Compounds with anticancer activity

Abstract

To provide a compound having anticancer activity, or a pharmaceutically acceptable salt thereof.SOLUTION: The present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof (wherein, L1 and L2 are the same or different to represent a group represented by the formula (A)-2, and S represents a group represented by the formula (S1)-1).SELECTED DRAWING: None

Description

REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority from Japanese Patent Application No. 2018-68816, filed on March 30, 2018, the entire disclosure of which is incorporated herein by reference. [Technical Field]

[0002] The present invention relates to a compound having anticancer activity or a pharmaceutically acceptable salt thereof, etc. [Background technology]

[0003] In humans, 46 bromodomain proteins that recognize acetylated lysines on histone proteins are known. One of these is the BET (bromodomain and extra-terminal domain) family, which recognizes acetyl-lysines on histones H3 and H4. The BET family includes BRD (bromodomain-containing protein) 2, BRD3, BRD4, and BRDT (bromodomain testis-specific protein). BET family proteins contain two bromodomains (BD1 and BD2) at their N-termini, and their sequences are highly conserved within the family. Furthermore, BET proteins have been reported to be involved in cancer proliferation [see Non-Patent Documents 1 and 2] and the progression of inflammation [see Non-Patent Document 3].

[0004] BRD4 recruits P-TEBb onto mitotic chromosomes, thereby enhancing the expression of proliferation-promoting genes. In NUT-midline carcinoma (NMC), the BRD4-NUT fusion protein has been shown to increase c-MYC protein expression [see Non-Patent Document 4]. It has also been reported that, among the genes whose expression is reduced by treatment with the BET inhibitor JQ-1 in human multiple myeloma-derived MM1.S cells, the degree of reduction in MYC gene expression is the most significant [see Non-Patent Document 5].

[0005] Clinical trials of representative BET inhibitors, such as RVX-208 / Apabetalone [see Non-Patent Document 6], I-BET762 / GSK-525762A [see Non-Patent Document 7], OTX-015 / MK8628 [see Non-Patent Document 8], CPI-0610 [see Non-Patent Document 9], TEN-010 [see Non-Patent Document 10], and ABBV-075 [see Non-Patent Document 11], are currently underway. Of these drugs, all except RVX-208 are being developed as cancer therapeutic agents.

[0006] In recent years, bivalent BET inhibitors have also been reported that exhibit stronger BET inhibitory activity by simultaneously inhibiting the BD1 and BD2 domains (see Non-Patent Document 12). Known examples of such bivalent BET inhibitors include compounds represented by the following formulae (P1) to (P5) (see Non-Patent Document 12, Patent Documents 1, 2, and 3). [ka] [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2013 / 033268 Brochure [Patent Document 2] International Publication No. 2015 / 081284 Brochure [Patent Document 3] International Publication No. 2017 / 091673 Brochure [Non-patent literature]

[0008] [Non-Patent Document 1] Nature, 2011, Vol. 478, pp. 524-528 [Non-patent document 2] Cell, 2011, Vol. 146, pp. 904-917 [Non-patent document 3] Nature, 2010, Vol. 468, pp. 1119-1123 [Non-patent document 4] Cancer Res., 2003, Vol. 63, pp. 304-307 [Non-patent document 5] Cell, 2013, Vol. 153, pp. 320-334 [Non-patent document 6] Proceedings of the National Academy of Sciences (Proc. Natl. Acad. Sci.), 2013, Vol. 110, pp. 19754-19759 [Non-Patent Document 7] J. Med. Chem., 2013, Vol. 56, pp. 7501-7515. [Non-patent document 8] Oncotarget, 2015, Vol. 6, pp. 17698-17712. [Non-Patent Document 9] Blood, 2015, Vol. 126, pp. 4255-4255 [Non-Patent Document 10] Molecular Cancer Therapeutics (Mol. Cancer Ther.), 2015, Vol. 14, A49 [Non-Patent Document 11] Cancer Res., 2016, Vol. 76, pp. 4718-4718. [Non-Patent Document 12] Nature Chemical Biology (Nat. Chem. Bio.), 2016, Vol. 112, pp. 1089-1096 Summary of the Invention

[0009] The present invention provides a compound having anticancer activity or a pharmaceutically acceptable salt thereof, and the like.

[0010] Recently, bivalent BET inhibitors have been reported that simultaneously inhibit the BD1 and BD2 domains, demonstrating stronger BET inhibitory activity than conventional BET inhibitors. However, their pharmacological activity remains insufficient, and compounds with stronger pharmacological effects are still needed.

[0011] In the present invention, two BET inhibitors serving as ligands are linked at specific binding positions via a spacer having a specific structure, thereby discovering a compound or a pharmaceutically acceptable salt thereof that has a strong BET inhibitory effect.

[0012] The present invention relates to the following (1) to (56). (1) A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, L 1 and L 2 are the same or different and represent a group represented by a formula selected from the group consisting of the following formulae (A) to (F), and S represents a group represented by a formula selected from the group consisting of the following formulae (S1) to (S18): [ka] R A1 , R A2 and R A3 are the same or different and each represents a hydrogen atom or a lower alkyl, R A5 represents a hydrogen atom, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted tetrahydropyridinyl, optionally substituted dihydro-1H-pyrrolyl or optionally substituted tetrahydro-1H-azepinyl, ring RA represents benzenediyl, cycloalkanediyl, pyridinediyl, piperidinediyl, azetidinediyl, pyrrolidinediyl or homopiperidinediyl; n 1Arepresents 0 or 1, R B1 represents a hydrogen atom, an optionally substituted lower alkoxycarbonylmethyl, an optionally substituted cycloalkyloxycarbonylmethyl, or -CHCONR B5 R B6 (In the formula, R B5 and R B6 are the same or different and each represent a hydrogen atom or an optionally substituted lower alkyl, or together with the adjacent nitrogen atom represent an optionally substituted nitrogen-containing aliphatic heterocyclic group, R B2 represents an optionally substituted lower alkyl, R B3 and R B4 are the same or different and each represents a halogen atom or an optionally substituted lower alkyl group, R C1 represents a hydrogen atom, a lower alkyl group, or a lower alkanoyl group; R C3 represents a hydrogen atom or hydroxy; The ring RC represents benzenediyl, piperidinediyl, azetidinediyl, pyrrolidinediyl, or homopiperidinediyl; R D1 represents an optionally substituted lower alkyl or an optionally substituted lower alkoxycarbonyl, R E1 and R F1 is R A1 is synonymous with R E2 and R F2 is R A2 is synonymous with R E3 and R F3 is R A3 is synonymous with R E5 and R F5 is R A5 is synonymous with, and R F7 represents a hydrogen atom or a halogen), [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with n 1a and n 1b are the same or different and each represents 0 or 1, X 1a and X 1b are the same or different and represent -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH-, R 1a and R 1b is R 1a represents a hydrogen atom, and R 1b represents a hydrogen atom or a lower alkyl, or R 1a and R 1b together represent a carbonyl, X 2a represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH- or -NH-SO2-; X 2b represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2- or -CH2-; Z 2 represents CH or N, n 3a and n 3b are the same or different and represent 1 or 2, X 3 represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -NH-C(=O)-NH- or -NH-CH2-; Z 3 represents CH or N, X 5a and X 5b are the same or different and represent -C(=O)-NH-, -NH-C(=O)-, -SO2-NH- or -NH-SO2-, n6 represents 1 or 2, Ar 6 represents triazolediyl, oxadiazolediyl, pyrazolediyl, thiophenediyl or tetrahydropyridinediyl, X 6 represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -CH2-NH-, -NH-CH2- or -NH-C(=O)-NH-; X 7 represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH- or -NH-C(=O)-NH-; n 7 represents 1, 2 or 3, Z 7 represents S, SO, or SO2 X 8a represents -C(=O)-, -CH2- or -NH-C(=O)-; X 8b represents a bond, -C(=O)-, -CH2- or -CH(OH)-; Ar 9 represents triazolediyl or oxazolediyl, Z 9 represents CH2 or NH, Z 10 represents O or NH, X 11a represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2- or -NH-C(=O)-NH-; X 11b represents -C(=O)-NH-, -NH-C(=O)- or -C(=O)-; X 12 represents -C(=O)-NH-, -NH-C(=O)-, SO2-NH-, -NH-SO2- or -NH-C(=O)-NH-; Z 12a represents CH2 or NH, Z 12b represents CH2 or O, Z 12c represents a bond, CH2 or O, n 13 represents 0, 1 or 2, n 16 represents 1 or 2, Z 16 represents a bond, CH2 or O, X 16 represents -CH2-O-, -C(=O)-NH-, -NH-C(=O)- or -NH-C(=O)-NH-, Ar 16 represents triazolediyl, oxadiazoldiyl or pyrazolediyl, n 17 represents 1 or 2, X 17 represents -C(=O)-NH-, -NH-C(=O)-, -NH-SO2- or -NH-C(=O)-NH-, and n 18a , n 18b and n 18c are the same or different and represent 1 or 2). (2) A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, L 1 and L 2 are the same or different and represent a group represented by a formula selected from the group consisting of the following formulae (A) to (F), and S represents a group represented by a formula selected from the group consisting of the following formulae (S1) to (S18): [ka] (In the formula, the wavy line represents the bonding site with S, R A1 , R A2 and R A3 are the same or different and each represents a hydrogen atom or a lower alkyl, R A5represents a hydrogen atom, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted tetrahydropyridinyl, optionally substituted dihydro-1H-pyrrolyl or optionally substituted tetrahydro-1H-azepinyl, ring RA represents benzenediyl, cycloalkanediyl, pyridinediyl, piperidinediyl, azetidinediyl, pyrrolidinediyl or homopiperidinediyl; n 1A represents 0 or 1, R B1 represents a hydrogen atom, an optionally substituted lower alkoxycarbonylmethyl, an optionally substituted cycloalkyloxycarbonylmethyl, or -CHCONR B5 R B6 (In the formula, R B5 and R B6 are the same or different and each represent a hydrogen atom or an optionally substituted lower alkyl, or together with the adjacent nitrogen atom represent an optionally substituted nitrogen-containing aliphatic heterocyclic group, R B2 represents an optionally substituted lower alkyl, R B3 and R B4 are the same or different and each represents a halogen atom or an optionally substituted lower alkyl group, R C1 represents a hydrogen atom, a lower alkyl group, or a lower alkanoyl group; R C3 represents a hydrogen atom or hydroxy; The ring RC represents benzenediyl, piperidinediyl, azetidinediyl, pyrrolidinediyl, or homopiperidinediyl; R D1 represents an optionally substituted lower alkyl or an optionally substituted lower alkoxycarbonyl, R E1 and R F1 is R A1 is synonymous with R E2 and RF2 is R A2 is synonymous with R E3 and R F3 is R A3 is synonymous with R E5 and R F5 is R A5 is synonymous with, and R F7 represents a hydrogen atom or a halogen), [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with n 1a and n 1b are the same or different and each represents 0 or 1, X 1a and X 1b are the same or different and represent -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH- (provided that (i) X 1a is -NH-SO2- and X 1b is -SO2-NH-, (ii) n 1a and n 1b is 0 and X 1a is -C(=O)-NH-, -SO2-NH-, -OC(=S)-NH-, -OC(=O)-NH- or -NH-C(=O)-NH-, and X 1b is -NH-C(=O)-, -NH-SO2-, -NH-C(=O)-O- or -NH-C(=O)-NH-; and (iii) X 1a is -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH-, and X 1b is -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH-), R 1a and R 1b is R 1a represents a hydrogen atom, and R 1b represents a hydrogen atom or a lower alkyl, or R 1a and R 1b together represent a carbonyl, X 2a represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH- or -NH-SO2-; X 2b represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2- or -CH2- (provided that X 2a is -NH-SO2- and X 2b (except when -SO2-NH-) Z 2 represents CH or N (provided that (i) Z 2 is N and X 2b is -NH-C(=O)-, -SO2-NH-, or -NH-SO2-, and (ii) Z 2 is CH and X 2b is -CH2-), n 3a and n 3b are the same or different and represent 1 or 2, X 3 represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -NH-C(=O)-NH- or -NH-CH2-; Z 3 represents CH or N (provided that (i) Z 3 is N and X 3 is -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -NH-C(=O)-NH- or -NH-CH2-, and (ii) Z 3 is N, and n 3a or n 3b except when is 1), X 5a and X 5bare the same or different and represent -C(=O)-NH-, -NH-C(=O)-, -SO2-NH- or -NH-SO2- (provided that X 5a is -NH-SO2- and X 5b (except when -SO2-NH-) n 6 represents 1 or 2, Ar 6 represents triazolediyl, oxadiazolediyl, pyrazolediyl, thiophenediyl or tetrahydropyridinediyl, X 6 represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -CH2-NH- or -NH-C(=O)-NH- (provided that (i) Ar 6 is oxadiazolediyl, pyrazolediyl, thiophenediyl or tetrahydropyridinediyl, and X 6 is -NH-SO2-, and (ii) n 6 is 1 and Ar 6 is pyrazolediyl or tetrahydropyridinediyl, and X 6 is -C(=O)-NH-, -SO2-NH-, -CH2-NH- or -NH-C(=O)-NH-), X 7 represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH- or -NH-C(=O)-NH-; n 7 represents 1, 2 or 3, Z 7 represents S, SO, or SO2 X 8a represents -C(=O)-, -CH2- or -NH-C(=O)-; X 8b represents a bond, -C(=O)-, -CH2- or -CH(OH)-; Ar 9 represents triazolediyl or oxazolediyl, Z 9 represents CH2 or NH (provided that (i) Ar 9is triazolediyl, and Z 9 is NH, and (ii) Ar 9 is oxazoldiyl, and Z 9 except when CH2), Z 10 represents O or NH, X 11a represents -C(=O)-NH-, -SO2-NH- or -NH-C(=O)-NH-; X 11b represents -C(=O)-NH- or -C(=O)-; X 12 represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH- or -NH-C(=O)-NH-; Z 12a represents CH2 or NH (where X 12 is -C(=O)-NH-, -SO2-NH- or -NH-C(=O)-NH-, and Z 12a (except when is NH), Z 12b represents CH2 or O (where Z 12a is NH and Z 12b except when is O), Z 12c represents a bond, CH2, or O (provided that (i) Z 12b is O and Z 12c is O, and (ii) Z 12a is NH and Z 12c is CH2 or O), n 13 represents 0, 1 or 2, n 16 represents 1 or 2, Z 16 represents a bond, CH2 or O, X 16 represents -CH2-O-, -C(=O)-NH-, -NH-C(=O)- or -NH-C(=O)-NH- (provided that Z 16 is O and X 16 is -NH-C(=O)- or -NH-C(=O)-NH-), Ar16 represents triazolediyl, oxadiazolediyl, or pyrazolediyl, provided that (i) X 16 is -CH2-O-, and Ar 16 is oxadiazolediyl or pyrazolediyl, and (ii) n 16 is 1 and X 16 is -C(=O)-NH- or -NH-C(=O)-NH-, and Ar 16 is pyrazoldiyl), n 17 represents 1 or 2, X 17 represents -C(=O)-NH-, -NH-C(=O)-, -NH-SO2- or -NH-C(=O)-NH-, and n 18a , n 18b and n 18c are the same or different and represent 1 or 2). (3) L 1 represents a group represented by formula (A), (B), (C), (D) or (F), and L 2 represents a group represented by formula (A), (B), (C) or (D), and S represents a group represented by formula (S1), or a pharmaceutically acceptable salt thereof. (4) L 1 represents a group represented by formula (A), and L 2 represents a group represented by formula (A), and S represents a group represented by formula (S2), or a pharmaceutically acceptable salt thereof. (5) L 1 represents a group represented by formula (A), (B) or (C), and L 2 represents a group represented by formula (A) or (B), and S represents a group represented by formula (S3), or a pharmaceutically acceptable salt thereof. (6) L 1 represents a group represented by formula (A), and L 2 represents a group represented by formula (A), and S is a group represented by formula (S4) or (S5), or a pharmaceutically acceptable salt thereof. (7) L 1 represents a group represented by formula (A), (B), (C) or (D), and L 2 represents a group represented by formula (A), (B) or (D), and S represents a group represented by formula (S6), or a pharmaceutically acceptable salt thereof. (8) L 1 represents a group represented by formula (A) or (B), and L 2 represents a group represented by formula (A), and S represents a group represented by formula (S7), or a pharmaceutically acceptable salt thereof. (9) L 1 represents a group represented by formula (A) or (B), and L 2 represents a group represented by formula (A), and S is a group represented by formula (S8), or a pharmaceutically acceptable salt thereof. (10) L 1 represents a group represented by formula (A), and L 2 represents a group represented by formula (A), and S is a group represented by formula (S9), or a pharmaceutically acceptable salt thereof. (11) L 1 represents a group represented by formula (A) or (B), and L 2 represents a group represented by formula (A), and S represents a group represented by formula (S10), or a pharmaceutically acceptable salt thereof. (12) L 1 represents a group represented by formula (A) or (B), and L 2 represents a group represented by formula (A) or (B), and S represents a group represented by formula (S11), or a pharmaceutically acceptable salt thereof. (13) L 1 represents a group represented by formula (A), and L 2 represents a group represented by formula (A), and S represents a group represented by formula (S12), (S13), (S14) or (S15), or a pharmaceutically acceptable salt thereof. (14) L 1represents a group represented by formula (E), and L 2 represents a group represented by formula (A), and S represents a group represented by formula (S16), (S17) or (S18), or a pharmaceutically acceptable salt thereof. (15) The compound according to any one of (1) to (14), wherein the formula (A) is the following formula (A)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line represents the binding site with S. R A1-1 represents a hydrogen atom, R A2-1 and R A3-1 are the same or different and each represent alkyl having 1 to 5 carbon atoms, R A5-1 represents a hydrogen atom, a fluorine atom, an alkyl having 1 to 5 carbon atoms which may have a substituent, an alkenyl having 2 to 6 carbon atoms which may have a substituent, or a tetrahydropyridinyl which may have a substituent, Ring RA-1 represents benzenediyl, cycloalkanediyl, pyridinediyl, or piperidinediyl, and n 1A-1 represents 0 or 1). (16) The compound according to any one of (1) to (3), (5), (7) to (9), (11), and (12), or a pharmaceutically acceptable salt thereof, wherein formula (B) is the following formula (B)-1: [ka] (In the formula, The wavy line represents the binding site with S. R B1-1 represents a hydrogen atom, an alkoxycarbonylmethyl having 1 to 5 carbon atoms which may have a substituent, a cycloalkyloxycarbonylmethyl which may have a substituent, or -CHCONR B5-1 R B6-1 (In the formula, R B5-1 and R B6-1are the same or different and each represent a hydrogen atom, an alkyl having 1 to 5 carbon atoms, or together with the adjacent nitrogen atom represent a nitrogen-containing aliphatic heterocyclic group which may have a substituent; R B2-1 represents an alkyl group having 1 to 5 carbon atoms which may have a substituent, and R B3-1 and R B4-1 represents an alkyl group having 1 to 5 carbon atoms which may have a substituent. (17) The compound according to any one of (1), (2), (3), (5), and (7), wherein formula (C) is the following formula (C)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line represents the binding site with S. R C1-1 represents a hydrogen atom, R C3-1 represents a hydrogen atom or hydroxy, and The ring RC-1 represents benzenediyl or piperidinediyl. (18) The compound according to any one of (1) to (3) and (7), wherein the formula (D) is the following formula (D)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line represents the binding site with S, and R D1-1 represents an alkyl having 1 to 5 carbon atoms which may have a substituent or an alkoxycarbonyl having 1 to 5 carbon atoms which may have a substituent). (19) The compound according to any one of (1), (2) and (14), wherein formula (E) is the following formula (E)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line represents the binding site with S. R E1-1represents a hydrogen atom, R E2-1 and R E3-1 are the same or different and each represent alkyl having 1 to 5 carbon atoms, and R E5-1 represents a hydrogen atom). (20) The compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof, wherein the formula (F) is the following formula (F)-1: [ka] (In the formula, The wavy line represents the binding site with S. R F1-1 represents a hydrogen atom, R F2-1 and R F3-1 are the same or different and each represent alkyl having 1 to 5 carbon atoms, R F5-1 represents a hydrogen atom, and R F7-1 represents a hydrogen atom or a fluorine atom). (21) The compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof, wherein S is the following formula (S1)-1: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with n 1a-1 and n 1b-1 are the same or different and each represents 0 or 1, X 1a-1 and X 1b-1 are the same or different and represent -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH- (provided that (i) X 1a-1 is -NH-SO2- and X 1b-1 is -SO2-NH-, (ii) n 1a-1 and n1b-1 is 0 and X 1a-1 is -C(=O)-NH-, -SO2-NH-, -OC(=S)-NH-, -OC(=O)-NH- or -NH-C(=O)-NH-, and X 1b-1 is -NH-C(=O)-, -NH-SO2-, -NH-C(=O)-O- or -NH-C(=O)-NH-; and (iii) X 1a-1 is -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH-, and X 1b-1 is -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH-), and R 1a-1 and R 1b-1 is R 1a-1 represents a hydrogen atom, and R 1b-1 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or R 1a-1 and R 1b-1 together represent a carbonyl). (22) The compound according to any one of (1), (2), and (4), or a pharmaceutically acceptable salt thereof, wherein S is the following formula (S2)-1: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with X 2a-1 represents -C(=O)-NH- or -NH-C(=O)-; X 2b-1 represents -C(=O)-NH-, -NH-C(=O)- or -CH2-, and Z 2-1 represents CH or N (wherein (i) Z 2-1 is N and X 2b-1 is -NH-C(=O)-, and (ii) Z 2-1 is CH and X 2b-1 (Except when -CH2-) (23) The compound according to any one of (1), (2), and (5), or a pharmaceutically acceptable salt thereof, wherein S is the following formula (S3)-1: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with n 3a-1 and n 3b-1 are the same or different and represent 1 or 2, X 3-1 represents -C(=O)-NH-, -NH-C(=O)-, -NH-C(=O)-NH- or -NH-CH2-, and Z 3-1 represents CH or N (wherein (i) Z 3-1 is N and X 3-1 is -NH-C(=O)-, -NH-C(=O)-NH- or -NH-CH2-, and (ii) Z 3-1 is N, and n 3a-1 or n 3b-1 Except when is 1). (24) The compound according to any one of (1), (2), and (6), or a pharmaceutically acceptable salt thereof, wherein S is the following formula (S5)-1: [ka] (In the formula, The wavy line is L 1 or L 2 represents a binding site for X 5a-1 and X 5b-1 are the same or different and represent -C(=O)-NH-, -NH-C(=O)- or -NH-SO2-). (25) The compound according to any one of (1), (2), and (7), or a pharmaceutically acceptable salt thereof, wherein S is the following formula (S6)-1: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with n 6-1 represents 1 or 2, Ar 6-1 represents triazolediyl, oxadiazoldiyl, pyrazolediyl, thiophenediyl or tetrahydropyridinediyl, and X 6-1 represents -C(=O)-NH-, -NH-C(=O)- or -CH2-NH- (provided that (i)n 6-1 is 1 and Ar 6-1 is pyrazolediyl or tetrahydropyridinediyl, and X 6-1 except when is -C(=O)-NH- or -CH2-NH-). (26) The compound according to any one of (1), (2), and (8), or a pharmaceutically acceptable salt thereof, wherein S is the following formula (S7)-1: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with X 7-1 represents -C(=O)-NH- or -NH-C(=O)-; n 7-1 represents 1, and Z 7-1 represents S, SO, or SO2). (27) The compound according to any one of (1), (2), and (9), or a pharmaceutically acceptable salt thereof, wherein S is the following formula (S8)-1: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with X 8a-1 represents -C(=O)- or -CH2-, and X 8b-1represents a bond, -C(=O)-, -CH2- or -CH(OH)-). (28) The compound according to any one of (1), (2) and (10), wherein S is the following formula (S9)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with Ar 9-1 represents triazolediyl or oxazolediyl, and Z 9-1 represents CH2 or NH (wherein (i) Ar 9-1 is triazolediyl, and Z 9-1 is NH, and (ii) Ar 9-1 is oxazoldiyl, and Z 9-1 except when CH2). (29) The compound according to any one of (1), (2) and (11), or a pharmaceutically acceptable salt thereof, wherein S is the following formula (S10)-1: [ka] (In the formula, The wavy line is L 1 or L 2 represents a binding site for Z 10-1 represents O or NH). (30) The compound according to any one of (1), (2) and (12), or a pharmaceutically acceptable salt thereof, wherein S is the following formula (S11)-1: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with X 11a-1 represents -C(=O)-NH-, and X 11b-1represents -C(=O)-NH- or -C(=O)-). (31) The compound according to any one of (1), (2) and (13), or a pharmaceutically acceptable salt thereof, wherein S is the following formula (S12)-1: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with X 12-1 represents -C(=O)-NH- or -NH-C(=O)-; Z 12a-1 represents CH2 or NH (where X 12-1 is -C(=O)-NH-, and Z 12a-1 (except when is NH), Z 12b-1 represents CH2 or O (where Z 12a-1 is NH and Z 12b-1 is O), and Z 12c-1 represents a bond or O (wherein (i) Z 12b-1 is O and Z 12c-1 is O, and (ii) Z 12a-1 is NH and Z 12c-1 Except when is O). (32) The compound according to any one of (1), (2) and (13), or a pharmaceutically acceptable salt thereof, wherein S is the following formula (S13)-1: [ka] (In the formula, The wavy line is L 1 or L 2 represents a binding site for n 13-1 represents 0 or 2). (33) The compound according to any one of (1), (2) and (14), or a pharmaceutically acceptable salt thereof, wherein S is the following formula (S16)-1: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with n 16-1 represents 1 or 2, Z 16-1 represents a bond, CH2 or O, X 16-1 represents -CH2-O- or -C(=O)-NH-, and Ar 16-1 represents triazolediyl, oxadiazolediyl, or pyrazolediyl (provided that (i) X 16-1 is -CH2-O-, and Ar 16-1 is oxadiazolediyl or pyrazolediyl, and (ii) n 16-1 is 1 and X 16-1 is -C(=O)-NH-, and Ar 16-1 (Except when is pyrazoldiyl) (34) The compound according to any one of (1), (2) and (14), or a pharmaceutically acceptable salt thereof, wherein S is the following formula (S17)-1: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with n 17-1 represents 1 or 2, and X 17-1 represents -C(=O)-NH-). (35) The compound according to any one of (1), (2) and (14), or a pharmaceutically acceptable salt thereof, wherein S is the following formula (S18)-1: [ka] (In the formula, The wavy line is L 1 or L 2 represents a binding site for n 18a-1 represents 2, and n18b-1 represents 2, and n 18c-1 represents 1). (36) L 1 and L 2 represents a group represented by formula (A), and S is a group represented by formula (S1), or a pharmaceutically acceptable salt thereof, In the formula (A), R A1 represents a hydrogen atom, and R A2 and R A3 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms; R A5 represents a hydrogen atom, the ring RA represents benzenediyl, and n 1A represents 0, and In the formula (S1), n 1a and n 1b represents 1, and X 1a and X 1b are the same or different and represent -C(=O)-NH- or -NH-C(=O)-, R 1a represents a hydrogen atom, and R 1b represents a hydrogen atom. (37) L 1 and L 2 represents a group represented by formula (A), and S is a group represented by formula (S1), or a pharmaceutically acceptable salt thereof, In the formula (A), R A1 represents a hydrogen atom, and R A2 and R A3 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms; R A5 represents a hydrogen atom, the ring RA represents benzenediyl or cycloalkanediyl, and n 1A represents 0, and In the formula (S1), n 1a and n 1b represents 0, X 1a and X 1bare the same or different and represent -C(=O)-NH-, -NH-C(=O)- or -NH-C(=O)-NH- (provided that X 1a is -C(=O)-NH- or -NH-C(=O)-NH-, and X 1b is -NH-C(=O)- or -NH-C(=O)-NH-), R 1a represents a hydrogen atom, and R 1b represents a hydrogen atom. (38) L 1 and L 2 represents a group represented by formula (A), and S is a group represented by formula (S1), or a pharmaceutically acceptable salt thereof, In the formula (A), R A1 represents a hydrogen atom, and R A2 and R A3 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms; R A5 represents a hydrogen atom, the ring RA represents benzenediyl or pyridinediyl, and n 1A represents 0, and In the formula (S1), n 1a and n 1b represents 1, X 1a and X 1b are the same or different and represent -C(=O)-NH- or -NH-C(=O)-, and R 1a represents a hydrogen atom, and R 1b represents a hydrogen atom. (39) L 1 and L 2 represents a group represented by formula (A), and S is a group represented by formula (S3), or a pharmaceutically acceptable salt thereof, In the formula (A), R A1 represents a hydrogen atom, and R A2 and R A3 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms; R A5represents a hydrogen atom, the ring RA represents benzenediyl or cycloalkanediyl, and n 1A represents 0, and In the formula (S3), n 3a and n 3b represents 2, and X 3 represents -C(=O)-NH-, and Z 3 represents N. (40) L 1 and L 2 represents a group represented by formula (A), and S is a group represented by formula (S3), or a pharmaceutically acceptable salt thereof, In the formula (A), R A1 represents a hydrogen atom, and R A2 and R A3 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms; R A5 represents a hydrogen atom, the ring RA represents benzenediyl or cycloalkanediyl, and n 1A represents 0, and In the formula (S3), n 3a and n 3b represents 1, and X 3 represents -C(=O)-NH-, and Z 3 represents CH. (41) L 1 and L 2 represents a group represented by formula (A), and S is a group represented by formula (S6), or a pharmaceutically acceptable salt thereof, In the formula (A), R A1 represents a hydrogen atom, and R A2 and R A3 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms; R A5 represents a hydrogen atom, the ring RA represents benzenediyl, and n 1A represents 0, and In the above formula (S6), n 6 represents 1, and Ar 6 represents oxadiazolediyl, and X6 represents -CH2-NH-. (42) L 1 and L 2 represents a group represented by formula (A), and S is a group represented by formula (S6), or a pharmaceutically acceptable salt thereof, In the formula (A), R A1 represents a hydrogen atom, and R A2 and R A3 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms; R A5 represents a hydrogen atom, the ring RA represents benzenediyl, and n 1A represents 0, and In the above formula (S6), n 6 represents 1, and Ar 6 represents triazolediyl, and X 6 represents -CH2-NH-. (43) L 1 and L 2 represents a group represented by formula (A), and S is a group represented by formula (S6), or a pharmaceutically acceptable salt thereof, In the formula (A), R A1 represents a hydrogen atom, and R A2 and R A3 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms; R A5 represents a hydrogen atom, the ring RA represents benzenediyl or cycloalkanediyl, and n 1A represents 0, and In the above formula (S6), n 6 represents 1, and Ar 6 represents oxadiazolediyl, and X 6 represents -C(=O)-NH-. (44) L 1 and L 2 represents a group represented by formula (A), and S is a group represented by formula (S6), or a pharmaceutically acceptable salt thereof, In the formula (A), R A1 represents a hydrogen atom, and R A2 and R A3 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms; R A5 represents a hydrogen atom, the ring RA represents benzenediyl or cycloalkanediyl, and n 1A represents 0, and In the above formula (S6), n 6 represents 2, and Ar 6 represents triazolediyl, and X 6 represents -C(=O)-NH-. (45) A pharmaceutical composition comprising the compound according to any one of (1) to (44) or a pharmaceutically acceptable salt thereof. (46) The pharmaceutical composition according to (45), further comprising a carrier. (47) The pharmaceutical composition according to (45) or (46), for inhibiting BET. (48) The pharmaceutical composition according to (45) or (46) for the treatment of cancer. (49) A method for treatment or prevention, comprising administering to a subject the compound according to any one of (1) to (44) or a pharmaceutically acceptable salt thereof. (50) The method for treating or preventing cancer according to (49), which is a method for treating or preventing cancer. (51) The compound according to any one of (1) to (44) or a pharmaceutically acceptable salt thereof for use as a medicine. (52) The compound according to any one of (1) to (44) or a pharmaceutically acceptable salt thereof for use in treating or preventing cancer. (53) Use of the compound according to any one of (1) to (44) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing cancer. (54) Use of the compound according to any one of (1) to (44) or a pharmaceutically acceptable salt thereof for the treatment or prevention of cancer. (55) A medicine comprising the compound according to any one of (1) to (44) or a pharmaceutically acceptable salt thereof as an active ingredient. (56) A preventive or therapeutic agent for cancer, comprising the compound according to any one of (1) to (44) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013] The present invention provides a compound having anticancer activity or a pharmaceutically acceptable salt thereof. The compounds of the present invention, as shown in (1) to (56) above, exhibit potent BET inhibitory activity by binding two specific BET inhibitors as ligands at specific binding positions via a spacer having a specific structure.

[0014] According to the present invention, there is provided a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, L 1 and L 2 are the same or different and represent a group represented by a formula selected from the group consisting of the following formulae (A) to (F), and S represents a group represented by a formula selected from the group consisting of the following formulae (S1) to (S18): [ka] (In the formula, the wavy line represents the bonding site with S, R A1 , R A2 and R A3 are the same or different and each represents a hydrogen atom or a lower alkyl, R A5 represents a hydrogen atom, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted tetrahydropyridinyl, optionally substituted dihydro-1H-pyrrolyl or optionally substituted tetrahydro-1H-azepinyl, ring RA represents benzenediyl, cycloalkanediyl, pyridinediyl, piperidinediyl, azetidinediyl, pyrrolidinediyl or homopiperidinediyl; n 1Arepresents 0 or 1, R B1 represents a hydrogen atom, an optionally substituted lower alkoxycarbonylmethyl, an optionally substituted cycloalkyloxycarbonylmethyl, or -CHCONR B5 R B6 (In the formula, R B5 and R B6 are the same or different and each represent a hydrogen atom or an optionally substituted lower alkyl, or together with the adjacent nitrogen atom represent an optionally substituted nitrogen-containing aliphatic heterocyclic group, R B2 represents an optionally substituted lower alkyl, R B3 and R B4 are the same or different and each represents a halogen atom or an optionally substituted lower alkyl group, R C1 represents a hydrogen atom, a lower alkyl group, or a lower alkanoyl group; R C3 represents a hydrogen atom or hydroxy; The ring RC represents benzenediyl, piperidinediyl, azetidinediyl, pyrrolidinediyl, or homopiperidinediyl; R D1 represents an optionally substituted lower alkyl or an optionally substituted lower alkoxycarbonyl, R E1 and R F1 is R A1 is synonymous with R E2 and R F2 is R A2 is synonymous with R E3 and R F3 is R A3 is synonymous with R E5 and R F5 is R A5 is synonymous with, and R F7 represents a hydrogen atom or a halogen), [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with n 1a and n 1b are the same or different and each represents 0 or 1, X 1a and X 1b are the same or different and represent -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH-, R 1a and R 1b is R 1a represents a hydrogen atom, and R 1b represents a hydrogen atom or a lower alkyl, or R 1a and R 1b together represent a carbonyl, X 2a represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH- or -NH-SO2-; X 2b represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2- or -CH2-; Z 2 represents CH or N, n 3a and n 3b are the same or different and represent 1 or 2, X 3 represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -NH-C(=O)-NH- or -NH-CH2-; Z 3 represents CH or N, X 5a and X 5b are the same or different and represent -C(=O)-NH-, -NH-C(=O)-, -SO2-NH- or -NH-SO2-, n6 represents 1 or 2, Ar 6 represents triazolediyl, oxadiazolediyl, pyrazolediyl, thiophenediyl or tetrahydropyridinediyl, X 6 represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -CH2-NH-, -NH-CH2- or -NH-C(=O)-NH-; X 7 represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH- or -NH-C(=O)-NH-; n 7 represents 1, 2 or 3, Z 7 represents S, SO, or SO2 X 8a represents -C(=O)-, -CH2- or -NH-C(=O)-; X 8b represents a bond, -C(=O)-, -CH2- or -CH(OH)-; Ar 9 represents triazolediyl or oxazolediyl, Z 9 represents CH2 or NH, Z 10 represents O or NH, X 11a represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2- or -NH-C(=O)-NH-; X 11b represents -C(=O)-NH-, -NH-C(=O)- or -C(=O)-; X 12 represents -C(=O)-NH-, -NH-C(=O)-, SO2-NH-, -NH-SO2- or -NH-C(=O)-NH-; Z 12a represents CH2 or NH, Z 12b represents CH2 or O, Z 12c represents a bond, CH2 or O, n 13 represents 0, 1 or 2, n 16 represents 1 or 2, Z 16 represents a bond, CH2 or O, X 16 represents -CH2-O-, -C(=O)-NH-, -NH-C(=O)- or -NH-C(=O)-NH-, Ar 16 represents triazolediyl, oxadiazoldiyl or pyrazolediyl, n 17 represents 1 or 2, X 17 represents -C(=O)-NH-, -NH-C(=O)-, -NH-SO2- or -NH-C(=O)-NH-, and n 18a , n 18b and n 18c are the same or different and represent 1 or 2).

[0015] According to a preferred embodiment of the present invention, there is provided a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, L 1 and L 2 are the same or different and represent a group represented by a formula selected from the group consisting of the following formulae (A) to (F), and S represents a group represented by a formula selected from the group consisting of the following formulae (S1) to (S18): [ka] (In the formula, the wavy line represents the bonding site with S, R A1 , R A2 and R A3 are the same or different and each represents a hydrogen atom or a lower alkyl, R A5represents a hydrogen atom, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted tetrahydropyridinyl, optionally substituted dihydro-1H-pyrrolyl or optionally substituted tetrahydro-1H-azepinyl, ring RA represents benzenediyl, cycloalkanediyl, pyridinediyl, piperidinediyl, azetidinediyl, pyrrolidinediyl or homopiperidinediyl; n 1A represents 0 or 1, R B1 represents a hydrogen atom, an optionally substituted lower alkoxycarbonylmethyl, an optionally substituted cycloalkyloxycarbonylmethyl, or -CHCONR B5 R B6 (In the formula, R B5 and R B6 are the same or different and each represent a hydrogen atom or an optionally substituted lower alkyl, or together with the adjacent nitrogen atom represent an optionally substituted nitrogen-containing aliphatic heterocyclic group, R B2 represents an optionally substituted lower alkyl, R B3 and R B4 are the same or different and each represents a halogen atom or an optionally substituted lower alkyl group, R C1 represents a hydrogen atom, a lower alkyl group, or a lower alkanoyl group; R C3 represents a hydrogen atom or hydroxy; The ring RC represents benzenediyl, piperidinediyl, azetidinediyl, pyrrolidinediyl, or homopiperidinediyl; R D1 represents an optionally substituted lower alkyl or an optionally substituted lower alkoxycarbonyl, R E1 and R F1 is R A1 is synonymous with R E2 and RF2 is R A2 is synonymous with R E3 and R F3 is R A3 is synonymous with R E5 and R F5 is R A5 is synonymous with, and R F7 represents a hydrogen atom or a halogen), [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with n 1a and n 1b are the same or different and each represents 0 or 1, X 1a and X 1b are the same or different and represent -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH- (provided that (i) X 1a is -NH-SO2- and X 1b is -SO2-NH-, (ii) n 1a and n 1b is 0 and X 1a is -C(=O)-NH-, -SO2-NH-, -OC(=S)-NH-, -OC(=O)-NH- or -NH-C(=O)-NH-, and X 1b is -NH-C(=O)-, -NH-SO2-, -NH-C(=O)-O- or -NH-C(=O)-NH-; and (iii) X 1a is -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH-, and X 1b is -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH-), R 1a and R 1b is R 1a represents a hydrogen atom, and R 1b represents a hydrogen atom or a lower alkyl, or R 1a and R 1b together represent a carbonyl, X 2a represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH- or -NH-SO2-; X 2b represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2- or -CH2- (provided that X 2a is -NH-SO2- and X 2b (except when -SO2-NH-) Z 2 represents CH or N (provided that (i) Z 2 is N and X 2b is -NH-C(=O)-, -SO2-NH-, or -NH-SO2-, and (ii) Z 2 is CH and X 2b is -CH2-), n 3a and n 3b are the same or different and represent 1 or 2, X 3 represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -NH-C(=O)-NH- or -NH-CH2-; Z 3 represents CH or N (provided that (i) Z 3 is N and X 3 is -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -NH-C(=O)-NH- or -NH-CH2-, and (ii) Z 3 is N, and n 3a or n 3b except when is 1), X 5a and X 5bare the same or different and represent -C(=O)-NH-, -NH-C(=O)-, -SO2-NH- or -NH-SO2- (provided that X 5a is -NH-SO2- and X 5b (except when -SO2-NH-) n 6 represents 1 or 2, Ar 6 represents triazolediyl, oxadiazolediyl, pyrazolediyl, thiophenediyl or tetrahydropyridinediyl, X 6 represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -CH2-NH- or -NH-C(=O)-NH- (provided that (i) Ar 6 is oxadiazolediyl, pyrazolediyl, thiophenediyl or tetrahydropyridinediyl, and X 6 is -NH-SO2-, and (ii) n 6 is 1 and Ar 6 is pyrazolediyl or tetrahydropyridinediyl, and X 6 is -C(=O)-NH-, -SO2-NH-, -CH2-NH- or -NH-C(=O)-NH-), X 7 represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH- or -NH-C(=O)-NH-; n 7 represents 1, 2 or 3, Z 7 represents S, SO, or SO2 X 8a represents -C(=O)-, -CH2- or -NH-C(=O)-; X 8b represents a bond, -C(=O)-, -CH2- or -CH(OH)-; Ar 9 represents triazolediyl or oxazolediyl, Z 9 represents CH2 or NH (provided that (i) Ar 9is triazolediyl, and Z 9 is NH, and (ii) Ar 9 is oxazoldiyl, and Z 9 except when CH2), Z 10 represents O or NH, X 11a represents -C(=O)-NH-, -SO2-NH- or -NH-C(=O)-NH-; X 11b represents -C(=O)-NH- or -C(=O)-; X 12 represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH- or -NH-C(=O)-NH-; Z 12a represents CH2 or NH (where X 12 is -C(=O)-NH-, -SO2-NH- or -NH-C(=O)-NH-, and Z 12a (except when is NH), Z 12b represents CH2 or O (where Z 12a is NH and Z 12b except when is O), Z 12c represents a bond, CH2, or O (provided that (i) Z 12b is O and Z 12c is O, and (ii) Z 12a is NH and Z 12c is CH2 or O), n 13 represents 0, 1 or 2, n 16 represents 1 or 2, Z 16 represents a bond, CH2 or O, X 16 represents -CH2-O-, -C(=O)-NH-, -NH-C(=O)- or -NH-C(=O)-NH- (provided that Z 16 is O and X 16 is -NH-C(=O)- or -NH-C(=O)-NH-), Ar16 represents triazolediyl, oxadiazolediyl, or pyrazolediyl, provided that (i) X 16 is -CH2-O-, and Ar 16 is oxadiazolediyl or pyrazolediyl, and (ii) n 16 is 1 and X 16 is -C(=O)-NH- or -NH-C(=O)-NH-, and Ar 16 is pyrazoldiyl), n 17 represents 1 or 2, X 17 represents -C(=O)-NH-, -NH-C(=O)-, -NH-SO2- or -NH-C(=O)-NH-, and n 18a , n 18b and n 18c are the same or different and represent 1 or 2).

[0016] Hereinafter, the compound represented by general formula (I) will be referred to as compound (I). The same applies to compounds having other formula numbers.

[0017] In this specification, examples of lower alkyl include linear or branched alkyl having 1 to 10 carbon atoms, and more specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.

[0018] In the present specification, examples of lower alkoxycarbonylmethyl include C 1-10Examples thereof include alkoxycarbonylmethyl (having 1 to 10 carbon atoms), more specifically, methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, isopropoxycarbonylmethyl, butoxycarbonylmethyl, isobutoxycarbonylmethyl, sec-butoxycarbonylmethyl, tert-butoxycarbonylmethyl, pentoxycarbonylmethyl, isopentoxycarbonylmethyl, neopentoxycarbonylmethyl, hexyloxycarbonylmethyl, heptoxycarbonylmethyl, octoxycarbonylmethyl, nonyloxycarbonylmethyl, dosiloxycarbonylmethyl, and the like, and preferably tert-butoxycarbonylmethyl.

[0019] In this specification, halogen refers to any of fluorine, chlorine, bromine and iodine atoms.

[0020] As used herein, lower alkanoyl includes, for example, C 2-11 Examples include alkanoyl (having 2 to 11 carbon atoms).

[0021] R A1 , R A2 and R A3 The lower alkyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, and even more preferably methyl or ethyl.

[0022] R A5 The lower alkyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, and even more preferably propyl.

[0023] R A5 The lower alkenyl in the formula (I) is preferably alkenyl having 2 to 6 carbon atoms, more preferably alkenyl having 2 to 4 carbon atoms, and even more preferably propenyl.

[0024] R A2-1 and R A3-1The alkyl having 1 to 5 carbon atoms in the formula (I) is preferably alkyl having 1 to 3 carbon atoms, and more preferably methyl or ethyl.

[0025] R A5-1 The alkyl having 1 to 5 carbon atoms in the formula (I) is preferably alkyl having 1 to 3 carbon atoms, and more preferably propyl.

[0026] R A5-1 In the above formula, the alkenyl having 2 to 6 carbon atoms is preferably an alkenyl having 2 to 4 carbon atoms, and more preferably propenyl.

[0027] The cycloalkanediyl in ring RA and ring RA-1 is preferably a cycloalkanediyl having 3 to 8 carbon atoms, more preferably cyclobutanediyl or cyclohexanediyl.

[0028] R B1 The lower alkoxycarbonylmethyl in the above formula (I) is preferably an alkoxycarbonylmethyl having 1 to 10 carbon atoms, more preferably ethoxycarbonylmethyl, propoxycarbonylmethyl or butoxycarbonylmethyl (preferably tert-butoxycarbonylmethyl).

[0029] R B1 and R B1-1 The cycloalkyloxycarbonylmethyl in the above formula is preferably a cycloalkyloxycarbonylmethyl having 3 to 8 carbon atoms, and more preferably cyclohexyloxycarbonylmethyl.

[0030] R B1-1 In the above formula, the alkoxycarbonylmethyl having 1 to 5 carbon atoms is preferably ethoxycarbonylmethyl, propoxycarbonylmethyl or butoxycarbonylmethyl (preferably tert-butoxycarbonylmethyl).

[0031] R B5 and R B6The lower alkyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 5 carbon atoms, and even more preferably ethyl.

[0032] R B5-1 and R B6-1 The lower alkyl in the formula (I) is an alkyl having 1 to 5 carbon atoms, preferably an alkyl having 1 to 5 carbon atoms, and more preferably ethyl.

[0033] R B5 and R B6 and R B5-1 and R B6-1 The nitrogen-containing aliphatic heterocyclic group in "which, together with the adjacent nitrogen atom, represents a nitrogen-containing aliphatic heterocyclic group which may have a substituent" is preferably a nitrogen-containing aliphatic heterocyclic group having 4 to 6 carbon atoms, more preferably azetidine, pyrrolidine, piperidine, piperazine or morpholine, and even more preferably piperazine.

[0034] R B2 The lower alkyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, and even more preferably methyl.

[0035] R B2-1 The alkyl having 1 to 5 carbon atoms in the formula (I) is preferably alkyl having 1 to 3 carbon atoms, and more preferably methyl.

[0036] R B3 and R B4 The halogen in the formula (I) is preferably a fluorine atom or a chlorine atom.

[0037] R B3 and R B4 The lower alkyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, and even more preferably methyl.

[0038] R B3-1 and R B4-1The alkyl having 1 to 5 carbon atoms in the formula (I) is preferably alkyl having 1 to 3 carbon atoms, and more preferably methyl.

[0039] R C1 The lower alkyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, and even more preferably methyl or ethyl.

[0040] R C1 The lower alkanoyl in the formula (I) is preferably an alkanoyl having 2 to 11 carbon atoms, more preferably an alkanoyl having 2 to 5 carbon atoms, and even more preferably acetyl.

[0041] R D1 The lower alkyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, and even more preferably ethyl.

[0042] R D1-1 In the above formula, the alkyl having 1 to 5 carbon atoms is more preferably an alkyl having 1 to 3 carbon atoms, and more preferably ethyl.

[0043] R D1 The lower alkoxycarbonyl in the above formula is preferably an alkoxycarbonyl having 1 to 5 carbon atoms, more preferably an alkoxycarbonyl having 1 to 3 carbon atoms, and even more preferably ethoxycarbonyl or methoxycarbonyl.

[0044] R D1-1 The alkoxycarbonyl having 1 to 5 carbon atoms in the formula (I) is preferably an alkoxycarbonyl having 1 to 3 carbon atoms, and more preferably ethoxycarbonyl or methoxycarbonyl.

[0045] R F7 The halogen in the formula (I) is preferably a fluorine atom.

[0046] R 1bThe lower alkyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, and even more preferably methyl or propyl (preferably isopropyl).

[0047] R A5 and R A5-1 The substituents in the "optionally substituted lower alkyl" and "optionally substituted alkyl having 1 to 5 carbon atoms" are, for example, one or more substituents selected from the group consisting of halogen, hydroxy, methoxy, ethoxy, nitro, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl, and preferably amino.

[0048] R A5 and R A5-1 The substituents in the "optionally substituted lower alkenyl" and "optionally substituted alkenyl having 2 to 6 carbon atoms" are, for example, one or more substituents selected from the group consisting of halogen, hydroxy, methoxy, ethoxy, nitro, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl, and preferably amino.

[0049] RA5 and R A5-1 Examples of the substituent in the "tetrahydropyridinyl which may be substituted" include halogen, methyl, ethyl, hydroxy, methoxy, ethoxy, nitro, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and the like, but it is preferably unsubstituted.

[0050] R A5 Examples of the substituent in the "dihydro-1H-pyrrolyl which may be substituted" include halogen, methyl, ethyl, hydroxy, methoxy, ethoxy, nitro, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and the like, and preferably it is unsubstituted.

[0051] R A5 Examples of the substituent in the "tetrahydro-1H-azepinyl which may be substituted" include halogen, methyl, ethyl, hydroxy, methoxy, ethoxy, nitro, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc., and it is preferably unsubstituted.

[0052] R B1 and R B1-1The substituents in the "optionally substituted lower alkoxycarbonylmethyl" and "optionally substituted alkoxycarbonylmethyl having 1 to 5 carbon atoms" are, for example, one or more substituents selected from the group consisting of halogen, hydroxy, methoxy, ethoxy, nitro, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl, and are preferably hydroxy, methoxy, or dimethylamino, and are also preferably unsubstituted.

[0053] R B1 and R B1-1 The substituents in the "cycloalkyloxycarbonylmethyl which may be substituted" are, for example, one or more substituents selected from the group consisting of halogen, methyl, ethyl, hydroxy, methoxy, ethoxy, nitro, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, and diethylcarbamoyl, and are preferably hydroxy.

[0054] R B5 and R B6 and R B5-1 and R B6-1The substituent in "representing a nitrogen-containing aliphatic heterocyclic group which, together with the adjacent nitrogen atom, may have a substituent" is, for example, one or more substituents selected from the group consisting of halogen, methyl, ethyl, hydroxy, methoxy, ethoxy, nitro, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, hydroxymethyl, hydroxyethyl, and hydroxypropyl, and is preferably hydroxyethyl.

[0055] R B2 and R B2-1 Examples of the substituent in the "optionally substituted lower alkyl" and "optionally substituted alkyl having 1 to 5 carbon atoms" include halogen, hydroxy, methoxy, ethoxy, nitro, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like, but preferably unsubstituted.

[0056] R B3 and R B4 and R B3-1 and R B4-1The substituents in the "optionally substituted lower alkyl" and "optionally substituted alkyl having 1 to 5 carbon atoms" are, for example, one or more substituents selected from the group consisting of halogen, hydroxy, methoxy, ethoxy, nitro, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl, and are preferably a fluorine atom or cyano. B3 and R B4 and R B3-1 and R B4-1 The "optionally substituted lower alkyl" and "optionally substituted alkyl having 1 to 5 carbon atoms" are particularly preferably unsubstituted lower alkyl and unsubstituted alkyl having 1 to 5 carbon atoms, respectively.

[0057] R D1 and R D1-1 Examples of the substituent in the "optionally substituted lower alkyl" and "optionally substituted alkyl having 1 to 5 carbon atoms" include halogen, hydroxy, methoxy, ethoxy, nitro, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like, but preferably unsubstituted.

[0058] RD1 and R D1-1 The substituents in the "optionally substituted lower alkoxycarbonyl" and the "optionally substituted alkoxycarbonyl having 1 to 5 carbon atoms" are, for example, one or more substituents selected from the group consisting of halogen, hydroxy, methoxy, ethoxy, nitro, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl, and are preferably hydroxy or dimethylamino, and are also preferably unsubstituted.

[0059] In the above formula (S1), X 1a and X 1b are the same or different and represent -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH-, preferably (i) X 1a is -NH-SO2- and X 1b is -SO2-NH-, (ii) n 1a and n 1b is 0 and X 1a is -C(=O)-NH-, -SO2-NH-, -OC(=S)-NH-, -OC(=O)-NH- or -NH-C(=O)-NH-, and X 1b is -NH-C(=O)-, -NH-SO2-, -NH-C(=O)-O- or -NH-C(=O)-NH-; and (iii) X 1a is -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH-, and X 1bExcept when is -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH-. where X 1a The bond on the left side of 1 and combines with X 1b The bond on the right side of 2 For example, compound number 1a in Table 1 below binds to L 1 and X 1a The bond on the left side of (-C(=O)-NH-) is bonded to L 1 -C(=O)-NH-, and L 2 and X 1b The bond on the right side of (-NH-C(=O)-) bonds to form -NH-C(=O)-L 2 This is a compound formed by the following formula:

[0060] In the above formula (S2), X 2a represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH- or -NH-SO2-, and X 2b represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2- or -CH2-, and preferably X 2a is -NH-SO2- and X 2b Same as above, except that X is -SO2-NH-. 2a The bond on the left side of 1 and combines with X 2b The bond on the right side of 2 and combine.

[0061] In the above formula (S3), X 3 represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -NH-C(=O)-NH- or -NH-CH2-. 3 The bond on the right side of 2 and combine.

[0062] In the above formula (S5), X 5a and X 5bare the same or different and represent -C(=O)-NH-, -NH-C(=O)-, -SO2-NH- or -NH-SO2-, and preferably X 5a is -NH-SO2- and X 5b Same as above, except that X is -SO2-NH-. 5a The bond on the left side of 1 and combines with X 5b The bond on the right side of 2 and combine.

[0063] In the above formula (S6), X 6 represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -CH2-NH- or -NH-C(=O)-NH-, and preferably (i) Ar 6 is oxadiazolediyl, pyrazolediyl, thiophenediyl or tetrahydropyridinediyl, and X 6 is -NH-SO2-, and (ii) n 6 is 1 and Ar 6 is pyrazolediyl or tetrahydropyridinediyl, and X 6 As above, except that X is -C(=O)-NH-, -SO2-NH-, -CH2-NH- or -NH-C(=O)-NH-. 6 The bond on the left side of 1 and combine.

[0064] In the above formula (S7), X 7 represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH- or -NH-C(=O)-NH-. 7 The bond on the left side of 1 and combine.

[0065] In the above formula (S8), X 8a represents -C(=O)-, -CH2- or -NH-C(=O)-, and X 8b represents a bond, -C(=O)-, -CH2- or -CH(OH)-. 8a The bond on the left side of1 and combines with X 8b The bond on the right side of 2 and combine.

[0066] In the above formula (S11), X 11a represents -C(=O)-NH-, -SO2-NH- or -NH-C(=O)-NH-, and X 11b represents -C(=O)-NH- or -C(=O)-. 11a The bond on the left side of 1 and combines with X 11b The bond on the right side of 2 and combine.

[0067] In the above formula (S12), X 12 represents -C(=O)-NH-, -NH-C(=O)-, -SO2-NH- or -NH-C(=O)-NH-. 11a The bond on the left side of 1 and combine.

[0068] In the above formula (S16), X 16 represents -CH2-O-, -C(=O)-NH-, -NH-C(=O)- or -NH-C(=O)-NH-, and preferably Z 16 is O and X 16 As above, except that X is -NH-C(=O)- or -NH-C(=O)-NH-. 16 The bond on the left side of 16 L via etc. 1 and combine.

[0069] In the above formula (S17), X 17 represents -C(=O)-NH-, -NH-C(=O)-, -NH-SO2- or -NH-C(=O)-NH-. 17 The bond on the right side of 2 and combine.

[0070] In general formula (I), L 1 and L 2are the same or different and each represents a group represented by one formula selected from the group consisting of formulas (A) to (F), and preferably, L 1 and L 2 At least one of the groups represented by formula (A) or (B) is preferably a group represented by formula (A) or (B), and more preferably, L 1 and L 2 At least one of the groups is a group represented by formula (A).

[0071] According to a preferred embodiment of the present invention, in general formula (I), L 1 and L 2 are the same or different and are groups represented by formula (A), (B), (C) or (D), S is preferably a group represented by one formula selected from the group consisting of formulas (S1) to (S15).

[0072] According to a preferred embodiment of the present invention, in general formula (I), L 1 or L 2 When is a group represented by formula (E), S is preferably a group represented by formula (S16), (S17) or (S18).

[0073] According to a preferred embodiment of the present invention, in general formula (I), L 1 When is a group represented by formula (F), S is preferably a group represented by any of the following: X 1a a group represented by formula (S1), wherein: X 2a a group represented by formula (S2) in which is —C(═O)—NH—; A group represented by formula (S3), A group represented by formula (S4), X 5a a group represented by formula (S5), wherein: X 6 a group represented by formula (S6), wherein: X 7 a group represented by formula (S7), wherein: X 8aa group represented by formula (S8), wherein: X 11a a group represented by formula (S11) in which is —C(═O)—NH—; X 12 a group represented by formula (S12) in which is —C(═O)—NH—; A group represented by formula (S14), or A group represented by formula (S15).

[0074] According to another preferred embodiment of the present invention, in general formula (I), L 2 is a group represented by formula (F), S is a group represented by any of the following: X 1b a group represented by formula (S1), wherein: X 2b a group represented by formula (S2) in which is —NH—C(═O)—; X 3 a group represented by formula (S3), wherein: A group represented by formula (S4), X 5b a group represented by formula (S5), wherein: n 13 a group represented by formula (S13) in which A group represented by formula (S15), or X 17 A group represented by formula (S17) in which is —NH—C(═O)—.

[0075] According to a preferred embodiment of the present invention, in the above formula (I), L 1 represents a group represented by formula (A), (B), (C), (D) or (F), and L 2 represents a group represented by formula (A), (B), (C) or (D), and S is a group represented by formula (S1), or a pharmaceutically acceptable salt thereof.

[0076] According to a preferred embodiment of the present invention, in the above formula (I), L 1 represents a group represented by formula (A) (preferably, formula (A1), formula (A5) or formula (A15)), and L 2represents a group represented by formula (A) (preferably formula (A1)), and S is a group represented by formula (S1), or a pharmaceutically acceptable salt thereof.

[0077] According to a preferred embodiment of the present invention, in the above formula (I), L 1 represents a group represented by formula (A), and L 2 represents a group represented by formula (A) and S is a group represented by formula (S2), or a pharmaceutically acceptable salt thereof.

[0078] According to a preferred embodiment of the present invention, in the above formula (I), L 1 represents a group represented by formula (A), (B) or (C), and L 2 represents a group represented by formula (A) or (B), and S is a group represented by formula (S3), or a pharmaceutically acceptable salt thereof.

[0079] According to a preferred embodiment of the present invention, in the above formula (I), L 1 represents a group represented by formula (A) (preferably, formula (A1) or formula (A5)), and L 2 represents a group represented by formula (A) (preferably, formula (A1) or formula (A5)), and S is a group represented by formula (S3), or a pharmaceutically acceptable salt thereof.

[0080] According to a preferred embodiment of the present invention, in the above formula (I), L 1 represents a group represented by formula (A), and L 2 represents a group represented by formula (A) and S is a group represented by formula (S4) or (S5), or a pharmaceutically acceptable salt thereof.

[0081] According to a preferred embodiment of the present invention, in the above formula (I), L 1 represents a group represented by formula (A), (B), (C) or (D), and L 2 represents a group represented by formula (A), (B) or (D), and S is a group represented by formula (S6), or a pharmaceutically acceptable salt thereof.

[0082] According to a preferred embodiment of the present invention, in the above formula (I), L 1 represents a group represented by formula (A) (preferably, formula (A1) or formula (A5)), and L 2 represents a group represented by formula (A) (preferably, formula (A1) or formula (A5)), and S is a group represented by formula (S6), or a pharmaceutically acceptable salt thereof.

[0083] According to a preferred embodiment of the present invention, in the above formula (I), L 1 represents a group represented by formula (A) or (B), and L 2 represents a group represented by formula (A) and S is a group represented by formula (S7), or a pharmaceutically acceptable salt thereof.

[0084] According to a preferred embodiment of the present invention, in the above formula (I), L 1 represents a group represented by formula (A) or (B), and L 2 represents a group represented by formula (A) and S is a group represented by formula (S8), or a pharmaceutically acceptable salt thereof.

[0085] According to a preferred embodiment of the present invention, in the above formula (I), L 1 represents a group represented by formula (A), and L 2 represents a group represented by formula (A) and S is a group represented by formula (S9), or a pharmaceutically acceptable salt thereof.

[0086] According to a preferred embodiment of the present invention, in the above formula (I), L 1 represents a group represented by formula (A) or (B), and L 2 represents a group represented by formula (A) and S is a group represented by formula (S10), or a pharmaceutically acceptable salt thereof.

[0087] According to a preferred embodiment of the present invention, in the above formula (I), L 1 represents a group represented by formula (A) or (B), and L 2In a more preferred embodiment of the present invention, there is provided a compound or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), L 1 represents a group represented by formula (A) or (B), and L 2 represents a group represented by formula (A), and S is a group represented by formula (S11), and the group represented by formula (S11) is 11b is a group where L is —C(═O)—; 2 In the group represented by formula (A), the ring RA is piperidinediyl, azetidinediyl, pyrrolidinediyl or homopiperidinediyl, or a pharmaceutically acceptable salt thereof is provided.

[0088] According to a preferred embodiment of the present invention, in the above formula (I), L 1 represents a group represented by formula (A), and L 2 represents a group represented by formula (A), and S is a group represented by formula (S12), (S13), (S14) or (S15), or a pharmaceutically acceptable salt thereof.

[0089] According to a preferred embodiment of the present invention, in the above formula (I), L 1 represents a group represented by formula (E), and L 2 represents a group represented by formula (A), and S is a group represented by formula (S16), (S17) or (S18), or a pharmaceutically acceptable salt thereof.

[0090] According to a preferred embodiment of the present invention, there is provided a compound represented by formula (I) above, wherein formula (A) is the following formula (A)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line represents the binding site with S. R A1-1 represents a hydrogen atom, R A2-1 and R A3-1are the same or different and each represents an alkyl group having 1 to 5 carbon atoms (preferably, R A2-1 represents methyl, and R A3-1 represents ethyl), R A5-1 represents a hydrogen atom, a fluorine atom, an optionally substituted alkyl having 1 to 5 carbon atoms (preferably an optionally substituted alkyl having 1 to 3 carbon atoms, more preferably an amino-substituted propyl), an optionally substituted alkenyl having 2 to 6 carbon atoms (preferably a propenyl optionally substituted with amino, more preferably an amino-substituted propenyl), or an optionally substituted tetrahydropyridinyl (preferably a tetrahydropyridinyl), Ring RA-1 represents benzenediyl, cycloalkanediyl (preferably cyclobutanediyl or cyclohexanediyl), pyridinediyl or piperidinediyl, and n 1A-1 represents 0 or 1 (preferably 0).

[0091] According to a more preferred embodiment of the present invention, there is provided a compound or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), the formula (A) is the above formula (A)-1, The wavy line represents the binding site with S. R A1-1 represents a hydrogen atom, R A2-1 and R A3-1 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms (preferably, R A2-1 represents methyl, and R A3-1 represents ethyl), R A5-1 represents a hydrogen atom, Ring RA-1 represents benzenediyl, cyclohexanediyl, or pyridinediyl, and n 1A-1 represents 0 or 1 (preferably 0); A compound or a pharmaceutically acceptable salt thereof is provided.

[0092] According to a preferred embodiment of the present invention, there is provided a compound represented by formula (I) above, wherein formula (B) is the following formula (B)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line represents the binding site with S. R B1-1 represents a hydrogen atom, an alkoxycarbonylmethyl having 1 to 5 carbon atoms which may have a substituent (preferably, an ethoxycarbonylmethyl which may have a substituent (more preferably, an ethoxycarbonyl substituted with hydroxy, an ethoxycarbonyl substituted with methoxy, or an ethoxycarbonyl substituted with dimethylamino), a propoxycarbonylmethyl which may have a substituent (more preferably, a propoxycarbonylmethyl substituted with methoxy) or a butoxycarbonylmethyl (more preferably, a tert-butoxycarbonylmethyl)), a cycloalkyloxycarbonylmethyl which may have a substituent (preferably, a cyclohexyloxycarbonylmethyl which may have a substituent (more preferably, a cyclohexylmethyl substituted with hydroxy)), or —CHCONR B5-1 R B6-1 (In the formula, R B5-1 and R B6-1 are the same or different and each represents a hydrogen atom or an alkyl having 1 to 5 carbon atoms (preferably, R B5-1 is a hydrogen atom, R B5-1 represents ethyl), or together with the adjacent nitrogen atom represents a nitrogen-containing aliphatic heterocyclic group which may have a substituent (preferably piperazine), R B2-1 represents an alkyl group having 1 to 5 carbon atoms (preferably methyl) which may have a substituent, and R B3-1 and R B4-1 represents an alkyl group having 1 to 5 carbon atoms (preferably methyl) which may have a substituent.

[0093] According to a more preferred embodiment of the present invention, there is provided a compound or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), formula (B) is the above formula (B)-1, The wavy line represents the binding site with S. R B1-1 represents tert-butoxycarbonylmethyl, R B2-1 represents an alkyl group having 1 to 5 carbon atoms (preferably methyl) which may have a substituent, and R B3-1 and R B4-1 represents an alkyl group having 1 to 5 carbon atoms (preferably methyl) which may have a substituent, A compound or a pharmaceutically acceptable salt thereof is provided.

[0094] According to a preferred embodiment of the present invention, there is provided a compound of formula (I) above, wherein formula (C) is the following formula (C)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line represents the binding site with S. R C1-1 represents a hydrogen atom, R C3-1 represents a hydrogen atom or hydroxy, and Ring RC-1 is benzenediyl or piperidinediyl (preferably R C3-1 is a hydrogen atom, the ring RC-1 is piperidinediyl, and R C3-1 When RC-1 is hydroxy, ring RC-1 is benzenediyl).

[0095] According to a preferred embodiment of the present invention, there is provided a compound of formula (I) above, wherein formula (D) is the following formula (D)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line represents the binding site with S. R D1-1represents an alkyl group having 1 to 5 carbon atoms which may have a substituent (preferably ethyl) or an alkoxycarbonyl group having 1 to 5 carbon atoms which may have a substituent (preferably ethoxycarbonyl substituted with hydroxy, ethoxycarbonyl substituted with diethylamino, or unsubstituted methoxycarbonyl).

[0096] According to a preferred embodiment of the present invention, there is provided a compound represented by formula (I) above, wherein formula (E) is the following formula (E)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line represents the binding site with S. R E1-1 represents a hydrogen atom, R E2-1 and R E3-1 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms (preferably, R E2-1 represents methyl, and R E3-1 represents ethyl), and R E5-1 represents a hydrogen atom).

[0097] According to a preferred embodiment of the present invention, there is provided a compound of formula (I) above, wherein formula (F) is the following formula (F)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line represents the binding site with S. R F1-1 represents a hydrogen atom, R F2-1 and R F3-1 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms (preferably, R F2-1 represents methyl, and R F3-1 represents ethyl), R F5-1 represents a hydrogen atom, and R F7-1 represents a hydrogen atom or a fluorine atom).

[0098] According to a preferred embodiment of the present invention, there is provided a compound of formula (I) above, wherein S is the following formula (S1)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with n 1a-1 and n 1b-1 are the same or different and each represents 0 or 1, X 1a-1 and X 1b-1 are the same or different and are -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH- (provided that (i) X 1a-1 is -NH-SO2- and X 1b-1 is -SO2-NH-, (ii) n 1a-1 and n 1b-1 is 0 and X 1a-1 is -C(=O)-NH-, -SO2-NH-, -OC(=S)-NH-, -OC(=O)-NH- or -NH-C(=O)-NH-, and X 1b-1 is -NH-C(=O)-, -NH-SO2-, -NH-C(=O)-O- or -NH-C(=O)-NH-; and (iii) X 1a-1 is -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH-, and X 1b-1 represents -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH-), and preferably, X 1a-1 and X 1b-1 are the same or different and are -C(=O)-NH-, -NH-C(=O)- or -NH-C(=O)-NH- (provided that (i) X 1ais -NH-C(=O)-NH-, and X 1b is —NH—C(═O)—NH—, and (ii) n 1a and n 1b is 0 and X 1a is -C(=O)-NH- or -NH-C(=O)-NH-, and X 1b represents -NH-C(=O)-), and more preferably, X 1a represents -NH-C(=O)- or -NH-C(=O)-NH-, and X 1b represents -C(=O)-NH-, and R 1a-1 and R 1b-1 is R 1a-1 represents a hydrogen atom, and R 1b-1 represents a hydrogen atom or an alkyl having 1 to 5 carbon atoms (preferably methyl or isopropyl), or R 1a-1 and R 1b-1 together represent a carbonyl).

[0099] According to a more preferred embodiment of the present invention, there is provided a compound represented by the above formula (I), wherein S is the above formula (S1)-1, or a pharmaceutically acceptable salt thereof, wherein in the above formula (S1)-1: The wavy line is L 1 or L 2 represents the binding site with n 1a-1 and n 1b-1 are the same or different and each represents 0 or 1, X 1a-1 and X 1b-1 are the same or different and are -C(=O)-NH-, -NH-C(=O)-, -SO2-NH-, -NH-SO2-, -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH- (provided that (i) X 1a-1 is -NH-SO2- and X 1b-1 is -SO2-NH-, (ii) n 1a-1 and n 1b-1 is 0 and X 1a-1is -C(=O)-NH-, -SO2-NH-, -OC(=S)-NH-, -OC(=O)-NH- or -NH-C(=O)-NH-, and X 1b-1 is -NH-C(=O)-, -NH-SO2-, -NH-C(=O)-O- or -NH-C(=O)-NH-; and (iii) X 1a-1 is -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH-, and X 1b-1 represents -OC(=S)-NH-, -OC(=O)-NH-, -NH-C(=O)-O- or -NH-C(=O)-NH-), and preferably, X 1a-1 and X 1b-1 are the same or different and are -C(=O)-NH-, -NH-C(=O)- or -NH-C(=O)-NH- (provided that (i) X 1a is -NH-C(=O)-NH-, and X 1b is —NH—C(═O)—NH—, and (ii) n 1a and n 1b is 0 and X 1a is -C(=O)-NH- or -NH-C(=O)-NH-, and X 1b represents -NH-C(=O)-), and more preferably, X 1a represents -NH-C(=O)- or -NH-C(=O)-NH-, and X 1b represents -C(=O)-NH-, and R 1a-1 represents a hydrogen atom, and R 1b-1 represents a hydrogen atom, A compound or a pharmaceutically acceptable salt thereof is provided.

[0100] According to a preferred embodiment of the present invention, there is provided a compound of formula (I) above, wherein S is the following formula (S2)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line is L 1 or L 2represents the binding site with X 2a-1 represents -C(=O)-NH- or -NH-C(=O)-; X 2b-1 represents -C(=O)-NH-, -NH-C(=O)- or -CH2-, and Z 2-1 represents CH or N (wherein (i) Z 2-1 is N and X 2b-1 is -NH-C(=O)-, and (ii) Z 2-1 is CH and X 2b-1 (Except when -CH2-)

[0101] According to a preferred embodiment of the present invention, there is provided a compound of formula (I) above, wherein S is the following formula (S3)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with n 3a-1 and n 3b-1 are the same or different and represent 1 or 2, X 3-1 represents -C(=O)-NH-, -NH-C(=O)-, -NH-C(=O)-NH- or -NH-CH2- (preferably -C(=O)-NH-), and Z 3-1 represents CH or N (wherein (i) Z 3-1 is N and X 3-1 is -NH-C(=O)-, -NH-C(=O)-NH- or -NH-CH2-, and (ii) Z 3-1 is N, and n 3a-1 or n 3b-1 Except when is 1).

[0102] According to a preferred embodiment of the present invention, there is provided a compound of formula (I) above, wherein S is formula (S5)-1 below, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line is L 1 or L 2 represents a binding site for X 5a-1 and X 5b-1 are each the same or different and are -C(=O)-NH-, -NH-C(=O)- or -NH-SO2- (preferably, X 5a is -C(=O)-NH- or -NH-SO2-, and X 5b represents -C(=O)-NH- or -NH-C(=O)-).

[0103] According to a preferred embodiment of the present invention, there is provided a compound of formula (I) above, wherein S is the following formula (S6)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with n 6-1 represents 1 or 2, Ar 6-1 represents triazolediyl, oxadiazoldiyl, pyrazolediyl, thiophenediyl or tetrahydropyridinediyl, and X 6-1 represents -C(=O)-NH-, -NH-C(=O)- or -CH2-NH- (provided that (i)n 6-1 is 1 and Ar 6-1 is pyrazolediyl or tetrahydropyridinediyl, and X 6-1 except when is -C(=O)-NH- or -CH2-NH-).

[0104] According to a preferred embodiment of the present invention, there is provided a compound of formula (I) above, wherein S is the following formula (S7)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with X 7-1 represents -C(=O)-NH- or -NH-C(=O)-; n 7-1 represents 1, and Z 7-1 represents S, SO, or SO2).

[0105] According to a preferred embodiment of the present invention, there is provided a compound of formula (I) above, wherein S is the following formula (S8)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with X 8a-1 represents -C(=O)- or -CH2-, and X 8b-1 represents a bond, -C(=O)-, -CH2- or -CH(OH)-).

[0106] According to a preferred embodiment of the present invention, there is provided a compound of the above formula (I), wherein S is the following formula (S9)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with Ar 9-1 represents triazolediyl or oxazolediyl, and Z 9-1 represents CH2 or NH (wherein (i) Ar 9-1 is triazolediyl, and Z 9-1 is NH, and (ii) Ar 9-1 is oxazoldiyl, and Z 9-1except when CH2).

[0107] According to a preferred embodiment of the present invention, there is provided a compound of formula (I) above, wherein S is the following formula (S10)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line is L 1 or L 2 represents a binding site for Z 10-1 represents O or NH).

[0108] According to a preferred embodiment of the present invention, there is provided a compound of formula (I) above, wherein S is the following formula (S11)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with X 11a-1 represents -C(=O)-NH-, and X 11b-1 represents -C(=O)-NH- or -C(=O)-).

[0109] According to a preferred embodiment of the present invention, there is provided a compound represented by the above formula (I), wherein S is represented by the following formula (S12)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with X 12-1 represents -C(=O)-NH- or -NH-C(=O)-; Z 12a-1 represents CH2 or NH (where X 12-1 is -C(=O)-NH-, and Z 12a-1(except when is NH), Z 12b-1 represents CH2 or O (where Z 12a-1 is NH and Z 12b-1 is O), and Z 12c-1 represents a bond or O (wherein (i) Z 12b-1 is O and Z 12c-1 is O, and (ii) Z 12a-1 is NH and Z 12c-1 Except when is O).

[0110] According to a preferred embodiment of the present invention, there is provided a compound of formula (I) above, wherein S is the following formula (S13)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line is L 1 or L 2 represents a binding site for n 13-1 represents 0 or 2).

[0111] According to a preferred embodiment of the present invention, there is provided a compound represented by the above formula (I), wherein S is represented by the following formula (S16)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with n 16-1 represents 1 or 2, Z 16-1 represents a bond, CH2 or O, X 16-1 represents -CH2-O- or -C(=O)-NH-, and Ar 16-1 represents triazolediyl, oxadiazolediyl, or pyrazolediyl (provided that (i) X 16-1 is -CH2-O-, and Ar16-1 is oxadiazolediyl or pyrazolediyl, and (ii) n 16-1 is 1 and X 16-1 is -C(=O)-NH-, and Ar 16-1 (Except when is pyrazoldiyl)

[0112] According to a preferred embodiment of the present invention, there is provided a compound represented by the above formula (I), wherein S is represented by the following formula (S17)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line is L 1 or L 2 represents the binding site with n 17-1 represents 1 or 2, and X 17-1 represents -C(=O)-NH-).

[0113] According to a preferred embodiment of the present invention, there is provided a compound represented by the above formula (I), wherein S is represented by the following formula (S18)-1, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, The wavy line is L 1 or L 2 represents a binding site for n 18a-1 represents 2, and n 18b-1 represents 2, and n 18c-1 represents 1).

[0114] According to a more preferred embodiment of the present invention, in the above formula (I), L 1 and L 2 represents a group represented by formula (A) (preferably formula (A1)), and S represents a group represented by formula (S1), or a pharmaceutically acceptable salt thereof, In the formula (A), R A1 represents a hydrogen atom, and R A2 and RA3 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms (preferably, R A2 represents methyl, and R A3 represents ethyl), R A5 represents a hydrogen atom, the ring RA represents benzenediyl, and n 1A represents 0, and In the formula (S1), n 1a and n 1b represents 1, and X 1a and X 1b are the same or different and represent -C(=O)-NH- or -NH-C(=O)-, R 1a represents a hydrogen atom, and R 1b represents a hydrogen atom, A compound or a pharmaceutically acceptable salt thereof is provided.

[0115] According to a more preferred embodiment of the present invention, in the above formula (I), L 1 and L 2 represents a group represented by formula (A) (preferably, formula (A1) or (A5)), and S represents a group represented by formula (S1), or a pharmaceutically acceptable salt thereof, In the formula (A), R A1 represents a hydrogen atom, and R A2 and R A3 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms (preferably, R A2 represents methyl, and R A3 represents ethyl), R A5 represents a hydrogen atom, the ring RA represents benzenediyl or cycloalkanediyl, and n 1A represents 0, and In the formula (S1), n 1a and n 1b represents 0, X 1a and X 1bare the same or different and represent -C(=O)-NH-, -NH-C(=O)- or -NH-C(=O)-NH- (preferably -NH-C(=O)- or -NH-C(=O)-NH-) (provided that X 1a is -C(=O)-NH- or -NH-C(=O)-NH-, and X 1b is -NH-C(=O)- or -NH-C(=O)-NH-), R 1a represents a hydrogen atom, and R 1b represents a hydrogen atom, A compound or a pharmaceutically acceptable salt thereof is provided.

[0116] According to a more preferred embodiment of the present invention, in the above formula (I), L 1 and L 2 represents a group represented by formula (A) (preferably, formula (A1) or (A15)), and S represents a group represented by formula (S1), or a pharmaceutically acceptable salt thereof, In the formula (A), R A1 represents a hydrogen atom, and R A2 and R A3 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms (preferably, R A2 represents methyl, and R A3 represents ethyl), R A5 represents a hydrogen atom, the ring RA represents benzenediyl or pyridinediyl, and n 1A represents 0, and In the formula (S1), n 1a and n 1b represents 1, X 1a and X 1b are the same or different and represent -C(=O)-NH- or -NH-C(=O)-, and R 1a represents a hydrogen atom, and R 1b represents a hydrogen atom, A compound or a pharmaceutically acceptable salt thereof is provided.

[0117] According to a more preferred embodiment of the present invention, in the above formula (I), L 1 and L 2 represents a group represented by formula (A) (preferably, formula (A1) or (A5)), and S represents a group represented by formula (S3), or a pharmaceutically acceptable salt thereof, In the formula (A), R A1 represents a hydrogen atom, and R A2 and R A3 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms (preferably, R A2 represents methyl, and R A3 represents ethyl), R A5 represents a hydrogen atom, the ring RA represents benzenediyl or cycloalkanediyl, and n 1A represents 0, and In the formula (S3), n 3a and n 3b represents 2, and X 3 represents -C(=O)-NH-, and Z 3 represents N, A compound or a pharmaceutically acceptable salt thereof is provided.

[0118] According to a more preferred embodiment of the present invention, in the above formula (I), L 1 and L 2 represents a group represented by formula (A) (preferably, formula (A1) or (A5)), and S represents a group represented by formula (S3), or a pharmaceutically acceptable salt thereof, In the formula (A), R A1 represents a hydrogen atom, and R A2 and R A3 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms (preferably, R A2 represents methyl, and R A3 represents ethyl), R A5 represents a hydrogen atom, the ring RA represents benzenediyl or cycloalkanediyl, and n 1A represents 0, and In the formula (S3), n 3aand n 3b represents 1, and X 3 represents -C(=O)-NH-, and Z 3 represents CH, A compound or a pharmaceutically acceptable salt thereof is provided.

[0119] According to a more preferred embodiment of the present invention, in the above formula (I), L 1 and L 2 represents a group represented by formula (A) (preferably formula (A1)), and S represents a group represented by formula (S6), or a pharmaceutically acceptable salt thereof, In the formula (A), R A1 represents a hydrogen atom, and R A2 and R A3 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms (preferably, R A2 represents methyl, and R A3 represents ethyl), R A5 represents a hydrogen atom, the ring RA represents benzenediyl, and n 1A represents 0, and In the above formula (S6), n 6 represents 1, and Ar 6 represents oxadiazolediyl, and X 6 represents -CH2-NH-; A compound or a pharmaceutically acceptable salt thereof is provided.

[0120] According to a more preferred embodiment of the present invention, in the above formula (I), L 1 and L 2 represents a group represented by formula (A) (preferably formula (A1)), and S represents a group represented by formula (S6), or a pharmaceutically acceptable salt thereof, In the formula (A), R A1 represents a hydrogen atom, and R A2 and R A3 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms (preferably, R A2 represents methyl, and R A3 represents ethyl), RA5 represents a hydrogen atom, the ring RA represents benzenediyl, and n 1A represents 0, and In the above formula (S6), n 6 represents 1, and Ar 6 represents triazolediyl, and X 6 represents -CH2-NH-; A compound or a pharmaceutically acceptable salt thereof is provided.

[0121] According to a more preferred embodiment of the present invention, in the above formula (I), L 1 and L 2 represents a group represented by formula (A) (preferably, formula (A1) or (A5)), and S represents a group represented by formula (S6), or a pharmaceutically acceptable salt thereof, In the formula (A), R A1 represents a hydrogen atom, and R A2 and R A3 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms (preferably, R A2 represents methyl, and R A3 represents ethyl), R A5 represents a hydrogen atom, the ring RA represents benzenediyl or cycloalkanediyl, and n 1A represents 0, and In the above formula (S6), n 6 represents 1, and Ar 6 represents oxadiazolediyl, and X 6 represents -C(=O)-NH-; A compound or a pharmaceutically acceptable salt thereof is provided.

[0122] According to a more preferred embodiment of the present invention, in the above formula (I), L 1 and L 2 represents a group represented by formula (A) (preferably, formula (A1) or (A5)), and S represents a group represented by formula (S6), or a pharmaceutically acceptable salt thereof, In the formula (A), R A1represents a hydrogen atom, and R A2 and R A3 are the same or different and each represents an alkyl group having 1 to 5 carbon atoms (preferably, R A2 represents methyl, and R A3 represents ethyl), R A5 represents a hydrogen atom, the ring RA represents benzenediyl or cycloalkanediyl, and n 1A represents 0, and In the above formula (S6), n 6 represents 2, and Ar 6 represents triazolediyl, and X 6 represents -C(=O)-NH-; A compound or a pharmaceutically acceptable salt thereof is provided.

[0123] Pharmaceutically acceptable salts of Compound (I) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, etc. Pharmaceutically acceptable acid addition salts of Compound (I) include, for example, inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc., and organic acid salts such as acetate, oxalate, maleate, fumarate, citrate, benzoate, methanesulfonate, etc. Pharmaceutically acceptable metal salts include, for example, alkali metal salts such as sodium salt, potassium salt, etc., alkaline earth metal salts such as magnesium salt, calcium salt, aluminum salt, zinc salt, etc. Pharmaceutically acceptable ammonium salts include, for example, ammonium, tetramethylammonium, etc. Pharmaceutically acceptable organic amine addition salts include, for example, addition salts of morpholine, piperidine, etc. Pharmaceutically acceptable amino acid addition salts include, for example, addition salts of lysine, glycine, phenylalanine, aspartic acid, glutamic acid, etc.

[0124] The compound of the present invention means a compound that has not only pharmacological activity but also favorable properties in one or more of the various evaluation items required for a pharmaceutical composition or a cancer treatment or prevention agent, such as physical stability, stability under physiological conditions, and safety to living organisms.

[0125] Method for producing compound (I) Next, the method for producing compound (I) will be explained. In the following production methods, if the defined groups are changed under the conditions of the production method or are inappropriate for carrying out the production method, the target compound can be produced by using a method for introducing and removing protecting groups commonly used in organic synthetic chemistry [e.g., the method described in Protective Groups in Organic Synthesis, third edition, by T.W. Greene, John Wiley & Sons Inc. (1999)]. Furthermore, the order of reaction steps such as introducing substituents can be changed as necessary. First, in compound (I), L, which corresponds to the ligand, 1 or L 2 A method for producing a compound having the chemical structure shown below will be described.

[0126] [Manufacturing method 1] In formula (A), ring RA is ring RA1, and n 1A The compound (a-10) has a chemical structure in which ≡0, and in which (i) a carboxy is bonded to the wavy line portion, (ii) a compound (a-14) has an amino is bonded to the wavy line portion, and (iii) a compound (a-12) has a halogen is bonded to the wavy line portion, can be produced by the following steps. [ka] (In the formula, R A1 , R A2 , R A3 and R A5 has the same meaning as above, X represents a halogen, and R A4 represents lower alkyl, ring RA1 represents benzenediyl or pyridinediyl, and P represents an amine-protecting group such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p-methoxybenzyl (PMB), etc.

[0127] (Process 1) Compound (a-2) can be produced by reacting compound (a-1) with 0.001 to 0.5 equivalents of a rhodium catalyst in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours. The rhodium catalyst includes, for example, tris(triphenylphosphine)carbonyl rhodium hydride.

[0128] Examples of the solvent include tetrahydrofuran (THF), acetonitrile, etc., which can be used alone or in combination.

[0129] Compound (a-1) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 13, p. 118, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0130] (Process 2) Compound (a-4) can be produced by reacting compound (a-a2), 1 to 5 equivalents of compound (a-2), and 1 to 5 equivalents of compound (a-3) in the presence of a catalytic amount of bismuth(III) chloride in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0131] Examples of the solvent include THF, acetonitrile, etc., which can be used alone or in combination.

[0132] Compound (a-3) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 15, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto. Compound (a-a2) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0133] (Step 3) Compound (a-6) can be produced by reacting compound (a-4) with 1 to 5 equivalents of compound (a-5) in the presence of 1 equivalent to a large excess of a base in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0134] Examples of the base include sodium hydride, potassium hydride, lithium diisopropylamide (LDA), lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, sodium methoxide, potassium ethoxide, potassium tert-butoxide, potassium carbonate, sodium hydroxide, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), triethylamine, N,N-diisopropylethylamine, pyridine, and 4-dimethylaminopyridine.

[0135] Examples of solvents include chloroform, dichloromethane, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), THF, and acetonitrile, which can be used alone or in combination.

[0136] Compound (a-5) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 16, p. 101, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0137] (Step 4) When P in compound (a-6) is, for example, Boc, compound (a-7) can be produced by reacting compound (a-6) in the presence of 1 equivalent to a large excess of an acid in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours. Examples of the acid include hydrochloric acid, sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, bis(trifluoromethanesulfonyl)imide, and the like.

[0138] Examples of the solvent include chloroform, dichloromethane, toluene, THF, acetonitrile, etc., which can be used alone or in combination.

[0139] Furthermore, when P in compound (a-6) is, for example, Cbz, compound (a-7) can be produced by reacting compound (a-6) in the presence of 0.001 equivalent to 0.5 equivalent of a palladium catalyst under a hydrogen atmosphere in a solvent at a temperature between −20° C. and the boiling point of the solvent used for 5 minutes to 120 hours.

[0140] Examples of the palladium catalyst include palladium on carbon and palladium hydroxide.

[0141] Examples of the solvent include methanol, ethanol, ethyl acetate, THF, 1,4-dioxane, etc., which can be used alone or in combination.

[0142] When P in compound (a-6) is, for example, PMB, compound (a-7) can be produced by reacting compound (a-6) in the presence of 1 to 5 equivalents of an oxidizing agent in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours. Alternatively, compound (a-7) can be produced by the same method as when P is Boc or Cbz.

[0143] Examples of the oxidizing agent include 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and ammonium cerium (IV) nitrate (CAN).

[0144] Examples of the solvent include chloroform, dichloromethane, dichloroethane, etc., which can be used alone or in combination.

[0145] (Step 5) Compound (a-9) can be produced by reacting compound (a-7), 1 to 5 equivalents of compound (a-8), and 0.001 to 2 equivalents of copper catalyst (II) in the presence of 1 equivalent to a large excess of a base, in an oxygen atmosphere, in a solvent, at a temperature between -20°C and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0146] Examples of copper catalysts include copper(II) acetate, copper(II) chloride, copper(II) oxide, and copper sulfate pentahydrate.

[0147] Examples of the base include pyridine, 4-dimethylaminopyridine, DBU, triethylamine, N,N-diisopropylethylamine, and the like.

[0148] Examples of the solvent include chloroform, dichloromethane, THF, acetonitrile, etc., which can be used alone or in combination.

[0149] Compound (a-8) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 18, p. 97, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0150] (Step 6) Compound (a-10) can be produced by reacting compound (a-9) in the presence of 1 equivalent to a large excess of a base in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0151] Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, and the like.

[0152] Examples of the solvent include methanol, ethanol, DMF, DMA, NMP, DMSO, THF, acetonitrile, and water, and these can be used alone or in combination.

[0153] (Step 7) Compound (a-13) can be produced by reacting compound (a-7) with 1 to 5 equivalents of compound (a-15) in the presence of 1 equivalent to a large excess of a base in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0154] Examples of the base include sodium hydride, potassium hydride, LDA, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, sodium methoxide, potassium ethoxide, potassium tert-butoxide, potassium carbonate, sodium hydroxide, DBU, triethylamine, and N,N-diisopropylethylamine.

[0155] Examples of the solvent include DMF, DMA, NMP, DMSO, THF, and acetonitrile, which can be used alone or in combination.

[0156] Compound (a-15) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 17, p. 396, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0157] (Step 8) Compound (a-14) can be produced by reacting compound (a-13) in the presence of 0.001 to 0.5 equivalents of a palladium catalyst under a hydrogen atmosphere in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0158] Examples of the palladium catalyst include palladium on carbon and palladium hydroxide.

[0159] Examples of the solvent include methanol, ethanol, ethyl acetate, THF, 1,4-dioxane, etc., which can be used alone or in combination.

[0160] (Step 9) Compound (a-12) can be produced in the same manner as in step 5 of production method 1, using compound (a-7) and 1 to 5 equivalents of compound (a-11).

[0161] Compound (a-11) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 18, p. 97, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0162] [Manufacturing method 1-2] In formula (A), ring RA is ring RA1, and n 1A (i) Compound (a-18) in which a carboxy is bonded to the wavy line portion, (ii) Compound (a-21) in which an amino is bonded to the wavy line portion, and (iii) Compound (a-23) in which a halogen is bonded to the wavy line portion, each having a chemical structure of 1, can be produced by the following steps. [ka] (In the formula, R A1 , R A2 , R A3 and R A5 has the same meaning as above, and R A4 represents lower alkyl, and X t1 represents a halogen, and ring RA1 represents benzenediyl or pyridinediyl).

[0163] (Process 1) Compound (a-17) can be produced by reacting compound (a-7) with 1 to 5 equivalents of compound (a-16) in the presence of 1 equivalent to a large excess of a base in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0164] Examples of the base include sodium hydride, potassium hydride, LDA, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, sodium methoxide, potassium ethoxide, potassium tert-butoxide, potassium carbonate, sodium hydroxide, DBU, triethylamine, and N,N-diisopropylethylamine.

[0165] Examples of the solvent include DMF, DMA, NMP, DMSO, THF, acetonitrile, dichloromethane, chloroform, etc., which can be used alone or in combination. Compound (a-16) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 13, p. 377, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0166] (Process 2) Compound (a-18) can be produced in the same manner as in step 6 of Production Method 1, using compound (a-17).

[0167] (Step 3) Compound (a-20) can be produced using compound (a-7) and 1 to 5 equivalents of compound (a-19) in the same manner as in step 1 of production method 1-2. Compound (a-19) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 13, p. 377, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0168] (Step 4) Compound (a-21) can be produced in the same manner as in step 8 of Production Method 1, using compound (a-20).

[0169] (Step 5) Compound (a-23) can be produced using compound (a-7) and 1 to 5 equivalents of compound (a-22) in the same manner as in step 1 of production method 1-2.

[0170] Compound (a-22) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 13, p. 377, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0171] [Manufacturing method 1-3] In formula (A), ring RA is ring RA2, and n 1A (i) Compound (a-26) in which carboxy is bonded to the wavy line portion, and (ii) Compound (a-29) in which amino is bonded to the wavy line portion, and among the compounds represented by formula (A), Compound (a-32) in which Ring RA is Ring RA3, can be produced by the following steps. [ka] (In the formula, R A1 , R A2 , R A3 , R A5 and P are as defined above, and R A4 represents lower alkyl, ring RA2 represents cycloalkanediyl, and ring RA3 represents piperidinediyl, azetidinediyl, pyrrolidinediyl, or homopiperidinediyl).

[0172] (Process 1) Compound (a-25) can be produced by reacting compound (a-7) with 1 to 5 equivalents of compound (a-24) in the presence of 1 to 5 equivalents of a reducing agent and 1 to 5 equivalents of an acid in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0173] The reducing agent includes sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like.

[0174] The acid includes hydrochloric acid, trifluoroacetic acid, acetic acid, and the like.

[0175] Examples of the solvent include methanol and ethanol, which can be used alone or in combination.

[0176] Compound (a-24) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 15, p. 153, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0177] (Process 2) Compound (a-26) can be produced in the same manner as in step 6 of Production Method 1, using compound (a-25).

[0178] (Step 3) Compound (a-28) can be produced using compound (a-7) and 1 to 5 equivalents of compound (a-27) in the same manner as in step 1 of production method 1-3.

[0179] Compound (a-27) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 15, p. 153, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0180] (Step 4) Compound (a-29) can be produced in the same manner as in step 4 of Production Method 1, using compound (a-28).

[0181] (Step 5) Compound (a-31) can be produced in the same manner as in step 1 of production method 1-3, using compound (a-7) and 1 to 5 equivalents of compound (a-30).

[0182] Compound (a-30) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 15, p. 153, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0183] (Step 6) Compound (a-32) can be produced in the same manner as in step 4 of Production Method 1, using compound (a-31).

[0184] [Manufacturing method 1-4] In formula (A), ring RA is ring RA2, and n 1A(i) Compound (a-35) in which carboxy is bonded to the wavy line portion, and (ii) Compound (a-38) in which amino is bonded to the wavy line portion, and among the compounds represented by formula (A), Compound (a-41) in which Ring RA is Ring RA3 can be produced by the following steps. [ka] (In the formula, R A1 , R A2 , R A3 , R A5 and P are as defined above, and R A4 represents lower alkyl, ring RA2 represents cycloalkanediyl, and ring RA3 represents piperidinediyl, azetidinediyl, pyrrolidinediyl, or homopiperidinediyl).

[0185] (Process 1) Compound (a-34) can be produced in the same manner as in step 1 of production method 1-3, using compound (a-7) and 1 to 5 equivalents of compound (a-33).

[0186] Compound (a-33) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 15, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0187] (Process 2) Compound (a-35) can be produced in the same manner as in step 6 of Production Method 1, using compound (a-34).

[0188] (Step 3) Compound (a-37) can be produced using compound (a-7) and 1 to 5 equivalents of compound (a-36) in the same manner as in step 1 of production method 1-3.

[0189] Compound (a-36) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 15, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0190] (Step 4) Compound (a-38) can be produced in the same manner as in step 4 of Production Method 1, using compound (a-37).

[0191] (Step 5) Compound (a-40) can be produced using compound (a-7) and 1 to 5 equivalents of compound (a-39) in the same manner as in step 1 of production method 1-3.

[0192] Compound (a-39) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 15, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0193] (Step 6) Compound (a-41) can be produced using compound (a-40) in the same manner as in step 4 of production method 1.

[0194] [Manufacturing method 2] In formula (B), R B1 R B7 (i) Compound (b-9) in which bromo is bonded to the wavy line portion, (ii) Compound (b-10) in which carboxy is bonded to the wavy line portion, and (iii) Compound (b-11) in which amino is bonded to the wavy line portion can be produced by the following steps. [ka] (In the formula, R B2 , R B3 and R B4 has the same meaning as above, and R B7 represents a hydrogen atom and tert-butoxycarbonylmethyl, and Fmoc represents 9-fluorenylmethyloxycarbonyl.

[0195] (Process 1) Compound (b-3) can be produced by reacting compound (b-1) with 1 to 5 equivalents of compound (b-2) in the presence of 1 to 5 equivalents of sulfur and 0.25 to 5 equivalents of a base in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0196] Examples of the base include pyrrolidine, piperidine, and morpholine.

[0197] Examples of the solvent include methanol, ethanol, DMF, DMA, NMP, DMSO, THF, and acetonitrile, and these can be used alone or in combination.

[0198] Compound (b-1) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 14, p. 517, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0199] Compound (b-2) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 15, p. 153, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0200] (Process 2) Compound (b-5) can be produced by reacting compound (b-3) with 1 to 5 equivalents of compound (b-4) in the presence of 1 equivalent to a large excess of a condensing agent, and optionally in the presence of 1 equivalent to a large excess of an additive, in a solvent at a temperature between -20°C and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0201] Examples of condensing agents include dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), and the like.

[0202] Examples of additives include 1-hydroxybenzotriazole monohydrate (HOBt), triethylamine, and N,N-diisopropylethylamine.

[0203] Examples of the solvent include chloroform, dichloromethane, DMF, DMA, THF, acetonitrile, etc., which can be used alone or in combination.

[0204] Compound (b-4) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 16, p. 175, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0205] (Step 3) Compound (b-6) can be produced by reacting compound (b-5) in the presence of 1 equivalent to a large excess of a base in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0206] Examples of the base include pyrrolidine, piperidine, and morpholine.

[0207] Examples of the solvent include methanol, ethanol, DMF, DMA, NMP, DMSO, THF, and acetonitrile, and these can be used alone or in combination.

[0208] (Step 4) Compound (b-7) can be produced by reacting compound (b-6) in the presence of 1 equivalent to a large excess of an acid in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0209] Examples of the acid include acetic acid, formic acid, hydrochloric acid, magnesium sulfate, and the like.

[0210] Examples of the solvent include methanol, ethanol, toluene, etc., which can be used alone or in combination.

[0211] (Step 5) Compound (b-9) can be produced by reacting compound (b-7) with 1 to 5 equivalents of compound (b-8) in the presence of 1 to a large excess of a base and 1 to 5 equivalents of a phosphate ester in a solvent at a temperature between −78° C. and the boiling point of the solvent used for 5 minutes to 120 hours.

[0212] Examples of the base include sodium hydride, potassium hydride, LDA, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, sodium methoxide, potassium ethoxide, potassium tert-butoxide, potassium carbonate, sodium hydroxide, DBU, triethylamine, and N,N-diisopropylethylamine.

[0213] Examples of the phosphate ester include diethyl chlorophosphate and dimethyl chlorophosphate.

[0214] Examples of the solvent include DMF, DMA, NMP, DMSO, THF, and acetonitrile, which can be used alone or in combination.

[0215] Compound (b-8) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 14, p. 406, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0216] (Step 6) Compound (b-10) can be produced by reacting compound (b-9) in the presence of 0.001 to 0.5 equivalents of a palladium catalyst, 0.001 to 0.5 equivalents of a phosphorus ligand, and 1 equivalent to a large excess of a base, in a carbon monoxide atmosphere, in a solvent, at a temperature between -20°C and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0217] Examples of palladium catalysts include palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2), and tris(dibenzylideneacetone)dipalladium (Pd2(dba)3).

[0218] Examples of the phosphorus ligand include triphenylphosphine, tributylphosphine, bis(diphenylphosphino)propane, bis(diphenylphosphino)butane, and bis(diphenylphosphino)ferrocene.

[0219] Examples of the base include sodium hydride, potassium hydride, LDA, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, sodium methoxide, potassium ethoxide, potassium tert-butoxide, potassium carbonate, sodium hydroxide, DBU, triethylamine, and N,N-diisopropylethylamine.

[0220] Examples of the solvent include DMF, DMA, NMP, DMSO, THF, acetonitrile, 1,4-dioxane, toluene, and water, which can be used alone or in combination.

[0221] (Step 7) Compound (b-11) can be produced by reacting compound (b-10) in the presence of 1 to 5 equivalents of diphenylphosphoryl azide and 1 equivalent to a large excess of a base in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0222] Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, DBU, triethylamine, N,N-diisopropylethylamine, and the like.

[0223] Examples of the solvent include THF, acetonitrile, 1,4-dioxane, toluene, water, etc., which can be used alone or in combination.

[0224] [Manufacturing method T2] In formula (B), R B1 R B9 (i) Compound (b-16) in which bromo is bonded to the wavy line portion, (ii) Compound (b-20) in which carboxy is bonded to the wavy line portion, and (iii) Compound (b-24) in which amino is bonded to the wavy line portion can be produced by the following steps. [ka] (In the formula, R B2 , R B3 , R B4 , R B5 and R B6 has the same meaning as above, and R B8 represents an optionally substituted lower alkyl or an optionally substituted cycloalkyl, R B9 is an optionally substituted lower alkoxycarbonylmethyl, an optionally substituted cycloalkyloxycarbonylmethyl, or -CHCONR B5 R B6 represents t Bu represents tert-butyl, Bn represents benzyl, and P represents an amine protecting group such as Cbz or Fmoc.

[0225] (Process 1) Compound (b-13) can be produced by reacting compound (b-12) in the presence of 1 equivalent to a large excess of an acid, without or in a solvent, at a temperature between 0°C and 150°C for 5 minutes to 120 hours. Compound (b-12) is a compound (b-9) obtained in step 5 of production method 2, in which R B7 is tert-butoxycarbonylmethyl.

[0226] Examples of the acid include hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, titanium tetrachloride, boron trifluoride, etc., which may be used alone or in combination.

[0227] Examples of solvents include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, 1,2-dimethoxyethane (DME), 1,4-dioxane, DMF, DMA, and NMP, which may be used alone or in combination.

[0228] (Process 2) Compound (b-16) can be produced in the same manner as in step 2 of production method 2, using compound (b-13) and 1 to 10 equivalents of compound (b-14) or compound (b-15).

[0229] Compound (b-14) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 14, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0230] Compound (b-15) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0231] (Step 3) Compound (b-18) can be produced by reacting compound (b-17) with 1 to 10 equivalents of benzyl bromide in the presence of 1 to 10 equivalents of a base, without or in a solvent, at a temperature between -20°C and 150°C for 5 minutes to 120 hours.

[0232] Compound (b-17) is a compound (b-10) obtained in step 6 of production method 2, in which R B7 is tert-butoxycarbonylmethyl.

[0233] Examples of the base include potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, DBU, and the like.

[0234] Examples of the solvent include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and pyridine, which may be used alone or in combination.

[0235] (Step 4) Compound (b-19) can be produced in the same manner as in steps 1 and 2 using compound (b-18) and 1 to 10 equivalents of compound (b-14) or compound (b-15).

[0236] (Step 5) Compound (b-20) can be produced by reacting compound (b-19) in the presence of 0.001 to 0.5 equivalents of a palladium catalyst under a hydrogen atmosphere in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0237] Examples of the palladium catalyst include palladium on carbon and palladium hydroxide.

[0238] Examples of the solvent include methanol, ethanol, ethyl acetate, THF, 1,4-dioxane, etc., which can be used alone or in combination.

[0239] (Step 6) Compound (b-22) can be produced by reacting compound (b-21) with 1 to 10 equivalents of compound (b-1t) in the presence of 1 to 10 equivalents of a base, without or in a solvent, at a temperature between -20°C and 150°C for 5 minutes to 120 hours.

[0240] Compound (b-1t) is commercially available, or can be obtained by a known method [for example, Organic Syntheses, Coll. Vol. 3, p. 167 (1955)] or a method similar thereto.

[0241] Compound (b-21) is a compound (b-11) obtained in step 7 of production method 2, in which R B7 is tert-butoxycarbonylmethyl.

[0242] Examples of the base include potassium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, DBU, 4-dimethylaminopyridine, and the like.

[0243] Examples of solvents include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine, and water, which may be used alone or in combination.

[0244] (Step 7) Compound (b-23) can be produced in the same manner as in steps 1 and 2 using compound (b-22) and 1 to 10 equivalents of compound (b-14) or compound (b-15).

[0245] (Step 8) Compound (b-24) can be produced in the same manner as in step 5 when P in compound (b-23) is, for example, Cbz, and in the same manner as in step 3 of production method 2 when P in compound (b-23) is, for example, Fmoc.

[0246] [Manufacturing method 3] In formula (C), R C3 Compound (c-7), which has a chemical structure in which R is hydroxy, the ring RC is benzenediyl, and carboxy is bonded to the wavy line portion, can be produced according to the following steps. [ka] (In the formula, R C1 is as defined above, X represents a halogen, and R C2 represents lower alkyl)

[0247] (Process 1) Compound (c-3) can be produced by reacting compound (c-1) with 1 to 5 equivalents of compound (c-2) in the presence of 1 equivalent to a large excess of a base in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0248] Examples of the base include sodium hydride, potassium hydride, butyllithium, LDA, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, sodium methoxide, potassium ethoxide, potassium tert-butoxide, potassium carbonate, sodium hydroxide, DBU, triethylamine, and N,N-diisopropylethylamine.

[0249] Examples of the solvent include DMF, DMA, NMP, DMSO, THF, and acetonitrile, which can be used alone or in combination.

[0250] Compound (c-2) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 13, p. 341, Maruzen Co., Ltd. (2004)] or a method similar thereto. (Process 2)

[0251] Compound (c-5) can be produced by reacting compound (c-3) with 1 to 5 equivalents of compound (c-4) in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0252] Examples of the solvent include THF, 1,4-dioxane, diethyl ether, toluene, etc., which can be used alone or in combination.

[0253] Compound (c-4) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 18, p. 78, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0254] (Step 3) Compound (c-6) can be produced by reacting compound (c-5) with 1 to 5 equivalents of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)isoxazole in the presence of 0.001 to 0.5 equivalents of a palladium catalyst and 1 equivalent to a large excess of a base, in a solvent, at a temperature between -20°C and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0255] Examples of the palladium catalyst include palladium acetate, palladium chloride, Pd(PPh3)4, bis(triphenylphosphine)palladium dichloride, Pd(dppf)Cl2, and Pd2(dba)3.

[0256] Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, DBU, triethylamine, N,N-diisopropylethylamine, and the like.

[0257] Examples of the solvent include DMF, DMA, NMP, DMSO, THF, acetonitrile, 1,4-dioxane, toluene, and water, which can be used alone or in combination.

[0258] (Step 4) Compound (c-7) can be produced in the same manner as in step 6 of Production Method 1, using compound (c-6).

[0259] [Manufacturing method Y4] In formula (C), R C3 is a hydrogen atom, and ring RC is ring RC1, and (i) compound (c-11) in which carboxy is bonded to the wavy line portion and (ii) compound (c-14) in which amino is bonded to the wavy line portion can be produced according to the following steps. [ka] (In the formula, R C1 and R C2 is as defined above, P represents an amine protecting group such as Boc, Cbz, or PMB, and ring RC1 represents piperidinediyl, azetidinediyl, pyrrolidinediyl, or homopiperidinediyl. One of the secondary amines forming ring RC1 serves as a reaction site with compound (c-8).

[0260] (Process 1) Compound (c-8) can be produced in the same manner as in step 3 of Production Method 3, using compound (c-3).

[0261] (Process 2) Compound (c-10) can be produced using compound (c-8) and 1 to 5 equivalents of (c-9) in the same manner as in step 1 of production method 1-3.

[0262] Compound (c-9) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0263] (Step 3) Compound (c-11) can be produced in the same manner as in step 6 of Production Method 1, using compound (c-10).

[0264] (Step 4) Compound (c-13) can be produced using compound (c-8) and 1 to 5 equivalents of compound (c-12) in the same manner as in step 1 of production method 1-3.

[0265] Compound (c-12) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0266] (Step 5) Compound (c-14) can be produced in the same manner as in step 4 of Production Method 1, using compound (c-13).

[0267] [Manufacturing method 4] Compound (d-6), (i) in which a carboxyl group is bonded to the wavy line portion, compound (d-9), (ii) in which an amino group is bonded to the wavy line portion, and compound (d-11), (iii) in which a bromo group is bonded to the wavy line portion, each having a chemical structure represented by formula (D) can be produced according to the following steps. [ka] (In the formula, R D1 is as defined above, and R D2 represents a lower alkyl, and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0268] (Process 1) Compound (d-3) can be produced by reacting cyclohexane-1,3-dione with 1 to 5 equivalents of compound (d-2) in the presence of 1 equivalent to a large excess of a base in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0269] Examples of the base include sodium hydride, potassium hydride, LDA, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, sodium methoxide, potassium ethoxide, potassium tert-butoxide, potassium carbonate, sodium hydroxide, DBU, triethylamine, and N,N-diisopropylethylamine.

[0270] Examples of the solvent include DMF, DMA, NMP, DMSO, THF, and acetonitrile, which can be used alone or in combination.

[0271] Compound (d-2) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 13, p. 374, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0272] (Process 2) Compound (d-5) can be produced by reacting compound (d-3) with 1 to 5 equivalents of compound (d-4) in the presence of 1 equivalent to a large excess of a base in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0273] Examples of the base include sodium hydride, potassium hydride, LDA, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, sodium methoxide, potassium ethoxide, potassium tert-butoxide, potassium carbonate, sodium hydroxide, DBU, triethylamine, and N,N-diisopropylethylamine.

[0274] Examples of the solvent include toluene, DMF, DMA, NMP, DMSO, THF, and acetonitrile, which can be used alone or in combination.

[0275] Compound (d-4) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0276] (Step 3) Compound (d-6) can be produced in the same manner as in step 6 of Production Method 1, using compound (d-5).

[0277] (Step 4) Compound (d-8) can be produced in the same manner as in step 2 using compound (d-3) and 1 to 5 equivalents of compound (d-7).

[0278] Compound (d-7) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0279] (Step 5) Compound (d-9) can be produced in the same manner as in step 4 of Production Method 1, using compound (d-8). (Step 6) Compound (d-11) can be produced in the same manner as in step 2 using compound (d-3) and 1 to 5 equivalents of compound (d-10).

[0280] Compound (d-10) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0281] [Manufacturing method Y5] Compound (e-1), which has a chemical structure represented by formula (E) and in which a hydrogen atom is bonded to the wavy line portion, can be obtained in the same manner as in step 4 of production method 1. [Manufacturing method Y6] Compound (f-5), which has a chemical structure represented by formula (F) and in which a carboxy is bonded to the wavy line portion, can be produced according to the following steps. [ka] (In the formula, R F1 , R F2 , R F3 , R F5 and R F7 has the same meaning as above, and R F4 and R F8 Each represents a lower alkyl.

[0282] (Process 1) Compound (f-1) can be produced in the same manner as in Step 1 of Production Method 1-3, using compound (f-f1) and 1 to 10 equivalents of 4-hydroxycyclohexan-1-one. Compound (f-f1) can be obtained in the same manner as in step 4 of production method 1.

[0283] (Process 2) Compound (f-2) can be produced by reacting compound (f-1) in the presence of 1 to 5 equivalents of an oxidizing agent in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0284] Examples of the oxidizing agent include Dess-Martin periodinane (DMP), DMSO / oxalyl chloride, sulfur trioxide-pyridine, and the like.

[0285] Examples of solvents include dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and DMSO, and these can be used alone or in combination.

[0286] (Step 3) Compound (f-4) can be produced by reacting 1 to 5 equivalents of compound (f-3) with 1 to 5 equivalents of a base in a solvent at a temperature between −78° C. and the boiling point of the solvent used for 5 to 30 minutes, then adding compound (f-2) to the reaction mixture and reacting at a temperature between −78° C. and the boiling point of the solvent used for 5 to 120 hours.

[0287] Examples of the base include sodium hydride, potassium tert-butoxide, LDA, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, DBU, and the like.

[0288] Examples of the solvent include THF, DME, hexamethylphosphoric triamide (HMPA), etc., which can be used alone or in combination.

[0289] Compound (f-3) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 4th edition, Vol. 24, p. 243, Maruzen Co., Ltd. (1994)] or a method similar thereto. (Step 4)

[0290] Compound (f-5) can be produced in the same manner as in step 6 of Production Method 1, using compound (f-4).

[0291] Next, a method for producing compound (I) using compounds (a-10), (a-12), (a-14), (a-18), (a-21), (a-23), (a-26), (a-29), (a-32), (a-35), (a-38), (a-41), (b-9), (b-10), (b-11), (b-16), (b-20), (b-24), (c-7), (c-11), (c-14), (d-6), (d-9), (d-11), (e-1), (f-1) and / or (f-5) obtained by the above-mentioned Production Method 1, Production Method 1-2, Production Method 1-3, Production Method 1-4, Production Method 2, Production Method T2, Production Method 3, Production Method Y4, Production Method 4 or Production Method Y6 will be described.

[0292] Here, compounds (a-10), (a-18), (a-26), (a-35), (b-10), (b-20), (c-7), (c-11), (d-6), and (f-5) are collectively referred to as L-COH(I-1). Similarly, compounds (a-14), (a-21), (a-29), (a-38), (b-11), (b-24), (c-14), and (d-9) are referred to as L-NH(I-2). Compounds (a-12) and (a-23) in which X is bromo, as well as (b-9), (b-16), and (d-11) are referred to as L-Br(I-3).

[0293] [Manufacturing method 5] Among the compounds (I) in which S is formula (S1), (i) X 1b Compound (I-13) in which X is —NH—C(═O)— 1b Compound (I-14) in which is -NH-SO2- can be prepared according to the following steps. [ka] (In the formula, R 1a , R 1b , n 1a , n 1b and X 1a is as defined above, and L is L 1 or L 2 and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0294] (Process 1) Compound (I-5) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-1) and 1 to 5 equivalents of compound (I-4).

[0295] Compound (I-4) can be obtained as a commercially available product or by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0296] (Process 2) Compound (I-7) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-2) and 1 to 5 equivalents of compound (I-6).

[0297] Compound (I-6) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 16, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0298] (Step 3) Compound (I-9) can be produced by reacting compound (I-2) with 1 to 5 equivalents of compound (I-8) in the presence of 1 equivalent to a large excess of a base in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0299] Examples of the base include triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and the like.

[0300] Examples of the solvent include chloroform, dichloromethane, DMF, DMA, NMP, DMSO, THF, and acetonitrile, which can be used alone or in combination.

[0301] Compound (I-8) is commercially available or can be obtained by a known method [for example, Organic Syntheses, Coll. Vol. 4, p. 571 (1963)] or a method similar thereto.

[0302] (Step 4) Compound (I-11) can be produced by (i) reacting compound (I-3) in the presence of 1 to 5 equivalents of 4-methoxyphenylmethanethiol, 0.001 to 3 equivalents of a palladium catalyst, 0.001 to 3 equivalents of a phosphorus ligand, and 1 equivalent to a large excess of a base, in a solvent at a temperature between room temperature and the boiling point of the solvent used, for 5 minutes to 120 hours, and then (ii) reacting the resulting compound in the presence of 1 to 5 equivalents of trichloroisocyanuric acid and 1 equivalent to a large excess of compound (I-4), in a solvent, at a temperature between -20°C and room temperature, for 5 minutes to 120 hours.

[0303] The palladium catalyst used in (i) includes, for example, Pd2(dba)3.

[0304] The phosphorus ligand used in (i) includes, for example, xantphos.

[0305] Examples of the base used in (i) include triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium tert-butoxide, sodium carbonate, potassium carbonate, and the like.

[0306] Examples of the solvent used in (i) include DMF, DMA, NMP, DMSO, THF, acetonitrile, 1,4-dioxane, etc., which can be used alone or in combination.

[0307] The solvent used in (ii) includes, for example, acetonitrile, water, etc., which can be used alone or in combination.

[0308] (Step 5) Compound (I-12) can be produced in the same manner as in step 4 of Production Method 1 using compound (I-5), (I-7), (I-9), (I-11), (I-2t), (I-3t), (I-5t), or (I-6t).

[0309] (Step 6) Compound (I-13) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-12) and 1 to 5 equivalents of compound (I-1).

[0310] (Step 7) Compound (I-14) can be produced in the same manner as in Step 4 of Production Method 5, using compound (I-12) and 1 to 5 equivalents of compound (I-3).

[0311] (Step 8) Compound (I-2t) can be produced by reacting compound (I-1t), 1 to 10 equivalents of compound (I-4), and 1 to 10 equivalents of a thiocarbonyl reagent in the presence of 1 to 10 equivalents of a base, in a solvent, at a temperature between -20°C and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0312] Examples of the thiocarbonyl reagent include thiophosgene, 1,1-thiocarbonyldiimidazole, and the like.

[0313] Examples of the base include triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and the like.

[0314] Examples of the solvent include dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DMF, NMP, and pyridine, which may be used alone or in combination.

[0315] Compound (I-1t) is collectively referred to as compound (I-1t), which includes compound (ly-58) obtained in step 1 of production method YS12-1 and compound (f-1) obtained in step 1 of production method Y6.

[0316] (Step 9) Compound (I-3t) can be produced by reacting compound (I-1t), 1 to 10 equivalents of compound (I-4), and 1 to 10 equivalents of a carbonyl reagent in the presence of 1 to 10 equivalents of a base, in a solvent, at a temperature between -20°C and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0317] Examples of the carbonyl reagent include phosgene, 1,1-carbonyldiimidazole (CDI), and the like.

[0318] Examples of the base include triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and the like.

[0319] Examples of the solvent include dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DMF, NMP, and pyridine, which may be used alone or in combination.

[0320] (Step 10) Compound (I-5t) can be produced in the same manner as in Step 9 using compound (I-2) and 1 to 10 equivalents of compound (I-4t).

[0321] Compound (I-4t) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 14, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto. (Step 11)

[0322] Compound (I-6t) can be produced in the same manner as in Step 9 using compound (I-2) and 1 to 10 equivalents of compound (I-4).

[0323] [Manufacturing method 6] Among the compounds (I) in which S is of the formula (S1), X 1b Compound (I-24), in which is —C(═O)—NH—, can be prepared according to the following steps. [ka] (In the formula, R 1a , R 1b , n 1a , n 1b and X 1a is as defined above, and L is L 1 or L 2 represents R e represents lower alkyl)

[0324] (Process 1) Compound (I-19) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-1) and 1 to 5 equivalents of compound (I-15).

[0325] Compound (I-15) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0326] (Process 2) Compound (I-20) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-2) and 1 to 5 equivalents of compound (I-16).

[0327] Compound (I-16) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 16, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0328] (Step 3) Compound (I-21) can be produced in the same manner as in Step 3 of Production Method 5, using compound (I-2) and 1 to 5 equivalents of compound (I-17).

[0329] Compound (I-17) is commercially available or can be obtained by a known method [for example, Organic Syntheses, Coll. Vol. 4, p. 571 (1963)] or a method similar thereto. (Step 4)

[0330] Compound (I-22) can be produced in the same manner as in Step 4 of Production Method 5, using compound (I-3) and 1 to 5 equivalents of compound (I-15).

[0331] (Step 5) Compound (I-23) can be produced in the same manner as in step 6 of Production Method 1 using compound (I-19), (I-20), (I-21), (I-22), (I-9t), (I-10t), (I-12t), or (I-13t).

[0332] (Step 6) Compound (I-24) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-23) and 1 to 5 equivalents of compound (I-2). (Step 7) Compound (I-9t) can be produced in the same manner as in Step 8 of Production Method 5, using compound (I-1t) and 1 to 10 equivalents of compound (I-15).

[0333] (Step 8) Compound (I-10t) can be produced in the same manner as in Step 9 of Production Method 5, using compound (I-1t) and 1 to 10 equivalents of compound (I-15).

[0334] (Step 9) Compound (I-12t) can be produced in the same manner as in Step 9 of Production Method 5, using compound (I-2) and 1 to 10 equivalents of compound (I-11t).

[0335] Compound (I-11t) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 14, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0336] (Step 10) Compound (I-13t) can be produced in the same manner as in Step 9 of Production Method 5, using compound (I-2) and 1 to 10 equivalents of compound (I-15).

[0337] [Manufacturing method 7] Among the compounds (I) in which S is of the formula (S1), X 1b is -SO2-NH-, (i) X 1a (ii) Compound (I-16t) in which X is —C(═O)—NH— 1a is -SO2-NH-, (iii) X 1a Compound (I-18t) in which is -OC(=S)-NH-, (iv) X 1a Compound (I-19t) in which is -OC(=O)-NH-, (v) X 1a Compound (I-20t) in which is —NH—C(═O)—NH—, (vi) X 1a is —NH—C(═O)—, and (vii) X 1a Compound (I-22t) in which is —NH—C(═O)—O— can be prepared according to the following steps. [ka] (In the formula, R 1a , R 1b , n 1a and n 1b is as defined above, and L is L 1 or L 2 represents R e represents a lower alkyl, and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0338] (Process 1) Compound (I-27) can be produced in the same manner as in Step 3 of Production Method 5, using compound (I-2) and 1 to 5 equivalents of compound (I-25).

[0339] Compound (I-25) is commercially available, or can be obtained by a known method [for example, Organic Syntheses, Coll. Vol. 4, p. 571 (1963)] or a method similar thereto.

[0340] (Process 2) Compound (I-28) can be produced in the same manner as in Step 3 of Production Method 5, using compound (I-2) and 1 to 5 equivalents of compound (I-26).

[0341] Compound (I-26) is commercially available or can be obtained by a known method [for example, Organic Syntheses, Coll. Vol. 4, p. 571 (1963)] or a method similar thereto.

[0342] (Step 3) Compound (I-29) can be produced in the same manner as in step 4 of Production Method 1, using compound (I-27).

[0343] (Step 4) Compound (I-30) can be produced in the same manner as in step 6 of Production Method 1, using compound (I-28).

[0344] (Step 5) Compound (I-16t) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-29) and 1 to 5 equivalents of compound (I-1).

[0345] (Step 6) Compound (I-17t) can be produced in the same manner as in Step 4 of Production Method 5, using compound (I-29) and 1 to 5 equivalents of compound (I-3).

[0346] (Step 7) Compound (I-21t) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-30) and 1 to 5 equivalents of compound (I-2).

[0347] (Step 8) Compound (I-18t) can be produced in the same manner as in Step 8 of Production Method 5, using compound (I-29) and 1 to 5 equivalents of compound (I-1t).

[0348] (Step 9) Compound (I-19t) can be produced in the same manner as in Step 9 of Production Method 5, using compound (I-29) and 1 to 5 equivalents of compound (I-1t).

[0349] (Step 10) Compound (I-20t) can be produced in the same manner as in Step 9 of Production Method 5, using compound (I-29) and 1 to 5 equivalents of compound (I-2).

[0350] (Step 11) Compound (I-15t) can be produced in the same manner as in Step 3 of Production Method 5, using compound (I-2) and 1 to 5 equivalents of compound (I-14t).

[0351] Compound (I-14t) is commercially available, or can be obtained by a known method [for example, Organic Syntheses, Coll. Vol. 4, p. 571 (1963)] or a method similar thereto. (Step 12)

[0352] Compound (I-22t) can be produced in the same manner as in Step 9 of Production Method 5, using compound (I-15t) and 1 to 5 equivalents of compound (I-2).

[0353] [Manufacturing method 8] Among the compounds (I) in which S is formula (S2), Z 2 is CH, and (i) X 2b Compound (I-41) in which X is —NH—C(═O)— 2b Compound (I-42) in which is -NH-SO2- can be prepared according to the following steps. [ka] (In the formula, X 2a is as defined above, and L is L 1 or L 2 and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0354] (Process 1) Compound (I-36) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-1) and 1 to 5 equivalents of compound (I-32).

[0355] Compound (I-32) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0356] (Process 2) Compound (I-37) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-2) and 1 to 5 equivalents of compound (I-33).

[0357] Compound (I-33) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 16, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0358] (Step 3) Compound (I-38) can be produced in the same manner as in Step 3 of Production Method 5, using compound (I-2) and 1 to 5 equivalents of compound (I-34).

[0359] Compound (I-34) is commercially available, or can be obtained by a known method [for example, Organic Syntheses, Coll. Vol. 4, p. 571 (1963)] or a method similar thereto.

[0360] (Step 4) Compound (I-39) can be produced in the same manner as in Step 4 of Production Method 5, using compound (I-3) and 1 to 5 equivalents of compound (I-32).

[0361] (Step 5) Compound (I-40) can be produced in the same manner as in step 4 of Production Method 1 using compound (I-36), (I-37), (I-38) or (I-39).

[0362] (Step 6) Compound (I-41) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-40) and 1 to 5 equivalents of compound (I-1).

[0363] (Step 7) Compound (I-42) can be produced in the same manner as in Step 4 of Production Method 5, using compound (I-40) and 1 to 5 equivalents of compound (I-3).

[0364] [Manufacturing method 9] Among the compounds (I) in which S is formula (S2), Z 2 is CH and X 2b Compound (I-52), in which is —C(═O)—NH—, can be prepared according to the following steps. [ka] (In the formula, X 2a is as defined above, and L is L 1 or L 2 represents R e represents lower alkyl)

[0365] (Process 1) Compound (I-47) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-1) and 1 to 5 equivalents of compound (I-43).

[0366] Compound (I-43) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0367] (Process 2) Compound (I-48) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-2) and 1 to 5 equivalents of compound (I-44).

[0368] Compound (I-44) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 16, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0369] (Step 3) Compound (I-49) can be produced in the same manner as in Step 3 of Production Method 5, using compound (I-2) and 1 to 5 equivalents of compound (I-45).

[0370] Compound (I-45) is commercially available, or can be obtained by a known method [for example, Organic Syntheses, Coll. Vol. 4, p. 571 (1963)] or a method similar thereto.

[0371] (Step 4) Compound (I-50) can be produced in the same manner as in Step 4 of Production Method 5, using compound (I-3) and 1 to 5 equivalents of compound (I-43).

[0372] (Step 5) Compound (I-51) can be produced in the same manner as in step 6 of Production Method 1 using compound (I-47), (I-48), (I-49) or (I-50).

[0373] (Step 6) Compound (I-52) can be produced in the same manner as in step 2 of Production Method 2, using compound (I-51) and 1 to 5 equivalents of compound (I-2).

[0374] [Manufacturing method 10] Among the compounds (I) in which S is formula (S2), Z 2 is CH and X 2b Compound (I-59) in which is -SO2-NH- can be prepared according to the following steps. [ka] (In the formula, X 2a is as defined above, and L is L 1 or L 2 represents R e represents a lower alkyl, and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0375] (Process 1) Compound (I-55) can be produced in the same manner as in Step 3 of Production Method 5, using compound (I-2) and 1 to 5 equivalents of compound (I-53).

[0376] Compound (I-53) is commercially available, or can be obtained by a known method [for example, Organic Syntheses, Coll. Vol. 4, p. 571 (1963)] or a method similar thereto.

[0377] (Process 2) Compound (I-56) can be produced in the same manner as in Step 3 of Production Method 5, using compound (I-2) and 1 to 5 equivalents of compound (I-54).

[0378] Compound (I-54) is commercially available or can be obtained by a known method [for example, Organic Syntheses, Coll. Vol. 4, p. 571 (1963)] or a method similar thereto.

[0379] (Step 3) Compound (I-57) can be produced in the same manner as in step 4 of Production Method 1, using compound (I-55).

[0380] (Step 4) Compound (I-58) can be produced in the same manner as in Step 6 of Production Method 1, using compound (I-56).

[0381] (Step 5) Among compounds (I-59), X 2a The compound in which is —C(═O)—NH— can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-57) and 1 to 5 equivalents of compound (I-1).

[0382] (Step 6) Among compounds (I-59), X 2a The compound in which is -SO2-NH- can be produced in the same manner as in Step 4 of Production Method 5, using compound (I-57) and 1 to 5 equivalents of compound (I-3).

[0383] (Step 7) Among compounds (I-59), X 2a The compound in which is —NH—C(═O)— can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-58) and 1 to 5 equivalents of compound (I-2).

[0384] [Manufacturing method YS2] Among the compounds (I) in which S is formula (S2), Z 2 is N, and (i) X 2b is —C(═O)—NH—, and (ii) X 2b The compound (I-32t) in which is -CH2- can be prepared according to the following steps. [ka] (In the formula, X 2a is as defined above, and L is L 1 or L 2and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0385] (Process 1) Compound (I-26t) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-1) and 1 to 10 equivalents of compound (I-23t).

[0386] Compound (I-23t) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0387] (Process 2) Compound (I-27t) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-2) and 1 to 10 equivalents of compound (I-24t).

[0388] Compound (I-24t) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 16, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0389] (Step 3) Compound (I-28t) can be produced in the same manner as in Step 3 of Production Method 5, using compound (I-2) and 1 to 10 equivalents of compound (I-25t).

[0390] Compound (I-25t) is commercially available, or can be obtained by a known method [for example, Organic Syntheses, Coll. Vol. 4, p. 571 (1963)] or a method similar thereto.

[0391] (Step 4) Compound (I-29t) can be produced in the same manner as in Step 4 of Production Method 5, using compound (I-3) and 1 to 10 equivalents of compound (I-23t).

[0392] (Step 5) Compound (I-30t) can be produced in the same manner as in step 4 of Production Method 1 using compound (I-26t), compound (I-27t), compound (I-28t), or compound (I-29t).

[0393] (Step 6) Compound (I-31t) can be produced in the same manner as in Step 9 of Production Method 5, using compound (I-30t) and 1 to 5 equivalents of compound (I-2). (Step 7)

[0394] Compound (I-32t) can be produced using compound (I-30t) and 1 to 5 equivalents of compound (I-40t) in the same manner as in step 1 of production method 1-3.

[0395] Compound (I-40t) can be obtained by step 10 of production method 17.

[0396] [Manufacturing method 11] Among the compounds (I) in which S is formula (S3), Z 3 is CH and X 3 is X 3a Compound (I-63) can be prepared according to the following steps. [ka] (In the formula, n 3a and n 3b is as defined above, and L is L 1 or L 2 represents X 3a represents -NH-C(=O)-, -NH-SO2-, -NH-C(=O)-NH- or -NHCH2-, and P represents an amine protecting group such as Boc, Cbz or PMB.

[0397] (Process 1) Compound (I-61) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-1) and 1 to 5 equivalents of compound (I-60).

[0398] Compound (I-60) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto. (Process 2)

[0399] Compound (I-62) can be produced in the same manner as in step 4 of Production Method 1, using compound (I-61).

[0400] (Step 3) Among compounds (I-63), X 3a The compound in which is —NH—C(═O)— can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-62) and 1 to 5 equivalents of compound (I-1).

[0401] (Step 4) Among compounds (I-63), X 3a The compound in which is -NH-SO2- can be produced in the same manner as in Step 4 of Production Method 5, using compound (I-62) and 1 to 5 equivalents of compound (I-3).

[0402] (Step 5) Among compounds (I-63), X 3a The compound in which is —NH—C(═O)—NH— can be produced in the same manner as in step 9 of production method 5, using compound (I-62) and 1 to 5 equivalents of compound (I-2).

[0403] (Step 6) Among compounds (I-63), X 3a The compound in which is -NHCH2- can be produced in the same manner as in Step 1 of Production Method 1-3, using compound (I-62) and 1 to 5 equivalents of compound (I-40t).

[0404] [Manufacturing method 12] Among the compounds (I) in which S is formula (S3), Z 3 is CH and X 3 is X 3bCompound (I-68) can be prepared according to the following steps. [ka] (In the formula, n 3a and n 3b is as defined above, and L is L 1 or L 2 represents X 3b represents -C(=O)-NH- or -SO2-NH-, and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0405] (Process 1) Among compounds (I-66), X 3b The compound in which is —C(═O)—NH— can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-2) and 1 to 5 equivalents of compound (I-64).

[0406] Compound (I-64) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 16, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0407] (Process 2) Among compounds (I-66), X 3b The compound in which is -SO2-NH- can be produced in the same manner as in Step 3 of Production Method 5, using compound (I-2) and 1 to 5 equivalents of compound (I-65).

[0408] Compound (I-65) is commercially available, or can be obtained by a known method [for example, Organic Syntheses, Coll. Vol. 4, p. 571 (1963)] or a method similar thereto.

[0409] (Step 3) Compound (I-67) can be produced in the same manner as in step 4 of Production Method 1, using compound (I-66).

[0410] (Step 4) Compound (I-68) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-67) and 1 to 5 equivalents of compound (I-1).

[0411] [Manufacturing method YS3] Among the compounds (I) in which S is formula (S3), Z 3 is N and X 3 is -C(=O)-NH-, and n 3a and n 3b The compound (I-35t) in which is 2 can be prepared according to the following steps. [ka] (Wherein, L is L 1 or L 2 and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0412] (Process 1) Compound (I-33t) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-1) and 1 to 10 equivalents of compound (I-36t).

[0413] Compound (I-36t) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0414] (Process 2) Compound (I-34t) can be produced in the same manner as in step 4 of Production Method 1, using compound (I-33t).

[0415] (Step 3) Compound (I-35t) can be produced in the same manner as in Step 9 of Production Method 5, using compound (I-34t) and 1 to 5 equivalents of compound (I-2).

[0416] [Manufacturing method 13] Compound (I) in which S is formula (S4) can be prepared according to the following steps. [ka] (Wherein, L is L 1 or L 2 and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0417] (Process 1) Compound (I-70) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-1) and 1 to 5 equivalents of compound (I-69).

[0418] Compound (I-69) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0419] (Process 2) Compound (I-71) can be produced in the same manner as in step 4 of Production Method 1, using compound (I-70).

[0420] (Step 3) Compound (I-72) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-71) and 1 to 5 equivalents of compound (I-1).

[0421] [Manufacturing method 14] Among the compounds (I) in which S is formula (S5), (i) X 5b Compound (I-82) in which X is —NH—C(═O)— 5b The compound (I-83) in which is -NH-SO2- can be prepared according to the following steps. [ka] (In the formula, X 5a is as defined above, and L is L 1 or L 2and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0422] (Process 1) Compound (I-77) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-1) and 1 to 5 equivalents of compound (I-73).

[0423] Compound (I-73) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0424] (Process 2) Compound (I-78) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-2) and 1 to 5 equivalents of compound (I-74).

[0425] Compound (I-74) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 16, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0426] (Step 3) Compound (I-79) can be produced in the same manner as in Step 3 of Production Method 5, using compound (I-2) and 1 to 5 equivalents of compound (I-75).

[0427] Compound (I-75) is commercially available, or can be obtained by a known method [for example, Organic Syntheses, Coll. Vol. 4, p. 571 (1963)] or a method similar thereto.

[0428] (Step 4) Compound (I-80) can be produced in the same manner as in Step 4 of Production Method 5, using compound (I-3) and 1 to 5 equivalents of compound (I-73).

[0429] (Step 5) Among compounds (I-81), X 5a The compound in which is —C(═O)—NH— can be produced in the same manner as in step 4 of production method 1 using compound (I-77).

[0430] (Step 6) Among compounds (I-81), X 5a The compound in which is —NH—C(═O)— can be produced in the same manner as in step 4 of production method 1 using compound (I-78).

[0431] (Step 7) Among compounds (I-81), X 5a The compound in which is -NH-SO2- can be produced in the same manner as in step 8 of production method 1 using compound (I-79).

[0432] (Step 8) Among compounds (I-81), X 5a The compound in which is -SO2-NH- can be produced in the same manner as in step 4 of production method 1 using compound (I-80).

[0433] (Step 9) Compound (I-82) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-81) and 1 to 5 equivalents of compound (I-1).

[0434] (Step 10) Compound (I-83) can be produced in the same manner as in Step 4 of Production Method 5, using compound (I-81) and 1 to 5 equivalents of compound (I-3).

[0435] [Manufacturing method 15] Among compounds (I) in which S is formula (S5), X 5b Compound (I-93), in which is —C(═O)—NH—, can be prepared according to the following steps. [ka] (In the formula, X 5ais as defined above, and L is L 1 or L 2 represents R e represents lower alkyl)

[0436] (Process 1) Compound (I-88) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-1) and 1 to 5 equivalents of compound (I-84).

[0437] Compound (I-84) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0438] (Process 2) Compound (I-89) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-2) and 1 to 5 equivalents of compound (I-85).

[0439] Compound (I-85) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 16, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0440] (Step 3) Compound (I-90) can be produced in the same manner as in Step 3 of Production Method 5, using compound (I-2) and 1 to 5 equivalents of compound (I-86).

[0441] Compound (I-86) is commercially available, or can be obtained by a known method [for example, Organic Syntheses, Coll. Vol. 4, p. 571 (1963)] or a method similar thereto.

[0442] (Step 4) Compound (I-91) can be produced in the same manner as in Step 4 of Production Method 5, using compound (I-3) and 1 to 5 equivalents of compound (I-84).

[0443] (Step 5) Compound (I-92) can be produced in the same manner as in step 6 of Production Method 1 using compound (I-88), (I-89), (I-90) or (I-91).

[0444] (Step 6) Compound (I-93) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-92) and 1 to 5 equivalents of compound (I-2).

[0445] [Manufacturing method 16] Among compounds (I) in which S is formula (S5), X 5b -SO 2- The compound (I-100) which is NH- can be prepared according to the following steps. [ka] (In the formula, X 5a is as defined above, and L is L 1 or L 2 represents R e represents lower alkyl)

[0446] (Process 1) Compound (I-96) can be produced in the same manner as in Step 3 of Production Method 5, using compound (I-2) and 1 to 5 equivalents of compound (I-94).

[0447] Compound (I-94) is commercially available, or can be obtained by a known method [for example, Organic Syntheses, Coll. Vol. 4, p. 571 (1963)] or a method similar thereto.

[0448] (Process 2) Compound (I-97) can be produced in the same manner as in Step 3 of Production Method 5, using compound (I-2) and 1 to 5 equivalents of compound (I-95).

[0449] Compound (I-95) is commercially available, or can be obtained by a known method [for example, Organic Syntheses, Coll. Vol. 4, p. 571 (1963)] or a method similar thereto.

[0450] (Step 3) Compound (I-98) can be produced in the same manner as in step 8 of Production Method 1, using compound (I-96).

[0451] (Step 4) Compound (I-99) can be produced in the same manner as in step 6 of Production Method 1, using compound (I-97).

[0452] (Step 5) Among compounds (I-100), X 5a The compound in which is —C(═O)—NH— can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-98) and 1 to 5 equivalents of compound (I-1).

[0453] (Step 6) Among compounds (I-100), X 5a The compound in which is -SO2-NH- can be produced in the same manner as in Step 4 of Production Method 5, using compound (I-98) and 1 to 5 equivalents of compound (I-3).

[0454] (Step 7) Among compounds (I-100), X 5a The compound in which is —NH—C(═O)— can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-99) and 1 to 5 equivalents of compound (I-2).

[0455] [Manufacturing method 17] Among the compounds (I) in which S is formula (S6), Ar 6 Compound (I-103), in which is a triazole, can be prepared according to the following steps. [ka] (In the formula, X 6 and n 6 is as defined above, and L is L 1 or L 2 (represents

[0456] (Process 1) Among compounds (I-101), X 6 The compound in which is —C(═O)—NH— can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-1) and 1 to 5 equivalents of compound (I-37t).

[0457] Compound (I-37t) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0458] (Process 2) Among compounds (I-101), X 6 The compound in which is —NH—C(═O)— can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-2) and 1 to 5 equivalents of compound (I-38t).

[0459] Compound (I-38t) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 16, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0460] (Step 3) Among compounds (I-101), X 6 The compound in which is -NH-SO2- can be produced in the same manner as in Step 3 of Production Method 5, using compound (I-2) and 1 to 5 equivalents of compound (I-39t).

[0461] Compound (I-39t) is commercially available, or can be obtained by a known method [for example, Organic Syntheses, Coll. Vol. 4, p. 571 (1963)] or a method similar thereto.

[0462] (Step 4) Among compounds (I-101), X 6 The compound in which is -SO2-NH- can be produced in the same manner as in Step 4 of Production Method 5, using compound (I-3) and 1 to 5 equivalents of compound (I-37t).

[0463] (Step 5) Compound (I-102) can be produced by reacting compound (I-2) with 1 to 5 equivalents of an azidation agent, optionally in the presence of 1 to 5 equivalents of an additive, in a solvent at a temperature between room temperature and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0464] Examples of the azidation agent include 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP).

[0465] Examples of additives include 4-dimethylaminopyridine (DMAP) and triethylamine.

[0466] Examples of the solvent include dichloromethane, acetonitrile, THF, etc., which can be used alone or in combination.

[0467] (Step 6) Compound (I-103) can be produced by reacting compound (I-101) with 1 to 5 equivalents of compound (I-102) in the presence of 0.001 to 2 equivalents of a copper catalyst and 0.001 to 2 equivalents of sodium L-ascorbate in a solvent at a temperature between room temperature and the boiling point of the solvent used for 5 minutes to 120 hours.

[0468] The copper catalyst includes, for example, copper sulfate pentahydrate.

[0469] Examples of the solvent include chloroform, dichloromethane, DMF, DMA, NMP, DMSO, THF, acetonitrile, water, 1,4-dioxane, and s-butanol, and these can be used alone or in combination.

[0470] (Step 7) Among compounds (I-101), X 6 The compound in which is -CH2-NH- can be produced using compound (I-40t) and 1 to 5 equivalents of compound (I-37t) in the same manner as in step 1 of production method 1-3.

[0471] (Step 8) Among compounds (I-101), X 6 The compound in which is —NH—C(═O)—NH— can be produced in the same manner as in Step 9 of Production Method 5, using compound (I-2) and 1 to 5 equivalents of compound (I-37t).

[0472] (Step 9) Compound (I-41t) can be produced by reacting compound (I-1) in the presence of 1 to 10 equivalents of a reducing agent in a solvent at a temperature between -78°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0473] Examples of the reducing agent include lithium aluminum hydride, diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, borane dimethyl sulfide complex, lithium borohydride, sodium borohydride, and the like.

[0474] Examples of the solvent include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, and NMP, which may be used alone or in combination.

[0475] (Step 10) Compound (I-40t) can be produced by reacting compound (I-41t) in the presence of 1 to 10 equivalents of an oxidizing agent in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0476] Examples of the oxidizing agent include manganese dioxide, DMP, sulfur trioxide-pyridine, DMSO / oxalyl chloride, and the like.

[0477] Examples of the solvent include dichloromethane, THF, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, etc., which may be used alone or in combination.

[0478] [Manufacturing method 18] Among the compounds (I) in which S is formula (S6), Ar 6 Compound (I-112), in which is 1,3,4-oxadiazoldiyl, can be prepared according to the following steps. [ka] (In the formula, X 6 and n 6 is as defined above, and L is L 1 or L 2 represents R e represents a lower alkyl, and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0479] (Process 1) Compound (I-106) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-1) and 1 to 5 equivalents of compound (I-104).

[0480] Compound (I-104) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 14, p. 406, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0481] (Process 2) Compound (I-107) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-1) and 1 to 5 equivalents of compound (I-105).

[0482] Compound (I-105) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 14, p. 406, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0483] (Step 3) Compound (I-108) can be produced by reacting compound (I-106) in the presence of 1 to 5 equivalents of triphenylphosphine, 1 to 5 equivalents of carbon tetrachloride, and 1 equivalent to a large excess of a base in a solvent at a temperature between room temperature and the boiling point of the solvent used for 5 minutes to 120 hours.

[0484] Examples of the base include triethylamine, N,N-diisopropylethylamine, DBU, pyridine, and the like.

[0485] Examples of the solvent include chloroform, dichloromethane, DMF, DMA, NMP, THF, acetonitrile, and 1,4-dioxane, and these can be used alone or in combination.

[0486] (Step 4) Compound (I-109) can be produced in the same manner as in Step 3 of Production Method 18, using compound (I-107).

[0487] (Step 5) Compound (I-110) can be produced in the same manner as in step 4 of Production Method 1, using compound (I-108).

[0488] (Step 6) Compound (I-111) can be produced in the same manner as in step 6 of Production Method 1, using compound (I-109).

[0489] (Step 7) Among compounds (I-112), X 6 The compound in which is —C(═O)—NH— can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-110) and 1 to 5 equivalents of compound (I-1).

[0490] (Step 8) Among compounds (I-112), X 6 The compound in which is -SO2-NH- can be produced in the same manner as in Step 4 of Production Method 5, using compound (I-110) and 1 to 5 equivalents of compound (I-3).

[0491] (Step 9) Among compounds (I-112), X 6 The compound in which is —NH—C(═O)— can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-111) and 1 to 5 equivalents of compound (I-2).

[0492] (Step 10) Among compounds (I-112), X 6 The compound in which is -CH2-NH- can be produced in the same manner as in Step 1 of Production Method 1-3 using compound (I-110) and 1 to 5 equivalents of compound (I-40t).

[0493] (Step 11) Among compounds (I-112), X 6 The compound in which is —NH—C(═O)—NH— can be produced in the same manner as in Step 9 of Production Method 5, using compound (I-110) and 1 to 5 equivalents of compound (I-2).

[0494] [Manufacturing method 19] Among the compounds (I) in which S is formula (S6), Ar 6 Compound (I-119) in which is 1,2,4-oxadiazoldiyl can be prepared according to the following steps. [ka] (In the formula, X 6 and n6 is as defined above, and L is L 1 or L 2 represents R e represents a lower alkyl, and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0495] (Process 1) Compound (I-115) can be produced by reacting compound (I-1) with 1 to 5 equivalents of compound (I-113) in the presence of 1 equivalent to a large excess of a condensing agent and 1 equivalent to a large excess of a base in a solvent at a temperature between 60°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0496] Examples of the condensing agent include DCC, EDC, HATU, and COMU.

[0497] Examples of the base include triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and the like.

[0498] Examples of the solvent include chloroform, dichloromethane, DMF, DMA, NMP, DMSO, THF, and acetonitrile, which can be used alone or in combination.

[0499] Compound (I-113) is commercially available, or can be obtained by a known method [for example, Chemical Reviews, Volume 62, Issue 2, p. 155 (1962)] or a method similar thereto.

[0500] (Process 2) Compound (I-116) can be produced in the same manner as in Step 1 of Production Method 19, using compound (I-1) and 1 to 5 equivalents of compound (I-114).

[0501] Compound (I-114) is commercially available, or can be obtained by a known method [for example, Chemical Reviews, Volume 62, Issue 2, p. 155 (1962)] or a method similar thereto.

[0502] (Step 3) Compound (I-117) can be produced in the same manner as in step 4 of Production Method 1, using compound (I-115).

[0503] (Step 4) Compound (I-118) can be produced in the same manner as in step 6 of Production Method 1, using compound (I-116).

[0504] (Step 5) Among compounds (I-119), X 6 The compound in which is —C(═O)—NH— can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-117) and 1 to 5 equivalents of compound (I-1).

[0505] (Step 6) Among compounds (I-119), X 6 The compound in which is -SO2-NH- can be produced in the same manner as in Step 4 of Production Method 5, using compound (I-117) and 1 to 5 equivalents of compound (I-3).

[0506] (Step 7) Among compounds (I-119), X 6 The compound in which is —NH—C(═O)— can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-118) and 1 to 5 equivalents of compound (I-2).

[0507] (Step 8) Among compounds (I-119), X 6 The compound in which is -CH2-NH- can be produced in the same manner as in Step 1 of Production Method 1-3 using compound (I-117) and 1 to 5 equivalents of compound (I-40t).

[0508] (Step 9) Among compounds (I-119), X 6 The compound in which is —NH—C(═O)—NH— can be produced in the same manner as in Step 9 of Production Method 5, using compound (I-117) and 1 to 5 equivalents of compound (I-2).

[0509] [Manufacturing method YS6-1] Among the compounds (I) in which S is formula (S6), Ar 6 is pyrazolediyl, (i) X 6 (ii) a compound (Iy-119) in which X is —C(═O)—NH—; 6 is -SO2-NH-, (iii) X 6 is —CH—NH—, (iv) X 6 is —NH—C(═O)—NH—; and (v) X 6 Compound (Iy-123) in which is —NH—C(═O)— can be prepared according to the following steps. [ka] (In the formula, n 6 is as defined above, and L is L 1 or L 2 represents R e represents lower alkyl, and R 6a represents a hydrogen atom or lower alkyl, and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0510] (Process 1) Compound (Iy-115) can be produced in the same manner as in Step 3 of Production Method 3, using compound (I-3) and 1 to 5 equivalents of compound (Iy-113).

[0511] Compound (Iy-113) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 18, p. 95, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0512] (Process 2) Compound (Iy-116) can be produced in the same manner as in Step 3 of Production Method 3, using compound (I-3) and 1 to 5 equivalents of compound (Iy-114).

[0513] Compound (Iy-114) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 18, p. 95, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0514] (Step 3) Compound (Iy-117) can be produced in the same manner as in step 4 of production method 1, using compound (Iy-115).

[0515] (Step 4) Compound (Iy-118) can be produced in the same manner as in step 6 of production method 1, using compound (Iy-116).

[0516] (Step 5) Compound (Iy-119) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-117) and 1 to 5 equivalents of compound (I-1).

[0517] (Step 6) Compound (Iy-120) can be produced in the same manner as in Step 4 of Production Method 5, using compound (Iy-117) and 1 to 5 equivalents of compound (I-3).

[0518] (Step 7) Compound (Iy-121) can be produced using compound (Iy-117) and 1 to 5 equivalents of compound (I-40t) in the same manner as in step 1 of production method 1-3.

[0519] (Step 8) Compound (Iy-122) can be produced in the same manner as in Step 9 of Production Method 5, using compound (Iy-117) and 1 to 5 equivalents of compound (I-2).

[0520] (Step 9) Compound (Iy-123) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-118) and 1 to 5 equivalents of compound (I-2).

[0521] [Manufacturing method YS6-2] Among the compounds (I) in which S is formula (S6), Ar 6 is tetrahydropyridinediyl, and (i) X 6 (ii) a compound (Iy-102a) in which X is —C(═O)—NH—; 6 is -SO2-NH- (Iy-102b), (iii) X 6 is —CH—NH—, (iv) X 6 is —NH—C(═O)—NH—; and (v) X 6 Compound (Iy-102e) in which is —NH—C(═O)— can be produced according to the following steps. [ka] (In the formula, n 6 is as defined above, and L is L 1 or L 2 represents R e represents lower alkyl, and R 6a represents a hydrogen atom or lower alkyl, X represents a halogen, and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0522] (Process 1) Compound (Iy-94) can be produced in the same manner as in Step 3 of Production Method 3, using compound (I-3) and 1 to 5 equivalents of compound (Iy-93).

[0523] Compound (Iy-93) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 18, p. 95, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0524] (Process 2) Compound (Iy-95) can be produced in the same manner as in step 4 of production method 1, using compound (Iy-94).

[0525] (Step 3) Compound (Iy-98) can be produced in the same manner as in Step 1 of Production Method 1-2, using compound (Iy-95) and 1 to 5 equivalents of compound (Iy-96).

[0526] Compound (Iy-96) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 13, p. 374, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0527] (Step 4) Compound (Iy-99) can be produced in the same manner as in Step 1 of Production Method 1-2, using compound (Iy-95) and 1 to 5 equivalents of compound (Iy-97).

[0528] Compound (Iy-97) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 13, p. 374, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0529] (Step 5) Compound (Iy-100) can be produced in the same manner as in step 4 of production method 1, using compound (Iy-98).

[0530] (Step 6) Compound (Iy-101) can be produced in the same manner as in step 6 of production method 1, using compound (Iy-99).

[0531] (Step 7) Compound (Iy-102a) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-100) and 1 to 5 equivalents of compound (I-1).

[0532] (Step 8) Compound (Iy-102b) can be produced in the same manner as in Step 4 of Production Method 5, using compound (Iy-100) and 1 to 5 equivalents of compound (I-3).

[0533] (Step 9) Compound (Iy-102c) can be produced using compound (Iy-100) and 1 to 5 equivalents of compound (I-40t) in the same manner as in step 1 of production method 1-3.

[0534] (Step 10) Compound (Iy-102d) can be produced in the same manner as in Step 9 of Production Method 5, using compound (Iy-100) and 1 to 5 equivalents of compound (I-2).

[0535] (Step 11) Compound (Iy-102e) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-101) and 1 to 5 equivalents of compound (I-2).

[0536] [Manufacturing method YS6-3] Among the compounds (I) in which S is formula (S6), Ar 6 is thiophenediyl, and (i) X 6 (ii) a compound (Iy-109) in which X is —C(═O)—NH—; 6 Compound (Iy-110) in which is -SO2-NH-, (iii) X 6 is —CH—NH—, (iv) X 6 is —NH—C(═O)—NH—; and (v) X 6 Compound (Iy-112a) in which is —NH—C(═O)— can be prepared according to the following steps. [ka] (In the formula, n 6 is as defined above, and L is L 1 or L 2represents R e represents lower alkyl, and R 6a represents a hydrogen atom or lower alkyl, and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0537] (Process 1) Compound (Iy-105) can be produced in the same manner as in Step 3 of Production Method 3, using compound (I-3) and 1 to 5 equivalents of compound (Iy-103).

[0538] Compound (Iy-103) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 18, p. 95, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0539] (Process 2) Compound (Iy-106) can be produced in the same manner as in Step 3 of Production Method 3, using compound (I-3) and 1 to 5 equivalents of compound (Iy-104).

[0540] Compound (Iy-104) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 18, p. 95, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0541] (Step 3) Compound (Iy-107) can be produced in the same manner as in step 4 of production method 1, using compound (Iy-105).

[0542] (Step 4) Compound (Iy-108) can be produced in the same manner as in step 6 of production method 1, using compound (Iy-106).

[0543] (Step 5) Compound (Iy-109) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-107) and 1 to 5 equivalents of compound (I-1).

[0544] (Step 6) Compound (Iy-110) can be produced in the same manner as in Step 4 of Production Method 5, using compound (Iy-107) and 1 to 5 equivalents of compound (I-3).

[0545] (Step 7) Compound (Iy-111) can be produced using compound (Iy-107) and 1 to 5 equivalents of compound (I-40t) in the same manner as in step 1 of production method 1-3.

[0546] (Step 8) Compound (Iy-112) can be produced in the same manner as in Step 9 of Production Method 5, using compound (Iy-107) and 1 to 5 equivalents of compound (I-2).

[0547] (Step 9) Compound (Iy-112a) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-108) and 1 to 5 equivalents of compound (I-2).

[0548] [Manufacturing method 20] Among compounds (I), compounds (I-126), (I-126a) and (I-126b) in which S is formula (S7) can be produced according to the following steps. [ka] (In the formula, X 7 and n 7 is as defined above, and L is L 1 or L 2 represents R e represents a lower alkyl, and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0549] (Process 1) Compound (I-122) can be produced by reacting compound (I-3) with 1 to 5 equivalents of compound (I-120) in the presence of 0.001 to 3 equivalents of a palladium catalyst, 0.001 to 3 equivalents of a phosphorus ligand, and 1 equivalent to a large excess of a base in a solvent at a temperature between room temperature and the boiling point of the solvent used for 5 minutes to 120 hours.

[0550] The palladium catalyst includes, for example, Pd2(dba)3.

[0551] Examples of phosphorus ligands include xantphos.

[0552] Examples of the base include triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium tert-butoxide, sodium carbonate, potassium carbonate, and the like.

[0553] Examples of the solvent include chloroform, dichloromethane, DMF, DMA, NMP, DMSO, THF, acetonitrile, and 1,4-dioxane, which can be used alone or in combination.

[0554] Compound (I-120) is commercially available, or can be obtained by a known method [for example, Organic Syntheses, Coll. Vol. 3, p. 363 (1955)] or a method similar thereto.

[0555] (Process 2) Compound (I-123) can be obtained in the same manner as in Step 1 of Production Method 20, using compound (I-3) and 1 to 5 equivalents of compound (I-121).

[0556] Compound (I-121) is commercially available or can be produced by known methods [for example, Organic Syntheses, Coll. Vol. 3, p. 363 (1955)] or methods analogous thereto.

[0557] (Step 3) Compound (I-124) can be produced in the same manner as in step 6 of Production Method 1, using compound (I-122).

[0558] (Step 4) Compound (I-125) can be produced in the same manner as in step 4 of Production Method 1, using compound (I-123).

[0559] (Step 5) Among compounds (I-126), X 7 The compound in which is —NH—C(═O)— can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-124) and 1 to 5 equivalents of compound (I-2).

[0560] (Step 6) Among compounds (I-126), X 7 The compound in which is —C(═O)—NH— can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-125) and 1 to 5 equivalents of compound (I-1).

[0561] (Step 7) Among compounds (I-126), X 7 The compound in which is -SO2-NH- can be produced in the same manner as in Step 4 of Production Method 5, using compound (I-125) and 1 to 5 equivalents of compound (I-3).

[0562] (Step 8) Among compounds (I-126), X 7 The compound in which is —NH—C(═O)—NH— can be produced in the same manner as in Step 9 of Production Method 5, using compound (I-125) and 1 to 5 equivalents of compound (I-2).

[0563] (Step 9) Compounds (I-126a) and (I-126b) can be produced by reacting compound (I-126) in the presence of 1 to 10 equivalents of an oxidizing agent in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0564] Examples of the oxidizing agent include metachloroperbenzoic acid (m-CPBA), benzoyl peroxide, peracetic acid, aqueous hydrogen peroxide, and sodium periodate.

[0565] Examples of the solvent include dichloromethane, 1,2-dichloroethane, toluene, etc., which may be used alone or in combination.

[0566] Compounds (I-126a) and (I-126b) can be obtained selectively either alone or as a mixture by adjusting the reaction conditions, such as the number of equivalents of the oxidizing agent and the temperature.

[0567] [Manufacturing method YS-8-1] Among compounds (I) in which S is formula (S8), X 8b Compound (Iy-85) in which is a bond can be prepared according to the following steps. [ka] (In the formula, X 8a is as defined above, and L is L 1 or L 2 where X represents a halogen and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0568] (Process 1) Compound (Iy-83) can be produced by (i) reacting compound (I-3) with 1 to 5 equivalents of bis(pinacolato)diboron, 0.001 to 3 equivalents of a palladium catalyst, and optionally 0.001 to 3 equivalents of a phosphorus ligand, in the presence of 1 equivalent to a large excess of a base, in a solvent at a temperature between room temperature and the boiling point of the solvent used, for 5 minutes to 120 hours, and then (ii) reacting the resulting compound with 1 to 5 equivalents of compound (I-127), 0.001 to 3 equivalents of a palladium catalyst, and optionally 0.001 to 3 equivalents of a phosphorus ligand, in the presence of 1 equivalent to a large excess of a base, in a solvent at a temperature between room temperature and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0569] Examples of the palladium catalyst used in (i) include Pd(dppf)Cl2, Pd2(dba)3, and Pd(PPh3)4.

[0570] The phosphorus ligand used in (i) includes, for example, tricyclohexylphosphine.

[0571] Examples of the base used in (i) include potassium acetate, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, etc.

[0572] Examples of the solvent used in (i) include chloroform, dichloromethane, DMF, DMA, NMP, DMSO, THF, acetonitrile, 1,4-dioxane, and water, and these can be used alone or in combination.

[0573] Examples of the palladium catalyst used in (ii) include Pd(dppf)Cl2, Pd2(dba)3, and Pd(PPh3)4.

[0574] Examples of the phosphorus ligand used in (ii) include triphenylphosphine and tricyclohexylphosphine.

[0575] Examples of the base used in (ii) include potassium acetate, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, etc.

[0576] Examples of the solvent used in (ii) include chloroform, dichloromethane, DMF, DMA, NMP, DMSO, THF, acetonitrile, 1,4-dioxane, and water, and these can be used alone or in combination.

[0577] Compound (I-127) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 13, p. 341, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0578] (Process 2) Compound (Iy-84) can be produced in the same manner as in step 4 of production method 1, using compound (Iy-83).

[0579] (Step 3) Among compounds (Iy-85), X 8a The compound in which is —C(═O)— can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-84) and 1 to 5 equivalents of compound (I-1).

[0580] (Step 4) Among compounds (Iy-85), X 8a The compound in which is -CH2- can be produced using compound (Iy-84) and 1 to 5 equivalents of compound (I-40t) in the same manner as in step 1 of production method 1-3.

[0581] (Step 5) Among compounds (Iy-85), X 8a The compound in which is —NH—C(═O)— can be produced in the same manner as in Step 9 of Production Method 5, using compound (Iy-84) and 1 to 5 equivalents of compound (I-2).

[0582] [Manufacturing method YS-8-2] Among the compounds (I) in which S is formula (S8), (i) X 8b (ii) Compound (Iy-92) in which X is —C(═O)— 8b Compound (Iy-91) in which is -CH2- and (iii) X 8b The compound (Iy-90) in which is —CH(OH)— can be produced according to the following steps. [ka] (In the formula, X 8a is as defined above, and L is L 1 or L 2 X represents a halogen, and P represents an amine protecting group such as Boc or Cbz.

[0583] (Process 1) Compound (Iy-87) can be produced by reacting 1 to 10 equivalents of compound (I-127) with 1 to 10 equivalents of an organometallic reagent in a solvent at a temperature between −78° C. and the boiling point of the solvent used for 5 minutes to 24 hours, and then adding compound (I-40t) to the reaction mixture and reacting at a temperature between −78° C. and the boiling point of the solvent used for 5 minutes to 120 hours.

[0584] Examples of organometallic reagents include n-butyllithium, s-butyllithium, t-butyllithium, isopropylmagnesium chloride-lithium chloride, etc. These organometallic reagents are commercially available, or can be obtained by known methods [e.g., Experimental Chemistry Lectures, 5th Edition, Vol. 18, p. 7 (Li), p. 59 (Mg), Maruzen Co., Ltd. (2004), etc.] or methods similar thereto.

[0585] Examples of the solvent include toluene, diethyl ether, THF, DME, 1,4-dioxane, and hexane, which may be used alone or in combination.

[0586] (Process 2) Compound (Iy-88) can be produced in the same manner as in step 4 of production method 1, using compound (Iy-87).

[0587] (Step 3) When P in compound (Iy-87) is, for example, Boc, compound (Iy-89) can be produced by reacting compound (Iy-87) in the presence of 1 equivalent to a large excess of an acid and 1 equivalent to a large excess of a reducing agent, either without a solvent or in a solvent, at a temperature between room temperature and 150°C for 5 minutes to 120 hours.

[0588] Examples of the acid include hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, titanium tetrachloride, and boron trifluoride.

[0589] Examples of the reducing agent include triethylsilane, diethylsilane, and triphenylsilane.

[0590] Examples of the solvent include toluene, dichloromethane, THF, DME, 1,4-dioxane, dichloroethane, etc., which may be used alone or in combination.

[0591] Furthermore, when P in compound (Iy-87) is, for example, Cbz, compound (Iy-89) can be produced by reacting compound (Iy-87) in the presence of 0.001 equivalent to 0.5 equivalent of a palladium catalyst and 1 equivalent to a large excess of an acid, in a solvent, under a hydrogen atmosphere, at a temperature between −20° C. and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0592] Examples of the palladium catalyst include palladium on carbon and palladium hydroxide.

[0593] Examples of the acid include hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, and methanesulfonic acid.

[0594] Examples of the solvent include methanol, ethanol, ethyl acetate, THF, 1,4-dioxane, etc., which can be used alone or in combination.

[0595] (Step 4) Among the compounds (Iy-90), X 8a The compound in which is —C(═O)— can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-88) and 1 to 5 equivalents of compound (I-1).

[0596] (Step 5) Among the compounds (Iy-90), X 8a The compound in which is —CH 2 — can be produced in the same manner as in Step 1 of Production Method 1-3 using compound (Iy-88) and 1 to 5 equivalents of compound (I-40t).

[0597] (Step 6) Among the compounds (Iy-90), X 8a The compound in which is —NH—C(═O)— can be produced in the same manner as in Step 9 of Production Method 5, using compound (Iy-88) and 1 to 5 equivalents of compound (I-2).

[0598] (Step 7) Among compounds (Iy-91), X 8a The compound in which is —C(═O)— can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-89) and 1 to 5 equivalents of compound (I-1).

[0599] (Step 8) Among compounds (Iy-91), X 8a The compound in which is -CH2- can be produced using compound (Iy-89) and 1 to 5 equivalents of compound (I-40t) in the same manner as in step 1 of production method 1-3.

[0600] (Step 9) Among compounds (Iy-91), X 8a The compound in which is —NH—C(═O)— can be produced in the same manner as in Step 9 of Production Method 5, using compound (Iy-89) and 1 to 5 equivalents of compound (I-2).

[0601] (Step 10) Compound (Iy-92) can be produced using compound (Iy-90) in the same manner as in step 2 of production method Y6.

[0602] [Manufacturing method YS9-1] Among compounds (I) in which S is formula (S9), Ar 9 is triazolediyl, and Z 9 Compound (Iy-75), in which is —CH 2 —, can be prepared according to the following steps. [ka] (Wherein, L is L 1 or L 2 (represents

[0603] (Process 1) Compound (Iy-72) can be produced by reacting compound (I-41t) in the presence of 1 to 10 equivalents of diphenylphosphoryl azide and a large excess of a base in a solvent at a temperature between room temperature and the boiling point of the solvent used for 5 minutes to 120 hours.

[0604] Examples of the base include potassium tert-butoxide, potassium carbonate, sodium hydroxide, DBU, triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and the like.

[0605] Examples of the solvent include toluene, dichloroethane, THF, 1,4-dioxane, etc., which can be used alone or in combination.

[0606] (Process 2) Compound (Iy-74) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-2) and 1 to 10 equivalents of propiolic acid.

[0607] (Step 3) Compound (Iy-75) can be produced in the same manner as in Step 6 of Production Method 17, using compound (Iy-74) and 1 to 5 equivalents of compound (Iy-72).

[0608] [Manufacturing method YS9-2] Among compounds (I) in which S is formula (S9), Ar 9 is oxazoldiyl, and Z 9 Compound (Iy-81) in which is —NH— can be prepared according to the following steps. [ka] (Wherein, L is L 1 or L 2 X represents a halogen, and R e represents lower alkyl, and P represents an amine protecting group such as trimethylsilyl, -C(=O)-CCl3, etc.

[0609] (Process 1) Compound (Iy-77) can be produced by reacting compound (I-2) with 1 to 10 equivalents of compound (Iy-76) in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0610] Compound (Iy-76) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 4th edition, Vol. 20, p. 473, Maruzen Co., Ltd. (2001)] or a method similar thereto.

[0611] Examples of the solvent include dichloromethane, toluene, acetonitrile, THF, 1,4-dioxane, etc., which may be used alone or in combination.

[0612] (Process 2) Compound (Iy-79) can be produced by reacting compound (Iy-77) with 1 to 10 equivalents of compound (Iy-78) in a solvent at a temperature between −20° C. and the boiling point of the solvent used for 5 minutes to 120 hours.

[0613] Compound (Iy-78) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 15, p. 153, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0614] Examples of the solvent include toluene, acetonitrile, ethanol, 1,4-dioxane, DMF, DMA, and NMP, which may be used alone or in combination.

[0615] (Step 3) Compound (Iy-80) can be produced in the same manner as in step 6 of production method 1, using compound (Iy-79).

[0616] (Step 4) Compound (Iy-81) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-80) and 1 to 5 equivalents of compound (I-2).

[0617] [Manufacturing method YS10-1] Among the compounds (I) in which S is of the formula (S10), Z 10 Compound (Iy-71) in which is —O— can be prepared according to the following steps. [ka] (Wherein, L is L 1 or L 2 represents R e represents lower alkyl)

[0618] (Process 1) Compound (Iy-69) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-2) and 1 to 5 equivalents of compound (Iy-68).

[0619] Compound (Iy-68) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 16, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0620] (Process 2) Compound (Iy-70) can be produced in the same manner as in step 6 of production method 1, using compound (Iy-69).

[0621] (Step 3) Compound (Iy-71) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-70) and 1 to 5 equivalents of compound (I-2).

[0622] [Manufacturing method YS10-2] Among the compounds (I) in which S is formula (S10), Z 10 The compound (I-46t) in which is —NH— can be prepared according to the following steps. [ka] (Wherein, L is L 1 or L 2 represents R e represents lower alkyl, and P represents an amine protecting group such as Boc, Cbz, PMB, or Fmoc.

[0623] (Process 1) Compound (I-43t) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-2) and 1 to 5 equivalents of compound (I-42t).

[0624] Compound (I-42t) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 16, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0625] (Process 2) Compound (I-44t) can be produced in the same manner as in step 6 of Production Method 1, using compound (I-43t).

[0626] (Step 3) Compound (I-45t) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-44t) and 1 to 5 equivalents of compound (I-2).

[0627] (Step 4) Compound (I-46t) can be produced using compound (I-45t) in the same manner as in step 4 of production method 1 when P in compound (I-45t) is, for example, Boc, Cbz, or PMB, and can be produced using compound (I-45t) in the same manner as in step 3 of production method 2 when P in compound (I-45t) is, for example, Fmoc.

[0628] [Manufacturing method YS11-1] Among compounds (I) in which S is formula (S11), X 11b Compound (Iy-116a) in which is —C(═O)—NH— can be prepared according to the following steps. [ka] (In the formula, X 11a is as defined above, and L is L 1 or L 2 and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0629] (Process 1) Compound (Iy-114a) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-2) and 1 to 5 equivalents of compound (Iy-113a).

[0630] Compound (Iy-113a) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 16, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0631] (Process 2) Compound (Iy-115a) can be produced in the same manner as in step 4 of production method 1, using compound (Iy-114a).

[0632] (Step 3) Among compounds (Iy-116a), X 11a The compound in which is —C(═O)—NH— can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-115a) and 1 to 5 equivalents of compound (I-1).

[0633] (Step 4) Among compounds (Iy-116a), X 11a The compound in which is —SO 2 —NH— can be produced in the same manner as in Step 4 of Production Method 5, using compound (Iy-115a) and 1 to 5 equivalents of compound (I-3).

[0634] (Step 5) Among compounds (Iy-116a), X 11a The compound in which is —NH—C(═O)—NH— can be produced in the same manner as in Step 9 of Production Method 5, using compound (Iy-115a) and 1 to 5 equivalents of compound (I-2).

[0635] [Manufacturing method YS11-2] L 1 In the compound (I) in which is (A) and S is formula (S11), the ring RA is ring RA3 and X 11b is -C(=O)-, and (i) X 11a (ii) a compound (Iy-118a) in which X is —C(═O)—NH—; 11a is -SO2-NH- (Iy-118b), and (iii) X 11a The compound (Iy-118c) in which is —NH—C(═O)—NH— can be prepared according to the following steps. [ka] (In the formula, R A1 , R A2 , R A3 , R A5 , n 1A and ring RA3 is as defined above, and L is L 2and P represents an amine protecting group such as Boc, Cbz, or PMB. One of the secondary amines forming the ring RA3 serves as a reaction site with the compound (Iy-113a).

[0636] (Process 1) Compound (Iy-117a) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-47t) and 1 to 5 equivalents of compound (Iy-113a).

[0637] Compound (I-47t) is collectively referred to as compound (I-47t), which includes compound (a-32) obtained in step 6 of production method 1-3 and compound (a-41) obtained in step 6 of production method 1-4.

[0638] Compound (Iy-113a) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 16, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0639] (Process 2) Compound (Iy-117b) can be produced in the same manner as in step 4 of production method 1, using compound (I-117a).

[0640] (Step 3) Compound (Iy-118a) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-117b) and 1 to 5 equivalents of compound (I-1).

[0641] (Step 4) Compound (Iy-118b) can be produced in the same manner as in Step 4 of Production Method 5, using compound (Iy-117b) and 1 to 5 equivalents of compound (I-3).

[0642] (Step 5) Compound (Iy-118c) can be produced in the same manner as in Step 9 of Production Method 5, using compound (Iy-117b) and 1 to 5 equivalents of compound (I-2).

[0643] [Manufacturing method YS12-1] Among the compounds (I) in which S is formula (S12), Z 12a is CH2, and (i) X 12 (ii) Compound (Iy-67) in which X is —C(═O)—NH— 12 is -SO2-NH-, and (iii) X 12 Compound (I-49t) in which is —NH—C(═O)—NH— can be prepared according to the following steps. [ka] (In the formula, Z 12b and Z 12c is as defined above, and n 12a and n 12b are the same or different and represent 0 or 1, and L is L 1 or L 2 where X represents a halogen and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0644] (Process 1) Compound (Iy-58) can be produced by (i) reacting compound (I-3) in the presence of 1 to 5 equivalents of bis(pinacolato)diboron, 0.001 to 3 equivalents of a palladium catalyst, and optionally 0.001 to 3 equivalents of a phosphorus ligand, and 1 equivalent to a large excess of a base, in a solvent at a temperature between room temperature and the boiling point of the solvent used, for 5 minutes to 120 hours, and then (ii) reacting the resulting compound in the presence of 1 equivalent to a large excess of an oxidizing agent, in a solvent, at a temperature between -20°C and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0645] Examples of the palladium catalyst used in (i) include Pd(dppf)Cl2, Pd2(dba)3, and Pd(PPh3)4.

[0646] The phosphorus ligand used in (i) includes, for example, tricyclohexylphosphine.

[0647] Examples of the base used in (i) include potassium acetate, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, etc.

[0648] Examples of the solvent used in (i) include chloroform, dichloromethane, DMF, DMA, NMP, DMSO, THF, acetonitrile, 1,4-dioxane, and water, and these can be used alone or in combination.

[0649] The oxidizing agent used in (ii) includes, for example, aqueous hydrogen peroxide, sodium perborate, etc.

[0650] Examples of the solvent used in (ii) include THF, 1,4-dioxane, water, etc., which can be used alone or in combination.

[0651] (Process 2) Compound (Iy-63) can be produced by reacting compound (I-3) with 1 to 10 equivalents of compound (Iy-60) in the presence of 0.001 to 3 equivalents of a palladium catalyst and, if necessary, 0.001 to 3 equivalents of a phosphorus ligand, in a solvent at a temperature between -20°C and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0652] Compound (Iy-60) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 18, p. 77, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0653] Examples of the palladium catalyst include Pd(dppf)Cl2, Pd2(dba)3, and Pd(PPh3)4.

[0654] Examples of the phosphorus ligand include tricyclohexylphosphine and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos).

[0655] Examples of the solvent include THF, DMF, DMA, and NMP, which may be used alone or in combination.

[0656] (Step 3) Compound (Iy-64) can be produced by reacting compound (I-1t) in the presence of 1 equivalent to 5 equivalents of compound (Iy-61) and 1 equivalent to a large excess of a base in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0657] Examples of the base include sodium hydride, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, DBU, potassium carbonate, cesium carbonate, and the like.

[0658] Examples of the solvent include toluene, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine, and acetonitrile, which may be used alone or in combination. Compound (Iy-61) is commercially available, or can be obtained by a known method [for example, Experimental Chemistry Lectures, 5th edition, Vol. 13, p. 374, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0659] Compound (I-1t) is collectively referred to as compound (I-1t), which includes compound (ly-58) obtained in step 1 and compound (f-1) obtained in step 1 of production method Y6.

[0660] (Step 4) Compound (Iy-65) can be produced by reacting compound (I-41t) with 1 to 10 equivalents of compound (Iy-62) in the presence of 1 to 10 equivalents of a base in a solvent at a temperature between -20°C and 150°C for 5 minutes to 120 hours.

[0661] Compound (Iy-62) is commercially available, or can be obtained by a known method [for example, Experimental Chemistry Lectures, 5th edition, Vol. 13, p. 374, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0662] Examples of the base include sodium hydride, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, DBU, and the like.

[0663] Examples of the solvent include toluene, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and pyridine, which may be used alone or in combination.

[0664] Compound (I-41t) can be obtained by Step 9 of Production Method 17.

[0665] (Step 5) Compound (Iy-66) can be produced in the same manner as in step 4 of production method 1 using compound (Iy-63), compound (Iy-64), or compound (Iy-65).

[0666] (Step 6) Compound (Iy-67) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-66) and 1 to 5 equivalents of compound (I-1).

[0667] (Step 7) Compound (I-48t) can be produced in the same manner as in Step 4 of Production Method 5, using compound (Iy-66) and 1 to 5 equivalents of compound (I-3).

[0668] (Step 8) Compound (I-49t) can be produced in the same manner as in Step 9 of Production Method 5, using compound (Iy-66) and 1 to 5 equivalents of compound (I-2).

[0669] [Manufacturing method YS12-2] Among the compounds (I) in which S is formula (S12), Z 12a is CH2 and X 12 Compound (Iy-67a) in which is —NH—C(═O)— can be prepared according to the following steps. [ka] (In the formula, Z 12b and Z 12c is as defined above, and n 12a and n 12b are the same or different and represent 0 or 1, and L is L 1 or L 2 X represents a halogen, and R e represents lower alkyl)

[0670] (Process 1) Compound (Iy-63a) can be produced using compound (I-3) and 1 to 5 equivalents of compound (Iy-60a) in the same manner as in step 2 of production method YS12-1.

[0671] Compound (Iy-60a) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 18, p. 77, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0672] (Process 2) Compound (Iy-64a) can be produced using compound (I-1t) and 1 to 5 equivalents of compound (Iy-61a) in the same manner as in step 3 of production method YS12-1.

[0673] Compound (Iy-61a) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 13, p. 374, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0674] Compound (I-1t) is collectively referred to as compound (I-1t), which includes compound (ly-58) obtained in step 1 of production method YS12-1 and compound (f-1) obtained in step 1 of production method Y6.

[0675] (Step 3) Compound (Iy-65a) can be produced using compound (I-41t) and 1 to 5 equivalents of compound (Iy-62a) in the same manner as in Step 4 of Production Method YS12-1.

[0676] Compound (Iy-62a) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 13, p. 374, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0677] Compound (I-41t) can be obtained by Step 9 of Production Method 17.

[0678] (Step 4) Compound (Iy-66a) can be produced in the same manner as in step 6 of production method 1 using compound (Iy-63a), compound (Iy-64a) or compound (Iy-65a).

[0679] (Step 5) Compound (Iy-67a) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-66a) and 1 to 5 equivalents of compound (I-2).

[0680] [Manufacturing method YS12-3] Among the compounds (I) in which S is formula (S12), Z 12a The compound (I-53t) in which is NH can be prepared according to the following steps. [ka] (Wherein, L is L 1 or L 2 and P represents an amine protecting group such as Boc, Cbz, or PMB. (Process 1)

[0681] Compound (I-51t) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-2) and 1 to 5 equivalents of compound (I-50t).

[0682] Compound (I-50t) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 16, p. 175, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0683] (Process 2) Compound (I-52t) can be produced in the same manner as in step 4 of production method 1, using compound (I-51t).

[0684] (Step 3) Compound (I-53t) can be produced in the same manner as in Step 1 of Production Method 1-3, using compound (I-52t) and 1 to 5 equivalents of compound (I-40t).

[0685] [Manufacturing method YS13] Among the compounds (I) in which S is represented by formula (S13), (i) n 13 Compound (Iy-53) and (ii) compound (Iy-54) in which n 13 n 13a Compound (Iy-57) can be prepared according to the following steps. [ka] (In the formula, n 13a represents 1 or 2, and L represents L 1 or L 2 X represents a halogen, and R e represents lower alkyl)

[0686] (Process 1) Compound (Iy-51) can be produced by reacting compound (I-2) with 1 to 10 equivalents of 3-(nitromethylene)oxetane in the presence of a large excess of base in a solvent at a temperature between -20°C and 150°C for 5 minutes to 120 hours.

[0687] Examples of the base include triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, DBU, and the like.

[0688] Examples of the solvent include toluene, diethyl ether, THF, DME, 1,4-dioxane, etc., which may be used alone or in combination.

[0689] (Process 2) Compound (Iy-52) can be produced in the same manner as in step 8 of production method 1, using compound (Iy-51).

[0690] (Step 3) Compound (Iy-53) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-52) and 1 to 5 equivalents of compound (I-1).

[0691] (Step 4) Compound (Iy-55) can be produced using compound (I-3) and 1 to 5 equivalents of compound (Iy-54) in the same manner as in step 2 of production method YS12-1.

[0692] Compound (Iy-54) is commercially available, or can be obtained by a known method [for example, Experimental Chemistry Lectures, 5th edition, Vol. 18, p. 77, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0693] (Step 5) Compound (Iy-56) can be produced in the same manner as in step 6 of production method 1, using compound (Iy-55).

[0694] (Step 6) Compound (Iy-57) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-52) and 1 to 5 equivalents of compound (Iy-56).

[0695] [Manufacturing method YS14] Among compounds (I), compound (Iy-49) in which S is formula (S14) can be produced according to the following steps. [ka] (Wherein, L is L 1 or L 2 represents R 14a represents a hydrogen atom or lower alkyl, and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0696] (Process 1) Compound (Iy-47) can be produced in the same manner as in Step 3 of Production Method 3, using compound (I-3) and 1 to 5 equivalents of compound (Iy-47a).

[0697] Compound (Iy-47a) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 18, p. 95, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0698] (Process 2) Compound (Iy-48) can be produced in the same manner as in step 4 of production method 1, using compound (Iy-47).

[0699] (Step 3) Compound (Iy-49) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-48) and 1 to 5 equivalents of compound (I-1).

[0700] [Manufacturing method YS15] Among the compounds (I), the compound (Iy-46c) in which S is represented by formula (S15) can be produced according to the following steps. [ka] (Wherein, L is L 1 or L 2 and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0701] (Process 1) Compound (Iy-46a) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-1) and 1 to 5 equivalents of compound (Iy-45).

[0702] Compound (Iy-45) is commercially available, or can be obtained by a known method [for example, Experimental Chemistry Lectures, 5th edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0703] (Process 2) Compound (Iy-46b) can be produced in the same manner as in step 4 of production method 1, using compound (Iy-46a).

[0704] (Step 3) Compound (Iy-46c) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-46b) and 1 to 5 equivalents of compound (I-1).

[0705] [Manufacturing method YS16-1-2] L 1 L E Among compounds (I) in which S is formula (S16), Ar 16 is triazolediyl, and (i) X 16 (ii) Compound (Iy-14) in which X is —C(═O)—NH— 16 (iii) Compound (Iy-20) in which X is —NH—C(═O)— 16 is —NH—C(═O)—NH—, and (iv) X 16 The compound (I-60t) in which is —CH 2 —O— can be prepared according to the following steps. [ka] (In the formula, R E1 , R E2 , R E3 , R E5 , n 16 and Z 16is as defined above, and L E is a group represented by formula (E), and L is L 2 X represents a halogen, and R e represents lower alkyl, and P represents an amine protecting group such as Boc, Cbz, PMB, or 2-nitrobenzenesulfonyl (Ns).

[0706] (Process 1) Compound (Iy-10) can be produced using compound (e-1) and 1 to 5 equivalents of compound (Iy-9) in the same manner as in step 1 of production method 1-2. Compound (e-1) can be obtained in the same manner as in step 4 of production method 1.

[0707] Compound (Iy-9) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 13, p. 374, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0708] (Process 2) Compound (Iy-11) can be produced in the same manner as in step 6 of production method 1, using compound (Iy-10).

[0709] (Step 3) Compound (Iy-13) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-11) and 1 to 5 equivalents of compound (Iy-12).

[0710] Compound (Iy-12) is commercially available, or can be obtained by a known method [for example, Experimental Chemistry Lectures, 5th edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0711] (Step 4) Compound (Iy-14) can be produced in the same manner as in Step 6 of Production Method 17, using compound (Iy-13) and 1 to 5 equivalents of compound (I-102).

[0712] (Step 5) Compound (Iy-16) can be produced using compound (e-1) and 1 to 5 equivalents of compound (Iy-15) in the same manner as in step 1 of production method 1-2.

[0713] Compound (Iy-15) is commercially available, or can be obtained by a known method [for example, Experimental Chemistry Lectures, 5th edition, Vol. 13, p. 374, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0714] (Step 6) Compound (Iy-17) can be produced in the same manner as in step 4 of production method 1, using compound (Iy-16).

[0715] (Step 7) Compound (Iy-19) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-17) and 1 to 5 equivalents of compound (Iy-18).

[0716] Compound (Iy-18) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 16, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0717] (Step 8) Compound (Iy-20) can be produced in the same manner as in Step 6 of Production Method 17, using compound (Iy-19) and 1 to 5 equivalents of compound (I-102).

[0718] (Step 9) Compound (Iy-17a) can be produced in the same manner as in Step 9 of Production Method 5, using compound (Iy-17) and 1 to 5 equivalents of compound (Iy-12).

[0719] (Step 10) Compound (Iy-17b) can be produced in the same manner as in Step 6 of Production Method 17, using compound (Iy-17a) and 1 to 5 equivalents of compound (I-102).

[0720] (Step 11) Compound (I-54t) can be produced in the same manner as in Step 6 of Production Method T2, using compound (e-1) and 1 to 5 equivalents of compound (b-1t).

[0721] (Step 12) Compound (I-56t) can be produced in the same manner as in Step 1 of Production Method 1-2, using compound (I-54t) and 1 to 10 equivalents of compound (I-55t).

[0722] Compound (I-55t) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 13, p. 374, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0723] (Step 13) Compound (I-58t) can be produced in the same manner as in Step 4 of Production Method YS12-1, using compound (I-56t) and 1 to 10 equivalents of compound (I-57t).

[0724] Compound (I-57t) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 13, p. 374, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0725] (Step 14) Compound (I-59t) can be produced in the same manner as in Step 6 of Production Method 17, using compound (I-58t) and 1 to 5 equivalents of compound (I-102).

[0726] (Step 15) When P in compound (I-59t) is, for example, Ns, compound (I-60t) can be produced by reacting compound (I-59t) in the presence of 1 equivalent to 10 equivalents of a thiol and 1 equivalent to a large excess of a base in a solvent at a temperature between -20°C and the boiling point of the solvent used for 5 minutes to 120 hours.

[0727] Examples of thiols include thiophenol, mercaptoacetic acid, and 2-mercaptoethanol.

[0728] Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, and the like.

[0729] Examples of the solvent include acetonitrile, DMF, DMSO, etc., which can be used alone or in combination.

[0730] [Manufacturing method YS16-2-2] Among the compounds (I) in which S is formula (S16), Ar 16 is pyrazolediyl, (i) X 16 (ii) Compound (Iy-7) in which X is —C(═O)—NH— 16 is —NH—C(═O)—, and (iii) X 16 Compound (Iy-7a) in which is -NH-C(=O)-NH-, and Ar 16 is oxadiazolediyl, (i) X 16 (ii) Compound (Iy-8) in which X is —C(═O)—NH— 16 Compound (Iy-28) in which is —NH—C(═O)— and (iii) X 16 Compound (Iy-8a) in which is —NH—C(═O)—NH— can be produced according to the following steps. [ka] (In the formula, n 16 and Z 16 is as defined above, and L E is a group represented by formula (E), and L is L 2 (represents

[0731] (Process 1) Compound (Iy-7) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-11) and 1 to 5 equivalents of compound (Iy-117d).

[0732] Compound (Iy-117d) can be obtained in the same manner as in Step 3 of Production Method YS6-1.

[0733] (Process 2) Compound (Iy-8) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-11) and 1 to 5 equivalents of compound (I-110a).

[0734] Compound (I-110a) can be obtained in the same manner as in Step 5 of Production Method 18.

[0735] (Step 3) Compound (Iy-27) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-17) and 1 to 5 equivalents of compound (Iy-118d).

[0736] Compound (Iy-118d) can be obtained in the same manner as in Step 4 of Production Method YS6-1.

[0737] (Step 4) Compound (Iy-28) can be produced in the same manner as in Step 2 of Production Method 2, using compound (Iy-17) and 1 to 5 equivalents of compound (I-111a).

[0738] Compound (I-111a) can be obtained in the same manner as in Step 6 of Production Method 18.

[0739] (Step 5) Compound (Iy-7a) can be produced in the same manner as in Step 9 of Production Method 5, using compound (Iy-17) and 1 to 5 equivalents of compound (Iy-117d).

[0740] (Step 6) Compound (Iy-8a) can be produced in the same manner as in Step 9 of Production Method 5, using compound (Iy-17) and 1 to 5 equivalents of compound (I-110a).

[0741] [Manufacturing method YS17] L 1 L E and S is formula (S17), (i) X 17 (ii) Compound (I-64t) in which X is —C(═O)—NH— 17 (iii) Compound (I-68t) in which X is —NH—C(═O)— 17 Compound (I-69t) and (iv) X 17 Compound (I-70t) in which is —NH—C(═O)—NH— can be prepared according to the following steps. [ka] (In the formula, R E1 , R E2 , R E3 , R E5 , n 17 is as defined above, and L E is a group represented by formula (E), and L is L 2 X represents a halogen, and R e represents a lower alkyl, and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0742] (Process 1) Compound (I-62t) can be produced in the same manner as in Step 1 of Production Method 1-2, using compound (e-1) and 1 to 10 equivalents of compound (I-61t).

[0743] Compound (I-61t) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 13, p. 374, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0744] (Process 2) Compound (I-63t) can be produced in the same manner as in step 6 of production method 1, using compound (I-62t).

[0745] (Step 3) Compound (I-64t) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-63t) and 1 to 5 equivalents of compound (I-2).

[0746] (Step 4) Compound (I-66t) can be produced in the same manner as in step 1 of production method 1-2, using compound (e-1) and 1 to 10 equivalents of compound (I-65t).

[0747] Compound (I-65t) is commercially available, or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 13, p. 374, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0748] (Step 5) Compound (I-67t) can be produced in the same manner as in step 4 of production method 1, using compound (I-66t).

[0749] (Step 6) Compound (I-68t) can be produced in the same manner as in Step 2 of Production Method 2, using compound (I-67t) and 1 to 5 equivalents of compound (I-1).

[0750] (Step 7) Compound (I-69t) can be produced in the same manner as in Step 4 of Production Method 5, using compound (I-67t) and 1 to 5 equivalents of compound (I-3).

[0751] (Step 8) Compound (I-70t) can be produced in the same manner as in Step 9 of Production Method 5, using compound (I-67t) and 1 to 5 equivalents of compound (I-2).

[0752] [Manufacturing method YS18] L 1 L E Compound (I) in which S is formula (S18) can be prepared according to the following steps. [ka] (In the formula, R E1 , R E2 , R E3 , R E5 , n 18a , n 18b and n 18c is as defined above, and L E is a group represented by formula (E), and L is L 2 where X represents a halogen and P represents an amine protecting group such as Boc, Cbz, or PMB.

[0753] (Process 1) Compound (I-72t) can be produced in the same manner as in Step 1 of Production Method 1-2, using compound (e-1) and 1 to 10 equivalents of compound (I-71t).

[0754] Compound (I-71t) is commercially available or can be obtained by a known method [e.g., Experimental Chemistry Lectures, 5th edition, Vol. 13, p. 374, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0755] (Process 2) Compound (I-73t) can be produced in the same manner as in step 4 of production method 1, using compound (I-72t).

[0756] (Step 3) Compound (I-74t) can be produced in the same manner as in step 9 of production method 5, using compound (I-73t) and 1 to 5 equivalents of compound (l-2).

[0757] The conversion of various functional groups in the production method of compound (I) can be carried out by known methods [for example, the methods described in Comprehensive Organic Transformations 2nd edition, R.C. Larock, Vch Verlagsgesellschaft Mbh (1999)] or in accordance with such methods.

[0758] The intermediates and target compounds in each of the above production methods can be isolated and purified by separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc. Alternatively, the intermediates can be subjected to the next reaction without any particular purification.

[0759] Compound (I) may exist as geometric isomers, stereoisomers such as optical isomers, tautomers, etc., and the present invention encompasses all possible isomers and mixtures thereof, including these. For example, compound numbers 2c and 2d in Table 2 below are optical isomers, and both of these are included in the scope of compound (I) of the present invention.

[0760] Some or all of the atoms in compound (I) may be replaced with their corresponding isotope atoms, and the present invention also encompasses compounds replaced with these isotope atoms. For example, some or all of the hydrogen atoms in compound (I) may be replaced with hydrogen atoms with an atomic weight of 2 (deuterium atoms).

[0761] Compounds in which some or all of the atoms in compound (I) are replaced with the corresponding isotope atoms can be produced by methods similar to the above-mentioned production methods using commercially available building blocks. Compounds in which some or all of the hydrogen atoms in compound (I) are replaced with deuterium atoms can also be produced by, for example, 1) a method of deuterizing carboxylic acids and the like under basic conditions using deuterium peroxide (see U.S. Pat. No. 3,849,458), 2) a method of deuterizing alcohols, carboxylic acids, and the like using an iridium complex as a catalyst and heavy water as a deuterium source [see J. Am. Chem. Soc., Vol. 124, No. 10, 2092 (2002)], or 3) a method of deuterizing fatty acids using palladium carbon as a catalyst and deuterium gas alone as a deuterium source [see LIPIDS, Vol. 9, No. 11, 2002]. 913 (1974)], 4) a method of deuterizing acrylic acid, methyl acrylate, methacrylic acid, methyl methacrylate, etc. using a metal such as platinum, palladium, rhodium, ruthenium, iridium, etc. as a catalyst and heavy water or heavy water and deuterium gas as a heavy hydrogen source (see JP-B-5-19536, JP-A-61-277648, and JP-A-61-275241), 5) a method of deuterizing acrylic acid, methyl methacrylate, etc. using a catalyst such as palladium, nickel, copper, or copper chromite, etc. and heavy water as a heavy hydrogen source (see JP-A-63-198638), etc.

[0762] When a salt of compound (I) is to be obtained, if compound (I) is obtained in the form of a salt, it can be purified as is. Alternatively, if compound (I) is obtained in the free form, compound (I) can be dissolved or suspended in an appropriate solvent, and an acid or base can be added to form a salt, which can then be isolated and purified.

[0763] Furthermore, Compound (I) and its pharmaceutically acceptable salts may exist in the form of adducts with water or various solvents, and these adducts are also encompassed by the present invention.

[0764] Compound (I) is preferably a compound shown in Tables 1 to 15 below. 1 or L 2 A1, A2, A5, A6, A9, A10, A11, A12, A14, A15, A16, A17, A18, A19, A20, A21, B1, B2, B3, B4, B5, B6, B7, B8, B9, C1, C2, D1, D2, D3, D4, E1, F1 and F2 respectively have the following structures. [ka] [ka] [ka]

[0765] [Table 1]

[0766] [Table 2]

[0767] [Table 3]

[0768] [Table 4]

[0769] [Table 5]

[0770] [Table 6]

[0771] [Table 7]

[0772] [Table 8]

[0773] [Table 9]

[0774] [Table 10]

[0775] [Table 11]

[0776] [Table 12]

[0777] [Table 13]

[0778] [Table 14]

[0779] [Table 15]

[0780] Although Compound (I) or a pharmaceutically acceptable salt thereof can be administered alone, it is usually desirable to provide it as a pharmaceutical formulation, which is intended for use in animals or humans, preferably humans.

[0781] The pharmaceutical preparations of the present invention may contain Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient, either alone or in combination with any other active ingredient for treatment. These pharmaceutical preparations may be prepared by mixing the active ingredient with one or more pharmaceutically acceptable carriers (e.g., diluents, solvents, excipients, etc.) and by any method well known in the technical field of pharmaceutical preparations.

[0782] The route of administration is preferably the most effective route for the treatment, and may be oral or parenteral, for example, intravenous.

[0783] Examples of dosage forms include tablets and injections.

[0784] Tablets suitable for oral administration can be prepared using excipients such as lactose, disintegrating agents such as starch, lubricants such as magnesium stearate, binders such as hydroxypropyl cellulose, and the like.

[0785] Suitable preparations for parenteral administration, such as injections, can be prepared using diluents or solvents such as saline solution, glucose solution, or a mixture of saline and glucose solution.

[0786] The dosage and frequency of administration of Compound (I) or a pharmaceutically acceptable salt thereof vary depending on factors such as the dosage form, the patient's age and body weight, and the nature and severity of the symptoms to be treated. Oral administration typically involves administering 0.01 to 1,000 mg, preferably 0.05 to 100 mg, per adult, once or several times per day. Parenteral administration, such as intravenous administration, typically involves administering 0.001 to 1,000 mg, preferably 0.01 to 100 mg, per adult, once or several times per day. However, these dosages and frequency of administration vary depending on the various conditions described above.

[0787] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof, which may contain a carrier. The pharmaceutical composition of the present invention is used with the same administration route, dosage form, etc. as the above-mentioned pharmaceutical formulation. Furthermore, the carrier that may be contained in the pharmaceutical composition of the present invention may be a diluent, solvent, excipient, etc., as in the above-mentioned pharmaceutical formulation. Furthermore, the pharmaceutical composition of the present invention is preferably used for inhibiting BET, or for treating or preventing cancer, more preferably for treating or preventing cancer. Here, "prevention" refers to substantially reducing the likelihood or severity of the pathology or biological symptoms of a disease, or delaying the onset of such pathology or biological symptoms, etc. The same applies to the following term "prevention."

[0788] According to another aspect of the present invention, there is provided a therapeutic or prophylactic method comprising administering Compound (I) or a pharmaceutically acceptable salt thereof (preferably, a prophylactically or therapeutically safe and effective amount of Compound (I) or a pharmaceutically acceptable salt thereof) to a subject (preferably a subject in need thereof). The subject includes animals other than humans, but is preferably a human. The same applies to the following subjects. The therapeutic or prophylactic method of the present invention is preferably used to inhibit BET or to treat or prevent cancer, more preferably to treat or prevent cancer.

[0789] According to another aspect of the present invention there is provided Compound (I) or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[0790] According to another aspect of the present invention, there is provided compound (I) or a pharmaceutically acceptable salt thereof for use in inhibiting BET or for use in the treatment or prevention of cancer (preferably for use in the treatment or prevention of cancer).

[0791] According to another aspect of the present invention, there is provided use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting BET or for the treatment or prevention of cancer (preferably for the treatment or prevention of cancer).

[0792] According to another aspect of the present invention, there is provided a use of compound (I) or a pharmaceutically acceptable salt thereof for inhibiting BET or for the treatment or prevention of cancer (preferably for the treatment or prevention of cancer).

[0793] According to another aspect of the present invention, there is provided a pharmaceutical comprising Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0794] According to another aspect of the present invention, there is provided a BET inhibitor or a prophylactic or therapeutic agent for cancer (preferably, a prophylactic or therapeutic agent for cancer) comprising compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient. [Example]

[0795] The present invention will be explained in more detail below with reference to examples, but the scope of the present invention is not limited to these examples.

[0796] The pharmacological actions of representative compounds of Compound (I) will be specifically explained by test examples.

[0797] [Test Example 1] Cell survival inhibitory effect SU-DHL-4 cells (Code No. ACC 495, Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH) were cultured at 37°C in a carbon dioxide incubator (95% air, 5% CO2) in RPMI 1640 medium (Code No. 11875-093, Thermo Fisher Scientific) supplemented with heat-inactivated fetal bovine serum (FBS: Code No. 10099-148, Thermo Fisher Scientific) to a final concentration of 10 vol% and penicillin / streptomycin solution (PS: Code No. 15140-122, Thermo Fisher Scientific) to a final concentration of 1 vol% at a concentration of 1 × 10 per 20-40 mL. 6 The cells were passaged twice a week to maintain a cell concentration of 0.1 cells / mL or less.

[0798] Cultured SU-DHL-4 cells were seeded at 2000 cells / well in a clear 384-well plate (Code No. 781182, Greiner Bio-One). After seeding, the cells were pre-incubated at 37°C in a CO incubator for 18–25 hours. Next, 1, 0.1, or 0.01 mmol / L DMSO solutions of the test compounds were prepared and diluted in RPMI 1640 medium containing FBS and PS in nine steps to a final concentration of 200x. A 1 / 200 volume of the dilution was added to each well. The final DMSO concentration was adjusted to 0.1 vol%. After addition of the test compounds, the cells were cultured at 37°C in a CO incubator for 72 hours. Next, 0.020 mL of Cell Counting Kit-8 (Code No. CK04, DOJINDO), diluted 2-fold or 4-fold with phosphate-buffered saline (PBS), was added to each well. The color reaction was allowed to proceed for 2-3 hours in a carbon dioxide incubator at 37°C, and the absorbance at a wavelength of 450 nm was measured using a SpectraMax 340PC (Molecular Devices). The cell viability inhibition rate was calculated using the following formula, and the concentration of the test compound that showed 90% cell viability inhibition rate (IC 90value) was calculated. Cell survival inhibition rate (%) = 100 - (AB) / (CB)×100 A: Absorbance of the well to which the test compound was added B: Absorbance of wells without cells added C: Absorbance of wells to which no test compound was added

[0799] The results are shown in the table below. [Table 16] TIFF0007631473000124.tif248143TIFF0007631473000125.tif247151TIFF0007631473 000126.tif246150TIFF0007631473000127.tif246157TIFF0007631473000128.tif96163

[0800] As described above, compound (I) of the present invention, which is a representative of the test compounds, exhibited a strong cell viability inhibitory effect on SU-DHL-4 cells. Furthermore, the inhibitory rate was much stronger than that of the known comparative compounds 1 and 2. Therefore, compound (I) of the present invention was found to be useful for preventing or treating cancer.

[0801] Comparative compound 1 is a compound described as example 14 in Patent Document 2, and comparative compound 2 is a compound described as MT1 in Patent Document 3. The comparative compounds were synthesized according to the methods described in the respective patent documents and used in this test.

[0802] [Test Example 2] Inhibitory effect on MYC mRNA expression SU-DHL-4 cells were cultured in RPMI1640 medium supplemented with FBS and PS at a final concentration of 10 vol% and 1 vol%, respectively, at 37°C in a carbon dioxide incubator (95% air, 5% CO). 6The cells were passaged twice a week to maintain a cell concentration of 0.1 cells / mL or less. Cultured SU-DHL-4 cells were plated in a clear 6-well plate (Code No. 140675, Thermo Fisher Scientific) at 6 × 10 5 Cells were seeded at 1000 cells / well. After seeding, the cells were pre-cultured at 37°C in a carbon dioxide incubator for 18 to 25 hours. Next, a 0.1 mmol / L DMSO solution of the test compound was prepared and diluted in the RPMI 1640 medium containing FBS and PS to 200 times the final concentration, and 1 / 200 volume of the solution was added to each well. The final DMSO concentration was adjusted to 0.1 vol%. After adding the test compound, the cells were cultured at 37°C in a carbon dioxide incubator for 6 hours.

[0803] Next, the cells were collected by centrifugation and used for mRNA extraction. (R) 16 The LEV simply RNA Purification Kit (Code No. AS1270, Promega) was used for mRNA recovery according to the manufacturer's recommended protocol attached to the kit. 0.001 mg of the recovered mRNA was converted to cDNA using SuperScript IV VILO Master Mix with ezDNase Enzyme (Code No. 11766050, Thermo Fisher Scientific). The cDNA was generated in a 0.020 mL reaction solution according to the manufacturer's recommended protocol. (R)A PCR System 9700 (Applied Biosystems) was used. The cDNA samples were diluted 10-fold by adding 0.180 mL of RNase-free water (Code No. 10977-023, Thermo Fisher Scientific) and used for quantitative real-time polymerase chain reaction (qRT-PCR). For the qRT-PCR standard curve, a cDNA sample containing DMSO as the test compound was diluted 5-fold by adding 0.08 mL of RNase-free water. Two further 5-fold dilutions were made, and these three samples were used for the standard curve.

[0804] The following reagents were used for qRT-PCR: TaqMan Gene Expression Assays, Inventoried (Primer probe: Code No. 4331182, Thermo Fisher Scientific, Assay ID: (i) MYC: Hs00153408_m1, (ii) ACTB: Hs01060665_g1, (iii) GAPDH: Hs04420697_g1, (iv) HPRT1: Hs02800695_m1), and 2X TaqMan® Fast Universal PCR Master Mix, no AmpErase® UNG (Master Mix: Code No. 4367846, Thermo Fisher Scientific).

[0805] Primer probe (0.001 mL), Master Mix (0.010 mL), water (0.004 mL), and the diluted cDNA sample (0.005 mL) were mixed and subjected to qRT-PCR analysis. qRT-PCR analysis was performed using a QuantStudio 7 Flex (Thermo Fisher Scientific) or 7500 Fast Real-Time PCR (Applied Biosystems) in Fast mode. MYC gene expression was measured using housekeeping genes ACTB, GAPDH, and HPRT1. The percent MYC mRNA expression suppression rate (%) was calculated using the test compound at a concentration of 100 nmol / L by correcting the values ​​using the following formula: Corrected MYC expression level = A / B A: MYC expression level B: Geometric mean expression levels of ACTB, GAPDH, and HPRT1 Using the corrected values, the MYC expression inhibition rate relative to wells to which no test compound was added was calculated using the following formula. MYC expression suppression rate (%) = 100 - C / D×100 C: Normalized MYC expression levels in wells to which the test compound was added D: Normalized MYC expression level in wells to which no test compound was added

[0806] The results are shown in the table below. [Table 17] TIFF0007631473000130.tif133166

[0807] As described above, compound (I) of the present invention, which is a representative test compound, strongly inhibited MYC mRNA expression. Furthermore, the inhibition rate was much stronger than that of known comparative compounds 1 and 2. Therefore, compound (I) of the present invention was found to be useful for preventing or treating cancer.

[0808] Comparative compound 1 is a compound described as example 14 in Patent Document 2, and comparative compound 2 is a compound described as MT1 in Patent Document 3. The comparative compounds were synthesized according to the methods described in the respective patent documents and used in this test.

[0809] [Test Example 3] Antitumor effect on SCID mouse subcutaneously transplanted DLBCL line SU-DHL-4 1 × 10 cells suspended in a 1:1 mixture of PBS and Matrigel (CORNING Code No. 354234) 7 The DLBCL cell line SU-DHL-4 (Code No. ACC 495, Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH) was implanted subcutaneously into the ventral side of male SCID mice. 18 days after implantation, body weight and tumor diameter were measured, and tumor volume was calculated using the following formula. The mice were then divided into two groups (n = 5) so that the mean tumor volume of each group was equivalent. E-workbook software (ID Business Solutions) was used for grouping and measurements. [Tumor volume (mm 3 ) = [Long axis of tumor (mm)] × [Shorter axis of tumor (mm)] 2 ×0.5 The study was conducted in two groups: a vehicle-treated group and a compound 1a-treated group (compound-treated group). Compound 1a was dissolved in 30% DMSO / 3% Tween 80 / physiological saline to a final concentration of 0.6 mg / mL and administered intravenously at 5 mL / kg (3 mg / kg) five times a week for two weeks. Vehicle-treated groups received 30% DMSO / 3% Tween 80 / physiological saline at 5 mL / kg intravenously, following the same schedule as the compound 1a-treated group. After the study began, body weight and tumor diameter were measured twice a week. Tumor volume on each measurement day was calculated using the formula above. Tumor growth rate (hereinafter referred to as V / V) was calculated by dividing the tumor volume V on each measurement day by the tumor volume V on the day the study began (Day 0). T / C was calculated by dividing the mean V / V of each group (T) by the mean V of the vehicle-treated group (C).

[0810] The results are shown in the table below (average values ​​of n=5 are shown). [Table 18]

[0811] As described above, the tumor volume, tumor growth rate, and T / C of the compound 1a-administered group were smaller than those of the solvent-administered group. On the other hand, no weight loss was observed in the compound 1a-administered group. In other words, compound 1a exhibited a strong antitumor effect against SU-DHL-4 subcutaneously transplanted tumors. Therefore, it was found that compound (I) of the present invention, which is represented by the test compound, is useful as a cancer therapeutic agent.

[0812] The proton nuclear magnetic resonance spectra ( 1 H NMR was measured at 300 MHz or 400 MHz, and exchangeable protons may not be clearly observed depending on the compound and measurement conditions. Signal multiplicity is indicated by the usual notation, with br indicating an apparently broad signal. ChemBioDraw Ultra version 14.0 was used to name each synthesized compound, as necessary.

[0813] [Reference example 1] 4-{[(2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}benzoic acid (Process 1) Aniline (25.0 g, 268.82 mmol) was dissolved in acetonitrile (200 mL), and acetaldehyde (15 mL, 268.8 mmol), bismuth(III) chloride (8.5 g, 26.9 mmol), and N-vinylformamide (22.67 mL, 322.6 mmol) were added, followed by stirring at room temperature for 36 hours. A saturated aqueous solution of sodium carbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give N-[(2S * ,4R * )-2-Methyl-1,2,3,4-tetrahydroquinolin-4-yl]formamide (18.0 g) was obtained.

[0814] (Process 2) N-[(2S * ,4R * )-2-Methyl-1,2,3,4-tetrahydroquinolin-4-yl]formamide (18.0 g, 94.7 mmol) was dissolved in dichloromethane (100 mL), pyridine (30.5 mL, 379.0 mmol) and propionyl chloride (8.3 mL, 94.7 mmol) were added, and the mixture was stirred at 0 °C for 1 hour. Water was added to the reaction mixture, which was then extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 19 / 1) to obtain N-[(2S * ,4R * )-2-Methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]formamide (15.0 g) was obtained.

[0815] (Step 3) N-[(2S * ,4R *)-2-Methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]formamide (15.0 g, 61.0 mmol) was dissolved in methanol (100 mL), and hydrochloric acid (5 mol / L, 18 mL) was added under ice-cooling, followed by stirring at 70 °C for 3 hours. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 19 / 1) to obtain 1-[(2S * ,4R * )-4-amino-2-methyl-3,4-dihydroquinolin-1(2H)-yl]propan-1-one (9.0 g, 3-step total yield 15%) was obtained.

[0816] (Step 4) 1-[(2S * ,4R * )-4-amino-2-methyl-3,4-dihydroquinolin-1(2H)-yl]propan-1-one (5.0 g, 22.9 mmol) was dissolved in dichloromethane (100 mL), [4-(methoxycarbonyl)phenyl]boronic acid (12.3 g, 68.8 mmol), triethylamine (12.9 mL, 91.7 mmol), and copper(II) acetate (6.2 g, 34.4 mmol) were added, and the mixture was stirred at room temperature under oxygen atmosphere for 24 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7 / 3) to obtain methyl 4-{[(2S * ,4R * )-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}benzoate (2.1 g, 18%) was obtained.

[0817] (Step 5) Methyl 4-{[(2S * ,4R *)-2-Methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}benzoate (2.1 g, 5.84 mmol) was purified by supercritical fluid chromatography (SFC) (Chiralcel OX-H (250 x 30 mm, 5 u), CO2 / methanol = 60 / 40, flow rate 90.0 g / min, retention time (rt) = 7.5 min) to give methyl 4-{[(2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}benzoate (750 mg, 36%). SFC (Chiralpak AD-H (250x4.6mm, 5u), methanol / CO2 = 25 / 75, flow rate 3.0 ml / min): rt = 5.38 min

[0818] (Step 6) Methyl 4-{[(2S * ,4R * )-2-Methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}benzoate (410 mg, 1.16 mmol) was dissolved in methanol (6.0 mL), and aqueous sodium hydroxide solution (4 mol / L, 1.45 mL) was added, followed by stirring at 50 °C overnight. Hydrochloric acid (1 mol / L) was added to the reaction mixture, which was then extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 4-{[(2S * ,4R * )-2-Methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}benzoic acid (390 mg, 99%) was obtained.

[0819] (Step 7) Using methyl 4-{[(2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}benzoate (2.0 g, 5.67 mmol) obtained in Step 5, 4-{[(2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}benzoic acid (1.92 g, 100%) was obtained in the same manner as in Step 6. ESI-MS m / z: 337 (M - H) - , 1 H-NMR (CDCl3,δ): 1.08-1.23 (m, 6H), 1.23-1.40 (m, 1H), 2.32-2.46 (m, 1H), 2.52-2.77 (m, 2H), 4.21-4.46 (m, 2H), 4.87-5.03 (m, 1H), 6.56-6.66 (m, 2H), 7.09-7.34 (m, 4H), 7.88-7.99 (m, 2H).

[0820] [Reference example 2] 1-{(2S,4R)-4-[(4-bromophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl}propan-1-one 1-[(2S * ,4R * )-4-amino-2-methyl-3,4-dihydroquinolin-1(2H)-yl]propan-1-one (15.0 g, 68.8 mmol) and (4-bromophenyl)boronic acid (13.76 g, 68.81 mmol) in the same manner as in Step 4 of Reference Example 1 to prepare 1-{(2S * ,4R * )-4-[(4-bromophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl}propan-1-one (15.0 g) was obtained. * ,4R * 1-{(2S,4R)-4-[(4-bromophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl}propan-1-one (15.0 g) was purified by SFC ((R,R) Whelk-01 (250x30mm, 5u), CO2 / methanol = 80 / 20, flow rate 100 g / min, rt = 10.63 min) to give 1-{(2S,4R)-4-[(4-bromophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl}propan-1-one (5.4 g, 21%). ESI-MS (M+H) +: 373, 1 H NMR (DMSO-d 6, δ): 0.99-1.04 (m, 6H), 1.13-1.20 (m, 1H), 2.20-2.25 (m, 1H), 2.55-2.61 (m, 2H), 4.14 (ddd, J = 11.98, 7.71, 4.12 Hz, 1H), 4.70-4.75 (m, 1H), 6.28 (d, J = 7.63 Hz, 1H), 6.59-6.62 (m, 2H), 7.10 (d, J = 7.50 Hz, 1H), 7.16-7.23 (m, 3H), 7.25-7.30 (m, 2H). SFC ((R,R) Whelk-01 (250x4.6mm, 5u), methanol / CO2=25 / 75, flow rate 3.0 ml / min): rt=7.29 min

[0821] [Reference example 3] (S)-4-{6-[2-(tert-butoxy)-2-oxoethyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl}benzoic acid tert-Butyl 2-[4-(4-bromophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetate (5.0 g, 10.0 mmol), synthesized according to the method described in WO2017030814, was dissolved in a mixed solvent of DMF and water (70 mL, 5:2). Potassium carbonate (2.1 g, 15.0 mmol), palladium acetate (0.67 g, 1.0 mmol), and bis(diphenylphosphino)propane (0.82 g, 2.0 mmol) were added, and the mixture was stirred at 100 °C for 16 hours under a carbon monoxide atmosphere. The reaction mixture was filtered through Celite, water was added to the filtrate, and the aqueous layer was washed with ethyl acetate. Citric acid was added to the aqueous layer, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (acetonitrile / 0.1% formic acid aqueous solution = 1 / 1) to give 4-{6-[2-(tert-butoxy)-2-oxoethyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl}benzoic acid (2.75 g). The resulting 4-{6-[2-(tert-butoxy)-2-oxoethyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl}benzoic acid (2.75 g) was purified by SFC (Chiralpak AD-H (250 x 30 mm, 5 u), CO2 / methanol = 70 / 30, flow rate 90 g / min, rt = 3.89 min) to give (S)-4-{6-[2-(tert-butoxy)-2-oxoethyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl}benzoic acid (1.68 g, 36%). ESI-MS (M+H) + : 467, 1 H NMR (DMSO-d 6,δ): 1.43 (s, 9H), 1.60 (d, J = 0.61 Hz, 3H), 2.42 (d, J = 0.61 Hz, 3H), 2.61 (s, 3H), 3.34-3.40 (m, 2H), 4.46 (dd, J = 8.24, 6.41 Hz, 1H), 7.52 (d, J = 8.54 Hz, 2H), 7.97 (d, J = 8.85 Hz, 2H), 13.14 (brs, 1H). SFC (Chiralpak AD-H (250x4.6mm, 5u), methanol / CO2 = 25 / 75, flow rate 3.0 ml / min): rt = 3.62 min

[0822] [Reference example 4] 4-(2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)benzoic acid (Process 1) (tert-Butoxycarbonyl)glycine (79 mg, 0.451 mmol) was dissolved in DMF (1.6 mL), and HATU (184 mg, 0.484 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.645 mmol) were added. The mixture was stirred at room temperature for 10 minutes. (2-Amino-4,5-dimethylthiophen-3-yl)(4-bromophenyl)methanone (100 mg, 0.322 mmol), synthesized according to the method described in WO2017030814, was added to the reaction mixture, and the mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100 / 0 to 80 / 20) to obtain tert-butyl (2-{[3-(4-bromobenzoyl)-4,5-dimethylthiophen-2-yl]amino}-2-oxoethyl)carbamate (110 mg, 73%).

[0823] (Process 2) tert-Butyl (2-{[3-(4-bromobenzoyl)-4,5-dimethylthiophen-2-yl]amino}-2-oxoethyl)carbamate (110 mg, 0.235 mmol) obtained in Step 1 was dissolved in dichloromethane (0.79 mL), trifluoroacetic acid (0.54 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue (110 mg) was dissolved in toluene (2.0 mL), pyridine (0.36 mL, 4.49 mmol) and molecular sieves 4A (300 mg) were added, and the mixture was refluxed overnight. The reaction mixture was suction filtered, and water was added to the obtained filtrate, followed by extraction twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100 / 0 to 90 / 10) to give 5-(4-bromophenyl)-6,7-dimethyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one (56 mg, 68%).

[0824] (Step 3) 5-(4-Bromophenyl)-6,7-dimethyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one (55 mg, 0.157 mmol) obtained in Step 2 was dissolved in THF (1.0 mL) and cooled to -78 °C. Potassium tert-butoxide (21 mg, 0.189 mmol) was added and stirred at room temperature for 30 minutes. The reaction mixture was cooled to -78 °C, and diethylphosphoryl chloride (0.027 mL, 0.189 mmol) was added. The mixture was stirred at -10 °C for 45 minutes. Acetohydrazine (18 mg, 0.236 mmol) and 1-butanol (1.0 mL) were added to the reaction mixture, and the mixture was stirred at 90 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100 / 0 to 90 / 10) to give 4-(4-bromophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (24 mg, 39%).

[0825] (Step 4) 4-(4-Bromophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (160 mg, 0.413 mmol) obtained in Step 3 was dissolved in a mixed solvent of DMF and water (2.2 mL, 10:1). Palladium acetate (9.3 mg, 0.041 mmol), 1,3-bis(diphenylphosphino)propane (34 mg, 0.083 mmol), and potassium carbonate (120 mg, 0.868 mmol) were added, and the mixture was stirred overnight at 80 °C under a carbon monoxide atmosphere. Hydrochloric acid (1 mol / L) was added to the reaction mixture, which was then extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was slurried with ethyl acetate to give 4-(2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)benzoic acid (170 mg, 100%). ESI-MS m / z: 351 (M - H) - : 1 H-NMR (DMSO-d6,δ): 2.40 (s, 3H), 2.63 (s, 3H), 2.90 (s, 3H), 4.17-4.20 (m, 1H), 5.26-5.33 (m, 1H), 7.53-7.59 (m, 2H), 7.94-8.02 (m, 2H).

[0826] [Reference example 5] 4-[(2-ethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)methyl]benzoic acid (Process 1) 2-(2-Oxobutyl)cyclohexane-1,3-dione (150 mg, 0.823 mmol), synthesized according to the method described in the literature (Eur. J. of Org. Chem. 2016, 5169-5179), was dissolved in toluene (1.2 ml), and methyl 4-(aminomethyl)benzoate hydrochloride (174 mg, 0.864 mmol) and triethylamine (0.23 ml, 1.65 mmol) were added. The mixture was stirred at room temperature for 15 minutes and then refluxed for 7 hours. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100 / 0 to 90 / 10) to obtain methyl 4-[(2-ethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)methyl]benzoate (120 mg, 47%).

[0827] (Process 2) Using methyl 4-[(2-ethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)methyl]benzoate (230 mg, 0.739 mmol) obtained in Step 1, 4-[(2-ethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)methyl]benzoic acid (170 mg, 77%) was obtained in the same manner as in Step 6 of Reference Example 1. ESI-MS m / z: 296 (M - H) - ; 1 H-NMR (CDCl3,δ):1.20 (t, J = 7.4 Hz, 3H), 2.06-2.18 (m, 2H), 2.41 (q, J = 7.4 Hz, 2H), 2.45-2.52 (m, 2H), 2.58-2.64 (m, 2H), 5.11 (s, 2H), 6.42 (s, 1H), 6.99 (d, J = 8.2 Hz, 2H), 8.06 (d, J = 8.2 Hz, 2H).

[0828] [Reference example 6] 4-{[3-(3,5-dimethylisoxazol-4-yl)-5-hydroxyphenyl](hydroxy)methyl}benzoic acid (Process 1) 3-Bromo-5-hydroxybenzaldehyde (3.7 g, 18.41 mmol) was dissolved in DMF (100 mL), and tert-butyldimethylchlorosilane (3.33 g, 22.09 mmol) and imidazole (1.38 g, 20.25 mmol) were added. The mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 90 / 10) to give 3-bromo-5-[(tert-butyldimethylsilyl)oxy]benzaldehyde (4.6 g, 79%).

[0829] (Process 2) 3-Bromo-5-[(tert-butyldimethylsilyl)oxy]benzaldehyde (800 mg, 2.54 mmol) obtained in Step 1 and [4-(ethoxycarbonyl)phenyl](iodo)zinc (0.5 mol / L in THF, 30.4 mL, 15.20 mmol) were mixed and stirred at room temperature for 24 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 95 / 5 to 50 / 50) to give ethyl 4-({3-bromo-5-[(tert-butyldimethylsilyl)oxy]phenyl}(hydroxy)methyl)benzoate (570 mg, 45%).

[0830] (Step 3) Ethyl 4-({3-bromo-5-[(tert-butyldimethylsilyl)oxy]phenyl}(hydroxy)methyl)benzoate (550 mg, 1.18 mmol) obtained in Step 2 was dissolved in a mixed solvent of 1,4-dioxane and water (24 mL, 5:1), and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)isoxazole (343 mg, 1.54 mmol), potassium carbonate (490 mg, 3.54 mmol), and Pd(dppf)Cl (87 mg, 0.12 mmol) were added and the mixture was stirred at 80 °C for 16 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography (petroleum ether / ethyl acetate=67 / 33) to obtain ethyl 4-({3-[(tert-butyldimethylsilyl)oxy]-5-(3,5-dimethylisoxazol-4-yl)phenyl}(hydroxy)methyl)benzoate (570 mg, 95%).

[0831] (Step 4) Using ethyl 4-({3-[(tert-butyldimethylsilyl)oxy]-5-(3,5-dimethylisoxazol-4-yl)phenyl}(hydroxy)methyl)benzoate (570 mg, 1.18 mmol) obtained in Step 3, 4-{[3-(3,5-dimethylisoxazol-4-yl)-5-hydroxyphenyl](hydroxy)methyl}benzoic acid (400 mg, 98%) was obtained in the same manner as in Step 6 of Reference Example 1. ESI-MS (M+H) + : 340, 1 H NMR (CD3OD, δ): 2.20 (s, 3H), 2.36 (s, 3H), 5.80 (s, 1H), 6.65-6.61 (t, J = 1.6 Hz, 1H), 6.80 (d, J = 1.2 Hz, 1 H), 6.84 (t, J = 1.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H).

[0832] [Reference example 7] 1-{(2S,4R)-4-[(4-aminophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl}propan-1-one (Process 1) 1-[(2S * ,4R * )-4-amino-2-methyl-3,4-dihydroquinolin-1(2H)-yl]propan-1-one (10.0 g, 45.87 mmol) was dissolved in DMF (150 mL), and 1-fluoro-4-nitrobenzene (9.7 mL, 91.74 mmol), N,N-diisopropylethylamine (8.0 mL, 45.87 mmol), and potassium carbonate (19 g, 137.61 mmol) were added. The mixture was stirred at 100 °C for 48 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 92 / 8 to 90 / 10) to give 1-{(2S * ,4R * )-2-methyl-4-[(4-nitrophenyl)amino)]-3,4-dihydroquinolin-1(2H)-yl}propan-1-one (4.7 g, 30%) was obtained. ESI-MS (M+H) + : 340.

[0833] (Process 2) 1-{(2S * ,4R *)-2-Methyl-4-[(4-nitrophenyl)amino]-3,4-dihydroquinolin-1(2H)-yl}propan-1-one (2.6 g, 7.66 mmol) was dissolved in a mixed solvent of ethanol, water, and THF (45 mL, 1:1:1), iron (2.13 g, 38.3 mmol) and ammonium chloride (0.6 g, 11.50 mmol) were added, and the mixture was stirred at 70 °C for 2 hours. The reaction mixture was filtered, and water was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 60 / 40 to 50 / 50) to give 1-{(2S * ,4R * )-4-[(4-aminophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl}propan-1-one (1.65 g, 70%) was obtained. ESI-MS (M+H) + : 310: 1 H-NMR (DMSO-d6,δ): 0.97-1.03 (m, 6H), 1.06-1.08 (m, 1H), 2.18-2.24 (m, 1H), 2.57-2.60 (m, 2H), 3.95-3.99 (m, 1H), 4.29 (brs, 2H), 4.68-4.70 (m, 1H), 5.17 (d, J = 8.4 Hz, 1H), 6.41-6.46 (m, 4H), 7.14-7.18 (m, 1H), 7.22-7.28 (m, 3H)

[0834] (Step 3) 1-{(2S * ,4R *1-{(2S,4R)-4-[(4-aminophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl}propan-1-one (530 mg) was purified by SFC (Chiralcel OJ-H (250x21mm, 5u), CO2 / methanol=85 / 15, flow rate 70 g / min, rt=6.36 min) to give 1-{(2S,4R)-4-[(4-aminophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl}propan-1-one (180 mg, 34%). ESI-MS (M+H) + : 310: 1 H-NMR (DMSO-d6,δ): 1.12-1.19 (m, 7H), 2.32-2.37 (m, 1H), 2.52-2.67 (m, 2H), 3.49 (brs, 2H), 4.08 (dd, J = 12.0, 3.5 Hz, 1H), 4.89-4.90 (m, 1H), 6.53 (d, J = 8.5 Hz, 2H), 6.64 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 7.5 Hz, 1H), 7.18-7.21 (m, 1H), 7.24-7.25 (m, 1H), 7.36 (d, J = 7.5 Hz, 1H). SFC (Chiralcel OJ-H (250x4.6mm, 5u), methanol / CO2 = 20 / 80, flow rate 3.0 ml / min): rt = 6.51 min

[0835] [Reference example 8] tert-Butyl (4-formylphenyl)((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (Process 1) Methyl 4-{[(2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}benzoate (0.5 g, 1.42 mmol) obtained in Step 5 of Reference Example 1 was dissolved in tetrahydrofuran (10 mL), and DMAP (0.693 g, 5.68 mmol) and di-tert-butyl dicarbonate (1.24 g, 5.68 mmol) were added, followed by stirring at 70 °C for 16 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=4 / 1) to obtain methyl 4-((tert-butoxycarbonyl)((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoate (0.5 g, 77%). ESI-MS m / z: 453 (M + H) +

[0836] (Process 2) Methyl 4-((tert-butoxycarbonyl)((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoate (0.50 g, 1.1 mmol) obtained in Step 1 was dissolved in methanol (10 mL), and 4 mol / L aqueous sodium hydroxide solution (10 mL) was added, followed by stirring at 80° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and aqueous citric acid solution was added until the resulting aqueous solution reached approximately pH 5. The resulting solid was suction filtered to give 4-((tert-butoxycarbonyl)((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoic acid (0.4 g, 83%). ESI-MS m / z: 439 (M + H) +

[0837] (Step 3) 4-((tert-Butoxycarbonyl)((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoic acid (0.40 g, 0.91 mmol) obtained in Step 2 was dissolved in dichloromethane (5 mL), and ethyl chloroformate (0.10 mL, 1.1 mmol) and triethylamine (0.38 mL, 2.74 mmol) were added, followed by stirring at room temperature for 5 hours. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in methanol (5 mL), and sodium borohydride (0.069 g, 1.83 mmol) was added at 0°C, followed by stirring at room temperature for 3 hours. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=7 / 3) to obtain tert-butyl (4-(hydroxymethyl)phenyl)((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (0.28 g, 72%). ESI-MS m / z: 425 (M + H) +

[0838] (Step 4) tert-Butyl (4-(hydroxymethyl)phenyl)((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (0.400 g, 0.94 mmol) obtained in Step 3 was dissolved in dichloromethane (5 mL), and DMP (0.480 g, 1.13 mmol) was added at 0 °C. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane and filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give tert-butyl (4-formylphenyl)((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (0.26 g, 65%). ESI-MS m / z: 423 (M + H) + : 1 H-NMR(DMSO-d6,δ):0.92-0.99(m, 6H), 1.34(s, 9H), 2.10-2.18(m, 1H), 2.36 (brs, 1H), 2.47-2.48 (m, 1H), 2.51-2.52 (m, 1H), 4.63-4.68 (m, 1H), 4.86 (brs, 1H), 7.34 (brs, 4H), 7.44 (d, J = 8.0 Hz, 2H), 7.88-7.90 (m, 2H), 9.97 (s, 1H).

[0839] [Reference example 9] 1-((2S,4R)-4-(((1r,4R)-4-aminocyclohexyl)amino)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)propan-1-one dihydrochloride (Process 1) 1-[(2S * ,4R * )-4-amino-2-methyl-3,4-dihydroquinolin-1(2H)-yl]propan-1-one (50.0 g, 230 mmol) was dissolved in methanol (600 mL), and acetic acid (68.80 mL, 1147 mmol), tert-butyl (4-oxocyclohexyl)carbamate (68.4 g, 344 mmol), and sodium borohydride (26.0 g, 689 mmol) were added, followed by stirring at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was mixed with water and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 7) to give tert-butyl (4-(((2S * ,4R *The crude product (17 g) of tert-butyl ((1R,4r)-4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclohexyl)carbamate was obtained. The crude product was purified by SFC (Chiralpak IA (250x30 mm, 5 u), CO2 / methanol = 85 / 15, flow rate 90.0 g / min, retention time (rt) = 6.7 min) to give tert-butyl ((1R,4r)-4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclohexyl)carbamate (6.0 g, 6.2%). SFC (Chiralpak AD-H (250x4.6mm, 5u), methanol / CO2 = 15 / 85, flow rate 3.0 ml / min): rt = 6.7 min ESI-MS m / z: 416.3 (M + H) +

[0840] (Process 2) Using tert-butyl ((1R,4r)-4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclohexyl)carbamate (6.0 g, 14 mmol) obtained in Step 1, 1-((2S,4R)-4-(((1r,4R)-4-aminocyclohexyl)amino)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)propan-1-one dihydrochloride (5.0 g, 89%) was obtained in the same manner as in Step 2 of Example 1a. ESIMS, (M + H) + , m / z: 316.41. 1H NMR (DMSO-d6, δ): 0.97 (t, J = 7.2 Hz, 3H), 1.04 (d, J = 6.4 Hz, 3H), 1.17-1.28 (m, 1H), 1.38-1.54 (m, 1H), 1.58-1.69 (m, 1H), 1.74-1.88 (m, 1H), 2.00-2.17 (m, 3H), 2.21-2.37 (m, 2H), 2.54-2.64 (m, 1H), 2.92-2.97 (m, 2H), 3.21-3.22 (m, 1H), 4.22-4.24 (m, 1H), 4.62-4.74 (m, 1H), 6.52 (brs, 1H), 7.31-7.41 (m, 3H), 7.56 (d, J = 7.67 Hz, 1H), 8.18 (brs, 3H), 9.63-9.93 (m, 2H).

[0841] [Reference example 10] 1-((2S * ,4R * )-4-(((1r,4R)-4-aminocyclohexyl)amino)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)propan-1-one dihydrochloride (Process 1) tert-Butyl (4-(((2S) obtained in Step 1 of Reference Example 9 * ,4R * The crude product (8.0 g) of tert-butyl ((1R,4r)-4-(((2S)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclohexyl)carbamate was purified by SFC (Chiralpak IA (250x30mm, 5u), CO2 / methanol = 85 / 15, flow rate 90.0 g / min, retention time (rt) = 7.62, 11.0 min) to give tert-butyl ((1R,4r)-4-(((2S) * ,4R * )-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclohexyl)carbamate (3.0 g, two-step total yield 6.7%) was obtained. SFC (Chiralpak AD-H (250x4.6mm, 5u), methanol / CO2 = 15 / 85, flow rate 3.0 ml / min): rt = 7.62, 11.0 min 1 H NMR (CDCl3, δ): 0.88-0.91 (m, 1H), 1.07 -1.12 (m, 6H), 1.16-1.40 (m, 4H), 1.44 (s, 9H), 2.01-2.06 (m, 4H), 2.24-2.28 (m, 1H), 2.48-2.61 (m, 2H), 2.63-2.66 (m, 1H), 3.46-3.60 (m, 2H), 4.36 (brs, 1H), 4.85 (brs, 1H), 7.09 (d, J = 7.0 Hz, 1H), 7.22-7.25 (m, 2H), 7.45-7.47 (m, 1H).

[0842] (Process 2) tert-Butyl ((1R,4r)-4-(((2S * ,4R * 1-((2S)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclohexyl)carbamate (3.0 g, 7.23 mmol) was used in the same manner as in Step 2 of Example 1a to prepare 1-((2S)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclohexyl)carbamate (3.0 g, 7.23 mmol). * ,4R * )-4-(((1r,4R)-4-aminocyclohexyl)amino)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)propan-1-one dihydrochloride (2.5 g, 90%) was obtained. ESIMS, (M + H) + , m / z: 316.3. 1H NMR (DMSO-d6, δ): 0.98 (t, J = 7.6 Hz, 3H), 1.04 (d, J = 6.4 Hz, 3H), 1.23-1.25 (m, 2H), 1.44-1.51 (m, 2H), 1.61-1.69 (m, 1H), 1.81-1.89 (m, 1H), 2.05-2.14 (m, 3H), 2.25-2.33 (m, 2H), 2.51-2.62 (m, 1H), 2.93-2.98 (m, 2H), 4.18-4.28 (m, 1H), 4.68-4.70 (m, 1H), 7.30-7.41 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 8.21 (brs, 3H), 9.82-9.88 (m, 2H).

[0843] [Reference example 11] (1R,4r)-4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclohexane-1-carboxylic acid (Process 1) 1-[(2S * ,4R * )-4-amino-2-methyl-3,4-dihydroquinolin-1(2H)-yl]propan-1-one (2.0 g, 9.2 mmol) and methyl 4-oxocyclohexane-1-carboxylate (2.86 g, 18.35 mmol) in the same manner as in Step 1 of Reference Example 9 to prepare methyl 4-(((2S * ,4R * The crude product was purified by SFC (Chiralpak IA (250x30mm, 5um), CO2 / methanol = 90 / 10, flow rate 90.0 g / min) to give methyl (1R,4r)-4-(((2S * ,4R *)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclohexane-1-carboxylate (0.240 g, 7.3%) was obtained. SFC (Chiralpak IA (250x4.6mm,5um), CO2 / methanol=90 / 10, flow rate 3 mL / min, retention time (rt)=8.0 min) 1 H NMR (CD3OD, δ): 0.89-1.01 (m, 1H), 1.03-1.10 (m, 6H), 1.21-1.36 (m, 2H), 1.39-1.57 (m, 2H), 1.93-2.14 (m, 4H), 2.15-2.22 (m, 1H), 2.24-2.38 (m, 2H), 2.49-2.60 (m, 1H), 2.62-2.70 (m, 1H), 2.72-2.83 (m, 1H), 3.63-3.70 (m, 3H), 4.76-4.79 (m, 1H), 7.21-7.46 (m, 4H).

[0844] (Process 2) Methyl (1R,4r)-4-(((2S * ,4R * (1R,4r)-4-(((2S)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclohexane-1-carboxylate (0.05 g, 0.14 mmol) in the same manner as in Step 2 of Example 2f. * ,4R * )-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclohexane-1-carboxylic acid (0.040 g, 83%) was obtained. ESIMS, (M + H) + , m / z: 345.60.

[0845] (Step 3) (1R,4r)-4-(((2S * ,4R *(1R,4r)-4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclohexane-1-carboxylic acid (250 mg, 0.725 mmol) was purified by SFC (Lux Cellulose-2 (250x30 mm, 5 um), CO2 / methanol = 75 / 25, flow rate 90.0 g / min, retention time (rt) = 2.3 min) to give (1R,4r)-4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclohexane-1-carboxylic acid (65 mg, 26%). SFC (Lux Cellulose-2 (250x4.6mm, 5um), CO2 / methanol = 55 / 45, flow rate 3.0 mL / min, retention time (rt) = 2.3 min) ESIMS, (M + H) + , m / z: 345.35. 1 H NMR (DMSO-d6, δ): 0.81-0.84 (m, 1H), 0.92-1.01 (m, 6H), 1.03-1.26 (m, 2H), 1.34 (qd, J = 12.72, 2.75 Hz, 2H), 1.85-2.02 (m, 4H), 2.09-2.19 (m, 2H), 2.53 (brs, 1H), 2.54-2.62 (m, 2H), 3.45 (dd, J = 11.90, 3.97 Hz, 1H), 4.56-4.68 (m, 1H), 7.19-7.25 (m, 3H), 7.47-7.51 (m, 1H).

[0846] [Reference example 12] 1-((2S,4R)-2-Methyl-4-(piperidin-4-ylamino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one dihydrochloride (Process 1) 1-[(2S * ,4R *tert-Butyl 4-(((2S)-4-amino-2-methyl-3,4-dihydroquinolin-1(2H)-yl]propan-1-one (1.5 g, 6.9 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (2.73 g, 13.76 mmol) was prepared in the same manner as in Step 1 of Reference Example 9. * ,4R * )-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)piperidine-1-carboxylate (2.4 g, 87%) was obtained. ESI-MS m / z: 402 (M + H) +

[0847] (Process 2) tert-Butyl 4-(((2S) obtained in Step 1 * ,4R * Using 1-((2S,4R)-2-methyl-4-(piperidin-4-ylamino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one dihydrochloride (1.9 g, 86%), 1-((2S,4R)-2-methyl-4-(piperidin-4-ylamino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one dihydrochloride (1.9 g, 86%) was obtained in the same manner as in Step 2 of Example 1a using 1-((2S,4R)-2-methyl-4-(piperidin-4-ylamino)-3,4-dihydroquinolin-1(2H)-yl)piperidine-1-carboxylate (2.4 g, 5.98 mmol). ESI-MS m / z: 302.23 (M + H) + : 1H-NMR (DMSO-d6,δ): 0.99 (t, J = 7.34 Hz, 3H), 1.05 (d, J = 6.36 Hz, 3H), 1.20-1.32 (m, 1H), 2.01-2.23 (m, 3H), 2.39 (t, J = 15.16 Hz, 2H), 2.55-2.62 (m, 1H), 2.82-3.02 (m, 3H), 3.37-3.39 (m, 2H), 3.64-3.68 (m, 1H), 4.28-4.32 (m, 1H), 4.67-4.70 (m, 1H), 7.30-7.41 (m, 3H), 7.57 (d, J = 7.83 Hz, 1H), 9.07-9.09 (m, 1H), 9.30 (d, J = 9.29 Hz, 1H), 10.16-10.21 (m, 2H).

[0848] [Reference example 13] 1-((2S,4R)-2-Methyl-4-(piperidin-4-ylamino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one dihydrochloride (Process 1) tert-Butyl 4-(((2S obtained in Step 1 of Reference Example 12 * ,4R * 4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)piperidine-1-carboxylate (3.0 g, 7.47 mmol) was purified by SFC (Chiralpak IG (30x250 mm), 5μ, CO2 / methanol=75 / 25, flow rate 90 g / min, rt=2.4 min) to give tert-butyl 4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)piperidine-1-carboxylate (0.900 g, 30%). SFC (Chiralpak IC-3 (150x4.6mm, 3µm), methanol / CO2 = 35 / 65, flow rate 3.0 ml / min): rt = 2.4 min ESI-MS m / z: 402.35 (M + H) + :1 H-NMR (DMSO-d6,δ): 0.98 (t, J = 7.3 Hz, 3H), 1.05 (d, J = 6.4 Hz, 3H), 1.17-1.25 (m, 1H), 1.38 (s, 9H), 1.52-1.60 (m, 1H), 1.70-1.75 (m, 1H), 2.09-2.23 (m, 3H), 2.54-2.67 (m, 1H), 2.79-2.95 (m, 3H), 3.55-3.61 (m, 1H), 4.03 (d, J = 8.8 Hz, 2H), 4.27-4.31 (m, 1H), 4.64-4.72 (m, 1H), 7.35-7.39 (m, 3H), 7.50 (d, J = 7.6 Hz, 1H), 9.58 (brs, 1H).

[0849] (Process 2) Using tert-butyl 4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)piperidine-1-carboxylate (0.800 g, 1.99 mmol) obtained in Step 1, the procedure was repeated in the same manner as in Step 2 of Example 1a to obtain 1-((2S,4R)-2-methyl-4-(piperidin-4-ylamino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one dihydrochloride (0.4 g, 53%). ESI-MS m / z: 302 (M + H) + : 1H-NMR (DMSO-d6,δ): 0.99 (t, J = 7.34 Hz, 3H), 1.05 (d, J = 6.14 Hz, 3H), 1.20-1.35 (m, 1H), 1.96-2.25 (m, 3H), 2.39 (t, J = 15.13 Hz, 2H), 2.54-2.67 (m, 1H), 2.85-3.04 (m, 3H), 3.32-3.34 (m, 2H), 3.66-3.69 (m, 1H), 4.26-4.32 (m, 1H), 4.68-4.72 (m, 1H), 7.26-7.43 (m, 3H), 7.58 (d, J = 7.45 Hz, 1H), 9.08 (d, J = 8.99 Hz, 1H), 9.27 (d, J = 8.4 Hz, 1H), 10.13-10.18 (m, 2H).

[0850] [Reference example 14] 1-((2S * ,4R * )-4-(((1r,3R)-3-aminocyclobutyl)amino)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)propan-1-one dihydrochloride (Process 1) 1-[(2S * ,4R * )-4-amino-2-methyl-3,4-dihydroquinolin-1(2H)-yl]propan-1-one (0.5 g, 2.29 mmol) and tert-butyl (3-oxocyclobutyl)carbamate (0.678 g, 3.66 mmol) in the same manner as in Step 1 of Reference Example 9. * ,4R * The crude product was purified by SFC (Chiralpak IG (30x250 mm), 5 μm, CO2 / ethanol=75 / 25, flow rate 90 g / min) to give tert-butyl ((1R,3r)-3-(((2S * ,4R *)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclobutyl)carbamate (120 mg, 13%) was obtained. ESI-MS m / z: 388 (M + H) + : 1 H-NMR (DMSO-d6,δ):0.79-0.84 (m, 1H), 0.92-0.99 (m, 6H), 1.37 (s, 9H), 1.99-2.04 (m, 3H), 2.06-2.33 (m, 3H), 2.54-2.61 (m, 2H), 3.23-3.25 (m, 1H), 3.46-3.49 (m, 1H), 4.02-4.05 (m, 1H), 4.57-4.63 (m, 1H), 7.14 (d, J = 7.2 Hz, 1H), 7.23-7.25 (m, 3H), 7.42-7.47 (m, 1H).

[0851] (Process 2) tert-Butyl ((1R,3r)-3-(((2S * ,4R * 1-((2S)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclobutyl)carbamate (0.25 g, 0.64 mmol) was prepared in the same manner as in Step 2 of Example 1a. * ,4R * )-4-(((1r,3R)-3-aminocyclobutyl)amino)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)propan-1-one dihydrochloride (0.21 g, 90%) was obtained. ESI-MS m / z: 288 (M + H) + : 1H-NMR (DMSO-d6,δ): 0.98 (t, J = 7.5 Hz, 3H), 1.03 (d, J = 6.5 Hz, 3H), 1.10-1.23 (m, 1H), 2.10-2.14 (m, 1H), 2.51-2.60 (m, 3H), 2.74-2.79 (m, 1H), 2.84-2.88 (m, 1H), 2.91-2.99 (m, 1H), 3.91-3.98 (m, 1H), 4.11-4.19 (m, 1H), 4.29-4.34 (m, 1H), 4.62-4.72 (m, 1H), 7.32-7.41 (m, 3H), 7.57 (d, J = 8.0 Hz, 1H), 8.42 (brs, 3H), 10.36 (brs, 1H), 10.44 (brs, 1H).

[0852] [Reference example 15] 4-((((2S * ,4R * )-2-Methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)methyl)benzoic acid (Process 1) 1-[(2S * ,4R * )-4-amino-2-methyl-3,4-dihydroquinolin-1(2H)-yl]propan-1-one (1.0 g, 4.6 mmol) was dissolved in DMF (3 mL), and methyl 4-(bromomethyl)benzoate (1.56 g, 6.88 mmol) and potassium carbonate (1.89 g, 13.8 mmol) were added, followed by stirring at 80 °C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (acetonitrile / water = 1 / 1) to give methyl 4-((((2S * ,4R * )-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)methyl)benzoate (1.0 g, 60%) was obtained. ESI-MS m / z: 367 (M + H) +

[0853] (Process 2) Methyl 4-((((2S obtained in step 1 * ,4R * )-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)methyl)benzoate (1.0 g, 2.73 mmol) in the same manner as in Step 2 of Example 2f to prepare 4-((((2S * ,4R * )-2-Methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)methyl)benzoic acid (0.6 g, 62%) was obtained. ESI-MS m / z: 353.34 (M + H) +

[0854] [Reference example 16] 1-((2S * ,4R * )-4-((5-aminopyridin-2-yl)amino)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)propan-1-one (Process 1) 1-[(2S * ,4R * )-4-amino-2-methyl-3,4-dihydroquinolin-1(2H)-yl]propan-1-one (1.0 g, 4.6 mmol) was dissolved in DMF (5 mL), 2-fluoro-5-nitropyridine (0.488 g, 3.44 mmol) and potassium carbonate (0.94 g, 6.88 mmol) were added, and the mixture was stirred at 70 °C for 1 hour. Water was added to the reaction mixture, and the resulting solid was filtered off with suction to obtain 1-((2S * ,4R * )-2-methyl-4-((5-nitropyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one (0.55 g, 71%) was obtained. ESI-MS m / z: 341 (M + H) +

[0855] (Process 2) 1-((2S) obtained in step 1 * ,4R * )-2-Methyl-4-((5-nitropyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one (0.55 g, 1.61 mmol) was dissolved in a mixed solvent of THF (3 mL), ethanol (3 mL), and water (3 mL). Iron powder (0.452 g, 8.08 mmol) and ammonium chloride (0.128 g, 2.42 mmol) were added, and the mixture was stirred at 60 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue, which was then extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-((2S * ,4R * )-4-((5-aminopyridin-2-yl)amino)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)propan-1-one (0.45 g, 90%) was obtained. ESI-MS m / z: 311 (M + H) +

[0856] [Reference example 17] 1-((2S,4R)-4-((5-aminopyridin-2-yl)amino)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)propan-1-one (Process 1) 1-((2S * ,4R * )-2-Methyl-4-((5-nitropyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one (940 mg, 2.76 mmol) was purified by SFC (CHIRALPAK IB, CO2 / methanol = 94 / 6, 30 mL / min, rt = 12.38 min) to give 1-((2S,4R)-2-methyl-4-((5-nitropyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one (230 mg, 24%). ESI-MS, (M+H) + , m / z: 341. 1H-NMR (CDCl3, δ): 1.10-1.20 (m, 6H), 1.33-1.44 (m, 1H), 2.29-2.43 (m, 1H), 2.53-2.64 (m, 1H), 2.66-2.76 (m, 1H), 4.90-5.04 (m, 1H), 5.69-5.96 (m, 1H), 6.48-6.59 (m, 1H), 7.16-7.25 (m, 3H), 7.29-7.36 (m, 1H), 8.21-8.27 (m, 1H), 9.00-9.04 (m, 1H).

[0857] (Process 2) 1-((2S,4R)-2-methyl-4-((5-nitropyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one (90 mg, 0.264 mmol) obtained in Step 1 was dissolved in a mixed solvent of ethanol (2 mL) and water (2 mL), and zinc powder (173 mg, 2.64 mmol) and sodium chloride (141 mg, 2.64 mmol) were added, followed by stirring under reflux for 1 hour. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (heptane / ethyl acetate = 4 / 6 to 0 / 10) to give 1-((2S,4R)-4-((5-aminopyridin-2-yl)amino)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)propan-1-one (52 mg, 63%). ESI-MS, (M+H) + , m / z: 311. 1H-NMR (CDCl3, δ): 1.12-1.17 (m, 6H), 2.27-2.39 (m, 1H), 2.51-2.61 (m, 1H), 2.62-2.71 (m, 1H), 3.27 (br s, 2H), 4.26 (d, J = 9.1 Hz, 1H), 4.46-4.54 (m, 1H), 4.87-4.95 (m, 1H), 6.35 (d, J = 8.6 Hz, 1H), 6.98 (dd, J = 8.6, 2.7 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.17-7.22 (m, 1H), 7.24-7.29 (m, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.72 (d, J = 3.2 Hz, 1H).

[0858] [Reference example 18] 1-((2S * ,4R * )-2-Methyl-4-((piperidin-4-ylmethyl)amino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one dihydrochloride (Process 1) 1-[(2S * ,4R * )-4-amino-2-methyl-3,4-dihydroquinolin-1(2H)-yl]propan-1-one (0.26 g, 1.0 mmol) was dissolved in dichloroethane (5 mL), and tert-butyl 4-formylpiperidine-1-carboxylate (0.239 g, 1.12 mmol), acetic acid (0.029 mL, 0.510 mmol), and sodium triacetoxyborohydride (0.433 g, 2.04 mmol) were added, followed by stirring at room temperature overnight. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7 / 3) to give tert-butyl 4-((((2S * ,4R *)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)methyl)piperidine-1-carboxylate (0.41 g, 98%) was obtained. ESI-MS m / z: 416 (M + H) +

[0859] (Process 2) tert-Butyl 4-((((2S obtained in step 1 * ,4R * )-2-Methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)methyl)piperidine-1-carboxylate (0.41 g, 0.98 mmol) was dissolved in ethyl acetate (5 mL), and hydrogen chloride / ethyl acetate solution (4 mol / L, 2.5 mL, 9.9 mmol) was added and stirred at room temperature for 3 hours. The reaction mixture was filtered under suction, and the resulting solid was dissolved in methanol and concentrated under reduced pressure to give 1-((2S * ,4R * )-2-Methyl-4-((piperidin-4-ylmethyl)amino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one dihydrochloride (0.43 g, quantitative) was obtained. ESI-MS m / z: 316 (M + H) +

[0860] [Reference example 19] 4-(((2S * ,4R * )-6-Fluoro-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoic acid (Process 1) Using 4-fluoroaniline (1.0 g, 9.0 mmol), N-((2S * ,4R * )-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)formamide (0.3 g, 16%) was obtained. ESI-MS m / z: 209 (M + H) +

[0861] (Process 2) N-((2S) obtained in step 1 * ,4R * )-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)formamide (1.0 g, 4.81 mmol) in the same manner as in Step 2 of Reference Example 1 to prepare N-((2S * ,4R * )-6-fluoro-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)formamide (1.0 g, 79%) was obtained. ESI-MS m / z: 265 (M + H) +

[0862] (Step 3) N-((2S) obtained in step 2 * ,4R * )-6-fluoro-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)formamide (1.0 g, 3.79 mmol) in the same manner as in Step 3 of Reference Example 1 to prepare 1-((2S * ,4R * )-4-amino-6-fluoro-2-methyl-3,4-dihydroquinolin-1(2H)-yl)propan-1-one (0.5 g, 56%) was obtained. ESI-MS m / z: 237 (M + H) +

[0863] (Step 4) 1-((2S) obtained in step 3 * ,4R * )-4-amino-6-fluoro-2-methyl-3,4-dihydroquinolin-1(2H)-yl)propan-1-one (0.3 g, 1.3 mmol) in the same manner as in Step 4 of Reference Example 1 to prepare methyl 4-(((2S * ,4R * )-6-fluoro-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoate (0.08 g, 10%) was obtained. ESI-MS m / z: 371 (M + H) +

[0864] (Step 5) Methyl 4-(((2S obtained in step 4 * ,4R * )-6-fluoro-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoate (0.9 g, 2.4 mmol) in the same manner as in Step 6 of Reference Example 1 to prepare 4-(((2S * ,4R * )-6-Fluoro-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)benzoic acid (0.65 g, 75%) was obtained. ESI-MS m / z: 357 (M + H) + : 1 H-NMR (CDCl3,δ): 1.14-1.22 (m, 6H), 1.25-1.34 (m, 1H), 2.32-2.38 (m, 1H), 2.53-2.59 (m, 1H), 2.66-2.73 (m, 1H), 4.24-4.31 (m, 2H), 4.96 (brs, 1H), 6.61 (d, J = 8.80 Hz, 2H), 6.93-7.02 (m, 2H), 7.15 (brs, 1H), 7.95 (d, J = 8.80 Hz, 2H).

[0865] [Reference example 20] tert-Butyl ((E)-3-((2S * ,4R * )-4-((4-aminophenyl)amino)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-7-yl)allyl)carbamate (Process 1) Using 3-bromoaniline (25.0 g, 145 mmol), N-((2S * ,4R * )-7-Bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)formamide (24 g, 62%) was obtained. ESI-MS m / z: 269 (M + H) +

[0866] (Process 2) N-((2S) obtained in step 1 * ,4R * )-7-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)formamide (24 g, 89 mmol) in the same manner as in Step 2 of Reference Example 1 to ...

Claims

1. The following formula (I): 【Chemistry 1】 (In the formula, L 1 and L 2 are the same or different and each represents a group represented by the following formula (A)-2, and S represents a group represented by the following formula (S1)-1: 【Chemistry 2】 (In the formula, The wavy line represents the binding site for S, and Ring RA-2 represents benzenediyl, cycloalkanediyl, pyridinediyl or piperidinediyl; 【Chemistry 3】 (In the formula, The wavy lines represent the binding sites for L1 or L2. n 1a-1 and n 1b-1 are the same or different and each represents 0 or 1; X 1a-1 and X 1b-1 are the same or different and each represents -C(=O)-NH-, -NH-C(=O)- or -NH-C(=O)-NH-; and R 1a-1 and R 1b-1 each represent a hydrogen atom, R 1b-1 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or R 1a-1 and R 1b-1 together represent a carbonyl group. or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier for treating DLBCL (diffuse large B-cell lymphoma).

2. L 1 and L 2 are the same or different and are selected from the group consisting of the following formulas: 【Chemistry 4】 The pharmaceutical composition according to claim 1, wherein the compound is selected from the group represented by one of the formulas:

3. The compound represented by formula (I) is a compound selected from the group consisting of the following compounds: N,N'-(propane-1,3-diyl)bis(4-{[(2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}benzamide), N,N'-(2-oxopropane-1,3-diyl)bis(4-{[(2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}benzamide), 4-{[(2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}-N-{2-[(4-{[(2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}phenyl)amino]-2-oxoethyl}benzamide, 4-{[(2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}-N-{(R)-1-[(4-{[(2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}phenyl)amino]-1-oxopropan-2-yl}benzamide, 4-{[(2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}-N-{(S)-1-[(4-{[(2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}phenyl)amino]-1-oxopropan-2-yl}benzamide, N-{(S)-3-methyl-1-[(4-{[(2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}phenyl)amino]-1-oxobutan-2-yl}-4-{[(2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}benzamide, 4-{[(2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}-N-{3-[(4-{[(2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}phenyl)amino]-3-oxopropyl}benzamide, N1,N5-bis(4-{[(2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}phenyl)glutaramide, 3-methyl-N1,N5-bis(4-{[(2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}phenyl)pentanediamide, N-(4-(((2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenyl)-2-(3-(4-(((2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenyl)ureido)acetamide, N 1 ,N 5 -bis(4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenyl)glutaramide, 4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-(2-(3-(4-(((2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenyl)ureido)ethyl)benzamide, (1R,4R)-4-(((2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-(2-((4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenyl)amino)-2-oxoethyl)cyclohexane-1-carboxamide, 4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-(3-((1R,4r)-4-(((2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclohexane-1-carboxamido)propyl)benzamide, N 1 -((1R,4r)-4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclohexyl)-N 5 -(4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenyl)glutaramide, 4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-(3-((1R,4r)-4-(((2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclohexane-1-carboxamido)-2-oxopropyl)benzamide, 2-(3-((1R,4R)-4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclohexyl)ureido)-N-(4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenyl)acetamide, (1R,4r)-4-(((2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-(2-(3-(4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenyl)ureido)ethyl)cyclohexane-1-carboxamide, N-((1R,4R)-4-(((2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)cyclohexyl)-2-(3-(4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenyl)ureido)acetamide, N 1 -(4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenyl)-N 5 -(6-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyridin-3-yl)glutaramide, N 1 -(4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenyl)-N 5 -(5-(((2S * ,4R * )-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyridin-2-yl)glutaramide, and 4-(((2S,4R)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)-N-(3-((6-(((2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)benzamide The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is selected from the group consisting of

4. A therapeutic agent for DLBCL (diffuse large B-cell lymphoma) comprising, as an active ingredient, a compound represented by formula (I) according to any one of claims 1 to 3 or a pharma- ceutically acceptable salt thereof.

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