TW202120511A - Heterocyclic compound - Google Patents

Abstract

To provide a novel heterocyclic compound which has an effect of inducing the degradation of IRAK-M protein and which is expected to be useful for preventing or treating cancer, fibrosis, infectious diseases, etc., and a medicine comprising the same. The invention provides a compound represented by formula (I), where the IRAK-M binder (M) is represented by formula (II) [in formula (II): Y represents CH or N; R01 represents H or Me; R03 is a group represented by structural formula BB (where: * represents a binding site to O; ** represents a binding site to A; and n is an integer of 0-2); A is a group represented by structural formula CC (where R05's independently represent a hydrogen atom or a C1-6 alkyl group) or *-SO2-*; R04 is a group represented by structural formula DD (where: * represents a binding site to A; and ** represents a binding site to the linker), an optionally substituted C1-6 alkylene group, an optionally substituted C3-10 cycloalkylene group, an optionally substituted C6-14 arylene group or a bond; and the arrow represents a bond to the linker (L)], or a pharmaceutically acceptable salt thereof.

Description

Heterocyclic compound

The present invention relates to a protein that has the decomposition and induction effect of interleukin-1 receptor-associated kinase-M (IRAK-M) protein, and is expected to be used for the prevention and treatment of cancer, fibrosis, and infections. And other heterocyclic compounds and medicines containing them.

In order to reduce disease-related proteins for treatment, an attempt was made to develop a compound that induces ubiquitination and proteasome decomposition of the target protein by E3 ligase (sometimes called Proteolysis Targeting Chimeras, PROTAC). ) Or Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Eraser (SNIPER), etc.) (Non-Patent Documents 1-9). IRAK-M is one of the IRAK family of protein kinases, and it is a pseudokinase with no kinase activity (Non-Patent Document 10). IRAK-M exists in the downstream of all Toll-like Receptors (TLR) except TLR3, and acts as a negative feedback regulator of the TLR/IL-1 receptor signaling pathway in biology. Proteins that function in the body (Non-Patent Document 11). Its performance is limited to a part of epithelial cells and immune cells, especially bone marrow cells, including bile duct epithelial cells, lung epithelial cells and intestinal epithelial cells. IRAK-M negatively controls the inducing information of inflammatory cytokines that mediate TLR in natural immune-active eligible cells such as macrophages or dendritic cells, and exerts the induction of endotoxin tolerance for immune stabilization. An important role for state maintenance (Non-Patent Document 12). It is reported that IRAK-M contributes to the use of tumor-associated macrophages, bone marrow-derived immunosuppressive cells and dendritic cells in the tumor microenvironment for immunosuppression, and therefore participates in cancer growth (Non-Patent Documents 13-15). Furthermore, it is reported that IRAK-M exerts an effect on its phagocytic ability, its defense ability against bacteria, and its ability to promote collagen production in alveolar macrophages, and it is associated with secondary infections after fibrosis, asthma, and sepsis, and hematopoietic effects. Infectious complications of stem cell transplantation (Non-Patent Documents 16-18) are also related. Therefore, IRAK-M is induced by linking the X-Linked Inhibitor of Apoptosis Protein (XIAP) binder, which is one of the E3 ligases, with the IRAK-M binder using a linker. The decomposed compound can be a promising therapeutic agent in cancer, fibrosis, infection, and IRAK-M protein-related diseases.

Patent Document 1 reports a compound as an inducer of IRAK-M proteolysis. Patent Documents 2 and 3 report compounds that are IRAK (especially IRAK-4) proteolysis inducers. Patent Documents 4 to 16 report compounds that use IAP conjugates to induce protein degradation. Patent Documents 17 to 20 report having N-(piperidin-4-yl)thieno[3,2-d]pyrimidin-4-amine or N-(piperidin-4-yl)thieno[3,2 -b] A compound of the pyridine-7-amine structure. [Prior Technical Literature] [Patent Literature]

[Patent Document 1] International Publication No. 2017/211924 [Patent Document 2] International Publication No. 2019/099926 [Patent Document 3] International Publication No. 2019/133531 [Patent Document 4] International Publication No. 2018/066545 [Patent Document 5] Japanese Patent Laid-Open No. 2013-056837 [Patent Document 6] International Publication No. 2016/169989 [Patent Document 7] International Publication No. 2016/172134 [Patent Document 8] International Publication No. 2017/011590 [Patent Document 9] International Publication No. 2017/182418 [Patent Document 10] International Publication No. 2017/201449 [Patent Document 11] Specification of U.S. Patent Application Publication No. 2018/0118733 [Patent Document 12] Specification of U.S. Patent Application Publication No. 2018/0134688 [Patent Document 13] International Publication No. 2018/119448 [Patent Document 14] International Publication No. 2018/119357 [Patent Document 15] Specification of U.S. Patent Application Publication No. 2019/0119271 [Patent Document 16] Specification of U.S. Patent Application Publication No. 2019/0175612 [Patent Document 17] International Publication No. 2016/040330 [Patent Document 18] International Publication No. 2013/019966 [Patent Document 19] Specification of U.S. Patent Application Publication No. 2013/0040957 [Patent Document 20] Chinese Patent Application Publication No. 103242341 [Non-Patent Literature]

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

[The problem to be solved by the invention]

The purpose of the present invention is to provide a novel heterocyclic compound with IRAK-M protein decomposing and inducing effect, which is expected to be used for the prevention and treatment of cancer, fibrosis, infectious diseases, etc., and a medicine containing the same. [Technical means to solve the problem]

The inventors of the present invention conducted intensive research in order to find an IRAK-M protein degradation inducer. As a result, they found that the IRAK-M protein of the compound represented by the following formula has excellent degradation inducing activity and may be used for the prevention and treatment of cancer, Fibrosis, infectious disease, etc., thereby completing the present invention.

That is, the present invention is as described below. [1] A compound represented by the following formula (I), or a pharmaceutically acceptable salt thereof:

。 [2]如上述[1]所記載之化合物、或其藥學上容許之鹽，其中上述IRAK-M結合物(M)以下述式(II)表示：[化1]

. [2] The compound as described in [1] above, or a pharmaceutically acceptable salt thereof, wherein the IRAK-M conjugate (M) is represented by the following formula (II):

[式中，Y為CH或N，R⁰¹ 為H或Me，R⁰³ 為以下之結構式：[化2]

[In the formula, Y is CH or N, R ⁰¹ is H or Me, and R ⁰³ is the following structural formula:

(此處，*表示鍵結於O之位置，**表示鍵結於A之位置，n為0～2之整數)所表示之基，A為以下之結構式：[化3]

(Here, * means the position of bonding to O, ** means the position of bonding to A, n is an integer from 0 to 2), and A is the following structural formula:

(此處，R⁰⁵ 分別獨立為氫原子或C1-6烷基)所表示之基、或*-SO₂ -*，R⁰⁴ 為以下之結構式：[化4]

(Here, R ^{05 is} independently a hydrogen atom or a C1-6 alkyl group) or *-SO ₂ -*, R ⁰⁴ is the following structural formula:

(此處，*表示鍵結於A之位置，**表示鍵結於連接基之位置)所表示之任一基、可經取代之C1-6伸烷基、可經取代之C3-10伸環烷基、可經取代之C6-14伸芳基、或鍵結鍵，箭頭表示對於連接基(L)之鍵結]。 [3]如上述[2]所記載之化合物、或其藥學上容許之鹽，其中上述IRAK-M結合物(M)以下述式(III)表示：[化5]

(Here, * means the position of bonding to A, ** means the position of bonding to the linking group) any of the groups represented, C1-6 alkylene which may be substituted, C3-10 alkylene which may be substituted Cycloalkyl, substituted C6-14 arylene group, or bonding bond, the arrow indicates the bond to the linking group (L)]. [3] The compound described in [2] above, or a pharmaceutically acceptable salt thereof, wherein the IRAK-M conjugate (M) is represented by the following formula (III):

[式中，Y為CH或N，R⁰¹ 為H或Me，A⁰¹ 為以下之結構式：[化6]

[In the formula, Y is CH or N, R ⁰¹ is H or Me, and A ⁰¹ is the following structural formula:

(此處，R⁰⁵ 分別獨立為氫原子或C1-6烷基)所表示之基、或*-SO₂ -*， R¹¹ 為以下之結構式：[化7]

(Here, R ^{05 is} each independently a hydrogen atom or a C1-6 alkyl group) represented by the group or *-SO ₂ -*, R ¹¹ is the following structural formula:

(此處，*表示鍵結於A⁰¹ 之位置，**表示鍵結於連接基之位置)所表示之任一基，箭頭表示對於連接基(L)之鍵結]。 [4]如上述[2]所記載之化合物，其中上述IRAK-M結合物(M)為由選自由以下之化合物所組成之群中之化合物所衍生之一價基： 5-((4-(噻吩并[3,2-b]吡啶-7-基氧基)哌啶-1-基)甲基)異㗁唑-3-醇(5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol)、 5-((4-((2-甲基噻吩并[3,2-b]吡啶-7-基)氧基)哌啶-1-基)甲基)異㗁唑-3-醇(5-((4- ((2-methylthieno [3,2-b] pyridin-7-yl) oxy)piperidin-1-yl) methyl)isoxazol-3-ol)、 1-甲基-5-((4-(噻吩并[3,2-b]吡啶-7-基氧基)哌啶-1-基)甲基)-1H-吡唑-3-醇(1-methyl-5- ((4-(thieno[3,2-b] pyridin-7-yloxy)piperidin-1-yl) methyl)-1H-pyrazol-3-ol)、及 4-((4-(噻吩并[3,2-d]嘧啶-4-基氧基)哌啶-1-基)磺醯基)苯酚(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol)。 [5]如上述[1]至[4]中任一項所記載之化合物、或其藥學上容許之鹽，其中連接基(L)為可含有雜原子之具有5-20個碳原子之基。 [6]如上述[1]至[4]中任一項所記載之化合物、或其藥學上容許之鹽，其中連接基(L)為以下所記載之結構式：[化8]

(Here, * indicates ^{the position of bonding to A 01} , ** indicates the position of bonding to the linking group), the arrow indicates the bonding to the linking group (L)]. [4] The compound described in [2] above, wherein the IRAK-M conjugate (M) is a monovalent group derived from a compound selected from the group consisting of the following compounds: 5-((4- (Thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoazol-3-ol (5-((4-(thieno[3,2-b ]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol), 5-((4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy Yl)piperidin-1-yl)methyl)isoazol-3-ol (5-((4- ((2-methylthieno [3,2-b] pyridin-7-yl) oxy)piperidin-1- yl) methyl)isoxazol-3-ol), 1-methyl-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl) -1H-Pyrazol-3-ol (1-methyl-5- ((4-(thieno[3,2-b] pyridin-7-yloxy)piperidin-1-yl) methyl)-1H-pyrazol-3- ol), and 4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol (4-((4-(thieno[ 3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol). [5] The compound as described in any one of [1] to [4] above, or a pharmaceutically acceptable salt thereof, wherein the linking group (L) is a group having 5-20 carbon atoms which may contain a heteroatom . [6] The compound described in any one of [1] to [4] above, or a pharmaceutically acceptable salt thereof, wherein the linking group (L) is the structural formula described below:

(此處，*表示鍵結於IRAK-M結合物(M)) 所表示之基、*-(CH₂ CH₂ O)n(CH₂ )m(NRCO)s(CH₂ )t-*(n為1～5之自然數，m為0、1、或2，s為0或1，t為0或1，R表示氫原子或C1-6烷基)、或鍵結鍵。 [7]如上述[1]至[6]中任一項所記載之化合物、或其藥學上容許之鹽，其中上述E3連接酶結合物(E)以下述式(IV)表示：[化9]

(Here, * means bonding to IRAK-M conjugate (M)), *-(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, R represents a hydrogen atom or a C1-6 alkyl group), or a bonding bond. [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):

[式中，R₀₁ 、R₀₂ 、R₀₃ 、R₀₄ 、R₀₅ 、R₀₆ 、R₀₇ 、及R₀₈ 分別獨立地表示氫原子或可互相形成環之C1-6烷基，D為下述式(V)：[化10]

[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 C1-6 alkyl group that can form a ring with each other, and D is the following Formula (V):

(式中，m表示0～2之整數，n表示0～2之整數，W₁₁ 表示亞甲基、二氟亞甲基、O、S、SO、SO₂ 、或NR，此處，R表示氫原子、C1-6烷基、C1-6烷基-羰基、C6-14芳基-羰基、或C1-6烷基磺醯基，T表示可經鹵化之C1-3烷基)、或下述式(VI)：[化11]

(In the formula, m represents an integer from 0 to 2, n represents an integer from 0 to 2, W ₁₁ represents methylene, difluoromethylene, 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, T represents a C1-3 alkyl group that can be halogenated), or Formula (VI):

(式中，Q表示氧原子、式-NR²¹ -(式中之R²¹ 表示氫原子、或可與C1-6烷基、P一起形成環之C1-6烷基)、或鍵結鍵，P表示氫原子、C1-6烷基或與連接基(L)之鍵結(包括與Q一起形成環且對於連接基(L)之鍵結))，E為下述式(VII)：[化12]

(In the formula, Q represents an oxygen atom, the formula -NR ^21- (where R ²¹ represents a hydrogen atom, or a C1-6 alkyl group that can form a ring together with a C1-6 alkyl group and P), or a bonding bond, P represents a hydrogen atom, a C1-6 alkyl group or a bond with the linking group (L) (including the formation of a ring with Q and the bond to the linking group (L)), and E is the following formula (VII):

(式中之R₂₁ 、R₂₂ 、R₂₃ 分別獨立地表示氫原子、鹵素原子、C1-6烷基、C1-6烷氧基、或可經取代之胺甲醯基，R₂₅ 、R₂₆ 分別獨立地表示氫原子、鹵素原子、C1-6烷基、C1-6烷氧基、可經取代之胺甲醯基、或對於連接基(L)之鍵結，R₂₄ 表示氫原子、甲基、或對於連接基(L)之鍵結；其中對於連接基(L)之鍵結為R₂₄ 、R₂₅ 或R₂₆ 之任一者)、或下述式(VIII)：[化13]

(In the formula, R ₂₁ , R ₂₂ , and R ₂₃ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or a substituted aminomethyl 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 substituted amine methanoyl group, or a bond to the linking group (L), and R ₂₄ represents a hydrogen atom, methyl Group, or the bonding to the linking group (L); wherein the bonding to the linking group (L) _{is any one of R 24} , R ₂₅ or R ₂₆ ), or the following formula (VIII):

(式中之R₃₁ 、R₃₂ 、R₃₃ 、R₃₄ 、R₃₅ 分別獨立地表示氫原子、鹵素原子、C1-6烷基、C1-6烷氧基、或可經取代之胺甲醯基，R表示氫原子、C1-6烷基或對於連接基(L)之鍵結)，D或E之任一者與連接基(L)鍵結]。 [8]如上述[1]至[7]中任一項所記載之化合物、或其藥學上容許之鹽，其中上述E3連接酶結合物(E)以下述式(IV)表示：[化14]

(In the formula, R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , and R ₃₅ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or a substituted amine methanoyl group , R represents a hydrogen atom, a C1-6 alkyl group or a bond to the linking group (L)), and either D or E is bonded to the linking group (L)]. [8] The compound according to any one of [1] to [7] above, or a pharmaceutically acceptable salt thereof, wherein the E3 ligase conjugate (E) is represented by the following formula (IV):

[式中，R₀₁ 、R₀₂ 、R₀₃ 、R₀₄ 、R₀₅ 、R₀₆ 、R₀₇ 、及R₀₈ 分別獨立地表示氫原子或甲基，D為下述式(V-1)：[化15]

[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, and D is the following formula (V-1):

(式中，W₁₁ 表示亞甲基或二氟亞甲基)、或下述式(VI-1)：[化16]

(In the formula, W ₁₁ represents a methylene group or a difluoromethylene group), or the following formula (VI-1):

(式中，Q表示對於連接基(L)之鍵結)， E為下述式(VII)：[化17]

(In the formula, Q represents the bond to the linking group (L)), E is the following formula (VII):

(式中之R₂₁ 、R₂₂ 、R₂₃ 分別獨立地表示氫原子、鹵素原子、C1-6烷基、或C1-6烷氧基，R₂₅ 、R₂₆ 分別獨立地表示氫原子、鹵素原子、C1-6烷基、或對於連接基(L)之鍵結，R₂₄ 表示氫原子、甲基、或對於連接基(L)之鍵結；其中對於連接基(L)之鍵結為R₂₄ 、R₂₅ 或R₂₆ 之任一者)、或下述式(VIII)：[化18]

(In the formula, R ₂₁ , R ₂₂ , and R ₂₃ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a C1-6 alkoxy group, and R ₂₅ and R ₂₆ each independently represent a hydrogen atom and a halogen atom , C1-6 alkyl group, or for the linkage of the linker (L), R ₂₄ represents a hydrogen atom, a methyl group, or the bond for the linker (L); wherein the bond for the linker (L) is R ₂₄ , R ₂₅ or R ₂₆ ), or the following formula (VIII):

(式中之R₃₁ 、R₃₂ 、R₃₃ 、R₃₄ 、R₃₅ 分別獨立地表示氫原子、鹵素原子、或C1-6烷基，R表示氫原子、C1-6烷基或對於連接基(L)之鍵結)，D或E之任一者與連接基(L)鍵結]。 [9]如上述[1]所記載之化合物、或其藥學上容許之鹽，其中上述IRAK-M結合物(M)以下述式(III)表示：[化19]

(In the formula, R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , and R ₃₅ each independently represent a hydrogen atom, a halogen atom, or a C1-6 alkyl group, and R represents a hydrogen atom, a C1-6 alkyl group, or the linking group ( The bond of L)), any one of D or E is bonded to the linking group (L)]. [9] The compound as described in [1] above, or a pharmaceutically acceptable salt thereof, wherein the IRAK-M conjugate (M) is represented by the following formula (III):

[式中，Y為CH或N，R⁰¹ 為H或Me，A⁰¹ 為*-CH₂ -*或*-SO₂ -*，R¹¹ 表示以下之結構式：[化20]

[In the formula, Y is CH or N, R ⁰¹ is H or Me, A ⁰¹ is *-CH ₂ -* or *-SO ₂ -*, R ¹¹ represents the following structural formula:

(此處，*表示鍵結於A之位置，**表示鍵結於連接基之位置)所表示之任一基， 箭頭表示對於連接基(L)之鍵結]， 連接基(L)為以下所記載之結構式：[化21]

(Here, * indicates the position of bonding to A, ** indicates the position of bonding to the linking group), the arrow indicates the bonding to the linking group (L)], the linking group (L) is The structural formula described below:

(此處，*表示鍵結於IRAK-M結合物(M))所表示之基、*-(CH₂ CH₂ O)n(CH₂ )m(NRCO)s(CH₂ )t-*(n為1～5之自然數，m為0、1、或2，s為0或1，t為0或1，R表示氫原子或C1-6烷基)、或鍵結鍵， E3連接酶結合物(E)以下述式(IV)表示：[化22]

(Here, * represents the group bound to IRAK-M conjugate (M)), *-(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, R represents a hydrogen atom or a C1-6 alkyl group), or a bonding bond, E3 ligase The conjugate (E) is represented by the following formula (IV):

[式中，R₀₁ 、R₀₂ 、R₀₃ 、R₀₄ 、R₀₅ 、R₀₆ 、R₀₇ 、及R₀₈ 分別獨立地表示氫原子或甲基，D為下述式(V-2)：[化23]

[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, and D is the following formula (V-2):

或下述式(VI-1)：[化24]

Or the following formula (VI-1):

(式中，Q表示對於連接基(L)之鍵結)， E為下述式(VII)：[化25]

(In the formula, Q represents the bond to the linking group (L)), E is the following formula (VII):

(式中之R₂₁ 、R₂₂ 、R₂₃ 分別獨立地表示氫原子、鹵素原子、C1-6烷基、或C1-6烷氧基，R₂₅ 、R₂₆ 分別獨立地表示氫原子、鹵素原子、C1-6烷基、或對於連接基(L)之鍵結，R₂₄ 表示氫原子、甲基、或對於連接基(L)之鍵結；其中對於連接基(L)之鍵結為R₂₄ 、R₂₅ 或R₂₆ 之任一者)、或下述式(VIII)：[化26]

(In the formula, R ₂₁ , R ₂₂ , and R ₂₃ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a C1-6 alkoxy group, and R ₂₅ and R ₂₆ each independently represent a hydrogen atom and a halogen atom , C1-6 alkyl group, or for the linkage of the linker (L), R ₂₄ represents a hydrogen atom, a methyl group, or the bond for the linker (L); wherein the bond for the linker (L) is R ₂₄ , R ₂₅ or R ₂₆ ), or the following formula (VIII):

(式中之R₃₁ 、R₃₂ 、R₃₃ 、R₃₄ 、R₃₅ 分別獨立地表示氫原子、鹵素原子、或C1-6烷基，R表示氫原子或對於連接基(L)之鍵結)，D或E之任一者與連接基(L)鍵結]。[化27]

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

[10] The compound as described in [1] above, or a pharmaceutically acceptable salt thereof, wherein the above compound is selected from the group consisting of the following compounds 1-11: Compound 1: 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propionylamine)acetyl)piper-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)isoazol-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),

[化28]

Compound 2: 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propionylamine)acetyl)piperidin-1-carbonyl)-6 -Methoxy-1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidine-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),

[化29]

Compound 3: 1-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperid-1-yl)-2-( (2R,5R)-5-methyl-2-((2-(2-(2-((5-((4-(thieno[3,2-b)pyridin-7-yloxy)piper (Pyridin-1-yl)methyl)isoazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperid-1-yl)ethane-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),

[化30]

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)isoazol-3-yl)oxy)ethoxy)ethyl (Oxy)ethoxy)-1H-indole-2-carbonyl)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propionamide ((S)-N -((S) -1- cyclohexyl -2- (4- (5,6- difluoro -1- methyl -3- (2- (2- (2- ((5- ((4- (thieno [3, 2-b] pyridine -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),

[化31]

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)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propane ((S)-N- ((S)-1-cyclohexyl-2- (4- (5,6-difluoro-1- (3-methyl-2-oxo-14- ((5- ((4 -(thieno [3,2-b] pyridine -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),

[化32]

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)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propionamide (( 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),

[化33]

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)pyrrolidine -1-yl)ethyl)-1H-indole-2-carbonyl)piperid-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),

[化34]

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)isoazol-3-yl)oxy (Yl)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)-2-oxoethyl)-2-(methyl ((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),

[化35]

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 (Yl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)-2-oxoethyl)-2-(methylamino) )Propylamide ((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),

[化36]

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 (Yl)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperidin-1-yl)-2-oxoethyl)-2-(methylamino)propionyl Amine ((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),

、 及[化37]

, 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)isoazol-3-yl)oxy)ethoxy)ethoxy)ethyl (Oxy)ethyl)-1H-indole-5-carbonyl)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propionamide ((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)

。[化38]

.

[11] A medicine comprising the compound described in any one of [1] to [10] above or a pharmaceutically acceptable salt thereof. [12] The medicine according to any one of [1] to [10] above, which is an IRAK-M proteolysis inducer. [13] The medicine according to any one of [1] to [10] above, which is a preventive or therapeutic agent for cancer. [14] The medicine as described in any one of [1] to [10] above, which is used in combination with other anticancer agents. [15] A method for inducing the breakdown of IRAK-M protein, characterized in that it administers the compound described in any one of [1] to [10] or a pharmaceutically acceptable salt thereof to a patient in need of treatment The effective amount. [16] A method for preventing or treating cancer, characterized in that it is effective by administering the compound described in any one of [1] to [10] above or a pharmaceutically acceptable salt thereof to a patient in need of treatment the amount. [Effects of Invention]

The compound of the present invention has the activity of inducing the decomposition of IRAK-M protein, and is useful as a preventive or therapeutic agent for cancer, fibrosis, and infection.

Hereinafter, with respect to the present invention, an exemplary embodiment is taken as an example to describe the compounds of the present invention, their production methods and uses, and preferred methods and materials that can be used in the implementation of the present invention. Furthermore, as long as there is no special description in the text, all technical and scientific terms used in this specification have the same meaning as those commonly understood by practitioners in the technical field to which the present invention belongs. In addition, any materials and methods equivalent or equivalent to those described in this specification can be used in the same manner in the implementation of the present invention. In addition, all publications and patents cited in this specification in relation to the invention described in this specification constitute a part of this specification as, for example, those showing methods or materials that can be used in the present invention. In addition, in this specification, the description of "A-B" which shows a numerical range means the numerical range including A and B as an end point. The same goes for "A to B". In this specification, "Me" means a methyl group except when it has a different meaning depending on the context before and after it. In this specification, there are cases where compound names such as substituents are described, and common names are used instead of official names, and these all mean the same compound.

Hereinafter, the definition of each substituent used in this specification will be explained in detail. Unless otherwise stated, each substituent has the following definitions.

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

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

In the present specification, as the "C1-3 alkyl group which may be halogenated", for example, a C1-3 alkyl group which may have 1 to 5 halogen atoms is exemplified. 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-di Fluorocyclopropyl.

In the present specification, as "C1-6 alkyl", for example, 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.

In the present specification, as the "C1-6 alkyl group which may be halogenated", for example, a C1-6 alkyl group which may have 1 to 7, preferably 1 to 5 halogen atoms can be cited. 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, second butyl, tertiary butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6 ,6-Trifluorohexyl.

In this specification, examples of "C2-6 alkenyl" include vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butene. Group, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3- Pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl.

In the present specification, examples of "C1-6 alkylsulfonyl" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, and butylsulfonyl , The second butylsulfonyl, the third butylsulfonyl.

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

In the present specification, as "C6-14 arylene", for example, phenylene, 1,5-naphthylene, 1,4-naphthylene, 2,3-naphthylene, 1,8- Anthrylene, 9,10-anthryl.

In the present specification, as "C1-6 alkoxy", for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, second butoxy, The third butoxy group, pentoxy group, and hexyloxy group.

In the present specification, as the "hydrocarbon group" (including the "hydrocarbon group" in the "substitutable hydrocarbon group"), for example, C1-3 alkyl, C1-6 alkyl, C1-6 alkylene, C2-6 Alkenyl, C6-14 aryl, C6-14 arylene. In this specification, as the "hydrocarbon group which may be substituted", for example, a hydrocarbon group which may have a substituent selected from the following substituent group A is mentioned.

[Substituent Group A] (1) Halogen atom, (2) C1-3 alkyl, (3) C1-6 alkoxy, (4) Amino group.

The number of the aforementioned substituents in the "substitutable hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.

In the present specification, as "C1-6 alkylene which may be substituted" or "C3-10 cycloalkylene which may be substituted", for example, the substituent group A (halogen atom, C1- (3) C1-6 alkylene or C3-10 cycloalkylene as the substituent of the alkyl group, C1-6 alkoxy group, and amino group. The number of the aforementioned substituents is, for example, 1 to 5. When the number of substituents is 2 or more, each substituent may be the same or different.

In the present specification, as "C6-14 aryl group which may be substituted" or "C6-14 aryl group which may be substituted", for example, it may have a substituent group A (halogen atom, C1-3 alkane C6-14 aryl group or C6-14 arylene group as the substituent of the 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, each substituent may be the same or different.

In the present specification, as the "aminomethanyl group which may be substituted", for example, it may have "self-respectively may have a substituent group A (halogen atom, C1-3 alkyl group, C1-6 alkoxy group, and (Amino) with 1 to 3 substituents (C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, 1 or 2 substituents selected from "aminomethanyl".

In the present specification, as "C1-6 alkylene", for example, methylene, 1,2-ethylene, 1,1-ethylene, 1,2-propylene, 1,3- Propylene, 2,2- Propylene, 1,4-Ethylene, 1,2-Ethylene, 1,3-Ethylene, 2,2-Ethylene, 1,5-Ethylene Base, 3,3-pentylene, 1,6-hexylene.

In the present specification, as "C3-10 cycloalkylene", for example, 1,1-cycloalkylene, cis-1,2-cycloalkylene, trans-1,2-cycloalkylene, 1,1-cyclobutylene, cis-1,2-cyclobutylene, trans-1,2-cyclobutylene, cis-1,3-cyclobutylene, trans-1,3-cyclobutylene Butyl, 1,1-cyclopentyl, cis-1,2-cyclopentyl, trans-1,2-cyclopentyl, cis-1,3-cyclopentyl, trans-1,3 -Cyclopentyl, 1,1-cyclohexyl, cis-1,2-cyclohexyl, trans-1,2-cyclohexyl, cis-1,3-cyclohexyl, trans-1,3- Cyclohexyl, cis-1,4-cyclohexyl, trans-1,4-cyclohexyl, 1,1-cycloheptyl, 1,1-cyclooctyl, 2,2-dimethyl 1 ,1-Cyclopropylene, 2,3-Dimethyl 1,1-Cyclopropylene, 2,2,3,3,4,4-Tetramethyl 1,1-Cyclobutyl, 7, 7-Shen Jiang Jiaji, 7,7-Shen Jiang Jia, 7,7-Shen Jiang Jia.

In this specification, "linker" refers to a chemical moiety (structure) used to bond a part of a target compound to another compound. Exemplary linkers are described in this specification. For example, in any compound described in this specification, a chemical structure for bonding a part of its structure to another part of the structure can be used as a linking group, which is equivalent to the linking group mentioned in this specification.

In the present specification, "a group having 5-20 carbon atoms that may contain heteroatoms" refers to a C5-20 straight or branched chain alkyl, alkenyl, alkenyl group that may contain at least one heteroatom selected from N and O. Cycloalkyl, aryl, arylalkyl or alkylaryl, and groups bonded to the same carbon atom may be bonded together to form a ring.

In this manual, "bonding bond" means a state where two groups adjacent to each other via a bond bond are bonded with a single bond. In addition, when a plurality of "bonding keys" are connected, it means that they are all connected to each other with a single key.

Hereinafter, each symbol of formula (II) will be described. Y is CH or N, preferably CH. R ⁰¹ is H or Me, preferably H. The arrow indicates the bond to the linker (L).

R ⁰³ is the following structural formula:

(此處，*表示鍵結於O之位置，**表示鍵結於A之位置，n為0～2之整數)所表示之基，最佳為以下之結構式：[化39]

(Here, * means the position of bonding to O, ** means the position of bonding to A, n is an integer from 0 to 2), the best is the following structural formula:

(此處，*表示鍵結於O之位置，**表示鍵結於A之位置)所表示之基。[化40]

(Here, * means the position of bonding to O, ** means the position of bonding to A).

A is the following structural formula:

(此處，R⁰⁵ 分別獨立為氫原子或C1-6烷基)所表示之基、或*-SO₂ -*，較佳為*-CH₂ -*、或*-SO₂ -*。[化41]

(Here, R ^{05 is} each independently a hydrogen atom or a C1-6 alkyl group) or *-SO ₂ -*, preferably *-CH ₂ -* or *-SO ₂ -*.

R ⁰⁴ is the following structural formula:

(此處，*表示鍵結於A之位置，**表示鍵結於連接基之位置)所表示之任一基、可經取代之C1-6伸烷基、可經取代之C3-10伸環烷基、可經取代之C6-14伸芳基、或鍵結鍵，較佳為上述結構式所表示之任一基。[化42]

(Here, * means the position of bonding to A, ** means the position of bonding to the linking group) any of the groups represented, C1-6 alkylene which may be substituted, C3-10 alkylene which may be substituted The cycloalkyl group, the C6-14 arylene group that may be substituted, or the bonding bond is preferably any group represented by the above structural formula.

As the "substituent group" of "substitutable C1-6 alkylene group", "substitutable C3-10 cycloalkylene group", and "substitutable C6-14 arylalkylene group" represented by ^{R 04} ", the substituent selected from the above-mentioned substituent group A can be mentioned. The number of substituents is, for example, 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.

Hereinafter, each symbol of formula (IV) will be described. 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 C1-6 alkyl group that can form a ring with each other, preferably each independently represents hydrogen The atom or the C1-6 alkyl group more preferably each independently represents a hydrogen atom or a C1-3 alkyl group, and it is still more preferable that each independently represents a hydrogen atom or a methyl group. Either D or E is bonded to the linking group (L).

D is the following formula (V):

(式中，m表示0～2之整數，n表示0～2之整數，W₁₁ 表示亞甲基、二氟亞甲基、O、S、SO、SO₂ 、或NR，此處，R表示氫原子、C1-6烷基、C1-6烷基-羰基、C6-14芳基-羰基、或C1-6烷基磺醯基，T表示可經鹵化之C1-3烷基)、或下述式(VI)：[化43]

(In the formula, m represents an integer from 0 to 2, n represents an integer from 0 to 2, W ₁₁ represents methylene, difluoromethylene, 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, T represents a C1-3 alkyl group that can be halogenated), or Formula (VI):

(式中，Q表示氧原子、式-NR²¹ -(式中之R²¹ 表示氫原子、或可與C1-6烷基、P一起形成環之烷基)、或鍵結鍵，P表示氫原子、C1-6烷基或與連接基(L)之鍵結(包括與Q一起形成環且對於連接基(L)之鍵結))表示。[化44]

(In the formula, Q represents an oxygen atom, the formula -NR ^21- (where R ²¹ represents a hydrogen atom, or an alkyl group that can form a ring together with a C1-6 alkyl group and P), or a bonding bond, and P represents hydrogen An atom, a C1-6 alkyl group or a bond with the linking group (L) (including a ring formed with Q and a bond to the linking group (L)) are represented.

D is preferably the following formula (V-2):

或下述式(VI-1)：[化45]

Or the following formula (VI-1):

(式中，Q表示對於連接基(L)之鍵結)。 上述D可於式(VI)中之P及Q、或式(VI-1)中之Q處對於連接基(L)之鍵結。[化46]

(In the formula, Q represents the bond to the linking group (L)). The above D can be bonded to the linking group (L) at P and Q in formula (VI), or Q in formula (VI-1).

E is the following formula (VII):

(式中之R₂₁ 、R₂₂ 、R₂₃ 分別獨立地表示氫原子、鹵素原子、C1-6烷基、C1-6烷氧基、或可經取代之胺甲醯基，較佳為R₂₁ 、R₂₂ 、R₂₃ 分別獨立地表示氫原子、鹵素原子、C1-6烷基、或C1-6烷氧基，R₂₅ 、R₂₆ 分別獨立地表示氫原子、鹵素原子、C1-6烷基、C1-6烷氧基、可經取代之胺甲醯基、或對於連接基(L)之鍵結，較佳為R₂₅ 、R₂₆ 分別獨立地表示氫原子、鹵素原子、C1-6烷基、C1-6烷氧基、或對於連接基(L)之鍵結，R₂₄ 表示氫原子、甲基、或對於連接基(L)之鍵結；其中對於連接基(L)之鍵結為R₂₄ 、R₂₅ 或R₂₆ 之任一者)、或下述式(VIII)：[化47]

(In the formula, R ₂₁ , R ₂₂ , and R ₂₃ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or a substituted aminomethyl group, preferably R ₂₁ , R ₂₂ and R ₂₃ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a C1-6 alkoxy group, and R ₂₅ and R ₂₆ each independently represent a hydrogen atom, a halogen atom, and a C1-6 alkyl group , C1-6 alkoxy group, substituted amine methanoyl group, or bonding to the linking group (L), preferably R ₂₅ and R ₂₆ each independently represent a hydrogen atom, a halogen atom, and C1-6 alkane Group, C1-6 alkoxy group, or for the bonding of the linking group (L), R ₂₄ represents a hydrogen atom, a methyl group, or the bonding to the linking group (L); wherein for the bonding of the linking group (L) Is any of R ₂₄ , R ₂₅ or R ₂₆ ), or the following formula (VIII):

(式中之R₃₁ 、R₃₂ 、R₃₃ 、R₃₄ 、R₃₅ 分別獨立地表示氫原子、鹵素原子、C1-6烷基、C1-6烷氧基、或可經取代之胺甲醯基，較佳為R₃₁ 、R₃₂ 、R₃₃ 、R₃₄ 、R₃₅ 分別獨立地表示氫原子、鹵素原子、或C1-6烷基，R表示氫原子、C1-6烷基或對於連接基(L)之鍵結).[化48]

(In the formula, R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , and R ₃₅ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or a substituted amine methanoyl group , Preferably R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , and R ₃₅ each independently represent 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 linking group ( L) the bond).

Hereinafter, the linking group (L) of formula (I) will be described. The linking group (L) is preferably a group with 5-20 carbon atoms that may contain heteroatoms, and more preferably is the structural formula described below:

所表示之基、*-(CH₂ CH₂ O)n(CH₂ )m(NRCO)s(CH₂ )t-*(n為1～5之自然數，m為0、1、或2，s為0或1，t為0或1，R表示氫原子或C1-6烷基)，或者為鍵結鍵，進而較佳為以下所記載之結構式：[化49]

The base represented, *-(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, R represents a hydrogen atom or a C1-6 alkyl group), or a bonding bond, which is more preferably the structural formula described below:

(此處，*表示鍵結於IRAK-M結合物(M))所表示之基、或*-(CH₂ CH₂ O)n-*(n為1～5之自然數)。[化50]

(Here, * represents the group bound to IRAK-M conjugate (M)) or *-(CH ₂ CH ₂ O)n-* (n is a natural number from 1 to 5).

In this specification, "compounds with additional functions" refer to conjugates of any protein present in the organism, cell penetrating peptides (CPP), or kinetophores that leave the compound in the intestinal tract (such as Short-chain peptides, sugars and polyethylene oxide capped with quaternary ammonium, etc.).

In this specification, "IRAK-M protein-related disorders" refer to diseases or disorders that are explained or inferred in relation to the IRAK-M protein itself or the abnormalities that it controls. The abnormality of protein includes, for example, the abnormal expression of protein in the living body or the existence of hyperplasia or mutant protein, but it is not limited to this.

The compound of the present invention included in the compound (I) can be used as a synthetic intermediate in the production of other compounds (I) of the present invention. In addition, it can also be used as a synthesis intermediate when producing IRAK-M proteolysis inducers other than compound (I).

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

Among them, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, examples include inorganic salts such as alkali metal salts (such as sodium salt, potassium salt, etc.), alkaline earth metal salts (such as calcium salt, magnesium salt, etc.), ammonium salt, etc.; When the compound has a basic functional group, for example, it can include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid; or with acetic acid, phthalic acid, fumaric acid, Salts of organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

The method for producing the compound of the present invention will be described below. The raw materials or reagents used in each step of the following manufacturing methods and the obtained compounds can form salts, respectively. As such a salt, for example, the same salt as the above-mentioned salt of the compound of the present invention can be cited.

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

The compound obtained in each step can be directly used in the next reaction in the state of the reaction liquid, or can also be used in the next reaction after being obtained in the form of a crude product. Or, according to conventional methods, the compounds obtained in each step can be isolated and/or refined from the reaction mixture using separation methods such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractionation, and chromatography.

When the raw materials or reagent compounds for each step are commercially available, the commercially available products can be used directly.

In the reaction of each step, the reaction time may vary according to the reagents or solvents used, and if there is no special description, it is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

In the reaction of each step, the reaction temperature may vary according to the reagents or solvents used, and unless otherwise specified, it is usually -78°C to 300°C, preferably -78°C to 150°C.

In the reaction of each step, the pressure may vary according to the reagents or solvents used, and unless otherwise specified, it is usually 1 atmosphere to 20 atmospheres, preferably 1 atmosphere to 3 atmospheres.

In the reaction of each step, for example, a microwave synthesis device such as Initiator manufactured by Biotage Corporation may be used. The reaction temperature may vary according to the reagents or solvents used, and unless otherwise specified, it is usually from room temperature to 300°C, preferably from 50°C to 250°C. The reaction time may vary according to the reagents or solvents used, and if there is no special description, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.

In the reaction of each step, when there is no special description, the reagent can be used in the range of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents relative to the raw material. In the case of 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 raw material. When the reagent is also used as a reaction solvent, the amount of solvent can be used for the reagent.

In the reaction of each step, when there is no special description, the reaction can be carried out without a solvent, or can be carried out by dissolving or suspending in a suitable solvent. As a specific example of a solvent, the solvent described in the Example, or the following can be mentioned. Alcohols: methanol, ethanol, tertiary butanol, 2-methoxyethanol, etc.; Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.; Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, hexane, etc.; Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.; Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Supplements: dimethyl sulfite, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Inorganic acids: hydrochloric acid, sulfuric acid, etc.; Esters: ethyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; water. The above-mentioned solvents can be used by mixing two or more kinds in an appropriate ratio.

When a base is used in the reaction of each step, for example, the base shown below or the base described in the examples can be used. Inorganic bases: sodium hydroxide, magnesium hydroxide, etc.; Alkaline salts: sodium carbonate, calcium carbonate, sodium bicarbonate, etc.; Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8 -Diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; Metal alkoxides: sodium ethoxide, potassium tertiary butoxide, etc.; Alkali metal hydrides: sodium hydride, etc.; Metallic amides: sodium amide, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, etc.; Organic lithiums: n-butyl lithium, etc.

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

As long as there is no special description, the reaction of each step can be carried out in accordance with a method known per se, such as the method described in the following documents, or the method described in the examples: 5th Edition Lectures on Experimental Chemistry, Volumes 13 to 19 (The Chemical Society of Japan Edited); New Laboratory Chemistry Lectures, Volumes 14 to 15 (Edited by the Chemical Society of Japan); Fine Organic Chemistry Revised 2nd Edition (LF Tietze, Th. Eicher, Nanjiangtang); Revised the structure and main points of organic name reaction (by Togo Hideo) , Kodansha); ORGANIC SYNTHESES Collective Volume I～VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (by Jie Jack Li, published by OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol. 1～Vol.14 (Elsevier Japan Co., Ltd.); Organic synthesis strategy for learning in name reaction (translated by Tomioka Kiyoshi, published by Chemical Doujin); Comprehensive Organic Transformations (VCH Publishers Inc.) published in 1989, etc.

In each step, the protection or deprotection reaction of the functional group can be carried out according to the method known per se, such as the method described in the following literature or the method described in the examples: "Protective Groups in Organic" published by Wiley-Interscience in 2007 Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts); "Protecting Groups 3rd Ed." (PJ Kocienski) published by Thieme in 2004, etc. Examples of protective groups for hydroxyl groups such as alcohols or phenolic hydroxyl groups include ether type protective groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; Carboxylate-type protecting groups such as acid esters; sulfonate-type protecting groups such as mesylate; carbonate-type protecting groups such as tert-butyl carbonate, etc. Examples of the protective group for the carbonyl group of the aldehyde include acetal-type protective groups such as dimethylacetal; cyclic acetal-type protective groups such as cyclic 1,3-dioxane. Examples of the protective group for the carbonyl group of a ketone include: ketal-type protective groups such as dimethyl ketal; cyclic ketal-type protective groups such as cyclic 1,3-dioxane; and oxime-type protective groups such as O-methyloxime Protecting groups; hydrazone-type protective groups such as N,N-dimethylhydrazone, etc. Examples of the protecting group of the carboxyl group include ester-type protecting groups such as methyl ester; amide-type protecting groups such as N,N-dimethylamide. Examples of the protecting group of thiol include ether type protecting groups such as benzyl sulfide; ester type protecting groups such as thioacetate, thiocarbonate, and thiocarbamate. Examples of protective groups for amino groups or aromatic heterocycles such as imidazole, pyrrole, and indole include: carbamate-type protective groups such as benzyl carbamate; amide-type protective groups such as acetamide; N- Alkylamine-type protecting groups such as triphenylmethylamine; sulfonamide-type protecting groups such as tosylamide, etc. The removal of the protective group can be carried out by a known method, such as a method using the following substances or a reduction method: acid, alkali, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutyl Ammonium fluoride, palladium acetate, trialkylsilyl halide (for example, trimethylsilyl iodide, trimethylsilyl bromide).

In each step, when the reduction reaction is carried out, the reducing agent used may include: lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutyl aluminum hydride (DIBAL -H), sodium borohydride, triacetoxytetramethylammonium borohydride and other metal hydrides; boranes such as borane tetrahydrofuran complexes; Raleigh nickel; Raleigh cobalt; hydrogen; formic acid; triethyl Base silane and so on. In the case of reducing the carbon-carbon double bond or the triple bond, there is a method of using catalysts such as palladium-carbon or Lindlar catalyst.

In each step, when the oxidation reaction is carried out, the oxidizing agent used can include: peroxygens such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, and tertiary butyl hydroperoxide; perchloric acid Perchlorates such as tetrabutylammonium; chlorates such as sodium chlorite; chlorites such as sodium chlorite; periodic acids such as sodium periodate; high-valent iodine reagents such as iodobenzene ; Manganese dioxide, potassium permanganate and other reagents containing manganese; lead tetraacetate and other lead compounds; pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent and other chromium-containing reagents; N- Halogen compounds such as bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano -1,4-Benzoquinone (DDQ) and so on.

In each step, when the free radical cyclization reaction is carried out, as the free radical initiator used, azo compounds such as azobisisobutyronitrile (AIBN); 4-4'-azo Water-soluble free radical initiators such as bis-4-cyanovaleric acid (ACPA); triethylboron in the presence of air or oxygen; benzyl peroxide, etc. In addition, as the free radical reaction reagent used, tributylstannane, tris(trimethylsilyl)silane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, and samarium iodide can be mentioned. Wait.

In each step, when the Wittig reaction is performed, the Wittig reagent used includes alkylene phosphanes and the like. The alkylenephosphanes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

In each step, when the Horner-Emmons reaction is performed, the reagents used include: phosphinyl acetate, trimethyl phosphinyl acetate, triethyl phosphinyl acetate, etc. Base acetates; alkali metal hydrides, organic lithiums and other bases.

In each step, when the Friedel-Crafts reaction is carried out, the reagents used include: a combination of a Lewis acid and a chlorine, or a Lewis acid and an alkylating agent (for example Halogenated alkyls, alcohols, olefins, etc.). Alternatively, an organic acid or an inorganic acid may be used instead of the Lewis acid, and an acid anhydride such as acetic anhydride may be used instead of the chlorine.

In each step, when performing an aromatic nucleophilic substitution reaction, as reagents, nucleophiles (for example, amines, imidazoles, etc.) and bases (for example, basic salts, organic bases, etc.) can be used.

In each step, perform nucleophilic addition reaction using carbon anion, nucleophilic 1,4-addition reaction using carbon anion (Michael addition reaction), or nucleophilic substitution reaction using carbon anion In this case, examples of bases for generating carbon anions include organic lithiums, metal alkoxides, inorganic bases, and organic bases.

In each step, when the Grignard reaction is carried out, the Grignard reagents include aryl magnesium halides such as phenyl magnesium bromide; alkyl magnesium halides such as methyl magnesium bromide . The Grignard reagent can be prepared by a known method. For example, it can be prepared by reacting an alkyl halide or an aryl halide with metallic magnesium using ether or tetrahydrofuran as a solvent.

In each step, in the case of Knoevenagel condensation reaction, as a reagent, an active methylene compound sandwiched between two electron withdrawing groups (such as malonic acid, diethyl malonate) can be used as a reagent. Esters, malononitrile, etc.) and bases (for example, organic bases, metal alkoxides, inorganic bases).

In each step, when performing the Vilsmeier-Haack reaction, as reagents, phosphatidyl chloride and amide derivatives (such as N,N-dimethylformamide, etc.) can be used as reagents. ).

In each step, in the case of carrying out the azidation reaction of alcohols, alkyl halides, and sulfonate esters, the azidation agent used includes: diphenyl azide phosphate (DPPA) , Trimethylsilyl azide, sodium azide, etc. For example, in the case of azidating alcohols, there is a method of using diphenyl azide phosphate and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or using Methods of azide trimethylsilane and Lewis acid, etc.

In each step, when the reductive amination reaction is performed, the reducing agent used includes sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid, and the like. When the raw material is an amine compound, as the carbonyl compound used, in addition to paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone can be cited. When the raw material is a carbonyl compound, the amines used include primary amines such as ammonia and methylamine; secondary amines such as dimethylamine.

In each step, when the Mitsunobu reaction is carried out, as reagents, azodicarboxylates (such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate ( DIAD), di-tertiary butyl azodicarboxylate, etc.) and triphenylphosphine.

In each step, when the esterification reaction, the amination reaction, or the urea reaction is carried out, the reagents used include: halides such as chlorine and bromine; acid anhydrides, active esters, and sulfuric acid Activated carboxylic acids such as esters. Examples of carboxylic acid activators include carbodiimide-based condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); 4- (4,6-Dimethoxy-1,3,5-tris-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM) and other tri-condensing agents; Carbonate-based condensation agents such as 1,1-carbonyldiimidazole (CDI); diphenyl azide phosphate (DPPA); benzotriazol-1-yloxy-tris(dimethylamino)phosphonium salt (BOP reagent ); 2-chloro-1-methyl-pyridinium iodide (Xiangshan reagent); sulfite chloride; lower alkyl haloformic acid esters such as ethyl chloroformate; O-(7-azabenzotriazole-1 -Radical) -N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; 2,4,6-tripropyl-1,3,5,2,4,6 -Trioxatriphosphine-2,4,6-trioxide (T3P); or a combination of these. When a carbodiimide-based condensing agent is used, 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) can be added to the reaction. And other additives.

In each step, when the coupling reaction is carried out, the metal catalyst used can be exemplified: palladium acetate (II), tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) ) Palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), 1,1'-bis(diphenylphosphine) dicene chloride Palladium compounds such as iron palladium(II) and palladium(II) acetate; nickel compounds such as tetrakis(triphenylphosphine) nickel(0); rhodium compounds such as tris(triphenylphosphine) rhodium(III) chloride; cobalt compounds; Copper compounds such as copper oxide and copper (I) iodide; platinum compounds, etc. Furthermore, a base may be added to the reaction, and examples of such bases include inorganic bases and alkaline salts.

In each step, when the thiocarbonylation reaction is carried out, as the thiocarbonylating agent, phosphorus pentasulfide can be typically used. In addition to phosphorus pentasulfide, 2,4-bis(4-methoxyphenyl) can also be used. -1,3,2,4-Dithiadiphosphetane-2,4-disulfide (Lawesson's reagent) etc. have 1,3,2,4-dithiadiphosphetine Alkyl-2,4-disulfide structure reagent.

In each step, when the Wohl-Ziegler reaction is performed, the halogenating agent used includes: N-iodosuccinimide, N-bromosuccinimide (NBS ), N-chlorosuccinimide (NCS), bromine, sulfonyl chloride, etc. Furthermore, the reaction can be accelerated by applying heat, light, or adding a radical initiator such as benzoyl peroxide and azobisisobutyronitrile to the reaction.

In each step, when the halogenation reaction of the hydroxyl group is carried out, the halogenating agent used includes hydrohalic acid and inorganic acid halides. Specifically, chlorination includes hydrochloric acid, sulfite Chlorine, phosphorus oxychloride, etc.; for bromination, 48% hydrobromic acid, etc. can be cited. In addition, a method of obtaining a halogenated alkyl body from an alcohol by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide or the like can also be used. Alternatively, a method of synthesizing a halogenated alkyl body through a two-stage reaction in which an alcohol is converted into a sulfonate and then reacted with lithium bromide, lithium chloride, or sodium iodide can be used.

In each step, when the Arbuzov reaction is carried out, the reagents used include: halogenated alkyls such as ethyl bromoacetate; triethyl phosphite or triisopropyl phosphite And other phosphites.

In each step, when the sulfonic acid esterification reaction is performed, the sulfonating agent used includes methanesulfonic acid chloride, p-toluenesulfonic acid chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and the like.

In each step, when the hydrolysis reaction is carried out, an acid or a base can be used as a reagent. In addition, in the case of performing the acid hydrolysis reaction of tertiary butyl ester, in order to reductively capture the tertiary butyl cation which is a by-product, formic acid, triethylsilane, or the like may be added.

In each step, when the dehydration reaction is carried out, the dehydrating agent used can include: sulfuric acid, phosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, oxidation Aluminum, polyphosphoric acid, etc.

In each step, in the case of carrying out the alkylation reaction of alcohols, amines, or aromatic heterocycles having NH groups in the ring (for example: imidazole, pyrazole), etc., as the alkylating agent, one can include: Substituted haloalkyl (e.g. methyl iodide), or substituted alkyl with optionally substituted C1-6 alkylsulfonyloxy group as the leaving group, or with C6 optionally substituted by C1-6 alkyl -14 Arylsulfonyloxy group may be substituted alkyl, or 2-chloro-2,2-difluorosodium acetate, 2,2-difluoro-2-(fluorosulfonyl)acetic acid, etc. In addition, examples of the base used include organic lithiums, metal alkoxides, inorganic bases, and organic bases.

In each step, when the fluorination reaction is carried out, the fluorinating agent used can include: DAST (diethylaminosulfur trifluoride), bis(2-methoxyethyl)aminotrifluoride Sulfur fluoride, 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor), 4-tertiary butyl-2,6 -Dimethylphenylsulfur trifluoride (FLUOLEAD) and so on.

In each step, when the Huisgen reaction is performed, as the reagents used, azide compounds and alkyne compounds can be used. As a catalyst, a monovalent copper ion can be mentioned, for example, copper iodide, copper chloride, copper cyanide, etc. are mentioned.

In each step, when the coupling reaction is carried out, the coupling reaction may include: Suzuki coupling, Stille coupling, Buchwald-Hartwig coupling, Negishi coupling, Mizoroki-Heck reaction, cyanation reaction using copper cyanide or zinc cyanide, etc. In addition to the above-mentioned reagents, the metal catalysts, phosphine ligands, and alkalis used in the coupling reaction can also be conventionally known methods (for example, JF Hartwig, S. Shekhar, Q. Shen, F. Barrios-Landeros, in The Chemistry of Anilines, Z. Rappoport, Ed., Wiley-Intersicence, New York (2007); L. Jiang, SL Buchwald, in Metal-Catalyzed Cross-Coupling Reactions, 2nd Ed., A. de Meijere, F. Diederich , Eds., Wiley-VCH, Weinheim, Germany (2004); JF Hartwig, in Handbook of Organopalladium Chemistry for Organic Synthesis, A. de Meijere, F. Diederich, Eds., Wiley, New York (2002); JF Hartwig, in Modern Amination Methods, A. Ricci, Ed., Wiley-VCH, Weinheim, (2000)), or use according to these methods.

Hereinafter, the production method of compound (I) will be described. Unless otherwise stated, each symbol in the following reaction formula has the same meaning as above. When the specific production method is not described, the raw material compound can be easily obtained on the market, or can be produced by a method known per se or according to the method and the method described in the examples.

In the reaction of each step, when there is a reactive site that causes a reaction other than the target, a protective group may be introduced into the reactive site in advance by a method known per se, if necessary, and the target reaction is still known per se. The method removes the protecting group. For example, when the raw material compound or intermediate has an amine group, a carboxyl group, or a hydroxyl group as a substituent, these groups can be protected by a protecting group commonly used in peptide chemistry. In this case, the target compound can be obtained by removing the protective group as necessary after the reaction.

Compound (I) can be synthesized from compound (1) as an IRAK-M conjugate or compound (4) as an E3 ligase conjugate by the method shown in the following scheme. In each process, the compound (I) and each reaction intermediate can independently form a salt.

Process 1

[化51]

Compound (3) can be amination reaction, Mitsunobu reaction, alkylation reaction or coupling of compound (1) or its reactive derivative and compound (2) or its reactive derivative as linker (L) The compound (I) can be produced by reaction, etc., by subjecting the compound (3) or its reactive derivative to the compound (4) or its reactive derivative to undergo an amination reaction, Mitsunobu reaction, alkylation reaction, or coupling reaction, etc. And manufacturing.

Compound (5) can be produced by subjecting compound (4) or its reactive derivative and compound (2) or its reactive derivative to amination reaction, Mitsunobu reaction, alkylation reaction or coupling reaction, etc., compound ( I) can be produced by subjecting compound (5) or its reactive derivative to compound (1) or its reactive derivative to undergo an amidation reaction, a Mitsunobu reaction, an alkylation reaction, or a coupling reaction.

Compound (3a) can be produced by subjecting compound (1) or its reactive derivative and compound (2a) or its reactive derivative to an amidation reaction, Mitsunobu reaction, alkylation reaction or coupling reaction, etc., compound ( 5a) It can be produced by subjecting compound (4) or its reactive derivative to compound (2b) or its reactive derivative to undergo an amination reaction, Mitsunobu reaction, alkylation reaction, or coupling reaction, etc., compound (I) It can be produced by subjecting compound (3a) and compound (5a) or these reactive derivatives to an amidation reaction, a Mitsunobu reaction, an alkylation reaction, a coupling reaction, a Whisgen reaction, or the like.

The method for producing the IRAK-M conjugate (M) (compound (1)) represented by the formula (II) below constituting a part of the compound (I) will be described below.

Process 2

[化52]

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

The compound (8) can be produced by subjecting the compound (6) and the compound (7) to an aromatic nucleophilic substitution reaction or a coupling reaction. The compound (II) can be produced by subjecting the compound (8) and the compound (9) or a reactive derivative thereof to an alkylation reaction, a sulfonation reaction, a reductive amination reaction, or the like.

L (compound (2)) as a part of the linking group (L), L ₁ (compound (2a)), L ₂ (compound (2b)) as a part of the linking group (L), which forms part of the compound (I), can be Commercially available products are used directly, or manufactured by a method known per se or in accordance with the method.

The following is the manufacturing method when the XIAP conjugate that constitutes a part of the E3 ligase conjugate, that is, E (compound (4)) is a compound represented by the following formula (IV-I), which constitutes a part of compound (I) Description.

Process 3

[化53]

Compound (12) can be produced by subjecting compound (10) to compound (11) or its reactive derivative to undergo an amidation reaction, etc. Compound (14) can be produced by combining compound (12) with compound (13) or Its reactive derivatives are produced by amination reaction and the like. The compound (IV-I) can be produced by subjecting the compound (14) to the compound (15) or a reactive derivative thereof to an amination reaction or the like. In addition, compound (16) can be produced by subjecting compound (10) to compound (15) or its reactive derivative to undergo an amination reaction, etc., and compound (17) can be produced by combining compound (16) with compound (11). ) Or its reactive derivative is manufactured by subjecting to amination reaction or the like. Compound (IV-I) can be produced by subjecting compound (17) to compound (13) or a reactive derivative thereof to amination reaction or the like.

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

Process 4

[化54]

Compound (18) can be produced by subjecting compound (16) and compound (17) to an amination reaction, etc., compound (IV-II) can be produced by subjecting compound (18) and compound (19) to an alkylation reaction, etc. And manufacturing. In addition, compound (20) can be produced by subjecting compound (10) and compound (17) to an amidation reaction, etc., and compound (21) can be produced by subjecting compound (20) and compound (19) to an alkylation reaction, etc. And manufacturing. The compound (IV-II) can be produced by subjecting the compound (21) to the compound (22) or a reactive derivative thereof to an amination reaction or the like.

The compound (I) thus obtained and the substituents in each intermediate can also be transformed (ie, the introduction of substituents or functional group transformation) by a method known per se to produce other compounds contained in compound (I) Compounds and corresponding intermediates or their salts.

The compound (I) obtained by the above-mentioned production method can be isolated and purified by well-known methods such as solvent extraction, pH conversion of the solution, inversion, crystallization, recrystallization, and chromatography.

When compound (I) contains optical isomers, stereoisomers, positional isomers, and rotamers, these are also included as compound (I), and can be separated by a conventionally known synthesis method. Techniques are obtained separately in the form of a single product. For example, when there is an optical isomer in the compound (I), the optical isomer resolved from the compound is also included in the compound (I). Here, the optical isomer can be produced by a method known per se.

Compound (I) may also be crystals. The crystal of the compound (I) (hereinafter sometimes referred to as the crystal of the present invention) can be produced by crystallizing the compound (I) by applying a conventionally known crystallization method. Compound (I) may also be a pharmaceutically acceptable co-crystal or co-crystal salt. Here, co-crystal or co-crystal salt means that each has different physical properties (for example, structure, melting point, heat of fusion, hygroscopicity, solubility, and stability) and is two or more kinds at room temperature. Unique solid crystalline substance. The co-crystal or co-crystal salt can be produced in accordance with a conventionally known co-crystallization method. The compound (I) may be a hydrate or a non-hydrate, and may be an ansolvate or a solvate. Furthermore, a ^{deuterium transformant obtained by converting 1} H to ² H (D) is also included in compound (I). Compound (I) can also ^{be labeled with isotopes (for example, 3} H, ¹³ C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²⁵ I). The isotope-labeled or substituted compound (I) can be used as a tracer (PET tracer) used in Positron Emission Tomography (PET), for example, and is expected to be useful in fields such as medical diagnosis.

Compound (I) can also be used as a prodrug. The prodrug of compound (I) is converted into the compound of compound (I) by the reaction of enzymes or gastric acid under physiological conditions in the organism, that is: enzymatic oxidation, reduction, hydrolysis, etc. change into the compound ( The compound of I); the compound of compound (I) due to hydrolysis caused by gastric acid, etc.

As the prodrugs of compound (I), examples include compounds in which the amine group of compound (I) is acylated, alkylated, or phosphorylated (for example, the amine group of compound (I) is acylated with eicosane or propylamine). , Pentylamino carbonylation, (5-methyl-2-oxo-1,3-dioxol-4-yl) methoxycarbonylation, tetrahydrofurylation, pyrrolidinyl methyl Compound (I) is a compound obtained by acetylation, alkylation, phosphorylation or boration of the hydroxyl group of compound (I) (for example, compound (I)) The hydroxy group is a compound formed by acetylation, palm acylation, acrylation, popen acylation, succinylation, fumaration, propylamine acylation or dimethylaminomethyl carbonylation); Compound (I) is a compound formed by esterification or amination of the carboxyl group (for example, the carboxyl group of compound (I) is ethylated, phenyl esterified, carboxymethylated, dimethylaminomethylated, pivaloyl Oxymethylation, ethoxycarbonyloxyethylation, phthalyl esterification, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester Compounds formed by ethylation of cyclohexyloxycarbonyl ethyl ester or methyl amide) and so on. These compounds can be produced from Compound (I) by a method known per se.

In addition, the prodrug of compound (I) may also be a compound (I) that changes to compound (I) under physiological conditions as described in "Development of Pharmaceuticals" Vol. 7, Molecular Design, pages 163 to 198 of Guangchuan Bookstore, 1990. In this specification, the prodrug may form a salt, and examples of the salt include those exemplified as the salt of the compound represented by formula (I) described above.

Compound (I) can be combined with additional functional compounds, such as Cell Penetrating Peptide (CPP) or pharmacokinetic groups that retain the compound in the intestines (e.g., short-chain peptides, sugars, and quaternary ammonium-terminated polymers). Ethylene oxide, etc.) are used in conjunction, and compound (I) can be combined with a compound with additional functions directly or via a linking group.

Compound (I) can also be used as a payload in an antibody (or peptide antigen recognition sequence)-drug complex (the above-mentioned part is equivalent to a drug). When the compound (I) is used as a payload, the compound (I) can be bound to an antibody (or a peptide antigen recognition sequence) directly or via a linker. When compound (I) is used as a payload, in addition to the linker exemplified in this specification, it can also be used such as 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.

Compound (I) or its prodrugs (in this specification, the combination is sometimes abbreviated as "the compound of the present invention") has IRAK-M decomposition-inducing activity, and is used as a preventive or therapeutic drug for cancer, a cancer growth inhibitor, It is useful as an inhibitor of cancer metastasis. The compound of the present invention exhibits proteolysis-inducing activity against IRAK-M, and the compound of the present invention is effective in pharmacodynamic performance, pharmacokinetics (such as absorption, distribution, metabolism, excretion), solubility (such as water solubility), and other pharmaceutical products. Interaction (e.g. drug metabolism enzyme inhibition), safety (e.g. acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, central toxicity), stability (e.g. chemical stability, stability against enzymes) ) Is also excellent, so it can be useful as a medicine. Among them, it can be expected to be effective in the treatment or prevention of cancer, but it is not limited to this. In addition, the compound of the present invention has the activity of inducing the decomposition of IRAK-M protein in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, and humans). With reference to its mechanism of action, It can be used for all diseases involved in IRAK-M protein (in this manual, sometimes abbreviated as "IRAK-M related diseases"), such as cancer [such as colorectal cancer (such as colon cancer, rectal cancer, anal cancer, familial colorectal cancer) , Hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumors), lung cancer (e.g. non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (e.g. pancreatic ductal carcinoma, pancreatic endocrine tumors) , Pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (e.g. mastoid adenocarcinoma, mucinous adenocarcinoma, adenosquamous epithelial carcinoma), duodenal cancer, small intestine cancer, breast cancer (e.g. invasive ductal carcinoma of the breast, non-invasive ductal carcinoma of the breast) , Inflammatory breast cancer), ovarian cancer (e.g. epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low-malignant tumor), testicular tumor, prostate cancer (e.g. hormone-dependent prostate cancer, Hormone-independent prostate cancer, prostate cancer ineffective for castration therapy), liver cancer (e.g. hepatocellular carcinoma, primary liver cancer, extrahepatic cholangiocarcinoma), thyroid cancer (e.g. medullary thyroid cancer), kidney cancer (e.g. Renal cell carcinoma (e.g. clear cell renal cell carcinoma), transitional epithelial carcinoma of the renal pelvis and ureter), uterine cancer (e.g. cervical cancer, uterine body cancer, uterine sarcoma), choriocarcinoma of pregnancy, brain tumors (e.g. neural tube Blastoma, glioma, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, poorly differentiated astrocytoma, pituitary adenoma), retinoblastoma, skin cancer (e.g. basal Cell tumor, malignant melanoma), sarcoma (e.g. rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, spindle cell sarcoma), malignant bone tumor, bladder cancer, blood cancer (e.g. multiple myeloma, leukemia (e.g. acute myelogenous leukemia, Chronic lymphatic leukemia), malignant lymphoma (B-cell lymphoma, diffuse large-cell B-cell lymphoma, MALT (mucosa-associated lymphatic tissue, mucosa-associated lymphatic tissue) lymphoma, follicular lymphoma, mantle cell Lymphoma), Hodgkin’s disease, chronic myeloproliferative disease), preventive or therapeutic agents for unidentified primary cancer), cancer growth inhibitors, cancer metastasis inhibitors, apoptosis promoters, precancerous lesions ( For example, medicines such as therapeutic agents for myelodysplastic syndrome).

In addition, IRAK-M-related diseases other than cancer include asthma, inflammatory bone disease, inflammatory lung disease, idiopathic pulmonary fibrosis, inflammatory bowel disease (such as Crohn’s disease, ulcerative colitis, etc.), multiple Sexual sclerosis, systemic inflammatory response syndrome (SIRS), sepsis, infectious complications of hematopoietic stem cell transplantation, influenza infection, acute respiratory syndrome (COVID-19 (Coronavirus Disease 2019, new coronavirus pneumonia), MERS (Middle East Respiratory Syndrome), SARS (Severe Acute Respiratory Syndrome, Severe Acute Respiratory Syndrome), acute bacterial meningitis, Helicobacter pylori infection, invasive staphylococcal infection, tuberculosis, systemic fungal infection, herpes simplex virus Infection, varicella-zoster virus infection, human papilloma virus infection, acute viral encephalitis, encephalitis, meningitis, decreased immune function associated with infection, etc.

The compound of the present invention can be directly or formulated into a pharmacologically acceptable carrier to prepare a medicine and be administered to mammals (preferably humans) orally or parenterally. 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, tablets (for example, sugar-coated tablets, film-coated tablets, sublingual tablets, buccal tablets, orally disintegrating tablets), pills, granules, powders, capsules (for example, soft Oral preparations such as capsules, microcapsules), syrups, emulsions, suspensions, films (e.g., disintegrating membranes in the oral cavity, oral mucosal adhesive films). In addition, as the dosage form of the medicine of the present invention, for example, injections, drops, transdermal preparations (for example, iontophoresis transdermal preparations), suppositories, ointments, transnasal preparations, transpulmonary preparations, eye drops, etc. can be cited. Oral medicine. In addition, the medicine of the present invention may also be a controlled-release preparation such as an immediate-release preparation and a sustained-release preparation (for example, a sustained-release microcapsule). As the dosage form of the medicine of the present invention, nanoparticle preparations or preparations using bacteria-derived membranes can also be used.

The medicine of the present invention can be produced by a known production method (for example, a method described in the Japanese Pharmacopoeia) generally used in the field of preparation technology. In addition, the medicine of the present invention may optionally contain appropriate amounts of excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifiers, and coloring agents commonly used in the field of preparations. , Preservatives, fragrances, flavors, stabilizers, thickeners and other additives. Examples of the above-mentioned pharmacologically acceptable carriers include these additives.

For example, tablets can be manufactured using excipients, binders, disintegrating agents, lubricants, etc., and pills and granules can be manufactured using excipients, binders, and disintegrating agents. In addition, powders and capsules can be manufactured using excipients, etc., syrups can be manufactured using sweeteners, etc., and emulsions or suspensions can be manufactured using suspending agents, surfactants, emulsifiers, and the like.

Examples of excipients include lactose, white sugar, glucose, starch, sucrose, microcrystalline cellulose, powdered licorice, mannitol, sodium bicarbonate, calcium phosphate, and calcium sulfate. Examples of binding agents include: 5 to 10% by weight starch paste solution, 10 to 20% by weight acacia or gelatin solution, 1 to 5% by weight tragacanth solution, carboxymethyl cellulose solution, sodium alginate Liquid, glycerin. Examples of disintegrants include starch and calcium carbonate. Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, and refined talc. Examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, and monosyrup. Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyoxy(40) stearate. Examples of the suspending agent include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, and bentonite. Examples of emulsifiers include gum arabic, tragacanth, gelatin, and polysorbate 80.

For example, when the medicine of the present invention is a lozenge, the lozenge can be added to the compound of the present invention, for example, excipients (e.g. lactose, sugar, starch), disintegrating agents (e.g. starch, etc.) according to a known method. , Calcium carbonate), binding agents (e.g. starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose) or lubricants (e.g. talc, magnesium stearate, polyethylene glycol 6000 ) And compression molding, and then, as needed, for the purpose of taste masking, enteric solubility, or durability, it is manufactured by coating by a method known per se. As the coating agent used for coating, for example, hydroxypropyl methylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween80, Pluronic F68, Cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, EUDRAGIT (manufactured by ROHM, Germany, methacrylic acid-acrylic acid copolymer) and pigments (For example, iron oxide, titanium dioxide).

As the above-mentioned injections, in addition to intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, intraperitoneal injections, drip injections, etc. are included.

The injection can be prepared by a known method, that is, by dissolving, suspending or emulsifying the compound of the present invention in a sterile aqueous or oily liquid. Examples of the aqueous liquid include isotonic liquid containing physiological saline, glucose, or other adjuvants (for example, D-sorbitol, D-mannitol, and sodium chloride). The aqueous liquid may contain appropriate dissolution aids, such as alcohols (e.g. ethanol), polyhydric alcohols (e.g. propylene glycol, polyethylene glycol), non-ionic surfactants (e.g. polysorbate 80, HCO (Hydrogenated Castor Oil, Hydrogenated castor oil)-50). As an oily liquid, sesame oil, soybean oil, etc. are mentioned. The oily liquid may contain appropriate dissolution aids. Examples of the dissolution aid include benzyl benzoate, benzyl alcohol, and the like. In addition, buffers (such as phosphate buffer, sodium acetate buffer), analgesics (such as benzalkonium chloride, procaine hydrochloride), stabilizers (such as human serum albumin, poly Ethylene glycol), preservatives (e.g. benzyl alcohol, phenol) and the like. The prepared injection can usually be filled into an ampoule.

The content of the compound of the present invention in the medicine of the present invention varies according to 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 100% by weight relative to the entire preparation. About 70% by weight.

The content of the additives in the medicine of the present invention varies according to 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 entire preparation.

The compound of the present invention is stable and has low toxicity and can be used safely. The daily dosage of the compound of the present invention varies according to the state or weight of the patient, the type of the compound, the route of administration, etc., for example, in the case of oral administration to the patient for the purpose of treating cancer, an adult (body weight of about 60 kg) The daily dosage of the compound of the present invention is about 1 to about 1000 mg, preferably about 3 to about 300 mg, and more preferably about 10 to about 200 mg, which can be divided into 1 time or divided into 2 to 3 times voted.

When the compound of the present invention is administered parenterally, it is usually administered in the form of a liquid (for example, injection). The single dose of the compound of the present invention also varies according to the subject of administration, subject organ, symptoms, administration method, etc., for example, it is preferable to administer about 0.01 to about 100 mg per 1 kg of body weight by intravenous injection or subcutaneous injection. , Preferably about 0.01 to about 50 mg, more preferably about 0.01 to about 20 mg of the compound of the present invention.

The compound of the present invention can be used in combination with other drugs. Specifically, the compound of the present invention can be used in combination with drugs such as hormone therapy agents, chemotherapeutics, immunotherapeutics, or agents that inhibit the effects of cell proliferation factors and their receptors. Hereinafter, the drug that can be used in combination with the compound of the present invention is abbreviated as a concomitant drug.

As the "hormone therapeutic agent", for example, fosfestrol (Fosfestrol), diethylstilbestrol, diethylstilbestrol, medroxyprogesterone acetate, megestrol acetate, chlorgestrol acetate, cyproterone acetate, and Nazol (danazol), allylestrol, gestrinone, mepartricin, raloxifene, ormeloxifene, levormeloxifene, anti Estrogen drugs (such as tamoxifen citrate, toremifene citrate), pill preparations, mepitiostane, testololactone, aminoglutamin, LH-RH (luteinising hormone-releasing hormone) , Luteinizing hormone releasing hormone) agonists (such as goserelin acetate, buserelin, leuprolide acetate), droloxifene (droloxifene), epitiostanol (epitiostanol), ethinyl estradiol sulfonate Diols, aromatase inhibitors (e.g. fadrozole hydrochloride, anastrozole, letrozole, exemestane, vorozole, formestane), antiandrogens (e.g. flutamide, bicalutamide) , Nilutamide, enzalutamide), 5α-reductase inhibitors (e.g. finasteride, epristeride, dutasteride), adrenocorticoid agents (e.g. dexamethasone) Methsone, prednisolone, betamethasone, triamcinolone), androgen synthesis inhibitors (such as abiraterone), drugs that delay the metabolism of retinols and retinols (such as liazole (liarozole)), thyroid hormones, and these DDS (Drug Delivery System) preparations.

As the "chemotherapeutic agent", for example, alkylating agents, metabolic antagonists, anticancer antibiotics, and plant-derived anticancer agents can be used.

As an "alkylating agent", for example, nitrogen mustard, chlorambucil-N-oxide, chlorsalicylic acid, cyclophosphamide, ifosfamide, thiotepa, carboquinone, and toluene can be used. Improsuvate, busulfan, nimustine hydrochloride, dibromomannitol, melphalan, dacarbazine, ramustine, estramustine sodium phosphate, triethylene melamine, carmus Tine, lomustine, streptozocin, pipepobromide, itoglu, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, hexamethylmelamine, ammoustine , Dibrospidium hydrochloride (dibrospidium hydrochloride), formustine, prenimustine, pumitepa, bendamustine hydrochloride (Ribomustin), temozolomide, sulfuran, ethidium Trofosfamide, netstatinate, adozelesin, cystemustine, bizelesin and the DDS preparations thereof.

As the "metabolic antagonist", for example, mercaptopurine, 6-mercaptopurine nucleoside, thioinosine, methotrexate, pemetrexed, enoxabine, cytarabine, ara Glycocytidine octadecyl phosphate, ancitabine hydrochloride, 5-FU-based drugs (e.g. fluorouracil, tegafur, UFT, deoxyfluridine, carmofur, galocitabine, pyrimethamine) Emitefur, capecitabine), aminopterin, nelarabine, Leucovorin calcium, thioguanine, butocin, butocin (Calcium folinate), Levomethrin tetrahydrofolate calcium, Cladribine, dipyriteflu, fludarabine, gemcitabine, hydroxyurea, pentostatin, piritrexim, idoxuridine , Mitoguanidine Hydrazone, Tiazofurine, Amamustine, Bendamustine and DDS preparations of these.

As "anti-cancer antibiotics", for example, actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pelomycin sulfate can be used , Daunorubicin Hydrochloride, Doxorubicin Hydrochloride, Aclarithromycin Hydrochloride, Pirubicin Hydrochloride, Epirubicin Hydrochloride, Neocarcinoma, Mithramycin, Sarkomycin , Carzinophilin (carzinophilin), mitotane, zorubicin hydrochloride (Zorubicin hydrochloride), mitoxantrone hydrochloride, idamycin hydrochloride and these DDS preparations (such as doxorubicin encapsulating PEG lipid body).

As the "plant-derived anticancer agent", for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, European paclitaxel, cabata Sai, vinorelbine and the DDS preparations.

As an "immunotherapy agent", for example: Biyi Nishu, Kesuzhen, Schizophyllan, Lentinan, Ubenimex, Interferon, Interleukin, Macrophage Colony Stimulating Factor, Granulocyte colony stimulating factor, erythropoietin, lymphotoxin (lymphotoxin), Bacillus Calmette-Guerin vaccine (BCG vaccine), corynebacterium parvum, levamisole, tore-like receptor (TLR) ) Agonist, polysaccharide K, procodazole, anti-CTLA4 (cytotoxic T-lymphocyte associated protein 4, cytotoxic T-lymphocyte associated protein 4) antibodies (such as ipilimumab, trimelimumab) , Anti-PD-1 (programmed cell death protein 1, programmed cell death protein 1) antibodies (such as nivolumab, pembrolizumab, cimiprizumab (cemiplimab), tislelizumab ( tislelizumab), sintilimab (sintilimab, toripalimab), anti-PD-L1 (programmed cell death ligand-1, programmed cell death ligand 1) antibodies (such as atezolimab) Anti-, Aviruzumab, Duvaluzumab), tumor lytic virus.

As the "cell proliferation factor" in the "agents for inhibiting the effect of cell proliferation factors and its receptors", any substance can be used as long as it is a substance that promotes cell proliferation. Usually, peptides with a molecular weight of 20,000 or less can be listed and used with A factor that binds to the receptor and acts at a low concentration. Specifically, you can use: (1) EGF (epidermal growth factor, epidermal growth factor) or a substance with substantially the same activity [such as TGFα], (2 ) Insulin or a substance with substantially the same activity as it [for example, insulin, IGF (insulin-like growth factor, insulin-like growth factor)-1, IGF-2], (3) FGF (fibroblast growth factor, fibroblast growth Factor) or a substance with substantially the same activity as it [such as acidic FGF, basic FGF, KGF (keratinocyte growth factor, keratinocyte growth factor), FGF-10], (4) other cell proliferation factors [such as CSF (colony stimulating factor, community stimulating factor), EPO (erythropoietin, erythropoietin), IL-2 (interleukin-2, interleukin-2), NGF (nerve growth factor, nerve growth factor), PDGF (platelet-derived growth factor) , Platelet-derived growth factor), TGFβ (transforming growth factor β), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), heregulin , Angiopoietin].

As the "receptor for cell proliferation factor", it can be any receptor as long as it has the ability to bind to the above-mentioned cell proliferation factor. Specifically, EGF receptors, modulin receptors (such as HER3( human EGFR-related 3, human EGFR-related substance 3)), 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.

As "agents that inhibit the effect of cell proliferation factors and their receptors", you can use: EGF inhibitors, TGFα inhibitors, modulin inhibitors, insulin inhibitors, IGF inhibitors, FGF inhibitors, KGF inhibitors, CSF inhibitors Agents, EPO inhibitors, IL-2 inhibitors, NGF inhibitors, PDGF inhibitors, TGFβ inhibitors, HGF inhibitors, VEGF inhibitors, angiogenin inhibitors, EGF receptor inhibitors, HER2 inhibitors, HER3 inhibitors Agents, 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 Agents, FGF receptor-4 inhibitors, VEGF receptor inhibitors, Tie-2 inhibitors, PDGF receptor inhibitors, Abl inhibitors, Raf inhibitors, FLT3 (FMS-like tyrosine kinase 3, FMS-like tyrosine kinase 3) Kinase 3) inhibitors, c-Kit inhibitors, Src inhibitors, PKC (protein kinase C, protein kinase C) inhibitors, Smo inhibitors, ALK (anaplastic lymphoma kinase, anaplastic lymphoma kinase) inhibitors, ROR1( receptor-tyrosine-kinase-like orphan receptor 1, Trk inhibitor, Ret inhibitor, mTOR (mammalian target of rapamycin, mammalian target of rapamycin) Inhibitors, Aurora inhibitors, PLK (Polo-like kinase, Polo-like kinase) inhibitors, MEK (mitogen-activated protein kinase kinase) (MEK1/2) inhibitors, MET (mesenchymal- epithelial transition, mesenchymal-epithelial cell conversion factor) inhibitor, CDK (cyclin-dependent kinase, cyclin-dependent kinase) inhibitor, Akt inhibitor, ERK (extracellular signal-regulated kinase, extracellular signal-regulated kinase) inhibitor , PI3K (phosphoinositide 3-kinase, phosphoinositide 3-kinase) inhibitors, etc. More specifically, anti-VEGF antibodies (such as Bevacizumab, Ramucirumab), anti-HER2 antibodies (such as Trastuzumab, Pertuzumab) can be used. (Pertuzumab)), anti-EGFR antibodies (e.g. Cetuximab, Panitumumab, Matuzumab, Nimotuzumab), anti-HGF antibodies, Imatinib, Erlotinib, Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapati Lapatinib, Vatalanib, Ibrutinib, Bosutinib, Cabozantinib, Crizotinib, Alectinib Alectinib, Vismodegib, Axitinib, Motesanib, Nilotinib, 6-[4-(4-ethylpiper)-1- Methyl)phenyl]-N-[1(R)-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (AEE-788), Vandetanib (Vandetanib ), Temsirolimus, Everolimus, Enzastaurin, Tozasertib, Phosphoric Acid 2-[N-[3-[4-[5- [N-(3-Fluorophenyl)aminocarbamylmethyl]-1H-pyrazol-3-ylamino]quinazolin-7-yloxy]propyl]-N-ethylamino] Ethyl ester (AZD-1152), 4-[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-2-yl Amino]benzoic acid, N-[2-methoxy-5-[(E)-2-(2,4,6-trimethoxyphenyl)vinylsulfonylmethyl]phenyl]glycamine Sodium salt (ON-1910Na), Volasertib, Selumetinib, Trametinib, N-[2(R),3-Dihydroxypropoxy]- 3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)benzamide (PD-0325901), Bosutinib, Regorafenib, Alpha Afatinib, Idelalisib, Ceritinib (C eritinib, Dabrafenib, Ponatinib, Lenvatinib, Midostaurin, Pazopanib, etc.

In addition to the above-mentioned drugs, the following can also be used as concomitant drugs: L-aspartase, L-arginase, arginine iminase, acetoglucurolactone, procarbazine hydrochloride, protoviolet Qualitative-cobalt complex salt, mercuropurin-sodium, topoisomerase I inhibitors (e.g. irinotecan, topotecan, indotecan (indotecan), indimitecan (Indimitecan)), extension Naoisomerase II inhibitors (e.g. Sobuzoxane), differentiation inducers (e.g. retinols, vitamin D), other angiogenesis inhibitors (e.g. nicotin, shark extract, COX-2 inhibitors) , Alpha-blockers (e.g. tasulosin hydrochloride), bisphosphonates (e.g. pamidronate, zoledronate), thalidomide, lenalidomide, pomalidomide, azalea Cytidine, Decitabine, Proteasome Inhibitors (e.g. Bortezomib, Carfilzomib, Ishazomib), NEDD8 Inhibitors (e.g. Pevonedistat), UAE (ubiquitin activating enzyme, ubiquitin activating enzyme) inhibitors , PARP (poly ADP ribose polymerase, poly ADP ribose polymerase) inhibitors (such as Olaparib, Niraparib, Veliparib), anti-CD20 Antibodies (e.g. Rituximab, Obinutuzumab), anti-CCR4 (CC chemokine receptor 4, CC chemokine receptor 4) antibodies (e.g. Mogamulizumab )) and other anti-tumor antibodies, antibody-drug complexes (for example, trastuzumab-maytansine, bentuximab), etc.

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, the following can be used as concomitant drugs: antibacterial drugs, antifungal drugs, non-steroidal anti-inflammatory drugs, steroid drugs, bronchial drugs Dilators, anticoagulants, antiplatelet drugs, thrombolytic drugs, immunomodulators, antiprotozoal drugs, antitussives and expectorants, sedatives, anesthetics, narcotic antagonists, antiulcer drugs, vitamin drugs, vitamin derivatives, antiallergic Sexual agents, antiasthmatic drugs, therapeutic drugs for atopic dermatitis, message transmission inhibitors, inflammatory mediator action inhibitors, inflammatory mediator action inhibitor antibodies, inflammatory mediator production inhibitors, anti-inflammatory mediator action Inhibitors, anti-inflammatory mediator action inhibitor antibodies, anti-inflammatory mediator production inhibitors, anti-fibrotic drugs, α1 adrenergic agonists, antiemetics, degeneration hemoglobin rise inhibitors, etc.

(1) Antibacterial drugs (i) Sulfonamides Sulfamethizole, sulfisoxazole, sulfamethoxazole, sulfamethizole, sulfasalazine, silver sulfadiazine, etc. (ii) Quinoline-based antibacterial drugs Nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, Fleroxacin and others. (iii) Anti-tuberculosis drugs Isoniazid, ethambutol (ethambutol hydrochloride), p-aminosalicylic acid (calcium p-aminosalicylate), pyridine carboxamide, ethionamide, ethionamide, ethionine Fuping, streptomycin sulfate, kangmycin sulfate, cycloserine, etc. (iv) Anti-acid bacteria Diaminodiphenyl sulfide, rifaxine. (v) Antiviral drugs Iodoside, acyclovir, vidarabine, ganciclovir, favipiravir, etc. (vi) Anti-HIV drugs Zidovudine, didanosine, zalcitabine, indinavir sulfate ethanol adduct, ritonavir, etc. (vii) Antitreponemal drugs (viii) Antibiotics Tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibekacin, kanendomycin, lividomycin, tobramycin, actomycin ( amikacin, fradiomycin, sisomicin, tetracycline, oxytetracycline, rolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalothin, cephalosporin Lin, ceftazidime, cefaclor, cephalexin, cefoxatin, cefadroxil, cefmandol, cefuroxime, cefotiam, cefotiam pivoxil, cefuroxime axetil, cefdinir, cefditoren Ceftazidime, ceftazidime, cefpiramide, cefsulodin, cefmenoxime, cefpodoxime proxetil, cefpirome, cefazollan, cefepime, cefsulodin, cefmenoxime, cefmetazole, cefminox, Cefoxitin, cefrazone, laoxycephalosporin, fluoxef, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thiomycin, sulfazecin ), aztreonam or these salts, griseofulvin, lankacidin, etc.

(2) Antifungal drugs (i) Polyene antibiotics (such as amphotericin B, nystatin, trichomycin), (ii) Griseofulvin, pyrrolidin, etc., (iii) Cytosine metabolism antagonists (e.g. flucytosine), (iv) Imidazole derivatives (e.g. econazole, clotrimazole, miconazole nitrate, bifonazole, croconazole), (v) Triazole derivatives (e.g. fluconazole, itraconazole, azole compounds [2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1- Methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3 (2H,4H)-1,2,4-triadimefon], (vi) Thiocarbamic acid derivatives (e.g. tolnaftate), (vii) Echinocandin derivatives (such as caspofungin, micafungin, anidulafungin), etc.

(3) Non-steroidal anti-inflammatory drugs Acetaminophen, phenacetin, acetamid, sylpyrin, antipyrine, migrenin, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxo Profen Sodium, Phenylbutazone, Indomethacin, Ibuprofen, Ketoprofen, Naproxen, Propylene, Flurbiprofen, Phentermine, Praprofen, Flofenine, Epizole, silamide hydrochloride, zaltoprofen, gabexate mesilate, camostat mesylate, ulinastatin, colchicine, probenecid , Sulpyridone, Phenylbromocoumarone, Allopurinol, Sodium Gold Thiomalate, Sodium Hyaluronate, Sodium Salicylate, Morphine Hydrochloride, Salicylic Acid, Atropine, Scopolamine, Morphine, Pixetine, L-morphine , Ketoprofen, naproxen, oxymorphone, meloxicam, celecoxib, rofecoxib or its salt, etc.

(4) Steroids Dexamethasone, diethylstilbestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinolone acetate, fluocinolone, prednisolone, methylprednisolone, Cortisone acetate, hydrocortisone, fluorometholone, beclomethasone dipropionate, estriol, etc.

(5) Bronchodilator Metaproterenol (metaproterenol), salmeterol, formoterol (formoterol), carmoterol (carmoterol) and so on.

(6) Anticoagulant Heparin sodium, sodium citrate, activated protein C, tissue factor pathway inhibitor, antithrombin III, dipeptide heparin sodium, warfarin potassium, argatroban, gabexate, sodium citrate, etc.

(7) Antiplatelet drugs Ozagrel sodium, ethyl icosapentate, belastodium, alprostadil, ticobidine hydrochloride, pentoxifylline, dipyridamole, etc.

(8) Thrombolytic drugs Tisokinase, urokinase, streptokinase, etc.

(9) Immunomodulatory drugs Cyclosporine, tacrolimus, guanrimmus, azathioprine, anti-lymphatic serum, dry sulfonated immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon, etc.

(10) Antiprotozoal drugs Metronidazole, tinidazole, ethamazine citrate, quinine hydrochloride, quinine sulfate, etc.

(11) Antitussive and expectorant Ephedrine Hydrochloride, Narcotine Hydrochloride, Codeine Phosphate, Dihydrocodeine Phosphate, Isoproterenol Hydrochloride, Ephedrine Hydrochloride, Methylephedrine Hydrochloride, Narcotine Hydrochloride, Aloramide, Chlophedianol, picoperidamine, cloperastine, protokylol, isoproterenol, salbutamol, terbutaline, oxymethebanol, morphine hydrochloride , Dextromethorphan hydrobromide (dextromethorphan hydrobromide), oxycodone hydrochloride, dimethylformane phosphate, tipperidine sea benzoate, pentoverine citrate, chlorbendanol hydrochloride, benzonatate ( benzonatate), pifenacine, bromhexine hydrochloride, ambuso hydrochloride, acetylcysteine, ethyl cysteine hydrochloride, carbocysteine, etc.

(12) Sedatives Chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital, pentobarbital, pentobarbital, thiopental, sodium thiometal, nitrazepam, estazolam, fluoride Flurazepam, haloxazolam, triazolam, flunitrazepam, bromoisovaleramide, chloral hydrate, sodium trichloroethyl phosphate, etc.

(13) Anesthetics (13-1) Local anesthetics Cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, obucaine hydrochloride, ethyl aminobenzoate , Oxethazaine, etc. (13-2) General anesthetics (i) Inhalation anesthetics (e.g. ether, halothane, nitrous oxide, isoflurane, enflurane) (ii) Intravenous anesthetics (for example, ketamine hydrochloride, droperidol, thiopental, sodium thiopental, pentobarbital), etc.

(14) Anesthetic antagonists Levolorphan (levallorphan), nalorphine (nalorphine), naloxone (naloxone) or its salt, etc.

(15) Anti-ulcer drugs Metoclopramide (metaclopromide), histidine hydrochloride, lansoprazole, metoclopramide (metoclopramide), pirenzepine, cimetidine, ranitidine, famotidine, urine suppresses stomach Sulfate, oxirain, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, glutathione, aluminum allantoin, teprenone, prostaglandin, etc.

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

(17) Vitamin derivatives Various derivatives of vitamins, such as ascorbic acid, 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol, 1-α-hydroxycholecalciferol and other vitamin D3 derivatives, 5,6-trans-ergot Vitamin D2 derivatives such as calcified sterol, etc.

(18) Anti-allergic agent Diphenhydramine, clofenilamine, trippinamine, clemizole, diphenyllaline, methamphetamine, cromolyn sodium, tranilast, repilast, amine Lexanol, Ibudilast, Codotifen, Terfenadine, Allergic Mequine, Azelastine, Epinastine, Ozagrel Hydrochloride, Pranomilast Hydrate, Setrilast, etc.

(19) Antiasthmatic drugs Isoproterenol Hydrochloride, Salbutamol Sulfate, Procaterol Hydrochloride, Terbutaline Sulfate, Temequinol Hydrochloride, Tobuterol Hydrochloride, Osinaline Sulfate, Fenoterol Hydrobromide, Ephedrine Hydrochloride , Ipratropium bromide, oxtropium bromide, flutropium bromide, theophylline, aminophylline, cromolyn sodium, tranilast, repirinast, ibudilast, codotifen, terfeil Nadine, Allergic Mequine, Azelastine, Epinastine, Ozagrel Hydrochloride, Prunkast Hydrate, Cetrilast, Dexamethasone, Prednisolone, Hydrocortisone, Propionic Acid Beclomethasone and others.

(20) Therapeutic drugs for atopic dermatitis Sodium cromolyn and so on.

(21) Antiemetics Phenanthrene derivatives, 5-HT3 receptor antagonists, etc.

(22) Anti-degeneration hemoglobin rise agent Methylene blue, ascorbic acid, etc.

(23) Integrin inhibitor Natalizumab, vedolizumab, AJM300, TRK-170, E-6007, etc.

(24) Anti-fibrosis drugs Pirfenidone, nintedanib, β-aminopropionitrile (BAPN), ursodeoxycholic acid, etc.

(25) Other Hydroxycam, diacerein, megestrol acetate, nicergoline, prostaglandins, etc.

By combining the compound of the present invention with a concomitant drug, the following excellent effects can be obtained: (1) Compared with the case of administering the compound of the present invention alone or a concomitant drug, the dosage can be reduced; (2) According to the patient The symptoms (mild, severe, etc.) of the present invention can be selected as the drug used in combination with the compound of the present invention; (3) the treatment period can be set to be longer; (4) the continuation of the therapeutic effect can be sought; (5) by the compound of the present invention When combined with concomitant drugs, synergistic effects can be obtained; etc.

Hereinafter, the case where the compound of the present invention and the concomitant drug are used in combination is referred to as "the concomitant agent of the present invention". When the concomitant agent of the present invention is used, the administration period of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug can be administered to the subject at the same time, or administered at intervals of time. In the case of interval time difference administration, the time difference varies according to the active ingredient, dosage form, and method of administration. For example, when the concomitant drug is administered first, it only needs to be 1 minute to 3 days after the administration of the concomitant drug The compound of the present invention may be administered within, preferably within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. In the case of administering the compound of the present invention first, as long as the concomitant drug is administered within 1 minute to 1 day after the administration of the compound of the present invention, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour. can. The dosage of the concomitant drug may be based on the dosage used clinically, and it can be appropriately selected according to the subject of administration, route of administration, disease, combination, etc.

As the form of administration when the compound of the present invention and the concomitant drug are used in combination, for example, (1) the administration of a single preparation obtained by simultaneously preparing the compound of the present invention and the concomitant drug; (2) the compound of the present invention and The two preparations obtained by the separate formulation of the concomitant drug are administered simultaneously in the same administration route; (3) The two preparations obtained by the separate preparation of the compound of the present invention and the concomitant drug are administered in the same administration route interval time difference. (4) The two preparations obtained by separately formulating the compound of the present invention and the concomitant drug were simultaneously administered in different administration routes; (5) The two preparations obtained by separately formulating the compound of the present invention and the concomitant drug The administration is carried out with a time difference between different administration routes (for example, administration in the order of compound of the present invention → concomitant drug, or administration in the reverse order). The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage. In addition, the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected according to the subject of administration, route of administration, disease of the subject, symptoms, combination, and the like. For example, when the subject of administration is a human, it is sufficient to use 0.01 to 100 parts by weight of the concomitant drug with respect to 1 part by weight of the compound of the present invention.

Furthermore, the compound of the present invention or the concomitant agent of the present invention can be used in combination with non-drug therapy. Specifically, the compound of the present invention or the concomitant agent of the present invention can be combined with, for example, (1) surgery, (2) boosting chemotherapy using angiotensin II, (3) gene therapy, (4) thermotherapy, ( 5) Cryotherapy, (6) Laser cauterization, (7) Non-pharmaceutical therapy combination of radiation therapy.

For example, by using the compound of the present invention or the concomitant agent of the present invention before or after the above-mentioned surgery, etc., or before or after a combination of these two or three treatments, prevention of tolerance performance and disease-free survival (Disease-Free Survival) can be obtained The prolongation of cancer, the suppression of cancer metastasis or recurrence, and the prolonged life expectancy.

In addition, treatment and supportive therapy using the compound of the present invention or the concomitant agent of the present invention can also be used [(i) Antibiotics (for example, β-lactam series such as pansporin) for various infectious diseases concurrently, The administration of macrolides such as clarithromycin); (ii) the administration of high-calorie infusions, amino acid preparations, and multivitamins to improve nutritional disorders; (iii) the administration of morphine to relieve pain (Iv) To improve side effects such as nausea, vomiting, loss of appetite, diarrhea, leukopenia, thrombocytopenia, decreased hemoglobin concentration, hair loss, liver injury, kidney injury, DIC (disseminated intravascular coagulation), fever, etc. The administration of medicaments; and (v) the administration of medicaments for inhibiting the multiple drug resistance of cancer, etc.] combination. [Example]

Further, the present invention will be described in detail with the following reference examples, examples, test examples and formulation examples, but these do not limit the present invention, and can be changed without departing from the scope of the present invention. "Room temperature" in the following examples generally means about 10°C to about 35°C. The ratio shown in the mixed solvent indicates a volume ratio unless otherwise specified. % Unless otherwise specified, it means mass %. In the case of silica gel column chromatography, when NH is described, aminopropyl silane-bonded silica gel is used, and in the case of C18, octadecyl-bonded silica gel is used. When C18 is described in HPLC (High Speed Liquid Chromatography), octadecyl-bonded silica gel is used. Unless otherwise specified, the ratio of the eluted solvent indicates the volume ratio. The following abbreviations are used in the following examples. MS: mass spectrum M: molar concentration DMSO-d ₆ : deuterated dimethyl sulfide ¹ H NMR: proton nuclear magnetic resonance LC/MS: liquid chromatography mass spectrometry ESI: electrospray free APCI: atmospheric pressure chemical ionization DCM: Dichloromethane DIEA: diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide HATU: 2-(7-azabenzotriazol-1-yl )-1,1,3,3-Tetramethylurea hexafluorophosphate TEA: Triethylamine THF: Tetrahydrofuran TFA: Trifluoroacetic acid

¹ H NMR is measured by Fourier transform type NMR. The analysis system uses ACD/SpecManager or MestreNova (trade name). There are cases where protons such as hydroxyl or amino groups have very gentle peaks are not described. MS is determined by LC/MS. As the ionization method, the ESI method or the APCI method is used. The data records the measured value (found). Molecular ion peaks ([M＋H] ⁺ , [M－H] ^-etc .) are usually observed, but in the case of compounds with tertiary butoxycarbonyl group, as a fragment ion, tertiary butoxy is sometimes observed The peak of carbonyl carbonyl (Boc) or tertiary butyl (tBu). In the case of compounds with carboxyl groups, etc., there are also cases where a peak with addition of sodium is observed. In addition, in the case of a compound having a hydroxyl group, as a fragment ion, a peak of water detachment may also be observed. In the case of salt, molecular ion peaks or fragment ion peaks of free bodies are usually observed. The unit of the sample concentration (c) under the optical rotation ([α] _{D) is g/100 mL.} The element analysis value (Anal.) records the calculated value (Calcd) and the measured value (Found).

Example 1 2-(4-((S)-2-Cyclohexyl-2-((S)-2-(Methylamino)propionylamine)acetyl)piperidin-1-carbonyl)-5,6- Difluoro-N,1-dimethyl-N-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidine -1-yl)methyl)isoazol-3-yl)oxy)ethoxy)ethoxy)ethyl)-1H-indole-3-formamide hydrochloride

A) 7-(piperidin-4-yloxy)thieno[3,2-b]pyridine dihydrochloride is added to 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (14.9 g) Add sodium hydride (60%, dispersed in liquid paraffin, 3.0 g) to the mixture with DMF (100 mL). The reaction mixture was stirred for 10 minutes, 7-chlorothieno[3,2-b]pyridine (10.4 g) was added, and the mixture was stirred overnight at 60°C. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Add 4 M hydrogen chloride to the obtained mixture of 4-(thieno[3,2-b]pyridin-7-yloxy)piperidine-1-carboxylic acid tert-butyl ester and ethyl acetate (100 mL) /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 collected by filtration to obtain the title compound (16.8 g). MS: [M＋H] ⁺ 235.2.

B) 3-(allyloxy)isoxazole-5-carboxylic acid methyl ester in 3-hydroxyisoxazole-5-carboxylic acid methyl ester (15.0 g), potassium carbonate (17.4 g) and DMF (200 mL Add 3-bromoprop-1-ene (13.6 mL) to the mixture of ), and stir at 60°C for 16 hours. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried with 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 obtain the title compound (16.6 g). MS: [M＋H] ⁺ 184.3.

C) (3-(allyloxy)isoxazol-5-yl)methanol in 3-(allyloxy)isoxazole-5-carboxylic acid methyl ester (16.6 g) and methanol (300 mL) Sodium borohydride (4.80 g) was added to the mixture. The reaction mixture was stirred at room temperature for 16 hours, and the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. After the organic layer was washed with water and saturated brine, it was dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (13.2 g). MS: [M＋H] ⁺ 156.3.

D) Methanesulfonic acid (3-(allyloxy) isoxazol-5-yl) methyl ester is added to (3-(allyloxy) isoxazol-5-yl)methanol (13.2 g) To the mixture of TEA (24 mL) and THF (200 mL) was added methanesulfonate chloride (9.94 mL). After the reaction mixture was stirred at room temperature for 1 hour, it was diluted with water, and the aqueous layer was extracted with ethyl acetate. After the organic layer was washed with saturated brine, and dried with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (18.9 g). MS: [M＋H] ⁺ 234.2.

E) 3-(allyloxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole Combine 7-(piperidin-4-yloxy)thieno[3,2-b]pyridine dihydrochloride (6.16 g), methanesulfonic acid (3-(allyloxy)isoxazole- A mixture of 5-yl) methyl ester (5.14 g), tetrabutylammonium iodide (4.44 g), potassium carbonate (9.70 g) and DMF (100 mL) was stirred for 24 hours. Water was added to the reaction mixture for filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with 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 obtain the title compound (6.25 g). MS: [M＋H] ⁺ 372.2.

F) (S)-4-(2-((Third-butoxycarbonyl)amino)-2-cyclohexylacetyl)piper-1-carboxylic acid benzyl ester at room temperature to (S)- 2-((Third-butoxycarbonyl)amino)-2-cyclohexylacetic acid (2.5 g), piperidine-1-carboxylic acid benzyl ester (2.14 g), DIEA (5.09 mL) and DMF (48.6 mL) Add HATU (5.54 g) to the mixture. 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 with 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 obtain the title compound (4.34 g). MS: [M＋H] ⁺ 460.2.

G) (S)-4-(2-amino-2-cyclohexylacetyl)piper-1-carboxylic acid benzyl ester hydrochloride at room temperature to (S)-4-(2-(( (Tertiary butoxycarbonyl) amino)-2-cyclohexyl acetyl) piper-1-carboxylic acid benzyl ester (4.34 g) and ethyl acetate (18.9 mL) add 4 M hydrogen chloride/ethyl acetate Ester solution (18.9 mL), and the reaction mixture was stirred at 45°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained crude product was recrystallized from ethyl acetate/hexane to obtain the title compound (2.96 g). MS: [M＋H] ⁺ 360.2.

H) 4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionamide)-2-cyclohexylacetinyl)piper𠯤- Benzyl 1-carboxylate to (S)-2-((tert-butoxycarbonyl)(methyl)amino)propionic acid (1.63 g), (S)-4-(2-amine) at room temperature Add HATU (4.26 g) to the mixture of 2-cyclohexyl acetyl) piperidine-1-carboxylic acid benzyl ester hydrochloride (2.96 g), DIEA (5.22 mL) and DMF (37.4 mL). 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 with 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 obtain the title compound (3.62 g). MS: [M＋H] ⁺ 545.4.

I) ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperid-1-yl)ethyl)amino)-1-oxopropane-2 -Yl)(methyl)carbamic acid tert-butyl 4-((S)-2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino)propanamide )-2-Cyclohexylacetyl)piper-1-carboxylic acid benzyl ester (3.62 g), a mixture of 10% palladium on carbon (362 mg) and ethyl acetate (67 mL) in a hydrogen atmosphere at atmospheric pressure, Stir at room temperature for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.46 g). MS: [M＋H] ⁺ 411.3.

J) 5,6-Difluoro-1-methyl-1H-indole-2-carboxylic acid methyl ester at room temperature to 5,6-difluoro-1H-indole-2-carboxylic acid (20 g) Add potassium carbonate (42.0 g) and methyl iodide (18.9 mL) to the mixture with DMF (200 mL). After the reaction mixture was stirred at the same temperature for 18 hours, it was stirred at 40°C for 6 hours. Water was added to the reaction mixture, and the precipitate was collected by filtration, and washed with hexane to obtain the title compound (20 g). ¹ H NMR (400 MHz, DMSO-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).

K) 5,6-Difluoro-3-methanyl-1-methyl-1H-indole-2-carboxylic acid methyl ester at -78℃ to 5,6-difluoro-1-methyl-1H -Add 1 M titanium tetrachloride/DCM solution (17.8 mL) and dichloromethyl methyl ether (1.7 mL) and DCM to the mixture of methyl indole-2-carboxylate (2 g) and DCM (20 mL) (2 mL) mixture. 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 solution. The precipitate was filtered through Celite, and the filtrate was extracted with DCM. The organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.9 g). 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).

L) 5,6-Difluoro-3-methanyl-1-methyl-1H-indole-2-carboxylic acid in 5,6-difluoro-3-methanyl-1-methyl-1H- Add lithium hydroxide monohydrate (3.73 g) to a mixture of indole-2-carboxylic acid methyl ester (15 g), THF (225 mL), methanol (75 mL), and water (75 mL), at room temperature Stir for 3 hours. The reaction mixture was concentrated under reduced pressure, and acidic conditions were made using potassium hydrogen sulfate aqueous solution. The obtained solid was filtered to obtain the title compound (13 g). MS: [M＋H] ⁺ 240.1.

M) 2-(4-((S)-2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino)propionamide)-2-cyclohexylacetoxy) Piper𠯤-1-carbonyl)-5,6-difluoro-1-methyl-1H-indole-3-carboxylic acid in ((S)-1-(((S)-1-cyclohexyl-2- Pendant oxy-2-(piper-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)aminocarboxylate (4.63 g), 5,6 -Difluoro-3-methanyl-1-methyl-1H-indole-2-carboxylic acid (2.45 g), DIEA (2.7 mL) and DMF (50 mL) was added with HATU (4.67 g). After the reaction mixture was stirred at room temperature for 2 hours, water was added, and extraction was performed with ethyl acetate. The organic layer was washed sequentially with 0.1 M hydrochloric acid, sodium bicarbonate aqueous solution and saturated brine, dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane). In the obtained ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-3-methanyl-1-methyl-1H-indole) -2-Carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)amino acid tert-butyl ester, 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 overnight at room temperature, sodium thiosulfate aqueous solution was added, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with 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 obtain the title compound (5.46 g). MS: [M＋H] ⁺ 648.5.

N) ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-3-((2-(2-(2-hydroxyethoxy) (Ethoxy)ethyl)(methyl)aminomethanyl)-1-methyl-1H-indole-2-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)- 1-oxopropan-2-yl)(methyl)aminocarboxylic acid tertiary butyl ester in 2-(4-((S)-2-((S)-2-((third butoxycarbonyl) (Methyl)amino)propionylamine)-2-cyclohexylacetyl)piper-1-carbonyl)-5,6-difluoro-1-methyl-1H-indole-3-carboxylic acid ( 5.46 g) and a mixture of 2-(2-(2-(methylamino)ethoxy)ethoxy)ethane-1-ol (1.65 g), DIEA (2.26 mL) and DMF (8 mL) HATU (3.85 g) was added. The reaction mixture was stirred at room temperature for 3 hours, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried with 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 obtain the title compound (3.10 g). MS: [M＋H] ⁺ 793.5.

O) 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoazol-3-ol in 3-(allyloxy Yl)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole (5.68 g), triethylsilane ( Add tetrakis(triphenylphosphine)palladium (884 mg) to the mixture of 7.3 mL) and THF (100 mL). 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 obtained compound was washed with ethyl acetate to obtain the title compound (2.50 g). 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).

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)ethyl (Oxy)ethoxy)ethyl)aminomethanyl)-1H-indole-2-carbonyl)piperid-1-yl)-2-oxoethyl)amino)-1-oxopropane- 2-yl)(methyl)carbamic acid tert-butyl ester in 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)aminomethanyl)-1-methyl-1H-indole-2-carbonyl)piperid-1-yl)-2 -Oxyethyl)amino)-1-oxopropan-2-yl)(methyl)aminocarboxylate (3.59 g), triphenylphosphine (5.94 g) and toluene (25 mL) Add di-tert-butyl azodicarboxylate (3.13 g) to the mixture. 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 ammonium acetate aqueous solution) to obtain the title compound (2.37 g). MS: [M＋H] ⁺ 1106.6.

Q) 2-(4-((S)-2-Cyclohexyl-2-((S)-2-(Methylamino)propionylamine)acetyl)piperidin-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) isoazol-3-yl) oxy) ethoxy) ethoxy) ethyl) -1H-indole-3-carboxamide hydrochloride in ((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)isoazol-3-yl)oxy)ethoxy)ethoxy (Base) ethyl) aminomethanyl) -1H-indole-2-carbonyl) piper (-1-yl)-2-oxoethyl) amino)-1-oxopropan-2-yl) ( To the mixture of tert-butyl methyl)carbamate (2.37 g) and ethyl acetate (10 mL) was added 4 M hydrogen chloride/ethyl acetate solution (16.1 mL), and stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain the title compound (2.16 g). ¹ H NMR (300 MHz, 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).

Example 2 2-(4-((S)-2-Cyclohexyl-2-((S)-2-(Methylamino)propionylamine)acetyl)piperidin-1-carbonyl)-6-methoxy Base-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-methanamide

A) Methyl 6-methoxy-1-methyl-1H-indole-2-carboxylate was added to methyl 6-methoxy-1H-indole-2-carboxylate (11.6 g Add sodium hydride (60%, dispersed in liquid paraffin, 2.93 g) to the mixture of) and DMF (100 mL). 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 with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (11.4 g). MS: [M＋H] ⁺ 220.0.

B) 6-Methoxy-1-methyl-1H-indole-2-carboxylic acid at room temperature to 6-methoxy-1-methyl-1H-indole-2-carboxylic acid methyl ester ( 11.4 g) and methanol (100 mL) were added 2 M aqueous sodium hydroxide solution (52.0 mL), and the reaction mixture was stirred at 60°C for 1 hour. After cooling the reaction mixture in an ice bath, it was neutralized with 1 M hydrochloric acid (110 mL), and the precipitate was collected by filtration to obtain the title compound (9.87 g). MS: [M＋H] ⁺ 206.0.

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

D) 4-(3-Methoxy-6-methoxy-1-methyl-1H-indole-2-carbonyl)piper-1-carboxylic acid tert-butyl ester in 4-(6-methoxy Add (chloromethylene) dimethyl to the mixture of methyl-1-methyl-1H-indole-2-carbonyl)piper-1-carboxylic acid tert-butyl ester (10.4 g) and DMF (100 mL) Ammonium chloride (7.13 g), and the reaction mixture was stirred at room temperature for 2 hours. After adding water to the reaction mixture and stirring for 30 minutes, the aqueous layer was extracted with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (10.6 g). MS: [M＋H] ⁺ 402.1.

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

F) ((S)-1-(((S)-1-cyclohexyl-2-(4-(3-methanyl-6-methoxy-1-methyl-1H-indole-2- (Carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)aminocarboxylic acid tert-butyl ester at room temperature to (S) -2-((Third-butoxycarbonyl)amino)-2-cyclohexylacetic acid (1.96 g), 6-methoxy-1-methyl-2-(piper𠯤-1-carbonyl)-1H- HATU (3.47 g) was added to the mixture of 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 with 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 product and ethyl acetate (38 mL) was added 4 M hydrogen chloride/ethyl acetate solution (38 mL) at room temperature, and the reaction mixture was stirred at the same temperature for 1 hour. Concentrate under pressure. To the obtained (S)-2-(4-(2-amino-2-cyclohexylethanoyl)piper𠯤-1-carbonyl)-6-methoxy-1-methyl- 1H-indole-3-carbaldehyde (3.35 g) and (S)-2-((tertiary butoxycarbonyl)(methyl)amino)propionic acid (1.55 g), DIEA (6.65 mL) and DMF ( 38.1 mL) of the mixture was added HATU (4.34 g). 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 with 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 obtain the title compound (2.12 g). MS: [M＋H] ⁺ 626.3.

G) 2-(4-((S)-2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetoxy) Piper𠯤-1-carbonyl)-6-methoxy-1-methyl-1H-indole-3-carboxylic acid to ((S)-1-(((S)-1-cyclohexyl) at room temperature -2-(4-(3-Methoxy-1-methyl-1H-indole-2-carbonyl)piperid-1-yl)-2-oxoethyl)amino group )-1-oxopropan-2-yl)(methyl)aminocarbamate (2.30 g), sodium dihydrogen phosphate (1.76 g), 2-methylbut-2-ene (1.95 mL) Add sodium chlorite (665 mg) to the mixture of tertiary 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 sodium thiosulfate aqueous solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried with 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 obtain the title compound (770 mg). MS: [M＋H] ⁺ 642.4

H) ((S)-1-(((S)-1-cyclohexyl-2-(4-(3-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl) Aminomethyl)-6-methoxy-1-methyl-1H-indole-2-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-1-oxopropane -2-yl)(methyl)carbamic acid tert-butyl ester will be 2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amine (Yl) propanylamine)-2-cyclohexylacetyl)piperidin-1-carbonyl)-6-methoxy-1-methyl-1H-indole-3-carboxylic acid (147 mg), triethyl A mixture of diol monoamine (41.0 mg), DIEA (120 μL), HATU (131 mg) and DMF (1.15 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and ethyl acetate, and extracted with ethyl acetate. After the organic layer was dried with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile/5 mM ammonium acetate aqueous solution) to obtain the title compound (133 mg). MS: [M＋H] ⁺ 773.5.

I) 4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylic acid tert-butyl ester in 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.42 g) Add sodium hydride (60%, dispersed in liquid paraffin, 0.577 g) to the mixture of DMF (60.1 mL). After the reaction mixture was stirred for 30 minutes, 4-chlorothieno[3,2-d]pyrimidine (2.05 g) was added, stirred at room temperature for 1 hour, diluted with ethyl acetate and water, and added to ethyl acetate. The aqueous layer is extracted. The organic layer was dried with 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 obtain the title compound (3.75 g). MS: [M＋H] ⁺ 336.0.

J) 4-(piperidin-4-yloxy)thieno[3,2-d]pyrimidine hydrochloride in 4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidine To the mixture of tert-butyl-1-carboxylate (3.75 g) and ethyl acetate (22.4 mL) was added 4 M hydrogen chloride/ethyl acetate solution (55.9 mL). After the reaction mixture was stirred for 30 minutes, the solvent was distilled off under reduced pressure. The residue was washed with ethyl acetate to obtain the title compound (3.25 g). 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).

K) 4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol in 4-(piperidin-4-yloxy ) Thieno[3,2-d]pyrimidine hydrochloride (215 mg) and pyridine (2.64 mL) were mixed with 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 ammonium acetate aqueous solution) to obtain the title compound (43.5 mg). 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).

L) 2-(4-((S)-2-Cyclohexyl-2-((S)-2-(Methylamino)propionylamine)acetyl)piperidin-1-carbonyl)-6- Methoxy-1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidine-1- Sulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide in 4-((4-(thieno[3,2-d]pyrimidine) -4-yloxy)piperidin-1-yl)sulfonyl)phenol (35.5 mg), ((S)-1-(((S)-1-cyclohexyl-2-(4-(3- ((2-(2-(2-Hydroxyethoxy)ethoxy)ethyl)aminomethanyl)-6-methoxy-1-methyl-1H-indole-2-carbonyl)piper -1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl) tertiary butyl carbamate (70.0 mg), triphenylphosphine (119 mg Add di-tert-butyl azodicarboxylate (62.6 mg) to the mixture of) and toluene (0.45 mL). The reaction mixture was stirred at room temperature for 2 hours, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile/5 mM ammonium acetate aqueous solution). Ethyl acetate (0.2 mL) was added to the obtained product, and a 4 M hydrogen chloride/ethyl acetate solution (679 μL) was added. The 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 ammonium acetate aqueous solution). The obtained product was dissolved in methanol, desalted with Amberlyst A21, and the solvent was distilled off under reduced pressure to obtain the title compound (19.5 mg). 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).

Example 3 1-((R)-4-(5,6-Difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiper-1-yl)-2-((2R, 5R)-5-methyl-2-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidine-1 -Yl)methyl)isoazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piper-1-yl)ethane-1-one hydrochloride

A) 5,6-Difluoro-1-methyl-1H-indole-2-carboxylic acid in 5,6-difluoro-1-methyl-1H-indole-2-carboxylic acid methyl ester (2 g ) Lithium hydroxide monohydrate (1.1 g) was added to a mixture of THF (14 mL), methanol (7 mL), and water (7 mL), 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, an aqueous potassium hydrogen sulfate solution was added to make it acidic, and extraction was performed with ethyl acetate. After washing the organic layer with saturated brine, it was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.8 g). MS: [M－H] ⁺ 210.0.

B) (R)-(5,6-Difluoro-1-methyl-1H-indol-2-yl)(3-methylpiperid-1-yl)methanone in 5,6-difluoro- To the mixture of 1-methyl-1H-indole-2-carboxylic acid (1.8 g) and DMF (45 mL), add DIEA (4.4 mL), (R)-2-methyl-piperidine (1.02 g), HATU (4.8 g). The reaction mixture was stirred at room temperature for 3 hours, poured into ice water, and extracted with ethyl acetate. After washing the organic layer with saturated brine, it was dried with 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). MS: [M＋H] ⁺ 294.4.

C) (R)-2-Chloro-1-(4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiper-1-yl)ethyl Alk-1-one is cooled in an ice bath to (R)-(5,6-difluoro-1-methyl-1H-indol-2-yl)(3-methylpiperid-1-yl)methyl To the mixture of ketone (1.9 g) and DCM (25 mL) was added TEA (1.35 mL) and chloroacetyl chloride (0.6 mL). The reaction mixture was stirred at room temperature for 3 hours, diluted with DCM, and washed with water and saturated brine. The organic layer was dried with 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 (1.8 g). MS: [M＋H] ⁺ 370.2.

D) 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl methanesulfonate is cooled in an ice bath to 2-(2-(2-benzyloxyethoxy)ethyl TEA (1.7 mL) and methanesulfonyl chloride (0.77 mL) were added to the mixture of oxy)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 with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (2.5 g) . ¹ H 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).

E) (2R,5R)-4-benzyl-2-methyl-5-(12-phenyl-2,5,8,11-tetraoxadodecyl)piper-1-carboxylic acid Tributyl ester in a mixture of (2R,5R)-4-benzyl-5-hydroxymethyl-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (700 mg) and DMF (10 mL) Add sodium hydride (60%, dispersed in liquid paraffin, 105 mg). The reaction mixture was stirred for 1 hour, and 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl methanesulfonate (695 mg) was added, followed by further stirring 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. After washing the organic layer with saturated brine, it was dried with 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 (900 mg). MS: [M＋H] ⁺ 543.2.

F) (2R,5R)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperidine-1-carboxylic acid Butyl ester in (2R,5R)-4-benzyl-2-methyl-5-(12-phenyl-2,5,8,11-tetraoxadodecyl)piper-1-carboxylic acid Add 10% palladium on carbon (200 mg) to the mixture of tert-butyl ester (900 mg), acetic acid (0.1 mL) and ethanol (10 mL). The reaction mixture was stirred for 16 hours at room temperature under normal pressure of hydrogen, and filtered through Celite, and the filtrate was concentrated under reduced pressure. 10% methanol/DCM was added to the residue, and the organic layer was washed with a saturated sodium bicarbonate aqueous solution, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (600 mg). 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).

G) (2R,5R)-4-(2-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperidine- 1-yl)-2-oxoethyl)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiper-1 -Tert-butyl carboxylate in (2R,5R)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperidine- Add TEA (0.3 mL), (R)-2-chloro-1-(4-(5,6-difluoro-1) to the mixture of tert-butyl 1-carboxylate (592 mg) and THF (15 mL) -Methyl-1H-indole-2-carbonyl)-2-methylpiper-1-yl)ethane-1-one (550 mg) and tetrabutylammonium iodide (549 mg) at 60℃ Stir for 24 hours. Ethyl acetate was added to the reaction mixture, washed with water and saturated brine in this order, the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to obtain the title compound (740 mg). MS: [M＋H] ⁺ 696.5.

H) (2R,5R)-4-(2-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperidine- 1-yl)-2-oxoethyl)-2-methyl-5-((2-(2-(2-((5-((4-(thieno[3,2-b)pyridine- 7-yloxy)piperidin-1-yl)methyl)isoazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperidin-1-carboxylic acid Tributyl ester in (2R,5R)-4-(2-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiper 𠯤-1-yl)-2-oxoethyl)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiper -1- tert-butyl carboxylate (30 mg), 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso 㗁Di-tert-butyl azodicarboxylate (29.7 mg) was added to the mixture of oxazol-3-ol (17.1 mg), triphenylphosphine (56.5 mg), and toluene (2 mL). The reaction mixture was stirred at room temperature for 16 hours, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography to obtain the title compound (26 mg). MS: [M＋H] ⁺ 1008.8.

I) 1-((R)-4-(5,6-Difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperid-1-yl)-2-(( 2R,5R)-5-methyl-2-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidine -1-yl)methyl)isoazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperid-1-yl)ethane-1-one hydrochloride To (2R,5R)-4-(2-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methyl under ice cooling Pipiper-1-yl)-2-oxoethyl)-2-methyl-5-((2-(2-(2-((5-((4-(thieno[3,2- b)Pyridin-7-yloxy)piperidin-1-yl)methyl)isoazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperidin-1 -Add 4 M hydrogen chloride/dioxane solution (0.3 mL) to the mixture of tert-butyl 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 obtain the title compound (19 mg). ¹ H NMR (400 MHz, DMSO-d ₆ , 100℃) δ 1.15-1.28 (6H, m), 2.19-2.36 (4H, m), 2.76-2.98 (3H, m), 3.20-4.36 (36H, m) ), 5.15 (1H, m), 5.66 (1H, s), 6.56 (1H, s), 7.30 (1H, d, J = 8.0 Hz), 7.53-7.59 (2H, m), 7.63 (1H, d, J = 8.0 Hz), 8.22 (1H, d, J = 8.0 Hz), 8.68 (1H, d, J = 8.0 Hz), 9.01-9.40 (1H, m).

Example 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)isoazol-3-yl)oxy)ethoxy)ethoxy) (Ethoxy)-1H-indole-2-carbonyl)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propionamide hydrochloride

A) 5,6-Difluoro-3-hydroxy-1-methyl-1H-indole-2-carboxylic acid methyl ester at 5～10℃ to 5,6-difluoro-3-methanyl-1 -Methyl-1H-indole-2-carboxylic acid methyl ester (3.5 g) and chloroform (50 mL) were added with 3-chloroperbenzoic acid (5.88 g) and p-toluenesulfonic acid (3.15 g). The reaction mixture was stirred at the same temperature for 2 hours. A 2 M ammonia/methanol solution (30 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, diluted with saturated aqueous sodium bicarbonate solution, and extracted with DCM. The organic layer was washed with a 10% sodium thiosulfate aqueous solution, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (3 g). 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).

B) 4-(5,6-Difluoro-3-hydroxy-1-methyl-1H-indole-2-carbonyl)piper-1-carboxylic acid tert-butyl ester under argon atmosphere and room temperature To 5,6-difluoro-3-hydroxy-1-methyl-1H-indole-2-carboxylic acid methyl ester (4.4 g), piperidine-1-carboxylic acid tert-butyl ester (5.1 g) and toluene Add 2 M trimethylaluminum/toluene solution (18.2 mL) to the mixture (45 mL). The reaction mixture was stirred at 100°C for 3 hours. Water was added to the reaction mixture, the precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was dried with 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 (3 g). MS: [M＋H] ⁺ 393.8.

C) 2-(2-(2-(Benzyloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate is cooled in an ice bath to 2-(2-(2-(benzyloxy) )Ethoxy)ethoxy)ethane-1-ol (5 g) and DCM (100 mL) add TEA (4.4 mL), DMAP (1.27 g), p-toluenesulfonyl chloride (4.8 g) to the mixture of DCM (100 mL) , The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM, and washed with water and saturated brine in this order. The organic layer was dried with 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 (5.2 g). MS: [M＋H] ⁺ 395.0.

D) 4-(3-(2-(2-(2-(Benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole -2-Carbonyl)piperidin-1-carboxylic acid tert-butyl ester in 4-(5,6-difluoro-3-hydroxy-1-methyl-1H-indole-2-carbonyl)piperidin-1- Add cesium carbonate (2.06 g) and 4-methylbenzenesulfonic acid 2-(2-(2-(benzyloxy)ethoxy) to the mixture of tert-butyl carboxylate (1 g) and DMF (10 mL) ) Ethoxy) ethyl ester (1.49 g), stirred at room temperature for 6 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. After washing the organic layer with saturated brine, it was dried with 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 (1.26 g). MS: [M＋H] ⁺ 618.0.

E) (3-(2-(2-(2-(Benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2 -Yl) (piperidin-1-yl) methyl ketone hydrochloride under ice-cooling to 4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl Oxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piper-1-carboxylic acid tert-butyl ester (1.2 g) and DCM (12 mL) 4 M hydrogen chloride/dioxane solution (2 mL). The reaction mixture was stirred at room temperature for 4 hours, and the solvent was distilled off under reduced pressure. The residue was washed with diethyl ether to obtain the title compound (1 g). MS: [M＋H] ⁺ 517.9.

F) (S)-(2-(4-(3-(2-(2-(2-(Benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1 -Methyl-1H-indole-2-carbonyl)piper𠯤-1-yl)-1-cyclohexyl-2-oxoethyl)aminocarboxylic acid tert-butyl ester in (3-(2-(2- (2-(Benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indol-2-yl)(piperidin-1-yl) Add DIEA (0.694 mL) to the mixture of ketone hydrochloride (1.1 g) and DMF (10 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 were added -3-(3-Dimethylaminopropyl)carbodiimide hydrochloride (458 mg). The reaction mixture was stirred at room temperature for 2 hours, the reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.1 g). MS: [M＋H] ⁺ 757.0.

G) (S)-2-amino-1-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6- Difluoro-1-methyl-1H-indole-2-carbonyl) piper𠯤-1-yl)-2-cyclohexylethane-1-one hydrochloride under ice-bath cooling to (S)-(2 -(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole -2-Carbonyl)piperidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino acid tert-butyl ester (1.1 g) and DCM (10 mL) add 4 M 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 obtain the title compound (1.1 g). MS: [M＋H] ⁺ 657.2.

H) ((S)-1-(((S)-2-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)- 5,6-Difluoro-1-methyl-1H-indole-2-carbonyl)piperidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropane -2-yl)(methyl)aminocarbamate at room temperature to (S)-2-amino-1-(4-(3-(2-(2-(2-(benzyloxy (Yl)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperid-1-yl)-2-cyclohexylethane Add DIEA (0.83 mL) to the mixture of -1-one hydrochloride (1.1 g) and DMF (10 mL). The reaction mixture was stirred for 15 minutes, (S)-2-(tert-butoxycarbonyl-methyl-amino)-propionic 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. After washing the organic layer with saturated brine, it was dried with 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 (850 mg). MS: [M＋H] ⁺ 842.1.

I) ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-3-(2-(2-(2-hydroxyethoxy)ethyl (Oxy)ethoxy)-1-methyl-1H-indole-2-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl )(Methyl)carbamic acid tert-butyl ester at room temperature to ((S)-1-(((S)-2-(4-(3-(2-(2-(2-(benzyloxy (Yl)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperid-1-yl)-1-cyclohexyl-2 -Oxyethyl)amino)-1-oxopropan-2-yl)(methyl)amino acid tert-butyl ester (850 mg) and ethanol (10 mL) add 10% palladium on carbon ( 200 mg), stirred for 3 hours in a hydrogen atmosphere at normal pressure. The reaction mixture was filtered through Celite and washed with ethanol, and the filtrate was concentrated under reduced pressure to obtain the title compound (740 mg). MS: [M＋H] ⁺ 752.6.

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

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)isoazol-3-yl)oxy)ethoxy)ethoxy (Yl)ethoxy)-1H-indole-2-carbonyl)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propionamide hydrochloride cooled in an ice bath Downward ((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)piperid-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl ) 4 M hydrogen chloride/dioxane solution (0.3 mL) was added to the mixture of tert-butyl carbamate (36 mg) and DCM (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diethyl ether and pentane to obtain the title compound (24 mg). ¹ H NMR (400 MHz, DMSO-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).

Example 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)isoazol-3-yl)oxy)-6,9,12-tri (Oxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperidin-1-yl)-2-oxoethyl)-2-(methylamino)propionamide salt Acid salt

A) ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1H-indole-2-carbonyl)piperid-1-yl)- ((S)-1-(((S)-1-cyclohexyl)((S)-1-(((S)-1-Cyclohexyl))(2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)aminocarboxylate -2-oxo-2-(piper-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)aminocarboxylate (2.29 g), HATU (2.89 g) was added to the mixture of 5,6-difluoro-1H-indole-2-carboxylic acid (1.00 g), DIEA (2.72 mL) and DMF (20 mL), 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 with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (2.64 g). MS: [M＋H-Boc] ⁺ 490.3.

B) 2-(2-(4-((S)-2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylethyl ((S)-1-(((S)-1-Cyclohexyl-2 -(4-(5,6-Difluoro-1H-indole-2-carbonyl)piperid-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl) A mixture of tert-butyl (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 with 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 obtain the title compound (2.96 g). MS: [M＋H] ⁺ 662.4.

C) 2-(2-(4-((S)-2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylethyl (Acidyl)piperidin-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid in 2-(2-(4-((S)-2-((S)-2 -((Third-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl)piper-1-carbonyl)-5,6-difluoro-1H-indole- To the mixture of methyl 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, 1 M hydrochloric acid was added to make it acidic, and extraction was performed with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (2.16 g). MS: [M＋H] ⁺ 648.4.

D) ((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)piperid-1-yl)-2-oxoethyl)amino)-1 -Pendant oxypropan-2-yl)(methyl)aminocarboxylic acid tertiary butyl ester in 2-(2-(4-((S)-2-((S)-2-((third butoxy (Carbonyl) (Methyl) Amino) Propanamide)-2-Cyclohexyl Acetyl) Piper-1-carbonyl)-5,6-Difluoro-1H-indol-1-yl)acetic acid (1.20 g ), 5,8,11-trioxa-2-azatridecane-13-ol (422 mg), DIEA (0.65 mL), and DMF (9.3 mL) add HATU (986 mg), Stir 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 with 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 obtain the title compound (695 mg). MS: [M＋H] ⁺ 837.5.

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-indole-2-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-1-oxopropane -2-yl)(methyl)carbamic acid tert-butyl ester in 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-indole-2-carbonyl)piperid-1-yl)-2 -Oxyethyl)amino)-1-oxopropan-2-yl)(methyl)aminocarboxylate (670 mg), triphenylphosphine (1.05 g) and toluene (8 mL) Add di-tert-butyl azodicarboxylate (553 mg) to the mixture, and stir 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 ammonium acetate aqueous solution) to obtain the title compound (575 mg). MS: [M＋H] ⁺ 1150.4.

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)isoazol-3-yl)oxy)-6,9,12 -Trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propionyl Amine hydrochloride in ((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)piperidin-1-yl)-2-oxoethyl)amino)-1- Add 4 M hydrogen chloride/ethyl acetate solution (2 mL) to the mixture of tert-butyl (575 mg) carbamate (575 mg) and ethyl acetate (1 mL). Stir at low temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (549 mg). ¹ H NMR (400 MHz, DMSO-d ₆ , 100℃) δ 0.95-1.32 (5H, m), 1.35-1.40 (3H, m), 1.57-1.78 (6H, m), 1.94-2.08 (2H, m) ), 2.18-2.27 (2H, m), 3.05-3.78 (32H, m), 3.84-3.95 (1H, m), 3.99-4.21 (2H, m), 4.28-4.33 (2H, m), 4.63-4.70 (1H, m), 4.93-5.03 (1H, m), 5.17-5.26 (2H, m), 6.32-6.40 (1H, m), 6.72 (1H, s), 7.07-7.17 (1H, m), 7.47 -7.59 (3H, m), 8.08-8.13 (1H, m), 8.39-8.48 (1H, m), 8.53-8.62 (1H, m), 8.63-8.93 (2H, m).

Example 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)pyrrolidine -1-yl)ethyl)-1H-indole-2-carbonyl)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propionamide hydrochloride

A) (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl )Methyl)isoxazole in 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole-3-ol( 398.8 mg), (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid (9H-茀-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, and TFA (5 mL) was added to the residue. The reaction mixture was stirred at room temperature for 5 minutes, diluted with water, and washed with ethyl acetate. The aqueous layer was made alkaline with 2 M sodium hydroxide aqueous solution, and extracted with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried with 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 obtain the title compound (199.4 mg). MS: [M＋H] ⁺ 415.2.

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 Yl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl )(Methyl)aminocarboxylic acid tertiary butyl ester in 2-(2-(4-((S)-2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino )Propylamine)-2-Cyclohexylacetyl)Piper-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), add 1-ethyl-3-(3-dimethylaminopropyl) carbon Diimide hydrochloride (118.3 mg). The reaction mixture was stirred at room temperature for 2 hours, water was added, the precipitate was collected by filtration, and washed with water to obtain the title compound (320.8 mg). MS: [M＋H] ⁺ 1044.3.

C) (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-( ((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl) (Pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propionamide hydrochloride In ((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)piperid-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl) To the mixture of tert-butyl (methyl)carbamate (380.2 mg) and ethyl acetate (1.5 mL) was added 4 M hydrogen chloride/ethyl acetate solution (1 mL). The reaction mixture was stirred at room temperature for one and a half hours, and diisopropyl ether was added. The precipitate was collected by filtration and washed with diisopropyl ether to obtain the title compound (280.3 mg). MS: [M＋H] ⁺ 944.2. Neutralize the title compound with saturated aqueous sodium bicarbonate solution, collect the precipitate, and measure ¹ H NMR in the form of the obtained free body. 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).

Example 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)pyrrolidine-1- (Yl)ethyl)-1H-indole-2-carbonyl)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propionamide

A) ((S)-1-(((S)-1-cyclohexyl-2-(4-(5-fluoro-1H-indole-2-carbonyl)piperid-1-yl)-2-side ((S)-1-(((S)-1-Cyclohexyl-2-(((S))-1-(((S)-1-cyclohexyl-2-yl)-1-oxopropan-2-yl)(methyl)aminocarboxylate) Pendant oxy-2-(piper-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)aminocarboxylate (7 g) and DMF (60 mL) was added to the mixture of 5-fluoro-1H-indole-2-carboxylic acid (3.36 g), 1-hydroxybenzotriazole (3.00g), DIEA (11.9 mL), 1-ethyl-3-( 3-Dimethylaminopropyl)carbodiimide hydrochloride (4.25 g). The reaction mixture was stirred at room temperature for 16 hours, water was added, and extraction was performed with ethyl acetate. The organic layer was washed sequentially with water, saturated aqueous ammonium chloride solution, saturated sodium bicarbonate aqueous solution, and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (9.5 g). MS: [M＋H] ⁺ 572.0.

B) 2-(2-(4-((S)-2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylethyl ((S)-1-(((S)-1-Cyclohexyl) (((S)-1-(((S))-1-Cyclohexyl)) ((S)-1-(((S)-1-carbonyl)-5-fluoro-1H-indol-1-yl)-1-yl) methyl acetate under ice cooling -2-(4-(5-Fluoro-1H-indole-2-carbonyl)piperid-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)( Potassium carbonate (6.89 g) and methyl bromoacetate (4.59 mL) were added to the mixture of tert-butyl methyl) carbamate (9.5 g) and DMF (50 mL), and the reaction mixture was stirred at room temperature for 16 hours , Add water and extract with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried with 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). MS: [M＋H] ⁺ 644.1.

C) 2-(2-(4-((S)-2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylethyl (Acetyl)piperidin-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetic acid in 2-(2-(4-((S)-2-((S)-2-(( (Tertiary butoxycarbonyl) (methyl) amino) propanamide) -2-cyclohexyl ethanoyl) piper𠯤-1-carbonyl)-5-fluoro-1H-indol-1-yl) methyl acetate 2 M aqueous sodium hydroxide solution (13.4 mL) was added to the mixture of ester (8.6 g) and methanol (25 mL), and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with water and washed with diethyl ether. The organic layer was extracted with a 0.01 M aqueous sodium hydroxide solution. The aqueous layer was made acidic with 6 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (8.1 g). MS: [M＋H] ⁺ 630.2.

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)pyrrole (Pyridin-1-yl) ethyl) -1H-indole-2-carbonyl) piper-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(form 2-(2-(4-((S)-2-((S)-2-((Third-butoxycarbonyl)(methyl)amino)propane) (Amine)-2-cyclohexylacetyl)piperidin-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetic acid (700 mg) and DMF (10 mL) add (S) -3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso Azole (506.8 mg), DIEA (0.78 mL), HATU (507.8 mg), and stirred at room temperature for 16 hours. Ice water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried with 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 (950 mg). MS: [M＋H] ⁺ 1025.8.

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

Example 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 (Yl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)-2-oxoethyl)-2-(methylamino) )Acrylamide

A) (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl )Methyl)isoxazole trihydrochloride, 3-hydroxyisoxazole-5-carboxylic acid methyl ester (3.79 g), (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid third Butyl ester (4.84 g) and triphenylphosphine (6.94 g) were azeotropically boiled in toluene, and 40% diethyl azodicarboxylate in toluene solution ( 14 mL). After the reaction mixture was stirred at room temperature for 1 hour, the solvent was distilled off to half under reduced pressure, and it was purified by silica gel column chromatography (ethyl acetate/hexane). In the obtained (S)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)isoxazole-5-carboxylic acid methyl ester and methanol (100 mL) Sodium borohydride (1.18 g) was added to the mixture. The reaction mixture was stirred at room temperature for 4 hours, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. In the obtained (S)-2-(((5-(hydroxymethyl)isoxazol-3-yl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester and THF (100 mL Add methanesulfonyl chloride (2.10 mL) to the mixture. The reaction mixture was stirred at room temperature for 2 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained (S)-2-(((5-(((methylsulfonyl)oxy)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidine-1-carboxy Tert-butyl ester, 7-(piperidin-4-yloxy)thieno[3,2-b]pyridine dihydrochloride (8.85 g), potassium carbonate (19.9 g), tetrabutylammonium iodide A mixture of (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 performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried with 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). In the obtained (S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole To a mixture of -3-yl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester and ethyl acetate (20 mL) was added 4 M hydrogen chloride/ethyl acetate (40 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). MS: [M＋H] ⁺ 415.2.

B) (S)-4-(5,6-Difluoro-1H-indole-2-carbonyl)-3-methylpiperidine-1-carboxylic acid tert-butyl ester in (S)-3-methyl Piper-1-carboxylic acid tert-butyl ester (1.12 g), 5,6-difluoro-1H-indole-2-carboxylic acid (1.00 g), DIEA (2.72 mL), and DMF (20 mL) HATU (2.89 g) was added to the mixture. The reaction mixture was stirred at room temperature for 1 hour, diluted with water and ethyl acetate, and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.61 g). MS: [M＋H-tBu] ⁺ 324.2.

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

D) 2-(2-((S)-4-((S)-2-((S)-2-((3rd butoxycarbonyl)(methyl)amino)propanamide)-2 -Cyclohexylacetyl)-2-methylpiper-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid methyl ester in 2-(2-((S)- 4-((S)-2-((Third-butoxycarbonyl)amino)-2-cyclohexylacetyl)-2-methylpiper-1-carbonyl)-5,6-difluoro- To a mixture of 1H-indol-1-yl) methyl 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. In the obtained 2-(2-((S)-4-((S)-2-amino-2-cyclohexylacetyl)-2-methylpiper-1-carbonyl)-5,6 -Difluoro-1H-indol-1-yl)acetate methyl ester hydrochloride, N-(tertiary butoxycarbonyl)-N-methyl-L-alanine (329 mg), DIEA (0.85 mL) Add HATU (616 mg) to the mixture of, and DMF (5 mL). The reaction mixture was stirred at room temperature for 1 hour, water and ethyl acetate were added, and extraction was performed with ethyl acetate. The organic layer was dried with 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 obtain the title compound (450 mg). MS: [M＋H] ⁺ 676.5.

E) 2-(2-((S)-4-((S)-2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino)propanamide)-2 -Cyclohexylacetyl)-2-methylpiper-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid in 2-(2-((S)-4- ((S)-2-((S)-2-((Third-butoxycarbonyl)(methyl)amino)propionamide)-2-cyclohexylacetyl)-2-methylpiperidine -1-carbonyl)-5,6-difluoro-1H-indol-1-yl)methyl acetate (225 mg) and methanol (1.6 mL) was added with 2 M aqueous sodium hydroxide solution (0.8 mL). The reaction mixture was stirred at room temperature for 1 hour, made acidic with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (221 mg). MS: [M＋H] ⁺ 662.4.

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)isoazol-3-yl) (Oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)-2-oxoethyl)amino)- 1-oxopropan-2-yl)(methyl)aminocarboxylic acid tert-butyl ester in 2-(2-((S)-4-((S)-2-((S)-2-(( (Tertiary butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetin)-2-methylpiper-1-carbonyl)-5,6-difluoro-1H-indyl Dole-1-yl)acetic acid (336 mg), (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridine-7- Add HATU (386 mg) to the mixture of (oxy)piperidin-1-yl)methyl)isoxazole trihydrochloride (319 mg), DIEA (0.53 mL), and DMF (3 mL). The reaction mixture was stirred at room temperature for 2 hours, water was added, the precipitate was collected by filtration, and purified by silica gel column chromatography (C18, acetonitrile/5 mM ammonium acetate aqueous solution/acetonitrile). To the obtained compound, ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (320 mg). MS: [M＋H] ⁺ 1058.5.

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-methylpiperidin-1-yl)-2-oxoethyl)-2-(methyl ((S)-1-(((S)-1-Cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-side oxy)) -2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole -3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)-2-oxoethyl )Amino)-1-oxopropan-2-yl)(methyl)aminocarbamate (320 mg) and ethyl acetate (2 mL) are added to the mixture of 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. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the precipitate was collected by filtration to obtain the title compound (216 mg). ¹ H NMR (300 MHz, 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)

Example 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)pyrrole (Pyridin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)-2-oxoethyl)-2-(methylamino)propionyl amine

A) (S)-4-((S)-2-((Third-butoxycarbonyl)amino)-2-cyclohexylacetyl)-2-methylpiperidine-1-carboxylic acid benzyl ester (S)-2-((Third-butoxycarbonyl)amino)-2-cyclohexylacetic acid (5 g), (S)-2-methylpiperidine-1-carboxylic acid benzyl ester hydrochloride (5.26 g), 1-hydroxybenzotriazole (3.4 g), DIEA (10.2 mL) and DMF (50 mL), add 1-ethyl-3-(3-dimethylaminopropyl) carbon Diimide hydrochloride (4.8 g). The reaction mixture was stirred at room temperature for 2 hours, ice water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate aqueous solution, and saturated brine in this order, and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (6.7 g). MS: [M＋H] ⁺ 474.2.

B) (S)-4-((S)-2-amino-2-cyclohexylacetyl)-2-methylpiperidine-1-carboxylic acid benzyl ester hydrochloride in (S)-4- ((S)-2-(((Third-butoxy)carbonyl)amino)-2-cyclohexylacetyl)-2-methylpiper-1-carboxylic acid benzyl ester (6.7 g) and DCM Add 4 M hydrogen chloride/dioxane solution (30 mL) to the mixture (60 mL). The reaction mixture was stirred at room temperature for 3 hours, and the solvent was distilled off under reduced pressure. The residue was washed with DCM to obtain the title compound (6 g). 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).

C) (S)-4-((S)-2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetoxy )-2-methylpiperidine-1-carboxylic acid benzyl ester is added to the mixture of N-(tert-butoxycarbonyl)-N-methyl-L-alanine (3 g) and DMF (30 mL) (S)-4-((S)-2-amino-2-cyclohexylacetyl)-2-methylpiperidine-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 hours, ice water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed sequentially with water, saturated sodium bicarbonate aqueous solution, and saturated brine, dried with 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 (6 g). MS: [M＋H] ⁺ 559.1.

D) ((S)-1-(((S)-1-cyclohexyl-2-((S)-3-methylpiperid-1-yl)-2-oxoethyl)amino group)- (S)-4-((S)-2-((S)-2-((Third-butoxycarbonyl) (1-oxopropan-2-yl)(methyl)aminocarboxylic acid tertiary butyl ester )(Methyl)amino)propanamide)-2-cyclohexylacetyl)-2-methylpiper-1-carboxylic acid benzyl ester (3.8 g) and ethanol (50 mL) add 10 % Palladium on carbon (1 g). The reaction mixture was stirred for 16 hours at room temperature under normal pressure hydrogen environment, and filtered through Celite. The filtrate was concentrated under reduced pressure to obtain the title compound (2.3 g). MS: [M＋H] ⁺ 425.2.

E) 2-(2-((S)-4-((S)-2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino)propanamide)-2 -Cyclohexylacetyl)-2-methylpiper-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetate methyl ((S)-1-(((S)- 1-cyclohexyl-2-((S)-3-methylpiper-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)amine Add HATU (1.21 g) to the mixture of tert-butyl carboxylate (901 mg), 5-fluoro-1H-indole-2-carboxylic acid (380 mg), DIEA (1.14 mL), and DMF (12 mL) . The reaction mixture was stirred at room temperature for 1 hour, poured into water, and the precipitate was collected by filtration and azeotroped in toluene. The obtained ((S)-1-(((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1H-indole-2-carbonyl)-3-methyl) (Piper-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamic acid tert-butyl ester, potassium carbonate (322 mg), 2- A mixture of methyl 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 with 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 obtain the title compound (979 mg). MS: [M＋H] ⁺ 658.4.

F) 2-(2-((S)-4-((S)-2-((S)-2-((tertiary butoxycarbonyl)(methyl)amino)propanamide)-2 -Cyclohexylacetyl)-2-methylpiper-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetic acid in 2-(2-((S)-4-((S )-2-((S)-2-((Third-butoxycarbonyl)(methyl)amino)propionamide)-2-cyclohexylacetin)-2-methylpiper-1- To a mixture of carbonyl)-5-fluoro-1H-indol-1-yl)methyl 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, 1 M hydrochloric acid was added to make it acidic, and extraction was performed with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (915 mg). MS: [M＋H] ⁺ 644.4.

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-methylpiperidin-1-yl)-2-oxoethyl)amino)-1-side Oxypropan-2-yl)(methyl)aminocarboxylic acid tert-butyl ester in 2-(2-((S)-4-((S)-2-((S)-2-((Third-Butyl) (Oxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl)-2-methylpiperidin-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)piperidine Add HATU (734 mg) to the mixture of -1-yl)methyl)isoxazole trihydrochloride (606 mg), DIEA (1.0 mL), and DMF (5 mL). The reaction mixture was stirred at room temperature for 2 hours, water was added, the precipitate was collected by filtration, and purified by silica gel column chromatography (C18, acetonitrile/5 mM ammonium acetate aqueous solution). The obtained compound was diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (367 mg). MS: [M＋H] ⁺ 1040.5.

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-methylpiperidin-1-yl)-2-oxoethyl)-2-(methylamino) Propamide is in ((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)isoazol-3-yl)oxy (Yl)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)-2-oxoethyl)amino)-1 Add 4 M hydrogen chloride/ethyl acetate solution (3 mL) to the mixture of tertiary butyl ester of -oxopropan-2-yl)(methyl)carbamate (367 mg) and ethyl acetate (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. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the precipitate was collected by filtration to obtain the title compound (249 mg). ¹ H NMR (300 MHz, 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).

Example 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)isoazol-3-yl)oxy)ethoxy)ethyl (Oxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride salt

A) 2-(Benzyloxy)-3,4-difluorobenzaldehyde is added to a mixture of 3,4-difluoro-2-hydroxy-benzaldehyde (5 g) and acetonitrile (50 mL) with 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 hours, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (7.0 g). 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).

B) (Z)-2-azido-3-(2-(benzyloxy)-3,4-difluorophenyl) methyl acrylate at -10℃ in an argon atmosphere to methyl azide acetate (3.15 mL), 2-(benzyloxy)-3,4-difluorobenzaldehyde (2.0 g) and methanol (10 mL) are added dropwise to a mixture of sodium methoxide (1.74 g) and methanol (10 mL) . The reaction mixture was stirred at the same temperature for 4 hours and at 4°C for 16 hours. Ice water was added, and the precipitate was collected by filtration to obtain the title compound (2.1 g). ¹ H NMR (400 MHz, DMSO-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).

C) 4-(Benzyloxy)-5,6-difluoro-1H-indole-2-carboxylic acid methyl ester will (Z)-2-azido-3-(2-(benzyloxy)-3 A mixture of methyl 4-difluorophenyl)acrylate (2.0 g) and xylene (30 mL) was stirred at 140°C for 2 hours. The reaction mixture was cooled, and the precipitate was collected by filtration to obtain the title compound (700 mg). ¹ H NMR (400 MHz, DMSO-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).

D) 4-(Benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carboxylic acid methyl ester in 4-(benzyloxy)-5,6-difluoro-1H -Add potassium carbonate (1.1 g) and methyl iodide (0.4 mL) to the mixture of methyl indole-2-carboxylate (1.7 g) and DMF (20 mL). The reaction mixture was stirred at room temperature for 2 hours, ice water was added, and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.5 g). MS: [M＋H] ⁺ 332.1.

E) 4-(Benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carboxylic acid in 4-(benzyloxy)-5,6-difluoro-1-methyl Add water (6 mL) and lithium hydroxide monohydrate (0.285 g) to a mixture of methyl-1H-indole-2-carboxylate (1.5 g) and THF (30 mL). 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 make it acidic, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.35 g). MS: [M＋H] ⁺ 318.1.

F) ((S)-1-(((S)-2-(4-(4-(benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl) Piper-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)aminocarboxylic acid tert-butyl ester in 4-(benzyl) Oxy)-5,6-difluoro-1-methyl-1H-indole-2-carboxylic acid (1.4 g) and DMF (20 mL) add ((S)-1-(((S )-1-cyclohexyl-2-oxo-2-(piper-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)aminocarboxylic acid tert-butyl Esters (1.81 g), HATU (2.52 g) and DIEA (1.9 mL). The reaction mixture was stirred at room temperature for 2 hours, ice water was added, and extraction was performed with ethyl acetate. After washing the organic layer with saturated sodium bicarbonate aqueous solution, water and saturated brine in this order, it was dried with 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 (2.1 g). MS: [M＋H] ⁺ 710.1.

G) ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-4-hydroxy-1-methyl-1H-indole-2-carbonyl )Piperidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)aminocarboxylate tert-butyl ester at ((S)-1-( ((S)-2-(4-(4-(Benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperidin-1-yl)-1- Add palladium to the mixture of cyclohexyl-2-oxoethyl (amino)-1-oxopropan-2-yl)(methyl)aminocarboxylate (2.1 g) and ethanol (50 mL) Carbon (400 mg), stirred for 2 hours at room temperature under a hydrogen atmosphere at normal pressure. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.7 g). MS: [M＋H] ⁺ 620.4.

H) 2-(2-(2-(2-(Benzyloxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonic acid (2-(2-(Benzyloxy)ethoxy)ethoxy)ethoxy)ethanol (15 g) and DCM (250 mL) add TEA (11.03 mL), DMAP (3.22 g), P-Toluenesulfonyl chloride (12.07 g), stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM, and washed with water and saturated brine. The organic layer was dried with 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 (14 g). MS: [M＋H] ⁺ 439.2.

I) ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-((1-phenyl-2,5 ,8,11-Tetraoxatridecane-13-yl)oxy)-1H-indole-2-carbonyl)piperid-1-yl)-2-oxoethyl)amino)-1- Pendant oxypropan-2-yl)(methyl)amino acid tert-butyl ester in ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro) -4-Hydroxy-1-methyl-1H-indole-2-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(form Add cesium carbonate (591 mg) and 4-methylbenzenesulfonic acid 2-(2-(2-(2-(benzyl) to the mixture of tert-butyl carbamate (450 mg) and DMF (5 mL). (Oxy)ethoxy)ethoxy)ethoxy)ethyl (573 mg). The reaction mixture was stirred at room temperature for 16 hours, ice water was added, and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried with 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 (490 mg). MS: [M＋H] ⁺ 886.4.

J) ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-4-(2-(2-(2-(2-hydroxyethoxy Ethoxy)ethoxy)ethoxy)ethoxy)-1-methyl-1H-indole-2-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-1- Pendant oxypropan-2-yl)(methyl)amino acid tert-butyl ester in ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro) -1-Methyl-4-((1-phenyl-2,5,8,11-tetraoxatridecane-13-yl)oxy)-1H-indole-2-carbonyl)piperidin- 1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)aminocarbamate (490 mg) in a mixture of ethanol (15 mL) Add palladium on carbon (100 mg). The reaction mixture was stirred for 16 hours at room temperature under a hydrogen atmosphere under normal pressure, then filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (360 mg). MS: [M＋H] ⁺ 796.2.

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)ethyl (Oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-1-oxopropane- ((S)-1-(((S)-1-Cyclohexyl-2-(4-(5,6-Difluoro-4-( 2-(2-(2-(2-(2-Hydroxyethoxy)ethoxy)ethoxy)ethoxy)-1-methyl-1H-indole-2-carbonyl)piperid-1-yl) -2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)aminocarboxylate (20 mg), 5-((4-(thieno[3, 2-b)Pyridin-7-yloxy)piperidin-1-yl)methyl)isoazol-3-ol (12.4 mg), a mixture of triphenylphosphine (32.9 mg) and toluene (2 mL) Add di-tert-butyl azodicarboxylate (17.3 mg). The reaction mixture was stirred at room temperature for 16 hours, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography to obtain the title compound (25 mg). MS: [M＋H] ⁺ 1109.8.

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)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propionamide Hydrochloride at 0 ℃ to ((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)isoxazole-3- (Yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperid-1-yl)-2-oxoethyl)amino)- To the mixture of 1-oxopropan-2-yl)(methyl)carbamic acid tert-butyl ester (25 mg) and DCM (1 mL) was added 4 M hydrogen chloride/dioxane solution (0.3 mL). The reaction mixture was stirred at room temperature for 1 hour, the solvent was distilled off under reduced pressure, and washed with diethyl ether to obtain the title compound (17 mg). ¹ H NMR (400 MHz, 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).

Example 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)isoazol-3-yl)oxy)ethoxy)ethoxy)ethoxy) (Ethyl)-1H-indole-5-carbonyl)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propionamide

A) ((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1H-indole-5-carbonyl)piperid-1-yl)-2- ((S)-1-(((S)-1-Cyclohexyl-2)((S)-1-(((S)-1-cyclohexyl-2 -Pendant oxy-2-(piper-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)aminocarboxylate (4 g) and DMF( Add 2-methyl-1H-indole-5-carboxylic acid (1.9 g), DIEA (6.8 mL), and HATU (4.45 g) to the mixture of 70 mL), and stir at room temperature for 16 hours. The reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. After washing the organic layer with water and saturated brine in this order, it was dried with 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 (4 g). MS: [M＋H] ⁺ 568.3.

B) ((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1-(1-phenyl-2,5,8,11-tetraoxa Tridecyl-13-yl)-1H-indole-5-carbonyl)piperid-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl ) Tertiary butyl carbamate in ((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1H-indole-5-carbonyl)piper𠯤- 1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)aminocarbamate (2 g) in a mixture of DMF (30 mL) Cesium carbonate (2.87 g) was added, and after stirring at room temperature for 5 minutes, 4-methylbenzenesulfonic acid 2-(2-(2-(2-(benzyloxy)ethoxy)ethoxy) was added Ethoxy) ethyl ester (2.78 g) was stirred at 80°C for 16 hours. The reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to obtain the title compound (1.3 g). MS: [M＋H] ⁺ 834.4.

C) ((S)-1-(((S)-1-cyclohexyl-2-(4-(1-(2-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethane (Oxy)ethyl)-2-methyl-1H-indole-5-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl) ((S)-1-(((S)-1-Cyclohexyl-2-(4-(2-methyl-1-(1-phenyl-2 ,5,8,11-Tetraoxatridecane-13-yl)-1H-indole-5-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-1-side Add 10% palladium on carbon (250 mg) to a mixture of oxypropan-2-yl)(methyl)carbamic acid tert-butyl ester (1.3 g) and ethanol (50 mL). Stir at ℃ for 16 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.1 g). MS: [M＋H] ⁺ 744.3.

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)isoazol-3-yl)oxy)ethoxy)ethoxy) (Ethoxy)ethyl)-1H-indole-5-carbonyl)piperid-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl) ((S)-1-(((S)-1-cyclohexyl-2-(4-(1-(2-(2-(2-(2-hydroxyethoxy )Ethoxy)ethoxy)ethyl)-2-methyl-1H-indole-5-carbonyl)piperid-1-yl)-2-oxoethyl)amino)-1-oxo Propan-2-yl)(methyl)carbamic acid tert-butyl ester (20 mg), 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidine-1 -Yl)methyl)isoazol-3-ol (10.6 mg), triphenylphosphine (35.2 mg) and toluene (2 mL) add di-tert-butyl azodicarboxylate (24.7 mg) , And 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). MS: [M＋H] ⁺ 1057.3.

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)isoazol-3-yl)oxy)ethoxy)ethoxy)ethoxy Yl)ethyl)-1H-indole-5-carbonyl)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propionamide at 0℃ to ((S )-1-(((S)-1-Cyclohexyl-2-(4-(2-methyl-1-(2-(2- (2-(2- ((5-((4-(thiophene And [3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl (Yl)-1H-indole-5-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)aminocarboxylic acid TFA (0.01 mL) was added to the mixture of butyl ester (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/20 mM ammonium bicarbonate aqueous solution) to obtain the title compound (4 mg). MS: [M＋H] ⁺ 957.8.

The produced Example Compounds 1 to 11 are shown below. For each compound, the compound name, structural formula, salt type, and MS value (MS is actually measured value) are shown.

Example No. 1 (Compound 1): 2-(4-((S)-2-Cyclohexyl-2-((S)-2-(Methylamino)propionylamine)acetyl)piperidin- 1-carbonyl)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridine -7-yloxy)piperidin-1-yl)methyl)isoazol-3-yl)oxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carbamide (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),

鹽之類型：HCl；MS值：1006.6[化55]

Type of salt: HCl; MS value: 1006.6

Example No. 2 (Compound 2): 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propionylamine)acetinyl)piperidin- 1-carbonyl)-6-methoxy-1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy (Yl)piperidin-1-yl)sulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-methanamide (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),

鹽之類型： - ；MS值：1046.5[化56]

Type of salt:-; MS value: 1046.5

Example No. 3 (Compound 3): 1-((R)-4-(5,6-Difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiper-1- Base)-2-((2R,5R)-5-methyl-2-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridine-7 -Yloxy)piperidin-1-yl)methyl)isoazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperidin-1-yl)ethane -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),

鹽之類型：HCl；MS值：909.7[化57]

Type of salt: HCl; MS value: 909.7

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)isoazol-3-yl)oxy )Ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propionamide ((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),

鹽之類型：HCl；MS值：966.4[化58]

Type of salt: HCl; MS value: 966.4

Example No. 5 (Compound 5): (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo Base-14-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoazol-3-yl)oxy )-6,9,12-Trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperid-1-yl)-2-oxoethyl)-2-( ((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),

鹽之類型：HCl；MS值：1050.3[化59]

Type of salt: HCl; MS value: 1050.3

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)isoazol-3-yl )Oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperidin-1-yl)-2-oxoethyl)-2-(methylamino) )Propamide ((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),

鹽之類型：HCl；MS值：944.2[化60]

Type of salt: HCl; MS value: 944.2

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)isoazol-3-yl)oxy )Methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperidin-1-yl)-2-oxoethyl)-2-(methylamino)propionyl Amine ((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),

鹽之類型： - ；MS值：926.1[化61]

Type of salt:-; MS value: 926.1

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)isoxazole -3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-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),

鹽之類型： - ；MS值：958.4[化62]

Type of salt:-; MS value: 958.4

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)isoxazole-3- (Yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-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),

鹽之類型： - ；MS值：940.4[化63]

Type of salt:-; MS value: 940.4

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)isoazol-3-yl )Oxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperid-1-yl)-2-oxoethyl)-2-(form ((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),

鹽之類型：HCl；MS值：1009.7、 及[化64]

Type of salt: HCl; MS value: 1009.7, and

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)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propionamide ( (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),

鹽之類型： - ；MS值：957.8[化65]

Type of salt:-; MS value: 957.8

Test Example 1: Determination of XIAP binding inhibitory activity Human XIAP binding inhibitory activity is obtained by using commercially available human XIAP_BIR3 region purified protein (R&D) to biotinylate the C-terminal Smac N-terminal peptide (AVPIAQK( Serial number: 1)) (hereinafter referred to as "b-Smac", PEPTIDE INSTITUTE Co., Ltd.) as a ligand, and measured by Homogeneous Time Resolved Fluorescence (HTRF) method. The HTRF method will be described in detail below. The reaction buffer (containing 100 mM NaCl, 0.1% BSA (Bovine Serum Albumin, bovine serum albumin), 0.1% Triton X-100, 25 mM HEPES (4-(2-Hydroxyethyl) piperazine-1-ethanesulfonic acid), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) buffer, pH 7.5) The diluted test compound was added to a 384-well white shallow pan (Greiner 784076) at 1 μL/well. And perform Flash centrifugation for 30 seconds. Then, after diluting the purified human XIAP_BIR3 protein with reaction buffer to 90 nM to obtain a sample diluent, the sample diluent was added at 4.5 μL/well to the white shallow pan, and flash centrifugation was performed for 30 seconds. Then, b-Smac diluted to 90 nM with the reaction buffer was added to the white shallow pan at 4.5 μL/well, and Flash centrifuged for 30 seconds. ^{Anti-6HIS-Cryptate (Eu 3+} Cryptate-conjugated mouse monoclonal antibody anti-6 Histidine, cisbio) diluted 100 times with HTRF detection buffer ( ^{cisbio), and Streptavidin-XL ent!} (Highgrade XL665) -Conjugated streptavidin, cisbio) was mixed in a volume of 1:1, and the obtained solution was added to the white shallow tray at 10 μL/well, and subjected to Flash centrifugation for 30 seconds, after which the white shallow tray was placed in the chamber Keep it in a dark place for more than 4 hours at warm temperature Place the white shallow base plate for the measurement of fluorescence intensity using EnVision (PerkinElmer) (excitation wavelength: 320 nm, fluorescence wavelength: 665 nm and 615 nm). The binding inhibition rate (%) is calculated based on 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). The XIAP binding inhibition rate of the test compound was evaluated. The XIAP binding inhibition rate when the concentration of the test compound is 3 μM is shown in the following table according to A≧75%, 75%>B≧50%, 50%>C≧25%, D<25%, or The 50% inhibitory concentration (IC50 value) is shown in the following table in terms of A<0.3 μM, 0.3 μM≦B<3 μM, and 3 μM≦C<30 μM.

[Table 1] 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 Example 11 -/B *Inhibition rate: Inhibition rate/IC50 value under 3 μM

The above results indicate that the compound of the present invention has excellent IAP (especially XIAP) binding (inhibiting) activity.

Test Example 2: Measurement of IRAK-M binding inhibitory activity The binding inhibitory activity of IRAK-M uses the active site-dependent competition assay KINOMEscan (registered trademark) (Goldstein, DM et al. High-throughput kinase profiling as a platform for drug discovery. Nat. Rev. Drug) provided by Eurofins DiscoverX. Discovery. 7, 391-397 (2008)). The IRAK-M binding inhibition rate of the test compound was evaluated. Show the %Ctrl when the concentration of the test compound is 1 μM in accordance with A＜25%, 50%＞B≧25%, 75%＞C≧50%, D≧75% in the following table, or IC50 value According to A<0.03 μM, 0.03 μM≦B<0.1 μM, 0.1 μM≦C<0.3 μM, 0.3 μM≦D<1 μM, they are shown in the following table. %Ctrl is calculated by the following formula. (The information value of the test compound-the information value of the positive control compound) / (the information value of the negative control compound-the information value of the positive control compound) × 100 Negative control compound = DMSO (100% Ctrl) Positive control compound = control compound (0% Ctrl)

[Table 2] Compound * Binding inhibitory activity Example 1 -/D Example 2 -/D Example 3 -/D Example 4 B/- Example 5 A/- Example 6 A/- Example 7 -/D Example 8 -/D Example 9 -/D Example 10 A/- Example 11 A/- *Binding inhibitory activity: %Ctrl/IC50 value under 1 μM

Test Example 3: In vitro degradation inducing activity of target protein Example The degradation inducing activity of compound target protein in vitro was evaluated by enzyme binding immunoassay (ELISA) according to the following analysis stages. The THP1 cells (ATCC, TIB-202) were supplemented with 10% FBS (Fetal Bovine Serum), 1X sodium pyruvate, 1X HEPES, D-(+)-glucose and 1% penicillin/streptomycin. Cultivated in RPMI (Roswell Park Memorial Institute)-1640. The THP1 cells seeded in 24-well plates ^{at 1×10 6} cells/well were treated with DMSO control and test compound, and cultured for 24 hours. The cells were recovered and dissolved in a lysis buffer (PBS (Phosphate Buffered Saline, phosphate buffered saline) containing 0.1% Triton X-100) supplemented with a protease inhibitor mixture (Roche, Cat# 11836170001) on ice for 30 minutes. After running for 30 seconds/stopping for 30 seconds (30sec ON/30sec OFF), the lysate was ultrasonically broken for 10 cycles, and then centrifuged at 4°C and 13 krpm for 10 minutes. The protein concentration was determined by BCA (bicinchoninic acid, bicinchoninic acid) analysis (Sigma, Cat # QPBCA-1KT). The ELISA analysis system uses the human IRAK3/IRAKM/IRAK-M ELISA kit (LifeSpan BioSciences, Cat # LS-F35271), and evaluates the protein quality of IRAK-M according to the kit's operating instructions. For the IRAK-M protein degradation rate of the test compound, the protein degradation rate (%) when the concentration of the test compound is 1 μM is A≧75%, 50%≦B<75%, 25%≦C<50%, D<25% is shown in the following table, or the 50% decomposition concentration (DC50 value) is as follows: A<0.03 μM, 0.03 μM≦B<0.1 μM, 0.1 μM≦C<0.3 μM, 0.3 μM≦D<1 μM Shown in the table below.

[table 3] Compound *Decomposition rate Example 1 -/D Example 2 C/- Example 3 C/- Example 4 A/- Example 5 -/D Example 6 -/B Example 7 -/A Example 8 -/A Example 9 -/A Example 10 -/C Example 11 A/- *Decomposition rate: protein decomposition rate under 1 μM/DC50 value

Test Example 4: The anti-tumor effect in mouse Lewis lung carcinoma cell inoculation model. For C57BL/6 mice (Charles River Laboratories Japan, male, 7-8W), mouse Lewis lung carcinoma cells LL/2 (Lewis lung carcinoma, LLC) ) (ATCC, CRL-1642) 2×10 ⁴ cells/mouse and Matrigel were subcutaneously inoculated into the flank of the mouse. Seven days after the inoculation, the tumor size was measured with an electronic vernier caliper, grouped so that the size of each group was the same, and the compound administration was started 8 days later. The tumor size is calculated using the formula of tumor long diameter×short diameter×short diameter÷2. The test compound was suspended in 0.5% methylcellulose or dissolved in physiological saline, and was administered subcutaneously 3 times every 3 days. The tumor size is measured regularly until 16 to 18 days after the start of the test. Two sets of verification are performed on the tumor size in the test compound administration group and the tumor size in the solvent administration group on the final day of the test. Fig. 1 shows the daily changes of tumor size in Examples 1, 6, 7, 8, and 9, each group. Each compound uses the salt shown in the figure. The graph represents the mean ± standard error. The above results indicate that these compounds have cancer growth inhibitory effects.

Formulation example 1 A medicine containing the compound of the present invention as an active ingredient can be produced by, for example, the following formulation. 1. Capsules (1) 40 mg of the compound obtained in Example 1 (2) Lactose 70 mg (3) Microcrystalline cellulose 9 mg (4) Magnesium stearate 1 mg 1 capsule 120 mg Mix 1/2 of (1), (2), (3) and (4) and then granulate. Add the rest (4) and seal the whole into a gelatin capsule.

2. Lozenges (1) 40 mg of the compound obtained in Example 1 (2) Lactose 58 mg (3) Corn starch 18 mg (4) Microcrystalline cellulose 3.5 mg (5) Magnesium stearate 0.5 mg 1 spindle 120 mg Mix 2/3 of (1), (2), (3), (4) and 1/2 of (5) and then granulate. The rest (4) and (5) are added to the granules and press-formed into tablets.

Formulation example 2 After dissolving 50 mg of the compound obtained in Example 1 in 50 mL of distilled water for injection in the Japanese Pharmacopoeia, add distilled water for injection in the Japanese Pharmacopoeia to make 100 mL. The solution was filtered under sterilization conditions, and then the solution was taken 1 mL each time, filled into vials for injection under sterilization conditions, freeze-dried and sealed.

The above detailed description simply explains the purpose and objects of the present invention, and does not limit the scope of the attached patent application. Practitioners understand that various changes and substitutions can be made to the described implementation modes without departing from the scope of the attached patent application based on the teachings described in this specification. [Industrial availability]

The compound of the present invention can decompose the target IRAK-M protein. Therefore, it is expected to provide effective drugs for the prevention or treatment of cancer and other IRAK-M-related diseases.

Figure 1 is 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. result. Each compound uses the salt shown in the figure. The graph represents the mean ± standard error.

Claims (16)

Or a pharmaceutically acceptable salt thereof, the compound is represented by the following formula (I): [化1]

. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the IRAK-M conjugate (M) is represented by the following formula (II): [化2]

[In the formula, Y is CH or N, R ⁰¹ is H or Me, and R ⁰³ is the following structural formula: [化3]

(Here, * means the position of bonding to O, ** means the position of bonding to A, n is an integer from 0 to 2), and A is the following structural formula: [化4]

(Here, R ^{05 is} each independently a hydrogen atom or a C1-6 alkyl group) represented by the group or *-SO ₂ -*, R ⁰⁴ is the following structural formula: [化5]

(Here, * means the position of bonding to A, ** means the position of bonding to the linking group) any of the groups represented, C1-6 alkylene which may be substituted, C3-10 alkylene which may be substituted Cycloalkyl, C6-14 arylene which may be substituted, or bonding bond, the arrow indicates the bonding to the linking group (L)]. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the IRAK-M conjugate (M) is represented by the following formula (III): [化6]

[In the formula, Y is CH or N, R ⁰¹ is H or Me, and A ⁰¹ is the following structural formula: [化7]

(Here, R ^{05 is} each independently a hydrogen atom or a C1-6 alkyl group) represented by the group, or *-SO ₂ -*, R ¹¹ represents the following structural formula: [化 8]

(Here, * indicates ^{the position of bonding to A 01} , ** indicates the position of bonding to the linking group), the arrow indicates the bonding to the linking group (L)]. The compound of claim 2, wherein the IRAK-M conjugate (M) is a univalent group derived from a compound selected from the group consisting of the following compounds: 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol (5- ((4- (thieno [3,2-b] pyridin-7-yloxy)piperidin-1-yl)methyl) isoxazol -3-ol), 5-((4-((2-Methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)methyl)isoxazol-3-ol (5- ((4- ((2-methylthieno [3,2-b] pyridin-7-yl) oxy) piperidin-1-yl) methyl) isoxazol -3-ol), 1-Methyl-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)-1H-pyrazol-3-ol(1 -methyl -5- ((4- (thieno [3,2-b] pyridin -7- yloxy) piperidin -1-yl) methyl) -1H-pyrazol-3-ol), and 4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol (4-((4-(thieno[3,2- d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol). The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the linking group (L) is a group having 5-20 carbon atoms that may contain a heteroatom. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the linker (L) is the structural formula described below: [化9]

(Here, * represents the group bound to IRAK-M conjugate (M)), *-(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, R represents a hydrogen atom or a C1-6 alkyl group), or a bonding bond. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the above-mentioned E3 ligase conjugate (E) is represented by the following formula (IV): [化10]

[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 C1-6 alkyl group that can form a ring with each other, and D is the following Formula (V) [化11]

(In the formula, m represents an integer from 0 to 2, n represents an integer from 0 to 2, W ₁₁ represents methylene, difluoromethylene, 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, T represents a C1-3 alkyl group that can be halogenated), or Formula (VI): [化12]

(In the formula, Q represents an oxygen atom, the formula -NR ^21- (where R ²¹ represents a hydrogen atom, or a C1-6 alkyl group that can form a ring together with a C1-6 alkyl group and P), or a bonding bond, P represents a hydrogen atom, a C1-6 alkyl group, or a bond with the linking group (L) (including the formation of a ring with Q and the bond to the linking group (L)), and E is the following formula (VII): [化13]

(In the formula, R ₂₁ , R ₂₂ , and R ₂₃ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or a substituted aminomethyl 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 substituted amine methanoyl group, or a bond to the linking group (L), and R ₂₄ represents a hydrogen atom, methyl Group, or the bonding to the linking group (L); wherein the bonding to the linking group (L) _{is any one of R 24} , R ₂₅ or R ₂₆ ), or the following formula (VIII): [formula 14]

(In the formula, R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , and R ₃₅ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or a substituted amine methanoyl group , R represents a hydrogen atom, a C1-6 alkyl group or a bond to the linking group (L)), and either D or E is bonded to the linking group (L)]. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the above-mentioned E3 ligase conjugate (E) is represented by the following formula (IV): [化15]

[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, and D is the following formula (V-1): [化16]

(In the formula, W ₁₁ represents a methylene group or a difluoromethylene group), or the following formula (VI-1) [formation 17]

(In the formula, Q represents the bond to the linking group (L)), E is the following formula (VII): [化18]

(In the formula, R ₂₁ , R ₂₂ , and R ₂₃ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a C1-6 alkoxy group, and R ₂₅ and R ₂₆ each independently represent a hydrogen atom and a halogen atom , C1-6 alkyl group, or for the linkage of the linker (L), R ₂₄ represents a hydrogen atom, a methyl group, or the bond for the linker (L); wherein the bond for the linker (L) is R ₂₄ , R ₂₅ or R ₂₆ ), or the following formula (VIII): [化19]

(In the formula, R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , and R ₃₅ each independently represent 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 linking group (L) the bond), either D or E is bonded to the linking group (L)]. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the IRAK-M conjugate (M) is represented by the following formula (III): [化20]

[In the formula, Y is CH or N, R ⁰¹ is H or Me, A ⁰¹ is *-CH ₂ -* or *-SO ₂ -*, R ¹¹ represents the following structural formula: [化21]

(Here, * indicates the position of bonding to A, ** indicates the position of bonding to the linking group), the arrow indicates the bonding to the linking group (L)], the linking group (L) is The structural formula described below: [化22]

(Here, * represents the bond to IRAK-M conjugate (M)), *-(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, R represents a hydrogen atom or a C1-6 alkyl group), or a bonding bond, E3 is connected The enzyme conjugate (E) is represented by the following formula (IV): [化23]

[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, and D is the following formula (V-2): [化24]

, Or the following formula (VI-1): [化25]

(In the formula, Q represents the bond to the linking group (L)), E is the following formula (VII): [化26]

(In the formula, R ₂₁ , R ₂₂ , and R ₂₃ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a C1-6 alkoxy group, and R ₂₅ and R ₂₆ each independently represent a hydrogen atom and a halogen atom , C1-6 alkyl group, or for the linkage of the linker (L), R ₂₄ represents a hydrogen atom, a methyl group, or the bond for the linker (L); wherein the bond for the linker (L) is R ₂₄ , R ₂₅ or R ₂₆ ), or the following formula (VIII): [化27]

(In the formula, R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , and R ₃₅ each independently represent a hydrogen atom, a halogen atom, or a C1-6 alkyl group, and R represents a hydrogen atom or a bond to the linking group (L)) , Either D or E is bonded to the linking group (L)]. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the following compounds 1-11: Compound 1: 2-(4-((S)-2-cyclohexyl-2 -((S)-2-(Methylamino)propionylamine)acetyl)piperidin-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)isoazol-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), [化28]

Compound 2: 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propionylamine)acetyl)piperidin-1-carbonyl)-6 -Methoxy-1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidine-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), [化29]

Compound 3: 1-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperid-1-yl)-2-( (2R,5R)-5-methyl-2-((2-(2-(2-((5-((4-(thieno[3,2-b)pyridin-7-yloxy)piper (Pyridin-1-yl)methyl)isoazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperid-1-yl)ethane-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)、 [化30]

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)isoazol-3-yl)oxy)ethoxy)ethyl (Oxy)ethoxy)-1H-indole-2-carbonyl)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propionamide ((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), [化31]

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)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propane Amide ((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), [化32]

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)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propionamide (( 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), [化33]

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)pyrrolidine -1-yl)ethyl)-1H-indole-2-carbonyl)piperid-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), [化34]

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)isoazol-3-yl)oxy (Yl)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)-2-oxoethyl)-2-(methyl ((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), [化35]

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 (Yl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)-2-oxoethyl)-2-(methylamino) )Propylamide ((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), [化36]

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 (Yl)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperidin-1-yl)-2-oxoethyl)-2-(methylamino)propionyl Amine ((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), [化37]

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)isoazol-3-yl)oxy)ethoxy)ethoxy) (Ethoxy)ethyl)-1H-indole-5-carbonyl)piperid-1-yl)-2-oxoethyl)-2-(methylamino)propionamide ((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), [化38]

. A medicine containing the compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof. The medicine according to any one of claims 1 to 10, which is an IRAK-M proteolysis inducer. The medicine according to any one of claims 1 to 10, which is a preventive or therapeutic agent for cancer. Such as the medicine of any one of claims 1 to 10, which is used in combination with other anticancer agents. A method for inducing the degradation of IRAK-M protein, which is characterized by administering an effective amount of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof to a patient in need of treatment. A method for the prevention or treatment of cancer, which is characterized by administering an effective amount of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

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