KR20220042136A - heterocyclic compound - Google Patents

Abstract

To provide a novel heterocyclic compound which has an effect of inducing degradation of IRAK-M protein and is expected to be useful for the prevention and treatment of cancer, fibrosis, infectious disease, and the like, and a medicament containing the same.
According to the present invention, the following formula (I): wherein the IRAK-M binder (M) is the following formula (II) [in formula (II), Y is CH or N, and R ⁰¹ is H or Me, R ⁰³ is a group represented by the following structural formula: BB (where * represents a bonding position to O, ** indicates a bonding position to A, and n is an integer of 0 to 2) and A is a group represented by the following structural formula: CC (wherein R ⁰⁵ is each independently a hydrogen atom or a C1-6 alkyl group), or *-SO ₂ -*, and R ⁰⁴ is Structural formula: any group represented by DD (where * represents a bonding position to A, ** indicates a bonding position to a linker), optionally substituted C1-6 alkylene group, optionally substituted C3- 10 cycloalkylene group, optionally substituted C6-14 arylene group, or a bond, and an arrow indicates a bond to the linker (L).], or a pharmaceutically acceptable salt thereof.

Description

heterocyclic compound

The present invention is a heterocyclic compound that has an interleukin-1 receptor-associated kinase M (interleukin-1 receptor-associated kinase-M, IRAK-M) protein degradation-inducing action, and is expected to be useful in the prevention and treatment of cancer, fibrosis, infection, etc. and to a medicament containing the same.

Compounds that induce ubiquitination and proteasome degradation of target proteins by E3 ligase for the purpose of treatment by reducing condition-related proteins (Proteolysis Targeting Chimeras (PROTAC) or Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP) )-dependent Protein Eraser (SNIPER), etc.) is being developed (Non-Patent Documents 1 to 9). IRAK-M is a member of the IRAK family of protein kinases, and is a pseudo-kinase having no kinase activity (Non-Patent Document 10). IRAK-M is a protein that exists downstream of all Toll-like receptors (TLR) except for TLR3 and functions as a negative feedback regulator of the TLR/interleukin 1 (IL-1) receptor signaling pathway in vivo. (Non-Patent Document 11). Its expression is localized in some epithelial cells including bile duct epithelial cells, lung epithelial cells and intestinal epithelial cells, and immune cells, particularly myeloid cells. IRAK-M plays an important role in maintaining immune homeostasis, such as induction of endotoxin tolerance, by negatively controlling the induction signal of inflammatory cytokines via TLR in cells responsible for natural immunity, such as macrophages and dendritic cells. is in charge (Non-Patent Document 12). It has been reported that IRAK-M participates in cancer proliferation by contributing to immunosuppression by tumor-associated macrophages, bone marrow-derived immunosuppressive cells, dendritic cells, and the like in the tumor microenvironment (Non-Patent Documents 13 to 15). In addition, IRAK-M has been reported to act on alveolar macrophages, such as its phagocytic ability, its protective ability against bacteria, and its ability to promote collagen production, fibrosis, asthma, secondary infection after sepsis, and infectious complications of hematopoietic stem cell transplantation (non- Patent Documents 16 to 18) and the like are also related. Therefore, compounds that induce the degradation of IRAK-M by linking the X-Linked Inhibitor of Apoptosis Protein (XIAP) binder, which is one type of E3 ligase, and the IRAK-M binder with a linker, are cancer, fibrosis, infectious disease, and IRAK-M It can be a promising therapeutic agent for protein-related diseases.

Patent Document 1 reports a compound as an IRAK-M protein degradation inducer.

Patent Documents 2 and 3 report a compound as an IRAK (especially IRAK-4) protein degradation inducer.

Patent Documents 4 to 16 report a compound that induces protein degradation using an IAP binder.

In Patent Documents 17 to 20, N-(piperidin-4-yl)thieno[3,2-d]pyrimidin-4-amine or N-(piperidin-4-yl)thieno[3, A compound having a 2-b]pyridin-7-amine structure has been reported.

International Publication No. 2017/211924 International Publication No. 2019/099926 International Publication No. 2019/133531 International Publication No. 2018/066545 Japanese Laid-Open Patent Publication No. 2013-056837 International Publication No. 2016/169989 International Publication No. 2016/172134 International Publication No. 2017/011590 International Publication No. 2017/182418 International Publication No. 2017/201449 US Patent Application Publication No. 2018/0118733 Specification Specification of US Patent Application Publication No. 2018/0134688 International Publication No. 2018/119448 International Publication No. 2018/119357 Specification of US Patent Application Publication No. 2019/0119271 : Specification of US Patent Application Publication No. 2019/0175612 International Publication No. 2016/040330 International Publication No. 2013/019966 Specification of US Patent Application Publication No. 2013/0040957 Chinese Patent Application Publication No. 103242341

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

It is an object of the present invention to provide a novel heterocyclic compound which has an effect of inducing degradation of IRAK-M protein and is expected to be useful for the prevention and treatment of cancer, fibrosis, infectious disease, and the like, and a medicament containing the same.

As a result of intensive studies to find an IRAK-M protein degradation inducing drug, the present inventors found that the compound represented by the following formula has excellent IRAK-M protein degradation inducing activity, preventing and preventing cancer, fibrosis, infectious disease, etc. From the point of being useful for treatment, the present invention has been completed.

That is, the present invention is as follows.

[1] The following formula (I):

[Formula 1]

A compound represented by , or a pharmaceutically acceptable salt thereof.

[2] The IRAK-M binder (M) is the following formula (II)

[Formula 2]

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

[Formula 3]

(Here, * represents a bonding position with respect to O, ** indicates a bonding position with respect to A, and n is an integer of 0 to 2.) is a group represented by, A is the following structural formula:

[Formula 4]

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

[Formula 5]

(Here, * represents a bonding position to A, ** indicates a bonding position to a linker.) Any group represented by, optionally substituted C1-6 alkylene group, optionally substituted C3-10 cycloalkyl a lene group, an optionally substituted C6-14 arylene group, or a bond, and an arrow indicates a bond to the linker (L).] The compound according to the above [1], or a pharmaceutically acceptable salt thereof.

[3] The IRAK-M binder (M) is the following formula (III)

[Formula 6]

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

[Formula 7]

(herein, R ⁰⁵ is each independently a hydrogen atom or a C1-6 alkyl group), or *-SO ₂ -*;

R ¹¹ is the following structural formula:

[Formula 8]

(Here, * indicates a bonding position to A ⁰¹ , ** indicates a bonding position to a linker.) Any group represented by , and an arrow indicates bonding to a linker (L).] 2], or a pharmaceutically acceptable salt thereof.

[4] The IRAK-M binder (M) is the following compound,

5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol (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 the above [2], which is a monovalent group derived from a compound selected from the group consisting of.

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

[6] Linker (L) is the structural formula described below:

[Formula 9]

(Here, * represents a bond to IRAK-M binder (M).)

A group represented by *-(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 bond, the compound according to any one of [1] to [4], or a pharmaceutical thereof Salts that are legally acceptable.

[7] The E3 ligase binder (E) has the following formula (IV):

[Formula 10]

[wherein, 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 which may form a ring with each other, D is, the formula (V):

[Formula 11]

(wherein m represents an integer of 0 to 2, n represents an integer of 0 to 2, W ₁₁ represents a methylene group, a difluoromethylene group, O, S, SO, SO ₂ , or NR; Here, R represents a hydrogen atom, a C1-6 alkyl group, a C1-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, or a C1-6 alkylsulfonyl group, and T represents a C1-3 alkyl group which may be halogenated. ), or the formula (VI):

[Formula 12]

(Wherein, Q is an oxygen atom, in the formula -NR ²¹ - (in the formula, R ²¹ represents a hydrogen atom, or a C1-6 alkyl group, or a C1-6 alkyl group which may form a ring together with P), or a bond. , P is a hydrogen atom, a C1-6 alkyl group, or a bond with the linker (L) (forms a ring together with Q and includes a bond to the linker (L)), and E is: Formula (VII):

[Formula 13]

(R ₂₁ , R ₂₂ , and R ₂₃ in the formula each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an optionally substituted carbamoyl group, R ₂₅ , R ₂₆ each independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, an optionally substituted carbamoyl group, or a bond to the linker (L), R ₂₄ is a hydrogen atom, a methyl group, or a bond to the linker (L), with the proviso that the bond to the linker (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 an optionally substituted carbamoyl group; , R represents a hydrogen atom, a C1-6 alkyl group, or a bond to the linker (L)), and either D or E is bonded to the linker (L).] 6] The compound according to any one of, or a pharmaceutically acceptable salt thereof.

[8] The E3 ligase binder (E) has the following formula (IV):

[Formula 15]

[Wherein, 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 a formula (V-1) :

[Formula 16]

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

[Formula 17]

(Wherein, Q represents a bond to the linker (L).)

E is the formula (VII):

[Formula 18]

(R ₂₁ , R ₂₂ , and R ₂₃ in the formula 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 are each independently a hydrogen atom; A halogen atom, a C1-6 alkyl group, or a bond to the linker (L), and R ₂₄ is a hydrogen atom, a methyl group, or a bond to the linker (L), provided that the bond to the linker (L) is R ₂₄ , R ₂₅ or R ₂₆ ), or Formula (VIII):

[Formula 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 is a hydrogen atom, a C1-6 alkyl group or a linker (L ), and either D or E is bonded to the linker (L).] The compound according to any one of [1] to [7], or a pharmaceutically thereof Acceptable salts.

[9] The IRAK-M binder (M) is the following formula (III):

[Formula 20]

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

[Formula 21]

(wherein * represents a bonding position to A, ** indicates a bonding position to a linker.) represents any group represented by

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

Linker (L) is the structural formula described below:

[Formula 22]

(Here, * represents a bond to IRAK-M binder (M).) A group represented by *-(CH ₂ CH ₂ O)n(CH ₂ )m(NRCO)s(CH ₂ )t- * (n is a natural number from 1 to 5, m is 0, 1, or 2, s is 0 or 1, t is 0 or 1, and R is a hydrogen atom or a C1-6 alkyl group.), or is a bonding hand,

E3 ligase binder (E) has the following formula (IV):

[Formula 23]

[Wherein, 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 a formula (V-2) :

[Formula 24]

or the following formula (VI-1):

[Formula 25]

(Wherein, Q represents a bond to the linker (L).)

E is the formula (VII):

[Formula 26]

(R ₂₁ , R ₂₂ , and R ₂₃ in the formula 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 are each independently a hydrogen atom; A halogen atom, a C1-6 alkyl group, or a bond to the linker (L), and R ₂₄ is a hydrogen atom, a methyl group, or a bond to the linker (L), provided that the bond to the linker (L) is R ₂₄ , R ₂₅ or R ₂₆ ), or Formula (VIII):

[Formula 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 linker (L) ), and either D or E is bonded to the linker (L).] The compound according to the above [1], or a pharmaceutically acceptable salt thereof.

[10] The following compounds 1 to 11:

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

[Formula 28]

Compound 2: 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-6-methoxy -1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sul Ponyl)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),

[Formula 29]

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

[Formula 30]

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

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

[Formula 32]

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

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

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

[Formula 35]

Compound 9: (S)-N-((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-((S)-2- (((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrol Din-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S)-N -((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-( thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)- 3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide),

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

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

[Formula 38]

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

[11] A medicament comprising the compound according to any one of [1] to [10] or a pharmaceutically acceptable salt thereof.

[12] The drug according to the above [11], which is an IRAK-M proteolysis inducing drug.

[13] The pharmaceutical according to the above [11] or [12], which is a preventive or therapeutic agent for cancer.

[14] The drug according to any one of [11] to [13], which is used in combination with another anticancer agent.

[15] A method for inducing IRAK-M protein degradation, comprising administering to a patient in need of treatment an effective amount of the compound according to any one of [1] to [10] or a pharmaceutically acceptable salt thereof.

[16] A method for preventing or treating cancer, comprising administering to a patient in need of treatment an effective amount of the compound according to any one of [1] to [10] or a pharmaceutically acceptable salt thereof.

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

1 is a diagram showing the transition of tumor size in each group by subcutaneous administration of the compounds of Examples 1, 6, 7, 8, and 9 3 times every 3 days using a Lewis lung cancer cell inoculation model. This is the confirmed result. For each compound, the salt shown in the figure was used. The figures represent mean ± standard error.

Hereinafter, the present invention will be described with respect to the compounds of the present invention, their preparation methods and uses, taking exemplary embodiments as examples, along with preferred methods and materials that can be used in the practice of the present invention. In addition, unless otherwise specified in the text, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any materials and methods equivalent to or equivalent to those described herein can be similarly used in the practice of the present invention. In addition, with respect to the invention described in this specification, all publications and patents cited in this specification shall represent, for example, methods, materials, and others that can be used in the present invention, and constitute a part of this specification. will be.

In addition, in this specification, description of "A-B" which shows a numerical range means the numerical range which includes A and B which are minor points. Moreover, it is the same also about "A-B".

In this specification, "Me" means a methyl group, except for the case where it shows a clearly different meaning depending on the context before and behind.

In the present specification, when a compound name such as a substituent is described, a conventional name may be used instead of the official name, but they mean the same compound.

Hereinafter, the definition of each substituent used in this specification is described in detail. Unless otherwise specified, each substituent has the following definition.

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

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

In the present specification, examples of the "C1-3 alkyl group which may be halogenated" include a C1-3 alkyl group which may have 1 to 5 halogen atoms. Specific examples include methyl, chloromethyl, fluoromethyl, dichloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, Tetrafluoroethyl, pentafluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, cyclopropyl, 1-fluorocyclopropyl, 2-chlorocyclopropyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl.

In the present specification, the "C1-6 alkyl group" includes, 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, and cyclohexyl.

In the present specification, the "C1-6 alkyl group which may be halogenated" includes, for example, a C1-6 alkyl group which may have 1 to 7, preferably 1 to 5 halogen atoms. Specific examples include methyl, chloromethyl, fluoromethyl, dichloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, Tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl , sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl.

In the present specification, the "C2-6 alkenyl group" includes, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3 -Butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hex cenyl and 5-hexenyl.

In the present specification, the "C1-6 alkylsulfonyl group" includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl can be heard

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 this specification, as "C6-14 arylene group", for example, phenylene, 1,5-naphthylene, 1,4-naphthylene, 2,3-naphthylene, 1,8-anthrylene, 9 , 10-anthrylene.

In the present specification, as "C1-6 alkoxy group", for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyl oxy.

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

[Substituent group A]

(1) a halogen atom;

(2) C1 - 3 alkyl group

(3) C1 - 6 alkoxy group

(4) amino group

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

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

In the present specification, as "c6-14 aryl group which may be substituted" or "c6-14 arylene group which may be substituted", for example, the aforementioned substituent group A (halogen atom, C1-3 alkyl group, C1-6 an alkoxy group and an amino group) which may have a substituent selected from a C6-14 aryl group or a C6-14 arylene group. The number of substituents is, for example, 1 to 3. When the number of substituents is two or more, each substituent may be same or different.

In the present specification, the "carbamoyl group which may be substituted" includes, for example, 1 to 3 substituents selected from "substituent group A (halogen atom, C1-3 alkyl group, C1-6 alkoxy group, and amino group). and a carbamoyl group which may have 1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, and a C3-10 cycloalkyl group which may each have.

In this specification, as "C1-6 alkylene group", for example, a methylene group, 1,2-ethylene group, 1,1-ethylene group, 1,2-propylene group, 1,3-propylene group, 2, 2-propylene group, 1,4-butylene group, 1,2-butylene group, 1,3-butylene group, 2,2-butylene group, 1,5-pentylene group, 3,3-pentylene group, 1,6 - A hexarene group is mentioned.

In the present specification, as "C3-10 cycloalkylene group", for example, 1,1-cyclopropylene group, cis-1,2-cyclopropylene group, trans-1,2-cyclopropylene group, 1,1- Cyclobutylene group, cis-1,2-cyclobutylene group, trans-1,2-cyclobutylene group, cis-1,3-cyclobutylene group, trans-1,3-cyclobutylene group, 1,1-cyclopentyl group Rene group, cis-1,2-cyclopentylene group, trans-1,2-cyclopentylene group, cis-1,3-cyclopentylene group, trans-1,3-cyclopentylene group, 1,1-cyclohexylene group , cis-1,2-cyclohexylene group, trans-1,2-cyclohexylene group, cis-1,3-cyclohexylene group, trans-1,3-cyclohexylene group, cis-1,4 -Cyclohexylene group, trans-1,4-cyclohexylene group, 1,1-cycloheptynylene group, 1,1-cyclooctynylene group, 2,2-dimethyl 1,1-cyclopropylene group, 2, 3-dimethyl 1,1-cyclopropylene group, 2,2,3,3,4,4-tetramethyl 1,1-cyclobutylene group, 7,7-norcaranylene group, 7,7-norpinarylene group , a 7,7-norbornanylene group.

In this specification, a "linker" refers to a chemical moiety (structure) used in order to couple a part of a target compound to another compound. Exemplary linkers are described herein. For example, in any of the compounds described herein, a chemical structure used for bonding a part of the structure with a structure of another part can be used as a linker, and corresponds to the linker as used herein.

In the present specification, the "group having 5 to 20 carbon atoms which may contain a hetero atom" means a C5 to 20 linear or branched alkyl group which may contain at least one hetero atom selected from N and O, al Groups that are kenyl, cycloalkyl, aryl, arylalkyl or alkylaryl groups and are bonded to the same carbon atom may be bonded together to form a ring.

In the present specification, the term "bonding hand" refers to a state in which two groups adjacent to each other through a bond are bonded by a single bond. In addition, when a plurality of "bonding hands" are connected, it indicates a state in which all of them are bonded together by a single bond.

Hereinafter, each symbol of Formula (II) is demonstrated.

Y is CH or N, preferably CH.

R ⁰¹ is H or Me, preferably H.

Arrows indicate binding to the linker (L).

R ⁰³ is the following structural formula:

[Formula 39]

(wherein * represents a bonding position to O, ** indicates a bonding position to A, and n is an integer of 0 to 2), and most preferably, the following structural formula:

[Formula 40]

(Here, * represents the bonding position with respect to O, ** represents the bonding position with respect to A.) It is a group represented by.

A is the following structural formula:

[Formula 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:

[Formula 42]

(Here, * represents a bonding position to A, ** indicates a bonding position to a linker.) Any group represented by, optionally substituted C1-6 alkylene group, optionally substituted C3-10 cycloalkyl It is a lene group, an optionally substituted C6-14 arylene group, or a bond, and is preferably any group represented by the above structural formula.

As the "substituent" of the "optionally substituted C1-6 alkylene group", "optionally substituted C3-10 cycloalkylene group", and "optionally substituted C6-14 arylene group" represented by R ⁰⁴ , the "substituent" is as described above. The substituent selected from the substituent group A is mentioned. The number of substituents is, for example, 1 to 3. When the number of substituents is two or more, each substituent may be same or different.

Hereinafter, each symbol of Formula (IV) is demonstrated.

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 which may form a ring with each other, preferably, each Each independently represents a hydrogen atom or a C1-6 alkyl group, more preferably, each independently represents a hydrogen atom or a C1-3 alkyl group, and still more preferably, each independently represents a hydrogen atom or a methyl group.

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

D is the formula (V):

[Formula 43]

(wherein m represents an integer of 0 to 2, n represents an integer of 0 to 2, W ₁₁ represents a methylene group, a difluoromethylene group, O, S, SO, SO ₂ , or NR; Here, R represents a hydrogen atom, a C1-6 alkyl group, a C1-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, or a C1-6 alkylsulfonyl group, and T represents a C1-3 alkyl group which may be halogenated. ), or the formula (VI):

[Formula 44]

(Wherein, Q is an oxygen atom, formula -NR ²¹ - (in formula, R ²¹ represents a hydrogen atom, or a C1-6 alkyl group or an alkyl group which may form a ring together with P), or a bond; P represents a hydrogen atom, a C1-6 alkyl group, or a bond with the linker (L) (which forms a ring together with Q and includes a bond to the linker (L)).

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

[Formula 45]

or the following formula (VI-1):

[Formula 46]

(Wherein, Q represents a bond to the linker (L).)

Said D can couple|bond with the linker (L) in P and Q in Formula (VI), or Q in Formula (VI-1).

E is the formula (VII):

[Formula 47]

(R ₂₁ , R ₂₂ , and R ₂₃ in the formula each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an optionally substituted carbamoyl 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 , R ₂₆ are each independently a hydrogen atom, a halogen atom, C1 - 6 alkyl group, C1-6 alkoxy group, optionally substituted carbamoyl group, or a bond to the linker (L), Preferably, R ₂₅ and R ₂₆ are each independently a hydrogen atom, a halogen atom, A C1-6 alkyl group, a C1-6 alkoxy group, or a bond to the linker (L), and R ₂₄ represents a hydrogen atom, a methyl group, or a bond to the linker (L), with the proviso that the bond to the linker (L) is any one of R ₂₄ , R ₂₅ or R ₂₆ ), or Formula (VIII):

[Formula 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 an optionally substituted carbamoyl group; , Preferably, R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , R ₃₅ each independently represent a hydrogen atom, a halogen atom, or a C1-6 alkyl group, and R is a hydrogen atom, a C1-6 alkyl group or a linker. (L) represents a bond to ) is

Hereinafter, the linker (L) of Formula (I) is demonstrated.

The linker (L) is preferably a group having 5 to 20 carbon atoms which may contain a hetero atom, and more preferably a structural formula described below:

[Formula 49]

A group represented by *-(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 bond, more preferably, the structural formula described below:

[Formula 50]

(Here, * represents a bond to the IRAK-M binder (M).) A group represented by, or *-(CH ₂ CH ₂ O)n-* (n is a natural number of 1 to 5) am.

As used herein, "a compound that adds a function" refers to a binder of any protein present in a living body, a cell penetrating peptide (CPP), or a kinetophore (e.g., a short-chain peptide, a sugar and polyethylene oxide capped with quaternary ammonium, etc.).

As used herein, the term "IRAK-M protein-related disease" is a disease or disease that is explained or estimated in relation to IRAK-M protein itself or abnormality in its control. The abnormality of the protein is not limited thereto, and examples thereof include abnormal expression or enhancement of the protein in vivo, and the presence of a mutant protein.

The compound of the present invention contained in the compound (I) can be used as a synthetic intermediate in the preparation of the other compound (I) of the present invention. It can also be used as a synthetic intermediate for the production of an IRAK-M protein degradation inducer other than compound (I).

When compound (I) is a salt, such salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. there is. As a preferable example of a metal salt, For example, alkali metal salts, such as a sodium salt and potassium salt; Alkaline earth metal salts, such as a calcium salt, a magnesium salt, and a barium salt; An aluminum salt etc. are mentioned. Preferred examples of salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine. , and salts with N,N'-dibenzylethylenediamine and the like. Preferred examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferred 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, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. salts may be mentioned. Preferred examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, and the like, and preferred examples of salts with acidic amino acids, for example, salts with aspartic acid and glutamic acid. there is.

Among these, a pharmaceutically acceptable salt is preferable. For example, when it has an acidic functional group in the compound, inorganic salts such as alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.), ammonium salt, etc., and the compound In the case of having a basic functional group therein, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and salts with organic acids such as benzenesulfonic acid and p-toluenesulfonic acid.

The manufacturing method of the compound of this invention is demonstrated below. The raw material and reagent used in each process in the following manufacturing methods, and the obtained compound may form salt, respectively. Examples of such salts include the same salts as those of the compounds of the present invention described above.

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. Conversely, when the compound obtained in each step is a salt, it can be converted into a free body or other desired salt by a method known per se.

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

When the compound of the raw material or reagent of each process is marketed, a commercial item can be used as it is.

In the reaction of each step, the reaction time may vary depending on the reagent or solvent used, but unless otherwise specified, is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

In the reaction of each step, the reaction temperature may vary depending on the reagent or solvent used, but unless otherwise specified, is usually -78°C to 300°C, preferably -78°C to 150°C.

In the reaction of each step, the pressure may vary depending on the reagent or solvent to be used, but unless otherwise stated, it is usually 1 atm to 20 atm, preferably 1 to 3 atm.

In the reaction of each step, for example, a microwave synthesis apparatus such as an initiator manufactured by Biotage may be used. The reaction temperature may vary depending on the reagent or solvent to be used, but unless otherwise specified, is usually room temperature to 300°C, preferably 50°C to 250°C. The reaction time may vary depending on the reagent or solvent to be used, but unless otherwise specified, is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.

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

In the reaction of each step, unless otherwise specified, these reactions are carried out without a solvent or by dissolving or suspending in a suitable solvent. As a specific example of a solvent, the solvent described in an Example or the following is mentioned.

Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc.;

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

Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.;

Saturated hydrocarbons: cyclohexane, hexane, etc.;

Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.;

Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.;

Nitriles: acetonitrile, etc.;

Sulfoxides: dimethyl sulfoxide etc.;

Aromatic organic bases: pyridine etc.;

Acid anhydrides: acetic anhydride, etc.;

Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.;

Inorganic acids: hydrochloric acid, sulfuric acid, etc.;

Esters: ethyl acetate etc.;

Ketones: acetone, methyl ethyl ketone, etc.;

water.

You may use the said solvent, mixing 2 or more types in an appropriate ratio.

When using a base in the reaction of each process, the base shown below or the base described in the Example is used, for example.

Inorganic bases: sodium hydroxide, magnesium hydroxide, etc.;

Basic salts: sodium carbonate, calcium carbonate, sodium hydrogen carbonate, etc.;

Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4. 0]-7-undecene, imidazole, piperidine, etc.;

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

Alkali metal hydrides: sodium hydride etc.;

Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.;

Organolithiums: n-butyllithium and the like.

When an acid or an 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 is 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.

The reaction of each step is a method known per se, for example, the 5th edition Experimental Chemistry Lecture, Volumes 13 to 19 (Japanese Chemical Society edition), unless otherwise specified; New Experimental Chemistry Lecture, Volumes 14 to 15 (Edited by the Japanese Chemical Society) ; Fine Organic Chemistry Revised 2nd Edition (L. F. Tietze, Th. Eicher, Nankouto) ; Revised organic life reaction its structure and points (by Hideo Togo, Kodansha) ; ORGANIC SYNTHESES Collective Volume I - VII (John Wiley & Sons Inc.) ; Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (Jie Jack Li, published by OXFORD UNIVERSITY); Comprehens iv Heterocyclic Chemistry III, Vol.1 - Vol.14 (Lzevir Japan Co., Ltd.); Organic Synthesis Strategies Learned from Human Reaction (Translated by Kiyoshi Tomioka, published by Chemistry Dongin) ; Comprehensive Organic Transformations (VCH Publishers Inc.) 1989 year, etc., or the method described in the Examples.

In each step, the protection or deprotection reaction of the functional group is a method known per se, for example, Wiley-Interscience's 2007 annual "Protectiv Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts ) ; The method described in Thieme's 2004 annual "Protecting Groups 3rd Ed." (by P. J. Kocienski) or the like, or the method described in Examples.

As a protecting group of hydroxyl groups, such as alcohol, and phenolic hydroxyl group, For example, Ether-type protective groups, such as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether, tetrahydropyranyl ether; Carboxylic acid ester type protective groups, such as acetate ester; sulfonic acid ester-type protecting groups such as methanesulfonic acid ester; Carbonic acid ester-type protecting groups, such as t-butyl carbonate, etc. are mentioned.

Examples of the protecting group for the carbonyl group of the aldehyde include acetal-type protecting groups such as dimethylacetal; and cyclic acetal protecting groups such as cyclic 1,3-dioxane.

As a protecting group of the carbonyl group of a ketone, For example, Ketal-type protecting groups, such as dimethyl ketal; cyclic ketal protecting groups such as cyclic 1,3-dioxane; Oxime-type protecting groups, such as O-methyloxime; Hydrazone-type protecting groups, such as N,N- dimethyl hydrazone, etc. are mentioned.

As a protecting group of a carboxyl group, For example, Ester-type protecting groups, such as a methyl ester; Amide-type protecting groups, such as N,N- dimethylamide, etc. are mentioned.

As a protecting group of a thiol, For example, Ether-type protecting groups, such as benzylthio ether; Ester protection groups, such as thioacetic acid ester, thiocarbonate, and thiocarbamate, etc. are mentioned.

As a protecting group of aromatic heterocyclic rings, such as an amino group and imidazole, a pyrrole, and an indole, For example, Carbamate-type protecting groups, such as a benzyl carbamate; amide-type protecting groups such as acetamide; alkylamine-type protecting groups, such as N-triphenylmethylamine, and sulfonamide-type protecting groups, such as methanesulfonamide, are mentioned.

Removal of the protecting group is carried out by methods known per se, for example, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilylhalide ( For example, it can be carried out using a method using trimethylsilyl iodine or trimethylsilyl bromide), a reduction method, or the like.

In each step, in the case of carrying out the reduction reaction, the reducing agents used include lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and hydride. metal hydrides such as triacetoxyborontetramethylammonium; Boranes, such as a borane tetrahydrofuran complex; Raney-Nickel ; Raney-Cobalt ; hydrogen ; formic acid; triethylsilane, etc. are mentioned. In the case of reducing a carbon-carbon double bond or a triple bond, there is a method of using a catalyst such as palladium-carbon or a Lindlar catalyst.

In each process, when performing an oxidation reaction, As an oxidizing agent used, Peracids, such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, and t-butyl hydroperoxide; perchlorates such as tetrabutylammonium perchlorate; Chlorates, such as sodium chlorate; chlorites such as sodium chlorite; Periodic acids, such as sodium periodate; High-valent iodine reagents, such as iodine sylbenzene; reagents having manganese, such as manganese dioxide and gallium permanganate; waxes such as lead tetraacetate; Reagents having chromium, such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and Jones' reagent; halogen compounds such as N-bromosuccinimide (NBS); Oxygen ; ozone; sulfur trioxide/pyridine complex; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

Each process WHEREIN: As a radical initiator used when performing radical cyclization reaction, Azo compounds, such as azobisisobutyronitrile (AIBN); water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA); triethylboron in the presence of air or oxygen; Benzoyl peroxide, etc. are mentioned. Examples of the radical reaction initiator used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, and samarium iodide.

In each step, when the Wittig reaction is performed, examples of the Wittig reagent used include alkylidenephosphoranes. The alkylidenephosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

In each process, when performing Horner-Emmons reaction, as a reagent used, Phosphonoacetic acid esters, such as methyl dimethyl phosphono acetate and diethyl phosphono ethyl acetate; and bases such as alkali metal hydrides and organolithiums.

In each step, when the Friedel-Crafts reaction is performed, the reagent used includes a combination of a Lewis acid and an acid chloride, or a combination of a Lewis acid and an alkylating agent (eg, 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 acid chloride.

In each step, when performing an aromatic nucleophilic substitution reaction, as a reagent, a nucleophilic agent (eg, amines, imidazole, etc.) and a base (eg, basic salts, organic bases, etc.) are used.

In each step, when performing a nucleophilic addition reaction with a carboanion, a nucleophilic 1,4-addition reaction with a carboanion (Michael addition reaction), or a nucleophilic substitution reaction with a carboanion, carbo As a base used in order to generate|occur|produce an anion, organolithium, metal alkoxides, inorganic bases, organic bases, etc. are mentioned.

Each process WHEREIN: When performing a Grignard reaction, As a Grignard reagent, Aryl magnesium halides, such as phenylmagnesium bromide; Alkyl magnesium halides, such as methyl magnesium bromide, are mentioned. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or an aryl halide with a metallic magnesium using ether or tetrahydrofuran as a solvent.

In each step, when the Knoevenagel condensation reaction is performed, as reagents, an active methylene compound (eg, malonic acid, diethyl malonate, malononitrile, etc.) and a base (eg, malonic acid, diethyl malonate, malononitrile, etc.) sandwiched between two electron withdrawing groups eg, organic bases, metal alkoxides, inorganic bases) are used.

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

In each step, in the case of carrying out the azidation reaction of alcohols, alkyl halides, and sulfonic acid esters, diphenyl phosphoryl azide (DPPA), trimethylsilyl azide, and azidation agents are used. sodium etc. are mentioned. For example, in the case of azidation of alcohols, a method using diphenylphosphorylazide and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) or trimethylsilylazide and a method of using a Lewis acid.

In each step, when the reductive amination reaction is performed, examples of the reducing agent used include sodium triacetoxyboron hydride, sodium cyanoborohydride, hydrogen, formic acid, and the like. When the substrate is an amine compound, examples of the carbonyl compound used include aldehydes such as acetaldehyde and ketones such as cyclohexanone in addition to paraformaldehyde. When the substrate is a carbonyl compound, examples of the amines used include primary amines such as ammonia and methylamine; Secondary amines, such as dimethylamine, etc. are mentioned.

In each step, when performing the Mitsunobu reaction, as reagents, azodicarboxylic acid esters (eg, azodicarboxylic acid diethyl (DEAD), azodicarboxylic acid diisopropyl (DIAD), azodicarboxylic acid acid ditert-butyl, etc.) and triphenylphosphine are used.

In each process, when performing an esterification reaction, an amidation reaction, or a urea reaction, As a reagent used, Halogenated acyl bodies, such as an acid chloride and an acid bromide; Activated carboxylic acids, such as an acid anhydride, an active ester, and a sulfuric ester, are mentioned. Examples of the carboxylic acid activator include carbodiimide-based condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine-based condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); Carbonic acid ester-type condensing agents, such as 1, 1- carbonyl diimidazole (CDI); diphenyl azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionyl chloride; haloformic acid lower alkyls such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU); sulfuric acid; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P); Or a combination of these, etc. are mentioned. When a carbodiimide-based condensing agent is used, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) may be further added to the reaction. .

In each step, when performing the coupling reaction, examples of the metal catalyst used include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), and dichlorobis (triphenylphosphine) palladium (II). , Dichlorobis(triethylphosphine)palladium (II), tris(dibenzylideneacetone)dipalladium (0), chloride 1,1'-bis(diphenylphosphino)ferrocenepalladium (II), palladium acetate (II) ) and other palladium compounds; Nickel compounds, such as tetrakis (triphenylphosphine) nickel (0); rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride; cobalt compound; copper compounds such as copper oxide and copper (I) iodide; A platinum compound etc. are mentioned. Further, a base may be added to the reaction, and examples of such a base include inorganic bases and basic salts.

In each step, when carrying out the thiocarbonylation reaction, diphosphorus pentasulfide is typically used as the thiocarbonylation agent, but in addition to diphosphorus pentasulfide, 2,4-bis(4-methoxyphenyl)-1 Even if a reagent having a 1,3,2,4-dithiadiphosphotane-2,4-disulfide structure such as ,3,4-dithiadiphosphotane-2,4-disulfide (Lawesson's reagent) is used do.

In each step, when the Wohl-Ziegler reaction is performed, halogenating agents used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, and chloride. Sulfuryl etc. are mentioned. Further, by adding a radical initiator such as heat, light, benzoyl peroxide or azobisisobutyronitrile to the reaction, the reaction can be accelerated.

In each step, when the hydroxyl group is halogenated, the halogenating agent used is an acid halide of hydrohalic acid and an inorganic acid, specifically, in chlorination, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc., in bromination , 48% hydrobromic acid, and the like. Moreover, you may use the method of obtaining a halogenated alkyl form from alcohol by the action|action of triphenylphosphine, carbon tetrachloride, carbon tetrabromide, etc. Alternatively, a method of synthesizing an alkyl halide compound through a two-step reaction in which alcohol is converted into a sulfonic acid ester and then reacted with lithium bromide, lithium chloride or sodium iodide may be used.

In each process, when performing Arbuzov reaction, As a reagent used, Halogenated alkyls, such as ethyl bromoacetate; Phosphites, such as a triethyl phosphite and a tri (isopropyl) phosphite, are mentioned.

In each step, when performing the sulfonic acid esterification reaction, examples of the sulfonylating agent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, and p-toluenesulfonic anhydride.

In each process, when performing a hydrolysis reaction, an acid or a base is used as a reagent. In addition, in the case of carrying out the acid hydrolysis reaction of t-butyl ester, formic acid, triethylsilane, or the like may be added in order to reductively trap by-produced t-butyl cation.

In each process, when performing a dehydration reaction, as a dehydrating agent used, sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'- dicyclohexylcarbodiimide, alumina, polyphosphoric acid, etc. are mentioned.

In each step, when performing an alkylation reaction with alcohols or amines or an aromatic heterocyclic ring having an NH group in the ring (eg imidazole, pyrazole), the alkylating agent is an optionally substituted alkyl halide (eg, iodomethane). ) or optionally substituted alkyl having an optionally substituted C1-6 alkylsulfonyloxy group as a leaving group, optionally substituted alkyl having a C6-14 arylsulfonyloxy group optionally substituted with a C1-6 alkyl group, or sodium 2-chloro-2,2-difluoroacetate, 2,2-difluoro-2-(fluorosulfonyl)acetic acid, and the like. Moreover, as a base to be used, organolithium, metal alkoxides, inorganic bases, organic bases, etc. are mentioned.

In each step, when the fluorination reaction is performed, examples of the fluorinating agent used include DAST (diethylamino sulfite fluoride), bis (2-methoxyethyl) amino sulfite fluoride, 1-chloromethyl-4-fluoro rho-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor), 4-tert-butyl-2,6-dimethylphenyl sulfite fluoride (FLUOLEAD), etc. are mentioned. there is.

In each step, when carrying out the Huisgen reaction, an azide compound and an alkyne compound are used as reagents used. Examples of the catalyst include monovalent copper ions such as copper iodide, copper chloride, and copper cyanide.

In each step, when a coupling reaction is performed, the coupling reaction includes Suzuki coupling, Stille coupling, Buchwald-Hartwig coupling, Negishi coupling, Mizoroki-Heck reaction, cyanide using copper cyanide or zinc cyanide. Aging reaction, etc. are mentioned. Reagents such as metal catalysts, phosphine ligands and bases used in the coupling reaction are added to the reagents described above, and methods known per se (eg, 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 a method similar to these.

Below, the manufacturing method of compound (I) is demonstrated.

Each symbol in the following reaction formula shows the same meaning as the above, unless otherwise stated. If a specific manufacturing method is not described, a commercially available compound can be easily obtained, or a raw material compound can be manufactured by a method known per se or a method equivalent thereto, and the method described in the Examples.

In the reaction of each step, if there is a reactive site where a reaction other than the intended reaction occurs, a protecting group is introduced into the reactive site in advance by means known per se if necessary, and after carrying out the desired reaction , the protecting group may also be removed by means known per se. For example, when a raw material compound or an intermediate has an amino group, a carboxyl group or a hydroxyl group as a substituent, these groups may be protected with a protecting group generally used in peptide chemistry and the like. In this case, after the reaction, the target compound can be obtained by removing the protecting group if necessary.

Compound (I) can be synthesized by the method shown in the following scheme rather than compound (1) which is an IRAK-M binder or compound (4) which is an E3 ligase binder. In each scheme, compound (I) and each reaction intermediate may each independently form a salt.

scheme 1

[Formula 51]

Compound (3) can be prepared by providing compound (1) or a reactive derivative thereof and compound (2), which is a linker (L), or a reactive derivative thereof, to amidation reaction, Mitsunobu reaction, alkylation reaction, coupling reaction, etc. and compound (I) can be prepared by subjecting compound (3) or a reactive derivative thereof and compound (4) or a reactive derivative thereof to amidation reaction, Mitsunobu reaction, alkylation reaction, coupling reaction, etc. .

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

Compound (3a) can be produced by subjecting compound (1) or a reactive derivative thereof and compound (2a) or a reactive derivative thereof to an amidation reaction, Mitsunobu reaction, alkylation reaction, coupling reaction, or the like, and compound (5a) ) can be produced by subjecting compound (4) or a reactive derivative thereof and compound (2b) or a reactive derivative thereof to an amidation reaction, a Mitsunobu reaction, an alkylation reaction or a coupling reaction, etc., wherein the compound (I) is , compound (3a) and compound (5a) or reactive derivatives thereof can be produced by subjecting them to amidation reaction, Mitsunobu reaction, alkylation reaction, coupling reaction, Huisgen reaction or the like.

The manufacturing method of IRAK-M binder (M) (compound (1)) represented by following formula (II) which comprises a part of compound (I) is demonstrated below.

scheme 2

[Formula 52]

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

Compound (8) can be produced by subjecting compound (6) and compound (7) to an aromatic nucleophilic substitution reaction, a coupling reaction, or the like.

Compound (II) can be produced by subjecting compound (8) and compound (9) or a reactive derivative thereof to an alkylation reaction, a sulfonylation reaction, a reductive amination reaction, or the like.

L (Compound (2)) as the linker (L) constituting a part of Compound (I), L ₁ (Compound (2a)), and L ₂ (Compound (2b)) which are part of the linker (L) are commercially available products as they are. Or, it can be prepared by a method known per se or a method equivalent thereto.

A preparation method in the case where E (compound (4)), which is an XIAP binder, which is one type of E3 ligase binder constituting a part of compound (I), is a compound represented by the following formula (IV-I) will be described below.

scheme 3

[Formula 53]

The compound (12) can be produced by subjecting the compound (10) and the compound (11) or a reactive derivative thereof to an amidation reaction or the like, and the compound (14) is the compound (12) and the compound (13) or a reactive derivative thereof. can be prepared by subjecting it to an amidation reaction or the like.

Compound (IV-I) can be produced by subjecting compound (14) and compound (15) or a reactive derivative thereof to an amidation reaction or the like.

Further, the compound (16) can be produced by subjecting the compound (10) and the compound (15) or a reactive derivative thereof to an amidation reaction or the like, and the compound (17) is the compound (16) and the compound (11) or its It can be produced by subjecting the reactive derivative to an amidation reaction or the like. Compound (IV-I) can be produced by subjecting compound (17) and compound (13) or a reactive derivative thereof to an amidation reaction or the like.

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

scheme 4

[Formula 54]

Compound (18) can be produced by subjecting compound (16) and compound (17) to an amidation reaction or the like, and compound (IV-II) can be prepared by providing compound (18) and compound (19) to an alkylation reaction or the like. can be manufactured.

Further, compound (20) can be produced by subjecting compound (10) and compound (17) to an amidation reaction or the like, and compound (21) can be prepared by providing compound (20) and compound (19) to an alkylation reaction or the like. can be manufactured. Compound (IV-II) can be produced by subjecting compound (21) and compound (22) or a reactive derivative thereof to an amidation reaction or the like.

By converting the substituents in the thus obtained compound (I) and each intermediate by means known per se (that is, introducing a substituent or converting a functional group), other compounds contained in the compound (I) and the corresponding intermediates Or these salts can also be manufactured.

Compound (I) obtained by the above production method can be isolated and purified by known means, for example, solvent extraction, pH change of a solution, diversion, crystallization, recrystallization, and chromatography.

When compound (I) contains optical isomers, stereoisomers, positional isomers and rotational isomers, these are also contained as compound (I), and each can be obtained as a single product by a synthetic method known per se and a separation method there is. For example, when an optical isomer exists 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 be a crystal.

Crystals of compound (I) (hereinafter, sometimes abbreviated as crystals of the present invention) can be produced by applying a crystallization method known per se to compound (I) to crystallize.

Compound (I) may be a pharmaceutically acceptable co-crystal or a co-crystal salt. Here, a co-crystal or a co-crystal salt is a crystalline substance composed of two or more distinct solids at room temperature, each having different physical properties (eg, structure, melting point, heat of fusion, hygroscopicity, solubility and stability). means A co-crystal or a co-crystal salt can be prepared according to a co-crystallization method known per se.

Compound (I) may be a hydrate, a non-hydrate, a non-solvate, or a solvate.

In addition, a deuterium conversion product obtained by converting ¹ H into ² H(D) is also included in the compound (I).

Compound (I) may be labeled with an isotope (eg, ³ H, ¹³ C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²⁵ I) or the like. Compound (I) labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) used in positron emission tomography (PET), and is useful in fields such as medical diagnosis. It is expected.

Compound (I) may be used as a prodrug.

A prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme or gastric acid under physiological conditions in a living body, that is, enzymatically causes oxidation, reduction, hydrolysis, etc. to compound (I) It is a compound that changes to compound (I) by causing hydrolysis or the like by gastric acid or the like.

As a prodrug of compound (I), the amino group of compound (I) is acylated, alkylated or phosphorylated (eg, the amino group of compound (I) is eicosanoylated, aranylated, pentylaminocarbonylated, (5) -methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidinylmethylation, pivaloyloxymethylation or tert-butylated compounds); Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated or borated (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, aranylated or dimethylaminomethylcarbonylated compounds); A compound in which the carboxyl group of the compound (I) is esterified or amidated (eg, the carboxyl group of the compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified , ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification, cyclohexyloxycarbonylethyl esterification or methylamidated compound) and the like. These compounds can be prepared as compound (I) by a method known per se.

Further, the prodrug of compound (I) may be changed to compound (I) under physiological conditions described on pages 163 to 198 of Molecular Design, Volume 7 of "Development of Pharmaceuticals", Hirokawa Bookstore, 1990.

In this specification, the prodrug may form the salt, and what was illustrated as a salt of the compound represented by Formula (I) mentioned above as such a salt is mentioned.

Compound (I) is a compound that adds a function, such as a Cell Penetrating Peptide (CPP) or a kinetophore that puts the compound in the intestinal tract (eg, a short-chain peptide, capped with sugar and quaternary ammonium). polyethylene oxide, etc.) may be used in connection with the compound (I), and the compound (I) may be bonded to a compound that adds a function directly or through a linker.

Compound (I) can also be used as a payload in an antibody (or peptidic antigen recognition sequence)-drug complex (a portion corresponding to the drug). When compound (I) is used as a payload, compound (I) can bind to an antibody (or a peptidic antigen recognition sequence) directly or via a linker.

When compound (I) is used as a payload, in addition to the linkers exemplified herein, Chem. Rev., 114, 9154-9218 (2014), Pharma. Linkers described in Res., 32, 3526-3540 (2015), Bioconjugate Chem., 21, 5-13 (2010), The AAPS journal, 17, 339-351 (2015), International Publication No. 2011/005761, etc. may be used.

Compound (I) or a prodrug thereof (in the present specification, they are collectively abbreviated as "the compound of the present invention" in some cases) has IRAK-M degradation-inducing activity, and is a preventive or therapeutic drug for cancer, cancer growth It may be useful as an inhibitor, an inhibitor of cancer metastasis.

The compound of the present invention exhibits proteolysis-inducing activity for IRAK-M, and the compound of the present invention exhibits drug efficacy, pharmacokinetics (eg, absorption, distribution, metabolism, excretion), solubility (eg, water solubility), other pharmaceuticals Interactions with (e.g., drug-metabolizing enzymes), safety (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, oncogenicity, central toxicity), stability (e.g. chemical stability, enzyme activity Since it is excellent also from a viewpoint of stability), it can be useful as a pharmaceutical. Especially, although it is anticipated that it is effective in the treatment or prevention of cancer, it is not limited to this.

The compound of the present invention also has an activity to induce degradation of IRAK-M protein in mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human), and its mechanism of action In view of this, all diseases involving IRAK-M protein (in this specification, it may be abbreviated as "IRAK-M-related diseases"), for example, cancer [eg, colon cancer (eg, colon cancer, rectal cancer, anus) Cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor), lung cancer (eg non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (eg pancreatic duct cancer, pancreatic endocrine tumor), pharynx Cancer, laryngeal cancer, esophageal cancer, stomach cancer (eg papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), duodenal cancer, small intestine cancer, breast cancer (eg invasive ductal cancer, non-invasive ductal cancer, inflammatory breast cancer), ovarian cancer (eg, epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low-grade tumor), testicular tumor, prostate cancer (e.g. hormone-dependent prostate cancer, hormone-independent prostate cancer, castration-resistant prostate cancer), Liver cancer (eg, hepatocellular carcinoma, primary liver cancer, extrahepatic cholangiocarcinoma), thyroid cancer (eg, hydrocephalus), kidney cancer (eg renal cell carcinoma (eg, cholangiocarcinoma), transitional epithelial cancer of the renal pelvis and ureter) , uterine cancer (eg cervical cancer, cervix cancer, uterine sarcoma), gestational villous cancer, brain tumor (eg medulloblastoma, glioma, pineal cell tumor, cytoblastoma, mastocytoma, anaplastic astrocytoma) , pituitary adenoma), retinoblastoma, skin cancer (eg basal cell carcinoma, malignant melanoma), sarcoma (eg rhabdomyosarcoma, leiomyosarcoma, soft sarcoma, spindle cell sarcoma), malignant bone tumor, bladder cancer, hematologic cancer (eg multiple Myeloma; myeloproliferative disease), cancer of unknown primary] prophylactic or therapeutic agent, cancer growth inhibitor; It can be used as a medicament, such as a cancer metastasis inhibitor, an apoptosis promoter, and a therapeutic agent for a precancerous lesion (eg, 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 (eg, Crohn's disease, ulcerative colitis, etc.), multiple sclerosis, systemic inflammatory response syndrome (SIRS). , sepsis, infectious complications of hematopoietic stem cell transplantation, influenza infection, acute respiratory syndrome (COVID-19, MERS, SARS), acute bacterial meningitis, Helicobacter pylori infection, invasive staphylococcal infection, tuberculosis, systemic fungal infection, herpes simplex virus Infectious diseases, varicella-zoster virus infection, human papillomavirus infection, acute viral encephalitis, encephalitis, meningitis, decreased immune function accompanying infection, etc. are mentioned.

The compound of the present invention can be administered orally or parenterally to a mammal (preferably a human) as a medicament either as it is or in combination with a pharmacologically acceptable carrier.

Hereinafter, a drug containing the compound of the present invention (sometimes abbreviated as "medicine of the present invention") will be described in detail. Formulations of the medicament of the present invention include, for example, tablets (eg, dragees, film-coated tablets, sublingual tablets, buccal tablets, orally disintegrating tablets), pills, granules, powders, capsules (eg, soft capsules, oral preparations such as microcapsules), syrups, emulsions, suspensions, and films (eg, orally disintegrating films, oral mucosal adhesive films). In addition, the dosage form of the pharmaceutical of the present invention includes, for example, parenteral preparations such as injections, ring gels, transdermal preparations (eg, iontophoresis transdermal preparations), suppositories, ointments, nasal preparations, transpulmonary preparations, and eye drops. can In addition, the pharmaceutical of the present invention may be a controlled-release preparation such as an immediate-release preparation or a sustained-release preparation (eg, sustained-release microcapsule).

As the pharmaceutical formulation of the present invention, a formulation using a nanoparticle formulation or a bacterial-derived membrane can also be used.

The medicament of the present invention can be manufactured by a known manufacturing method (eg, the method described in the Japanese Pharmacopoeia) generally used in the field of formulation technology. In addition, in the medicament of the present invention, if necessary, excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifiers, colorants, preservatives, fragrances, flavoring agents, and stabilizers commonly used in the pharmaceutical field Additives, such as a viscous agent and a viscous agent, can be contained suitably in an appropriate amount.

Examples of the pharmacologically acceptable carrier include these additives.

For example, a tablet may be prepared using an excipient, a binder, a disintegrant, a lubricant, and the like, and pills and granules may be prepared using an excipient, a binder, a disintegrant. In addition, powders and capsules may be prepared using excipients, etc., syrups may be prepared using sweetening agents, and emulsions or suspending agents may be prepared using suspending agents, surfactants, emulsifiers, and the like.

Examples of the excipient include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium hydrogen carbonate, calcium phosphate, and calcium sulfate.

Examples of the binder include 5 to 10 wt% starch paste solution, 10 to 20 wt% gum arabic solution or gelatin solution, 1 to 5 wt% traganth solution, carboxymethyl cellulose solution, sodium alginate solution, and glycerin.

Examples of the disintegrant include starch and calcium carbonate.

Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, and purified talc.

Examples of the sweetener include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, and sweet syrup.

Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyoxyl 40 stearate.

Examples of the suspending agent include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, and bentonite. Examples of the emulsifier include gum arabic, traganth, gelatin, and polysorbate 80.

For example, when the medicament of the present invention is a tablet, the tablet is prepared according to a method known per se to the compound of the present invention, for example, an excipient (eg, lactose, sucrose, starch), a disintegrant (eg, starch) , calcium carbonate), binder (eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose) or lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000) And, then, if necessary, for the purpose of masking, enteric or persistence of taste, it can be prepared by coating by a method known per se. Coating agents used for coating include, for example, hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxy Propylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, eudragit (manufactured by Rohm, Germany, methacrylic acid/acrylic acid copolymer) and pigments (eg, iron dandelion, titanium dioxide) can be used.

Examples of the injection include subcutaneous injections, intradermal injections, intramuscular injections, intraperitoneal injections, Ringgel injections, and the like, in addition to intravenous injections.

Such injections are prepared by methods known per se, that is, by dissolving, suspending or emulsifying the compound of the present invention in a sterile aqueous or oily solution. Examples of the aqueous solution include physiological saline, an isotonic solution containing glucose and other adjuvants (eg, D-sorbitol, D-mannitol, sodium chloride), and the like. The aqueous solution contains a suitable dissolution aid, for example alcohol (eg ethanol), polyalcohol (eg propylene glycol, polyethylene glycol), nonionic surfactant (eg polysorbate 80, HCO-50) and there may be Examples of the oily liquid include sesame oil and soybean oil. The oily liquid may contain a suitable dissolution aid. As the solubilizing agent, benzyl benzoate, benzyl alcohol, etc. are mentioned. In addition, the injection includes buffers (eg, phosphate buffer, sodium acetate buffer), analgesics (eg, benzalkonium chloride, procaine hydrochloride), stabilizers (eg, human serum albumin, polyethylene glycol), preservatives (eg, benzyl alcohol) , phenol) and the like may be blended. The prepared injection solution can be usually filled in an ampoule.

The content of the compound of the present invention in the medicament of the present invention varies depending on the form of the preparation, but is usually about 0.01 to about 100% by weight, preferably about 2 to about 85% by weight, more preferably about 5 to about 70% by weight.

The content of the additive in the medicament of the present invention varies depending on the form of the preparation, but is usually from about 1 to about 99.9% by weight, preferably from about 10 to about 90% by weight, based on the entire preparation.

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

When the compound of the present invention is administered parenterally, it is usually administered in the form of a solution (eg, injection). One dose of the compound of the present invention varies depending on the administration subject, target organ, symptoms, administration method, etc., for example, usually about 0.01 to about 100 mg per 1 kg of body weight, preferably about 0.01 to about It is preferred to administer 50 mg, more preferably about 0.01 to about 20 mg of a compound of the present invention by intravenous or subcutaneous injection.

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 a drug such as a hormone therapy agent, a chemotherapeutic agent, an immunotherapeutic agent or a cell growth factor, and a drug that inhibits the action of its receptor. Hereinafter, a drug that can be used in combination with the compound of the present invention is abbreviated as a concomitant drug.

As "hormone therapy agent", for example, phosgestrol, diethylstilbestrol, chlorotrianicene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazole, allylestre Nol, Gestrinone, Mepartricin, Raloxifene, Ormeloxifene, Levormeloxifene, Antiestrogen drugs (eg, citrate tamoxifen, citrate tremiphene), Peel agent, Mepitiostan, Testolactone, Aminogluteth Mead, LH-RH agonist (eg, goserelin acetate, buserelin, leuprorelin acetate), doroloxifene, epithiostanol, ethynyl estradiol sulfonate, aromatase inhibitor (eg, fadrozole hydrochloride, Anastrozole, letrozole, exemestane, vorozol, formestane), anti-androgens (eg flutamide, bicalutamide, nilutamide, enzalutamide), 5α-reductase inhibitors (eg , finasteride, epristeride, dutasteride), corticosteroid drugs (e.g. dexamethasone, prednisolone, betamethasone, triamcinolone), androgen synthesis inhibitors (e.g. abiraterone), retinoids and drugs that slow the metabolism of retinoids ( eg, liarosol), thyroid hormones, and their DDS (Drug Delivory System) formulations can be used.

As the "chemotherapeutic agent", for example, an alkylating agent, an anti-metabolic agent, an anticancer antibiotic, or a plant-derived anticancer agent can be used.

Examples of the "alkylating agent" include nitrogen mustard, nitrogen hydrochloride mustard-N-oxide, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carbocon, tosylic acid improsulfan, busulfan, hydrochloric acid Nimustine, mitobronitol, melphalan, dacarbazine, ranimustine, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etoglucide, carboplatin, cisplatin , miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, fumitepa, ribomustine, temozolomide, threosulfan, trophosphamide, Ginostatin stimalamer, adozelesin, cystemustine, bizelesin and their DDS preparations can be used.

As the "metabolic antagonist", for example, mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine phosphate, ancitabine hydrochloride, 5-FU Drugs (e.g., fluorouracil, tegafur, UFT, doxyfluridine, camofur, gallocitabine, emitefur, capecitabine), aminopterin, nelzarabine, leucovorin calcium, thioguanine, Butosin, polynate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritrexime, idoxuridine, mitoguazone, thia Zopurin, ambamustine, bendamustine and their DDS formulations can be used.

Examples of the "anticancer antibiotic" include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, Doxorubicin hydrochloride, acrarubicin hydrochloride, pyrarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin, mithramycin, sarcomycin, carzinophylline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and These DDS preparations (eg, doxorubicin-encapsulated PEG liposomes) can be used.

"Plant-derived anticancer agents" include, for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, cabazitaxel, vinorelbine, and DDSs thereof. formulations may be used.

"Immune therapy agents" include, for example, fishivanil, crestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine , Corynebacterium parvum, levamisole, Toll-like receptor (TLR) agonist, polysaccharide K, procodazole, anti-CTLA4 antibody (eg, ipilimumab, tremelimumab), anti-PD-1 antibody ( eg, nivolumab, pembrolizumab, semipliumab, tislerizumab, cintilimab, torifalimab), anti-PD-L1 antibody (eg, atezolizumab, avelumab, durvalumab), oncolytic Viruses may be used.

The "cell growth factor" in "a cell growth factor and a drug that inhibits the action of its receptor" may be any substance as long as it promotes cell proliferation, and is usually a peptide having a molecular weight of 20,000 or less, and binds to a receptor factors that exert their action at low concentrations by Substances having substantially the same activity [eg, insulin, IGF (insulin-like growth factor)-1, IGF-2], (3) FGF (fibroblast growth factor) or substances having substantially the same activity as [eg, Acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10], (4) other cell growth factors [eg, CSF (colony stimulating factor), EPO (Erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGFβ (transforming growth factorβ), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), hereglin, angiopoietin] can be used. .

The "cell growth factor receptor" may be any receptor as long as it has the ability to bind to the cell growth factor described above, and specifically, EGF receptor, hereglin receptor (eg HER3), insulin receptor, IGF receptor-1, IGF Receptor-2, FGF receptor-1 or FGF receptor-2, NGF receptor, TGFβ receptor, HGF receptor, VEGF receptor, angiopoietin receptor (eg, Tie2), PDGF receptor, etc. may be used.

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

In addition to the above drugs, L-asparaginase, L-arginase, arginine diiminase, aceglaton, procarbazine hydrochloride, protoporphyrin/cobalt complex salt, mercury hematoporphyrin/sodium, topoisomerase I inhibition Drugs (eg irinotecan, topotecan, indotecan, Indimitecan), topoisomerase II inhibitors (eg sobuzuoxane), differentiation inducers (eg retinoids, vitamin D), other angiogenesis inhibitors (eg Puma) Guilin, shark extract, COX-2 inhibitor), α-blocker (eg tamsulosin hydrochloride), bisphosphonic acid (eg pamidronate, zoledronate), thalidomide, lenalidomide, foam Lidomide, azacitizine, decitabine, proteasome inhibitors (eg bortezomib, carfilzomib, ixazomib), NEDD8 inhibitors (eg Pevonedistat), UAE inhibitors, PARP inhibitors (eg Olaparib, Niraparib, Veliparib), anti-CD20 antibody (eg Rituximab, Obinutuzumab), anti-CCR4 antibody (eg Mogamulizumab), etc. Anti-tumor antibody, antibody drug complex (eg, trastuzumab emtansine, brentuximab vedotin) etc. can also be used as a concomitant drug.

When the compound of the present invention is used for an IRAK-M related disease other than cancer, in addition to the above concomitant drugs, for example, an antibacterial drug, an antifungal drug, a non-steroidal anti-inflammatory drug, a steroid drug, a bronchodilator, an anticoagulant drug , antiplatelet drug, thrombolytic drug, immune modulator, anti-antigen drug, antitussive, expectorant, sedative, anesthetic, narcotic antagonist, anti-ulcer drug, vitamin drug, vitamin derivative, anti-allergic drug, anti-asthma drug, atopic drug Dermatitis treatment drug, signal transduction inhibitor, inflammatory mediator activity inhibitory drug, inflammatory mediator activity inhibitory antibody, inflammatory mediator production inhibitory drug, anti-inflammatory mediator activity inhibitory drug, anti-inflammatory mediator activity inhibitory antibody, anti-inflammatory mediator activity inhibitory drug, anti-inflammatory A fibroblast agent, an α1 adrenergic agonist, an antiemetic drug, an anti-methemoglobin increase inhibitor, etc. can be used as a concomitant drug.

(1) antibacterial drugs

(i) Bacterial disease prophylaxis

sulfamethizol, sulfisoxazole, sulfamonomethoxine, sulfamethizol, sarazosulfapyridine, sulfadiazine silver, etc.

(ii) Quinoline antibacterial drugs

Nalidexic acid, pipemic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosyl santhofloxacin, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, floxacin, etc.

(iii) anti-tuberculosis drugs

Isoniazid, ethanebutol (ethanebutol hydrochloride), paraaminosalicylic acid (calcium paraaminosalicylate), pyrazinamide, ethionamide, prothionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine, etc.

(iv) antibacterial drugs

diaminodiphenylsulfone, rifampicillin, and the like.

(v) antiviral drugs

Aidoxuridine, acyclovir, vitarabine, ganciclovir, favipyravir, etc.

(vi) Anti-HIV drugs

Zidovudine, didanosine, zalcitabine, indinavir sulfate ethanol adduct, ritonavir, etc.

(vii) anti-spiroheta drugs

(viii) antibiotics

tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibecacin, kanendomycin, libidomycin, tobramycin, amikacin, pradiomycin, sisomycin, tetracycline, oxytetracycline, lolly tetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalotin, cefapyrin, cephaloridine, cefachlor, cephalexin, ceproxadin, cefadroxil, cefamandol, cefuroxime, cell Thiam, cefothiamhexetyl, ceproxime axetil, cefdinir, cefditorenefivoxil, ceftazidim, cefpyramide, cefslodin, cefmenoxime, cefpodoximeproxetil, cefpyrome, cefozofran , cefepime, cefsulodin, cefmenoxime, cefmetazole, cefminox, cefoxitin, cefbuferazone, lactamoxef, flomoxef, cefazolin, cefotaxime, cefoperazone, ceftizoxim, pastor Lactam, thienamycin, sulfasecin, aztreonam or salts thereof, glycerofluvin, lancasidine, and the like.

(2) antifungal drugs

(i) polyene antibiotics (eg, amphotericin B, nystatin, tricomycin);

(ii) glycerofluvin, pyrrolenitrine, etc.;

(iii) cytosine metabolite antagonists (eg, flucytosine);

(iv) imidazole derivatives (eg, econazole, clotrimazole, miconazole nitrate, biphonazole, croconazole);

(v) triazole derivatives (eg, fluconazole, itraconazole, azole compounds [2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1 ,2,4-triazolone],

(vi) thiocarbamic acid derivatives (eg tolnaftate);

(vii) Echinocandin derivatives (eg, caspofungin, micafungin, anidulafungin) and the like.

(3) Non-steroidal anti-inflammatory drugs

Acetaminophen, phenacetin, etensamide, sulfirin, antipyrine, migranin, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, Naproxen, oxaprozin, pullurbiprofen, fenbufen, pranoprofen, floctafenin, epirizole, thiaramid hydrochloride, zaltoprofen, mesylate gabexate, mesylate chamostat, ulinastatin, colchicine, pro Beneside, sulfinpyrazone, benzbromarone, allopurinol, sodium thiomalate gold, sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, petidine, levorphanol, ketoprofen , naproxen, oxymorphone, meloxicam, celecoxib, rofecoxib or a salt thereof, and the like.

(4) steroid drugs

Dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinoloneacetonide, fluosinonide, fluocinoloneacetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometron, becromethasone propionate, becromethasone propionate ol etc.

(5) bronchodilator

Metaproterenol, Salmeterol, Formoterol, Carmoterol, etc.

(6) anticoagulants

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

(7) antiplatelet drugs

Ozagrel sodium, ethyl eicosapentaate, beraprost sodium, alprostadil, ticlopidine hydrochloride, pentoxifyrine, zipyridamor, etc.

(8) thrombolytic drugs

thysokinase, urokinase, streptokinase, etc.

(9) immunomodulators

Cyclosporine, tacrolimus, gusperimus, azathioprine, anti-lymphatic serum, dry sulfonated immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon, etc.

(10) Anti-antigen drugs

Metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate, etc.

(11) Jinhae and expectorant medicine

Ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrine hydrochloride, methyl ephedrine hydrochloride, noscapine hydrochloride, allocramide, chlorpedianol, picoperidamine, cloperastine, protokyrol , isoproterenol, salbutamol, terbutaline, oxymethebanol, morphine hydrochloride, dextromethorphan hydrobromide, oxycodone hydrochloride, dimemorphan phosphate, tipepidine hybenzate, pentoxiberine citrate, chloro hydrochloride Pedanol, benzonatate, guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, acetylcysteine, ethylcysteine hydrochloride, carbocysteine, etc.

(12) sedatives

Chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital, amobarbital, pentobarbital, sodium thiopental, sodium thiamiral, nitrazepam, estazolam, flurazapam, haloxazolam, triazolam, flu Nitrazepam, bromovaleryl urea, water chloral, triclofos sodium, etc.

(13) anesthetics

(13-1) local anesthetic

Cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxetazane) and the like.

(13-2) general anesthetic

(i) inhalation anesthetics (e.g., ethers, halothane, nitrous oxide, isoflurane, enflurane)

(ii) Intravenous anesthetics (eg, ketamine hydrochloride, droperidol, sodium thiopental, thiamiralnat, pentobarbital), etc.

(14) narcotic antagonists

Levalorphan, nalorphine, naloxone or a salt thereof, and the like.

(15) anti-ulcer drugs

methacropromide, histidine hydrochloride, lansoprazole, metoclopramide, pyrenzepine, cimetidine, ranitidine, famotidine, urogastrin, oxetazane, proglumid, omeprazole, sucralfate, sulfiride, cetraxate, Geparnat, aldioxa, teprenone, prostaglandins, etc.

(16) vitamin pills

(i) Vitamin A class: vitamin A1, vitamin A2 and retinol palmitate

(ii) Vitamin D class: Vitamins D1, D2, D3, D4 and D5

(iii) Vitamin E: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, nicotinic acid dl-α-tocopherol

(iv) Vitamin K class: Vitamin K1, K2, K3 and K4

(v) folic acid (vitamin M)

(vi) B vitamins: vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6 and vitamin B12

(vii) biotin (vitamin H) and the like.

(17) vitamin derivatives

various derivatives of vitamins, for example, vitamin D3 derivatives such as ascorbic acid, 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol, 1-α-hydroxycholecalciferol; Vitamin D2 derivatives such as 5,6-trans-ergocalciferol and the like.

(18) Anti-allergic drugs

Diphenhydramine, chlorpheniramine, triperenamine, clemizole, diphenylpyralin, methoxyphenamine, sodium chromoglycate, tranilast, lepirinast, amlexanox, ibudilast, ketotifen , terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, franlukast hydrate, seratrodast, etc.

(19) Anti-asthma

Isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimethoquinol hydrochloride, tulobuterol hydrochloride, orciprenaline sulfate, phenoterol hydrobromide, ephedrine hydrochloride, ipratropium bromide, bromide Oxytropium, flutropium bromide, theophyrine, aminopyrine, sodium chromogliate, tranilast, lepirinast, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, hydrochloride Grel, franlukast hydrate, seratrodast, dexamethasone, prednisolone, hydrocortisone, beclomethasone propionate, etc.

(20) Atopic dermatitis treatment drug

sodium chromoglycate, etc.

(21) anti-weed

phenothiazine derivatives, 5-HT3 receptor antagonists, and the like.

(22) methemoglobin elevation inhibitors

methylene blue, ascorbic acid, etc.

(23) integrin inhibitors

Natalizumab, Vedolizumab, AJM300, TRK-170, E-6007, etc.

(24) anti-fibrinogen

Pirfenidone, nintedanib, β-aminopropionitrile (BAPN), ursodeoxycholic acid, and the like.

(25) other

Hydroxycam, diacerin, megestrolacetic acid, nicergoline, prostaglandins, etc.

By combining the compound of the present invention and a concomitant drug, (1) compared to the case of administering the compound of the present invention or the concomitant drug alone, the dosage can be reduced, and (2) the patient's symptoms (mild, severe, etc.) Therefore, the drug used in combination with the compound of the present invention can be selected, (3) the treatment period can be set long, (4) the treatment effect can be sustained, and (5) the compound of the present invention and the concomitant drug can be used in combination. , excellent effects such as synergistic effect can be obtained.

Hereinafter, the case where the compound of the present invention and a concomitant drug are used in combination will be referred to as "combination agent of the present invention".

In the use of the combined agent of the present invention, the administration timing of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered simultaneously to the administration target or may be administered with a time difference. In the case of administration with a time difference, the time difference varies depending on the administered active ingredient, dosage form, and administration method. For example, when the combination drug is administered first, within 1 minute to 3 days after administration of the combination drug, preferably The compound of the present invention may be administered within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the compound of the present invention is administered first, the concomitant drug may be administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, and more preferably within 15 minutes to 1 hour after administration of the compound of the present invention. . The dosage of the concomitant drug may be according to the dosage used clinically, and may be appropriately selected according to the administration target, administration route, disease, combination, and the like.

The dosage form in the case of using the compound of the present invention and the concomitant drug in combination includes, for example, (1) administration of a single agent obtained by simultaneously formulating the compound of the present invention and the concomitant drug, (2) the compound of the present invention and the concomitant drug Simultaneous administration of the two preparations obtained by separately formulating them in the same administration route, (3) administration with a time difference in the same administration route of the two preparations obtained by separately formulating the compound of the present invention and a concomitant drug, (4) ) simultaneous administration of two agents obtained by separately formulating the compound of the present invention and the concomitant drug in different routes of administration, (5) in different routes of administration of the two agents obtained by separately formulating the compound of the present invention and the concomitant drug administration with a time difference (eg, administration in the order of the compound of the present invention → administration of the concomitant drug, or administration in the reverse order).

The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected according to the administration target, administration route, target disease, symptom, combination, and the like. For example, when the administration target is a human, 0.01 to 100 parts by weight of the concomitant drug may be used with respect to 1 part by weight of the compound of the present invention.

Moreover, the compound of this invention or the combination agent of this invention can be used together with non-pharmaceutical therapy. Specifically, the compound of the present invention or the combination of the present invention is, for example, (1) surgery, (2) boosting chemotherapy using angiotensin II or the like, (3) gene therapy, (4) hyperthermia, ( Obtained in combination with non-pharmaceutical therapy of 5) cryotherapy, (6) laser cauterization, and (7) radiation therapy.

For example, by using the compound of the present invention or the combined agent of the present invention before or after the above surgery, or before or after treatment combining these 2 or 3 types, resistance development can be inhibited and disease-free survival (Disease-Free Survival) ), suppression of cancer metastasis or recurrence, and life-sustaining effects can be obtained.

In addition, treatment with the compound of the present invention or the combination of the present invention and supportive therapy [(i) antibiotics for the co-occurrence of various infectious diseases (eg, β-lactams such as pansporin, macros such as clarithromycin) Ride system), (ii) administration of high-calorie fluids, amino acid preparations, and multivitamins for the improvement of nutritional disorders, (iii) administration of morphine for pain relief, (iv) nausea, vomiting, anorexia, diarrhea, decreased white blood cell count , thrombocytopenia, lowering of hemoglobin concentration, hair loss, liver disorders, kidney disorders, DIC, fever, etc., administration of drugs for improving side effects and (v) administration of drugs for suppressing multidrug resistance of cancer, etc.] can also be combined. .

Example

The present invention is further described in detail with reference to the following reference examples, examples, test examples, and formulation examples, but these do not limit the present invention, and may be changed without departing from the scope of the present invention.

"Room temperature" in the following examples usually indicates about 10°C to about 35°C. The ratio shown in the mixed solvent represents the volume ratio unless otherwise specified. % represents weight% unless otherwise indicated.

In silica gel column chromatography, aminopropylsilane-bonded silica gel was used when NH was used, and octadecyl-bound silica gel was used when C18 was used. In HPLC (High Performance Liquid Chromatography), octadecyl-bonded silica gel was used in the case of C18. The ratio of the elution solvent indicates the volume ratio unless otherwise specified.

In the following examples, the following abbreviations are used.

MS: Mass Spectrum

M: molarity

DMSO-d ₆ : heavy dimethyl sulfoxide

¹ H NMR: proton nuclear magnetic resonance

LC/MS: Liquid Chromatography Mass Spectrometry

ESI: Electrospray Ionization

APCI: Atmospheric Pressure Chemical Ionization

DCM: dichloromethane

DIEA: diisopropylethylamine

DMAP: 4-dimethylaminopyridine

DMF: N,N-dimethylformamide

HATU: 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

TEA: triethylamine

THF: tetrahydrofuran

TFA: trifluoroacetic acid

¹ H NMR was measured by Fourier transform NMR. ACD/SpecManager or MestreNova (trade name) was used for analysis. Peaks in which protons such as a hydroxyl group or an amino group are very gentle may not be described.

MS was measured by LC/MS. As the ionization method, the ESI method or the APCI method was used. Data are presented as found. Usually, molecular ion peaks ([M+H] ⁺ , [MH] ^- , etc.) are observed, but in the case of a compound having a tert-butoxycarbonyl group, as a fragment ion, a tert-butoxycarbonyl (Boc) group or tert A peak from which the -butyl (tBu) group is detached is sometimes observed. In the case of a compound having a carboxyl group or the like, a peak to which sodium is added may be observed in some cases. Moreover, in the case of the compound which has a hydroxyl group, the peak from which water detached|desorbed as a fragment ion may be observed. In the case of a salt, a molecular ion peak or a fragment ion peak of a free body is usually observed.

The unit of the sample concentration (c) in the rotational degree ([α] _D ) is g/100 ml.

As for the elemental analysis value (Anal.), a calculated value (Calcd) and an actual value (Found) were described.

Example 1

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

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

To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (14.9 g) and DMF (100 ml) was added sodium hydride (60%, dispersed in liquid paraffin, 3.0 g) under ice cooling. The reaction mixture was stirred for 10 minutes, 7-chlorothieno[3,2-b]pyridine (10.4 g) was added, and stirred at 60°C overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a mixture of the obtained tert-butyl 4-(thieno[3,2-b]pyridin-7-yloxy)piperidine-1-carboxylate and ethyl acetate (100 ml), a 4 M hydrogen chloride/ethyl acetate solution ( 100 ml) was added. 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) methyl 3-(allyloxy)isoxazole-5-carboxylate

To a mixture of methyl 3-hydroxyisoxazole-5-carboxylate (15.0 g), potassium carbonate (17.4 g) and DMF (200 ml) was added 3-bromopropa-1-ene (13.6 ml) and stirred at 60°C for 16 hours. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (16.6 g).

MS: [M+H] ⁺ 184.3.

C) (3-(allyloxy)isoxazol-5-yl)methanol

To a mixture of methyl 3-(allyloxy)isoxazole-5-carboxylate (16.6 g) and methanol (300 mL) was added sodium borohydride (4.80 g). The reaction mixture was stirred at room temperature for 16 hours, and the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (13.2 g).

MS: [M+H] ⁺ 156.3.

D) (3-(allyloxy)isoxazol-5-yl)methyl methanesulfonate

To a mixture of (3-(allyloxy)isoxazol-5-yl)methanol (13.2 g), TEA (24 mL) and THF (200 mL) was added methanesulfonylchloride (9.94 mL) under ice cooling. The reaction mixture was stirred at room temperature for 1 hour, diluted with water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated 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

7-(piperidin-4-yloxy)thieno[3,2-b]pyridine dihydrochloride (6.16 g), (3-(allyloxy)isoxazol-5-yl)methyl methanesulfonate (5.14) g), tetrabutylammonium iodine (4.44 g), potassium carbonate (9.70 g), and a mixture of DMF (100 mL) were stirred at room temperature for 24 hours. Water was added to the reaction mixture, filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated 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) benzyl (S)-4-(2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)piperazine-1-carboxylate

(S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (2.5 g), benzylpiperazine-1-carboxylate (2.14 g), DIEA (5.09 ml) and DMF ( 48.6 mL) was added HATU (5.54 g) at room temperature. The reaction mixture was stirred at the same temperature for 6 hours. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (4.34 g).

MS: [M+H] ⁺ 460.2.

G) Benzyl (S)-4-(2-amino-2-cyclohexylacetyl)piperazine-1-carboxylate hydrochloride

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

MS : [M+H] ⁺ 360.2.

H) benzyl 4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl)piperazine-1-carboxyl rate

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

MS: [M+H] ⁺ 545.4.

I) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperazin-1-yl)ethyl)amino)-1-oxopropan-2-yl )(methyl)carbamat

Benzyl 4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl)piperazine-1-carboxylate ( 3.62 g), a mixture of 10% palladium carbon (362 mg) and ethyl acetate (67 ml) was stirred at room temperature under atmospheric pressure under a hydrogen atmosphere for 1 hour. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.46 g).

MS: [M+H] ⁺ 411.3.

J) methyl 5,6-difluoro-1-methyl-1H-indole-2-carboxylate

To a mixture of 5,6-difluoro-1H-indole-2-carboxylic acid (20 g) and DMF (200 mL), potassium carbonate (42.0 g) and iodomethane (18.9 mL) were added at room temperature. The reaction mixture was stirred at the same temperature for 18 hours and then at 40°C for 6 hours. Water was added to the reaction mixture, and the precipitate was collected by filtration and washed with hexane to obtain the title compound (20 g).

K) methyl 5,6-difluoro-3-formyl-1-methyl-1H-indole-2-carboxylate

1 M titanium tetrachloride/DCM solution (17.8 mL) and dichloromethylmethyl in a mixture of methyl 5,6-difluoro-1-methyl-1H-indole-2-carboxylate (2 g) and DCM (20 mL) A mixture of ether (1.7 mL) and DCM (2 mL) was added at -78 °C. The reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with water and neutralized with saturated aqueous sodium hydrogen carbonate solution. The precipitate was filtered through Celite, and the filtrate was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.9 g).

L) 5,6-difluoro-3-formyl-1-methyl-1H-indole-2-carboxylic acid

of methyl 5,6-difluoro-3-formyl-1-methyl-1H-indole-2-carboxylate (15 g) with THF (225 mL), methanol (75 mL) and water (75 mL) Lithium hydroxide monohydrate (3.73 g) was added to the mixture, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and acidified with an aqueous potassium hydrogen sulfate solution. The obtained solid was collected by filtration to obtain the title compound (13 g).

MS: [M+H] ⁺ 240.1.

M) 2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl)piperazine-1- carbonyl)-5,6-difluoro-1-methyl-1H-indole-3-carboxylic acid

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperazin-1-yl)ethyl)amino)-1-oxopropan-2-yl)( Methyl)carbamat (4.63 g), 5,6-difluoro-3-formyl-1-methyl-1H-indole-2-carboxylic acid (2.45 g), DIEA (2.7 mL) with DMF (50 mL) was added HATU (4.67 g). After the reaction mixture was stirred at room temperature for 2 hours, water was added and extraction was performed with ethyl acetate. The organic layer was washed sequentially with 0.1 M hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane). Obtained tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-3-formyl-1-methyl-1H-indole-2) -carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat, sodium dihydrogenphosphate (4.90 g), 2-methylbuta- To a mixture of 2-ene (3.58 g) and tert-butyl alcohol (90 mL)/water (30 mL) was added sodium chlorite (2.24 g). The reaction mixture was stirred at room temperature overnight, an aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated 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) tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-3-((2-(2-(2-hydro Roxyethoxy)ethoxy)ethyl)(methyl)carbamoyl)-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropane -2-yl) (methyl) carbamat

2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl)piperazine-1-carbonyl )-5,6-difluoro-1-methyl-1H-indole-3-carboxylic acid (5.46 g) with 2-(2-(2-(methylamino)ethoxy)ethoxy)ethane-1- To a mixture of ol (1.65 g), DIEA (2.26 mL) and DMF (8 mL) was added HATU (3.85 g). The reaction mixture was stirred at room temperature for 3 hours, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to obtain the title compound (3.10 g).

MS: [M+H] ⁺ 793.5.

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

3-(allyloxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole (5.68 g), triethyl To a mixture of silane (7.3 mL) and THF (100 mL) was added tetrakistriphenylphosphinepalladium (884 mg). The reaction mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol), and the obtained compound was washed with ethyl acetate to obtain the title compound (2.50 g).

P) tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(methyl(2-(2) -(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy) to oxy)ethoxy)ethyl)carbamoyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)car bar mart

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

MS: [M+H] ⁺ 1106.6.

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

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(methyl(2-(2-( 2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy) ethoxy)ethyl)carbamoyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat To a mixture of (2.37 g) and ethyl acetate (10 ml) was added a 4 M hydrogen chloride/ethyl acetate solution (16.1 ml), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated to give the title compound (2.16 g).

Example 2

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

A) methyl 6-methoxy-1-methyl-1H-indole-2-carboxylate

To a mixture of methyl 6-methoxy-1H-indole-2-carboxylate (11.6 g) and DMF (100 mL) was added sodium hydride (60%, dispersed in liquid paraffin, 2.93 g) under ice cooling. After the reaction mixture was stirred at the same temperature for 15 minutes, iodomethane (3.88 ml) was added to the reaction mixture, and the reaction mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added water (150 ml) and 1 M hydrochloric acid (250 ml) under ice cooling, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated 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

To a mixture of methyl 6-methoxy-1-methyl-1H-indole-2-carboxylate (11.4 g) and methanol (100 mL) was added 2 M aqueous sodium hydroxide solution (52.0 mL) at room temperature, and the reaction mixture was It stirred at 60 degreeC for 1 hour. The reaction mixture was cooled under ice-cooling, 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) tert-Butyl 4-(6-methoxy-1-methyl-1H-indole-2-carbonyl)piperazine-1-carboxylate

6-Methoxy-1-methyl-1H-indole-2-carboxylic acid (9.87 g), tert-butyl piperazine-1-carboxylate (9.41 g), 1-hydroxybenzotriazole monohydrate (8.10) g) and DMF (150 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.14 g), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled on ice, water was added, and the precipitate was collected by filtration to obtain the title compound (16.8 g).

MS: [M+H] ⁺ 374.1.

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

(chloromethylene)dimethyl in a mixture of tert-butyl 4-(6-methoxy-1-methyl-1H-indole-2-carbonyl)piperazine-1-carboxylate (10.4 g) and DMF (100 mL) Ammonium chloride (7.13 g) was added and the reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and after stirring for 30 minutes, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (10.6 g).

MS: [M+H] ⁺ 402.1.

E) 6-Methoxy-1-methyl-2-(piperazine-1-carbonyl)-1H-indole-3-carbaaldehyde hydrochloride

tert-Butyl 4-(3-formyl-6-methoxy-1-methyl-1H-indole-2-carbonyl)piperazine-1-carboxylate (10.6 g), dimethylsulfide (25 ml) and To a mixture of ethyl acetate (100 ml) was added a 4 M hydrogen chloride/ethyl acetate solution (198 ml), 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) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(3-formyl-6-methoxy-1-methyl-1H-indole-2-carr) Bornyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat

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

MS: [M+H] ⁺ 626.3.

G) 2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl)piperazine-1- carbonyl)-6-methoxy-1-methyl-1H-indole-3-carboxylic acid

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(3-formyl-6-methoxy-1-methyl-1H-indole-2-carbonyl) Piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat (2.30 g), sodium dihydrogen phosphate (1.76 g), 2-methylbuta- To a mixture of 2-ene (1.95 mL), tert-butyl alcohol (29.4 mL), and water (7.4 mL) was added sodium chlorite (665 mg) at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and a saturated aqueous sodium thiosulfate solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to obtain the title compound (770 mg).

MS: [M+H] ⁺ 642.4

H) tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(3-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl) )carbamoyl)-6-methoxy-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)( methyl)carbamat

2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl)piperazine-1-carbonyl )-6-methoxy-1-methyl-1H-indole-3-carboxylic acid (147 mg), triethylene glycol monoamine (41.0 mg), DIEA (120 μl), HATU (131 mg) and DMF (1.15) ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted by adding water and ethyl acetate, followed by extraction with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile/5 mM aqueous ammonium acetate solution) to obtain the title compound (133 mg).

MS: [M+H] ⁺ 773.5.

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

To a mixture of tert-butyl-4-hydroxypiperidine-1-carboxylate (2.42 g) and DMF (60.1 ml) was added sodium hydride (60%, dispersed in liquid paraffin, 0.577 g). After the reaction mixture was stirred for 30 minutes, 4-chlorothieno[3,2-d]pyrimidine (2.05 g) was added, stirred for 1 hour at room temperature, diluted with ethyl acetate and water, and the aqueous layer was washed with ethyl acetate extracted. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (3.75 g).

MS: [M+H] ⁺ 336.0.

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

To a mixture of tert-butyl 4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (3.75 g) and ethyl acetate (22.4 ml) 4 M hydrogen chloride/ Ethyl acetate solution (55.9 mL) was added. 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).

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

To a mixture of 4-(piperidin-4-yloxy)thieno[3,2-d]pyrimidine hydrochloride (215 mg) and pyridine (2.64 ml), 4-hydroxybenzene-1-sulfonylchloride (152 mg) was added. The reaction mixture was stirred for 16 hours, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile/5 mM aqueous ammonium acetate solution) to obtain the title compound (43.5 mg).

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

4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol (35.5 mg), tert-butyl ((S)-1 -(((S)-1-Cyclohexyl-2-(4-(3-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamoyl)-6-methoxy- 1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat (70.0 mg), tri To a mixture of phenylphosphine (119 mg) and toluene (0.45 mL) was added di-tert-butylazodicarboxylate (62.6 mg). 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 aqueous ammonium acetate solution). Ethyl acetate (0.2 ml) was added to the obtained product, 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 aqueous ammonium acetate 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).

Example 3

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

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

Lithium hydroxide 1 in a mixture of methyl 5,6-difluoro-1-methyl-1H-indole-2-carboxylate (2 g) with THF (14 mL), methanol (7 mL) and water (7 mL) Hydrate (1.1 g) was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, acidified by addition of an aqueous potassium hydrogen sulfate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (1.8 g).

MS: [MH] ⁺ 210.0.

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

DIEA (4.4 mL), (R)-2-methyl-piperazine in a mixture of 5,6-difluoro-1-methyl-1H-indole-2-carboxylic acid (1.8 g) and DMF (45 mL) (1.02 g), HATU (4.8 g) was added. The reaction mixture was stirred at room temperature for 3 hours, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/DCM) to 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-methylpiperazin-1-yl)ethane- 1-on

A mixture of (R)-(5,6-difluoro-1-methyl-1H-indol-2-yl)(3-methylpiperazin-1-yl)methanone (1.9 g) and DCM (25 mL) To this, TEA (1.35 mL) and chloroacetyl chloride (0.6 mL) were added under ice cooling. The reaction mixture was stirred at room temperature for 3 hours, diluted with DCM, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (1.8 g).

MS: [M+H] ⁺ 370.2.

D) 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl methanesulfonate

To a mixture of 2-(2-(2-benzyloxyethoxy)ethoxy)ethanol (2 g) and DCM (15 ml) was added TEA (1.7 ml) and methanesulfonylchloride (0.77 ml) under ice cooling. The reaction mixture was stirred at room temperature for 12 hours, diluted with DCM, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (2.5 g).

E) tert-Butyl (2R,5R)-4-benzyl-2-methyl-5-(12-phenyl-2,5,8,11-tetraoxadodecyl)piperazine-1-carboxylate

Sodium hydride (60%; dispersion in liquid paraffin, 105 mg) was added. The reaction mixture was stirred for 1 hour, 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl methanesulfonate (695 mg) was added, and the mixture was stirred at 60°C for further 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 stirred at 60°C for further 5 hours. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated 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) tert-Butyl (2R,5R)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperazine-1-carboxylate

tert-Butyl (2R,5R)-4-benzyl-2-methyl-5-(12-phenyl-2,5,8,11-tetraoxadodecyl)piperazine-1-carboxylate (900 mg), To a mixture of acetic acid (0.1 mL) and ethanol (10 mL) was added 10% palladium carbon (200 mg). The reaction mixture was stirred for 16 hours at room temperature under a hydrogen atmosphere at atmospheric pressure, filtered through Celite, and the filtrate was concentrated under reduced pressure. 10% methanol/DCM was added to the residue, the organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (600 mg).

G) tert-Butyl (2R,5R)-4-(2-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpipette Razin-1-yl)-2-oxoethyl)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperazine-1-carboxylate

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

MS: [M+H] ⁺ 696.5.

H) tert-Butyl (2R,5R)-4-(2-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpipette Razin-1-yl)-2-oxoethyl)-2-methyl-5-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridine-7) -yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperazine-1-carboxylate

tert-Butyl (2R,5R)-4-(2-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperazine- 1-yl)-2-oxoethyl)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperazine-1-carboxylate (30 mg), 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol (17.1 mg), triphenyl To a mixture of phosphine (56.5 mg), and toluene (2 mL) was added di-tert-butylazodicarboxylate (29.7 mg). The reaction mixture was stirred at room temperature for 16 hours, and the solvent was distilled off under reduced pressure. The residue was separated and purified by 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-methylpiperazin-1-yl)-2-((2R ,5R)-5-methyl-2-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1) -yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperazin-1-yl)ethan-1-one hydrochloride

tert-Butyl (2R,5R)-4-(2-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperazine- 1-yl)-2-oxoethyl)-2-methyl-5-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-ylox) c)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperazine-1-carboxylate (25 mg) with DCM (1 ml ) was added 4 M hydrogen chloride/dioxane solution (0.3 ml) under ice cooling. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was washed with ether and pentane to give the title compound (19 mg).

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)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)- 1H-Indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride

A) methyl 5,6-difluoro-3-hydroxy-1-methyl-1H-indole-2-carboxylate

In a mixture of methyl 5,6-difluoro-3-formyl-1-methyl-1H-indole-2-carboxylate (3.5 g) and chloroform (50 mL) 3-chloroperbenzoic acid (5.88 g) and p -Toluenesulfonic acid (3.15 g) was added at 5 to 10°C. The reaction mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added a 2 M ammonia/methanol solution (30 mL), and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, diluted with a saturated aqueous sodium hydrogen carbonate solution, and extracted with DCM. The organic layer was washed with a 10% aqueous sodium thiosulfate solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (3 g).

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

Methyl 5,6-difluoro-3-hydroxy-1-methyl-1H-indole-2-carboxylate (4.4 g), tert-butyl piperazine 1-carboxylate (5.1 g) and toluene (45 ml), a 2M trimethylaluminum/toluene solution (18.2 ml) was added under an argon atmosphere at room temperature. The reaction mixture was stirred at 100° C. for 3 hours. Water was added to the reaction mixture, the precipitate was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (3 g).

MS: [M+H] ⁺ 393.8.

C) 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate

To a mixture of 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethan-1-ol (5 g) and DCM (100 ml), TEA (4.4 ml), DMAP (1.27 g), p- Toluenesulfonylchloride (4.8 g) was added under ice cooling, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM and washed sequentially with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (5.2 g).

MS: [M+H] ⁺ 395.0.

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

tert-Butyl 4-(5,6-difluoro-3-hydroxy-1-methyl-1H-indole-2-carbonyl)piperazine-1-carboxylate (1 g) with DMF (10 mL) To a mixture of cesium carbonate (2.06 g) and 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (1.49 g) were added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. 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-indol-2-yl)(pipeline Razin-1-yl)methanone hydrochloride

tert-Butyl 4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-car To a mixture of bornyl)piperazine-1-carboxylate (1.2 g) and DCM (12 mL) was added 4 M hydrogen chloride/dioxane solution (2 mL) under ice cooling. The reaction mixture was stirred at room temperature for 4 hours, and the solvent was 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) tert-Butyl (S)-(2-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1 -Methyl-1H-indole-2-carbonyl)piperazin-1-yl)-1-cyclohexyl-2-oxoethyl)carbamat

(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indol-2-yl)(piperazine- To a mixture of 1-yl)methanone hydrochloride (1.1 g) and DMF (10 mL) was added DIEA (0.694 mL). The reaction mixture was stirred at room temperature for 15 min, (S)-tert-butoxycarbonylamino-cyclohexylacetic acid (0.512 g), 1-hydroxybenzotriazole (366 mg) and 1-ethyl-3-(3 -Dimethylaminopropyl)carbodiimide hydrochloride (458 mg) was added. 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 over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (1.1 g).

MS: [M+H] ⁺ 757.0.

G) (S)-2-amino-1-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1 -Methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-cyclohexylethan-1-one hydrochloride

tert-Butyl (S)-(2-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl -In a mixture of -1H-indole-2-carbonyl)piperazin-1-yl)-1-cyclohexyl-2-oxoethyl)carbamat (1.1 g) and DCM (10 mL) 4 M hydrogen chloride/dioxane The solution (10 mL) was added under ice cooling. 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) tert-butyl ((S)-1-(((S)-2-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5 ,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl) (methyl)carbamat

(S)-2-amino-1-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl To a mixture of -1H-indole-2-carbonyl)piperazin-1-yl)-2-cyclohexylethan-1-one hydrochloride (1.1 g) and DMF (10 ml) was added DIEA (0.83 ml) at room temperature. did 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 stirred at room temperature for 16 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated 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) tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-3-(2-(2-(2-hydroxyl)) Ethoxy)ethoxy)ethoxy)-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl ) carba mart

tert-Butyl ((S)-1-(((S)-2-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6 -difluoro-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl ) To a mixture of carbamat (850 mg) and ethanol (10 ml), 10% palladium carbon (200 mg) was added at room temperature, and the mixture was stirred under a hydrogen atmosphere at atmospheric pressure for 3 hours. The reaction mixture was filtered through Celite, washed with ethanol, and the filtrate was concentrated under reduced pressure to obtain the title compound (740 mg).

MS: [M+H] ⁺ 752.6.

J) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(2-(2-() 2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy) Ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-3-(2-(2-(2-hydroxyethoxy) )ethoxy)ethoxy)-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)car Bamat (40 mg), 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol (21.1 mg ), triphenylphosphine (69.7 mg) and toluene (1.5 ml) was added di-tert-butylazodicarboxylate (36.7 mg), stirred at room temperature for 16 hours, and the reaction mixture was concentrated under reduced pressure. did The residue was separated and purified by 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)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy )-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(2-(2-(2-) ((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy )ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat (36 mg) and To a mixture of DCM (1 mL) was added a 4 M hydrogen chloride/dioxane solution (0.3 mL) under ice cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diethyl ether and pentane to obtain the title compound (24 mg).

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)isoxazol-3-yl)oxy)-6,9,12-trioxa-3- Azatetradecyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride

A) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1H-indole-2-carbonyl)piperazine-1 -yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat

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

MS: [M+H-Boc] ⁺ 490.3.

B) methyl 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl)pipe Razine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetate

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1H-indole-2-carbonyl)piperazin-1-yl) )-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat (2.64 g), potassium carbonate (681 mg), methyl 2-bromoacetate (753 mg) and DMF ( 20 ml) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (2.96 g).

MS: [M+H] ⁺ 662.4.

C) 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl)piperazine -1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid

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

MS: [M+H] ⁺ 648.4.

D) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(14-hydroxy-3-methyl-2)) -oxo-6,9,12-trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropane-2 -yl) (methyl) carbamat

2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl)piperazine-1 -carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid (1.20 g), 5,8,11-trioxa-2-azatridecan-13-ol (422 mg), HATU (986 mg) was added to a mixture of DIEA (0.65 mL), and DMF (9.3 mL), and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and ethyl acetate, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (695 mg).

MS: [M+H] ⁺ 837.5.

E) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-) ((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)-6,9, 12-trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)car bar mart

5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol (265 mg), tert-butyl (( S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(14-hydroxy-3-methyl-2-oxo-6,9; 12-trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)car To a mixture of Bamat (670 mg), triphenylphosphine (1.05 g) and toluene (8 ml) was added di-tert-butylazodicarboxylate (553 mg), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (C18, acetonitrile/5 mM aqueous ammonium acetate solution) to obtain the title compound (575 mg).

MS: [M+H] ⁺ 1150.4.

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

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-(() 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)-6,9,12- Trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat To a mixture of (575 mg) and ethyl acetate (1 ml) was added a 4 M hydrogen chloride/ethyl acetate solution (2 ml), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (549 mg).

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)pyrrolidin-1- yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride

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

5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol (398.8 mg), (9H-fluorene -9-yl)methyl(S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (389.2 mg), triphenylphosphine (378.8 mg), and toluene (5 ml) -tert-Butyl azodicarboxylate (332.5 mg) was added. The reaction mixture was stirred at room temperature for 30 min 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, concentrated under reduced pressure, and TFA (5 mL) was added to the residue. The reaction mixture was stirred at room temperature for 5 minutes, diluted with water, and washed with ethyl acetate. The aqueous layer was made basic with 2 M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated 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) tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)) -2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl ) pyrrolidin-1-yl) ethyl) -1H-indole-2-carbonyl) piperazin-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) car bar mart

2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl)piperazine-1 -carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid (199.8 mg), (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4- (thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole (140.7 mg), DIEA (107 μl), 1-hydroxybenzotriazole (83.37 mg), and to a mixture of DMF (3 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (118.3 mg). The reaction mixture was stirred at room temperature for 2 hours, water was added, and the precipitate was collected by filtration and washed with water to 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-((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)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2) -(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pi Rollidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat (380.2 mg) and ethyl acetate (1.5 ml) was added 4 M hydrogen chloride/ethyl acetate solution (1 ml). The reaction mixture was stirred at room temperature for 1 hour and 30 minutes, and diisopropyl ether was added. The precipitate was collected by filtration and washed with diisopropyl ether to obtain the title compound (280.3 mg).

MS: [M+H] ⁺ 944.2.

The title compound was neutralized in a saturated aqueous sodium hydrogen carbonate solution, and the precipitates were collected to obtain a free body, and ¹ H NMR was measured.

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)pyrrolidin-1-yl)ethyl )-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide

A) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5-fluoro-1H-indole-2-carbonyl)piperazin-1-yl) -2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperazin-1-yl)ethyl)amino)-1-oxopropan-2-yl)( 5-fluoro-1H-indole-2-carboxylic acid (3.36 g), 1-hydroxybenzotriazole (3.00 g), DIEA in a mixture of methyl)carbamat (7 g) and DMF (60 mL) (11.9 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.25 g) was added. 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 aqueous sodium hydrogen carbonate solution and saturated brine, and dried over 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) methyl 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl)pipe Razine-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetate

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5-fluoro-1H-indole-2-carbonyl)piperazin-1-yl)-2 Potassium carbonate (6.89 g), methylbromoacetate (4.59 ml) in a mixture of -oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat (9.5 g) and DMF (50 ml) was added under ice cooling, 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 and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (8.6 g).

MS: [M+H] ⁺ 644.1.

C) 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl)piperazine -1-carbonyl)-5-fluoro-1H-indol-1-yl)acetic acid

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

MS: [M+H] ⁺ 630.2.

D) tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-((S)-2- (((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrol Din-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat

2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl)piperazine-1 (S)-3-(pyrrolidin-2-ylmethoxy)-5 in a mixture of -carbonyl)-5-fluoro-1H-indol-1-yl)acetic acid (700 mg) and DMF (10 ml) -((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole (506.8 mg), DIEA (0.78 ml), HATU (507.8 mg) ) was added and stirred at room temperature for 16 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (950 mg).

MS: [M+H] ⁺ 1025.8.

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

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(() (5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidine- 1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat (60 mg) ) and ethyl acetate (0.2 ml), a 4 M hydrogen chloride/ethyl acetate solution (0.043 ml) was added, and the mixture was stirred at room temperature for 4 hours. (S)-N-[(S)-1-cyclohexyl-2-[4-(5-fluoro-1-{2-oxo-2-[(S)-2-[(S)-2-[] ({5-[(4-{thieno[3,2-b]pyridin-7-yloxy}piperidin-1-yl)methyl]-1,2-oxazol-3-yl}oxy)methyl ]pyrrolidin-1-yl]ethyl}-1H-indole-2-carbonyl)piperazin-1-yl]-2-oxoethyl]-2-(methylamino)propanamide hydrochloride and water (0.2 ml) Saturated aqueous sodium hydrogen carbonate solution (0.043 ml) was added to the mixture of . 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).

Example 8

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

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

Methyl 3-hydroxyisoxazole-5-carboxylate (3.79 g), tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.84 g) and triphenylphosphine (6.94 g) was azeotroped with toluene, and a 40% diethylazodicarboxylate toluene solution (14 ml) was added to the mixture of the residue and toluene (50 ml) under ice cooling. After the reaction mixture was stirred at room temperature for 1 hour, the solvent was distilled off to half under reduced pressure, and purified by silica gel column chromatography (ethyl acetate/hexane). Hydrogenation to a mixture of obtained methyl (S)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)isoxazole-5-carboxylate and methanol (100 ml) Sodium boron (1.18 g) was added. 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 over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a mixture of the obtained tert-butyl (S)-2-(((5-(hydroxymethyl)isoxazol-3-yl)oxy)methyl)pyrrolidine-1-carboxylate and THF (100 mL) Methanesulfonylchloride (2.10 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, and saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Obtained tert-butyl (S)-2-(((5-(((methylsulfonyl)oxy)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidine-1-carboxylate, 7- A mixture of (piperidin-4-yloxy)thieno[3,2-b]pyridine dihydrochloride (8.85 g), potassium carbonate (19.9 g), tetrabutylammonium iodine (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. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane). Obtained tert-butyl (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-carboxylate 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) tert-Butyl (S)-4-(5,6-difluoro-1H-indole-2-carbonyl)-3-methylpiperazine-1-carboxylate

tert-Butyl (S)-3-methylpiperazine-1-carboxylate (1.12 g), 5,6-difluoro-1H-indole-2-carboxylic acid (1.00 g), DIEA (2.72 ml) , and to a mixture of DMF (20 mL) was added HATU (2.89 g). The reaction mixture was stirred at room temperature for 1 hour, diluted with water and ethyl acetate, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (1.61 g).

MS: [M+H-tBu] ⁺ 324.2.

C) methyl 2-(2-((S)-4-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)-2-methylpiperazine-1-carbox Bornyl)-5,6-difluoro-1H-indol-1-yl)acetate

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

MS: [M+H] ⁺ 591.5.

D) methyl 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclo Hexylacetyl)-2-methylpiperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetate

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

MS: [M+H] ⁺ 676.5.

E) 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexyl Acetyl)-2-methylpiperazine-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid

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

MS: [M+H] ⁺ 662.4.

F) tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2- ((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl )oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)amino)-1-oxopropane- 2-yl)(methyl)carbamat

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

MS: [M+H] ⁺ 1058.5.

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

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-(() S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy )methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2- To a mixture of yl)(methyl)carbamat (320 mg) and ethyl acetate (2 ml) was added a 4 M hydrogen chloride/ethyl acetate solution (2 ml). The reaction mixture was stirred at room temperature for 1 hour and 30 minutes, and the solvent was distilled off under reduced pressure. 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).

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)pyrrolidin-1 -yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide

A) benzyl (S)-4-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)-2-methylpiperazine-1-carboxylate

(S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (5 g), benzyl (S)-2-methylpiperazine-1-carboxylate hydrochloride (5.26 g), To a mixture of 1-hydroxybenzotriazole (3.4 g), DIEA (10.2 ml) and DMF (50 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.8 g). . The reaction mixture was stirred at room temperature for 2 hours, ice water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed sequentially with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (6.7 g).

MS: [M+H] ⁺ 474.2.

B) Benzyl (S)-4-((S)-2-amino-2-cyclohexylacetyl)-2-methylpiperazine-1-carboxylate hydrochloride

Benzyl (S)-4-((S)-2-(((tert-butoxy)carbonyl)amino)-2-cyclohexylacetyl)-2-methylpiperazine-1-carboxylate (6.7 g) To a mixture of and DCM (60 mL) was added 4 M hydrogen chloride/dioxane solution (30 mL). The reaction mixture was stirred at room temperature for 3 hours, and the solvent was distilled off under reduced pressure. The residue was washed with DCM to obtain the title compound (6 g).

C) benzyl (S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl)-2- Methylpiperazine-1-carboxylate

In a mixture of N-(tert-butoxycarbonyl)-N-methyl-L-alanine (3 g) and DMF (30 ml) benzyl (S)-4-((S)-2-amino-2-cyclo Hexylacetyl)-2-methylpiperazine-1-carboxylate hydrochloride (6 g), DIEA (10.3 mL), and HATU (7.3 g) were added. 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 aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (6 g).

MS: [M+H] ⁺ 559.1.

D) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-((S)-3-methylpiperazin-1-yl)-2-oxoethyl)amino)-1 -oxopropan-2-yl) (methyl) carbamat

Benzyl (S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl)-2-methylpipette To a mixture of razine-1-carboxylate (3.8 g) and ethanol (50 ml) was added 10% palladium carbon (1 g). The reaction mixture was stirred for 16 hours at room temperature under a hydrogen atmosphere at atmospheric pressure, followed by celite filtration. The filtrate was concentrated under reduced pressure to obtain the title compound (2.3 g).

MS: [M+H] ⁺ 425.2.

E) methyl 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclo Hexylacetyl)-2-methylpiperazine-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetate

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-((S)-3-methylpiperazin-1-yl)-2-oxoethyl)amino)-1-oxo A mixture of propan-2-yl)(methyl)carbamat (901 mg), 5-fluoro-1H-indole-2-carboxylic acid (380 mg), DIEA (1.14 mL), and DMF (12 mL) HATU (1.21 g) was added. The reaction mixture was stirred at room temperature for 1 hour, poured into water, and the precipitate was collected by filtration and azeotroped with toluene. Obtained tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1H-indole-2-carbonyl)-3-methyl piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat, potassium carbonate (322 mg), methyl 2-bromoacetate (356 mg) and A mixture of DMF (12 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and ethyl acetate, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (979 mg).

MS: [M+H] ⁺ 658.4.

F) 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexyl Acetyl)-2-methylpiperazine-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetic acid

Methyl 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl )-2-methylpiperazine-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetate (979 mg) and methanol (8 ml) in a mixture of 2 M aqueous sodium hydroxide solution (3.72 ml) was added. The reaction mixture was stirred at room temperature for 1 hour, acidified by addition of 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (915 mg).

MS: [M+H] ⁺ 644.4.

G) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S) )-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy) methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl ) (methyl) carbamat

2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-2-cyclohexylacetyl) -2-methylpiperazine-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetic acid (621 mg), (S)-3-(pyrrolidin-2-ylmethoxy)-5 -((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole trihydrochloride (606 mg), DIEA (1.0 mL), and DMF (5 mL) was added HATU (734 mg). The reaction mixture was stirred at room temperature for 2 hours, water was added, and the precipitate was collected by filtration, and purified by silica gel column chromatography (C18, acetonitrile/5 mM ammonium acetate aqueous solution). The 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 over anhydrous sodium sulfate, and the solvent was evaporated 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-((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)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-) 2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl) pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)( To a mixture of methyl)carbamat (367 mg) and ethyl acetate (2 ml) was added a 4 M hydrogen chloride/ethyl acetate solution (3 ml). The reaction mixture was stirred at room temperature for 1 hour and 30 minutes, and the solvent was distilled off under reduced pressure. 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).

Example 10

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

A) 2-(benzyloxy)-3,4-difluorobenzaldehyde

To a mixture of 3,4-difluoro-2-hydroxy-benzaldehyde (5 g) and acetonitrile (50 ml) were added potassium carbonate (6.56 g), benzylbromide (4.51 ml) and sodium iodide (2.37 g). did 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).

B) methyl (Z)-2-azide-3-(2-(benzyloxy)-3,4-difluorophenyl)acrylate

Sodium methoxide (1.74 g) and methanol (10 mL) in a mixture of methyl azide acetate (3.15 mL), 2-(benzyloxy)-3,4-difluorobenzaldehyde (2.0 g) and methanol (10 mL) was added dropwise at -10°C under an argon atmosphere. 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).

C) methyl 4-(benzyloxy)-5,6-difluoro-1H-indole-2-carboxylate

A mixture of methyl (Z)-2-azide-3-(2-(benzyloxy)-3,4-difluorophenyl)acrylate (2.0 g) and xylene (30 ml) was stirred at 140° C. for 2 hours. stirred. The reaction mixture was cooled, and the precipitate was collected by filtration to obtain the title compound (700 mg).

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

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

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

MS: [M+H] ⁺ 318.1.

F) tert-Butyl ((S)-1-(((S)-2-(4-(4-(benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carr) Bornyl)piperazin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat

To a mixture of 4-(benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carboxylic acid (1.4 g) and DMF (20 mL) tert-butyl ((S)-1 -(((S)-1-Cyclohexyl-2-oxo-2-(piperazin-1-yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat (1.81 g) , HATU (2.52 g) and DIEA (1.9 mL) were added. The reaction mixture was stirred at room temperature for 2 hours, ice water was added, and extraction was performed with ethyl acetate. The organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (2.1 g).

MS: [M+H] ⁺ 710.1.

G) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-4-hydroxy-1-methyl-1H-indole-) 2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat

tert-Butyl ((S)-1-(((S)-2-(4-(4-(benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl) In a mixture of piperazin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat (2.1 g) and ethanol (50 mL), Palladium carbon (400 mg) was added, and the mixture was stirred at room temperature for 2 hours 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-methylbenzenesulfonate

2-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)ethanol (15 g) and DCM (250 ml) in a mixture of TEA (11.03 ml), DMAP (3.22 g), p-toluenesulfonylchloride (12.07 g) was added under ice cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was diluted with DCM and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (14 g).

MS: [M+H] ⁺ 439.2.

I) tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-((1-phenyl-2) ,5,8,11-tetraoxatridecan-13-yl)oxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropane-2 -yl) (methyl) carbamat

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-4-hydroxy-1-methyl-1H-indole-2- Carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat (450 mg) and DMF (5 mL) in a mixture of cesium carbonate ( 591 mg) and 2-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (573 mg) were added. The reaction mixture was stirred at room temperature for 16 hours, ice water was added, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (490 mg).

MS: [M+H] ⁺ 886.4.

J) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-4-(2-(2-(2-(2) -Hydroxyethoxy)ethoxy)ethoxy)ethoxy)-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropane- 2-yl)(methyl)carbamat

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-((1-phenyl-2,5) ,8,11-tetraoxatridecan-13-yl)oxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl ) (methyl) To a mixture of carbamat (490 mg) and ethanol (15 ml) was added palladium carbon (100 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 16 hours, filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (360 mg).

MS: [M+H] ⁺ 796.2.

K) tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-(2-(2-() 2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy) Ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl) Karbamat

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-4-(2-(2-(2-(2-hyde) Roxyethoxy)ethoxy)ethoxy)ethoxy)-1-methyl-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropane-2- yl)(methyl)carbamat (20 mg), 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazole- To a mixture of 3-ol (12.4 mg), triphenylphosphine (32.9 mg) and toluene (2 ml) was added di-tert-butylazodicarboxylate (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 separated and purified by 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)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide hydrochloride

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-(2-(2-(2-) (2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy )ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carba To a mixture of mart (25 mg) and DCM (1 ml) was added 4 M hydrogen chloride/dioxane solution (0.3 ml) at 0°C. The reaction mixture was stirred at room temperature for 1 hour, the solvent was distilled off under reduced pressure, and the mixture was washed with diethyl ether to obtain the title compound (17 mg).

Example 11

(S)-N-((S)-1-cyclohexyl-2-(4-(2-methyl-1-(2-(2-(2-(2-((5-((4-(thie)) no[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

A) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1H-indole-5-carbonyl)piperazin-1-yl)- 2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperazin-1-yl)ethyl)amino)-1-oxopropan-2-yl)( To a mixture of methyl)carbamat (4 g) and DMF (70 mL) were added 2-methyl-1H-indole-5-carboxylic acid (1.9 g), DIEA (6.8 mL), and HATU (4.45 g). and stirred at room temperature for 16 hours. The reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (4 g).

MS: [M+H] ⁺ 568.3.

B) tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1-(1-phenyl-2,5,8,11-tetraoxa) tridecan-13-yl)-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1H-indole-5-carbonyl)piperazin-1-yl)-2- Cesium carbonate (2.87 g) was added to a mixture of oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat (2 g) and DMF (30 ml), and the mixture was stirred at room temperature for 5 minutes. Then, 2-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (2.78 g) was added, and the mixture was stirred at 80°C for 16 hours. The reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. 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) tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(1-(2-(2-(2-(2-hydroxyethoxy)ethoxy) )ethoxy)ethyl)-2-methyl-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carba Mart

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1-(1-phenyl-2,5,8,11-tetraoxatridecane) -13-yl)-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat (1.3 g) 10% palladium carbon (250 mg) was added to the mixture of ethanol (50 ml) and ethanol (50 ml), and it stirred at 25 degreeC in the hydrogen atmosphere of normal pressure 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) tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1-(2-(2-(2-(2-((5) -((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy )ethyl)-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat

to tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(1-(2-(2-(2-(2-hydroxyethoxy)ethoxy) oxy)ethyl)-2-methyl-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat ( 20 mg), 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol (10.6 mg), tri To a mixture of phenylphosphine (35.2 mg) and toluene (2 ml) was added di-tert-butylazodicarboxylate (24.7 mg), followed by stirring at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was separated and purified by 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-((4-4-) (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

tert-Butyl ((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1-(2-(2-(2-(2-((5-() (4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl )-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamat (17 mg) with DCM (1 mL), TFA (0.01 mL) was added at 0°C, and stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was separated and purified by HPLC (C18, mobile phase: acetonitrile/20 mM aqueous ammonium bicarbonate solution) to obtain the title compound (4 mg).

MS: [M+H] ⁺ 957.8.

The prepared Example compounds 1-11 are shown below. For each compound, the compound name, structural formula, salt type, and MS value (MS is an actual value) are shown.

Example No. 1 (Compound 1): 2-(4-((S)-2-Cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl )-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-ylox) cy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide (2-(4-((S) -2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2) -((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)-1H-indole -3-carboxamide),

[Formula 55]

Type of salt: HCl; MS value: 1006.6

Example No. 2 (Compound 2): 2-(4-((S)-2-Cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl )-6-methoxy-1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)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),

[Formula 56]

Types of salts: - ; MS level: 1046.5

Example No. 3 (Compound 3): 1-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperazin-1-yl )-2-((2R,5R)-5-methyl-2-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-ylox) c)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperazin-1-yl)ethan-1-one (1-(( R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperazin-1-yl)-2-((2R,5R)-5-methyl-2-( (2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy) ethoxy)ethoxy)methyl)piperazin-1-yl)ethan-1-one),

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

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

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

[Formula 60]

Type of salt: HCl; MS level: 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)isoxazol-3-yl)oxy)methyl) pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S)-N-( (S)-1-cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-) b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)- 2-oxoethyl)-2-(methylamino)propanamide),

[Formula 61]

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

[Formula 62]

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

[Formula 63]

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

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

[Formula 65]

Types of salts: - ; MS value: 957.8

Test Example 1: Measurement of XIAP binding inhibitory activity

Human XIAP binding inhibitory activity was determined by using a commercially available human XIAP_BIR3 domain purified protein (R&D) and using a C-terminal biotinylated Smac N-terminal peptide (AVPIAQK (SEQ ID NO: 1)) (hereinafter "b-" Smac"; Peptide Laboratories Co., Ltd.) was used as a ligand, and measurement was performed by Homogeneous Time Resolved Fluorescence (HTRF) method.

The HTRF method will be described in detail below.

1 µl/well of a test compound diluted with a reaction buffer (25 mM HEPES buffer containing 100 mM NaCl, 0.1% BSA, 0.1% Triton X-100, pH 7.5) in a 384-well white shallow-bottomed plate (Greiner 784076) ) and flash centrifugation for 30 seconds. Subsequently, the purified human XIAP_BIR3 domain protein was diluted with reaction buffer to a concentration of 90 nM to obtain a sample dilution, and then the diluted sample was added to the white shallow-bottomed plate at 4.5 µL/well, followed by flash centrifugation for 30 seconds. Subsequently, b-Smac diluted to 90 nM with the reaction buffer was added to the white shallow-bottomed plate at 4.5 µL/well, followed by flash centrifugation for 30 seconds. Anti-6 HIS-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) at a volume of 1:1 was added to the white shallow-bottomed plate at 10 μl/well, followed by flash centrifugation for 30 seconds, and then the white shallow-bottomed plate was washed. It was left to stand at room temperature in a dark place for 4 hours or more. The white shallow-bottomed plate after standing was subjected to measurement of fluorescence intensity (excitation wavelength: 320 nm, fluorescence wavelength: 665 nm and 615 nm) by EnVision (ParkinElmer).

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

The XIAP binding inhibition rate of the test compound was evaluated. When the concentration of the test compound is 3 µM, the XIAP binding inhibition rate is determined by A≥75%, 75%>B≥50%, 50%>C≥25%, D<25%, or 50% inhibitory concentration (IC50 value) is shown in the table below, with A < 0.3 µM, 0.3 µM ≤ B < 3 µM, and 3 µM ≤ C < 30 µM.

*Inhibition rate: Inhibition rate/IC50 value at 3 μM

From the above results, it was shown that the compound of the present invention has excellent IAP (particularly XIAP) binding (inhibition) activity.

Test Example 2: Measurement of IRAK-M binding inhibitory activity

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

(Signal value of test compound - Signal value of positive control compound) / (Signal value of negative control compound - Signal value of positive control compound) x 100

Negative control compound = DMSO (100% Ctrl)

Positive Control Compound = Control Compound (0%Ctrl)

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

Test Example 3: Degradation-inducing activity of target protein in Invitro

The degradation-inducing activity of the Example compound in Invitro was evaluated by enzyme-linked immunoassay (ELISA) according to the following assay steps. THP1 cells (ATCC, TIB-202) were cultured in RPMI-1640 supplemented with 10% FBS, 1X sodium pyruvate, 1X HEPES, D-(+)-glucose and 1% penicillin/streptomycin. THP1 cells seeded at 1 × 10 ⁶ cells/well in a 24-well plate were treated with DMSO control and a test compound, and cultured for 24 hours. Cells were harvested and lysed on ice for 30 minutes using a lysis buffer (PBS containing 0.1% Triton X-100) to which a protease inhibitor cocktail (Roche, Cat#11836170001) was added. After ultrasonic disruption of the lysate was performed at 30 sec ON/30 sec OFF, 10 cycles, centrifugation was performed at 4° C. and 13 krpm for 10 minutes. Protein concentration was determined by BCA assay (Sigma, Cat # QPBCA-1 KT). The ELISA assay was performed using the Human IRAK3/IRAKM/IRAK-M ELISA Kit (LifeSpan BioSciences, Cat # LS-F35271) to evaluate the protein amount of IRAK-M according to the protocol of the kit. With respect to the IRAK-M protein degradation rate of the test compound, the protein degradation rate (%) at a concentration of 1 µM of the test compound is A ≥ 75%, 50% ≤ B < 75%, 25% ≤ C < 50%, D < 25 The % or 50% decomposition concentration (DC50 value) is shown in the table below as A < 0.03 µM, 0.03 µM ≤ B < 0.1 µM, 0.1 µM ≤ C < 0.3 µM, 0.3 µM ≤ D < 1 µM.

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

Test Example 4: Antitumor effect in mouse Lewis lung cancer cell inoculation model

C57BL/6 mice (Nippon Charles River, male, 7-8 W) were treated with mouse Lewis lung carcinoma cells LL/2 (Lewis lung carcinoma, LLC) (ATCC, CRL-1642) 2 × 10 ⁴ cells/mouse with Matrigel Together, the mice were inoculated subcutaneously in the flank. After 7 days of inoculation, the tumor size was measured with an electron nogis, grouping was performed so that each group had the same size, and administration of the compound was started from 8 days after the inoculation. The tumor size was calculated using the formula of the major axis × minor axis × minor axis ÷ 2 of the tumor.

The test compound was suspended in 0.5% methylcellulose or dissolved in physiological saline, and administered subcutaneously three times every three days. Tumor size was measured regularly until 16 to 18 days after the start of the test, and two groups were assayed for the tumor size in the test compound administration group and the tumor size in the solvent administration group on the last day of the test.

Examples 1, 6, 7, 8 and 9, and the day-to-day transition of the tumor size of each group are shown in Fig. 1 . For each compound, the salt shown in the figure was used. The figures represent mean ± standard error.

From the above results, it was shown that these compounds have a cancer proliferation inhibitory action.

Formulation Example 1

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

1. Capsules

(1) the compound obtained in Example 1 40 mg

(2) lactose 70 mg

(3) microcrystalline cellulose 9 mg

(4) magnesium stearate 1 mg

1 capsule 120 mg

After mixing 1/2 of (1), (2), (3) and (4), it is granulated. The remainder (4) is added to this, and the whole is enclosed in a gelatin capsule.

2. Refining

(1) the compound obtained in Example 1 40 mg

(2) lactose 58 mg

(3) Corn Starch 18 mg

(4) microcrystalline cellulose 3.5 mg

(5) magnesium stearate 0.5 mg

1 tablet 120 mg

2/3 of (1), (2), (3), (4) and 1/2 of (5) are mixed, and then granulated. The remaining (4) and (5) are added to the granules and press-molded into tablets.

Formulation Example 2

50 mg of the compound obtained in Example 1 was dissolved in 50 ml of distilled water for injection from Japanese Pharmacopoeia, and then distilled water for injection from Japanese Pharmacopoeia was added to make 100 ml. This solution is filtered under sterile conditions, then 1 ml of this solution is taken, filled into injection vials under sterile conditions, freeze-dried and sealed.

The above detailed description merely explains the object and subject of the present invention, and does not limit the appended claims. Various modifications and substitutions to the described embodiments will become apparent to those skilled in the art from the teachings set forth herein without departing from the appended claims.

Industrial Applicability

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

SEQUENCE LISTING <110> FIMECS, Inc. <120> Heterocyclic Compound <130> 20FOT009-WO0 <150> JP2019-141700 <151> 2019-07-31 <160> 1 <170> PatentIn version 3.5 <210> 1 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> a partial sequence of Smac peptide <400> 1 Ala Val Pro Ile Ala Gln Lys 1 5

Claims (16)

Formula (I):

A compound represented by , or a pharmaceutically acceptable salt thereof. The method of claim 1,
The IRAK-M binder (M) is the following formula (II)

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

(Here, * represents a bonding position with respect to O, ** indicates a bonding position with respect to A, and n is an integer of 0 to 2.) is a group represented by, A is the following structural formula:

(herein, R ⁰⁵ is each independently a hydrogen atom or a C1-6 alkyl group), or *-SO ₂ -*, and R ⁰⁴ is the following structural formula:

(Here, * represents a bonding position to A, ** indicates a bonding position to a linker.) Any group represented by, optionally substituted C1-6 alkylene group, optionally substituted C3-10 cycloalkyl a lene group, an optionally substituted C6-14 arylene group, or a bond, and an arrow indicates a bond to the linker (L).], or a pharmaceutically acceptable salt thereof. 3. The method of claim 2,
The IRAK-M binder (M) is the following formula (III)

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

(herein, R ⁰⁵ is each independently a hydrogen atom or a C1-6 alkyl group), or *-SO ₂ -*;
R ¹¹ is the following structural formula:

(wherein * represents a bonding position to A ⁰¹ , ** indicates a bonding position to a linker.) Any group represented by, an arrow indicates a bonding to a linker (L).] a compound represented by, or A pharmaceutically acceptable salt thereof. 3. The method of claim 2,
IRAK-M binder (M), 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)
A monovalent group derived from a compound selected from the group consisting of, a compound, or a pharmaceutically acceptable salt thereof. 5. The method according to any one of claims 1 to 4,
A compound, or a pharmaceutically acceptable salt thereof, wherein the linker (L) is a group having 5 to 20 carbon atoms which may contain a hetero atom. 5. The method according to any one of claims 1 to 4,
Linker (L) is the structural formula described below:

(Here, * represents a bond to IRAK-M binder (M).) A group represented by *-(CH ₂ CH ₂ O)n(CH ₂ )m(NRCO)s(CH ₂ )t- * (n is a natural number from 1 to 5, m is 0, 1, or 2, s is 0 or 1, t is 0 or 1, and R is a hydrogen atom or a C1-6 alkyl group.), or A compound that is a bond, or a pharmaceutically acceptable salt thereof. 7. The method according to any one of claims 1 to 6,
The E3 ligase binder (E) has the following formula (IV):

[wherein, 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 which may form a ring with each other, D is, the formula (V)

(wherein m represents an integer of 0 to 2, n represents an integer of 0 to 2, W ₁₁ represents a methylene group, a difluoromethylene group, O, S, SO, SO ₂ , or NR; Here, R represents a hydrogen atom, a C1-6 alkyl group, a C1-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, or a C1-6 alkylsulfonyl group, and T represents a C1-3 alkyl group which may be halogenated. ), or the formula (VI):

(Wherein, Q is an oxygen atom, formula -NR ^21- (in formula, R ²¹ represents a hydrogen atom, or a C1-6 alkyl group or a C1-6 alkyl group which may form a ring together with P), or a bond represents a hand, P represents a hydrogen atom, a C1-6 alkyl group, or a bond with the linker (L) (forms a ring together with Q and includes a bond to the linker (L)),
E is the formula (VII):

(R ₂₁ , R ₂₂ , and R ₂₃ in the formula each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an optionally substituted carbamoyl group, R ₂₅ , R ₂₆ each independently represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, an optionally substituted carbamoyl group, or a bond to the linker (L), R ₂₄ is a hydrogen atom, a methyl group, or a bond to the linker (L), with the proviso that the bond to the linker (L) is any one of R ₂₄ , R ₂₅ or R ₂₆ ), or the following formula (VIII):

(In the formula, R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ , and R ₃₅ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an optionally substituted carbamoyl group; , R represents a hydrogen atom, a C1-6 alkyl group, or a bond to the linker (L)), and either D or E is bonded to the linker (L).] acceptable salts. 8. The method according to any one of claims 1 to 7,
The E3 ligase binder (E) has the following formula (IV):

[Wherein, 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 a formula (V-1) :

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

(Wherein, Q represents a bond to the linker (L).)
E is the formula (VII):

(R ₂₁ , R ₂₂ , and R ₂₃ in the formula 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 are each independently a hydrogen atom; A halogen atom, a C1-6 alkyl group, or a bond to the linker (L), and R ₂₄ is a hydrogen atom, a methyl group, or a bond to the linker (L), provided that the bond to the linker (L) is R ₂₄ , R ₂₅ or R ₂₆ ), or Formula (VIII):

(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 is a hydrogen atom, a C1-6 alkyl group, or a linker ( It represents a bond to L).) and either D or E is bonded to the linker (L).] A compound, or a pharmaceutically acceptable salt thereof. The method of claim 1,
The IRAK-M binder (M) is the following formula (III):

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

(herein, * indicates a bonding position to A, ** indicates a bonding position to a linker.) represents any group represented by , an arrow indicates a bonding to a linker (L)],
Linker (L) is the structural formula described below:

(Here, * represents a bond to IRAK-M binder (M).) A group represented by *-(CH ₂ CH ₂ O)n(CH ₂ )m(NRCO)s(CH ₂ )t- * (n is a natural number from 1 to 5, m is 0, 1, or 2, s is 0 or 1, t is 0 or 1, and R is a hydrogen atom or a C1-6 alkyl group.), or is a bonding hand,
E3 ligase binder (E) has the following formula (IV):

[Wherein, 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 a formula (V-2) :

, or the following formula (VI-1):

(Wherein, Q represents a bond to the linker (L).)
E is the formula (VII):

(R ₂₁ , R ₂₂ , and R ₂₃ in the formula 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 are each independently a hydrogen atom; A halogen atom, a C1-6 alkyl group, or a bond to the linker (L), and R ₂₄ is a hydrogen atom, a methyl group, or a bond to the linker (L), provided that the bond to the linker (L) is R ₂₄ , R ₂₅ or R ₂₆ ), or Formula (VIII):

(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 linker (L) ), and either D or E is bonded to the linker (L).] A compound, or a pharmaceutically acceptable salt thereof. The method of claim 1,
The following compounds 1 to 11:
Compound 1: 2-(4-((S)-2-Cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-5,6- Difluoro-N,1-dimethyl-N-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-) 1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide (2-(4-((S)-2-cyclohexyl-2 -((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-((5-( (4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide),

Compound 2: 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-6-methoxy -1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sul Ponyl)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),

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

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

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

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

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

Compound 8: (S)-N-((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)) -2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl )pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S )-N-((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5- ((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole- 2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide),

Compound 9: (S)-N-((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-((S)-2- (((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrol Din-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S)-N -((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-( thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)- 3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide),

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

and
Compound 11: (S)-N-((S)-1-cyclohexyl-2-(4-(2-methyl-1-(2-(2-(2-(2-((5-((4) -(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)- 1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((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),

A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof. A medicament comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof. 12. The method of claim 11,
IRAK-M proteolysis inducing drug, a medicament. 13. The method according to claim 11 or 12,
A medicament, which is a preventive or therapeutic agent for cancer. 14. The method according to any one of claims 11 to 13,
Medicines used in combination with other anticancer agents. 11. A method for inducing IRAK-M protein degradation, comprising administering to a patient in need of treatment an effective amount of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof. A method for preventing or treating cancer, comprising 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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