Heterocyclic compound

Abstract

Provided are novel heterocyclic compounds having an effect of inducing the degradation of IRAK-M protein and expected to be useful for the prevention and treatment of cancers, fibrosis, infectious diseases, etc., and pharmaceuticals containing the same. According to the present invention, there is provided a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, wherein the above IRAK-M conjugate (M) is represented by the following formula (II), [In formula (II), Y is CH or N, R 01 is H or Me, R 03 is a group represented by the following structural formula BB, (wherein, * represents the bonding position to O, ** represents the bonding position to A, and n is an integer of 0 to 2.), A is a group represented by the following structural formula CC or *-SO 2 -*, (wherein R 05 are each independently a hydrogen atom or a C1-6 alkyl group), R 04 is any group represented by the following structural formula DD, a C1-6 alkylene group which may be substituted, a C3-10 cycloalkylene group which may be substituted, a C6-14 arylene group which may be substituted or a bonding bond, (wherein, * represents the bonding position to A, ** represents the bonding position to the linker.), and the arrow represents the bond to the linker (L).].

Description

Technical Field

[0001] The present invention relates to a heterocyclic compound having an action of inducing degradation of interleukin-1 receptor-associated kinase-M (IRAK-M) protein and expected to be useful for prevention and treatment of cancer, fibrosis, infectious diseases, etc., and a pharmaceutical product containing the same. Background Art

[0002] For the purpose of treatment based on the reduction of disease-related proteins, attempts have been made to develop compounds that utilize E3 ligases to induce ubiquitination and proteasomal degradation of target proteins (sometimes referred to as Proteolysis Targeting Chimeras (PROTAC) or Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Eraser (SNIPER), etc.). (Non-Patent Documents 1 to 9). IRAK-M is one of the IRAK family of protein kinases and is a pseudokinase without kinase activity (Non-Patent Document 10). IRAK-M exists downstream of all Toll-like Receptors (TLRs) except TLR3 and is a protein that 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 limited to a part of epithelial cells including bile duct epithelial cells, lung epithelial cells, and intestinal epithelial cells, and immune cells, especially myeloid cells. IRAK-M plays an important role in maintaining immune homeostasis such as the induction of endotoxin tolerance by negatively controlling TLR-mediated inflammatory cytokine induction signals in innate immune active cells such as macrophages and dendritic cells (Non-Patent Document 12). It has been reported that IRAK-M contributes to immunosuppression of tumor-associated macrophages, myeloid-derived immunosuppressive cells, and dendritic cells in the tumor microenvironment, thus participating in cancer proliferation (Non-Patent Documents 13 to 15). In addition, it has been reported that IRAK-M acts on its phagocytic ability, antibacterial defense ability, collagen production promotion ability, etc. in alveolar macrophages, and is also related to fibrosis, asthma, secondary infection after sepsis, infectious complications of hematopoietic stem cell transplantation (Non-Patent Documents 16 to 18), etc. Therefore, a compound that induces the degradation of IRAK-M by linking an X-Linked Inhibitor of Apoptosis Protein (XIAP) conjugate, which is one type of E3 ligase, to an IRAK-M conjugate with a linker can be a promising therapeutic agent for cancer, fibrosis, infectious diseases, and IRAK-M protein-related diseases.

[0003] Compounds as IRAK-M protein degradation inducers are reported in Patent Document 1.

[0004] Compounds as IRAK (especially IRAK-4) protein degradation inducers are reported in Patent Documents 2 and 3.

[0005] Compounds that induce proteolysis using IAP conjugates have been reported in Patent Documents 4 to 16.

[0006] Compounds having the structure of N-(piperidin-4-yl)thieno[3,2-d]pyrimidin-4-amine or N-(piperidin-4-yl)thieno[3,2-b]pyridin-7-amine have been reported in Patent Documents 17 to 20.

[0007] Prior Art Documents

[0008] Patent Documents

[0009] Patent Document 1: International Publication No. 2017 / 211924

[0010] Patent Document 2: International Publication No. 2019 / 099926

[0011] Patent Document 3: International Publication No. 2019 / 133531

[0012] Patent Document 4: International Publication No. 2018 / 066545

[0013] Patent Document 5: Japanese Patent Application Laid-Open No. 2013-056837

[0014] Patent Document 6: International Publication No. 2016 / 169989

[0015] Patent Document 7: International Publication No. 2016 / 172134

[0016] Patent Document 8: International Publication No. 2017 / 011590

[0017] Patent Document 9: International Publication No. 2017 / 182418

[0018] Patent Document 10: International Publication No. 2017 / 201449

[0019] Patent Document 11: U.S. Patent Application Publication No. 2018 / 0118733 Specification

[0020] Patent Document 12: U.S. Patent Application Publication No. 2018 / 0134688 Specification

[0021] Patent Document 13: International Publication No. 2018 / 119448

[0022] Patent Document 14: International Publication No. 2018 / 119357

[0023] Patent Document 15: U.S. Patent Application Publication No. 2019 / 0119271 Specification

[0024] Patent Document 16: US Patent Application Publication No. 2019 / 0175612 Specification

[0025] Patent Document 17: WO 2016 / 040330

[0026] Patent Document 18: WO 2013 / 019966

[0027] Patent Document 19: US Patent Application Publication No. 2013 / 0040957 Specification

[0028] Patent Document 20: Chinese Patent Application Publication No. 103242341 Gazette

[0029] Non-Patent Literature

[0030] Non-Patent Literature 1: Science, Mar 17, 2017; 355(6330): 1163 - 1167

[0031] Non-Patent Literature 2: Cell Chem Biol, Jan 18, 2018; 25(1): 67 - 77.e3

[0032] Non-Patent Literature 3: Cell Chem Biol, Sep 21, 2017; 24(9): 1181 - 1190

[0033] Non-Patent Literature 4: ACS Chem Biol, Apr 21, 2017; 12(4): 892 - 898

[0034] Non-Patent Literature 5: Cell Chem Biol, Jan 18, 2018; 25(1): 78 - 87.e5

[0035] Non-Patent Literature 6: Nat Rev Drug Discov, Feb 2017; 16(2): 101 - 114

[0036] Non-Patent Literature 7: Nat Chem Biol, Aug 2015; 11(8): 611 - 7

[0037] Non-Patent Literature 8: Chemistry & Biology, 2010, 17(6): 551 - 555

[0038] Non-Patent Literature 9: Chembiochem, 2005, 6(1): 40 - 46

[0039] Non-Patent Literature 10: J Biol Chem, Jul 2, 1999; 274(27): 19403 - 19410

[0040] Non-Patent Document 11: Cell, Jul 26, 2002; 110(2): 191-202

[0041] Non-Patent Document 12: Infect Dis Rep, Jan 1, 2010; 2(1). pii: e9

[0042] Non-Patent Document 13: Oncogene, May 26, 2011; 30(21): 2475-2484

[0043] Non-Patent Document 14: J Immunol, Oct 1, 2010; 185(7): 4223-4232

[0044] Non-Patent Document 15: Mol Immunol, Jul 2007; 44(14): 3453-3461

[0045] Non-Patent Document 16: J Immunol, Feb 15, 2015; 194(4): 1894-1904

[0046] Non-Patent Document 17: J Clin Invest, Sep 2006; 116(9): 2532-2542, Epub Aug 17, 2006

[0047] Non-Patent Document 18: J Immunol, Jun 1, 2010; 184(11): 6299-6308 Summary of the Invention

[0048] Problems to be Solved by the Invention

[0049] An object of the present invention is to provide a novel heterocyclic compound having an IRAK-M protein degradation-inducing effect and expected to be useful for the prevention and treatment of cancers, fibrosis, infectious diseases, etc., and a pharmaceutical containing the same.

[0050] Means for Solving the Problems

[0051] The present inventors conducted intensive studies to discover an IRAK-M protein degradation inducer, and as a result, found that the compound represented by the following formula has excellent IRAK-M protein degradation-inducing activity and is useful for the prevention and treatment of cancers, fibrosis, infectious diseases, etc., and thus completed the present invention.

[0052] That is, the present invention is as follows.

[0053] [1] A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof,

[0054] [Chemical Formula 1]

[0055]

[0056] [2] The compound or a pharmaceutically acceptable salt thereof according to [1] above, wherein the above IRAK-M conjugate (M) is represented by the following formula (II),

[0057] [Chemical formula 2]

[0058]

[0059] [In the formula, Y is CH or N, R 01 is H or Me, R 03 is a group represented by the following structural formula,

[0060] [Chemical formula 3]

[0061]

[0062] (Here, * represents the bonding position to O, ** represents the bonding position to A, and n is an integer from 0 to 2.), A is a group represented by the following structural formula or *-SO 2 -*,

[0063] [Chemical formula 4]

[0064]

[0065] (Here, R 05 are each independently a hydrogen atom or a C1-6 alkyl group.),

[0066] R 04 is any group represented by the following structural formula, a C1-6 alkylene group which may be substituted, a C3-10 cycloalkylene group which may be substituted, a C6-14 arylene group which may be substituted or a bonding bond,

[0067] [Chemical formula 5]

[0068]

[0069] (Here, * represents the bonding position to A, ** represents the bonding position to the linker.),

[0070] The arrow represents the bond to the linker (L).].

[0071] [3] The compound or a pharmaceutically acceptable salt thereof according to [2] above, wherein the above IRAK-M conjugate (M) is represented by the following formula (III),

[0072] [Chemical formula 6]

[0073]

[0074] [In the formula, Y is CH or N, and R 01 is H or Me, and A 01 is a group represented by the following structural formula or *-SO 2 -*,

[0075] [Chemical formula 7]

[0076]

[0077] (Here, R 05 are each independently a hydrogen atom or a C1-6 alkyl group),

[0078] R 11 is any group represented by the following structural formula,

[0079] [Chemical formula 8]

[0080]

[0081] (Here, * represents the bonding position to A 01 and ** represents the bonding position to the linker.).

[0082] The arrow represents the bond to the linker (L).].

[0083] [4] The compound according to [2] above, wherein the above IRAK-M conjugate (M) is a monovalent group derived from a compound selected from the following compounds,

[0084] 5-((4-(Thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol,

[0085] 5-((4-((2-Methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)methyl)isoxazol-3-ol,

[0086] 1-methyl-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)-1H-pyrazol-3-ol, and

[0087] 4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol.

[0088] [5] The compound according to any one of [1] to [4] above or a pharmaceutically acceptable salt thereof, wherein the linker (L) is a group having 5 to 20 carbon atoms which may contain a heteroatom.

[0089] [6] The compound according to any one of [1] to [4] above or a pharmaceutically acceptable salt thereof, wherein the linker (L) is a group represented by the following structural formula, *-(CH 2 CH 2 O)n(CH 2 )m(NRCO)s(CH 2 )t-*, or a bonding bond,

[0090] [Chemical Formula 9]

[0091]

[0092] (Here, * represents the bond to the IRAK-M conjugate (M).)

[0093] (n is a natural number from 1 to 5, m is 0, 1 or 2, s is 0 or 1, t is 0 or 1, and R represents a hydrogen atom or a C1-6 alkyl group.).

[0094] [7] The compound according to any one of [1] to [6] above or a pharmaceutically acceptable salt thereof, wherein the E3 ligase conjugate (E) is represented by the following formula (IV),

[0095] [Chemical Formula 10]

[0096]

[0097] [In the formula, R 01 , R 02 , R 03 , R 04 , R 05 , R06 , R 07 and R 08 Each independently represents a hydrogen atom or a C1-6 alkyl group which may form a ring with each other,

[0098] D is the following formula (V) or the following formula (VI),

[0099] [Chemical formula 11]

[0100]

[0101] (wherein, m represents an integer of 0 to 2, n represents an integer of 0 to 2, W 11 represents methylene, difluoromethylene, 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 or a C1-6 alkylsulfonyl group, and T represents a C1-3 alkyl group which may be halogenated. ),

[0102] [Chemical formula 12]

[0103]

[0104] (wherein, Q represents an oxygen atom, 21 -(Formula-NR 21 -R in 21 represents a hydrogen atom, or a C1-6 alkyl group, or a C1-6 alkyl group that can form a ring together with P. ) or a bonding bond, P represents a hydrogen atom, a C1-6 alkyl group, or a bond to the linker (L) (the bond to the linker (L) includes a bond that forms a ring together with Q and is bonded to the linker (L)). ),

[0105] E is the following formula (VII) or the following formula (VIII),

[0106] [Chemical formula 13]

[0107]

[0108] (R in the formula 21 , R 22 , R 23 Each independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an optionally substituted carbamoyl group, R 25 , R 26 Each independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, an optionally substituted carbamoyl group, or a bond to the linker (L). 24 represents a hydrogen atom, a methyl group, or a bond to a linker (L). 24 , R25 or R 26 any one of).

[0109] [Chemical Formula 14]

[0110]

[0111] (wherein R 31 , R 32 , R 33 , R 34 , R 35 each independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or a carbamoyl group that may be substituted, and R represents a hydrogen atom, a C1-6 alkyl group, or a bond to the linker (L)). Either D or E is bonded to the linker (L).].

[0112] [8] The compound according to any one of the above [1] to [7] or a pharmaceutically acceptable salt thereof, wherein the E3 ligase conjugate (E) is represented by the following formula (IV),

[0113] [Chemical Formula 15]

[0114]

[0115] [wherein, R 01 , R 02 , R 03 , R 04 , R 05 , R 06 , R 07 and R 08 each independently represents a hydrogen atom or a methyl group,

[0116] D is the following formula (V-1) or the following formula (VI-1),

[0117] [Chemical Formula 16]

[0118]

[0119] (wherein, W 11 represents a methylene group or a difluoromethylene group.).

[0120] [Chemical Formula 17]

[0121]

[0122] (wherein, Q represents a bond to the linker (L)).

[0123] E is the following formula (VII) or the following formula (VIII),

[0124] [Chemical Formula 18]

[0125]

[0126] (In the formula, R 21 , R 22 , R 23 each independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a C1-6 alkoxy group, and R 25 , R 26 each independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a bond to the linker (L), and R 24 represents a hydrogen atom, a methyl group, or a bond to the linker (L). Among them, the bond to the linker (L) is any one of R 24 , R 25 or R 26 .),

[0127] [Chemical Formula 19]

[0128]

[0129] (In the formula, R 31 , R 32 , R 33 , R 34 , R 35 each independently represents a hydrogen atom, a halogen atom, or a C1-6 alkyl group, and R represents a hydrogen atom, a C1-6 alkyl group, or a bond to the linker (L).), Either D or E is bonded to the linker (L).].

[0130] [9] The compound according to [1] above or a pharmaceutically acceptable salt thereof, wherein the above IRAK-M conjugate (M) is represented by the following formula (III),

[0131] [Chemical Formula 20]

[0132]

[0133] [In the formula, Y is CH or N, R 01 is H or Me, A 01 is *-CH 2 -* or *-SO 2 -*, and R 11 represents any group shown by the following structural formula,

[0134] [Chemical Formula 21]

[0135]

[0136] (Here, * represents the bonding position to A, and ** represents the bonding position to the linker.),

[0137] The arrow indicates the bond to the linker (L).

[0138] The linker (L) is a group represented by the structural formula described below, *-(CH 2 CH 2 O)n(CH 2 )m(NRCO)s(CH 2 )t-*, or a bonding bond,

[0139] [Chemical formula 22]

[0140]

[0141] (Here, * indicates the bond to the IRAK-M conjugate (M).)

[0142] (n is a natural number from 1 to 5, m is 0, 1 or 2, s is 0 or 1, t is 0 or 1, and R represents a hydrogen atom or a C1-6 alkyl group.),

[0143] The E3 ligase conjugate (E) is represented by the following formula (IV),

[0144] [Chemical formula 23]

[0145]

[0146] [In the formula, R 01 , R 02 , R 03 , R 04 , R 05 , R 06 , R 07 and R 08 each independently represent a hydrogen atom or a methyl group, D is the following formula (V-2) or the following formula (VI-1),

[0147] [Chemical formula 24]

[0148]

[0149] [Chemical formula 25]

[0150]

[0151] (In formula (VI-1), Q represents the bond to the linker (L).),

[0152] E is the following formula (VII) or the following formula (VIII),

[0153] [Chemical formula 26]

[0154]

[0155] (In the formula, R 21 , R 22 , R 23 each independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a C1-6 alkoxy group, and R 25 , R 26 each independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a bond to the linker (L), and R 24 represents a hydrogen atom, a methyl group, or a bond to the linker (L). Among them, the bond to the linker (L) is any one of R 24 , R 25 or R 26 .),

[0156] [Chemical Formula 27]

[0157]

[0158] (In the formula, R 31 , R 32 , R 33 , R 34 , R 35 each independently represents a hydrogen atom, a halogen atom, or a C1-6 alkyl group, and R represents a hydrogen atom or a bond to the linker (L).), Either D or E is bonded to the linker (L).].

[0159]

[10] The compound or its pharmaceutically acceptable salt according to [1] above, which is selected from the following Compounds 1 to 11,

[0160] Compound 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 (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),

[0161] [Chemical Formula 28]

[0162]

[0163] Compound 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 (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),

[0164] [Chemical Formula 29]

[0165]

[0166] Compound 3: 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]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperazin-1-yl)ethan-1-one),

[0167] [Chemical Formula 30]

[0168]

[0169] Compound 4: (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,

[0170] [Chemical Formula 31]

[0171]

[0172] Compound 5: (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,

[0173] [Chemical Formula 32]

[0174]

[0175] Compound 6: (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),

[0176] [Chemical Formula 33]

[0177]

[0178] Compound 7: (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),

[0179] [Chemical Formula 34]

[0180]

[0181] Compound 8: (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),

[0182] [Chemical Formula 35]

[0183]

[0184] Compound 9: (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),

[0185] [Chemical Formula 36]

[0186]

[0187] Compound 10: (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),

[0188] [Chemical Formula 37]

[0189]

[0190] , and

[0191] Compound 11: (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

[0192] [Chemical Formula 38]

[0193]

[0194]

[11] A pharmaceutical product, which contains the compound described in any one of the above [1] to

[10] or a pharmaceutically acceptable salt thereof.

[0195]

[12] The pharmaceutical product according to the above

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

[0196]

[13] The pharmaceutical product according to the above

[11] or

[12] , which is a prophylactic or therapeutic agent for cancer.

[0197]

[14] The pharmaceutical product according to any one of the above

[11] to

[13] , which is used in combination with other anticancer agents.

[0198]

[15] A method for inducing TRAK-M protein degradation, which is characterized by administering an effective amount of the compound described in any one of the above [1] to

[10] or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

[0199]

[16] A method for preventing or treating cancer, which is characterized by administering an effective amount of the compound described in any one of the above [1] to

[10] or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

[0200] Effects of the Invention

[0201] The compounds of the present invention have the activity of inducing the degradation of IRAK-M protein and can be used as prophylactic or therapeutic agents for cancer, fibrosis, and infectious diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0202] Figure 1 Using a Lewis lung cancer cell inoculation model, the compounds of Examples 1, 6, 7, 8, and 9 were subcutaneously administered 3 times every 3 days, and the daily changes in tumor size in each group were confirmed. Each compound used the salt shown in the figure. The figure represents the mean ± standard error. DETAILED DESCRIPTION OF THE INVENTION

[0203] Hereinafter, by way of illustrative embodiments, the compounds of the present invention, their manufacturing methods, and uses will be described using preferred methods and materials that can be used in the implementation of the present invention. It should be noted that unless otherwise specified in the text, all technical terms and scientific terms used in this specification have the same meaning as those commonly understood by those skilled in the technical field to which the present invention belongs. In addition, any materials and methods equivalent or identical to those described in this specification can be equally used in the implementation of the present invention. In addition, all publications and patents cited in this specification in connection with the invention described herein, such as publications and patents indicating methods, materials, etc. that can be used in the present invention, constitute a part of this specification.

[0204] It should be noted that in this specification, the description of the numerical range "A to B" means a numerical range including A and B as endpoints. The same applies to "A through B".

[0205] In this specification, "Me" means methyl, unless otherwise clearly indicated by the context.

[0206] In this specification, when naming compounds such as substituents, common names are sometimes used instead of formal names, but they refer to the same compound.

[0207] Hereinafter, the definitions of each substituent used in this specification will be described in detail. Unless otherwise specified, each substituent has the following definitions.

[0208] In this specification, examples of the "halogen atom" include fluorine, chlorine, bromine, and iodine.

[0209] In this specification, examples of the "C1-3 alkyl" include methyl, ethyl, propyl, isopropyl, and cyclopropyl.

[0210] In this specification, examples of the "C1-3 alkyl group that can be halogenated" include C1-3 alkyl groups 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, 2,3-difluorocyclopropyl.

[0211] In this specification, examples of the "C1-6 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, cyclohexyl.

[0212] In this specification, examples of the "C1-6 alkyl group that can be halogenated" include C1-6 alkyl groups that can have 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, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl.

[0213] In this specification, examples of the "C2-6 alkenyl group" include vinyl, 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, 5-hexenyl.

[0214] In this specification, examples of the "C1-6 alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl.

[0215] In this specification, examples of the "C6-14 aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl.

[0216] In this specification, examples of the "C6-14 arylene group" include a phenylene group, 1,5-naphthylene group, 1,4-naphthylene group, 2,3-naphthylene group, 1,8-anthrylene group, and 9,10-anthrylene group.

[0217] In this specification, examples of the "C1-6 alkoxy group" include a methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, and hexyloxy group.

[0218] In this specification, examples of the "hydrocarbon group" (including the "hydrocarbon group" in the "optionally substituted hydrocarbon group") include a C1-3 alkyl group, C1-6 alkyl group, C1-6 alkylene group, C2-6 alkenyl group, C6-14 aryl group, and C6-14 arylene group. In this specification, examples of the "optionally substituted hydrocarbon group" include a hydrocarbon group having a substituent selected from the following substituent group A.

[0219] [Substituent group A]

[0220] (1) A halogen atom,

[0221] (2) A C1-3 alkyl group,

[0222] (3) A C1-6 alkoxy group,

[0223] (4) An amino group.

[0224] The number of the above 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 substituents may be the same or different.

[0225] In this specification, examples of the "optionally substituted C1-6 alkylene group" or "optionally substituted C3-10 cycloalkylene group" include a C1-6 alkylene group or C3-10 cycloalkylene group that may have a substituent selected from the above substituent group A (halogen atom, C1-3 alkyl group, C1-6 alkoxy group, and amino group). The number of the above substituents is, for example, 1 to 5. When the number of substituents is 2 or more, the substituents may be the same or different.

[0226] In this specification, examples of the "optionally substituted C6-14 aryl group" or "optionally substituted C6-14 arylene group" include a C6-14 aryl group or C6-14 arylene group that may have a substituent selected from the above substituent group A (halogen atom, C1-3 alkyl group, C1-6 alkoxy group, and amino group). The number of substituents is, for example, 1 to 3. When the number of substituents is 2 or more, the substituents may be the same or different.

[0227] In this specification, examples of the "carbamoyl group that can be substituted" include: a carbamoyl group that can have "one or two substituents selected from C1-6 alkyl, C2-6 alkenyl, and C3-10 cycloalkyl, each of which can have 1 to 3 substituents selected from the substituent group A (halogen atom, C1-3 alkyl, C1-6 alkoxy, and amino)".

[0228] In this specification, examples of the "C1-6 alkylene group" include methylene, 1,2-ethylene, 1,1-ethylene, 1,2-propylene, 1,3-propylene, 2,2-propylene, 1,4-butylene, 1,2-butylene, 1,3-butylene, 2,2-butylene, 1,5-pentylene, 3,3-pentylene, and 1,6-hexylene.

[0229] In this specification, examples of the "C3-10 cycloalkylene group" include 1,1-cyclopropylene, cis-1,2-cyclopropylene, trans-1,2-cyclopropylene, 1,1-cyclobutylene, cis-1,2-cyclobutylene, trans-1,2-cyclobutylene, cis-1,3-cyclobutylene, trans-1,3-cyclobutylene, 1,1-cyclopentylene, cis-1,2-cyclopentylene, trans-1,2-cyclopentylene, cis-1,3-cyclopentylene, trans-1,3-cyclopentylene, 1,1-cyclohexylene, cis-1,2-cyclohexylene, trans-1,2-cyclohexylene, cis-1,3-cyclohexylene, trans-1,3-cyclohexylene, cis-1,4-cyclohexylene, trans-1,4-cyclohexylene, 1,1-cycloheptylene, 1,1-cyclooctylene, 2,2-dimethyl-1,1-cyclopropylene, 2,3-dimethyl-1,1-cyclopropylene, 2,2,3,3,4,4-tetramethyl-1,1-cyclobutylene, 7,7-norcaranylene group, 7,7-norpinanylene group, and 7,7-norbornanylene group.

[0230] In this specification, a "linker" refers to a chemical moiety (structure) used to bind a part of a target compound to another compound. Exemplary linkers are described in this specification. For example, in any of the compounds described in this specification, a chemical structure used to bind one part of its structure to another part can be used as a linker, which corresponds to the linker described in this specification.

[0231] In this specification, the "group having 5 to 20 carbon atoms that can contain a heteroatom" refers to a C5-20 straight-chain or branched-chain alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, or alkylaryl group that can contain at least one heteroatom selected from N and O, and groups bonded to the same carbon atom can bond together to form a ring.

[0232] In this specification, the "bonding bond" indicates a state in which two adjacent groups are bonded by a single bond via the bonding bond. Additionally, when multiple "bonding bonds" are connected, it indicates a state in which all of them are bonded to each other by single bonds.

[0233] Hereinafter, each symbol in formula (II) will be described.

[0234] Y is CH or N, preferably CH.

[0235] R 01 is H or Me, preferably H.

[0236] The arrow indicates the bond to the linker (L).

[0237] R 03 is a group represented by the following structural formula,

[0238] [Chemical formula 39]

[0239]

[0240] (Here, * represents the bonding position to O, ** represents the bonding position to A, and n is an integer from 0 to 2), and most preferably is a group represented by the following structural formula,

[0241] [Chemical formula 40]

[0242]

[0243] (Here, * represents the bonding position to O, ** represents the bonding position to A.).

[0244] A is a group represented by the following structural formula or *-SO 2 -*,

[0245] [Chemical formula 41]

[0246]

[0247] (Here, R 05 are each independently a hydrogen atom or a C1-6 alkyl group.), preferably *-CH 2 -* or *-SO 2 -*.

[0248] R 04 is any group represented by the following structural formula, a C1-6 alkylene group that can be substituted, a C3-10 cycloalkylene group that can be substituted, a C6-14 arylene group that can be substituted, or a bonding bond,

[0249] [Chemical formula 42]

[0250]

[0251] (Here, * represents the bonding position with A, and ** represents the bonding position with the linker.), and is preferably any group represented by the above structural formula.

[0252] As R 04 For the "substituents" of the "optionally substituted C1-6 alkylene group", "optionally substituted C3-10 cycloalkylene group", and "optionally substituted C6-14 arylene group" shown, substituents selected from the above substituent group A can be cited. The number of substituents is, for example, 1 to 3. When the number of substituents is 2 or more, the substituents may be the same or different.

[0253] Hereinafter, each symbol in formula (IV) will be described.

[0254] R 01 、R 02 、R 03 、R 04 、R 05 、R 06 、R 07 and R 08 each independently represents a hydrogen atom or a C1-6 alkyl group that can form a ring with each other, preferably each independently represents a hydrogen atom or a C1-6 alkyl group, more preferably each independently represents a hydrogen atom or a C1-3 alkyl group, and still more preferably each independently represents a hydrogen atom or a methyl group.

[0255] Either D or E is bonded to the linker (L).

[0256] D is represented by the following formula (V) or the following formula (VI),

[0257] [Chemical formula 43]

[0258]

[0259] (In formula (V), m represents an integer of 0 to 2, n represents an integer of 0 to 2, and W 11 represents a methylene group, a difluoromethylene group, O, S, SO, SO 2 or NR, where R represents a hydrogen atom, a C1-6 alkyl group, a C1-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, or a C1-6 alkylsulfonyl group, and T represents a C1-3 alkyl group that can be halogenated.),

[0260] [Chemical formula 44]

[0261]

[0262] (In formula (VI), Q represents an oxygen atom, the formula -NR 21 -(in the formula -NR 21 - the R in21 represents a hydrogen atom, or a C1-6 alkyl group, an alkyl group that can form a ring together with P.) or a bonding bond, and P represents a hydrogen atom, a C1-6 alkyl group or a bond with the linker (L) (the bond with the linker (L) includes a bond that forms a ring together with Q and is bonded to the linker (L)).).

[0263] D is preferably the following formula (V-2) or the following formula (VI-1),

[0264] [Chemical formula 45]

[0265]

[0266] [Chemical formula 46]

[0267]

[0268] (In formula (VI-1), Q represents a bond to the linker (L).).

[0269] The above D can be bonded to the linker (L) at P and Q in formula (VI), or at Q in formula (VI-1).

[0270] E is the following formula (VII) or the following formula (VIII),

[0271] [Chemical formula 47]

[0272]

[0273] (R in formula (VII) 21 , R 22 , R 23 each independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or a carbamoyl group that can be substituted. Preferably, R 21 , R 22 , R 23 each independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a C1-6 alkoxy group. R 25 , R 26 each independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a carbamoyl group that can be substituted, or a bond to the linker (L). Preferably, R 25 , R 26 each independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or a bond to the linker (L). R 24 represents a hydrogen atom, a methyl group, or a bond to the linker (L). Among them, the bond to the linker (L) is any one of R 24 , R 25 or R 26 .)

[0274] [Chemical Formula 48]

[0275]

[0276] (R in formula (VIII) 31 , R 32 , R 33 , R 34 , R 35 each independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or a carbamoyl group that may be substituted. Preferably, R 31 , R 32 , R 33 , R 34 , R 35 each independently represents a hydrogen atom, a halogen atom, or a C1-6 alkyl group, and R represents a hydrogen atom, a C1-6 alkyl group, or a bond to the linker (L).).

[0277] Hereinafter, the linker (L) of formula (I) will be described.

[0278] The linker (L) is preferably a group having 5 to 20 carbon atoms that may contain a heteroatom, more preferably a group represented by the following structural formula, *-(CH 2 CH 2 O)n(CH 2 )m(NRCO)s(CH 2 )t-*(n is a natural number from 1 to 5, m is 0, 1 or 2, s is 0 or 1, t is 0 or 1, and R represents a hydrogen atom or a C1-6 alkyl group.) or a bonding bond,

[0279] [Chemical Formula 49]

[0280]

[0281] Even more preferably, it is a group represented by the following structural formula or *-(CH 2 CH 2 O)n-*(n is a natural number from 1 to 5.).

[0282] [Chemical Formula 50]

[0283]

[0284] (Here, * represents a bond to the IRAK-M conjugate (M).).

[0285] In this specification, the "compound with additional functions" refers to any conjugate of a protein present in an organism, a cell-penetrating peptide (CPP), or a kinetophore (e.g., short-chain peptides, sugars, and polyethylene oxide capped with quaternary ammonium, etc.) that retains the compound in the intestine.

[0286] In this specification, the "IRAK-M protein-related disease" means: a disorder or disease that is explained or speculated based on the correlation with the IRAK-M protein itself or its abnormal control. Abnormalities of the protein may include, but are not limited to, abnormal expression, overexpression, and the presence of mutant proteins in the organism.

[0287] The compound of the present invention contained in compound (I) can be used as a synthetic intermediate in the production of other compounds (I) of the present invention. Additionally, it can also be used as a synthetic intermediate in the production of IRAK-M protein degradation-inducing drugs other than compound (I).

[0288] When compound (I) is a salt, such salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. Preferred 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. Preferred examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, methylpyridine, 2,6-dimethylpyridine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc. Preferred examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Preferred 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. Preferred examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc., and preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.

[0289] Among them, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, inorganic salts such as alkali metal salts (e.g., sodium salts, potassium salts, etc.) and alkaline earth metal salts (e.g., calcium salts, magnesium salts, etc.), and ammonium salts can be mentioned. Additionally, when the compound has a basic functional group, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., or 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. can be mentioned.

[0290] Hereinafter, the method for producing the compound of the present invention will be described. In each step of the following production methods, the raw materials, reagents, and the obtained compounds may each form salts. Examples of such salts include the same salts as those of the compound of the present invention described above, etc.

[0291] When the compound obtained in each step is a free compound, it can be converted into the target salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted into a free form or another type of salt as the target by a method known per se.

[0292] The compounds obtained in each step can also be directly obtained in the form of a reaction solution or in the form of a crude product and then used in subsequent reactions. Alternatively, the compounds obtained in each step can be separated and / or purified from the reaction mixture by separation methods such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc. according to conventional methods.

[0293] When the compounds of the raw materials and reagents in each step are commercially available, the commercially available products can be directly used.

[0294] In the reactions of each step, the reaction time may vary depending on the reagents and solvents used. In the absence of special description, it is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

[0295] In the reactions of each step, the reaction temperature may vary depending on the reagents and solvents used. In the absence of special description, it is usually -78°C to 300°C, preferably -78°C to 150°C.

[0296] In the reactions of each step, the pressure may vary depending on the reagents and solvents used. In the absence of special description, it is usually 1 atmosphere to 20 atmospheres, preferably 1 atmosphere to 3 atmospheres.

[0297] In the reactions of each step, for example, a microwave synthesis apparatus such as Initiator manufactured by Biotage may sometimes be used. The reaction temperature may vary depending on the reagents and solvents used. In the absence of special description, it is usually room temperature to 300°C, preferably 50°C to 250°C. The reaction time may vary depending on the reagents and solvents used. In the absence of special description, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.

[0298] In the reactions of each step, unless otherwise specified, reagents can be used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate. When using a reagent as a catalyst, the reagent can be used in an amount of 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalent, relative to the substrate. When the reagent also serves as the reaction solvent, the amount of the reagent can be the amount of the solvent.

[0299] In the reactions of each step, unless otherwise specified, these reactions are carried out without solvent or with the substrate dissolved or suspended in a suitable solvent. Specific examples of the solvent include the solvents described in the examples or the following solvents.

[0300] Alcohols: methanol, ethanol, tert-butanol, 2-methoxyethanol, etc.;

[0301] Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.;

[0302] Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.;

[0303] Saturated hydrocarbons: cyclohexane, hexane, etc.;

[0304] Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.;

[0305] Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.;

[0306] Nitriles: acetonitrile, etc.;

[0307] Sulfoxides: dimethyl sulfoxide, etc.;

[0308] Aromatic organic bases: pyridine, etc.;

[0309] Acid anhydrides: acetic anhydride, etc.;

[0310] Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.;

[0311] Inorganic acids: hydrochloric acid, sulfuric acid, etc.;

[0312] Esters: ethyl acetate, etc.;

[0313] Ketones: acetone, methyl ethyl ketone, etc.;

[0314] Water.

[0315] Two or more of the above solvents can be used in an appropriate ratio.

[0316] When using a base in the reactions of each step, for example, the following bases or the bases described in the examples can be used.

[0317] Inorganic bases: sodium hydroxide, magnesium hydroxide, etc.;

[0318] Alkaline salts: sodium carbonate, calcium carbonate, sodium bicarbonate, etc.;

[0319] 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.

[0320] Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc.;

[0321] Alkali metal hydrides: sodium hydride, etc.

[0322] Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.

[0323] Organic lithium: n-butyl lithium, etc.

[0324] When an acid or an acidic catalyst is used in the reaction of each step, for example, the acids and acidic catalysts shown below or the acids and acidic catalysts described in Examples can be used.

[0325] Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.;

[0326] Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.;

[0327] Lewis acid: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ferric chloride, etc.

[0328] Unless otherwise specified, the reactions in each step can be carried out according to methods well-known per se, for example, those described in the 5th Edition of the Experimental Chemistry Lectures, Volumes 13 to 19 (edited by the Chemical Society of Japan); the New Experimental Chemistry Lectures, Volumes 14 to 15 (edited by the Chemical Society of Japan); Revised Precise Organic Chemistry, 2nd Edition (L.F. Tietze, Th. Eicher, Nankodo); Revised Organic Name Reactions, Their Structures and Key Points (in Japanese: Kaitei Yuki Jinmei Hannou Sono Shikumi to Point) (written by Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume I to VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (written by Jie Jack Li, published by OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Volumes 1 to 14 (Elsevier Japan K.K.); Organic Synthesis Strategies Learned from Name Reactions (in Japanese: Jinmei Hannou ni Manabu Yuki Gousei Senryaku) (translated and supervised by Kiyoshi Tomioka, published by Kagaku Doujin); Comprehensive Organic Transformations (VCH Publishers Inc.), published in 1989, etc., or the methods described in the examples.

[0329] In each step, the protection or deprotection reactions of functional groups can be carried out according to methods well-known per se, for example, those described in "Protective Groups in Organic Synthesis, 4th Ed." (written by Theodora W. Greene, Peter G.M. Wuts), published by Wiley-Interscience in 2007; "Protecting Groups 3rd Ed." (written by P.J. Kocienski), published by Thieme in 2004, etc., or the methods described in the examples.

[0330] Examples of protecting groups for hydroxyl groups such as alcohols and phenolic hydroxyl groups include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylic acid ester-type protecting groups such as acetate; sulfonic acid ester-type protecting groups such as methanesulfonate; and carbonate ester-type protecting groups such as tert-butyl carbonate.

[0331] As a protecting group for the carbonyl group of an aldehyde, for example, acetal-type protecting groups such as dimethyl acetal can be cited; cyclic acetal-type protecting groups such as cyclic 1,3-dioxane, etc.

[0332] As a protecting group for the carbonyl group of a ketone, for example, ketal-type protecting groups such as dimethyl ketal can be cited; cyclic ketal-type protecting groups such as cyclic 1,3-dioxane; oxime-type protecting groups such as o-methyl oxime; hydrazone-type protecting groups such as N,N-dimethyl hydrazone, etc.

[0333] As a protecting group for a carboxyl group, for example, ester-type protecting groups such as methyl ester can be cited; amide-type protecting groups such as N,N-dimethyl amide, etc.

[0334] As a protecting group for a thiol, for example, ether-type protecting groups such as benzyl thioether can be cited; ester-type protecting groups such as thioacetate, thiocarbonate, thiocarbamate, etc.

[0335] As a protecting group for an amino group, imidazole, pyrrole, indole and other aromatic heterocycles, for example, the following can be cited: carbamate-type protecting groups such as benzyl carbamate; amide-type protecting groups such as acetamide; alkylamine-type protecting groups such as N-tritylmethylamine, sulfonamide-type protecting groups such as methanesulfonamide, etc.

[0336] The removal of the protecting group can be carried out by methods known per se, for example, methods using acids, bases, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylhalosilanes (such as trimethyl iodide silane, trimethyl bromide silane), reduction methods, etc.

[0337] In each step, when a reduction reaction is carried out, as the reducing agent used, the following can be cited: metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, tetramethylammonium triacetoxyborohydride; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane, etc. When reducing a carbon-carbon double bond or triple bond, there is a method using a catalyst such as palladium-carbon, Lindlar catalyst, etc.

[0338] In each step, when an oxidation reaction is carried out, examples of the oxidizing agent used include: peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, tert-butyl hydroperoxide; perchlorates such as tetrabutylammonium perchlorate; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodic acids such as sodium periodate; hypervalent iodine reagents such as iodobenzene dichloride; manganese-containing reagents such as manganese dioxide, potassium permanganate; lead compounds such as lead tetraacetate; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide·pyridine complex; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), etc.

[0339] In each step, when a radical cyclization reaction is carried out, examples of the radical initiator used include: azo compounds such as azobisisobutyronitrile (AIBN); water-soluble radical initiators such as 4,4'-azobis-4-cyanovaleric acid (ACPA); triethylboron in the presence of air or oxygen; benzoyl peroxide, etc. In addition, examples of the radical reaction reagent used include tributylstannane, tris(trimethylsilyl)silane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, etc.

[0340] In each step, when a Wittig reaction is carried out, examples of the Wittig reagent used include alkylidene phospholanes (Japanese: アルキリデンホスホラン), etc. Alkylidene phospholanes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

[0341] In each step, when a Horner-Emmons reaction is carried out, examples of the reagent used include: phosphonyl acetate esters such as methyl dimethylphosphonylacetate, ethyl diethylphosphonylacetate; bases such as alkali metal hydrides, organolithiums, etc.

[0342] In each step, when a Friedel-Crafts reaction is carried out, examples of the reagent used include a combination of a Lewis acid and an acyl chloride, or a combination of a Lewis acid and an alkylating agent (such as haloalkanes, alcohols, olefins, etc.). Alternatively, an organic acid or an inorganic acid can be used instead of the Lewis acid, and an acid anhydride such as acetic anhydride can be used instead of the acyl chloride.

[0343] In each step, when an aromatic nucleophilic substitution reaction is carried out, as the reagent, a nucleophile (such as amines, imidazole, etc.) and a base (such as basic salts, organic bases, etc.) can be used.

[0344] In each step, in the case of performing a nucleophilic addition reaction using a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) using a carbanion, or a nucleophilic substitution reaction using a carbanion, examples of the base used to generate the carbanion include organolithiums, metal alkoxides, inorganic bases, organic bases, and the like.

[0345] In each step, in the case of performing a Grignard reaction, examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide; alkylmagnesium halides such as methylmagnesium bromide. The Grignard reagent can be prepared by a method known per se. For example, using an ether or tetrahydrofuran as a solvent, reacting an alkyl halide or an aryl halide with metallic magnesium.

[0346] In each step, in the case of performing a Knoevenagel condensation reaction, as reagents, an active methylene compound (such as malonic acid, diethyl malonate, malononitrile, etc.) sandwiched between two electron-withdrawing groups and a base (such as organic bases, metal alkoxides, inorganic bases) can be used.

[0347] In each step, in the case of performing a Vilsmeier-Haack reaction, as reagents, phosphoryl chloride and an amide derivative (such as N,N-dimethylformamide, etc.) can be used.

[0348] In each step, in the case of performing an azidation reaction of alcohols, alkyl halides, or sulfonic acid esters, examples of the azidating agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide, etc. For example, in the case of azidating an alcohol, there are methods using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), methods using trimethylsilyl azide and a Lewis acid, etc.

[0349] In each step, in the case of performing a reductive amination reaction, examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid, etc. In the case where the substrate is an amine compound, examples of the carbonyl compound used include aldehydes such as acetaldehyde in addition to paraformaldehyde, and ketones such as cyclohexanone. In the case where the substrate is a carbonyl compound, examples of the amine used include primary amines such as ammonia and methylamine; secondary amines such as dimethylamine, etc.

[0350] In each step, in the case of performing a Mitsunobu reaction, as reagents, azodicarboxylates (such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate, etc.) and triphenylphosphine can be used.

[0351] In each process, in the case of carrying out an esterification reaction, an amidation reaction, or a ureation reaction, examples of the reagents used include: acyl halides such as acyl chlorides and acyl bromides; activated carboxylic acids such as acid anhydrides, active ester bodies, and sulfate ester bodies. Examples of 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); diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-tris(dimethylamino)phosphonium salt (BOP reagent); 2-chloro-1-methylpyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl halocarbonates such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorin-2,4,6-trioxide (T3P); or a combination thereof, etc. In the case of using a carbodiimide-based condensing agent, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) can be further added to the reaction.

[0352] In each process, in the case of carrying out a coupling reaction, examples of the metal catalysts used include: palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (Japanese: ジクロロビス(トリエチルホスフィン)パラジウム(II)), palladium(II) acetate, etc. palladium compounds; 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; platinum compounds, etc. An alkali can also be added to the reaction, and examples of such an alkali include inorganic bases and basic salts, etc.

[0353] In each process, in the case of carrying out a thiocarbonylation reaction, as the thiocarbonylating agent, phosphorus pentasulfide can typically be used, but in addition to phosphorus pentasulfide, reagents having a 1,3,2,4-dithiaphosphetane-2,4-disulfide structure such as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiaphosphetane-2,4-disulfide (Lawesson reagent) can also be used.

[0354] In each step, in the case of performing the Wohl-Ziegler reaction, examples of the halogenating agent used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfonyl chloride, and the like. In addition, by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction, the reaction can be accelerated.

[0355] In each step, in the case of performing the halogenation reaction of a hydroxyl group, examples of the halogenating agent used include hydrohalic acids and acyl halides of inorganic acids. Specifically, in the case of chlorination, examples include hydrochloric acid, thionyl chloride, phosphoryl chloride, etc.; in the case of bromination, examples include 48% hydrobromic acid, etc. In addition, a method of obtaining a haloalkane from an alcohol by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide can also be used. Alternatively, a method of synthesizing a haloalkane through a two-step reaction of converting an alcohol into a sulfonate ester and then reacting with lithium bromide, lithium chloride, or sodium iodide can also be used.

[0356] In each step, in the case of performing the Arbuzov reaction, examples of the reagents used include: haloalkanes such as ethyl bromoacetate; phosphite esters such as triethyl phosphite and tris(isopropyl) phosphite.

[0357] In each step, in the case of performing the sulfonation reaction, examples of the sulfonylating agent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, etc.

[0358] In each step, in the case of performing a hydrolysis reaction, an acid or a base can be used as the reagent. In addition, in the case of performing an acid hydrolysis reaction of a tert-butyl ester, formic acid, triethylsilane, etc. are sometimes added to reductively capture the by-produced tert-butyl cation.

[0359] In each step, in the case of performing a dehydration reaction, examples of the dehydrating agent used include sulfuric acid, phosphorus pentoxide, phosphoryl chloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid, etc.

[0360] In each step, in the case of performing an alkylation reaction of an alcohol, an amine, or an aromatic heterocycle having an NH group in the ring (such as imidazole, pyrazole), examples of the alkylating agent include: a haloalkane that can be substituted (such as iodomethane) or an alkyl group that can be substituted and has a C1-6 alkylsulfonyloxy group that can be substituted as a leaving group, or an alkyl group that can be substituted and has a C6-14 arylsulfonyloxy group that can be substituted with a C1-6 alkyl group, or sodium 2-chloro-2,2-difluoroacetate, 2,2-difluoro-2-(fluorosulfonyl)acetic acid, etc. In addition, examples of the base used include organolithiums, metal alkoxides, inorganic bases, organic bases, etc.

[0361] In each step, when a fluorination reaction is carried out, examples of the fluorinating agent used include DAST (diethylaminosulfur trifluoride), bis(2-methoxyethyl)aminosulfur trifluoride, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor), 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (FLUOLEAD), and the like.

[0362] In each step, when a Huisgen reaction is carried out, an azide compound and an alkyne compound can be used as the reagents used. Examples of the catalyst include monovalent copper ions such as copper iodide, copper chloride, and copper cyanide.

[0363] In each step, when a coupling reaction is carried out, examples of the coupling reaction include Suzuki coupling, Stille coupling, Buchwald-Hartwig coupling, Negishi coupling, Mizoroki-Heck reaction, a cyanation reaction using copper cyanide or zinc cyanide, and the like. Reagents such as metal catalysts, phosphine ligands, and bases used in the coupling reaction can be used by methods known per se (for example, the methods described in J.F. Hartwig, S. Shekhar, Q. Shen, F. Barrios-Landeros, in The Chemistry of Anilines, Z. Rappoport, Ed., Wiley-Interscience, 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, New York (2002); J.F. Hartwig, in Modern Amination Methods, A. Ricci, Ed., Wiley-VCH, Weinheim, (2000)) or methods based on them.

[0364] Hereinafter, the production method of the compound (I) will be described.

[0365] Unless otherwise specified, each symbol in the following reaction formulas represents the same meaning as above. In the case where the specific preparation method is not described, the starting compounds can be easily obtained as commercially available products, or can be prepared by methods known per se or methods based thereon and the methods described in the examples.

[0366] When carrying out the reactions of each step, in the case where there are reactive sites where reactions other than the target reaction occur, a protecting group can be introduced into the reactive sites in advance by methods known per se as needed, and the protecting group can still be removed by methods known per se after carrying out the target reaction. For example, when the starting compounds and intermediates have amino, carboxyl or hydroxyl groups as substituents, these groups can be protected by protecting groups commonly used in peptide chemistry and the like. In this case, after the reaction, the protecting group is removed as needed, whereby the target compound can be obtained.

[0367] Compound (I) can be synthesized from compound (1) as an IRAK-M conjugate or compound (4) as an E3 ligase conjugate by the methods shown in the following schemes. In each scheme, compound (I) and each reaction intermediate can independently form salts.

[0368] Scheme 1

[0369] [Chemical formula 51]

[0370]

[0371] Compound (3) can be prepared by subjecting compound (1) or its reactive derivative to an amidation reaction, Mitsunobu reaction, alkylation reaction or coupling reaction with compound (2) or its reactive derivative as a linker (L), and compound (I) can be prepared by subjecting compound (3) or its reactive derivative to an amidation reaction, Mitsunobu reaction, alkylation reaction or coupling reaction with compound (4) or its reactive derivative.

[0372] Compound (5) can be prepared by subjecting compound (4) or its reactive derivative to an amidation reaction, Mitsunobu reaction, alkylation reaction or coupling reaction with compound (2) or its reactive derivative, and compound (I) can be prepared by subjecting compound (5) or its reactive derivative to an amidation reaction, Mitsunobu reaction, alkylation reaction or coupling reaction with compound (1) or its reactive derivative.

[0373] Compound (3a) can be prepared by subjecting compound (1) or its reactive derivative to an amidation reaction, Mitsunobu reaction, alkylation reaction, or coupling reaction with compound (2a) or its reactive derivative. Compound (5a) can be prepared by subjecting compound (4) or its reactive derivative to an amidation reaction, Mitsunobu reaction, alkylation reaction, or coupling reaction with compound (2b) or its reactive derivative. Compound (I) can be prepared by subjecting compound (3a) and compound (5a) or their reactive derivatives to an amidation reaction, Mitsunobu reaction, alkylation reaction, coupling reaction, or Huisgen reaction, etc.

[0374] Hereinafter, a method for producing the IRAK-M conjugate (M) (compound (1)) represented by the following formula (II) which is a part of compound (I) will be described.

[0375] Scheme 2

[0376] [Chemical formula 52]

[0377]

[0378] In Scheme 2, X 1 represents a halogen atom or a leaving group.

[0379] Compound (8) can be prepared by subjecting compound (6) to an aromatic nucleophilic substitution reaction or a coupling reaction with compound (7), etc.

[0380] Compound (II) can be prepared by subjecting compound (8) to an alkylation reaction, sulfonylation reaction, or reductive amination reaction with compound (9) or its reactive derivative.

[0381] L (compound (2)), which is a linker (L) that is a part of compound (I), L 1 (compound (2a)), L 2 (compound (2b)) can be directly used as a commercially available product, or can be prepared by a method known per se or a method based thereon.

[0382] Hereinafter, a method for producing the case where E (compound (4)) in the E3 ligase conjugate which is a part of compound (I), namely the XIAP conjugate, is a compound represented by the following formula (IV-I) will be described.

[0383] Scheme 3

[0384] [Chemical formula 53]

[0385]

[0386] Compound (12) can be produced by subjecting Compound (10) to an amidation reaction with Compound (11) or a reactive derivative thereof, and Compound (14) can be produced by subjecting Compound (12) to an amidation reaction with Compound (13) or a reactive derivative thereof.

[0387] Compound (IV-I) can be produced by subjecting Compound (14) to an amidation reaction with Compound (15) or a reactive derivative thereof.

[0388] In addition, compound (16) can be prepared by subjecting compound (10) to an amidation reaction with compound (15) or a reactive derivative thereof, and compound (17) can be prepared by subjecting compound (16) to an amidation reaction with compound (11) or a reactive derivative thereof. Compound (IV-I) can be prepared by subjecting compound (17) to an amidation reaction with compound (13) or a reactive derivative thereof.

[0389] Next, the production method in the case where E (compound (4)) is a compound represented by the following formula (IV-II) is described.

[0390] Process 4

[0391] [Chemical formula 54]

[0392]

[0393] Compound (18) can be produced by subjecting Compound (16) and Compound (17) to an amidation reaction, and Compound (IV-II) can be produced by subjecting Compound (18) and Compound (19) to an alkylation reaction.

[0394] In addition, compound (20) can be prepared by subjecting compound (10) to an amidation reaction with compound (17), and compound (21) can be prepared by subjecting compound (20) to an alkylation reaction with compound (19). Compound (IV-II) can be prepared by subjecting compound (21) to an amidation reaction with compound (22) or a reactive derivative thereof.

[0395] By converting the substituents in the compound (I) and the intermediates thus obtained (i.e., introduction of substituents, functional group conversion) by a method known per se, other compounds contained in the compound (I) and the corresponding intermediates or salts thereof can be produced.

[0396] The compound (I) obtained by the above production method can be isolated and purified by a known method, such as solvent extraction, solution pH conversion, phase transfer (Japanese: 廢溶), crystallization, recrystallization, and chromatography.

[0397] When the compound (I) contains optical isomers, stereoisomers, positional isomers, or rotamers, they are also included as the compound (I) and can be obtained in the form of single products by synthetic methods and separation methods known per se. For example, when the compound (I) has optical isomers, the optical isomers resolved from the compound are also included in the compound (I).

[0398] Here, the optical isomers can be produced by methods known per se.

[0399] The compound (I) can be a crystal.

[0400] The crystal of the compound (I) (hereinafter sometimes simply referred to as the crystal of the present invention) can be produced by crystallizing the compound (I) by applying a crystallization method known per se.

[0401] The compound (I) can be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, the cocrystal or cocrystal salt refers to a crystalline substance composed of two or more unique solids at room temperature, each having different physical properties (such as structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). The cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.

[0402] The compound (I) can be a hydrate, an anhydrate, a solvate-free compound, or a solvate.

[0403] In addition, the deuterium conversion product obtained by converting 1 H to 2 H(D) is also included in the compound (I).

[0404] The compound (I) can be labeled with isotopes (such as 3 H, 13 C, 14 C, 18 F, 35 S, 125 I), etc. The compound (I) labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) used in positron emission tomography (PET) and is expected to be useful in the field of medical diagnosis and the like.

[0405] The compound (I) can be used as a prodrug.

[0406] The prodrug of compound (I) is a compound that is converted into compound (I) under physiological conditions in a living body, i.e., a compound that is converted into compound (I) through enzymatic oxidation, reduction, hydrolysis, etc., or a compound that is converted into compound (I) through hydrolysis caused by gastric acid, etc.

[0407] Examples of the prodrug of compound (I) include: compounds obtained by acylating, alkylating, or phosphorylating the amino group of compound (I) (e.g., compounds obtained by eicosanoylating, alanylating, pentylaminocarbonylating, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylating, tetrahydrofuranylating, pyrrolidinylmethylating, pivaloyloxymethylating, or tert-butylating the amino group of compound (I)); compounds obtained by acylating, alkylating, phosphorylating, or borylating the hydroxyl group of compound (I) (e.g., compounds obtained by acetylating, palmitoylating, propionylating, pivaloylating, succinylating, fumaroylating, alanylating, or dimethylaminomethylcarbonylating the hydroxyl group of compound (I)); compounds obtained by esterifying or amidating the carboxyl group of compound (I) (e.g., compounds obtained by ethylating, phenylating, carboxymethylating, dimethylaminomethyl esterifying, pivaloyloxymethyl esterifying, ethoxycarbonyloxyethylating, phthalidyl esterifying, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl esterifying, cyclohexyloxycarbonylethylating, or methylamidating the carboxyl group of compound (I)), etc. These compounds can be prepared from compound (I) by methods known per se.

[0408] In addition, the prodrug of compound (I) can be a prodrug that is converted into compound (I) under physiological conditions as described in "Drug Development", Volume 7, Molecular Design, pages 163 - 198, published by Hirokawa Shoten in 1990.

[0409] In this specification, the prodrug can form a salt, and examples of such salts include the substances exemplified as the salts of the compound represented by the above formula (I).

[0410] Compound (I) can be used by linking it with a compound having an appended function, such as a cell-penetrating peptide (CPP) or a kinetophore that causes the compound to stay in the intestine (e.g., short-chain peptides, sugars, and polyethylene oxides capped with quaternary ammonium, etc.). Compound (I) can be directly or via a linker bound to a compound having an appended function.

[0411] Compound (I) can also be used as an effector molecule (Japanese: ペイ口ード) (above, the part equivalent to the drug) in an antibody (or peptide antigen recognition sequence)-drug complex. When compound (I) is used as an effector molecule, compound (I) can be bound to the antibody (or peptide antigen recognition sequence) directly or via a linker.

[0412] When compound (I) is used as an effector molecule, in addition to the linkers exemplified in the present specification, linkers 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), International Publication No. 2011 / 005761, etc. can also be used.

[0413] Compound (I) or a prodrug thereof (hereinafter collectively referred to as "compounds of the present invention") has an activity of inducing the degradation of IRAK-M and can be used as a preventive or therapeutic drug for cancer, a cancer growth inhibitor, or a cancer metastasis inhibitor.

[0414] The compounds of the present invention exhibit proteolysis-inducing activity against IRAK-M, and are also excellent in terms of pharmacodynamics, pharmacokinetics (e.g., absorption, distribution, metabolism, excretion), solubility (e.g., water solubility), interaction with other pharmaceuticals (e.g., drug-metabolizing enzyme inhibition), safety (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, central nervous system toxicity), and stability (e.g., chemical stability, stability to enzymes), and therefore can be used as pharmaceuticals. Among them, it is expected to be effective for the treatment or prevention of cancer, but is not limited thereto.

[0415] The compounds of the present invention can also be used as agents having the activity of inducing the degradation of IRAK-M protein in mammals (such as mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans). According to their mechanism of action, they are useful for all diseases related to IRAK-M protein (sometimes simply referred to as "IRAK-M-related diseases" in this specification), such as cancer [e.g., colorectal cancer (such as colon cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor), lung cancer (such as non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (such as pancreatic ductal carcinoma, pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (such as papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), duodenal cancer, small intestine cancer, breast cancer (such as invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer), ovarian cancer (such as ovarian epithelial cancer, extragonadal germ cell tumor, ovarian germ cell tumor, low malignant potential ovarian tumor), testicular cancer, prostate cancer (such as hormone-dependent prostate cancer, non-hormone-dependent prostate cancer, castration-resistant prostate cancer), liver cancer (such as hepatocellular carcinoma, primary liver cancer, extrahepatic bile duct cancer), thyroid cancer (such as medullary thyroid cancer), kidney cancer (such as renal cell carcinoma (such as clear cell renal cell carcinoma), metastatic cell carcinoma in the renal pelvis and ureter), uterine cancer (such as cervical cancer, endometrial cancer, uterine sarcoma), gestational choriocarcinoma, brain tumor (such as medulloblastoma, glioma, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, pituitary adenoma), retinoblastoma, skin cancer (such as basal cell carcinoma, malignant melanoma), sarcoma (such as rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, spindle cell sarcoma), malignant bone tumor, bladder cancer, blood cancer (such as multiple myeloma, leukemia (such as 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] preventive or therapeutic agents, cancer proliferation inhibitors, cancer metastasis inhibitors, apoptosis promoters, therapeutic agents for precancerous lesions (such as myelodysplastic syndrome), etc.

[0416] In addition, as IRAK-M-related diseases other than cancer, the following can be cited: asthma, inflammatory bone disease, inflammatory lung disease, idiopathic pulmonary fibrosis, inflammatory bowel disease (such as 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 distress syndrome (COVID-19, MERS, SARS), acute bacterial meningitis, Helicobacter pylori infection, invasive Staphylococcus infection, tuberculosis, systemic fungal infection, herpes simplex virus infection, varicella-zoster virus infection, human papillomavirus infection, acute viral encephalitis, encephalitis, meningitis, immune function reduction caused by infection, etc.

[0417] The compounds of the present invention can be administered orally or parenterally to mammals (preferably humans) directly or in combination with a pharmaceutically acceptable carrier as a medicine.

[0418] Hereinafter, the medicine containing the compound of the present invention (sometimes abbreviated as "the medicine of the present invention") will be described in detail. As the dosage form of the medicine of the present invention, for example, oral preparations such as tablets (such as sugar-coated tablets, film-coated tablets, sublingual tablets, buccal tablets, rapidly disintegrating tablets in the oral cavity), pills, granules, powders, capsules (such as soft capsules, microcapsules), syrups, emulsions, suspensions, films (such as orally disintegrating films, oral mucosa-adhesive films) can be cited. In addition, as the dosage form of the medicine of the present invention, for example, parenteral preparations such as injections, infusions, transdermal agents (such as iontophoresis transdermal preparations), suppositories, ointments, nasal agents, pulmonary agents, eye drops can also be cited. In addition, the medicine of the present invention can be a controlled release preparation such as an immediate release preparation, a sustained release preparation (such as a sustained release microcapsule).

[0419] As the dosage form of the medicine of the present invention, nanoparticle preparations and preparations using membranes derived from bacteria can also be used.

[0420] The medicine of the present invention can be manufactured by a well-known manufacturing method commonly used in the pharmaceutical technology field (such as the method described in the Japanese Pharmacopoeia). In addition, excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifiers, colorants, preservatives, fragrances, flavoring agents, stabilizers, thickeners and other additives commonly used in the pharmaceutical field can be appropriately and moderately contained in the medicine of the present invention as needed.

[0421] As the above-mentioned pharmaceutically acceptable carrier, these additives can be cited.

[0422] For example, tablets can be manufactured using excipients, binders, disintegrants, lubricants, etc. Pills and granules can be manufactured using excipients, binders, and disintegrants. Additionally, powders and capsules can be manufactured using excipients, etc. Syrups can be manufactured using sweeteners, etc. Emulsions or suspensions can be manufactured using suspending agents, surfactants, emulsifiers, etc.

[0423] Examples of excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, glycyrrhiza powder, mannitol, sodium bicarbonate, calcium phosphate, and calcium sulfate.

[0424] Examples of binders include 5-10 wt% starch paste, 10-20 wt% gum arabic solution or gelatin solution, 1-5 wt% tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, and glycerol.

[0425] Examples of disintegrants include starch and calcium carbonate.

[0426] Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, and purified talc.

[0427] Examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerol, and simple syrup.

[0428] Examples of surfactants include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyethylene oxide 40 stearate.

[0429] Examples of suspending agents include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, and bentonite. Examples of emulsifiers include gum arabic, tragacanth, gelatin, and polysorbate 80.

[0430] For example, when the pharmaceutical of the present invention is a tablet, the tablet can be compression-molded by adding, according to methods known per se, excipients (such as lactose, sucrose, starch), disintegrants (such as starch, calcium carbonate), binders (such as starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose), or lubricants (such as talc, magnesium stearate, polyethylene glycol 6000) to the compound of the present invention, and then, if necessary, coated by methods known per se for the purpose of taste masking, enteric solubility, or sustained release. As the coating agent used in the coating, for example, hydroxypropyl methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxyethyl cellulose acetate succinate, Eudragit (manufactured by ROHM GmbH, Germany, copolymer of methacrylic acid and acrylic acid), and pigments (such as iron oxide red, titanium dioxide) can be used.

[0431] As the above-mentioned injection, in addition to intravenous injections, it also includes subcutaneous injections, intradermal injections, intramuscular injections, intraperitoneal injections, drip injections, etc.

[0432] The injection is prepared by methods known per se, that is, the compound of the present invention is dissolved, suspended, or emulsified in a sterile aqueous liquid or an oily liquid. As the aqueous liquid, physiological saline, isotonic solutions containing glucose and other adjuvants (such as D-sorbitol, D-mannitol, sodium chloride), etc. can be mentioned. This aqueous solution can contain appropriate solubilizers, such as alcohols (such as ethanol), polyols (such as propylene glycol, polyethylene glycol), nonionic surfactants (such as polysorbate 80, HCO-50). As the oily liquid, sesame oil, soybean oil, etc. can be mentioned. This oily liquid can contain appropriate solubilizers. As the solubilizer, benzyl benzoate, benzyl alcohol, etc. can be mentioned. In addition, buffers (such as phosphate buffer, sodium acetate buffer), pain relievers (such as benzalkonium chloride, procaine hydrochloride), stabilizers (such as human serum albumin, polyethylene glycol), preservatives (such as benzyl alcohol, phenol), etc. can be formulated in the injection. The prepared injection can usually be filled into ampoules.

[0433] The content of the compound of the present invention in the pharmaceutical of the present invention varies depending on the form of the preparation, and 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 relative to the whole preparation.

[0434] The content of the additive in the pharmaceutical of the present invention varies depending on the form of the preparation, and is usually about 1 to about 99.9% by weight, preferably about 10 to about 90% by weight relative to the whole preparation.

[0435] The compounds of the present invention are stable and have low toxicity, and can be used safely. The daily dosage of the compounds of the present invention varies depending on the patient's condition, body weight, type of compound, route of administration, etc. For example, when orally administered to a patient for the purpose of treating cancer, the daily dosage for an adult (body weight of 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, in terms of the compounds of the present invention, and they can be administered once or divided into 2 to 3 times.

[0436] When the compounds of the present invention are administered non-orally, they are usually administered in the form of a liquid preparation (such as an injection). The single dosage of the compounds of the present invention varies depending on the administration subject, target organ, symptoms, administration method, etc. For example, usually about 0.01 to about 100 mg, preferably about 0.01 to about 50 mg, and more preferably about 0.01 to about 20 mg of the compounds of the present invention per 1 kg body weight are preferably administered by intravenous injection or subcutaneous injection.

[0437] The compounds of the present invention can be used in combination with other drugs. Specifically, the compounds of the present invention can be used in combination with drugs such as hormone therapy agents, chemotherapy agents, immunotherapy agents, or agents that inhibit the action of cell growth factors and their receptors. Hereinafter, the drugs that can be used in combination with the compounds of the present invention are briefly referred to as concomitant drugs.

[0438] As the "hormone therapy agent", for example, diethylstilbestrol diphosphate, diethylstilbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, raloxifene, ormeloxifene, levormeloxifene, anti-estrogen drugs (such as tamoxifen citrate, toremifene citrate), pill preparations, mepitiostane, dihydrotestolactone, aminoglutethimide, LH-RH agonists (such as goserelin acetate, buserelin, leuprorelin acetate), droloxifene, cyclothiazide, ethinyl estradiol sulfonate, aromatase inhibitors (such as fadrozole hydrochloride, anastrozole, letrozole, exemestane, vorozole, formestane), anti-androgen drugs (such as flutamide, bicalutamide, nilutamide, enzalutamide), 5α-reductase inhibitors (such as finasteride, etisteride, dutasteride), adrenal cortical hormone-based agents (such as dexamethasone, prednisolone, betamethasone, triamcinolone acetonide), androgen synthesis inhibitors (such as abiraterone), retinoids and agents that delay the metabolism of retinoids (such as liarozole), thyroid hormones, and their DDS (Drug Delivery System) preparations.

[0439] As the "chemotherapy agent", for example, alkylating agents, antimetabolites, anticancer antibiotics, and anticancer agents of plant origin can be used.

[0440] As the “alkylating agent”, for example, nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carboquinone, improsulfan toluenesulfonate, busulfan, nimustine hydrochloride, dibromomannitol, melphalan, dacarbazine, ranimustine, estramustine sodium phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etoglu, carboplatin, cisplatin, miplatin, nedaplatin, oxaliplatin, hexamethylmelamine, aminomustine, dibromospironium chloride hydrochloride, fotemustine, prednimustine, puromycin, bendamustine, temozolomide, trofosfamide, nistatins, adolesine, cysteamine nitrosourea, bisezolesine, and DDS preparations thereof can be used.

[0441] As the "anti-metabolite", for example, mercaptopurine, 6-mercaptopurine nucleoside, thioinosine, methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine sodium octadecyl phosphate, ancitabine hydrochloride, 5-FU-based drugs (for example, fluorouracil, tegafur, UFT, doxifluridine, carmofur, galocitabine, imipenem, capecitabine), aminopterin, nelarabine, calcium leucovorin, thioguanine, glycinethiopurine, calcium leucovorin, calcium leucovorin, cladribine, ethiproxil, fludarabine, gemcitabine, hydroxyurea, pentostatin, piroxine, iodoxuridine, mitoxantrone, thiazofurine, aminostine, bendamustine and their DDS preparations can be used.

[0442] As the "anticancer antibiotics", for example, actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocarcinostatis, mithramycin, sarcopeniain, carcinoglucon, mitotane, daunorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and their DDS preparations (e.g., PEG liposomes encapsulating doxorubicin) can be used.

[0443] As the “plant-derived anticancer agent”, for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, cabazitaxel, vinorelbine, and DDS preparations thereof can be used.

[0444] As an "immunotherapeutic agent", for example, picibanil, krestin, schizophyllan, lentinan, bestatin, interferon, interleukin, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacterium parvum, levamisole, Toll-like receptor (TLR) agonist, polysaccharide K, picobenzadazole, anti-CTLA4 antibody (e.g., ipilimumab, tremelimumab), anti-PD-1 antibody (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, sintilimab, toripalimab), anti-PD-L1 antibody (e.g., atezolizumab, avelumab, durvalumab), oncolytic virus can be used.

[0445] As the "cytokine" in the "agent for inhibiting the action of cytokines and their receptors", any substance can be used as long as it is a substance that promotes cell proliferation. Examples include peptides with a molecular weight of usually 20,000 or less and factors that act at low concentrations by binding to receptors. Specifically, the following can be used: (1) EGF (epidermal growth factor) or a substance having substantially the same activity as it [e.g., TGFα], (2) insulin or a substance having substantially the same activity as it [e.g., insulin, IGF (insulin-like growth factor)-1, IGF-2], (3) FGF (fibroblast growth factor) or a substance having substantially the same activity as it [e.g., acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10], (4) other cytokines [e.g., CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGFβ (transforming growth factor β), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), amphiregulin, angiopoietin].

[0446] As the "receptor of cell growth factor", any receptor with the ability to bind to the above-mentioned cell growth factor can be used, specifically, EGF receptor, amphiregulin receptor (such as 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 (such as Tie2), PDGF receptor, etc. can be used.

[0447] As the "agent for inhibiting the action of cell growth factors and their receptors", EGF inhibitors, TGFα inhibitors, amphiregulin 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, FGF receptor-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, etc. can be used. More specifically, anti-VEGF antibodies (such as Bevacizumab, Ramucirumab), anti-HER2 antibodies (such as Trastuzumab, Pertuzumab), anti-EGFR antibodies (such as Cetuximab, Panitumumab, Matuzumab, Nimotuzumab), anti-HGF antibodies, Imatinib, Erlotinib, Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatalanib, Ibrutinib, Bosutinib, 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 phosphate (AZD-1152), 4-[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-ylamino]benzoic acid, Sodium N-[2-Methoxy-5-[(E)-2-(2,4,6-trimethoxyphenyl)vinylsulfonylmethyl]phenyl]glycinate (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, etc.

[0448] In addition to the above drugs, L-asparaginase, L-arginase, arginine deiminase, acetoglucuronide, procarbazine hydrochloride, protoporphyrin-cobalt complex, mercuroporphyrin-sodium, topoisomerase I inhibitors (such as irinotecan, topotecan, indotecan, indimitecan), topoisomerase II inhibitors (such as sobuzoxane), differentiation inducers (such as retinoids, vitamin D), other angiogenesis inhibitors (such as fumagillin, shark extract, COX-2 inhibitors), α-blockers (such as tamsulosin hydrochloride), bisphosphonates (such as pamidronate, zoledronate), thalidomide, lenalidomide, pomalidomide, azacitidine, decitabine, proteasome inhibitors (such as bortezomib, carfilzomib) Anti-tumor antibodies such as rituximab and obinutuzumab, and antibody-drug complexes (such as tocilizumab-emtansine and belentuzumab-vedotin) can also be used as concomitant drugs.

[0449] When the compound of the present invention is used for IRAK-M-related diseases other than cancer, in addition to the above-mentioned concomitant drugs, for example, antibacterial drugs, antifungal drugs, nonsteroidal anti-inflammatory drugs, steroid drugs, bronchodilators, anticoagulants, antiplatelet drugs, thrombolytic drugs, immunomodulators, antiprotozoal drugs, antitussive / expectorants, sedatives, anesthetics, anesthetic antagonists, antiulcer drugs, vitamin drugs, vitamin derivatives, antiallergic drugs, antiasthmatic drugs, therapeutic drugs for atopic dermatitis, signal transduction inhibitors, inflammatory mediator action inhibitors, inflammatory mediator action inhibitory antibodies, inflammatory mediator production inhibitors, anti-inflammatory mediator action inhibitors, anti-inflammatory mediator action inhibitors, anti-inflammatory mediator action inhibitors, anti-inflammatory mediator production inhibitors, anti-fibrotic drugs, α1-adrenergic agonists, antiemetics, methemoglobin increase inhibitors, etc. can be used as concomitant drugs.

[0450] (1) Antimicrobial drugs

[0451] (i) Sulfonamides

[0452] Sulfathiazol, sulfamethoxazole, sulfamethoxazole, sulfamethoxazole, sulfasalazine, silver sulfadiazine, etc.

[0453] (ii) Quinoline antibacterial drugs

[0454] Nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin, etc.

[0455] (iii) Anti-tuberculosis drugs

[0456] Isoniazid, ethambutol (ethambutol hydrochloride), para-aminosalicylic acid (para-aminosalicylic acid calcium), pyrazinamide, ethionamide, prothionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine, etc.

[0457] (iv) Mycobacterial drugs (Japanese: acid-fast drugs)

[0458] Dapsone (Japanese: ジアミノジフェ二ルスルホン), rifampicin.

[0459] (v) Antiviral drugs

[0460] Iodine glucoside, acyclovir, adenosine, ganciclovir, favipiravir, etc.

[0461] (vi) Anti-HIV drugs

[0462] Zidovudine, didanosine, zalcitabine, indinavir sulfate ethanolate, ritonavir, etc.

[0463] (vii) Anti-treponemal drugs

[0464] (viii) Antibiotics

[0465] Tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibekacin, kanamycin, cyanomycin, tobramycin, amikacin, neomycin, sisomicin, tetracycline, oxytetracycline, pyrrolidone methyltetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalosporin, cefapirin, ceftriaxone, cefaclor, cephalexin, cefoxadine, cefadroxil, cefmandole, cefuroxime, ceftiom, ceftiom hexyl axetil, cefuroxime Octyl axetil, cefdinir, cefditoren pivoxil, ceftazidime, cefpiramide, cefsulodin, cefmenoxime, cefpodoxime, cefpirome, cefazolin, cefepime, cefsulodin, cefmenoxime, cefmetazole, cefminox, cefoxitin, cefbuperazone, latamoxef, fluoxetine, cefazolin, cefotaxime, cefoperazone, ceftizoxime, latamoxef, thiamycin, sulfonamide, aztreonam or their salts, griseofulvin, lankacidin, etc.

[0466] (2) Antifungal drugs

[0467] (i) Polyene antibiotics (e.g. amphotericin B, nystatin, trichostatin),

[0468] (ii) Griseofulvin, Pyrrolnitrin, etc.,

[0469] (iii) Cytosine antimetabolites (such as Flucytosine),

[0470] (iv) Imidazole derivatives (such as Econazole, Clotrimazole, Miconazole Nitrate, Bifonazole, Cloconazole),

[0471] (v) Triazole derivatives (such as 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]),

[0472] (vi) Thiocarbamate derivatives (such as Tolnaftate),

[0473] (vii) Echinocandin derivatives (such as Caspofungin, Micafungin, Anidulafungin), etc.

[0474] (3) Non-steroidal anti-inflammatory drugs

[0475] Paracetamol, Phenacetin, Ethylsalicylamide, Analgin, Antipyrine, Migrenin, Aspirin, Mefenamic Acid, Flufenamic Acid, Diclofenac Sodium, Loxoprofen Sodium, Phenylbutazone, Indomethacin, Ibuprofen, Ketoprofen, Naproxen, Oxaprozin, Flurbiprofen, Fenbufen, Pranoprofen, Frovatriptan, Epirizole, Tiaramide Hydrochloride, Zaltoprofen, Gabexate Mesilate, Camostat Mesilate, Ulinastatin, Colchicine, Probenecid, Sulfinpyrazone, Benzbromarone, Allopurinol, Sodium Aurothiomalate, Sodium Hyaluronate, Sodium Salicylate, Morphine Hydrochloride, Salicylic Acid, Atropine, Scopolamine, Morphine, Pethidine, Levorphanol, Ketoprofen, Naproxen, Oxymorphone, Meloxicam, Celecoxib, Rofecoxib or their salts, etc.

[0476] (4) Steroid drugs

[0477] Dexamethasone, Diethylstilbestrol, Methimazole, Betamethasone, Triamcinolone, Triamcinolone Acetonide, Fluocinolone Acetonide, Fluocinonide, Prednisolone, Methylprednisolone, Cortisone Acetate, Hydrocortisone, Fluorometholone, Beclomethasone Dipropionate, Estriol, etc.

[0478] (5) Bronchodilators

[0479] Metaproterenol, Salmeterol, Formoterol, Carmoterol, etc.

[0480] (6) Anticoagulants

[0481] Heparin sodium, sodium citrate, activated protein C, tissue factor pathway inhibitor, antithrombin III, dalteparin sodium, warfarin potassium, argatroban, gabexate, sodium citrate, etc.

[0482] (7) Antiplatelet drugs

[0483] Ozagrel sodium, eicosapentaenoic acid ethyl ester, beraprost sodium, alprostadil, ticlopidine hydrochloride, pentoxifylline, dipyridamole, etc.

[0484] (8) Thrombolytic drugs

[0485] Tiretokinase, urokinase, streptokinase, etc.

[0486] (9) Immunomodulatory drugs

[0487] Cyclosporine, tacrolimus, gurislimus, azathioprine, antilymphoid serum, dried sulfonated immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon, etc.

[0488] (10) Antiprotozoal drugs

[0489] Metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate, etc.

[0490] (11) Antitussive and expectorant drugs

[0491] Ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride, allolamide, chlorhexidine, ethylpiperidone, cloperastine, piperazine, isoproterenol, salbutamol, terbutaline, drotibanol, morphine hydrochloride, dextromethorphan hydrobromide, oxycodone hydrochloride, dimethorphan phosphate, tipedine, vincilin citrate, chlorhexidine hydrochloride, benzonatate, guaifenesin, bisoline, ambroxol hydrochloride, acetylcysteine, ethylcysteine ​​hydrochloride, carboxymethylcysteine, etc.

[0492] (12) Sedatives

[0493] Chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital, amobarbital, pentobarbital, thiopental sodium, thiopental sodium, nitrazepam, estazolam, flurazepam, haloxazolam, triazolam, flunitrazepam, bromisoval, chloral hydrate, sodium trichloroethyl phosphate, etc.

[0494] (13) Anesthetics

[0495] (13-1) Local anesthetics

[0496] Cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, pantocaine hydrochloride, carbocaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, benzocaine, oxethazine) etc.

[0497] (13-2) General anesthetics

[0498] (i) Inhalation anesthetics (such as ether, halothane, nitrous oxide, isoflurane, enflurane)

[0499] (ii) Intravenous anesthetics (such as ketamine hydrochloride, droperidol, thiopental sodium, thiamylal sodium, pentobarbital) etc.

[0500] (14) Anesthetic antagonists

[0501] Levallorphan, nalorphine, naloxone or its salts etc.

[0502] (15) Anti-ulcer drugs

[0503] Metoclopramide, histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, uro-gastrone, oxyethazine, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate, aluminum allantoin, teprenone, prostaglandins etc.

[0504] (16) Vitamins

[0505] (i) Vitamin A group: Vitamin A1, Vitamin A2 and retinol palmitate

[0506] (ii) Vitamin D group: Vitamin D1, D2, D3, D4 and D5

[0507] (iii) Vitamin E group: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, nicotinic acid d1-α-tocopherol

[0508] (iv) Vitamin K group: Vitamin K1, K2, K3 and K4

[0509] (v) Folic acid (Vitamin M)

[0510] (vi) Vitamin B group: Vitamin B1, Vitamin B2, Vitamin B3, Vitamin B5, Vitamin B6 and Vitamin B12

[0511] (vii) Biotin (Vitamin H) etc.

[0512] (17) Vitamin derivatives

[0513] Various derivatives of vitamins, such as ascorbic acid, 5,6-trans-cholecalciferol, 2,5-dihydroxycholecalciferol, vitamin D3 derivatives such as 1-α-hydroxycholecalciferol, and vitamin D2 derivatives such as 5,6-trans-ergocalciferol, etc.

[0514] (18) Antihistamines

[0515] Diphenhydramine, Chlorpheniramine, Tripelennamine, Clomipramine, Dimenhydrinate, Methoxyphenamine, Sodium Cromoglicate, Tranilast, Ripasudil, Amlexanox, Ibudilast, Ketotifen, Terfenadine, Mequitazine, Azelastine, Epinastine, Sodium Ozagrel, Pranlukast Hydrate, Seratrodast, etc.

[0516] (19) Anti-asthma drugs

[0517] Isoprenaline Hydrochloride, Salbutamol Sulfate, Isoetharine Hydrochloride, Terbutaline Sulfate, Tretoquinol Hydrochloride, Tulobuterol Hydrochloride, Orciprenaline Sulfate, Fenoterol Hydrobromide, Ephedrine Hydrochloride, Ipratropium Bromide, Oxybutynin Chloride, Flutropium Bromide, Theophylline, Aminophylline, Sodium Cromoglicate, Tranilast, Ripasudil, Ibudilast, Ketotifen, Terfenadine, Mequitazine, Azelastine, Epinastine, Sodium Ozagrel, Pranlukast Hydrate, Seratrodast, Dexamethasone, Prednisolone, Hydrocortisone, Beclomethasone Dipropionate, etc.

[0518] (20) Drugs for treating atopic dermatitis

[0519] Sodium Cromoglicate, etc.

[0520] (21) Antiemetics

[0521] Phenothiazine derivatives, 5-HT3 receptor antagonists, etc.

[0522] (22) Inhibitors of methemoglobin elevation

[0523] Methylene Blue, Ascorbic Acid, etc.

[0524] (23) Integrin inhibitors

[0525] Natalizumab, Vedolizumab, AJM300, TRK-170, E-6007, etc.

[0526] (24) Anti-fibrotic drugs

[0527] Pirfenidone, Nintedanib, β-Aminopropionitrile (BAPN), Ursodeoxycholic Acid, etc.

[0528] (25) Others

[0529] Hydroxycamptothecin (Japanese: ヒドロキシカンプトテシン), diacerein, megestrol acetate, nicergoline, prostaglandin, etc.

[0530] By combining the compound of the present invention with concomitant drugs, excellent effects such as the following can be obtained, namely, (1) compared with the case of administering the compound of the present invention or the concomitant drug alone, the dosage thereof can be reduced, (2) the drug to be used in combination with the compound of the present invention can be selected according to the symptoms of the patient (mild, severe, etc.), (3) the treatment period can be set longer, (4) the continuity of the treatment effect can be achieved, (5) by combining the compound of the present invention and the concomitant drug, a synergistic effect can be obtained.

[0531] Hereinafter, the case of combining the compound of the present invention and the concomitant drug is referred to as "the combination therapy of the present invention".

[0532] When using the combination therapy of the present invention, the administration time of the compound of the present invention and the concomitant drug is not limited. The compound of the present invention and the concomitant drug can be administered to the administration subject simultaneously, or can be administered with a time difference. In the case of administering with a time difference, the time difference varies depending on the active ingredient, dosage form, and administration method of the drug administered. For example, in the case of first administering the concomitant drug, the compound of the present invention can 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 administering the concomitant drug. In the case of first administering the compound of the present invention, the concomitant drug can 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 administering the compound of the present invention. The dosage of the concomitant drug may be the dosage used clinically, and can be appropriately selected according to the administration subject, administration route, disease, combination, etc.

[0533] As the administration method when combining the compound of the present invention and the concomitant drug, for example, the following can be cited: (1) administration of a single preparation obtained by formulating the compound of the present invention and the concomitant drug simultaneously, (2) simultaneous administration of two preparations obtained by formulating the compound of the present invention and the concomitant drug separately, using the same administration route, (3) administration with a time difference of two preparations obtained by formulating the compound of the present invention and the concomitant drug separately, using the same administration route, (4) simultaneous administration of two preparations obtained by formulating the compound of the present invention and the concomitant drug separately, using different administration routes, (5) administration with a time difference of two preparations obtained by formulating the compound of the present invention and the concomitant drug separately, using different administration routes (for example, administration in the order of the compound of the present invention → concomitant drug, or administration in the reverse order).

[0534] The dosage of the concomitant drug can be appropriately selected based on the dosages used clinically. In addition, the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected according to 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 can be used relative to 1 part by weight of the compound of the present invention.

[0535] In addition, the compound of the present invention or the combination drug of the present invention can be used in combination with non-pharmacological therapies. Specifically, the compound of the present invention or the combination drug of the present invention can be combined with the following non-pharmacological therapies, for example: (1) surgery, (2) pressor chemotherapy using angiotensin II, etc., (3) gene therapy, (4) hyperthermia, (5) cryotherapy, (6) laser cauterization, (7) radiotherapy.

[0536] For example, by using the compound of the present invention or the combination drug of the present invention before or after the above-mentioned surgery, etc., or before or after a treatment combining two or three of these therapies, effects such as preventing the expression of drug resistance, prolonging the disease-free survival period, inhibiting cancer metastasis or recurrence, and prolonging life can be obtained.

[0537] In addition, the treatment using the compound of the present invention or the combination drug of the present invention can also be combined with supportive therapies [(i) administration of antibiotics (such as β-lactams like cefotiam, macrolides like clarithromycin, etc.) for the complication of various infectious diseases, (ii) administration of high-energy infusions, amino acid preparations, and compound vitamin preparations for improving malnutrition, (iii) administration of morphine for relieving pain, (iv) administration of agents for improving side effects such as nausea, vomiting, anorexia, diarrhea, leukopenia, thrombocytopenia, decrease in hemoglobin concentration, hair loss, liver disease, kidney disease, DIC, fever, etc., and (v) administration of agents for inhibiting multiple drug resistance of cancer, etc.].

[0538] Examples

[0539] The present invention will be described in more detail with the following reference examples, examples, test examples, and formulation examples, but these do not limit the present invention, and changes can be made without departing from the scope of the present invention.

[0540] "Room temperature" in the following examples generally means about 10°C to about 35°C. The ratios given in mixed solvents represent volume ratios unless otherwise specified. % represents weight % unless otherwise specified.

[0541] In silica gel column chromatography, when it is described as NH, aminopropylsilyl-bonded silica gel is used, and when it is described as C18, octadecylsilyl-bonded silica gel is used. In HPLC (high performance liquid chromatography), when it is described as C18, octadecylsilyl-bonded silica gel is used. The ratio of the elution solvents represents the volume ratio unless otherwise specified.

[0542] In the following examples, the following abbreviated symbols are used.

[0543] MS: Mass spectrometry

[0544] M: Molar concentration

[0545] DMSO-d 6 : Deuterated dimethyl sulfoxide

[0546] 1 H NMR: Proton nuclear magnetic resonance

[0547] LC / MS: Liquid chromatography mass spectrometry

[0548] ESI: Electrospray ionization

[0549] APCI: Atmospheric pressure chemical ionization

[0550] DCM: Dichloromethane

[0551] DIEA: Diisopropylethylamine

[0552] DMAP: 4-Dimethylaminopyridine

[0553] DMF: N,N-Dimethylformamide

[0554] HATU: 2-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

[0555] TEA: Triethylamine

[0556] THF: Tetrahydrofuran

[0557] TFA: Trifluoroacetic acid

[0558] Measured by Fourier transform type NMR 1 H NMR. Analyses were performed using ACD / SpecManager or MestreNova (trade name), etc. For protons such as hydroxyl and amino groups, the peaks are very broad, and sometimes they are not recorded.

[0559] MS was measured by LC / MS. As the ionization method, the ESI method or the APCI method was used. The data recorded are the measured values (found). Usually, the molecular ion peaks ([M+H] + 、[M-H]- etc.), but in the case of a compound having a tert-butoxycarbonyl group, a peak after removal of the tert-butoxycarbonyl group (Boc) or tert-butyl group (tBu) may sometimes be observed as a fragment ion. In the case of a compound having a carboxyl group or the like, a peak adducted with sodium may sometimes be observed. In addition, in the case of a compound having a hydroxyl group, a peak after removal of water may sometimes be observed as a fragment ion. In the case of a salt, a molecular ion peak or fragment ion peak in the free form is usually observed.

[0560] Optical rotation ([α] D ) The unit of the sample concentration (c) is g / 100 mL.

[0561] The elemental analysis values (Anal.) are recorded as calculated values (Calcd) and found values (Found).

[0562] Example 1

[0563] 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

[0564] A) 7-(Piperidin-4-yloxy)thieno[3,2-b]pyridine dihydrochloride

[0565] To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (14.9 g) and DMF (100 mL) under ice-cooling was added sodium hydride (60%, dispersed in liquid paraffin, 3.0 g). The reaction mixture was stirred for 10 minutes, 7-chlorothieno[3,2-b]pyridine (10.4 g) was added, and the mixture was stirred at 60 °C overnight. 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, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resulting mixture of tert-butyl 4-(thieno[3,2-b]pyridin-7-yloxy)piperidine-1-carboxylate and ethyl acetate (100 mL) was added a 4 M hydrogen chloride / ethyl acetate solution (100 mL). After the reaction mixture was stirred at room temperature for 2 hours, diisopropyl ether (70 mL) was added, and the precipitate was filtered off to obtain the title compound (16.8 g).

[0566] MS: [M+H] + 235.2.

[0567] B) Methyl 3-(allyloxy)isoxazole-5-carboxylate

[0568] To a mixture of methyl 3-hydroxyisoxazole-5-carboxylate (15.0 g), potassium carbonate (17.4 g) and DMF (200 mL) was added 3-bromoprop-1-ene (13.6 mL). The mixture was stirred at 60 °C for 16 h. 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, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (16.6 g).

[0569] MS: [M+H] + 184.3.

[0570] C) (3-(Allyloxy)isoxazol-5-yl)methanol

[0571] 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 h, and the solvent was removed by distillation 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, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to give the title compound (13.2 g).

[0572] MS: [M+H] + 156.3.

[0573] D) (3-(Allyloxy)isoxazol-5-yl)methyl methanesulfonate

[0574] To a mixture of (3-(allyloxy)isoxazol-5-yl)methanol (13.2 g), TEA (24 mL) and THF (200 mL) under ice-cooling was added methanesulfonyl chloride (9.94 mL). The reaction mixture was stirred at room temperature for 1 h, diluted with water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to give the title compound (18.9 g).

[0575] MS: [M+H] + 234.2.

[0576] E) 3-(Allyloxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole

[0577] 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 h. Water was added to the reaction mixture and the mixture was 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 distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (6.25 g).

[0578] MS: [M+H] + 372.2.

[0579] F) (S)-4-(2-((tert-Butoxycarbonyl)amino)-2-cyclohexylacetyl)piperazine-1-carboxylic acid benzyl ester

[0580] To a mixture of (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (2.5 g), piperazine-1-carboxylic acid benzyl ester (2.14 g), DIEA (5.09 mL) and DMF (48.6 mL) at room temperature was added HATU (5.54 g). The reaction mixture was stirred at the same temperature for 6 h. 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 distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (4.34 g).

[0581] MS: [M+H] + 460.2.

[0582] G) (S)-4-(2-Amino-2-cyclohexylacetyl)piperazine-1-carboxylic acid benzyl ester hydrochloride

[0583] To a mixture of (S)-4-(2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)piperazine-1-carboxylic acid benzyl ester (4.34 g) and ethyl acetate (18.9 mL) at room temperature was added 4 M hydrogen chloride / ethyl acetate solution (18.9 mL). The reaction mixture was stirred at 45 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the resulting crude product was recrystallized from ethyl acetate / hexane to give the title compound (2.96 g).

[0584] MS: [M+H] + 360.2.

[0585] H) Benzyl 4-((S)-2-((S)-2-((tert-Butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)piperazine-1-carboxylate

[0586] To a mixture of (S)-2-((tert-Butoxycarbonyl)(methyl)amino)propanoic acid (1.63 g), (S)-4-(2-Amino-2-cyclohexylacetyl)piperazine-1-carboxylate hydrochloride (2.96 g), DIEA (5.22 mL) and DMF (37.4 mL) at room temperature was added HATU (4.26 g). 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 distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.62 g).

[0587] MS: [M+H] + 545.4.

[0588] I) tert-Butyl ((S)-1-(((S)-1-Cyclohexyl-2-oxo-2-(piperazin-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0589] 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 under a hydrogen atmosphere at atmospheric pressure at room temperature for 1 hour. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (2.46 g).

[0590] MS: [M+H] + 411.3.

[0591] J) Methyl 5,6-difluoro-1-methyl-1H-indole-2-carboxylate

[0592] To a mixture of 5,6-difluoro-1H-indole-2-carboxylic acid (20 g) and DMF (200 mL) at room temperature was added potassium carbonate (42.0 g) and methyl iodide (18.9 mL). 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 filtered off and washed with hexane to give the title compound (20 g).

[0593] 1 H NMR (400 MHz, DMSO-d 6) δ 3.85 (3H, s), 3.99 (3H, s), 7.26 (1H, s), 7.70 (1H, dd, J = 8.24 Hz, 10.84 Hz), 7.78 (1H, dd, J = 6.96 Hz, 11.68 Hz).

[0594] K) Methyl 5,6-difluoro-3-formyl-1-methyl-1H-indole-2-carboxylate

[0595] To a mixture of methyl 5,6-difluoro-1-methyl-1H-indole-2-carboxylate (2 g) and DCM (20 mL) at -78 °C was added a 1 M solution of titanium tetrachloride in DCM (17.8 mL) and a mixture of dichloromethyl methyl ether (1.7 mL) and DCM (2 mL). 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 diatomaceous earth, and the filtrate was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (1.9 g).

[0596] 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0597] L) 5,6-Difluoro-3-formyl-1-methyl-1H-indole-2-carboxylic acid

[0598] To a mixture of methyl 5,6-difluoro-3-formyl-1-methyl-1H-indole-2-carboxylate (15 g) in THF (225 mL), methanol (75 mL), and water (75 mL) was added lithium hydroxide monohydrate (3.73 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and adjusted to acidic conditions using aqueous potassium bisulfate. The resulting solid was filtered to give the title compound (13 g).

[0599] MS: [M+H] + 240.1.

[0600] M) 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

[0601] 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). After the reaction mixture was stirred at room temperature for 2 hours, water was added and the mixture was extracted 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 distilled off 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-butanol (90 mL) / water (30 mL) was added sodium chlorite (2.24 g). The reaction mixture was stirred at room temperature overnight, an aqueous solution of sodium thiosulfate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off 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).

[0602] MS: [M+H] + 648.5.

[0603] N)((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

[0604] 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)ethanol (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 distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (3.10 g).

[0605] MS: [M+H] + 793.5.

[0606] O)5-((4-(Thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol

[0607] 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 tetrakis(triphenylphosphine)palladium (884 mg). The reaction mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol), and the resulting compound was washed with ethyl acetate to give the title compound (2.50 g).

[0608] 1 H NMR (300 MHz, DMSO-d 6 ) 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).

[0609] P) ((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)carbamic acid tert-butyl ester

[0610] To a mixture of 5-((4-(Thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol (1.50 g), ((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)carbamic acid tert-butyl ester (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 distilled off 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 (2.37 g).

[0611] MS: [M+H] + 1106.6.

[0612] Q) 2-(4-((S)-2-Cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazin-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

[0613] 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) was added 4 M hydrogen chloride / ethyl acetate solution (16.1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give the title compound (2.16 g).

[0614] 1 H NMR(300MHz, DMSO-d 6 ) 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).

[0615] Example 2

[0616] 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

[0617] A) Methyl 6-methoxy-1-methyl-1H-indole-2-carboxylate

[0618] To a mixture of methyl 6-methoxy-1H-indole-2-carboxylate (11.6 g) and DMF (100 mL) under ice-cooling was added sodium hydride (60%, dispersed in liquid paraffin, 2.93 g). After the reaction mixture was stirred at the same temperature for 15 minutes, methyl iodide (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, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (11.4 g).

[0619] MS: [M+H] + 220.0.

[0620] B) 6-Methoxy-1-methyl-1H-indole-2-carboxylic acid

[0621] To a mixture of methyl 6-methoxy-1-methyl-1H-indole-2-carboxylate (11.4 g) and methanol (100 mL) at room temperature was added 2 M aqueous sodium hydroxide solution (52.0 mL), and the reaction mixture was stirred at 60 °C for 1 hour. After the reaction mixture was cooled under ice-cooling, it was neutralized with 1 M hydrochloric acid (110 mL), and the precipitate was filtered to obtain the title compound (9.87 g).

[0622] MS: [M+H] + 206.0.

[0623] 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 reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled with ice, water was added, and the precipitate was filtered to obtain the title compound (16.8 g).

[0624] MS: [M+H] + 374.1.

[0625] D) tert-Butyl 4-(3-formyl-6-methoxy-1-methyl-1H-indole-2-carbonyl)piperazine-1-carboxylate

[0626] 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) was added (chloromethylene)dimethylammonium chloride (7.13 g), and the reaction mixture was stirred at room temperature for 2 h. Water was added to the reaction mixture, and after stirring for 30 min, 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 distilled off under reduced pressure to give the title compound (10.6 g).

[0627] MS: [M+H] + 402.1.

[0628] E) 6-Methoxy-1-methyl-2-(piperazine-1-carbonyl)-1H-indole-3-carbaldehyde hydrochloride

[0629] 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) was added 4 M hydrogen chloride / ethyl acetate solution (198 mL), and the reaction mixture was stirred at room temperature for 1 h. Diisopropyl ether was added to the reaction mixture, and the precipitate was filtered off and washed with diisopropyl ether to give the title compound (8.1 g).

[0630] MS: [M+H] + 302.0.

[0631] F) ((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)carbamic acid tert-butyl ester

[0632] At room temperature, HATU (3.47 g) was added 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), 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 distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). At room temperature, 4 M hydrogen chloride / ethyl acetate solution (38 mL) was added to a mixture of the resulting product and ethyl acetate (38 mL), and the reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. At room temperature, HATU (4.34 g) was added to a mixture of the resulting (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). 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 distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.12 g).

[0633] MS: [M+H] + 626.3.

[0634] 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

[0635] At room temperature, sodium chlorite (665 mg) was added 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-butanol (29.4 mL) and water (7.4 mL). 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 solution, 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 distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (770 mg).

[0636] MS: [M+H] + 642.4

[0637] H)((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

[0638] 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. Water and ethyl acetate were added to the reaction mixture for dilution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (C18, acetonitrile / 5 mM aqueous ammonium acetate solution) gave the title compound (133 mg).

[0639] MS: [M+H] + 773.5.

[0640] I) tert-butyl 4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate

[0641] 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). After stirring the reaction mixture for 30 minutes, 4-chlorothieno[3,2-d]pyrimidine (2.05 g) was added, and 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 distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.75 g).

[0642] MS: [M+H] + 336.0.

[0643] J) 4-(Piperidin-4-yloxy)thieno[3,2-d]pyrimidine hydrochloride

[0644] 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) was added 4M hydrogen chloride / ethyl acetate solution (55.9 mL). After stirring the reaction mixture for 30 minutes, the solvent was distilled off under reduced pressure. The residue was washed with ethyl acetate to give the title compound (3.25 g).

[0645] 1 H NMR (300 MHz, DMSO-d 6 ) 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).

[0646] K) 4-((4-(Thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol

[0647] 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 distilled off 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 (43.5 mg).

[0648] 1 H NMR (300 MHz, DMSO-d 6)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).

[0649] L) 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

[0650] To a mixture of 4-((4-(Thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol (35.5 mg), ((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 tert-butyl ester (70.0 mg), triphenylphosphine (119 mg) and toluene (0.45 mL) was added di-tert-butyl azodicarboxylate (62.6 mg). The reaction mixture was stirred at room temperature for 2 h and the solvent was distilled off 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, 4M hydrogen chloride / ethyl acetate solution (679 μL) was added, and the mixture was stirred at room temperature for 1 h and the solvent was distilled off 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 distilled off under reduced pressure to give the title compound (19.5 mg).

[0651] 1 H NMR (300 MHz, DMSO-d 6)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).

[0652] Example 3

[0653] 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

[0654] A) 5,6 - difluoro - 1 - methyl - 1H - indole - 2 - carboxylic acid

[0655] 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, the residue was dissolved in water, acidified with an aqueous solution of potassium bisulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.8 g).

[0656] MS: [M - H] + 210.0.

[0657] B) (R)-(5,6 - difluoro - 1 - methyl - 1H - indol - 2 - yl)(3 - methylpiperazin - 1 - yl)methanone

[0658] To a mixture of 5,6 - difluoro - 1 - methyl - 1H - indole - 2 - carboxylic acid (1.8 g) and DMF (45 mL) were added DIEA (4.4 mL), (R)-2 - methyl - piperazine (1.02 g), and HATU (4.8 g). 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 distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol / DCM) to obtain the title compound (1.9 g).

[0659] MS: [M+H] + 294.4.

[0660] (R)-2-chloro-1-(4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperazin-1-yl)ethan-1-one

[0661] Under ice-cooling, triethylamine (1.35 mL) and chloroacetyl chloride (0.6 mL) were added 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). The reaction mixture was stirred at room temperature for 3 hours, diluted with DCM, washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.8 g).

[0662] MS: [M+H] + 370.2.

[0663] D) 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl methanesulfonate

[0664] Under ice-cooling, triethylamine (1.7 mL) and methanesulfonyl chloride (0.77 mL) were added to a mixture of 2-(2-(2-benzyloxyethoxy)ethoxy)ethanol (2 g) and DCM (15 mL). 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 distilled off under reduced pressure to give the title compound (2.5 g).

[0665] 1 1H NMR (400 MHz, CDCl 3 ) 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).

[0666] E) (2R,5R)-4-benzyl-2-methyl-5-(12-phenyl-2,5,8,11-tetraoxadodecyl)piperazine-1-carboxylic acid tert-butyl ester

[0667] To a mixture of tert-butyl (2R,5R)-4-benzyl-5-hydroxymethyl-2-methylpiperazine-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, 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl methanesulfonate (695 mg) was added, and the mixture was further stirred at 60 °C for 4 hours. The reaction mixture was cooled to room temperature, 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl methanesulfonate (556 mg) was added, and the mixture was further stirred at 60 °C for 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, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (900 mg).

[0668] MS: [M+H] + 543.2.

[0669] F) tert-butyl (2R,5R)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperazine-1-carboxylate

[0670] 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 for 16 hours under a hydrogen atmosphere at atmospheric pressure, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. 10% methanol / DCM was added to the residue, the organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (600 mg).

[0671] 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0672] (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-carboxylic acid tert-butyl ester

[0673] To a mixture of (2R,5R)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (592 mg) and THF (15 mL) were added 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), and the mixture was stirred at 60 °C for 24 h. Ethyl acetate was added to the reaction mixture, and after washing successively with water and saturated brine, the organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (740 mg).

[0674] MS: [M+H] + 696.5.

[0675] (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-carboxylic acid tert-butyl ester

[0676] To a mixture of (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-carboxylic acid tert-butyl ester (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 h and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography to give the title compound (26 mg).

[0677] MS: [M+H] + 1008.8.

[0678] 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

[0679] Under ice-cooling, 4M hydrogen chloride / dioxane solution (0.3 mL) was added 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). The reaction mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was washed with ether and pentane to give the title compound (19 mg).

[0680] 1 H NMR (400 MHz, DMSO-d 6 , 100 °C) 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).

[0681] Example 4

[0682] (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

[0683] A) Methyl 5,6-difluoro-3-hydroxy-1-methyl-1H-indole-2-carboxylate

[0684] At 5 - 10 °C, 3-chloroperoxybenzoic acid (5.88 g) and p-toluenesulfonic acid (3.15 g) were added to a mixture of methyl 5,6-difluoro-3-formyl-1-methyl-1H-indole-2-carboxylate (3.5 g) and chloroform (50 mL). 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 it was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, diluted with saturated aqueous sodium bicarbonate, and extracted with DCM. The organic layer was washed with 10% aqueous sodium thiosulfate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (3 g).

[0685] 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.81 (3H, s), 3.82 (3H, s), 7.56 - 7.69 (2H, m), 9.36 (1H, s).

[0686] B) tert-Butyl 4-(5,6-difluoro-3-hydroxy-1-methyl-1H-indole-2-carbonyl)piperazine-1-carboxylate

[0687] Under an argon atmosphere, at room temperature, 2M trimethylaluminum / toluene solution (18.2 mL) was added 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). The reaction mixture was stirred at 100 °C for 3 hours. Water was added to the reaction mixture, the precipitate was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (3 g).

[0688] MS: [M + H] + 393.8.

[0689] C) 2-(2-(2-(Benzyloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate

[0690] Under ice-cooling, triethylamine (4.4 mL), 4-dimethylaminopyridine (1.27 g), and p-toluenesulfonyl chloride (4.8 g) were added to a mixture of 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethanol (5 g) and DCM (100 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and washed successively with water and saturated brine. The organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (5.2 g).

[0691] MS: [M+H] + 395.0.

[0692] D) tert-Butyl 4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperazine-1-carboxylate

[0693] 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). The mixture was stirred at room temperature for 6 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.26 g).

[0694] MS: [M+H] + 618.0.

[0695] E) (3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indol-2-yl)(piperazin-1-yl)methanone hydrochloride

[0696] 4M hydrogen chloride / dioxane solution (2 mL) was added 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) under ice-cooling. The reaction mixture was stirred at room temperature for 4 h and the solvent was distilled off under reduced pressure. The residue was washed with diethyl ether to give the title compound (1 g).

[0697] MS: [M+H] + 517.9.

[0698] (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)carbamic acid tert-butyl ester

[0699] 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 sodium sulfate and the solvent was distilled off under reduced pressure to give the title compound (1.1 g).

[0700] MS: [M+H] + 757.0.

[0701] (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-cyclohexylethane-1-one hydrochloride

[0702] To a mixture of (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)carbamic acid tert-butyl ester (1.1 g) and DCM (10 mL) under ice-cooling was added 4M hydrogen chloride / dioxane solution (10 mL). The reaction mixture was stirred at room temperature for 3 hours, and the solvent was distilled off under reduced pressure to give the title compound (1.1 g).

[0703] MS: [M+H] + 657.2.

[0704] ((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)carbamic acid tert-butyl ester

[0705] At room temperature, DIEA (0.83 mL) was added 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-cyclohexylethane-1-one hydrochloride (1.1 g) and DMF (10 mL). The reaction mixture was stirred for 15 minutes, (S)-2-(tert-butoxycarbonyl-methyl-amino)-propanoic acid (0.323 g) and HATU (0.905 g) were added, and the mixture was stirred 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, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (850 mg).

[0706] MS: [M+H] + 842.1.

[0707] I) ((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)carbamic acid tert-butyl ester

[0708] At room temperature, 10% palladium on carbon (200 mg) was added to a mixture of ((S)-1-(((S)-2-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1H-indole-2-carbonyl)piperazin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamic acid tert-butyl ester (850 mg) and ethanol (10 mL). The mixture was stirred under a hydrogen atmosphere at atmospheric pressure for 3 hours. The reaction mixture was filtered through diatomaceous earth, washed with ethanol, and the filtrate was concentrated under reduced pressure to give the title compound (740 mg).

[0709] MS: [M+H] + 752.6.

[0710] J) ((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)carbamic acid tert-butyl ester

[0711] To a mixture of 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) was added di-tert-butyl azodicarboxylate (36.7 mg). The mixture was stirred at room temperature for 16 h and the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to give the title compound (36 mg).

[0712] MS: [M+H] + 1064.8.

[0713] 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

[0714] 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 / dioxane solution (0.3 mL) under ice-cooling. The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was washed with diethyl ether and pentane to give the title compound (24 mg).

[0715] 1 H NMR (400 MHz, DMSO-d 6)δ 1.03 - 1.23 (5H, m), 1.33 (3H, d, J = 6.76 Hz), 1.60 - 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).

[0716] Example 5

[0717] (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

[0718] A) ((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 tert-butyl ester

[0719] To a mixture of ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperazin-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate tert-butyl ester (2.29 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), and the mixture was 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 distilled off under reduced pressure to obtain the title compound (2.64 g).

[0720] MS: [M + H - Boc] + 490.3.

[0721] 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

[0722] 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 distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.96 g).

[0723] MS: [M+H] + 662.4.

[0724] 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

[0725] 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 distilled off under reduced pressure to give the title compound (2.16 g).

[0726] MS: [M+H] + 648.4.

[0727] 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

[0728] 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) was added HATU (986 mg), and the mixture 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 distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (695 mg).

[0729] MS: [M+H] + 837.5.

[0730] E) ((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-indol-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamic acid tert-butyl ester

[0731] To a mixture of 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol (265 mg), ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(14-hydroxy-3-methyl-2-oxo-6,9,12-trioxa-3-azatetradecyl)-1H-indol-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamic acid tert-butyl ester (670 mg), triphenylphosphine (1.05 g), and toluene (8 mL) was added di-tert-butyl azodicarboxylate (553 mg), 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 give the title compound (575 mg).

[0732] MS: [M+H] + 1150.4.

[0733] (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

[0734] 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) was added 4 M hydrogen chloride / ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (549 mg).

[0735] 1H NMR (400 MHz, DMSO-d 6 , 100 °C) 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).

[0736] Example 6

[0737] (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

[0738] A) (S)-3-(Pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole

[0739] To a mixture of 5-((4-(Thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol (398.8 mg), (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid (9H-fluoren-9-yl)methyl ester (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. 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 2M aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to give the title compound (199.4 mg).

[0740] MS: [M+H] + 415.2.

[0741] B) ((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)carbamic acid tert-butyl ester

[0742] 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, the precipitate was filtered off and washed with water to give the title compound (320.8 mg).

[0743] MS: [M+H] + 1044.3.

[0744] 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-indol-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride To a mixture of ((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-indol-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate tert-butyl ester (380.2 mg) and ethyl acetate (1.5 mL) was added 4M hydrogen chloride / ethyl acetate solution (1 mL). The reaction mixture was stirred at room temperature for one and a half hours, diisopropyl ether was added. The precipitate was filtered off and washed with diisopropyl ether to give the title compound (280.3 mg).

[0745] MS: [M+H] + 944.2.

[0746] The title compound was neutralized with saturated aqueous sodium bicarbonate, the precipitate was collected to give the resulting free form, and 1 H NMR was measured.

[0747] 1 H NMR (300 MHz, DMSO-d 6) 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).

[0748] Example 7

[0749] (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

[0750] A) ((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 tert-butyl ester

[0751] To a mixture of ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperazin-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate tert-butyl ester (7 g) and DMF (60 mL) was added 5-fluoro-1H-indole-2-carboxylic acid (3.36 g), 1-hydroxybenzotriazole (3.00 g), DIEA (11.9 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.25 g). The reaction mixture was stirred at room temperature for 16 h, water was added, and the mixture was extracted 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 distilled off under reduced pressure to give the title compound (9.5 g).

[0752] MS: [M+H] + 572.0.

[0753] 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

[0754] Under ice-cooling, potassium carbonate (6.89 g) and methyl bromoacetate (4.59 mL) were added to a mixture of ((S)-1-(((S)-1-cyclohexyl-2-(4-(5-fluoro-1H-indol-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate tert-butyl ester (9.5 g) and DMF (50 mL). 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 distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (8.6 g).

[0755] MS: [M+H] + 644.1.

[0756] 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

[0757] 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) was added 2 M aqueous sodium hydroxide solution (13.4 mL). 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 adjusted to acidic 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 distilled off under reduced pressure to obtain the title compound (8.1 g).

[0758] MS: [M+H] + 630.2.

[0759] D) ((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)carbamic acid tert-butyl ester

[0760] 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) was added (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), HATU (507.8 mg), and the mixture was 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 successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (950 mg).

[0761] MS: [M+H] + 1025.8.

[0762] 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

[0763] 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) was added 4 M hydrogen chloride / ethyl acetate solution (0.043 mL), and the mixture was stirred at room temperature for 4 hours. The precipitated solid was filtered off, and to a 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 (obtained) and water (0.2 mL) at room temperature was added saturated aqueous sodium hydrogen carbonate solution (0.043 mL). The reaction mixture was stirred at room temperature for 30 minutes, and the precipitated solid was filtered off to give the title compound (46 mg).

[0764] 1 H NMR(400MHz, DMSO-d 6 , 100℃) δ1.07 - 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 = 5.3Hz, 1H), 7.01 - 7.06(m, 1H), 7.12 - 7.21(m, 1H), 7.20 - 7.29(m, 1H), 7.34(d, J = 8.5Hz, 1H), 7.42 - 7.55(m, 2H), 7.67(s, 1H), 7.95(d, J = 5.1Hz, 1H), 8.49(d, J = 5.2Hz, 1H).

[0765] Example 8

[0766] (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

[0767] A) (S)-3-(Pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole trihydrochloride

[0768] Methyl 3-hydroxyisoxazole-5-carboxylate (3.79 g), (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.84 g) and triphenylphosphine (6.94 g) were azeotroped with toluene, and a 40% solution of diethyl azodicarboxylate in toluene (14 mL) was added to the residue and a mixture of toluene (50 mL) under ice-cooling. After the reaction mixture was stirred at room temperature for 1 hour, the solvent was distilled off under reduced pressure to half, and purification was carried out 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 extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Methanesulfonyl chloride (2.10 mL) was added to a mixture of the resulting (S)-2-(((5-(hydroxymethyl)isoxazol-3-yl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester and THF (100 mL). The reaction mixture was stirred at room temperature for 2 hours, saturated aqueous sodium hydrogen carbonate was added, and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A mixture of the resulting (S)-2-(((5-(((methylsulfonyl)oxy)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester, 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 extraction was carried out with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane). 4M hydrogen chloride / ethyl acetate (40 mL) was added to a mixture of the resulting (S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester and ethyl acetate (20 mL). The reaction mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure to obtain the title compound (8.03 g).

[0769] MS: [M+H] + 415.2.

[0770] B) (S)-tert-butyl 4-(5,6-difluoro-1H-indole-2-carbonyl)-3-methylpiperazine-1-carboxylate

[0771] 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 h, diluted with water and ethyl acetate, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure to give the title compound (1.61 g).

[0772] MS: [M+H-tBu] + 324.2.

[0773] C) Methyl 2-(2-((S)-4-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)-2-methylpiperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetate

[0774] 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 h. Water and ethyl acetate were added to the reaction mixture and it was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed by distillation 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) was added 4M hydrogen chloride / ethyl acetate solution (21.2 mL). The reaction mixture was stirred at room temperature for 1 h and the solvent was removed by distillation 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 h, water and ethyl acetate were added, and it was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure to give the title compound (639 mg).

[0775] MS: [M+H] + 591.5.

[0776] D) Methyl 2-(2-((S)-4-((S)-2-((S)-2-((tert-Butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-2-methylpiperazin-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetate

[0777] To a mixture of methyl 2-(2-((S)-4-((S)-2-((tert-Butoxycarbonyl)amino)-2-cyclohexylacetyl)-2-methylpiperazin-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 distilled off under reduced pressure. To the resulting mixture of methyl 2-(2-((S)-4-((S)-2-amino-2-cyclohexylacetyl)-2-methylpiperazin-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, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (450 mg).

[0778] MS: [M+H] + 676.5.

[0779] E) 2-(2-((S)-4-((S)-2-((S)-2-((tert-Butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-2-methylpiperazin-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid

[0780] To a mixture of methyl 2-(2-((S)-4-((S)-2-((S)-2-((tert-Butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-2-methylpiperazin-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, adjusted to acidic with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (221 mg).

[0781] MS: [M+H] + 662.4.

[0782] F) ((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

[0783] 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 h, water was added, the precipitate was filtered off, and purification was carried out by silica gel column chromatography (C18, acetonitrile / 5 mM aqueous ammonium acetate / acetonitrile). Ethyl acetate and saturated aqueous sodium bicarbonate were added to the resulting compound, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (320 mg).

[0784] MS: [M+H] + 1058.5.

[0785] G) (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

[0786] 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 one and a half hours, and the solvent was distilled off under reduced pressure. Saturated aqueous sodium bicarbonate was added to the residue, and the precipitate was filtered off to give the title compound (216 mg).

[0787] 1 H NMR(300MHz, DMSO-d 6 ) 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)

[0788] Example 9

[0789] (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

[0790] A) (S)-4-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)-2-methylpiperazine-1-carboxylic acid benzyl ester

[0791] To a mixture of (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (5 g), (S)-2-methylpiperazine-1-carboxylic acid benzyl ester 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 h, 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 solution, saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (6.7 g).

[0792] MS: [M+H] + 474.2.

[0793] B) (S)-4-((S)-2-Amino-2-cyclohexylacetyl)-2-methylpiperazine-1-carboxylic acid benzyl ester hydrochloride

[0794] To a mixture of (S)-4-((S)-2-(((tert-butoxy)carbonyl)amino)-2-cyclohexylacetyl)-2-methylpiperazine-1-carboxylic acid benzyl ester (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 h, and the solvent was distilled off under reduced pressure. The residue was washed with DCM to give the title compound (6 g).

[0795] 1 H NMR (400 MHz, DMSO-d 6 ) 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) (S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-2-methylpiperazine-1-carboxylic acid benzyl ester

[0797] To a mixture of N-(tert-butoxycarbonyl)-N-methyl-L-alanine (3 g) and DMF (30 mL) was added (S)-4-((S)-2-amino-2-cyclohexylacetyl)-2-methylpiperazine-1-carboxylic acid benzyl ester hydrochloride (6 g), DIEA (10.3 mL), and HATU (7.3 g). The reaction mixture was stirred at room temperature for 16 h, 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 distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (6 g).

[0798] MS: [M+H] + 559.1.

[0799] D) ((S)-1-(((S)-1-cyclohexyl-2-((S)-3-methylpiperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamic acid tert-butyl ester

[0800] To a mixture of (S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-2-methylpiperazine-1-carboxylic acid benzyl ester (3.8 g) and ethanol (50 mL) was added 10% palladium on carbon (1 g). The reaction mixture was stirred at room temperature for 16 h under a hydrogen atmosphere at atmospheric pressure and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give the title compound (2.3 g).

[0801] MS: [M+H] + 425.2.

[0802] E) Methyl 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-2-methylpiperazin-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetate

[0803] 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 filtered off and azeotroped with toluene. The resulting mixture of 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 distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (979 mg).

[0804] MS: [M+H] + 658.4.

[0805] F) 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-2-methylpiperazin-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetic acid

[0806] To a mixture of methyl 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-2-methylpiperazin-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 distilled off under reduced pressure to give the title compound (915 mg).

[0807] MS: [M+H] + 644.4.

[0808] G) ((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)carbamic acid tert-butyl ester

[0809] 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, the precipitate was filtered off, and purification was carried out by silica gel column chromatography (C18, acetonitrile / 5 mM aqueous ammonium acetate). The resulting compound was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (367 mg).

[0810] MS: [M+H] + 1040.5.

[0811] (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 one and a half hours, and the solvent was distilled off under reduced pressure. Saturated aqueous sodium bicarbonate was added to the residue, and the precipitate was filtered to obtain the title compound (249 mg).

[0812] 1 H NMR(300MHz, DMSO-d 6 ) 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).

[0813] Example 10

[0814] (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

[0815] A) 2-(Benzyloxy)-3,4-difluorobenzaldehyde

[0816] To a mixture of 3,4-difluoro-2-hydroxy-benzaldehyde (5 g) and acetonitrile (50 mL) were added potassium carbonate (6.56 g), benzyl bromide (4.51 mL) and sodium iodide (2.37 g). The reaction mixture was stirred at 60 °C for 6 h, filtered through diatomaceous earth, 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).

[0817] 1 H NMR (400 MHz, DMSO-d 6 ): 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).

[0818] B) Methyl (Z)-2-azido-3-(2-(benzyloxy)-3,4-difluorophenyl)acrylate

[0819] At -10 °C, a mixture of methyl azidoacetate (3.15 mL), 2-(benzyloxy)-3,4-difluorobenzaldehyde (2.0 g) and methanol (10 mL) was added dropwise to a mixture of sodium methoxide (1.74 g) and methanol (10 mL) under an argon atmosphere. The reaction mixture was stirred at the same temperature for 4 h and then at 4 °C for 16 h. Ice water was added, and the precipitate was filtered off to give the title compound (2.1 g).

[0820] 1 H NMR (400 MHz, DMSO-d 6 ): 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).

[0821] C) Methyl 4-(benzyloxy)-5,6-difluoro-1H-indole-2-carboxylate

[0822] 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 h. The reaction mixture was cooled, and the precipitate was filtered off to give the title compound (700 mg).

[0823] 1 H NMR (400 MHz, DMSO-d 6):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).

[0824] D) Methyl 4-(benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carboxylate

[0825] To a mixture of methyl 4-(benzyloxy)-5,6-difluoro-1H-indole-2-carboxylate (1.7 g) and DMF (20 mL) was added potassium carbonate (1.1 g) and methyl iodide (0.4 mL). The reaction mixture was stirred at room temperature for 2 hours, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.5 g).

[0826] MS: [M + H] + 332.1.

[0827] E) 4-(Benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carboxylic acid

[0828] To a mixture of methyl 4-(benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carboxylate (1.5 g) and THF (30 mL) was added water (6 mL) and lithium hydroxide monohydrate (0.285 g). The reaction mixture was stirred at room temperature for 6 hours, the solvent was distilled off under reduced pressure, 1 M hydrochloric acid was added to adjust to acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.35 g).

[0829] MS: [M + H] + 318.1.

[0830] 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

[0831] 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 ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperazin-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)carbamic acid tert-butyl ester (1.81 g), HATU (2.52 g) and DIEA (1.9 mL). The reaction mixture was stirred at room temperature for 2 h, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate, water, saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.1 g).

[0832] MS: [M+H] + 710.1.

[0833] G) ((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)carbamic acid tert-butyl ester

[0834] To a mixture of ((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)carbamic acid tert-butyl ester (2.1 g) and ethanol (50 mL) was added palladium on carbon (400 mg), and the mixture was stirred at room temperature for 2 h under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound (1.7 g).

[0835] MS: [M+H] + 620.4.

[0836] H) 2-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate

[0837] Under ice-cooling, to a mixture of 2-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethanol (15 g) and DCM (250 mL) were added TEA (11.03 mL), DMAP (3.22 g), p-toluenesulfonyl chloride (12.07 g), and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM, washed with water and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (14 g).

[0838] MS: [M+H] + 439.2.

[0839] I) ((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)carbamic acid tert-butyl ester

[0840] To a mixture of ((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)carbamic acid tert-butyl ester (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 h, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (490 mg).

[0841] MS: [M+H] + 886.4.

[0842] J) ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-4-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamic acid tert-butyl ester

[0843] To a mixture of ((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)carbamic acid tert-butyl ester (490 mg) and ethanol (15 mL) was added palladium on carbon (100 mg). The reaction mixture was stirred at room temperature for 16 h under an atmospheric hydrogen atmosphere, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound (360 mg).

[0844] MS: [M+H] + 796.2.

[0845] K) ((S)-1-(((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)amino)-1-oxopropan-2-yl)(methyl)carbamic acid tert-butyl ester

[0846] To a mixture of ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-4-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamic acid tert-butyl ester (20 mg), 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol (12.4 mg), triphenylphosphine (32.9 mg) and toluene (2 mL) was added di-tert-butyl azodicarboxylate (17.3 mg). The reaction mixture was stirred at room temperature for 16 h and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography to give the title compound (25 mg).

[0847] MS: [M+H] + 1109.8.

[0848] L) (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

[0849] To a mixture of tert-butyl ((S)-1-(((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)amino)-1-oxopropan-2-yl)(methyl)carbamate (25 mg) and DCM (1 mL) was added 4 M hydrogen chloride / dioxane solution (0.3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, the solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to give the title compound (17 mg).

[0850] 1 H NMR(400MHz, DMSO-d 6 ) δ 0.83 - 1.34 (9H, m), 1.60 - 1.69 (5H, m), 2.07 - 2.18 (3H, m), 3.17 (3H, s), 3.44 - 3.74 (25H, m), 3.85 - 4.66 (9H, m), 5.01 - 5.27 (2H, m), 6.63 (1H, bs), 6.81 (1H, s), 7.36 - 7.44 (2H, m), 7.66 (1H, d, J = 5.32 Hz), 8.35 - 8.36 (1H, m), 8.74 - 8.80 (2H, m), 9.10 - 9.11 (1H, m), 11.36 (1H, brs).

[0851] Example 11

[0852] (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

[0853] A) ((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0854] 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 g) and DMF (70 mL), add 2-methyl-1H-indole-5-carboxylic acid (1.9 g), DIEA (6.8 mL) and HATU (4.45 g), and stir at room temperature for 16 hours. Dilute the reaction mixture with water, and extract the aqueous layer with ethyl acetate. Wash the organic layer successively with water and saturated brine, dry over anhydrous sodium sulfate, and distill off the solvent under reduced pressure. Purify the residue by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (4 g).

[0855] MS: [M+H] + 568.3.

[0856] B) tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1-(1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0857] To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (2 g) and DMF (30 mL), add cesium carbonate (2.87 g), stir at room temperature for 5 minutes, then add 2-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (2.78 g), and stir at 80 °C for 16 hours. Dilute the reaction mixture with water, and extract the aqueous layer with ethyl acetate. Wash the organic layer with water and saturated brine, dry over anhydrous sodium sulfate, and distill off the solvent under reduced pressure. Purify the residue by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (1.3 g).

[0858] MS: [M+H] + 834.4.

[0859] C) tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(1-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)-2-methyl-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0860] A mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1-(1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (1.3 g) and ethanol (50 mL) was added to 10% palladium on carbon (250 mg), and the mixture was stirred at 25 °C for 16 hours under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.1 g).

[0861] MS: [M+H] + 744.3.

[0862] D) ((S)-1-(((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)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0863] To a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(1-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)-2-methyl-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (20 mg), 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol (10.6 mg), triphenylphosphine (35.2 mg) and toluene (2 mL) was added di-tert-butyl azodicarboxylate (24.7 mg), and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography to obtain the title compound (17 mg).

[0864] MS: [M+H] + 1057.3.

[0865] E) (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

[0866] At 0 °C, TFA (0.01 mL) was added to a mixture of tert-butyl ((S)-1-(((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)amino)-1-oxopropan-2-yl)(methyl)carbamate (17 mg) and DCM (1 mL), and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (C18, mobile phase: acetonitrile / aqueous solution of 20 mM ammonium bicarbonate) to obtain the title compound (4 mg).

[0867] MS: [M+H] + 957.8.

[0868] The prepared Example Compounds 1 to 11 are shown below. For each compound, the compound name, structural formula, type of salt, and MS value (MS is the measured value) are shown.

[0869] Example No. 1 (Compound 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 (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),

[0870] [Chemical Formula 55]

[0871]

[0872] Type of salt: HCl; MS value: 1006.6

[0873] Example No. 2 (Compound 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 (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),

[0874] [Chemical Formula 56]

[0875]

[0876] Type of salt: -; MS value: 1046.5

[0877] Example No. 3 (Compound 3): 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]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperazin-1-yl)ethan-1-one),

[0878] [Chemical Formula 57]

[0879]

[0880] Type of salt: HCl; MS value: 909.7

[0881] Example No. 4 (Compound 4): (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),

[0882] [Chemical Formula 58]

[0883]

[0884] Type of salt: HCl; MS value: 966.4

[0885] Example No. 5 (Compound 5): (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,

[0886] [Chemical Formula 59]

[0887]

[0888] Type of salt: HCl; MS value: 1050.3

[0889] Example No. 6 (Compound 6): (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,

[0890] [Chemical Formula 60]

[0891]

[0892] Type of salt: HCl; MS value: 944.2

[0893] Example No. 7 (Compound 7): (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),

[0894] [Chemical Formula 61]

[0895]

[0896] Type of salt: -; MS value: 926.1

[0897] Example No. 8 (Compound 8): (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),

[0898] [Chemical Formula 62]

[0899]

[0900] Type of salt: -; MS value: 958.4

[0901] Example No. 9 (Compound 9): (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),

[0902] [Chemical Formula 63]

[0903]

[0904] Type of salt: -; MS value: 940.4

[0905] Example No. 10 (Compound 10): (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),

[0906] [Chemical Formula 64]

[0907]

[0908] Type of salt: HCl; MS value: 1009.7,

[0909] and

[0910] Example No. 11 (Compound 11): (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)oxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide l-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),

[0911] [Chemical formula 65]

[0912]

[0913] Salt type: -; MS value: 957.8

[0914] Experimental Example 1: Determination of XIAP binding inhibitory activity

[0915] The human XIAP binding inhibitory activity was measured by the Homogeneous Time Resolved Fluorescence (HTRF) method using a commercially available purified protein of the human XIAP BIR3 domain (Japanese: ド、メイン精製蛋白) (R&D) and a Smac N-terminal peptide (AVPIAQK (SEQ ID NO: 1)) biotinylated at the C-terminus by a conventional method (hereinafter referred to as "b-Smac"; Peptide Research Institute Co., Ltd.) as a ligand.

[0916] The HTRF method is described below in detail.

[0917] The test compound diluted with reaction buffer (25 mM HEPES buffer containing 100 mM NaCl, 0.1% BSA, 0.1% Triton X-100, pH 7.5) was added to a 384-well white low-binding plate (Greiner 784076) at 1 μL / well, and subjected to 30-second Flash centrifugation. Next, after diluting the purified human XIAP_BIR3 domain protein to 90 nM with the reaction buffer to obtain a sample dilution, the sample dilution was added to the above white low-binding plate at 4.5 μL / well, and subjected to 30-second Flash centrifugation. Next, b-Smac diluted to 90 nM with the reaction buffer was added to the above white low-binding plate at 4.5 μL / well, and subjected to 30-second Flash centrifugation. Anti-6HIS-Cryptate (Eu 3+ Cryptate-conjugated mouse monoclonal antibody anti-6Histidine; cisbio) and Streptavidin-XL ent！ (Highgrade XL665-conjugated streptavidin; cisbio) mixed at a volume ratio of 1:1 were added to the above white low-binding plate at 10 μL / well, and after 30-second Flash centrifugation, the white low-binding plate was placed in the dark at room temperature for more than 4 hours. The placed white low-binding plate was used for the measurement of fluorescence intensity using EnVision (PerkinElmer) (excitation wavelength: 320 nm, fluorescence wavelengths: 665 nm and 615 nm).

[0918] The binding inhibition rate (%) was calculated from the HTRF ratio in the presence of the test compound relative to the HTRF ratio in the absence of the test compound (fluorescence intensity at 665 nm / fluorescence intensity at 615 nm).

[0919] The XIAP binding inhibition rate of the test compound was evaluated. The XIAP binding inhibition rate when the concentration of the test compound was 3 μM was shown in the following table as A≥75%, 75%>B≥50%, 50%>C≥25%, D<25%, or the 50% inhibitory concentration (IC50 value) was shown in the following table as A<0.3 μM, 0.3 μM≤B<3 μM, 3 μM≤C<30 μM.

[0920] [Table 1]

[0921] Compound *Inhibition rate Example 1 - / B Example 2 - / B Example 3 - / A Example 4 C / - Example 5 - / C Example 6 - / C Example 7 - / C Example 8 - / C Example 9 - / C Example 10 - / B Embodiment 11 - / B

[0922] *Inhibitory rate: Inhibitory rate at 3 μM / IC50 value

[0923] According to the above results, the compounds of the present invention have excellent IAP (especially XIAP) binding (inhibitory) activity.

[0924] Test Example 2: Determination of IRAK-M binding inhibitory activity

[0925] The binding inhibitory activity of IRAK-M was determined using the active site-dependent competition assay KINOMEscan (registered trademark) provided by Eurofins DiscoverX (Goldstein, D.M. et al. High-throughput kinase profiling as a platform for drug discovery. Nat. Rev. Drug Discovery. 7, 391-397 (2008)). The IRAK-M binding inhibitory rate of the test compound was evaluated. The %Ctrl values at a test compound concentration of 1 μM are shown in the following table as A < 25%, 50% > B ≥ 25%, 75% > C ≥ 50%, D ≥ 75%, or the IC50 values are shown in the following table as A < 0.03 μM, 0.03 μM ≤ B < 0.1 μM, 0.1 μM ≤ C < 0.3 μM, 0.3 μM ≤ D < 1 μM. %Ctrl was calculated by the following formula.

[0926] (Signal value of test compound - Signal value of positive control compound) / (Signal value of negative control compound - Signal value of positive control compound) × 100

[0927] Negative control compound = DMSO (100% Ctrl)

[0928] Positive control compound = Control compound (0% Ctrl)

[0929] [Table 2]

[0930] Compound *Binding inhibitory activity Example 1 - / D Example 2 - / D Example 3 - / D Example 4 B / - Example 5 enter / - Example 6 A / - Example 7 - / D Example 8 - / D Example 9 - / D Example 10 A / - Embodiment 11 A / -

[0931] *Binding inhibitory activity: %Ctrl / IC50 value at 1 μM

[0932] Test Example 3: Activity of inducing degradation of target protein in vitro

[0933] The in vitro target protein degradation-inducing activity of the example compounds was evaluated by enzyme-linked immunosorbent assay (ELISA) according to the following analysis steps. THP1 cells (ATCC, TIB-202) were cultured in RPMI-1640 supplemented with 10% FBS, 1X sodium pyruvate, 1X HEPES, D-(+)-glucose, and 1% penicillin / streptomycin. THP1 cells seeded at 1×106 cells / well in a 24-well plate were treated with DMSO control and the test compound and cultured for 24 hours. The cells were harvested and lysed on ice for 30 minutes using a lysis buffer (PBS containing 0.1% Triton X-100) supplemented with a protease inhibitor mixture (Roche, Cat#11836170001). After sonication of the lysate for 10 cycles at 30 seconds ON / 30 seconds OFF, centrifugation was performed at 4°C and 13,000 rpm for 10 minutes. The protein concentration was determined by BCA assay (Sigma, Cat#QPBCA-1KT). The ELISA assay was performed using a Human IRAK3 / IRAKM / IRAK-M ELISA kit (LifeSpan BioSciences, Cat#LS-F35271), and the protein amount of IRAK-M was evaluated according to the kit protocol. Regarding the IRAK-M protein degradation rate of the test compound, the protein degradation rate (%) at a concentration of 1 μM of the test compound was shown in the following table as A≥75%, 50%≤B<75%, 25%≤C<50%, D<25%, or the 50% degradation concentration (DC50 value) was shown in the following table as A<0.03 μM, 0.03 μM≤B<0.1 μM, 0.1 μM≤C<0.3 μM, 0.3 μM≤D<1 μM.

[0934] [Table 3]

[0935] Compound *Decomposition rate Example 1 - / D Example 2 ℃ / - Example 3 C / - Example 4 A / - Example 5 - / D Example 6 - / B Example 7 - / A Example 8 - / A Example 9 - / A Example 10 - / C Embodiment 11 A / -

[0936] *Degradation rate: Protein degradation rate at 1 μM / DC50 value

[0937] Test Example 4: Antitumor effect in a mouse Lewis lung cancer cell inoculation model

[0938] For C57BL / 6 mice (Charles River Japan, male, 7 - 8 weeks old), mouse Lewis lung cancer cells LL / 2 (Lewis lung carcinoma, LLC) (ATCC, CRL-1642) 2×10 4Cells / mice were subcutaneously inoculated into the flanks of mice together with Matrigel. Seven days after inoculation, tumor size was measured using an electronic caliper, and the groups were divided in such a way that the sizes were equal in each group. Compounds were started to be used 8 days later. Tumor size was calculated using the formula of long diameter × short diameter × short diameter ÷ 2 of the tumor.

[0939] The test compound was suspended in 0.5% methylcellulose or dissolved in physiological saline and administered subcutaneously 3 times every 3 days. Until 16 - 18 days after the start of the experiment, tumor size was regularly measured, and a two - group test was performed on the tumor size in the test compound administration group and the solvent administration group on the last day of the experiment.

[0940] The daily changes in tumor size of each group in Examples 1, 6, 7, 8, and 9 are shown in Figure 1 . The salts shown in the figure were used for each compound. The figure shows the mean ± standard error.

[0941] The above results indicate that these compounds have an inhibitory effect on cancer cell proliferation.

[0942] Formulation Example 1

[0943] A drug containing the compound of the present invention as an active ingredient can be manufactured, for example, by the following formulation.

[0944] 1. Capsules

[0945]

[0946] Mix 1 / 2 of (1), (2), (3), and (4), and granulate. Add the remaining (4) thereto and encapsulate all of them in gelatin capsules.

[0947] 2. Tablets

[0948]

[0949] Mix (1), (2), (3), 2 / 3 of (4), and 1 / 2 of (5), and granulate. Add the remaining (4) and (5) to the granules and press them into tablets.

[0950] Formulation Example 2

[0951] Dissolve 50 mg of the compound obtained in Example 1 in 50 mL of distilled water for injection of the Japanese Pharmacopoeia, and then add distilled water for injection of the Japanese Pharmacopoeia to make 100 mL. Filter this solution under sterile conditions, then take 1 mL of this solution each, fill it into vials for injection under sterile conditions, and freeze - dry and seal it.

[0952] The above detailed description only illustrates the purpose and object of the present invention and does not limit the scope of the appended patent claims. Without departing from the scope of the appended claims, various changes and substitutions to the described embodiments will be obvious to those skilled in the art according to the teachings recorded in this specification.

[0953] Industrial Applicability

[0954] The compound of the present invention can decompose the target IRAK-M protein. Therefore, it is expected to provide a drug effective for the prevention or treatment of cancer and other IRAK-M related diseases. Sequence Listing <110> Panmax Co., Ltd. <120> Heterocyclic Compound <130> 20FOT009-WO0 <150> JP2019-141700 <151> 2019-07-31 <160> 1 <170> PatentIn version 3.5 <210> 1 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Partial Sequence of Smac Peptide <400> 1 Ala Val Pro Ile Ala Gln Lys 1 5

Claims

1. A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, （I） wherein the IRAK-M conjugate (M) is represented by the following formula (III), (III) In formula (III), Y is CH or N, R 01 is H, A 01 is *-CH 2 -* or *-SO 2 -*, R 11 represents any group shown by the following structural formula Here, * represents the bonding position with A 01 and ** represents the bonding position with the linker (L). The arrow represents the bond to the linker (L), The linker (L) is a group represented by the structural formula described below or *-(CH 2 CH 2 O)n(CH 2 )m(NRCO)s(CH 2 )t-*, Here, * represents the bond to the IRAK-M conjugate (M), n is a natural number from 1 to 5, m is 0, 1 or 2, s is 0 or 1, t is 0 or 1, and R represents a hydrogen atom or a methyl group, The E3 ligase conjugate (E) is represented by the following formula (IV), In formula (IV), R 01 , R 02 , R 03 , R 04 , R 05 , R 06 , R 07 and R 08 each independently represents a hydrogen atom or a methyl group, and D is the following formula (V-2) or the following formula (VI-1), In formula (VI-1), Q represents the bond to the linker (L), E is the following formula (VII), (VII) R in formula (VII) 21 R 22 R 23 each independently represents a hydrogen atom, fluorine, or a methoxy group, and R 25 R 26 each independently represents a hydrogen atom or a bond to the linker (L), and R 24 represents a methyl group or a bond to the linker (L); wherein, For the bond of the linker (L) is R 24 , R 25 or R 26 either one of them Either D or E is bonded to the linker (L).

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, The IRAK-M conjugate (M) is a monovalent group derived from the following compound: 5-((4-(Thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol, or 4-((4-(Thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol.

3. A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, （I） which is selected from the following compounds 1 to 11, Compound 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, Compound 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, Compound 3: 1-((R)-4-(5,6-Difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperazine-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)piperazine-1-yl)ethan-1-one, Compound 4: (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)piperazine-1-yl)-2-oxoethyl)-2-(methylamino)propanamide, Compound 5: (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, Compound 6: (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, Compound 7: (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, Compound 8: (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, Compound 9: (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, Compound 10: (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, and Compound 11: (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, 。 4. A pharmaceutical product, which contains the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical product according to claim 4, which is an IRAK-M proteolysis inducer.

6. The pharmaceutical product according to claim 4 or 5, which is a prophylactic or therapeutic agent for cancer.

7. The pharmaceutical product according to claim 4 or 5, which is used in combination with other anticancer agents.

8. Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prophylaxis or treatment of lung cancer.

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