JP2021024787A - Heterocyclic compound - Google Patents

Abstract

To provide a novel heterocyclic compound having IRAK-M protein decomposition inducing action and a pharmaceutical containing the same.SOLUTION: The present invention relates to a compound represented by formula (I), where the IRAK-M binder (M) is represented by formula (II), or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: Figure 1

Description

The present invention has an interleukin-1 receptor-associated kinase-M (IRAK-M) protein degradation-inducing action, and prevents and treats cancer, fibrosis, infectious diseases, etc. The present invention relates to a heterocyclic compound expected to be useful in the art and a drug containing the heterocyclic compound.

It is called a compound that induces ubiquitination and proteasome degradation of the target protein by E3 ligase (Proteolysis Targeting Chimeras (PROTAC) or Specific and Nongenetic IAP-dependent Protein Eraser (SNIPER), etc.) for the purpose of treatment by reducing pathological condition-related proteins. (Sometimes) has been attempted (Non-Patent Documents 1 to 9).
IRAK-M is a member of the IRAK family of protein kinases, and is a pseudokinase having no kinase activity (Non-Patent Document 10). IRAK-M is located downstream of all Toll-like receptors (TLRs) except TLR3 and acts as a negative feedback regulator of the TLR / interleukin-1 (IL-1) receptor signaling pathway in vivo. It is a protein that functions in (Non-Patent Document 11). Its expression is localized to some epithelial cells, including bile duct epithelial cells, lung epithelial cells and intestinal epithelial cells, and to immune cells, especially myeloid cells. IRAK-M plays an important role in maintaining immune homeostasis such as induction of endotoxin tolerance by negatively controlling TLR-mediated induction signals of inflammatory cytokines in innate immune cells such as macrophages and dendritic cells. (Non-Patent Document 12). It has been reported that IRAK-M contributes to cancer growth by contributing to immunosuppression by tumor-related macrophages, bone marrow-derived immunosuppressive cells, dendritic cells, etc. in the tumor microenvironment (Non-Patent Documents 13 to 15). ). Furthermore, IRAK-M has been reported to act on alveolar macrophages on its phagocytosis, defense against bacteria, and collagen production promotion, resulting in fibrosis, asthma, secondary infection after sepsis, and hematopoietic stem cell transplantation. It is also involved in sexual complications (Non-Patent Documents 16-18). Therefore, compounds that induce the degradation of IRAK-M by linking the E3 ligase binding binder and the IRAK-M binding binder with a linker are promising in cancer, fibrosis, infectious diseases, and IRAK-M protein-related diseases. It can be a therapeutic drug.

Patent Document 1 reports a compound as an IRAK-M proteolysis inducer.
Patent Documents 2 and 3 report compounds as IRAK (particularly IRAK-4) proteolysis inducers.
Patent Documents 4 to 16 report compounds that induce proteolysis using an IAP binder. Patent Documents 17 to 20 describe N- (piperidine-4-yl) thieno [3,2-d] pyrimidine-4-amine or N- (piperidine-4-yl) thieno [3,2-b] pyridine-. Compounds with a 7-amine structure have been reported.

International Publication No. 2017/21 1924 International Publication No. 2019/099926 International Publication No. 2019/133531 International Publication No. 2018/066545 Japanese Unexamined Patent Publication No. 2013-056837 International Publication No. 2016/169989 International Publication No. 2016/172134 International Publication No. 2017/01 1590 International Publication No. 2017/182418 International Publication No. 2017/2014 49 U.S. Patent Application Publication No. 2018/0118733 U.S. Patent Application Publication No. 2018/0134688 International Publication No. 2018/119448 International Publication No. 2018/119357 U.S. Patent Application Publication No. 2019/0119271 U.S. Patent Application Publication No. 2019/0175612 International Publication No. 2016/040330 International Publication No. 2013/019966 U.S. Patent Application Publication No. 2013/0040957 Publication of Chinese Patent Application 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.e 5. 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): 19403-10. Cell. 2002 Jul 26; 110 (2): 191-202. Infect Dis Rep. 2010 Jan 1; 2 (1). Pii: e9. Oncogene. 2011 May 26; 30 (21): 2475-84. J Immunol. 2010 Oct 1; 185 (7): 4223-32. Mol Immunol. 2007 Jul; 44 (14): 3453-61. J Immunol. 2015 Feb 15; 194 (4): 1894-904. J Clin Invest. 2006 Sep; 116 (9): 2532-42. Epub 2006 Aug 17. J Immunol. 2010 Jun 1; 184 (11): 6299-308.

An object of the present invention is to obtain a novel heterocyclic compound which has an IRAK-M protein degradation-inducing action and is expected to be useful for the prevention / treatment of cancer, fibrosis, infectious diseases, etc., and a drug containing the same. To provide.

As a result of diligent studies to find an IRAK-M proteolysis inducer, the present inventors have found that the compound represented by the following formula has excellent IRAK-M protein degradation-inducing activity, and cancer and fibrosis. The present invention has been completed because it can be useful for the prevention and treatment of infectious diseases and the like.

That is, the present invention is as follows.
[1] The following formula (I):

A compound represented by, or a pharmaceutically acceptable salt thereof.
[2] The IRAK-M binder (M) has the following formula (II).

[In the formula, X is S, Y is CH or N, Z is O, R ⁰¹ is H or Me, R ⁰² is H, and R ⁰³ is the following structural formula:

It is a group represented by (where n is 0 to 2), and A is the following structural formula:

(Here, R ⁰⁵ is a group represented by a hydrogen atom or a C1-6 alkyl group independently of each other), or * -SO _2- *, and R ⁰⁴ is the following structural formula:

(Here, V is CH or N.) Any group represented by, optionally substituted alkyl group, optionally substituted aryl group or bond, arrow is linker (L). ) Is shown. ], The compound according to the above [1], or a pharmaceutically acceptable salt thereof.
[3] The IRAK-M binder (M) has the following formula (III).

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

(Here, R ¹² is a group represented by a hydrogen atom or a C1-6 alkyl group, respectively), or * -SO _2- *.
R ¹¹ has the following structural formula:

One of the groups represented by, the arrow indicates the bond to the linker (L). ], The compound according to the above [2] represented by, or a pharmaceutically acceptable salt thereof.
[4] The IRAK-M binder is the following compound,
5-((4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-ol,
5-((4-((2-Methylthieno [3,2-b] Pyridine-7-yl) Oxy) Piperidine-1-yl) Methyl) Isoxazole-3-ol
1-Methyl-5-((4- (thieno [3,2-b] pyridin-7-yloxy) piperidine-1-yl) methyl) -1H-pyrazole-3-ol
4-((4- (Thieno [3,2-d] pyrimidin-4-yloxy) piperidine-1-yl) sulfonyl) is a monovalent group derived from a compound selected from the group consisting of phenol, as described above [ 2].
[5] The compound according to any one of the above [1] to [4], wherein the linker (L) is a group having 5-20 carbon atoms which may contain a hetero atom, or a pharmacy thereof. Tolerable salt.
[6] The structural formula (L) described below is:

One of the groups represented by, *-(CH ₂ CH ₂ O) n- * (n is 1-5), or any one of the above [1] to [4] which is a mere bonder. The compound according to, or a pharmaceutically acceptable salt thereof.
[7] The E3 ligase binder has the following formula (IV):

[In the formula, D is the following formula (V)

(In the formula, m represents 0 to 2, n represents 0 to 2, W ₁₁ represents a methylene group, a difluoromethylene group, O, S, SO, SO ₂ , or NR, where R is hydrogen. Indicates an atom, C1-6 alkyl group, C1-6 alkyl-carbonyl group, C6-14 aryl-carbonyl group, or C1-6 alkylsulfonyl group, where T indicates a C1-3 alkyl group which may be halogenated. .) And E is the following equation (VI):

_{(R 21} , R ₂₂ , and R ₂₃ in the formula independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an amide group, and R ₂₅ and R ₂₆ are Each independently indicates a bond to a hydrogen atom, halogen atom, C1-6 alkyl group, C1-6 alkoxy group, amide group, or linker, and R ₂₄ indicates a bond to a hydrogen atom, methyl group, or linker. ) Or the following formula (VII):

_{(R 31} , R _32, R ₃₃ , R ₃₄ , and R ₃₅ in the formula each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an amide group, and R Indicates a bond to a hydrogen atom, a C1-6 alkyl group or a linker).) The compound according to any one of the above [1] to [6], or a pharmaceutically acceptable salt thereof.

[8] The following compounds:
2- (4-((S) -2-Cyclohexyl-2-((S) -2- (methylamino) propanamide) acetyl) piperazine-1-carbonyl) -5,6-difluoro-N, 1-dimethyl -N- (2- (2-((2-((5-((4- (thieno [3,2-b] pyridine-7-yloxy) piperidine-1-yl) methyl) isooxazole-3-yl)) Oxy) ethoxy) ethoxy) ethyl) -1H-indole-3-carboxamide,
2- (4-((S) -2-Cyclohexyl-2-((S) -2- (methylamino) propanamide) 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,
1-((R) -4- (5,6-difluoro-1-methyl-1H-indol-2-carbonyl) -2-methylpiperazin-1-yl) -2-((2R, 5R) -5- Methyl-2-((2- (2- (2-((5-((4- (thieno [3,2-b] pyridin-7-yloxy) piperidine-1-yl) methyl) isooxazole-3- Il) oxy) ethoxy) ethoxy) ethoxy) methyl) piperazine-1-yl) ethane-1-one,
(S) -N-((S) -1-Cyclohexyl-2- (4- (5,6-difluoro-1-methyl-3- (2- (2- (2-((5-((4-) 4-) (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-yl) Oxy) ethoxy) ethoxy) ethoxy) -1H-Indol-2-carbonyl) Piperazine-1 -Il) -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] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-yl) Oxy)-6,9,12-Trioxa-3-azatetradecyl) -1H-Indol- 2-carbonyl) piperazine-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] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isooxazole-3-yl) Oxy) Methyl) Pyrrolidine-1-yl) Ethyl) -1H-Indol-2 -Carbonyl) piperazine-1-yl) -2-oxoethyl) -2- (methylamino) propanamide,
(S) -N-((S) -1-Cyclohexyl-2-(4- (5-Fluoro-1- (2-oxo-2-((S) -2-(((5-((4-4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isooxazole-3-yl) Oxy) Methyl) Pyrrolidine-1-yl) Ethyl) -1H-Indol-2-carbonyl ) Piperazine-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] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isooxazole-3-yl) Oxy) Methyl) Pyrrolidine-1-yl) Ethyl) -1H -Indol-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-(((S) -2-(((5-) ((4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isooxazole-3-yl) Oxy) Methyl) Pyrrolidine-1-yl) Ethyl) -1H-Indol -2-carbonyl) -3-methylpiperazin-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- (5-( (4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-yl) Oxy) ethoxy) ethoxy) ethoxy) ethoxy) -1H-Indol-2- Carbonyl) piperazine-1-yl) -2-oxoethyl) -2- (methylamino) propanamide, and
(S) -N-((S) -1-Cyclohexyl-2- (4- (2-Methyl-1- (2- (2- (2- (2-((5-((4- (Chieno]) 3,2-b] Pyridine-7-yloxy) piperidine-1-yl) methyl) isooxazole-3-yl) oxy) ethoxy) ethoxy) ethoxy) ethyl) -1H-indole-5-carbonyl) piperazin-1- Il) -2-oxoethyl) -2- (methylamino) propanamide,
The compound according to the above [1] selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[9] A drug containing the compound according to any one of the above [1] to [8] or a pharmaceutically acceptable salt thereof.
[10] The medicament according to any one of the above [1] to [8], which is a proteolysis inducer.
[11] The medicament according to any one of the above [1] to [8], which is a preventive or therapeutic agent for cancer.
[12] The medicament according to any one of the above [1] to [8], which is used in combination with other anticancer agents.
[13] IRAK, which comprises administering to a patient in need of treatment an effective amount of the compound according to any one of the above [1] to [8] or a pharmaceutically acceptable salt thereof. -Method for inducing M proteolysis.
[14] Cancer characterized by administering to a patient in need of treatment an effective amount of the compound according to any one of the above [1] to [8] or a pharmaceutically acceptable salt thereof. Prevention or treatment method.

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

Using the Lewis lung cancer cell inoculation model, Examples 1, 25, 26, 27, 28, and 38 were subcutaneously administered three times every three days, and the changes in tumor size of each group over time were confirmed. For each compound, the salt shown in the figure was used. The figure shows the mean ± standard error.

Hereinafter, the present invention will be described with respect to the compounds of the present invention, methods and uses thereof, by way of examples of exemplary embodiments, together with preferred methods and materials that can be used in the practice of the present invention. Unless otherwise specified in the text, all technical terms and scientific terms used in the present specification have the same meanings as generally understood by those skilled in the art to which the present invention belongs. Also, any material and method equivalent to or similar to that described herein can be used similarly in the practice of the present invention. In addition, all publications and patents cited herein in connection with the invention described herein are described herein, for example, as indicating methods, materials, etc. that can be used in the present invention. It constitutes a part.

Hereinafter, the definition of each substituent used in the present specification will be 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- Includes fluorocyclopropyl, 2,2-difluorocyclopropyl, and 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, and the like. Examples thereof include isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.

In the present specification, examples of the "C1-6 alkyl group which may be halogenated" include C1-6 alkyl groups which may have 1 to 7 halogen atoms. Specific examples include methyl, chloromethyl, 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-tri Fluoropentyl, hexyl, 6,6,6-trifluorohexyl can be mentioned.

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. Examples thereof include -2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.

In the present specification, the "C2-6 alkynyl group" includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl. , 4-Pentynyl, 1-Hexynyl, 2-Hexynyl, 3-Hexynyl, 4-Hexynyl, 5-Hexynyl, 4-Methyl-2-pentynyl.

In the present specification, the "C3-10 cycloalkyl group" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2]. ] Octyl, bicyclo [3.2.1] Octyl, adamantyl.

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

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

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

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

In the present specification, examples of the "C1-6 alkoxy group which may be halogenated" include a C1-6 alkoxy group which may have 1 to 7 halogen atoms. Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, and pentyl. Examples include oxy and hexyloxy.

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

In the present specification, examples of the "C1-6 alkylthio group which may be halogenated" include C1-6 alkylthio groups which may have 1 to 7 halogen atoms. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio.

In the present specification, the "C1-6 alkyl-carbonyl group" includes, for example, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethyl. Examples include propanoyl, hexanoyl and heptanoil.

In the present specification, examples of the "C1-6 alkyl-carbonyl group which may be halogenated" include a C1-6 alkyl-carbonyl group which may have 1 to 7 halogen atoms. .. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, the "C1-6 alkoxy-carbonyl group" includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyl. Examples thereof include oxycarbonyl and hexyloxycarbonyl.

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

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

In the present specification, examples of the "5- to 14-membered aromatic heterocyclic carbonyl group" include nicotinoyle, isonicotinoyl, tenoyl, and floyl.

In the present specification, examples of the "3- to 14-membered non-aromatic heterocyclic carbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

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

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

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

In the present specification, examples of the "C1-6 alkylsulfonyl group which may be halogenated" include a C1-6 alkylsulfonyl group which may have 1 to 7 halogen atoms. Specific examples include methyl sulfonyl, difluoromethyl sulfonyl, trifluoromethyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl, butyl sulfonyl, 4,4,4-trifluorobutyl sulfonyl, pentyl sulfonyl and hexyl sulfonyl.

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

In the present specification, the "substituent" includes, for example, a halogen atom, a cyano group, a nitro group, a optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, and substituted. May amino group, optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, optionally substituted sulfamoyl group, optionally substituted hydroxy group, optionally substituted sulfanyl ( SH) groups and optionally substituted silyl groups can be mentioned.

In the present specification, the "hydrocarbon group" (including the "hydrocarbon group" in the "optionally substituted hydrocarbon group") includes, for example, a C1-6 alkyl group, a C2-6 alkenyl group, and a C2-. Examples thereof include a 6-alkynyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6-14 aryl group and a C7-16 aralkyl group.

In the present specification, examples of the "optionally substituted hydrocarbon group" include a hydrocarbon group which may have a substituent selected from the following substituent group A.

[Substituent group A]
(1) Halogen atom,
(2) Nitro group,
(3) Cyanide group,
(4) Oxo group,
(5) Hydroxy group,
(6) C1-6 alkoxy group, which may be halogenated,
(7) C6-14 aryloxy group (eg, phenoxy, naphthoxy),
(8) C7-16 aralkyloxy group (eg, benzyloxy),
(9) 5- to 14-membered aromatic heterocyclic oxy groups (eg, pyridyloxy),
(10) 3- to 14-membered non-aromatic heterocyclic oxy groups (eg, morpholinyloxy, piperidinyloxy),
(11) C1-6 alkyl-carbonyloxy group (eg acetoxy, propanoyloxy),
(12) C6-14 aryl-carbonyloxy group (eg, benzoyloxy, 1-naphthyloxy, 2-naphthyloxy),
(13) C1-6 alkoxy-carbonyloxy group (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),
(14) Mono- or di-C1-6 alkyl-carbamoyloxy groups (eg, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy),
(15) C6-14 aryl-carbamoyloxy group (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy),
(16) 5- to 14-membered aromatic heterocyclic carbonyloxy group (eg, nicotinoyyloxy),
(17) 3- to 14-membered non-aromatic heterocyclic carbonyloxy group (eg, morpholinylcarbonyloxy, piperidinylcarbonyloxy),
(18) C1-6 alkylsulfonyloxy groups that may be halogenated (eg, methylsulfonyloxy, trifluoromethylsulfonyloxy),
(19) C6-14 arylsulfonyloxy groups optionally substituted with C1-6 alkyl groups (eg, phenylsulfonyloxy, toluenesulfonyloxy),
(20) C1-6 alkylthio group which may be halogenated,
(21) 5- to 14-membered aromatic heterocyclic group,
(22) 3- to 14-membered non-aromatic heterocyclic group,
(23) Holmil group,
(24) Carboxy group,
(25) C1-6 alkyl-carbonyl group, which may be halogenated,
(26) C6-14 aryl-carbonyl group,
(27) 5- to 14-membered aromatic heterocyclic carbonyl group,
(28) 3- to 14-membered non-aromatic heterocyclic carbonyl group,
(29) C1-6 alkoxy-carbonyl group,
(30) C6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),
(31) C7-16 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, phenethyloxycarbonyl),
(32) Carbamoyl group,
(33) Thiocarbamoyl group,
(34) Mono- or di-C1-6 alkyl-carbamoyl group,
(35) C6-14 aryl-carbamoyl group (eg, phenylcarbamoyl),
(36) 5- to 14-membered aromatic heterocyclic carbamoyl groups (eg, pyridylcarbamoyl, thienylcarbamoyl),
(37) 3- to 14-membered non-aromatic heterocyclic carbamoyl groups (eg, morpholinyl carbamoyl, piperidinyl carbamoyl),
(38) C1-6 alkylsulfonyl group, which may be halogenated,
(39) C6-14 arylsulfonyl group,
(40) 5- to 14-membered aromatic heterocyclic sulfonyl groups (eg, pyridylsulfonyl, thienylsulfonyl),
(41) C1-6 alkylsulfinyl group, which may be halogenated,
(42) C6-14 arylsulfinyl groups (eg, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl),
(43) 5- to 14-membered aromatic heterocyclic sulfinyl groups (eg, pyridylsulfinyl, thienylsulfinyl),
(44) Amino group,
(45) Mono- or di-C1-6 alkylamino groups (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N- Methylamino),
(46) Mono- or di-C6-14 arylamino groups (eg, phenylamino),
(47) 5- to 14-membered aromatic heterocyclic amino groups (eg, pyridylamino),
(48) C7-16 aralkylamino group (eg, benzylamino),
(49) Formylamino group,
(50) C1-6 alkyl-carbonylamino group (eg, acetylamino, propanoylamino, butanoylamino),
(51) (C1-6 alkyl) (C1-6 alkyl-carbonyl) amino group (eg, N-acetyl-N-methylamino),
(52) C6-14 aryl-carbonylamino group (eg, phenylcarbonylamino, naphthylcarbonylamino),
(53) C1-6 alkoxy-carbonylamino group (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino),
(54) C7-16 aralkyloxy-carbonylamino group (eg, benzyloxycarbonylamino),
(55) C1-6 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino),
(56) C6-14 arylsulfonylamino groups optionally substituted with C1-6 alkyl groups (eg, phenylsulfonylamino, toluenesulfonylamino),
(57) C1-6 alkyl group, which may be halogenated,
(58) C2-6 alkenyl group,
(59) C2-6 alkynyl group,
(60) C3-10 cycloalkyl group,
(61) C3-10 cycloalkenyl group and (62) C6-14 aryl group.

The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5. When the number of substituents is two or more, each substituent may be the same or different.
In the present specification, the "heterocyclic group" (including the "heterocyclic group" in the "optionally substituted heterocyclic group") includes, for example, a nitrogen atom, a sulfur atom and a sulfur atom in addition to a carbon atom as ring constituent atoms. Examples thereof include (i) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups and (iii) 7 to 10-membered heterobridged ring groups each containing 1 to 4 heteroatoms selected from oxygen atoms. ..

In the present specification, examples of the "optionally substituted C6-14 aryl group" include a C6-14 aryl group which may have a substituent selected from the above-mentioned substituent group A. The number of substituents in the "optionally substituted C6-14 aryl group" is, for example, 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.

In the present specification, the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") is selected from, for example, a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. Examples thereof include 5- to 14-membered aromatic heterocyclic groups containing 1 to 4 heteroatoms.

In the present specification, examples of the “optionally substituted aromatic heterocyclic group” include an aromatic heterocyclic group which may have a substituent selected from the above-mentioned Substituent Group A. The number of substituents in the "optionally substituted aromatic heterocyclic group" is, for example, 1 to 3. When the number of substituents is two or more, each substituent may be the same or different.

In the present specification, examples of the "nitrogen-containing aromatic heterocyclic group" include "aromatic heterocyclic groups" containing at least one nitrogen atom as a ring-constituting atom.

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

In the present specification, the "acyl group" is, for example, one to be selected from a halogen atom, a C1-6 alkoxy group which may be halogenated, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group. C1-6 alkyl group, C2-6 alkenyl group, C3-10 cycloalkyl group, C3-10 cycloalkenyl group, C6-14 aryl group, C7-16 aralkyl, which may have three substituents, respectively. A formyl group, a carboxy group, a carbamoyl group, which may have one or two substituents selected from a group, a 5- to 14-membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, respectively. , Thiocarbamoyl group, sulfino group, sulfo group, sulfamoyl group, phosphono group.

Examples of the "acyl group" include a hydrocarbon-sulfonyl group, a heterocyclic-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocyclic-sulfinyl group.

Here, the hydrocarbon-sulfonyl group is a sulfonyl group to which a hydrocarbon group is bonded, the heterocyclic-sulfonyl group is a sulfonyl group to which a heterocyclic group is bonded, and the hydrocarbon-sulfinyl group is a hydrocarbon group. Means a sulfinyl group bonded with, and a heterocyclic-sulfinyl group means a sulfinyl group to which a heterocyclic group is bonded.

In the present specification, the "optionally substituted amino group" includes, for example, "C1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group A, respectively." C2-6 alkenyl group, C3-10 cycloalkyl group, C6-14 aryl group, C7-16 aralkyl group, C1-6 alkyl-carbonyl group, C6-14 aryl-carbonyl group, C7-16 aralkyl-carbonyl group, 5 Or 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C1- It may have one or two substituents selected from a 6-alkyl-carbamoyl group, a mono- or di-C7-16 aralkyl-carbamoyl group, a C1-6 alkylsulfonyl group and a C6-14arylsulfonyl group. Amino groups can be mentioned.

In the present specification, the "optionally substituted carbamoyl group" includes, for example, "C1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group A, respectively." C2-6 alkenyl group, C3-10 cycloalkyl group, C6-14 aryl group, C7-16 aralkyl group, C1-6 alkyl-carbonyl group, C6-14 aryl-carbonyl group, C7-16 aralkyl-carbonyl group, 5 Or 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C1- Included are carbamoyl groups that may have "one or two substituents selected from 6 alkyl-carbamoyl groups and mono- or di-C7-16 aralkyl-carbamoyl groups".

In the present specification, the "optionally substituted thiocarbamoyl group" includes, for example, a C1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group A, respectively. , C2-6 alkenyl group, C3-10 cycloalkyl group, C6-14 aryl group, C7-16 aralkyl group, C1-6 alkyl-carbonyl group, C6-14 aryl-carbonyl group, C7-16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C1 Included are thiocarbamoyl groups which may have "one or two substituents selected from a -6 alkyl-carbamoyl group and a mono- or di-C7-16 aralkyl-carbamoyl group".

In the present specification, the "optionally substituted sulfamoyl group" includes, for example, "C1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group A, respectively." C2-6 alkenyl group, C3-10 cycloalkyl group, C6-14 aryl group, C7-16 aralkyl group, C1-6 alkyl-carbonyl group, C6-14 aryl-carbonyl group, C7-16 aralkyl-carbonyl group, 5 Or 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C1- 6 Sulfamoyl groups may have "one or two substituents selected from alkyl-carbamoyl groups and mono- or di-C7-16 aralkyl-carbamoyl groups".

In the present specification, the "optionally substituted hydroxy group" includes, for example, "C1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group A, respectively." C2-6 alkenyl group, C3-10 cycloalkyl group, C6-14 aryl group, C7-16 aralkyl group, C1-6 alkyl-carbonyl group, C6-14 aryl-carbonyl group, C7-16 aralkyl-carbonyl group, 5 Or 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C1- Examples thereof include hydroxy groups which may have "substituents selected from 6 alkyl-carbamoyl groups, mono- or di-C7-16 aralkyl-carbamoyl groups, C1-6 alkylsulfonyl groups and C6-14 arylsulfonyl groups". ..

In the present specification, the "optionally substituted sulfanyl group" includes, for example, "C1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group A, respectively." C2-6 alkenyl group, C3-10 cycloalkyl group, C6-14 aryl group, C7-16 aralkyl group, C1-6 alkyl-carbonyl group, C6-14 aryl-carbonyl group and 5-14 member aromatic heterocyclic group Examples thereof include a sulfanyl group which may have a "substituted group selected from" and a halogenated sulfanyl group.

In the present specification, the "optionally substituted silyl group" includes, for example, "C1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group A, respectively." Examples thereof include a silyl group which may have "1 to 3 substituents selected from a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group and a C7-16 aralkyl group".

In the present specification, the "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") is, for example, a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom. Examples thereof include non-aromatic heterocyclic groups containing 1 to 4 heteroatoms selected from the above.
Specific examples include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrazolydinyl, morpholinyl, oxylanyl, oxetanyl, oxolanyl, oxanyl, dioxanyl, oxepanyl, thiolanyl, oxathianyl, triazaspironyl, eg 7-Triazaspiro [4.4] nonyl), thiadiazaspironyl (eg, 7-thia-1,3-diazaspiro [4.4] nonyl), dioxide thiazaspironyl (eg, 7,7-). Dioxide-7-thia-1,3-diazaspiro [4.4] nonyl) and the like.

As used herein, the term "linker" refers to a chemical moiety (structure) used to bind a portion of a compound of interest to another compound. An exemplary linker is described herein. For example, in any of the compounds described herein, the chemical structure used to bind one part of the structure to the other part of the structure can be used as a linker, as referred to herein. Corresponds to. The linker preferably used in the present invention is not limited to this, but ^{is a structure represented by "L X} " (x is an arbitrary numerical value) in the present specification, and one or more atomic groups in the structure. Can be mentioned as a combined structure.

In the present specification, the "C1-6 alkylene group" includes, for example, a methylene group, a 1,2-ethylene group, a 1,1-ethylene group, a 1,2-propylene group, a 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 -Hexalene group is mentioned.

In the present specification, the "C3-10 cycloalkylene group" includes, for example, 1,1-cyclopropylene group, cis-1,2-tycropropylene 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-cyclopenti Lene 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-cycloheptinylene group, 1,1-cyclooctynylene group, 2,2-dimethyl1,1-cyclopropylene group, 2,3 -Dimethyl 1,1-cyclopropylene group, 2,2,3,3,4,5-tetramethyl 1,1-cyclobutylene group, 7,7-norcaranilene group, 7,7-norpinanilene group, 7,7- Examples include the norbornanilen group.

In the present specification, the "C3-10 cycloalkenylene group" includes, for example, 1,2-cyclopropenylene group, 1,2-cyclobutenylene group, 1,2-cyclopentenylene group, 1,2-cyclohexeni. Examples include a len group and a 2-bornen-2,3-yl group.

As used herein, the term "binding hand" refers to a state in which two adjacent substituents are bonded in a single bond via a binding hand. When a plurality of "bonding hands" are connected, all of them are combined to indicate a single bond.

As used herein, the term "compound that adds function" refers to a binder of any protein present in the body, a cell penetrating peptide (CPP), or a kinetophore (eg, a short chain peptide) that retains the compound in the intestinal tract. It means (such as polyethylene oxide capped with sugar and quaternary ammonium).

As used herein, "IRAK-M protein-related disease" is a disease or disease for which the disease is described or speculated in the context of an abnormality in the IRAK-M protein. Protein abnormalities are not limited to this, and examples thereof include abnormal expression and enhancement of proteins in vivo and the presence of mutant proteins. The pathogenic protein-related diseases include, but are not limited to, cancer, inflammatory diseases, autoimmune diseases, bone / joint degenerative diseases, central diseases, heart diseases, metabolic diseases, and infectious diseases.

The compound of the present invention contained in the compound (I) can be used as a synthetic intermediate in producing the other compound (I) of the present invention. It can also be used as a synthetic intermediate in the production of IRAK-M proteolysis inducers other than compound (I).

When the 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, basic or acidic amino acids. Examples include salt. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferable examples of salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N'-dibenzyl. Examples include salts with ethylenediamine and the like. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene. Examples thereof include salts with succinic acid, p-toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Can be mentioned.

Of these, pharmaceutically acceptable salts are preferable. For example, when the compound has an acidic functional group, it is an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, etc.), or an ammonium salt. Etc., and when the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitrate, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, shu Examples thereof include salts with organic acids such as acids, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.

The method for producing the compound of the present invention will be described below. The raw materials and reagents used in each step in the following production methods, and the obtained compounds may each form salts. Examples of such a salt include those similar to the above-mentioned salt of the compound of the present invention.

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

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

When a compound of a raw material or a reagent for each step is commercially available, the commercially available product can be used as it is.

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

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

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

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

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

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

When a base is used in the reaction of each step, for example, the base shown below or the base described in Examples is used.
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 .;
Organolithium: n-butyllithium, etc.

When an acid or an acidic catalyst is used in the reaction of each step, for example, the acid or acidic catalyst shown below, or the acid or acidic catalyst described in 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.

Unless otherwise specified, the reaction of each step is a method known per se, for example, 5th Edition Experimental Chemistry Course, Volumes 13-19 (Chemical Society of Japan); New Experimental Chemistry Course, Volumes 14-15 (Japan). Chemical Society of Japan); Precision Organic Chemistry Revised 2nd Edition (LF Tietze, Th. Eicher, Nanedo); Revised Organic Name Reaction Mechanism and Points (Hideo Togo, Kodansha); John Willey & Sons Inc.); Modeln Organic Chemistry in the Laboratory A Collection of Standard Experiments Expert Chemistry (Jie Jack Li), Published by Jie Jack Li X 1-Vol. 14 (Elzevia Japan Co., Ltd.); Organic Synthesis Strategy Learned from Name Reactions (Translated by Kiyoshi Tomioka, published by Kagaku-Dojin); Method described in Comprehensive Organic Transformations (VCH Publicers Inc.), 1989, etc. Alternatively, it is carried out according to the method described in the examples.

In each step, the protecting or deprotecting reaction of the functional group is carried out by a method known per se, for example, Wiley-Interscience, 2007, "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter G. Written); The method is carried out according to the method described in "Protecting Groups 3rd Ed." (Written by PJ Kocienski), 2004, published by Thiemé, or the method described in Examples.
Examples of the protecting group for hydroxyl groups such as alcohols and phenolic hydroxyl groups include ether-type protecting groups such as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether, and tetrahydropyranyl ether; and carboxylic acid ester-type protecting groups such as acetate. Sulfonic acid ester-type protecting groups such as methane sulfonic acid ester; carbonate ester-type protecting groups such as t-butyl carbonate and the like.
Examples of the protecting group for the carbonyl group of the aldehyde include an acetal-type protecting group such as dimethyl acetal; and a cyclic acetal-type protecting group such as cyclic 1,3-dioxane.
Examples of the protecting group for the carbonyl group of the ketone include a ketal-type protecting group such as dimethyl ketal; a cyclic ketal-type protecting group such as cyclic 1,3-dioxane; an oxime-type protecting group such as O-methyloxime; N, N- Examples include hydrazone-type protecting groups such as dimethylhydrazone.
Examples of the carboxy-protecting group include ester-type protecting groups such as methyl ester; and amide-type protecting groups such as N and N-dimethylamide.
Examples of the thiol protecting group include ether-type protecting groups such as benzylthioether; ester-type protecting groups such as thioacetic acid ester, thiocarbonate, and thiocarbamate.
Examples of the amino group and the protecting group for the aromatic heterocycle such as imidazole, pyrrole, and indol include a carbamate-type protecting group such as benzyl carbamate; an amide-type protecting group such as acetamide; and an alkylamine such as N-triphenylmethylamine. Examples thereof include type protecting groups and sulfonamide-type protecting groups such as methanesulfonamide.
Protecting groups can be removed by methods known per se, such as acids, bases, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide). It can be carried out by using a method using (do, trimethylsilyl bromide) or a reduction method.

When the reduction reaction is carried out in each step, the reducing agents used include lithium aluminum borohydride, sodium triacetoxyboran borohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), and sodium borohydride. , Metal hydrides such as triacetoxyborohydride tetramethylammonium hydride; boranes such as borane tetrahydrofuran complex; lane nickel; lane cobalt; hydrogen; formic acid; triethylsilane and the like. When reducing a carbon-carbon double bond or triple bond, there is a method using a catalyst such as a palladium-carbon or Lindlar catalyst.

When the oxidation reaction is carried out in each step, the oxidizing agents used include peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide and t-butylhydroperoxide; and tetrabutylammonium perchlorate. Perchlorates; Chlorates such as sodium chlorate; Subchlorates such as sodium chlorate; Perioic acids such as sodium periodate; High valence iodine reagents such as iodosylbenzene; Manganese dioxide, excess Manganese-containing reagents such as potassium manganate; Leads such as lead tetraacetate; Chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagents; N-bromosuccinimide (NBS) Halogen compounds such as; oxygen; ozone; sulfur trioxide / pyridine complex; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

When the radical cyclization reaction is carried out in each step, the radical initiator used is an azo compound such as azobisisobutyronitrile (AIBN); 4-4'-azobis-4-cyanopentanoic acid (ACPA). Water-soluble radical initiators such as; triethylboron in the presence of air or oxygen; benzoyl peroxide and the like. Examples of the radical reaction reagent used include tributylstanane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, and samarium iodide.

When the Wittig reaction is carried out in each step, examples of the Wittig reagent used include alkylidene phosphorans and the like. Alkylidene phosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

When the Horner-Emmons reaction is carried out in each step, the reagents used are phosphonoacetic acid esters such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; bases such as alkali metal hydrides and organolithiums. Can be mentioned.

When the Friedel-Crafts reaction is carried out in each step, the reagents used are a combination of Lewis acid and acid chloride, or a combination of Lewis acid and an alkylating agent (eg, alkyl halides, alcohols, olefins, etc.). Can be mentioned. Alternatively, an organic acid or an inorganic acid can be used instead of Lewis acid, and an acid anhydride such as acetic anhydride can be used instead of acid chloride.

When performing an aromatic nucleophilic substitution reaction in each step, a nucleophile (eg, amines, imidazole, etc.) and a base (eg, basic salts, organic bases, etc.) are used as reagents.

In each step, when a nucleophilic addition reaction with a carbanion, a nucleophilic 1,4-addition reaction with a carbanion (Michael addition reaction), or a nucleophilic substitution reaction with a carbanion is performed, the base used to generate the carbanion. Examples thereof include organolithiums, metal alkoxides, inorganic bases, and organic bases.

When the Grignard reaction is carried out in each step, examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide; and alkylmagnesium halides such as methylmagnesium bromide. Grignard reagents 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.

When the Knoevenagel condensation reaction is carried out in each step, the reagents include active methylene compounds (eg, malonic acid, diethyl malonate, malononitrile, etc.) and bases (eg, organic bases, etc.) sandwiched between two electron attracting groups. Metal alkoxides, inorganic bases) are used.

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

When the azide reaction of alcohols, alkyl halides and sulfonic acid esters is carried out in each step, examples of the azidizing agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide and sodium azide. For example, when azide alcohols, there are a method using diphenylphosphoryl azide and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), a method using trimethylsilyl azide and Lewis acid, and the like.

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

When the Mitsunobu reaction is carried out in each step, the reagents include azodicarboxylic acid esters (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), ditert-butyl azodicarboxylate, etc.) and triphenyl. Hosphin is used.

When an esterification reaction, an amidation reaction, or a urea conversion reaction is carried out in each step, the reagents used are acid halides, acid halides and other halide acylates; acid anhydrides, active esters, and sulfate esters. Examples thereof include activated carboxylic acids. Carboxylic acid activators include carbodiimide-based condensing agents such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD); 4- (4,6-dimethoxy-1,3,5- Triazine-2-yl) -4-methylmorpholinium chloride-n-hydrate (DMT-MM) and other triazine-based condensing agents; 1,1-carbonyldiimidazole (CDI) and other carbonate-based condensing agents; diphenyl Phosphic acid azide (DPPA); benzotriazole-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukoyama reagent); thionyl chloride; Lower alkyl; O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; 2,4,6-tripropyl -1,3,5,2,4,6-trioxatriphosphorinan-2,4,6-trioxide (T3P); or a combination thereof can be 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.

When the coupling reaction is carried out in each step, the metal catalysts used are palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), and dichlorobis (triethyl). Palladium compounds such as phosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), 1,1'-bis (diphenylphosphino) ferrocene palladium (II), palladium (II) acetate; tetrakis (tri) Nickel compounds such as phenylphosphine) nickel (0); rhodium compounds such as tris (triphenylphosphine) rhodium (III); cobalt compounds; copper compounds such as copper oxide and copper (I) iodide; platinum compounds and the like. Be done. Further, a base may be added to the reaction, and examples of such a base include inorganic bases and basic salts.

When the thiocarbonylation reaction is carried out in each step, diphosphorus pentasulfide is typically used as the thiocarbonylating agent, but in addition to diphosphorus pentasulfide, 2,4-bis (4-methoxyphenyl) ) -1,3,2,4-dithiadiphosphethane-2,4-disulfide (Lawesson's reagent) and other reagents having a 1,3,2,4-dithiadiphosphethane-2,4-disulfide structure May be used.

When the Wohl-Ziegler reaction is carried out in each step, the halogenating agents used include N-iodosuccinate imide, N-bromosuccinimide (NBS), N-chlorosuccinate imide (NCS), bromine, sulfyl chloride and the like. Can be mentioned. Furthermore, the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction.

When the hydroxy group halogenation reaction is carried out in each step, the halogenating agent used is an acid halide of a hydrohalic acid and an inorganic acid, specifically, hydrochloric acid, thionyl chloride, and oxy for chlorination. For bromination such as phosphorus chloride, 48% hydrobromic acid and the like can be mentioned. Further, a method of obtaining an alkyl halide from an alcohol by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide may be used. Alternatively, a method may be used in which an alkyl halide is synthesized through a two-step reaction such as converting an alcohol into a sulfonic acid ester and then reacting it with lithium bromide, lithium chloride or sodium iodide.

When the Arbuzov reaction is carried out in each step, the reagents used include alkyl halides such as ethyl bromoacetate; phosphites such as triethyl phosphite and tri (isopropyl) phosphite.

When the sulfonic acid esterification reaction is carried out in each step, examples of the sulfonylating agent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic acid anhydride, and p-toluenesulfonic acid anhydride.

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

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

In each step, when an alkylation reaction such as alcohols or amines or an aromatic heterocycle having an NH group in the ring (eg, imidazole, pyrazole) is carried out, the alkylating agent may be a halogen which may be substituted. Alkylated alkyl (eg iodomethane) or optionally substituted C1-6 alkylsulfonyloxy group optionally substituted alkyl or optionally substituted with C1-6 alkyl group C6- Examples include substituted alkyl having a 14arylsulfonyloxy group, sodium 2-chloro-2,2-difluoroacetate, 2,2-difluoro-2- (fluorosulfonyl) acetic acid and the like. Examples of the base used include organic lithiums, metal alkoxides, inorganic bases, and organic bases.

When the fluorination reaction is carried out in each step, the fluorinating agent used is DAST (diethylaminosulfatrifluoride), bis (2-methoxyethyl) aminosulfatrifluoride, 1-chloromethyl-4-fluoro-1. , 4-Diazonia bicyclo [2.2.2] octanebis (tetrafluoroborate) (Selectfluor), 4-tert-butyl-2,6-dimethylphenyl sulfatrifluoride (FLUOLEAD) and the like.

When the Huisgen reaction is carried out in each step, an azide compound and an alkyne compound are used as the reagents used. Examples of the catalyst include monovalent copper ions, for example, copper iodide, copper chloride, copper cyanide and the like.

When the coupling reaction is carried out in each step, Suzuki coupling, Stille coupling, Buchwald-Hartwig coupling, Negishi coupling, Mizorogi-Heck reaction, copper cyanated or zinc cyanide were used as the coupling reaction. Cyanation reaction and the like can be mentioned. Reagents such as metal catalysts, phosphine ligands, and bases used in the coupling reaction can be added to the reagents described above by 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 thereto.

The method for producing compound (I) will be described below.
Unless otherwise specified, each symbol in the following reaction formula has the same meaning as described above. Unless a specific production method is described, the starting compound can be easily obtained on the market, or can be produced by a method known per se or a method similar thereto and a method described in Examples.

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

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

Scheme 1

The compound (3) is obtained by subjecting the compound (1) or a reactive derivative thereof and the linker compound (2) or a reactive derivative thereof to an amidation reaction, a Mitsunobu reaction, an alkylation reaction, a coupling reaction or the like. Compound (I) can be produced by combining compound (3) or a reactive derivative thereof with compound (4) or a reactive derivative thereof by amidation reaction, Mitsunobu reaction, alkylation reaction or coupling reaction, etc. It can be manufactured by attaching to.

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

Compound (3a) is produced by subjecting compound (1) or a reactive derivative thereof and compound (2a) or a reactive derivative thereof to an amidation reaction, a Mitsunobu reaction, an alkylation reaction, a coupling reaction or the like. The compound (5a) can be obtained 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, a coupling reaction or the like. Compound (I) can be produced by subjecting compound (3a) and compound (5a) or a reactive derivative thereof to an amidation reaction, a Mitsunobu reaction, an alkylation reaction, a coupling reaction, a Huisgen reaction, or the like. By attaching it, it can be manufactured.

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

Scheme 2

In Scheme 2, X ₁ represents a halogen atom or 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)), which is a linker constituting a part of compound (I), L ₁ (Compound (2a)), L ₂ (Compound (2b)), which is a part of the linker, are commercially available products as they are. It can be used or produced by a method known per se or a method similar thereto.

The production method when E (Compound (4)), which is an XIAP binder constituting a part of Compound (I), is a compound represented by the following formula (IV-I) will be described below.

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

Scheme 3

Compound ('11) can be produced by subjecting compound (9) and compound (10) or a reactive derivative thereof to an amidation reaction or the like, and compound (13) and compound (12) or a reactivity thereof. It can be produced by subjecting the derivative to an amidation reaction or the like.
Compound (IV) can be produced by subjecting compound (13) and compound (14) or a reactive derivative thereof to an amidation reaction or the like.
Further, compound (15) can be produced by subjecting compound (9) and compound (14) or a reactive derivative thereof to an amidation reaction or the like, and compound (16) is compound (15) and compound. It can be produced by subjecting (10) or a reactive derivative thereof to an amidation reaction or the like. Compound (IV) can be produced by subjecting compound (16) and compound (12) or a reactive derivative thereof to an amidation reaction or the like.

The compound (I) thus obtained and the substituents in each intermediate are converted (that is, introduction of a substituent, conversion of a functional group, or introduction of a linker and a ligand of a protein) by means known per se. Also, another compound contained in compound (I) and the corresponding intermediates or salts thereof can be produced. Common known methods are used as methods for introducing substituents, functional group conversions, or linkers and protein ligands, such as halogen atoms (eg, fluorine, chlorine, bromine, iodine) or halogenated. May be C1-6 alkylsulfonyl-oxy group [eg, methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy (trifurate)] methyl group, cyclopropyl group, vinyl group, cyano group, formyl Conversion of group, carbonyl group, carboxyl group, hydroxyl group, amino group, boryl group, etc.; conversion of formyl group to ethynyl group by Safer's Gilbert carbon increase reaction; conversion to carboxy group by hydrolysis of ester; carboxy group Conversion to carbamoyl group by amidation; conversion to hydroxymethyl group by reduction of carboxy group; conversion to alcohol form by reduction of carbonyl group or alkylation; reductive amination of carbonyl group; oximation of carbonyl group; Amino group acylation; Amino group ureatization; Amino group sulfonylation; Amino group alkylation; Active halogen substitution or amination with amine; Hydroxy group alkylation; Hydroxy group substitution or amination; Heterocycle Alkylation of nitrogen; acylation of heterocyclic nitrogen atom; sulfonylation of heterocyclic nitrogen atom; etc.

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

When compound (I) contains optical isomers, steric isomers, positional isomers, and rotational isomers, these are also contained as compound (I), and they are also contained as compound (I) by a synthesis method and a separation method known per se. Can be obtained as a single item. For example, when the optical isomer is present in the compound (I), the optical isomer separated 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 crystalline.
The crystal of compound (I) (hereinafter, may be abbreviated as the crystal of the present invention) can be produced by applying a crystallization method known per se to compound (I) to crystallize it.
Compound (I) may be a pharmaceutically acceptable co-crystal or co-crystal salt. Here, a co-crystal or a co-crystal salt is unique to two or more at room temperature, each having different physical properties (eg, structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a solid. The co-crystal or co-crystal salt can be produced according to a co-crystallization method known per se.
Compound (I) may be a hydrate, a non-hydrate, a solvate, or a solvate.
Further, a deuterium converter obtained by converting 1H to 2H (D) is also included in compound (I).
Compound (I) may be labeled with an isotope (eg, 3H, 13C, 14C, 18F, 35S, 125I) or the like. The isotope-labeled or substituted compound (I) can be used as a tracer (PET tracer) used in, for example, positron emission tomography (PET), and is useful in fields such as medical diagnosis. There is expected.

Compound (I) may be used as a prodrug.
The 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 vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, or the like. It is a compound that changes to compound (I) by causing hydrolysis or the like due to gastric acid or the like.

As a prodrug of compound (I),
Compounds in which the amino group of compound (I) is acylated, alkylated or phosphorylated (eg, the amino group of compound (I) is ecosanoyylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-). 1,3-Dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated compounds);
Compounds in which the hydroxy group of compound (I) is acylated, alkylated, phosphorylated or booxide (eg, the hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated , Alanylated or dimethylaminomethylcarbonylated compounds); compounds in which the carboxy group of compound (I) is esterified or amidated (eg, the carboxy group of compound (I) is ethyl esterified, phenyl esterified, carboxy) Methyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl Examples thereof include esterified, cyclohexyloxycarbonylethyl esterified or methylamided compounds). These compounds can be produced from compound (I) by a method known per se.

In addition, the prodrug of compound (I) changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, "Drug Development," Vol. 7, Molecular Design, pp. 163 to 198. It may be.
In the present specification, the prodrug may form a salt, and examples of such salt include those exemplified as salts of the compounds represented by the above formulas (I) and compound (II).

Compound (I) is a compound that adds function, such as a cell penetrating peptide (CPP) or a kinetophore (eg, short chain peptide, sugar and quaternary ammonium capped poly) that retains the compound in the intestinal tract. It may be used in combination with (ethylene oxide, etc.) or the like, and the compound (I) may be bonded to the compound to which the function is added, either directly or via a linker.

Compound (I) can also be used as a payload in an antibody (or peptide antigen recognition sequence) -drug complex (above, the portion corresponding to the drug). When compound (I) is used as a payload, compound (I) can bind to an antibody (or peptide antigen recognition sequence) directly or via a linker.
When compound (I) is used as the payload, in addition to the linkers exemplified herein, Chem. Rev., 114, 9154-9218 (2014), Pharma. Res. 32, 3526-3540 (2015), Bioconjugate Chem Linkers such as those described in .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 (these may be collectively abbreviated as "the compound of the present invention" in the present specification) has a degradation-inducing activity of IRAK-M and is a prophylactic or therapeutic agent for cancer. , Can be useful as a cancer growth inhibitor, a cancer metastasis inhibitor.
The compound of the present invention exhibits proteolysis-inducing activity against IRAK-M, and the compound of the present invention has efficacy expression, pharmacokinetics (eg, absorbability, distribution, metabolism, excretion), solubility (eg, water-soluble), Interaction with other drugs (eg, drug-metabolizing enzyme inhibitory action), safety (eg, acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, central toxicity), stability (eg, central toxicity) Since it is also excellent in chemical stability and enzyme stability, it can be useful as a medicine. Among them, it is expected to be effective for the treatment or prevention of cancer, but the present invention is not limited thereto.
The compounds of the present invention also have the activity of inducing degradation of the IRAK-M protein in mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans). In the light of the mechanism of action, any disease involving the IRAK-M protein (sometimes abbreviated as "IRAK-M-related disease" herein), eg, cancer [eg, colon cancer (eg, colon) Cancer, rectal cancer, anal cancer, familial colon cancer, hereditary nonpolyposis colon cancer, gastrointestinal stromal tumor), lung cancer (eg, non-small cell lung cancer, small cell lung cancer, malignant mesoderma), mesopharyngoma, Pancreatic cancer (eg, pancreatic duct cancer, pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, glandular squamous epithelial cancer), duodenal cancer, small bowel cancer, breast cancer (eg, eg) Invasive mammary duct cancer, non-invasive mammary duct cancer, inflammatory breast cancer), ovarian cancer (eg, epithelial ovarian cancer, extragonal embryonic cell tumor, ovarian embryonic cell tumor, low-grade ovarian tumor), testicular tumor, Prostate cancer (eg, hormone-dependent prostate cancer, hormone-independent prostate cancer, castration-resistant prostate cancer), liver cancer (eg, hepatocellular carcinoma, primary liver cancer, extrahepatic bile duct cancer), thyroid cancer (eg, extrahepatic bile duct cancer) Thyroid medullary cancer), kidney cancer (eg, renal cell carcinoma (eg, clear cell type renal cell carcinoma), renal pelvis and urinary tract transition epithelial cancer), uterine cancer (eg, cervical cancer, uterine body cancer, Uterosarcoma), gestational chorionic villus cancer, brain tumors (eg, medullary cell tumor, glioma, pineapple stellate tumor, hairy cell stellate tumor, diffuse stellate tumor, degenerative stellate tumor, Hydrite adenoma), retinoblastoma, skin cancer (eg, basal cell tumor, malignant melanoma), sarcoma (eg, horizontal print myoma, smooth myoma, soft sarcoma, spindle cell sarcoma), malignant bone tumor, bladder Cancer, blood cancer (eg, multiple myeloma, leukemia (eg, acute myeloid leukemia, chronic lymphocytic leukemia), malignant lymphoma (B-cell lymphoma, diffuse large B-cell lymphoma, MALT lymphoma, follicle) Sexual lymphoma, mantle cell lymphoma), Hodgkin's disease, chronic myeloproliferative disease), cancer of unknown primary] prophylactic or therapeutic agent, cancer growth inhibitor, cancer metastasis inhibitor, apoptosis promoter, precancer It can be used as a medicine for treating lesions (eg, myeloid atypia syndrome).

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.), and diabetes. , Systemic inflammatory response syndrome. Group (SIRS), sepsis, infectious complications of hematopoietic stem cell transplantation, influenza infection, acute bacterial meningitis, helicobacter pylori infection, invasive staphylococcal infection, tuberculosis, systemic Examples include sexual fungal infection, simple herpesvirus infection, varicella-zoster virus infection, human papillomavirus infection, acute viral encephalitis, encephalitis, meningitis, and decreased immune function associated with the infection.

The compound of the present invention can be administered orally or parenterally to a mammal (preferably human) as a pharmaceutical, either as it is or by blending a pharmacologically acceptable carrier.
Hereinafter, a drug containing the compound of the present invention (may be abbreviated as “the drug of the present invention”) will be described in detail. Dosage forms of the medicament of the present invention include, for example, tablets (eg, sugar-coated tablets, film-coated tablets, sublingual tablets, buccal tablets, orally fast-disintegrating tablets), pills, granules, powders, capsules (eg, soft capsules). Agents, microcapsules), syrups, emulsions, suspensions, film agents (eg, sublingual films, oral mucosal patches) and other oral agents. The dosage forms of the medicament of the present invention include, for example, injections, infusions, transdermal agents (eg, iontophoresis transdermal agents), suppositories, ointments, nasal agents, pulmonary agents, and eye drops. And parenteral preparations such as. In addition, the medicament of the present invention may be a release-controlled preparation such as an immediate-release preparation, a sustained-release preparation (eg, sustained-release microcapsules).
As the dosage form of the medicament of the present invention, a nanoparticle preparation or a preparation using a bacterial-derived membrane can also be used.

The medicament of the present invention can be produced by a known production method generally used in the field of formulation technology (eg, the method described in the Japanese Pharmacopoeia). In addition, the medicament of the present invention includes excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifiers, and colorants commonly used in the field of formulation, if necessary. , Preservatives, fragrances, flavoring agents, stabilizers, thickeners and other additives can be appropriately contained.
Examples of the pharmacologically acceptable carrier described above include these additives.

For example, tablets can be made with excipients, binders, disintegrants, lubricants and the like, and pills and granules can be made with excipients, binders, disintegrants and the like. Further, powders and capsules can be produced using excipients and the like, syrups can be produced using sweeteners and the like, and emulsions or suspending agents can be produced using suspending agents, surfactants, emulsifiers and the like.

Examples of excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, citrus powder, mannitol, sodium hydrogen carbonate, calcium phosphate and calcium sulfate.
Examples of the binder include 5 to 10% by weight starch paste solution, 10 to 20% by weight Arabic rubber solution or gelatin solution, 1 to 5% by weight tragant solution, carboxymethyl cellulose solution, sodium alginate solution, and glycerin.
Examples of disintegrants include starch and calcium carbonate.
Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, and purified talc.
Examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, and simple syrup.
Examples of surfactants include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyoxyl 40 stearate.
Examples of suspending agents include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose and bentonite. Examples of emulsifiers include gum arabic, tragant, gelatin and polysorbate 80.

For example, when the medicament of the present invention is a tablet, the tablet can be added to the compound of the present invention according to a method known per se, for example, an excipient (eg, lactose, sucrose, starch), a disintegrant (eg, starch, carbonate). Calcium), binders (eg starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose) or lubricants (eg talc, magnesium stearate, polyethylene glycol 6000) are added and compression molded, then required It can be produced by coating by a method known per se for the purpose of taste masking, enteric or persistent. Examples of the coating agent used for coating include hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, and hydroxymethyl cellulose acetate succinate. Eudragit (Roam, Germany, methacrylic acid / acrylic acid copolymer) and dyes (eg, Bengala, titanium dioxide) can be used.

In addition to intravenous injections, the injections include subcutaneous injections, intradermal injections, intramuscular injections, intraperitoneal injections, drip injections and the like.

Such injections are prepared by a method known per se, that is, by dissolving, suspending or emulsifying the compound of the invention in a sterile aqueous or oily solution. Examples of the aqueous solution include physiological saline, isotonic solutions containing glucose and other auxiliary agents (eg, D-sorbitol, D-mannitol, sodium chloride) and the like. The aqueous solution contains suitable solubilizers such as alcohols (eg ethanol), polyalcohols (eg propylene glycol, polyethylene glycol), nonionic surfactants (eg polysorbate 80, HCO-50). You may. Examples of the oily liquid include sesame oil and soybean oil. The oily liquid may contain a suitable dissolution aid. Examples of the solubilizing agent include benzyl benzoate and benzyl alcohol. In addition, the injection includes a buffer (eg, phosphate buffer, sodium acetate buffer), a soothing agent (eg, benzylconium chloride, procaine hydrochloride), and a stabilizer (eg, human serum albumin, polyethylene glycol). , Preservatives (eg, benzyl alcohol, phenol) and the like may be blended. The prepared injection solution can usually be 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, based on the entire preparation. More preferably, it is 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 about 1 to about 99.9% by weight, preferably about 10 to about 90% by weight, based on the whole preparation. is there.

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

When the compound of the present invention is administered parenterally, it is usually administered in the form of a liquid preparation (eg, injection). The single dose of the compound of the present invention varies depending on the administration subject, target organ, symptom, administration method, etc., but for example, it is usually about 0.01 to about 100 mg, preferably about 0.01 to about 50 mg per 1 kg of body weight. More preferably, about 0.01 to about 20 mg of the compound of the present invention is administered by intravenous 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 drug that inhibits the action of a cell growth factor and its receptor. Hereinafter, a drug that can be used in combination with the compound of the present invention is abbreviated as a concomitant drug.

Examples of the "hormone therapeutic agent" include phosfestol, diethylstilbestrol, chlorotrianisen, medroxyprogesterone acetate, megestrol acetate, chlormaginone acetate, ciproterone acetate, dannazole, allylestradiol, guestlinone, mepartricin, etc. Laroxyphene, olmeroxyphene, revolmeroxyphene, anti-estrogen drugs (eg, tamoxyphene citrate, tremiphen citrate), pills, mepitiostane, testrolactone, aminoglutetiimide, LH-RH agonists (eg, gosereline acetate, Buserelin, leuprorelin acetate), droroxyphene, epithiostanol, ethinylestradiol sulfonate, aromatase inhibitors (eg, fadrosole hydrochloride, anastrozole, letrozole, exemestane, borozole, formestan), antiandrogens (eg) , Flutamide, bicalutamide, niltamide, enzalutamide), 5α-reductase inhibitors (eg, finasteride, epristeride, dutasteride), corticosteroids (eg, dexamethasone, prednisolone, betamethasone, triamsinolone), androgen synthesis inhibitors (eg, avirateron) ), Retinoids and agents that slow the metabolism of retinoids (eg, letrozole), thyroid hormones, and their DDS (Drug Delivery System) preparations can be used.

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

Examples of the "alkylating agent" include nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl, cyclophosfamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, and melphalan. Farang, dacarbazine, lanimustin, sodium estramustine phosphate, triethylenemelamine, carmustine, romustin, streptozocin, pipobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride Prednimustin, pumitepa, ribomstin, temozolomide, treosfamide, trophosfamide, diostatin stimalamer, adzelesin, cisplatin, bizelesin and their DDS formulations can be used.

Examples of the "antimetabolite" include mercaptopurine, 6-mercaptopurine riboside, thioinosin, methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine octofusphate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, etc.) UFT, doxiflulysine, carmofur, gallositabin, emitefur, capecitabine), aminopterin, nerzarabin, leucovorin calcium, tabloid, butosine, forinate calcium, levofolinate calcium, cladribine, emitefur, fludarabin, gemcitabine, hydroxycarbamide, Idoxyuridine, mitoguazone, cytarabine, ambamustin, bendamstin and their DDS preparations can be used.

Examples of the "anticancer antibiotic" include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, acralubicin hydrochloride, pyrarubicin hydrochloride, and epirubicin hydrochloride. , Neocartinostatin, misramycin, zarkomycin, cartinophylline, mittan, sorbicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and their DDS preparations (eg, doxorubicin-encapsulating PEG liposomes) can be used.

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

Examples of the "immunotherapeutic agent" include pisibanil, crestin, cisophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulator, granulocyte colony stimulator, erythropoietin, phosphotoxin, BCG vaccine, corynebacterium parbum. , Revamizol, Polysaccharide K, Procodazole, Anti-CTLA4 antibody (eg, ipilimumab, tremelimumab), Anti-PD-1 antibody (eg, nivolumab, pembrolizumab), Anti-PD-L1 antibody (eg, atezolizumab, avelumab, durvalumab) obtain.

The "cell growth factor" in "a drug that inhibits the action of a cell growth factor and its receptor" may be any substance that promotes cell growth, and usually has a molecular weight of 20,000 or less. Examples of peptides that exert their effects at low concentrations by binding to receptors include, specifically, (1) EGF (epidermal growth factor) or a substance having substantially the same activity as that [eg, eg. TGFα], (2) Insulin or a substance having substantially the same activity as it [eg, insulin, IGF (insulin-like growth factor) -1, IGF-2], (3) FGF (fibroblast growth factor) or a substance thereof. Substances having substantially the same activity [eg, acidic FGF, basic FGF, KGF (keratinopathy factor), FGF-10], (4) other cell growth factors [eg, CSF (colory stimulating factor), EPO (Erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-developed growth factor), TGFβ (transforming growth factor), HGF (transforming growth factorβ), HGF , Helegrine, Angiopoetin] can be used.

The "receptor of the cell growth factor" may be any receptor having the ability to bind to the above-mentioned cell growth factor, and specifically, an EGF receptor and a hellegrin receptor (eg, HER3). ), Insurin receptor, IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, NGF receptor, TGFβ receptor, HGF receptor, VEGF receptor, angiopoetin receptor ( For example, Tie2), PDGF receptor and the like can be used.

Examples of "drugs that inhibit the action of cell growth factors and their receptors" include EGF inhibitors, TGFα inhibitors, haregulin inhibitors, insulin inhibitors, IGF inhibitors, FGF inhibitors, KGF inhibitors, CSF inhibitors, and the like. EPO inhibitor, IL-2 inhibitor, NGF inhibitor, PDGF inhibitor, TGFβ inhibitor, HGF inhibitor, VEGF inhibitor, angiopoetin inhibitor, EGF receptor inhibitor, HER2 inhibitor, HER3 inhibitor, HER4 inhibitor Agents, insulin receptor inhibitors, IGF-1 receptor inhibitors, IGF-2 receptor inhibitors, FGF receptor-1 inhibitors, FGF receptor-2 inhibitors, FGF receptor-3 inhibitors, FGF receptors Body-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 Inhibitors, ERK inhibitors, PI3K inhibitors and the like can be used. More specifically, anti-VEGF antibodies (eg, Bevacizumab, Ramucurumab), anti-HER2 antibodies (eg, Trastuzumab, Pertuzumab), anti-EGFR antibodies (eg, Cetuximab, Panitumuba, Matuzumab, Anti-Gymab, Matuzumab, Nimuta). , Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatalanib, Imatinib, Bostinib, Cabozantib, Crizotinib, Crizotinib, Crizotinib, Axitinib, Vismodinib, Axitinib, Vismodinib, -[1 (R) -phenylethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (AEE-788), Vandetanib, Temsilolimus, Everolimus, Enzastaurin, Tozasertib, 2-[N-[ 3- [4- [5- [5- [N- (3-fluorophenyl) carbamoylmethyl] -1H-pyrazol-3-ylamino] quinazoline-7-yloxy] propyl] -N-ethylamino] ethyl ester (AZD-1152) , 4- [9-Chloro-7- (2,6-difluorophenyl) -5H-pyrimid [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), Volassertib, Serofenib, Trastuzumab, N- [2 (R), 3-dihydroxy Propoxy] -3,4-difluoro-2- (2-fluoro-4-iodophenylamino) benzamide (PD-0325901), Bostinib, Regorafenib, Afatinib, Imatinib, Cetuximab, Dabrafenib and the like can be used.

In addition to the above drugs, L-asparaginase, L-arginase, arginine deiminase, acegraton, procarbazine hydrochloride, protoporphyrin-cobalt complex salt, mercury hematoporphyrin sodium, topotecanase I inhibitor (eg, irinotecan, topotecan, indotecan, Indimitecan) ), Topotecanase II inhibitors (eg, sobzoxane), differentiation inducers (eg, retinoids, vitamin Ds), other angiogenesis inhibitors (eg, fumagirin, shark extract, COX-2 inhibitors), α-blockers (Eg, tamthrosin hydrochloride), bisphosphonic acid (eg, pamidronate, zoredronate), salidomid, renalide, pomalide, azacitidine, decitabine, proteasome inhibitors (eg, bortezomib, calphizomib, iximab), NEDD8 inhibitors (eg, EdD8) Antitumor antibodies such as inhibitors, PARP inhibitors (eg, Olaparib, Niraparib, Veliparib), anti-CD20 antibodies (eg, Rituximab, Obinutuzumab), anti-CCR4 antibodies (eg, Mogamulizumab), antibody drug complexes (eg, truss) Tumabuemtancin, brentuximabbedotin) and the like can also be used as concomitant drugs.

When the compound of the present invention is used for purposes other than cancer, in addition to the above-mentioned concomitant drugs, for example, antibacterial agents, antifungal agents, non-steroidal anti-inflammatory agents, steroid agents, anticoagulants, antiplatelet agents, thrombolytics Drugs, immunomodulators, antigenic insects, antitussives / abstinence drugs, sedatives, anesthetics, drug antagonists, anti-inflammatory drugs, hyperlipidemia drugs, arteriosclerosis drugs, HDL enhancers, unstable plaque stability Chemicals, myocardial protective drugs, hypothyroidism drugs, nephrosis syndrome drugs, chronic renal failure drugs, diuretics, hypertension drugs, heart failure drugs, muscle relaxants, anti-epileptic drugs, cardiotonics, vasodilators , Vascular contractors, arrhythmia drugs, diabetes drugs, pressor drugs, tranquilizers, anti-psychiatric drugs, Alzheimer's disease drugs, anti-Parkinson drugs, muscle atrophic spinal cord sclerosis drugs, neuronutrient factors, antidepressants Drugs, schizophrenia drugs, vitamin drugs, vitamin derivatives, arthritis drugs, anti-rheumatic drugs, anti-allergic drugs, anti-asthma drugs, atopic dermatitis drugs, allergic rhinitis drugs, frequent urine / urinary incontinence drugs , Proteolytic agents, proteolytic enzyme inhibitors, anti-SIDS agents, anti-septic agents, anti-septic shock agents, endotoxin antagonists or antibodies, signaling inhibitors, inflammatory mediator action inhibitors, inflammatory mediator action inhibitory antibodies, Anti-inflammatory mediator production inhibitor, anti-inflammatory mediator action inhibitor, anti-inflammatory mediator action inhibitor antibody, anti-inflammatory mediator production inhibitor, α1 adrenergic agonist, antiemetic agent, methemoglobin elevation inhibitor, etc. are used as concomitant drugs. Can be

(1) Antibacterial drug
(i) Sulfafurazole Sulfamethizole, sulfisoxazole, sulfamonomethoxyne, sulfamethizole, salazosulfapyridine, silver sulfadiazine, etc.
(ii) Kinolin-based antibacterial agents Nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosilate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, freloxacin, etc.
(iii) Antituberculous drugs isoniazid, ethambutol (ethambutol hydrochloride), para-aminosalicylic acid (calcium para-aminosalicylate), pyrazinamide, etionamide, prothionamide, rifampicin, streptomycin sulfate, canamycin sulfate, cycloserine and the like.
(iv) Antimycobacterial drugs diaminodiphenyl sulfone, rifampicin, etc.
(v) Antiviral drugs idoxuridine, acyclovir, vitaminabin, ganciclovir, etc.
(vi) Anti-HIV drugs zidovudine, didanosine, zalcitabine, indinavir sulfate ethanol adduct, ritonavir, etc.
(vii) Anti-spirochetes
(viii) Antibiotics Tetracycline Hydrochloride, Ampicillin, Piperacillin, Gentamycin, Dibecacin, Canendomycin, Ribidomycin, Tobramycin, Amicacin, Fradiomycin, Sisomycin, Tetracycline, Oxytetracycline, Loritetracycline, Doxycycline, Ampicillin, Piperacillin, Ticillin Cefazolin, cephalolysin, cefchlorin, cephalexin, cefloxazine, cefadoroxyl, cefamandole, cefoxime, cefotiam, cefotiam hexetyl, cefloxim axetyl, cefdinir, cefditorene pivoxil, cefdinir, cefditorene pivoxil, ceftadidim, cefpyramid Cetil, cefpyrom, cefosoplan, cefepim, cefslogin, cefmenoxime, cefmethazole, cefminox, cefoxime, cefbuperazone, ratamokinacef, fromoxef, cefazolin, cefotaxime, cefoperazone, cefotaxime, cefoperazone, cefotizoxime, cefoperazone, ceftizoxime, cefoperazone, ceftizoxime, cefoperazone

(2) Antifungal drug
(i) Polyene antibiotics (eg, amphotericin B, nystatin, tricomycin)
(ii) Griseofulvin, pyrrolnitrin, etc.
(iii) Cytosine antimetabolite (eg, flucytosine)
(iv) Imidazole derivatives (eg, econazole, clotrimazole, miconazole nitrate, bifonazole, clotrimazole)
(v) Triazole derivatives (eg, fluconazole, itraconazole, azole compounds [2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1) , 2,4-Triazole-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) Equinocandine derivatives (eg, caspofanzine, micafanzine, anidurafanzine), etc.

(3) Nonsteroidal anti-inflammatory drugs acetaminophen, phenacetin, etenzamid, sulpyrine, antipyrine, miglenin, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin , Flurubiprofen, fembuphen, planoprofen, floctaphenin, epilyzole, thiaramid hydrochloride, zartprofen, gabexate mesilate, camostat mesilate, urinastatin, corhitin, probened, sulfine pyrazone, benzbromalone, alloprinol, sodium gold thioappleate, Sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, atropin, scopolamine, morphine, petidin, levorfinol, ketoprofen, naproxen, oxymorphone, meloxicam, selecoxib, lofecoxib or salts thereof, etc.

(4) Topical steroids dexamethasone, hexestrol, methimazole, betamesazone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, propionate, etc.

(5) Anticoagulants Sodium heparin, sodium citrate, activated protein C, tissue factor pathway inhibitor, antithrombin III, sodium dalteparin, warfarin potassium, argatroban, gabexate, sodium citrate and the like.

(6) Antiplatelet agents Ozacrel sodium, ethyl icosapentaate, beraprost sodium, alprostadil, ticlopidine hydrochloride, pentoxifylline, dipyridamole and the like.

(7) Thrombolytic drug Thisokinase, urokinase, streptokinase, etc.

(8) Immunomodulators cyclosporin, tacrolimus, gusperimus, azathioprine, antilymphatic serum, dried sulfonated immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon and the like.

(9) Antiprotozoal agents Metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate and the like.

(10) Antitussives and abstinence agents Efedrin hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodein phosphate, isoproterenol hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride, allocramide, chlorfezanol, picoperidamine, cloperastin, protoquilol , Isoproterenol, salbutamol, terbutalin, oxypetevanol, morphine hydrochloride, dextropetorphan hydrobromide, oxycodon hydrochloride, dimorphan phosphate, tipepidin hibenzate, pentoxiberin citrate, clofedanol hydrochloride, benzonate, guaifenecin, Bromhexine hydrochloride, ambroxol hydrochloride, acetylcysteine, ethylcysteine hydrochloride, carbocysteine, etc.

(11) Sedatives Chlorpromazine hydrochloride, atropin sulfate, phenobarbital, barbital, amobarbital, pentobarbital, thiopental sodium, thiamiral sodium, nitrazepam, estazolam, flunitrazepam, haloxazolam, triazolam, flunitrazepam, bromvalerylurea, chloral hydrate. Sodium etc.

(12) Anesthetic (12-1) Local anesthetic Cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxesazein) and the like.
(12-2) General anesthetic
(i) Inhalational anesthetics (eg, ether, halothane, nitrous oxide, influrane, enflurane), (ii) Intravenous anesthetics (eg, ketamine hydrochloride, droperidol, sodium thiopental, sodium thiamiral, pentobarbital), etc.

(13) Narcotic antagonists levallorphan, nalorphine, naloxone or salts thereof.

(14) Anti-ulcer drug metaclopromid, histidine hydrochloride, lansoprazole, metclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrin, oxesazein, proglumide, omeprazole, sucralfate, sulpylide, cetraxate, gefarnate, aldioxa, etc. ..

(15) Hyperlipidemia therapeutic agent HMG-CoA reductase inhibitor (eg, fluvastatin, seribastatin, atorvastatin, etc.), fibrate drug (eg, symfibrate, clofibrate aluminum, clinofibrate, phenofibrate, etc.), bile Acid adsorbents (eg, cholestiramine, etc.), nicotinic acid preparations (eg, nicomol, niceritrol, tocopherol nicotinate, etc.), Probucol and its derivatives, polyunsaturated fatty acid derivatives (eg, ethyl icosapentate, polyenphosphatidyl) Colin, melanamide, etc.), plant sterols (eg, gamma-orizanol, soysterol, etc.), elastase, sodium dextran sulfate, squalane synthase inhibitors, squalane epoxidase inhibitors, CETP inhibitors, 2-chloro-3- [4 -(2-Methyl-2-phenylpropoxy) phenyl] ethyl propionate, LDL receptor enhancer, cholesterol absorption inhibitor (Ezetimibe, etc.), MTP inhibitor, ileal bile acid transporter inhibitor, SCAP ligand, FXR ligand, etc. ..

(16) Atherosclerosis therapeutic agents MMP inhibitors, chymase inhibitors, ACAT inhibitors (Avasimibe, Eflucimive, etc.), apoA-I Milano and similar substances, scavenger receptor inhibitors, 15-lipoxygenase inhibitors, phospholipase A2 inhibitors Drugs, ABCA1 activators, LXR ligands, sphingomyelinase inhibitors paraoxonase activators, estrogen receptor agonists, etc.

(17) HDL-increasing drug Squalene synthase inhibitor, CETP inhibitor, LPL activator, etc.

(18) Vulnerable plaque stabilizer MMP inhibitor, chimase inhibitor, ACAT inhibitor, lipid-rich plaque retraction agent, etc.

(19) Cardioplegic agents Oral agents for cardiac ATP-K, endothelin antagonists, urotensin antagonists, etc.

(20) Therapeutic agent for hypothyroidism Dry thyroid gland (thyleoid), levothyroxine sodium (tyrazine S), liothyronine sodium (thyronine, tyromine) and the like.

(21) Prednisolone (prednisolone), sodium prednisolone succinate (prednisolone), methylprednisolone sodium succinate (sol medrol), betamethasone (Linderon), etc. for the treatment of nephrotic syndrome.

(22) Drugs for treating chronic renal failure Diuretics [eg, furosemide (Lasix), bumetanide (Lunetron), azosemide (Diart)], antihypertensive drugs [eg, ACE inhibitors, enalapril maleate (renibase), calcium antagonists (manidipine) ), Α receptor blocker, AII antagonist (candesartan)], etc.

(23) Diuretics Thiazide-based diuretics (ventilhydrochlorothiazide, cyclopentiazide, ethiazide, hydrochlorothiazide, hydroflumethazide, methicrotiazide, penfluthiazide, polythiazide, trichlormethiazide, etc.), loop diuretics (chlortalidone, clofenamide, indapamide, etc.) , Mefluside, methiclan, sotrazone, tribamide, kinetazone, metrazone, fresemid, etc.), potassium-retaining diuretics (spironolactone, triamterene, etc.).

(24) Antihypertensive drug
(i) Sympathomimetics α2 stimulants (eg, clonidine, guanabends, guanfacin, methyldopa, etc.), ganglion blockers (eg, hexamethonium, trimetafan, etc.), presynaptic blockers (eg, alseroxy) Ron, dimethylaminoreserpinate, lecinamine, reserpin, syrosingopin, etc.), neuron blockers (eg, betanidine, guanethidine, etc.), α1 blockers (eg, bunazosin, doxazosin, prazosin, terazosin, urapidil, etc.), β-blockers (eg, beta-blockers) For example, purplanolol, etc. roll, timolol, nipragyrol, bunitrolol, indenolol, penbutrol, carteolol, carvedilol, pindolol, acebutrol, atenolol, bisoprolol, metoprol, labetalol, amosulalol, arotinolol, etc.).
(ii) Vasodilators Calcium channel antagonists (eg, manidipine, nicardipine, nilvadipine, nisoldipine, nitrendipine, benidipine, amlodipine, alanidipine, etc.), phthalazine derivatives (eg, budralazine, cadralazine, ecarazine, hydralazine, todralazine, etc.), etc.
(iii) ACE inhibitors alacepril, captopril, silazapril, delapril, enalapril, lydinopril, temocapril, trandolapril, quinapril, imidapril, benazepril, verindopril, etc.
(iv) AII antagonists losartan, candesartan, valsartan, telmisartan, irbesartan, forasartan, etc.
(v) Diuretics (eg diuretics mentioned above)

(25) Heart failure therapeutic agents Cardiotonic agents (eg, digitoxin, digoxin, methyldigoxin, lanatoside C, prosciralidine, etc.), α, β stimulants (eg, epinephrine, norepinephrine, isoproterenol, dopamine, docarpamine, dobutamine, denopamine Etc.), Phosphodiesterase inhibitors (eg amlinone, milrinone, orprinone hydrochloride, etc.) Calcium channel susceptibility enhancers (eg, pimoventane, etc.), nitrates (eg, nitroglycerin, isosorbide nitrate, etc.) Inhibitors, etc.), diuretics (eg, diuretics mentioned above), carperitide, ubidecalenone, vesnarinone, aminophilin, etc.

(26) Muscle relaxants Pridinol, tubocurarine, pancuronium, tolperisone hydrochloride, chlorphenesine carbamate, baclofen, chlormezanone, mephenesin, clozoxazone, eperisone, tizanidine and the like.

(27) Antiepileptic drugs phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, trimethadione, carbamazepine, phenobarbital, primidone, sultium, sodium parproate, clonazepam, diazepam, nitrazepam, etc.

(28) Cardiotonic agents Aminophylline, etilefrine, dopamine, dobutamine, denopamine, aminophylline, amrinone, pimobendan, ubidecalenone, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like.

(29) Vasodilators Oxyfedrin, diltiazem, tolazoline, hexobenzine, bamethane, clonidine, methyldopa, guanabenz and the like.

(30) Vasoconstrictor dopamine, dobutamine denopamine, etc.

(31) Antiarrhythmic drug
(i) Sodium channel blockers (eg, quinidine, procainamide, disopyramide, azimarin, cibenzoline, lidocaine, diphenylhydantoin, mexiletine, propafenone, flecainide, pilsicainide, phenytoin, etc.),
(ii) Beta blockers (eg, propranolol, alpenolol, bufetrol, oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol, carteolol, arotinolol, etc.),
(iii) Potassium channel blockers (eg, amiodarone, etc.),
(iv) Calcium channel blockers (eg verapamil, diltiazem, etc.), etc.

(32) Pressor agents Dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like.

(33) Antidiabetic agents sulfonylurea agents (eg, tolbutamide, chlorpropamide, glycopyramide, acetohexamide, trazamide, glibenclamide, glybsol, etc.), biguanide agents (eg, metformin hydrochloride, buformin hydrochloride, etc.), α-glucosidase Inhibitors (eg, boglibose, acarbose, etc.), insulin-improving drugs (eg, pioglitazone, rosiglitazone, troglitazone, etc.), insulin, glucagon, antidiabetic complications (eg, epalrestat, etc.), DPP4 inhibitors (eg, epalrestat, etc.) , Citagliptin, bildaglycin, allogliptin, linagliptin, etc.), etc.

(34) Mental stabilizers diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam, cloxazolam, clotiazepam, bromazepam, etizolam, fludiazepam, hydroxydine and the like.

(35) Antipsychotics Chlorpromazine hydrochloride, prochlorperazine, trifloperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine enanthate, prochlorperazine maleate, levomepromazine maleate, promethazine hydrochloride, haloperidol, bromperidol , Spiperone, Reselpin, Chlorpromazine hydrochloride, Sulpyride, Zotepine, etc.

(36) Alzheimer's disease therapeutic agent
(i) Cholinesterase inhibitors such as donepezil, rivastigmine, and galantamine,
(ii) Brain function activators such as idebenone, memantine, and vinpocetine.

(37) Antiparkinsonian drugs L-dopa, deprenyl, carbidopa + levodopa, pergolide, ropinirole, cabergoline, pramipexole, entacapone, razavemid, etc.

(38) Amyotrophic lateral sclerosis therapeutic agents riluzole, mecasermin, gabapentin and the like.

(39) Antidepressants imipramine, chromipramine, noxiptiline, phenelzine, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, myanserin hydrochloride, maprotiline hydrochloride, sulfiride, fluvoxamine maleate, trazodone hydrochloride and the like.

(40) Therapeutic agents for schizophrenia, such as olanzapine, risperidone, quetiapine, and iroperidone.

(41) Vitamin medicine
(i) Vitamin A: Vitamin A1, Vitamin A2 and Retinol Palmitate
(ii) Vitamins: Vitamins D1, D2, D3, D4 and D5
(iii) Vitamin Es: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, dl-α-tocopherol nicotinate
(iv) Vitamins K: Vitamins 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) etc.

(42) Vitamin Derivatives Vitamin D3 derivatives such as ascorbic acid, 5,6-trans-choleciferol, 2,5-hydroxycholecalciferol, 1-α-hydroxycholecalciferol, 5, Vitamin D2 derivatives such as 6-trans-ergocalciferol.

(43) Antiallergic agents diphenhydramine, chlorpheniramine, tryperenamine, cremisol, diphenylpyraline, methoxyphenamine, sodium cromoglycate, tranilast, repilinast, amlexanox, ibudilast, ketotifen, terfenazine, mequitazine, azelastine, epinastine, ozagure hydrochloride. Stroke hydrate, ceratrodust, etc.

(44) Anti-asthmatic agents Isoprenalin hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimetokinol hydrochloride, tulobuterol hydrochloride, orsiprenalin sulfate, phenotelol hydrobromide, ephedrine hydrochloride, ipratropium bromide, oxytropium bromide, bromide Flutropium, theophylline, aminophylline, sodium cromoglycate, tranilast, repyrinast, ibudilast, ketotiphen, terfenazine, mequitadine, azelastin, ephedrine, ozagrel hydrochloride, pranlukast hydrate, ceratrodust, dexamethasone, prednisolone, hydrocortisone, propion.

(45) Sodium cromoglycate, a therapeutic agent for atopic dermatitis, etc.

(46) Therapeutic agent for allergic rhinitis Sodium chlormoglycate, chlorpheniramine maleate, alienmemazine tartrate, clemastine fumarate, homochlorcyclizine hydrochloride, terfenadine, mequitazine and the like.

(47) Flavoxate hydrochloride, a therapeutic agent for pollakiuria and urinary incontinence.

(48) Anti-septic agents rBPI-21 (bacterial permeability increasing protein), BI-51017 (antithrombin III), SC-59735 (rTFPI), r-PAF acetylhydrase, LY-203638 (r- Peptide compounds such as activated protein C), anti-TNF-α antibody, anti-CD14 antibody, CytoFab, alkaline phosphatase (LPS inactivating agent), JTE-607, eritoran, S-5920, FR-167653, ONO-1714. , ONO-5046 (siverestat), GW-273629, RWJ-67657, GR-270773, NOX-100, INO-1001, and other non-peptide compounds.

(49) Prognosis improving drug eritoran after coronary artery bypass grafting.

(50) Antiemetic agent Phenothiazine derivative, 5-HT3 receptor antagonist and the like.

(51) Methemoglobin elevation inhibitor Methylene blue, ascorbic acid, etc.

(52) Anticytocytogene drug (I) Protein preparation (i) TNF inhibitor Etanercept, infliximab, adalimumab, sertrizumab pegol, golimumab, PASSTNF-α, soluble TNF-α receptor, TNF-α binding protein, anti-TNF -Α antibody, etc.
(Ii) Interleukin-1 inhibitor Anakinra (interleukin-1 receptor antagonist), soluble interleukin-1 receptor, etc.
(Iii) Interleukin-6 inhibitor tocilizumab (anti-interleukin-6 receptor antibody), anti-interleukin-6 antibody and the like.
(Iv) Interleukin-10 drug Interleukin-10 etc.
(V) Interleukin-12 / 23 inhibitors ustekinumab, briaquinumab (anti-interleukin-12 / 23 antibody) and the like.
(Vi) Interleukin-17 inhibitor Secukinumab, exekitumab, brodalumab, etc. (II) Non-protein preparation (i) MAPK inhibitor BMS-582949, etc.
(Ii) Gene regulators NF-κ, NF-κB, IKK-1, IKK-2, AP-1, and other inhibitors of molecules involved in signal transduction.
(Iii) Cytokine production inhibitors iguratimod, tetomilast, etc.
(Iv) TNF-α converting enzyme inhibitor (v) Interleukin-1β converting enzyme inhibitor VX-765 and the like.
(Vi) Interleukin-6 antagonist HMPL-004 and the like.
(Vii) Interleukin-8 inhibitor IL-8 antagonist, CXCR1 & CXCR2 antagonist, cephalexin and the like.
(Viii) Chemokine antagonist CCR9 antagonist (CCX-282, CCX-025), MCP-1 antagonist and the like.
(Ix) Interleukin-2 receptor antagonist deniroukin, Difchitox, etc.
(X) Therapeutic vaccines
TNF-α vaccine, etc.
(Xi) Gene therapy drug A gene therapy drug aimed at enhancing the expression of genes having an anti-inflammatory effect such as interleukin-4, interleukin-10, soluble interleukin-1 receptor, and soluble TNF-α receptor. ..
(Xii) Antisense compound ISIS-104838 and the like.

(53) Integrin inhibitors Natalizumab, vedolizumab, AJM300, TRK-170, E-6007 and the like.

Antidepressants (eg, amitriptyline, imipramine, clomipramine, desipramine, doxepin, nortriptyline, duloxetine, milnacipran, fluoxetine, paroxetine, sertraline, citaloplum, etc.)
Anticonvulsants (eg, carbamazepine, pregabalin, gabapentin, lamotridin, phenytoin, valproic acid, etc.)
Narcotics (eg, morphine, oxycodone, fentanyl, methadone, codeine, tramadol, etc.)

(54) Others Hydroxycam, diacelin, megestrol acetic acid, fake logoline, prostaglandins, etc.

By combining the compound of the present invention and the concomitant drug, the dose thereof can be reduced as compared with the case where the compound of the present invention or the concomitant drug is administered alone, and (2) the patient's symptoms (mild, severe, etc.) ), The drug to be used in combination with the compound of the present invention can be selected, (3) the treatment period can be set longer, (4) the therapeutic effect can be sustained, and (5) the drug used in combination with the compound of the present invention. By using in combination with, excellent effects such as a synergistic effect can be obtained.

Hereinafter, the case where the compound of the present invention and the concomitant drug are used in combination is referred to as "the concomitant drug of the present invention".
When using the concomitant drug of the present invention, the administration time 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 to the administration subject at the same time or with a time lag. It may be administered. When administered at different times, the time difference varies depending on the active ingredient to be administered, the dosage form, and the administration method. For example, when the concomitant drug is administered first, it is preferably within 1 minute to 3 days after the concomitant drug is administered. 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, more preferably within 15 minutes to 1 hour after the administration of the compound of the present invention. .. The dose of the concomitant drug may be based on the dose clinically used, and may be appropriately selected depending on the administration target, administration route, disease, combination and the like.

When the compound of the present invention and the concomitant drug are used in combination, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, and (2) concomitant use with the compound of the present invention. Simultaneous administration of two preparations obtained by separately formulating a drug by the same route of administration, (3) Same administration route of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug (4) Simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different routes of administration, (5) The compound of the present invention and the concomitant drug Examples thereof include administration of the two preparations obtained by separately formulating at different routes of administration (for example, administration 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. In addition, the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on 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.

Furthermore, the compounds of the present invention or concomitant agents of the present invention can be used in combination with non-drug therapies. Specifically, the compound of the present invention or the concomitant drug of the present invention is, for example, (1) surgery, (2) pressor chemotherapy using angiotensin II or the like, (3) gene therapy, (4) hyperthermia, (5). It can be combined with cryotherapy, (6) laser ablation, and (7) radiation therapy.

For example, by using the compound of the present invention or the concomitant drug of the present invention before or after the surgery or the like, or before or after the treatment in which two or three of these are combined, the development of resistance is prevented and the disease-free stage (Disease-Free Survival) is achieved. ), Suppression of cancer metastasis or recurrence, life extension, etc. can be obtained.

In addition, treatment with the compound of the present invention or the concomitant drug of the present invention and supportive care [(i) antibiotics for the complication of various infectious diseases (for example, β-lactam system such as pansporin, macrolide system such as clarithromycin) Administration, (ii) high-calorie infusion for improving nutritional disorders, amino acid preparations, administration of multivitamins, (iii) administration of morphine for pain relief, (iv) nausea, vomiting, loss of appetite, diarrhea, leukocyte depletion, Administration of drugs that improve side effects such as thrombocytopenia, decreased hemoglobinometry, hair loss, liver damage, renal damage, DIC, fever, etc. and (v) administration of drugs to suppress multidrug resistance of cancer] It can also be combined.

The present invention will be further described in detail with reference to the following Reference Examples, Examples, Test Examples and Formulation Examples, but these are not intended to limit the present invention and may be changed without departing from the scope of the present invention. Good.
“Room temperature” in the following examples usually indicates about 10 ° C to about 35 ° C. The ratio shown in the mixed solvent indicates the volume ratio unless otherwise specified. % Indicates the weight% unless otherwise specified.
In silica gel column chromatography, aminopropylsilane-bonded silica gel was used when NH was described, and octadecyl-bonded silica gel was used when C18 was described. In HPLC (High Performance Liquid Chromatography), when described as C18, octadecyl-bonded silica gel was used. The ratio of elution solvents indicates the volume ratio unless otherwise specified.
The following abbreviations are used in the following examples.
MS: Mass spectrum
M: Molarity
DMSO-d ₆ : Deuterated dimethyl sulfoxide
¹ H NMR: Proton nuclear magnetic resonance
LC / MS: Liquid chromatograph mass spectrometry
ESI: Electrospray ionization
APCI: Atmospheric pressure chemical ionization
DCM: Dichloromethane
DIEA: Diisopropylethylamine
DMAP: 4-dimethylaminopyridine
DMF: N, N-dimethylformamide
HATU: 2- (7-azabenzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
TBTU: 1- [bis (dimethylamino) methylene] -1H-benzotriazolium 3-oxide tetrafluoroborate
TEA: Triethylamine
THF: tetrahydrofuran
TFA: Trifluoroacetic acid

¹ H NMR was measured by Fourier transform NMR. ACD / SpecManager or MestreNova (trade name) was used for the analysis. It may not be described for peaks where protons such as hydroxyl groups and amino groups are very gentle.
MS was measured by LC / MS. As the ionization method, the ESI method or the APCI method was used. The data is the measured value (found). Normally, molecular ion peaks ([M + H] ⁺ , [MH] ^-, etc.) are observed, but in the case of compounds having a tert-butoxycarbonyl group, the fragment ion is a tert-butoxycarbonyl group or a tert-butyl group. Desorption peaks may be observed. In the case of a compound having a carboxyl group or the like, a peak with sodium added may be observed. Further, in the case of a compound having a hydroxyl group, a peak in which water is eliminated may be observed as a fragment ion. In the case of salts, free molecular ion peaks or fragment ion peaks are usually observed.
The unit of sample concentration (c) at optical rotation ([α] _{D) is g / 100 mL.}
For the elemental analysis value (Anal.), The calculated value (Calcd) and the measured value (Found) are described.

Example 1
2- (4-((S) -2-Cyclohexyl-2-((S) -2- (methylamino) propanamide) acetyl) piperidine-1-carbonyl) -5,6-difluoro-N, 1-dimethyl -N- (2- (2-((2-((5-((4- (thieno [3,2-b] pyridine-7-yloxy) piperidine-1-yl) methyl) isooxazole-3-yl)) Oxy) ethoxy) ethoxy) ethyl) -1H-indole-3-carboxamide hydrochloride

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

Mixture of (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) HATU (5.54 g) was added to the mixture at room temperature. The reaction mixture was stirred at the same temperature for 6 hours. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (4.34 g).
^{MS: [M + H] +} 460.2.

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

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

C) Benzyl 4-((S) -2-((S) -2-((tert-butoxycarbonyl) (methyl) amino) propanamide) -2-cyclohexylacetyl) piperazine-1-carboxylate

(S) -2-((tert-butoxycarbonyl) (methyl) amino) propanoic acid (1.63 g), (S) -benzyl4- (2-amino-2-cyclohexylacetyl) piperazin-1-carboxylate hydrochloride HATU (4.26 g) was added to the mixture of (2.96 g), DIEA (5.22 mL) and DMF (37.4 mL) at room temperature. The reaction mixture was stirred at the same temperature for 6 hours. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.62 g).
MS: [M + H] ⁺ 545.4.

D) tert-Butyl ((S) -1-(((S) -1-cyclohexyl-2-oxo-2-(piperazin-1-yl) ethyl) amino) -1-oxopropan-2-yl) ( Methyl) carbamate

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

E) Methyl 5,6-difluoro-1-methyl-1H-indole-2-carboxylate
Potassium carbonate (42.03 g) and iodomethane (18.9 mL) were added to the mixture of 5,6-difluoro-1H-indole-2-carboxylic acid (20 g) and DMF (200 mL) 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 give the title compound (20 g).
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 3.85 (3H, s), 3.99 (3H, s), 7.26 (1H, s), 7.70 (1H, dd, J = 8.24 Hz, 10.84 Hz), 7.78 (1H, dd, J = 6.96 Hz, 11.68 Hz).

F) Methyl 5,6-difluoro-3-formyl-1-methyl-1H-indole-2-carboxylate Methyl 5,6-difluoro-1-methyl-1H-indole-2-carboxylate (2 g) and DCM A 1M titanium tetrachloride / DCM solution (17.8 mL) and a mixture of dichloromethyl methyl ether (1.7 mL) and DCM (2 mL) were added to the mixture (20 mL) at -78 ° C. The reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with water and neutralized with saturated aqueous sodium 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 evaporated under reduced pressure to give the title compound (1.9 g).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.99 (3H, s), 4.02 (3H, s), 8.0 (1H, dd, J = 6.92 Hz, 11.4 Hz), 8.12 (1H, dd, J = 8.24 Hz, 10.76 Hz), 10.34 (1H, s).

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

Hydrate to a mixture of methyl 5,6-difluoro-3-formyl-1-methyl-1H-indol-2-carboxylate (15 g) and THF (225 mL), methanol (75 mL), water (75 mL) Lithium monohydrate (3.73 g) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and subjected to acidic conditions using an aqueous potassium sulfate solution. The obtained solid was collected by filtration to give the title compound (13 g).
MS: [M + H] ⁺ 240.1.

H) 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) HATU (4.67) in a mixture of carbamate (4.63 g), 5,6-difluoro-3-formyl-1-methyl-1H-indole-2-carboxylic acid (2.45 g), DIEA (2.7 mL) and DMF (50 mL) g) was added. The reaction mixture was stirred at room temperature for 2 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 0.1 M hydrochloric acid, aqueous sodium 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). The resulting 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) carbamalate, sodium dihydrogen phosphate (4.90 g), 2-methylbut-2-ene (3.58 g) To the mixture of tert-butanol (90 mL) / water (30 mL) was added sodium phosphate (2.24 g). The reaction mixture was stirred at room temperature overnight, 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 give the title compound (5.46 g).
MS: [M + H] ⁺ 648.5.

I) 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) piperazine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate

2- (4-((S) -2-((S) -2-((tert-butoxycarbonyl) (methyl) amino) propanamide) -2-cyclohexylacetyl) piperazin-1-carbonyl) -5,6 -Difluoro-1-methyl-1H-indol-3-carboxylic acid (5.46 g) and 2- (2- (2- (methylamino) ethoxy) ethoxy) ethane-1-ol (1.65 g), DIEA (2.26 mL) ) And DMF (8 mL) were added HATU (3.85 g). The reaction mixture was stirred at room temperature for 3 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (3.10 g).
MS: [M + H] ⁺ 793.5.

J) 5-((4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-ol

3- (allyloxy) -5-((4- (thieno [3,2-b] pyridine-7-yloxy) piperidine-1-yl) methyl) isoxazole (5.68 g), triethylsilane (5.33 g) and THF Tetrakistriphenylphosphine palladium (884 mg) was added to the mixture (100 mL). The reaction mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol), and the obtained compound was washed with ethyl acetate to give the title compound (2.50 g).
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 1.68-1.84 (2H, m), 1.95-2.09 (2H, m), 2.35-2.49 (2H, m), 2.63-2.75 (2H, m), 3.58 (2H, s), 4.74-4.87 (1H, m), 5.93 (1H, s), 7.07 (1H, d, J = 5.5 Hz), 7.50 (1H, d, J = 5.6 Hz), 8.04 (1H, s) d, J = 5.4 Hz), 8.50 (1H, d, J = 5.4 Hz), 11.16 (1H, s).

K) tert-Butyl ((S) -1-(((S) -1-cyclohexyl-2- (4- (5,6-difluoro-1-methyl-3-) methyl (2- (2- (2) -((5-((4- (Tieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isooxazole-3-yl) Oxy) ethoxy) ethoxy) Ethyl) Carbamoyl)- 1H-indole-2-carbonyl) piperidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate

5-((4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isooxazole-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) piperidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate (3.59 g), triphenylphosphine (5.94 g) and toluene Di-tert-butylazodicarboxylate (3.13 g) was added to the mixture (25 mL). The reaction mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile / 5 mM ammonium acetate aqueous solution) to give the title compound (2.37 g).
MS: [M + H] ⁺ 1106.6.

L) 2- (4-((S) -2-Cyclohexyl-2-((S) -2- (methylamino) propanamide) acetyl) piperidine-1-carbonyl) -5,6-difluoro-N, 1 -Dimethyl-N- (2- (2- (2-((5-((4- (thieno [3,2-b] pyridin-7-yloxy) piperidine-1-yl) methyl) isooxazole-3- Il) 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- (2-) (5-((4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isooxazole-3-yl) Oxy) ethoxy) ethoxy) Ethyl) Carbamoyl) -1H- Indole-2-carbonyl) Piperazin-1-yl) -2-oxoethyl) Amino) -1-oxopropan-2-yl) (Methyl) Carbamate (2.37 g) and ethyl acetate (10 mL) in a mixture of 4M hydrogen chloride / Ethyl acetate solution (2.34 g) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give the title compound (2.16 g).
^{1 1} H NMR (DMSO-d ₆ , 300 MHz) δ 0.72-1.26 (7H, m), 1.35 (3H, d, J = 6.8 Hz), 1.50-1.83 (7H, m), 2.11-2.48 (7H, m) ), 2.97 (3H, s), 3.20-3.97 (21H, m), 4.13-4.37 (2H, m), 4.39-4.82 (3H, m), 4.90-5.59 (2H, m), 6.65 (1H, s) ), 7.46 (1H, dd, J = 10.9, 7.9 Hz), 7.54-7.96 (4H, m), 8.53 (1H, d, J = 5.6 Hz), 8.66-9.12 (2H, m), 9.27-9.65 ( 1H, m), 11.79-12.71 (1H, m).

Example 2
2- (4-((S) -2-Cyclohexyl-2-((S) -2- (methylamino) propanamide) 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

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

Sodium hydride (60%, dispersed in liquid paraffin, 2.93 g) was added to a mixture of methyl 6-methoxy-1H-indole-2-carboxylate (11.6 g) and DMF (100 mL) under ice cooling. After stirring the reaction mixture 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. Water (150 mL) and 1M hydrochloric acid (250 mL) were added to the reaction mixture under ice-cooling, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 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), add 2M aqueous sodium hydroxide solution (52.0 mL) at room temperature and add the reaction mixture at 60 ° C. Stirred for 1 hour. The reaction mixture was cooled under ice-cooling, neutralized with 1M hydrochloric acid (110 mL), and the precipitate was collected by filtration to give 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-indol-2-carboxylic acid (9.87 g), tert-butyl piperazin-1-carboxylate (9.41 g), 1-hydroxybenzotriazole monohydrate (8.10 g) and DMF 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (10.14 g) was added to the mixture (150 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was ice-cooled, water was added, and the precipitate was collected by filtration to give 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

A mixture of tert-butyl 4- (6-methoxy-1-methyl-1H-indol-2-carbonyl) piperazin-1-carboxylate (10.4 g) and DMF (100 mL) with (chloromethylene) dimethylammonium chloride (7.13) g) was added and the reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, the mixture was stirred for 30 minutes, 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 give the title compound (10.6 g).
MS: [M + H] ⁺ 402.1.

E) 6-Methoxy-1-methyl-2- (piperazin-1-carbonyl) -1H-indole-3-carbaldehyde hydrochloride

tert-Butyl 4- (3-formyl-6-methoxy-1-methyl-1H-indol-2-carbonyl) piperazin-1-carboxylate (10.6 g), dimethyl sulfide (25 mL) and ethyl acetate (100 mL) A 4M hydrogen chloride / ethyl acetate solution (198 mL) was added to the mixture, 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 give the title compound (8.1 mg).
MS: [M + H] ⁺ 302.0.

F) tert-butyl ((S) -1-(((S) -1-cyclohexyl-2-(4- (3-formyl-6-methoxy-1-methyl-1H-indole-2-carbonyl) piperazine- 1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate

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

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

tert-Butyl ((S) -1-(((S) -1-cyclohexyl-2-(4- (3-formyl-6-methoxy-1-methyl-1H-indole-2-carbonyl) piperazin-1-) Il) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate (2.30 g), sodium dihydrogen phosphate (1.76 g), 2-methylbut-2-ene (1.95 mL), Sodium chlorite (665 mg) was added to the mixture of tert-butyl alcohol (29.4 mL) and water (7.4 mL) at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium thiosulfate solution, 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 (methanol / ethyl acetate) to give the title compound (770 mg).
MS: [M + H] ⁺ 648.5.

D04716-76
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) piperazine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate

2- (4-((S) -2-((S) -2-((tert-butoxycarbonyl) (methyl) amino) propanamide) -2-cyclohexylacetyl) piperazin-1-carbonyl) -6-methoxy A mixture of -1-methyl-1H-indole-3-carboxylic acid (147 mg), triethylene glycol monoamine (41.0 mg), DIEA (120 μl), HATU (131 mg) and DMF (1.12 mL) at room temperature 1 Stirred for hours. Water and ethyl acetate were added to the reaction mixture to dilute the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile / 5 mM ammonium acetate aqueous solution) to give the title compound (133 mg).
MS: [M + H] ⁺ 773.5.

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

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

J) 4- (Piperidin-4-yloxy) Thieno [3,2-d] Pyrimidine Hydrochloride

4M Hydrogen Chloride / Ethyl Acetate Solution (55.9 mL) in a mixture of tert-butyl 4- (thieno [3,2-d] pyrimidin-4-yloxy) piperidin-1-carboxylate (3.75 g) and ethyl acetate (22.4 mL) ) Was added. After stirring the reaction mixture for 30 minutes, the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (3.25 g).
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 2.00-2.12 (2H, m), 2.17-2.33 (2H, m), 3.02-3.37 (4H, m), 5.52-5.67 (1H, m), 7.62 (1H, d, J = 5.29 Hz), 8.40 (1H, d, J = 5.29 Hz), 8.79 (1H, s), 8.98-9.34 (2H, m).

K) 4-((4- (Tieno [3,2-d] pyrimidine-4-yloxy) piperidine-1-yl) sulfonyl) phenol

4-Hydroxybenzene-1-sulfonyl chloride (152 mg) was added to a mixture of 4- (piperidine-4-yloxy) thieno [3,2-d] pyrimidine hydrochloride (215 mg) and pyridine (2.64 mL). The reaction mixture was stirred for 16 hours and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (C18, acenitrile / 5 mM ammonium acetate aqueous solution) to give the title compound (3.75 g).
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 1.75-1.95 (2H, m), 2.00-2.19 (2H, m), 2.83-3.01 (2H, m), 3.05-3.21 (2H, m), 5.15 -5.51 (1H, m), 6.96 (2H, d, J = 8.69 Hz), 7.46-7.72 (3H, m), 8.32 (1H, d, J = 5.29 Hz), 8.70 (1H, s), 10.10- 11.07 (1H, m).

L) 2- (4-((S) -2-Cyclohexyl-2-((S) -2- (methylamino) propanamide) 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 -Indol-3-Carboxamide

4-((4- (Tieno [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-indol-2-carbonyl) piperazine Di-tert in a mixture of -1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate (70.0 mg), triphenylphosphine (119 mg) and toluene (0.45 mL) -Butylazodicarboxylate (62.6 mg) was added. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile / 5 mM ammonium acetate aqueous solution). Add ethyl acetate (0.2 mL), add 4M hydrogen chloride / ethyl acetate solution (679 μL), 1 at room temperature
Stir for hours. The residue was purified by silica gel column chromatography (C18, acetonitrile / 5 mM ammonium acetate aqueous solution). The salt was desalted with Amberlyst A21 in methanol, and the solvent was evaporated under reduced pressure to give the title compound (19.5 mg).
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 0.63-4.78 (54H, m) 5.26-5.43 (1H, m) 6.75-6.95 (1H, m) 7.05-7.20 (3H, m) 7.37-7.51 (1H) , m) 7.55 (1H, d, J = 5.29 Hz) 7.65 (2H, d, J = 9.06 Hz) 7.75-7.85 (1H, m) 7.88-7.99 (1H, m) 8.30 (1H, d, J = 5.29) Hz) 8.69 (1H, s).

Example 3
1-((R) -4- (5,6-difluoro-1-methyl-1H-indol-2-carbonyl) -2-methylpiperazin-1-yl) -2-((2R, 5R) -5- Methyl-2-((2- (2- (2-((5-((4- (thieno [3,2-b] pyridin-7-yloxy) piperidine-1-yl) methyl) isooxazole-3- Il) oxy) ethoxy) ethoxy) ethoxy) methyl) piperazine-1-yl) ethane-1-one hydrochloride

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

B) 5,6-difluoro-1-methyl-2-(((3R) -3-methylpiperazine-1-yl) carbonyl) -1H-indole

DIEA (4.4 mL), (R) -2-methyl-piperazine (1.02 g) in a mixture of 5,6-difluoro-1-methyl-1H-indole-2-carboxylic acid (1.8 g) and DMF (45 mL) , 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 give the title compound (1.9 g).
MS: [M + H] ⁺ 294.3.

C) 2-Chloro-1-((2R) -4-((5,6-difluoro-1-methyl-1H-indole-2-yl) carbonyl) -2-methylpiperazin-1-yl) ethane-1 -on

In a mixture of 5,6-difluoro-1-methyl-2-(((3R) -3-methylpiperazin-1-yl) carbonyl) -1H-indole (1.9 g, 6.48 mmol) and DCM (25 mL), TEA (1.35 ml) and chloroacetyl chloride (0.6 ml) were added under ice-cooling. The reaction mixture was stirred at room temperature for 3 hours, diluted with DCM and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.8 g).
MS: [M + H] ⁺ 370.2.

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

TEA (1.7 mL) and methanesulfonyl chloride (0.77 mL) were added to a mixture of 2- (2- (2-benzyloxy-ethoxy) -ethoxy) -ethanol (2 g) and DCM (15 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 give the title compound (2.5 g).
^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 3.02-3.05 (3H, m), 3.61-3.65 (8H, m), 3.74-3.76 (2H, m), 4.34-4.36 (2H, m), 4.54 (2H) , s), 7.27-7.33 (5H, m).

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

Sodium hydride (60%, liquid paraffin) in a mixture of tert-butyl (2R, 5R) -4-benzyl-5-hydroxymethyl-2-methyl-piperazin-1-carboxylate (700 mg) and DMF (10 mL) , 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 stirred at 60 ° C. for an additional 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 an additional 5 hours. The reaction mixture was diluted with water 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 give the title compound (900 mg).
MS: [M + H] ⁺ 543.2.

F) tert-butyl (2R, 5R) -5-((2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) methyl) -2-methylpiperazin-1-carboxylate

tert-Butyl (2R, 5R) -4-benzyl-2-methyl-5- (12-phenyl-2,5,8,11-tetraoxadodecane-1-yl) piperazin-1-carboxylate (900 mg) , 10% palladium carbon (200 mg) was added to the mixture of acetic acid (0.1 mL) and ethanol (10 mL). The reaction mixture was stirred under normal pressure hydrogen atmosphere at room temperature for 16 hours, 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 saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (600 mg).
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 1.12 (3H, d, J = 6.72 Hz), 1.39 (9H, s), 2.41 (1H, dd, J = 2.74, 12.5 Hz), 2.88-2.94 ( 2H, m), 3.07 (1H, dd, J = 4.16, 13.5 Hz), 3.31-3.52 (15H, m), 3.60-3.62 (1H, m), 3.98 (1H, bs).

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

tert-Butyl (2R, 5R) -5-((2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) methyl) -2-methylpiperazin-1-carboxylate (592 mg) and THF (15 mL) TEA (0.3 ml), 2-chloro-1-((2R) -4-((5,6-difluoro-1-methyl-1H-indol-2-yl) carbonyl) -2-methylpiperazin-in the mixture of 1-Il) Ethane-1-one (550 mg) and tetrabutylammonium iodide (549 mg) were added, and the mixture was stirred at 60 ° C. for 24 hours. Ethyl acetate was added to the reaction mixture, the mixture was 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 (methanol / ethyl acetate) to give the title compound (740 mg).
MS: [M + H] ⁺ 696.5.

G) tert-Butyl (2R, 5R) -4-(2-((2R) -4-((5,6-difluoro-1-methyl-1H-indol-2-yl) carbonyl)) -2-methylpiperazine -1-yl) -2-oxoethyl) -2-methyl-5-(1-(5-((4- (thieno [3,2-b] pyridine-7-yloxy) piperidine-1-yl) methyl) -1,2-oxazol-3-yl) -1,4,7,10-tetraoxaundecane-11-yl) piperazine-1-carboxylate

tert-butyl (2R, 5R) -4-(2-((2R) -4-((5,6-difluoro-1-methyl-1H-indol-2-yl) carbonyl))-2-methylpiperazin-1 -Il) -2-oxoethyl) -5-((2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) methyl) -2-methylpiperazin-1-carboxylate (30 mg), 5-((4) -(Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-ol (17.1 mg), triphenylphosphine (56.5 mg), and toluene (2 mL) Di-tert-butylazodicarboxylate (29.7 mg) was added to the mixture. The reaction mixture was stirred at room temperature for 16 hours and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography to give the title compound (26 mg).
MS: [M + H] ⁺ 1008.8.

H) 1-((R) -4- (5,6-difluoro-1-methyl-1H-indol-2-carbonyl) -2-methylpiperazin-1-yl) -2-((2R, 5R)- 5-Methyl-2-((2- (2- (2-((5-((4- (thieno [3,2-b] pyridin-7-yloxy) piperidine-1-yl) methyl) isoxazole- 3-Il) Oxy) ethoxy) ethoxy) ethoxy) Methyl) Piperazine-1-yl) Ethan-1-one hydrochloride

tert-butyl (2R, 5R) -4-(2-((2R) -4-((5,6-difluoro-1-methyl-1H-indol-2-yl) carbonyl))-2-methylpiperazin-1 -Il) -2-oxoethyl) -2-methyl-5-(1-(5-((4- (thieno [3,2-b] pyridine-7-yloxy) piperidine-1-yl) methyl) -1 , 2-Oxazole-3-yl) -1,4,7,10-Tetraoxazoledecane-11-yl) 4M hydrogen chloride / dioxane in a mixture of piperazine-1-carboxylate (25 mg) and DCM (1 mL) The solution (0.3 mL) was added under ice cooling. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The residue was washed with ether and pentane to give the title compound (19 mg).
^{1 1} H NMR (400 MHz, DMSO-d ₆ , 100 ° C) δ 1.15-1.28 (6H, m), 2.19-2.36 (4H, m), 2.76-2.98 (3H, m), 3.20-4.36 (36H, m) ), 5.15 (1H, m), 5.66 (1H, s), 6.56 (1H, s), 7.30 (1H, d, J = 8.0 Hz), 7.53-7.59 (2H, m), 7.63 (1H, d, J = 8.0 Hz), 8.22 (1H, d, J = 8.0 Hz), 8.68 (1H, d, J = 8.0 Hz), 9.01-9.40 (1H, m).

Example 4
(S) -N-((S) -1-Cyclohexyl-2- (4- (5,6-difluoro-1-methyl-3- (2- (2- (2-((5-((4-) 4-) (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-yl) Oxy) ethoxy) ethoxy) ethoxy) -1H-Indol-2-carbonyl) Piperazine-1 -Il) -2-oxoethyl) -2- (methylamino) propanamide hydrochloride

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

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

B) tert-Butyl 4-[(5,6-difluoro-3-hydroxy-1-methyl-1H-indol-2-yl) carbonyl] piperazin-1-carboxylate methyl 5,6-difluoro-3-hydroxy- Argon 2M trimethylaluminum / toluene solution (18.2 mL) in a mixture of 1-methyl-1H-indole-2-carboxylate (4.4 g), tert-butyl piperazine 1-carboxylate (5.1 g) and toluene (45 mL) It was added at room temperature in an atmosphere. 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 give the title compound (3 g).
MS: [M + H] ⁺ 393.8.

C) 4- (3- (2- [2- (2-benzyloxy-ethoxy) -ethoxy] -ethoxy) -5,6-difluoro-1-methyl-1H-indole-2-carbonyl) -piperazine-1 -Carboxylic acid tert-butyl ester

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

D) (3- (2- (2- (2-benzyloxy-ethoxy) -ethoxy) -ethoxy) -5,6-difluoro-1-methyl-1H-indole-2-yl) -piperazine-1-yl -Metanon hydrochloride

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

E) tert-Butyl N-((1S) -2-(4-((3- (2- (2- (2- (benzyloxy) ethoxy) ethoxy) ethoxy) -5,6-difluoro-1-methyl) -1H-indole-2-yl) carbonyl) piperazine-1-yl) -1-cyclohexyl-2-oxoethyl) carbamate

4- (3- (2- (2- (2-benzyloxy-ethoxy) -ethoxy) -ethoxy) -5,6-difluoro-1-methyl-1H-indole-2-carbonyl) -piperazin-1-ium DIEA (0.694 ml) was added to the mixture of chloride (1.1 g) and DMF (10 mL). The reaction mixture was stirred at room temperature for 15 minutes and (S) -tert-butoxycarbonylamino-cyclohexylacetic acid (0.512 g), 1-hydroxybenzotriazole (366 mg, 2.39 mmol) and 1-ethyl-3- (3-dimethyl). Aminopropyl) 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 give the title compound (1.1 g).
MS: [M + H] ⁺ 757.0.

F) (1S) -2- (4-((3- (2- (2- (2- (benzyloxy) ethoxy) ethoxy) ethoxy) -5,6-difluoro-1-methyl-1H-indole-2 -Il) carbonyl) -piperazine-1-yl) -1-cyclohexyl-2-oxoethane-1-amine hydrochloride

tert-Butyl N-((1S) -2-(4-((3- (2- (2- (2- (benzyloxy) ethoxy) ethoxy) ethoxy) -5,6-difluoro-1-methyl-1H -Indol-2-yl) carbonyl) piperazine-1-yl) -1-cyclohexyl-2-oxoethyl) Ice 4M hydrogen chloride / dioxane solution (10 mL) in a mixture of carbamate (1.1 g) and DCM (10 mL) Added cold. The reaction mixture was stirred at room temperature for 3 hours and the solvent was evaporated under reduced pressure to give the title compound (1.1 g).
MS: [M + H] ⁺ 657.2.

G) tert-Butyl N-[(1S) -1-(((1S) -2-(4-((3- (2- (2- (2- (benzyloxy) ethoxy) ethoxy) ethoxy) -5) , 6-difluoro-1-methyl-1H-indole-2-yl) carbonyl) piperazine-1-yl) -1-cyclohexyl-2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate

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

H) tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((5,6-difluoro-3- (2- (2- (2-hydroxyethoxy)) ) Ethoxy) ethoxy) -1-methyl-1H-indole-2-yl) carbonyl) piperazine-1-yl) -2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate

tert-Butyl N-((1S) -1-(((1S) -2-(4-((3- (2- (2- (2- (benzyloxy) ethoxy) ethoxy) ethoxy) -5,6 -Difluoro-1-methyl-1H-indole-2-yl) carbonyl) piperazin-1-yl) -1-cyclohexyl-2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate (850 mg) and ethanol (10) 10% Palladium on carbon (50% hydrated) (200 mg) was added to the mixture of mL) at room temperature, and the mixture was stirred under a hydrogen atmosphere under normal pressure for 3 hours. The reaction mixture was filtered through Celite, washed with ethanol, and the filtrate was concentrated under reduced pressure to give the title compound (740 mg).
MS: [M + H] ⁺ 752.6.

I) tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((5,6-difluoro-1-methyl-3-(2- (2- (2-( 2-((5-((4- (Tieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) -1,2-Oxazole-3-yl) Oxy) ethoxy) ethoxy) Ethoxy) -1H-indole-2-yl) carbonyl) -piperazine-1-yl) -2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate

tert-butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((5,6-difluoro-3- (2- (2- (2-hydroxyethoxy) ethoxy) ) Ethoxy) -1-methyl-1H-indol-2-yl) carbonyl) piperidine-1-yl) -2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate (40 mg), 5-((4-4-) (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-ol (21.1 mg), triphenylphosphine (69.7 mg) and toluene (1.5 mL) in a mixture Di-tert-butylazodicarboxylate (36.7 mg) was added, the mixture was stirred at room temperature for 16 hours, and the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to give the title compound (36 mg).
MS: [M + H] ⁺ 1064.8.

J) (S) -N-((S) -1-Cyclohexyl-2- (4- (5,6-difluoro-1-methyl-3- (2- (2- (2-((5-(() 4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-yl) Oxy) ethoxy) ethoxy) ethoxy) -1H-Indol-2-carbonyl) Piperazine -1-yl) -2-oxoethyl) -2- (methylamino) propanamide hydrochloride

tert-butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((5,6-difluoro-1-methyl-3-(2- (2- (2- (2-) ((5-((4- (Thieno (3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) -1,2-Oxazole-3-yl) Oxy) ethoxy) ethoxy) ethoxy) -1H-indole-2-yl) carbonyl) -piperazine-1-yl) -2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate (36 mg) and DCM (1 mL) in a mixture of 4M hydrogen chloride / A dioxane solution (0.3 mL) was added under ice-cooling and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diethyl ether and pentane to give the title compound (24 mg).
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 1.03-1.23 (5H, m), 1.33 (3H, d, J = 6.76 Hz), 1.60-1.68 (4H, m), 2.16 (2H, m), 2.32 (2H, m), 3.12-3.20 (3H, m), 3.47-3.50 (8H, m), 3.57-3.74 (15H, m), 3.85-3.86 (2H, m), 4.14 (2H, s), 4.31 (2H, s), 4.54-4.64 (3H, m), 5.08-5.29 (2H, m), 6.63 (1H, s), 7.46 (1H, m), 7.65-7.69 (2H, m), 8.35 ( 1H, m), 8.79-8.80 (2H, m), 9.14 (1H, s), 11.7 (1H, br).

Example 5
(S) -N-((S) -1-cyclohexyl-2-(4- (5,6-difluoro-1- (3-methyl-2-oxo-14-)-((5-((4- (thieno) [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-yl) Oxy)-6,9,12-Trioxa-3-azatetradecyl) -1H-Indol- 2-carbonyl) piperazine-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) piperazin-1-yl) -2) -Oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate

tert-Butyl ((S) -1-(((S) -1-cyclohexyl-2-oxo-2-(piperazin-1-yl) ethyl) amino) -1-oxopropan-2-yl) (methyl) HATU (2.89 g, 1.5 Eq, 7.61 mmol) in a mixture of carbamate (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 the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound.
MS: [M + H-Boc] ⁺ 490.3.

B) Methyl 2-(2- (4-((S) -2-((S) -2-((tert-butoxycarbonyl) (methyl) amino) propanamide) -2-cyclohexylacetyl) piperazine-1- Carbonyl) -5,6-difluoro-1H-indole-1-yl) acetyl

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) carbamalate (2.64 g), potassium carbonate (681 mg), methyl 2-bromoacetate (753 mg) and DMF (20 mL) at room temperature for 16 hours. Stirred. 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 give 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-indole-1-yl) acetic acid

Methyl 2-(2-(4-((S) -2-((S) -2-((tert-butoxycarbonyl) (methyl) amino) propanamide) -2-cyclohexylacetyl) piperazine-1-carbonyl) Sodium hydroxide (834 mg) was added to a mixture of -5,6-difluoro-1H-indole-1-yl) acetyl (2.76 g) and methanol (20 mL). The reaction mixture was stirred at room temperature for 2 hours, acidified by adding 1M 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 give 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) piperazine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate

2-(2-(4-((S) -2-((S) -2-((tert-butoxycarbonyl) (methyl) amino) propanamide) -2-cyclohexylacetyl) piperazin-1-carbonyl)- 5,6-difluoro-1H-indol-1-yl) acetic acid (1.20 g), 5,8,11-trioxa-2-azatridecane-13-ol (422 mg), DIEA (479 mg), and DMF (9.3 mg). HATU (986 mg) was added to the mixture of mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 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] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-yl) Oxy)-6,9,12-Trioxa-3-azatetra Decyl) -1H-indole-2-carbonyl) piperazine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate
5-((4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isooxazole-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) piperidine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate (670 mg), triphenylphosphine (1.05 g) Di-tert-butylazodicarboxylate (553 mg) was added to the mixture of toluene (8 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (C18, aqueous acetonitrile / 5 mM ammonium acetate) to give 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-((4-4-) (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-yl) Oxy)-6,9,12-Trioxa-3-azatetradecyl) -1H- Indol-2-carbonyl) piperazine-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] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-yl) Oxy) -6,9,12-Trioxa-3-azatetradecyl) -1H-Indol-2-carbonyl) piperazine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) In a mixture of carbamate (575 mg) and ethyl acetate (1 mL) A 4M hydrogen chloride / ethyl acetate solution (364 mg) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (549 mg).
^{1 1} H NMR (400 MHz, DMSO-d ₆ , 100 ° C) δ 0.95-1.32 (5H, m), 1.35-1.40 (3H, m), 1.57-1.78 (6H, m), 1.94-2.08 (2H, m) ), 2.18-2.27 (2H, m), 3.05-3.78 (32H, m), 3.84-3.95 (1H, m), 3.99-4.21 (2H, m), 4.28-4.33 (2H, m), 4.63-4.70 (1H, m), 4.93-5.03 (1H, m), 5.17-5.26 (2H, m), 6.32-6.40 (1H, m), 6.72 (1H, s), 7.07-7.17 (1H, m), 7.47 -7.59 (3H, m), 8.08-8.13 (1H, m), 8.39-8.48 (1H, m), 8.53-8.62 (1H, m), 8.63-8.93 (2H, m).

Example 6
(S) -N-((S) -1-Cyclohexyl-2-(4- (5,6-difluoro-1- (2-oxo-2-((S) -2-(((5-(() 4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isooxazole-3-yl) Oxy) Methyl) Pyrrolidine-1-yl) Ethyl) -1H-Indol-2 -Carbonyl) piperazine-1-yl) -2-oxoethyl) -2- (methylamino) propanamide hydrochloride

A) tert-butyl ((S) -1-(((S) -1-cyclohexyl-2- (4- (5,6-difluoro-1- (2-oxo-2-((S) -2-) (((5-((4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-yl) Oxy) Methyl) Pyrrolidine-1-yl) Ethyl ) -1H-indol-2-carbonyl) piperazine-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate

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] pyridine) -7-Iloxy) piperidine-1-yl) methyl) isooxazole (140.7 mg), DIEA (107 μL), 1-hydroxybenzotriazole (83.37 mg), and 1-ethyl-3 in a mixture of DMF (3 mL) -(3-Dimethylaminopropyl) carbodiimide hydrochloride (118.3 mg) was added. The reaction mixture was stirred at room temperature for 2 hours, water was added, the precipitate was collected by filtration and washed with water to give the title compound (320.8 mg).
MS: [M + H] ⁺ 1044.3.

B) (S) -N-((S) -1-Cyclohexyl-2- (4- (5,6-difluoro-1- (2-oxo-2-((S) -2-(((S) -2-(((5-) ((4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isooxazole-3-yl) Oxy) Methyl) Pyrrolidine-1-yl) Ethyl) -1H-Indol -2-carbonyl) Piperazine-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] Pyridine-7-yloxy) piperidine-1-yl) methyl) isooxazole-3-yl) oxy) methyl) pyrrolidine-1-yl) ethyl)- 1H-Indol-2-carbonyl) Piperidine-1-yl) -2-oxoethyl) Amino) -1-oxopropan-2-yl) (Methyl) 4M in a mixture of carbamate (380.2 mg) and ethyl acetate (1.5 mL) A hydrogen chloride / ethyl acetate solution (1 mL) was added. The reaction mixture was stirred at room temperature for 1.5 hours and diisopropyl ether was added. The precipitate was collected by filtration and washed with diethyl ether to give the title compound (280.3 mg).
^{1 1} H NMR (DMSO-d ₆ , 300 MHz) δ 0.78-1.27 (7H, m), 1.45-2.21 (19H, m), 2.41 (3H, s), 2.58-2.78 (2H, m), 2.86-3.03 (1H, m), 3.18-3.85 (10H, m), 4.02-4.31 (3H, m), 4.53-4.87 (3H, m), 5.04-5.38 (2H, m), 6.10-6.39 (1H, m) , 6.76 (1H, s), 7.05 (1H, dd, J = 5.6, 2.7 Hz), 7.49 (1H, dd, J = 5.5, 2.1 Hz), 7.62 (1H, dd, J = 10.9, 8.0 Hz), 7.66-7.84 (1H, m), 7.93 (1H, d, J = 8.6 Hz), 8.02 (1H, dd, J = 5.4, 3.3 Hz), 8.49 (1H, d, J = 5.4 Hz)

Example 7
(S) -N-((S) -1-Cyclohexyl-2-(4- (5-Fluoro-1- (2-oxo-2-((S) -2-(((5-((4-4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isooxazole-3-yl) Oxy) Methyl) Pyrrolidine-1-yl) Ethyl) -1H-Indol-2-carbonyl ) Piperazine-1-yl) -2-oxoethyl) -2- (methylamino) propanamide

A) tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((5-fluoro-1H-indole-2-yl) carbonyl) piperazine-1-yl) )-2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate

tert-butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-oxo-2- (piperazin-1-yl) ethyl) carbamoyl) ethyl) -N-methylcarbamate (7 g) ) And DMF (60 mL) in a mixture of 5-fluoro-1H-indole-2-carboxylic acid (3.36 g), 1-hydroxybenzotriazole (3.00 g), DIEA (11.9 mL), 1-ethyl-3- ( 3-Dimethylaminopropyl) carbodiimide hydrochloride (4.25 g) was added. The reaction mixture was stirred at room temperature for 16 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (9.5 g).
MS: [M + H] ⁺ 572.0.

B) Methyl 2-((4-((2S) -2-((2S) -2-(((tert-butoxy) carbonyl) (methyl) amino) propanamide) -2-cyclohexylacetyl) piperazine -1-yl) carbonyl) -5-fluoro-1H-indole-1-yl) acetyl

tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((5-fluoro-1H-indole-2-yl) carbonyl) piperazin-1-yl)- 2-Oxoethyl) Carbamoyl) Ethyl) -N-Methylcarbamate (9.5 g) and DMF (50 mL) were mixed with potassium carbonate (6.89 g) and methylbromoacetate (4.59 mL) under ice cooling for reaction. The mixture was stirred at room temperature for 16 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (8.6 g).
MS: [M + H] ⁺ 644.1.

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

Methyl 2-((4-((2S) -2-((2S) -2-(((tert-butoxy) carbonyl) (methyl) amino) propanamide) -2-cyclohexylacetyl) piperazin-1 -Il) Carbonyl) -5-fluoro-1H-indol-1-yl) Add 2M aqueous sodium hydroxide solution (13.4 mL) to a mixture of acetyl (8.6 g) and methanol (25 mL) and mix the reaction mixture at room temperature 20 Stir for minutes. The reaction mixture was diluted with water and ethyl acetate, and the organic layer was extracted with 0.01 M aqueous sodium hydroxide solution. The aqueous layer was acidified with 6M 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 give the title compound (8.1 g).
MS: [M + H] ⁺ 630.2.

D) tert-butyl N-((1S) -1-(((1S) -1-cyclohexyl-2- (4- (5-fluoro-1-(2-oxo-2-((2S) -2-S) -2-) (((5-((4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) -1,2-Oxazole-3-yl) Oxy) Methyl) Pyrrolidine-1 -Il) Ethyl) -1H-Indol-2-carbonyl) Piperazine-1-yl) -2-oxoethyl) Carbamoyl) Ethyl) -N-Methylcarbamate

2- (2-((4-((2S) -2-((2S) -2-(((tert-butoxy) carbonyl) (methyl) amino) propanamide) -2-cyclohexylacetyl) piperazine-1- 1-((3-(((2S) -Pyrridine-2-yl) methoxy) in a mixture of (yl) carbonyl) -5-fluoro-1H-indol-1-yl) acetic acid (700 mg) and DMF (10 mL) ) -1,2-Oxazole-5-yl) Methyl) -4- (thieno [3,2-b] pyridine-7-yloxy) piperidine (506.8 mg), DIEA (0.78 mL), HATU (507.8 mg) In addition, it was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in this 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 give 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] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isooxazole-3-yl) Oxy) Methyl) Pyrrolidine-1-yl) Ethyl) -1H-Indol-2 -Carbonyl) piperazine-1-yl) -2-oxoethyl) -2- (methylamino) propanamide

tert-butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4- (5-fluoro-1-(2-oxo-2-((2S) -2-(( (5-((4- (Thieno [3,2-b] Pyridine-7-yloxy) piperidine-1-yl) methyl) -1,2-oxazole-3-yl) oxy) methyl) pyrrolidine-1-yl ) Ethyl) -1H-indole-2-carbonyl) piperidine-1-yl) -2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate (878 mg), ethyl acetate (1 mL) in a mixture of 4M chloride A hydrogen / ethyl acetate solution (4 mL) was added, and the mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The residue was dissolved in water (0.2 mL) and saturated aqueous sodium hydrogen carbonate solution was added. The precipitate was collected by filtration to give the title compound (687 mg).
^{1 1} H NMR (DMSO-d ₆ , 400 MHz, at 100 ° C) δ 0.89-1.30 (m, 7H), 1.34 (d, J = 6.8 Hz, 3H), 1.46-1.78 (m, 7H), 2.17 (s , 6H), 2.29-2.42 (m, 1H), 3.17 (s, 2H), 3.64 (s, 9H), 3.83-3.90 (m, 2H), 4.09-4.35 (m, 5H), 4.38-4.71 (m) , 4H), 5.03-5.48 (m, 3H), 6.73 (s, 1H), 7.11 (d, J = 9.8 Hz, 1H), 7.38 (d, J = 9.4 Hz, 1H), 7.45-7.52 (m, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.67 (s, 1H), 8.37 (s, 1H), 8.75 (d, J = 7.8 Hz, 1H), 8.82 (s, 2H), 9.17 ( s, 1H).
MS: [M + H] ⁺ 926.6.

Example 8
(S) -N-((S) -1-Cyclohexyl-2-((S) -4-(5,6-difluoro-1- (2-oxo-2-((S) -2-((() 5-((4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isooxazole-3-yl) Oxy) Methyl) Pyrrolidine-1-yl) Ethyl) -1H -Indol-2-carbonyl) -3-methylpiperazin-1-yl) -2-oxoethyl) -2- (methylamino) propanamide

A) 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 DMF (20) HATU (2.89 g) was added to the mixture of mL). The reaction mixture was stirred at room temperature for 1 hour, diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.61 g).
MS: [M + H-tBu] ⁺ 324.2.

B) Methyl 2-(2-((S) -4-((S) -2-((tert-butoxycarbonyl) amino) -2-cyclohexylacetyl) -2-methylpiperazine-1-carbonyl) -5, 6-Difluoro-1H-Indole-1-yl) Acetate

tert-Butyl (S) -4- (5,6-difluoro-1H-indol-2-carbonyl) -3-methylpiperazin-1-carboxylate (1.61 g), potassium carbonate (762 mg, 1.3 Eq, 5.52 mmol) ), Methyl 2-bromoacetate (1.04 g), and DMF (15 mL) were stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). With the obtained tert-butyl (S) -4- (5,6-difluoro-1- (2-methoxy-2-oxoethyl) -1H-indole-2-carbonyl) -3-methylpiperazin-1-carboxylate A 4M hydrogen chloride / ethyl acetate solution (3.09 g) was added to the mixture of ethyl acetate (10 mL). The reaction mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The resulting methyl (S) -2- (5,6-difluoro-2- (2-methylpiperazin-1-carbonyl) -1H-indole-1-yl) acetate hydrochloride, (S) -2-(( tert-butoxycarbonyl) amino) -2-cyclohexylacetic acid (1.20 g), methyl (S) -2- (5,6-difluoro-2- (2-methylpiperazin-1-carbonyl) -1H-indole-1- HATU (3.22 g) was added to a mixture of yl) acetate hydrochloride (1.64 g), DIEA (3.0 mL), and DMF (20 mL). The reaction mixture was stirred at room temperature for 1 hour, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (639 mg).
MS: [M + H] ⁺ 591.5.

C) Methyl 2-(2-((S) -4-((S) -2-((S) -2-((tert-butoxycarbonyl) (methyl) amino) propanamide) -2-cyclohexylacetyl)) -2-Methylpiperazin-1-carbonyl) -5,6-difluoro-1H-indole-1-yl) acetyl

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

D) 2-(2-((S) -4-((S) -2-((S) -2-((tert-butoxycarbonyl) (methyl) amino) propanamide) -2-cyclohexylacetyl)- 2-Methylpiperazin-1-carbonyl) -5,6-difluoro-1H-indole-1-yl) acetic acid

Methyl 2-(2-((S) -4-((S) -2-((S) -2-((tert-butoxycarbonyl) (methyl) amino) propanamide) -2-cyclohexylacetyl) -2 -Methylpiperazin-1-carbonyl) -5,6-difluoro-1H-indol-1-yl) Sodium hydroxide (66.6 mg) was added to a mixture of acetyl (225 mg) and methanol (1.6 mL). The reaction mixture was stirred at room temperature for 1 hour, acidified with 1M 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 give the title compound (221 mg).
MS: [M + H] ⁺ 662.4.

E) tert-butyl ((S) -1-(((S) -1-cyclohexyl-2-((S) -4-(5,6-difluoro-1-(2-oxo-2-((S) ) -2-(((5-((4- (Thieno [3,2-b] Pyridine-7-yloxy) piperidine-1-yl) methyl) isooxazole-3-yl) oxy) methyl) pyrrolidine-1 -Il) ethyl) -1H-indole-2-carbonyl) -3-methylpiperazin-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate

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 (175 mg), (S) -3- (pyrrolidin-2-ylmethoxy) -5-((4- (thieno [3,2-b] pyridine) HATU (205 mg) was added to a mixture of -7-yloxy) piperidine-1-yl) methyl) isooxazole trihydrochloride (156 mg), DIEA (0.24 mL), and DMF (3 mL). The reaction mixture was stirred at room temperature for 2 hours, water was added, and the precipitate was collected by filtration and purified by silica gel column chromatography (C18, acetonitrile / 5 mM aqueous ammonium acetate solution / acetonitrile). Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the obtained compound, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (136 mg).
MS: [M + H] ⁺ 1058.5.

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

Example 9
(S) -N-((S) -1-Cyclohexyl-2-((S) -4- (5-Fluoro-1- (2-oxo-2-((S) -2-(((S) -2-(((5-) ((4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isooxazole-3-yl) Oxy) Methyl) Pyrrolidine-1-yl) Ethyl) -1H-Indol -2-carbonyl) -3-methylpiperazin-1-yl) -2-oxoethyl) -2- (methylamino) propanamide

A) Benzyl (2S) -4-((2S) -2-(((tert-butoxy) carbonyl) amino) -2-cyclohexylacetyl) -2-methylpiperazin-1-carboxylate

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

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

Benzyl (2S) -4-((2S) -2-(((tert-butoxy) carbonyl) amino) -2-cyclohexylacetyl) -2-methylpiperazin-1-carboxylate (6.7 g) and DCM (60 mL) ) Was added with a 4M hydrogen chloride / dioxane solution (30 mL). The reaction mixture was stirred at room temperature for 3 hours and the solvent was evaporated under reduced pressure. The residue was washed with DCM to give the title compound (6 g).
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 1.60-1.70 (6H, m), 2.85-3.18 (4H, m), 3.37-3.47 (1H, m), 3.57 (4H, s), 3.77-3.87 (1H, m), 4.13-4.29 (3H, m), 5.10-5.14 (2H, m), 7.33-7.37 (5H, m), 8.06-8.04 (3H, m).

C) Benzyl (2S) -4-((2S) -2-((2S) -2-(((tert-butoxy) carbonyl) (methyl) amino) propanamide) -2-cyclohexylacetyl) -2-methyl Piperazine-1-carboxylate

Benzyl (2S) -4-((2S) -2-amino) in a mixture of (2S) -2-(((tert-butoxy) carbonyl) (methyl) amino) propanoic acid (3 g) and DMF (30 mL) -2-Cyclohexylacetyl) -2-methylpiperazin-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 successively 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 give the title compound (6 g).
MS: [M + H] ⁺ 559.1.

D) tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-((3S) -3-methylpiperazin-1-yl) -2-oxoethyl) carbamoyl) ethyl)- N-Methylcarbamate

Benzyl (2S) -4-((2S) -2-((2S) -2-(((tert-butoxy) carbonyl) (methyl) amino) propanamide) -2-cyclohexylacetyl) -2-methylpiperazin- To a mixture of 1-carboxylate (3.8 g) and ethanol (50 mL) was added 10% palladium carbon (50% hydrous) (1 g). The reaction mixture was stirred at room temperature for 16 hours under normal pressure hydrogen atmosphere and filtered through Celite. The filtrate was concentrated under reduced pressure to give 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-cyclohexylacetyl)) -2-Methylpiperazin-1-carbonyl) -5-fluoro-1H-indole-1-yl) acetyl

tert-butyl ((S) -1-(((S) -1-cyclohexyl-2-((S) -3-methylpiperazin-1-yl) -2-oxoethyl) amino) -1-oxopropane-2 -HATU (1.21 g) in a mixture of yl) (methyl) carbamate (901 mg), 5-fluoro-1H-indole-2-carboxylic acid (380 mg), DIEA (1.14 mL), and DMF (12 mL). added. The reaction mixture was stirred at room temperature for 1 hour, poured into water, the precipitate was collected by filtration and azeotroped with toluene. The obtained tert-butyl ((S) -1-(((S) -1-cyclohexyl-2-((S) -4- (5-fluoro-1H-indole-2-carbonyl) -3-methylpiperazin) -1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate,

A mixture of potassium carbonate (322 mg), methyl 2-bromoacetate (356 mg) and DMF (12 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (979 mg).
MS: [M + H] ⁺ 658.4.

F) 2-(2-((S) -4-((S) -2-((S) -2-((tert-butoxycarbonyl) (methyl) amino) propanamide) -2-cyclohexylacetyl)- 2-Methylpiperazin-1-carbonyl) -5-fluoro-1H-indole-1-yl) acetic acid

Methyl 2-(2-((S) -4-((S) -2-((S) -2-((tert-butoxycarbonyl) (methyl) amino) propanamide) -2-cyclohexylacetyl) -2 -Methylpiperazin-1-carbonyl) -5-fluoro-1H-indol-1-yl) Sodium hydroxide (298 mg) was added to a mixture of acetyl (979 mg) and methanol (8 mL). The reaction mixture was stirred at room temperature for 1 hour, acidified by adding 1M 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 give 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)-)- 2-(((5-((4- (Thieno [3,2-b] Pyridine-7-yloxy) piperidine-1-yl) methyl) isooxazole-3-yl) oxy) methyl) pyrrolidine-1-yl ) Ethyl) -1H-indole-2-carbonyl) -3-methylpiperazin-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate

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 (175 mg), (S) -3- (pyrrolidin-2-ylmethoxy) -5-((4- (thieno [3,2-b] pyridine) HATU (205 mg) was added to a mixture of -7-yloxy) piperidine-1-yl) methyl) isooxazole trihydrochloride (156 mg), DIEA (0.24 mL), and DMF (3 mL). The reaction mixture was stirred at room temperature for 2 hours, water was added, the precipitate was collected by filtration, and purified by silica gel column chromatography (C18, aqueous acetonitrile / 5 mM ammonium acetate). Ethyl acetate and an 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 give the title compound (136 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] Pyridine-7-yloxy) piperidine-1-yl) methyl) isooxazole-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] Pyridine-7-yloxy) piperidin-1-yl) methyl) isooxazole-3-yl) oxy) methyl) pyrrolidine-1-yl) ethyl ) -1H-Indol-2-carbonyl) -3-methylpiperazin-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate (367 mg) and ethyl acetate (2) A 4M hydrogen chloride / ethyl acetate solution (3 mL) was added to the mixture of mL). The reaction mixture was stirred at room temperature for 1 and a half hours, and the solvent was evaporated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the precipitate was collected by filtration to give the title compound (249 mg).
^{1 1} H NMR (DMSO-d ₆ , 300 MHz) δ 0.74-1.34 (10H, m), 1.38-2.25 (19H, m), 2.33-2.46 (2H, m), 2.60-3.50 (8H, m), 3.55 -3.71 (3H, m), 3.79-4.94 (8H, m), 5.00-5.50 (2H, m), 6.03-6.43 (1H, m), 6.61-6.82 (1H, m), 6.98-7.19 (2H, m) m), 7.26-7.71 (3H, m), 7.89 (1H, t, J = 9.7 Hz), 7.98-8.13 (1H, m), 8.49 (1H, d, J = 5.5 Hz).

Example 10
(S) -N-((S) -1-Cyclohexyl-2- (4- (5,6-difluoro-1-methyl-4-) (2- (2- (2- (2-((5- (5-( (4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-yl) Oxy) ethoxy) ethoxy) ethoxy) ethoxy) -1H-Indol-2- Carbonyl) piperazine-1-yl) -2-oxoethyl) -2- (methylamino) propanamide hydrochloride

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

Potassium carbonate (6.561 g), benzyl bromide (4.51 ml) and sodium iodide (2.372 g) were added to a mixture of 3,4-difluoro-2-hydroxy-benzaldehyde (5 g) and acetonitrile (50 mL). The reaction mixture was stirred at 60 ° C. for 6 hours, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (7.0 g).
^{1 1} H NMR (400 MHz, DMSO-d ₆ ): δ 5.33 (2H, s), 7.30-7.42 (4H, m), 7.45-7.47 (2H, m), 7.55-7.59 (1H, m), 10.04 ( 1H, s).

B) Methyl (2Z) -2-Azide-3- [2- (benzyloxy) -3,4-difluorophenyl] Propa-2-enoart

A mixture of methyl azidoacetate (3.146 ml), 2- (benzyloxy) -3,4-difluorobenzaldehyde (2.0 g) and methanol (10 mL) with a mixture of sodium methoxide (1.743 g) and methanol (10 mL)- It was added 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 give the title compound (2.1 g).
^{1 1} H NMR (400 MHz, DMSO-d ₆ ): δ 3.83 (3H, s), 5.14 (2H, s), 6.94 (1H, s), 7.26 (1H, m), 7.38-7.40 (5H, m) , 7.97 (1H, t, J = 6.9 Hz).

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

A mixture of methyl (2Z) -2-azido-3- (2- (benzyloxy) -3,4-difluorophenyl) propa-2-enoate (2.0 g) and xylene (30 mL) is stirred at 140 ° C for 2 hours. did. The reaction mixture was cooled and the precipitate was collected by filtration to give the title compound (700 mg).
^{1 1} H NMR (400 MHz, DMSO-d ₆ ): δ 3.87 (3H, s), 5.41 (2H, s), 7.05 (1H, m), 7.26 (1H, s), 7.32-7.41 (3H, m) , 7.47-7.49 (2H, m), 12.19 (1H, s).

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

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

E) 4- (benzyloxy) -5,6-difluoro-1-methyl-1H-indole-2-carboxylic acid

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

F) tert-Butyl N-((1S) -1-(((1S) -2-(4-((4- (benzyloxy) -5, 6-difluoro-1-methyl-1H-indole-2-) Indole) carbonyl) piperazine-1-yl) -1-cyclohexyl-2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate

Tert-Butyl N-((1S) -1-) in a mixture of 4- (benzyloxy) -5,6-difluoro-1-methyl-1H-indole-2-carboxylic acid (1.4 g) and DMF (20 mL) (((1S) -1-cyclohexyl-2-oxo-2- (piperazin-1-yl) ethyl) carbamoyl) ethyl) -N-methylcarbamate (1.81 g), HATU (2.52 g) and DIEA (1.9 ml) ) Was added. The reaction mixture was stirred at room temperature for 2 hours, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 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 give the title compound (2.1 g).
^{MS: [M + H] +} 710.1.

G) tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((5,6-difluoro-4-hydroxy-1-methyl-1H-indole-2) -Il) carbonyl) piperazine-1-yl) -2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate

tert-Butyl N-((1S) -1-(((1S) -2-(4-((4- (benzyloxy) -5, 6-difluoro-1-methyl-1H-indol-2-yl)) Add palladium carbon (400 mg) to a mixture of carbonyl) piperazin-1-yl) -1-cyclohexyl-2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate (2.1 g) and ethanol (50 mL). The mixture was stirred at room temperature for 2 hours under a normal pressure hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (1.7 g).
MS: [M + H] ⁺ 620.4.

H) tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((5,6-difluoro-1-methyl-4-((1-phenyl-2)) , 5,8,11-Tetraoxatridecane-13-yl) oxy) -1H-indole-2-yl) carbonyl) piperazine-1-yl) -2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate

tert-butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((5,6-difluoro-4-hydroxy-1-methyl-1H-indol-2-yl) ) Carbonyl) piperazin-1-yl) -2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate (450 mg) and DMF (5 mL) in a mixture of cesium carbonate (591 mg) and toluene-4-sulfonic acid 2-(2- (2- (2-benzyloxy-ethoxy) -ethoxy) -ethoxy) -ethyl ester (573 mg) was added. The reaction mixture was stirred at room temperature for 16 hours, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (490 mg).
MS: [M + H] ⁺ 886.4.

I) tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2- (4-((5,6-difluoro-4- (2- (2- (2- (2)) -Hydroxyethoxy) ethoxy) ethoxy-) ethoxy) -1-methyl-1H-indole-2-yl) carbonyl) piperazine-1-yl) -2-oxoethyl) carbamoyl) ethyl) -N-methyl-carbamate

tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((5,6-difluoro-1-methyl-4-((1-phenyl-2,5)) , 8,11-Tetraoxatridecane-13-yl) oxy) -1H-indole-2-yl) carbonyl) piperazin-1-yl) -2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate (490) Palladium on carbon (100 mg) was added to the mixture of mg) and ethanol (15 mL). The reaction mixture was stirred under normal pressure hydrogen atmosphere at room temperature for 16 hours, filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (360 mg).
MS: [M + H] ⁺ 796.2.

J) tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((5,6-difluoro-1-methyl-4-((1- (5-) ((4- (Thieno [3,2-b) Pyridine-7-yloxy) Piperidine-1-yl) Methyl) -1,2-Oxazole-3-yl) -1,4,7,10-Tetraoxadodecane -12-yl) oxy) -1H-indole-2-yl) carbonyl) piperazine-1-yl) -2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate

tert-butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((5,6-difluoro-4- (2- (2- (2- (2-hydroxy) Ethoxy) ethoxy) ethoxy-) ethoxy) -1-methyl-1H-indol-2-yl) carbonyl) piperidine-1-yl) -2-oxoethyl) carbamoyl) ethyl) -N-methyl-carbamate (20 mg), 5-((4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-ol (12.4 mg), Triphenylphosphine (32.9 mg) and Toluene ( Di-tert-butylazodicarboxylate (17.3 mg) was added to the mixture of 2 mL). The reaction mixture was stirred at room temperature for 16 hours and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography to give the title compound (25 mg).
MS: [M + H] ⁺ 1109.8.

K) (S) -N-((S) -1-Cyclohexyl-2- (4- (5,6-difluoro-1-methyl-4- (2- (2- (2- (2-((5)) -((4- (Chieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-yl) Oxy) ethoxy) ethoxy) ethoxy) ethoxy) -1H-Indol- 2-carbonyl) piperazine-1-yl) -2-oxoethyl) -2- (methylamino) propanamide hydrochloride

tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((5,6-difluoro-1-methyl-4-((1- (5-(() 4- (Thieno [3,2-b) Pyridine-7-yloxy) Piperidine-1-yl) Methyl) -1,2-Oxazole-3-yl) -1,4,7,10-Tetraoxadodecane-12 -Il) Oxy) -1H-Indol-2-yl) Carbonyl) Piperazine-1-yl) -2-oxoethyl) Carbamoyl) Ethyl) -N-Methylcarbamate (25 mg) and DCM (1 mL) A 4M hydrogen chloride / dioxane solution (0.3 mL) was added at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour, the solvent was evaporated under reduced pressure, ether was added, and the precipitate was collected by filtration to give the title compound (17 mg).
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 0.83-1.34 (9H, m), 1.60-1.69 (5H, m), 2.07-2.18 (3H, m), 3.17 (3H, s), 3.44-3.74 (25H, m), 3.85-4.66 (9H, m), 5.01-5.27 (2H, m), 6.63 (1H, bs), 6.81 (1H, s), 7.36-7.44 (2H, m), 7.66 (1H) , d, J = 5.32 Hz), 8.35-8.36 (1H, m), 8.74-8.80 (2H, m), 9.10-9.11 (1H, m), 11.36 (1H, brs).

Example 11
(S) -N-((S) -1-Cyclohexyl-2- (4- (2-Methyl-1- (2- (2- (2- (2-((5-((4- (Chieno]) 3,2-b] Pyridine-7-yloxy) piperidine-1-yl) methyl) isooxazole-3-yl) oxy) ethoxy) ethoxy) ethoxy) ethyl) -1H-indole-5-carbonyl) piperazin-1- Il) -2-oxoethyl) -2- (methylamino) propanamide

A) tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((2-methyl-1H-indole-5-yl) carbonyl) piperazine-1-yl) ) -2-
Oxoethyl) carbamoyl) ethyl) -N-methylcarbamate

tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-oxo-2- (piperazin-1-yl) ethyl) carbamoyl) ethyl) -N-methylcarbamate (4 g) 2-Methyl-1H-indole-5-carboxylic acid (1.9 g), DIEA (6.8 ml), and HATU (4.45 g) were added to a mixture of 9.74 mmol) and DMF (70 mL) 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 this 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 give the title compound (4 g).
MS: [M + H] ⁺ 568.3.

B) tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((2-methyl-1- (1-phenyl-2,5,8,11-) Tetraoxatridecane-13-yl) -1H-indole-5-yl) carbonyl) piperazine-1-yl) -2-oxoethyl) carbamoyl) ethyl] -N-methylcarbamate

tert-butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((2-methyl-1H-indole-5-yl) carbonyl) piperazin-1-yl)- 2-Oxoethyl) Carbamoyl) Ethyl) -N-Methylcarbamate (2 g) and DMF (30 mL) are mixed with cesium carbonate (2.87 g), stirred for 5 minutes at room temperature, and then 1-phenyl-2,5. , 8,11-Tetraoxatridecane-13-yl 4-methylbenzene-1-sulfonate (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 give the title compound (1.3 g).
MS: [M + H] ⁺ 834.4.

C) tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((1- (2- (2- (2- (2-hydroxyethoxy) ethoxy)) Ethoxy) ethyl) -2-methyl-1H-indole-5-yl) carbonyl) piperazine-1-yl) -2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate

tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((2-methyl-1-(1-phenyl-2,5,8,11-tetraoxa)) Tridecane-13-yl) -1H-indole-5-yl) carbonyl) piperazin-1-yl) -2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate (1.3 g) and ethanol (50 mL) 10% Palladium on carbon (50% hydrous) (250 mg) was added to the mixture, and the mixture was stirred at 25 ° C. for 16 hours under a hydrogen atmosphere under normal pressure. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (1.1 g).
MS: [M + H] ⁺ 744.3.

D) tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((2-methyl-1- (1- (5-((4- (thieno]) 3,2-b] Pyridine-7-yloxy) piperidine-1-yl) methyl) -1,2-oxazole-3-yl) -1,4,7,10-tetraoxadodecane-12-yl) -1H -Indol-5-yl) carbonyl) piperazine-1-yl) -2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate

tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((1-(2-(2-(2-(2-hydroxyethoxy) ethoxy) ethoxy)) Ethyl) -2-methyl-1H-indole-5-yl) carbonyl) piperidine-1-yl) -2-oxoethyl) carbamoyl) ethyl) -N-methylcarbamate (20 mg), 5-((4- (4- (4-) To a mixture of thieno [3,2-b] pyridine-7-yloxy) piperidine-1-yl) methyl) isooxazole-3-ol (10.6 mg), triphenylphosphine (35.2 mg) and toluene (2 mL), Di-tert-butylazodicarboxylate (24.7 mg) was added, and the mixture was stirred at 25 ° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography to give the title compound (17 mg).
MS: [M + H] ⁺ 1057.3.

E) (2S) -N-((1S) -1-cyclohexyl-2-(4-((2-methyl-1- (1- (5-((4- (thieno [3,2-b]] pyridine) -7-Iloxy) Piperidine-1-yl) Methyl) -1,2-Oxazole-3-yl) -1,4,7,10-Tetraoxadodecane-12-yl) -1H-Indol-5-yl) Carbonyl) piperazine-1-yl) -2-oxoethyl) -2- (methylamino) propanamide

tert-Butyl N-((1S) -1-(((1S) -1-cyclohexyl-2-(4-((2-methyl-1-(1-(5-((4- (thieno [3,,) 2-b] Pyridine-7-yloxy) piperidine-1-yl) methyl) -1,2-oxazole-3-yl) -1,4,7,10-tetraoxadodecane-12-yl) -1H-indole -5-Il) Carbonyl) Piperazine-1-yl) -2-oxoethyl) Carbamoyl) Ethyl) -N-Methylcarbamate (17 mg) and DCM (1 mL) mixed with TFA (0.01 ml) at 0 ° C. And stirred at 25 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC preparative HPLC (C18, mobile phase: acetonitrile / 20 mM ammonium bicarbonate aqueous solution) to give the title compound (4 mg).
MS: [M + H] ⁺ 957.7.

The produced Example compounds are shown in Tables 1-1 to 1-4 below. MS in the table shows the measured value.

Test Example 1: Measurement of XIAP binding inhibitory activity The human XIAP binding inhibitory activity is a Smac N-terminal peptide (AVPIAQK (SEQ ID NO: 1)) in which the C-terminal is biotinylated by a conventional method using a commercially available human XIAP_BIR3 domain purified protein (R & D). ) (Hereinafter referred to as "b-Smac"; Peptide Institute, Ltd.) was used as a ligand for measurement by the Homogeneous Time Resolved Fluorescence (HTRF) method.
The HTRF method will be described in detail below.
The test compound diluted with the reaction Buffer was added to a 384-well white shallow bottom plate (Greiner 784076) at 1 μL / well and Flash centrifugation was performed for 30 seconds. Subsequently, the human XIAP_BIR3 domain purified protein is diluted with a reaction Buffer (25 mM HEPES Buffer containing 100 mM NaCl, 0.1% BSA, 0.1% triton X-100, pH 7.5) to 90 nM, and the sample diluent is diluted. After that, the sample diluent was added to the white shallow bottom plate at 4.5 μL / well, and Flash centrifugation was performed for 30 seconds. Subsequently, b-Smac diluted to 90 nM with the reaction Buffer was added to the above white shallow bottom plate at 4.5 μL / well, and Flash centrifugation was performed for 30 seconds. Anti-6 HIS-Cryptate (Eu3 + Cryptate-conjugated mouse monoclonal antibody anti-6 Histidine; cisbio) diluted 100-fold with HTRF detection buffer (cisbio), and Streptavidin-XL ^ent! (Highgrade XL665-conjugated streptavidin; cisbio) 1 A solution mixed in a volume of 1: 1 was added to the above white shallow bottom plate at 10 μL / well, and Flash centrifugation was performed for 30 seconds, and then the white shallow bottom plate was left in a dark place at room temperature for 4 hours or more. The white shallow bottom plate after standing was subjected to fluorescence intensity measurement (excitation wavelength: 320 nm, fluorescence wavelength: 665 nm and 615 nm) by EnVision (PerkinElmer).
The binding inhibition rate (%) was calculated from the HTRF ratio in the presence of the test compound with respect to the HTRF ratio (fluorescence intensity at 665 nm / fluorescence intensity at 615 nm) in the absence of the test compound.
Regarding the XIAP binding inhibition rate of the test compound, the XIAP binding inhibition rate when the concentration of the test compound is 3 μM is A ≧ 75%, 75%> B ≧ 50%, 50%> C ≧ 25%, D> 25. % Or 50% inhibition concentration (IC50 value) is shown in the table below with A <0.3 μM, 0.3 μM ≦ B <3 μM, 3 μM ≦ C <30 μM.

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

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

Test Example 2: Measurement of IRAK-M binding inhibitory activity
IRAK-M binding inhibitory activity is an active site-dependent competitive measurement method provided by DiscoverX KINOMEscan (Goldstein, DM et al. High-throughput kinase profiling as a platform for drug discovery. Nat. Rev. Drug Discovery. 7, 391- It was measured using 397 (2008)). Regarding the IRAK-M binding inhibition rate of the test compound, the IRAK-M binding inhibition rate when the concentration of the test compound is 1 μM is A ≧ 75%, 75%> B ≧ 50%, 50%> C ≧ 25%. , D> 25%, or IC50 values are shown in the table below with A <0.03 μM, 0.03 μM ≦ B <0.1 μM, 0.1 μM ≦ C <0.3 μM, 0.3 μM ≦ D <1 μM. % Ctrl at 1 μM is shown in Table x with A ≧ 75%, 75%> B ≧ 50%, 50%> C ≧ 25%, and D> 25%. % Ctrl was calculated by 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 vitro The degradation-inducing activity of target protein in vitro of Example compounds was evaluated by enzyme-linked immunosorbent assay (ELISA) according to the following assay steps. THP1 cells were purchased from ATCC and cultured in RPMI-1640 supplemented with 10% FBS, 1X Sodium Pyruvate, 1X HEPES, D- (+)-Glucose and 1% penicillin / streptomycin. THP1 cells seeded on a 24-well plate at 1 × 10 ⁶ cells / well were treated with DMSO control and test compound and cultured for 24 hours. Cells were harvested and lysed on ice for 30 minutes using lysis buffer (PBS containing 0.1% Triton X-100) supplemented with a protease inhibitor cocktail (Roche, Cat # 11836170001). The lysate was sonicated at 30 sec ON / 30 sec OFF for 10 cycles and then centrifuged at 4 ° C and 13 rpm for 10 minutes. Protein concentration was determined by BCA assay (Sigma, Cat # QPBCA-1KT). The ELISA assay used the Human IRAK3 / IRAKM / IRAK-M ELISA Kit (LifeSpan BioSciences, Cat # LS-F35271) and evaluated the protein content of IRAK-M according to the kit protocol. Regarding the IRAK-M proteolytic rate of the test compound, the proteolytic rate (%) at a concentration of 1 μM of the test compound was A ≧ 75%, 50% ≦ B <75%, 25% ≦ C <50%, D < The DC50 values at 25% or DC50 are shown in the table below with 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: Proteolysis rate at 1 μM / DC50 value

Test Example 4: Antitumor effect in mouse LL2 model
C57BL / 6 mice (Charles River, Japan, male, 7-8W) with mice Lewis lung carcinoma cells LL / 2 (Lewis lung carcinoma, LLC) (ATCC, CRL-1642) 2 × 10 ⁴ cells / mouse with Matrigel on the side of the mouse Subcutaneous inoculation. Tumor size was measured with an electronic caliper 7 days after inoculation, grouped so as to be the same size as each group, and administration of the compound was started 8 days later. The tumor size was calculated using the formula: major axis x minor axis x minor axis ÷ 2 of the tumor.
The test compound was suspended in 0.5% metrocellulose or dissolved in physiological saline, and subcutaneously administered 3 times every 3 days. Tumor size was measured regularly from 16 to 18 days after the start of the test, and two groups were tested for tumor size in the test compound administration group and tumor size in the solvent administration group on the final day of the test.
FIG. 1 shows the changes over time in tumor size in each group of Examples 1, 6, 7, 8, and 9. For each compound, the salt shown in the figure was used. The figure shows the mean ± standard error.
From the above results, it was shown that these compounds have a cancer growth inhibitory effect.

Formulation Example 1
A drug containing the compound of the present invention as an active ingredient can be produced, for example, by the following formulation.
1. 1. Capsule (1) Compound 40 mg obtained in Example 1
(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), granulate. The remaining (4) is added to this, and the whole is sealed in a gelatin capsule.

2. 2. Tablets (1) Compound 40 mg obtained in Example 1
(2) Lactose 58 mg
(3) Cornstarch 18 mg
(4) Microcrystalline cellulose 3.5 mg
(5) Magnesium stearate 0.5 mg
1 tablet 120 mg
After mixing 2/3 of (1), (2), (3), (4) and 1/2 of (5), the granules are granulated. The remaining (4) and (5) are added to the granules and pressure molded into tablets.

Preparation example 2
After dissolving 50 mg of the compound obtained in Example 1 in 50 mL of distilled water for Japanese Pharmacopoeia, add distilled water for Japanese Pharmacopoeia to make 100 mL. The solution is filtered under sterile conditions, then 1 mL of this solution is taken, filled into injection vials under sterile conditions, lyophilized and sealed.

The above detailed description merely describes the purpose and subject matter of the present invention, and does not limit the scope of the appended claims. Various changes and substitutions to the described embodiments will be apparent to those skilled in the art from the teachings set forth herein, without departing from the appended claims.

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

Claims (14)

The following formula (I):
A compound represented by, or a pharmaceutically acceptable salt thereof. The IRAK-M binder (M) has the following formula (II).
[In the formula, X is S, Y is CH or N, Z is O, R ⁰¹ is H or Me, R ⁰² is H, and R ⁰³ is the following structural formula:
It is a group represented by (where n is 0 to 2), and A is the following structural formula:
(Here, R ⁰⁵ is a group represented by a hydrogen atom or a C1-6 alkyl group independently of each other), or * -SO _2- *, and R ⁰⁴ is the following structural formula:
(Here, V is CH or N.) Any group represented by, optionally substituted alkyl group, optionally substituted aryl group or bond, arrow is linker (L). ) Is shown. ], The compound according to claim 1, or a pharmaceutically acceptable salt thereof. The IRAK-M binder (M) has the following formula (III).
[In the formula, Y is CH or N,
R ⁰¹ is H or Me,
A ⁰¹ has the following structural formula:
(Here, R ¹² is a group represented by a hydrogen atom or a C1-6 alkyl group, respectively), or * -SO _2- *.
R ¹¹ has the following structural formula:
One of the groups represented by, the arrow indicates the bond to the linker (L). ], The compound according to claim 2, or a pharmaceutically acceptable salt thereof. IRAK-M binder is the following compound,
5-((4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-ol,
5-((4-((2-Methylthieno [3,2-b] Pyridine-7-yl) Oxy) Piperidine-1-yl) Methyl) Isoxazole-3-ol
1-Methyl-5-((4- (thieno [3,2-b] pyridin-7-yloxy) piperidine-1-yl) methyl) -1H-pyrazole-3-ol
4-((4- (Thieno [3,2-d] pyrimidin-4-yloxy) piperidine-1-yl) sulfonyl) is a monovalent group derived from a compound selected from the group consisting of phenol, claim. 2. The compound according to 2. The compound according to any one of claims 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. .. The linker (L) has the structural formula described below:
The group according to any one of claims 1 to 4, which is any group represented by, *-(CH ₂ CH ₂ O) n- * (n is 1-5), or a mere bonder. A compound, or a pharmaceutically acceptable salt thereof. The E3 ligase binder has the following formula (IV):
[In the formula, D is the following formula (V)
(In the formula, m represents 0 to 2, n represents 0 to 2, W ₁₁ represents a methylene group, a difluoromethylene group, O, S, SO, SO ₂ , or NR, where R is hydrogen. Indicates an atom, C1-6 alkyl group, C1-6 alkyl-carbonyl group, C6-14 aryl-carbonyl group, or C1-6 alkylsulfonyl group, where T indicates a C1-3 alkyl group which may be halogenated. .) And E is the following equation (VI):
_{(R 21} , R ₂₂ , and R ₂₃ in the formula independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an amide group, and R ₂₅ and R ₂₆ are Each independently indicates a bond to a hydrogen atom, halogen atom, C1-6 alkyl group, C1-6 alkoxy group, amide group, or linker, and R ₂₄ indicates a bond to a hydrogen atom, methyl group, or linker. ) Or the following formula (VII):
_{(R 31} , R _32, R ₃₃ , R ₃₄ , and R ₃₅ in the formula each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an amide group, and R Indicates a bond to a hydrogen atom, a C1-6 alkyl group or a linker).) The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. The following compounds:
2- (4-((S) -2-Cyclohexyl-2-((S) -2- (methylamino) propanamide) acetyl) piperazine-1-carbonyl) -5,6-difluoro-N, 1-dimethyl -N- (2- (2-((2-((5-((4- (thieno [3,2-b] pyridine-7-yloxy) piperidine-1-yl) methyl) isooxazole-3-yl)) Oxy) ethoxy) ethoxy) ethyl) -1H-indole-3-carboxamide,
2- (4-((S) -2-Cyclohexyl-2-((S) -2- (methylamino) propanamide) 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,
1-((R) -4- (5,6-difluoro-1-methyl-1H-indol-2-carbonyl) -2-methylpiperazin-1-yl) -2-((2R, 5R) -5- Methyl-2-((2- (2- (2-((5-((4- (thieno [3,2-b] pyridin-7-yloxy) piperidine-1-yl) methyl) isooxazole-3- Il) oxy) ethoxy) ethoxy) ethoxy) methyl) piperazine-1-yl) ethane-1-one,
(S) -N-((S) -1-Cyclohexyl-2- (4- (5,6-difluoro-1-methyl-3- (2- (2- (2-((5-((4-) 4-) (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-yl) Oxy) ethoxy) ethoxy) ethoxy) -1H-Indol-2-carbonyl) Piperazine-1 -Il) -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] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-yl) Oxy)-6,9,12-Trioxa-3-azatetradecyl) -1H-Indol- 2-carbonyl) piperazine-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] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isooxazole-3-yl) Oxy) Methyl) Pyrrolidine-1-yl) Ethyl) -1H-Indol-2 -Carbonyl) piperazine-1-yl) -2-oxoethyl) -2- (methylamino) propanamide,
(S) -N-((S) -1-Cyclohexyl-2-(4- (5-Fluoro-1- (2-oxo-2-((S) -2-(((5-((4-4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isooxazole-3-yl) Oxy) Methyl) Pyrrolidine-1-yl) Ethyl) -1H-Indol-2-carbonyl ) Piperazine-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] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isooxazole-3-yl) Oxy) Methyl) Pyrrolidine-1-yl) Ethyl) -1H -Indol-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-(((S) -2-(((5-) ((4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isooxazole-3-yl) Oxy) Methyl) Pyrrolidine-1-yl) Ethyl) -1H-Indol -2-carbonyl) -3-methylpiperazin-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- (5-( (4- (Thieno [3,2-b] Pyridine-7-yloxy) Piperidine-1-yl) Methyl) Isoxazole-3-yl) Oxy) ethoxy) ethoxy) ethoxy) ethoxy) -1H-Indol-2- Carbonyl) piperazine-1-yl) -2-oxoethyl) -2- (methylamino) propanamide, and
(S) -N-((S) -1-Cyclohexyl-2- (4- (2-Methyl-1- (2- (2- (2- (2-((5-((4- (Chieno]) 3,2-b] Pyridine-7-yloxy) piperidine-1-yl) methyl) isooxazole-3-yl) oxy) ethoxy) ethoxy) ethoxy) ethyl) -1H-indole-5-carbonyl) piperazin-1- Il) -2-oxoethyl) -2- (methylamino) propanamide,
The compound according to claim 1 selected from the group consisting of, or a pharmaceutically acceptable salt thereof. A medicament containing the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof. The medicament according to any one of claims 1 to 8, which is a proteolysis inducer. The medicament according to any one of claims 1 to 8, which is a preventive or therapeutic agent for cancer. The medicament according to any one of claims 1 to 8, which is used in combination with another anticancer agent. Induction of IRAK-M proteolysis, characterized in that an effective amount of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment. Method. A method for preventing or treating cancer, which comprises administering to a patient in need of treatment an effective amount of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.