Polycyclic compound

Abstract

The present invention addresses the problem of providing: a novel compound having CRBN binding activity; a novel compound having CRBN binding activity and target protein binding activity; a target protein degradation inducer which comprises the compound; and a medicine which contains the compound. The present invention pertains to: a compound represented by general formula (I) (wherein each symbol is as defined in the description) or a salt thereof; and a medicine which contains the compound.

Description

Polycyclic compounds

[0001] The present invention relates to a novel compound having cereblon (CRBN) E3 ligase binding activity and target protein binding activity, a target protein degradation inducer containing said compound, and a medicine, etc. containing said compound.

[0002] Recently, the usefulness of heterobifunctional molecules, which combine a target protein-binding moiety and an endogenous effector molecule-recruiting moiety via a linker, has been reported. These heterobifunctional molecules bring the target protein and the endogenous effector molecule into physical proximity, thereby causing a change in the target protein and exerting the desired effect (Non-Patent Document 1).

[0003] Targeted protein degradation (TPD) is one such technique that utilizes heterobifunctional molecules. TPD induces degradation of a target protein. It uses heterobifunctional molecules, each consisting of a binder moiety that binds to the target protein and a binder moiety that binds to an E3 ligase, linked via a linker. This induces intracellular complex formation between the target protein and the E3 ligase, resulting in ubiquitination and degradation of the target protein, demonstrating potent physiological activity. While over 600 E3 ligases have been identified, only a limited number of them have been used in TPD, particularly cereblon (CRBN) and von Hippel-Lindau (VHL) (Non-Patent Document 2). In particular, binder moieties that bind to CRBN (also known as "CRBN ligands") have been widely used in TPD, and their diverse structures and usefulness have been reported (Patent Documents 1-9, Non-Patent Document 3). Proteins reported to be targeted by TPD include androgen receptor (AR), estrogen receptor (ER), and bromodomain (BRD) (Non-patent literature 4-6).

[0004] International Publication No. 2017 / 197051 International Publication No. 2018 / 237026 International Publication No. 2019 / 060693 International Publication No. 2019 / 060742 International Publication No. 2019 / 099868 International Publication No. 2019 / 199816 International Publication No. 2020 / 210630 International Publication No. 2022 / 081927 International Publication No. 2022 / 081928

[0005] Liwen Hua, et al., J. Med. Chem., 2022: 65: 8091-8112Chaoguo Cao, et al., Chem. Soc. Rev., 2022: 51: 7066-7114Alexander Kazantsev and Mikhail Krasavin, Expert Opinion on Therapeutic Patents, 2022: 32: 2: 171-190Xiaojuan Jia, et.al., Biomedicine & Pharmacotherapy, 158 (2023) 114112Xin Lin, et al., European Journal of Medicinal Chemistry, 206 (2020) 112689Chao Wang, et al., Journal of Enzyme Inhibition and Medicinal Chemistry, 2022, Vol. 37, No. 1, 1694-1703

[0006] An object of the present invention is to provide a novel compound having cereblon (CRBN) E3 ligase binding activity (hereinafter sometimes referred to as "CRBN binding activity"). Another object of the present invention is to provide a novel compound having CRBN binding activity and target protein binding activity, as well as a target protein degradation inducer containing the compound. A further object of the present invention is to provide a composition, pharmaceutical composition, or medicament containing the compound, which contains the compound and induces target protein degradation by binding to CRBN and the target protein. Another object of the present invention is to provide an intermediate that can be used in the production of the compound.

[0007] As a result of intensive studies, the present inventors have found that a polycyclic compound represented by the following general formula (I) has CRBN-binding activity. The present inventors have also found that a polycyclic compound represented by the following general formula (I) has CRBN-binding activity and target protein-binding activity, and further found that the compound represented by general formula (I) can degrade a target protein and can exert a desired therapeutic effect on a disease associated with the target protein by degrading the target protein, thereby completing the present invention.

[0008] That is, the present invention relates to the following: [1] A compound represented by the following formula (I):

[0009]

[0010] wherein T is a target protein binding motif, L is a linker, and E is a group represented by the following formula (II):

[0011]

[0012] (In formula (II), * represents a bonding position with L at any bondable site in the chemical formula in [ ], and X represents CH ２ or C(=O), and Y is N(R ３ ) or CH(R ３ ) and Z is CH ２ or C(=O), and R １ , R ２ , and R ３ are each independently a hydrogen atom, or R １ and R ２ are bonded to each other and together with the carbon atoms to which they are attached form a 4- to 7-membered aliphatic heterocycle containing one nitrogen atom as a ring-constituting atom and which may be substituted with one substituent, or a 4- to 7-membered aliphatic ring which may be substituted with one substituent, and R ３ is a hydrogen atom, or R １ and R ３ are bonded to each other to form R １ and the carbon atom to which R ３is bonded together with the atom to which it is bonded to form a 4- to 7-membered aliphatic heterocycle which contains one or two nitrogen atoms as ring-constituting atoms and which may be substituted with one substituent, or a 4- to 7-membered aliphatic ring which may be substituted with one substituent, and R ２ [2] A compound represented by the following formula (III):

[0013]

[0014] (In formula (III), X １ is CH ２ or C(=O), and Y １ is N or CH, Z １ is CH ２ or C(=O), n １ and n ２ are each independently 1 or 2; １ -* is N-*, CH-O-*, or CH-C(=O)-*, and * is the bonding position to L. [2-2] The compound or salt thereof according to the above [1], wherein E is a group represented by the following formula:

[0015]

[0016] (wherein * indicates the bonding position to L) [3] The compound or salt thereof according to the above [1], wherein E is a group represented by the following formula (IV):

[0017]

[0018] (In formula (IV), X ２ is CH ２ or C(=O), and Y ２ is NH or CH ２ and Z ２ is CH ２ or C(=O), n ３ and n ４ are each independently an integer of 1 to 3, and n ３ +n ４ is an integer from 2 to 5, and W ２-* is N-*, CH-O-*, or CH-C(=O)-*, and * is the bonding position to L. [3-2] The compound or salt thereof according to the above [1], wherein E is a group represented by the following formula:

[0019]

[0020] (wherein * represents the bonding position to L) or a salt thereof. [4] The compound or salt thereof according to any one of the above [1] to [3-2], wherein the target protein is steroidogenic factor-1 (SF-1), anaplastic lymphoma kinase (ALK), or estrogen receptor (ER). [5] T is a group represented by the following formula:

[0021]

[0022] (In the formula, the wavy line indicates the bonding position with L, and in formula (VIII), A is —O— or —CF ２ - and R Ｔ１ is a halogen, —O—C optionally substituted with 1 to 3 halogens １－６ Alkyl, —N(H)—C １－３ Alkyl, —N(C １－３ alkyl) ２ or a 4- to 6-membered heterocycloalkyl containing one nitrogen atom as a ring atom, R Ｔ２ and R Ｔ３ are each independently a hydrogen atom or C １－６ alkyl, R Ｔ４ is C optionally substituted with 1 to 3 halogen atoms. １－６ alkyl, —C(═O)—C optionally substituted with 1 to 3 halogens; １－６ alkyl, C optionally substituted with one trifluoromethyl ３－６ cycloalkylmethyl, or a 6-membered heteroaryl containing one or two nitrogen atoms as ring-constituting atoms (the heteroaryl may be substituted with one halogen atom), and ring Q Ｔ１ is a halogen and C １－３a benzene ring which may have one or two substituents independently selected from the group consisting of alkyl; a 6- to 12-membered monocyclic or bicyclic aromatic heterocycle containing one or two nitrogen atoms as ring-constituting atoms; C ４－７ Cycloalkane ring, or C ４－７ is a cycloalkene ring, Ｔ１ represents a single bond, —O—, —CH ２ - or -C(=O)-, and ring Q Ｔ２ represents a benzene ring optionally substituted with one halogen atom, C ４－７ a cycloalkane ring, a C optionally substituted with one halogen atom; ４－７ [5-2] The compound or salt thereof according to any one of the above [1] to [4], wherein T is a group selected from the group consisting of a cycloalkene ring, a piperidine ring, or a 7-azaspiro[3.5]nonane ring.

[0023]

[0024] (In formula (VIII), A is —O— or —CF ２ - and R Ｔ１ is a halogen, —O—C optionally substituted with 1 to 3 halogens １－６ Alkyl, —N(H)—C １－３ Alkyl, —N(C １－３ alkyl) ２ or a 4- to 6-membered heterocycloalkyl containing one nitrogen atom as a ring atom, R Ｔ２ and R Ｔ３ are each independently a hydrogen atom or C １－６ alkyl, R Ｔ４ is C optionally substituted with 1 to 3 halogen atoms. １－６ alkyl, —C(═O)—C optionally substituted with 1 to 3 halogens; １－６ alkyl, C optionally substituted with one trifluoromethyl ３－６ cycloalkylmethyl, or a 6-membered heteroaryl containing one or two nitrogen atoms as ring-constituting atoms (the heteroaryl may be substituted with one halogen atom), and ring Q Ｔ１ is a halogen and C １－３a benzene ring which may have one or two substituents independently selected from the group consisting of alkyl; a 6- to 12-membered monocyclic or bicyclic aromatic heterocycle containing one or two nitrogen atoms as ring-constituting atoms; C ４－７ Cycloalkane ring, or C ４－７ is a cycloalkene ring, Ｔ１ represents a single bond, —O—, —CH ２ - or -C(=O)-, and ring Q Ｔ２ represents a benzene ring optionally substituted with one halogen atom, C ４－７ a cycloalkane ring, a C optionally substituted with one halogen atom; ４－７ [5-3] The compound or salt thereof according to any one of the above [1] to [4], wherein T is a group represented by the following formula:

[0025]

[0026] (wherein the wavy line indicates the bonding position to L). [6] The compound or salt thereof according to any one of the above [1] to [4], wherein L is a group selected from the group consisting of the following formula:

[0027]

[0028] (In the formula, n ５ is an integer from 1 to 6, and n ６ is an integer of 0 to 6, the wavy line is the bonding position to T, and * is the bonding position to E), or a salt thereof. [7] The compound or salt thereof according to any one of the above [1] to [5-3], wherein L is a group selected from the group consisting of the following formula:

[0029]

[0030] (wherein the wavy line represents the bonding position to T, and * represents the bonding position to E) or a salt thereof. [8] The compound or salt thereof according to any one of the above [1] to [6], wherein E is a group selected from the group consisting of the following formula (III):

[0031]

[0032] (In formula (III), X １ is CH ２ or C(=O), and Y １ is N or CH, Z １ is CH ２ or C(=O), n １ and n ２ are each independently 1 or 2; １ -* is N-*, CH-O-*, or CH-C(=O)-*, and * is the bonding position to L), and T is a group represented by the following formula (VIII):

[0033]

[0034] (In formula (VIII), A is —O— or —CF ２ - and R Ｔ１ is a halogen, —O—C optionally substituted with 1 to 3 halogens １－６ Alkyl, —N(H)—C １－３ Alkyl, —N(C １－３ alkyl) ２ or a 4- to 6-membered heterocycloalkyl containing one nitrogen atom as a ring atom, R Ｔ２ and R Ｔ３ are each independently a hydrogen atom or C １－６ alkyl, R Ｔ４ is C optionally substituted with 1 to 3 halogen atoms. １－６ alkyl, —C(═O)—C optionally substituted with 1 to 3 halogens; １－６ alkyl, C optionally substituted with one trifluoromethyl ３－６ cycloalkylmethyl, or a 6-membered heteroaryl containing one or two nitrogen atoms as ring-constituting atoms (the heteroaryl may be substituted with one halogen atom), and ring Q Ｔ１ is a halogen and C １－３ a benzene ring which may have one or two substituents independently selected from the group consisting of alkyl; a 6- to 12-membered monocyclic or bicyclic aromatic heterocycle containing one or two nitrogen atoms as ring-constituting atoms; C ４－７ Cycloalkane ring, or C ４－７is a cycloalkene ring, Ｔ１ represents a single bond, —O—, —CH ２ - or -C(=O)-, and ring Q Ｔ２ represents a benzene ring optionally substituted with one halogen atom, C ４－７ a cycloalkane ring, a C optionally substituted with one halogen atom; ４－７ a cycloalkene ring, a piperidine ring, or a 7-azaspiro[3.5]nonane ring, and the wavy line indicates the bonding position to L), and L is a group represented by the following formula:

[0035]

[0036] (In the formula, n ５ is an integer from 1 to 6, and n ６ is an integer of 0 to 6, the wavy line is the bonding position to T, and * is the bonding position to E). [9] The compound or salt thereof according to the above [1], wherein E is a group selected from the group consisting of the following formula (III):

[0037]

[0038] (In formula (III), X １ is CH ２ and Y １ is N and Z １ is CH ２ or C(=O), n １ is 1, and n ２ is 2, and W １ -* is N-*, and * is the bonding position to L), and T is a group represented by the following formula (VIII):

[0039]

[0040] (In formula (VIII), A is —O—, and R Ｔ１ is -O-CH ３ or -O-CF ３ and R Ｔ２ is methyl, R Ｔ３ is methyl, R Ｔ４ is C optionally substituted with 1 to 3 halogen atoms. １－６is alkyl, and ring Q Ｔ１ is a benzene ring optionally substituted with one halogen atom, and L Ｔ１ is a single bond, and ring Q Ｔ２ is C optionally substituted with one halogen ４－７ is a cycloalkene ring, and the wavy line indicates the bonding position to L), and L is a group represented by the following formula:

[0041]

[0042] The compound or salt thereof according to the above-mentioned [1], which is a group represented by the following formula: (wherein the wavy line indicates the bonding position to T, and * indicates the bonding position to E).

[10] (7aR)-1-(2,6-dioxopiperidin-3-yl)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione, (7aS)-1-(2,6-dioxopiperidin-3-yl)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione, 3-[(7aS)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-1(13H)-yl]piperidine-2,6-dione, and 3-[(7aR)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,

[11] A compound or a salt thereof selected from the group consisting of {5-tetrahydro[biphenyl]-4-yl]methyl}-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-1(13H)-yl]piperidine-2,6-dione.

[12] A pharmaceutical comprising, as an active ingredient, the compound or a salt thereof described in any of [1] to

[10] above.

[13] The pharmaceutical according to

[11] above, for treating castration-resistant prostate cancer, adrenocortical carcinoma, Leydig tumor, hormone-sensitive prostate cancer, breast cancer, Cushing's syndrome, or primary aldosteronism.

[13] A method for treating castration-resistant prostate cancer, adrenocortical carcinoma, Leydig tumor, hormone-sensitive prostate cancer, breast cancer, Cushing's syndrome, or primary aldosteronism in a subject, comprising administering to the subject an effective amount of the compound according to any one of [1] to

[10] above or a salt thereof.

[14] A compound according to any one of [1] to

[10] above or a salt thereof for use in treating castration-resistant prostate cancer, adrenocortical carcinoma, Leydig tumor, hormone-sensitive prostate cancer, breast cancer, Cushing's syndrome, or primary aldosteronism.

[15] Use of the compound according to any one of [1] to

[10] above or a salt thereof in the manufacture of a medicament for treating castration-resistant prostate cancer, adrenocortical carcinoma, Leydig tumor, hormone-sensitive prostate cancer, breast cancer, Cushing's syndrome, or primary aldosteronism.

[16] A compound represented by the following formula (V):

[0043]

[0044] (In formula (V), X is CH ２ or C(=O), and Y is N(R ３ ) or CH(R ３ ) and Z is CH ２ or C(=O), and R １ , R ２ , and R ３ are each independently a hydrogen atom, or R １ and R ２are bonded to each other and together with the carbon atoms to which they are attached contain one nitrogen atom as a ring member and one hydroxy group, carboxy group, or C １－６ a 4- to 7-membered aliphatic heterocycle optionally substituted with an alkyl group, or one hydroxy group, carboxy group, or C １－６ form a 4- to 7-membered aliphatic ring optionally substituted with an alkyl group, and R ３ is a hydrogen atom, or R １ and R ３ are bonded to each other to form R １ and the carbon atom to which R ３ and a ring structure including, together with the atom to which it is attached, one or two nitrogen atoms as ring-constituting atoms, and one hydroxy group, carboxy group, or C １－６ a 4- to 7-membered aliphatic heterocycle optionally substituted with an alkyl group, or one hydroxy group, carboxy group, or C １－６ form a 4- to 7-membered aliphatic ring optionally substituted with an alkyl group, and R ２

[17] A compound represented by the following formula (VI):

[0045]

[0046] (In formula (VI), X １ is CH ２ or C(=O), and Y １ is N or CH, Z １ is CH ２ or C(=O), n １ and n ２ are each independently 1 or 2, and W ３ is NH, CH—OH, or CH—CO ２

[18] The compound or salt thereof according to the above

[16] , wherein X is １ is CH ２ and Y １ is N and Z １ is CH ２ or C(=O), n １ is 1, and n ２ is 2, and W ３

[19] The compound or salt thereof according to the above

[17] , wherein is NH.

[19] The compound or salt thereof according to the above

[17] ,

[0047]

[0048] (In formula (VII), X ２ is CH ２ or C(=O), and Y ２ is NH or CH ２ and Z ２ is CH ２ or C(=O), n ３ and n ４ are each independently an integer of 1 to 3, and n ３ +n ４ is an integer from 2 to 5, and W ４ is NH, CH—OH, or CH—CO ２

[20] The compound or salt thereof according to the above

[16] , wherein X is ２ is CH ２ and Y ２ is NH or CH ２ and Z ２ is CH ２ or C(=O), n ３ is an integer from 1 to 2, and n ４ is an integer from 1 to 2, and W ４The compound or salt thereof according to the above

[19] , wherein is NH.

[21] (7aS)-1-(2,6-dioxopiperidin-3-yl)-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione, (7aR)-1-(2,6-dioxopiperidin-3-yl)-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione, 3-[(7aS)-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxalin-1(13H)-yl]piperidine-2,6-dione, and 3-[(7aR)-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxalin-1(13H)-yl]piperidine-2,6-dione, or a salt thereof.

[22] (7aS)-1-(2,6-dioxopiperidin-3-yl)-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione monohydrochloride, (7aR)-1-(2,6-dioxopiperidin-3-yl)-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione monohydrochloride, Any one compound selected from the group consisting of 3-[(7aS)-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxalin-1(13H)-yl]piperidine-2,6-dione dihydrochloride, and 3-[(7aR)-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxalin-1(13H)-yl]piperidine-2,6-dione dihydrochloride. For example, when item numbers are indicated as ranges, such as "[1] to [3-2]" or "[1] to [8]," if there is an item in the range that includes a sub-number such as [2-2], the item that includes that sub-number will also be included in the range.

[0049] The compound represented by general formula (I) of the present invention or a salt thereof (a pharmaceutically acceptable salt) has CRBN-binding activity and target protein-binding activity, and therefore can be used in the treatment of diseases that can be treated by degradation of each target protein.

[0050] FIG. 1 shows the results of SDS-PAGE and Western blotting to detect and visualize the ER protein (ERα) degradation activity at various concentrations when Examples 29B, 33C, and 35E were used as test compounds.

[0051] 1. Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. In the event of a discrepancy between the meaning defined herein and the meaning commonly understood by those of ordinary skill in the art, the meaning defined herein shall prevail. Preferred methods and materials are described below; however, methods and materials similar or equivalent to those described herein can be used in practicing or testing the present invention. All references (including patent and non-patent literature) described herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and are not intended to be limiting.

[0052] As used herein, "halogen" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0053] As used herein, "alkyl" means straight or branched chain alkyl. １－６ "Alkyl" means an alkyl having 1 to 6 carbon atoms, １－３ "Alkyl" means an alkyl having 1 to 3 carbon atoms. Examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0054] In the present specification, "aliphatic ring" means a monocyclic or bicyclic hydrocarbon ring having no aromaticity. The ring is exemplified by a saturated ring or an unsaturated ring, with a saturated ring being a preferred embodiment. The aliphatic ring is exemplified by a monocyclic ring being a preferred embodiment. In the present specification, "3- to 6-membered aliphatic ring" and "4- to 7-membered aliphatic ring" mean an aliphatic ring consisting of 3 to 6 carbon atoms and an aliphatic ring consisting of 4 to 7 carbon atoms, respectively. Examples of "aliphatic rings" include 4- to 7-membered cycloalkane rings (C ４－７cycloalkane ring); 4- to 7-membered cycloalkene ring (C such as cyclobutene, cyclopentene, cyclohexene, cycloheptene, etc. ４－７ Examples of suitable cycloalkane rings include, but are not limited to, monocyclic cycloalkanes, fused bicyclic cycloalkanes, spirocyclic rings, or bridged cycloalkanes in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms.

[0055] As used herein, "cycloalkyl" refers to a monovalent group derived from a cycloalkane ring. As used herein, for example, 3- to 6-membered cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., are defined as "C ３－６ It is written as "cycloalkyl".

[0056] As used herein, "aliphatic heterocycle" refers to a non-aromatic monocyclic or bicyclic ring containing, as ring-constituting atoms, one or more heteroatoms selected from atoms other than carbon, such as nitrogen, oxygen, and sulfur. Examples of such rings include saturated rings (heterocycloalkane rings) and unsaturated rings (heterocycloalkene rings), with saturated rings being preferred. A monocyclic ring is a preferred embodiment of the aliphatic heterocycle. A "four- to seven-membered aliphatic heterocycle" refers to an aliphatic heterocycle consisting of four to seven ring-constituting atoms. Examples of "aliphatic heterocycles" include, but are not limited to, azetidine, pyrrolidine, pyrroline, piperidine, piperazine, dihydroazepine, azepine, tetrahydrofuran, tetrahydropyran, pyran, morpholine, tetrahydrothiophene, and thiane. Further, another embodiment of the "aliphatic heterocycle" includes, but is not limited to, a spiro ring (for example, a 7-azaspiro[3.5]nonane ring, etc.), or a bridged heterocycloalkane ring or bridged heterocycloalkene ring in which two non-adjacent atoms of the ring are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms.

[0057] In the present specification, examples of the "4- to 7-membered aliphatic heterocycle containing one nitrogen atom as a ring-constituting atom" include, but are not limited to, azetidine, pyrrolidine, pyrroline, piperidine, dihydroazepine, azepine, etc.

[0058] In the present specification, examples of the "4- to 7-membered aliphatic heterocycle containing one or two nitrogen atoms as ring-constituting atoms" include, but are not limited to, azetidine, pyrrolidine, pyrroline, piperidine, dihydroazepine, azepine, imidazolidine, pyrazolidine, piperazine, etc.

[0059] As used herein, "heterocycloalkyl" refers to a monovalent group derived from a heterocycloalkane ring. Examples of "heterocycloalkyl" include oxiranyl, thiaarnyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, pyranyl, tetrahydrothiopyranyl, thiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, thiomorpholinyl, 1,4-dithianyl, Piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thieazepanyl, 1,4-azaphosphinanyl, 1,4-diazepanyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, 1,2-tetrahydrothiazinyl 1,3-tetrahydrodiazin-2-yl, tetrahydroazepinyl, chromanyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, 7-azaspiro[3.5]nonyl, 7-oxa-1-aza-spiro[4.4]nonyl, 3-aza Examples include bicyclo[3.1.0]hexyl, indolinyl, dihydroindolinyl, octahydro-1H-indolyl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptyl, 3,4-dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, tetrahydro-1H-benzo[d]azepinyl, and the like.

[0060] As used herein, "4- to 6-membered heterocycloalkyl containing one nitrogen atom as a ring-constituting atom" refers to a heterocycloalkyl having a total of 4 to 6 carbon atoms and one nitrogen atom as ring-constituting atoms. Examples of "4- to 6-membered heterocycloalkyl containing one nitrogen atom as a ring-constituting atom" include azetidinyl, pyrrolidinyl, piperidinyl, etc.

[0061] As used herein, the term "aromatic heterocycle" refers to a monocyclic or polycyclic ring containing one or more heteroatoms other than carbon, such as nitrogen, oxygen, and sulfur, as ring-constituting atoms, and at least one of the rings being an aromatic ring. Examples of the "aromatic heterocycle" include, but are not limited to, monocyclic or bicyclic aromatic heterocycles such as thiophene, pyrrole, pyrazole, triazole, oxazole, oxadiazole, thiazole, pyridine, pyrimidine, pyridazine, pyrazine, quinoline, quinoxaline, benzothiophene, benzimidazole, benzotriazole, and benzofuran.

[0062] In this specification, examples of the "6- to 12-membered monocyclic or bicyclic aromatic heterocycle containing one or two nitrogen atoms as ring-constituting atoms" include, but are not limited to, 6-membered rings such as pyridine, pyrazine, pyrimidine, and pyridazine; 7-membered rings such as azepine, 1,2-diazepine, 1,3-diazepine, and 1,4-diazepine; 8-membered rings such as azocine; 9-membered rings such as azonine; 6 / 5-membered fused rings such as indole, isoindole, indazole, benzimidazole, and imidazopyridine (including imidazo[1,2-a]pyridine); and 6 / 6-membered fused rings such as quinoline, isoquinoline, quinazoline, quinoxaline, and cinnoline.

[0063] As used herein, "heteroaryl" refers to a monovalent group derived from an aromatic heterocycle. Examples of "heteroaryl" include, but are not limited to, thienyl, pyrrolyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, quinolyl, quinoxalyl, benzothiophenyl, benzimidazolyl, benzotriazolyl, and benzofuranyl.

[0064] In the present specification, examples of the "6-membered heteroaryl containing one or two nitrogen atoms as ring-constituting atoms" include, but are not limited to, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, and the like.

[0065] In this specification, unless otherwise specified, the symbols:

[0066]

[0067] means that it is bonded to the other side of the paper (α-configuration), and the symbol:

[0068]

[0069] means that the bond is on the front side of the paper (β-configuration), and the symbol:

[0070]

[0071] means a mixture of α- and β-configuration.

[0072] As used herein, "pharmaceutically acceptable" means that it is not significantly toxic and can be used as a medicine. Therefore, as used herein, a "pharmaceutically acceptable salt" means a salt that is not significantly toxic and can be used as a medicine.

[0073] As used herein, "prevention" includes preventing the onset of a disease, delaying the onset of a disease, and preventing the development of a pathological condition.

[0074] As used herein, "treatment" includes curing a disease, ameliorating the pathology of a disease (e.g., one or more symptoms), and inhibiting the progression (of the severity) of a disease.

[0075] As used herein, "effective amount" or "therapeutically effective amount" means an amount effective for treating, preventing the progression of, or alleviating existing symptoms of a subject being treated. The effective amount can be appropriately determined according to conventional methods, taking into account the desired therapeutic effects and side effects.

[0076] As used herein, the term "subject" refers to a subject to which a pharmaceutical (pharmaceutical composition) containing an effective amount of an active ingredient is administered to prevent and / or treat (or improve) a disease or the pathology of a disease. The "subject" includes humans and non-human animals, particularly mammals (e.g., humans, mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.).

[0077] <2. Targeted Protein Degradation Inducer> In one embodiment of the present invention, a target protein degradation inducer is provided, the target protein degradation inducer being a compound represented by the following formula (I):

[0078]

[0079] wherein T is a target protein binding motif, L is a linker, and E is a group represented by the following formula (II):

[0080]

[0081] (In formula (II), * represents a bonding position with L at any bondable site in the chemical formula in [ ], and X represents CH ２ or C(=O), and Y is N(R ３ ) or CH(R ３ ) and Z is CH ２ or C(=O), and R １ , R ２ , and R ３ are each independently a hydrogen atom, or R １ and R ２ are bonded to each other and together with the carbon atoms to which they are attached form a 4- to 7-membered aliphatic heterocycle containing one nitrogen atom as a ring-constituting atom and which may be substituted with one substituent, or a 4- to 7-membered aliphatic ring which may be substituted with one substituent, and R ３ is a hydrogen atom, or R １ and R ３ are bonded to each other to form R １ and the carbon atom to which R ３is bonded together with the atom to which it is bonded to form a 4- to 7-membered aliphatic heterocycle which contains one or two nitrogen atoms as ring-constituting atoms and which may be substituted with one substituent, or a 4- to 7-membered aliphatic ring which may be substituted with one substituent, and R ２ is a group represented by the formula: wherein R is a hydrogen atom; or a salt thereof.

[0082] In one aspect of the present invention, T in the above formula (I) is a target protein binding motif. The target protein binding motif refers to a moiety containing a partial structure that binds to a target protein. The target protein is not particularly limited as long as it is a target protein in a targeted protein degradation inducer, but examples include steroidogenic factor-1 (SF-1), anaplastic lymphoma kinase (ALK), or estrogen receptor (ER), and in another aspect, SF-1 is an example. The target protein also includes proteins that are known as target proteins in targeted protein degradation inducers. The target protein binding motif is not particularly limited as long as it is a moiety that contains a target protein binding partial structure in a targeted protein degradation inducer. The target protein binding motif also includes target protein binding motifs in known targeted protein degradation inducers. T is represented by the following formula:

[0083]

[0084] (In the formula, the wavy line indicates the bonding position with L, and in formula (VIII), A is —O— or —CF ２ - and R Ｔ１ is a halogen, —O—C optionally substituted with 1 to 3 halogens １－６ Alkyl, —N(H)—C １－３ Alkyl, —N(C １－３ alkyl) ２ or a 4- to 6-membered heterocycloalkyl containing one nitrogen atom as a ring atom, R Ｔ２ and R Ｔ３ are each independently a hydrogen atom or C １－６ alkyl, R Ｔ４ is C optionally substituted with 1 to 3 halogen atoms. １－６alkyl, —C(═O)—C optionally substituted with 1 to 3 halogens; １－６ alkyl, C optionally substituted with one trifluoromethyl ３－６ cycloalkylmethyl, or a 6-membered heteroaryl containing one or two nitrogen atoms as ring-constituting atoms (the heteroaryl may be substituted with one halogen atom), and ring Q Ｔ１ is a halogen and C １－３ a benzene ring which may have one or two substituents independently selected from the group consisting of alkyl; a 6- to 12-membered monocyclic or bicyclic aromatic heterocycle containing one or two nitrogen atoms as ring-constituting atoms; C ４－７ Cycloalkane ring, or C ４－７ is a cycloalkene ring, Ｔ１ represents a single bond, —O—, —CH ２ - or -C(=O)-, and ring Q Ｔ２ represents a benzene ring optionally substituted with one halogen atom, C ４－７ a cycloalkane ring, a C optionally substituted with one halogen atom; ４－７ cycloalkene ring, piperidine ring, or 7-azaspiro[3.5]nonane ring).

[0085] In another embodiment of the above formula (VIII), A is —O—. Ｔ１ is methoxy. Ｔ２ is methyl. Ｔ３ is methyl. Ｔ４ is C optionally substituted with 1 to 3 halogen atoms. １－６ alkyl, —C(═O)—C optionally substituted with 1 to 3 halogens; １－６ Ring Q is alkyl, or a 6-membered heteroaryl containing 1 or 2 nitrogen atoms as ring-constituting atoms (the heteroaryl may be substituted with 1 halogen), and in another embodiment, it is 3,3,3-trifluoro-2,2-dimethylpropyl. Ｔ１ is a halogen and C １－３L is a benzene ring or a pyridine ring, which may have one substituent selected from the group consisting of alkyl, and in another embodiment, it is a benzene ring. Ｔ１ is a single bond, —O—, or —C(═O)—. Ｔ２ is a benzene ring, C ４－７ Cycloalkane ring, C ４－７ In another embodiment, C is a cycloalkene ring or a piperidine ring. ４－７ It is a cycloalkene ring or a piperidine ring.

[0086] In one embodiment of the present invention, specific examples of T include the following formula:

[0087]

[0088] (wherein the wavy line indicates the bonding position to L).

[0089] Here, the partial structure T represented by the above formula (VIII) can be produced by the method described in WO 2025 / 070690 or a method similar thereto.

[0090] Also, the following formula:

[0091]

[0092] The partial structure T represented by the following formula:

[0093]

[0094] The partial structure T represented by the following formula can be produced by the method described in J. Med. Chem., 1967, 10, 2, 138-144, or a method analogous thereto.

[0095] In one aspect of the present invention, L in the above formula (I) is a linker. The linker is not particularly limited as long as it has a structure that links T and E in the above formula (I). T and E may be directly linked as long as the desired effect (e.g., target protein inhibitory activity or target protein decomposition activity) is achieved. That is, L also includes a single bond.

[0096] L can be the linker moiety of any target protein degradation inducer that has been confirmed to be useful, such as the linker moieties disclosed in Patent Documents 1-9 and Non-Patent Documents 1-6, or the linker moieties of ARV-471, ARV-110, CFT8634, ARV-766, AR-LDD, GT20029, NX-2127, HSK29116, BGB-16673, DT-2216, FHD-609, LNK01002, KT-474, KT-413, NX-5948, KT-333, CG001419, CFT7455, CFT1946, or CFT8919, which have been reported to have been subjected to clinical or preclinical trials. In one embodiment of the present invention, the linker has the linker structure shown, for example, in Table 2 of Non-Patent Document 2, specifically, the linker structure shown in the following formula:

[0097]

[0098] (wherein n and m each independently represent an integer of 1 to 10).

[0099] Another embodiment of L is a group represented by the following formula:

[0100]

[0101] (In the formula, n ５ is an integer from 1 to 6, and n ６ is an integer of 0 to 6, the wavy line indicates the bonding position to T, and * indicates the bonding position to E). Further, another embodiment of L is a group selected from the group consisting of the following formula:

[0102]

[0103] (wherein the wavy line indicates the position of bonding to T, and * indicates the position of bonding to E).

[0104] In one embodiment of the present invention, E in the above formula (I) is represented by the following formula (II):

[0105]

[0106] Examples include groups represented by the following formula:

[0107] In the above formula (II), * represents a bonding position with L at any bondable site in the chemical formula in [ ], and X represents CH ２ or C(=O). Y is N(R ３ ) or CH(R ３ ) is an example of another embodiment of Y. ３ Z is exemplified by CH ２ or C(=O). １ , R ２ , and R ３ are each independently a hydrogen atom, or R １ and R ２ are bonded to each other and together with the carbon atoms to which they are attached contain one nitrogen atom as a ring member and one substituent (e.g., hydroxy group, carboxy group, C １－６ a 4- to 7-membered aliphatic heterocycle optionally substituted with one substituent (e.g., a hydroxy group, a carboxy group, a C １－６ alkyl group, etc.), and R ３ is a hydrogen atom, or R １ and R ３ are bonded to each other to form R １ and the carbon atom to which R ３ is bonded to an atom, and contains one or two nitrogen atoms as ring-constituting atoms, and one substituent (e.g., a hydroxy group, a carboxy group, １－６ a 4- to 7-membered aliphatic heterocycle optionally substituted with one substituent (e.g., a hydroxy group, a carboxy group, a C １－６ alkyl group, etc.), and R ２ is exemplified by a hydrogen atom.

[0108] R １ and R ２are bonded to each other and together with the carbon atoms to which they are bonded form a 4- to 7-membered aliphatic heterocycle which contains one nitrogen atom as a ring-constituting atom and which may be substituted with one substituent, or a 4- to 7-membered aliphatic ring which may be substituted with one substituent, and R ３ is a hydrogen atom, examples of the group (E) represented by the formula (II) include groups represented by the following formula (IV):

[0109]

[0110] Examples include groups represented by the following formula:

[0111] In the above formula (IV), X ２ As for CH ２ or C(=O). ２ As the alkyl group, NH or CH ２ Examples include: Y ２ In another embodiment, CH ２ Examples include: Z ２ As for CH ２ or C(=O). ３ and n ４ are each independently an integer of 1 to 3 (wherein n ３ +n ４ is an integer from 2 to 5), ２ Examples of -* include N-*, CH-O-*, or CH-C(=O)-* (where * indicates the bonding position to L).

[0112] Specific examples of E represented by the above formula (IV) include:

[0113]

[0114] (wherein * indicates the bonding position to L) is exemplified. Examples of the "4- to 7-membered aliphatic heterocycle containing one nitrogen atom as a ring-constituting atom" include azetidine, pyrrolidine, pyrroline, piperidine, dihydroazepine, and azepine, and preferred embodiments include azetidine, pyrrolidine, and piperidine. Examples of the "4- to 7-membered aliphatic ring" include cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclobutene, cyclopentene, cyclohexene, and cycloheptene, and preferred embodiments include cyclobutane, cyclopentane, cyclohexane, and cycloheptane. Among these, "4- to 7-membered aliphatic heterocycles containing one nitrogen atom as a ring-constituting atom" are preferred.

[0115] Also, R １ and R ３ are bonded to each other to form R １ and the carbon atom to which R ３ is bonded together with the atom to which it is bonded to form an optionally substituted 4- to 7-membered aliphatic heterocycle or an optionally substituted 4- to 7-membered aliphatic ring containing one or two nitrogen atoms as ring-constituting atoms, and ２ is a hydrogen atom, examples of the group (E) represented by the formula (II) include groups represented by the following formula (III):

[0116]

[0117] Examples include groups represented by the following formula:

[0118] In the above formula (III), X １ As for CH ２ or C(=O). １ Examples of Y include N and CH. １ Another embodiment of Z is N. １ As for CH ２ or C(=O). １ and n ２ are each independently 1 or 2. １Examples of -* include N-*, CH-O-*, and CH-C(=O)-* (where * indicates the bonding position to L). １ Another embodiment of the above is N-*.

[0119] Specific examples of E represented by the above formula (III) include, for example,

[0120]

[0121] (wherein * indicates the bonding position with L) is exemplified. Examples of the "4- to 7-membered aliphatic heterocycle containing one or two nitrogen atoms as ring-constituting atoms" include azetidine, pyrrolidine, pyrroline, piperidine, dihydroazepine, azepine, imidazolidine, pyrazolidine, and piperazine, and preferred embodiments include azetidine, pyrrolidine, piperidine, and piperazine. Furthermore, examples of the "4- to 7-membered aliphatic ring" include cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclobutene, cyclopentene, cyclohexene, and cycloheptene, and preferred embodiments include cyclobutane, cyclopentane, cyclohexane, and cycloheptane. Among these, "4- to 7-membered aliphatic heterocycles containing one or two nitrogen atoms as ring-constituting atoms" are preferred.

[0122] In one embodiment of the present invention, T in the above formula (I) is a binding motif for a target protein selected from steroidogenic factor-1 (SF-1), anaplastic lymphoma kinase (ALK), and estrogen receptor (ER); and L is a single bond or a group represented by the following formula:

[0123]

[0124] (wherein n and m each independently represent an integer of 1 to 10); and E is a divalent group selected from the group consisting of the following formula (III):

[0125]

[0126] (In formula (III), X １ is CH ２ or C(=O), and Y １is N or CH, Z １ is CH ２ or C(=O), n １ and n ２ are each independently 1 or 2; １ -* is N-*, CH-O-*, or CH-C(=O)-*, and * is the bonding position to L), or a salt thereof.

[0127] In one embodiment of the present invention, T in the above formula (I) is a binding motif for a target protein selected from steroidogenic factor-1 (SF-1), anaplastic lymphoma kinase (ALK), and estrogen receptor (ER); and L is one of the following:

[0128]

[0129] (In the formula, n ５ is an integer from 1 to 6, and n ６ is an integer of 0 to 6, the wavy line is the bonding position to T, and * is the bonding position to E); and E is a group selected from the group consisting of the following formula:

[0130] (wherein * is the bonding position to L) or a salt thereof.

[0131] In one embodiment of the present invention, T in the above formula (I) is the following formula:

[0132]

[0133] (wherein the wavy line is the bonding position to L);

[0134]

[0135] wherein the wavy line represents the position of attachment to T, and * represents the position of attachment to E; and wherein E is a group selected from the group consisting of the following formula:

[0136] (wherein * is the bonding position to L) or a salt thereof.

[0137] In another embodiment of the present invention, T in the above formula (I) is a binding motif for a target protein selected from steroidogenic factor-1 (SF-1), anaplastic lymphoma kinase (ALK), and estrogen receptor (ER); and L is a single bond or a group represented by the following formula:

[0138]

[0139] (wherein n and m each independently represent an integer of 1 to 10); and E is a divalent group selected from the group consisting of the following formula (IV):

[0140]

[0141] (In formula (IV), X ２ is CH ２ or C(=O), and Y ２ is NH or CH ２ and Z ２ is CH ２ or C(=O), n ３ and n ４ are each independently an integer of 1 to 3, and n ３ +n ４ is an integer from 2 to 5, and W ２ -* is N-*, CH-O-*, or CH-C(=O)-*, and * is the bonding position to L), or a salt thereof.

[0142] In another embodiment of the present invention, T in the above formula (I) is a binding motif for a target protein selected from steroidogenic factor-1 (SF-1), anaplastic lymphoma kinase (ALK), and estrogen receptor (ER); and L is one of the following:

[0143]

[0144] (In the formula, n ５ is an integer from 1 to 6, and n ６is an integer of 0 to 6, the wavy line is the bonding position to T, and * is the bonding position to E); and E is a group selected from the group consisting of the following formula:

[0145]

[0146] (wherein * is the bonding position to L) or a salt thereof.

[0147] In another embodiment of the present invention, T in the above formula (I) is the following formula:

[0148]

[0149] (wherein the wavy line indicates the bonding position to L), wherein L is one of the following:

[0150]

[0151] wherein the wavy line represents the position of attachment to T, and * represents the position of attachment to E; and wherein E is a group selected from the group consisting of the following formula:

[0152]

[0153] (wherein * is the bonding position to L) or a salt thereof.

[0154] In yet another embodiment of the present invention, the present invention is directed to the following group: (7aR)-1-(2,6-dioxopiperidin-3-yl)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione, (7aS)-1-(2,6-dioxopiperidin-3-yl)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione, 3-[(7aS)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-1(13H)-yl]piperidine-2,6-dione, and 3-[(7aR)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-2-oxo-4,5,7,7a,8,9,10,A compound or a salt thereof selected from 11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-1(13H)-yl]piperidine-2,6-dione is provided. All of these compounds are included in the compound represented by formula (I) or a salt thereof.

[0155] 3. Salts, Isomers, Prodrugs, etc. As described above, the term "pharmaceutically acceptable salt" in the present invention refers to a salt that can be used as a medicine. When the compound of the present invention has an acidic group, it can form a basic salt (also referred to as a "base addition salt") by reacting it with a base, and when it has a basic group, it can form an acid salt (also referred to as an "acid addition salt") by reacting it with an acid. Therefore, in one aspect of the present invention, the pharmaceutically acceptable salt of the compound represented by formula (I) is a basic salt, and in another aspect of the present invention, the pharmaceutically acceptable salt of the compound represented by formula (I) is an acid salt.

[0156] Suitable examples of the "basic salt" in the present invention include alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkaline earth metal salts such as magnesium salt and calcium salt; organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, and picoline salt; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt, and aspartic acid salt.

[0157] Suitable examples of the "acid salt" in the present invention include hydrohalide salts such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; lower alkane sulfonate salts such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonate salts such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, and maleate; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate.

[0158] The compound of the present invention or a pharmaceutically acceptable salt thereof may take up water molecules and become a hydrate when left in the air or recrystallized, and such hydrates are also included in the present invention. Furthermore, the compound of the present invention or a pharmaceutically acceptable salt thereof may absorb a certain solvent when left in a solvent or recrystallized, and become a solvate, and such solvates are also included in the present invention. Furthermore, the compound of the present invention or a pharmaceutically acceptable salt thereof may exist as an amorphous or crystalline form.

[0159] In addition, the compound of the present invention or a pharmaceutically acceptable salt thereof may be labeled with one or more pharmaceutically acceptable radioactive or non-radioactive isotopes. Examples of isotopes that can be incorporated into the compound of the present invention or a pharmaceutically acceptable salt thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, etc., specifically, ２ H. ３ H. １１ C. １３ C. １４ C. １３ N. １５ N. １５ O. １７ O. １８ O. １８Examples of isotopically labeled compounds include, but are not limited to, F. Radioactive or non-radioactive labeled compounds may be useful to help determine or measure the effectiveness of compounds of the present invention, for example, by characterizing their site or mode of action, or binding affinity to pharmacologically important sites of action. Such isotopically labeled compounds can be prepared by conventional techniques generally known to those skilled in the art.

[0160] The compounds of the present invention, their pharmaceutically acceptable salts, or solvates thereof may exist in various isomers, such as geometric isomers of cis or trans isomers, tautomers, rotational isomers, and optical isomers (including enantiomers and diastereomers) such as d- and l-isomers, depending on the types and combinations of substituents. Unless otherwise specified, the compounds of the present invention include all such isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any ratio. Mixtures of these isomers can be separated by known resolution methods.

[0161] The present invention also encompasses prodrugs of the compounds of the present invention. A prodrug is a compound having a group that can be converted into an amino group, a hydroxy group, a carboxy group, or the like of the compound by hydrolysis or under physiological conditions. Examples of groups that form such prodrugs include those described in Prog. Med., Vol. 5, pp. 2157-2161, 1985, etc. More specific examples of the prodrug include: (1) when the compound of the present invention has an amino group, compounds in which the amino group has been acylated, alkylated or phosphorylated (for example, compounds in which the amino group has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated), and (2) when the compound of the present invention has a hydroxy group, compounds in which the hydroxy group has been acylated, alkylated, phosphorylated or borated (for example, compounds in which the hydroxy group has been acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated), and (3) When the compound of the present invention has a carboxy group, examples of the compound include compounds in which the carboxy group is esterified or amidated (for example, compounds in which the carboxy group is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified, amidated, or methylamidated).

[0162] 4. Compositions and Pharmaceutical Uses In one aspect of the present invention, there is provided a composition or pharmaceutical composition (hereinafter sometimes referred to as the "composition of the present invention") for inducing degradation of a target protein, comprising a compound represented by formula (I) above or a pharmaceutically acceptable salt thereof, or a medicament containing the compound. In another aspect of the present invention, there is provided a method for treating a target protein-associated disease, comprising administering an effective amount of a compound represented by formula (I) above or a pharmaceutically acceptable salt thereof to a subject in need of such treatment. In yet another aspect of the present invention, there is provided a compound represented by formula (I) above or a pharmaceutically acceptable salt thereof for use in treating a target protein-associated disease. In addition, in yet another aspect of the present invention, there is provided a method for using a compound represented by formula (I) above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a target protein-associated disease.

[0163] In the present invention, "a composition for inducing the degradation of a target protein" refers to a composition intended to induce the degradation of a target protein. "A composition for inducing the degradation of a target protein" includes not only compositions intended solely to induce the degradation of a target protein, but also compositions that include the induction of degradation of a target protein as one of their purposes. "A composition for inducing the degradation of a target protein" typically includes compositions whose intended use is to induce the degradation of a target protein as listed in the accompanying instructions, packaging, promotional materials, etc. of the composition, but also includes compositions that substantially or substantially include the induction of degradation of a target protein as one of their intended uses, even if such a statement is not made.

[0164] In the present invention, the term "medicine" refers to a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Because the compounds of the present invention have target protein degradation activity, they can be used as compositions for treating and / or preventing diseases associated with target proteins, more specifically, diseases in which target proteins (particularly SF-1, ALK, or ER) are involved in the onset or progression of the disease. Examples of such diseases include, but are not limited to, castration-resistant prostate cancer, adrenocortical carcinoma, Leydig tumor, hormone-sensitive prostate cancer, breast cancer, and other cancers, Cushing's syndrome, and primary aldosteronism. Thus, in one aspect of the present invention, the medicament of the present invention is a medicament for treating cancer such as castration-resistant prostate cancer, adrenocortical carcinoma, Leydig tumor, hormone-sensitive prostate cancer, or breast cancer, Cushing's syndrome, or primary aldosteronism; in a further aspect of the present invention, the medicament of the present invention is a medicament for treating castration-resistant prostate cancer or adrenocortical carcinoma; in another aspect of the present invention, the medicament of the present invention is a medicament for treating castration-resistant prostate cancer; and in yet another aspect of the present invention, the medicament of the present invention is a medicament for treating adrenocortical carcinoma. When the medicament of the present invention contains a pharmaceutically acceptable carrier, the medicament may be referred to as the "pharmaceutical composition of the present invention."

[0165] The route of administration of such a composition to humans or other animals may be any of oral administration using tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration using intra-articular, intravenous, intramuscular, etc. injections, suppositories, eye drops, eye ointments, transdermal liquids, ointments, transdermal patches, transmucosal liquids, transmucosal patches, inhalants, etc. However, considering that the molecular weight of the compound of the present invention is not extremely large, oral administration is preferred from the viewpoint of reducing the burden of taking medication.

[0166] Solid compositions for oral administration include tablets, powders, granules, etc. Such solid compositions contain, in addition to the compound of the present invention, at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminometasilicate, etc. Such solid compositions may contain inert additives, such as lubricants such as magnesium stearate, disintegrants such as sodium carboxymethyl starch, stabilizers, and solubilizers, according to conventional methods. Tablets or pills may be coated with a sugar coating or a film of a gastric or enteric material, if necessary.

[0167] Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. A commonly used inert diluent, such as purified water or ethanol, can be added to such liquid compositions. In addition to the inert diluent, such liquid compositions may contain adjuvants such as solubilizers and wetting agents, sweeteners, flavors, fragrances, preservatives, etc.

[0168] Injectable preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, emulsions, etc. Examples of injectable solvents include aqueous solvents such as distilled water for injection and physiological saline, and non-aqueous solvents such as propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such injectable compositions may further contain an isotonicity agent, preservative, wetting agent, emulsifier, dispersant, stabilizer, and / or solubilizer. These injectable compositions can be sterilized, for example, by filtration through a bacteria-retaining filter, addition of a sterilizing agent, or irradiation. Alternatively, these injectable compositions can be prepared as sterile solid compositions, which can be dissolved or suspended in sterile water or a sterile injectable solvent prior to use.

[0169] Examples of topical preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, and eye ointments. These topical preparations may contain commonly used ointment bases, lotion bases, aqueous or non-aqueous solvents, suspending agents, emulsifiers, and the like. Examples of ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glycerin monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, and sorbitan sesquioleate.

[0170] Transmucosal preparations, such as inhalants and nasal preparations, may be in solid, liquid, or semisolid form and can be prepared according to conventional methods. Transmucosal preparations may contain, for example, known excipients, as well as pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, etc., as appropriate. These transmucosal preparations can be administered using an appropriate inhalation or insufflation device. For example, known devices or nebulizers, such as metered-dose inhalers, can be used to administer the compounds of the present invention alone or as a powder of a formulated mixture, or in combination with a pharmaceutically acceptable carrier as a solution or suspension. Dry powder inhalers and the like may be for single or multiple administrations, and dry powders or powder-containing capsules can be used. Appropriate propellants can also be used for dry powder inhalers and the like. For example, the preparations may be in the form of a pressurized aerosol spray using a suitable gas, such as a chlorofluoroalkane, a hydrofluoroalkane, or carbon dioxide.

[0171] The composition (pharmaceutical composition) of the present invention may contain other active ingredients, or may be used in combination with another composition containing other active ingredients. Such combinations may be administered simultaneously, separately, consecutively, or at a desired time interval. Simultaneous administration preparations may be formulated as a combined preparation or separately.

[0172] The amount of the compound of the present invention loaded into the composition or the amount administered to the subject is not particularly limited as long as it is an amount effective for achieving the purpose, and can be appropriately selected depending on the purpose of use, the age, weight, symptoms, health condition, progress of the disease, etc. The frequency of administration of the composition of the present invention is not particularly limited and can be appropriately selected depending on the purpose, and for example, the daily dose may be administered once a day or may be administered in divided doses.

[0173] 5. Combination Use The compound of the present invention or a pharmaceutically acceptable salt thereof, a composition for inducing degradation of a target protein, a pharmaceutical composition, or a medicine containing the compound or a pharmaceutically acceptable salt thereof may be used in combination with other antitumor agents. Examples of other antitumor agents include alkylating agents, antimetabolites, antitumor antibiotics, microtubule inhibitors, topoisomerase inhibitors, BRMs (biological response regulators), hormones, vitamins, antitumor antibodies, molecularly targeted drugs, and other antitumor agents.

[0174] More specifically, examples of the alkylating agent include alkylating agents such as nitrogen mustard, nitrogen mustard-N-oxide, and chlorambucil; aziridine alkylating agents such as carboquone and thiotepa; epoxide alkylating agents such as dibromomannitol and dibromodalcitol; nitrosourea alkylating agents such as carmustine, lomustine, semustine, nimustine hydrochloride, streptozocin, chlorozotocin, and ranimustine; busulfan, improsulfan tosylate, and dacarbazine.

[0175] Examples of the various antimetabolites include purine antimetabolites such as 6-mercaptopurine, 6-thioguanine, and thioinosine; pyrimidine antimetabolites such as fluorouracil, tegafur, tegafur-uracil, carmofur, doxifluridine, broxuridine, cytarabine, enocitabine, and capecitabine; folate antimetabolites such as methotrexate, trimetrexate, and pemetrexed; and active folate agents such as levofolinate.

[0176] Examples of antitumor antibiotics include anthracycline antibiotic antitumor agents such as daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin, epirubicin, and amrubicin; mitomycin C, bleomycin, peplomycin, chromomycin A3, and actinomycin D.

[0177] Examples of microtubule inhibitors include vinca alkaloids such as vindesine, vincristine, vinblastine, and vinorelbine; taxanes such as paclitaxel, docetaxel, and cabazitaxel; and eribulin.

[0178] Examples of topoisomerase inhibitors include epipodophyllotoxins such as etoposide and teniposide, and camptothecin derivatives such as irinotecan.

[0179] Examples of BRM include tumor necrosis factor and indomethacin.

[0180] Examples of hormone agents include hydrocortisone, cortisone acetate, fludrocortisone, fludrocortisone acetate, dexamethasone, methylprednisolone, prednisolone, prasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, methenolone, fosfestrol, ethinyl estradiol, chlormadinone, glucocorticoids, medroxyprogesterone, bicalutamide, enzalutamide, apalutamide, grollutamide, flutamide, anastrozole, exemestane, letrozole, abiraterone, goserelin, leuprorelin, toremifene, degarerx, mitotane, and tamoxifen.

[0181] Examples of vitamins include vitamin C and vitamin A.

[0182] Examples of anti-tumor antibodies and molecularly targeted drugs include anti-tumor antibodies (including modified forms thereof) such as trastuzumab, rituximab, cetuximab, pertuzumab, nimotuzumab, pembrolizumab, camrelizumab, denosumab, bevacizumab, infliximab, and ramucirumab; kinase inhibitors such as imatinib, gefitinib, erlotinib, sunitinib, lapatinib, eganelisib, sorafenib, dasatinib, nilotinib, vemurafenib, osimertinib, apatinib, and cabozantinib; PARP inhibitors such as olaparib, rucaparib, velparib, and niraparib; and molecularly targeted drugs such as OR-449.

[0183] Other antitumor agents include, for example, platinum compounds such as cisplatin, carboplatin, and oxaliplatin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, aceglatone, sizofiran, picibanil, procarbazine, pipobroman, neocarzinostatin, hydroxyurea, ubenimex, and krestin.

[0184] Furthermore, the compound of the present invention or a pharmaceutically acceptable salt thereof, a composition for inducing degradation of a target protein, a pharmaceutical composition, or a medicament containing the compound or a pharmaceutically acceptable salt thereof may be used in combination with an antibody-drug conjugate (ADC) containing the above-mentioned antitumor agent as a payload, or a targeted protein degradation inducer having the above-mentioned antitumor agent as a target protein ligand.

[0185] The compound of the present invention or a pharmaceutically acceptable salt thereof, a composition for inducing degradation of a target protein, a pharmaceutical composition, or a medicine containing the compound or a pharmaceutically acceptable salt thereof may be administered simultaneously with or separately from the above-mentioned concomitant drug, and may be prepared as a combined drug or a kit preparation.

[0186] In the treatment of adrenocortical carcinoma, examples of antitumor agents that can be suitably used in combination with the compound of the present invention or a pharmaceutically acceptable salt thereof, a composition for inducing degradation of a target protein, a pharmaceutical composition, or a medicine containing the compound or a pharmaceutically acceptable salt thereof include one or more selected from anthracycline compounds such as doxorubicin, platinum compounds such as cisplatin and carboplatin, antitumor antibodies such as nivolumab, pembrolizumab and camrelizumab, molecularly targeted drugs such as eganelisib, apatinib, cabozantinib and OR-449, mitotane, and etoposide.

[0187] In the treatment of castration-resistant prostate cancer, antitumor agents that can be suitably used in combination with the compound of the present invention or a pharmaceutically acceptable salt thereof, a composition for inducing degradation of a target protein, a pharmaceutical composition, or a medicine containing the compound or a pharmaceutically acceptable salt thereof include one or more selected from hormonal agents such as abiraterone, enzalutamide, grollutamide, apalutamide, etc.; microtubule inhibitors such as docetaxel, cabazitaxel, etc.; PARP inhibitors such as olaparib, rucaparib, etc.; androgen receptor degradation inducers such as ARV-110, ARV-766, CC-94676, etc.; CYP11A1 enzyme inhibitors such as ODM-208, etc.; and antitumor antibodies such as nivolumab, pembrolizumab, camrelizumab, etc.

[0188] <6. Novel Intermediate> In one embodiment of the present invention, a novel intermediate is prepared by the method of the present invention.

[0189]

[0190] is exemplified as a novel intermediate for producing the compound of the present invention.

[0191] In the above formula (V), X is CH ２ or C(=O). Y is N(R ３ ) or CH(R ３ ) is an example of another embodiment of Y. ３ Z is exemplified by CH ２ or C(=O). １ , R ２ , and R ３are each independently a hydrogen atom, or R １ and R ２ are bonded to each other and together with the carbon atoms to which they are attached contain one nitrogen atom as a ring member and one hydroxy group, carboxy group, or C １－６ a 4- to 7-membered aliphatic heterocycle optionally substituted with an alkyl group, or one hydroxy group, carboxy group, or C １－６ form a 4- to 7-membered aliphatic ring optionally substituted with an alkyl group, and R ３ is a hydrogen atom, or R １ and R ３ are bonded to each other to form R １ and the carbon atom to which R ３ and a ring structure including, together with the atom to which it is attached, one or two nitrogen atoms as ring-constituting atoms, and one hydroxy group, carboxy group, or C １－６ a 4- to 7-membered aliphatic heterocycle optionally substituted with an alkyl group, or one hydroxy group, carboxy group, or C １－６ form a 4- to 7-membered aliphatic ring optionally substituted with an alkyl group, and R ２ is exemplified by a hydrogen atom.

[0192] R １ and R ２ are bonded to each other and together with the carbon atoms to which they are attached contain one nitrogen atom as a ring member and one hydroxy group, carboxy group, or C １－６ a 4- to 7-membered aliphatic heterocycle optionally substituted with an alkyl group, or one hydroxy group, carboxy group, or C １－６ form a 4- to 7-membered aliphatic ring optionally substituted with an alkyl group, and R ３ is a hydrogen atom, examples of the compound represented by the formula (V) include compounds represented by the following formula (VII):

[0193]

[0194] Examples include compounds represented by the following formula:

[0195] In the above formula (VII), X ２ As for CH ２or C(=O). ２ As the alkyl group, NH or CH ２ Examples include: Y ２ In another embodiment, CH ２ Examples include: Z ２ As for CH ２ or C(=O). ３ and n ４ are each independently an integer of 1 to 3 (wherein n ３ +n ４ is an integer from 2 to 5), ４ NH, CH—OH, or CH—CO ２ H is exemplified. Examples of the "4- to 7-membered aliphatic heterocycle containing one nitrogen atom as a ring-constituting atom" include azetidine, pyrrolidine, pyrroline, piperidine, dihydroazepine, and azepine, and preferred embodiments include azetidine, pyrrolidine, and piperidine. Furthermore, examples of the "4- to 7-membered aliphatic ring" include cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclobutene, cyclopentene, cyclohexene, and cycloheptene, and preferred embodiments include cyclobutane, cyclopentane, cyclohexane, and cycloheptane. Among these, "4- to 7-membered aliphatic heterocycles containing one nitrogen atom as a ring-constituting atom" are preferred.

[0196] Also, R １ and R ３ are bonded to each other to form R １ and the carbon atom to which R ３ and a ring structure including, together with the atom to which it is attached, one or two nitrogen atoms as ring-constituting atoms, and one hydroxy group, carboxy group, or C １－６ a 4- to 7-membered aliphatic heterocycle optionally substituted with an alkyl group, or one hydroxy group, carboxy group, or C １－６ form a 4- to 7-membered aliphatic ring optionally substituted with an alkyl group, and R ２ is a hydrogen atom, examples of the compound represented by the formula (V) include compounds represented by the following formula (VI):

[0197]

[0198] An example of the embodiment is shown below.

[0199] In the above formula (VI), X １ As for CH ２ or C(=O). １ Examples of Y include N and CH. １ Another embodiment of Z is N. １ As for CH ２ or C(=O). １ and n ２ are each independently 1 or 2. ３ NH, CH—OH, or CH—CO ２ H is an example. ３ Another embodiment of is NH. Examples of the "4- to 7-membered aliphatic heterocycle containing one or two nitrogen atoms as ring-constituting atoms" include azetidine, pyrrolidine, pyrroline, piperidine, dihydroazepine, azepine, imidazolidine, pyrazolidine, and piperazine, and preferred embodiments include azetidine, pyrrolidine, piperidine, and piperazine. Examples of the "4- to 7-membered aliphatic ring" include cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclobutene, cyclopentene, cyclohexene, and cycloheptene, and preferred embodiments include cyclobutane, cyclopentane, cyclohexane, and cycloheptane. Among these, "4- to 7-membered aliphatic heterocycles containing one or two nitrogen atoms as ring-constituting atoms" are preferred.

[0200] In yet another embodiment of the present invention, a compound of the following group corresponding to the compound represented by formula (V) or a salt thereof: (7aS)-1-(2,6-dioxopiperidin-3-yl)-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione, (7aR)-1-(2,6-dioxopiperidin-3-yl)-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione, 3-[(7aS)-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxalin-1(13H)-yl]piperidine-2,6-dione, and 3-[(7aR)-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxalin-1(13H)-yl]piperidine-2,6-dione, or a salt thereof.

[0201] In yet another embodiment of the present invention, a compound of the following group corresponding to the compound represented by formula (V) or a salt thereof: (7aS)-1-(2,6-dioxopiperidin-3-yl)-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione monohydrochloride, (7aR)-1-(2,6-dioxopiperidin-3-yl)-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione monohydrochloride, 3-[(7aS)-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-1(13H)-yl]piperidine-2,6-dione dihydrochloride, and and 3-[(7aR)-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-1(13H)-yl]piperidine-2,6-dione dihydrochloride or a salt thereof.

[0202] The compound of formula (V) can be used as a production intermediate for the compound of the present invention (the compound of formula (I)), and is useful as such a production intermediate, as will be described in detail in the following general production methods and examples.

[0203] <7. General Production Methods> Representative production methods for the compounds of the present invention or pharmaceutically acceptable salts thereof will be described below.

[0204] The compounds of the present invention can be produced by various production methods. The production methods shown below and the Reference Examples and Examples described later are merely examples, and the present invention should not be construed as being limited to these.

[0205] Each raw material compound may form a salt as long as it does not inhibit the reaction, and examples of such salts include the same pharmaceutically acceptable salts as those of the compounds mentioned above.

[0206] Unless a specific production method is described, the starting material compounds can be easily obtained from commercial sources and used, or can be produced by known methods or methods similar thereto. Furthermore, the production intermediates produced in the following production methods may be isolated and purified by methods such as column chromatography (including normal phase and reverse phase) using silica gel or alumina, recrystallization, reprecipitation, distillation, etc., or can be used directly in the next reaction without isolation and purification.

[0207] The contents of all patent, non-patent, or literature references expressly cited in this specification are hereby incorporated by reference in their entirety.

[0208] The compounds of the present invention, their pharmaceutically acceptable salts, and their production intermediates can be produced by various known production methods utilizing the characteristics based on the types of their basic skeletons or substituents. Examples of known production methods include those described in "ORGANIC FUNCTIONAL GROUP PREPARATIONS," 2nd Edition, ACADEMIC PRESS, INC., 1989, and "Comprehensive Organic Transformations," 2nd Edition, VCH Publishers Inc., 1999.

[0209] In this case, depending on the type of functional group present in the compound of the present invention, it may be effective in terms of production technology to protect the functional group with an appropriate protecting group at the stage of a raw material or intermediate, or to replace the functional group with a group that can be easily converted into the functional group.

[0210] Examples of such functional groups include an amino group, a hydroxy group, a formyl group, a carbonyl group, and a carboxy group, and examples of protecting groups for these groups include those described in P.G. Wuts, "Protective Groups in Organic Synthesis," 5th Edition, Wiley, 2014.

[0211] The protecting group or the group that can be easily converted into the functional group may be appropriately selected depending on the reaction conditions of the production method for producing the compound of the present invention.

[0212] According to such a method, after the functional group is introduced and the reaction is carried out, the protecting group can be removed or converted into the desired functional group as necessary to obtain the desired compound.

[0213] A prodrug of the compound of the present invention can be produced by introducing a specific group into a raw material or intermediate, or by carrying out a reaction using the resulting compound, in the same manner as in the case of the above-mentioned protecting group. The reaction for producing the prodrug can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration, hydrogenation, etc.

[0214] In each of the following methods, functional group conversion and use of protecting groups in production intermediates used in each step can be carried out by known methods or methods equivalent thereto, or by methods described in the examples below or methods equivalent thereto.

[0215] In the description of the general production methods, symbols used in the formulae without a definition have the same meanings as defined above.

[0216] A general method for producing the compound of formula (I) of the present invention will be described below. In this specification, the following abbreviations may be used. THF: tetrahydrofuran, DMF: N,N-dimethylformamide, DMA: N,N-dimethylacetamide, DMSO: dimethyl sulfoxide, IPA: isopropyl alcohol, DCM: dichloromethane, HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (CAS Registry Number: 148893-10-1), DIPEA: N,N-diisopropylethylamine, Bn: benzyl, SEM: 2-(trimethylsilyl)ethoxymethyl, Boc: tert-butoxycarbonyl, tBu: tert-butyl, Cbz: benzyloxycarbonyl, Et: ethyl, Ns: 2-nitrobenzenesulfonyl, TBS: tert-butyldimethylsilyl, HOAt: 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (CAS Registry Number: 39968-33-7) XantPhos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (CAS Registry Number: 161265-03-8) Xphos Pd G4: (SP-4-3)-[Dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium (CAS Registry Number: 1599466-81-5) SPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (CAS Registry Number: 1375325-64-6) Pd(dppf)Cl2·DCM: [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) DCM adduct (CAS Registry Number: 95464-05-4)

[0217] (Method A) The compound represented by formula (I) can be prepared according to the following method.

[0218]

[0219] wherein T, L, and E are as defined above, and E′ is a compound represented by the following general formula:

[0220]

[0221] (In the formula, * indicates the bonding position with L at any bondable site in the chemical formula in [ ], and the wavy line indicates R Ｅ are the bonding positions with X, Y, Z, and R １ , and R ２ has the same meaning as above), and R Ｅ is the following formula:

[0222]

[0223] (In the formula, Pg １ is a protecting group for a carboxy group (e.g., a methyl group, an ethyl group, a Bn group, a tBu group, etc.), and Pg ２ is a group selected from the group consisting of imide protecting groups (e.g., SEM group, Boc group, benzyloxymethyl group, etc.), and R Ｅ But the following formula:

[0224]

[0225] (In the formula, Pg １ has the same meaning as defined above), the first step can be carried out by deprotecting the protecting group of compound a1.]

[0226] The deprotection reaction in this step can be carried out by a method commonly used for deprotecting a nitrogen atom-protecting group. For example, when the protecting group is an SEM group, the deprotection reaction in this step can be carried out by reacting compound a1 with an acid such as trifluoroacetic acid in a dichloromethane (DCM) solvent to remove the trimethylsilylethyl group, and then reacting the resulting compound with a base such as N,N'-dimethylethylenediamine in a solvent such as ethyl acetate.

[0227] R Ｅ But the following formula:

[0228]

[0229] (In the formula, Pg １ has the same meaning as defined above), this step can be carried out by a cyclization reaction.

[0230] The cyclization reaction in this step is carried out by Pg １ When Pg is a tert-butyl group, the cyclization reaction can be carried out by, for example, reacting compound a1 with an acid such as benzenesulfonic acid under heating in a solvent such as acetonitrile. １ When is a methyl group or an ethyl group, the reaction can be carried out, for example, by reacting compound a1 with a base such as potassium tert-butoxide in a solvent such as THF.

[0231] R Ｅ But the following formula:

[0232]

[0233] In the case where the group is represented by the formula:

[0234] The catalytic hydrogen reduction reaction in this step can be carried out, for example, by treating compound a1 with a metal catalyst such as palladium on carbon under a hydrogen atmosphere in a solvent such as ethyl acetate or ethanol.

[0235] Below formula (V):

[0236]

[0237] [In the formula, X, Y, Z, R １ , and R ２ has the same meaning as defined above] (compound (V)) can be produced by the following Method B or Method C.

[0238] (B method)

[0239]

[0240] [In the formula, X, Y, Z, R １ , R ２ , and R Ｅ has the same meaning as above.]

[0241] The first step is a step of converting compound b1 to compound (V). The conversion reaction in this step can be carried out under the same reaction conditions as in the first step of Method A.

[0242] (C method)

[0243]

[0244] [In the formula, X, Y, Z, R １ , R ２ , and R Ｅ has the same meaning as above, and Pg ３ is a protecting group attached to any protectable functional group in the chemical formula within [ ] (for example, but not limited to, a Boc group, a Bn group, a Cbz group, a tBu group, etc.).

[0245] The first step is a step of converting compound c1 into compound c2. This step can be carried out under the same reaction conditions as in the first step of Method A. Ｅ But the following formula:

[0246]

[0247] and Pg ３ When is a Boc group, the deprotection reaction in this step can be carried out by reacting compound c1 with hydrogen chloride or an acid such as trifluoroacetic acid in a solvent such as DCM to obtain a deprotected product, and then reacting the resulting product with di-tert-butyl dicarbonate (CAS Registry Number: 24424-99-5) in a solvent such as DCM in the presence of a base such as triethylamine.

[0248] The second step is to remove the protecting group Pg ３ This is a process for obtaining compound (V) from compound c2 by the deprotection reaction of Pg ３ When Pg is, for example, a Boc group or a tBu group, the deprotection reaction can be carried out by reacting compound c2 with an acid such as hydrogen chloride, trifluoroacetic acid, or p-toluenesulfonic acid in a solvent such as DCM or acetonitrile. ３is, for example, a Cbz group or a Bn group, the deprotection reaction can also be carried out by treating compound c2 with a metal catalyst such as palladium on carbon or palladium hydroxide on carbon in a solvent such as ethanol or THF under a hydrogen atmosphere.

[0249] Next, equation a1:

[0250]

[0251] wherein T, L, E′ and R Ｅ has the same meaning as above].

[0252] (Method D) In ​​compound a1, L is -L １ -C(=O)-L ２ Compound d3, which is a group represented by -, can be produced according to the following method.

[0253]

[0254] wherein E′ and R Ｅ is the same as defined above, and T is not particularly limited, but may be, for example, a group represented by the above formula (VIII) (specifically, for example, a group represented by the following formula:

[0255]

[0256] (Wherein, the wavy line represents L １ and L １ and L ２ are each independently a single bond or a partial structure of L.

[0257] The first step is a step of dehydrating and condensing compound d1 and compound d2 to obtain compound d3. This dehydration and condensation reaction can be carried out, for example, by reacting compound d1 with compound d2 in a solvent such as DMF in the presence of a condensing agent such as HATU. Alternatively, this condensation reaction can be carried out by reacting compound d1 with a chlorinating agent such as oxalyl chloride in a solvent such as DCM in the presence of a catalytic amount of DMF to obtain an acid chloride, and then reacting the resulting acid chloride with compound d2 in a solvent such as DCM in the presence of a base such as DIPEA.

[0258] (Method E) In compound a1, L is -L １ -CH ２ -L ２ Compound e3, which is a group represented by -, can be prepared according to the following method.

[0259]

[0260] [In the formula, E', R Ｅ , L １ , and L ２ has the same meaning as defined above, and T is not particularly limited, but may be, for example, the following formula:

[0261]

[0262] (Wherein, the wavy line represents L １ is a group represented by the following formula:

[0263] The first step is a step of obtaining compound e3 from compound e1 and compound e2 by reductive amination. This reductive amination can be carried out, for example, by reacting compound e1 with compound e2 in a solvent such as DCM or methanol in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride. In this step, it may be preferable to add an acid such as acetic acid. Alternatively, this reductive amination can be carried out, for example, by using a Dean-Stark apparatus to react compound e1 with compound e2 under heating in a solvent such as toluene, to obtain an imine, which can then be reacted with a reducing agent such as sodium borohydride in a solvent such as methanol.

[0264] (Method F) In compound a1, L is -L １ -C(=O)-L ２ Compound f3, which is a group represented by -, can be produced according to the following method.

[0265]

[0266] [In the formula, E', R Ｅ , L １ , and L ２ has the same meaning as defined above, and T is not particularly limited, but may be, for example, the following formula:

[0267]

[0268] (Wherein, the wavy line represents L １ is a group represented by the following formula:

[0269] The first step is a step in which compound f3 is obtained by dehydration condensation of compound f1 and compound f2. This dehydration condensation reaction can be carried out under the same reaction conditions as in the first step of Method D.

[0270] Next, the following equation (2):

[0271]

[0272] wherein E′ and R Ｅ has the same meaning as above, and L" is a single bond or a partial structure of L. Compound (2) is a raw material for compound a1. Note that d2, e2, and f2 are each an embodiment of compound (2).

[0273] (Method G) A compound (2) in which E′ is a compound represented by the following formula:

[0274]

[0275] (In the formula, R １ , R ２ , Y, and Z are as defined above, * indicates the bonding position with L″, and the wavy line indicates R Ｅ Compound g4, which is a group represented by the following formula:

[0276]

[0277] [In the formula, Y, Z, R １ , R ２ , R Ｅ , L″, and Pg ３ has the same meaning as defined above, and Lg is a leaving group such as a halogen atom.

[0278] The first step is a step of obtaining compound g2 from compound g1 by converting the hydroxy group into a leaving group such as a halogen atom. Examples of the leaving group Lg in this step include a chloro group, and this step can be performed by reacting compound g1 with a chlorinating agent such as phosphoryl chloride in a solvent such as DCM, or can also be performed in the presence of a base such as DIPEA.

[0279] The second step is to obtain compound g3 from compound g2 by intramolecular alkylation, which can be carried out by heating compound g2 in a solvent such as DMA in the presence of a catalyst such as sodium bromide and a base such as DIPEA or potassium carbonate.

[0280] The third step is a step of obtaining compound g4 from compound g3 by deprotection of the protecting group. This deprotection reaction can be carried out under the same reaction conditions as in the second step of Method C. When the protecting group is a Boc group, this deprotection reaction can also be carried out by reacting compound g3 with an acid such as triethylsilyl trifluoromethanesulfonate in a solvent such as DCM in the presence of a base such as 2,4,6-trimethylpyridine.

[0281] The fourth step is a step of obtaining an aldehyde (compound g5) from an alcohol (compound g1) by oxidation of the hydroxy group. The oxidation reaction in this step can be carried out, for example, by a method using an activating agent such as DMSO or oxalyl chloride (Synthesis, 1990, 10, 857-870) or a method using a hypervalent iodine compound such as 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (CAS Registry Number: 87413-09-0) as an oxidizing agent (J. Org. Chem., 2011, 76, 5, 1185-1197).

[0282] The fifth step is a step of obtaining compound g3 from compound g5 by intramolecular reductive amination, which can be carried out under the same reaction conditions as in the first step of Method E.

[0283] (Method H) A compound (2) in which E′ is a compound represented by the following formula:

[0284]

[0285] (In the formula, R １ , R ２ , Y, and Z are as defined above, * indicates the bonding position with L″, and the wavy line indicates R Ｅ Compound h4, which is a group represented by the following formula (wherein the bond position is a bond position with the group): can be prepared according to the following method.

[0286]

[0287] [In the formula, Y, Z, R １ , R ２ , R Ｅ , L'', Pg １ , and Pg ３ has the same meaning as above.]

[0288] The first step is to add a protecting group Pg １ This is a process for obtaining compound h2 from compound h1 by deprotection of the protecting group. For example, when the protecting group is a Bn group, the deprotection reaction can be carried out by treating compound h1 with a metal catalyst such as palladium carbon or palladium hydroxide carbon under a hydrogen atmosphere in a solvent such as ethanol. When the protecting group is a tBu group, the deprotection reaction can be carried out by reacting compound h1 with an acid such as hydrogen chloride or trifluoroacetic acid in a solvent such as DCM.

[0289] The second step is a step of obtaining compound h3 from compound h2 by intramolecular condensation reaction. The condensation reaction can be carried out, for example, by reacting compound h2 with a chlorinating agent such as 1-chloro-N,N,2-trimethyl-1-propen-1-amine (CAS Registry Number: 26189-59-3) in a solvent such as toluene in the presence of a base such as DIEPA, and then heating the resulting acid chloride.

[0290] The third step is the addition of the protecting group Pg ３ This is a step of obtaining compound h4 from compound h3 by the deprotection reaction of the formula (1). This deprotection reaction can be carried out under the same reaction conditions as in the third step of Method G.

[0291] (Method I) In the compound (2), L″ is —NR ｉ -L ｉ -CH ２ Compound i4, which is a group represented by -, can be prepared according to the following method.

[0292]

[0293] wherein E′ and R Ｅ has the same meaning as above, and L ｉ is a partial structure of L″, and R ｉ is a hydrogen atom or C １－６ is an alkyl group, Lg is a leaving group, and Pg ４ is a protecting group for an amino group.

[0294] The first step is to alkylate compound i1 with compound i2 to obtain compound i3. The alkylation reaction can be carried out by mixing compound i1 and compound i2 in a solvent such as DMF or acetonitrile in the presence of a base such as potassium carbonate or DIPEA, and heating the mixture.

[0295] The second step is to remove the protecting group Pg of compound i3. ４ This deprotection reaction can be carried out under the same reaction conditions as in the third step of Method G to obtain compound i4.

[0296] (Method J) In compound (2), L″ is —O ２ C-L ｉ -CH ２ Compound j4, which is a group represented by -, can be produced according to the following method.

[0297]

[0298] [In the formula, E', R Ｅ , and Pg １ has the same meaning as above, and L ｊ is a partial structure of L″, and Lg is a leaving group.

[0299] The first step is to alkylate compound j2 using compound j1 to obtain compound j3. This alkylation reaction can be carried out under the same reaction conditions as in the first step of Method I.

[0300] The second step is a step of obtaining Compound j4 from Compound j3 by deprotection of the carboxy-protecting group. This deprotection reaction can be carried out under the same reaction conditions as in the first step of Method H.

[0301] Next, a compound of the following formula e1, which is a raw material compound of compound a1:

[0302]

[0303] (Wherein, T and L １ has the same meaning as above), the production method of compound e1 is shown below.

[0304] Among compounds e1, L １ But, -L ｋ -CH ２ Compound k7, which is a group represented by -, can be produced according to the following method (Method K).

[0305]

[0306] [Wherein, T and Pg １ is as defined above, Lg is a leaving group, and L ｋ Is, L １ It is a partial structure of

[0307] The first step is a step of alkylating compound k1 with compound k2 to obtain compound k4. This alkylation reaction can be carried out under the same reaction conditions as in the first step of Method I.

[0308] The second step is a step of reducing compound k3 to obtain compound k4. The reduction reaction can be carried out by reacting compound k3 with a reducing agent such as lithium aluminum hydride in a solvent such as THF under ice-cooling.

[0309] The third step is a step of oxidizing compound k4 to obtain compound k5. This oxidation reaction can be carried out under the same reaction conditions as in the fourth step of Method G.

[0310] The fourth step is a step of obtaining compound k6 from compound k5 by Wittig reaction. The Wittig reaction can be carried out by reacting aldehyde k5 with a phosphorus ylide obtained by adding a base such as sodium bis(trimethylsilyl)amide to (methoxymethyl)triphenylphosphonium chloride (CAS Registry Number: 4009-98-7) in a solvent such as THF under cooling.

[0311] The fifth step is a step of hydrolyzing compound k6 to obtain compound k7. The hydrolysis reaction can be carried out by reacting compound k6 with an acid such as paratoluenesulfonic acid monohydrate in a solvent such as DCM.

[0312] Next, a raw material compound of compound a1, the following formula d1:

[0313]

[0314] (Wherein, T and L １ The method for producing compound d1 represented by the following formula (wherein R is as defined above) is shown below.

[0315] (L method)

[0316]

[0317] [In the formula, T, L １ , and Pg １ has the same meaning as defined above, and Lg is a leaving group.

[0318] The first step is to alkylate compound l1 with compound l2 to obtain compound l3. This alkylation reaction can be carried out under the same reaction conditions as in the first step of Method I.

[0319] The second step is a step of obtaining compound 14 from compound 13 by deprotection of the carboxy-protecting group. This deprotection reaction can be carried out under the same reaction conditions as in the first step of Method H.

[0320] Next, the following equation (5):

[0321]

[0322] [In the formula, R １ , R ２ , R ３ , R Ｅ , Pg ３ and L″ are as defined above, and R ４ is a hydroxymethyl group, a carboxy group, or a group convertible thereto] (compound (5)). Compound (5) is a raw material compound for compound (2).

[0323] (Method M) In compound (5), Z is —C(═O)— and Y is —NR ３ Compound m4, which is -, can be produced according to the following method (first and second steps, or third and fourth steps).

[0324]

[0325] [In the formula, R １ , R ２ , R ３ , R Ｅ , L″, and Pg ３ has the same meaning as above, and R ｍ is a halogen atom, and R ４ is a hydroxymethyl group, a carboxy group, or a group convertible thereto.]

[0326] The first step is a step of converting compound m1 into compound m2 by carboxylation. The carboxylation reaction can be carried out, for example, by reacting compound m1 with water under heating in a solvent such as 1,4-dioxane, in the presence of a base such as triethylamine, a ligand such as XantPhos, and a metal catalyst such as palladium(II) acetate, under a carbon monoxide atmosphere.

[0327] The second step is a step in which compound m4 is obtained by dehydration condensation of compound m2 and compound m3. This condensation reaction can be carried out under the same reaction conditions as in the first step of Method D.

[0328] The third step is a step of converting compound m1 into compound m5 by carbonylation. The carbonylation reaction can be carried out, for example, by reacting compound m1 with 2,4,6-trichlorophenyl formate (CAS Registry Number: 4525-65-9) under heating in a solvent such as toluene, in the presence of a base such as triethylamine, a ligand such as XantPhos, and a metal catalyst such as palladium(II) acetate, under a carbon monoxide atmosphere.

[0329] The fourth step is a step of amidating compound m3 with compound m5 to obtain compound m4. The amidation reaction can be carried out, for example, by reacting compound m3 with compound m5 in a solvent such as acetonitrile in the presence of a base such as DIPEA and a catalyst such as 4-dimethylaminopyridine while heating. In this reaction, it may be preferable to add HOAt.

[0330] (Method N) In compound (5), Z is —CH ２ Compound n3, which is -, can be prepared according to the following method.

[0331]

[0332] [In the formula, Y, R １ , R ２ , R ４ , R Ｅ , L″, and Pg ３ has the same meaning as above, and R ｎ is a halogen atom, and M is a group of the formula:

[0333]

[0334] is any group selected from the group consisting of:

[0335] The first step is to obtain compound n3 by subjecting compound n1 and compound n2 to Suzuki coupling reaction. The coupling reaction can be carried out by reacting compound n1 and compound n2 with heating in a mixed solvent of water and an organic solvent such as 1,4-dioxane, toluene, or THF, in the presence of a metal catalyst such as Xphos Pd G4, Sphos Pd G2, or Pd(dppf)Cl2.DCM, and a base such as potassium carbonate, tripotassium phosphate, or cesium carbonate, under a nitrogen atmosphere.

[0336] Below formula n1:

[0337]

[0338] (In the formula, Y, R １ , R ２ , R ４ , L'', M, and Pg ３ The method for producing the compound (compound n1) represented by the formula (wherein n is as defined above) is shown below.

[0339] (Method O) In compound n1, Y is —CHR ３ Compounds o2, o3, and o4, each of which is -, can be prepared according to the following method.

[0340]

[0341] [In the formula, R １ , R ２ , R ３ , R ４ , L″, and Pg ３ has the same meaning as above.]

[0342] The first step is to obtain compound o2 by hydroboration of compound o1. The hydroboration can be carried out by reacting compound o1 with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS Registry Number: 25015-63-8) in a solvent such as DCM in the presence of a metal catalyst such as chloro(1,5-cyclooctadiene)iridium(I) (dimer) (CAS Registry Number: 12112-67-3) and a ligand such as 1,2-bis(diphenylphosphino)ethane (CAS Registry Number: 1663-45-2).

[0343] The second step is a step of obtaining compound o3 by a fluorination reaction of compound o2. The fluorination reaction can be carried out by reacting compound o2 with potassium hydrogen fluoride (CAS Registry Number: 7789-29-9) in a solvent such as methanol or water.

[0344] The third step is to obtain compound o4 by hydroboration of compound o1. The hydroboration can be carried out by reacting compound o1 with 9-borabicyclo[3.3.1]nonane (CAS Registry Number: 280-64-8) under heating in a solvent such as THF.

[0345] (Method P) In compound n1, Y is —NR ３ - and M is -BF ３ Compound p3, which is K, can be prepared according to the following method.

[0346]

[0347] [In the formula, R １ , R ２ , R ３ , R ４ , L″, and Pg ３ has the same meaning as defined above, and Lg is a leaving group such as a halogen atom.

[0348] The first step is to alkylate compound p1 with compound p2 to obtain compound p3. The alkylation reaction can be carried out by reacting compound p1 with compound p2 under heating in a solvent such as THF.

[0349] Next, the following equation (7):

[0350]

[0351] (In the formula, X １ and R Ｅ The method for producing a compound (compound (7)) represented by the formula (wherein R is as defined above) is shown below. Compound (7) is a starting compound for compound (5).

[0352] (Q method)

[0353]

[0354] [In the formula, R Ｅ has the same meaning as above, and X １ and X ２ are each independently a halogen atom.

[0355] The first step is to obtain compound q2 by reduction of compound q1. The reduction can be carried out, for example, by reacting compound q1 with a reducing agent such as 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate diethyl (CAS Registry Number: 1149-23-1) in the presence of an acid such as boronic acid or paratoluenesulfonic acid in a solvent such as dichloroethane under heating.

[0356] The second step is a step of obtaining compound q4 from compound q2 and compound q3 by a urea reaction. The urea reaction can be carried out by reacting compound q2 with triphosgene in a solvent such as DCM in the presence of a base such as triethylamine or pyridine to obtain carbamoyl chloride, and then reacting the resulting carbamoyl chloride with compound q3 in a solvent such as DCM in the presence of a base such as triethylamine.

[0357] The third step is to obtain compound (7) by intramolecular cyclization of compound q4. This cyclization can be carried out, for example, by reacting compound q4 with a copper catalyst such as copper(I) iodide under heating in a solvent such as DMSO in the presence of a ligand such as trans-4-hydroxy-L-proline and a base such as tripotassium phosphate. The reaction temperature is preferably 80°C to 160°C.

[0358] (Method R) Raw material compounds T-H and T-L １ -CO ２ H, T-L １ -CHO, and T-L １ -H can be produced by the methods described in the examples below, known methods, or methods based on these methods. For example, T-H can be produced by the method shown below.

[0359]

[0360] [In the formula, Pg ４ is a protecting group for a carboxy group (e.g., methyl, ethyl, benzyl, tert-butyl, etc.), M is a metal or a metal halide (e.g., magnesium halide, lithium, zinc halide, etc.), R ａ１ is C optionally substituted with 1 to 3 halogen atoms １－６ C optionally substituted with an alkyl group or one trifluoromethyl group ３－６ is a cycloalkyl group, R ａ２ is the following formula:

[0361]

[0362] (In the formula, R Ｘ is —H or a group that can be converted to —H, and Q Ｔ１ , L Ｔ１ , and Q Ｔ２ has the same meaning as above), and R ａ３ is a 6-membered heteroaryl group containing one or two nitrogen atoms as ring-constituting atoms (the heteroaryl group may be substituted with one halogen atom), and X ３ is a halogen atom, and A, R Ｔ１ , R Ｔ２ , and R Ｔ３ has the same meaning as above.]

[0363] The first step is a step of obtaining compound r3 by aldol condensation reaction of compound r1 and compound r2. The aldol condensation reaction in this step can be carried out by reacting compound r1 with compound r2 using, for example, acetic acid and piperidine as catalysts.

[0364] The second step is a step of obtaining compound r5 by 1,4-nucleophilic addition of compound r4 to the α,β-unsaturated ester of compound r3. The 1,4-nucleophilic addition reaction in this step can be carried out, for example, by reacting compound r3 with compound r4 in a solvent such as THF in the presence of a copper reagent such as copper(II) bromide. The reaction temperature is preferably from -78°C to room temperature.

[0365] The third step is a step of obtaining compound r6 by hydrolysis of the ester of compound r5 and decarboxylation of the resulting carboxy group. The hydrolysis and decarboxylation in this step can be carried out, for example, by reacting compound r5 with a base such as sodium hydroxide under heating in a solvent such as ethylene glycol.

[0366] The fourth step is a step of reducing the cyano group of compound r6 to obtain compound r7. The reduction reaction in this step can be carried out, for example, by reacting compound r6 with a reducing agent such as lithium aluminum hydride under heating in a solvent such as THF.

[0367] The fifth step is a step of obtaining compound r9 from compound r7 and compound r8 by reductive amination. The reductive amination in this step can be carried out, for example, by reacting compound r7 and compound r8 with a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloromethane or methanol. In this reaction, it may be preferable to add an acid such as acetic acid. Alternatively, the reductive amination in this step can be carried out, for example, using a Dean-Stark apparatus, by reacting compound r7 with compound r8 in a solvent such as toluene, heating the resulting imine, and then reacting the resulting imine with a reducing agent such as sodium borohydride in a solvent such as methanol.

[0368] The sixth step is a step in which compound r9 and compound r10 are condensed to obtain compound r11. The condensation reaction in this step can be carried out, for example, by reacting compound r9 and compound r10 with a condensing agent such as HATU in a solvent such as DMF. Alternatively, the condensation reaction in this step can be carried out by reacting compound r10 with oxalyl chloride or the like in a solvent such as dichloromethane to obtain an acid chloride, which can be reacted with compound r9 in a solvent such as dichloromethane in the presence of a base such as DIPEA.

[0369] The seventh step is a step of reducing the carbonyl group of compound r11 to obtain compound r12. The reduction reaction in this step can be carried out, for example, by reacting compound r11 with a reducing agent such as borane-THF complex under heating in a solvent such as THF.

[0370] Step eight is a step of obtaining compound r14 from compound r9 and compound r13 by Buchwald amination or aromatic nucleophilic substitution. The Buchwald amination in this step can be carried out, for example, in a solvent such as 1,4-dioxane, in the presence of a base such as cesium carbonate or a metal catalyst such as RuPhos Pd G3 or BrettPhos Pd G3, by reacting compound r9 with compound r13 under heating. The aromatic nucleophilic substitution in this step can be carried out, for example, in a solvent such as 2-butanol or N,N-dimethylacetamide, in the presence of a base such as 1,8-diazabicyclo[5.4.0]-7-undecene or potassium carbonate, by reacting compound r9 with compound r13 under heating.

[0371] <8. Activity> In one embodiment of the present invention, the compound of the present invention specifically binds to CRBN. The binding activity to CRBN can be measured using any known method, for example, by reacting a test substance (the compound of the present invention), a molecule known to specifically bind to CRBN (particularly the CRBN ligand-binding domain (LBD)) (e.g., HTRF Thalidomide-Red ligand), and CRBN (particularly the CRBN-LBD), and quantifying the reduction in the binding rate to CRBN by the molecule known to specifically bind to CRBN (e.g., IC 50 Generally, in such test systems, the IC 50 A test substance with an IC value of 100 μM or less is considered to specifically bind to CRBN. Thus, in one aspect of the present invention, the compounds of the present invention have an IC value of 100 μM or less with respect to reducing the rate of binding to CRBN by the compounds of the present invention or molecules known to specifically bind to CRBN (e.g., HTRF Thalidomide-Red ligand).50 value, preferably 10 μM or less 50 particularly preferably has an IC value of 1 μM or less 50 In another embodiment of the present invention, the compound of the present invention has an IC value of 100 μM or less with respect to reducing the binding rate of a CRBN-specific binding molecule, HTRF Thalidomide-Red ligand, to CRBN-LBD in the test system and test conditions disclosed in Test Example 1 of the present specification. 50 value, preferably 10 μM or less 50 particularly preferably has an IC value of 1 μM or less 50 It has a value.

[0372] In one embodiment of the present invention, the compound of the present invention has target protein degradation-inducing activity. Target protein degradation-inducing activity can be measured using any known method, for example, by adding a test substance to cells expressing a target protein, culturing the cells for a certain period of time, and then quantifying the expression level of the target protein. Target protein degradation-inducing activity can also be measured, for example, by knocking in an easily detectable peptide tag (e.g., HiBiT tag) at the endogenous target protein gene locus in cells expressing the target protein, adding a test substance to the cells, culturing the cells for a certain period of time, and then observing the expression level of the peptide tag. Generally, in such a test system, the concentration that induces 50% degradation of the target protein (DC 50 A test compound having a DC value of 100 μM or less against a target protein is considered to have SF-1 degradation-inducing activity. 50 value, preferably a DC of 10 μM or less 50 particularly preferably a DC value of 1 μM or less 50 In another embodiment of the present invention, the compounds of the present invention have a DC value of 100 μM or less against a target protein in the test system and test conditions disclosed in Test Examples 2, 6, and 7 herein. 50 value, preferably a DC of 10 μM or less 50 particularly preferably a DC value of 1 μM or less50 It has a value.

[0373] In one embodiment of the present invention, the compounds of the present invention have growth inhibitory activity against tumors whose development or progression is involved in a target protein. In another embodiment of the present invention, the compounds of the present invention have growth inhibitory activity against adrenocortical carcinoma. In yet another embodiment of the present invention, the compounds of the present invention have growth inhibitory activity against NCI-H295R cells, an adrenocortical carcinoma cell line. The tumor cell growth inhibitory activity of the compounds of the present invention can be measured using any known method, and typically can be measured by adding a test substance (the compound of the present invention) to model cells of the target tumor, culturing them for a certain period of time, and then quantifying the growth rate of the tumor cells. Generally, in such a test system, the concentration that inhibits tumor cell growth by 50% (GI 50 A test substance having a GI value of 100 μM or less is considered to have growth inhibitory activity. Thus, in one embodiment of the present invention, the compounds of the present invention have a GI value of 100 μM or less against tumor cells (e.g., NCI-H295R cells). 50 value, preferably a GI of 10 μM or less 50 particularly preferably a GI of 1 μM or less 50 In another embodiment of the present invention, the compound of the present invention has a GI value of 100 μM or less against tumor cells (e.g., NCI-H295R cells) in the test system and under the test conditions disclosed in Test Example 3 herein. 50 value, preferably a GI of 10 μM or less 50 particularly preferably a GI of 1 μM or less 50 It has a value.

[0374] In one embodiment of the present invention, the compounds of the present invention have antitumor activity against tumor cells in which the target protein is involved in the development or progression of tumors, such as NCI-H295R cells, an adrenocortical carcinoma cell line, VCaP cells, a prostate cancer cell line, or animal models (e.g., mice) subcutaneously transplanted with tumors derived from prostate cancer patients. The antitumor activity in transplant models can be measured using any known method, for example, by the protocol described in Test Example 5 of the present specification.

[0375] The present invention will be described in detail by the following examples, but these are merely examples and do not limit the present invention, and may be modified within the scope of the present invention.

[0376] In the following examples, "%" indicates mol / mol% for yields, vol% for solvents used in chromatography, and wt% for others. "Room temperature" usually indicates about 10°C to about 35°C.

[0377] Nuclear magnetic resonance spectra (hereinafter referred to as 1H-NMR, resonance frequency 400 MHz or 500 MHz) were recorded with chemical shift values ​​as δ values ​​(ppm) using tetramethylsilane as a standard substance or the chemical shift value of the deuterated solvent used as the reference value.

[0378] Other abbreviations used in the text have the following meanings: s: singlet d: doublet dd: doublet of doublets t: triplet q: quartet m: multiplet br: broad J: coupling constant Hz: Hertz CDCl3: deuterated chloroform DMSO-D6: deuterated dimethyl sulfoxide CD3OD: deuterated methanol 1 H-NMR: Proton nuclear magnetic resonance HPLC: High-performance liquid chromatography SFC: Supercritical fluid chromatography sCO2: Supercritical carbon dioxide APCI: Atmospheric pressure chemical ionization ESI: Electrospray ionization TLC: Thin layer chromatography

[0379] Unless otherwise specified, the reagents, solvents, equipment, etc. used in the following examples are commercially available. Furthermore, unless otherwise specified, the raw material compounds are known compounds and are either commercially available or synthesized and identified according to known methods or methods equivalent thereto.

[0380] <Reference Example 1> Ethyl cyano(2,2-dimethyltetrahydro-4H-pyran-4-ylidene)acetate

[0381] To 2,2-dimethyltetrahydro-2H-pyran-4-one (CAS Registry Number: 1194-16-7) (200 g, 1.56 mol) was added ethyl cyanoacetate (CAS Registry Number: 105-56-6) (175 mL, 1.65 mol) over 10 minutes under ice cooling. Acetic acid (18 mL, 0.32 mol) was added dropwise over 5 minutes, and piperidine (31 mL, 0.31 mol) was added dropwise over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 41 hours. The reaction mixture was diluted with ethyl acetate (2 L) and washed sequentially with 1 mol / L aqueous sodium hydroxide solution (1.5 L), water (1.5 L), and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure and dried under reduced pressure to give the title compound (324 g, 1.45 mol, 93% yield).

[0382] <Reference Example 2> Ethyl cyano[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]acetate

[0383] To a solution of the compound obtained in <Reference Example 1> (8.92 g, 39.2 mmol) in THF (131 mL) was added copper(I) bromide dimethyl sulfide complex (CAS Registry Number: 54678-23-8) (0.805 g, 3.92 mmol) at -78°C, and the mixture was stirred at the same temperature for 2 hours. Then, 4-methoxyphenylmagnesium bromide (CAS Registry Number: 13139-86-1) (0.50 mol / L THF solution, 100 mL, 50 mmol) was added dropwise at the same temperature over 20 minutes. The reaction mixture was stirred for 1.5 hours while warming to room temperature, and then left at room temperature overnight. Copper(I) bromide dimethyl sulfide complex (0.805 g, 3.92 mmol) was added to the reaction mixture at -78 °C and stirred at the same temperature for 5 minutes. 4-Methoxyphenylmagnesium bromide (0.50 mol / L THF solution, 47 mL, 23.5 mmol) was then added dropwise over 5 minutes at the same temperature, and the mixture was stirred for 6 hours while warming to room temperature. 1 mol / L hydrochloric acid (80 mL) was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (6.72 g, 20.3 mmol, 52% yield).

[0384] <Reference Example 3> [4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]acetonitrile

[0385] To a solution of the compound obtained in <Reference Example 2> (10.8 g, 32.6 mmol) in ethylene glycol (109 mL) was added sodium hydroxide (3.26 g, 81.5 mmol) at room temperature, and the mixture was stirred at 150°C for 7 hours and then left to stand at room temperature overnight. Under ice-cooling, ice, water, and 1 mol / L hydrochloric acid were added to the reaction mixture, and the pH was adjusted to 1-2. Extraction was performed with DCM. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (5.91 g, 22.8 mmol, 70% yield).

[0386] <Reference Example 4> 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethanamine

[0387] To a solution of the compound obtained in <Reference Example 3> (8.72 g, 33.6 mmol) in THF (224 mL), lithium aluminum hydride (3.19 g, 84.1 mmol) was added over 10 minutes under ice cooling. The mixture was stirred for 1.5 hours while warming to room temperature, 4 hours at 35°C, and 2 hours at 50°C. After cooling, water (3.2 mL) was added to the reaction solution under ice cooling, followed by 1 mol / L aqueous sodium hydroxide solution (3.2 mL) and water (9.0 mL). The resulting precipitate was filtered through Celite and washed with THF. The volatiles were evaporated under reduced pressure, and the residue was purified by amine-modified silica gel column chromatography (hexane / ethyl acetate, ethyl acetate / methanol) to obtain the title compound (1.74 g, 6.61 mmol, 20% yield).

[0388] <Reference Example 5> 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethanamine

[0389] The racemic compound obtained in Reference Example 4 was optically resolved by chiral HPLC [column: CHIRALCEL OZ-H (registered trademark, Daicel Corporation), mobile phase: hexane / IPA = 60 / 40 (V / V)] to obtain the title compound as the component eluted later. Analysis conditions: Column: CHIRALCEL OJ-H (registered trademark, Daicel Corporation), size: 0.46 cm × 25 cm, flow rate: 1.0 mL / min, temperature: 30°C, mobile phase: hexane / IPA / diethylamine = 70 / 30 / 0.2 (V / V / V), retention time: R-isomer <Reference Example 5> 5.1 minutes, S-isomer 6.7 minutes

[0390] <Reference Example 6> 3,3,3-trifluoro-N-{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}-2,2-dimethylpropanamide

[0391] HATU (43.8 g, 115 mmol) was added to a solution of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (CAS Registry Number: 889940-13-0) (18.0 g, 115 mmol) in DMF (150 mL), and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was cooled to 0°C and stirred for 5 minutes. A solution of the compound obtained in <Reference Example 5> (25.2 g, 95.7 mmol) in DMF (150 mL) and DIPEA (50 mL, 287 mmol) were added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with aqueous sodium bicarbonate, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (36.2 g, 90.2 mmol, yield 94%).

[0392] <Reference Example 7> 3,3,3-trifluoro-N-{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}-2,2-dimethylpropan-1-amine

[0393] To a solution of the compound obtained in <Reference Example 6> (24.7 g, 61.5 mmol) in THF (60 mL) was added borane-THF complex (0.89 mol / L THF solution, 240 mL, 210 mmol), and the mixture was stirred under heating and reflux for 9 hours. After the reaction mixture was cooled to room temperature, methanol (60 mL) was added, and the mixture was stirred under heating and reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / methanol) to obtain the title compound (22.1 g, 57.0 mmol, yield 93%).

[0394] <Reference Example 8> tert-Butyl 4'-formyl-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate

[0395] A suspension of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (WO2017051355) (1.14 g, 3.70 mmol), 4-bromobenzaldehyde (CAS Registry Number: 1122-91-4) (694 mg, 3.75 mmol), Pd(dppf)Cl2·DCM (306 mg, 0.375 mmol), and potassium carbonate (2.0 mol / L aqueous solution, 3.5 mL, 7.0 mmol) in 1,4-dioxane (7.5 mL) was stirred at 90°C under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added. Insoluble matter was removed by filtration through Celite, and the two layers were separated. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (836 mg, 2.92 mmol, yield 79%).

[0396] <Reference Example 9> tert-butyl (4R)-4'-formyl-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate <Reference Example 10> tert-butyl (4S)-4'-formyl-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate

[0397] The racemic compound obtained in <Reference Example 8> was purified by chiral SFC [column: CHIRALPAK IG (registered trademark, Daicel Corporation), mobile phase: sCO2 / acetonitrile = 60 / 40 (V / V)] to obtain the R-isomer compound of <Reference Example 9> as the first eluted component, and the S-isomer compound of <Reference Example 10> as the second eluted component. Analysis conditions: Column: CHIRALPAK IG-3 (registered trademark, Daicel Corporation), size: 0.46 cm × 5 cm, flow rate: 3.0 mL / min, temperature: 35°C, mobile phase: sCO2 / acetonitrile (0.05% diethylamine) = 60 / 40 (V / V), retention time: R-isomer <Reference Example 9> 0.9 min, S-isomer <Reference Example 10> 1.4 min

[0398] <Reference Example 11> tert-Butyl (4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate

[0399] A solution of the compound obtained in <Reference Example 7> (16.7 g, 43.1 mmol) and the compound obtained in <Reference Example 9> (12.8 g, 44.7 mmol) in DCM (200 mL) was stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (18.6 g, 87.8 mmol) was added to the reaction solution, and the mixture was stirred for 5 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction solution, and the mixture was extracted with DCM. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (26.2 g, 39.8 mmol, yield 92%).

[0400] <Reference Example 12> [(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methanol

[0401] Under ice cooling, a solution of the compound obtained in <Reference Example 11> (26.2 g, 39.8 mmol) in THF (200 mL) was added dropwise to a suspension of lithium aluminum hydride (3.01 g, 79.3 mmol) in THF (170 mL). The reaction mixture was stirred at the same temperature for 2.5 hours. Sodium sulfate decahydrate and ethyl acetate were added to the reaction mixture, and the mixture was stirred at room temperature. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (23.8 g, 40.5 mmol, yield: quantitative).

[0402] <Reference Example 13> 4-(piperidin-4-yloxy)benzaldehyde monohydrochloride

[0403] The title compound was obtained in the same manner as in Example 6B using tert-butyl 4-(4-formylphenoxy)piperidine-1-carboxylate (WO2015069110 A1).

[0404] <Reference Example 14> tert-Butyl [4-(4-formylphenoxy)piperidin-1-yl]acetate

[0405] To a suspension of the compound obtained in <Reference Example 13> (4.79 g, 19.8 mmol) and potassium carbonate (8.16 g, 59.0 mmol) in DMF (45 mL), tert-butyl bromoacetate (CAS Registry Number: 5292-43-3) (3.5 mL, 24 mmol) was added and stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (5.67 g, 17.8 mmol, yield 90%).

[0406] <Reference Example 15> tert-Butyl [4-(4-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}phenoxy)piperidin-1-yl]acetate

[0407] Acetic acid (0.864 mL, 15.1 mmol) was added to a solution of the compound obtained in Reference Example 7 (1.95 g, 5.03 mmol) and the compound obtained in Reference Example 14 (3.20 g, 10.0 mmol) in methanol (25 mL), and the mixture was stirred at room temperature for 25 minutes. Sodium cyanoborohydride (1.73 g, 27.5 mmol) was added to the reaction mixture, and the mixture was stirred overnight. Sodium cyanoborohydride (639 mg, 10.2 mmol) was then added, and the mixture was stirred for 3 hours. Saturated aqueous sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.71 g, 3.92 mmol, 78% yield).

[0408] <Reference Example 16> [4-(4-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}phenoxy)piperidin-1-yl]acetic acid dihydrochloride

[0409] The title compound was obtained by the same method as in <Reference Example 22> using the compound obtained in <Reference Example 15>.

[0410] <Reference Example 17> 3-Bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione

[0411] To a suspension of 3-bromopiperidine-2,6-dione (CAS Registry Number: 62595-74-8) (25.5 g, 133 mmol) in DCM (250 mL) was added DIPEA (45 mL, 258 mmol) and [2-(chloromethoxy)ethyl]trimethylsilane (CAS Registry Number: 76513-69-4) (29 mL, 170 mmol) sequentially under ice cooling, and the mixture was stirred at the same temperature for 40 minutes. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was washed with water, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (36.5 g, 113 mmol, 85% yield).

[0412] <Reference Example 18> tert-Butyl 2'-fluoro-4'-formyl-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate

[0413] 4-Bromo-3-fluorobenzaldehyde (CAS Registry Number: 133059-43-5) (4.00 g, 19.7 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-cyclohexene-1-carboxylate (CAS Registry Number: 1562375-30-7) (6.38 g, 20.7 mmol), Pd(dppf)Cl.sub.2·DCM (0.804 g, 0.985 mmol), and sodium carbonate (6.27 g, 59.2 mmol) were dissolved in a mixed solvent of 1,4-dioxane (45 mL) and water (5 mL) and heated and stirred at 85°C for 4 hours under a nitrogen atmosphere. After returning the reaction solution to room temperature, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (6.03 g, 19.8 mmol, quantitative yield).

[0414] <Reference Example 19> tert-butyl (4S)-2'-fluoro-4'-formyl-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate <Reference Example 20> tert-butyl (4R)-2'-fluoro-4'-formyl-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate

[0415] The racemic compound of Reference Example 18 was purified by chiral HPLC [column: CHIRALPAK IG (registered trademark, Daicel Corporation), mobile phase: acetonitrile] to give the R-isomer compound of Reference Example 20 as the first eluted component, and the S-isomer compound of Reference Example 19 as the second eluted component. Analysis conditions: Column: CHIRALPAK IG (registered trademark, Daicel Corporation), size: 0.46 cm x 25 cm, flow rate: 1.0 mL / min, temperature: 40°C, mobile phase: acetonitrile, retention time: R-isomer <Reference Example 20> 4.8 minutes, S-isomer <Reference Example 19> 5.6 minutes

[0416] <Reference Example 21> tert-Butyl (4R)-2'-fluoro-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate

[0417] The compound obtained in <Reference Example 20> (0.115 g, 0.378 mmol) and the compound obtained in <Reference Example 7> (0.147 g, 0.379 mmol) were dissolved in DCM (4 mL), and sodium triacetoxyborohydride (0.157 g, 0.741 mmol) was added, followed by stirring at room temperature for 20 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with DCM. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.196 g, 0.290 mmol, 77% yield).

[0418] <Reference Example 22> (4R)-2'-Fluoro-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-carboxylic acid monohydrochloride

[0419] The compound obtained in <Reference Example 21> (0.196 g, 0.290 mmol) was dissolved in DCM (2 mL), and 4 mol / L hydrogen chloride / 1,4-dioxane solution (1.2 mL, 4.8 mmol) was added, followed by stirring at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure to give the title compound (0.237 g, 0.361 mmol, yield: quantitative).

[0420] <Reference Example 23> 5,8-Dibromo-1,2,3,4-tetrahydroquinoxaline

[0421] Sodium borohydride (4.67 g, 123 mmol) was added to a suspension of 5,8-dibromoquinoxaline (CAS Registry Number: 148231-12-3) (4.47 g, 15.5 mmol) in ethanol (75 mL), and the mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature, and water was added. The mixture was concentrated under reduced pressure and extracted with DCM. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. IPA was added to the residue, and the mixture was dissolved at 60°C and stirred at room temperature. The precipitated solid was collected by filtration, washed with hexane, and dried under reduced pressure at 60°C to obtain the title compound (2.64 g, 9.04 mmol, 58% yield).

[0422] <Reference Example 24> 5,8-Dibromo-N-(2,6-dioxopiperidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0423] A solution of the compound obtained in <Reference Example 23> (6.31 g, 21.6 mmol) in DCM (40 mL) was ice-cooled, and a solution of triphosgene (2.69 g, 9.08 mmol) in DCM (40 mL) was added dropwise. After stirring at the same temperature for 5 minutes, triethylamine (6.00 mL, 43.3 mmol) was added dropwise, and the mixture was stirred at the same temperature for 45 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. 3-Aminopiperidine-2,6-dione monohydrochloride (CAS Registry Number: 24666-56-6) (3.91 g, 23.8 mmol) and triethylamine (15 mL, 108 mmol) were added to a solution of the residue in acetonitrile (110 mL), and the mixture was stirred at 50°C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with a slurry of IPA / diethyl ether to obtain the title compound (6.77 g, 15.2 mmol, yield 70%).

[0424] <Reference Example 25> 5,8-Dibromo-N-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0425] To a solution of the compound obtained in <Reference Example 24> (6.77 g, 15.2 mmol) in DMF (60 mL) was added 1,8-diazabicyclo[5.4.0]-7-undecene (CAS Registry Number: 6674-22-2) (4.53 mL, 30.4 mmol) and [2-(chloromethoxy)ethyl]trimethylsilane (CAS Registry Number: 76513-69-4) (4.0 mL, 23 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was heated to 40°C and stirred for 30 minutes, then allowed to cool to room temperature. [2-(chloromethoxy)ethyl]trimethylsilane (CAS Registry Number: 76513-69-4) (0.53 mL, 3.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was allowed to stand overnight at room temperature, and then water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (7.54 g, 13.1 mmol, yield 86%).

[0426] <Reference Example 26> 3-(7-bromo-2-oxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxaline-1(2H)-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione

[0427] A suspension of the compound obtained in <Reference Example 25> (7.54 g, 13.1 mmol), copper(I) iodide (250 mg, 1.31 mmol), trans-4-hydroxy-L-proline (CAS Registry Number: 51-35-4) (345 mg, 2.63 mmol), and tripotassium phosphate (5.55 g, 26.2 mmol) in DMSO (52 mL) was stirred at 80°C for 2 hours. The reaction mixture was allowed to cool to room temperature and then filtered through Celite to remove insoluble matter. The filtrate was diluted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (4.51 g, 9.10 mmol, 70% yield).

[0428] <Reference Example 27> 2,4,6-Trichlorophenyl 1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxaline-7-carboxylate

[0429] A solution of the compound obtained in <Reference Example 26> (1.00 g, 2.02 mmol), palladium(II) acetate (22 mg, 0.098 mmol), XantPhos (117 mg, 0.202 mmol), and 2,4,6-trichlorophenyl formate (CAS Registry Number: 4525-65-9) (680 mg, 3.02 mmol) in toluene (10 mL) was degassed and purged with nitrogen. Triethylamine (0.560 mL, 4.04 mmol) was added, and the mixture was stirred at 110°C under a carbon monoxide atmosphere for 4 hours. Palladium(II) acetate (22 mg, 0.098 mmol) and XantPhos (117 mg, 0.202 mmol) were added to the reaction mixture, and the mixture was stirred again at 110°C for 4 hours and then allowed to cool to room temperature. The reaction mixture was filtered through Celite, washed with ethyl acetate, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (814 mg, 1.27 mmol, yield 63%).

[0430] Example 1A: tert-Butyl (3R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]carbonyl}piperazine-1-carboxylate

[0431] A suspension of the compound obtained in <Reference Example 27> (7.28 g, 11.4 mmol), tert-butyl (3R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)piperazine-1-carboxylate (WO2019110751 A1) (3.82 g, 11.6 mmol), HOAt (1.55 g, 11.4 mmol), and 4-dimethylaminopyridine (CAS Registry Number: 1122-58-3) (129 mg, 1.06 mmol) in acetonitrile (55 mL) was stirred at 50°C for 21 hours. The reaction solution was heated to 60°C and stirred for 8 hours. The reaction solution was cooled to room temperature, and saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate, ethyl acetate / methanol) and amine-modified silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (5.95 g, 7.70 mmol, yield 68%).

[0432] Example 1B: tert-butyl (3R)-4-{[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]carbonyl}-3-(hydroxymethyl)piperazine-1-carboxylate

[0433] Tetrabutylammonium fluoride (CAS Registry Number: 429-41-4) (1 mol / L THF solution, 2.7 mL, 2.7 mmol) was added to a solution of the compound obtained in <Example 1A> (1.04 g, 1.35 mmol) and acetic acid (0.154 mL, 2.69 mmol) in THF (4 mL), and the mixture was stirred at room temperature for 17.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (565 mg, 0.858 mmol, 64% yield).

[0434] Example 1C: tert-Butyl (7aS)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2,13-dioxo-1,4,5,7a,8,10,11,13-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-9(7H)-carboxylate

[0435] DMSO (1.4 mL, 20 mmol) was added dropwise to a solution of oxalyl chloride (0.687 mL, 8.01 mmol) in DCM (10 mL) at -78°C over 15 minutes, and the reaction mixture was stirred at the same temperature for 10 minutes. A solution of the compound obtained in Example 1B (2.64 g, 4.01 mmol) in DCM (14 mL) was added dropwise to the reaction mixture over 35 minutes, followed by the dropwise addition of triethylamine (2.2 mL, 16 mmol) over 10 minutes. After stirring the reaction mixture for 30 minutes, methanol, saturated aqueous sodium thiosulfate, and saturated aqueous sodium bicarbonate were added, followed by extraction with DCM. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (40 mL), and sodium triacetoxyborohydride (2.28 g, 10.8 mmol) was added. The mixture was stirred at room temperature for 20 hours. The reaction mixture was added with saturated aqueous sodium bicarbonate and water, and extracted with DCM. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / IPA) and amine-modified silica gel column chromatography (ethyl acetate / IPA) to give the title compound (2.11 g, 3.29 mmol, 82% yield).

[0436] Example 1D (7aR)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0437] To a solution of the compound obtained in <Example 1C> (489 mg, 0.763 mmol) in acetonitrile (4 mL), paratoluenesulfonic acid monohydrate (CAS Registry Number: 6192-52-5) (350 mg, 1.84 mmol) was added, and the mixture was stirred at room temperature for 5.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by amine-modified silica gel column chromatography (DCM / IPA) to obtain the title compound (220 mg, 0.407 mmol, 53% yield).

[0438] Example 1E tert-butyl (3R)-4-(3-methoxy-4-nitrophenyl)-3-methylpiperazine-1-carboxylate

[0439] A mixture of 4-fluoro-2-methoxy-1-nitrobenzene (CAS Registry Number: 448-19-1) (19.1 g, 112 mmol), tert-butyl (3R)-3-methyl-1-piperazinecarboxylate (CAS Registry Number: 163765-44-4) (44.7 g, 223 mmol), potassium carbonate (46.3 g, 335 mmol), and DMSO (280 mL) was stirred at 120° C. for 22.5 hours. Water and ethyl acetate were added to the reaction mixture, and the resulting solid was collected by filtration to obtain the title compound (16.8 g, 47.8 mmol, 43% yield).

[0440] Example 1F: tert-butyl (3R)-4-(4-amino-3-methoxyphenyl)-3-methylpiperazine-1-carboxylate

[0441] A mixture of the compound obtained in Example 1E (16.8 g, 47.8 mmol), 10% palladium carbon (8.11 g), and THF (600 mL) was stirred under a hydrogen atmosphere at room temperature for 7 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain the title compound (15.6 g, 48.5 mmol, quantitative yield).

[0442] Example 1G: tert-butyl (3R)-4-[4-({5-chloro-4-[2-(propan-2-ylsulfonyl)anilino]pyrimidin-2-yl}amino)-3-methoxyphenyl]-3-methylpiperazine-1-carboxylate

[0443] A mixture of the compound obtained in Example 1F (5.47 g, 17.0 mmol), 2,5-dichloro-N-[2-(isopropylsulfonyl)phenyl]-4-pyrimidinamine (CAS Registry Number: 761440-16-8) (6.48 g, 18.7 mmol), palladium(II) acetate (382 mg, 1.70 mmol), XantPhos (985 mg, 1.70 mmol), cesium carbonate (16.6 g, 51.1 mmol), and 1,4-dioxane (80 mL) was heated under reflux and stirred for 4 hours. Ethyl acetate was added to the reaction mixture, and the mixture was filtered through Celite. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.23 g, 3.53 mmol, 21% yield).

[0444] Example 1H: 5-chloro-N 2 -{2-Methoxy-4-[(2R)-2-methylpiperazin-1-yl]phenyl}-N 4 -[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine dihydrochloride

[0445] The title compound was obtained in the same manner as in Example 6B using the compound obtained in Example 1G.

[0446] Example 1I: 3-{2-[(7aR)-1-[1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl]-2,13-dioxo-1,4,5,7a,8,10,11,13-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxalin-9(7H)-yl]ethoxy}propanoic acid monohydrochloride

[0447] The title compound was obtained by using the compound obtained in <Example 1D> and tert-butyl 3-(2-bromoethoxy)propanoate (CAS registration number: 1393330-36-3) and performing the same operations as in <Example 35B> and <Reference Example 22> in this order.

[0448] Example 1J (7aR)-9-[2-(3-{(3R)-4-[4-({5-chloro-4-[2-(propan-2-ylsulfonyl)anilino]pyrimidin-2-yl}amino)-3-methoxyphenyl]-3-methylpiperazin-1-yl}-3-oxopropoxy)ethyl]-1-(2,6-dioxopiperidin-3-yl)-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0449] The title compound was obtained in the same manner as in Example 11A using the compound obtained in Example 1I and the compound obtained in Example 1H.

[0450] Example 2A tert-Butyl 3-[2-(2-{2-[(7aR)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2,13-dioxo-1,4,5,7a,8,10,11,13-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxalin-9(7H)-yl]ethoxy}ethoxy)ethoxy]propanoate

[0451] The title compound was obtained in the same manner as in Example 35B using the compound obtained in Example 1D and tert-butyl 3-{2-[2-(2-iodoethoxy)ethoxy]ethoxy}propanoate (Tetrahedron, 2011, 67, 12, 2251-2259.).

[0452] Example 2B 3-[2-(2-{2-[(7aR)-1-[1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl]-2,13-dioxo-1,4,5,7a,8,10,11,13-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxalin-9(7H)-yl]ethoxy}ethoxy)ethoxy]propanoic acid monohydrochloride

[0453] The title compound was obtained by the same method as in <Reference Example 22> using the compound obtained in <Example 2A>.

[0454] Example 2C (7aR)-9-(2-{2-[2-(3-{(3R)-4-[4-({5-chloro-4-[2-(propan-2-ylsulfonyl)anilino]pyrimidin-2-yl}amino)-3-methoxyphenyl]-3-methylpiperazin-1-yl}-3-oxopropoxy)ethoxy]ethoxy}ethyl)-1-(2,6-dioxopiperidin-3-yl)-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0455] The title compound was obtained in the same manner as in Example 11A using the compound obtained in Example 2B and the compound obtained in Example 1H.

[0456] Example 3A (4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-carbaldehyde

[0457] DMSO (0.095 mL, 1.3 mmol) was added to a solution of oxalyl chloride (0.0571 mL, 0.666 mmol) in DCM (2 mL) at -78°C, and the mixture was stirred at the same temperature for 20 minutes. A solution of the compound obtained in Reference Example 12 (301 mg, 0.512 mmol) in DCM (2 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for 40 minutes. After that, triethylamine (0.284 mL, 2.05 mmol) was added, and the mixture was stirred for 5 minutes. The mixture was then warmed to room temperature and stirred for 50 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (259 mg, 0.442 mmol, 86% yield).

[0458] Example 3B (7aR)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0459] To a DCM (1 mL) solution of the compound obtained in Example 1D (97.2 mg, 0.180 mmol) and the compound obtained in Example 3A (115 mg, 0.196 mmol), sodium triacetoxyborohydride (73.2 mg, 0.345 mmol) was added and stirred at room temperature for 16 hours. Aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with DCM. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (118 mg, 0.106 mmol, 59% yield).

[0460] Example 3C (7aR)-1-(2,6-dioxopiperidin-3-yl)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0461] Trifluoroacetic acid (0.5 mL) was added to a solution of the compound obtained in Example 3B (118 mg, 0.106 mmol) in DCM (0.5 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1 mL), and N,N'-dimethylethylenediamine (CAS Registry Number: 110-70-3) (0.0137 mL, 0.127 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / methanol), and the resulting solid was washed with hexane / ethyl acetate and then dried at 60°C under reduced pressure to obtain the title compound (75.0 mg, 0.0765 mmol, 72% yield).

[0462] Example 4A: tert-Butyl (3S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]carbonyl}piperazine-1-carboxylate

[0463] A suspension of tert-butyl (3S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)piperazine-1-carboxylate (WO2021000885 A1) (3.71 g, 11.2 mmol), the compound obtained in <Reference Example 27> (4.98 g, 7.78 mmol), DIPEA (4.0 mL, 23 mmol), HOAt (1.06 g, 7.79 mmol), and 4-dimethylaminopyridine (CAS Registry Number: 1122-58-3) (101 mg, 0.827 mmol) in acetonitrile (15 mL) was stirred at 50°C for 72 hours. The reaction mixture was cooled to room temperature, and saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) and amine-modified silica gel column chromatography (hexane / ethyl acetate, ethyl acetate / methanol) to obtain the title compound (4.71 g, 6.09 mmol, yield 78%).

[0464] Example 4B: tert-butyl (3S)-4-{[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]carbonyl}-3-(hydroxymethyl)piperazine-1-carboxylate

[0465] Tetrabutylammonium fluoride (CAS Registry Number: 429-41-4) (1.0 mol / L THF solution, 14 mL, 14 mmol) was added to a solution of the compound obtained in <Example 4A> (5.50 g, 7.11 mmol) and acetic acid (0.814 mL, 14.2 mmol) in THF (18 mL), and the mixture was stirred at room temperature for 16 hours. Aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (4.22 g, 6.41 mmol, 90% yield).

[0466] Example 4C: tert-Butyl (7aR)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2,13-dioxo-1,4,5,7a,8,10,11,13-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-9(7H)-carboxylate

[0467] To a solution of the compound obtained in Example 4B (4.22 g, 6.41 mmol) in DCM (30 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (CAS Registry Number: 87413-09-0) (3.19 g, 7.52 mmol) was added under ice cooling, and the mixture was stirred at the same temperature for 4.5 hours. A saturated aqueous solution of sodium thiosulfate, a saturated aqueous solution of sodium bicarbonate, and water were added to the reaction mixture, followed by extraction with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / methanol). The residue was dissolved in DCM (30 mL), and sodium triacetoxyborohydride (3.33 g, 15.7 mmol) was added. After stirring for 1 hour, DCM (30 mL) was added, and the mixture was further stirred at room temperature for 11 hours. Sodium triacetoxyborohydride (650 mg, 3.07 mmol) was added to the reaction mixture, and the mixture was stirred for 6 hours. Water was then added and the mixture was extracted with DCM. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (2.61 g, 4.07 mmol, 64% yield).

[0468] Example 4D (7aS)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0469] To a solution of the compound obtained in Example 4C (1.68 g, 2.62 mmol) in acetonitrile (13 mL), paratoluenesulfonic acid monohydrate (CAS Registry Number: 6192-52-5) (1.01 g, 5.31 mmol) was added, and the mixture was stirred at room temperature for 23.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by amine-modified silica gel column chromatography (ethyl acetate / IPA, DCM / IPA) to obtain the title compound (1.08 g, 2.00 mmol, 76% yield).

[0470] Example 4E (7aS)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0471] To a DCM (9 mL) solution of the compound obtained in Example 3A (504 mg, 0.860 mmol) and the compound obtained in Example 4D (450 mg, 0.832 mmol), sodium triacetoxyborohydride (382 mg, 1.80 mmol) was added, and the mixture was stirred at room temperature for 16.5 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with DCM. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (911 mg, 0.820 mmol, 99% yield).

[0472] Example 4F (7aS)-1-(2,6-dioxopiperidin-3-yl)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0473] Trifluoroacetic acid (1 mL) was added to a solution of the compound obtained in <Example 4E> (911 mg, 0.820 mmol) in DCM (2 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. A saturated aqueous solution of sodium bicarbonate was added, and the two layers were separated. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in ethyl acetate (8 mL), and then N,N'-dimethylethylenediamine (CAS Registry Number: 110-70-3) (0.106 mL, 0.986 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / methanol, ethyl acetate / methanol), and the resulting solid was washed with hexane / ethyl acetate and then dried at 60°C under reduced pressure to obtain the title compound (655 mg, 0.668 mmol, yield 81%).

[0474] Example 5A (7aS)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-9-{[4-(4-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}phenoxy)piperidin-1-yl]acetyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0475] The title compound was obtained in the same manner as in Example 11A using the compound obtained in Example 1D and the compound obtained in Reference Example 16.

[0476] Example 5B (7aS)-1-(2,6-dioxopiperidin-3-yl)-9-{[4-(4-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}phenoxy)piperidin-1-yl]acetyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0477] The title compound was obtained by the same method as in Example 4F using the compound obtained in Example 5A.

[0478] Example 6A tert-Butyl (7aR)-1-(2,6-dioxopiperidin-3-yl)-2,13-dioxo-1,4,5,7a,8,10,11,13-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-9(7H)-carboxylate

[0479] To a solution of the compound obtained in Example 4C (42.6 mg, 0.0665 mmol) in DCM (0.5 mL), 4 mol / L hydrogen chloride / 1,4-dioxane solution (0.5 mL) was added and stirred at room temperature for 70 hours. The reaction mixture was concentrated under reduced pressure, and then triethylamine (0.0510 mL, 0.368 mmol), DCM (1 mL), and di-tert-butyl dicarbonate (CAS Registry Number: 24424-99-5) (33.3 mg, 0.153 mmol) were added and stirred at room temperature for 20 hours. The reaction mixture was purified by silica gel column chromatography (DCM / methanol and ethyl acetate / methanol) to obtain the title compound (19.2 mg, 0.0376 mmol, 57% yield).

[0480] Example 6B (7aS)-1-(2,6-dioxopiperidin-3-yl)-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione monohydrochloride

[0481] To a solution of the compound obtained in Example 6A (19.2 mg, 0.0376 mmol) in DCM (0.5 mL) was added a 4 mol / L hydrogen chloride / 1,4-dioxane solution (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The precipitated solid was washed with ethyl acetate and then dried under reduced pressure to obtain the title compound (11.8 mg, 0.0264 mmol, 70% yield).

[0482] Example 7A [(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]acetaldehyde

[0483] A suspension of (methoxymethyl)triphenylphosphonium chloride (CAS Registry Number: 4009-98-7) (0.170 g, 0.496 mmol) in THF (1.0 mL) was cooled to -78°C, and sodium bis(trimethylsilyl)amide (1.16 mol / L THF solution, 0.38 mL, 0.44 mmol) was added and stirred at the same temperature for 1 hour. Next, a solution of the compound obtained in Example 3A (0.0646 g, 0.110 mmol) in THF (1.2 mL) was added dropwise to the reaction mixture. The mixture was stirred at the same temperature for 1 hour, then warmed to room temperature and stirred 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 organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (2.2 mL), and p-toluenesulfonic acid monohydrate (CAS RN: 6192-52-5) (0.145 g, 0.762 mmol) was added. The mixture was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, followed by extraction with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.0468 g, 0.0780 mmol, 71% yield).

[0484] Example 7B (7aR)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-9-{2-[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]ethyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0485] The title compound was obtained in the same manner as in Example 4E using the compound obtained in Example 7A and the compound obtained in Example 1D.

[0486] Example 7C (7aR)-1-(2,6-dioxopiperidin-3-yl)-9-{2-[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]ethyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0487] The title compound was obtained by the same method as in Example 4F using the compound obtained in Example 7B.

[0488] Example 8A tert-Butyl (7aS)-1-(2,6-dioxopiperidin-3-yl)-2,13-dioxo-1,4,5,7a,8,10,11,13-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-9(7H)-carboxylate

[0489] A 4 mol / L hydrogen chloride / 1,4-dioxane solution (0.5 mL) was added to a DCM (0.5 mL) solution of the compound obtained in Example 1C (45.7 mg, 0.0713 mmol), and the mixture was stirred at room temperature for 5 days. The reaction mixture was concentrated under reduced pressure, and the resulting solid was washed with ethyl acetate. Triethylamine (0.0546 mL, 0.394 mmol) and di-tert-butyl dicarbonate (CAS Registry Number: 24424-99-5) (34.4 mg, 0.158 mmol) were added to a DCM (1 mL) suspension of the solid obtained by drying under reduced pressure at 60°C, and the mixture was stirred at room temperature for 23 hours. The reaction mixture was purified by silica gel column chromatography (ethyl acetate / methanol and DCM / methanol) to obtain the title compound (23.2 mg, 0.0454 mmol, 64% yield).

[0490] Example 8B (7aR)-1-(2,6-dioxopiperidin-3-yl)-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione monohydrochloride

[0491] To a solution of the compound obtained in <Example 8A> (23.2 mg, 0.0454 mmol) in DCM (0.5 mL) was added 4 mol / L hydrogen chloride / 1,4-dioxane solution (0.5 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting solid was washed with ethyl acetate and dried under reduced pressure to obtain the title compound (18.8 mg, 0.0421 mmol, yield 93%).

[0492] Example 9A: 1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxaline-7-carboxylic acid

[0493] A suspension of the compound obtained in <Reference Example 26> (1.37 g, 2.77 mmol), XantPhos (307 mg, 0.531 mmol), palladium(II) acetate (63.0 mg, 0.281 mmol), and triethylamine (1.2 mL, 8.7 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 90°C for 6 hours under a carbon monoxide atmosphere. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with DCM. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate, ethyl acetate / methanol) to obtain the title compound (586 mg, 1.27 mmol, 46% yield).

[0494] Example 9B: Benzyl 4-amino-4-(hydroxymethyl)piperidine-1-carboxylate

[0495] The title compound was obtained using 4-amino-1-[(benzyloxy)carbonyl]-4-piperidinecarboxylic acid (CAS registration number: 115655-41-9) in the same manner as in <Reference Example 7>.

[0496] Example 9C: Benzyl 1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2,10-dioxo-1,2,4,5,9,10-hexahydro-1′H-spiro[1,4-diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline-8,4′-piperidine]-1′-carboxylate

[0497] The title compound was obtained by using the compound obtained in <Example 9A> and the compound obtained in <Example 9B> and carrying out the same operations as in <Example 11A> and <Example 4C> in this order.

[0498] Example 9D: 1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-4,5-dihydrospiro[1,4-diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline-8,4′-piperidine]-2,10(1H,9H)-dione

[0499] A mixture of the compound obtained in Example 9C (35.3 mg, 0.0512 mmol), 20% palladium hydroxide on carbon (14.4 mg), and ethanol (1.71 mL) was degassed and purged with hydrogen, and then stirred at room temperature for 2 hours and at 60°C for 4 hours. The reaction mixture was purged with nitrogen and filtered through Celite. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (20.2 mg, 0.0364 mmol, 71% yield).

[0500] Example 9E: 1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-1'-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-4,5-dihydrospiro[1,4-diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline-8,4'-piperidine]-2,10(1H,9H)-dione

[0501] The title compound was obtained in the same manner as in Example 4E using the compound obtained in Example 9D and the compound obtained in Example 3A.

[0502] Example 9F: 1-(2,6-dioxopiperidin-3-yl)-1'-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-4,5-dihydrospiro[1,4-diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline-8,4'-piperidine]-2,10(1H,9H)-dione

[0503] The title compound was obtained by the same method as in Example 4F using the compound obtained in Example 9E.

[0504] Example 10A: tert-butyl 4-(4-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}phenoxy)piperidine-1-carboxylate

[0505] The title compound was obtained in the same manner as in <Reference Example 15> using the compound obtained in <Reference Example 7> and tert-butyl 4-(4-formylphenoxy)piperidine-1-carboxylate (WO2015069110 A1).

[0506] Example 10B: 3,3,3-trifluoro-N-{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}-2,2-dimethyl-N-[4-(piperidin-4-yloxy)benzyl]propan-1-amine dihydrochloride

[0507] The title compound was obtained in the same manner as in Example 6B using the compound obtained in Example 10A.

[0508] Example 10C: 3-[4-(4-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}phenoxy)piperidin-1-yl]propan-1-ol

[0509] To a solution of the compound obtained in <Example 10B> (0.234 g, 0.360 mmol) in acetonitrile (2.4 mL), DIPEA (0.30 mL, 1.7 mmol) and 3-bromo-1-propanol (CAS Registry Number: 627-18-9) (0.10 mL, 1.2 mmol) were added, and the mixture was stirred for 8 hours at 50° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by amine-modified silica gel column chromatography (hexane / ethyl acetate, ethyl acetate / methanol) to obtain the title compound (0.176 g, 0.277 mmol, yield 77%).

[0510] Example 10D: 3-[4-(4-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}phenoxy)piperidin-1-yl]propanal

[0511] The title compound was obtained in the same manner as in Example 3A using the compound obtained in Example 10C.

[0512] Example 10E (7aR)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-9-{3-[4-(4-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}phenoxy)piperidin-1-yl]propyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0513] The title compound was obtained in the same manner as in Example 4E using the compound obtained in Example 10D and the compound obtained in Example 1D.

[0514] Example 10F (7aR)-1-(2,6-dioxopiperidin-3-yl)-9-{3-[4-(4-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}phenoxy)piperidin-1-yl]propyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0515] The title compound was obtained by the same method as in Example 4F using the compound obtained in Example 10E.

[0516] Example 11A (7aS)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-9-{[(4R)-2'-fluoro-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]carbonyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0517] To a solution of the compound obtained in Example 1D (55.9 mg, 0.103 mmol), the compound obtained in Reference Example 22 (73.5 mg, 0.112 mmol), and DIPEA (0.090 mL, 0.52 mmol) in DMF (1 mL) was added HATU (51.9 mg, 0.136 mmol), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water and saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (114 mg, 0.09980 mmol, 97% yield).

[0518] Example 11B (7aS)-1-(2,6-dioxopiperidin-3-yl)-9-{[(4R)-2′-fluoro-4′-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]carbonyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0519] The title compound was obtained by the same method as in Example 4F using the compound obtained in Example 11A.

[0520] Example 12A: tert-Butyl {2-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]ethyl}carbamate

[0521] (tert-Butyldimethylsilyloxy)acetaldehyde (CAS Registry Number: 102191-92-4) (0.49 mL, 2.6 mmol) and N-(tert-butoxycarbonyl)-1,2-diaminoethane (CAS Registry Number: 57260-73-8) (0.45 mL, 2.8 mmol) were added to methanol (7.8 mL) and stirred at room temperature for 50 minutes. Sodium borohydride (0.212 g, 5.60 mmol) was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by amine-modified silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.744 g, 2.34 mmol, 91% yield).

[0522] Example 12B: tert-Butyl {2-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl){[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]carbonyl}amino]ethyl}carbamate

[0523] The title compound was obtained in the same manner as in Example 11A using the compound obtained in Example 12A and the compound obtained in Example 9A.

[0524] Example 12C: tert-butyl {2-[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2,10-dioxo-1,4,5,7,8,10-hexahydro[1,4]diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxalin-9(2H)-yl]ethyl}carbamate

[0525] The compound obtained in Example 12B was used to carry out the same operations as in Example 4B and Example 1C in this order to obtain the title compound.

[0526] Example 12D: 9-(2-aminoethyl)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-4,5,8,9-tetrahydro[1,4]diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline-2,10(1H,7H)-dione

[0527] The title compound was obtained in the same manner as in Example 4D using the compound obtained in Example 12C.

[0528] Example 12E: 1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-9-[2-({[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}amino)ethyl]-4,5,8,9-tetrahydro[1,4]diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline-2,10(1H,7H)-dione

[0529] The title compound was obtained in the same manner as in Example 4E using the compound obtained in Example 12D and the compound obtained in Example 3A.

[0530] Example 12F: 1-(2,6-dioxopiperidin-3-yl)-9-[2-({[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}amino)ethyl]-4,5,8,9-tetrahydro[1,4]diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline-2,10(1H,7H)-dione

[0531] The title compound was obtained by the same method as in Example 4F using the compound obtained in Example 12E.

[0532] Example 13A: tert-butyl {2-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]ethyl}methylcarbamate

[0533] The title compound was obtained using N-(tert-butoxycarbonyl)-N-methyl-1,2-ethylenediamine (CAS registration number: 121492-06-6) and in the same manner as in Example 12A.

[0534] Example 13B: tert-Butyl {2-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl){[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]carbonyl}amino]ethyl}methylcarbamate

[0535] The title compound was obtained in the same manner as in Example 11A using the compound obtained in Example 13A and the compound obtained in Example 9A.

[0536] Example 13C: tert-butyl {2-[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2,10-dioxo-1,4,5,7,8,10-hexahydro[1,4]diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxalin-9(2H)-yl]ethyl}methylcarbamate

[0537] The compound obtained in <Example 13B> was used and the same procedures as in <Example 4B> and <Example 1C> were carried out in this order to obtain the title compound.

[0538] Example 13D: 1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-9-[2-(methylamino)ethyl]-4,5,8,9-tetrahydro[1,4]diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline-2,10(1H,7H)-dione

[0539] The title compound was obtained in the same manner as in Example 4D using the compound obtained in Example 13C.

[0540] Example 13E: 1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-9-{2-[{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}(methyl)amino]ethyl}-4,5,8,9-tetrahydro[1,4]diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline-2,10(1H,7H)-dione

[0541] The title compound was obtained in the same manner as in Example 4E using the compound obtained in Example 13D and the compound obtained in Example 3A.

[0542] Example 13F: 1-(2,6-dioxopiperidin-3-yl)-9-{2-[{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}(methyl)amino]ethyl}-4,5,8,9-tetrahydro[1,4]diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline-2,10(1H,7H)-dione

[0543] The title compound was obtained by the same method as in Example 4F using the compound obtained in Example 13E.

[0544] Example 14A tert-butyl 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]methyl}piperidine-1-carboxylate

[0545] 9-Borabicyclo[3.3.1]nonane (CAS Registry Number: 280-64-8) (0.5 mol / L THF solution, 1.6 mL, 0.80 mmol) was added to a solution of tert-butyl 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methylidenepiperidine-1-carboxylate (Bioorganic & Medicinal Chemistry Letters, 2005, 15, 5, 1375-1378.) (181 mg, 0.530 mmol) in THF (0.5 mL), and the mixture was stirred at 80°C for 1 hour. The compound obtained in Reference Example 26 (203 mg, 0.410 mmol), potassium carbonate (116 mg, 0.839 mmol), Pd(dppf)Cl.sub.2-DCM (40.1 mg, 0.0491 mmol), and water (0.5 mL) were added to the reaction mixture, which was then stirred at 80°C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (205 mg, 0.270 mmol, yield 66%).

[0546] Example 14B: tert-butyl 4-{[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]methyl}-3-(hydroxymethyl)piperidine-1-carboxylate

[0547] The title compound was obtained by the same method as in Example 4B using the compound obtained in Example 14A.

[0548] Example 14C: tert-butyl 1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,4,5,7a,8,10,11,11a,12-decahydroimidazo[1,5,4-de]pyrido[4',3':5,6]azepino[3,2,1-ij]quinoxaline-9(7H)-carboxylate

[0549] The title compound was obtained by the same method as in Example 1C using the compound obtained in Example 14B.

[0550] Example 14D: 3-(2-oxo-4,5,7,7a,8,9,10,11,11a,12-decahydroimidazo[1,5,4-de]pyrido[4',3':5,6]azepino[3,2,1-ij]quinoxaline-1(2H)-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione

[0551] The title compound was obtained in the same manner as in Example 4D using the compound obtained in Example 14C.

[0552] Example 14E: 3-[9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-2-oxo-4,5,7,7a,8,9,10,11,11a,12-decahydroimidazo[1,5,4-de]pyrido[4',3':5,6]azepino[3,2,1-ij]quinoxaline-1(2H)-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione

[0553] The title compound was obtained in the same manner as in Example 4E using the compound obtained in Example 14D and the compound obtained in Example 3A.

[0554] Example 14F: 3-[9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-2-oxo-4,5,7,7a,8,9,10,11,11a,12-decahydroimidazo[1,5,4-de]pyrido[4',3':5,6]azepino[3,2,1-ij]quinoxaline-1(2H)-yl]piperidine-2,6-dione

[0555] The title compound was obtained by the same method as in Example 4F using the compound obtained in Example 14E.

[0556] Example 15A tert-butyl 3-amino-3-(hydroxymethyl)azetidine-1-carboxylate

[0557] To a solution of 3-ethyl 1-tert-butyl 3-amino-1,3-azetidinedicarboxylate (CAS RN: 1011479-72-3) (845 mg, 3.46 mmol) in THF (16.8 mL), lithium aluminum hydride (2 mol / L THF solution, 3.69 mL, 7.38 mmol) was added under ice cooling and stirred at the same temperature for 2.5 hours. Sodium sulfate decahydrate (845 mg, 7.38 mmol) was added to the reaction mixture under ice cooling and stirred at room temperature for 1 hour. After filtration through Celite, the mixture was washed with THF / MeOH and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform / methanol) to afford the title compound (328 mg, 1.62 mmol, 48% yield).

[0558] Example 15B tert-butyl 3-({[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]carbonyl}amino)-3-(hydroxymethyl)azetidine-1-carboxylate

[0559] The title compound was obtained in the same manner as in Example 11A using the compound obtained in Example 15A and the compound obtained in Example 9A.

[0560] Example 15C: tert-Butyl 1'-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2',10'-dioxo-1',2',4',5',9',10'-hexahydro-1H-spiro[azetidine-3,8'-[1,4]diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline]-1-carboxylate

[0561] The title compound was obtained in the same manner as in Example 1C using the compound obtained in Example 15B.

[0562] Example 15D: 1'-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-4',5'-dihydrospiro[azetidine-3,8'-[1,4]diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline]-2',10'(1'H,9'H)-dione

[0563] The title compound was obtained in the same manner as in Example 4D using the compound obtained in Example 15C.

[0564] Example 15E: 1'-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-1-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-4',5'-dihydrospiro[azetidine-3,8'-[1,4]diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline]-2',10'(1'H,9'H)-dione

[0565] The title compound was obtained in the same manner as in Example 4E using the compound obtained in Example 15D and the compound obtained in Example 3A.

[0566] Example 15F: 1'-(2,6-dioxopiperidin-3-yl)-1-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-4',5'-dihydrospiro[azetidine-3,8'-[1,4]diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline]-2',10'(1'H,9'H)-dione

[0567] The title compound was obtained by the same method as in Example 4F using the compound obtained in Example 15E.

[0568] Example 16A tert-butyl (2S,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methylpiperazine-1-carboxylate

[0569] To a solution of tert-butyl (2S,5S)-5-(hydroxymethyl)-2-methyl-1-piperazinecarboxylate (CAS Registry Number: 2375424-00-1) (221 mg, 0.960 mmol) and triethylamine (0.399 mL, 2.88 mmol) in DCM (5 mL), tert-butyldimethylchlorosilane (CAS Registry Number: 18162-48-6) (221 mg, 1.47 mmol) and 4-dimethylaminopyridine (CAS Registry Number: 1122-58-3) (10.2 mg, 0.0835 mmol) were added and stirred at room temperature for 6 hours. tert-Butyldimethylchlorosilane (CAS Registry Number: 18162-48-6) (94.6 mg, 0.628 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (307 mg, 0.891 mmol, yield 93%).

[0570] Example 16B: tert-butyl (2S,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]carbonyl}-2-methylpiperazine-1-carboxylate

[0571] The title compound was obtained in the same manner as in Example 11A using the compound obtained in Example 16A and the compound obtained in Example 9A.

[0572] Example 16C: tert-butyl (7aR,10S)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-10-methyl-2,13-dioxo-1,4,5,7a,8,10,11,13-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-9(7H)-carboxylate

[0573] The compound obtained in <Example 16B> was used and the same procedures as in <Example 4B> and <Example 1C> were carried out in this order to obtain the title compound.

[0574] Example 16D (7aS,10S)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-10-methyl-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0575] The title compound was obtained in the same manner as in Example 4D using the compound obtained in Example 16C.

[0576] Example 16E (7aS,10S)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-10-methyl-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0577] The title compound was obtained in the same manner as in Example 4E using the compound obtained in Example 16D and the compound obtained in Example 3A.

[0578] Example 16F (7aS,10S)-1-(2,6-dioxopiperidin-3-yl)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-10-methyl-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0579] The title compound was obtained by the same method as in Example 4F using the compound obtained in Example 16E.

[0580] Example 17A tert-butyl 4-ethenyl-4-(hydroxymethyl)piperidine-1-carboxylate

[0581] To a solution of di-tert-butyl dicarbonate (CAS Registry Number: 24424-99-5) (1.09 g, 4.99 mmol) in THF (21 mL), (4-ethenyl-4-piperidinyl)methanol (CAS Registry Number: 2411269-58-2) (0.536 g, 3.80 mmol) and DIPEA (1.7 mL, 9.8 mmol) were added and the mixture was stirred at room temperature for 37 hours. Next, di-tert-butyl dicarbonate (CAS Registry Number: 24424-99-5) (0.410 g, 1.88 mmol) and DIPEA (0.50 mL, 2.9 mmol) were added to the reaction mixture and the mixture was stirred at 50 °C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.507 g, 2.10 mmol, yield 55%).

[0582] Example 17B tert-butyl 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-ethenylpiperidine-1-carboxylate

[0583] To a solution of the compound obtained in Example 17A (0.505 g, 2.09 mmol) in DMF (3.3 mL), tert-butyldimethylchlorosilane (CAS Registry Number: 18162-48-6) (0.396 g, 2.63 mmol) and imidazole (0.326 g, 4.79 mmol) were added and stirred at room temperature for 2 hours. The reaction mixture was diluted with diethyl ether and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.643 g, 1.81 mmol, 86% yield).

[0584] Example 17C: tert-Butyl 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{2-[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]ethyl}piperidine-1-carboxylate

[0585] The title compound was obtained by the same method as in Example 14A using the compound obtained in Example 17B.

[0586] Example 17D: tert-butyl 4-{2-[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]ethyl}-4-(hydroxymethyl)piperidine-1-carboxylate

[0587] The title compound was obtained in the same manner as in Example 4B using the compound obtained in Example 17C.

[0588] Example 17E tert-butyl 1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,4,5,9,10-hexahydro-1′H-spiro[azepino[1,2,3-de]imidazo[4,5,1-ij]quinoxaline-8,4′-piperidine]-1′-carboxylate

[0589] The title compound was obtained in the same manner as in Example 1C using the compound obtained in Example 17D.

[0590] Example 17F: 3-(2-oxo-4,5,9,10-tetrahydrospiro[azepino[1,2,3-de]imidazo[4,5,1-ij]quinoxaline-8,4'-piperidine]-1(2H)-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione

[0591] The title compound was obtained in the same manner as in Example 4D using the compound obtained in Example 17E.

[0592] Example 17G: 3-[1'-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-2-oxo-4,5,9,10-tetrahydrospiro[azepino[1,2,3-de]imidazo[4,5,1-ij]quinoxaline-8,4'-piperidine]-1(2H)-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione

[0593] The title compound was obtained in the same manner as in Example 4E using the compound obtained in Example 17F and the compound obtained in Example 3A.

[0594] Example 17H: 3-[1'-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-2-oxo-4,5,9,10-tetrahydrospiro[azepino[1,2,3-de]imidazo[4,5,1-ij]quinoxaline-8,4'-piperidine]-1(2H)-yl]piperidine-2,6-dione

[0595] The title compound was obtained by the same method as in Example 4F using the compound obtained in Example 17G.

[0596] Example 18A: 3-[1'-{[(4R)-2'-fluoro-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]carbonyl}-2-oxo-4,5,9,10-tetrahydrospiro[azepino[1,2,3-de]imidazo[4,5,1-ij]quinoxaline-8,4'-piperidine]-1(2H)-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione

[0597] The title compound was obtained in the same manner as in Example 11A using the compound obtained in Example 17F and the compound obtained in Reference Example 22.

[0598] Example 18B: 3-[1'-{[(4R)-2'-fluoro-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]carbonyl}-2-oxo-4,5,9,10-tetrahydrospiro[azepino[1,2,3-de]imidazo[4,5,1-ij]quinoxaline-8,4'-piperidine]-1(2H)-yl]piperidine-2,6-dione

[0599] The title compound was obtained by the same method as in Example 4F using the compound obtained in Example 18A.

[0600] Example 19A: Potassium {[(2S)-4-(tert-butoxycarbonyl)-2-(hydroxymethyl)piperazin-1-yl]methyl}(trifluoro)borate

[0601] A suspension of tert-butyl (3S)-3-(hydroxymethyl)-1-piperazinecarboxylate (CAS Registry Number: 314741-40-7) (5.17 g, 23.9 mmol) and potassium (bromomethyl)trifluoroborate (CAS Registry Number: 888711-44-2) (4.81 g, 23.9 mmol) in THF (24 mL) was heated to reflux and stirred for 4.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. After that, acetone (120 mL) and potassium carbonate (3.30 g, 23.9 mmol) were added and the mixture was stirred at room temperature for 40 minutes. Insoluble matter was filtered off through Celite, washed with acetone, and the filtrate was concentrated under reduced pressure to give the title compound (7.06 g, 21.0 mmol, 88% yield).

[0602] Example 19B tert-butyl (3S)-4-{[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]methyl}-3-(hydroxymethyl)piperazine-1-carboxylate

[0603] A suspension of the compound obtained in <Reference Example 25> (9.54 g, 16.6 mmol), the compound obtained in <Example 19A> (11.2 g, 33.3 mmol), Xphos Pd G4 (1.38 g, 1.60 mmol), and cesium carbonate (17.0 g, 52.2 mmol) in 1,4-dioxane (80 mL) and water (8 mL) was stirred at 85°C under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with DCM. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (8.13 g, 12.6 mmol, 76% yield).

[0604] Example 19C tert-butyl (3S)-3-(chloromethyl)-4-{[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]methyl}piperazine-1-carboxylate

[0605] To a solution of the compound obtained in <Example 19B> (2.90 g, 4.50 mmol) and DIPEA (4.5 mL, 26 mmol) in DCM (9 mL), phosphoryl chloride (CAS Registry Number: 10025-87-3) (3.08 g, 20.1 mmol) was added under ice cooling, and the mixture was stirred at the same temperature for 15 minutes. After that, the mixture was warmed to room temperature and stirred for an additional 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The organic layer was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.20 g, 3.32 mmol, 74% yield).

[0606] Example 19D tert-butyl (7aR)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,4,5,7a,8,10,11,13-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-9(7H)-carboxylate

[0607] A suspension of the compound obtained in Example 19C (303 mg, 0.457 mmol), potassium carbonate (193 mg, 1.40 mmol), and sodium bromide (CAS Registry Number: 7647-15-6) (8.0 mg, 0.078 mmol) in N,N-dimethylacetamide (2 mL) was stirred at 110°C for 9 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate, ethyl acetate / methanol) to obtain the title compound (90.7 mg, 0.145 mmol, 32% yield).

[0608] Example 19E: 3-[(7aS)-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-1(13H)-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione

[0609] To a solution of the compound obtained in Example 19D (59.9 mg, 0.0956 mmol) in DCM (1 mL), 2,4,6-trimethylpyridine (CAS Registry Number: 108-75-8) (0.0503 mL, 0.382 mmol) and triethylsilyl trifluoromethanesulfonate (CAS Registry Number: 79271-56-0) (0.0756 mL, 0.335 mmol) were added under ice cooling, and the mixture was stirred at the same temperature for 45 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with DCM. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by amine-modified silica gel column chromatography (DCM / IPA) to obtain the title compound (34.2 mg, 0.0649 mmol, 68% yield).

[0610] Example 19F: 3-[(7aS)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-1(13H)-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione

[0611] To a DCM (0.5 mL) solution of the compound obtained in Example 19E (18.8 mg, 0.0357 mmol) and the compound obtained in Example 3A (25.1 mg, 0.0429 mmol), sodium triacetoxyborohydride (25.0 mg, 0.118 mmol) was added and stirred at room temperature for 1.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with DCM. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (30.3 mg, 0.0276 mmol, 77% yield).

[0612] Example 19G: 3-[(7aS)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-1(13H)-yl]piperidine-2,6-dione

[0613] Trifluoroacetic acid (0.5 mL) was added to a solution of the compound obtained in <Example 19F> (30.3 mg, 0.0276 mmol) in DCM (0.5 mL), and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1 mL), and N,N'-dimethylethylenediamine (CAS Registry Number: 110-70-3) (0.0035 mL, 0.033 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (12.7 mg, 0.0131 mmol, 48% yield).

[0614] Example 20A: 4-benzyl 1-tert-butyl 4-ethenylpiperidine-1,4-dicarboxylate

[0615] To a solution of 1-{[(tert-butyl)oxy]carbonyl}-4-ethenyl-4-piperidinecarboxylic acid (CAS Registry Number: 1082207-48-4) (160 mg, 0.626 mmol) in DMF (4.1 mL) was added sodium bicarbonate (210 mg, 2.50 mmol) and benzyl bromide (CAS Registry Number: 100-39-0) (0.149 mL, 1.25 mmol) at room temperature, and the mixture was stirred at 60 °C under a nitrogen atmosphere for 3 hours. The reaction mixture was diluted with ethyl acetate and washed twice with 10% brine and once with saturated brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (183 mg, 0.529 mmol, 84% yield).

[0616] Example 20B: 4-benzyl 1-tert-butyl 4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]piperidine-1,4-dicarboxylate

[0617] The title compound was obtained by the same method as in Example 26B using the compound obtained in Example 20A.

[0618] Example 20C: Potassium (2-{4-[(benzyloxy)carbonyl]-1-(tert-butoxycarbonyl)piperidin-4-yl}ethyl)(trifluoro)borate

[0619] To a solution of the compound obtained in <Example 20B> (192 mg, 0.405 mmol) in methanol (3.2 mL) and water (0.8 mL), potassium hydrogen fluoride (CAS registration number: 7789-29-9) (126 mg, 1.62 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and azeotroped three times with toluene (3 mL). Acetonitrile (10 mL) was added to the residue, and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to obtain the title compound (194 mg, 0.427 mmol, yield: quantitative).

[0620] Example 20D: 4-benzyl 1-tert-butyl 4-{2-[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]ethyl}piperidine-1,4-dicarboxylate

[0621] A solution of the compound obtained in <Reference Example 26> (105 mg, 0.211 mmol), the compound obtained in <Example 20C> (144 mg, 0.317 mmol), SPhos Pd G2 (30.5 mg, 0.0423 mmol), and tripotassium phosphate (112 mg, 0.529 mmol) in toluene (1.75 mL) and water (0.35 mL) was stirred at 80°C for 8 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (42.4 mg, 0.0648 mmol, 30% yield).

[0622] Example 20E: 1-(tert-butoxycarbonyl)-4-{2-[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]ethyl}piperidine-4-carboxylic acid

[0623] A suspension of the compound obtained in Example 20D (21.5 mg, 0.0282 mmol) and 20% palladium hydroxide on carbon (4 mg) in ethanol (0.56 mL) was stirred under a hydrogen atmosphere at room temperature for 9.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (19.6 mg) as a crude product, which was used in the next reaction without further purification.

[0624] Example 20F: tert-butyl 1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2,7-dioxo-1,2,4,5,9,10-hexahydro-1′H-spiro[azepino[1,2,3-de]imidazo[4,5,1-ij]quinoxaline-8,4′-piperidine]-1′-carboxylate

[0625] To a solution of the compound obtained in <Example 20E> (19.2 mg, 0.0286 mmol) in toluene (1.4 mL), DIPEA (0.015 mL, 0.0861 mmol) and 1-chloro-N,N,2-trimethyl-1-propen-1-amine (CAS Registry Number: 26189-59-3) (0.0076 mL, 0.0574 mmol) were added and the mixture was stirred at room temperature for 2.5 hours. The mixture was then stirred at 80°C for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (12.9 mg, 0.0197 mmol, 69% yield for two steps).

[0626] Example 20G: 1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-4,5,9,10-tetrahydrospiro[azepino[1,2,3-de]imidazo[4,5,1-ij]quinoxaline-8,4′-piperidine]-2,7(1H)-dione

[0627] The title compound was obtained in the same manner as in Example 4D using the compound obtained in Example 20F.

[0628] Example 20H: 1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-1'-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-4,5,9,10-tetrahydrospiro[azepino[1,2,3-de]imidazo[4,5,1-ij]quinoxaline-8,4'-piperidine]-2,7(1H)-dione

[0629] The title compound was obtained in the same manner as in Example 4E using the compound obtained in Example 20G and the compound obtained in Example 3A.

[0630] Example 20I: 1-(2,6-dioxopiperidin-3-yl)-1'-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-4,5,9,10-tetrahydrospiro[azepino[1,2,3-de]imidazo[4,5,1-ij]quinoxaline-8,4'-piperidine]-2,7(1H)-dione

[0631] The title compound was obtained in the same manner as in Example 4F using the compound obtained in Example 20H.

[0632] Example 21A: tert-butyl (3S)-4-(2,3-difluoro-4-nitrobenzoyl)-3-(hydroxymethyl)piperazine-1-carboxylate

[0633] A solution of 2,3-difluoro-4-nitrobenzoic acid (CAS Registry Number: 1806370-35-3) (500 mg, 2.34 mmol) in DCM (20 mL) was added with DMF (0.01 mL) and oxalyl chloride (0.4 mL) and stirred at room temperature for 1 hour. The solvent was then evaporated under reduced pressure to give the crude acid chloride. tert-Butyl (3S)-3-(hydroxymethyl)-1-piperazinecarboxylate (CAS Registry Number: 314741-40-7) (556 mg, 2.57 mmol) was dissolved in DCM (20 mL) and saturated aqueous sodium bicarbonate (10 mL) was added. The crude acid chloride obtained above was then added and stirred at room temperature. The reaction mixture was separated, and the aqueous layer was extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (894 mg, 2.23 mmol, yield 95%).

[0634] Example 21B tert-butyl (3S)-4-{3-[benzyl(methyl)amino]-2-fluoro-4-nitrobenzoyl}-3-(hydroxymethyl)piperazine-1-carboxylate

[0635] To a solution of the compound obtained in <Example 21A> (748 mg, 1.86 mmol) in ethanol (15 mL), N-methylbenzylamine (CAS Registry Number: 103-67-3) (0.72 mL, 5.6 mmol) and DIPEA (1.30 mL, 7.45 mmol) were added, and the mixture was stirred at 70°C for 4 hours. The reaction mixture was returned to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (900 mg, 1.79 mmol, yield 96%).

[0636] Example 21C: tert-butyl (12aS)-10-[benzyl(methyl)amino]-9-nitro-6-oxo-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-carboxylate

[0637] To a solution of the compound obtained in <Example 21B> (900 mg, 1.79 mmol) in DMF (20 mL), sodium hydride (55% oil, 234 mg, 5.37 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 6 hours. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (723 mg, 1.50 mmol, yield 84%).

[0638] Example 21D tert-butyl (12aS)-9-amino-10-(methylamino)-6-oxo-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-carboxylate

[0639] To a solution of the compound obtained in <Example 21C> (723 mg, 1.50 mmol) in ethanol (15 mL), 20% palladium hydroxide on carbon (300 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 4.5 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate / methanol) to obtain the title compound (417 mg, 1.15 mmol, yield 77%).

[0640] Example 21E tert-butyl (11aS)-1-methyl-2,6-dioxo-1,2,3,6,8,9,11a,12-octahydroimidazo[4,5-i]pyrazino[2,1-c][1,4]benzoxazepine-10(11H)-carboxylate

[0641] A solution of triphosgene (CAS reg. no.: 32315-10-9) (151 mg, 0.509 mmol) in THF (2.0 mL) was added to a solution of the compound obtained in <Example 21D> (369 mg, 1.02 mmol) in THF (10 mL) under ice-cooling, and after stirring for 5 minutes, pyridine (0.147 mL, 1.83 mmol) was added, and the mixture was heated to 60°C and stirred at the same temperature for 5 hours. After returning the reaction mixture to room temperature, a saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate / methanol) to obtain the title compound (209 mg, 0.538 mmol, 53% yield).

[0642] Example 21F: tert-butyl (11aS)-3-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-1-methyl-2,6-dioxo-1,2,3,6,8,9,11a,12-octahydroimidazo[4,5-i]pyrazino[2,1-c][1,4]benzoxazepine-10(11H)-carboxylate

[0643] A suspension of the compound obtained in Example 21E (209 mg, 0.538 mmol), the compound obtained in Reference Example 17 (434 mg, 1.35 mmol), and cesium carbonate (526 mg, 1.61 mmol) in DMF (5.0 mL) was stirred at 60°C for 3.5 hours. The reaction mixture was returned to room temperature, and then extracted with water and ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate / methanol) to obtain the title compound (215 mg, 0.341 mmol, yield 63%).

[0644] Example 21G (11aS)-3-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-1-methyl-1,3,8,9,10,11,11a,12-octahydroimidazo[4,5-i]pyrazino[2,1-c][1,4]benzoxazepine-2,6-dione

[0645] The title compound was obtained in the same manner as in Example 4D using the compound obtained in Example 21F.

[0646] Example 21H: (11aS)-3-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-10-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-1-methyl-1,3,8,9,10,11,11a,12-octahydroimidazo[4,5-i]pyrazino[2,1-c][1,4]benzoxazepine-2,6-dione

[0647] The title compound was obtained in the same manner as in Example 4E using the compound obtained in Example 21G and the compound obtained in Example 3A.

[0648] Example 21I: (11aS)-3-(2,6-dioxopiperidin-3-yl)-10-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-1-methyl-1,3,8,9,10,11,11a,12-octahydroimidazo[4,5-i]pyrazino[2,1-c][1,4]benzoxazepine-2,6-dione

[0649] The title compound was obtained by the same method as in Example 4F using the compound obtained in Example 21H.

[0650] Example 22A tert-butyl (11aS)-3-(2,6-dioxopiperidin-3-yl)-1-methyl-2,6-dioxo-1,2,3,6,8,9,11a,12-octahydroimidazo[4,5-i]pyrazino[2,1-c][1,4]benzoxazepine-10(11H)-carboxylate

[0651] The title compound was obtained in the same manner as in Example 27A using the compound obtained in Example 21F.

[0652] Example 22B (11aS)-3-(2,6-dioxopiperidin-3-yl)-1-methyl-1,3,8,9,10,11,11a,12-octahydroimidazo[4,5-i]pyrazino[2,1-c][1,4]benzoxazepine-2,6-dione monohydrochloride

[0653] The title compound was obtained by the same method as in Example 6B using the compound obtained in Example 22A.

[0654] Example 23A tert-butyl (2S,4R)-4-(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

[0655] To a solution of (2S,4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (CAS Registry Number: 54631-81-1) (5.00 g, 15.6 mmol) in THF (15 mL), borane-THF complex (1.00 mol / L THF solution, 25 mL, 25 mmol) was added under ice cooling and stirred at room temperature for 1.5 hours. Methanol (15 mL) was added to the reaction mixture, which was then concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (4.85 g, 15.6 mmol, quantitative yield).

[0656] Example 23B [(2S,4R)-4-(benzyloxy)pyrrolidin-2-yl]methanol monohydrochloride

[0657] The title compound was obtained by the same method as in Example 6B using the compound obtained in Example 23A.

[0658] Example 23C (2S,4R)-4-(benzyloxy)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyrrolidine

[0659] Using the compound obtained in <Example 23B>, the title compound was obtained in the same manner as in <Example 16A>.

[0660] Example 23D: 3-[7-{[(2S,4R)-4-(benzyloxy)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyrrolidin-1-yl]carbonyl}-2-oxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxaline-1(2H)-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione

[0661] The title compound was obtained in the same manner as in Example 4A using the compound obtained in Example 23C.

[0662] Example 23E: 3-[7-{[(2S,4R)-4-(benzyloxy)-2-(hydroxymethyl)pyrrolidin-1-yl]carbonyl}-2-oxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione

[0663] The title compound was obtained in the same manner as in Example 4B using the compound obtained in Example 23D.

[0664] Example 23F (7aS,9R)-9-(benzyloxy)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-4,5,7a,8,9,10-hexahydro-2H,7H-imidazo[1,5,4-de]pyrrolo[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,12(1H)-dione

[0665] The title compound was obtained in the same manner as in Example 1C using the compound obtained in Example 23E.

[0666] Example 23G (7aS,9R)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-9-hydroxy-4,5,7a,8,9,10-hexahydro-2H,7H-imidazo[1,5,4-de]pyrrolo[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,12(1H)-dione

[0667] A solution of the compound obtained in <Example 23F> (522 mg, 0.826 mmol) in ethanol (4 mL) and THF (4 mL) was purged with nitrogen, followed by the addition of 20% palladium hydroxide on carbon (175 mg) and stirring under a hydrogen atmosphere at 60°C for 7 hours. The reaction mixture was purged with nitrogen, filtered through Celite, and the filtrate was concentrated under reduced pressure. A solution of the residue in ethanol (4 mL) and acetic acid (4 mL) was purged with nitrogen, followed by the addition of 20% palladium hydroxide on carbon (300 mg) and stirring under a hydrogen atmosphere at room temperature for 1.5 hours. The reaction mixture was purged with nitrogen, followed by filtration through Celite. The filtrate was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (369 mg, 0.681 mmol, 82% yield).

[0668] Example 23H (7aS,9R)-1-(2,6-dioxopiperidin-3-yl)-9-hydroxy-4,5,7a,8,9,10-hexahydro-2H,7H-imidazo[1,5,4-de]pyrrolo[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,12(1H)-dione

[0669] Trifluoroacetic acid (1.00 mL, 13.1 mmol) was added to a DCM (5 mL) solution of the compound obtained in <Example 23G> (369 mg, 0.681 mmol), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with DCM. A saturated aqueous solution of sodium bicarbonate was added, and the layers were separated. The aqueous layer was neutralized with 1 mol / L hydrochloric acid and then concentrated under reduced pressure. Acetonitrile (20 mL) was added to the residue, and the mixture was sonicated. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was slurry-washed with ethyl acetate and then dried at 60°C under reduced pressure to obtain the title compound (176 mg, 0.427 mmol, yield 63%).

[0670] Example 24A tert-butyl (2S,4S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-cyanopyrrolidine-1-carboxylate

[0671] To a solution of tert-butyl (2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-[(methylsulfonyl)oxy]pyrrolidine-1-carboxylate (WO2001047897 A1) (3.73 g, 9.11 mmol) in DMSO (20 mL), sodium cyanide (CAS Registry Number: 143-33-9) (663 mg, 13.5 mmol) was added and the mixture was stirred at 80°C for 18 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (988 mg, 2.90 mmol, 32% yield).

[0672] Example 24B: Benzyl (3S,5S)-5-(hydroxymethyl)pyrrolidine-3-carboxylate

[0673] Hydrochloric acid (36%, 1.97 g, 19.5 mmol) was added to the compound obtained in <Example 24A> (183 mg, 0.537 mmol) and stirred at 100°C for 2 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure to give a light brown solid. To a mixture of this solid, benzyl alcohol (1 mL), and toluene (1 mL), p-toluenesulfonic acid monohydrate (CAS Registry Number: 6192-52-5) (100 mg, 0.526 mmol) was added and stirred at 110°C for 1.5 hours. The reaction mixture was allowed to cool to room temperature, and then saturated aqueous sodium bicarbonate was added, followed by extraction with chloroform / IPA (3 / 1). The organic layer was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / methanol) to give the title compound (45.5 mg, 0.193 mmol, 36% yield).

[0674] Example 24C: Benzyl (3S,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyrrolidine-3-carboxylate

[0675] To a solution of the compound obtained in <Example 24B> (48.3 mg, 0.205 mmol) in DCM (2 mL), triethylamine (0.060 mL, 0.433 mmol) and tert-butyldimethylchlorosilane (CAS Registry Number: 18162-48-6) (40 mg, 0.265 mmol) were added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction solution, and the mixture was extracted with DCM. The organic layer was dried over magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / methanol) to obtain the title compound (44.5 mg, 0.127 mmol, yield 62%).

[0676] Example 24D: Benzyl (3S,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-{[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]carbonyl}pyrrolidine-3-carboxylate

[0677] The title compound was obtained in the same manner as in Example 11A using the compound obtained in Example 24C and the compound obtained in Example 9A.

[0678] Example 24E: Benzyl (3S,5S)-1-{[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]carbonyl}-5-(hydroxymethyl)pyrrolidine-3-carboxylate

[0679] The title compound was obtained in the same manner as in Example 4B using the compound obtained in Example 24D.

[0680] Example 24F: Benzyl (7aS,9S)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2,12-dioxo-1,4,5,7a,8,9,10,12-octahydro-2H,7H-imidazo[1,5,4-de]pyrrolo[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-9-carboxylate

[0681] The title compound was obtained in the same manner as in Example 1C using the compound obtained in Example 24E.

[0682] Example 24G: Benzyl (7aS,9S)-1-(2,6-dioxopiperidin-3-yl)-2,12-dioxo-1,4,5,7a,8,9,10,12-octahydro-2H,7H-imidazo[1,5,4-de]pyrrolo[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-9-carboxylate

[0683] The title compound was obtained by the same method as in Example 4F using the compound obtained in Example 24F.

[0684] Example 24H (7aS,9S)-1-(2,6-dioxopiperidin-3-yl)-2,12-dioxo-1,4,5,7a,8,9,10,12-octahydro-2H,7H-imidazo[1,5,4-de]pyrrolo[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-9-carboxylic acid

[0685] A solution of the compound obtained in <Example 24G> (14.2 mg, 0.0268 mmol) in ethanol (1 mL) was purged with nitrogen, and then 20% palladium hydroxide on carbon (10 mg) was added and stirred under a hydrogen atmosphere at room temperature for 2 hours. After purging the reaction solution with nitrogen, Celite was added and the mixture was stirred. Insoluble matter was filtered off and washed with DCM. The filtrate was concentrated under reduced pressure to give the title compound (10.3 mg, 0.0234 mmol, 87% yield).

[0686] Example 25A tert-butyl (7aR,10S)-1-(2,6-dioxopiperidin-3-yl)-10-methyl-2,13-dioxo-1,4,5,7a,8,10,11,13-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-9(7H)-carboxylate

[0687] The title compound was obtained in the same manner as in Example 6A using the compound obtained in Example 16C.

[0688] Example 25B (7aS,10S)-1-(2,6-dioxopiperidin-3-yl)-10-methyl-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione monohydrochloride

[0689] The title compound was obtained by the same method as in Example 6B using the compound obtained in Example 25A.

[0690] Example 26A: 3-methyl-2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-benzimidazol-4-yl trifluoromethanesulfonate

[0691] To a solution of 4-hydroxy-3-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-benzimidazol-2-one (ACS Medicinal Chemistry Letters, 2019, 10, 2, 196-202.) (3.03 g, 10.3 mmol) in DCM (50 mL) were added triethylamine (2.85 mL, 20.6 mmol) and trifluoromethanesulfonic anhydride (CAS Registry Number: 358-23-6) (2.08 mL, 12.4 mmol), and the mixture was stirred at room temperature for 19.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with DCM. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (3.53 g, 8.28 mmol, yield 80%).

[0692] Example 26B: 1-benzyl 4-tert-butyl (2R)-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]piperazine-1,4-dicarboxylate

[0693] To a solution of 1-benzyl 4-tert-butyl (2R)-2-ethenylpiperazine-1,4-dicarboxylate (WO2015013835 A1) (1.91 g, 5.52 mmol) in DCM (27 mL), chloro(1,5-cyclooctadiene)iridium(I) (dimer) (CAS Registry Number: 12112-67-3) (185 mg, 0.275 mmol) and 1,2-bis(diphenylphosphino)ethane (CAS Registry Number: 1663-45-2) (220 mg, 0.552 mmol) were added, and the mixture was stirred at room temperature for 15 minutes. After cooling the reaction mixture on ice, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS RN: 25015-63-8) (1.20 mL, 8.35 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.00 g, 4.22 mmol, 76% yield).

[0694] Example 26C: 1-benzyl 4-tert-butyl (2R)-2-[2-(3-methyl-2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-benzimidazol-4-yl)ethyl]piperazine-1,4-dicarboxylate

[0695] A suspension of the compound obtained in Example 26A (1.25 g, 2.93 mmol), the compound obtained in Example 26B (1.50 g, 3.16 mmol), Pd(dppf)Cl.sub.2-DCM (240 mg, 0.294 mmol), and tripotassium phosphate (2.00 g, 9.42 mmol) in 1,4-dioxane (20 mL)-water (4 mL) was degassed and purged with nitrogen, and then stirred at 100°C for 1.5 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed sequentially with saturated aqueous sodium bicarbonate and saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (939 mg, 1.50 mmol, 51% yield).

[0696] <Example 26D> Benzyl (2R)-2-[2-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)ethyl]piperazine-1-carboxylate

[0697] Trifluoroacetic acid (3 mL) was added to a DCM (5 mL) solution of the compound obtained in Example 26C (972 mg, 1.56 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (8 mL), and N,N'-dimethylethylenediamine (CAS Registry Number: 110-70-3) (0.170 mL, 1.58 mmol) was added. The mixture was stirred at room temperature for 1 hour, and the reaction mixture was concentrated under reduced pressure. The residue was purified by amine-modified silica gel column chromatography (DCM / methanol) to obtain the title compound (521 mg, 1.32 mmol, 85% yield).

[0698] <Example 26E> 1-benzyl 4-tert-butyl (2R)-2-[2-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)ethyl]piperazine-1,4-dicarboxylate

[0699] To a solution of the compound obtained in <Example 26D> (521 mg, 1.32 mmol) in DCM (13 mL), di-tert-butyl dicarbonate (CAS Registry Number: 24424-99-5) (320 mg, 1.47 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (472 mg, 0.954 mmol, 72% yield).

[0700] <Example 26F> 1-benzyl 4-tert-butyl (2R)-2-[2-(5-iodo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)ethyl]piperazine-1,4-dicarboxylate

[0701] N-iodosuccinimide (CAS Registry Number: 516-12-1) (255 mg, 1.13 mmol) was added to a DMF (9.5 mL) solution of the compound obtained in <Example 26E> (472 mg, 0.954 mmol), and the mixture was stirred at 50°C for 20 hours. After the reaction mixture was allowed to cool to room temperature, water and a saturated aqueous solution of sodium thiosulfate were added, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (240 mg, 0.387 mmol, 41% yield).

[0702] <Example 26G> 1-benzyl 4-tert-butyl (2R)-2-(2-{3-methyl-2-oxo-5-[(2,4,6-trichlorophenoxy)carbonyl]-2,3-dihydro-1H-benzimidazol-4-yl}ethyl)piperazine-1,4-dicarboxylate

[0703] Using the compound obtained in <Example 26F>, the title compound was obtained in the same manner as in <Reference Example 27>.

[0704] Example 26H: tert-butyl (11aR)-1-methyl-2,6-dioxo-1,2,3,6,8,9,11,11a,12,13-decahydro-10H-imidazo[4,5-g]pyrazino[1,2-b][2]benzazepine-10-carboxylate

[0705] To a solution of the compound obtained in Example 26G (192 mg, 0.267 mmol) in ethanol (3 mL) was added 20% palladium hydroxide on carbon (80 mg) under a nitrogen atmosphere, followed by stirring at room temperature for 1.5 hours under a hydrogen atmosphere. After purging the reaction mixture with nitrogen, Celite was added and the mixture was stirred. Insoluble material was filtered off and washed with DCM, and the filtrate was concentrated under reduced pressure. To a solution of the residue in acetonitrile (15 mL), 4-dimethylaminopyridine (CAS Registry Number: 1122-58-3) (5 mg, 0.04 mmol) and DIPEA (0.120 mL, 0.689 mmol) were added and the mixture was stirred at 60°C for 1.5 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (67.3 mg, 0.174 mmol, yield 65%).

[0706] Example 26I: tert-butyl (11aR)-3-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-1-methyl-2,6-dioxo-1,2,3,6,8,9,11,11a,12,13-decahydro-10H-imidazo[4,5-g]pyrazino[1,2-b][2]benzazepine-10-carboxylate

[0707] The title compound was obtained by the same method as in Example 21F using the compound obtained in Example 26H.

[0708] Example 26J tert-Butyl (11aR)-3-(2,6-dioxopiperidin-3-yl)-1-methyl-2,6-dioxo-1,2,3,6,8,9,11,11a,12,13-decahydro-10H-imidazo[4,5-g]pyrazino[1,2-b][2]benzazepine-10-carboxylate

[0709] The title compound was obtained by the same method as in Example 27A using the compound obtained in Example 26I.

[0710] Example 26K (11aR)-3-(2,6-dioxopiperidin-3-yl)-1-methyl-9,10,11,11a,12,13-hexahydro-1H-imidazo[4,5-g]pyrazino[1,2-b][2]benzazepine-2,6(3H,8H)-dione monohydrochloride

[0711] The title compound was obtained in the same manner as in Example 6B using the compound obtained in Example 26J.

[0712] Example 27A tert-butyl (7aR)-1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,4,5,7a,8,10,11,13-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-9(7H)-carboxylate

[0713] Trifluoroacetic acid (0.5 mL) was added to a DCM (0.5 mL) solution of the compound obtained in Example 19D (90.7 mg, 0.145 mmol), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then concentrated under reduced pressure. DCM (1 mL), triethylamine (0.201 mL, 1.45 mmol), and di-tert-butyl dicarbonate (CAS Registry Number: 24424-99-5) (66.1 mg, 0.303 mmol) were added to the residue, and the mixture was stirred at room temperature for 16.5 hours. The reaction mixture was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (44.0 mg, 0.0886 mmol, 61% yield).

[0714] Example 27B: 3-[(7aS)-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxalin-1(13H)-yl]piperidine-2,6-dione dihydrochloride

[0715] To a solution of the compound obtained in <Example 27A> (23.8 mg, 0.0479 mmol) in DCM (0.5 mL) was added 4 mol / L hydrogen chloride / 1,4-dioxane solution (0.5 mL), and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, washed with ethyl acetate, and then dried under reduced pressure at 50 °C to obtain the title compound (19.2 mg, 0.0409 mmol, yield 85%).

[0716] Example 28A: N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxaline-7-carboxamide

[0717] The title compound was obtained in the same manner as in Example 11A using the compound obtained in Example 9A and 2-{[tert-butyl(dimethyl)silyl]oxy}ethanamine (CAS Registry Number: 101711-55-1).

[0718] Example 28B: 1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-4,5,8,9-tetrahydro[1,4]diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline-2,10(1H,7H)-dione

[0719] The compound obtained in Example 28A was used and the same procedures as in Example 4B and Example 4C were carried out in this order to obtain the title compound.

[0720] Example 28C: 1-(2,6-dioxopiperidin-3-yl)-4,5,8,9-tetrahydro[1,4]diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline-2,10(1H,7H)-dione

[0721] The title compound was obtained by the same method as in Example 4F using the compound obtained in Example 28B.

[0722] Example 29A (7aR)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-9-[(1-{4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenyl}piperidin-4-yl)methyl]-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0723] The title compound was obtained in the same manner as in Example 4E using the compound obtained in Example 1D and 1-{4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenyl}piperidine-4-carbaldehyde (WO2018102725 A1).

[0724] Example 29B (7aR)-1-(2,6-dioxopiperidin-3-yl)-9-[(1-{4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenyl}piperidin-4-yl)methyl]-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0725] The title compound was obtained by the same method as in Example 4F using the compound obtained in Example 29A.

[0726] Example 30A tert-butyl 1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2,4,5,7a,8,10,11,11a,12-decahydroimidazo[1,5,4-de]pyrido[4',3':5,6]azepino[3,2,1-ij]quinoxaline-9(7H)-carboxylate

[0727] The title compound was obtained in the same manner as in Example 27A using the compound obtained in Example 14C.

[0728] Example 30B: 3-(2-oxo-4,5,7,7a,8,9,10,11,11a,12-decahydroimidazo[1,5,4-de]pyrido[4',3':5,6]azepino[3,2,1-ij]quinoxalin-1(2H)-yl)piperidine-2,6-dione monohydrochloride

[0729] The title compound was obtained by the same method as in Example 6B using the compound obtained in Example 30A.

[0730] Example 31A: tert-butyl 1-(2,6-dioxopiperidin-3-yl)-2,7-dioxo-1,2,4,5,9,10-hexahydro-1′H-spiro[azepino[1,2,3-de]imidazo[4,5,1-ij]quinoxaline-8,4′-piperidine]-1′-carboxylate

[0731] The title compound was obtained by the same method as in Example 27A using the compound obtained in Example 20F.

[0732] Example 31B: 1-(2,6-dioxopiperidin-3-yl)-4,5,9,10-tetrahydrospiro[azepino[1,2,3-de]imidazo[4,5,1-ij]quinoxaline-8,4'-piperidine]-2,7(1H)-dione monohydrochloride

[0733] The title compound was obtained by the same method as in Example 6B using the compound obtained in Example 31A.

[0734] Example 32A: Benzyl 1-(2,6-dioxopiperidin-3-yl)-2,10-dioxo-1,2,4,5,9,10-hexahydro-1'H-spiro[1,4-diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline-8,4'-piperidine]-1'-carboxylate

[0735] Trifluoroacetic acid (0.5 mL) was added to a solution of the compound obtained in <Example 9C> (62.7 mg, 0.0910 mmol) in DCM (0.5 mL), and the mixture was stirred at room temperature for 70 minutes. The reaction mixture was diluted with DCM, saturated aqueous sodium bicarbonate solution was added, the two phases were separated, and the aqueous phase was extracted with DCM. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (1 mL), and N,N'-dimethylethylenediamine (CAS Registry Number: 110-70-3) (0.0118 mL, 0.110 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with DCM and methanol, saturated aqueous sodium bicarbonate solution was added, the two phases were separated, and the aqueous layer was extracted with DCM. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to obtain the title compound (33.6 mg, 0.0602 mmol, yield 66%).

[0736] Example 32B: 1-(2,6-dioxopiperidin-3-yl)-4,5-dihydrospiro[1,4-diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline-8,4′-piperidine]-2,10(1H,9H)-dione

[0737] To a suspension of the compound obtained in <Example 32A> (30.3 mg, 0.0542 mmol) in ethanol (1 mL)-ethyl acetate (1 mL) was added 10% palladium on carbon (66.8 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 3.5 hours. 10% palladium on carbon (123 mg) was added to the reaction mixture, and the mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through a PTFE filter and washed with THF. The filtrate was concentrated under reduced pressure, and the resulting solid was washed with diethyl ether to give the title compound (4.8 mg, 0.011 mmol, 21% yield).

[0738] Example 33A: tert-butyl (2-{2-[2-(2-bromoethoxy)ethoxy]ethoxy}ethyl)methylcarbamate

[0739] The title compound was obtained in the same manner as in Example 35A using tert-butyl (2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)methylcarbamate (CAS registration number: 2248492-01-3).

[0740] Example 33B tert-butyl {2-[2-(2-{2-[(7aR)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2,13-dioxo-1,4,5,7a,8,10,11,13-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxalin-9(7H)-yl]ethoxy}ethoxy)ethoxy]ethyl}methylcarbamate

[0741] Using the compound obtained in <Example 33A>, the title compound was obtained in the same manner as in <Example 35B>.

[0742] Example 33C (7aR)-1-(2,6-dioxopiperidin-3-yl)-9-[1-(1-{4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenyl}piperidin-4-yl)-2-methyl-5,8,11-trioxa-2-azatridecan-13-yl]-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0743] Trifluoroacetic acid (0.5 mL) was added to a DCM (0.5 mL) solution of the compound obtained in Example 33B (27.4 mg, 0.0330 mmol). After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. To the residue, DCM (1 mL), triethylamine (0.0458 mL, 0.330 mmol), 1-{4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenyl}piperidine-4-carbaldehyde (WO2018102725 A1) (13.8 mg, 0.0335 mmol), and sodium triacetoxyborohydride (27.1 mg, 0.128 mmol) were added and the mixture was stirred at room temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM / methanol. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (8.4 mg, 0.0084 mmol, yield 26%).

[0744] Example 34A: Potassium {[(2R)-4-(tert-butoxycarbonyl)-2-(hydroxymethyl)piperazin-1-yl]methyl}(trifluoro)borate

[0745] The title compound was obtained in the same manner as in Example 19A using tert-butyl (3R)-3-(hydroxymethyl)-1-piperazinecarboxylate (CAS registration number: 278788-66-2).

[0746] Example 34B: tert-butyl (3R)-4-{[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]methyl}-3-(hydroxymethyl)piperazine-1-carboxylate

[0747] Using the compound obtained in <Example 34A>, the title compound was obtained in the same manner as in <Example 19B>.

[0748] Example 34C: tert-butyl (3R)-3-(chloromethyl)-4-{[1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[1,5,4-de]quinoxalin-7-yl]methyl}piperazine-1-carboxylate

[0749] Using the compound obtained in <Example 34B>, the title compound was obtained in the same manner as in <Example 19C>.

[0750] Example 34D tert-butyl (7aS)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2-oxo-1,4,5,7a,8,10,11,13-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-9(7H)-carboxylate

[0751] The title compound was obtained in the same manner as in Example 19D using the compound obtained in Example 34C.

[0752] Example 34E tert-butyl (7aS)-1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,4,5,7a,8,10,11,13-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-9(7H)-carboxylate

[0753] The title compound was obtained in the same manner as in Example 27A using the compound obtained in Example 34D.

[0754] Example 34F: 3-[(7aR)-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-1(13H)-yl]piperidine-2,6-dione dihydrochloride

[0755] The title compound was obtained in the same manner as in Example 27B using the compound obtained in Example 34E.

[0756] Example 35A tert-butyl [2-(2-bromoethoxy)ethyl]methylcarbamate

[0757] To a solution of tert-butyl [2-(2-hydroxyethoxy)ethyl]methylcarbamate (CAS RN: 1628679-52-6) (188 mg, 0.857 mmol) in THF (4 mL), triphenylphosphine (446 mg, 1.70 mmol) and carbon tetrabromide (553 mg, 1.67 mmol) were added. After stirring at room temperature for 50 minutes, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (159 mg, 0.563 mmol, 66% yield).

[0758] Example 35B tert-butyl (2-{2-[(7aR)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-2,13-dioxo-1,4,5,7a,8,10,11,13-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxalin-9(7H)-yl]ethoxy}ethyl)methylcarbamate

[0759] A suspension of the compound obtained in Example 35A (41.9 mg, 0.148 mmol), the compound obtained in Example 1D (62.6 mg, 0.116 mmol), and potassium carbonate (55.3 mg, 0.400 mmol) in DMF (1 mL) was stirred at 60°C for 9 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (61.4 mg, 0.0828 mmol, 72% yield).

[0760] Example 35C (7aR)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-9-{2-[2-(methylamino)ethoxy]ethyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0761] Using the compound obtained in <Example 35B>, the title compound was obtained in the same manner as in <Example 4D>.

[0762] Example 35D (7aR)-1-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-9-[2-(2-{[(1-{4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenyl}piperidin-4-yl)methyl](methyl)amino}ethoxy)ethyl]-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0763] The title compound was obtained in the same manner as in Example 4E using the compound obtained in Example 35C and 1-{4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenyl}piperidine-4-carbaldehyde (WO2018102725 A1).

[0764] Example 35E (7aR)-1-(2,6-dioxopiperidin-3-yl)-9-[2-(2-{[(1-{4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenyl}piperidin-4-yl)methyl](methyl)amino}ethoxy)ethyl]-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2′,1′:3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione

[0765] The title compound was obtained by the same method as in Example 4F using the compound obtained in Example 35D.

[0766] Example 36A: 1'-(2,6-dioxopiperidin-3-yl)-4',5'-dihydrospiro[azetidine-3,8'-[1,4]diazepino[1,7,6-de]imidazo[4,5,1-ij]quinoxaline]-2',10'(1'H,9'H)-dione

[0767] To a solution of the compound obtained in Example 15C (121 mg, 0.193 mmol) in DCM (0.5 mL) was added trifluoroacetic acid (0.5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure. The residue was purified by amine-modified silica gel column chromatography (DCM / IPA) to give the title compound (5.4 mg, 0.014 mmol, yield 7.1%).

[0768] Example 37A: 3-[(7aR)-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-1(13H)-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione

[0769] Using the compound obtained in <Example 34D>, the title compound was obtained in the same manner as in <Example 19E>.

[0770] Example 37B: 3-[(7aR)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-1(13H)-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione

[0771] Using the compound obtained in <Example 37A> and <Example 3A>, the title compound was obtained in the same manner as in <Example 4E>.

[0772] Example 37C: 3-[(7aR)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-1(13H)-yl]piperidine-2,6-dione

[0773] Using the compound obtained in <Example 37B>, the title compound was obtained in the same manner as in <Example 4F>.

[0774] Example 38A: tert-butyl (4S)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate

[0775] The title compound was obtained in the same manner as in <Reference Example 11> using the compound obtained in <Reference Example 10>.

[0776] Example 38B (4S)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-carbaldehyde

[0777] The compound obtained in <Example 38A> was used and the same operations as in <Reference Example 12> and <Example 3A> were carried out in this order to obtain the title compound.

[0778] Example 38C: 3-[(7aS)-9-{[(4S)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-1(13H)-yl]piperidine-2,6-dione

[0779] The title compound was obtained by using the compound obtained in <Example 38B> and the compound obtained in <Example 19E> and carrying out the same operations as in <Example 19F> and <Example 19G> in this order.

[0780] Example 39A: 3-(2-oxo-4,5,9,10-tetrahydrospiro[azepino[1,2,3-de]imidazo[4,5,1-ij]quinoxaline-8,4'-piperidine]-1(2H)-yl)piperidine-2,6-dione

[0781] Trifluoroacetic acid (0.8 mL) was added to a solution of the compound obtained in <Example 17E> (100 mg, 0.156 mmol) in DCM (0.8 mL). After stirring at room temperature for 1.5 hours, the reaction mixture was diluted with toluene and concentrated under reduced pressure. The residue was suspended in ethyl acetate (1.6 mL), and then triethylamine (0.13 mL, 0.94 mmol) and N,N'-dimethylethylenediamine (CAS Registry Number: 110-70-3) (0.050 mL, 0.47 mmol) were added. The mixture was stirred at room temperature for 4.5 hours. After concentrating the reaction mixture under reduced pressure, the residue was washed sequentially with hexane / IPA and acetonitrile and dried at 60 °C under reduced pressure to obtain the title compound (51 mg, 0.12 mmol, 80% yield).

[0782] The structural formulae of the compounds described in the examples are shown below.

[0783] In the table, Ex indicates the reference example number or the example number, and Structure indicates the structural formula.

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813] The physicochemical data of the compounds described in the examples are shown below.

[0814] In the table, Ex indicates the reference example number or the example number, and Data indicates physicochemical data.

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844] Test Example 1: Evaluation of CRBN Binding Activity The binding activity of each compound to CRBN was evaluated using competition with HTRF Thalidomide-Red ligand for CRBN partial proteins. 150 nM His-Avi-3C-hCRBN (318-426, C366S), 80 nM HTRF Thalidomide-Red ligand, 0.8 μg / mL MAb Anti 6His-Eu cryptate, and each test compound (8-point dilution series prepared at a common ratio of 3 starting from a final concentration of 50 μM) were mixed in HTRF PROTAC Binding Buffer 1 and incubated at room temperature for 3 hours. HTRF signals were measured using a plate reader (Biotek Synergy NEO2, Agilent). The ratio for each well was calculated using the following formula:

[0845]

[0846] Subsequently, the T / C for each test compound treatment was calculated using the following formula:

[0847]

[0848] The T / C at each concentration was analyzed using GraphPad Prism9 for Windows 64-bit (GraphPad Software Inc. Version 9.1.0) to determine the concentration of each test compound that inhibits 50% of the binding of HTRF Thalidomide-Red ligand to CRBN (IC 50 The IC value for CRBN of the test compound corresponding to each Example number (Ex) was calculated. 50 The values ​​(unit: μM) are shown in Table 59.

[0849]

[0850] Test Example 2: Evaluation of SF1 Degradation Induction in the Human Adrenocortical Carcinoma Cell Line NCI-H295R. Using the human adrenocortical carcinoma cell line NCI-H295R (ATCC, CRL-2128) as a host, NCI-H295R SF-1-HiBiT cells, in which a HiBiT tag was knocked into the endogenous SF1 locus, were cultured in DMEM / F12 medium (Thermo Fisher Scientific Inc.) containing 2.5% Nu-Serum™ Growth Medium Supplement (Corning) and 1% Corning ITS+ Premix Universal Culture Supplement (Corning) at 37°C in a 5% CO2 incubator. NCI-H295R SF-1-HiBiT cells were seeded at 1 x 104 cells / 50 μL / well in a 384-well plate (Thermo Fisher Scientific Inc.) and cultured for 24 hours in a 37°C, 5% CO2 incubator. DMSO solutions of each test compound were serially diluted with DMSO using a D300e Digital Dispenser (TECAN) and added to a 384-well plate. The plates were then incubated at 37°C in a 5% CO2 incubator for 24 hours. The final DMSO concentration in the medium was adjusted to 0.1% (v / v). The test compounds were added at concentrations ranging from 10,000 nM to 4.6 nM or 1,000 nM to 0.46 nM, with a common ratio of 3. After incubation, the medium was discarded, and 20 μL / well of Nano-Glo® HiBiT Lytic Detection System (Promega, Cat. No. N3040) was added and mixed using a plate mixer. Luminescence signals were then detected using a multimode plate reader (EnVision Xcite, PerkinElmer). The SF1 proteolysis rate was calculated using the following formula: (C) = 1 / (T) ...

[0851]

[0852] The obtained data was analyzed using GraphPad Prism9 (GraphPad Software Inc.) or Genedata Screener (Genedata AG) to determine the concentration that induces 50% degradation of SF1 (DC 50 The SF1 HiBit DC value of the test compound corresponding to each Example number (Ex) was calculated. 50 The values ​​(unit: nM) are shown in Table 60.

[0853] Test Example 3: Evaluation of Growth Inhibitory Effect on NCI-H295R Cells. NCI-H295R cells were cultured in DMEM / F12 medium (Thermo Fisher Scientific, Inc.) containing 2.5% US Charcoal / Dextran Treated FBS (Hyclone) and 1% Corning ITS+ Premix Universal Culture Supplement (Corning). A DMSO solution of each test compound was serially diluted with DMSO using a D300e Digital Dispenser (TECAN) and added to a 384-well plate (Thermo Fisher Scientific Inc.). NCI-H295R cells were seeded into the 384-well plate at 2 x 10 cells / 40 μL / well and cultured at 37°C in a 5% CO2 incubator for 7 days. The final DMSO concentration in the medium was adjusted to 0.1% (v / v), and the test compound concentrations ranged from 10,000 nM to 0.038 nM, with a 4-fold common ratio. On the first day of culture (day 0) and on day 7 of culture (day 7), 10 μL / well of CellTiter-Glo® 2.0 Assay (Promega) was added, and luminescence signals were detected using a multimode plate reader (EnVision, PerkinElmer). The cell proliferation rate was calculated using the following formula based on the luminescence intensity on the day of compound addition (C0), the luminescence intensity of the compound-free group after 7 days of culture (C7), and the luminescence intensity of the compound-added group (T7).

[0854]

[0855] The concentration of each compound that inhibits 50% of the proliferation of NCI-H295R cells (GI50 The cell viability at each concentration and the compound concentration were plotted on a semi-logarithmic scale to calculate the cell viability. 50 The values ​​(unit: nM) are shown in Table 60.

[0856]

[0857] Test Example 4: Evaluation of SF1 target gene expression changes in NCI-H295R. NCI-H295R cells were cultured in DMEM / F12 medium (Thermo Fisher Scientific Inc.) containing 2.5% Nu-Serum™ Growth Medium Supplement (Corning) and 1% Corning ITS+ Premix Universal Culture Supplement (Corning) at 37°C in a 5% CO2 incubator. A DMSO solution of each test compound was serially diluted with DMSO using a D300e Digital Dispenser (TECAN), and the compounds were added to a 96-well plate (FALCON). NCI-H295R cells were seeded into the 96-well plate containing the test compound at a concentration of 1 x 104 cells / 50 μL / well and cultured at 37°C in a 5% CO2 incubator for 24 hours. The final DMSO concentration in the medium was adjusted to 0.1% (v / v), and the test compound concentrations ranged from 1000 nM to 0.32 nM, with a 5x common ratio. After incubation, the medium was discarded, and 50 μL / well of chilled D-PBS (Sigma-Aldrich) was added to wash the cells. The D-PBS was then discarded. After washing, 25 μL / well of Cells-to-CT™ Bulk Lysis Reagents (Thermo Fisher Scientific, Inc.) was added to the washed wells and mixed for 5 minutes on a plate mixer. 2.5 μL / well of stop solution was added to prepare cell lysates. The cell lysate was dispensed into a 96-well plate (Corning) at 10 μL / well, and Cells-to-CT Bulk RT Reagents (Thermo Fisher Scientific, Inc.) was added at 40 μL / well. The reverse transcription reaction was then carried out at 37°C for 50 minutes using a thermal cycler. The reverse transcriptase was inactivated by heating at 95°C for 5 minutes, and the plate was then stored at 10°C.PrimerProbe mix was prepared by mixing PrimeTime® Gene Expression Master Mix (Integrated DNA Technologies), PrimeTime™ qPCR Probe Assays (Integrated DNA Technologies) for the target genes CYP11A1, CYP17A1, CYP21A2, and STAR, and the control gene ACTB (Integrated DNA Technologies), and nuclease-free water in a ratio of 20:1:1:10. The PrimerProbe mix was added to a 384-well plate at 8 μL / well, and 2 μL / well of the cDNA obtained by reverse transcription was added. Real-time PCR was performed under fast cycling conditions (95°C for 3 minutes, followed by 40 cycles of 95°C for 5 seconds and 62°C for 30 seconds), and the fluorescent signal was measured. The resulting data were analyzed using GraphPad Prism 9 (GraphPad Software Inc.) to determine the concentration required for a 50% reduction in mRNA expression (IC). 50 The IC values ​​for CYP11A1, CYP17A1, CYP21A2, and STAR of the test compounds corresponding to each Example number (Ex) were calculated. 50 The values ​​(unit: nM) are shown in Table 61.

[0858] <Test Example 5> Evaluation of antitumor activity in a subcutaneously transplanted NCI-H295R cell model (adrenal cortical carcinoma) NCI-H295R cells were subcutaneously transplanted into the right flank of female NSG mice at a ratio of 1.0 to 2.0 × 107 cells / head. 3Once the mice reach this age, they are divided into groups of 4 to 5 mice each to ensure there are no differences between groups. Female NSG mice are purchased from Charles River Japan. Starting on the day of grouping, each test compound is orally administered at a dose of 30 mg / kg / day once daily for 10 to 11 days (QD x 10 to 11). Individual estimated tumor volume is measured from the day of grouping until 11 to 12 days after implantation (the end of the study). The vehicle-control group receives 0.5% methylcellulose containing 6.2-6.4 mM mesylate.

[0859] The antitumor activity against the NCI-H295R cell subcutaneous transplant model in Test Example 5 was calculated using the following formula on the final day of each test. The tumor growth inhibition rate R (unit: %) of the test compound corresponding to each Example number (Ex) is shown in Table 61.

[0860]

[0861]

[0862] Test Example 6: Evaluation of ALK proteolytic activity. NCI-H2228ALK HiBiT-C cells, which stably express a construct with a HiBiT tag attached to the C-terminus of the EML4-ALK fusion gene, were prepared using the human ALK-positive lung cancer cell line NCI-H2228 (ATCC, CRL-5935) as a host. They were cultured in RPMI-1640 medium (Thermo Fisher Scientific Inc.) containing 10% fetal bovine serum in a 5% CO2 incubator set at 37°C. 1 x 10 NCI-H2228-HiBiT cells were cultured in RPMI-1640 medium (Thermo Fisher Scientific Inc.) containing 10% fetal bovine serum in a 5% CO2 incubator set at 37°C. 4Cells were seeded into a 384-well plate (Thermo Fisher Scientific Inc.) at 50 μL / well and cultured for 24 hours in a 5% CO2 incubator at 37°C. DMSO solutions of each test compound were serially diluted with DMSO using a D300e Digital Dispenser (TECAN). The DMSO solution was added to the 384-well plate and cultured for 24 hours in a 5% CO2 incubator at 37°C. The final DMSO concentration in the culture medium was adjusted to 0.1% (v / v). Test compound concentrations ranged from 10,000 nM to 4.6 nM or 1,000 nM to 0.46 nM, with a common ratio of 3. After incubation, the medium was discarded, and 20 μL / well of Nano-Glo® HiBiT Lytic Detection System (Promega, Cat. No. N3040) was added and the plate was mixed using a plate mixer. Luminescence signals were then detected using a multimode plate reader (EnVision Xcite, PerkinElmer). The ALK protein degradation rate was calculated from the luminescence intensity (C) of the test compound-free group and the luminescence intensity (T) of the test compound-added group according to the following formula.

[0863]

[0864] The obtained data were analyzed using GraphPad Prism9 (GraphPad Software Inc.) or Genedata Screener (Genedata AG) to determine the concentration that induces 50% degradation of ALK (DC 50 The ALK HiBit DC values ​​of the test compounds corresponding to each Example number (Ex) were calculated. 50 The values ​​(unit: nM) are shown in Table 62.

[0865]

[0866] Test Example 7: Evaluation of ER proteolytic activity Human breast cancer cell line MCF7 (ATCC, HTB-22) was cultured at 1 x 10 cells per well in a 12-well plate using EMEM medium (Thermo Fisher Scientific Inc.) containing 0.01 mg / mL insulin (Merck KGaA) and 10% fetal bovine serum (GE Healthcare). 5Cells were seeded at 1 mL per well and cultured in a 5% CO2 incubator at 37°C. The day after seeding, serial dilutions of each test compound in DMSO were made using a D300e Digital Dispenser (TECAN). The dilutions were added to a 12-well plate and cultured for 24 hours in a CO2 incubator at 37°C. The final DMSO concentration in the culture medium was adjusted to 0.01% (v / v). The test compounds were cultured at a concentration range of 1000 nM to 0.15 nM, with a common ratio of 3. After incubation, the medium was discarded and washed once with PBS (Wako Chemicals). The cells were lysed in RIPA buffer (Thermo Fisher Scientific Inc.) containing 1% Halt Protease and Phosphatase Inhibitor Cocktail (Thermo Fisher Scientific Inc.), sonicated, and centrifuged to recover the supernatant. The protein concentration in the supernatant was measured using a BCA Protein Assay Kit (Thermo Fisher Scientific). The supernatant was then mixed with Laemmli SDS sample buffer, non-reducing (ALFA), and NuPAGE Sample Reducing Agent (Thermo Fisher Scientific Inc.) and heated at 95°C for 5 minutes to prepare a sample. The resulting sample was subjected to SDS-PAGE and Western blotting. Primary antibodies used were estrogen receptor α (D8H8) Rabbit mAb (Cell Signaling Technology, Inc.) and vinculin (E1E9V)XP Rabbit mAb (Cell Signaling Technology, Inc.), and the secondary antibody was an HRP-linked anti-rabbit IgG antibody (Cell Signaling Technology, Inc.).The luminescence signal obtained using Luminata Forte Western HRP Substrate (Millipore) was detected and visualized using Amersham ImageQuant800 (Cytiva) to obtain data (Figure 1).

[0867] The compound of the present invention or a pharmaceutically acceptable salt thereof has excellent CRBN-binding activity and target protein-binding activity. Therefore, the present invention can provide a therapeutic agent for diseases associated with each target protein, specifically, diseases in which the onset or progression of a target protein (particularly SF-1, ALK, or ER) is involved (e.g., castration-resistant prostate cancer, adrenocortical carcinoma, Leydig tumor, hormone-sensitive prostate cancer, breast cancer, Cushing's syndrome, primary aldosteronism, etc.).

[0868] This application is based on Japanese Patent Application No. 2024-146016 filed on August 27, 2024 in Japan, the contents of which are incorporated in their entirety herein.

Claims

1. The following formula (I): wherein T is a target protein binding motif, L is a linker, and E is a group represented by the following formula (II): (In formula (II), * represents a bonding position with L at any bondable site in the chemical formula in [ ], and X represents CH ２ or C(=O), and Y is N(R ３ ) or CH(R ３ ) and Z is CH ２ or C(=O), and R １ , R ２ , and R ３ are each independently a hydrogen atom, or R １ and R ２ are bonded to each other and together with the carbon atoms to which they are attached form a 4- to 7-membered aliphatic heterocycle containing one nitrogen atom as a ring-constituting atom and which may be substituted with one substituent, or a 4- to 7-membered aliphatic ring which may be substituted with one substituent, and R ３ is a hydrogen atom, or R １ and R ３ are bonded to each other to form R １ and the carbon atom to which R ３ is bonded together with the atom to which it is bonded to form a 4- to 7-membered aliphatic heterocycle which contains one or two nitrogen atoms as ring-constituting atoms and which may be substituted with one substituent, or a 4- to 7-membered aliphatic ring which may be substituted with one substituent, and R ２ is a hydrogen atom), or a salt thereof.

2. E is represented by the following formula (III): (In formula (III), X １ is CH ２ or C(=O), and Y １ is N or CH, Z １ is CH ２ or C(=O), n １ and n ２ are each independently 1 or 2; １ 2. The compound or salt thereof according to claim 1, wherein -* is N-*, CH-O-*, or CH-C(=O)-*, and * is the bonding position to L.

3. E is represented by the following formula (IV): (In formula (IV), X ２ is CH ２ or C(=O), and Y ２ is NH or CH ２ and Z ２ is CH ２ or C(=O), n ３ and n ４ are each independently an integer of 1 to 3, and n ３ +n ４ is an integer from 2 to 5, and W ２ 2. The compound or salt thereof according to claim 1, wherein -* is N-*, CH-O-*, or CH-C(=O)-*, and * is the bonding position to L.

4. The compound or salt thereof according to any one of claims 1 to 3, wherein the target protein is steroidogenic factor-1 (SF-1), anaplastic lymphoma kinase (ALK), or estrogen receptor (ER).

5. T is of the formula: (In the formula, the wavy line indicates the bonding position with L, and in formula (VIII), A is —O— or —CF ２ - and R Ｔ１ is a halogen, —O—C optionally substituted with 1 to 3 halogens １－６ Alkyl, —N(H)—C １－３ Alkyl, —N(C １－３ alkyl) ２ or a 4- to 6-membered heterocycloalkyl containing one nitrogen atom as a ring atom, R Ｔ２ and R Ｔ３ are each independently a hydrogen atom or C １－６ alkyl, R Ｔ４ is C optionally substituted with 1 to 3 halogen atoms. １－６ alkyl, —C(═O)—C optionally substituted with 1 to 3 halogens; １－６ alkyl, C optionally substituted with one trifluoromethyl ３－６ cycloalkylmethyl, or a 6-membered heteroaryl containing one or two nitrogen atoms as ring-constituting atoms (the heteroaryl may be substituted with one halogen atom), and ring Q Ｔ１ is halogen and C １－３ a benzene ring which may have one or two substituents independently selected from the group consisting of alkyl; a 6- to 12-membered monocyclic or bicyclic aromatic heterocycle containing one or two nitrogen atoms as ring-constituting atoms; C ４－７ Cycloalkane ring, or C ４－７ is a cycloalkene ring, Ｔ１ represents a single bond, —O—, —CH ２ - or -C(=O)-, and ring Q Ｔ２ represents a benzene ring optionally substituted with one halogen atom, C ４－７ a cycloalkane ring, a C optionally substituted with one halogen atom; ４－７ 5. The compound or salt thereof according to claim 1, wherein R is a cycloalkene ring, a piperidine ring, or a 7-azaspiro[3.5]nonane ring.

6. L has the formula: (In the formula, n ５ is an integer from 1 to 6, and n ６ is an integer of 0 to 6, the wavy line is a bonding position to T, and * is a bonding position to E).

7. L is: The compound or salt thereof according to any one of claims 1 to 6, wherein the compound is a group selected from the group consisting of: (wherein, the wavy line indicates the bonding position to T, and * indicates the bonding position to E).

8. E is a compound represented by the following formula (III): (In formula (III), X １ is CH ２ or C(=O), and Y １ is N or CH, Z １ is CH ２ or C(=O), n １ and n ２ are each independently 1 or 2; １ -* is N-*, CH-O-*, or CH-C(=O)-*, and * is the bonding position to L), and T is a group represented by the following formula (VIII): (In formula (VIII), A is —O— or —CF ２ - and R Ｔ１ is a halogen, —O—C optionally substituted with 1 to 3 halogens １－６ Alkyl, —N(H)—C １－３ Alkyl, —N(C １－３ alkyl) ２ or a 4- to 6-membered heterocycloalkyl containing one nitrogen atom as a ring atom, R Ｔ２ and R Ｔ３ are each independently a hydrogen atom or C １－６ alkyl, R Ｔ４ is C optionally substituted with 1 to 3 halogen atoms. １－６ alkyl, —C(═O)—C optionally substituted with 1 to 3 halogens; １－６ alkyl, C optionally substituted with one trifluoromethyl ３－６ cycloalkylmethyl, or a 6-membered heteroaryl containing one or two nitrogen atoms as ring-constituting atoms (the heteroaryl may be substituted with one halogen atom), and ring Q Ｔ１ is halogen and C １－３ a benzene ring which may have one or two substituents independently selected from the group consisting of alkyl; a 6- to 12-membered monocyclic or bicyclic aromatic heterocycle containing one or two nitrogen atoms as ring-constituting atoms; C ４－７ Cycloalkane ring, or C ４－７ is a cycloalkene ring, Ｔ１ represents a single bond, —O—, —CH ２ - or -C(=O)-, and ring Q Ｔ２ represents a benzene ring optionally substituted with one halogen atom, C ４－７ a cycloalkane ring, a C optionally substituted with one halogen atom; ４－７ a cycloalkene ring, a piperidine ring, or a 7-azaspiro[3.5]nonane ring, and the wavy line indicates the bonding position to L), (In the formula, n ５ is an integer from 1 to 6, and n ６ is an integer of 0 to 6, the wavy line is the bonding position to T, and * is the bonding position to E), or a salt thereof according to claim 1 .

9. E is a compound represented by the following formula (III): (In formula (III), X １ is CH ２ and Y １ is N and Z １ is CH ２ or C(=O), n １ is 1, and n ２ is 2, and W １ -* is N-*, and * is the bonding position to L), and T is a group represented by the following formula (VIII): (In formula (VIII), A is —O—, and R Ｔ１ is -O-CH ３ , or —O—CF ３ and R Ｔ２ is methyl, R Ｔ３ is methyl, R Ｔ４ is C optionally substituted with 1 to 3 halogen atoms. １－６ is alkyl, and ring Q Ｔ１ is a benzene ring optionally substituted with one halogen atom, Ｔ１ is a single bond, and ring Q Ｔ２ is C optionally substituted with one halogen ４－７ is a cycloalkene ring, and the wavy line indicates the bonding position to L), and L is a group represented by the following formula: The compound or salt thereof according to claim 1, which is a group represented by the following formula: (wherein the wavy line indicates the bonding position to T, and * indicates the bonding position to E).

10. (7aR)-1-(2,6-dioxopiperidin-3-yl)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione, (7aS)-1-(2,6-dioxopiperidin-3-yl)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione, 3-[(7aS)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-1(13H)-yl]piperidine-2,6-dione, and 3-[(7aR)-9-{[(4R)-4'-{[{2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl}(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl}-2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl}-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-1(13H)-yl]piperidine-2,6-dione or a salt thereof.

11. A medicine containing the compound or salt thereof according to any one of claims 1 to 10 as an active ingredient.

12. The pharmaceutical composition according to claim 11, for treating castration-resistant prostate cancer, adrenocortical carcinoma, Leydig tumor, hormone-sensitive prostate cancer, breast cancer, Cushing's syndrome, or primary aldosteronism.

13. A method for treating castration-resistant prostate cancer, adrenocortical carcinoma, Leydig tumor, hormone-sensitive prostate cancer, breast cancer, Cushing's syndrome, or primary aldosteronism in a subject, comprising administering to the subject an effective amount of a compound or salt thereof according to any one of claims 1 to 10.

14. A compound or salt thereof according to any one of claims 1 to 10 for use in the treatment of castration-resistant prostate cancer, adrenocortical carcinoma, Leydig tumor, hormone-sensitive prostate cancer, breast cancer, Cushing's syndrome, or primary aldosteronism.

15. Use of a compound or salt thereof according to any one of claims 1 to 10 in the manufacture of a medicament for treating castration-resistant prostate cancer, adrenocortical carcinoma, Leydig tumor, hormone-sensitive prostate cancer, breast cancer, Cushing's syndrome or primary aldosteronism.

16. The following formula (V): (In formula (V), X is CH ２ or C(=O), and Y is N(R ３ ) or CH(R ３ ) and Z is CH ２ or C(=O), and R １ , R ２ , and R ３ are each independently a hydrogen atom, or R １ and R ２ are bonded to each other and together with the carbon atoms to which they are attached contain one nitrogen atom as a ring member and one hydroxy group, carboxy group, or C １－６ a 4- to 7-membered aliphatic heterocycle optionally substituted with an alkyl group, or one hydroxy group, carboxy group, or C １－６ form a 4- to 7-membered aliphatic ring optionally substituted with an alkyl group, and R ３ is a hydrogen atom, or R １ and R ３ are bonded to each other to form R １ and the carbon atom to which R ３ and a ring structure including, together with the atom to which it is attached, one or two nitrogen atoms as ring-constituting atoms, and one hydroxy group, carboxy group, or C １－６ a 4- to 7-membered aliphatic heterocycle optionally substituted with an alkyl group, or one hydroxy group, carboxy group, or C １－６ form a 4- to 7-membered aliphatic ring optionally substituted with an alkyl group, and R ２ is a hydrogen atom) or a salt thereof.

17. A compound of the following formula (VI): (In formula (VI), X １ is CH ２ or C(=O), and Y １ is N or CH, Z １ is CH ２ or C(=O), n １ and n ２ are each independently 1 or 2, and W ３ is NH, CH—OH, or CH—CO ２ 17. The compound or salt thereof according to claim 16, wherein:

18. X １ is CH ２ and Y １ is N and Z １ is CH ２ or C(=O), n １ is 1, and n ２ is 2, and W ３ The compound or salt thereof according to claim 17, wherein is NH.

19. The following formula (VII): (In formula (VII), X ２ is CH ２ or C(=O), and Y ２ is NH or CH ２ and Z ２ is CH ２ or C(=O), n ３ and n ４ are each independently an integer of 1 to 3, and n ３ +n ４ is an integer from 2 to 5, and W ４ is NH, CH—OH, or CH—CO ２ 17. The compound or salt thereof according to claim 16, wherein:

20. X ２ is CH ２ and Y ２ is NH or CH ２ and Z ２ is CH ２ or C(=O), n ３ is an integer from 1 to 2, and n ４ is an integer from 1 to 2, and W ４ The compound or salt thereof according to claim 19, wherein is NH.

21. (7aS)-1-(2,6-dioxopiperidin-3-yl)-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione, (7aR)-1-(2,6-dioxopiperidin-3-yl)-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxaline-2,13(1H)-dione, 3-[(7aS)-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxalin-1(13H)-yl]piperidine-2,6-dione, and 3-[(7aR)-2-oxo-4,5,7,7a,8,9,10,11-octahydro-2H-imidazo[1,5,4-de]pyrazino[2',1':3,4][1,4]diazepino[6,7,1-ij]quinoxalin-1(13H)-yl]piperidine-2,6-dione, or a salt thereof.

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