Heterocyclic compound

Abstract

To provide a new heterocyclic compound which has an IRAK-M protein decomposition-inducing action and is expected to be useful for the prevention and treatment of cancer, fibrosis, infectious diseases and the like, and to provide a medicine containing the same.SOLUTION: The present invention provides a compound represented by the following formula (I): or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to heterocyclic compounds that induce the degradation of interleukin-1 receptor-associated kinase-M (IRAK-M) protein and are expected to be useful in the prevention and treatment of cancer, fibrosis, infectious diseases, etc., and to pharmaceuticals containing the same. [Background technology]

[0002] For the purpose of treatment by reducing pathology-related proteins, attempts have been made to develop compounds that induce ubiquitination of target proteins by E3 ligase and proteasomal degradation (sometimes referred to as Proteolysis Targeting Chimeras (PROTACs) or Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Erasers (SNIPERs)) (Non-Patent Documents 1 to 9). IRAK-M is a member of the IRAK family of protein kinases and is a pseudokinase with no kinase activity (Non-Patent Document 10). IRAK-M exists downstream of all Toll-like receptors (TLRs) except TLR3 and functions in vivo as a negative feedback regulator of the TLR / interleukin-1 (IL-1) receptor signaling pathway (Non-Patent Document 11). Its expression is restricted to certain epithelial cells, including bile duct epithelial cells, lung epithelial cells, and intestinal epithelial cells, as well as immune cells, particularly myeloid cells. IRAK-M negatively regulates TLR-mediated inflammatory cytokine induction signals in innate immune cells such as macrophages and dendritic cells, thereby playing an important role in maintaining immune homeostasis, including the induction of endotoxin tolerance (Non-Patent Document 12). IRAK-M has been reported to contribute to cancer growth by contributing to immunosuppression by tumor-associated macrophages, bone marrow-derived immunosuppressive cells, dendritic cells, and other factors in the tumor microenvironment (Non-Patent Documents 13-15). Furthermore, IRAK-M has been reported to affect the phagocytic activity, antibacterial defense, and collagen production promotion of alveolar macrophages, and is also involved in fibrosis, asthma, secondary infections after sepsis, and infectious complications of hematopoietic stem cell transplantation (Non-Patent Documents 16-18). Therefore, compounds that induce IRAK-M degradation by linking E3 ligase (e.g., Von Hippel-Lindau (VHL), Cereblon (CRBN), X-Linked Inhibitor of Apoptosis Protein (XIAP), Murine Double Minute 2 (MDM2), DDB1 / CUL4-associated factor (DCAF)15) binders with IRAK-M binders via a linker may be promising therapeutic agents for cancer, fibrosis, infectious diseases, and IRAK-M protein-related diseases.

[0003] Patent Document 1 reports a compound as an IRAK-M protein degradation inducer. Patent Documents 2 and 3 report compounds as IRAK (particularly IRAK-4) protein degradation inducers. Patent Documents 4 to 16 report compounds that utilize IAP binders to induce protein degradation. Patent Documents 17 to 35 report compounds as IAP antagonists. Patent Documents 36 to 39 report compounds having an N-(piperidin-4-yl)thieno[3,2-d]pyrimidin-4-amine or N-(piperidin-4-yl)thieno[3,2-b]pyridin-7-amine structure. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2017 / 211924 [Patent Document 2] International Publication No. 2019 / 099926 [Patent Document 3] International Publication No. 2019 / 133531 [Patent Document 4] International Publication No. 2018 / 066545 [Patent Document 5] Japanese Patent Application Laid-Open No. 2013-056837 [Patent Document 6] International Publication No. 2016 / 169989 [Patent Document 7] International Publication No. 2016 / 172134 [Patent Document 8] International Publication No. 2017 / 011590 [Patent Document 9] International Publication No. 2017 / 182418 [Patent Document 10] International Publication No. 2017 / 201449 [Patent Document 11] US Patent Application Publication No. 2018 / 0118733 [Patent Document 12] US Patent Application Publication No. 2018 / 0134688 [Patent Document 13] International Publication No. 2018 / 119448 [Patent Document 14] International Publication No. 2018 / 119357 [Patent Document 15] US Patent Application Publication No. 2019 / 0119271 [Patent Document 16] US Patent Application Publication No. 2019 / 0175612 [Patent Document 17] International Publication No. 2006 / 113376 [Patent Document 18] International Publication No. 2007 / 104162 [Patent Document 19] International Publication No. 2007 / 106192 [Patent Document 20] International Publication No. 2007 / 131366 [Patent Document 21] US Patent Application Publication No. 2007 / 0093428 [Patent Document 22] International Publication No. 2008 / 016893 [Patent Document 23] International Publication No. 2008 / 045905 [Patent Document 24] International Publication No. 2008 / 079735 [Patent Document 25] International Publication No. 2008 / 128171 [Patent Document 26] International Publication No. 2010 / 142994 [Patent Document 27] International Publication No. 2011 / 002684 [Patent Document 28] International Publication No. 2011 / 098904 [Patent Document 29] International Publication No. 2012 / 143726 [Patent Document 30] Japanese Patent Application Laid-Open No. 2012-106958 [Patent Document 31] Japanese Patent Application Laid-Open No. 2012-176934 [Patent Document 32] US Patent Application Publication No. 2013 / 0172264 [License 33] U.S. Patent and Trademark Office Publication No. 2014 / 0135270 [Patent Document 34] International Publication No. 2014 / 023708 [License 35] International Publication No. 2014 / 060770 [License 36] International Publication No. 2016 / 040330 [License 37] International Publication No. 2013 / 019966 [License 38] U.S. Patent and Trademark Publication No. 2013 / 0040957 [License 39] China Patent Publication No. 103242341 [Non-licensed literature]

[0005] [Non-licensed Document 1] Science, 2017 Mar 17; 355(6330): 1163-1167 [Non-licensed Document 2] Cell Chem Biol, 2018 Jan 18; 25(1): 67-77.e3 [Non-licensed Document 3] Cell Chem Biol, 2017 Sep 21; 24(9): 1181-1190 [Non-licensed Document 4] ACS Chem Biol, 2017 Apr 21; 12(4): 892-898 [Non-licensed Document 5] Cell Chem Biol, 2018 Jan 18; 25(1): 78-87.e5 [Non-licensed Document 6] Nat Rev Drug Discov, 2017 Feb; 16(2): 101-114 [Non-licensed Document 7] Nat Chem Biol, 2015 Aug; 11(8): 611-7 [Non-patent document 8] Chemistry & Biology, 2010, 17(6): 551-555 [Non-Patent Document 9] Chembiochem, 2005, 6(1): 40-46 [Non-Patent Document 10] J Biol Chem, 1999 Jul 2; 274(27): 19403-19410 [Non-Patent Document 11] Cell, 2002 Jul 26; 110(2): 191-202 [Non-Patent Document 12] Infect Dis Rep, 2010 Jan 1; 2(1). pii: e9 [Non-Patent Document 13] Oncogene, 2011 May 26; 30(21): 2475-2484 [Non-Patent Document 14] J Immunol, 2010 Oct 1; 185(7): 4223-4232 [Non-Patent Document 15] Mol Immunol, 2007 Jul; 44(14): 3453-3461 [Non-Patent Document 16] J Immunol, 2015 Feb 15; 194(4): 1894-1904 [Non-Patent Document 17] J Clin Invest, 2006 Sep; 116(9): 2532-2542, Epub 2006 Aug 17 [Non-Patent Document 18] J Immunol, 2010 Jun 1; 184(11): 6299-6308 Summary of the Invention [Problem to be solved by the invention]

[0006] The object of the present invention is to provide novel heterocyclic compounds that induce degradation of IRAK-M protein and are expected to be useful in the prevention and treatment of cancer, fibrosis, infectious diseases, etc., and pharmaceuticals containing the same. [Means for solving the problem]

[0007] The present inventors have conducted extensive research to find an IRAK-M protein degradation inducer, and as a result have found that the compound represented by the following formula has excellent IRAK-M protein degradation-inducing activity. This may be useful in the prevention and treatment of cancer, fibrosis, infectious diseases, etc., and has led to the completion of the present invention.

[0008] That is, the present invention is as follows. [1] Formula (I):

[0009] [ka] or a pharmaceutically acceptable salt thereof. [2] The compound according to [1] above, or a pharmaceutically acceptable salt thereof, wherein the E3 ligase binder (E) is selected from the group consisting of an IAP binder, a CRBN binder, a VHL binder, an MDM2 binder, and a DCAF15 binder. [3] The IRAK-M binder (M) is represented by the following formula (II):

[0010] [ka] [Wherein, X represents S, O, or NR, where R represents a hydrogen atom or a C1-6 alkyl group; Y represents CH or N; Z represents O or NH; R 01represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a cyano group, a halogen atom, an optionally substituted phenyl group, an optionally substituted ester group, or an optionally substituted 5-membered heterocyclic group, R 02 represents a hydrogen atom, a C1-6 alkyl group, or a halogen atom, R 03 represents an optionally substituted C1-6 alkylene group, an optionally substituted C6-14 arylene group, an optionally substituted heterocyclic group, or a bond, A has the following structural formula:

[0011] [ka] (where R 05 are each independently a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a C1-6 alkoxy group.) represents a group represented by *-SO2-*, *-CO-CH2-*, *-CO-NH-*, *-O-*, an optionally substituted C1-6 alkylene group, or a bond; R 04 has the following structural formula:

[0012] [ka] (where * indicates the bonding position to A, and ** indicates the bonding position to the linker), an optionally substituted C1-6 alkylene group, an optionally substituted C3-10 cycloalkylene group, an optionally substituted C6-14 arylene group, an optionally substituted hetero 5- or 6-membered ring group, an ester bond, or a bond, and the arrow indicates the bond to the linker (L). The compound according to the above [1], which is represented by the following formula: or a pharmaceutically acceptable salt thereof.

[0013] [4] In the formula II, R 01represents a hydrogen atom, a C1-6 alkyl group, a C2-3 alkynyl group, a cyano group, a halogen atom, an optionally substituted phenyl group, an optionally substituted ester group, or an optionally substituted 5-membered heterocyclic group, R 03 represents an optionally substituted arylene group, an optionally substituted heterocyclic group, or a bond, R 04 has the following structural formula:

[0014] [ka] (* indicates the bonding position to A, ** indicates the bonding position to the linker), an optionally substituted C alkylene group, an optionally substituted C cycloalkylene group, an optionally substituted C arylene group, an optionally substituted pyrazolinediyl group, an optionally substituted oxazolidinediyl group, an optionally substituted isoxazolidinediyl group, an ester bond, or a bond, and an arrow indicates the bond to the linker (L), or a pharmaceutically acceptable salt thereof.

[0015] [5] In the formula II, R 01 is a hydrogen atom, a methyl group, a cyano group, an iodine atom, a phenyl group, or a group having the following structural formula:

[0016] [ka] and represents any group represented by R 02 represents a hydrogen atom, a methyl group, or a chlorine atom; R 03 has the following structural formula:

[0017] [ka] (wherein n is 0, 1 or 2, W is NR (wherein R is a hydrogen atom, a C1-6 alkyl group, or an acyl group), SO2, SO, S, or O, each V is independently CH or N (provided that any one of the Vs is CH), and each U is independently CH, N, NH, O, or S (provided that two or more Us cannot be O or S)), an optionally substituted C1-6 alkylene group, or a bond, R 04 has the following structural formula:

[0018] [ka] (wherein * indicates the bonding position to A, ** indicates the bonding position to the linker, V is CH or N, and U is each independently CH, N, NH, O, or S (with the proviso that two or more Us cannot be O or S)), an optionally substituted C1-6 alkylene group, an optionally substituted C3-10 cycloalkylene group, an optionally substituted C6-14 arylene group, or a bond, or a pharmaceutically acceptable salt thereof.

[0019] [6] In the formula II, X is S, Z is O, and R 01 is H or a methyl group, and R 02 is H and R 03 has the following structural formula:

[0020] [ka] (where * indicates the bonding position to O, ** indicates the bonding position to A, and n is 0, 1 or 2), A has the following structural formula:

[0021] [ka] (where R 05 are each independently a hydrogen atom or a C alkyl group; R 04 has the following structural formula:

[0022] [ka] (wherein V is CH or N, * indicates the bonding position to A, and ** indicates the bonding position to the linker), an optionally substituted C1-6 alkylene group, an optionally substituted C3-10 cycloalkylene group, or an optionally substituted C6-14 arylene group, or a pharmaceutically acceptable salt thereof.

[0023] [7] The IRAK-M binder (M) is represented by the following formula (III):

[0024] [ka] [In the formula, Y represents CH or N, R 01 represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-3 alkynyl group, a cyano group, a halogen atom, an optionally substituted phenyl group, an optionally substituted ester group, or an optionally substituted 5-membered heterocyclic group, A 01 has the following structural formula:

[0025] [ka] (where R 12 are each independently a hydrogen atom or a C alkyl group), *-SO2-*, or *-CO-CH2-*, R 11 has the following structural formula:

[0026] [ka] (where * indicates the bonding position to A, and ** indicates the bonding position to the linker), an optionally substituted C1-6 alkylene group, an optionally substituted C3-10 cycloalkylene group, an optionally substituted C6-14 arylene group, or a bond, and the arrow indicates the bond to the linker (L). The compound according to the above [3], or a pharmaceutically acceptable salt thereof,

[0027] [8] In Formula III, R 01 is a hydrogen atom or a methyl group, A 01 but, The following structural formula:

[0028] [ka] (where R 12 are each independently a hydrogen atom or a C alkyl group), or *-SO2-*, R 11 has the following structural formula:

[0029] [ka] (wherein * indicates the bonding position to A, and ** indicates the bonding position to the linker), or a pharmaceutically acceptable salt thereof.

[0030] [9] The IRAK-M binder (M) is the following compound: N-(3-(methylsulfonyl)phenyl)thieno[3,2-d]pyrimidin-4-amine,

[0031] [ka]

[0032] 4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol),

[0033] [ka]

[0034] 3-(allyloxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole,

[0035] [ka]

[0036] 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol,

[0037] [ka]

[0038] 3-(allyloxy)-5-(1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)ethyl)isoxazole,

[0039] [ka]

[0040] 3-(allyloxy)-5-(1-(4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)ethyl)isoxazole,

[0041] [ka]

[0042] (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole,

[0043] [ka]

[0044] 3-((tetrahydrofuran-3-yl)oxy)-4-(thieno[3,2-d]pyrimidin-4-ylamino)benzamide,

[0045] [ka]

[0046] N,6-diphenylthieno[3,2-d]pyrimidin-4-amine,

[0047] [ka]

[0048] N-(2-methoxyphenyl)-6-phenylthieno[3,2-d]pyrimidin-4-amine,

[0049] [ka]

[0050] N-(cyclopropylmethyl)-6-phenylthieno[3,2-d]pyrimidin-4-amine,

[0051] [ka]

[0052] 6-phenyl-N-(pyridin-2-yl)thieno[3,2-d]pyrimidin-4-amine,

[0053] [ka]

[0054] 6-phenyl-N-(pyridin-3-ylmethyl)thieno[3,2-d]pyrimidin-4-amine,

[0055] [ka]

[0056] N-phenethyl-6-phenylthieno[3,2-d]pyrimidin-4-amine,

[0057] [ka]

[0058] 4-(thieno[3,2-d]pyrimidin-4-ylamino)benzamide,

[0059] [ka]

[0060] N-(2-((tetrahydrofuran-3-yl)oxy)phenyl)thieno[3,2-d]pyrimidin-4-amine,

[0061] [ka]

[0062] 3-(thieno[3,2-d]pyrimidin-4-ylamino)benzamide,

[0063] [ka]

[0064] N-(pyridin-4-yl)thieno[3,2-d]pyrimidin-4-amine,

[0065] [ka]

[0066] N-(2-(trifluoromethyl)pyridin-4-yl)thieno[3,2-d]pyrimidin-4-amine,

[0067] [ka]

[0068] N-(2-methoxypyridin-4-yl)thieno[3,2-d]pyrimidin-4-amine,

[0069] [ka]

[0070] N-(2-(trifluoromethyl)pyridin-3-yl)thieno[3,2-d]pyrimidin-4-amine,

[0071] [ka]

[0072] N-(3-methyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-amine,

[0073] [ka]

[0074] N-(1H-benzo[d]imidazol-5-yl)thieno[3,2-d]pyrimidin-4-amine,

[0075] [ka]

[0076] 5-(thieno[3,2-d]pyrimidin-4-ylamino)isoindoline-1,3-dione,

[0077] [ka]

[0078] N-(1H-indazol-6-yl)thieno[3,2-d]pyrimidin-4-amine,

[0079] [ka]

[0080] 5-(thieno[3,2-d]pyrimidin-4-ylamino)isobenzofuran-1(3H)-one,

[0081] [ka]

[0082] Methyl 4-((cyclopropylmethyl)amino)thieno[3,2-d]pyrimidine-6-carboxylate,

[0083] [ka]

[0084] 6-(1-methyl-1H-pyrazol-4-yl)-4-((1-methylpiperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0085] [ka]

[0086] 6-ethynyl-4-((1-methylpiperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0087] [ka]

[0088] 4-((2-chlorothieno[3,2-d]pyrimidin-4-yl)amino)benzamide,

[0089] [ka]

[0090] 6-iodo-4-((tetrahydro-2H-pyran-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0091] [ka]

[0092] 6-iodo-4-((tetrahydro-2H-thiopyran-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0093] [ka]

[0094] 6-iodo-4-((1-methylpiperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0095] [ka]

[0096] 4-((6-iodothieno[3,2-d]pyrimidin-4-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide,

[0097] [ka]

[0098] 4-((1-((2,6-difluorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0099] [ka]

[0100] 4-((1-(methylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0101] [ka]

[0102] 4-((1-((2-methoxyethyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0103] [ka]

[0104] 4-((1-(benzylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0105] [ka]

[0106] tert-butyl 4-(((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)methyl)piperidine-1-carboxylate,

[0107] [ka]

[0108] ethyl 3-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)propanoate,

[0109] [ka]

[0110] 4-((1-(cyclopropylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0111] [ka]

[0112] 4-((1-((2-chlorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0113] [ka]

[0114] 4-((1-((2-methoxyphenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0115] [ka]

[0116] 4-((1-(o-tolylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0117] [ka]

[0118] 4-((1-((2-(4-fluorophenoxy)phenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0119] [ka]

[0120] 4-((1-((2-fluorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0121] [ka]

[0122] 4-((1-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0123] [ka]

[0124] 4-((1-((4-methoxyphenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0125] [ka]

[0126] 4-((1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0127] [ka]

[0128] 4-((1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0129] [ka]

[0130] 4-((1-((3-methoxyphenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0131] [ka]

[0132] 4-((1-(4-methylbenzenesulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0133] [ka]

[0134] 4-((1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0135] [ka]

[0136] 4-((1-((3-chlorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0137] [ka]

[0138] 4-((1-(pyridin-3-ylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0139] [ka]

[0140] 4-((1-((1-benzyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine),

[0141] [ka]

[0142] 4-((1-((6-methoxypyridin-3-yl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0143] [ka]

[0144] 4-((1-((1,4-dimethyl-1H-pyrazol-5-yl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0145] [ka]

[0146] 4-((1-(isobutylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0147] [ka]

[0148] 4-((1-(phenethylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0149] [ka]

[0150] 4-((1-((3-phenoxyphenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0151] [ka]

[0152] N-(4-ethoxyphenyl)thieno[3,2-d]pyrimidin-4-amine,

[0153] [ka]

[0154] N-(3,4-dimethoxyphenyl)-2,6-dimethylthieno[3,2-d]pyrimidin-4-amine,

[0155] [ka]

[0156] 7-((1-(prop-2-yn-1-yl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine,

[0157] [ka]

[0158] 1-methyl-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)-1H-pyrazol-3-ol,

[0159] [ka]

[0160] 7-((1-((3-(allyloxy)-1-methyl-1H-pyrazol-5-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine,

[0161] [ka]

[0162] 3-(allyloxy)-5-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)methyl)isoxazole,

[0163] [ka]

[0164] 3-(prop-2-yn-1-yloxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole,

[0165] [ka]

[0166] 3-(allyloxy)-5-((4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)methyl)isoxazole,

[0167] [ka]

[0168] 7-((1-((1-methyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine,

[0169] [ka]

[0170] 7-((1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine,

[0171] [ka]

[0172] 7-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine,

[0173] [ka]

[0174] 7-((1-((1,5-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine,

[0175] [ka]

[0176] 7-((1-((1-methyl-1H-pyrazol-5-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine,

[0177] [ka]

[0178] 3,5-dimethyl-4-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole,

[0179] [ka]

[0180] 7-((1-(thiazol-2-ylmethyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine,

[0181] [ka]

[0182] 7-((1-((2-methylthiazol-5-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine,

[0183] [ka]

[0184] 2-(1H-pyrazol-1-yl)-1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)ethan-1-one,

[0185] [ka]

[0186] 1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one,

[0187] [ka]

[0188] 2-allyl-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3(2H)-one,

[0189] [ka]

[0190] 3-(2-methoxyethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole,

[0191] [ka]

[0192] 7-((1-((3-(allyloxy)isoxazol-5-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine-2-carbonitrile),

[0193] [ka]

[0194] 5-((4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)methyl)isoxazol-3-ol,

[0195] [ka]

[0196] , and 5-(1-(4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)ethyl)isoxazol-3-ol,

[0197] [ka] The compound according to the above [3], which is a monovalent group derived from a compound selected from the group consisting of

[0198]

[10] The IRAK-M binder (M) is the following compound: 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol,

[0199] [ka]

[0200] 5-((4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)methyl)isoxazol-3-ol,

[0201] [ka]

[0202] 1-methyl-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)-1H-pyrazol-3-ol,

[0203] [ka]

[0204] , and 4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol

[0205] [ka] The compound according to the above [9], wherein the compound is a monovalent group derived from a compound selected from the group consisting of:

[0206]

[11] The linker (L) is represented by the formula (L1): -B1-B2-L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 wherein B1 and B2 each independently represent the following structural formula:

[0207] [ka] (However, B1 and B2 cannot both have this structure.), *-O-*, *-NR 06 -*(where R 06is a hydrogen atom or a C1-6 alkyl group.), *-CO2-*, *-CO-*, *-SO2-*, an optionally substituted C1-6 alkylene group, an optionally substituted C2-6 alkenylene group, an optionally substituted C2-6 alkynylene group, an optionally substituted C3-10 cycloalkylene group, an optionally substituted C6-14 arylene group, or a bond; L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 are each independently The following structural formula:

[0208] [ka] (wherein m represents an integer of 1 to 4, n represents an integer of 1 to 4, and each A independently represents N, CHCO, or CHCHO) 1 ~L 7 Two or more of the following cannot have this structure: a bond, an oxygen atom, a sulfur atom, a C1-6 alkylene group, a C3-10 cycloalkylene group, a carbonyl group, an imino group optionally substituted with a C1-6 alkyl group, an ethynylene group, a vinylene group optionally substituted with a C1-6 alkyl group, a C3-10 cycloalkenylene group, a phenylene group, a thiazolyldiyl group, a non-aromatic heterocyclic group optionally substituted with a C1-6 alkyl group or a halogen atom, a pyrrolidinediyl group optionally substituted with a fluorine atom, a morpholinediyl group optionally substituted with a C1-6 alkyl group, an azetidinediyl group optionally substituted with a fluorine atom, a group of the formula -SO2-, a group of the formula -CH2CHO-, a group of the formula -OCH2CH2-, a group of the formula -COCH2-, a group of the formula -CH2CO-, a group of the formula -CO2-, a group of the formula -OCO-, a group of the formula -COCHR 101 NR 102 -, formula -OCH2CHR 103 NR 104 -, formula-NR 105 CHR 106 CO-, formula-NR107 CO-, formula-CONR 108 -, formula -SO2NR 109 -, formula-NR 110 SO2-, or formula -NR 111 CHR 112 CH2O-(R in the above formula 101 , R 103 , R 106 , and R 112 each independently represents a hydrogen atom, a C alkyl group, a 3-guanidinopropyl group, a carbamoylmethyl group, a carboxymethyl group, a mercaptomethyl group, a 2-carbamoylethyl group, a 2-carboxyethyl group, an imidazol-4-ylmethyl group, a 4-aminobutyl group, a 2-methylthioethyl group, a benzyl group, a hydroxymethyl group, a 1-hydroxyethyl group, an indol-3-ylmethyl group, a 4-hydroxyphenylmethyl group, or a pyridylmethyl group; R 102 , R 104 , R 105 , R 107 , R 108 , R 109 , R 110 , and R 111 each independently represent a hydrogen atom or a C1-6 alkyl group. ) or together represent one bond. ) The compound according to any one of the above [3] to

[10] , or a pharmaceutically acceptable salt thereof.

[0209]

[12] B1 and B2 each independently represent the following structural formula:

[0210] [ka] (However, B1 and B2 cannot both have this structure.), *-O-*, *-NR 06 -*(where R 06is a hydrogen atom or a C alkyl group.), *-CO-*, an optionally substituted C alkylene group, an optionally substituted C arylene group, an optionally substituted C alkynylene group, or a bond, or a pharmaceutically acceptable salt thereof.

[13] B1 and B2 each independently represent the following structural formula:

[0211] [ka] (However, B1 and B2 cannot both have this structure.), *-O-*, a C1-6 alkylene group, or a bond, or a pharmaceutically acceptable salt thereof.

[14] The linker (L) has the following structural formula:

[0212] [ka] (where * indicates binding to an IRAK-M binder (M).) or a pharmaceutically acceptable salt thereof, wherein n is an integer of 1 to 5, m is 0, 1, or 2, s is 0 or 1, t is 0 or 1, and R is a hydrogen atom or a C1-6 alkyl group.

[0213]

[15] The E3 ligase binder (E) is represented by the following formula (IV):

[0214] [ka] [wherein D represents a fragment structure of a substance that binds to IAP together with the piperazine ring, E represents a nitrogen-containing aromatic heterocyclic group, and R 01 , R 02 , R03 , R 04 , R 05 , R 06 , R 07 , and R 08 each independently represent a hydrogen atom or a C1-6 alkyl group which may together form a ring, and either D or E is bonded to a linker (L).] or a pharmacologically acceptable salt thereof according to any one of the above [3] to

[14] .

[0215]

[16] The D is represented by the following formula (V):

[0216] [ka] (In the formula, R 11 represents a hydrogen atom or a hydroxyl group, and R 12 and R 13 are each independently a hydrogen atom, a C alkyl group, a C cycloalkylene group, a carbonyl group, an imino group optionally substituted with a C alkyl group, an ethynylene group optionally substituted with a C alkyl group, a vinylene group optionally substituted with a C alkyl group, a pyrazole group optionally substituted with a C alkyl group, a C cycloalkenylene group, a phenylene group, a thiazolylene group, a pyrrolidinediyl group optionally substituted with a fluorine atom, an azetidinediyl group optionally substituted with a fluorine atom, or any of the above groups bonded to a linker (L) (provided that R 12 and R 13 and T represents an optionally halogenated C1-3 alkyl group, or the following formula (VI):

[0217] [ka] (Wherein m represents 0, 1, or 2, n represents 0, 1, or 2, W 11represents a methylene group, a difluoromethylene group, O, S, SO, SO, or NR (wherein R represents a hydrogen atom, a C alkyl group, a C alkyl-carbonyl group, a C aryl-carbonyl group, a C alkylsulfonyl group, or a bond to a linker), and T represents an optionally halogenated C alkyl group), or the following formula (VII):

[0218] [ka] (wherein Q is an oxygen atom, a group of the formula -NR 21 -(R 21 represents a hydrogen atom, a C1-6 alkyl group, or a C1-6 alkyl group which may form a ring together with P.) or a bond, and P represents a hydrogen atom, a C1-6 alkyl group, or a bond to a linker (including forming a ring together with Q and a bond to a linker).), or a pharmacologically acceptable salt thereof.

[17] The D is R in formula (V). 12 or R 13 , W in formula (VI) 11 or the compound according to the above

[16] , or a pharmaceutically acceptable salt thereof, wherein either P in formula (VII) is bonded to a linker (L).

[0219]

[18] The E is represented by the following formula:

[0220] [ka] (wherein each A independently represents C or N, each R bonded to N independently represents a hydrogen atom, a C alkyl group, or an amide group, and each of the other R independently represents a hydrogen atom, a halogen atom, a C alkyl group, a C alkoxy group, or an amide group) (wherein, when E is bonded to a linker, it is bonded to the linker at any position represented by R in the above formula), the compound according to the above

[15] or

[16] , or a pharmaceutically acceptable salt thereof.

[0221]

[19] The E is represented by the following formula:

[0222] [ka] (wherein R bonded to N each independently represents a hydrogen atom, a C1-6 alkyl group, or an amide group, and the other R each independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an amide group) (wherein, when E is bonded to a linker, it is bonded to the linker at any one of the positions represented by R in the above formula), the compound according to the above-mentioned

[18] , or a pharmaceutically acceptable salt thereof.

[0223]

[20] The E is represented by the following formula (VIII):

[0224] [ka] (In the formula, R 21 , R 22 , and R 23 each independently represents a hydrogen atom, a halogen atom, a C alkyl group, a C alkoxy group, or an amide group; R 25 and R 26 each independently represents a hydrogen atom, a halogen atom, a C alkyl group, a C alkoxy group, an amide group, or a bond to a linker; R 24indicates a hydrogen atom, a methyl group, or a bond to a linker, provided that the bond to the linker is 24 , R 25 , or R 26 ) is any one of the following.) The compound according to the above

[18] , or a pharmaceutically acceptable salt thereof.

[21] The E is represented by the following formula (IX):

[0225] [ka] (In the formula, R 31 , R 32、 R 33 , R 34 , and R 35 each independently represent a hydrogen atom, a halogen atom, a C alkyl group, a C alkoxy group, or an amide group, and R represents a hydrogen atom, a C alkyl group, or a bond to a linker.

[0226]

[22] The following compound: 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide (2-(4-((S)-2-cyclohexyl-2-(( S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-((5-((4-(thie no[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide),

[0227] [ka]

[0228] 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-6-methoxy-1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide (2-(4-((S)-2-cyclohexyl-2-((S )-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-6-methoxy-1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide),

[0229] [ka]

[0230] 1-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperazin-1-yl)-2-((2R,5R)-5-methyl-2-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperazin-1-yl)ethan-1-one (1-((R)-4-(5,6-difluoro-1- methyl-1H-indole-2-carbonyl)-2-methylpiperazin-1-yl)-2-((2R,5R)-5-methyl-2-((2-(2-(2-((5-((4-(thieno[3,2-b]py ridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperazin-1-yl)ethan-1-one),

[0231] [ka]

[0232] (S)—N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S)—N-((S)-1-cyclohexyl- 2-(4-(5,6-difluoro-1-methyl-3-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol- 3-yl)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide),

[0233] [ka]

[0234] (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)-6,9,12-trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S)-N-((S)-1-cyclohexyl- 2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl )oxy)-6,9,12-trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide),

[0235] [ka]

[0236] (S)—N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S)—N-((S)-1-cyclohexyl- 2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl )oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide),

[0237] [ka]

[0238] (S)—N-((S)-1-cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S)—N-((S)-1-cyclohexyl- 2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)o xy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide),

[0239] [ka]

[0240] (S)-N-((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy )methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide),

[0241] [ka]

[0242] (S)-N-((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S)-N-((S)-1-cyclohexyl-2 -((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy) methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide),

[0243] [ka]

[0244] (S)—N—((S)-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-2-(methylamino)propanamide ((S)—N—((S)-2-(4-(5,6-diflu- oro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidi n-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-2-(methylamino)propanamide),

[0245] [ka]

[0246] (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-(2-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S)-N-((S)-1-cyclohexyl-2 -(4-(5,6-difluoro-1-methyl-4-(2-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3- yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide),

[0247] [ka]

[0248] , and (S)-N-((S)-1-cyclohexyl-2-(4-(2-methyl-1-(2-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide((S)-N-((S)-1-cyclohexyl -2-(4-(2-methyl-1-(2-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)ox y)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide),

[0249] [ka] The compound according to the above [1], selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0250]

[23] The compound according to any one of the above [3] to

[14] , wherein the E3 ligase binder (E) is a Smac peptide mimetics compound, or a pharmaceutically acceptable salt thereof.

[24] The Smac peptide mimetics compound is represented by the following formula (S1):

[0251] [ka] (wherein R represents an optionally substituted alkyl group or an optionally substituted cycloalkyl group, ring A represents an optionally substituted heterocycle, and ring B represents an optionally substituted ring, and either ring B or R is bonded to the linker), or a pharmaceutically acceptable salt thereof.

[25] The compound according to the above

[24] , wherein, in the formula S1, R is a cycloalkyl group, B is an optionally substituted aryl group, and A is a thiazoldiyl group, or a pharmaceutically acceptable salt thereof.

[0252]

[26] The Smac peptide mimetics compound is represented by the following formula (I-1) or the following formula (I-2):

[0253] [ka] (In the formula, R 1 and R 2 each independently represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted aryl group; R 3 and R 4 each independently represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted alkoxy group, an optionally substituted heteroaryl group, or an optionally substituted heterocyclyl group; R 5 , R 6 , R 7 , and R 8 each independently represents a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted cycloalkyl group, and Linker represents a bond to a linker.), and the following formula (I-3):

[0254] [ka] [In the formula, R is represented by the following formula:

[0255] [ka] (Wherein, ring A is a C4-8 membered aliphatic ring, a C3-6 cycloalkylene, or (CH2) 1-4 wherein ring B is an optionally substituted aryl ring or an optionally substituted heteroaryl ring containing a nitrogen atom.), and Linker is a bond to a linker.], the following formula (I-4):

[0256] [ka] (wherein, each Y is independently H or a C alkyl group, X is CH, O, or N, R is H, a methyl group, or a hydroxymethyl group, and L is a bond to a linker), the following formula (I-5), the following formula (I-6), the following formula (I-7):

[0257] [ka] (wherein, each Y independently represents H or a C alkyl group, X represents CH, O, or N, and L represents a bond to a linker.) or the following formula (I-8):

[0258] [ka] (wherein each Y is independently H or a C alkyl group; each X is independently CH, O, NH, or NR (where R is a C alkyl group) (wherein Xs may join together to form a ring); R is H, a methyl group, or a hydroxymethyl group; and L is a bond to a linker, although L may be bonded to X.) The compound according to the above

[23] , which is an IAP represented by the formula: or a pharmaceutically acceptable salt thereof.

[0259]

[27] The compound according to any one of the above [3] to

[14] , wherein the E3 ligase binder (E) is a CRBN binder selected from the group consisting of thalidomide, lenalidomide, pomalidomide, their isomers, and their derivatives, or a pharmaceutically acceptable salt thereof.

[28] The CRBN binder is represented by the following formula (C1-C6):

[0260] [ka] (Wherein W represents CH2, CHR, C=O, SO2, NH, or an N-alkyl group; each X independently represents O, S, or H2; Y represents CH2, -C=CR', NH, an N-alkyl group, an N-aryl group, an N-heteroaryl group, an N-cycloalkyl group, an N-heterocyclyl group, O, or S; Z represents O, S, or H2; G and G' each independently represent H, an alkyl group, OH, R'OCOOR, R'OCONRR'', a CH2-heterocyclyl group optionally substituted with R', or a benzyl group optionally substituted with R'; Q1, Q2, Q3, and Q4 represent carbons substituted with R', N, or N-oxide; A represents H, an optionally substituted alkyl group, a cycloalkyl group, Cl, or F; R represents CONR'R'', -OR', -NR'R'', -SR', -SO2R', -SO2NR'R'', -CR'R''-, -CR'NR'R''-, aryl group, hetaryl group, alkyl group, cycloalkyl group, heterocyclyl group, -P(0)(OR')R'', -P(0)R'R'', -OP(0)(OR')R'', -OP(0)R'R'', halogen atom, trifluoromethyl group 、 Cyano group, -NR'S02NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N-CN)NR'R'', -NR'C(=N-CN)R'', -NR'C(=C-N02)NR'R'', -S02NR'COR'', nitro group 、-CO2R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=0)(C=N-R')R'', pentafluorosulfanyl group or trifluoromethoxy group, R' and R'' each independently represent a bond, H, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted heterocycle, an optionally substituted -C(=O)R, or an optionally substituted heterocyclyl group, a wavy line indicates that the bond is stereospecific ((R) or (S)) or non-stereospecific, and Rn each independently represent 1 to 4 functional groups or atoms, where n=1 indicates a bond to a linker, and where n is 2, 3, or 4, one of the functional groups or atoms indicates a bond to a linker.

[0261]

[29] The E3 ligase binder (E) is represented by the following formula (V1):

[0262] [ka] [In the formula, W 21 is an optionally substituted aryl group, an optionally substituted heteroaryl group, or a group of the formula:

[0263] [ka] (In the formula, R 65 , R 66 each independently represents hydrogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted heteroaryl group, or R 65 , R 66 and together with the carbon atom to which they are attached form an optionally substituted cycloalkyl group, R 67represents an optionally substituted heterocyclyl group, an optionally substituted alkoxy group, an optionally substituted heteroaryl group, an optionally substituted aryl group, a group represented by the following formula:

[0264] [ka] (where R 68 represents H or an optionally substituted alkyl group, and R 69 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkylcarbonyl group, an optionally substituted (cycloalkyl)alkylcarbonyl group, an optionally substituted aralkylcarbonyl group, an optionally substituted arylcarbonyl group, an optionally substituted (heterocyclyl)carbonyl group, or an optionally substituted aralkyl group; R 70 each independently represents a halogen atom, an optionally substituted alkoxy group, a cyano group, an optionally substituted alkyl group, a haloalkyl group, a haloalkoxy group, or a bond to a linker, and p represents 0 to 3. 70 indicates a bond to the linker, then p=1. 61 , R 62 each independently represents a hydrogen atom or an optionally substituted alkyl group; W 22 represents a benzene ring or a 5- to 10-membered heteroaryl ring, and R 63 is H, halogen atoms, OH, NO2, NR 61 R 62 , OR 62 ,CONR 61 R 62 , N.R. 61 COR 62、 SO2NR 61 R 62 , N.R. 61 SO2R 62, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocyclyl group; R 64 represents a hydrogen atom, a halogen atom, an optionally substituted alkyl group, a hydroxy group, an optionally substituted alkoxy group, or a bond to a linker, and o is 0, 1, 2, 3, or 4. 64 represents a bond to a linker, then o=1.], or a pharmaceutically acceptable salt thereof.

[0265]

[30] The compound according to any one of the above [3] to

[14] , wherein the E3 ligase binder (E) is an MDM2 binder selected from the group consisting of imidazoline derivatives, spiroindolinone derivatives, pyrrolidone derivatives, piperidinone derivatives, morpholinone derivatives, pyrrolopyrimidine derivatives, imidazolopyridine derivatives, thiazoloimidazoline derivatives, pyrrolopyrrolidinone derivatives, and isoquinolinone derivatives, or a pharmaceutically acceptable salt thereof.

[31] The E3 ligase binder (E) is represented by the following formula:

[0266] [ka] (In the formula, X represents a halogen atom or a cyano group, R represents a hydrogen atom or a methyl group, Y represents sulfonamide or CHNH, and L represents a bond to a linker.) The compound according to any one of the above [3] to

[14] , which is a DCAF15 binder selected from the group consisting of compounds represented by the following formula: and derivatives thereof, or a pharmaceutically acceptable salt thereof.

[32] A medicine comprising the compound according to any one of the above [1] to

[31] or a pharmaceutically acceptable salt thereof.

[33] The pharmaceutical agent according to

[32] above, which is an IRAK-M protein degradation inducer.

[34] The pharmaceutical agent according to

[32] or

[33] above, which is a preventive or therapeutic agent for cancer.

[35] The pharmaceutical agent according to any one of the above

[32] to

[34] , which is used in combination with another anticancer agent.

[36] A method for inducing IRAK-M protein degradation, comprising administering to a patient in need of treatment an effective amount of the compound according to any one of [1] to

[31] above or a pharmaceutically acceptable salt thereof.

[37] A method for preventing or treating cancer, comprising administering to a patient in need of treatment an effective amount of the compound according to any one of [1] to

[31] above or a pharmaceutically acceptable salt thereof. [Effects of the Invention]

[0267] The compounds of the present invention have the activity of inducing the degradation of IRAK-M protein, and may be useful as preventive or therapeutic agents for cancer, fibrosis, and infectious diseases. [Brief explanation of the drawings]

[0268] [Figure 1] Using a Lewis lung carcinoma cell inoculation model, Examples 1, 25, 26, 27, 28, and 38 were administered subcutaneously three times every three days, and the daily changes in tumor size in each group were observed. The salts shown in the figure were used for each compound. The figure shows the mean ± standard error. DETAILED DESCRIPTION OF THE INVENTION

[0269] The present invention will be described below with reference to exemplary embodiments of the compounds of the present invention, their preparation methods, and applications, along with preferred methods and materials that can be used in carrying out the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. In addition, any materials and methods equivalent to or similar to those described herein can be similarly used in carrying out the present invention. In addition, all publications and patents cited in this specification in connection with the inventions described herein are incorporated by reference, for example, to methods, materials, and the like that can be used in the present invention. In this specification, the expression "A to B" indicating a range of values ​​means a range of values ​​including the endpoints A and B. The same applies to "A to B." In this specification, when describing compound names such as substituents, common names may be used instead of formal names, but they all mean the same compound.

[0270] The definition of each substituent used in the present specification will be described in detail below. Unless otherwise specified, each substituent has the following definition.

[0271] In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.

[0272] In the present specification, examples of the "C1-3 alkyl group" include methyl, ethyl, propyl, isopropyl and cyclopropyl.

[0273]

[0023] In the present specification, examples of the "optionally halogenated C1-3 alkyl group" include a C1-3 alkyl group optionally having 1 to 5 halogen atoms. Specific examples include methyl, chloromethyl, fluoromethyl, dichloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, cyclopropyl, 1-fluorocyclopropyl, 2-chlorocyclopropyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, and 2,3-difluorocyclopropyl.

[0274] In the present specification, examples of the "C alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0275]

[0023] In the present specification, examples of the "optionally halogenated C1-6 alkyl group" include a C1-6 alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples include methyl, chloromethyl, fluoromethyl, dichloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, 2,2-difluorocyclopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, difluorocyclobutyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, fluorocyclopentyl, hexyl, and 6,6,6-trifluorohexylfluorocyclohexyl.

[0276] In the present specification, examples of a "C2-6 alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.

[0277] As used herein, examples of a "C2-6 alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 4-methyl-2-pentynyl. As used herein, a "C2-3 alkynyl group" means one having 2 or 3 carbon atoms, and examples include ethynyl, 1-propynyl, and 2-propynyl.

[0278] In the present specification, examples of the "C3-10 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and adamantyl.

[0279] In the present specification, examples of the "C3-10 cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

[0280] In the present specification, examples of the "C6-14 aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

[0281] In the present specification, examples of the "C7-16 aralkyl group" include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

[0282] In the present specification, examples of the "C1-6 alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

[0283]

[0023] In the present specification, examples of the "optionally halogenated C1-6 alkoxy group" include a C1-6 alkoxy group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

[0284] In the present specification, examples of the "C3-10 cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

[0285] In the present specification, examples of the "C1-6 alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.

[0286]

[0023] In the present specification, examples of the "optionally halogenated C alkylthio group" include a C alkylthio group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio.

[0287]

[0023] In the present specification, examples of the "C3-10 cycloalkylthio group (the sulfur atom of which may be oxidized)" include a cyclopropylthio group, a cyclohexylthio group, a cyclopentylsulfinyl group, and a cyclohexylsulfonyl group.

[0288] In the present specification, examples of the "C1-6 alkyl-carbonyl group" include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl and heptanoyl.

[0289]

[0023] In the present specification, examples of the "optionally halogenated C alkyl-carbonyl group" include a C alkyl-carbonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

[0290] In the present specification, examples of the "C1-6 alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl.

[0291] In the present specification, examples of the "C6-14 aryl-carbonyl group" include benzoyl, 1-naphthoyl and 2-naphthoyl.

[0292] In the present specification, examples of the "C7-16 aralkyl-carbonyl group" include phenylacetyl and phenylpropionyl.

[0293] As used herein, examples of the "5- to 14-membered aromatic heterocyclic carbonyl group" include nicotinoyl, isonicotinoyl, thenoyl and furoyl.

[0294]

[0033] In the present specification, examples of the "3- to 14-membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl.

[0295] In the present specification, examples of the "mono- or di-C1-6 alkyl-carbamoyl group" include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

[0296] In the present specification, examples of the "mono- or di-C7-16 aralkyl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl.

[0297] In the present specification, examples of the "C1-6 alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.

[0298]

[0023] In the present specification, examples of the "optionally halogenated C alkylsulfonyl group" include a C alkylsulfonyl group optionally having 1 to 7 halogen atoms. Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl.

[0299] In the present specification, examples of the "C6-14 arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

[0300] In the present specification, examples of the "C6-14 arylene group" include phenylene, 1,5-naphthylene, 1,4-naphthylene, 2,3-naphthylene, 1,8-anthrylene and 9,10-anthrylene.

[0301] In the present specification, examples of the "substituent" include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group, and an optionally substituted silyl group.

[0302]

[0023] In the present specification, examples of "hydrocarbon groups" (including "hydrocarbon groups" in "optionally substituted hydrocarbon groups") include C alkyl groups, C alkyl groups, C alkylene groups, C alkenyl groups, C alkynyl groups, C cycloalkyl groups, C cycloalkylene groups, C cycloalkenyl groups, C aryl groups, C arylene groups, and C aralkyl groups.

[0303] In the present specification, examples of the "optionally substituted hydrocarbon group" include hydrocarbon groups which may have a substituent selected from the following Substituent Group A.

[0304] [Substituent group A] (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) an optionally halogenated C1-6 alkoxy group, (7) C6-14 aryloxy group (e.g., phenoxy, naphthoxy), (8) C7-16 aralkyloxy group (e.g., benzyloxy), (9) 5- to 14-membered aromatic heterocyclic oxy group (e.g., pyridyloxy), (10) 3- to 14-membered non-aromatic heterocyclic oxy group (e.g., morpholinyloxy, piperidinyloxy), (11) C1-6 alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy), (12) C6-14 aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), (13) C1-6 alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) a mono- or di-C alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy), (15) C6-14 aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy), (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), (17) 3- to 14-membered non-aromatic heterocyclylcarbonyloxy groups (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) optionally halogenated C alkylsulfonyloxy groups (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy), (19) a C6-14 arylsulfonyloxy group optionally substituted by a C1-6 alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy), (20) an optionally halogenated C1-6 alkylthio group, (21) a 5- to 14-membered aromatic heterocyclic group, (22) a 3- to 14-membered non-aromatic heterocyclic group, (23) a formyl group, (24) a carboxy group, (25) an optionally halogenated C alkyl-carbonyl group, (26) a C6-14 aryl-carbonyl group, (27) a 5- to 14-membered aromatic heterocyclic carbonyl group, (28) a 3- to 14-membered non-aromatic heterocyclic carbonyl group, (29) a C1-6 alkoxy-carbonyl group, (30) C6-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), (31) C7-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) a carbamoyl group, (33) a thiocarbamoyl group, (34) a mono- or di-C alkyl-carbamoyl group, (35) C aryl-carbamoyl group (e.g., phenylcarbamoyl), (36) 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) 3- to 14-membered non-aromatic heterocyclic carbamoyl group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) an optionally halogenated C alkylsulfonyl group, (39) a C6-14 arylsulfonyl group, (40) 5- to 14-membered aromatic heterocyclic sulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl), (41) an optionally halogenated C alkylsulfinyl group, (42) C6-14 arylsulfinyl group (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g., pyridylsulfinyl, thienylsulfinyl), (44) amino group, (45) mono- or di-C alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino), (46) mono- or di-C arylamino group (e.g., phenylamino), (47) 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), (48) C7-16 aralkylamino group (e.g., benzylamino), (49) formylamino group, (50) C alkyl-carbonylamino group (e.g., acetylamino, propanoylamino, butanoylamino), (51) (C alkyl) (C alkyl-carbonyl) amino group (e.g., N-acetyl-N-methylamino), (52) C6-14 aryl-carbonylamino group (e.g., phenylcarbonylamino, naphthylcarbonylamino), (53) C1-6 alkoxy-carbonylamino group (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (54) C7-16 aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (55) C alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), (56) a C6-14 arylsulfonylamino group optionally substituted by a C1-6 alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino), (57) an optionally halogenated C1-6 alkyl group, (58) a C2-6 alkenyl group, (59) a C2-6 alkynyl group, (60) C3-10 cycloalkyl group, (61) a C3-10 cycloalkenyl group, and (62) C6-14 aryl group.

[0305] The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different. In the present specification, examples of the "heterocyclic group" (including the "heterocyclic group" in the "optionally substituted heterocyclic group") include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a 7- to 10-membered bridged heterocyclic group, each of which contains, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom.

[0306] In the present specification, examples of the "optionally substituted C6-14 aryl group" include a C6-14 aryl group optionally having a substituent selected from the aforementioned substituent group A. The number of substituents in the "optionally substituted C6-14 aryl group" is, for example, 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0307] In the present specification, examples of the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, and pyrazolopyridinyl. and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as thienyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

[0308] In the present specification, examples of the "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.Preferable examples of the "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxolanyl, oxanyl, dioxanyl, thiolanyl, oxathianyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperi 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as dihydropyridinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl; dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, and dihydrobenziso Thiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro and 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups such as triahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl, triazaspirononyl (e.g., 1,3,7-triazaspiro[4.4]nonyl), thiadiazaspirononyl (e.g., 7-thia-1,3-diazaspiro[4.4]nonyl), and dioxidethiadiazaspirononyl (e.g., 7,7-dioxide-7-thia-1,3-diazaspiro[4.4]nonyl).

[0309] In the present specification, the term "nitrogen-containing aromatic heterocyclic group" includes, among "aromatic heterocyclic groups", those containing at least one nitrogen atom as a ring-constituting atom.

[0310] In the present specification, examples of the "optionally substituted heterocyclic group" include a heterocyclic group which may have a substituent selected from the above-mentioned Substituent Group A. The number of substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0311] In the present specification, examples of the "acyl group" include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group, each of which optionally has "1 or 2 substituents selected from a C alkyl group, a C alkenyl group, a C cycloalkyl group, a C cycloalkenyl group, a C aryl group, a C aralkyl group, a 5- to 14-membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an optionally halogenated C alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group".

[0312] Furthermore, the term "acyl group" also includes hydrocarbon-sulfonyl groups, heterocyclic-sulfonyl groups, hydrocarbon-sulfinyl groups, and heterocyclic-sulfinyl groups.

[0313] Here, the term "hydrocarbon-sulfonyl group" refers to a sulfonyl group having a hydrocarbon group bonded thereto, the term "heterocycle-sulfonyl group" refers to a sulfonyl group having a heterocyclic group bonded thereto, the term "hydrocarbon-sulfinyl group" refers to a sulfinyl group having a hydrocarbon group bonded thereto, and the term "heterocycle-sulfinyl group" refers to a sulfinyl group having a heterocyclic group bonded thereto.

[0314] Preferable examples of the "acyl group" include a formyl group, a carboxy group, a C1-6 alkyl-carbonyl group, a C2-6 alkenyl-carbonyl group (e.g., crotonoyl), a C3-10 cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), a C3-10 cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered aryl-carbonyl group, a 5- to 14-membered aryl- ... Non-aromatic heterocyclic carbonyl group, C1-6 alkoxy-carbonyl group, C6-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), C7-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl group, mono- or di-C1-6 alkyl-carbamoyl group, mono- or di-C2-6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C3-10 cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), aryl), mono- or di-C6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C7-16 aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C1-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C2-6 alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C3-10 cycloalkyl-thiocarbamoyl group thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C6-14 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C7-16 aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl), sulfino group, C1-6 alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl), sulfo group, C1-6 alkylsulfonyl group,Examples thereof include a C arylsulfonyl group, a phosphono group, and a mono- or di-C alkylphosphono group (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0315]

[0033] In the present specification, examples of an "optionally substituted amino group" include an amino group optionally having "1 or 2 substituents selected from a C alkyl group, a C alkenyl group, a C cycloalkyl group, a C aryl group, a C aralkyl group, a C alkyl-carbonyl group, a C aryl-carbonyl group, a C aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C alkyl-carbamoyl group, a mono- or di-C aralkyl-carbamoyl group, a C alkylsulfonyl group and a C arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from Substituent group A".

[0316] Preferable examples of the optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C alkyl)amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C alkenylamino group (e.g., diallylamino), a mono- or di-C cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono- or di-C aryl ... amino group (e.g., phenylamino), mono- or di-C7-16 aralkylamino group (e.g., benzylamino, dibenzylamino), mono- or di-(optionally halogenated C1-6 alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), mono- or di-C6-14 aryl-carbonylamino group (e.g., benzoylamino), mono- or di-C7-16 aralkyl-carbonylamino group (e.g., benzylcarbonylamino), mono- or di-5- to 14-membered aromatic heterocyclic carbonyl group carbonylamino group (e.g., nicotinoylamino, isonicotinoylamino), mono- or di-3 to 14-membered non-aromatic heterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), mono- or di-C alkoxy-carbonylamino group (e.g., tert-butoxycarbonylamino), 5 to 14-membered aromatic heterocyclylamino group (e.g., pyridylamino), carbamoylamino group, (mono- or di-C alkyl-carbamoyl)amino group (e.g., methylcarbamoylamino), (mono- or di- Examples of the (C7-16 aralkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino), a C1-6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), a C6-14 arylsulfonylamino group (e.g., phenylsulfonylamino), a (C1-6 alkyl)(C1-6 alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino), and a (C1-6 alkyl)(C6-14 aryl-carbonyl)amino group (e.g., N-benzoyl-N-methylamino).

[0317]

[0033] In the present specification, examples of an "optionally substituted carbamoyl group" include a carbamoyl group optionally having "1 or 2 substituents selected from a C alkyl group, a C alkenyl group, a C cycloalkyl group, a C aryl group, a C aralkyl group, a C alkyl-carbonyl group, a C aryl-carbonyl group, a C aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C alkyl-carbamoyl group and a mono- or di-C aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from Substituent group A".

[0318] Preferable examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C alkyl-carbamoyl group, a mono- or di-C alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C aryl-carbamoyl group (e.g., Examples include a mono- or di-C aralkyl-carbamoyl group, a mono- or di-C alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl), and a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl).

[0319]

[0033] In the present specification, examples of an "optionally substituted thiocarbamoyl group" include a thiocarbamoyl group optionally having "1 or 2 substituents selected from a C alkyl group, a C alkenyl group, a C cycloalkyl group, a C aryl group, a C aralkyl group, a C alkyl-carbonyl group, a C aryl-carbonyl group, a C aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C alkyl-carbamoyl group and a mono- or di-C aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from Substituent group A".

[0320] Preferable examples of the optionally substituted thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a mono- or di-C alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- or di-C cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or di-C cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or di-C alkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or di-C alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- or di-C cycloalkyl ... alken -C6-14 aryl-thiocarbamoyl groups (e.g., phenylthiocarbamoyl), mono- or di-C7-16 aralkyl-thiocarbamoyl groups (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), mono- or di-C1-6 alkyl-carbonyl-thiocarbamoyl groups (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C6-14 aryl-carbonyl-thiocarbamoyl groups (e.g., benzoylthiocarbamoyl), and 5- to 14-membered aromatic heterocyclylthiocarbamoyl groups (e.g., pyridylthiocarbamoyl).

[0321]

[0033] In the present specification, examples of an "optionally substituted sulfamoyl group" include a sulfamoyl group optionally having "1 or 2 substituents selected from a C alkyl group, a C alkenyl group, a C cycloalkyl group, a C aryl group, a C aralkyl group, a C alkyl-carbonyl group, a C aryl-carbonyl group, a C aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C alkyl-carbamoyl group and a mono- or di-C aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from Substituent group A".

[0322] Preferable examples of the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-C alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), a mono- or di-C cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), a mono- or di-C alkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), a mono- or di-C alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), a mono- or di-C alkyl ... -C6-14 aryl-sulfamoyl groups (e.g., phenylsulfamoyl), mono- or di-C7-16 aralkyl-sulfamoyl groups (e.g., benzylsulfamoyl, phenethylsulfamoyl), mono- or di-C1-6 alkyl-carbonyl-sulfamoyl groups (e.g., acetylsulfamoyl, propionylsulfamoyl), mono- or di-C6-14 aryl-carbonyl-sulfamoyl groups (e.g., benzoylsulfamoyl), and 5- to 14-membered aromatic heterocyclylsulfamoyl groups (e.g., pyridylsulfamoyl).

[0323]

[0033] In the present specification, examples of an "optionally substituted hydroxy group" include a hydroxy group optionally having "a substituent selected from a C alkyl group, a C alkenyl group, a C cycloalkyl group, a C aryl group, a C aralkyl group, a C alkyl-carbonyl group, a C aryl-carbonyl group, a C aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C alkyl-carbamoyl group, a mono- or di-C aralkyl-carbamoyl group, a C alkylsulfonyl group and a C arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from Substituent group A".

[0324] Preferable examples of the optionally substituted hydroxy group include a hydroxy group, a C alkoxy group, a C alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C cycloalkyloxy group (e.g., cyclohexyloxy), a C aryloxy group (e.g., phenoxy, naphthyloxy), a C aralkyloxy group (e.g., benzyloxy, phenethyloxy), a C alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C aryl-carbonyloxy group (e.g., benzoyloxy), a C aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy, nyloxy), 5- to 14-membered aromatic heterocyclylcarbonyloxy groups (e.g., nicotinoyloxy), 3- to 14-membered non-aromatic heterocyclylcarbonyloxy groups (e.g., piperidinylcarbonyloxy), C alkoxy-carbonyloxy groups (e.g., tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclyloxy groups (e.g., pyridyloxy), carbamoyloxy groups, C alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy), C aralkyl-carbamoyloxy groups (e.g., benzylcarbamoyloxy), C alkylsulfonyloxy groups (e.g., methylsulfonyloxy, ethylsulfonyloxy), and C arylsulfonyloxy groups (e.g., phenylsulfonyloxy).

[0325]

[0033] In the present specification, examples of the "optionally substituted sulfanyl group" include a sulfanyl group optionally having "a substituent selected from a C alkyl group, a C alkenyl group, a C cycloalkyl group, a C aryl group, a C aralkyl group, a C alkyl-carbonyl group, a C aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from Substituent group A", and a halogenated sulfanyl group.

[0326] Preferable examples of the optionally substituted sulfanyl group include a sulfanyl (—SH) group, a C alkylthio group, a C alkenylthio group (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C cycloalkylthio group (e.g., cyclohexylthio), a C arylthio group (e.g., phenylthio, naphthylthio), a C aralkylthio group (e.g., benzylthio, phenethylthio), a C alkyl-carbonylthio group (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), a C aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-membered aromatic heterocyclylthio group (e.g., pyridylthio) and a halogenated thio group (e.g., pentafluorothio).

[0327]

[0023] In the present specification, examples of the "optionally substituted silyl group" include a silyl group optionally having "1 to 3 substituents selected from a C alkyl group, a C alkenyl group, a C cycloalkyl group, a C aryl group and a C aralkyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A." Examples of the optionally substituted silyl group include a tri-C alkylsilyl group (e.g., trimethylsilyl, tert-butyl(dimethyl)silyl).

[0328] As used herein, the term "linker" refers to a chemical moiety (structure) used to connect a portion of a compound of interest to another compound. Exemplary linkers are described herein. For example, in any compound described herein, a chemical structure used to connect a portion of the structure to another portion of the structure can be used as a linker, and corresponds to the linker referred to herein. Although not limited thereto, linkers preferably used in the present invention are those referred to herein as "L X " (x is any number), and structures in which one or more atomic groups are further bonded to the structure.

[0329] In the present specification, examples of the "C alkylene group" include a methylene group, a 1,2-ethylene group, a 1,1-ethylene group, a 1,2-propylene group, a 1,3-propylene group, a 2,2-propylene group, a 1,4-butylene group, a 1,2-butylene group, a 1,3-butylene group, a 2,2-butylene group, a 1,5-pentylene group, a 3,3-pentylene group, and a 1,6-hexalene group.

[0330]

[0033] In the present specification, examples of the "C3-10 cycloalkylene group" include a 1,1-cyclopropylene group, a cis-1,2-cyclopropylene group, a trans-1,2-cyclopropylene group, a 1,1-cyclobutylene group, a cis-1,2-cyclobutylene group, a trans-1,2-cyclobutylene group, a cis-1,3-cyclobutylene group, a trans-1,3-cyclobutylene group, a 1,1-cyclopentylene group, a cis-1,2-cyclopentylene group, a trans-1,2-cyclopentylene group, a cis-1,3-cyclopentylene group, a trans-1,3-cyclopentylene group, a 1,1-cyclohex ... Examples of the cyclohexylene group include a cis-1,2-cyclohexylene group, a trans-1,2-cyclohexylene group, a cis-1,3-cyclohexylene group, a trans-1,3-cyclohexylene group, a cis-1,4-cyclohexylene group, a trans-1,4-cyclohexylene group, a 1,1-cycloheptynylene group, a 1,1-cyclooctynylene group, a 2,2-dimethyl-1,1-cyclopropylene group, a 2,3-dimethyl-1,1-cyclopropylene group, a 2,2,3,3,4,4-tetramethyl-1,1-cyclobutylene group, a 7,7-norcaranylene group, a 7,7-norpinanylene group, and a 7,7-norbornanylene group.

[0331] In the present specification, examples of the "C3-10 cycloalkenylene group" include a 1,2-cyclopropenylene group, a 1,2-cyclobutenylene group, a 1,2-cyclopentenylene group, a 1,2-cyclohexenylene group and a 2-bornen-2,3-yl group.

[0332] In this specification, the term "bond" refers to a state in which two adjacent substituents are bonded via a bond by a single bond. When multiple "bonds" are linked, it refers to a state in which all of them are bonded together by a single bond.

[0333] Each symbol in formula (II) will be explained below. X is S, O, or NR (wherein R is a hydrogen atom or a C1-6 alkyl group, preferably a methyl group), and is preferably S. Y represents CH or N, preferably CH. Z represents O or NH, and is preferably O. The arrow indicates the bond to the linker (L). R 01 represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a cyano group, a halogen atom, an optionally substituted phenyl group, an optionally substituted ester group, or an optionally substituted 5-membered heterocyclic group, preferably a hydrogen atom, a C1-6 alkyl group, a C2-3 alkynyl group, a cyano group, a halogen atom, an optionally substituted phenyl group, an optionally substituted ester group, or an optionally substituted 5-membered heterocyclic group, more preferably a hydrogen atom, a methyl group, a cyano group, an iodine atom, a phenyl group, or a group represented by the following structural formula:

[0334] [ka] and particularly preferably a hydrogen atom.

[0335] R 01 Examples of the "substituent" of the "optionally substituted phenyl group", "optionally substituted ester group", and "optionally substituted 5-membered heterocyclic group" represented by the following formula (I) include substituents selected from the above-mentioned Substituent Group A. The number of substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different. R01 Examples of the "hetero 5-membered ring group" of the "optionally substituted hetero 5-membered ring group" represented by the following formula include pyrazole, imidazole, thiazole, oxazole, isoxazole, thiophene, furan, pyrrole, thiadiazole, oxadiazole, thiatriazole, and oxatriazole, and preferably pyrazole.

[0336] R 02 represents a hydrogen atom, a C1-6 alkyl group, or a halogen atom, preferably a hydrogen atom, a methyl group, or a chlorine atom, and more preferably a hydrogen atom.

[0337] R 03 represents an optionally substituted C1-6 alkylene group, an optionally substituted C6-14 arylene group, an optionally substituted heterocyclic group, or a bond, preferably an optionally substituted C6-14 arylene group, an optionally substituted heterocyclic group, or a bond, more preferably a group represented by the following structural formula:

[0338] [ka] (wherein n is 0, 1 or 2, W is NR (wherein R is a hydrogen atom, a C1-6 alkyl group, or an acyl group), SO2, SO, S, or O, each V is independently CH or N (provided that any one of the Vs is CH), and each U is independently CH, N, NH, O, or S (provided that two or more Us cannot be O or S)), an optionally substituted C1-6 alkylene group, or a bond, and more preferably a group represented by the following structural formula:

[0339] [ka] (wherein n is 0, 1 or 2), and most preferably a group represented by the following structural formula:

[0340] [ka] It is a group represented by the following formula:

[0341] R 03 Examples of the "substituent" of the "optionally substituted C1-6 alkylene group", "optionally substituted arylene group", and "optionally substituted heterocyclic group" represented by the following formula include substituents selected from the above-mentioned Substituent Group A. The number of substituents is, for example, 1 to 4. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0342] A has the following structural formula:

[0343] [ka] (where R 05 are each independently a hydrogen atom, a halogen atom, a C alkyl group, or a C alkoxy group.) *-SO2-*, *-CO-CH2-*, *-CO-NH-*, *-O-*, an optionally substituted C alkylene group, or a bond, and preferably a group represented by the following structural formula:

[0344] [ka] (where R 05 are each independently a hydrogen atom or a C1-6 alkyl group), *-SO2-*, or *-CO-CH2-*.

[0345] Examples of the "substituent" of the "optionally substituted C1-6 alkylene group" represented by A include substituents selected from the aforementioned Substituent Group A. The number of substituents is, for example, 1 to 7. When the number of substituents is 2 or more, the respective substituents may be the same or different. The C1-6 alkyl group is preferably a C1-3 alkyl group.

[0346] R 04 has the following structural formula:

[0347] [ka] (* indicates the bonding position to A, and ** indicates the bonding position to the linker), an optionally substituted C alkylene group, an optionally substituted C cycloalkylene group, an optionally substituted C arylene group, an optionally substituted hetero 5- or 6-membered ring group, an ester bond, or a bond, and preferably represents a group represented by the following structural formula:

[0348] [ka] (* indicates the bonding position to A, and ** indicates the bonding position to the linker), an optionally substituted C alkylene group, an optionally substituted C cycloalkylene group, an optionally substituted C arylene group, an optionally substituted pyrazolinediyl group, an optionally substituted oxazolinediyl group, an optionally substituted isoxazolinediyl group, an ester bond or a bond, and more preferably a group represented by the following structural formula:

[0349] [ka] (wherein * indicates the bonding position to A, ** indicates the bonding position to the linker, V is CH or N, and each U is independently CH, N, NH, O, or S (provided that two or more Us cannot be O or S)), an optionally substituted C alkylene group, an optionally substituted C cycloalkylene group, an optionally substituted C arylene group, or a bond, and more preferably a group represented by the following structural formula:

[0350] [ka] (wherein V is CH or N, * indicates the position of attachment to A, and ** indicates the position of attachment to the linker).

[0351] R 04 Examples of the "substituents" of the "optionally substituted C1-6 alkylene group," "optionally substituted C3-10 cycloalkylene group," "optionally substituted arylene group," "optionally substituted hetero 5- or 6-membered ring group," "optionally substituted pyrazolinediyl group," "optionally substituted oxazolinediyl group," and "optionally substituted isoxazolinediyl group" represented by the formula (I) include substituents selected from the above-mentioned Substituent Group A. The number of substituents is, for example, 1 to 4. When the number of substituents is 2 or more, the respective substituents may be the same or different. R 04 Examples of the "hetero 5- to 6-membered ring group" of the "optionally substituted hetero 5- to 6-membered ring group" represented by the formula (I) include pyrazole, imidazole, thiazole, oxazole, isoxazole, thiophene, furan, pyrrole, thiadiazole, oxadiazole, thiatriazole, oxatriazole, pyridine, pyrazine, pyrimidine, and pyridazine, and preferably a divalent group derived from a pyrazole, oxazole, or isoxazole group.

[0352] Each symbol in formula (III) will be explained below. R 01 is as described for formula (II). The arrow indicates the bond to the linker (L). A 01 has the following structural formula:

[0353] [ka] (where R 12 are each independently a hydrogen atom or a C1-6 alkyl group.) represents a group represented by the structure *—SO2—*, or *—CO—CH2—*, and preferably a group represented by the structure above or *—SO2—*.

[0354] R 11 has the following structural formula:

[0355] [ka] (where * indicates the bonding position to A, and ** indicates the bonding position to the linker), an optionally substituted C alkylene group, an optionally substituted C cycloalkylene group, an optionally substituted C arylene group, or a bond, and preferably represents a group represented by the following structural formula:

[0356] [ka] (wherein * indicates the bonding position to A, and ** indicates the bonding position to the linker), an optionally substituted C alkylene group, an optionally substituted C cycloalkylene group, an optionally substituted C arylene group, or a bond, and more preferably, a group represented by the following structural formula:

[0357] [ka] (where * indicates the position of attachment to A, and ** indicates the position of attachment to the linker).

[0358] R 11 Examples of the "substituent" of the "optionally substituted C1-6 alkylene group", "optionally substituted C3-10 cycloalkylene group", and "optionally substituted aryl group" represented by the following formula include substituents selected from the above-mentioned Substituent Group A. The number of substituents is, for example, 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0359] Each symbol in formula (IV) will be explained below. R 01 , R 02 , R 03 , R 04 , R 05 , R 06 , R 07 , and R 08 are each independently a hydrogen atom or a C1-6 alkyl group which may form a ring with others, preferably are each independently a hydrogen atom or a C1-6 alkyl group, more preferably are each independently a hydrogen atom or a C1-3 alkyl group. Either D or E is bound to a linker (L).

[0360] D shows the fragment structure of the substance that binds to IAP together with the piperazine ring. D is, for example, a compound represented by the following formula (V):

[0361] [ka] (In the formula, R 11 represents a hydrogen atom or a hydroxyl group, and R 12 and R 13are each independently a hydrogen atom, a C alkyl group, a C cycloalkylene group, a carbonyl group, an imino group optionally substituted with a C alkyl group, an ethynylene group optionally substituted with a C alkyl group, a vinylene group optionally substituted with a C alkyl group, a pyrazole group optionally substituted with a C alkyl group, a C cycloalkenylene group, a phenylene group, a thiazolylene group, a pyrrolidinediyl group optionally substituted with a fluorine atom, an azetidinediyl group optionally substituted with a fluorine atom, or any of the above groups bonded to a linker (L) (provided that R 12 and R 13 and T represents an optionally halogenated C1-3 alkyl group, or the following formula (VI):

[0362] [ka] (Wherein m represents 0, 1, or 2, n represents 0, 1, or 2, W 11 represents a methylene group, a difluoromethylene group, O, S, SO, SO2, or NR (wherein R represents a hydrogen atom, a C1-6 alkyl group, a C1-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C1-6 alkylsulfonyl group, or a bond to a linker), and T represents an optionally halogenated C1-3 alkyl group), or the following formula (VII):

[0363] [ka] (wherein Q is an oxygen atom, a group of the formula -NR 21 -(R 21 represents a hydrogen atom, a C1-6 alkyl group, or a C1-6 alkyl group which may form a ring together with P.) or a bond, and P represents a hydrogen atom, a C1-6 alkyl group, or a bond to a linker (which forms a ring together with Q and includes a bond to a linker). The D is R in formula (V). 12or R 13 , W in formula (VI) 11 or P in formula (VII) can be attached to the linker (L).

[0364] E represents a nitrogen-containing aromatic heterocyclic group. E may be, for example, a group represented by the following formula:

[0365] [ka] (wherein each A independently represents C or N, each R bonded to N independently represents a hydrogen atom, a C alkyl group, or an amide group, and each other R independently represents a hydrogen atom, a halogen atom, a C alkyl group, a C alkoxy group, or an amide group) (wherein, when E is bonded to a linker, it is bonded to the linker at any one of the positions represented by R in the above formula), and preferably represented by the following formula:

[0366] [ka] (wherein each R bonded to N independently represents a hydrogen atom, a C1-6 alkyl group, or an amide group, and each of the other R independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an amide group), and when E is bonded to a linker, it can be bonded to the linker at any one of the positions represented by R in the above formula.

[0367] A preferred embodiment of E is the following formula (VIII):

[0368] [ka] (In the formula, R 21 , R 22 , and R 23each independently represents a hydrogen atom, a halogen atom, a C alkyl group, a C alkoxy group, or an amide group; R 25 and R 26 each independently represents a hydrogen atom, a halogen atom, a C alkyl group, a C alkoxy group, an amide group, or a bond to a linker; R 24 indicates a hydrogen atom, a methyl group, or a bond to a linker. However, the bond to a linker is indicated by R 24 , R 25 , or R 26 It is one of the following.

[0369] Another preferred embodiment of E is a group represented by the following formula (IX):

[0370] [ka] (In the formula, R 31 , R 32、 R 33 , R 34 , and R 35 each independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an amido group, and R represents a hydrogen atom, a C1-6 alkyl group, or a bond to a linker.

[0371] The linker of formula (I) will be described below. The linker (L) has the formula (L1): -B1-B2-L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 wherein B1 and B2 each independently represent a group represented by the following structural formula:

[0372] [ka] (However, B1 and B2 cannot both have this structure.), *-O-*, *-NR 06-*(where R 06 is a hydrogen atom or a C1-6 alkyl group.), *-CO2-*, *-CO-*, *-SO2-*, an optionally substituted alkylene group, an optionally substituted C2-6 alkenylene group, an optionally substituted C2-6 alkynylene group, an optionally substituted C3-10 cycloalkylene group, an optionally substituted C6-14 arylene group, or a bond, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 are each independently The following structural formula

[0373] [ka] (wherein m represents an integer of 1 to 4, n represents an integer of 1 to 4, and each A independently represents N, CHCO, or CHCHO) 1 ~L 7 Two or more of the following cannot have this structure: a bond, an oxygen atom, a sulfur atom, a C1-6 alkylene group, a C3-10 cycloalkylene group, a carbonyl group, an imino group optionally substituted with a C1-6 alkyl group, an ethynylene group, a vinylene group optionally substituted with a C1-6 alkyl group, a C3-10 cycloalkenylene group, a phenylene group, a thiazolyldiyl group, a non-aromatic heterocyclic group optionally substituted with a C1-6 alkyl group or a halogen atom, a pyrrolidinediyl group optionally substituted with a fluorine atom, a morpholinediyl group optionally substituted with a C1-6 alkyl group, an azetidinediyl group optionally substituted with a fluorine atom, a group of the formula -SO2-, a group of the formula -CH2CHO-, a group of the formula -OCH2CH2-, a group of the formula -COCH2-, a group of the formula -CH2CO-, a group of the formula -CO2-, a group of the formula -OCO-, a group of the formula -COCHR 101 NR 102 -, formula -OCH2CHR 103 NR 104 -, formula-NR 105 CHR106 CO-, formula-NR 107 CO-, formula-CONR 108 -, formula -SO2NR 109 -, formula-NR 110 SO2-, or formula -NR 111 CHR 112 CH2O-(R in the above formula 101 , R 103 , R 106 , and R 112 each independently represents a hydrogen atom, a C alkyl group, a 3-guanidinopropyl group, a carbamoylmethyl group, a carboxymethyl group, a mercaptomethyl group, a 2-carbamoylethyl group, a 2-carboxyethyl group, an imidazol-4-ylmethyl group, a 4-aminobutyl group, a 2-methylthioethyl group, a benzyl group, a hydroxymethyl group, a 1-hydroxyethyl group, an indol-3-ylmethyl group, a 4-hydroxyphenylmethyl group, or a pyridylmethyl group; R 102 , R 104 , R 105 , R 107 , R 108 , R 109 , R 110 , and R 111 are each independently a hydrogen atom or a C1-6 alkyl group; or are taken together to represent one bond;

[0374] Preferably, B1 and B2 each independently represent the following structural formula:

[0375] [ka] (However, B1 and B2 cannot both have this structure.), *-O-*, *-NR 06 -*(where R 06 is a hydrogen atom or a C alkyl group.), *-CO-*, an optionally substituted C alkylene group, an optionally substituted C arylene group, an optionally substituted C alkynylene group, or a bond, and more preferably,

[0376] [ka] (provided that B1 and B2 do not both have this structure), *-O-*, a C1-6 alkylene group, or a bond, and more preferably the above group (provided that B1 and B2 do not both have this structure) or a bond.

[0377] The linker (L) preferably has the following structural formula:

[0378] [ka] (where * indicates a bond to the IRAK-M binder (M)), *-(CH2CHO)n(CH2)m(NRCO)s(CH2)t-* (n is an integer of 1 to 5, m is 0, 1 or 2, s is 0 or 1, t is 0 or 1, and R is a hydrogen atom or a C1-6 alkyl group), or a bond, more preferably The following structural formula:

[0379] [ka] or *-(CH2CH2O)n(CH2)m(NRCO)s(CH2)t-* (n is an integer of 1 to 5, m is 0, 1 or 2, s is 0 or 1, t is 0 or 1, and R is a hydrogen atom or a C1-6 alkyl group).

[0380] The "substituents" of the "optionally substituted C1-6 alkylene group," "optionally substituted C2-6 alkenylene group," "optionally substituted C2-6 alkynylene group," "optionally substituted C3-10 cycloalkylene group," and "optionally substituted C6-14 arylene group" shown in the linker can include substituents selected from the above-mentioned Substituent Group A. The number of substituents is, for example, 1 to 4. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0381] As used herein, the term "compound that adds a function" refers to any protein binder present in the body, a cell penetrating peptide (CPP), or a kinetophore that retains a compound in the intestinal tract (e.g., polyethylene oxide capped with a short peptide, sugar, or quaternary ammonium, etc.).

[0382] As used herein, the term "Smac peptide mimetics" refers to compounds that bind to the same space occupied by the Smac N-terminal peptide AVPIAQK (SEQ ID NO: 1) (particularly AVPI (SEQ ID NO: 2)) when it binds to XIAP, and exhibit inhibitory effects on Smac peptide binding.

[0383] As used herein, the term "IRAK-M protein-related disease" refers to a disease or disorder that is explained or suspected to be related to the IRAK-M protein itself or its regulation. Abnormalities in the protein include, but are not limited to, abnormal or enhanced expression of the protein in vivo and the presence of mutant proteins.

[0384] The compounds of the present invention included in Compound (I) can be used as synthetic intermediates in producing other Compounds (I) of the present invention, and can also be used as synthetic intermediates in producing IRAK-M protein degradation inducers other than Compound (I).

[0385] When Compound (I) is a salt, examples of such salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. Suitable examples of metal salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts, and barium salts; and aluminum salts. Suitable examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, and N,N'-dibenzylethylenediamine. Suitable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. Suitable examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc. Suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.

[0386] Among these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, examples thereof include inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.) and alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.), ammonium salts, etc., and when the compound has a basic functional group, examples thereof include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

[0387] The method for producing the compound of the present invention is described below. The raw materials and reagents used in each step of the production method, as well as the resulting compound, may each form a salt. Examples of such salts include those similar to the salts of the compound of the present invention described above.

[0388] When the compound obtained in each step is a free compound, it can be converted into the desired salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted into the free form or another desired type of salt by a method known per se.

[0389] The compound obtained in each step can be used in the next reaction either as a reaction solution or as a crude product, or the compound obtained in each step can be isolated and / or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc., according to a conventional method.

[0390] When the raw materials and reagent compounds for each step are commercially available, the commercially available products can be used as they are.

[0391] In the reaction of each step, the reaction time may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

[0392] In the reactions of each step, the reaction temperature may vary depending on the reagents and solvents used, but is usually from -78°C to 300°C, preferably from -78°C to 150°C, unless otherwise specified.

[0393] In the reactions of each step, the pressure may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually 1 atm to 20 atm, preferably 1 atm to 3 atm.

[0394] In the reactions of each step, a microwave synthesis apparatus such as Biotage's Initiator may be used. The reaction temperature may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually room temperature to 300°C, preferably 50°C to 250°C. The reaction time may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.

[0395] In the reactions of each step, unless otherwise specified, the reagent is used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate. When a reagent is used as a catalyst, the reagent is used in an amount of 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalents, relative to the substrate. When a reagent also serves as a reaction solvent, the reagent is used in the amount of the solvent.

[0396] Unless otherwise specified, the reactions in each step are carried out without solvent or by dissolving or suspending in a suitable solvent. Specific examples of the solvent include those described in the Examples and the following: Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc.; Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.; Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, hexane, etc.; Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.; Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Sulfoxides: dimethyl sulfoxide, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Inorganic acids: hydrochloric acid, sulfuric acid, etc.; Esters: ethyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; water. The above solvents may be used by mixing two or more kinds in an appropriate ratio.

[0397] When a base is used in the reaction of each step, for example, the bases shown below or the bases described in the Examples are used. Inorganic bases: sodium hydroxide, magnesium hydroxide, etc.; Basic salts: sodium carbonate, calcium carbonate, sodium bicarbonate, etc.; Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc.; Alkali metal hydrides: sodium hydride, etc.; Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; Organolithium compounds: n-butyllithium, etc.

[0398] When an acid or an acid catalyst is used in the reaction of each step, for example, the acids and acid catalysts shown below or the acids and acid catalysts described in the Examples are used. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.

[0399] Unless otherwise specified, the reactions in each step are carried out by a method known per se, for example, in Experimental Chemistry Lectures, 5th Edition, Vol. 13-19 (edited by the Chemical Society of Japan); New Experimental Chemistry Lectures, Vol. 14-15 (edited by the Chemical Society of Japan); Precision Organic Chemistry, Revised 2nd Edition (L.F. Tietze, Th. Eicher, Nankodo); Revised Organic Named Reactions: Their Mechanisms and Key Points (by Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volumes I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory: A Collection of Standard Experimental Procedures (by Jie Jack Li, Oxford University Press); Comprehensive Heterocyclic Chemistry III, Vol. 1-14 (Elsevier Japan Co., Ltd.); Organic Synthesis Strategies Learned from Named Reactions (translated and supervised by Kiyoshi Tomioka, published by Kagaku Dojin); Comprehensive Organic Transformations (VCH Publishers Inc., 1989, or in accordance with the method described in the Examples.

[0400] In each step, the protection or deprotection reaction of a functional group is carried out according to a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter G.M. Wuts), published by Wiley-Interscience, 2007; "Protecting Groups, 3rd Ed." (P.J. Kocienski), published by Thieme, 2004, or the method described in the Examples. Examples of the protecting group for the hydroxyl group of an alcohol or the like or a phenolic hydroxyl group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylic acid ester-type protecting groups such as acetate ester; sulfonic acid ester-type protecting groups such as methanesulfonate ester; and carbonate-type protecting groups such as t-butyl carbonate. Examples of the protecting group for the carbonyl group of an aldehyde include acetal-type protecting groups such as dimethyl acetal; and cyclic acetal-type protecting groups such as cyclic 1,3-dioxane. Examples of protecting groups for the carbonyl group of ketones include ketal-type protecting groups such as dimethyl ketal; cyclic ketal-type protecting groups such as cyclic 1,3-dioxane; oxime-type protecting groups such as O-methyloxime; and hydrazone-type protecting groups such as N,N-dimethylhydrazone. Examples of the protecting group for a carboxy group include ester-type protecting groups such as methyl ester; and amide-type protecting groups such as N,N-dimethylamide. Examples of the thiol-protecting group include ether-type protecting groups such as benzylthioether; and ester-type protecting groups such as thioacetate, thiocarbonate, and thiocarbamate. Examples of protecting groups for amino groups and aromatic heterocycles such as imidazole, pyrrole, and indole include carbamate-type protecting groups such as benzylcarbamate; amide-type protecting groups such as acetamide; alkylamine-type protecting groups such as N-triphenylmethylamine; and sulfonamide-type protecting groups such as methanesulfonamide. The protecting group can be removed by a method known per se, for example, a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or a trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or a reduction method.

[0401] In each step, when a reduction reaction is carried out, examples of the reducing agent to be used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and tetramethylammonium triacetoxyborohydride; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane; etc. When a carbon-carbon double bond or triple bond is reduced, a catalyst such as palladium-carbon or Lindlar's catalyst may be used.

[0402] In the oxidation reactions carried out in each step, examples of oxidizing agents that can be used include peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, and t-butyl hydroperoxide; perchlorates such as tetrabutylammonium perchlorate; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodates such as sodium periodate; high-valent iodine reagents such as iodosylbenzene; manganese-containing reagents such as manganese dioxide and potassium permanganate; lead compounds such as lead tetraacetate; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and Jones reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0403] When a radical cyclization reaction is carried out in each step, examples of the radical initiator used include azo compounds such as azobisisobutyronitrile (AIBN), water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA), triethylboron in the presence of air or oxygen, benzoyl peroxide, etc. Examples of the radical reaction reagent used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, etc.

[0404] When a Wittig reaction is carried out in each step, examples of the Wittig reagent used include alkylidenephosphoranes, etc. The alkylidenephosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

[0405] When Horner-Emmons reaction is carried out in each step, examples of the reagent to be used include phosphonoacetates such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; and bases such as alkali metal hydrides and organolithium compounds.

[0406] When a Friedel-Crafts reaction is carried out in each step, the reagent used may be a combination of a Lewis acid and an acid chloride, or a combination of a Lewis acid and an alkylating agent (e.g., alkyl halides, alcohols, olefins, etc.). Alternatively, an organic acid or an inorganic acid may be used instead of the Lewis acid, and an acid anhydride such as acetic anhydride may be used instead of the acid chloride.

[0407] In each step, when an aromatic nucleophilic substitution reaction is carried out, a nucleophile (eg, amines, imidazole, etc.) and a base (eg, basic salts, organic bases, etc.) are used as reagents.

[0408] In each step, when a nucleophilic addition reaction by a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) by a carbanion, or a nucleophilic substitution reaction by a carbanion is carried out, examples of the base used to generate the carbanion include organolithiums, metal alkoxides, inorganic bases, and organic bases.

[0409] When a Grignard reaction is carried out in each step, examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide and alkylmagnesium halides such as methylmagnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or aryl halide with metallic magnesium using ether or tetrahydrofuran as a solvent.

[0410] In each step, when a Knoevenagel condensation reaction is carried out, an active methylene compound sandwiched between two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile etc.) and a base (e.g., organic bases, metal alkoxides, inorganic bases) are used as reagents.

[0411] In each step, when the Vilsmeier-Haack reaction is carried out, phosphoryl chloride and an amide derivative (eg, N,N-dimethylformamide, etc.) are used as reagents.

[0412] In each step, when an azidation reaction of alcohols, alkyl halides, or sulfonate esters is carried out, examples of the azidation agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide, etc. For example, when azidating alcohols, there are methods using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and methods using trimethylsilyl azide and a Lewis acid.

[0413] When a reductive amination reaction is carried out in each step, examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid, etc. When the substrate is an amine compound, examples of the carbonyl compound used include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, examples of the amine used include ammonia, primary amines such as methylamine, and secondary amines such as dimethylamine.

[0414] When Mitsunobu reaction is carried out in each step, azodicarboxylic acid esters (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate, etc.) and triphenylphosphine are used as reagents.

[0415] In each step, when an esterification reaction, an amidation reaction, or a urea reaction is carried out, examples of the reagent to be used include acyl halides such as acid chlorides and acid bromides; and activated carboxylic acids such as acid anhydrides, activated esters, and sulfate esters. Carboxylic acid activators include carbodiimide-based condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine-based condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoric acid azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate; and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium. Examples of suitable condensing agents include hexafluorophosphate (HATU), sulfuric acid, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P), and combinations thereof. When using a carbodiimide condensing agent, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) may also be added to the reaction.

[0416] In each step, when a coupling reaction is carried out, examples of the metal catalyst to be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride, and palladium(II) acetate; nickel compounds such as tetrakis(triphenylphosphine)nickel(0); rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride; cobalt compounds; copper compounds such as copper oxide and copper(I) iodide; and platinum compounds. A base may also be added to the reaction, and examples of such bases include inorganic bases and basic salts.

[0417] When a thiocarbonylation reaction is carried out in each step, diphosphorus pentasulfide is typically used as the thiocarbonylating agent. However, in addition to diphosphorus pentasulfide, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure, such as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent), may also be used.

[0418] When performing the Wohl-Ziegler reaction in each step, examples of halogenating agents that can be used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. Furthermore, the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction.

[0419] When a halogenation reaction of a hydroxy group is carried out in each step, the halogenating agent used may be a hydrohalic acid or an acid halide of an inorganic acid, specifically, for chlorination, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc., or for bromination, 48% hydrobromic acid, etc. Alternatively, a method may be used in which an alkyl halide is obtained from an alcohol by the reaction of triphenylphosphine with carbon tetrachloride or carbon tetrabromide, etc. Alternatively, a method may be used in which an alkyl halide is synthesized via a two-step reaction, in which the alcohol is converted to a sulfonic acid ester and then reacted with lithium bromide, lithium chloride, or sodium iodide.

[0420] When Arbuzov reaction is carried out in each step, examples of the reagent to be used include alkyl halides such as ethyl bromoacetate and the like; and phosphites such as triethyl phosphite and tri(isopropyl) phosphite and the like.

[0421] When a sulfonate esterification reaction is carried out in each step, examples of the sulfonylating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and the like.

[0422] In each step, when a hydrolysis reaction is performed, an acid or base is used as a reagent. When performing acid hydrolysis of t-butyl esters, formic acid or triethylsilane may be added to reductively trap the by-product t-butyl cation.

[0423] When a dehydration reaction is carried out in each step, examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid, and the like.

[0424] In each step, when alkylating alcohols, amines, or aromatic heterocycles having an NH group in the ring (e.g., imidazole, pyrazole), etc., examples of the alkylating agent include optionally substituted alkyl halides (e.g., iodomethane), optionally substituted alkyls having an optionally substituted C alkylsulfonyloxy group as a leaving group, or optionally substituted alkyls having a C arylsulfonyloxy group optionally substituted with a C alkyl group, sodium 2-chloro-2,2-difluoroacetate, 2,2-difluoro-2-(fluorosulfonyl)acetic acid, etc. Examples of the base used include organolithiums, metal alkoxides, inorganic bases, organic bases, etc.

[0425] When a fluorination reaction is carried out in each step, examples of the fluorinating agent to be used include DAST (diethylaminosulfur trifluoride), bis(2-methoxyethyl)aminosulfur trifluoride, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor), 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (FLUOLEAD), and the like.

[0426] In each step, when the Huisgen reaction is carried out, an azide compound and an alkyne compound are used as reagents, and a monovalent copper ion such as copper iodide, copper chloride, or copper cyanide is used as a catalyst.

[0427] When a coupling reaction is carried out in each step, examples of the coupling reaction include Suzuki coupling, Stille coupling, Buchwald-Hartwig coupling, Negishi coupling, Mizoroki-Heck reaction, and cyanation reaction using copper cyanide or zinc cyanide. Reagents such as metal catalysts, phosphine ligands, and bases used in the coupling reaction can be prepared according to known methods [e.g., J.F. Hartwig, S. Shekhar, Q. Shen, F. Barrios-Landeros, in The Chemistry of Anilines, Z. Rappoport, Ed., Wiley-Intersicence, New York (2007); L. Jiang, S.L. Buchwald, in Metal-Catalyzed Cross-Coupling Reactions, 2nd Ed., A. de Meijere, F. Diederich, Eds., Wiley-VCH, Weinheim, Germany (2004); J.F. Hartwig, in Handbook of Organopalladium Chemistry for Organic Synthesis, A. de Meijere, F. Diederich, Eds., Wiley-VCH, Weinheim, (2000)] or a method equivalent thereto.

[0428] The method for producing compound (I) is explained below. Unless otherwise specified, each symbol in the following reaction schemes has the same meaning as defined above. Unless a specific production method is described, the starting compounds are commercially available and easily available, or can be produced by known methods or methods similar thereto or the methods described in the Examples.

[0429] When carrying out the reaction in each step, if there is a reactive site where a reaction other than the target reaction occurs, a protecting group may be introduced into the reactive site in advance by a means known per se, as necessary, and after the target reaction is carried out, the protecting group may be removed by a means known per se. For example, when the starting compound or intermediate has an amino group, a carboxy group, or a hydroxyl group as a substituent, these groups may be protected with a protecting group commonly used in peptide chemistry, etc. In this case, the target compound can be obtained by removing the protecting group after the reaction, as necessary.

[0430] Compound (I) can be synthesized from compound (1), an IRAK-M binder, or compound (4), an E3 ligase binder, by the methods shown in the following schemes. In each scheme, compound (I) and each reaction intermediate may independently form a salt.

[0431] Scheme 1

[0432] [ka]

[0433] Compound (3) can be produced by subjecting compound (1) or a reactive derivative thereof and compound (2) or a reactive derivative thereof, which is the linker (L), to an amidation reaction, Mitsunobu reaction, alkylation reaction, coupling reaction, or the like, and compound (I) can be produced by subjecting compound (3) or a reactive derivative thereof and compound (4) or a reactive derivative thereof to an amidation reaction, Mitsunobu reaction, alkylation reaction, coupling reaction, or the like.

[0434] Compound (5) can be produced by subjecting compound (4) or a reactive derivative thereof and compound (2) or a reactive derivative thereof to an amidation reaction, Mitsunobu reaction, alkylation reaction, coupling reaction, or the like, and compound (I) can be produced by subjecting compound (5) or a reactive derivative thereof and compound (1) or a reactive derivative thereof to an amidation reaction, Mitsunobu reaction, alkylation reaction, coupling reaction, or the like.

[0435] Compound (3a) can be produced by subjecting compound (1) or a reactive derivative thereof and compound (2a) or a reactive derivative thereof to an amidation reaction, Mitsunobu reaction, alkylation reaction, coupling reaction, or the like. Compound (5a) can be produced by subjecting compound (4) or a reactive derivative thereof and compound (2b) or a reactive derivative thereof to an amidation reaction, Mitsunobu reaction, alkylation reaction, coupling reaction, or the like. Compound (I) can be produced by subjecting compound (3a) and compound (5a) or their reactive derivatives to an amidation reaction, Mitsunobu reaction, alkylation reaction, coupling reaction, or the like.

[0436] The method for producing the IRAK-M binder (M) (compound (1)) represented by the following formula (II), which constitutes a part of compound (I), is described below.

[0437] Scheme 2

[0438] [ka]

[0439] In Scheme 2, X1 represents a halogen atom or a leaving group.

[0440] Compound (10) can be produced by subjecting compound (6) and compound (7) to an aromatic nucleophilic substitution reaction, a coupling reaction, etc. Compound (10) can also be produced by subjecting compound (8) and compound (9) to an alkylation reaction, an aromatic nucleophilic substitution reaction, a coupling reaction, etc. Compound (II) can be produced by subjecting compound (10) and compound (11) or their reactive derivatives to an amidation reaction, Mitsunobu reaction, alkylation reaction, sulfonylation reaction, reductive amination reaction, coupling reaction, etc. Compound (II) can also be produced by subjecting compound (6) and compound (12) to an aromatic nucleophilic substitution reaction, coupling reaction, etc.

[0441] L (compound (2)), which is the linker (L) constituting a part of compound (I), and L1 (compound (2a)) and L2 (compound (2b)), which are parts of the linker, may be commercially available products as they are, or may be produced by a method known per se or a method similar thereto.

[0442] E (compound (4)), an E3 ligase binder constituting part of compound (I), can be a commercially available product used as is, or can be produced by a known method or a method similar thereto, or by the method described below.

[0443] The production method when E (compound (4)) is a compound represented by the following formula (IV-I) is described below.

[0444] Scheme 3

[0445] [ka]

[0446] Compound (15) can be produced by subjecting compound (13) and compound (14) or a reactive derivative thereof to an amidation reaction or the like, and compound (17) can be produced by subjecting compound (15) and compound (16) to an amidation reaction or the like. Compound (IV-I) can be produced by subjecting compound (17) and compound (18) or a reactive derivative thereof to an amidation reaction or the like. Compound (19) can be produced by subjecting compound (13) and compound (16) or a reactive derivative thereof to an amidation reaction or the like, and compound (20) can be produced by subjecting compound (19) and compound (18) or a reactive derivative thereof to an amidation reaction or the like. Compound (IV-I) can be produced by subjecting compound (20) and compound (14) or a reactive derivative thereof to an amidation reaction or the like.

[0447] The production method when E (compound (4)) is a compound represented by the following formula (IV-II) is described below.

[0448] Scheme 4

[0449] [ka]

[0450] Compound (17') can be produced by subjecting compound (15) and compound (16') or a reactive derivative thereof to an amidation reaction or the like, and compound (IV-II) can be produced by subjecting compound (17') and compound (18) or a reactive derivative thereof to an amidation reaction or the like. Compound (19') can be produced by subjecting compound (13) and compound (16') or a reactive derivative thereof to an amidation reaction or the like, and compound (20') can be produced by subjecting compound (19') and compound (18) or a reactive derivative thereof to an amidation reaction or the like. Compound (IV-II) can be produced by subjecting compound (20') and compound (14) or a reactive derivative thereof to an amidation reaction or the like.

[0451] The production method when E (compound (4)) is a compound represented by the following formula (IV-III) will be explained below. Scheme 5

[0452] [ka]

[0453] Compound (22) can be produced by subjecting compound (15) and compound (21) to an amidation reaction or the like, and compound (IV-III) can be produced by subjecting compound (22) and compound (23) to an alkylation reaction or the like. Compound (24) can be produced by subjecting compound (13) and compound (21) to an amidation reaction or the like, and compound (25) can be produced by subjecting compound (24) and compound (23) to an alkylation reaction or the like. Compound (IV-III) can be produced by subjecting compound (25) and compound (14) or a reactive derivative thereof to an amidation reaction or the like.

[0454] By converting the substituents in compound (I) and each intermediate thus obtained by a method known per se (i.e., introducing a substituent or converting a functional group), it is also possible to produce other compounds included in compound (I) and corresponding intermediates or salts thereof.

[0455] Compound (I) obtained by the above-mentioned production method can be isolated and purified by known means, such as solvent extraction, pH change of the solution, dissolution transfer, crystallization, recrystallization, and chromatography.

[0456] When compound (I) contains optical isomers, stereoisomers, positional isomers, or rotational isomers, these are also included in compound (I), and each can be obtained as a single product by a synthesis method or separation method known per se. For example, when compound (I) contains optical isomers, optical isomers resolved from the compound are also included in compound (I). Here, the optical isomers can be produced by methods known per se.

[0457] Compound (I) may be crystalline. The crystals of Compound (I) (hereinafter sometimes abbreviated as the crystals of the present invention) can be produced by crystallizing Compound (I) using a crystallization method known per se. Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, a cocrystal or cocrystal salt refers to a crystalline substance composed of two or more distinct solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). A cocrystal or cocrystal salt can be prepared by a known cocrystallization method. Compound (I) may be a hydrate, a non-hydrate, a non-solvate, or a solvate. moreover, 1 H 2 Deuterium-converted compounds converted to H(D) are also encompassed by Compound (I). Compound (I) may contain an isotope (e.g., 3 H, 13 C. 14 C. 18 F, 35 S, 125 Compound (I) labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) for use in positron emission tomography (PET), and is expected to be useful in fields such as medical diagnosis.

[0458] Compound (I) may be used as a prodrug. A prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, i.e., a compound that is converted to compound (I) by enzymatic oxidation, reduction, hydrolysis, or the like, or a compound that is converted to compound (I) by hydrolysis, etc., caused by gastric acid, or the like.

[0459] Prodrugs of compound (I) include: a compound in which the amino group of compound (I) has been acylated, alkylated or phosphorylated (e.g., a compound in which the amino group of compound (I) has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated); Examples include compounds in which the hydroxy group of compound (I) is acylated, alkylated, phosphorylated, or borated (e.g., compounds in which the hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethylcarbonylated); and compounds in which the carboxy group of compound (I) is esterified or amidated (e.g., compounds in which the carboxy group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, or methylamidized). These compounds can be produced from compound (I) by methods known per se.

[0460] Furthermore, the prodrug of compound (I) may be one that is converted into compound (I) under physiological conditions, as described in "Drug Development," Hirokawa Shoten, 1990, Vol. 7, Molecular Design, pp. 163 to 198. In the present specification, the prodrug may be in the form of a salt, and examples of such salts include those exemplified as salts of the compound represented by formula (I) above.

[0461] Compound (I) may be used by linking it to a compound that adds a function, such as a cell penetrating peptide (CPP) or a kinetophore that retains the compound in the intestinal tract (e.g., polyethylene oxide capped with a short peptide, sugar, or quaternary ammonium, etc.), and compound (I) can be bound to the compound that adds a function directly or via a linker.

[0462] Compound (I) can also be used as a payload (the moiety corresponding to the drug described above) in an antibody (or a peptidic antigen-recognition sequence)-drug conjugate. When compound (I) is used as a payload, compound (I) can be bound to an antibody (or a peptidic antigen-recognition sequence) directly or via a linker. When compound (I) is used as a payload, in addition to the linkers exemplified herein, linkers such as those described in Chem.Rev., 114, 9154-9218 (2014), Pharma. Res. 32, 3526-3540 (2015), Bioconjugate Chem. 21, 5-13 (2010), The AAPS journal, 17, 339-351 (2015), WO 2011 / 005761, etc. may be used.

[0463] Compound (I) or a prodrug thereof (hereinafter, these may be collectively referred to as the "compound of the present invention") has an activity of inducing the degradation of IRAK-M, and may be useful as a preventive or therapeutic agent for cancer, a cancer growth inhibitor, or a cancer metastasis inhibitor. The compounds of the present invention exhibit proteolysis-inducing activity against IRAK-M, and are also excellent in terms of pharmacological efficacy, pharmacokinetics (e.g., absorption, distribution, metabolism, excretion), solubility (e.g., water solubility), interactions with other pharmaceuticals (e.g., drug-metabolizing enzyme inhibitory activity), safety (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, central toxicity), and stability (e.g., chemical stability, stability against enzymes), and therefore may be useful as pharmaceuticals. In particular, the compounds are expected to be effective in the treatment or prevention of cancer, but are not limited thereto. The compounds of the present invention also have the activity of inducing degradation of IRAK-M protein in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, and humans), and in light of their mechanism of action, are effective in treating any disease in which IRAK-M protein is involved (sometimes abbreviated herein as "IRAK-M-associated disease"), such as cancer [e.g., colorectal cancer (e.g., colon cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor)], lung cancer (e.g., non-polyposis colorectal cancer), and other cancers. small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic ductal carcinoma, pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), duodenal cancer, small intestine cancer, breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low malignant potential tumor), testicular tumor, prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer, castration-resistant prostate cancer), liver cancer (e.g., hepatocellular carcinoma, cystic carcinoma, primary liver cancer, extrahepatic bile duct cancer), thyroid cancer (e.g., medullary thyroid carcinoma), kidney cancer (e.g., renal cell carcinoma (e.g., clear cell renal cell carcinoma), transitional cell carcinoma of the renal pelvis and ureter), uterine cancer (e.g., cervical cancer, uterine cancer, uterine sarcoma), gestational choriocarcinoma, brain tumors (e.g., medulloblastoma, glioma, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, pituitary adenoma), retinoblastoma, skin cancer (e.g., basal cell carcinoma, malignant melanoma), sarcomas (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, spindle cell

[0111] The compound of the present invention can be used as a pharmaceutical agent for the prevention or treatment of various cancers (e.g., sarcoma), malignant bone tumor, bladder cancer, blood cancer (e.g., multiple myeloma, leukemia (e.g., acute myeloid leukemia, chronic lymphocytic leukemia), malignant lymphoma (B-cell lymphoma, diffuse large B-cell lymphoma, MALT lymphoma, follicular lymphoma, mantle cell lymphoma), Hodgkin's disease, chronic myeloproliferative disorder), cancer of unknown primary origin), cancer proliferation inhibitor, cancer metastasis inhibitor, apoptosis promoter, precancerous lesion (e.g., myelodysplastic syndrome), and the like.

[0464] In addition, IRAK-M-associated diseases other than cancer include asthma, inflammatory bone disease, inflammatory lung disease, idiopathic pulmonary fibrosis, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, etc.), multiple sclerosis, systemic inflammatory response syndrome (SIRS), sepsis, infectious complications of hematopoietic stem cell transplantation, influenza infection, acute respiratory syndromes (COVID-19, MERS, SARS), acute bacterial meningitis, Helicobacter pylori infection, invasive staphylococcal infection, tuberculosis, systemic fungal infection, herpes simplex virus infection, varicella-zoster virus infection, human papillomavirus infection, acute viral encephalitis, encephalitis, meningitis, and immune dysfunction associated with infection.

[0465] The compound of the present invention can be administered orally or parenterally to mammals (preferably humans) as a pharmaceutical, either as it is or mixed with a pharmacologically acceptable carrier. Hereinafter, a pharmaceutical comprising the compound of the present invention (sometimes abbreviated as "the pharmaceutical of the present invention") will be described in detail. Examples of dosage forms of the pharmaceutical of the present invention include oral preparations such as tablets (e.g., sugar-coated tablets, film-coated tablets, sublingual tablets, buccal tablets, orally rapidly disintegrating tablets), pills, granules, powders, capsules (e.g., soft capsules, microcapsules), syrups, emulsions, suspensions, and films (e.g., orally disintegrating films, oral mucosal patch films). Examples of dosage forms of the pharmaceutical of the present invention also include parenteral preparations such as injections, drip infusions, transdermal preparations (e.g., iontophoretic transdermal preparations), suppositories, ointments, nasal preparations, pulmonary preparations, and eye drops. The pharmaceutical of the present invention may also be a controlled-release preparation such as an immediate-release preparation or a sustained-release preparation (e.g., sustained-release microcapsules). As the dosage form of the medicament of the present invention, nanoparticle preparations and preparations using bacterial membranes can also be used.

[0466] The medicament of the present invention can be produced by a known production method commonly used in the pharmaceutical field (e.g., the method described in the Japanese Pharmacopoeia). Furthermore, the medicament of the present invention can contain, as needed, appropriate amounts of additives commonly used in the pharmaceutical field, such as excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifiers, colorants, preservatives, flavoring agents, flavoring agents, stabilizers, and thickeners. The above-mentioned pharmacologically acceptable carriers include these additives.

[0467] For example, tablets can be manufactured using excipients, binders, disintegrants, lubricants, etc., pills and granules can be manufactured using excipients, binders, disintegrants, etc. Powders and capsules can be manufactured using excipients, etc., syrups can be manufactured using sweeteners, etc., and emulsions or suspensions can be manufactured using suspending agents, surfactants, emulsifiers, etc.

[0468] Examples of excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, and calcium sulfate. Examples of binders include 5 to 10% by weight starch paste solution, 10 to 20% by weight gum arabic solution or gelatin solution, 1 to 5% by weight tragacanth solution, carboxymethylcellulose solution, sodium alginate solution, and glycerin. Examples of disintegrants include starch and calcium carbonate. Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, and purified talc. Examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, and simple syrup. Examples of surfactants include sodium lauryl sulfate, polysorbate 80, sorbitan mono-fatty acid ester, and polyoxyl 40 stearate. Examples of suspending agents include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, and bentonite. Examples of emulsifying agents include gum arabic, tragacanth, gelatin, and polysorbate 80.

[0469] For example, when the medicament of the present invention is a tablet, the tablet can be produced by adding, for example, an excipient (e.g., lactose, sucrose, starch), a disintegrant (e.g., starch, calcium carbonate), a binder (e.g., starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose), or a lubricant (e.g., talc, magnesium stearate, polyethylene glycol 6000) to the compound of the present invention, compressing the mixture, and then coating the mixture, if necessary, for taste masking, enteric coating, or sustained release, by a method known per se. Examples of coating agents that can be used for coating include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (Rohm, Germany, methacrylic acid-acrylic acid copolymer), and pigments (e.g., red iron oxide, titanium dioxide).

[0470] The injections include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, intraperitoneal injections, drip infusion injections, and the like.

[0471] Such injections are prepared by known methods, i.e., by dissolving, suspending, or emulsifying the compound of the present invention in a sterile aqueous or oily liquid. Examples of aqueous liquids include physiological saline, isotonic solutions containing glucose or other adjuvants (e.g., D-sorbitol, D-mannitol, sodium chloride), and the like. The aqueous liquid may contain a suitable solubilizing agent, such as alcohol (e.g., ethanol), polyalcohol (e.g., propylene glycol, polyethylene glycol), or nonionic surfactant (e.g., polysorbate 80, HCO-50). Examples of oily liquids include sesame oil and soybean oil. The oily liquid may also contain a suitable solubilizing agent, such as benzyl benzoate or benzyl alcohol. The injection may also contain buffers (e.g., phosphate buffer, sodium acetate buffer), soothing agents (e.g., benzalkonium chloride, procaine hydrochloride), stabilizers (e.g., human serum albumin, polyethylene glycol), preservatives (e.g., benzyl alcohol, phenol), etc. The prepared injection solution can usually be filled into ampoules.

[0472] The content of the compound of the present invention in the pharmaceutical of the present invention varies depending on the form of the formulation, but is usually about 0.01 to about 100% by weight, preferably about 2 to about 85% by weight, and more preferably about 5 to about 70% by weight, based on the total weight of the formulation.

[0473] The content of the additives in the pharmaceutical of the present invention varies depending on the form of the preparation, but is usually about 1 to about 99.9% by weight, preferably about 10 to about 90% by weight, based on the total weight of the preparation.

[0474] The compound of the present invention is stable, has low toxicity, and can be used safely. The daily dose of the compound of the present invention varies depending on the condition and body weight of the patient, the type of compound, the route of administration, etc. For example, when orally administered to a patient for the purpose of treating cancer, the daily dose of the compound of the present invention for an adult (body weight about 60 kg) is about 1 to about 1000 mg, preferably about 3 to about 300 mg, and more preferably about 10 to about 200 mg, of the compound of the present invention, and this can be administered once or in 2 to 3 divided doses.

[0475] When the compound of the present invention is administered parenterally, it is usually administered in the form of a liquid preparation (e.g., an injection). The single dose of the compound of the present invention varies depending on the subject, target organ, symptoms, administration method, etc., but it is usually preferred to administer about 0.01 to about 100 mg, preferably about 0.01 to about 50 mg, more preferably about 0.01 to about 20 mg of the compound of the present invention per kg of body weight by intravenous or subcutaneous injection.

[0476] The compound of the present invention can be used in combination with other drugs. Specifically, the compound of the present invention can be used in combination with drugs such as hormone therapy agents, chemotherapy agents, immunotherapy agents, or drugs that inhibit the action of cell growth factors and their receptors. Hereinafter, drugs that can be used in combination with the compound of the present invention will be abbreviated as "concomitant drugs."

[0477] Examples of "hormonal therapeutic agents" include fosfestrol, diethylstilbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, raloxifene, ormeloxifene, levormeloxifene, antiestrogens (e.g., tamoxifen citrate, toremifene citrate), birth control pills, mepitiostane, testololactone, aminoglutethimide, LH-RH agonists (e.g., goserelin acetate, buserelin, leuprorelin acetate), droloxifene, epithiostanol, Ethinyl estradiol sulfonate, aromatase inhibitors (e.g., fadrozole hydrochloride, anastrozole, letrozole, exemestane, vorozole, formestane), antiandrogens (e.g., flutamide, bicalutamide, nilutamide, enzalutamide), 5α-reductase inhibitors (e.g., finasteride, epristeride, dutasteride), corticosteroids (e.g., dexamethasone, prednisolone, betamethasone, triamcinolone), androgen synthesis inhibitors (e.g., abiraterone), retinoids and agents that slow retinoid metabolism (e.g., liarozole), thyroid hormones, and their DDS (Drug Delivery System) formulations may be used.

[0478] Examples of "chemotherapeutic agents" that can be used include alkylating agents, antimetabolites, anticancer antibiotics, and plant-derived anticancer agents.

[0479] Examples of the "alkylating agent" include nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, estramustine sodium phosphate, triethylenemelamine, carmustine, lomustine, streptomycin, and benzophenone. Putozocin, pipobroman, etoglucide, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustine, temozolomide, treosulfan, trofosfamide, zinostatin stimalamer, adozelesin, systostin, bizelesin, and DDS formulations thereof may be used.

[0480] Examples of the "antimetabolite" that can be used include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, galocitabine, emitefur, capecitabine), aminopterin, nelzarabine, leucovorin calcium, thioagnin, butosin, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, piritrexim, idoxuridine, mitoguazone, tiazofurin, ambamustine, bendamustine, and DDS formulations thereof.

[0481] Examples of "anticancer antibiotics" that can be used include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin, mithramycin, sarkomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and DDS formulations thereof (e.g., doxorubicin-encapsulated PEG liposomes).

[0482] Examples of "plant-derived anticancer agents" that can be used include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, cabazitaxel, vinorelbine, and DDS formulations thereof.

[0483] Examples of the "immunotherapeutic agent" that can be used include picibanil, krestin, sizofiran, lentinan, ubenimex, interferon, interleukin, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole, Toll-like receptor (TLR) agonists, polysaccharide K, procodazole, anti-CTLA4 antibodies (e.g., ipilimumab, tremelimumab), anti-PD-1 antibodies (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, sintilimab, toripalimab), anti-PD-L1 antibodies (e.g., atezolizumab, avelumab, durvalumab), and oncolytic viruses.

[0484] The "cell growth factor" in the "agent that inhibits the action of cell growth factors and their receptors" may be any substance that promotes cell growth, and typically includes peptides with a molecular weight of 20,000 or less that exert their effects at low concentrations by binding to a receptor. Specifically, examples include: (1) EGF (epidermal growth factor) or substances with substantially the same activity as EGF (e.g., TGFα), (2) insulin or substances with substantially the same activity as insulin (e.g., insulin, IGF (insulin-like growth factor)-1, IGF-2), (3) FGF (fibroblast growth factor) or substances with substantially the same activity as FGF (fibroblast growth factor) (e.g., acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10), (4) other cell growth factors (e.g., CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), and the like. factor), TGFβ (transforming growth factor β), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), heregulin, angiopoietin] can be used.

[0485] The "cell growth factor receptor" may be any receptor that has the ability to bind to the above-mentioned cell growth factor, and specific examples that may be used include EGF receptor, heregulin receptor (e.g., HER3), insulin receptor, IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, NGF receptor, TGFβ receptor, HGF receptor, VEGF receptor, angiopoietin receptor (e.g., Tie2), PDGF receptor, etc.

[0486] "Drugs that inhibit the action of cell growth factors and their receptors" include EGF inhibitors, TGFα inhibitors, heregulin inhibitors, insulin inhibitors, IGF inhibitors, FGF inhibitors, KGF inhibitors, CSF inhibitors, EPO inhibitors, IL-2 inhibitors, NGF inhibitors, PDGF inhibitors, TGFβ inhibitors, HGF inhibitors, VEGF inhibitors, angiopoietin inhibitors, EGF receptor inhibitors, HER2 inhibitors, HER3 inhibitors, HER4 inhibitors, insulin receptor inhibitors, IGF-1 receptor inhibitors, IGF-2 receptor inhibitors, and FGF receptor inhibitors. -1 inhibitors, FGF receptor-2 inhibitors, FGF receptor-3 inhibitors, FGF receptor-4 inhibitors, VEGF receptor inhibitors, Tie-2 inhibitors, PDGF receptor inhibitors, Abl inhibitors, Raf inhibitors, FLT3 inhibitors, c-Kit inhibitors, Src inhibitors, PKC inhibitors, Smo inhibitors, ALK inhibitors, ROR1 inhibitors, Trk inhibitors, Ret inhibitors, mTOR inhibitors, Aurora inhibitors, PLK inhibitors, MEK (MEK1 / 2) inhibitors, MET inhibitors, CDK inhibitors, Akt inhibitors, ERK inhibitors, PI3K inhibitors, and the like may be used.More specifically, anti-VEGF antibodies (e.g., Bevacizumab, Ramucurumab), anti-HER2 antibodies (e.g., Trastuzumab, Pertuzumab), anti-EGFR antibodies (e.g., Cetuximab, Panitumumab, Matuzu mab, Nimotuzumab), anti-HGF antibody, Imatinib, Erlotinib, Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatalanib, Ibrutinib, Bo sutinib, Cabozantinib, Crizotinib, Alectinib, Vismodegib, Axitinib, Motesanib, Nilotinib, 6-[4-(4-ethylpiperazin-1-ylmethyl)phenyl]-N-[1(R)-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (AEE-788), Vandetanib, Temsirolimus, Everolimus, Enzastaurin, Tozasertib, 2-[N-[ 3-[4-[5-[N-(3-fluorophenyl)carbamoylmethyl]-1H-pyrazol-3-ylamino]quinazolin-7-yloxy]propyl]-N-ethylamino]ethyl ester (AZD-1152), 4-[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-ylamino]benzoic acid, N-[2-methoxy-5-[(E)-2-(2,4,6-trimethoxyphenyl)vinylsulfonylmethyl]phenyl]glycine sodium salt (ON- 1910Na), Volasertib, Selumetinib, Trametinib, N-[2(R),3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide (PD-0325901), Bosutinib, Regorafenib, Afatinib, Idelalisib, Ceritinib, Dabrafenib, Ponatinib, Lenvatinib, Midostaurin, Pazopanib, and the like may be used.

[0487] In addition to the above drugs, L-asparaginase, L-arginase, arginine deiminase, aceglatone, procarbazine hydrochloride, protoporphyrin-cobalt complex, mercury hematoporphyrin sodium, topoisomerase I inhibitors (e.g., irinotecan, topotecan, indotecan, indimitecan), topoisomerase II inhibitors (e.g., sobuzoxane), differentiation inducers (e.g., retinoids, vitamin D), other angiogenesis inhibitors (e.g., fumagillin, shark extract, COX-2 inhibitors), α-blockers (e.g., tamsulosin hydrochloride), bisphosphonates (e.g., pamidronate, zoledrone Other drugs that may be used in combination include antitumor antibodies such as thalidomide, lenalidomide, pomalidomide, azacitidine, decitabine, proteasome inhibitors (e.g., bortezomib, carfizomib, ixazomib), NEDD8 inhibitors (e.g., pevonedistat), UAE inhibitors, PARP inhibitors (e.g., olaparib, niraparib, veliparib), anti-CD20 antibodies (e.g., rituximab, obinutuzumab), and anti-CCR4 antibodies (e.g., mogamulizumab), and antibody-drug conjugates (e.g., trastuzumab emtansine, brentuximab vedotin).

[0488] When the compound of the present invention is used for the treatment of IRAK-M-related diseases other than cancer, in addition to the above-mentioned concomitant drugs, for example, antibacterial agents, antifungal agents, nonsteroidal anti-inflammatory drugs, steroid drugs, bronchodilators, anticoagulants, antiplatelet drugs, thrombolytic drugs, immunomodulators, antiprotozoal drugs, antitussives / expectorants, sedatives, anesthetics, narcotic antagonists, antiulcer drugs, vitamins, vitamin derivatives, antiallergic drugs, antiasthmatic drugs, drugs for treating atopic dermatitis, signal transduction inhibitors, inflammatory mediator activity inhibitors, inflammatory mediator activity-inhibiting antibodies, inflammatory mediator production inhibitors, anti-inflammatory mediator activity inhibitors, anti-inflammatory mediator activity inhibitors, anti-inflammatory mediator activity-inhibiting antibodies, anti-inflammatory mediator production inhibitors, antifibrotic drugs, α1 adrenergic agonists, antiemetics, and agents for preventing increase in methemoglobin may be used as concomitant drugs.

[0489] (1) Antibiotics (i) Sulfa drugs Sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfamethizole, salazosulfapyridine, silver sulfadiazine and the like. (ii) Quinoline antibacterial agents Nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin and the like. (iii) Antituberculosis drugs Isoniazid, ethambutol (ethambutol hydrochloride), para-aminosalicylic acid (para-aminosalicylic acid calcium), pyrazinamide, ethionamide, prothionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and the like. (iv) Mycobacterial drugs diaminodiphenyl sulfone, rifampicillin and the like. (v) antiviral drugs Idoxuridine, acyclovir, vitarabine, ganciclovir, favipiravir and the like. (vi) anti-HIV drugs Zidovudine, didanosine, zalcitabine, indinavir sulfate ethanolate, ritonavir and the like. (vii) antispirochetal drugs (viii) Antibiotics Tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin, sisomicin, tetracycline, oxytetracycline, rolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalothin, cephapirin, cephaloridine, cefaclor, cephalexin, cefroxadine, cefadroxil, cefamandole, cefuroxime, cefotiam, cefotiam hexetil, cefuromycin ceftazidime, cefpiramide, cefsulodin, cefmenoxime, cefpodoxime proxetil, cefpirome, cefozopran, cefepime, cefsulodin, cefmenoxime, cefmetazole, cefminox, cefoxitin, cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, aztreonam or a salt thereof, griseofulvin, lankacidins and the like.

[0490] (2) Antifungal drugs (i) Polyene antibiotics (e.g., amphotericin B, nystatin, trichomycin), (ii) griseofulvin, pyrrolnitrin, etc. (iii) cytosine antimetabolite (e.g., flucytosine), (iv) imidazole derivatives (e.g., econazole, clotrimazole, miconazole nitrate, bifonazole, cloconazole), (v) triazole derivatives (e.g., fluconazole, itraconazole, azole compounds [2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone], (vi) thiocarbamic acid derivatives (e.g., tolnaftate), (vii) Echinocandin derivatives (e.g., caspofungin, micafungin, anidulafungin), etc.

[0491] (3) Nonsteroidal anti-inflammatory drugs Acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine, migrenin, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine, epirizole, tiaramide hydrochloride, zaltoprofen, mesin Examples of steroids include gabexate mesilate, camostat mesilate, ulinastatin, colchicine, probenezide, sulfinpyrazone, benzbromarone, allopurinol, sodium gold thiomalate, sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol, ketoprofen, naproxen, oxymorphone, meloxicam, celecoxib, rofecoxib, and a salt thereof.

[0492] (4) Steroid drugs Dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, beclomethasone propionate, estriol and the like.

[0493] (5) Bronchodilators Metaproterenol, salmeterol, formoterol, carmoterol and the like.

[0494] (6) Anticoagulants Heparin sodium, sodium citrate, activated protein C, tissue factor pathway inhibitor, antithrombin III, dalteparin sodium, warfarin potassium, argatroban, gabexate, sodium citrate, etc.

[0495] (7) Antiplatelet drugs ozacrel sodium, ethyl icosapentate, beraprost sodium, alprostadil, ticlopidine hydrochloride, pentoxifylline, dipyridamole and the like.

[0496] (8) Thrombolytic drugs Tisokinase, urokinase, streptokinase, etc.

[0497] (9) Immunomodulators Cyclosporine, tacrolimus, gusperimus, azathioprine, antilymphocyte serum, dried sulfonated immunoglobulin, erythropoietin, colony-stimulating factor, interleukin, interferon and the like.

[0498] (10) Antiprotozoal drugs Metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate, etc.

[0499] (11) Antitussives and expectorants Examples of antihistamines include ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride, alloclamide, chlorphedianol, picoperidamine, cloperastine, protokylol, isoproterenol, salbutamol, terbutaline, oxypetebanol, morphine hydrochloride, dextromethorphan hydrobromide, oxycodone hydrochloride, dimorphan phosphate, tipepidine hibenzate, pentoxyverine citrate, clofedanol hydrochloride, benzonatate, guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, acetylcysteine, ethylcysteine ​​hydrochloride, carbocysteine ​​and the like.

[0500] (12) Sedatives Chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital, amobarbital, pentobarbital, thiopental sodium, thiamylal sodium, nitrazepam, estazolam, flurazapam, haloxazolam, triazolam, flunitrazepam, bromvalerylurea, chloral hydrate, triclofos sodium and the like.

[0501] (13) Anesthetics (13-1) Local anesthetics cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxethazaine) and the like. (13-2) General anesthetics (i) Inhalation anesthetics (e.g., ether, halothane, nitrous oxide, influrane, enflurane) (ii) Intravenous anesthetics (e.g., ketamine hydrochloride, droperidol, thiopental sodium, thiamylal sodium, pentobarbital), etc.

[0502] (14) Narcotic antagonists levallorphan, nalorphine, naloxone or a salt thereof, etc.

[0503] (15) Antiulcer drugs Metaclopromide, histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrin, oxethazaine, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate, aldioxa, teprenone, prostaglandin and the like.

[0504] (16) Vitamin medicine (i) Vitamin A: Vitamin A1, Vitamin A2 and Retinol Palmitate (ii) Vitamin D: Vitamin D1, D2, D3, D4 and D5 (iii) Vitamin E: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, dl-α-tocopherol nicotinate (iv) Vitamin K: Vitamin K1, K2, K3 and K4 (v) Folic acid (vitamin M) (vi) Vitamin B: Vitamin B1, Vitamin B2, Vitamin B3, Vitamin B5, Vitamin B6 and Vitamin B12 (vii) Biotin (vitamin H), etc.

[0505] (17) Vitamin Derivatives Various derivatives of vitamins, for example, ascorbic acid, vitamin D3 derivatives such as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol, and 1-α-hydroxycholecalciferol, vitamin D2 derivatives such as 5,6-trans-ergocalciferol, and the like.

[0506] (18) Antiallergic drugs Diphenhydramine, chlorpheniramine, tripelennamine, clemizole, diphenylpyraline, methoxyphenamine, sodium cromoglycate, tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast and the like.

[0507] (19) Antiasthmatic drugs Isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimetoquinol hydrochloride, tulobuterol hydrochloride, orciprenaline sulfate, fenoterol hydrobromide, ephedrine hydrochloride, ipratropium bromide, oxitropium bromide, flutropium bromide, theophylline, aminophylline, sodium cromoglycate, tranilast, repirinast, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast, dexamethasone, prednisolone, hydrocortisone, beclomethasone propionate and the like.

[0508] (20) Atopic dermatitis treatment drugs sodium cromoglycate and the like.

[0509] (21) Antiemetics Phenothiazine derivatives, 5-HT3 receptor antagonists, etc.

[0510] (22) Methemoglobin increase inhibitors Methylene blue, ascorbic acid, etc.

[0511] (23) Integrin inhibitors Natalizumab, vedolizumab, AJM300, TRK-170, E-6007 and the like.

[0512] (24) Antifibrotic drugs Pirfenidone, nintedanib, β-aminopropionitrile (BAPN), ursodeoxycholic acid, etc.

[0513] (25) Other Hydroxycam, diacerin, megestrol acetate, nicerogoline, prostaglandins, etc.

[0514] By combining the compound of the present invention with a concomitant drug, excellent effects can be obtained, such as: (1) the dosage can be reduced compared to when the compound of the present invention or the concomitant drug is administered alone; (2) the drug to be used in combination with the compound of the present invention can be selected depending on the patient's symptoms (mild, severe, etc.); (3) the treatment period can be set longer; (4) the therapeutic effect can be sustained; and (5) a synergistic effect can be obtained by using the compound of the present invention and the concomitant drug in combination.

[0515] Hereinafter, the compound of the present invention used in combination with a concomitant drug will be referred to as the "concomitant drug of the present invention." When using the combination drug of the present invention, the administration timing of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered simultaneously or at different times to the subject. When the administration is at different times, the time difference varies depending on the active ingredient, dosage form, and administration method. For example, when the concomitant drug is administered first, the compound of the present invention may be administered within 1 minute to 3 days, preferably within 10 minutes to 1 day, and more preferably within 15 minutes to 1 hour, after the administration of the concomitant drug. When the compound of the present invention is administered first, the concomitant drug may be administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, and more preferably within 15 minutes to 1 hour, after the administration of the compound of the present invention. The dosage of the concomitant drug may be similar to the dosage used in clinical practice and may be appropriately selected depending on the subject, administration route, disease, combination, etc.

[0516] Examples of dosage forms when the compound of the present invention and the concomitant drug are used in combination include: (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug; (2) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug via the same administration route; (3) administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug via the same administration route with a time lag; (4) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug via different administration routes; and (5) administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug via different administration routes with a time lag (for example, administration in the order of the compound of the present invention → the concomitant drug, or administration in the reverse order). The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage. The compounding ratio of the compound of the present invention to the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptoms, combination, etc. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.

[0517] Furthermore, the compound of the present invention or the combination drug of the present invention can be used in combination with non-drug therapies. Specifically, the compound of the present invention or the combination drug of the present invention can be used in combination with non-drug therapies such as (1) surgery, (2) hypertensive chemotherapy using angiotensin II or the like, (3) gene therapy, (4) hyperthermia, (5) cryotherapy, (6) laser ablation, and (7) radiation therapy.

[0518] For example, by using the compound of the present invention or the concomitant drug of the present invention before or after the above-mentioned surgery or the like, or before or after a combination of two or three of these treatments, effects such as preventing the development of resistance, extending disease-free survival, suppressing cancer metastasis or recurrence, and prolonging life can be obtained.

[0519] Furthermore, treatment with the compound of the present invention or the combination drug of the present invention can be combined with supportive care [(i) administration of antibiotics (e.g., β-lactams such as pansporin, macrolides such as clarithromycin) for various concomitant infectious diseases, (ii) administration of high-calorie infusion, amino acid preparations, and multivitamin preparations for improving nutritional disorders, (iii) administration of morphine for pain relief, (iv) administration of drugs for improving side effects such as nausea, vomiting, loss of appetite, diarrhea, leukopenia, thrombocytopenia, decreased hemoglobin concentration, alopecia, liver damage, kidney damage, DIC, fever, and the like, and (v) administration of drugs for suppressing multidrug resistance of cancer, etc.].

[0520] The present invention will be further explained in detail by the following Reference Examples, Examples, Test Examples and Formulation Examples, but these do not limit the present invention and may be modified within the scope of the present invention. In the following examples, "room temperature" generally refers to a temperature between about 10°C and about 35°C. Ratios shown for mixed solvents are by volume unless otherwise specified. % means % by weight unless otherwise specified. In silica gel column chromatography, NH indicates aminopropylsilane-bonded silica gel, and C18 indicates octadecyl-bonded silica gel. In HPLC (high-performance liquid chromatography), C18 indicates octadecyl-bonded silica gel. The ratio of elution solvents is by volume unless otherwise specified. The following abbreviations are used in the following examples: MS: Mass spectrum M: Molar concentration DMSO-d6: deuterated dimethyl sulfoxide 1 H NMR: Proton nuclear magnetic resonance LC / MS: Liquid Chromatography Mass Spectrometry ESI: Electrospray ionization APCI: Atmospheric Pressure Chemical Ionization DCM: dichloromethane DIEA: Diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide HATU: 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate TBTU: 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide tetrafluoroborate TEA: Triethylamine THF: tetrahydrofuran TFA: Trifluoroacetic acid

[0521] 1 H NMR was measured by Fourier transform NMR. Analysis was performed using ACD / SpecManager or MestreNova (trade name). Very gentle peaks of protons such as hydroxyl and amino groups may not be recorded. MS was measured by LC / MS. ESI or APCI was used as the ionization method. The data shown are the actual measurements (found). Usually, the molecular ion peak ([M+H] + , [MH] - For compounds with a tert-butoxycarbonyl group, peaks resulting from the elimination of the tert-butoxycarbonyl (Boc) group or tert-butyl (tBu) group may be observed as fragment ions. For compounds with a carboxyl group, peaks resulting from the addition of sodium may be observed. For compounds with a hydroxyl group, peaks resulting from the elimination of water may be observed as fragment ions. For salts, the free molecular ion peak or fragment ion peak is usually observed. Optical rotation ([α] D The sample concentration (c) in (c) is in g / 100 mL. The elemental analysis values ​​(Anal.) are listed as calculated values ​​(Calcd) and actually measured values ​​(Found).

[0522] Reference example 1 N-(3-(methylsulfonyl)phenyl)thieno[3,2-d]pyrimidin-4-amine To a mixture of 4-chlorothieno[3,2-d]pyrimidine (14 mg) and 2-propanol (1 mL), 3-(methylsulfonyl)aniline (16.4 mg) and concentrated hydrochloric acid (2.06 μL) were added. The reaction mixture was stirred overnight at 80 °C, the solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC (C18, mobile phase: acetonitrile / 10 mM aqueous ammonium bicarbonate) to give the title compound (10.1 mg). 1 H NMR (400 MHz, DMSO-d6) δ 3.23 (3H, s), 7.52 (1H, d, J = 5.4 Hz), 7.61-7.68 (2H, m), 8.28-8.33 (2H, m), 8.42 (1H, s), 8.67 (1H, s), 10.09 (1H, s).

[0523] Reference example 2 4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol A) tert-Butyl 4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate To a mixture of tert-butyl-4-hydroxypiperidine-1-carboxylate (2.42 g) and DMF (60.1 mL) was added sodium hydride (60%, dispersed in liquid paraffin, 0.577 g). The reaction mixture was stirred for 30 minutes, then 4-chlorothieno[3,2-d]pyrimidine (2.05 g) was added. The mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.75 g). MS: [M+H] + 336.0.

[0524] B) 4-(piperidin-4-yloxy)thieno[3,2-d]pyrimidine hydrochloride To a mixture of tert-butyl 4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (3.75 g) and ethyl acetate (22.4 mL), 4M hydrogen chloride / ethyl acetate solution (55.9 mL) was added. The reaction mixture was stirred for 30 minutes, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to obtain the title compound (3.25 g). 1 H NMR (300 MHz, DMSO-d6) δ 2.00-2.12 (2H, m), 2.17-2.33 (2H, m), 3.02-3.37 (4H, m), 5.52-5.67 (1H, m), 7.62 (1H, d, J = 5.29 Hz), 8.40 (1H, d, J = 5.29 Hz), 8.79 (1H, s), 8.98-9.34 (2H, m).

[0525] C) 4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol To a mixture of 4-(piperidin-4-yloxy)thieno[3,2-d]pyrimidine hydrochloride (215 mg) and pyridine (2.64 mL) was added 4-hydroxybenzene-1-sulfonyl chloride (152 mg). The reaction mixture was stirred for 16 hours, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile / 5 mM aqueous ammonium acetate) to give the title compound (43.5 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.75-1.95 (2H, m), 2.00-2.19 (2H, m), 2.83-3.01 (2H, m), 3.05-3.21 (2H, m), 5.15-5.51 (1H, m), 6.96 (2H, d, J = 8.69 Hz), 7.46-7.72 (3H, m), 8.32 (1H, d, J = 5.29 Hz), 8.70 (1H, s), 10.10-11.07 (1H, m).

[0526] Reference example 3 3-(allyloxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole A) 7-(piperidin-4-yloxy)thieno[3,2-b]pyridine dihydrochloride To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (14.9 g) and DMF (100 mL), sodium hydride (60%, dispersed in liquid paraffin, 3.0 g) was added under ice cooling. The reaction mixture was stirred for 10 minutes, and 7-chlorothieno[3,2-b]pyridine (10.4 g) was added and stirred at 60 °C overnight. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a mixture of the resulting tert-butyl 4-(thieno[3,2-b]pyridin-7-yloxy)piperidine-1-carboxylate and ethyl acetate (100 mL), a 4M hydrogen chloride / ethyl acetate solution (100 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, and then diisopropyl ether (70 mL) was added. The precipitate was collected by filtration to give the title compound (16.8 g). MS: [M+H] + 235.2.

[0527] B) Methyl 3-(allyloxy)isoxazole-5-carboxylate To a mixture of methyl 3-hydroxyisoxazole-5-carboxylate (15.0 g), potassium carbonate (17.4 g), and DMF (200 mL), 3-bromoprop-1-ene (24 mL) was added and stirred at 60 °C for 16 hours. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (16.6 g). MS: [M+H] + 184.3.

[0528] C) (3-(allyloxy)isoxazol-5-yl)methanol To a mixture of methyl 3-(allyloxy)isoxazole-5-carboxylate (16.6 g) and methanol (300 mL) was added sodium borohydride (4.80 g). The reaction mixture was stirred at room temperature for 16 hours, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (13.2 g). MS: [M+H] + 156.3.

[0529] D) (3-(allyloxy)isoxazol-5-yl)methyl methanesulfonate To a mixture of (3-(allyloxy)isoxazol-5-yl)methanol (13.2 g), TEA (24 mL), and THF (200 mL) was added methanesulfonyl chloride (9.94 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour, then diluted with water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (18.9 g). MS: [M+H] + 234.2.

[0530] E) 3-(allyloxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole A mixture of 7-(piperidin-4-yloxy)thieno[3,2-b]pyridine dihydrochloride (6.16 g), (3-(allyloxy)isoxazol-5-yl)methyl methanesulfonate (5.14 g), tetrabutylammonium iodide (4.44 g), potassium carbonate (9.70 g), and DMF (100 mL) was stirred at room temperature for 24 hours. Water was added to the reaction mixture, which was then filtered. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (6.25 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.68-1.85 (2H, m), 1.95-2.10 (2H, m), 2.36-2.49 (2H, m), 2.63-2.76 (2H, m), 3.63 (2H, s), 4.64-4.74 (2H, m), 4.74-4.87 (1H, m), 5.25-5.35 (1H, m), 5.35-5.49 (1H, m), 6.05 (1H, ddt, J = 17.3, 10.7, 5.4 Hz), 6.20 (1H, s), 7.07 (1H, d, J = 5.5 Hz), 7.50 (1H, d, J = 5.3 Hz), 8.04 (1H, d, J = 5.4 Hz), 8.50 (1H, d, J = 5.4 Hz).

[0531] Reference example 4 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol To a mixture of 3-(allyloxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole (5.68 g), triethylsilane (7.3 mL), and THF (100 mL) was added tetrakistriphenylphosphine palladium (884 mg). The reaction mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol), and the obtained compound was washed with ethyl acetate to obtain the title compound (2.50 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.68-1.84 (2H, m), 1.95-2.09 (2H, m), 2.35-2.49 (2H, m), 2.63-2.75 (2H, m), 3.58 (2H, s), 4.74-4.87 (1H, m), 5.93 (1H, s), 7.07 (1H, d, J = 5.5 Hz), 7.50 (1H, d, J = 5.6 Hz), 8.04 (1H, d, J = 5.4 Hz), 8.50 (1H, d, J = 5.4 Hz), 11.16 (1H, s).

[0532] Reference example 5 3-(Allyloxy)-5-(1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)ethyl)isoxazole (enantiomer) A) 3-(allyloxy)isoxazole-5-carboxylic acid To a mixture of methyl 3-(allyloxy)isoxazole-5-carboxylate (1 g), THF (10 mL), and methanol (2 mL) was added lithium hydroxide monohydrate (687 mg) and water (2 mL). The reaction mixture was stirred at room temperature for 3 hours, then diluted with water and washed with ethyl acetate. The aqueous layer was adjusted to pH 3 with potassium hydrogen sulfate and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (670 mg). 1H NMR (400 MHz, DMSO-d6) δ 4.76 (2H, d, J = 5.56 Hz), 5.31 (1H, d, J = 10.44 Hz), 5.43 (1H, d, J = 17.32 Hz), 6.01-6.08 (1H, m), 6.96 (1H, s), 13.7-14.9 (1H, brs).

[0533] B) 3-(allyloxy)-N-methoxy-N-methylisoxazole-5-carboxamide To a mixture of 3-(allyloxy)isoxazole-5-carboxylic acid (660 mg), N,O-dimethylhydroxylamine hydrochloride (570 mg), and DMF (20 mL) was added DIEA (3.4 mL) and TBTU (2.5 g), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to afford the title compound (700 mg). MS: [M+H] + 213.1.

[0534] C) 1-(3-(allyloxy)isoxazol-5-yl)ethan-1-one To a mixture of 3-(allyloxy)-N-methoxy-N-methylisoxazole-5-carboxamide (600 mg) and THF (20 mL), 3M methylmagnesium bromide in diethyl ether (1.41 mL) was added at -78 °C. The reaction mixture was allowed to warm to room temperature over 2 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (350 mg). 1H NMR (400 MHz, CDCl3) δ 2.54 (3H, s), 4.79 (2H, d, J = 4.6 Hz), 5.33 (1H, dd, J = 1.0, 10.6 Hz), 5.43 (1H, dd, J = 1.3, 17.2 Hz), 5.96-6.13 (1H, m), 6.49 (1H, s).

[0535] D) 1-(3-(allyloxy)isoxazol-5-yl)ethan-1-ol To a mixture of 1-(3-(allyloxy)isoxazol-5-yl)ethan-1-one (250 mg) and methanol (20 mL) was added sodium borohydride (85 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours, water was added, and the mixture was extracted with DCM. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (225 mg). MS: [M+H] + 170.0.

[0536] E) 1-(3-(allyloxy)isoxazol-5-yl)ethyl methanesulfonate To a mixture of 1-(3-(allyloxy)isoxazol-5-yl)ethan-1-ol (220 mg) and DCM (20 mL), DIEA (0.45 mL) and methanesulfonyl chloride (0.152 mL) were added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (190 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.64 (3H, d, J = 6.6 Hz), 3.25 (3H, s), 4.72 (2H, d, J = 5.5 Hz), 5.30 (1H, d, J = 10.5 Hz), 5.42 (1H, d, J = 17.2 Hz), 5.83 (1H, q, J = 6.6 Hz), 5.98-6.12 (1H, m), 6.48 (1H, s).

[0537] F) 3-(allyloxy)-5-(1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)ethyl)isoxazole (racemic) To a mixture of 7-(piperidin-4-yloxy)thieno[3,2-b]pyridine (270 mg) and methanol (20 mL) was added TEA (0.32 mL). The reaction mixture was stirred for 10 minutes, and then 1-(3-(allyloxy)isoxazol-5-yl)ethyl methanesulfonate (211 mg) was added. The reaction mixture was stirred at 80 °C for 16 hours, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (70 mg). MS: [M+H] + 385.8.

[0538] G) 3-(allyloxy)-5-(1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)ethyl)isoxazole (enantiomer) 3-(Allyloxy)-5-(1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)ethyl)isoxazole (racemic) (60 mg) was purified by HPLC (Chiralpak IA (21 x 250 mm), mobile phase: ethanol / ethyl acetate / hexane (system containing 0.1% isopropylamine)) to obtain the title compound (12 mg, the compound with the shorter retention time). 1H NMR (400 MHz, CDCl3) δ 1.44 (3H, d, J = 7.0 Hz), 1.86-2.03 (2H, m), 2.03-2.18 (2H, m), 2.24-2.66 (2H, m), 2.72-2.96 (2H, m), 3.78-3.96 (1H, m), 4.56-4.68 (1H, m), 4.74 (2H, d, J = 5.7 Hz), 5.31 (1H, d, J = 10.5 Hz), 5.43 (1H, d, J = 17.0 Hz), 5.76 (1H, s), 5.99-6.14 (1H, m), 6.65 (1H, d, J = 5.5 Hz), 7.50 (1H, d, J = 5.6 Hz), 7.66 (1H, d, J = 5.4 Hz), 8.51 (1H, d, J = 5.4 Hz).

[0539] Reference example 6 3-(Allyloxy)-5-(1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)ethyl)isoxazole (enantiomer) 3-(Allyloxy)-5-(1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)ethyl)isoxazole (racemic) (60 mg) was purified by HPLC (Chiralpak IA (21 x 250 mm), mobile phase: ethanol / ethyl acetate / hexane (system containing 0.1% isopropylamine)) to obtain the title compound (10 mg, the compound with the longer retention time). 1H NMR (400 MHz, CDCl3) δ 1.45 (3H, d, J = 7.0 Hz), 1.87-2.03 (2H, m), 2.03-2.22 (2H, m), 2.26-2.69 (2H, m), 2.69-2.96 (2H, m), 3.77-3.99 (1H, m), 4.56-4.69 (1H, m), 4.74 (2H, d, J = 5.8 Hz), 5.31 (1H, d, J = 10.5 Hz), 5.43 (1H, d, J = 17.4 Hz), 5.77 (1H, s), 5.99-6.14 (1H, m), 6.65 (1H, d, J = 5.5 Hz), 7.50 (1H, d, J = 5.4 Hz), 7.66 (1H, d, J = 5.5 Hz), 8.52 (1H, d, J = 5.5 Hz).

[0540] Reference example 7 3-(allyloxy)-5-(1-(4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)ethyl)isoxazole (racemic) A) 7-chloro-2-methylthieno[3,2-b]pyridine To a mixture of 7-chlorothieno[3,2-b]pyridine (2 g) and THF (30 mL) was added 2 M lithium diisopropylamide THF solution (12.96 mL) at -78 °C under an argon atmosphere. The reaction mixture was stirred at 0 °C for 1 hour, and methyl iodide (2.35 mL) was added. The reaction mixture was stirred at 0 to 25 °C for 2 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.9 g). MS: [M+H] + 183.8.

[0541] B) tert-butyl 4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidine-1-carboxylate To a mixture of 7-chloro-2-methylthieno[3,2-b]pyridine (1.9 g), tert-butyl 4-hydroxypiperidine-1-carboxylate (2.29 g), and DMF (30 mL) was added sodium hydride (60%, dispersed in liquid paraffin, 620 mg). The reaction mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate, and washed with water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2 g). MS: [M+H] + 348.5.

[0542] C) 2-Methyl-7-(piperidin-4-yloxy)thieno[3,2-b]pyridine trifluoroacetate To a mixture of tert-butyl 4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidine-1-carboxylate (2 g) and DCM (20 mL) was added TFA (4.4 mL). The reaction mixture was stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure to give the title compound (1.4 g). 1 H NMR (400 MHz, DMSO-d6) δ1.93-2.08 (2H, m), 2.16-2.31 (2H, m), 2.74 (3H, s), 3.05-3.42 (4H, m), 5.25-5.34 (1H, m), 7.51 (1H, d, J = 1.5 Hz), 7.61 (1H, d, J = 6.8 Hz), 8.60-8.88 (2H, m), 8.89 (1H, d, J = 6.8 Hz).

[0543] D) 3-(allyloxy)-5-(1-(4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)ethyl)isoxazole (racemic) To a mixture of 2-methyl-7-(piperidin-4-yloxy)thieno[3,2-b]pyridine trifluoroacetate (100 mg) and methanol (5 mL) was added TEA (0.08 mL). The reaction mixture was stirred at room temperature for 10 minutes, and 1-(3-(allyloxy)isoxazol-5-yl)ethyl methanesulfonate (74.3 mg) was added. The reaction mixture was stirred at 80 °C for 16 hours, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (38 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.34 (3H, d, J = 7.04 Hz), 1.71-1.73 (2H, m), 1.90-2.12 (2H, m), 2.29-2.32 (1H, m), 2.44-2.50 (2H, m), 2.57 (3H, s), 2.71-2.87 (1H, m), 3.89-3.90 (1H, m), 4.69-4.73 (3H, m), 5.29 (1H, d, J = 10.4 Hz), 5.40-5.44 (1H, m), 6.02-6.09 (1H, m), 6.16 (1H, s), 6.97 (1H, d, J = 5.52 Hz), 7.18 (1H, s), 8.38 (1H, d, J = 5.44 Hz).

[0544] Reference example 8 3-(Allyloxy)-5-(1-(4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)ethyl)isoxazole (enantiomer) 3-(Allyloxy)-5-(1-(4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)ethyl)isoxazole (racemic) (30 mg) was purified by HPLC (Chiralpak IA (21 x 250 mm), mobile phase: ethanol / ethyl acetate / hexane (system containing 0.1% isopropylamine)) to obtain the title compound (8 mg, the compound with the shorter retention time). 1H NMR (400 MHz, DMSO-d6) δ 1.34 (3H, d, J = 7.0 Hz), 1.60-1.82 (2H, m), 1.91-2.06 (2H, m), 2.25-2.35 (1H, m), 2.44-2.54 (1H, m), 2.58 (3H, s), 2.60-2.69 (1H, m), 2.69-2.81 (1H, m), 3.89 (1H, q, J = 7.1 Hz), 4.67-4.76 (3H, m), 5.30 (1H, d, J = 10.9 Hz), 5.42 (1H, d, J = 17.1 Hz), 5.98-6.13 (1H, m), 6.16 (1H, s), 6.97 (1H, d, J = 5.5 Hz), 7.18 (1H, d, J = 1.5 Hz), 8.38 (1H, d, J = 5.4 Hz).

[0545] Reference example 9 3-(Allyloxy)-5-(1-(4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)ethyl)isoxazole (enantiomer) 3-(Allyloxy)-5-(1-(4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)ethyl)isoxazole (racemic) (30 mg) was purified by HPLC (Chiralpak IA (21 x 250 mm), mobile phase: ethanol / ethyl acetate / hexane (system containing 0.1% isopropylamine)) to obtain the title compound (8 mg, the compound with a longer retention time). 1H NMR (400 MHz, DMSO-d6) δ 1.34 (3H, d, J = 7.0 Hz), 1.62-1.80 (2H, m), 1.92-2.07 (2H, m), 2.24-2.37 (1H, m), 2.40-2.48 (1H, m), 2.58 (3H, s), 2.58-2.70 (1H, m), 2.68-2.82 (1H, m), 3.89 (1H, q, J = 7.0 Hz), 4.67-4.78 (3H, m), 5.30 (1H, d, J = 10.5 Hz), 5.42 (1H, d, J = 17.3 Hz), 5.99-6.13 (1H, m), 6.16 (1H, s), 6.97 (1H, d, J = 5.6 Hz), 7.19 (1H, d, J = 1.5 Hz), 8.38 (1H, d, J = 5.5 Hz).

[0546] Reference example 10 (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole trihydrochloride Methyl 3-hydroxyisoxazole-5-carboxylate (3.79 g), tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.84 g), and triphenylphosphine (6.94 g) were azeotroped with toluene. To a mixture of the residue and toluene (50 mL), 40% diethyl azodicarboxylate in toluene (14 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour, and then half of the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). Sodium borohydride (1.18 g) was added to a mixture of the resulting methyl (S)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)isoxazole-5-carboxylate and methanol (100 mL). The reaction mixture was stirred at room temperature for 4 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a mixture of the obtained tert-butyl (S)-2-(((5-(hydroxymethyl)isoxazol-3-yl)oxy)methyl)pyrrolidine-1-carboxylate and THF (100 mL) was added methanesulfonyl chloride (2.10 mL). The reaction mixture was stirred at room temperature for 2 hours, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. A mixture of the obtained tert-butyl (S)-2-(((5-(((methylsulfonyl)oxy)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidine-1-carboxylate, 7-(piperidin-4-yloxy)thieno[3,2-b]pyridine dihydrochloride (8.85 g), potassium carbonate (19.9 g), tetrabutylammonium iodide (5.32 g), and DMF (50 mL) was stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane).To a mixture of the obtained tert-butyl (S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidine-1-carboxylate and ethyl acetate (20 mL), 4 M hydrogen chloride / ethyl acetate (40 mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure to obtain the title compound (8.03 g). 1 H NMR (300 MHz, CD3OD) δ 1.82-1.95(m, 1H), 2.05-2.18(m, 2H), 2.23-2.43(m, 3H), 2.45-2.69 (m, 2H), 3.35-3.40 (m, 3H), 3.50-3.67 (m, 4H), 4.03-4.12 (m, 1H), 4.41-4.48 (m, 1H), 4.60-4.65(m, 3H), 5.38-5.47 (m, 1H), 6.62 (d, J = 5.4 Hz, 1H), 7.64-7.69 (m, 1H), 7.71 (dd, J = 6.1, 1.8 Hz, 1H), 8.47-8.55 (m, 1H), 8.85 (dd, J = 6.6, 1.8 Hz, 1H).

[0547] The Reference Example compounds prepared by the above-mentioned production methods, the methods shown in the Reference Examples, or methods similar thereto are listed below. The MS values ​​listed below the compounds are actually measured values.

[0548] Reference Example No. 1: N-(3-(methylsulfonyl)phenyl)thieno[3,2-d]pyrimidin-4-amine,

[0549] [ka] MS:306.1

[0550] Reference Example No. 2: 4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol,

[0551] [ka] MS:392.2

[0552] Reference Example No. 3: 3-(allyloxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole,

[0553] [ka] MS:372.2

[0554] Reference Example No. 4: 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol,

[0555] [ka] MS:332.2

[0556] Reference Example No. 5: 3-(allyloxy)-5-(1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)ethyl)isoxazole (enantiomer) (3-(allyloxy)-5-(1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)ethyl)isoxazole),

[0557] [ka] MS:385.8

[0558] Reference Example No. 6: 3-(allyloxy)-5-(1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)ethyl)isoxazole (enantiomer) (3-(allyloxy)-5-(1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)ethyl)isoxazole),

[0559] [ka] MS:385.9

[0560] Reference Example No. 7: 3-(allyloxy)-5-(1-(4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)ethyl)isoxazole (racemic mixture)

[0561] [ka] MS:399.7

[0562] Reference Example No. 8: 3-(allyloxy)-5-(1-(4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)ethyl)isoxazole (enantiomer) (3-(allyloxy)-5-(1-(4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)ethyl)isoxazole),

[0563] [ka] MS:399.7

[0564] Reference Example No. 9: 3-(allyloxy)-5-(1-(4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)ethyl)isoxazole (enantiomer) (3-(allyloxy)-5-(1-(4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)ethyl)isoxazole),

[0565] [ka] MS:399.7

[0566] Reference Example No. 10: (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole,

[0567] [ka] Salt type: 3HCl; MS: 415.2

[0568] Reference Example No. 11: 3-((tetrahydrofuran-3-yl)oxy)-4-(thieno[3,2-d]pyrimidin-4-ylamino)benzamide

[0569] [ka] MS:357.2

[0570] Reference Example No. 12: N,6-diphenylthieno[3,2-d]pyrimidin-4-amine

[0571] [ka] MS:304.2

[0572] Reference Example No. 13: N-(2-methoxyphenyl)-6-phenylthieno[3,2-d]pyrimidin-4-amine

[0573] [ka] MS:334.2

[0574] Reference Example No. 14: N-(cyclopropylmethyl)-6-phenylthieno[3,2-d]pyrimidin-4-amine

[0575] [ka] MS:282.2

[0576] Reference Example No. 15: 6-phenyl-N-(pyridin-2-yl)thieno[3,2-d]pyrimidin-4-amine,

[0577] [ka] MS:305.2

[0578] Reference Example No. 16: 6-phenyl-N-(pyridin-3-ylmethyl)thieno[3,2-d]pyrimidin-4-amine

[0579] [ka] MS:319.2

[0580] Reference Example No. 17: N-phenethyl-6-phenylthieno[3,2-d]pyrimidin-4-amine,

[0581] [ka] MS:332.2

[0582] Reference Example No. 18: 4-(thieno[3,2-d]pyrimidin-4-ylamino)benzamide,

[0583] [ka] MS:271.2

[0584] Reference Example No. 19: N-(2-((tetrahydrofuran-3-yl)oxy)phenyl)thieno[3,2-d]pyrimidin-4-amine

[0585] [ka] MS:314.2

[0586] Reference Example No. 20: 3-(thieno[3,2-d]pyrimidin-4-ylamino)benzamide

[0587] [ka] MS:271.1

[0588] Reference Example No. 21: N-(pyridin-4-yl)thieno[3,2-d]pyrimidin-4-amine

[0589] [ka] MS:229.1

[0590] Reference Example No. 22: N-(2-(trifluoromethyl)pyridin-4-yl)thieno[3,2-d]pyrimidin-4-amine

[0591] [ka] MS:297.0

[0592] Reference Example No. 23: N-(2-methoxypyridin-4-yl)thieno[3,2-d]pyrimidin-4-amine

[0593] [ka] MS:259.1

[0594] Reference Example No. 24: N-(2-(trifluoromethyl)pyridin-3-yl)thieno[3,2-d]pyrimidin-4-amine

[0595] [ka] MS:297.1

[0596] Reference Example No. 25: N-(3-methyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-amine

[0597] [ka] MS:309.1

[0598] Reference Example No. 26: N-(1H-benzo[d]imidazol-5-yl)thieno[3,2-d]pyrimidin-4-amine

[0599] [ka] MS:268.1

[0600] Reference Example No. 27: 5-(thieno[3,2-d]pyrimidin-4-ylamino)isoindoline-1,3-dione,

[0601] [ka] MS:297.1

[0602] Reference Example No. 28: N-(1H-indazol-6-yl)thieno[3,2-d]pyrimidin-4-amine

[0603] [ka] MS:268.1

[0604] Reference Example No. 29: 5-(thieno[3,2-d]pyrimidin-4-ylamino)isobenzofuran-1(3H)-one,

[0605] [ka] MS:284.1

[0606] Reference Example No. 30: methyl 4-((cyclopropylmethyl)amino)thieno[3,2-d]pyrimidine-6-carboxylate

[0607] [ka] MS:264.1

[0608] Reference Example No. 31: 6-(1-methyl-1H-pyrazol-4-yl)-4-((1-methylpiperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0609] [ka] MS:330.2

[0610] Reference Example No. 32: 6-ethynyl-4-((1-methylpiperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0611] [ka] MS:274.1

[0612] Reference Example No. 33: 4-((2-chlorothieno[3,2-d]pyrimidin-4-yl)amino)benzamide,

[0613] [ka] MS:305.0

[0614] Reference Example No. 34: 6-iodo-4-((tetrahydro-2H-pyran-4-yl)oxy)thieno[3,2-d]pyrimidine

[0615] [ka] MS:363.1

[0616] Reference Example No. 35: 6-iodo-4-((tetrahydro-2H-thiopyran-4-yl)oxy)thieno[3,2-d]pyrimidine

[0617] [ka] MS:379.1

[0618] Reference Example No. 36: 6-iodo-4-((1-methylpiperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0619] [ka] MS:376.1

[0620] Reference Example No. 37: 4-((6-iodothieno[3,2-d]pyrimidin-4-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide

[0621] [ka] MS:411.1

[0622] Reference Example No. 38: 4-((1-((2,6-difluorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0623] [ka] MS:412.0

[0624] Reference Example No. 39: 4-((1-(methylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0625] [ka] MS:314.1

[0626] Reference Example No. 40: 4-((1-((2-methoxyethyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0627] [ka] MS:358.2

[0628] Reference Example No. 41: 4-((1-(benzylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0629] [ka] MS:390.1

[0630] Reference Example No. 42: tert-butyl 4-(((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)methyl)piperidine-1-carboxylate,

[0631] [ka] MS:497.3

[0632] Reference Example No. 43: ethyl 3-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)propanoate,

[0633] [ka] MS:400.1

[0634] Reference Example No. 44: 4-((1-(cyclopropylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0635] [ka] MS:340.0

[0636] Reference Example No. 45: 4-((1-((2-chlorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0637] [ka] MS:410.0

[0638] Reference Example No. 46: 4-((1-((2-methoxyphenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0639] [ka] MS:406.1

[0640] Reference Example No. 47: 4-((1-(o-tolylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0641] [ka] MS:390.1

[0642] Reference Example No. 48: 4-((1-((2-(4-fluorophenoxy)phenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,

[0643] [ka] MS:486.1

[0644] Reference Example No. 49: 4-((1-((2-fluorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0645] [ka] MS:394.1

[0646] Reference Example No. 50: 4-((1-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0647] [ka] MS:460.0

[0648] Reference Example No. 51: 4-((1-((4-methoxyphenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0649] [ka] MS:406.1

[0650] Reference Example No. 52: 4-((1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0651] [ka] MS:410.0

[0652] Reference Example No. 53: 4-((1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0653] [ka] MS:394.1

[0654] Reference Example No. 54: 4-((1-((3-methoxyphenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0655] [ka] MS:406.1

[0656] Reference Example No. 55: 4-((1-(4-methylbenzenesulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0657] [ka] MS:390.1

[0658] Reference Example No. 56: 4-((1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0659] [ka] MS:394.1

[0660] Reference Example No. 57: 4-((1-((3-chlorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0661] [ka] MS:410.0

[0662] Reference Example No. 58: 4-((1-(pyridin-3-ylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0663] [ka] MS:377.1

[0664] Reference Example No. 59: 4-((1-((1-benzyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0665] [ka] MS:456.1

[0666] Reference Example No. 60: 4-((1-((6-methoxypyridin-3-yl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0667] [ka] MS:407.1

[0668] Reference Example No. 61: 4-((1-((1,4-dimethyl-1H-pyrazol-5-yl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0669] [ka] MS:394.1

[0670] Reference Example No. 62: 4-((1-(isobutylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0671] [ka] MS:356.1

[0672] Reference Example No. 63: 4-((1-(phenethylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0673] [ka] MS:404.1

[0674] Reference Example No. 64: 4-((1-((3-phenoxyphenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine

[0675] [ka] MS:468.1

[0676] Reference Example No. 65: N-(4-ethoxyphenyl)thieno[3,2-d]pyrimidin-4-amine

[0677] [ka] MS:272.2

[0678] Reference Example No. 66: N-(3,4-dimethoxyphenyl)-2,6-dimethylthieno[3,2-d]pyrimidin-4-amine

[0679] [ka] MS:316.2

[0680] Reference Example No. 67: 7-((1-(prop-2-yn-1-yl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine

[0681] [ka] MS:272.8

[0682] Reference Example No. 68: 1-methyl-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)-1H-pyrazol-3-ol,

[0683] [ka] MS:345.2

[0684] Reference Example No. 69: 7-((1-((3-(allyloxy)-1-methyl-1H-pyrazol-5-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine

[0685] [ka] MS:384.9

[0686] Reference Example No. 70: 3-(allyloxy)-5-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)methyl)isoxazole,

[0687] [ka] MS:372.7

[0688] Reference Example No. 71: 3-(prop-2-yn-1-yloxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole,

[0689] [ka] MS:369.8

[0690] Reference Example No. 72: 3-(allyloxy)-5-((4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)methyl)isoxazole,

[0691] [ka] MS:386.3

[0692] Reference Example No. 73: 7-((1-((1-methyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine

[0693] [ka] MS:329.2

[0694] Reference Example No. 74: 7-((1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine

[0695] [ka] MS:343.0

[0696] Reference Example No. 75: 7-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine

[0697] [ka] MS:357.0

[0698] Reference Example No. 76: 7-((1-((1,5-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine

[0699] [ka] MS:343.0

[0700] Reference Example No. 77: 7-((1-((1-methyl-1H-pyrazol-5-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine

[0701] [ka] MS:329.2

[0702] Reference Example No. 78: 3,5-dimethyl-4-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole,

[0703] [ka] MS:344.1

[0704] Reference Example No. 79: 7-((1-(thiazol-2-ylmethyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine

[0705] [ka] MS:331.8

[0706] Reference Example No. 80: 7-((1-((2-methylthiazol-5-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine

[0707] [ka] MS:346.1

[0708] Reference Example No. 81: 2-(1H-pyrazol-1-yl)-1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)ethan-1-one,

[0709] [ka] MS:343.2

[0710] Reference Example No. 82: 1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one,

[0711] [ka] MS:344.0

[0712] Reference Example No. 83: 3-(allyloxy)-5-(1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)ethyl)isoxazole (racemic mixture)

[0713] [ka] MS:385.8

[0714] Reference Example No. 84: 2-allyl-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3(2H)-one,

[0715] [ka] MS:372.2

[0716] Reference Example No. 85: 3-(2-methoxyethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole,

[0717] [ka] MS:389.8

[0718] Reference Example No. 86: 7-((1-((3-(allyloxy)isoxazol-5-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine-2-carbonitrile),

[0719] [ka] MS:396.6

[0720] Reference Example No. 87: 5-((4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)methyl)isoxazol-3-ol,

[0721] [ka] MS: 345.9, and

[0722] Reference Example No. 88: 5-(1-(4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)ethyl)isoxazol-3-ol,

[0723] [ka] MS:360.0

[0724] Example 1 2-(4-((S)-2-Cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide hydrochloride

[0725] A) Benzyl (S)-4-(2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)piperazine-1-carboxylate To a mixture of (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (2.5 g), benzyl piperazine-1-carboxylate (2.14 g), DIEA (5.09 mL), and DMF (48.6 mL) was added HATU (5.54 g) at room temperature. The reaction mixture was stirred at the same temperature for 6 hours. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (4.34 g). MS: [M+H] + 460.2.

[0726] B) Benzyl (S)-4-(2-amino-2-cyclohexylacetyl)piperazine-1-carboxylate hydrochloride To a mixture of benzyl (S)-4-(2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)piperazine-1-carboxylate (4.34 g) and ethyl acetate (18.9 mL), 4 M hydrogen chloride / ethyl acetate solution (18.9 mL) was added at room temperature, and the reaction mixture was stirred at 45° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained crude product was recrystallized from ethyl acetate / hexane to obtain the title compound (2.96 g). MS: [M+H] + 360.2.

[0727] C) Benzyl 4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-1-carboxylate To a mixture of (S)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid (1.63 g), benzyl (S)-4-(2-amino-2-cyclohexylacetyl)piperazine-1-carboxylate hydrochloride (2.96 g), DIEA (5.22 mL), and DMF (37.4 mL) was added HATU (4.26 g) at room temperature. The reaction mixture was stirred at the same temperature for 6 hours. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.62 g). MS: [M+H]+ 545.4.

[0728] D) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperazin-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate A mixture of benzyl 4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-1-carboxylate (3.62 g), 10% palladium on carbon (362 mg), and ethyl acetate (67 mL) was stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (2.46 g). MS: [M+H] + 411.3.

[0729] E) Methyl 5,6-difluoro-1-methyl-1H-indole-2-carboxylate To a mixture of 5,6-difluoro-1H-indole-2-carboxylic acid (20 g) and DMF (200 mL), potassium carbonate (42.0 g) and iodomethane (18.9 mL) were added at room temperature. The reaction mixture was stirred at the same temperature for 18 hours and then at 40 °C for 6 hours. Water was added to the reaction mixture, and the precipitate was collected by filtration and washed with hexane to obtain the title compound (20 g). 1 H NMR (400 MHz, DMSO-d6)δ 3.85 (3H, s), 3.99 (3H, s) 7.26 (1H, s), 7.70 (1H, dd, J = 8.24 Hz, 10.84Hz), 7.78 (1H, dd, J =6.96 Hz, 11.68 Hz).

[0730] F) Methyl 5,6-difluoro-3-formyl-1-methyl-1H-indole-2-carboxylate To a mixture of methyl 5,6-difluoro-1-methyl-1H-indole-2-carboxylate (2 g) and DCM (20 mL) was added 1M titanium tetrachloride / DCM solution (17.8 mL) and a mixture of dichloromethyl methyl ether (1.7 mL) and DCM (2 mL) at -78 °C. The reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with water and neutralized with saturated aqueous sodium bicarbonate. The precipitate was filtered through Celite, and the filtrate was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (1.9 g). 1 H NMR (400 MHz, DMSO-d6) δ 3.99 (3H, s), 4.02 (3H, s), 8.0 (1H, dd, J = 6.92 Hz, 11.4 Hz), 8.12 (1H, dd, J = 8.24 Hz, 10.76 Hz), 10.34 (1H, s).

[0731] G) 5,6-difluoro-3-formyl-1-methyl-1H-indole-2-carboxylic acid To a mixture of methyl 5,6-difluoro-3-formyl-1-methyl-1H-indole-2-carboxylate (15 g), THF (225 mL), methanol (75 mL), and water (75 mL), lithium hydroxide monohydrate (3.73 g) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and acidified with aqueous potassium hydrogen sulfate. The resulting solid was collected by filtration to give the title compound (13 g). MS: [M+H] + 240.1.

[0732] H) 2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-5,6-difluoro-1-methyl-1H-indole-3-carboxylic acid To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperazin-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (4.63 g), 5,6-difluoro-3-formyl-1-methyl-1H-indole-2-carboxylic acid (2.45 g), DIEA (2.7 mL), and DMF (50 mL) was added HATU (4.67 g). The reaction mixture was stirred at room temperature for 2 hours, followed by addition of water and extraction with ethyl acetate. The organic layer was washed successively with 0.1 M hydrochloric acid, aqueous sodium bicarbonate, and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). To a mixture of the obtained tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-3-formyl-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate, sodium dihydrogen phosphate (4.90 g), 2-methylbut-2-ene (3.58 g), and tert-butyl alcohol (90 mL) / water (30 mL), sodium chlorite (2.24 g) was added. The reaction mixture was stirred overnight at room temperature, and aqueous sodium thiosulfate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane and methanol / ethyl acetate) to give the title compound (5.46 g). MS: [M+H] + 648.5.

[0733] I) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-3-((2-(2-hydroxyethoxy)ethoxy)ethyl)(methyl)carbamoyl)-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of 2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-5,6-difluoro-1-methyl-1H-indole-3-carboxylic acid (5.46 g), 2-(2-(2-(methylamino)ethoxy)ethoxy)ethan-1-ol (1.65 g), DIEA (2.26 mL), and DMF (8 mL) was added HATU (3.85 g). The reaction mixture was stirred at room temperature for 3 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (3.10 g). MS: [M+H] + 793.5.

[0734] J) 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol To a mixture of 3-(allyloxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole (5.68 g), triethylsilane (7.3 mL), and THF (100 mL) was added tetrakistriphenylphosphine palladium (884 mg). The reaction mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol), and the obtained compound was washed with ethyl acetate to obtain the title compound (2.50 g). 1H NMR (300 MHz, DMSO-d6) δ 1.68-1.84 (2H, m), 1.95-2.09 (2H, m), 2.35-2.49 (2H, m), 2.63-2.75 (2H, m), 3.58 (2H, s), 4.74-4.87 (1H, m), 5.93 (1H, s), 7.07 (1H, d, J = 5.5 Hz), 7.50 (1H, d, J = 5.6 Hz), 8.04 (1H, d, J = 5.4 Hz), 8.50 (1H, d, J = 5.4 Hz), 11.16 (1H, s).

[0735] K) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(methyl(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)carbamoyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol (1.50 g), tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-3-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)(methyl)carbamoyl)-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (3.59 g), triphenylphosphine (5.94 g), and toluene (25 mL) was added di-tert-butyl azodicarboxylate (3.13 g). The reaction mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile / 5 mM aqueous ammonium acetate solution) to obtain the title compound (2.37 g). MS: [M+H]+ 1106.6.

[0736] L) 2-(4-((S)-2-Cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide hydrochloride To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(methyl(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)carbamoyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (2.37 g) and ethyl acetate (10 mL), 4 M hydrogen chloride / ethyl acetate solution (16.1 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated to afford the title compound (2.16 g). 1 H NMR (300 MHz, DMSO-d6) δ 0.72-1.26 (7H, m), 1.35 (3H, d, J = 6.8 Hz), 1.50-1.83 (7H, m), 2.11-2.48 (7H, m), 2.97 (3H, s), 3.20-3.97 (21H, m), 4.13-4.37 (2H, m), 4.39-4.82 (3H, m), 4.90-5.59 (2H, m), 6.65 (1H, s), 7.46 (1H, dd, J = 10.9, 7.9 Hz), 7.54-7.96 (4H, m), 8.53 (1H, d, J = 5.6 Hz), 8.66-9.12 (2H, m), 9.27-9.65 (1H, m), 11.79-12.71 (1H, m).

[0737] Example 2 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-6-methoxy-1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide

[0738] A) Methyl 6-methoxy-1-methyl-1H-indole-2-carboxylate To a mixture of methyl 6-methoxy-1H-indole-2-carboxylate (11.6 g) and DMF (100 mL), sodium hydride (60%, dispersed in liquid paraffin, 2.93 g) was added under ice-cooling. The reaction mixture was stirred at the same temperature for 15 minutes, after which iodomethane (3.88 mL) was added to the reaction mixture, and the reaction mixture was stirred at the same temperature for 1 hour. Water (150 mL) and 1 M hydrochloric acid (250 mL) were added to the reaction mixture under ice-cooling, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (11.4 g). MS: [M+H] + 220.0.

[0739] B) 6-Methoxy-1-methyl-1H-indole-2-carboxylic acid To a mixture of methyl 6-methoxy-1-methyl-1H-indole-2-carboxylate (11.4 g) and methanol (100 mL) was added 2 M aqueous sodium hydroxide solution (52.0 mL) at room temperature, and the reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled on ice and neutralized with 1 M hydrochloric acid (110 mL), and the precipitate was collected by filtration to obtain the title compound (9.87 g). MS: [M+H] + 206.0.

[0740] C) tert-butyl 4-(6-methoxy-1-methyl-1H-indole-2-carbonyl)piperazine-1-carboxylate To a mixture of 6-methoxy-1-methyl-1H-indole-2-carboxylic acid (9.87 g), tert-butyl piperazine-1-carboxylate (9.41 g), 1-hydroxybenzotriazole monohydrate (8.10 g), and DMF (150 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.14 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled with ice, water was added, and the precipitate was collected by filtration to give the title compound (16.8 g). MS: [M+H] + 374.1.

[0741] D) tert-Butyl 4-(3-formyl-6-methoxy-1-methyl-1H-indole-2-carbonyl)piperazine-1-carboxylate To a mixture of tert-butyl 4-(6-methoxy-1-methyl-1H-indole-2-carbonyl)piperazine-1-carboxylate (10.4 g) and DMF (100 mL), (chloromethylene)dimethylammonium chloride (7.13 g) was added, and the reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and after stirring for 30 minutes, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (10.6 g). MS: [M+H] + 402.1.

[0742] E) 6-Methoxy-1-methyl-2-(piperazine-1-carbonyl)-1H-indole-3-carbaldehyde hydrochloride To a mixture of tert-butyl 4-(3-formyl-6-methoxy-1-methyl-1H-indole-2-carbonyl)piperazine-1-carboxylate (10.6 g), dimethyl sulfide (25 mL), and ethyl acetate (100 mL), 4 M hydrogen chloride / ethyl acetate solution (198 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. Diisopropyl ether was added to the reaction mixture, and the precipitate was collected by filtration and washed with diisopropyl ether to obtain the title compound (8.1 g). MS: [M+H] + 302.0.

[0743] F) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(3-formyl-6-methoxy-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (1.96 g), 6-methoxy-1-methyl-2-(piperazine-1-carbonyl)-1H-indole-3-carbaldehyde hydrochloride (2.57 g), DIEA (2.66 mL), and DMF (38 mL) was added HATU (3.47 g) at room temperature, and the reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). To a mixture of the obtained product and ethyl acetate (38 mL), 4 M hydrogen chloride / ethyl acetate solution (38 mL) was added at room temperature, and the reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To a mixture of the obtained (S)-2-(4-(2-amino-2-cyclohexylacetyl)piperazine-1-carbonyl)-6-methoxy-1-methyl-1H-indole-3-carbaldehyde (3.35 g), (S)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid (1.55 g), DIEA (6.65 mL), and DMF (38.1 mL), HATU (4.34 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.12 g). MS: [M+H] + 626.3.

[0744] G) 2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-6-methoxy-1-methyl-1H-indole-3-carboxylic acid To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(3-formyl-6-methoxy-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (2.30 g), sodium dihydrogen phosphate (1.76 g), 2-methylbut-2-ene (1.95 mL), tert-butyl alcohol (29.4 mL), and water (7.4 mL) was added sodium chlorite (665 mg) at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium thiosulfate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to obtain the title compound (770 mg). MS: [M+H] + 642.4

[0745] H) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(3-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamoyl)-6-methoxy-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate A mixture of 2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl) (methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-6-methoxy-1-methyl-1H-indole-3-carboxylic acid (147 mg), triethylene glycol monoamine (41.0 mg), DIEA (120 μL), HATU (131 mg), and DMF (1.15 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile / 5 mM aqueous ammonium acetate solution) to give the title compound (133 mg). MS: [M+H] + 773.5.

[0746] I) 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-6-methoxy-1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide Di-tert-butyl azodicarboxylate (62.6 mg) was added to a mixture of 4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol (35.5 mg), tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(3-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamoyl)-6-methoxy-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (70.0 mg), triphenylphosphine (119 mg), and toluene (0.45 mL). The reaction mixture was stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile / 5 mM aqueous ammonium acetate solution). Ethyl acetate (0.2 mL) was added to the resulting product, and a 4M hydrogen chloride / ethyl acetate solution (679 μL) was added. The mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile / 5 mM aqueous ammonium acetate solution). The resulting product was dissolved in methanol, desalted with Amberlyst A21, and the solvent was evaporated under reduced pressure to give the title compound (19.5 mg). 1 H NMR (300 MHz, DMSO-d6) δ 0.63-4.78 (54H, m) 5.26-5.43 (1H, m) 6.75-6.95 (1H, m) 7.05-7.20 (3H, m) 7.37-7.51 (1H, m) 7.55 (1H, d, J = 5.29 Hz) 7.65 (2H, d J = 9.06 Hz) 7.75-7.85 (1H, m) 7.88-7.99 (1H, m) 8.30 (1H, d, J = 5.29 Hz) 8.69 (1H, s).

[0747] Example 17 1-((R)-4-(5,6-Difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperazin-1-yl)-2-((2R,5R)-5-methyl-2-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperazin-1-yl)ethan-1-one hydrochloride

[0748] A) 5,6-difluoro-1-methyl-1H-indole-2-carboxylic acid To a mixture of methyl 5,6-difluoro-1-methyl-1H-indole-2-carboxylate (2 g), THF (14 mL), methanol (7 mL), and water (7 mL) was added lithium hydroxide monohydrate (1.1 g), and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water and acidified with aqueous potassium hydrogen sulfate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.8 g). MS: [MH] + 210.0.

[0749] B) (R)-(5,6-Difluoro-1-methyl-1H-indol-2-yl)(3-methylpiperazin-1-yl)methanone To a mixture of 5,6-difluoro-1-methyl-1H-indole-2-carboxylic acid (1.8 g) and DMF (45 mL), DIEA (4.4 mL), (R)-2-methyl-piperazine (1.02 g), and HATU (4.8 g) were added. The reaction mixture was stirred at room temperature for 3 hours, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / DCM) to give the title compound (1.9 g). MS: [M+H] + 294.4.

[0750] C) (R)-2-chloro-1-(4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperazin-1-yl)ethan-1-one To a mixture of (R)-(5,6-difluoro-1-methyl-1H-indol-2-yl)(3-methylpiperazin-1-yl)methanone (1.9 g) and DCM (25 mL), TEA (1.35 mL) and chloroacetyl chloride (0.6 mL) were added under ice-cooling. The reaction mixture was stirred at room temperature for 3 hours, diluted with DCM, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.8 g). MS: [M+H] + 370.2.

[0751] D) 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl methanesulfonate To a mixture of 2-(2-(2-benzyloxyethoxy)ethoxy)ethanol (2 g) and DCM (15 mL), TEA (1.7 mL) and methanesulfonyl chloride (0.77 mL) were added under ice-cooling. The reaction mixture was stirred at room temperature for 12 hours, diluted with DCM, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (2.5 g). 1 H NMR (400 MHz, CDC13) δ 3.02-3.05 (3H, m), 3.61-3.65 (8H, m), 3.74-3.76 (2H, m), 4.34-4.36 (2H, m), 4.54 (2H, s), 7.27-7.33 (5H, m).

[0752] E) tert-Butyl (2R,5R)-4-benzyl-2-methyl-5-(12-phenyl-2,5,8,11-tetraoxadodecyl)piperazine-1-carboxylate To a mixture of tert-butyl (2R,5R)-4-benzyl-5-hydroxymethyl-2-methyl-piperazine-1-carboxylate (700 mg) and DMF (10 mL) was added sodium hydride (60%, dispersed in liquid paraffin, 105 mg). The reaction mixture was stirred for 1 hour, and 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl methanesulfonate (695 mg) was added, followed by stirring at 60 °C for an additional 4 hours. The reaction mixture was cooled to room temperature, and 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl methanesulfonate (556 mg) was added, followed by stirring at 60 °C for an additional 5 hours. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to afford the title compound (900 mg). MS: [M+H] + 543.2.

[0753] F) tert-Butyl (2R,5R)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperazine-1-carboxylate To a mixture of tert-butyl (2R,5R)-4-benzyl-2-methyl-5-(12-phenyl-2,5,8,11-tetraoxadodecyl)piperazine-1-carboxylate (900 mg), acetic acid (0.1 mL), and ethanol (10 mL) was added 10% palladium on carbon (200 mg). The reaction mixture was stirred at room temperature under atmospheric hydrogen atmosphere for 16 hours, filtered through Celite, and the filtrate was concentrated under reduced pressure. 10% methanol / DCM was added to the residue, and the organic layer was washed with saturated aqueous sodium bicarbonate and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (600 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.12 (3H, d, J = 6.72 Hz), 1.39 (9H, s), 2.41 (1H, dd, J = 2.74, 12.5 Hz), 2.88-2.94 (2H, m), 3.07 (1H, dd, J = 4.16, 13.5 Hz), 3.31-3.52 (15H, m), 3.60-3.62 (1H, m), 3.98 (1H, bs).

[0754] G) tert-Butyl (2R,5R)-4-(2-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperazin-1-yl)-2-oxoethyl)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperazine-1-carboxylate To a mixture of tert-butyl (2R,5R)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperazine-1-carboxylate (592 mg) and THF (15 mL), TEA (0.3 mL), (R)-2-chloro-1-(4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperazin-1-yl)ethan-1-one (550 mg), and tetrabutylammonium iodide (549 mg) were added and stirred at 60 °C for 24 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to obtain the title compound (740 mg). MS: [M+H] + 696.5.

[0755] H) tert-Butyl (2R,5R)-4-(2-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperazin-1-yl)-2-oxoethyl)-2-methyl-5-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperazine-1-carboxylate To a mixture of tert-butyl (2R,5R)-4-(2-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperazin-1-yl)-2-oxoethyl)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperazine-1-carboxylate (30 mg), 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol (17.1 mg), triphenylphosphine (56.5 mg), and toluene (2 mL) was added di-tert-butyl azodicarboxylate (29.7 mg). The reaction mixture was stirred at room temperature for 16 hours, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography to give the title compound (26 mg). MS: [M+H] + 1008.8.

[0756] I) 1-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperazin-1-yl)-2-((2R,5R)-5-methyl-2-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperazin-1-yl)ethan-1-one hydrochloride To a mixture of tert-butyl (2R,5R)-4-(2-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperazin-1-yl)-2-oxoethyl)-2-methyl-5-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperazine-1-carboxylate (25 mg) and DCM (1 mL) was added 4 M hydrogen chloride / dioxane solution (0.3 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The residue was washed with ether and pentane to obtain the title compound (19 mg). 1 H NMR (400 MHz, DMSO-d6, 100 ℃) δ 1.15-1.28 (6H, m), 2.19-2.36 (4H, m), 2.76-2.98 (3H, m), 3.20-4.36 (36H, m), 5.15 (1H, m), 5.66 (1H, s), 6.56 (1H, s), 7.30 (1H, d, J = 8.0 Hz), 7.53-7.59 (2H, m), 7.63 (1H, d, J = 8.0 Hz), 8.22 (1H, d, J = 8.0 Hz), 8.68 (1H, d, J = 8.0 Hz), 9.01-9.40 (1H, m).

[0757] Example 21 (S)-N-((S)-1-Cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride

[0758] A) Methyl 5,6-difluoro-3-hydroxy-1-methyl-1H-indole-2-carboxylate To a mixture of methyl 5,6-difluoro-3-formyl-1-methyl-1H-indole-2-carboxylate (3.5 g) and chloroform (50 mL), 3-chloroperbenzoic acid (5.88 g) and p-toluenesulfonic acid (3.15 g) were added at 5-10°C. The reaction mixture was stirred at the same temperature for 2 hours. 2M ammonia / methanol solution (30 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, diluted with saturated aqueous sodium bicarbonate, and extracted with DCM. The organic layer was washed with 10% aqueous sodium thiosulfate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3 g). 1 H NMR (400 MHz, DMSO-d6) δ 3.81 (3H, s), 3.82 (3H, s), 7.56-7.69 (2H, m), 9.36 (1H, s).

[0759] B) tert-butyl 4-(5,6-difluoro-3-hydroxy-1-methyl-1H-indole-2-carbonyl)piperazine-1-carboxylate To a mixture of methyl 5,6-difluoro-3-hydroxy-1-methyl-1H-indole-2-carboxylate (4.4 g), tert-butyl piperazine 1-carboxylate (5.1 g), and toluene (45 mL) was added 2M trimethylaluminum / toluene solution (18.2 mL) at room temperature under an argon atmosphere. The reaction mixture was stirred at 100 °C for 3 hours. Water was added to the reaction mixture, the precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3 g). MS: [M+H] + 393.8.

[0760] C) 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate To a mixture of 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethan-1-ol (5 g) and DCM (100 mL), TEA (4.4 mL), DMAP (1.27 g), and p-toluenesulfonyl chloride (4.8 g) were added under ice-cooling, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (5.2 g). MS: [M+H] + 395.0.

[0761] D) tert-Butyl 4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperazine-1-carboxylate Cesium carbonate (2.06 g) and 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (1.49 g) were added to a mixture of tert-butyl 4-(5,6-difluoro-3-hydroxy-1-methyl-1H-indole-2-carbonyl)piperazine-1-carboxylate (1 g) and DMF (10 mL), and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.26 g). MS: [M+H] + 618.0.

[0762] E) (3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indol-2-yl)(piperazin-1-yl)methanone hydrochloride To a mixture of tert-butyl 4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperazine-1-carboxylate (1.2 g) and DCM (12 mL) was added 4 M hydrogen chloride / dioxane solution (2 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 4 hours, and the solvent was evaporated under reduced pressure. The residue was washed with diethyl ether to obtain the title compound (1 g). MS: [M+H] + 517.9.

[0763] F) tert-Butyl (S)-(2-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-1-cyclohexyl-2-oxoethyl)carbamate To a mixture of (3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indol-2-yl)(piperazin-1-yl)methanone hydrochloride (1.1 g) and DMF (10 mL) was added DIEA (0.694 mL). The reaction mixture was stirred at room temperature for 15 minutes, and (S)-tert-butoxycarbonylamino-cyclohexylacetic acid (0.512 g), 1-hydroxybenzotriazole (366 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (458 mg) were added. The reaction mixture was stirred at room temperature for 2 hours, poured into ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (1.1 g). MS: [M+H] + 757.0.

[0764] G) (S)-2-Amino-1-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-cyclohexylethan-1-one hydrochloride To a mixture of tert-butyl (S)-(2-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-1-cyclohexyl-2-oxoethyl)carbamate (1.1 g) and DCM (10 mL) was added 4 M hydrogen chloride / dioxane solution (10 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hours, and the solvent was evaporated under reduced pressure to obtain the title compound (1.1 g). MS: [M+H] + 657.2.

[0765] H) tert-Butyl ((S)-1-(((S)-2-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of (S)-2-amino-1-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-cyclohexylethan-1-one hydrochloride (1.1 g) and DMF (10 mL) was added DIEA (0.83 mL) at room temperature. The reaction mixture was stirred for 15 minutes, and then (S)-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid (0.323 g) and HATU (0.905 g) were added, followed by stirring at room temperature for 16 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (850 mg). MS: [M+H] + 842.1.

[0766] I) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of tert-butyl ((S)-1-(((S)-2-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (850 mg) and ethanol (10 mL), 10% palladium on carbon (200 mg) was added at room temperature and stirred under a hydrogen atmosphere at atmospheric pressure for 3 hours. The reaction mixture was filtered through Celite and washed with ethanol. The filtrate was concentrated under reduced pressure to afford the title compound (740 mg). MS: [M+H] + 752.6.

[0767] J) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl) (methyl)carbamate (40 mg), 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol (21.1 mg), triphenylphosphine (69.7 mg), and toluene (1.5 mL) were added to a mixture of di-tert-butyl azodicarboxylate (36.7 mg), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography to obtain the title compound (36 mg). MS: [M+H] + 1064.8.

[0768] K) (S)-N-((S)-1-Cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (36 mg) and DCM (1 mL) was added 4 M hydrogen chloride in dioxane solution (0.3 mL) under ice cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diethyl ether and pentane to obtain the title compound (24 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.03-1.23 (5H, m), 1.33 (3H, d, J = 6.76 Hz), 1.06-1.68 (4H, m), 2.16 (2H, m), 2.32 (2H, m), 3.12-3.20 (3H, m), 3.47-3.50 (8H, m), 3.57-3.74 (15H, m), 3.85-3.86 (2H, m), 4.14 (2H, s), 4.31 (2H, s), 4.54-4.64 (3H, m), 5.08-5.29 (2H, m), 6.63 (1H, s), 7.46 (1H, m), 7.65-7.69 (2H, m), 8.35 (1H, m), 8.79-8.80 (2H, m), 9.14 (1H, s), 11.7 (1H, br).

[0769] Example 24 (S)-N-((S)-1-Cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)-6,9,12-trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride

[0770] A) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperazin-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (2.29 g), 5,6-difluoro-1H-indole-2-carboxylic acid (1.00 g), DIEA (2.72 mL), and DMF (20 mL), HATU (2.89 g) was added and stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (2.64 g). MS: [M+H-Boc] + 490.3.

[0771] B) Methyl 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetate A mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (2.64 g), potassium carbonate (681 mg), methyl 2-bromoacetate (753 mg), and DMF (20 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (2.96 g). MS: [M+H] + 662.4.

[0772] C) 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid To a mixture of methyl 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetate (2.76 g) and methanol (20 mL) was added 2 M aqueous sodium hydroxide solution (10.4 mL). The reaction mixture was stirred at room temperature for 2 hours, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (2.16 g). MS: [M+H] + 648.4.

[0773] D) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(14-hydroxy-3-methyl-2-oxo-6,9,12-trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid (1.20 g), 5,8,11-trioxa-2-azatridecan-13-ol (422 mg), DIEA (0.65 mL), and DMF (9.3 mL), HATU (986 mg) was added and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to afford the title compound (695 mg). MS: [M+H] + 837.5.

[0774] E) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)-6,9,12-trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate Di-tert-butyl azodicarboxylate (553 mg) was added to a mixture of 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol (265 mg), tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(14-hydroxy-3-methyl-2-oxo-6,9,12-trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (670 mg), triphenylphosphine (1.05 g), and toluene (8 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (C18, acetonitrile / 5 mM aqueous ammonium acetate solution) to obtain the title compound (575 mg). MS: [M+H] + 1150.4.

[0775] F) (S)-N-((S)-1-Cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)-6,9,12-trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)-6,9,12-trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (575 mg) and ethyl acetate (1 mL), 4 M hydrogen chloride / ethyl acetate solution (2 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to afford the title compound (549 mg). 1 H NMR (400 MHz, DMSO-d6, 100 ℃) δ 0.95-1.32 (5H, m), 1.35-1.40 (3H, m), 1.57-1.78 (6H, m), 1.94-2.08 (2H, m), 2.18-2.27 (2H, m), 3.05-3.78 (32H, m), 3.84-3.95 (1H, m), 3.99-4.21 (2H, m), 4.28-4.33 (2H, m), 4.63-4.70 (1H, m), 4.93-5.03 (1H, m), 5.17-5.26 (2H, m), 6.32-6.40 (1H, m), 6.72 (1H, s), 7.07-7.17 (1H, m), 7.47-7.59 (3H, m), 8.08-8.13 (1H, m), 8.39-8.48 (1H, m), 8.53-8.62 (1H, m), 8.63-8.93 (2H, m).

[0776] Example 25 (S)-N-((S)-1-Cyclohexyl-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride

[0777] A) (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole To a mixture of 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol (398.8 mg), (9H-fluoren-9-yl)methyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (389.2 mg), triphenylphosphine (378.8 mg), and toluene (5 mL) was added di-tert-butyl azodicarboxylate (332.5 mg). The reaction mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue was dissolved in DMF (4 mL) and tetrabutylammonium fluoride (6 mL). The reaction mixture was stirred at room temperature for 15 minutes and concentrated under reduced pressure, and TFA (5 mL) was added to the residue. The reaction mixture was stirred at room temperature for 5 minutes, diluted with water, and washed with ethyl acetate. The aqueous layer was made basic with 2 M aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to afford the title compound (199.4 mg). MS: [M+H] + 415.2.

[0778] B) tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid (199.8 mg), (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole (140.7 mg), DIEA (107 μL), 1-hydroxybenzotriazole (83.37 mg), and DMF (3 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (118.3 mg). The reaction mixture was stirred at room temperature for 2 hours, water was added, and the precipitate was collected by filtration and washed with water to give the title compound (320.8 mg). MS: [M+H] + 1044.3.

[0779] C) (S)-N-((S)-1-Cyclohexyl-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (380.2 mg) and ethyl acetate (1.5 mL) was added 4 M hydrogen chloride / ethyl acetate solution (1 mL). The reaction mixture was stirred at room temperature for 1.5 hours, and diisopropyl ether was added. The precipitate was collected by filtration and washed with diisopropyl ether to obtain the title compound (280.3 mg). MS: [M+H] + 944.2. The title compound was neutralized with saturated aqueous sodium bicarbonate solution, and the precipitate was collected to obtain a free form, which was then measured for 1H NMR. 1 H NMR (300 MHz, DMSO-d6) δ 0.78-1.27 (7H, m), 1.45-2.21 (19H, m), 2.41 (3H, s),2.58-2.78 (2H, m), 2.86-3.03 (1H, m), 3.18-3.85 (10H, m), 4.02-4.31 (3H, m), 4.53-4.87 (3H, m), 5.04-5.38 (2H, m), 6.10-6.39 (1H, m), 6.76 (1H, s), 7.05 (1H, dd, J = 5.6, 2.7 Hz), 7.49 (1H, dd, J = 5.5, 2.1 Hz), 7.62 (1H, dd, J = 10.9, 8.0 Hz), 7.66-7.84 (1H, m), 7.93 (1H, d, J = 8.6 Hz), 8.02 (1H, dd, J = 5.4, 3.3 Hz), 8.49 (1H, d, J = 5.4 Hz).

[0780] Example 26 (S)—N-((S)-1-Cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide

[0781] A) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5-fluoro-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperazin-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (7 g) and DMF (60 mL) were added 5-fluoro-1H-indole-2-carboxylic acid (3.36 g), 1-hydroxybenzotriazole (3.00 g), DIEA (11.9 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.25 g). The reaction mixture was stirred at room temperature for 16 hours, followed by addition of water and extraction with ethyl acetate. The organic layer was washed successively with water, saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (9.5 g). MS: [M+H] + 572.0.

[0782] B) Methyl 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetate To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5-fluoro-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (9.5 g) and DMF (50 mL), potassium carbonate (6.89 g) and methyl bromoacetate (4.59 mL) were added under ice-cooling. The reaction mixture was stirred at room temperature for 16 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (8.6 g). MS: [M+H] + 644.1.

[0783] C) 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetic acid To a mixture of methyl 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetate (8.6 g) and methanol (25 mL), 2 M aqueous sodium hydroxide solution (13.4 mL) was added, and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with water and washed with diethyl ether. The organic layer was extracted with 0.01 M aqueous sodium hydroxide solution. The aqueous layer was acidified with 6 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (8.1 g). MS: [M+H] + 630.2.

[0784] D) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetic acid (700 mg) and DMF (10 mL), (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole (506.8 mg), DIEA (0.78 mL), and HATU (507.8 mg) were added and stirred at room temperature for 16 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, successively, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (950 mg). MS: [M+H] + 1025.8.

[0785] E) (S)—N-((S)-1-cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (60 mg) and ethyl acetate (0.2 mL), a 4 M hydrogen chloride / ethyl acetate solution (0.043 mL) was added and stirred at room temperature for 4 hours. The precipitate was collected by filtration, and the resulting mixture of (S)-N-[(S)-1-cyclohexyl-2-[4-(5-fluoro-1-{2-oxo-2-[(S)-2-[({5-[(4-{thieno[3,2-b]pyridin-7-yloxy}piperidin-1-yl)methyl]-1,2-oxazol-3-yl}oxy)methyl]pyrrolidin-1-yl]ethyl}-1H-indole-2-carbonyl)piperazin-1-yl]-2-oxoethyl]-2-(methylamino)propanamide hydrochloride and water (0.2 mL) was added with saturated aqueous sodium bicarbonate (0.043 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, and the precipitate was collected by filtration to give the title compound (46 mg). 1H NMR (400 MHz, DMSO-d6, 100 ℃) δ 1.07-1.25 (m, 6H), 1.55-1.76 (m, 6H), 1.76-1.88 (m, 2H), 1.88-2.12 (m, 7H), 2.24 (s, 3H), 2.32 (s, 2H), 2.70-2.79 (m, 2H), 2.95-3.05 (m, 2H), 3.57-3.72 (m, 12H), 4.09-4.40 (m, 3H), 4.65 (s, 1H), 4.79 (s, 1H), 5.17-5.23 (m, 2H), 5.99-6.29 (m, 1H), 6.70 (s, 1H), 6.98 (d, J = 5.3 Hz, 1H), 7.01-7.06 (m, 1H), 7.12-7.21 (m, 1H), 7.20-7.29 (m, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.42-7.55 (m, 2H), 7.67 (s, 1H), 7.95 (d, J = 5.1 Hz, 1H), 8.49 (d, J = 5.2 Hz, 1H).

[0786] Example 27 (S)—N-((S)-1-Cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide

[0787] A) tert-Butyl (S)-4-(5,6-difluoro-1H-indole-2-carbonyl)-3-methylpiperazine-1-carboxylate To a mixture of tert-butyl (S)-3-methylpiperazine-1-carboxylate (1.12 g), 5,6-difluoro-1H-indole-2-carboxylic acid (1.00 g), DIEA (2.72 mL), and DMF (20 mL) was added HATU (2.89 g). The reaction mixture was stirred at room temperature for 1 hour, diluted with water and ethyl acetate, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.61 g). MS: [M+H-tBu] + 324.2.

[0788] B) Methyl 2-(2-((S)-4-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)-2-methylpiperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetate A mixture of tert-butyl (S)-4-(5,6-difluoro-1H-indole-2-carbonyl)-3-methylpiperazine-1-carboxylate (1.61 g), potassium carbonate (762 mg), methyl 2-bromoacetate (0.629 mL), and DMF (15 mL) was stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). To a mixture of the obtained tert-butyl (S)-4-(5,6-difluoro-1-(2-methoxy-2-oxoethyl)-1H-indole-2-carbonyl)-3-methylpiperazine-1-carboxylate and ethyl acetate (10 mL), 4M hydrogen chloride / ethyl acetate solution (21.2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. To a mixture of the obtained methyl (S)-2-(5,6-difluoro-2-(2-methylpiperazine-1-carbonyl)-1H-indol-1-yl)acetate hydrochloride, (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (1.20 g), DIEA (3.0 mL), and DMF (20 mL) was added HATU (3.22 g). The reaction mixture was stirred at room temperature for 1 hour, and water and ethyl acetate were added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (639 mg). MS: [M+H] + 591.5.

[0789] C) Methyl 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-2-methylpiperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetate To a mixture of methyl 2-(2-((S)-4-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)-2-methylpiperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetate (639 mg) and ethyl acetate (3 mL) was added 4 M hydrogen chloride / ethyl acetate solution (5 mL). The reaction mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. To a mixture of the obtained methyl 2-(2-((S)-4-((S)-2-amino-2-cyclohexylacetyl)-2-methylpiperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetate hydrochloride, N-(tert-butoxycarbonyl)-N-methyl-L-alanine (329 mg), DIEA (0.85 mL), and DMF (5 mL) was added HATU (616 mg). The reaction mixture was stirred at room temperature for 1 hour, and water and ethyl acetate were added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (450 mg). MS: [M+H] + 676.5.

[0790] D) 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-2-methylpiperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid To a mixture of methyl 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-2-methylpiperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetate (225 mg) and methanol (1.6 mL) was added 2 M aqueous sodium hydroxide solution (0.8 mL). The reaction mixture was stirred at room temperature for 1 hour, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (221 mg). MS: [M+H] + 662.4.

[0791] E) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-2-methylpiperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid (336 mg), (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole trihydrochloride (319 mg), DIEA (0.53 mL), and DMF (3 mL) was added HATU (386 mg). The reaction mixture was stirred at room temperature for 2 hours, water was added, and the precipitate was collected by filtration and purified by silica gel column chromatography (C18, acetonitrile / 5 mM aqueous ammonium acetate / acetonitrile). Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the obtained compound, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (320 mg). MS: [M+H] + 1058.5.

[0792] F) (S)—N-((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (320 mg) and ethyl acetate (2 mL) was added 4 M hydrogen chloride / ethyl acetate solution (2 mL). The reaction mixture was stirred at room temperature for 1.5 hours, and the solvent was evaporated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution, and the precipitate was collected by filtration to obtain the title compound (216 mg). 1 H NMR (300 MHz, DMSO-d6) δ 0.77-1.33 (10H, m), 1.40-2.24 (19H, m), 2.31-2.46 (2H, m), 2.58-3.49 (8H, m), 3.53-3.70 (3H, m), 3.82-4.86 (8H, m), 5.01-5.48 (2H, m), 6.07-6.39 (1H, m), 6.67-6.81 (1H, m), 7.05 (1H, dd, J = 5.6, 1.9 Hz), 7.49 (1H, dd, J = 5.6, 3.0 Hz), 7.62 (1H, dd, J = 10.9, 8.1 Hz), 7.68-7.83 (1H, m), 7.89 (1H, t, J = 9.4 Hz), 7.97-8.07 (1H, m), 8.49 (1H, d, J = 5.7 Hz)

[0793] Example 28 (S)—N-((S)-1-Cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide

[0794] A) Benzyl (S)-4-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)-2-methylpiperazine-1-carboxylate To a mixture of (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (5 g), benzyl (S)-2-methylpiperazine-1-carboxylate hydrochloride (5.26 g), 1-hydroxybenzotriazole (3.4 g), DIEA (10.2 mL), and DMF (50 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.8 g). The reaction mixture was stirred at room temperature for 2 hours, ice water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium bicarbonate, and saturated brine, then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (6.7 g). MS: [M+H] + 474.2.

[0795] B) Benzyl (S)-4-((S)-2-amino-2-cyclohexylacetyl)-2-methylpiperazine-1-carboxylate hydrochloride To a mixture of benzyl (S)-4-((S)-2-(((tert-butoxy)carbonyl)amino)-2-cyclohexylacetyl)-2-methylpiperazine-1-carboxylate (6.7 g) and DCM (60 mL) was added 4 M hydrogen chloride / dioxane solution (30 mL). The reaction mixture was stirred at room temperature for 3 hours, and the solvent was evaporated under reduced pressure. The residue was washed with DCM to obtain the title compound (6 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.01-1.25 (8H, m), 1.59-1.70 (6H, m), 2.85-3.18 (3H, m), 3.77-4.28 (5H, m), 5.10 (2H, s), 7.33-7.37 (5H, m), 8.06-8.04 (3H, m).

[0796] C) Benzyl (S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-2-methylpiperazine-1-carboxylate To a mixture of N-(tert-butoxycarbonyl)-N-methyl-L-alanine (3 g) and DMF (30 mL) was added benzyl (S)-4-((S)-2-amino-2-cyclohexylacetyl)-2-methylpiperazine-1-carboxylate hydrochloride (6 g), DIEA (10.3 mL), and HATU (7.3 g). The reaction mixture was stirred at room temperature for 16 hours, ice water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium bicarbonate, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (6 g). MS: [M+H] + 559.1.

[0797] D) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-((S)-3-methylpiperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of benzyl (S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-2-methylpiperazine-1-carboxylate (3.8 g) and ethanol (50 mL) was added 10% palladium on carbon (1 g). The reaction mixture was stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 16 hours and then filtered through Celite. The filtrate was concentrated under reduced pressure to give the title compound (2.3 g). MS: [M+H] + 425.2.

[0798] E) Methyl 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-2-methylpiperazine-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetate To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-((S)-3-methylpiperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (901 mg), 5-fluoro-1H-indole-2-carboxylic acid (380 mg), DIEA (1.14 mL), and DMF (12 mL) was added HATU (1.21 g). The reaction mixture was stirred at room temperature for 1 hour, poured into water, and the precipitate was collected by filtration and azeotroped with toluene. A mixture of the obtained tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate, potassium carbonate (322 mg), methyl 2-bromoacetate (356 mg), and DMF (12 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (979 mg). MS: [M+H] + 658.4.

[0799] F) 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-2-methylpiperazine-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetic acid To a mixture of methyl 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-2-methylpiperazine-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetate (979 mg) and methanol (8 mL) was added 2 M aqueous sodium hydroxide solution (3.72 mL). The reaction mixture was stirred at room temperature for 1 hour, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (915 mg). MS: [M+H] + 644.4.

[0800] G) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-2-methylpiperazine-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetic acid (621 mg), (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole trihydrochloride (606 mg), DIEA (1.0 mL), and DMF (5 mL) was added HATU (734 mg). The reaction mixture was stirred at room temperature for 2 hours, water was added, and the precipitate was collected by filtration and purified by silica gel column chromatography (C18, acetonitrile / 5 mM ammonium acetate aqueous solution). The resulting compound was diluted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (367 mg). MS: [M+H] + 1040.5.

[0801] H) (S)—N-((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (367 mg) and ethyl acetate (2 mL) was added 4 M hydrogen chloride / ethyl acetate solution (3 mL). The reaction mixture was stirred at room temperature for 1.5 hours, and the solvent was evaporated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution, and the precipitate was collected by filtration to obtain the title compound (249 mg). 1 H NMR (300 MHz, DMSO-d6) δ 0.74-1.34 (10H, m), 1.38-2.25 (19H, m), 2.33-2.46 (2H, m), 2.60-3.50 (8H, m), 3.55-3.71 (3H, m), 3.79-4.94 (8H, m), 5.00-5.50 (2H, m), 6.03-6.43 (1H, m), 6.61-6.82 (1H, m), 6.98-7.19 (2H, m), 7.26-7.71 (3H, m), 7.89 (1H, t, J = 9.7 Hz), 7.98-8.13 (1H, m), 8.49 (1H, d, J = 5.5 Hz).

[0802] Example 48 (S)-N-((S)-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-2-(methylamino)propanamide trifluoroacetate

[0803] A) Benzyl (S)-4-(2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetyl)piperazine-1-carboxylate To a mixture of (S)-2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid (230 mg) and DMF (10 mL), benzyl piperazine-1-carboxylate (172.7 mg), 1-hydroxybenzotriazole (137.7 mg), DIEA (0.41 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (195.4 mg) were added and stirred at room temperature for 16 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (300 mg). MS: [M+H] + 496.0.

[0804] B) Benzyl 4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-(4,4-difluorocyclohexyl)acetyl)piperazine-1-carboxylate To a mixture of benzyl (S)-4-(2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetyl)piperazine-1-carboxylate (300 mg) and DCM (20 mL), 4 M hydrogen chloride in dioxane (5 mL) was added and stirred at room temperature for 3 hours, and then the solvent was evaporated under reduced pressure. To a mixture of the obtained benzyl (S)-4-(2-amino-2-(4,4-difluorocyclohexyl)acetyl)piperazine-1-carboxylate and DMF (10 mL), N-(tert-butoxycarbonyl)-N-methyl-L-alanine (122.9 mg), DIEA (0.42 mL), and HATU (299.3 mg) were added and stirred at room temperature for 16 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (300 mg). MS: [M+H] + 580.9.

[0805] C) tert-Butyl ((S)-1-(((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-(piperazin-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of benzyl 4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-(4,4-difluorocyclohexyl)acetyl)piperazine-1-carboxylate (300 mg) and ethanol (10 mL), 10% palladium on carbon (90 mg) was added and stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 16 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (220 mg). MS: [M+H] + 447.1.

[0806] D) tert-Butyl ((S)-1-(((S)-2-(4-(5,6-difluoro-1H-indole-2-carbonyl)piperazin-1-yl)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of tert-butyl ((S)-1-(((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-(piperazin-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (200 mg) and DMF (15 mL), 5,6-difluoro-1H-indole-2-carboxylic acid (88.3 mg), DIEA (0.31 mL), and HATU (221.4 mg) were added and stirred at room temperature for 16 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (170 mg). MS: [M+H] + 626.3.

[0807] E) Benzyl 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-(4,4-difluorocyclohexyl)acetyl)piperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetate To a mixture of tert-butyl ((S)-1-(((S)-2-(4-(5,6-difluoro-1H-indole-2-carbonyl)piperazin-1-yl)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (150 mg) and DMF (10 mL), benzyl 2-bromoacetate (0.076 mL) and cesium carbonate (194.8 mg) were added and stirred at room temperature for 16 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (150 mg). MS: [M+H] + 773.9.

[0808] F) 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-(4,4-difluorocyclohexyl)acetyl)piperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid A mixture of benzyl 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-(4,4-difluorocyclohexyl)acetyl)piperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetate (150 mg) and ethanol (10 mL) was purged with nitrogen, and then 10% palladium on carbon (60 mg) was added and stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 16 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (123 mg). MS: [M+H] + 684.1.

[0809] G) tert-Butyl ((S)-1-(((S)-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-(4,4-difluorocyclohexyl)acetyl)piperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid (50 mg) and DMF (5 mL), (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole (30.3 mg), DIEA (0.051 mL), and HATU (36.1 mg) were added and stirred at room temperature for 16 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (methanol / DCM) to obtain the title compound (52 mg). MS: [M+H] + 1080.4.

[0810] H) (S)-N-((S)-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-2-(methylamino)propanamide trifluoroacetate To a mixture of tert-butyl ((S)-1-(((S)-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (52 mg) and DCM (5 mL) was added TFA (0.037 mL) and stirred at room temperature for 16 hours. The reaction mixture was evaporated under reduced pressure to afford the title compound (44 mg). MS: [M+H] + 980.6.

[0811] Example 51 (S)-N-((S)-1-Cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-(2-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride

[0812] A) 2-(benzyloxy)-3,4-difluorobenzaldehyde To a mixture of 3,4-difluoro-2-hydroxybenzaldehyde (5 g) and acetonitrile (50 mL), potassium carbonate (6.56 g), benzyl bromide (4.51 mL), and sodium iodide (2.37 g) were added. The reaction mixture was stirred at 60 °C for 6 hours, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (7.0 g). 1H NMR (400 MHz, DMSO-d6): δ 5.33 (2H, s), 7.30-7.42 (4H, m), 7.45-7.47 (2H, m),7.55-7.59 (1H, m), 10.04 (1H, s).

[0813] B) Methyl (Z)-2-azido-3-(2-(benzyloxy)-3,4-difluorophenyl)acrylate To a mixture of methyl azidoacetate (3.15 mL), 2-(benzyloxy)-3,4-difluorobenzaldehyde (2.0 g), and methanol (10 mL) was added dropwise a mixture of sodium methoxide (1.74 g) and methanol (10 mL) at -10 °C under an argon atmosphere. The reaction mixture was stirred at the same temperature for 4 hours and then at 4 °C for 16 hours. Ice water was added, and the precipitate was collected by filtration to obtain the title compound (2.1 g). 1 H NMR (400 MHz, DMSO-d6): δ 3.83 (3H, s), 5.14 (2H, s), 6.94 (1H, s), 7.26 (1H, m), 7.38-7.40 (5H, m), 7.97 (1H, t, J = 6.9 Hz).

[0814] C) Methyl 4-(benzyloxy)-5,6-difluoro-1H-indole-2-carboxylate A mixture of methyl (Z)-2-azido-3-(2-(benzyloxy)-3,4-difluorophenyl)acrylate (2.0 g) and xylene (30 mL) was stirred at 140° C. for 2 hours. The reaction mixture was cooled, and the precipitate was collected by filtration to obtain the title compound (700 mg). 1 H NMR (400 MHz, DMSO-d6): δ 3.87 (3H, s), 5.41 (2H, s), 7.05 (1H, m), 7.26 (1H, s), 7.32-7.41 (3H, m), 7.47-7.49 (2H, m), 12.19 (1H,s).

[0815] D) Methyl 4-(benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carboxylate To a mixture of methyl 4-(benzyloxy)-5,6-difluoro-1H-indole-2-carboxylate (1.7 g) and DMF (20 mL) were added potassium carbonate (1.1 g) and methyl iodide (0.4 mL). The reaction mixture was stirred at room temperature for 2 hours, followed by the addition of ice water and extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.5 g). MS: [M+H] + 332.1.

[0816] E) 4-(benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carboxylic acid To a mixture of methyl 4-(benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carboxylate (1.5 g) and THF (30 mL), water (6 mL) and lithium hydroxide monohydrate (0.285 g) were added. The reaction mixture was stirred at room temperature for 6 hours, the solvent was evaporated under reduced pressure, and the mixture was acidified with 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.35 g). MS: [M+H] + 318.1.

[0817] F) tert-Butyl ((S)-1-(((S)-2-(4-(4-(benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of 4-(benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carboxylic acid (1.4 g) and DMF (20 mL) was added tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperazin-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (1.81 g), HATU (2.52 g), and DIEA (1.9 mL). The reaction mixture was stirred at room temperature for 2 hours, followed by the addition of ice water and extraction with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.1 g). MS: [M+H] + 710.1.

[0818] G) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-4-hydroxy-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate Palladium on carbon (400 mg) was added to a mixture of tert-butyl ((S)-1-(((S)-2-(4-(4-(benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (2.1 g) and ethanol (50 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to afford the title compound (1.7 g). MS: [M+H] + 620.4.

[0819] H) 2-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate To a mixture of 2-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)ethanol (15 g) and DCM (250 mL), TEA (11.03 mL), DMAP (3.22 g), and p-toluenesulfonyl chloride (12.07 g) were added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (14 g). MS: [M+H] + 439.2.

[0820] I) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-4-hydroxy-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (450 mg) and DMF (5 mL) were added cesium carbonate (591 mg) and 2-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (573 mg). The reaction mixture was stirred at room temperature for 16 hours, followed by addition of ice water and extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to afford the title compound (490 mg). MS: [M+H] + 886.4.

[0821] J) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-dif...

Claims

1. The following formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof.

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the E3 ligase binder (E) is selected from the group consisting of an IAP binder, a CRBN binder, a VHL binder, an MDM2 binder, and a DCAF15 binder.

3. The IRAK-M binder (M) is represented by the following formula (II): 【Chemistry 2】 [Wherein, X represents S, O, or NR, R represents a hydrogen atom or a C1-6 alkyl group, Y represents CH or N, Z represents O or NH, and R 01 represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a cyano group, a halogen atom, an optionally substituted phenyl group, an optionally substituted ester group, or an optionally substituted 5-membered heterocyclic group; R 02 represents a hydrogen atom, a C1-6 alkyl group, or a halogen atom, and R 03 represents an optionally substituted C1-6 alkylene group, an optionally substituted C6-14 arylene group, an optionally substituted heterocyclic group, or a bond, and A represents the following structural formula: 【Transformation 3】 (where R 05 are each independently a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a C1-6 alkoxy group, ２ -*, *-CO-CH ２ represents -*, *-CO-NH-*, *-O-*, an optionally substituted C1-6 alkylene group, or a bond; R 04 has the following structural formula: 【Chemistry 4】 (where * indicates the bonding position to A, and ** indicates the bonding position to the linker), an optionally substituted C1-6 alkylene group, an optionally substituted C3-10 cycloalkylene group, an optionally substituted C6-14 arylene group, an optionally substituted hetero 5- or 6-membered ring group, an ester bond, or a bond, and the arrow indicates the bond to the linker (L). ], or a pharmaceutically acceptable salt thereof.

4. In the formula II, R 01 represents a hydrogen atom, a C1-6 alkyl group, a C2-3 alkynyl group, a cyano group, a halogen atom, an optionally substituted phenyl group, an optionally substituted ester group, or an optionally substituted 5-membered heterocyclic group; R 03 represents an optionally substituted arylene group, an optionally substituted heterocyclic group, or a bond, and R 04 has the following structural formula: 【Transformation 5】 (where * indicates the bonding position to A, and ** indicates the bonding position to the linker), an optionally substituted C1-6 alkylene group, an optionally substituted C3-10 cycloalkylene group, an optionally substituted C6-14 arylene group, an optionally substituted pyrazolinediyl group, an optionally substituted oxazolidinediyl group, an optionally substituted isoxazolidinediyl group, an ester bond, or a bond, and an arrow indicates the bond to the linker (L), or a pharmaceutically acceptable salt thereof.

5. In the formula II, R 01 is a hydrogen atom, a methyl group, a cyano group, an iodine atom, a phenyl group, or a group having the following structural formula: 【Transformation 6】 R represents any of the groups represented by 02 represents a hydrogen atom, a methyl group, or a chlorine atom; R 03 has the following structural formula: 【Transformation 7】 (wherein n is 0, 1 or 2, W is NR (wherein R is a hydrogen atom, a C1-6 alkyl group, or an acyl group), SO ２ , SO, S, or O, each V is independently CH or N (provided that any one of the Vs is CH), and each U is independently CH, N, NH, O, or S (provided that two or more Us cannot be O or S).), an optionally substituted C1-6 alkylene group, or a bond, and R 04 has the following structural formula: 【Transformation 8】 (where * indicates the bonding position to A, ** indicates the bonding position to the linker, V is CH or N, and each U is independently CH, N, NH, O, or S (with the proviso that two or more Us cannot be O or S)), an optionally substituted C1-6 alkylene group, an optionally substituted C3-10 cycloalkylene group, an optionally substituted C6-14 arylene group, or a bond, or a pharmaceutically acceptable salt thereof.

6. In the formula II, X is S, Z is O, and R 01 is H or a methyl group, and R 02 is H and R 03 has the following structural formula: 【Chemistry 9】 (where * indicates the bonding position to O, ** indicates the bonding position to A, and n is 0, 1 or 2), and A is a group represented by the following structural formula: 【Chemistry 10】 (where R 05 are each independently a hydrogen atom or a C1-6 alkyl group, a group represented by *-SO ２ -*, or *-CO-CH ２ -* and R 04 has the following structural formula: 【Chemistry 11】 (wherein V is CH or N, * indicates the bonding position to A, and ** indicates the bonding position to the linker), an optionally substituted C1-6 alkylene group, an optionally substituted C3-10 cycloalkylene group, or an optionally substituted C6-14 arylene group, or a pharmaceutically acceptable salt thereof.

7. The IRAK-M binder (M) is represented by the following formula (III): 【Chemistry 12】 [wherein Y represents CH or N, and R 01 represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-3 alkynyl group, a cyano group, a halogen atom, an optionally substituted phenyl group, an optionally substituted ester group, or an optionally substituted 5-membered heterocyclic group; A 01 has the following structural formula: 【Chemistry 13】 (where R 12 are each independently a hydrogen atom or a C1-6 alkyl group), 2 -*, or *-CO-CH ２ - indicates *, R 11 has the following structural formula: 【Chemistry 14】 (where * indicates the bonding position to A, and ** indicates the bonding position to the linker), an optionally substituted C1-6 alkylene group, an optionally substituted C3-10 cycloalkylene group, an optionally substituted C6-14 arylene group, or a bond, and the arrow indicates bonding to the linker (L). ], or a pharmaceutically acceptable salt thereof.

8. In Formula III, R 01 is a hydrogen atom or a methyl group, and A 01 has the following structural formula: 【Chemistry 15】 (where R 12 are each independently a hydrogen atom or a C1-6 alkyl group), or *-SO ２ -* and R 11 has the following structural formula: 【Chemistry 16】 (wherein * indicates the position of attachment to A, and ** indicates the position of attachment to the linker), or a pharmaceutically acceptable salt thereof.

9. The IRAK-M binder (M) is a compound selected from the group consisting of: N-(3-(methylsulfonyl)phenyl)thieno[3,2-d]pyrimidin-4-amine, 4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol, 3-(allyloxy) 3-(allyloxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole, 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole, 3-(allyloxy)-5-(1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)ethyl)isoxazole; 3-(allyloxy)-5-(1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)ethyl)isoxazole; 3-(allyloxy)-5-(1-(4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)ethyl)isoxazole, (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole), 3-((tetrahydrofuran-3-yl)oxy)-4-(thieno[3,2-d]pyrimidin-4-ylamino)benzamide), N,6-diphenylthieno[3,2-d]pyrimidin-4-amine yrimidin-4-amine), N-(2-methoxyphenyl)-6-phenylthieno[3,2-d]pyrimidin-4-amine, N-(cyclopropylmethyl)-6-phenylthieno[3,2-d]pyrimidin-4-amine, 6-phenyl-N-(pyridin-2-yl) ) thieno[3,2-d]pyrimidin-4-amine (6-phenyl-N-(pyridin-2-yl)thieno[3,2-d]pyrimidin-4-amine), 6-phenyl-N-(pyridin-3-ylmethyl)thieno[3,2-d]pyrimidin-4-amine (6-phenyl-N-(pyridin-3-ylmethyl)thieno[3,2-d]pyrimidin-4-amine), N-phenethyl-6-phenylthieno[3,2-d]pyrimidin-4-amine thieno[3,2-d]pyrimidin-4-amine, 4-(thieno[3,2-d]pyrimidin-4-ylamino)benzamide, N-(2-((tetrahydrofuran-3-yl)oxy)phenyl)thieno[3,2-d]pyrimidin-4-amine, 3-(thieno[3,3-(thieno[3,2-d]pyrimidin-4-ylamino)benzamide, N-(pyridin-4-yl)thieno[3,2-d]pyrimidin-4-amine, N-(2-(trifluoromethyl)pyridin-4-yl)thieno[3,2-d]pyrimidin-4-amine o[3,2-d]pyrimidin-4-amine), N-(2-methoxypyridin-4-yl)thieno[3,2-d]pyrimidin-4-amine, N-(2-(trifluoromethyl)pyridin-3-yl)thieno[3,2-d]pyrimidin-4-amine, N-(3 N-(3-methyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-amine, N-(1H-benzo[d]imidazol-5-yl)thieno[3,2-d]pyrimidin-4-amine, 5-(thieno 5-(thieno[3,2-d]pyrimidin-4-ylamino)isoindoline-1,3-dione, N-(1H-indazol-6-yl)thieno[3,2-d]pyrimidin-4-amine, 5-(thieno[3,2-d]pyrimidin-4-ylamino)isobenzofuran-1(3H)-one, 5-(thieno[3,2-d]pyrimidin-4-ylamino)isoindoline-1,3-dione, N-(1H-indazol-6-yl)thieno[3,2-d]pyrimidin-4-amine, 5-(thieno[3,2-d]pyrimidin-4-ylamino)isobenzofuran-1(3H)-one2-d]pyrimidin-4-ylamino)isobenzofuran-1(3H)-one), methyl 4-((cyclopropylmethyl)amino)thieno[3,2-d]pyrimidine-6-carboxylate, 6-(1-methyl-1H-pyrazol-4-yl)-4-((1-methylpiperidin-4-yl)oxy)thieno[3,2-d]pyrimidine pyrimidine), 6-ethynyl-4-((1-methylpiperidin-4-yl)oxy)thieno[3,2-d]pyrimidine, 4-((2-chlorothieno[3,2-d]pyrimidin-4-yl)amino)benzamide )amino)benzamide), 6-iodo-4-((tetrahydro-2H-pyran-4-yl)oxy)thieno[3,2-d]pyrimidine, 6-iodo-4-((tetrahydro-2H-thiopyran-4-yl)oxy)thieno[3,2-d]pyrimidine 2H-thiopyran-4-yl)oxy)thieno[3,2-d]pyrimidine, 6-iodo-4-((1-methylpiperidin-4-yl)oxy)thieno[3,2-d]pyrimidine, 4-((6-iodothieno[3,2-d]pyrimidin-4-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide4-((1-((2,6-difluorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine; 4-((1-((2,6-difluorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine; 4-((1-(methylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine dine), 4-((1-((2-methoxyethyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine, 4-((1-(benzylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine, tert-butyl tert-butyl 4-(((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)methyl)piperidine-1-carboxylate, ethyl 3-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)propanoate 3-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)propanoate, 4-((1-(cyclopropylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine2-d]pyrimidine), 4-((1-((2-chlorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine), 4-((1-((2-methoxyphenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine), 4-((1-(o-tolylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine, 4-((1-((2-(4-fluorophenoxy)phenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine, 4-((1-((2-(4-fluorophenoxy)phenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine 4-((1-((2-fluorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine), 4-((1-((2-fluorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine, 4-((1-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine 4-((1-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine, 4-((1-((4-methoxyphenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine,2-d]pyrimidine), 4-((1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine), 4-((1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine), 4-((1-((3-methoxyphenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine, 4-((1-((3-methoxyphenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine, 4-((1-(4-methylbenzenesulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine , 4-((1-((3-fluorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine, 4-((1-((3-chlorophenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine 4-((1-(pyridin-3-ylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine), 4-((1-((1-benzyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine2-d]pyrimidine (4-((1-((1-benzyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine), 4-((1-((6-methoxypyridin-3-yl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine ne), 4-((1-((1,4-dimethyl-1H-pyrazol-5-yl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine, 4-((1-((1,4-dimethyl-1H-pyrazol-5-yl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine, 4-((1-(isobutylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine 4-((1-(phenethylsulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine, 4-((1-((3-phenoxyphenyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine enyl)sulfonyl)piperidin-4-yl)oxy)thieno[3,2-d]pyrimidine, N-(4-ethoxyphenyl)thieno[3,2-d]pyrimidin-4-amine, N-(3,4-dimethoxyphenyl)-2,6-dimethylthieno[3,2-d]pyrimidin-4-amine), 7-((1-(prop-2-yn-1-yl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine, 1-methyl-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)-1H-pyrazol-3-ol thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)-1H-pyrazol-3-ol, 7-((1-((3-(allyloxy)-1-methyl-1H-pyrazol-5-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine (7-((1-((3-(allyloxy)-1-methyl-1H-pyrazol-5-yl)methyl)piperidin-4-yl)oxy)thieno[, 3,2-b]pyridine), 3-(allyloxy)-5-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)methyl)isoxazole), 3-(prop-2-yn-1-yloxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole 3-(prop-2-yn-1-yloxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole, 3-(allyloxy)-5-((4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)methyl)isoxazole ethyl)isoxazole), 7-((1-((1-methyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine), 7-((1-((1-methyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine), 7-((1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine imethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine), 7-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine), 7-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine),7-((1-((1,5-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine, 7-((1-((1-methyl-1H-pyrazol-5-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine )piperidin-4-yl)oxy)thieno[3,2-b]pyridine), 3,5-dimethyl-4-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole), 7-((1-(thiazol-2-ylmethyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine 1-(thiazol-2-ylmethyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine, 7-((1-((2-methylthiazol-5-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine, 2-(1H-pyrazol-1-yl)-1-(4-(thieno[3,2-b]pyridine-7-yl) 2-(1H-pyrazol-1-yl)-1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)ethan-1-one, 1-(4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one,3-triazol-2-yl)ethan-1-one), 2-allyl-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3(2H)-one, 3-(2-methoxyethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3(2H)-one 3-(2-methoxyethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole, 7-((1-((3-(allyloxy)isoxazol-5-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine-2-carbonitrile (7-((1-((3-(allyloxy)isoxazol-5-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine-2-carbonitrile lyloxy)isoxazol-5-yl)methyl)piperidin-4-yl)oxy)thieno[3,2-b]pyridine-2-carbonitrile), 5-((4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)methyl)isoxazol-3-ol (5-((4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)me The compound according to claim 3, wherein the aryl group is a monovalent group derived from a compound selected from the group consisting of 5-(1-(4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)ethyl)isoxazol-3-ol, and 5-(1-(4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)ethyl)isoxazol-3-ol.

10. The IRAK-M binder (M) is a compound selected from the group consisting of: 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol, 5-((4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)methyl)isoxazol-3-ol, 1-methyl-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol 10. The compound according to claim 9, wherein the aryl group is a monovalent group derived from a compound selected from the group consisting of 1-methyl-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)-1H-pyrazol-3-ol, and 4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol.

11. The linker (L) is represented by the formula (L1): -B 1 -B 2 -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 - [In the formula, B 1 and B 2 are each independently represented by the following structural formula: 【Chemistry 17】 A group represented by (wherein B 1 and B 2 However, both of them do not have this structure.), *-O-*, *-NR 06 -* (where R 06 is a hydrogen atom or a C1-6 alkyl group. ２ -*, *-CO-*, *-SO ２ -*, an optionally substituted C1-6 alkylene group, an optionally substituted C2-6 alkenylene group, an optionally substituted C2-6 alkynylene group, an optionally substituted C3-10 cycloalkylene group, an optionally substituted C6-14 arylene group, or a bond; L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 are each independently represented by the following structural formula: [Chemistry 18] (In the formula, m represents an integer of 1 to 4, n represents an integer of 1 to 4, and each A is independently N, CHCO, or CHCH 2 O) (wherein L 1 ~L 7 Two or more of the above cannot have this structure.), a bond, an oxygen atom, a sulfur atom, a C1-6 alkylene group, a C3-10 cycloalkylene group, a carbonyl group, an imino group optionally substituted with a C1-6 alkyl group, an ethynylene group, a vinylene group optionally substituted with a C1-6 alkyl group, a C3-10 cycloalkenylene group, a phenylene group, a thiazolyldiyl group, a non-aromatic heterocyclic group optionally substituted with an optionally substituted C1-6 alkyl group or a halogen atom, a pyrrolidinediyl group optionally substituted with a fluorine atom, a morpholinediyl group optionally substituted with an optionally substituted C1-6 alkyl group, an azetidinediyl group optionally substituted with a fluorine atom, a group of the formula -SO 2 -, formula -CH 2 CH 2 O-, formula -OCH 2 CH 2 -, formula - COCH 2 -, formula -CH 2 CO-, formula -CO 2 -, formula -OCO-, formula -COCHR 101 NR 102 -, formula -OCH 2 CHR 103 NR 104 -, formula -NR 105 CHR 106 CO-, formula-NR 107 CO-, formula-CONR 108 -, formula -SO 2 NR 109 -, formula -NR 110 SO 2 - or the formula -NR 111 CHR 112 CH 2 O- (R in the above formula 101 , R 103 , R 106 , and R 112 each independently represents a hydrogen atom, a C1-6 alkyl group, a 3-guanidinopropyl group, a carbamoylmethyl group, a carboxymethyl group, a mercaptomethyl group, a 2-carbamoylethyl group, a 2-carboxyethyl group, an imidazol-4-ylmethyl group, a 4-aminobutyl group, a 2-methylthioethyl group, a benzyl group, a hydroxymethyl group, a 1-hydroxyethyl group, an indol-3-ylmethyl group, a 4-hydroxyphenylmethyl group, or a pyridylmethyl group; R 102 , R 104 , R 105 , R 107 , R 108 , R 109 , R 110 , and R 111 each independently represent a hydrogen atom or a C1-6 alkyl group; or together represent one bond; ), or a pharmaceutically acceptable salt thereof.

12. B 1 and B 2 are each independently represented by the following structural formula: 【Chemistry 19】 A group represented by (wherein B 1 and B 2 However, both of them do not have this structure.), *-O-*, *-NR 06 -* (where R 06 is a hydrogen atom or a C1-6 alkyl group.), *-CO-*, an optionally substituted C1-6 alkylene group, an optionally substituted C6-14 arylene group, an optionally substituted C2-6 alkynylene group, or a bond, or a pharmaceutically acceptable salt thereof.

13. B 1 and B 2 are each independently represented by the following structural formula: 【Chemistry 20】 A group represented by (wherein B 1 and B 2 and the like do not both have this structure.), *-O-*, a C1-6 alkylene group, or a bond, or a pharmaceutically acceptable salt thereof.

14. The linker (L) has the structural formula: 【Chemistry 21】 (Here, * indicates binding to an IRAK-M binder (M).) any group represented by *-(CH 2 CH 2 O)n(CH 2 )m(NRCO)s (CH 2 )t -* (n is an integer of 1 to 5, m is 0, 1, or 2, s is 0 or 1, t is 0 or 1, and R is a hydrogen atom or a C1-6 alkyl group), or a bond, or a pharmaceutically acceptable salt thereof.

15. The E3 ligase binder (E) has the following formula (IV): 【Chemistry 22】 [wherein D represents a fragment structure of a substance that binds to IAP together with the piperazine ring, E represents a nitrogen-containing aromatic heterocyclic group, and R 01 , R 02 , R 03 , R 04 , R 05 , R 06 , R 07、 and R 08 and each independently represent a hydrogen atom or a C1-6 alkyl group which may together form a ring, and either D or E is bonded to a linker (L).

15. The compound according to any one of claims 3 to 14, or a pharmacologically acceptable salt thereof.

16. The D is represented by the following formula (V): 【Chemistry 23】 (In the formula, R 11 represents a hydrogen atom or a hydroxyl group, and R 12 and R 13 are each independently a hydrogen atom, a C1-6 alkyl group, a C3-10 cycloalkylene group, a carbonyl group, an imino group optionally substituted with a C1-6 alkyl group, an ethynylene group optionally substituted with a C1-6 alkyl group, a vinylene group optionally substituted with a C1-6 alkyl group, a pyrazole group optionally substituted with a C1-6 alkyl group, a C3-10 cycloalkenylene group, a phenylene group, a thiazolylene group, a pyrrolidinediyl group optionally substituted with a fluorine atom, an azetidinediyl group optionally substituted with a fluorine atom, or any of the above groups bonded to a linker (L) (with the proviso that R 12 and R 13 and T represents an optionally halogenated C1-3 alkyl group, or a group represented by the following formula (VI): 【Chemistry 24】 (Wherein, m represents 0, 1, or 2; n represents 0, 1, or 2; W 11 is a methylene group, a difluoromethylene group, O, S, SO, SO 2 or NR (wherein R represents a hydrogen atom, a C1-6 alkyl group, a C1-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C1-6 alkylsulfonyl group, or a bond to a linker), and T represents an optionally halogenated C1-3 alkyl group), or the following formula (VII): 【Chemistry 25】 (wherein Q is an oxygen atom, a group of the formula -NR 21 - (R in the formula 21 represents a hydrogen atom, a C1-6 alkyl group, or a C1-6 alkyl group which may form a ring together with P; or represents a bond, and P represents a hydrogen atom, a C1-6 alkyl group, or a bond to a linker (which forms a ring together with Q and includes a bond to a linker).), or a pharmaceutically acceptable salt thereof.

17. The D is R in formula (V). 12 or R 13 , W in formula (VI) 11 or P in formula (VII) is linked to a linker (L), or a pharmaceutically acceptable salt thereof.

18. The E is represented by the following formula: 【Chemistry 26】 (wherein each A independently represents C or N, each R bonded to N independently represents a hydrogen atom, a C1-6 alkyl group, or an amide group, and each of the other R independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an amide group) (wherein, when E is bonded to a linker, it is bonded to the linker at any position represented by R in the above formula), or a pharmaceutically acceptable salt thereof.

19. The E is represented by the following formula: 【Chemistry 27】 (wherein R bonded to N each independently represents a hydrogen atom, a C1-6 alkyl group, or an amide group, and the other R each independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an amide group) (wherein, when E is bonded to a linker, it is bonded to the linker at any one of the positions represented by R in the above formula), or a pharmaceutically acceptable salt thereof.

20. The E is represented by the following formula (VIII): 【Chemistry 28】 (In the formula, R 21 , R 22 , and R 23 each independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an amide group; R 25 and R 26 each independently represents a hydrogen atom, a halogen atom, a C alkyl group, a C alkoxy group, an amide group, or a bond to a linker; R 24 indicates a hydrogen atom, a methyl group, or a bond to a linker, provided that the bond to the linker is 24 , R 25 , or R 26 19. The compound of claim 18, wherein:

21. The E is represented by the following formula (IX): 【Chemistry 29】 (In the formula, R 31 , R 32、 R 33 , R 34 , and R 35 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an amide group, and R represents a hydrogen atom, a C1-6 alkyl group, or a bond to a linker, or a pharmaceutically acceptable salt thereof.

22. The following compounds: 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide (2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino) propanamido)acetyl)piperazine-1-carbonyl)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide), 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino) 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-6-methoxy-1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide, 1-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperazin-1-yl)-2-((2R,5R)-5-methyl-2-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperazin-1-yl)ethan-1-one (1-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperazin-1-yl)-2-((2R,5R)-5-methyl-2-((2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-y l)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)methyl)piperazin-1-yl)ethan-1-one), (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-one (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamin o)propanamide), (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)-6,9,12-trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)-6,9,1 2-trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide), (S)-N-((S)-1-cy Cyclohexyl-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(2-ox o-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethy l)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide), (S)-N-((S)-1-cyclohexyl-2-(4-(5-fluoro-1-( 2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S)-N-((S)-1-cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide), (S)-N-((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5 -((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S)-N-((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2 -b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide), (S)-N-((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2 -(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S)-N-((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-me thylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide), (S)-N-((S)-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thi) eno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-2-(methylamino)propanamide ((S)-N-((S)-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno ... -yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-2-(methylamino)propanamide), (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-(2-(2- (2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide), and (S)-N-((S)-1-cyclohexyl-2-(4-(2-methyl-1-(2-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl 2. The compound according to claim 1, selected from the group consisting of (S)-N-((S)-1-cyclohexyl-2-(4-(2-methyl-1-(2-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide, or a pharmaceutically acceptable salt thereof.

23. The compound according to any one of claims 3 to 14, wherein the E3 ligase binder (E) is a Smac peptide mimetics compound, or a pharmaceutically acceptable salt thereof.

24. The Smac peptide mimetics compound has the following formula (S1): 【Transformation 30】 (wherein R represents an optionally substituted alkyl group or an optionally substituted cycloalkyl group, ring A represents an optionally substituted heterocycle, and ring B represents an optionally substituted ring, and is bonded to the linker at either ring B or R), or a pharmaceutically acceptable salt thereof.

25. 25. The compound according to claim 24, wherein, in formula S1, R is a cycloalkyl group, B is an optionally substituted aryl group, and A is a thiazoldiyl group, or a pharmaceutically acceptable salt thereof.

26. The Smac peptide mimetics compound is represented by the following formula (I-1) or the following formula (I-2): 【Chemistry 31】 (In the formula, R 1 and R 2 each independently represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted aryl group; R 3 and R 4 each independently represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted alkoxy group, an optionally substituted heteroaryl group, or an optionally substituted heterocyclyl group; R 5 , R 6 , R 7 , and R 8 each independently represents a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted cycloalkyl group, and Linker represents a bond to a linker), the following formula (I-3): 【Chemistry 32】 [In the formula, R is represented by the following formula: 【Transformation 33】 (Wherein, ring A is a C4-8 membered aliphatic ring, a C3-6 cycloalkylene, or (CH 2 ) 1-4 wherein ring B is an optionally substituted aryl ring or an optionally substituted heteroaryl ring containing a nitrogen atom. ), and Linker is a bond to a linker. ], the following formula (I-4): 【Transformation 34】 wherein each Y is independently H or a C alkyl group; X is CH, O, or N; and R 1 is H, a methyl group, or a hydroxymethyl group, and L is a bond to a linker.), the following formula (I-5), the following formula (I-6), the following formula (I-7): 【Chemistry 35】 (wherein each Y independently represents H or a C1-3 alkyl group, X represents CH, O, or N, and L represents a bond to a linker), or the following formula (I-8): 【Transformation 36】 wherein each Y is independently H or a C1-3 alkyl group, and each X is independently CH 2 , O, NH, or NR (R is a C1-3 alkyl group) (wherein X may join together to form a ring), R 1 is H, a methyl group, or a hydroxymethyl group, and L is a bond to the linker, although L may also be bonded to X.

24. The compound of claim 23, which is an IAP represented by the formula: or a pharmaceutically acceptable salt thereof.

27. The compound according to any one of claims 3 to 14, or a pharmaceutically acceptable salt thereof, wherein the E3 ligase binder (E) is a CRBN binder selected from the group consisting of thalidomide, lenalidomide, pomalidomide, their isomers, and their derivatives.

28. The CRBN binder has the following formula (C1-C6): 【Chemistry 37】 (Wherein W is CH ２ , CHR, C=O, SO ２ , NH, or an N-alkyl group, and each X is independently O, S, or H. ２ Y represents CH ２ , -C=CR', NH, N-alkyl group, N-aryl group, N-heteroaryl group, N-cycloalkyl group, N-heterocyclyl group, O or S, and Z is O, S or H ２ G and G' each independently represent H, an alkyl group, OH, R'OCOOR, R'OCONRR'', or CH optionally substituted with R'. ２ -heterocyclyl group or benzyl group optionally substituted with R', and Q １ , Q ２ , Q ３ , Q ４ represents a carbon substituted with R', N, or N-oxide; A represents H, an optionally substituted alkyl group, a cycloalkyl group, Cl, or F; R represents CONR'R'', -OR', -NR'R'', -SR', -SO 2 R', -S0 2 NR'R'', -CR'R''-, -CR'NR'R''-, aryl group, hetaryl group, alkyl group, cycloalkyl group, heterocyclyl group, -P(0)(OR')R'', -P(0)R'R'', -OP(0)(OR')R'', -OP(0)R'R'', halogen atom, trifluoromethyl group 、 Cyano group, -NR'S0 2 NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N-CN)NR'R'', -NR'C(=N-CN)R'', -NR'C(=C-N0 2 )NR'R'', -S0 2 NR'COR'', nitro group 、 -C0 2 R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=0)(C=N-R')R'', pentafluorosulfanyl group, or trifluoromethoxy group; R' and R'' each independently represent a bond, H, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted heterocycle, an optionally substituted -C(=O)R, or an optionally substituted heterocyclyl group; a wavy line indicates that the bond is stereospecific ((R) or (S)) or non-stereospecific; and Rn each independently represent 1 to 4 functional groups or atoms, where n=1 indicates a bond to a linker, or where n is 2, 3, or 4, one of the functional groups or atoms indicates a bond to a linker.

29. The E3 ligase binder (E) has the following formula (V1): 【Transformation 38】 [In the formula, W 21 is an optionally substituted aryl group, an optionally substituted heteroaryl group, or a group represented by the following formula: 【Chemistry 39】 (In the formula, R 65 , R 66 each independently represents hydrogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted heteroaryl group, or R 65 , R 66 and together with the carbon atom to which they are attached form an optionally substituted cycloalkyl group, R 67 represents an optionally substituted heterocyclyl group, an optionally substituted alkoxy group, an optionally substituted heteroaryl group, an optionally substituted aryl group, a group represented by the following formula: 【Chemistry 40】 where R 68 represents H or an optionally substituted alkyl group, and R 69 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkylcarbonyl group, an optionally substituted (cycloalkyl)alkylcarbonyl group, an optionally substituted aralkylcarbonyl group, an optionally substituted arylcarbonyl group, an optionally substituted (heterocyclyl)carbonyl group, or an optionally substituted aralkyl group; R 70 each independently represents a halogen atom, an optionally substituted alkoxy group, a cyano group, an optionally substituted alkyl group, a haloalkyl group, a haloalkoxy group, or a bond to a linker, and p represents 0 to 3. 70 indicates a bond to a linker, then p=1. 61 , R 62 each independently represents a hydrogen atom or an optionally substituted alkyl group; W 22 represents a benzene ring or a 5- to 10-membered heteroaryl ring, and R 63 is H, halogen atoms, OH, NO 2 , N.R. 61 R 62 , OR 62 ,CONR 61 R 62 , N.R. 61 COR 62、 SO 2 NR 61 R 62 , N.R. 61 SO 2 R 62 , an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocyclyl group; R 64 represents a hydrogen atom, a halogen atom, an optionally substituted alkyl group, a hydroxy group, an optionally substituted alkoxy group, or a bond to a linker, and o is 0, 1, 2, 3, or 4. 64 represents a bond to a linker, then o=1.] or a pharmaceutically acceptable salt thereof.

30. The compound according to any one of claims 3 to 14, or a pharmaceutically acceptable salt thereof, wherein the E3 ligase binder (E) is an MDM2 binder selected from the group consisting of imidazoline derivatives, spiroindolinone derivatives, pyrrolidone derivatives, piperidinone derivatives, morpholinone derivatives, pyrrolopyrimidine derivatives, imidazolopyridine derivatives, thiazol-1imidazoline derivatives, pyrrolopyrrolidinone derivatives, and isoquinolinone derivatives.

31. The E3 ligase binder (E) has the following formula: 【Chemistry 41】 (wherein X represents a halogen atom or a cyano group, R represents a hydrogen atom or a methyl group, and Y represents a sulfonamide or CH 2 NH, and L indicates a bond to the linker. The compound according to any one of claims 3 to 14, which is a DCAF15 binder selected from the group consisting of compounds represented by the formula: and derivatives thereof, or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical comprising the compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof.

33. The pharmaceutical agent according to any one of claims 32, which is an IRAK-M protein degradation inducer.

34. The pharmaceutical agent according to claim 32 or 33, which is a preventive or therapeutic agent for cancer.

35. The pharmaceutical agent according to any one of claims 32 to 34, which is used in combination with another anticancer agent.

36. A method for inducing IRAK-M proteolysis, comprising administering to a patient in need of treatment an effective amount of the compound of any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof.

37. A method for preventing or treating cancer, comprising administering to a patient in need thereof an effective amount of the compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof.

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