference Example E-12 (0.049 g) and HOBt hydrate (0.046 g) were added at room temperature. The reaction mixture was stirred at 60° C. for 1.5 hours and then allowed to cool to room temperature. 2 mol / L aqueous potassium carbonate solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was washed with 2 mol / L aqueous potassium carbonate solution and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to give the title compound (0.047 g).

[0217] Example E-5 (R)-1-Cyclopropylethyl (3-(N-(2-fluorobenzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate (R)-1-Cyclopropylethyl (3-(N-(2-fluorobenzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate (R) To a mixture of Reference Example E-12 (0.015 g) and THF (1 mL), Example D-4 (0.020 g), DIPEA (0.023 g), and HOBt hydrate (0.013 g) were added at room temperature. The reaction mixture was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. 2 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 2 mol / L aqueous sodium hydroxide solution and water and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-80 / 20) to obtain the title compound (0.019 g).

[0218] Example E-6 was synthesized in the same manner as in Example E-3, except that Example D-5 and Reference Example E-13 were used instead of Example D-2 and Reference Example E-11.

[0219] Example E-7 (1-(trifluoromethyl)cyclopropyl)methyl (3-(N-(3-chlorobenzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate. To a mixture of Example D-5 (0.031 g), TEA (0.026 g), and MeCN (1 mL), Reference Example E-2 (0.034 g) and HOBt hydrate (0.026 g) were added at room temperature. The reaction mixture was stirred at 60° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and poured into 1 mol / L aqueous potassium carbonate solution, and the mixture was extracted with DCM. The extract was washed with 1 mol / L aqueous potassium carbonate solution and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to give the title compound (0.033 g).

[0220] Example E-8 (R)-1-Cyclopropylethyl (3-(N-(3-chlorobenzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Example D-5 (0.035 g), TEA (0.030 g), MeCN (0.5 mL), and DCM (0.5 mL), Reference Example E-12 (0.037 g) and HOBt hydrate (0.030 g) were added at room temperature. The reaction mixture was stirred at 60° C. for 2 hours and then at room temperature for 62 hours. The reaction mixture was poured into a 1 mol / L aqueous potassium carbonate solution, and the mixture was extracted with DCM. The extract was washed with a 1 mol / L aqueous potassium carbonate solution and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to obtain the title compound (0.027 g).

[0221] Example E-9 1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl (3-(N-(3-chlorobenzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Example D-5 (0.035 g), TEA (0.030 g), MeCN (0.5 mL), and DCM (0.5 mL), Reference Example E-3 (0.051 g) and HOBt hydrate (0.030 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was poured into 1 mol / L aqueous potassium carbonate solution, and the mixture was extracted with DCM. The extract was washed with 1 mol / L aqueous potassium carbonate solution and then 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 / 85 / 15) to obtain the title compound (0.013 g).

[0222] Example E-10 (3-(N-(3-chloro-2-fluorobenzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate (R)-1-Cyclopropylethyl ester Example D-6 (0.030 g), DIPEA (0.031 g), Reference Example E-12 (0.024 g), HOBt hydrate (0.018 g), and THF (1 mL) were stirred at 50 °C for 1 hour and then allowed to cool to room temperature. 2 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 2 mol / L aqueous sodium hydroxide solution and water and then concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-81 / 19) to give the title compound (0.026 g).

[0223] Example E-11 (R)-1,1,1-trifluoropropan-2-yl (3-(N-(3-chloro-5-fluorobenzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate. To a mixture of Reference Example C-6 (0.015 g), N-carbamoylglycine (0.005 g), DIPEA (0.015 g), and MeCN (1 mL), T3P (1.7 mol / L in ethyl acetate) (0.046 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 13 hours. The reaction mixture was poured into water, 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 amino silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 60 / 40) to obtain the title compound (0.014 g).

[0224] Example E-12 was synthesized in the same manner as in Example E-7, except that Example D-7 and Reference Example E-15 were used instead of Example D-5 and Reference Example E-2.

[0225] Example E-13 (R)-1,1,1-trifluoropropan-2-yl (3-(N-(3-chloro-5-methoxybenzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Reference Example C-5 (0.013 g), DIPEA (0.018 g), and MeCN (1 mL), 3-chloro-5-methoxybenzyl bromide (0.011 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, N-carbamoylglycine (0.011 g), DIPEA (0.019 g), and MeCN (1 mL), T3P (1.7 mol / L in ethyl acetate) (0.057 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 3 hours. The reaction mixture was poured into water, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified sequentially by amino silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 60 / 40) and silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 60 / 40) to give the title compound (0.003 g).

[0226] Example E-14: 3-Hydroxy-3-methylbutyl (3-(N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate. To a mixture of Example D-8 (0.018 g), TEA (0.014 g), and MeCN (0.5 mL), Reference Example E-4 (0.019 g) and HOBt hydrate (0.014 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 86 hours. The reaction mixture was poured into 1 mol / L aqueous potassium carbonate solution, and the mixture was extracted with DCM. The extract was washed with 1 mol / L aqueous potassium carbonate solution and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 70 / 30). To the obtained title compound was added 1 mol / L aqueous potassium carbonate solution, and the mixture was extracted with DCM. The extract was washed with 1 mol / L aqueous potassium carbonate solution and then concentrated under reduced pressure to give the title compound (0.019 g).

[0227] Example E-15 3-Methoxy-3-methylbutyl (3-(N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate A mixture of Example D-8 (0.020 g), TEA (0.013 g), Reference Example E-5 (0.014 g), HOBt hydrate (0.008 g), and THF (2 mL) was stirred at room temperature for 1 hour. 2 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 2 mol / L aqueous sodium hydroxide solution and water, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0-56 / 44) to give the title compound (0.010 g).

[0228] Example E-16 was synthesized in the same manner as in Example E-14, except that Reference Example E-16 was used instead of Reference Example E-4.

[0229] Example E-17 (2,2-difluorocyclopropyl)methyl (3-(N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate. To a mixture of Example D-8 (0.020 g), TEA (0.015 g), and THF (1 mL), Reference Example E-17 (0.030 g) and HOBt hydrate (0.016 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 15 hours. The reaction mixture was poured into a 1 mol / L aqueous potassium carbonate solution, and the mixture was extracted with DCM. The extract was washed with a 1 mol / L aqueous potassium carbonate solution and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-80 / 20) to obtain the title compound (0.014 g).

[0230] Example E-18 (1-methylcyclopropyl)methyl (3-(N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate. To a mixture of Example D-8 (0.025 g), TEA (0.019 g), and MeCN (0.5 mL), Reference Example E-13 (0.021 g) and HOBt hydrate (0.019 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 64 hours. The reaction mixture was poured into a 1 mol / L aqueous potassium carbonate solution, and the mixture was extracted with DCM. The extract was washed with a 1 mol / L aqueous potassium carbonate solution and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 80 / 20) to obtain the title compound (0.019 g).

[0231] Example E-19 was synthesized in the same manner as in Example E-18, except that Reference Example E-6 was used instead of Reference Example E-13.

[0232] Example E-20 was synthesized in the same manner as in Example E-18, except that Reference Example E-7 was used instead of Reference Example E-13.

[0233] Example E-21 (3-(N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate isopropyl chloroformate (0.008 g) was added to a mixture of Example D-8 (0.020 g), DIPEA (0.016 g) and THF (1 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0-49 / 51) to obtain the title compound (0.019 g).

[0234] Example E-22 was synthesized in the same manner as in Example E-17, except that (R) Reference Example E-14 was used instead of Reference Example E-17.

[0235] Example E-23 1,1,1-trifluoropropan-2-yl (3-(N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate A mixture of Example D-8 (0.020 g), DIPEA (0.020 g), Reference Example E-18 (0.017 g), HOBt hydrate (0.012 g), and THF (1 mL) was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. 2 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 2 mol / L aqueous sodium hydroxide solution and water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-80 / 20) to obtain the title compound (0.019 g).

[0236] Example E-24 (R)-1-Cyclopropylethyl (3-(N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Example D-8 (0.020 g), TEA (0.015 g), and THF (1 mL), Reference Example E-12 (0.017 g) and HOBt hydrate (0.016 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 15 hours. The reaction mixture was poured into 1 mol / L aqueous potassium carbonate solution, and the mixture was extracted with DCM. The extract was washed with 1 mol / L aqueous potassium carbonate solution and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0-80 / 20) to obtain the title compound (0.018 g).

[0237] Example E-25 was synthesized in the same manner as in Example E-23, except that Reference Example E-8 was used instead of Reference Example E-18.

[0238] Example E-26 3,3-Difluorocyclobutyl (3-(N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Example D-8 (0.020 g), TEA (0.015 g), and THF (0.5 mL), a solution of Reference Example E-15 (0.017 g) in THF (0.5 mL) and HOBt hydrate (0.016 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into 1 mol / L aqueous potassium carbonate solution, and the mixture was extracted with DCM. The extract was washed with 1 mol / L aqueous potassium carbonate solution and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-80 / 20) to obtain the title compound (0.017 g).

[0239] Example E-27 (3-(N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate 1-methylcyclopropyl ester Example D-8 (0.020 g), DIPEA (0.020 g), Reference Example E-19 (0.014 g), HOBt hydrate (0.012 g), and THF (1 mL) were stirred at 50 °C for 1 hour and then allowed to cool to room temperature. 2 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 2 mol / L aqueous sodium hydroxide solution and water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-80 / 20) to give the title compound (0.020 g).

[0240] Example E-28 Thiazol-2-ylmethyl (3-(N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate A mixture of Example D-8 (0.020 g), DIPEA (0.016 g), Reference Example E-20 (0.021 g), HOBt hydrate (0.012 g), and THF (1 mL) was stirred at 50 ° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate. The mixture was washed with 2 mol / L aqueous sodium hydroxide solution and water, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-80 / 20) to give the title compound (0.019 g).

[0241] Example E-29 was synthesized in the same manner as in Example E-10, except that Example D-9 and Reference Example E-16 were used instead of Example D-6 and Reference Example E-12.

[0242] Example E-30 was synthesized in the same manner as in Example E-7, except that Example D-9 and Reference Example E-9 were used instead of Example D-5 and Reference Example E-2.

[0243] Example E-31 (3-(N-(3-fluoro-5-(trifluoromethyl)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate isopropyl chloroformate (0.070 g) was added to a mixture of Example D-9 (0.079 g), DIPEA (0.149 g) and DCM (2.5 mL) at room temperature. The reaction mixture was stirred at the same temperature for 3.5 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 amino silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to obtain the title compound (0.062 g).

[0244] Example E-32 (3-(N-(3-chloro-5-(trifluoromethyl)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate Cyclopropyl ester To a mixture of Reference Example C-9 (0.035 g), DIPEA (0.074 g), and MeCN (0.5 mL), 3-chloro-5-(trifluoromethyl)benzyl bromide (0.043 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, DIPEA (0.074 g), and MeCN (1 mL), N-carbamoylglycine (0.025 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 15 minutes. To the reaction mixture, T3P (1.7 mol / L in ethyl acetate) (0.167 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 15 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to give the title compound (0.030 g).

[0245] Example E-33 (3-(N-(3,5-bis(trifluoromethyl)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate Isopropyl ester 3,5-Bis(trifluoromethyl)benzaldehyde (0.026 g) was added to a mixture of Reference Example C-10 (0.020 g), TEA (0.011 g), and THF (2 mL) at room temperature. The reaction mixture was stirred at the same temperature for 10 minutes. Sodium triacetoxyborohydride (0.029 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes, then at 50°C for 2 hours, and then allowed to cool to room temperature. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of the residue, N-carbamoylglycine (0.016 g), DIPEA (0.035 g), and MeCN (6 mL), T3P (1.7 mol / L in ethyl acetate) (0.064 mL) was added at room temperature. The reaction mixture was stirred at the same temperature overnight. 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 (eluent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to give the title compound (0.016 g).

[0246] Example E-34 was synthesized in the same manner as in Example E-10, except that Example D-10 and Reference Example E-16 were used instead of Example D-6 and Reference Example E-12.

[0247] Example E-35 (2,2-difluorocyclopropyl)methyl (3-(N-(3-(trifluoromethoxy)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Example D-10 (0.035 g), TEA (0.023 g), and MeCN (1 mL), Reference Example E-17 (0.032 g) and HOBt hydrate (0.024 g) were added at room temperature. The reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and poured into 1 mol / L aqueous potassium carbonate solution, and the mixture was extracted with DCM. The extract was washed with 2 mol / L aqueous potassium carbonate solution and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to obtain the title compound (0.032 g).

[0248] Example E-36 was synthesized in the same manner as in Example E-35, except that Reference Example E-9 was used instead of Reference Example E-17.

[0249] Example E-37 (3-(N-(3-(trifluoromethoxy)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate isopropyl chloroformate (0.011 g) was added to a mixture of Example D-10 (0.030 g), DIPEA (0.028 g) and THF (1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluting solvent: ethyl acetate / methanol=100 / 0-81 / 19) to obtain the title compound (0.019 g).

[0250] Example E-38 3,3-Difluorocyclobutyl (3-(N-(3-(trifluoromethoxy)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Example D-10 (0.065 g), TEA (0.043 g), and MeCN (1 mL), Reference Example E-15 (0.051 g) and HOBt hydrate (0.044 g) were added at room temperature. The reaction mixture was stirred at 60°C for 1.5 hours and then allowed to cool to room temperature. To the reaction mixture was added 2 mol / L aqueous potassium carbonate solution, and the mixture was extracted with DCM. The extract was washed with 2 mol / L aqueous potassium carbonate solution and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to obtain the title compound (0.066 g).

[0251] Example E-39 1-Methylcyclopropyl (3-(N-(3-(trifluoromethoxy)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Reference Example E-19 (0.017 g) and THF (1 mL), Example D-10 (0.030 g), DIPEA (0.028 g), and HOBt hydrate (0.017 g) were added at room temperature. The reaction mixture was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. 2 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 2 mol / L aqueous sodium hydroxide solution and water and then concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-81 / 19) to obtain the title compound (0.030 g).

[0252] Example E-40 (3-(N-(3-Fluoro-5-(trifluoromethoxy)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate Isopropyl DIPEA (0.026 g) was added to a mixture of Reference Example C-10 (0.030 g) and THF (1 mL) at room temperature. A mixture of 3-fluoro-5-(trifluoromethoxy)benzaldehyde (0.028 g) and THF (0.5 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. Sodium borohydride (0.015 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Sodium borohydride (0.015 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1 hour, and then at 60 ° C. for 1 hour. Cyclopentyl methyl ether (2 mL) was added to the reaction mixture at 60 °C. The reaction mixture was stirred at 70 °C for 2 hours and then allowed to cool to room temperature. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. N-carbamoylglycine (0.024 g), HOBt hydrate (0.035 g), and EDC-HCl (0.039 g) were added to a mixture of the residue and DMF (1 mL) at room temperature. The reaction mixture was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. Water and saturated aqueous sodium bicarbonate solution were added to the reaction mixture, 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 aminosilica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-81 / 19) to give the title compound (0.029 g).

[0253] Example E-41 (3-(N-(2-Fluoro-5-(trifluoromethoxy)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate Isopropyl ester Reference Example C-10 (0.030 g), DIPEA (0.026 g), and THF (2 mL) were mixed with 2-fluoro-5-(trifluoromethoxy)benzaldehyde (0.034 g) and sodium triacetoxyborohydride (0.058 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. To a mixture of the residue and DMF (1 mL), N-carbamoylglycine (0.024 g), HOBt hydrate (0.035 g), and EDC-HCl (0.039 g) were added at room temperature. The reaction mixture was stirred at 50°C for 2 hours and then allowed to cool to room temperature. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, 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 amino silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 81 / 19) to give the title compound (0.029 g).

[0254] Example E-42 was synthesized in the same manner as in Example E-8, except that Example D-11 and Reference Example E-2 were used instead of Example D-5 and Reference Example E-12.

[0255] Example E-43 (R)-1-Cyclopropylethyl (3-(N-(3-(difluoromethoxy)benzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Example D-11 (0.032 g), TEA (0.022 g), MeCN (0.5 mL), and DCM (0.5 mL), Reference Example E-12 (0.027 g) and HOBt hydrate (0.022 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 2.5 hours and then at 60 °C for 5 hours, and then allowed to cool to room temperature. 1 mol / L aqueous potassium carbonate solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was washed with 1 mol / L aqueous potassium carbonate solution and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to obtain the title compound (0.017 g).

[0256] Example E-44 was synthesized in the same manner as in Example E-1, except that Example D-11 and Reference Example E-10 were used instead of Example D-2 and Reference Example E-1.

[0257] Example E-45 (R)-1-Cyclopropylethyl (3-(N-(3-(difluoromethoxy)-5-fluorobenzyl)-2-ureidoacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Example D-12 (0.020 g), TEA (0.013 g), and THF (1 mL), Reference Example E-12 (0.014 g) and HOBt hydrate (0.013 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 15 hours. The reaction mixture was poured into a 1 mol / L aqueous potassium carbonate solution, and the mixture was extracted with DCM. The extract was washed with a 1 mol / L aqueous potassium carbonate solution and then concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-80 / 20) to obtain the title compound (0.009 g).

[0258] Example E-46 was synthesized in the same manner as in Example E-45, except that Example D-13 was used instead of Example D-12.

[0259] Example F-1 N1-phenethyl-N1-(3-(3-(3-(trifluoromethyl)phenyl)propanamido)bicyclo[1.1.1]pentan-1-yl)succinamide To a mixture of Example D-1 (0.030 g), DIPEA (0.017 g), and DCM (1 mL), 3-(3-(trifluoromethyl)phenyl)propanoyl chloride (0.063 g) was added at room temperature. The reaction mixture was stirred at the same temperature overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate 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 / methanol = 100 / 0 / 0-0 / 100 / 0-0 / 85 / 15) to obtain the title compound (0.008 g).

[0260] Example F-2 N1-(3-(3-cyclopentylureido)bicyclo[1.1.1]pentan-1-yl)-N1-phenethylsuccinamide To a mixture of Example D-1 (0.030 g), pyridine (0.011 g), and DCE (1 mL), 4-nitrophenyl chloroformate (0.027 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. To the reaction mixture, cyclopentanamine (0.023 g) and DIPEA (0.040 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 5.5 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, 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=100 / 0 / 0-0 / 100 / 0-0 / 85 / 15) and amino silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=100 / 0 / 0-0 / 100 / 0-0 / 95 / 5) to obtain the title compound (0.003 g).

[0261] Example F-3 (R)—N1-(3-(3-(6-fluoro-2,3-dihydrobenzofuran-3-yl)ureido)bicyclo[1.1.1]pentan-1-yl)-N1-phenethylsuccinamide To a mixture of Reference Example B-11 (0.018 g), methanol (0.5 mL), and THF (0.5 mL), 4 mol / L aqueous lithium hydroxide solution (0.028 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours. Water and 1 mol / L hydrochloric acid were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, DMT-MM (0.015 g), and MeCN (1 mL), 15 mol / L aqueous ammonia (0.004 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by Method A (eluent: n-hexane / ethyl acetate / methanol=50 / 50 / 0-0 / 100 / 0 / -0 / 95 / 5) to obtain the title compound (0.010 g).

[0262] Example F-4 N-(3-(2-phenoxyacetamido)bicyclo[1.1.1]pentan-1-yl)-N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamide To a mixture of Example D-8 (0.020 g), DIPEA (0.016 g), and THF (1 mL), phenoxyacetyl chloride (0.011 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0-52 / 48) to obtain the title compound (0.009 g).

[0263] Example F-5 N-(3-(3-((tetrahydrofuran-2-yl)methyl)ureido)bicyclo[1.1.1]pentan-1-yl)-N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamide To a mixture of Example D-8 (0.020 g), DIPEA (0.026 g), and THF (2 mL), triphosgene (0.006 g) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes. To the reaction mixture, (tetrahydrofuran-2-yl)methanamine (0.007 g) and TEA (0.007 g) were added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. 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 (eluting solvent: ethyl acetate / methanol=100 / 0-80 / 20) to obtain the title compound (0.008 g).

[0264] Example G-1 tert-Butyl (3-(2-(((benzyloxy)carbonyl)amino)-N-phenethylacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Reference Example B-2 (0.100 g), N-((benzyloxy)carbonyl)glycine (0.083 g), TEA (0.100 g) and MeCN (1 mL), HATU (0.163 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 2.5 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, 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 / 10-50 / 50) to obtain the title compound (0.145 g).

[0265] Example G-2 (R)-(3-(4-amino-3-hydroxy-4-oxo-N-phenethylbutanamido)bicyclo[1.1.1]pentan-1-yl)carbamate tert-Butyl (R)-(3-(4-amino-3-hydroxy-4-oxo-N-phenethylbutanamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Reference Example D-1 (0.025 g), methanol (0.5 mL), and THF (0.5 mL), 4 mol / L aqueous lithium hydroxide solution (0.044 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Water and 1 mol / L hydrochloric acid (0.5 mL) were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue and DMF (0.64 mL), DIPEA (0.038 g) and HATU (0.066 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 1 minute. 15 mol / L aqueous ammonia (0.32 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 20 minutes. 1 mol / L aqueous sodium hydroxide solution (1 mL) was added to the reaction mixture at room temperature. The mixture was stirred at the same temperature for 10 minutes. 1 mol / L hydrochloric acid (2 mL) was added to the mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 90 / 10) to give the title compound (0.018 g).

[0266] Example G-3 tert-Butyl (3-(2-acetamido-N-phenethylacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Reference Example B-5 (0.018 g), TEA (0.008 g), and DCM (0.5 mL), acetyl chloride (0.005 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into saturated aqueous sodium bicarbonate, 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 obtain the title compound (0.017 g).

[0267] Example G-4 tert-Butyl (3-(2-(3-methylureido)-N-phenethylacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Reference Example B-5 (0.018 g), DIPEA (0.033 g), and THF (0.5 mL), triphosgene (0.006 g) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes. Methylamine hydrochloride (0.006 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours. Methylamine hydrochloride (0.007 g) and THF (0.5 mL) were added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 45 minutes. DIPEA (0.020 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1 hour, then at 50° C. for 1 hour, and then allowed to cool to room temperature. To the reaction mixture was added saturated aqueous ammonium chloride, 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 (0.014 g).

[0268] Example G-5 tert-Butyl (3-(2-(3,3-dimethylureido)-N-phenethylacetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Reference Example B-5 (0.018 g), DIPEA (0.033 g), and THF (1 mL), triphosgene (0.006 g) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes. Dimethylamine hydrochloride (0.007 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a 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 (eluting solvent: ethyl acetate / methanol=100 / 0-90 / 10) to obtain the title compound (0.017 g).

[0269] Example G-6 tert-Butyl (3-(3-(2-amino-2-oxoethyl)-1-phenethylureido)bicyclo[1.1.1]pentan-1-yl)carbamate To a mixture of Reference Example D-2 (0.037 g), methanol (0.5 mL), and THF (0.5 mL), 4 mol / L aqueous lithium hydroxide solution (0.064 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. Water and 1 mol / L hydrochloric acid (0.5 mL) were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, 15 mol / L aqueous ammonia (0.017 mL), and MeCN (0.5 mL) was added DMT-MM (0.035 g) at room temperature. The reaction mixture was stirred at the same 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 concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: ethyl acetate / methanol=100 / 0 to 90 / 10) to obtain the title compound (0.028 g).

[0270] Example G-7 tert-Butyl (3-(2-(carbamoyloxy)-N-(3-(trifluoromethyl)benzyl)acetamido)bicyclo[1.1.1]pentan-1-yl)carbamate 4-Nitrophenyl chloroformate (0.024 g) was added to a mixture of Reference Example D-5 (0.039 g), TEA (0.014 g), DMAP (0.002 g) and DCM (1 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. 15 mol / L aqueous ammonia (0.188 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was partitioned with saturated aqueous sodium bicarbonate and DCM. The organic layer was separated and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=50 / 50 / 0-0 / 100 / 0-0 / 85 / 15) to obtain the title compound (0.008 g).

[0271] The structural formulas, physical properties, and TSHR antagonist activity (see Test Example 1) of the examples are shown in the table below.

[0272]

[0273] Test Example 1: Measurement of antagonist activity using TSH-induced cAMP production as an index in human TSHR stably expressing CHO cells

[0274] 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: Expressed as B. IC 50 If the value could not be calculated, it was expressed as C.

[0275] As shown in the above table, the compounds of the present invention were found to have human TSHR antagonist activity.

[0276] 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

Formula (I): [During the ceremony, V is C 1-6 alkylene, or a single bond; R 1 is a group selected from the group consisting of the following (a) to (h): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group A 1-6 Alkyl, (b) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group A 6-10 aryl, (c) a 5- or 6-membered heteroaryl unsubstituted or substituted with 1 to 3 groups selected from the substituent group A; (d) a 9- or 10-membered heteroaryl unsubstituted or substituted with 1 to 3 groups selected from Substituent Group A; (e) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group A 3-10 cycloalkyl, (f) a 3- to 10-membered heterocycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A; (g) The following group unsubstituted or substituted with 1 to 3 groups selected from Substituent Group A: and (h) the following group unsubstituted or substituted with 1 to 3 groups selected from the substituent group A: Ring U and ring W each independently represent C 5-8 cycloalkyl, or 5- to 8-membered heterocycloalkyl; Substituent group A is a halogen atom, cyano, C 1-6 Alkyl, hydroxy, amino, -C(O)OR 12 , Haro C 1-6 Alkyl, Cyano C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl C 1-6 Alkyl, C 3-10 Cycloalkyl C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkoxy C 1-6 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl, 5- or 6-membered heteroarylC 1-6 Alkyl, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-10 Cycloalkyl C 2-6 Alkynyl, halohydroxy C 1-6 The group consisting of alkyl, and -SF5; When substituted with two or three groups selected from Substituent Group A, each group may be the same or different; R 12 is a hydrogen atom or C 1-6 is alkyl; R 2 , and R 2' are each independently a hydrogen atom or C 1-6 is alkyl; R 2 is R 1 Together with C 5-8 may form a cycloalkyl, or a 5- to 8-membered heterocycloalkyl; R 3 is a group selected from the group consisting of the following (i) to (vii): and R 5 , and R 5' are each independently a hydrogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl or hydroxy C 1-6 is alkyl; R 5 , and R 5' may be taken together to form a 3- to 10-membered heterocycloalkyl; R 6 is C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl or C 3-10 is cycloalkyl; R 7 is C 1-6 Alkyl, HaloC 1-6 Alkyl, C 3-10 Cycloalkyl, or C 6-10 Aryl C 1-6 is alkyl; R 8 , and R 8’ are each independently a hydrogen atom, C 1-6 alkyl, or hydroxy; R 4 is a halogen atom, cyano, C 1-6 Alkyl, hydroxy, -NR 9 R 9' , Haro C 1-6 Alkyl, Cyano C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, -NR 13 C(O)OR 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 11 R 11' , -OC(O)NR 11 R 11' , -(C 1-6 (Alkylene)-NR 13 C(O)OR 10 , -(C 1-6 (Alkylene)-NR 13 C(O)R 11 , -(C 1-6 (Alkylene)-NR 13 C(O)NR 11 R 11' , or -(C 1-6 (alkylene)-OC(O)NR 11 R 11' and R 13 is a hydrogen atom or C 1-6 is alkyl; R 9 , and R 9' are each independently a hydrogen atom or C 1-6 is alkyl; R 10 is a group selected from the group consisting of the following (i) to (o): (i) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group B 1-6 Alkyl, (j) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group B 3-10 cycloalkyl, (k) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group B 3-10 Cycloalkyl C 1-6 Alkyl, (l) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl C 1-6 Alkyl, (m) 3- to 10-membered heterocycloalkyl C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 1-6 Alkyl, (n) 5- or 6-membered heteroaryl C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 1-6 alkyl, and (o) a 9- or 10-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; Substituent group B is a halogen atom, cyano, hydroxy, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryloxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl C 1-6 Alkyl, and C 3-10 Cycloalkyl C 1-6 The group consisting of alkoxy; When substituted with two or more groups selected from Substituent Group B, each group may be the same or different; R 11 , and R 11' are each independently a group selected from the group consisting of the following (p) to (x): (p) hydrogen atom, (q) unsubstituted or substituted with 1 to 6 groups selected from the substituent group C 1-6 Alkyl, (r) unsubstituted or substituted with 1 to 6 groups selected from the substituent group C 3-10 cycloalkyl, (s) unsubstituted or substituted with 1 to 6 groups selected from the substituent group C 3-10 Cycloalkyl C 1-6 Alkyl, (t) Unsubstituted or substituted with 1 to 3 groups selected from the substituent group C 6-10 Aryl C 1-6 Alkyl, (u) 3- to 10-membered heterocycloalkyl C unsubstituted or substituted with 1 to 3 groups selected from the substituent group C 1-6 Alkyl, (v) 5- or 6-membered heteroaryl C unsubstituted or substituted with 1 to 3 groups selected from the substituent group C 1-6 Alkyl, (w) a 9- or 10-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group C, and (x) the following group unsubstituted or substituted with 1 to 3 groups selected from the substituent group C: Ring Z is C 5-8 cycloalkyl, or 5- to 8-membered heterocycloalkyl; The substituent group C is a halogen atom, cyano, hydroxy, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryloxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl C 1-6 Alkyl, and C 3-10 Cycloalkyl C 1-6 The group consisting of alkoxy; When substituted with two or more groups selected from the substituent group C, each group may be the same or different; R 11 , and R 11' may be taken together to form a 3- to 10-membered heterocycloalkyl. or a pharmacologically acceptable salt thereof.

10. The compound of claim 1 , wherein: Substituent group A is a halogen atom, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkoxy C 1-6 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-6 The group consisting of alkoxy, 5- or 6-membered heteroaryl, and -SF5; R 5 , and R 5' are each independently a hydrogen atom or C 1-6 is alkyl; R 6 But C 1-6 is alkyl; R 7 But C 1-6 Alkyl or C 6-10 Aryl C 1-6 is alkyl; R 8 , and R 8’ are each independently a hydrogen atom or hydroxy; R 4 But halogen atoms, C 1-6 Alkyl, hydroxy, -NR 9 R 9' , hydroxy C 1-6 Alkyl, -NR 13 C(O)OR 10 , -NR 13 C(O)R 11 , -NR 13 C(O)NR 11 R 11' , or -OC(O)NR 11 R 11' and R 13 is a hydrogen atom; Substituent group B is a halogen atom, hydroxy, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, and C 3-10 The group consisting of cycloalkyl; The substituent group C is a halogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryloxy, and C 3-10 Compounds whose group consists of cycloalkyl; or a pharmacologically acceptable salt thereof.

3. The compound of claim 2, wherein: V is -CH2- or a single bond; R 1 is a group selected from the group consisting of the following (a) to (d): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group A 6-10 aryl, (b) a 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A; (c) the following group unsubstituted or substituted with 1 to 3 groups selected from the substituent group A: and (d) the following group unsubstituted or substituted with 1 to 3 groups selected from Substituent Group A: Ring U and ring W have the same meanings as in claim 1; Compounds in which Substituent Group A has the same meaning as in claim 2; or a pharmacologically acceptable salt thereof.

4. The compound of claim 3, wherein: R 3 is a group selected from the group consisting of the following (i) to (iv): and R 5 , R 5' , and R 6 has the same meaning as in claim 2; or a pharmacologically acceptable salt thereof.

5. The compound of claim 4, wherein: R 4 But -NHC(O)OR 10 , -NHC(O)R 11 , -NHC(O)NR 11 R 11' , or -OC(O)NR 11 R 11' and R 10 is a group selected from the group consisting of the following (a) to (d): (a) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group B 1-6 Alkyl, (b) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group B 3-10 cycloalkyl, (c) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group B 3-10 Cycloalkyl C 1-6 alkyl, and (d) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl C 1-6 Alkyl; Substituent group B has the same meaning as in claim 2; R 11 , and R 11' are each independently a group selected from the group consisting of the following (e) to (i): (e) a hydrogen atom, (f) unsubstituted or substituted with 1 to 6 groups selected from the substituent group C 1-6 Alkyl, (g) unsubstituted or substituted with 1 to 6 groups selected from the substituent group C 3-10 cycloalkyl, (h) unsubstituted or substituted with 1 to 3 groups selected from the substituent group C 6-10 Aryl C 1-6 alkyl, and (i) the following group unsubstituted or substituted with 1 to 3 groups selected from the substituent group C: Ring Z is a 5- to 8-membered heterocycloalkyl; The substituent group C is a halogen atom, C 1-6 Alkyl, C 6-10 Aryloxy and haloC 1-6 Compounds whose group consists of alkyl; or a pharmacologically acceptable salt thereof.

6. The compound of claim 5, wherein: Substituent group A is a halogen atom, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, and C 3-10 The group consisting of cycloalkoxy; R 2 , and R 2' is a hydrogen atom; R 3 is the following group: R 5 , and R 5' is a hydrogen atom; R 4 But -NHC(O)OR 10 and R 10 is a group selected from the group consisting of the following (a) to (d): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 1-6 Alkyl, (b) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 3-10 cycloalkyl, (c) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 3-10 Cycloalkyl C 1-6 alkyl, and (d) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl C 1-6 Alkyl; Substituent group B is a halogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl, and C 3-10 Compounds whose group consists of cycloalkyl; or a pharmacologically acceptable salt thereof. Formula (IA): [During the ceremony, V a is -CH2- or a single bond; R 1a is a group selected from the group consisting of the following (a) to (d): (a) Unsubstituted or substituted group A a C substituted with 1 to 3 groups selected from 6-10 aryl, (b) Unsubstituted or substituted group A a a 5- or 6-membered heteroaryl substituted with 1 to 3 groups selected from (c) Unsubstituted or substituted group A a the following group substituted with 1 to 3 groups selected from: and (d) Unsubstituted or substituted group A a the following group substituted with 1 to 3 groups selected from: Ring U a , and ring W a are each independently 5-8 cycloalkyl, or 5- to 8-membered heterocycloalkyl; Substituent group A a is a halogen atom, cyano, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, and C 3-10 The group consisting of cycloalkoxy; Substituent group A a When substituted with two or three groups selected from the following, each group may be the same or different; R 10a is a group selected from the group consisting of the following (e) to (h): (e) Unsubstituted or substituted group B a C substituted with 1 to 3 groups selected from 1-6 Alkyl, (f) Unsubstituted or substituted group B a C substituted with 1 to 3 groups selected from 3-10 cycloalkyl, (g) Unsubstituted or substituted group B a C substituted with 1 to 3 groups selected from 3-10 Cycloalkyl C 1-6 alkyl, and (h) Unsubstituted or substituted group B a C substituted with 1 to 3 groups selected from 6-10 Aryl C 1-6 Alkyl; Substituent group B a is a halogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl, and C 3-10 The group consisting of cycloalkyl; Substituent group B a When the substituted group is 2 or 3 groups selected from the following, each group may be the same or different. or a pharmacologically acceptable salt thereof. A compound selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof, and a pharmaceutical additive. The pharmaceutical composition according to claim 9, which is a pharmaceutical composition for treating a thyroid-related disease.

11. The pharmaceutical composition according to claim 10, wherein the thyroid-related disease is hyperthyroidism, Graves' disease, or thyroid eye disease.

Images