TWI862653B - Heterocyclic compound - Google Patents

Abstract

The present invention provides a novel heterocyclic compound and a medicine containing the same which has the effect of inducing the degradation of IRAK-M protein and is expected to be useful for the prevention and treatment of cancer, fibrosis, infection, etc. The present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula (I): Here, the IRAK-M conjugate (M) is represented by the following formula (II): [In the formula, Y is CH or N, R ⁰¹ is H or Me, and R ⁰³ is the following structural formula: (Here, * indicates the position of bonding to O, ** indicates the position of bonding to A, and n is an integer from 0 to 2) The base represented by A is the following structural formula: (herein, R ⁰⁵ is independently a hydrogen atom or a C1-6 alkyl group), or *-SO ₂ -*, R ⁰⁴ is the following structural formula: (Here, * indicates the position of bonding to A, ** indicates the position of bonding to the linking group), any group represented by, a C1-6 alkylene group which may be substituted, a C3-10 cycloalkylene group which may be substituted, a C6-14 arylene group which may be substituted, or a bonding bond, and the arrow indicates the bonding to the linking group (L)].

Description

Heterocyclic compounds

The present invention relates to a heterocyclic compound and a medicine containing the same that has the ability to induce the degradation of interleukin-1 receptor-associated kinase-M (IRAK-M) protein and is expected to be useful for the prevention and treatment of cancer, fibrosis, infections, etc.

In order to treat the disease by reducing the disease-related proteins, attempts have been made to develop a compound that induces ubiquitination and proteasomal degradation of the target protein by E3 ligase (sometimes called Proteolysis Targeting Chimeras (PROTAC) or Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Eraser, SNIPER, etc.) (Non-patent Documents 1-9). IRAK-M is a member of the IRAK family of protein kinases and is a pseudokinase without kinase activity (Non-patent Document 10). IRAK-M exists downstream of all toll-like receptors (TLRs) except TLR3, and is a protein that functions as a negative feedback regulator of the TLR/interleukin 1 (IL-1) receptor signal transduction pathway in the body (non-patent document 11). Its expression is limited to a portion of epithelial cells including bile duct epithelial cells, lung epithelial cells and intestinal epithelial cells, as well as immune cells, especially bone marrow cells. IRAK- M plays an important role in maintaining immune homeostasis, such as inducing endotoxin tolerance, by negatively controlling the induction messages of inflammatory cytokines that mediate TLR in naturally immune-active competent cells such as macrophages or dendritic cells (non-patent document 12). It has been reported that IRAK-M contributes to the immunosuppression of tumor-associated macrophages or bone marrow-derived immunosuppressive cells and dendritic cells in the tumor microenvironment, and therefore participates in cancer growth (non-patent documents 13~15). Furthermore, it has been reported that IRAK-M plays a role in the phagocytic ability or defense against bacteria, collagen production promotion ability, etc. of alveolar macrophages, and is also related to fibrosis, asthma, secondary infection after sepsis, infectious complications of hematopoietic stem cell transplantation (non-patent literature 16-18), etc. Therefore, compounds that induce IRAK-M decomposition by linking X-Linked Inhibitor of Apoptosis Protein (XIAP) binder, which is one of the E3 ligases, to IRAK-M binder using a linker can become promising therapeutic drugs for cancer, fibrosis, infectious diseases, and IRAK-M protein-related diseases.

Patent document 1 reports a compound that acts as an inducer of IRAK-M protein degradation.

Patent documents 2 and 3 report compounds that act as inducers of IRAK (especially IRAK-4) protein degradation.

Patent documents 4 to 16 report compounds that utilize IAP binding sites to induce protein degradation.

Patent documents 17 to 20 report compounds having the structure of N-(piperidin-4-yl)thieno[3,2-d]pyrimidin-4-amine or N-(piperidin-4-yl)thieno[3,2-b]pyridine-7-amine.

[Prior Art Literature] [Patent Literature]

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

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

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

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

[Patent Document 5] Japanese Patent Publication No. 2013-056837

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

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

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

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

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

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

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

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

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

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

[Patent Document 16] U.S. Patent Application Publication No. 2019/0175612

[Patent Document 17] International Publication No. 2016/040330

[Patent Document 18] International Publication No. 2013/019966

[Patent Document 19] Specification of U.S. Patent Application Publication No. 2013/0040957

[Patent Document 20] China Patent Application Publication No. 103242341

[Non-patent literature]

[Non-patent literature 1] Science, 2017 Mar 17; 355(6330): 1163-1167

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

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

[Non-patent literature 4] ACS Chem Biol, 2017 Apr 21; 12(4): 892-898

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

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

[Non-patent literature 7] Nat Chem Biol, 2015 Aug; 11(8): 611-7

[Non-patent document 8]Chemistry & Biology, 2010, 17(6): 551-555

[Non-patent literature 9] Chembiochem, 2005, 6(1): 40-46

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

[Non-patent literature 11] Cell, 2002 Jul 26; 110(2): 191-202

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

[Non-patent literature 13] Oncogene, 2011 May 26; 30(21): 2475-2484

[Non-patent literature 14] J Immunol, 2010 Oct 1; 185(7): 4223-4232

[Non-patent literature 15] Mol Immunol, 2007 Jul; 44(14): 3453-3461

[Non-patent literature 16] J Immunol, 2015 Feb 15; 194(4): 1894-1904

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

[Non-patent literature 18] J Immunol, 2010 Jun 1; 184(11): 6299-6308

The purpose of the present invention is to provide a novel heterocyclic compound and a medicine containing the same that has the effect of inducing the decomposition of IRAK-M protein and is expected to be used for the prevention and treatment of cancer, fibrosis, infections, etc.

The inventors of the present invention have conducted intensive research to find an inducer of IRAK-M protein degradation, and found that the compound represented by the following formula has excellent IRAK-M protein degradation inducing activity and may be used to prevent and treat cancer, fibrosis, infections, etc., thus completing the present invention.

That is, the present invention is as follows.

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

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

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

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

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

(Here, * indicates the position of bonding to A, ** indicates the position of bonding to the linking group) represents any group, a substituted C1-6 alkylene group, a substituted C3-10 cycloalkylene group, a substituted C6-14 arylene group, or a bonding bond, and the arrow indicates the bonding to the linking group (L)].

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

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

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

(Here, * indicates the position of bonding to A ⁰¹ , ** indicates the position of bonding to the linking group) any group represented by, the arrow indicates the bonding to the linking group (L)].

唑-3-醇(5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-ol)、5-((4-((2-甲基噻吩并[3,2-b]吡啶-7-基)氧基)哌啶-1-基)甲基)異

唑-3-醇(5-((4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)methyl)isoxazol-3-ol)、 1-甲基-5-((4-(噻吩并[3,2-b]吡啶-7-基氧基)哌啶-1-基)甲基)-1H-吡唑-3-醇(1-methyl-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)-1H-pyrazol-3-ol)、及4-((4-(噻吩并[3,2-d]嘧啶-4-基氧基)哌啶-1-基)磺醯基)苯酚(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol)。 [4] The compound as described in [2] above, wherein the IRAK-M conjugate (M) is a monovalent group derived from a compound selected from the group consisting of: 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

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

oxazol-3-ol (5-((4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)methyl)isoxazol-3-ol), 1-methyl-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)-1H-pyrazol-3-ol), and 4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol.

[5] A compound as described in any one of [1] to [4] above, or a pharmaceutically acceptable salt thereof, wherein the linking group (L) is a group having 5 to 20 carbon atoms which may contain a heteroatom.

[6] The compound as described in any one of [1] to [4] above, or a pharmaceutically acceptable salt thereof, wherein the linker (L) is a compound having the following structural formula:

(Here, * indicates binding to IRAK-M complex (M))

The group represented by, *-(CH ₂ CH ₂ O)n(CH ₂ )m(NRCO)s(CH ₂ )t-* (n is a natural number of 1 to 5, m is 0, 1, or 2, s is 0 or 1, t is 0 or 1, R represents a hydrogen atom or a C1-6 alkyl group), or a bond.

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

[In the formula, R ₀₁ , R ₀₂ , R ₀₃ , R ₀₄ , R ₀₅ , R ₀₆ , R ₀₇ , and R ₀₈ each independently represent a hydrogen atom or a C1-6 alkyl group that can form a ring with each other, and D is the following formula (V):

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

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

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

(wherein R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ and R ₃₅ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an optionally substituted aminoformyl group, and R represents a hydrogen atom, a C1-6 alkyl group, or a bond to the linking group (L), and either D or E is bonded to the linking group (L)].

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

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

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

(wherein Q represents a bond to the linker (L)), and E is the following formula (VII):

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

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

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

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

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

(herein, * represents a bond to the IRAK-M conjugate (M)), a group represented by *-(CH ₂ CH ₂ O)n(CH ₂ )m(NRCO)s(CH ₂ )t-* (n is a natural number of 1 to 5, m is 0, 1, or 2, s is 0 or 1, t is 0 or 1, R represents a hydrogen atom or a C1-6 alkyl group), or a bond, the E3 ligase conjugate (E) is represented by the following formula (IV):

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

Or the following formula (VI-1):

(wherein, Q represents a bond to the linker (L)), and E is the following formula (VII): [Chemical 26]

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

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

-1-羰基)-5,6-二氟-N,1-二甲基-N-(2-(2-(2-((5-((4-(噻吩并[3,2-b]吡啶-7-基氧基)哌啶-1-基)甲基)異

唑-3-基)氧基)乙氧基)乙氧基)乙基)-1H-吲 哚-3-甲醯胺(2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide)、

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

-1-carbonyl)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

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

-1-羰基)-6-甲氧基-1-甲基-N-(2-(2-(2-(4-((4-(噻吩并[3,2-d]嘧啶-4-基氧基)哌啶-1-基)磺醯基)苯氧基)乙氧基)乙氧基)乙基)-1H-吲哚-3-甲醯胺(2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-6-methoxy-1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide)、[化29]

Compound 2: 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propionylamide)acetyl)piperidin

-1-carbonyl)-6-methoxy-1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide (2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-6-methoxy-1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide), [Chemical 29]

-1-基)-2-((2R,5R)-5-甲基-2-((2-(2-(2-((5-((4-(噻吩并[3,2-b]吡啶-7-基氧基)哌啶-1-基)甲基)異

唑-3-基)氧基)乙氧基)乙氧基)乙氧基)甲基)哌

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

Compound 3: 1-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperidin

-1-yl)-2-((2R,5R)-5-methyl-2-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperidin

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

唑-3-基)氧基)乙氧基)乙氧基)乙氧基)-1H-吲哚-2-羰基)哌

-1-基)-2-側氧乙基)-2-(甲基胺基)丙醯胺((S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridine-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide)、

Compound 4: (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperidin

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

唑-3-基)氧基)-6,9,12-三氧雜-3-氮雜十四烷基)-1H-吲哚-2-羰基)哌

-1-基)-2-側氧 乙基)-2-(甲基胺基)丙醯胺((S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-((5-((4-(thieno[3,2-b]pyridine-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)-6,9,12-trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide)、

Compound 5: (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)-6,9,12-trioxa-3-aza-tetradecyl)-1H-indole-2-carbonyl)piperidin

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

唑-3-基)氧基)甲基)吡咯啶-1-基)乙基)-1H-吲哚-2-羰基)哌

-1-基)-2-側氧乙基)-2-(甲基胺基)丙醯胺((S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide)、

Compound 6: (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperidin-1-yl)

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

唑-3-基)氧基)甲基)吡咯啶-1-基)乙基)-1H-吲哚-2-羰基)哌

-1-基)-2-側氧乙基)-2-(甲基胺基)丙醯胺((S)-N-((S)-1-cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide)、

Compound 7: (S)-N-((S)-1-cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperidin-1-yl)

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

唑-3-基)氧基)甲基)吡咯啶-1-基)乙基)-1H-吲哚-2-羰基)-3-甲基哌

-1-基)-2-側氧乙基)-2-(甲基胺基)丙醯胺((S)-N-((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide)、

Compound 8: (S)-N-((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)

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

唑-3-基)氧基)甲基)吡咯啶-1-基)乙基)-1H-吲哚-2-羰基)-3-甲基哌

-1-基)-2-側氧乙基)-2-(甲基胺基)丙醯胺((S)-N-((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide)、

Compound 9: (S)-N-((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)

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

唑-3-基)氧基)乙氧基)乙氧基)乙氧基)乙氧基)-1H-吲哚-2-羰基)哌

-1-基)-2-側氧乙基)-2-(甲基胺基)丙醯胺((S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-(2-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide)、

Compound 10: (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-(2-(2-(2-(2-(5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperidin

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

唑-3-基)氧基)乙氧基)乙氧基)乙氧基)乙基)-1H-吲哚-5-羰基)哌

-1-基)-2-側氧乙基)-2-(甲基胺基)丙醯胺((S)-N-((S)-1-cyclohexyl-2-(4-(2-methyl-1-(2-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide)

and compound 11: (S)-N-((S)-1-cyclohexyl-2-(4-(2-methyl-1-(2-(2-(2-(2-(5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperidin

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

[11] A medicine comprising a compound as described in any one of [1] to [10] above or a pharmaceutically acceptable salt thereof.

[12] The drug described in [11] above is an IRAK-M protein degradation inducer.

[13] The medicine described in [11] above is a cancer preventive or therapeutic agent.

[14] The drugs described in [11] above are used in combination with other anticancer agents.

[15] A method for inducing the degradation of IRAK-M protein, characterized in that an effective amount of a compound described in any one of [1] to [10] above or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment.

[16] A method for preventing or treating cancer, characterized in that an effective amount of a compound described in any one of [1] to [10] above or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment.

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

Figure 1 shows the results of using a Lewis lung cancer cell inoculation model, where the compounds of Examples 1, 6, 7, 8, and 9 were subcutaneously administered three times every three days, and the daily changes in tumor size of each group were confirmed. Each compound used the salt indicated in the figure. The figure represents the mean ± standard error.

Hereinafter, the present invention will be described with reference to exemplary embodiments, the compounds of the present invention, the methods for producing the compounds and their uses, and the preferred methods and materials that can be used in the implementation of the present invention. Furthermore, unless otherwise specified, all technical terms and scientific terms used in this specification have the same meanings as those commonly understood by practitioners in the technical field to which the present invention belongs. In addition, any materials and methods that are the same or identical to those described in this specification can be used in the implementation of the present invention in the same manner. In addition, all publications and patents cited in this specification related to the invention described in this specification, for example, as methods or materials that can be used in the present invention, constitute a part of this specification.

Furthermore, in this specification, the description of "A~B" indicating a numerical range means a numerical range including A and B as endpoints. The same applies to "A to B".

In this specification, "Me" means methyl, except where it clearly has a different meaning according to the context.

In this specification, there are cases where the names of compounds such as substituents are recorded, and where customary names are used instead of formal names, all of which refer to the same compound.

The following is a detailed description of the definitions of each substituent used in this specification. Unless otherwise specified, each substituent has the following definition.

In this specification, examples of "halogen atoms" include fluorine, chlorine, bromine, and iodine.

In this specification, "C1-3 alkyl" includes, for example, methyl, ethyl, propyl, isopropyl, and cyclopropyl.

In this specification, "C1-3 alkyl groups which may be halogenated" include, for example, C1-3 alkyl groups which may have 1 to 5 halogen atoms. Specific examples include: methyl, chloromethyl, fluoromethyl, dichloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, cyclopropyl, 1-fluorocyclopropyl, 2-chlorocyclopropyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl.

In this specification, "C1-6 alkyl" includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In this specification, "halogenated C1-6 alkyl" includes, for example, C1-6 alkyl groups having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples include: methyl, chloromethyl, fluoromethyl, dichloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl.

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

In this specification, examples of "C1-6 alkylsulfonyl" include: methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, t-butylsulfonyl.

In this specification, "C6-14 aryl" includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.

In this specification, examples of "C6-14 aryl" include phenyl, 1,5-naphthyl, 1,4-naphthyl, 2,3-naphthyl, 1,8-anthryl, and 9,10-anthryl.

In this specification, "C1-6 alkoxy" includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

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

[Substituent group A]

(1) Halogen atom, (2) C1-3 alkyl group, (3) C1-6 alkoxy group, (4) amino group.

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

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

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

In this specification, as "substitutable carbamoyl groups", for example, carbamoyl groups having "1 or 2 substituents selected from C1-6 alkyl groups, C2-6 alkenyl groups, and C3-10 cycloalkyl groups which may have 1 to 3 substituents selected from substituent group A (halogen atoms, C1-3 alkyl groups, C1-6 alkoxy groups, and amino groups)" can be listed.

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

In the present specification, examples of the "C3-10 cycloalkylene group" include 1,1-cyclopropylene, cis-1,2-cyclopropylene, trans-1,2-cyclopropylene, 1,1-cyclobutylene, cis-1,2-cyclobutylene, trans-1,2-cyclobutylene, cis-1,3-cyclobutylene, trans-1,3-cyclobutylene, 1,1-cyclopentylene, cis-1,2-cyclopentylene, trans-1,2-cyclopentylene, cis-1,3-cyclopentylene, trans-1,3-cyclopentylene, 1,1-cyclohexylene, cyclohexyl, cis-1,2-cyclohexyl, trans-1,2-cyclohexyl, cis-1,3-cyclohexyl, trans-1,3-cyclohexyl, cis-1,4-cyclohexyl, trans-1,4-cyclohexyl, 1,1-cycloheptyl, 1,1-cyclooctyl, 2,2-dimethyl1,1-cyclopropyl, 2,3-dimethyl1,1-cyclopropyl, 2,2,3,3,4,4-tetramethyl1,1-cyclobutyl, 7,7-norcaryl, 7,7-norpinyl, 7,7-norbornyl.

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

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

In this manual, "key binding" means the state where two bases connected via the key binding are bound by a single key. Also, when multiple "key bindings" are connected, it means that all of them are bound to each other by a single key.

Below, each symbol of formula (II) is explained.

Y is CH or N, preferably CH.

R ⁰¹ is H or Me, preferably H.

Arrows indicate bonds to the linker (L).

R ⁰³ has the following structural formula:

(Here, * indicates a bond at an O position, ** indicates a bond at an A position, and n is an integer from 0 to 2) The base represented by is preferably of the following structural formula:

(Here, * indicates the position bonded to O, ** indicates the position bonded to A) The base represented.

A is the following structural formula: [Chemical 41]

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

R ⁰⁴ has the following structural formula:

(Here, * indicates the position of bonding to A, ** indicates the position of bonding to the linking group) any group represented by, a substituted C1-6 alkylene group, a substituted C3-10 cycloalkylene group, a substituted C6-14 arylene group, or a bonding bond, preferably any group represented by the above structural formula.

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

Below, each symbol of formula (IV) is explained.

R ₀₁ , R ₀₂ , R ₀₃ , R ₀₄ , R ₀₅ , R ₀₆ , R ₀₇ , and R ₀₈ each independently represent a hydrogen atom or a C1-6 alkyl group which can form a ring with each other, preferably each independently represent a hydrogen atom or a C1-6 alkyl group, more preferably each independently represent a hydrogen atom or a C1-3 alkyl group, and even more preferably each independently represent a hydrogen atom or a methyl group.

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

D is of the following formula (V):

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

(wherein Q represents an oxygen atom, a formula -NR ²¹ -(wherein R ²¹ represents a hydrogen atom, or a C1-6 alkyl group which can form a ring together with P), or a bond, and P represents a hydrogen atom, a C1-6 alkyl group, or a bond to a linking group (L) (including a bond to a linking group (L) which forms a ring together with Q)).

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

Or the following formula (VI-1):

(In the formula, Q represents the bond to the linker (L)).

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

E is the following formula (VII):

(In the formula, R ₂₁ , R ₂₂ , and R ₂₃ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an optionally substituted aminoformyl group; preferably, R ₂₁ , R ₂₂ , and R ₂₃ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a C1-6 alkoxy group; R ₂₅ , and R ₂₆ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, an optionally substituted aminoformyl group, or a bond to the linking group (L); preferably, R ₂₅ , and R ₂₆ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or a bond to the linking group (L); ₂₄ represents a hydrogen atom, a methyl group, or a bond to the linking group (L); wherein the bond to the linking group (L) is any one of R ₂₄ , R ₂₅ or R ₂₆ ), or the following formula (VIII):

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

The following is an explanation of the linking group (L) of formula (I).

The linking group (L) is preferably a group having 5 to 20 carbon atoms which may contain a heteroatom, and more preferably has the following structural formula:

The group represented by, *-(CH ₂ CH ₂ O)n(CH ₂ )m(NRCO)s(CH ₂ )t-* (n is a natural number of 1 to 5, m is 0, 1, or 2, s is 0 or 1, t is 0 or 1, R represents a hydrogen atom or a C1-6 alkyl group), or is a bond, and is preferably a structure described below:

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

In this specification, "compounds with additional functions" refers to any protein conjugates existing in the organism, cell penetrating peptides (CPP), or kinetophores that retain compounds in the intestine (such as short-chain peptides, sugars, and polyethylene oxides terminated with quaternary ammonium, etc.).

In this manual, "IRAK-M protein-related diseases" are diseases or illnesses that are described or inferred by their association with abnormalities in the IRAK-M protein itself or its control. Protein abnormalities For example, abnormal expression or hyperactivity of proteins in organisms, and the presence of mutant proteins can be listed, but are not limited to these.

The compounds of the present invention included in compound (I) can be used as synthetic intermediates in the production of other compounds (I) of the present invention. In addition, they can also be used as synthetic intermediates in the production of IRAK-M protein degradation inducers other than compound (I).

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

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

The following is a description of the method for preparing the compound of the present invention. The raw materials or reagents used in each step of the following preparation method, and the obtained compound can form salts respectively. As such salts, for example, the same salts as the salts of the compound of the present invention described above can be listed.

When the compound obtained in each step is a free compound, it can be converted into the target salt by a known method. Conversely, when the compound obtained in each step is a salt, it can be converted into a free compound or other types of target salts by a known method.

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

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

In the reaction of each step, the reaction time may vary depending on the reagent or solvent used. 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 or solvent used. Unless otherwise specified, it is usually -78℃~300℃, preferably -78℃~150℃.

In the reaction of each step, the pressure may vary according to the reagent or solvent used. Unless otherwise specified, it is usually 1 atmosphere to 20 atmospheres, preferably 1 atmosphere to 3 atmospheres.

In the reaction of each step, a microwave synthesis device such as the Initiator manufactured by Biotage is sometimes used. The reaction temperature may vary depending on the reagent or solvent used. 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 or solvent used. Unless otherwise specified, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.

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

In the reactions of each step, unless otherwise specified, the reactions may be carried out without a solvent, or by dissolving or suspending in an appropriate solvent. Specific examples of solvents include the solvents described in the embodiments, 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.; 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.

Two or more of the above solvents can be mixed and used in appropriate ratios.

When a base is used in the reaction of each step, for example, the bases shown below or the bases described in the examples can be used.

Inorganic bases: sodium hydroxide, magnesium hydroxide, etc.; alkaline salts: sodium carbonate, calcium carbonate, sodium bicarbonate, etc.; Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazobicyclo[2.2.2]octane, 1,8-diazobicyclo[2.2.2]octane Bicyclo[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 bis(trimethylsilyl)amide, etc.; organic lithiums: n-butyl lithium, 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 the embodiments can be used.

Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ferric chloride, etc.

Unless otherwise specified, the reaction of each step can be carried out according to a known method, such as the method described in the following documents, or the method described in the embodiments: Lectures on Experimental Chemistry, 5th edition, Volumes 13 to 19 (edited by the Chemical Society of Japan); Lectures on New Experimental Chemistry, Volumes 14 to 15 (edited by the Chemical Society of Japan); Precision Organic Chemistry, Revised 2nd Edition (L.F.Tietze, Th.Eicher, Nankodo); Revised Organic Synthesis, Its Structure and Key Points (written by Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volumes I to VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (written by Jie Jack Li, published by OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol.1~Vol.14 (Elsevier Japan Co., Ltd.); Organic Synthesis Strategies Learned from Human Name Reactions (Translated by Kiyoshi Tomioka, published by Kagaku Dojin); Comprehensive Organic Transformations (VCH Publishers Inc.) published in 1989, etc.

In each step, the protection or deprotection reaction of the functional group can be carried out according to the known methods, such as the methods described in the following literature, or the methods described in the embodiments: "Protective Groups in Organic Synthesis, 4th Ed." published by Wiley-Interscience in 2007 (Theodora W. Greene, Peter G. M. Wuts); "Protecting Groups 3rd Ed." published by Thieme in 2004 (P. J. Kocienski), etc.

Examples of protective groups for hydroxyl groups of alcohols or phenolic hydroxyl groups include: ether-type protective groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylate-type protective groups such as acetate; sulfonate-type protective groups such as methanesulfonate; and carbonate-type protective groups such as tert-butyl carbonate.

烷等環狀縮醛型保護基等。 Examples of protective groups for the carbonyl group of aldehydes include: acetal-type protective groups such as dimethyl acetal; cyclic 1,3-dimethyl acetal;

Alkane and other cyclic acetal type protecting groups, etc.

烷等環狀縮酮型保護基；O-甲基肟等肟型保護基；N,N-二甲基腙等腙型保護基等。 Examples of protective groups for the carbonyl group of ketones include: ketal-type protective groups such as dimethyl ketal; cyclic 1,3-dimethyl ketal;

Cyclic ketal protecting groups such as oxime; oxime protecting groups such as O-methyloxime; hydrazone protecting groups such as N,N-dimethylhydrazone, etc.

Examples of carboxyl protecting groups include: ester-type protecting groups such as methyl ester; amide-type protecting groups such as N,N-dimethylamide, etc.

Examples of thiol protecting groups include: ether-type protecting groups such as benzyl sulfide; ester-type protecting groups such as thioacetate, thiocarbonate, and thiocarbamate.

Examples of protective groups for amino groups or aromatic heterocycles such as imidazole, pyrrole, and indole include: carbamate-type protective groups such as benzyl carbamate; amide-type protective groups such as acetamide; alkylamine-type protective groups such as N-triphenylmethylamine; sulfonamide-type protective groups such as methanesulfonamide, etc.

The removal of the protecting group can be carried out by known methods, such as methods using the following substances or reduction methods, etc.: acid, alkali, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, sodium acetate, trialkylsilane halides (e.g., trimethylsilyl iodide, trimethylsilyl bromide).

In each step, when a reduction reaction is performed, the reducing agent used may include: lithium aluminum hydroxide, sodium triacetyloxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydroxide (DIBAL-H), sodium borohydride, tetramethylammonium triacetyloxyborohydride and other metal hydrides; boranes such as borane tetrahydrofuran complex; nickel reynolds; cobalt reynolds; hydrogen; formic acid; triethylsilane, etc. When reducing a carbon-carbon double bond or triple bond, there is a method using a catalyst such as palladium-carbon or Lindlar catalyst.

In each step, when an oxidation reaction is performed, the oxidizing agent used may include: peroxides such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, and tert-butyl hydrogen peroxide; perchlorates such as tetrabutylammonium perchlorate; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodic acids such as sodium periodate; high-valence iodine reagents such as iodoacetylbenzene; manganese dioxide, potassium permanganate; Manganese-containing reagents such as lead tetraacetate; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones's reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complex; zirconium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), etc.

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

In each step, when the Wittig reaction is performed, examples of the Wittig reagent used include alkylene phosphanes. Alkylene phosphanes can be prepared by a known method, such as reacting a phosphonium salt with a strong base.

In each step, when the Horner-Emmons reaction is carried out, the reagents used include: phosphonoacetic acid esters such as trimethyl phosphonoacetate and triethyl phosphonoacetate; and bases such as alkali metal hydrides and organic lithium.

In each step, when the Friedel-Crafts reaction is performed, the reagent used may be a combination of a Lewis acid and an acyl chloride, or a combination of a Lewis acid and an alkylating agent (such as halogenated alkyls, alcohols, alkenes, etc.). Alternatively, an organic acid or an inorganic acid may be used instead of a Lewis acid, or an acid anhydride such as acetic anhydride may be used instead of an acyl chloride.

In each step, when an aromatic nucleophilic substitution reaction is performed, a nucleophilic agent (such as amines, imidazoles, etc.) and a base (such as alkaline salts, organic bases, etc.) can be used as a reagent.

In each step, when a nucleophilic addition reaction using a carbon anion, a nucleophilic 1,4-addition reaction using a carbon anion (Michael addition reaction), or a nucleophilic substitution reaction using a carbon anion is performed, the base used to generate the carbon anion may include organic lithium, metal alkoxides, inorganic bases, organic bases, etc.

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

In each step, when the Knoevenagel condensation reaction is carried out, active methylene compounds (such as malonic acid, diethyl malonate, malononitrile, etc.) and bases (such as organic bases, metal alkoxides, inorganic bases) sandwiching two electron-withdrawing groups can be used as reagents.

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

In each step, when performing the aziridation reaction of alcohols, alkyl halides, and sulfonates, the aziridation agent used can be listed as: diphenyl phosphate azidation (DPPA), trimethylsilane azidation, sodium azidation, etc. For example, when performing the aziridation of alcohols, there are methods of using diphenyl phosphate azidation and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or using trimethylsilane azidation and Lewis acid.

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

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

-2-基)-4-甲基氯化嗎啉鎓-n-水合物(DMT-MM)等三

系縮合劑；1,1-羰基二咪唑(CDI)等碳酸酯系縮合劑；疊氮磷酸二苯酯(DPPA)；苯并三唑-1-基氧基-三(二甲胺基)鏻鹽(BOP試劑)；碘化2-氯-1-甲基-吡啶鎓(向山試劑)；亞硫醯氯；氯甲酸乙酯等鹵甲酸低級烷基酯；O-(7-氮雜苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸鹽 (HATU)；硫酸；2,4,6-三丙基-1,3,5,2,4,6-三氧雜三磷雜環己烷-2,4,6-三氧化物(T3P)；或該等之組合等。於使用碳二醯亞胺系縮合劑之情形時，可進而於反應中添加1-羥基苯并三唑(HOBt)、N-羥基琥珀醯亞胺(HOSu)、二甲胺基吡啶(DMAP)等添加劑。 In each step, when performing esterification, amidation, or ureidation, the reagents used include: acyl chloride, acyl bromide, and other acyl halide; acid anhydride, active ester, sulfate, and other activated carboxylic acids. As the activating agent for carboxylic acid, the condensation agent of carbodiimide such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); 4-(4,6-dimethoxy-1,3,5-trimethoxy-1,4-dimethoxy-2-yl)-1-(4,6-dimethoxy-1,3,5-tri ...

-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM) and other

a condensation agent; a carbonate condensation agent such as 1,1-carbonyldiimidazole (CDI); diphenyl phosphate azide (DPPA); benzotriazol-1-yloxy-tris(dimethylamino)phosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); sulfinyl chloride; a lower alkyl halogen formate such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; 2,4,6-tripropyl-1,3,5,2,4,6-trioxacyclohexane-2,4,6-trioxide (T3P); or a combination thereof. When a carbodiimide-based condensation agent is used, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) may be further added to the reaction.

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

In each step, when the thiocarbonylation reaction is performed, phosphorus pentasulfide can be used as a thiocarbonylating agent. In addition to phosphorus pentasulfide, a reagent having a 1,3,2,4-dithiodiphosphinobutane-2,4-disulfide structure such as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiodiphosphinobutane-2,4-disulfide (Lawesson reagent) can also be used.

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

In each step, when the halogenation reaction of the hydroxyl group is carried out, as the halogenating agent used, hydrohalogenated acid and acyl halide of inorganic acid can be listed. Specifically, for chlorination, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc. can be listed; for bromination, 48% hydrobromic acid, etc. can be listed. In addition, a method of obtaining a halogenated alkyl body from an alcohol by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide can also be used. Alternatively, a method of synthesizing a halogenated alkyl body by converting an alcohol into a sulfonic acid ester and then reacting it with lithium bromide, lithium chloride or sodium iodide in a two-stage reaction can be used.

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

In each step, when the sulfonation reaction is carried out, the sulfonylating agent used may include: methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, etc.

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

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

In each step, when an alkylation reaction of alcohols, amines or aromatic heterocycles having an NH group in the ring (e.g., imidazole, pyrazole) is performed, examples of the alkylating agent include: substituted halogenated alkyl (e.g., iodomethane), or substituted alkyl having a substituted C1-6 alkylsulfonyloxy group as a detachable group, or substituted alkyl having a C6-14 arylsulfonyloxy group substituted by a C1-6 alkyl group, or 2-chloro-2,2-difluoroacetic acid sodium, 2,2-difluoro-2-(fluorosulfonyl)acetic acid, etc. In addition, examples of the base used include: organic lithium, metal alkoxides, inorganic bases, organic bases, etc.

In each step, when the fluorination reaction is carried out, the fluorinating agent used may include: DAST (diethylaminosulfur trifluoride), bis(2-methoxyethyl)aminosulfur trifluoride, 1-chloromethyl-4-fluoro-1,4-diazotized biscyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor), 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (FLUOLEAD), etc.

In each step, when the Huisgen reaction is carried out, azide compounds and alkyne compounds can be used as reagents. As catalysts, monovalent copper ions can be listed, such as copper iodide, copper chloride, copper cyanide, etc.

In each step, when a coupling reaction is performed, examples of the coupling reaction include Suzuki coupling, Stille coupling, Buchwald-Hartwig coupling, Negishi coupling, Mizoroki-Heck reaction, and cyanation reaction using copper cyanide or zinc cyanide. The metal catalyst, phosphine ligand, and alkali reagent used in the coupling reaction may be prepared by conventional methods (for example, J.F.Hartwig, S.Shekhar, Q.Shen, F.Barrios-Landeros, in The Chemistry of Anilines, Z. Rappoport, Ed., Wiley-Intersicence, New York (2007); L.Jiang, S.L.Buchwald, in Metal-Catalyzed Cross-Coupling Reactions, 2nd Ed., A.de Meijere, F.Diederich, Eds., Wiley-VCH, Weinheim, Germany (2004); J.F.Hartwig, in Handbook of Organopalladium Chemistry for Organic Synthesis, A.de Meijere, F.Diederich, Eds., Wiley, New York (2002); J.F.Hartwig, in Modern Amination Methods, A.Ricci, Ed., Wiley-VCH, Weinheim, (2000)), or use in accordance with such methods.

The following is a description of the method for producing compound (I).

Unless otherwise specified, the symbols in the following reaction formula have the same meanings as above. When the specific preparation method is not described, the raw material compound can be easily obtained from the market, or can be prepared by a known method or a method described in the embodiment.

When performing the reaction of each step, if there is a reactive site that causes a reaction other than the target, a protecting group can be introduced into the reactive site in advance by a known method as needed, and the protecting group can be removed by a known method after the target reaction. For example, when the raw material compound or intermediate has an amino group, a carboxyl group or a hydroxyl group as a substituent, the group can be protected by a protecting group commonly used in peptide chemistry. In this case, the target compound can be obtained by removing the protecting group as needed after the reaction.

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

Process 1

Compound (3) can be produced by subjecting compound (1) or its reactive derivative to amidation reaction, Mitsunobu reaction, alkylation reaction or coupling reaction, etc. with compound (2) or its reactive derivative as linker (L). Compound (I) can be produced by subjecting compound (3) or its reactive derivative to amidation reaction, Mitsunobu reaction, alkylation reaction or coupling reaction, etc. with compound (4) or its reactive derivative.

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

Compound (3a) can be produced by subjecting compound (1) or its reactive derivative to amidation reaction, Mitsunobu reaction, alkylation reaction or coupling reaction, etc. Compound (5a) can be produced by subjecting compound (4) or its reactive derivative to amidation reaction, Mitsunobu reaction, alkylation reaction or coupling reaction, etc. Compound (I) can be produced by subjecting compound (3a) and compound (5a) or their reactive derivatives to amidation reaction, Mitsunobu reaction, alkylation reaction, coupling reaction or Huisgen reaction, etc.

The following is a description of the method for producing the IRAK-M conjugate (M) (compound (1)) represented by formula (II) which constitutes a part of compound (I).

Process 2

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

Compound (8) can be prepared by subjecting compound (6) and compound (7) to aromatic nucleophilic substitution reaction or coupling reaction.

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

L (compound (2)) as a linker (L) constituting a part of compound (I), L ₁ (compound (2a)), and L ₂ (compound (2b)) as a part of the linker (L) can be directly used as commercial products or can be prepared by a known method or a method in accordance therewith.

The following is a description of the production method when the XIAP conjugate, namely E (compound (4)), which is one type of E3 ligase conjugate constituting a part of compound (I) is a compound represented by the following formula (IV-I).

Process 3

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

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

Furthermore, compound (16) can be produced by subjecting compound (10) to an amidation reaction with compound (15) or a reactive derivative thereof, and compound (17) can be produced by subjecting compound (16) to an amidation reaction with compound (11) or a reactive derivative thereof. Compound (IV-I) can be produced by subjecting compound (17) to an amidation reaction with compound (13) or a reactive derivative thereof.

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

Process 4

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

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

Other compounds and corresponding intermediates or salts contained in the compound (I) and intermediates thus obtained can also be prepared by transforming the substituents in the compound (I) and intermediates obtained in this way (i.e., introduction of substituents or functional group transformation) using a known method.

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

When compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and can be obtained as single products by conventionally known synthesis techniques and separation techniques. For example, when optical isomers exist in compound (I), the optical isomers separated from the compound are also included in compound (I).

Here, optical isomers can be produced by methods known per se.

Compound (I) may also be crystalline.

The crystal of compound (I) (hereinafter sometimes referred to as the crystal of the present invention) can be produced by crystallizing compound (I) using a conventionally known crystallization method.

Compound (I) may also be a pharmaceutically acceptable co-crystal or co-crystallized salt. Here, co-crystal or co-crystallized salt means a crystalline substance that contains two or more unique solids each having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility and stability) at room temperature. Co-crystals or co-crystallized salts can be prepared according to the co-crystallization method known in the art.

Compound (I) may be a hydrate or a non-hydrate, a solvent-free compound or a solvent compound.

Furthermore, deuterated forms obtained by converting ¹ H to ² H (D) are also included in compound (I).

Compound (I) may also be labeled with an isotope (e.g., ³ H, ¹³ C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²⁵ I), etc. Compound (I) labeled or substituted with an isotope can be used as a tracer for use in positron emission tomography (PET) (PET tracer), and is expected to be useful in the field of medical diagnosis, etc.

Compound (I) can also be used as a prodrug.

The prodrug of compound (I) is a compound that is converted into compound (I) by utilizing an enzyme or gastric acid reaction under physiological conditions in the body, that is, a compound that undergoes enzymatic oxidation, reduction, hydrolysis, etc. to become compound (I); a compound that undergoes hydrolysis caused by gastric acid, etc. to become compound (I).

As prodrugs of compound (I), there can be mentioned: compounds in which the amino group of compound (I) is acylated, alkylated or phosphorylated (for example, compounds in which the amino group of compound (I) is eicosylated, propylamine acylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxacyclopentene-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidinylmethylated, t-pentanoyloxymethylated or tert-butylated); compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated or borated (for example, compounds in which the hydroxyl group of compound (I) is ethylamine acylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxacyclopentene-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidinylmethylated, t-pentanoyloxymethylated or tert-butylated); Compounds obtained by esterification or amidation of the carboxyl group of compound (I) (e.g. compounds obtained by ethyl esterification, benzyl esterification, carboxyl methyl esterification, dimethylamino methyl esterification, ethyl esterification, phthalyl esterification, (5-methyl-2-oxo-1,3-dioxacyclopentene-4-yl) methyl esterification, cyclohexyloxycarbonyl ethyl esterification or methyl amidation of the carboxyl group of compound (I)). Such compounds can be prepared from compound (I) by methods known per se.

Furthermore, the prodrug of compound (I) may also be a compound that changes into compound (I) under physiological conditions as described in the 1990 edition of "Development of Pharmaceuticals" Vol. 7, Molecular Design, pp. 163 to 198 of Hirokawa Bookstore.

In this specification, prodrugs may form salts, and as such salts, those exemplified as salts of the compounds represented by formula (I) described above may be cited.

Compound (I) can be used in conjunction with a compound with additional functions, such as a cell penetrating peptide (CPP) or a pharmacological group that retains the compound in the intestine (e.g., a short-chain peptide, sugar, and polyethylene oxide terminated with quaternary ammonium, etc.). Compound (I) can be directly or via a linker to a compound with additional functions.

Compound (I) can also be used as an effective carrier (the above-mentioned part equivalent to the drug) in an antibody (or peptide antigen recognition sequence)-drug complex. When compound (I) is used as an effective carrier, compound (I) can be directly or via a linker to the antibody (or peptide antigen recognition sequence).

When compound (I) is used as an effective carrier, in addition to the linking groups exemplified in this specification, linking groups described in Chem. Rev., 114, 9154-9218 (2014), Pharma. Res., 32, 3526-3540 (2015), Bioconjugate Chem., 21, 5-13 (2010), The AAPS journal, 17, 339-351 (2015), International Publication No. 2011/005761, etc. can also be used.

Compound (I) or its prodrug (in this specification, these are sometimes referred to as "compounds of the present invention") has the activity of inducing the decomposition of IRAK-M and can be useful as a preventive or therapeutic drug for cancer, a cancer growth inhibitor, or a cancer metastasis inhibitor.

The compounds of the present invention exhibit proteolysis-inducing activity against IRAK-M, and are also excellent in terms of pharmacodynamics, pharmacokinetic properties (e.g., absorption, distribution, metabolism, excretion), solubility (e.g., water solubility), interaction with other drugs (e.g., drug metabolic enzyme inhibition), safety (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, central toxicity), and stability (e.g., chemical stability, stability against enzymes), and therefore can be useful as medicines. Among them, it can be expected to be effective in the treatment or prevention of cancer, but it is not limited to this.

In addition, the compounds of the present invention have the activity of inducing the decomposition of IRAK-M protein in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, and humans). Based on the mechanism of action, the compounds of the present invention can be used as the treatment for all diseases in which IRAK-M protein is involved (sometimes referred to as "IRAK-M-related diseases" in this specification), such as cancer [e.g., colorectal cancer (e.g., colon cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumors), lung cancer (e.g., non-small cell lung cancer, Lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (e.g. pancreatic duct cancer, pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (e.g. papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous epithelial carcinoma), duodenal cancer, small intestine cancer, breast cancer (e.g. invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer), ovarian cancer (e.g. epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low-grade tumor), testicular cancer, prostate cancer (e.g. hormone-dependent prostate cancer), prostate cancer, hormone-independent prostate cancer, castration-refractory prostate cancer), liver cancer (e.g. hepatocellular carcinoma, primary liver cancer, extrahepatic bile duct carcinoma), thyroid cancer (e.g. medullary thyroid carcinoma), kidney cancer (e.g. renal cell carcinoma (e.g. clear cell renal cell carcinoma), transitional cell carcinoma of the renal pelvis and ureter), uterine cancer (e.g. cervical cancer, uterine carcinoma, uterine sarcoma), gestational choriocarcinoma, brain tumors (e.g. medulloblastoma, neuroglioma, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytic tumors, dysdifferentiated astrocytomas, pituitary adenomas), retinoblastomas, skin cancers (e.g., basal cell tumors, malignant melanomas), sarcomas (e.g., rhabdomyosarcomas, leiomyosarcomas, soft tissue sarcomas, spindle cell sarcomas), malignant bone tumors, bladder cancer, blood cancers (e.g., multiple myeloma, leukemias (e.g., acute myeloid leukemia, chronic lymphocytic leukemia), malignant lymphomas (B-cell lymphoma, diffuse large B-cell lymphoma, MALT (mucosa-associated Drugs used to prevent or treat cancer (such as myeloproliferative disorder, mucosal lymphoid tissue) lymphoma, follicular lymphoma, mantle cell lymphoma), Hodgkin's disease, chronic myeloproliferative disease), cancer of unknown primary, growth inhibitors for cancer, metastasis inhibitors for cancer, cell apoptosis promoters, and treatments for precancerous lesions (such as myelodysplastic syndrome).

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

The compounds of the present invention can be directly or formulated with a pharmacologically acceptable carrier to prepare medicines and be administered orally or parenterally to mammals (preferably humans).

The following is a detailed description of the medicine containing the compound of the present invention (sometimes referred to as "the medicine of the present invention"). Examples of the dosage form of the medicine of the present invention include tablets (e.g., sugar-coated tablets, film-coated tablets, sublingual tablets, buccal tablets, orally rapidly disintegrating tablets), pills, granules, powders, capsules (e.g., soft capsules, microcapsules), syrups, emulsions, suspensions, films (e.g., orally disintegrating films, oral mucosal adhesive films), and the like. In addition, the dosage form of the drug of the present invention includes, for example, injections, drops, transdermal preparations (such as ion introduction transdermal preparations), suppositories, ointments, nasal preparations, pulmonary preparations, eye drops and other non-oral preparations. In addition, the drug of the present invention may also be a controlled release preparation such as a rapid-release preparation, a sustained-release preparation (such as a sustained-release microcapsule).

As the dosage form of the medicine of the present invention, nanoparticle preparations or preparations using bacterial-derived membranes can also be used.

The medicine of the present invention can be manufactured by a known manufacturing method commonly used in the field of pharmaceutical preparation technology (e.g., the method described in the Japanese Pharmacopoeia). In addition, the medicine of the present invention can contain appropriate amounts of additives such as excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifiers, colorants, preservatives, fragrances, flavoring agents, stabilizers, thickeners, etc. commonly used in the field of pharmaceutical preparations as needed.

As the above-mentioned pharmacologically acceptable carriers, the additives can be listed.

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

Examples of excipients include: lactose, white sugar, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, and calcium sulfate.

Examples of binders include: 5 to 10% by weight starch paste, 10 to 20% by weight gum arabic or gelatin, 1 to 5% by weight astragalus gelatin, 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 refined talc.

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

Examples of surfactants include sodium lauryl sulfate, polysorbate 80, sorbitan monoester, and stearic acid polyoxyethylene (40).

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

For example, when the drug of the present invention is a tablet, the tablet can be manufactured by adding a shaping agent (e.g., lactose, white sugar, starch), a disintegrant (e.g., starch, calcium carbonate), a binder (e.g., starch, gum arabic, carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose) or a lubricant (e.g., talc, magnesium stearate, polyethylene glycol 6000) to the compound of the present invention according to a known method and performing compression molding, and then coating the tablet according to a known method for the purpose of taste masking, enteric solubility or sustained release. Coating agents used for coating include, for example: hydroxypropyl methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween80, Pluronic F68, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetate succinate, EUDRAGIT (manufactured by ROHM, Germany, methacrylic acid-acrylic acid copolymer) and pigments (e.g., iron oxide, titanium dioxide).

The above-mentioned injections include, in addition to intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, intraperitoneal injections, drip injections, etc.

The injection can be prepared by a known method, that is, by dissolving, suspending or emulsifying the compound of the present invention in a sterile aqueous liquid or oily liquid. As the aqueous liquid, there can be mentioned isotonic liquids containing physiological saline, glucose or other adjuvants (e.g. D-sorbitol, D-mannitol, sodium chloride), etc. The aqueous liquid can contain a suitable dissolving aid, such as alcohol (e.g. ethanol), polyols (e.g. propylene glycol, polyethylene glycol), non-ionic surfactants (e.g. polysorbate 80, HCO (Hydrogenated Castor Oil)-50). As the oily liquid, there can be mentioned sesame oil, soybean oil, etc. The oily liquid can contain a suitable dissolving aid. As the dissolving aid, there can be mentioned benzyl benzoate, benzyl alcohol, etc. In addition, buffers (such as phosphate buffer, sodium acetate buffer), analgesics (such as benzyl ammonium chloride, procaine hydrochloride), stabilizers (such as human serum albumin, polyethylene glycol), preservatives (such as benzyl alcohol, phenol), etc. can also be prepared in the injection. The prepared injection can usually be filled into an ampoule.

The content of the compound of the present invention in the medicine of the present invention varies depending on the form of the preparation, and is generally about 0.01 to about 100% by weight relative to the entire preparation, preferably about 2 to about 85% by weight, and more preferably about 5 to about 70% by weight.

The content of the additive in the medicine of the present invention varies depending on the form of the preparation, and is generally about 1 to about 99.9% by weight relative to the entire preparation, preferably about 10 to about 90% by weight.

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

When the compound of the present invention is administered non-orally, it is usually administered in the form of a liquid (e.g., an injection). The single dose of the compound of the present invention also varies depending on the subject, target organ, symptoms, administration method, etc. For example, it is preferably administered by intravenous injection or subcutaneous injection, usually about 0.01 to about 100 mg, preferably about 0.01 to about 50 mg, and more preferably about 0.01 to about 20 mg of the compound of the present invention per 1 kg of body weight.

The compounds of the present invention can be used in combination with other drugs. Specifically, the compounds of the present invention can be used in combination with hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents, or drugs that inhibit the action of cell proliferation factors and their receptors. In the following, drugs that can be used in combination with the compounds of the present invention are referred to as combined drugs.

As the "hormone therapy", for example, fosfestrol, diethylstilbestrol, chlorethoxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestradiol, gestrinone, mepartricin, raloxifene, ormeloxifene, levormeloxifene, antiestrogens (e.g., tamoxifen citrate, toremifene citrate), pill preparations, mepitiostane, testololactone, aminoglutethimide, LH-RH (luteinizing hormone-releasing hormone, luteinizing hormone-releasing hormone) agonists (e.g., goserelin acetate, buserelin, leuprolide acetate), droloxifene, epitiostanol, ethinyl estradiol sulfonate, aromatase inhibitors (e.g., fadrozole hydrochloride, anastrozole, letrozole, exemestane, vorozole, formestane), antiandrogens (e.g., flutamide, bicalutamide, nilutamide, enzalutamide, ide), 5α-reductase inhibitors (e.g. finasteride, epristeride, dutasteride), adrenocortical hormone drugs (e.g. dexamethasone, prednisolone, betamethasone, triamcinolone), androgen synthesis inhibitors (e.g. abiraterone), drugs that delay retinol and retinol metabolism (e.g. liarozole), thyroid hormones, and their DDS (Drug Delivery System) preparations.

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

As the "alkylating agent", for example, nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambucil, cyclophosphamide, isocyclophosphamide, thiotepa, carboquinone, improsulfan tosylate, busulfan, nimustine hydrochloride, dibromomannitol, melphalan, dacarbazine, ranimustine, estramustine sodium phosphate, triethylmelamine, carmustine, lomustine, streptozocin, pipobroman, itoglu, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, hexamethylmelamine, amoxicillin, dibromospiramycin hydrochloride, and dibromospiramycin hydrochloride can be used. hydrochloride), fotemustine, pyrimustine, pumitepa, ribomustin, temozolomide, sulsulfuron, trofosfamide, nastatin, adozelesin, cystemustine, bizelesin and their DDS preparations.

As the "metabolic antagonist", for example, hydroxypurine, 6-hydroxypurine nucleoside, thioinosine, methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine octadecyl phosphate, ancitabine hydrochloride, 5-FU series drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, galocitabine, emitefur, capecitabine), aminopterin, nelarabine, leucovorin calcium, thioguanine, butocin, calcium leucovorin, oxazolidinone ... folinate), calcium tetrahydrofolate, cladribine, fludarabine, gemcitabine, hydroxyurea, pentostatin, pirtrexim, idoxuridine, mitoguanidine, tiazofurine, amoxicillin, bendamustine and their DDS preparations.

As "anticancer antibiotics", for example, actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pelocycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclamycin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neostatin, mithramycin, sarkomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idamycin hydrochloride and their DDS preparations (e.g., doxorubicin-encapsulated PEG liposomes).

As "plant-derived anticancer agents", for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, europaclitaxel, cabazitaxel, vinorelbine and their DDS preparations can be used.

As "immunotherapeutic agents", for example, the following can be used: Biyi Nishu, Kesuzhen, Schizophyllan, Lentinan, Ubenimex, Interferon, Interleukin, Macrophage Colony Stimulating Factor, Granulocyte Colony Stimulating Factor, Erythropoietin, Lymphotoxin, Bacillus Calmette-Guerin (BCG vaccine), Corynebacterium parvum, Levamisole, TLR agonists, Polysaccharide K, Procodazole, Anti-CTLA4 (cytotoxic T-lymphocyte associated protein 4) antibodies (e.g., Ipilimumab, Tremelimumab), Anti-PD-1 (programmed cell death protein 1, programmed cell death protein 1) antibodies (such as nivolumab, pembrolizumab, cemiplimab, tislelizumab, sintilimab, toripalimab), anti-PD-L1 (programmed cell death ligand-1, programmed cell death ligand 1) antibodies (such as atezolizumab, avelumab, durvalumab), oncolytic viruses.

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

As a "receptor of a cell proliferation factor", any receptor having the ability to bind to the above-mentioned cell proliferation factor can be used. Specifically, the following can be used: EGF receptor, heregulin receptor (such as HER3 (human EGFR-related 3)), insulin receptor, IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, NGF receptor, TGFβ receptor, HGF receptor, VEGF receptor, angiogenin receptor (such as Tie2), PDGF receptor, etc.

-1-基甲基)苯基]-N-[1(R)-苯基乙基]-7H-吡咯并[2,3-d]嘧啶-4-胺(AEE-788)、凡德他尼(Vandetanib)、替西羅莫司(Temsirolimus)、依維莫司(Everolimus)、恩雜妥林(Enzastaurin)、陶紮色替(Tozasertib)、磷酸2-[N-[3-[4-[5-[N-(3-氟苯基)胺甲醯基甲基]-1H-吡唑-3-基胺基]喹唑啉-7-基氧基]丙基]-N-乙基胺基]乙酯(AZD-1152)、4-[9-氯-7-(2,6-二氟苯基)-5H-嘧啶并[5,4-d][2]苯并氮呯-2-基胺基]苯甲酸、N-[2-甲氧基-5-[(E)-2-(2,4,6-三甲氧基苯基)乙烯基磺醯基甲基]苯基]甘胺酸鈉鹽(ON-1910Na)、伏拉色替(Volasertib)、司美替尼(Selumetinib)、曲美替尼(Trametinib)、N-[2(R),3-二羥基丙氧基]-3,4-二氟-2-(2-氟-4-碘苯基胺基)苯甲醯胺(PD-0325901)、瑞戈非尼(Regorafenib)、阿法替尼(Afatinib)、艾代拉里斯 (Idelalisib)、色瑞替尼(Ceritinib)、達拉非尼(Dabrafenib)、泊那替尼(Ponatinib)、侖伐替尼(Lenvatinib)、米哚妥林(Midostaurin)、帕唑帕尼(Pazopanib)等。 As "agents that inhibit the action of cell proliferation factors and their receptors", the following can be used: EGF inhibitors, TGFα inhibitors, heregulin inhibitors, insulin inhibitors, IGF inhibitors, FGF inhibitors, KGF inhibitors, CSF inhibitors, EPO inhibitors, IL-2 inhibitors, NGF inhibitors, PDGF inhibitors, TGFβ inhibitors, HGF inhibitors, VEGF inhibitors, angiogenin inhibitors, EGF receptor inhibitors , HER2 inhibitors, HER3 inhibitors, HER4 inhibitors, insulin receptor inhibitors, IGF-1 receptor inhibitors, IGF-2 receptor inhibitors, FGF receptor-1 inhibitors, FGF receptor-2 inhibitors, FGF receptor-3 inhibitors, FGF receptor-4 inhibitors, VEGF receptor inhibitors, Tie-2 inhibitors, PDGF receptor inhibitors, Abl inhibitors, Raf inhibitors, FLT3 (FMS-like tyrosine kinase 3, FMS-like tyrosine kinase 3) inhibitors, c-Kit inhibitors, Src inhibitors, PKC (protein kinase C, protein kinase C) inhibitors, Smo inhibitors, ALK (anaplastic lymphoma kinase, anaplastic lymphoma kinase) inhibitors, ROR1 (receptor-tyrosine-kinase-like orphan receptor 1, receptor tyrosine kinase-like orphan receptor 1) inhibitors, Trk inhibitors, Ret inhibitors, mTOR (mammalian target of rapamycin, mammalian target of rapamycin) inhibitors, Aurora inhibitors, PLK (Polo-like kinase, Polo-like kinase) inhibitors, MEK (mitogen-activated protein kinase Kinase (mitogen-activated protein kinase kinase) (MEK1/2) inhibitors, MET (mesenchymal-epithelial transition) inhibitors, CDK (cyclin-dependent kinase) inhibitors, Akt inhibitors, ERK (extracellular signal-regulated kinase) inhibitors, PI3K (phosphoinositide 3-kinase) inhibitors, etc. More specifically, anti-VEGF antibodies (e.g., Bevacizumab, Ramucirumab), anti-HER2 antibodies (e.g., Trastuzumab, Pertuzumab), anti-EGFR antibodies (e.g., Cetuximab, Panitumumab, Matuzumab, Nimotuzumab), anti-HGF antibodies, Imatinib, Erlotinib, Gefitinib, ), Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatalanib, Ibrutinib, Bosutinib, Cabozantinib, Crizotinib, Alectinib, Vismodegib, Axitinib, Motesanib, Nilotinib, 6-[4-(4-ethylpiperidinib)]

-1-ylmethyl)phenyl]-N-[1(R)-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (AEE-788), Vandetanib, Temsirolimus, Everolimus, Enzastaurin, Tozasertib, 2-[N -[3-[4-[5-[N-(3-fluorophenyl)aminomethyl]-1H-pyrazol-3-ylamino]quinazolin-7-yloxy]propyl]-N-ethylamino]ethyl ester (AZD-1152), 4-[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-2-ylamino]benzoic acid, N-[2-methoxy-5-[(E)-2-(2,4,6 [(2-( ...

In addition to the above drugs, the following can also be used as a concomitant drug: L-asparaginase, L-argininase, arginine iminase, acetoglucuronide, procarbazine hydrochloride, protoporphyrin-cobalt ylate, mercurophorosin-sodium, topoisomerase I inhibitors (e.g., irinotecan, topotecan, indotecan, indimitecan), topoisomerase II inhibitors (e.g., sobuzoxane), differentiation inducing agents (e.g., retinols, vitamins Vitamin D), other angiogenesis inhibitors (e.g., niacin, shark extract, COX-2 inhibitors), α-blockers (e.g., tasulosin hydrochloride), bisphosphonates (e.g., pamidronate, zoledronic acid), thalidomide, lenalidomide, pomalidomide, azacitidine, decitabine, proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib), NEDD8 inhibitors (e.g., pevonedistat), UAE (ubiquitin activating enzyme, ubiquitin activating enzyme) inhibitors, PARP (poly ADP ribose polymerase, poly ADP ribose polymerase) inhibitors (such as Olaparib, Niraparib, Veliparib), anti-CD20 antibodies (such as Rituximab, Obinutuzumab), anti-CCR4 (CC chemokine receptor 4) antibodies (such as Mogamulizumab) and other anti-tumor antibodies, antibody-drug complexes (such as trastuzumab-mertansine, brentuximab), etc.

When the compounds of the present invention are used for IRAK-M-related diseases other than cancer, in addition to the above-mentioned concomitant drugs, the following can be used as concomitant drugs: antibacterial drugs, antifungal drugs, nonsteroidal anti-inflammatory drugs, steroid drugs, bronchodilators, anticoagulants, antiplatelet drugs, thrombolytic drugs, immunomodulators, antiprotozoal drugs, antitussive expectorants, sedatives, anesthetics, anesthetic antagonists, anti-ulcer drugs, vitamins Drugs, vitamin derivatives, antiallergic agents, antiasthmatic drugs, atopic dermatitis therapeutic drugs, signal transduction inhibitors, inflammatory mediator action inhibitors, inflammatory mediator action inhibitor antibodies, inflammatory mediator production inhibitors, anti-inflammatory mediator action inhibitors, anti-inflammatory mediator action inhibitor antibodies, anti-inflammatory mediator production inhibitors, anti-fibrotic drugs, α1 adrenaline agonists, antiemetics, methemoglobin increase inhibitors, etc.

(1) Antibacterial drugs

(i) Sulfonamides

唑、磺胺間甲氧嘧啶、柳氮磺胺吡啶、磺胺嘧啶銀等。 Sulfadiazine, sulfamethoxazole

Azoles, sulfamethoxazole, sulfasalazine, silver sulfadiazine, etc.

(ii) Quinoline antibacterial drugs

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

(iii) Anti-tuberculosis drugs

羧胺、乙硫異煙胺、丙硫異煙胺、利福平、硫酸鏈黴素、硫酸康黴素、環絲胺酸等。 Isoniazid, ethambutol (ethambutol hydrochloride), para-aminosalicylic acid (calcium para-aminosalicylate), pyridoxine

Carboxamide, ethionamide, propylthionamide, rifampicin, streptomycin sulfate, concomitant sulfate, cycloserine, etc.

(iv)Anticobacterial drugs

Diaminodiphenylsulfone, rifampicin, etc.

(v) Antiviral drugs

Iodine glycoside, acyclovir, vidarabine, ganciclovir, favipiravir, etc.

(vi) Anti-HIV drugs

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

(vii) Anti-treponemal drugs

(viii) Antibiotics

Tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin, sisomicin, tetracycline, terpenoids, rolitetracycline, doxycycline, ticarcillin, cephalothin, cefpiroxine, ceftriaxone, cefaclor, cephalexin, cefuroxime, cefuroxime, cefuroxime Cefuroxime, ceftiam, ceftiam axetil, cefuroxime axetil, cefdinir, cefdirox, ceftazidime, cefpiramide, cefsulodin, cefmenoxime, cefpodoxime proxetil, cefpirome, cefazolin, cefepime, cefmetazole, cefminox, cefoxitin, cefoperazone, latamoxef, fluoxef, cefazolin, ceftriaxone, cefoperazone, ceftriaxone, moxalactam, thiomycin, sulfazecin, aztreonam or their salts, griseofulvin, lankacidin, etc.

(2) Antifungal drugs

(i) polyene antibiotics (e.g. amphotericin B, nystatin, trichomycin), (ii) griseofulvin, pyrrolidone, etc., (iii) cytosine metabolism antagonists (e.g. flucytosine), (iv) imidazole derivatives (e.g. econazole, clomiphene, miconazole nitrate, bifonazole, croconazole), (v) triazole derivatives (e.g. fluconazole, itraconazole, azole compounds [2-[ (1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone], (vi) thiocarbamic acid derivatives (e.g. tolnaftate), (vii) echinocandin derivatives (e.g. caspofungin, micafungin, anidulafungin), etc.

(3) Nonsteroidal anti-inflammatory drugs

丙

、氟比洛芬、芬特明、普拉洛芬、夫洛非寧、依匹唑、鹽酸噻拉米特、紮托布洛芬、甲磺酸加貝酯(gabexate mesilate)、甲磺酸卡莫司他、烏司他丁(ulinastatin)、秋水仙鹼、丙磺舒、磺吡酮、苯溴香豆酮、別嘌呤醇、硫代蘋果酸鈉金、玻尿酸鈉、水楊酸鈉、鹽酸嗎啡、水楊酸、阿托品、東莨菪鹼、嗎啡、配西汀、左旋嗎泛、氧化嗎啡酮(oxymorphone)、美洛昔康、塞來昔布、羅非昔布或其鹽等。 Acetaminophen, phenacetin, ethyl salicylate, serpyrine, antipyrine, migrenin, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen,

C

, flurbiprofen, phentermine, pranoprofen, fulofenine, epiriazole, thiamide hydrochloride, zatoprofen, gabexate mesilate, camostat mesylate, ulinastatin, colchicine, probenecid, sulfinpyrazone, benzbromocoumarone, allopurinol, sodium thiocarbate, sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pyrethrine, levomotor, oxymorphone, meloxicam, celecoxib, rofecoxib or its salt, etc.

(4) Steroid drugs

Dexamethasone, estradiol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinolone acetate, fluocinolone, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, beclomethasone dipropionate, estriol, etc.

(5) Bronchodilators

Metaproterenol, salmeterol, formoterol, carmoterol, etc.

(6) Anticoagulants

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

(7) Antiplatelet drugs

Ozagrel sodium, ethyl icosapentate, belastat sodium, alprostadil, tadalafil hydrochloride, oxathiapiprolin, dipyridamole, etc.

(8) Thrombolytic drugs

Tisokinase, urokinase, streptokinase, etc.

(9) Immunomodulatory drugs

Cyclosporine, tacrolimus, gurisolimus, azathioprine, antilymphocyte serum, dried sulfonated immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon, etc.

(10) Antiprotozoal drugs

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

(11) Antitussive and expectorant

Ephedrine hydrochloride, narcotine hydrochloride, codeine phosphate, codeine dihydrophosphate, isoproterenol hydrochloride, methylephedrine hydrochloride, alloclamation, chlophedianol, picoperidamine, cloperastine, protokylol, isoproterenol, salbutamol, terbutaline, oxymethebanol, morphine hydrochloride, dextromethorphan hydrobromide hydrobromide), oxycodone hydrochloride, dimethomorph phosphate, tipedine hydrochloride, pentovir citrate, clopheniramine hydrochloride, benzonatate, pifenacine, bromhexine hydrochloride, ambusol hydrochloride, acetylcysteine, ethyl cysteine hydrochloride, carbocysteine, etc.

(12) Sedatives

Chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital, amobarbital, pentobarbital, sodium thiopental, sodium thiomethalin, nitrazepam, estazolam, flurazepam, haloxalazole, triazolam, flunitrazepam, bromopentylurea, chloral hydrate, sodium trichloroethyl phosphate, etc.

(13)Anesthetics

(13-1) Local anesthetics

Cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxethazaine, etc.

(13-2) General anesthetics

(i) Inhaled anesthetics (e.g. ether, halothane, nitrous oxide, isoflurane, enflurane)

(ii) Intravenous anesthetics (e.g. ketamine hydrochloride, droperidol, sodium pentobarbital, sodium thiomethalin, pentobarbital), etc.

(14)Anesthetic antagonists

Levalorphan, nalorphine, naloxone or their salts, etc.

(15) Anti-ulcer drugs

Metoclopramide, histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrone, oxadiazine, aprotinin, omeprazole, sucralfate, sulpiride, cetraxate, gefitinib, aluminum allantoin, teprenone, prostaglandins, etc.

(16) Vitamin medicine

(i) Vitamin A: Vitamin A1, Vitamin A2 and Retinyl Palmitate

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

(iii) Vitamin E: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, dl-α-tocopheryl nicotinate

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

(v) Folic acid (vitamin M)

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

(vii) Biotin (vitamin H), etc.

(17) Vitamin derivatives

Various derivatives of vitamins, such as ascorbic acid, 5,6-trans-cholecalcified alcohol, 2,5-hydroxycholecalcified alcohol, 1-α-hydroxycholecalcified alcohol and other vitamin D3 derivatives, 5,6-trans-ergocalcified alcohol and other vitamin D2 derivatives, etc.

(18) Antiallergic agents

Diphenhydramine, chlorpheniramine, tripelennamine, clemizole, diphenylpyralid, methamphetamine, sodium cromoglycate, tranilast, repilast, aminexanox, ibutilast, cadotifen, terfenadine, mequitable tablets, azelastine, epinastine, ozagrel hydrochloride, pranlast hydrate, serotonin, etc.

(19) Antiasthmatic drugs

Isoproterenol hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, termequinol hydrochloride, tolbuterol hydrochloride, metaproterenol sulfate, fenoterol hydrobromide, ephedrine hydrochloride, ipratropium bromide, oxtropium bromide, flutropium bromide, theophylline, amine theophylline, sodium cromoglycate, tranilast, repilast, ibutilast, cadotifen, terfenadine, mequinol tablets, azelastine, epinastine, ozagrel hydrochloride, pranlast hydrate, serostat, dexamethasone, prednisolone, hydrocortisone, beclomethasone dipropionate, etc.

(20) Atopic dermatitis treatment drugs

Sodium cromoglycate, etc.

(21) Antiemetics

衍生物、5-HT3受體拮抗劑等。 Morphothiocarb

Derivatives, 5-HT3 receptor antagonists, etc.

(22) Methylhemoglobin increase inhibitor

Methylene blue, ascorbic acid, etc.

(23) Integrin inhibitors

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

(24) Anti-fibrotic drugs

Pirfenidone, nintedanib, β-aminopropionitrile (BAPN), ursodeoxycholic acid, etc.

(25) Others

Hydroxycam, diacerein, megestrol acetate, nicergoline, prostaglandins, etc.

By combining the compound of the present invention with a concomitant drug, the following superior effects can be obtained: (1) Compared with the case where the compound of the present invention or a concomitant drug is administered alone, the dosage can be reduced; (2) The drug to be used in combination with the compound of the present invention can be selected according to the patient's symptoms (mild, severe, etc.); (3) The treatment period can be set to be longer; (4) The duration of the therapeutic effect can be sought; (5) By using the compound of the present invention in combination with a concomitant drug, a synergistic effect can be obtained; etc.

Hereinafter, the combination of the compound of the present invention and a drug will be referred to as "the combination agent of the present invention".

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

Examples of administration modes when the compound of the present invention is used in combination with a concomitant drug include: (1) administration of a single formulation obtained by co-formulating the compound of the present invention and the concomitant drug; (2) simultaneous administration of two formulations obtained by separately formulating the compound of the present invention and the concomitant drug via the same administration route; (3) administration of two formulations obtained by separately formulating the compound of the present invention and the concomitant drug via the same administration route. (4) the compound of the present invention and the concomitant drug are separately formulated and the two preparations are administered simultaneously via different administration routes; (5) the compound of the present invention and the concomitant drug are separately formulated and the two preparations are administered via different administration routes with a time difference (for example, administration in the order of the compound of the present invention → the concomitant drug, or administration in the reverse order).

The dosage of the concomitant drug can be appropriately selected based on the dosage used clinically. In addition, the ratio of the compound of the present invention to the concomitant drug can be appropriately selected according to the subject of administration, route of administration, target disease, symptoms, combination, etc. For example, when the subject of administration is a human, 0.01 to 100 parts by weight of the concomitant drug can be used relative to 1 part by weight of the compound of the present invention.

Furthermore, the compound of the present invention or the concomitant of the present invention can be used in combination with non-drug therapies. Specifically, the compound of the present invention or the concomitant of the present invention can be combined with non-drug therapies such as (1) surgery, (2) pressor chemotherapy using vasopressin II, etc., (3) gene therapy, (4) hyperthermia therapy, (5) cryotherapy, (6) laser ablation, and (7) radiation therapy.

For example, by using the compound of the present invention or the concomitant agent of the present invention before or after the above-mentioned surgery, or before or after a combination of two or three of the above-mentioned treatments, the effects of preventing the expression of resistance, prolonging the disease-free period, inhibiting cancer metastasis or recurrence, and prolonging life can be achieved.

In addition, the treatment and supportive therapy using the compound of the present invention or the combination of the present invention [(i) administration of antibiotics for complications of various infectious diseases (e.g., β-lactams such as pansporin, macrolides such as clarithromycin); (ii) administration of high-calorie infusions, amino acid preparations, and multivitamin preparations for improving nutritional disorders; (iii) administration of morphine for relieving pain; (iv) improvement of symptoms such as nausea, vomiting, loss of appetite, diarrhea, leukopenia, thrombocytopenia, decreased hemoglobin concentration, hair loss, liver damage, kidney damage, DIC (disseminated intravascular coagulation)] coagulation, diffuse intravascular coagulation), fever, etc.; and (v) the administration of drugs used to inhibit multidrug resistance of cancer, etc.] combinations.

[Implementation example]

The present invention is further described in detail by the following reference examples, embodiments, test examples and preparation examples, but these do not limit the present invention and can be varied within the scope of the present invention.

In the following examples, "room temperature" generally refers to about 10°C to about 35°C. Ratios shown in mixed solvents are by volume unless otherwise specified. % refers to mass % unless otherwise specified.

When NH is recorded in silica column chromatography, aminopropylsilane-bonded silica is used, and when C18 is recorded, octadecyl-bonded silica is used. When C18 is recorded in HPLC (high performance liquid chromatography), octadecyl-bonded silica is used. The ratio of elution solvents is expressed as a volume ratio unless otherwise specified.

The following abbreviations are used in the following examples.

MS: mass spectrometry

M: Molar concentration

DMSO-d ₆ : Deuterated dimethyl sulfoxide

¹ H NMR: Proton Nuclear Magnetic Resonance

LC/MS: Liquid chromatography mass spectrometry

ESI: Electrospray Ionization

APCI: atmospheric pressure chemical ionization

DCM: dichloromethane

DIEA: diisopropylethylamine

DMAP: 4-dimethylaminopyridine

DMF: N,N-dimethylformamide

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

TEA: triethylamine

THF: Tetrahydrofuran

TFA: trifluoroacetic acid

¹ H NMR was measured by Fourier transform NMR. ACD/SpecManager or MestreNova (trade name) was used for analysis. There were cases where very gentle peaks of protons such as hydroxyl groups and amino groups were not recorded.

MS is measured by LC/MS. As an ionization method, the ESI method or the APCI method is used. The data record the found value. Usually, the molecular ion peak ([M+H] ⁺ , [MH] ^- , etc.) is observed, but in the case of a compound having a tert-butoxycarbonyl group, a peak of tert-butoxycarbonyl (Boc) or tert-butyl (tBu) dissociation is sometimes observed as a fragment ion. In the case of a compound having a carboxyl group, etc., there are cases where a peak of sodium addition is observed. In addition, in the case of a compound having a hydroxyl group, there are cases where a peak of water dissociation is observed as a fragment ion. In the case of a salt, a molecular ion peak or a fragment ion peak of the ion is usually observed.

The unit of sample concentration (c) under optical rotation ([α] _D ) is g/100mL.

The element analysis value (Anal.) records the calculated value (Calcd) and the measured value (Found).

Example 1

-1-羰 基)-5,6-二氟-N,1-二甲基-N-(2-(2-(2-((5-((4-(噻吩并[3,2-b]吡啶-7-基氧基)哌啶-1-基)甲基)異

唑-3-基)氧基)乙氧基)乙氧基)乙基)-1H-吲哚-3-甲醯胺鹽酸鹽 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propionamido)acetyl)piperidin

-1-carbonyl)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide hydrochloride

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

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

MS: [M+H] ⁺ 235.2.

B) 3-(allyloxy)isopropyl

Methyl oxadiazole-5-carboxylate

唑-5-羧酸甲酯(15.0g)、碳酸鉀(17.4g)及DMF(200mL)之混合物中添加3-溴丙-1-烯(13.6mL)，於60℃下攪拌16小時。利用乙酸乙酯及水稀釋反應混合物，利用乙酸乙酯對水層進行萃取。利用水及飽和食鹽水將有機層洗淨後，利用無水硫酸鎂加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣，而獲得標題化合物(16.6g)。 3-Hydroxyiso

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

MS: [M+H] ⁺ 184.3.

C)(3-(allyloxy)iso

oxazol-5-yl)methanol

唑-5-羧酸甲酯(16.6g)與甲醇(300mL)之混合物中添加硼氫化鈉(4.80g)。將反應混合物於室溫下攪拌16小時，將溶劑於減壓下蒸餾去除。利用乙酸乙酯及水稀釋殘渣，利用乙酸乙酯對水層進行萃取。利用水及飽和食鹽水將有機層洗淨後，利用無水硫酸鎂加以乾燥，將溶劑於減壓下蒸餾去除，而獲得標題化合物(13.2g)。 3-(allyloxy)isopropyl

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

MS: [M+H] ⁺ 156.3.

D) Methanesulfonic acid (3-(allyloxy) isobutyl

oxazol-5-yl)methyl ester

唑-5-基)甲醇(13.2g)、TEA(24mL)及THF(200mL)之混合物中添加甲磺醯氯(9.94mL)。將反應混合物於室溫下攪拌1小時後，利用水進行稀釋，並利用乙酸乙酯對水層進行萃取。利用飽和食鹽水將有機層洗淨後，利用無水硫酸鎂加以乾燥，將溶劑於減壓下蒸餾去除，而獲得標題化合物(18.9g)。 Under ice cooling, (3-(allyloxy)isopropyl

Methanesulfonyl chloride (9.94 mL) was added to a mixture of 1,2-dioxazol-5-yl)methanol (13.2 g), TEA (24 mL) and THF (200 mL). The reaction mixture was stirred at room temperature for 1 hour, diluted with water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (18.9 g).

MS: [M+H] ⁺ 234.2.

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

Azoles

唑-5-基)甲酯(5.14g)、四丁基碘化銨(4.44g)、碳酸鉀(9.70g)及DMF(100mL)之混合物攪拌24小時。於反應混合物中添加 水進行過濾，利用乙酸乙酯對濾液進行萃取。利用水及飽和食鹽水洗淨有機層，並利用無水硫酸鎂加以乾燥後，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(NH、乙酸乙酯/己烷)精製殘渣，而獲得標題化合物(6.25g)。 7-(Piperidin-4-yloxy)thieno[3,2-b]pyridine dihydrochloride (6.16 g), methanesulfonic acid (3-(allyloxy)isopropyl)

A mixture of 1,4-dioxazol-5-yl)methyl ester (5.14 g), tetrabutylammonium iodide (4.44 g), potassium carbonate (9.70 g) and DMF (100 mL) was stirred for 24 hours. Water was added to the reaction mixture and filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to obtain the title compound (6.25 g).

MS: [M+H] ⁺ 372.2.

F) (S)-4-(2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)piperidin

-1-Carboxylic acid benzyl ester

-1-羧酸苄酯(2.14g)、DIEA(5.09mL)及DMF(48.6mL)之混合物中添加HATU(5.54g)。將反應混合物於相同溫度下攪拌6小時。利用乙酸乙酯及水稀釋反應混合物，利用乙酸乙酯對水層進行萃取。利用無水硫酸鎂將有機層加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣，而獲得標題化合物(4.34g)。 At room temperature, (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (2.5 g), piperidine

HATU (5.54 g) was added to a mixture of benzyl-1-carboxylate (2.14 g), DIEA (5.09 mL) and DMF (48.6 mL). The reaction mixture was stirred at the same temperature for 6 hours. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (4.34 g).

MS: [M+H] ⁺ 460.2.

G) (S)-4-(2-amino-2-cyclohexylacetyl)piperidin

-1-Carboxylic acid benzyl ester hydrochloride

-1-羧酸苄酯(4.34g)與乙酸乙酯(18.9mL)之混合物中添加4M氯化氫/乙酸乙酯溶液(18.9mL)，將反應混合物於45℃下攪拌1小時。將反應混合物於減壓下濃縮，將所獲得之粗產物自乙酸乙酯/己烷中再結晶，而獲得標題化合物(2.96g)。 At room temperature, (S)-4-(2-((tert-butyloxycarbonyl)amino)-2-cyclohexylacetyl)piperidin

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

MS: [M+H] ⁺ 360.2.

H) 4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)piperidin

-1-Carboxylic acid benzyl ester

-1-羧酸苄酯鹽酸鹽(2.96g)、DIEA(5.22mL)及DMF(37.4mL)之混合物中添加HATU(4.26g)。將反應混合物於相同溫度下攪拌6小時。利用乙酸乙酯及水稀釋反應混合物，利用乙酸乙酯對水層進行萃取。利用無水硫酸鎂將有機層加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣，而獲得標題化合物(3.62g)。 (S)-2-((tert-butoxycarbonyl)(methyl)amino)propionic acid (1.63 g), (S)-4-(2-amino-2-cyclohexylacetyl)piperidin

HATU (4.26 g) was added to a mixture of benzyl-1-carboxylate hydrochloride (2.96 g), DIEA (5.22 mL) and DMF (37.4 mL). The reaction mixture was stirred at the same temperature for 6 hours. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (3.62 g).

MS: [M+H] ⁺ 545.4.

I) ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperidin

tert-butyl)-1-(1-yl)ethyl)amino)-1-oxopropane-2-yl)(methyl)carbamate

-1-羧酸苄酯(3.62g)、10%鈀碳(362mg)及乙酸乙酯(67mL)之混合物於常壓之氫氣環境下、室溫下攪拌1小時。將觸媒過濾去除，將濾液於減壓下濃縮，而獲得標題化合物(2.46g)。 4-((S)-2-((S)-2-((tert-butyloxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)piperidin

A mixture of benzyl-1-carboxylate (3.62 g), 10% palladium on carbon (362 mg) and ethyl acetate (67 mL) was stirred under a hydrogen atmosphere at normal pressure at room temperature for 1 hour. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to obtain the title compound (2.46 g).

MS: [M+H] ⁺ 411.3.

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

Potassium carbonate (42.0 g) and iodomethane (18.9 mL) were added to a 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 filtered and washed with hexane to obtain the title compound (20 g).

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

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

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

¹ H NMR(400MHz, DMSO-d ₆ )δ 3.99(3H,s),4.02(3H,s),8.0(1H,dd,J=6.92Hz,11.4Hz),8.12(1H,dd,J=8.24 Hz,10.76Hz),10.34(1H,s).

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

Lithium hydroxide monohydrate (3.73 g) was added to a mixture of 5,6-difluoro-3-formyl-1-methyl-1H-indole-2-carboxylic acid methyl ester (15 g) and THF (225 mL), methanol (75 mL), and water (75 mL), and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and an aqueous potassium hydrogen sulfate solution was used to make acidic conditions. The obtained solid was filtered to obtain the title compound (13 g).

MS: [M+H] ⁺ 240.1.

M) 2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)piperidin

-1-carbonyl)-5,6-difluoro-1-methyl-1H-indole-3-carboxylic acid

-1-基)乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(4.63g)、5,6-二氟-3-甲醯基-1-甲基-1H-吲哚-2-羧酸(2.45g)、DIEA(2.7mL)及DMF(50mL)之混合物中添加HATU(4.67g)。將反應混合物於室溫下攪拌2小時後，添加水，利用乙酸乙酯進行萃取。依序利用0.1M鹽酸、碳酸氫鈉水溶液及飽和食鹽水洗淨有機層，利用無水硫酸鎂加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣。於所獲得之((S)-1-(((S)-1-環己基-2-(4-(5,6-二氟-3-甲醯基-1-甲基-1H-吲哚-2-羰基)哌

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯、磷酸二氫鈉(4.90g)、2-甲基丁-2-烯(3.58g)及第三丁醇(90mL)/水(30mL)之混合物中添加亞氯酸鈉(2.24g)。將反應混合物於室溫下徹夜攪拌，添加硫代硫酸鈉水溶液，利用乙酸乙酯進行萃取。利用水及飽和食鹽水洗淨有機層，並利用無水硫酸鎂加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷及甲醇/乙酸乙酯)精製殘渣，而獲得標題化合物(5.46g)。 In ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperidin

HATU (4.67 g) was added to a mixture of (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). The reaction mixture was stirred at room temperature for 2 hours, and then water was added and extracted with ethyl acetate. The organic layer was washed with 0.1 M hydrochloric acid, aqueous sodium bicarbonate solution and saturated brine in sequence, dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-3-formyl-1-methyl-1H-indole-2-carbonyl)piperidin

To a mixture of (4.90 g of (2-( ...

MS: [M+H] ⁺ 648.5.

N)((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-3-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)(methyl)aminoformyl)-1-methyl-1H-indole-2-carbonyl)piperidin

tert-butyl (1-hydroxyethyl)amino)-1-hydroxypropane-2-yl)(methyl)carbamate

-1-羰基)-5,6-二氟-1-甲基-1H-吲哚-3-羧酸(5.46g)與2-(2-(2- (甲基胺基)乙氧基)乙氧基)乙烷-1-醇(1.65g)、DIEA(2.26mL)及DMF(8mL)之混合物中添加HATU(3.85g)。將反應混合物於室溫下攪拌3小時，添加水，利用乙酸乙酯進行萃取。利用飽和碳酸氫鈉水溶液及飽和食鹽水洗淨有機層，利用無水硫酸鎂加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(甲醇/乙酸乙酯)精製殘渣，而獲得標題化合物(3.10g)。 2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)piperidin

To a mixture of 2-(2-(2-(methylamino)ethoxy)ethoxy)ethane-1-ol (1.65 g), DIEA (2.26 mL) and DMF (8 mL) was added HATU (3.85 g). The reaction mixture was stirred at room temperature for 3 hours, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to obtain the title compound (3.10 g).

MS: [M+H] ⁺ 793.5.

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

Oxazolin-3-ol

唑(5.68g)、三乙基矽烷(7.3mL)及THF(100mL)之混合物中添加四(三苯基膦)鈀(884mg)。將反應混合物於室溫下攪拌1小時，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(甲醇)精製殘渣，並利用乙酸乙酯將所獲得之化合物洗淨，而獲得標題化合物(2.50g)。 3-(allyloxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

To a mixture of oxadiazole (5.68 g), triethylsilane (7.3 mL) and THF (100 mL) was added tetrakis(triphenylphosphine)palladium (884 mg). The reaction mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol), and the obtained compound was washed with ethyl acetate to obtain the title compound (2.50 g).

¹ H NMR (300MHz, 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=5.5Hz),7.50(1H,d,J=5.6Hz),8.04(1H,d,J=5.4Hz),8.50(1H,d,J= 5.4Hz),11.16(1H,s).

P)((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(methyl(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)aminoformyl)-1H-indole-2-carbonyl)piperidin

tert-butyl (1-hydroxyethyl)amino)-1-hydroxypropane-2-yl)(methyl)carbamate

唑-3-醇 (1.50g)、((S)-1-(((S)-1-環己基-2-(4-(5,6-二氟-3-((2-(2-(2-羥基乙氧基)乙氧基)乙基)(甲基)胺甲醯基)-1-甲基-1H-吲哚-2-羰基)哌

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(3.59g)、三苯基膦(5.94g)及甲苯(25mL)之混合物中添加偶氮二羧酸二第三丁酯(3.13g)。將反應混合物於室溫下攪拌1小時，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(C18、乙腈/5mM乙酸銨水溶液)精製殘渣，而獲得標題化合物(2.37g)。 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

oxazol-3-ol (1.50 g), ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-3-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)(methyl)aminoformyl)-1-methyl-1H-indole-2-carbonyl)piperidin-3-ol (1.50 g), ( ...

To a mixture of tert-butyl azodicarboxylate (3.59 g), triphenylphosphine (5.94 g) and toluene (25 mL) was added di-tert-butyl azodicarboxylate (3.13 g). The reaction mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile/5 mM ammonium acetate aqueous solution) to obtain the title compound (2.37 g).

MS: [M+H] ⁺ 1106.6.

Q) 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propionamido)acetyl)piperidin

-1-carbonyl)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide hydrochloride

唑-3-基)氧基)乙氧基)乙氧基)乙基)胺甲醯基)-1H-吲哚-2-羰基)哌

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(2.37g)與乙酸乙酯(10mL)之混合物中添加4M氯化氫/乙酸乙酯溶液(16.1mL)，於室溫下攪拌1小時。將反應混合物濃縮，而獲得標題化合物(2.16g)。 ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(methyl(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)aminoformyl)-1H-indole-2-carbonyl)piperidin

To a mixture of tert-butyl ((2-( ...))))))))))))))

^1H NMR (300MHz, DMSO-d ₆ )δ 0.72-1.26(7H,m),1.35(3H,d,J=6.8Hz),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=10.9,7.9Hz),7.54-7.96( 4H,m),8.53(1H,d, J=5.6Hz),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)propionamido)acetyl)piperidin

-1-carbonyl)-6-methoxy-1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide A) 6-methoxy-1-methyl-1H-indole-2-carboxylic acid methyl ester

Sodium hydroxide (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-bath cooling. The reaction mixture was stirred at the same temperature for 15 minutes, and then 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-bath cooling, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (11.4 g).

MS: [M+H] ⁺ 220.0.

B) 6-methoxy-1-methyl-1H-indole-2-carboxylic acid

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

MS: [M+H] ⁺ 206.0.

C) 4-(6-methoxy-1-methyl-1H-indole-2-carbonyl)piperidin

-1-carboxylic acid tert-butyl ester

-1-羧酸第三丁酯(9.41g)、1-羥基苯并三唑一水合物(8.10g)及DMF(150mL)之混合物中添加1-乙基-3-(3-二甲胺基丙基)碳二醯亞胺鹽酸鹽(10.14g)，將反應混合物於室溫下攪拌2小時。將反應混合物進行冰浴冷卻，添加水，濾取析出物而獲得標題化合物(16.8g)。 6-methoxy-1-methyl-1H-indole-2-carboxylic acid (9.87 g), piperidine

To a mixture of tert-butyl-1-carboxylate (9.41 g), 1-hydroxybenzotriazole monohydrate (8.10 g) and DMF (150 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.14 g), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled in an ice bath, water was added, and the precipitate was filtered to obtain the title compound (16.8 g).

MS: [M+H] ⁺ 374.1.

D) 4-(3-Methyl-6-methoxy-1-methyl-1H-indole-2-carbonyl)piperidin

-1-carboxylic acid tert-butyl ester

-1-羧酸第三丁酯(10.4g)及DMF(100mL)之混合物中添加(氯亞甲基)二甲基氯化銨(7.13g)，將反應混合物於室溫下攪拌2小時。於反應混合物中添加水並攪拌30分鐘後，利用乙酸乙酯對水層進行萃取。利用水及飽和食鹽水洗淨有機層後，利用無水硫酸鎂加以乾燥，將溶劑於減壓下蒸餾去除，而獲得標題化合物(10.6g)。 4-(6-methoxy-1-methyl-1H-indole-2-carbonyl)piperidin

To a mixture of tert-butyl-1-carboxylate (10.4 g) and DMF (100 mL) was added (chloromethylene) dimethylammonium chloride (7.13 g), and the reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and stirred for 30 minutes, and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (10.6 g).

MS: [M+H] ⁺ 402.1.

E) 6-methoxy-1-methyl-2-(piperidin

-1-Carboxyl)-1H-indole-3-carboxaldehyde hydrochloride

-1-羧酸第三丁酯(10.6g)、二甲硫醚(25mL)及乙酸乙酯(100mL)之混合物中添加4M氯化氫/乙酸乙酯溶液(198mL)，將反應混合物於室溫下攪拌1小時。於反應混合物中添加二異丙醚，濾取析出物，利用二異丙醚洗淨而獲得標題化合 物(8.1g)。 4-(3-Methyl-6-methoxy-1-methyl-1H-indole-2-carbonyl)piperidin

To a mixture of tert-butyl-1-carboxylate (10.6 g), dimethyl sulfide (25 mL) and ethyl acetate (100 mL) was added 4 M hydrogen chloride/ethyl acetate solution (198 mL), and the reaction mixture was stirred at room temperature for 1 hour. Diisopropyl ether was added to the reaction mixture, and the precipitate was filtered and washed with diisopropyl ether to obtain the title compound (8.1 g).

MS: [M+H] ⁺ 302.0.

F)((S)-1-(((S)-1-cyclohexyl-2-(4-(3-methyl-6-methoxy-1-methyl-1H-indole-2-carbonyl)piperidin

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-羰基)-1H-吲哚-3-甲醛鹽酸鹽(2.57g)、DIEA(2.66mL)及DMF(38mL)之混合物中添加HATU(3.47g)，將反應混合物於相同溫度下攪拌1小時。利用乙酸乙酯及水稀釋反應混合物，利用乙酸乙酯對水層進行萃取。利用無水硫酸鎂將有機層加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣。於室溫下向所獲得之產物與乙酸乙酯(38mL)之混合物中添加4M氯化氫/乙酸乙酯溶液(38mL)，將反應混合物於相同溫度下攪拌1小時，將反應混合物於減壓下濃縮。於室溫下向所獲得之(S)-2-(4-(2-胺基-2-環己基乙醯基)哌

-1-羰基)-6-甲氧基-1-甲基-1H-吲哚-3-甲醛(3.35g)與(S)-2-((第三丁氧基羰基)(甲基)胺基)丙酸(1.55g)、DIEA(6.65mL)及DMF(38.1mL)之混合物中添加HATU(4.34g)。將反應混合物於相同溫度下攪拌1小時。利用乙酸乙酯及水稀釋反應混合物，利用乙酸乙酯對水層進行萃取。利用無水硫酸鎂將有機層加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣，而獲得標題化合物(2.12g)。 At room temperature, (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (1.96 g), 6-methoxy-1-methyl-2-(piperidin

To a mixture of (2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-(4-(2-1-carbonyl)-1H-indole-3-carboxaldehyde hydrochloride (2.57 g)', DIEA (2.66 mL) and DMF (38 mL) was added HATU (3.47 g), and the reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane). To a mixture of the obtained product and ethyl acetate (38 mL) was added 4 M hydrogen chloride/ethyl acetate solution (38 mL) at room temperature, and the reaction mixture was stirred at the same temperature for 1 hour, and the reaction mixture was concentrated under reduced pressure. The obtained (S)-2-(4-(2-amino-2-cyclohexylacetyl)piperidin

To a mixture of (S)-2-((tert-butoxycarbonyl)(methyl)amino)propionic acid (1.55 g), DIEA (6.65 mL) and DMF (38.1 mL) was added HATU (4.34 g). The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (2.12 g).

MS: [M+H] ⁺ 626.3.

G) 2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionamido)-2-cyclohexylacetyl)piperidin

-1-carbonyl)-6-methoxy-1-methyl-1H-indole-3-carboxylic acid

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(2.30g)、磷酸二氫鈉(1.76g)、2-甲基丁-2-烯(1.95mL)、第三丁醇(29.4mL)、及水(7.4mL)之混合物中添加亞氯酸鈉(665mg)。將反應混合物於相同溫度下攪拌4小時。利用乙酸乙酯及飽和硫代硫酸鈉水溶液稀釋反應混合物，利用乙酸乙酯對水層進行萃取。依序利用水及飽和食鹽水洗淨有機層，利用無水硫酸鎂加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(甲醇/乙酸乙酯)精製殘渣，而獲得標題化合物(770mg)。 ((S)-1-(((S)-1-cyclohexyl-2-(4-(3-methyl-6-methoxy-1-methyl-1H-indole-2-carbonyl)piperidin

To a mixture of (2.30 g of ((1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester (2.30 g), sodium dihydrogen phosphate (1.76 g), 2-methylbut-2-ene (1.95 mL), tert-butanol (29.4 mL), and water (7.4 mL) was added sodium chlorite (665 mg). The reaction mixture was stirred at the same temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and a saturated aqueous sodium thiosulfate solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in sequence, dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to obtain the title compound (770 mg).

MS: [M+H] ⁺ 642.4

H)((S)-1-(((S)-1-cyclohexyl-2-(4-(3-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)aminocarbonyl)-6-methoxy-1-methyl-1H-indole-2-carbonyl)piperidin

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-羰基)-6-甲氧基-1-甲基-1H-吲哚-3-羧酸(147mg)、三乙二醇單胺(41.0mg)、DIEA(120μL)、HATU(131mg)及DMF(1.15mL)之混合物於室溫下攪拌1小時。於反應混合物中添加水與乙酸乙酯進行稀釋，利用乙酸乙酯進行萃取。利用無水硫酸鎂將有機層加以乾燥後，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(C18、乙腈/5mM乙酸銨水溶液)精製殘渣，而獲得標題化合物(133mg)。 2-(4-((S)-2-((S)-2-((tert-butyloxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)piperidin

A mixture of (147 mg, 6-methoxy-1-methyl-1H-indole-3-carboxylic acid (147 mg), triethylene glycol monoamine (41.0 mg), DIEA (120 μL), HATU (131 mg) and DMF (1.15 mL) was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture for dilution, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile/5 mM ammonium acetate aqueous solution) to obtain the title compound (133 mg).

MS: [M+H] ⁺ 773.5.

I) 4-(Thieno[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylic acid tert-butyl ester

Sodium hydroxide (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). The reaction mixture was stirred for 30 minutes, and then 4-chlorothieno[3,2-d]pyrimidine (2.05 g) was added, stirred at room temperature for 1 hour, diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (3.75 g).

MS: [M+H] ⁺ 336.0.

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

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

^1H NMR (300MHz, 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=5.29Hz),8.40(1H,d,J=5.29Hz),8.79(1H,s),8.98-9.34(2H,m).

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

4-Hydroxybenzene-1-sulfonyl chloride (152 mg) was added to a mixture of 4-(piperidin-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 distilled off under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile/5 mM ammonium acetate aqueous solution) to obtain the title compound (43.5 mg).

^1H NMR (300MHz, 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=8.69Hz),7.46-7.72(3H,m),8.32(1H,d,J=5.29Hz),8.70(1H,s),10.10-11.07(1H,m).

L) 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propionamido)acetyl)piperidin

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

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(70.0mg)、三苯基膦(119mg)及甲苯(0.45mL)之混合物中添加偶氮二羧酸二第三丁酯(62.6mg)。將反應混合物於室溫下攪拌2小時，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(C18、乙腈/5mM乙酸銨水溶液)精製殘渣。於所獲得之產物中添加乙酸乙酯(0.2mL)，並添加4M氯化氫/乙酸乙酯溶液(679μL)，於室溫下攪拌1小時，於減壓下將溶劑蒸餾去除。利用矽膠管柱層析法(C18、乙腈/5mM乙酸銨水溶液)精製殘渣。將所獲得之產物溶解於甲醇中，利用Amberlyst A21進行除鹽，將溶劑於減壓下蒸餾去除而獲得標題化合物(19.5mg)。 4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol (35.5 mg), ((S)-1-(((S)-1-cyclohexyl-2-(4-(3-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)aminocarbonyl)-6-methoxy-1-methyl-1H-indole-2-carbonyl)piperidin-1-yl)sulfonyl)phenol (35.5 mg),

To a mixture of tert-butyl azodicarboxylate (70.0 mg), triphenylphosphine (119 mg) and toluene (0.45 mL) was added di-tert-butyl azodicarboxylate (62.6 mg). The reaction mixture was stirred at room temperature for 2 hours, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile/5 mM ammonium acetate aqueous solution). Ethyl acetate (0.2 mL) was added to the obtained product, and a 4 M hydrogen chloride/ethyl acetate solution (679 μL) was added, and the mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (C18, acetonitrile/5 mM ammonium acetate aqueous solution). The obtained product was dissolved in methanol, desalted using Amberlyst A21, and the solvent was distilled off under reduced pressure to obtain the title compound (19.5 mg).

¹ H NMR (300MHz, 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=5.29Hz)7.65 (2H,d,J=9.06Hz)7.75-7.85(1H,m)7.88-7.99(1H,m)8.30(1H,d,J=5.29Hz)8.69(1H,s).

Example 3 1-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperidin

-1-yl)-2-((2R,5R)-5-methyl-2-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperidin

-1-yl)ethane-1-one hydrochloride A) 5,6-difluoro-1-methyl-1H-indole-2-carboxylic acid

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

MS: [MH] ^- 210.0.

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

-1-yl)methanone

(1.02g)、HATU(4.8g)。將反應混合物於室溫下攪拌3小時，注入至冰水中，利用乙酸乙酯進行萃取。利 用飽和食鹽水洗淨有機層後，利用無水硫酸鈉加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(甲醇/DCM)精製殘渣，而獲得標題化合物(1.9g)。 To a mixture of 5,6-difluoro-1-methyl-1H-indole-2-carboxylic acid (1.8 g) and DMF (45 mL) were added DIEA (4.4 mL), (R)-2-methyl-piperidin

(1.02 g), HATU (4.8 g). The reaction mixture was stirred at room temperature for 3 hours, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol/DCM) to obtain the title compound (1.9 g).

MS: [M+H] ⁺ 294.4.

C) (R)-2-Chloro-1-(4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperidin

-1-yl)ethane-1-one

-1-基)甲酮(1.9g)與DCM(25mL)之混合物中添加TEA(1.35mL)與氯乙醯氯(0.6mL)。將反應混合物於室溫下攪拌3小時，以DCM進行稀釋，並利用水及飽和食鹽水洗淨。利用無水硫酸鈉將有機層加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣，而獲得標題化合物(1.8g)。 Under ice-cooling, (R)-(5,6-difluoro-1-methyl-1H-indol-2-yl)(3-methylpiperidin

To a mixture of (1.9 g of 4-(2-yl)methanone (1.9 g) and DCM (25 mL) were added TEA (1.35 mL) and chloroacetyl chloride (0.6 mL). The reaction mixture was stirred at room temperature for 3 hours, diluted with DCM, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (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-benzyloxyethoxy)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 distilled off under reduced pressure to obtain the title compound (2.5 g).

¹ H NMR (400MHz, CDCl ₃ )δ 3.02-3.05(3H,m),3.61-3.65(8H,m),3.74-3.76(2H,m),4.34-4.36(2H,m),4.54(2H, s),7.27-7.33(5H, m).

E) (2R,5R)-4-Benzyl-2-methyl-5-(12-phenyl-2,5,8,11-tetraoxadodecyl)piperidin

-1-carboxylic acid tert-butyl ester

-1-羧酸第三丁酯(700mg)與DMF(10mL)之混合物中添加氫化鈉(60%，分散於液態石蠟中，105mg)。將反應混合物攪拌1小時，並添加甲磺酸2-(2-(2-(苄氧基)乙氧基)乙氧基)乙酯(695mg)，於60℃下進一步攪拌4小時。將反應混合物冷卻至室溫，添加甲磺酸2-(2-(2-(苄氧基)乙氧基)乙氧基)乙酯(556mg)，於60℃下進一步攪拌5小時。於反應混合物中添加水，利用乙酸乙酯對水層進行萃取。利用飽和食鹽水洗淨有機層後，利用無水硫酸鈉加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣，而獲得標題化合物(900mg)。 (2R,5R)-4-Benzyl-5-hydroxymethyl-2-methyl-piperidin

To a mixture of tert-butyl-1-carboxylate (700 mg) and DMF (10 mL) was added sodium hydroxide (60%, dispersed in liquid paraffin, 105 mg). The reaction mixture was stirred for 1 hour, and 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl methanesulfonate (695 mg) was added, and the mixture was further stirred at 60°C for 4 hours. The reaction mixture was cooled to room temperature, and 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl methanesulfonate (556 mg) was added, and the mixture was further stirred at 60°C for 5 hours. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (900 mg).

MS: [M+H] ⁺ 543.2.

F) (2R,5R)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperidin

-1-carboxylic acid tert-butyl ester

-1-羧酸第三丁酯(900mg)、乙酸(0.1mL)及乙醇(10mL)之混合物中添加10%鈀碳(200mg)。將反應混合物於常壓之氫氣環境下、室溫下攪拌16小時，並進行矽藻土過濾，將濾液於減壓下濃縮。於殘渣中添加10%甲醇/DCM，利用飽和碳酸氫鈉水溶液洗淨有機層後，利用無水硫酸鈉加以乾燥，將溶劑於減壓下蒸餾去除，而獲得標題化合物(600mg)。 (2R,5R)-4-benzyl-2-methyl-5-(12-phenyl-2,5,8,11-tetraoxadodecyl)piperidin

10% palladium carbon (200 mg) was added to a mixture of tert-butyl-1-carboxylate (900 mg), acetic acid (0.1 mL) and ethanol (10 mL). The reaction mixture was stirred at room temperature under a hydrogen atmosphere at normal pressure 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 a saturated sodium bicarbonate aqueous solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (600 mg).

^1H NMR (400MHz, DMSO-d ₆ )δ 1.12(3H,d,J=6.72Hz),1.39(9H,s),2.41(1H,dd,J=2.74,12.5Hz),2.88-2.94(2H,m) ,3.07(1H,dd,J=4.16,13.5Hz),3.31-3.52(15H,m),3.60-3.62(1H,m),3.98(1H,brs).

G)(2R,5R)-4-(2-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperidin

-1-yl)-2-oxoethyl)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperidin

-1-carboxylic acid tert-butyl ester

-1-羧酸第三丁酯(592mg)與THF(15mL)之混合物中添加TEA(0.3mL)、(R)-2-氯-1-(4-(5,6-二氟-1-甲基-1H-吲哚-2-羰基)-2-甲基哌

-1-基)乙烷-1-酮(550mg)及四丁基碘化銨(549mg)，於60℃下攪拌24小時。於反應混合物中添加乙酸乙酯，依序利用水及飽和食鹽水洗淨後，利用無水硫酸鈉將有機層加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(甲醇/乙酸乙酯)精製殘渣，而獲得標題化合物(740mg)。 (2R,5R)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperidin

To a mixture of tert-butyl-1-carboxylate (592 mg) and THF (15 mL) were added TEA (0.3 mL), (R)-2-chloro-1-(4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperidin

-1-yl)ethane-1-one (550 mg) and tetrabutylammonium iodide (549 mg) were stirred at 60°C for 24 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine in sequence. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to obtain the title compound (740 mg).

MS: [M+H] ⁺ 696.5.

H)(2R,5R)-4-(2-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperidin

-1-yl)-2-oxoethyl)-2-methyl-5-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperidin

-1-carboxylic acid tert-butyl ester

-1-基)-2-側氧乙基)-5-((2-(2-(2-羥基乙氧基)乙氧基)乙氧基)甲基)-2-甲 基哌

-1-羧酸第三丁酯(30mg)、5-((4-(噻吩并[3,2-b]吡啶-7-基氧基)哌啶-1-基)甲基)異

唑-3-醇(17.1mg)、三苯基膦(56.5mg)、及甲苯(2mL)之混合物中添加偶氮二羧酸二第三丁酯(29.7mg)。將反應混合物於室溫下攪拌16小時，將溶劑於減壓下蒸餾去除。利用製備薄層層析法精製殘渣，而獲得標題化合物(26mg)。 (2R,5R)-4-(2-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperidin

-1-yl)-2-oxoethyl)-5-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)-2-methylpiperidin

-1-carboxylic acid tert-butyl ester (30 mg), 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

To a mixture of oxazol-3-ol (17.1 mg), triphenylphosphine (56.5 mg), and toluene (2 mL) was added di-tert-butyl azodicarboxylate (29.7 mg). The reaction mixture was stirred at room temperature for 16 hours, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography to obtain the title compound (26 mg).

MS: [M+H] ⁺ 1008.8.

I) 1-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperidin

-1-yl)-2-((2R,5R)-5-methyl-2-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperidin

-1-yl)ethane-1-one hydrochloride

-1-基)-2-側氧乙基)-2-甲基-5-((2-(2-(2-((5-((4-(噻吩并[3,2-b]吡啶-7-基氧基)哌啶-1-基)甲基)異

唑-3-基)氧基)乙氧基)乙氧基)乙氧基)甲基)哌

-1-羧酸第三丁酯(25mg)與DCM(1mL)之混合物中添加4M氯化氫/二

烷溶液(0.3mL)。將反應混合物於室溫下攪拌1小時，將溶劑於減壓下蒸餾去除。利用醚與戊烷洗淨殘渣，而獲得標題化合物(19mg)。 Under ice-cooling, (2R,5R)-4-(2-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperidin

-1-yl)-2-oxoethyl)-2-methyl-5-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperidin

To a mixture of tert-butyl-1-carboxylate (25 mg) and DCM (1 mL) was added 4 M hydrogen chloride/dichloromethane.

The reaction mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was washed with ether and pentane to obtain the title compound (19 mg).

¹ H NMR(400MHz, DMSO-d ₆ ,100℃)δ 1.15-1.28(6H,m),2.19-2.36(4H,m),2.76-2.98(3H,m),3.20-4.36(36H,m),5.15(1H,m),5.66(1H,s), 6.56(1H,s),7.30( 1H,d,J=8.0Hz),7.53-7.59(2H,m),7.63(1H,d,J=8.0Hz),8.22(1H,d,J=8.0Hz),8.68(1H,d,J =8.0Hz),9.01-9.40(1H,m).

Example 4 (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperidin

-1-yl)-2-oxoethyl)-2-(methylamino)propionamide hydrochloride A) 5,6-difluoro-3-hydroxy-1-methyl-1H-indole-2-carboxylic acid methyl ester

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

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

B) 4-(5,6-difluoro-3-hydroxy-1-methyl-1H-indole-2-carbonyl)piperidin

-1-carboxylic acid tert-butyl ester

-1-羧酸第三丁酯(5.1g)及甲苯(45mL)之混合物中添加2M三甲基鋁/甲苯溶液(18.2mL)。將反應混合物於100℃下攪拌3小時。於反應混合物中添加水，過濾去除析出物，利用乙酸乙酯對濾液進行萃取。 利用無水硫酸鈉將有機層加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣，而獲得標題化合物(3g)。 In an atmosphere of argon, 5,6-difluoro-3-hydroxy-1-methyl-1H-indole-2-carboxylic acid methyl ester (4.4 g), piperidine

2M trimethylaluminum/toluene solution (18.2 mL) was added to a mixture of tert-butyl-1-carboxylate (5.1 g) and toluene (45 mL). The reaction mixture was stirred at 100°C for 3 hours. Water was added to the reaction mixture, the precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (3 g).

MS: [M+H] ⁺ 393.8.

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

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

MS: [M+H] ⁺ 395.0.

D) 4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperidin

-1-carboxylic acid tert-butyl ester

-1-羧酸第三丁酯(1g)與DMF(10mL)之混合物中添加碳酸銫(2.06g)與4-甲基苯磺酸2-(2-(2-(苄氧基)乙氧基)乙氧基)乙酯(1.49g)，於室溫下攪拌6小時。於反應混合物中添加水，利用乙酸乙酯進行萃取。利用飽和食鹽水洗淨有機層後，利用無水硫酸鈉加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣，而獲得標題化合物(1.26g)。 4-(5,6-difluoro-3-hydroxy-1-methyl-1H-indole-2-carbonyl)piperidin

To a mixture of tert-butyl-1-carboxylate (1 g) and DMF (10 mL), cesium carbonate (2.06 g) and 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (1.49 g) were added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (1.26 g).

MS: [M+H] ⁺ 618.0.

E)(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indol-2-yl)(piperidin

-1-yl)methanone hydrochloride

-1-羧酸第三丁酯(1.2g)與DCM(12mL)之混合物中添加4M氯化氫/二

烷溶液(2mL)。將反應混合物於室溫下攪拌4小時，將溶劑於減壓下蒸餾去除。利用二乙醚洗淨殘渣，而獲得標題化合物(1g)。 Under ice cooling, 4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperidin

To a mixture of tert-butyl-1-carboxylate (1.2 g) and DCM (12 mL) was added 4 M hydrogen chloride/dichloromethane.

The reaction mixture was stirred at room temperature for 4 hours, and the solvent was distilled off under reduced pressure. The residue was washed with diethyl ether to obtain the title compound (1 g).

MS: [M+H] ⁺ 517.9.

F)(S)-(2-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperidin

-1-yl)-1-cyclohexyl-2-oxoethyl)carbamic acid tert-butyl ester

-1-基)甲酮鹽酸鹽(1.1g)與DMF(10mL)之混合物中添加DIEA(0.694mL)。將反應混合物於室溫下攪拌15分鐘，並添加(S)-第三丁氧基羰基胺基-環己基乙酸(0.512g)、1-羥基苯并三唑(366mg)及1-乙基-3-(3-二甲胺基丙基)碳二醯亞胺鹽酸鹽(458mg)。將反應混合物於室溫下攪拌2小時，將反應混合物注入至冰水中，利用乙酸乙酯進行萃取。利用無水硫酸鈉將有機層加以乾燥，將溶劑於減壓下蒸餾去除，而獲得標題化合物(1.1g)。 (3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indol-2-yl)(piperidin

To a mixture of (1-(2-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-dimethylaminopropyl)carbodiimide)hydrochloride)methyl)acetate))) hydrochloride (1.1 g)) and DMF (10 mL) was added DIEA (0.694 mL). The reaction mixture was stirred at room temperature for 15 minutes, and (S)-tert-butoxycarbonylamino-cyclohexylacetic acid (0.512 g), 1-hydroxybenzotriazole (366 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (458 mg)) were added. The reaction mixture was stirred at room temperature for 2 hours, poured into ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.1 g).

MS: [M+H] ⁺ 757.0.

G)(S)-2-amino-1-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperidin

-1-yl)-2-cyclohexylethane-1-one hydrochloride

-1-基)-1-環己基-2-側氧乙基)胺基甲酸第三丁酯(1.1g)與DCM(10mL)之混合物中添加4M氯化氫/二

烷溶液(10mL)。將反應混合物於室溫下攪拌3小時，將溶劑於減壓下蒸餾去除，而獲得標題化合物(1.1g)。 Under ice cooling, (S)-(2-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperidin

To a mixture of tert-butyl (1-yl)-1-cyclohexyl-2-oxoethyl)carbamate (1.1 g) and DCM (10 mL) was added 4 M hydrogen chloride/dichloromethane.

The reaction mixture was stirred at room temperature for 3 hours, and the solvent was distilled off under reduced pressure to obtain the title compound (1.1 g).

MS: [M+H] ⁺ 657.2.

H)((S)-1-(((S)-2-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperidin

tert-butyl ((1-cyclohexyl)-2-oxoethyl)amino)-1-oxopropane-2-yl) (methyl) carbamate

-1-基)-2-環己基乙烷-1-酮鹽酸鹽(1.1g)與DMF(10mL)之混合物中添加DIEA(0.83mL)。將反應混合物攪拌15分鐘，添加(S)-2-(第三丁氧基羰基-甲基-胺基)-丙酸(0.323g)與HATU(0.905g)，於室溫下攪拌16小時。將反應混合物注入至冰水中，利用乙酸乙酯進行萃取。利用飽和食鹽水洗淨有機層後，利用無水硫酸鈉加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣，而獲得標題化合物(850mg)。 (S)-2-amino-1-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperidin

To a mixture of (S)-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid (0.323 g) and HATU (0.905 g) was added DIEA (0.83 mL). The reaction mixture was stirred for 15 minutes, and (S)-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid (0.323 g) and HATU (0.905 g) were added and stirred at room temperature for 16 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (850 mg).

MS: [M+H] ⁺ 842.1.

I) ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-1-methyl-1H-indole-2-carbonyl)piperidin

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-基)-1-環己基-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(850mg)與乙醇(10mL)之混合物中添加10%鈀碳(200mg)，於常壓之氫氣環境下攪拌3小時。將反應混合物進行矽藻土過濾，並利用乙醇洗淨，將濾液於減壓下濃縮，而獲得標題化合物(740mg)。 ((S)-1-(((S)-2-(4-(3-(2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethoxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperidin

To a mixture of tert-butyl (( ...)))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))

MS: [M+H] ⁺ 752.6.

J)((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperidin

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(40mg)、5-((4-(噻吩并[3,2-b]吡啶-7-基氧基)哌啶-1-基)甲基)異

唑-3-醇(21.1mg)、三苯基膦(69.7mg)及甲苯(1.5mL)之混合物中添加偶氮二羧酸二第三丁酯(36.7mg)，於室溫下攪拌16小時、將反應混合物於減壓下濃縮。利用製備薄層層析法精製殘渣，而獲得標題化合物(36mg)。 ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-1-methyl-1H-indole-2-carbonyl)piperidin

tert-butyl 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isobutyl ester (40 mg),

To a mixture of oxazol-3-ol (21.1 mg), triphenylphosphine (69.7 mg) and toluene (1.5 mL) was added di-tert-butyl azodicarboxylate (36.7 mg), stirred at room temperature for 16 hours, and the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to obtain the title compound (36 mg).

MS: [M+H] ⁺ 1064.8.

K)(S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperidin

-1-yl)-2-oxoethyl)-2-(methylamino)propionamide hydrochloride

唑-3-基)氧基)乙氧基)乙氧基)乙氧基)-1H-吲哚-2-羰基)哌

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(36mg)與DCM(1mL)之混合物中添加4M氯化氫/二

烷溶液(0.3mL)，於室溫下攪拌2小時。將反應混合物於減壓下濃縮，利用二乙醚與戊烷洗淨殘渣，而獲得標題化合物(24mg)。 Under ice-cooling, ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperidin

To a mixture of tert-butyl (1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (36 mg) and DCM (1 mL) was added 4 M hydrogen chloride/dichloromethane.

The mixture was concentrated under reduced pressure and the residue was washed with diethyl ether and pentane to obtain the title compound (24 mg).

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

Example 5 (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)-6,9,12-trioxa-3-aza-tetradecyl)-1H-indole-2-carbonyl)piperidin

-1-yl)-2-oxoethyl)-2-(methylamino)propionamide hydrochloride A)((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1H-indole-2-carbonyl)piperidin

(-1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-基)乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(2.29g)、5,6-二氟-1H-吲哚-2-羧酸(1.00g)、DIEA(2.72mL)及DMF(20mL)之混合物中添加HATU(2.89g)，於室溫下攪拌1小時。於反應混合物中添加水與乙酸乙酯，利用乙酸乙酯對水層進行萃取。利用無水硫酸鎂將有機層加以乾燥，將溶劑於減壓下蒸餾去除而獲得標題化合物(2.64g)。 In ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperidin

To a mixture of (2.29 g), 5,6-difluoro-1H-indole-2-carboxylic acid (1.00 g), DIEA (2.72 mL) and DMF (20 mL) was added HATU (2.89 g), and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (2.64 g).

MS: [M+H-Boc] ⁺ 490.3.

B) 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)piperidin

-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid methyl ester

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(2.64g)、碳酸鉀(681mg)、2-溴乙酸甲酯(753mg)及DMF(20mL)之混合物於室溫下攪拌16小時。利用水與乙酸乙酯稀釋反應混合物，利用乙酸乙酯對水層進行萃取。利用無水硫酸鎂將有機層加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣，而獲得標題化合物(2.96g)。 ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1H-indole-2-carbonyl)piperidin

A mixture of tert-butyl (( ...

MS: [M+H] ⁺ 662.4.

C) 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)piperidin

-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid

-1-羰基)-5,6-二氟-1H-吲哚-1-基)乙酸甲酯(2.76g)與甲 醇(20mL)之混合物中添加2M氫氧化鈉水溶液(10.4mL)。將反應混合物於室溫下攪拌2小時，添加1M鹽酸製成酸性，利用乙酸乙酯進行萃取。利用無水硫酸鎂將有機層加以乾燥，將溶劑於減壓下蒸餾去除而獲得標題化合物(2.16g)。 2-(2-(4-((S)-2-((S)-2-((tert-butyloxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)piperidin

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

MS: [M+H] ⁺ 648.4.

D)((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(14-hydroxy-3-methyl-2-oxo-6,9,12-trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperidin

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-羰基)-5,6-二氟-1H-吲哚-1-基)乙酸(1.20g)、5,8,11-三氧雜-2-氮雜十三烷-13-醇(422mg)、DIEA(0.65mL)、及DMF(9.3mL)之混合物中添加HATU(986mg)，於室溫下攪拌1小時。利用水與乙酸乙酯稀釋反應混合物，利用乙酸乙酯進行萃取。利用無水硫酸鎂將有機層加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣而獲得標題化合物(695mg)。 2-(2-(4-((S)-2-((S)-2-((tert-butyloxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)piperidin

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

MS: [M+H] ⁺ 837.5.

E)((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)-6,9,12-trioxa-3-aza-tetradecyl)-1H-indole-2-carbonyl)piperidin

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

唑-3-醇 (265mg)、((S)-1-(((S)-1-環己基-2-(4-(5,6-二氟-1-(14-羥基-3-甲基-2-側氧基-6,9,12-三氧雜-3-氮雜十四烷基)-1H-吲哚-2-羰基)哌

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(670mg)、三苯基膦(1.05g)及甲苯(8mL)之混合物中添加偶氮二羧酸二第三丁酯(553mg)，於室溫下攪拌1小時。將反應混合物於減壓下濃縮，利用矽膠管柱層析法(C18、乙腈/5mM乙酸銨水溶液)精製殘渣，而獲得標題化合物(575mg)。 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

oxazol-3-ol (265 mg), ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(14-hydroxy-3-methyl-2-oxo-6,9,12-trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperidin

To a mixture of tert-butyl azodicarboxylate (670 mg), triphenylphosphine (1.05 g) and toluene (8 mL) was added di-tert-butyl azodicarboxylate (553 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (C18, acetonitrile/5 mM ammonium acetate aqueous solution) to obtain the title compound (575 mg).

MS: [M+H] ⁺ 1150.4.

F)(S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)-6,9,12-trioxa-3-aza-tetradecyl)-1H-indole-2-carbonyl)piperidin

-1-yl)-2-((2-hydroxyethyl)-2-(methylamino)propionamide hydrochloride

唑-3-基)氧基)-6,9,12-三氧雜-3-氮雜十四烷基)-1H-吲哚-2-羰基)哌

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(575mg)與乙酸乙酯(1mL)之混合物中添加4M氯化氫/乙酸乙酯溶液(2mL)，於室溫下攪拌1小時。將反應混合物於減壓下濃縮，而獲得標題化合物(549mg)。 ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)-6,9,12-trioxa-3-aza-tetradecyl)-1H-indole-2-carbonyl)piperidin

To a mixture of tert-butyl ((1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (575 mg) and ethyl acetate (1 mL) was added 4 M hydrogen chloride/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (549 mg).

¹ H NMR(400MHz, DMSO-d ₆ ,100℃)δ 0.95-1.32(5H,m),1.35-1.40(3H,m),1.57-1.78(6H,m),1.94-2.08(2H,m), 2.18-2.27(2H,m),3.05-3.78(32H,m),3.84-3.95(1H,m),3.99-4.21(2H,m) ,4.28-4.33(2H,m),4.63-4.70(1H,m),4.93-5.03(1H,m),5.17-5.26(2H,m) ,6.32-6.40(1H,m),6.72(1H,s),7.07-7.17(1H,m),7.47-7.59(3H,m),8.08- 8.13(1H,m),8.39-8.48(1H,m),8.53-8.62(1H,m),8.63-8.93(2H,m).

Example 6 (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperidin-1-yl)

-1-yl)-2-oxoethyl)-2-(methylamino)propionamide hydrochloride A)(S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

Azoles

唑-3-醇(398.8mg)、(S)-2-(羥甲基)吡咯啶-1-羧酸(9H-茀-9-基)甲酯(389.2mg)、三苯基膦(378.8mg)、及甲苯(5mL)之混合物中添加偶氮二羧酸二第三丁酯(332.5mg)。將反應混合物於室溫下攪拌30分鐘，並於減壓下濃縮。將殘渣溶解於DMF(4mL)與四丁基氟化銨(6mL)中。將反應混合物於室溫下攪拌15分鐘，並於減壓下濃縮，於殘渣中添加TFA(5mL)。將反應混合物於室溫下攪拌5分鐘，利用水進行稀釋，並利用乙酸乙酯洗淨。利用2M氫氧化鈉水溶液將水層製成鹼性，利用乙酸乙酯進行萃取。利用水及飽和食鹽水洗淨有機層後，利用無水硫酸鎂加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(NH、甲醇/乙酸乙酯)精製殘渣，而獲得標題化合物(199.4mg)。 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

To a mixture of oxazol-3-ol (398.8 mg), (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid (9H-fluoren-9-yl)methyl ester (389.2 mg), triphenylphosphine (378.8 mg), and toluene (5 mL) was added di-tert-butyl azodicarboxylate (332.5 mg). The reaction mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue was dissolved in DMF (4 mL) and tetrabutylammonium fluoride (6 mL). The reaction mixture was stirred at room temperature for 15 minutes and concentrated under reduced pressure, and TFA (5 mL) was added to the residue. The reaction mixture was stirred at room temperature for 5 minutes, diluted with water, and washed with ethyl acetate. The aqueous layer was made alkaline with a 2M sodium hydroxide aqueous solution and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to obtain the title compound (199.4 mg).

MS: [M+H] ⁺ 415.2.

B)((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperidin-1-yl)

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-羰基)-5,6-二氟-1H-吲哚-1-基)乙酸(199.8mg)、(S)-3-(吡咯啶-2-基甲氧基)-5-((4-(噻吩并[3,2-b]吡啶-7-基氧基)哌啶-1-基)甲基)異

唑(140.7mg)、DIEA(107μL)、1-羥基苯并三唑(83.37mg)、及DMF(3mL)之混合物中添加1-乙基-3-(3-二甲胺基丙基)碳二醯亞胺鹽酸鹽(118.3mg)。將反應混合物於室溫下攪拌2小時，添加水，濾取析出物，以水洗淨而獲得標題化合物(320.8mg)。 2-(2-(4-((S)-2-((S)-2-((tert-butyloxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)piperidin

-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid (199.8 mg), (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (118.3 mg) was added to a mixture of oxadiazole (140.7 mg), DIEA (107 μL), 1-hydroxybenzotriazole (83.37 mg), and DMF (3 mL). The reaction mixture was stirred at room temperature for 2 hours, water was added, and the precipitate was filtered and washed with water to obtain the title compound (320.8 mg).

MS: [M+H] ⁺ 1044.3.

C)(S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperidin-1-yl)

-1-yl)-2-oxoethyl)-2-(methylamino)propionamide hydrochloride

唑-3-基)氧基)甲基)吡咯啶-1-基)乙基)-1H-吲哚-2-羰基)哌

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(380.2mg)與乙酸乙酯(1.5mL)之混合物中添加4M氯化氫/乙酸乙酯溶液(1mL)。將反應混合物於室溫下攪拌1個半小時，並添加二異丙醚。濾取析出物，利用二異丙醚洗淨而獲得標 題化合物(280.3mg)。 ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperidin-1-yl)

To a mixture of tert-butyl (( ...

MS: [M+H] ⁺ 944.2.

The title compound was neutralized with a saturated aqueous sodium bicarbonate solution, and the precipitate was collected and measured for ¹ H NMR as a free form.

^1H NMR (300MHz, DMSO-d ₆ )δ 0.78-1.27(7H,m),1.45-2.21(19H,m),2.41(3H,s),2.58-2.78(2H,m),2.86-3.03(1H,m),3.1 8-3.85(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=5.6,2.7Hz),7.49(1H,dd,J=5.5,2.1Hz),7.62(1H,dd,J=10.9,8.0Hz ),7.66-7.84(1H,m),7.93(1H,d,J=8.6Hz),8.02(1H,dd,J=5.4,3.3Hz),8.49(1H,d,J=5.4Hz).

Example 7 (S)-N-((S)-1-cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperidin-1-yl)

-1-yl)-2-oxoethyl)-2-(methylamino)propionamide A)((S)-1-(((S)-1-cyclohexyl-2-(4-(5-fluoro-1H-indole-2-carbonyl)piperidin

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-基)乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(7g)與DMF(60mL)之混合物中添加5-氟-1H-吲哚-2-羧酸(3.36g)、1-羥基苯并三唑(3.00g)、DIEA(11.9mL)、1-乙基-3-(3-二甲胺基丙基)碳二醯亞胺鹽酸鹽(4.25g)。將反應混 合物於室溫下攪拌16小時，添加水，利用乙酸乙酯進行萃取。依序利用水、飽和氯化銨水溶液、飽和碳酸氫鈉水溶液及飽和食鹽水洗淨有機層，利用無水硫酸鈉加以乾燥。將溶劑於減壓下蒸餾去除而獲得標題化合物(9.5g)。 In ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperidin

5-Fluoro-1H-indole-2-carboxylic acid (3.36 g), 1-hydroxybenzotriazole (3.00 g), DIEA (11.9 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.25 g) were added to a mixture of tert-butyl (1-yl)ethyl)amino)-1-oxopropane-2-yl) (methyl)carbamate (7 g) and DMF (60 mL). The reaction mixture was stirred at room temperature for 16 hours, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with water, saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution, and saturated brine in sequence, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound (9.5 g).

MS: [M+H] ⁺ 572.0.

B) 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)piperidin

-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetic acid methyl ester

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(9.5g)與DMF(50mL)之混合物中添加碳酸鉀(6.89g)、溴乙酸甲酯(4.59mL)，將反應混合物於室溫下攪拌16小時，添加水，利用乙酸乙酯進行萃取。依序利用水及飽和食鹽水洗淨有機層，利用無水硫酸鈉加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣，而獲得標題化合物(8.6g)。 Under ice-cooling, ((S)-1-(((S)-1-cyclohexyl-2-(4-(5-fluoro-1H-indole-2-carbonyl)piperidin

To a mixture of tert-butyl (( ...

MS: [M+H] ⁺ 644.1.

C) 2-(2-(4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)piperidin

-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetic acid

-1-羰基)-5-氟-1H-吲哚-1-基)乙酸甲酯(8.6g)與甲醇(25mL)之混合物中添加2M氫氧化鈉水溶液(13.4mL)，將反應混合物於室溫下攪拌20分鐘。利用水稀釋反應混合物，利用二乙醚洗淨。利用0.01M 氫氧化鈉水溶液萃取有機層。利用6M鹽酸使水層成為酸性，利用乙酸乙酯進行萃取。利用飽和食鹽水洗淨有機層，利用無水硫酸鈉加以乾燥，將溶劑於減壓下蒸餾去除而獲得標題化合物(8.1g)。 2-(2-(4-((S)-2-((S)-2-((tert-butyloxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)piperidin

To a mixture of methyl (5-(2-(4-fluoro-1H-indol-1-yl)-5-fluoro-1H-indol-1-yl)acetate (8.6 g) and methanol (25 mL) was added 2 M aqueous sodium hydroxide solution (13.4 mL), and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with water and washed with diethyl ether. The organic layer was extracted with 0.01 M aqueous sodium hydroxide solution. The aqueous layer was made acidic with 6 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (8.1 g).

MS: [M+H] ⁺ 630.2.

D)((S)-1-(((S)-1-cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperidin-1-yl)

tert-butyl (1-hydroxyethyl)amino)-1-hydroxypropane-2-yl)(methyl)carbamate

-1-羰基)-5-氟-1H-吲哚-1-基)乙酸(700mg)與DMF(10mL)之混合物中添加(S)-3-(吡咯啶-2-基甲氧基)-5-((4-(噻吩并[3,2-b]吡啶-7-基氧基)哌啶-1-基)甲基)異

唑(506.8mg)、DIEA(0.78mL)、HATU(507.8mg)，並於室溫下攪拌16小時。於反應混合物中添加冰水，利用乙酸乙酯進行萃取。依序利用水、飽和食鹽水洗淨有機層，利用無水硫酸鈉加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣，而獲得標題化合物(950mg)。 2-(2-(4-((S)-2-((S)-2-((tert-butyloxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)piperidin

To a mixture of (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isothiazolin-1-yl)-1-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isothiazolin-1-yl)acetic acid (700 mg) and DMF (10 mL) was added (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isothiazolin-1-yl)acetic acid (700 mg) and DMF (10 mL).

azole (506.8 mg), DIEA (0.78 mL), HATU (507.8 mg), and stirred at room temperature for 16 hours. Ice water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in sequence, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (950 mg).

MS: [M+H] ⁺ 1025.8.

E)(S)-N-((S)-1-cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperidin-1-yl)

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

唑-3-基)氧基)甲基)吡咯啶-1-基)乙基)-1H-吲哚-2-羰基)哌

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(60mg)、乙酸乙酯(0.2mL)之混合物中添加4M氯化氫/乙酸乙酯溶液(0.043mL)，並於室溫下攪拌4小時。濾取析出物，於室溫下向所獲得之(S)-N-[(S)-1-環己基-2-[4-(5-氟-1-{2-側氧基-2-[(S)-2-[({5-[(4-{噻吩并[3,2-b]吡啶-7-基氧基}哌啶-1-基)甲基]-1,2-

唑-3-基}氧基)甲基]吡咯啶-1-基]乙基}-1H-吲哚-2-羰基)哌

-1-基]-2-側氧乙基]-2-(甲基胺基)丙醯胺鹽酸鹽與水(0.2mL)之混合物中添加飽和碳酸氫鈉水溶液(0.043mL)。將反應混合物於室溫下攪拌30分鐘，濾取析出物，而獲得標題化合物(46mg)。 ((S)-1-(((S)-1-cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4- (thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperidin-1-yl)

To a mixture of (S)-N-[(S)-1-cyclohexyl-2-[4-(5-fluoro-1-{2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamic acid tert-butyl ester (60 mg) and ethyl acetate (0.2 mL) was added 4 M hydrogen chloride/ethyl acetate solution (0.043 mL), and the mixture was stirred at room temperature for 4 hours. The precipitate was filtered and added to the obtained (S)-N-[(S)-1-cyclohexyl-2-[4-(5-fluoro-1-{2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate at room temperature.

oxazol-3-yl}oxy)methyl]pyrrolidin-1-yl]ethyl}-1H-indole-2-carbonyl)piperidin

To a mixture of 1-hydroxy-2-(1-yl)-2-oxoethyl]-2-(methylamino)propionamide hydrochloride and water (0.2 mL) was added saturated aqueous sodium bicarbonate solution (0.043 mL). The reaction mixture was stirred at room temperature for 30 minutes, and the precipitate was filtered to obtain the title compound (46 mg).

¹ H NMR(400MHz, DMSO-d ₆ ,100℃)δ 1.07-1.25(m,6H),1.55-1.76(m,6H),1.76-1.88(m,2H),1.88-2.12(m,7H),2.24(s,3H),2.32(s,2H), 2.70- 2.79(m,2H),2.95-3.05(m,2H),3.57-3.72(m,12H),4.09-4.40(m,3H),4.65(s,1H),4.79(s,1H),5.17- 5.23( m,2H),5.99-6.29(m,1H),6.70(s,1H),6.98(d,J=5.3Hz,1H),7.01-7.06(m,1H),7.12-7.21(m,1H) ,7.20-7.2 9(m,1H),7.34(d,J=8.5Hz,1H),7.42-7.55(m,2H),7.67(s,1H),7.95(d,J=5.1Hz,1H),8.49(d ,J=5.2Hz,1H).

Example 8 (S)-N-((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)

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

Azoles trihydrochloride

唑-5-羧酸甲酯(3.79g)、(S)-2-(羥甲基)吡咯啶-1-羧酸第三丁酯(4.84g)及三苯基膦(6.94g)於甲苯中共沸，於冰浴冷卻下向殘渣與甲苯(50mL)之混合物中添加40%偶氮二羧酸二乙酯甲苯溶液(14mL)。將反應混合物於室溫下攪拌1小時後，於減壓下將溶劑蒸餾去除至一半為止，利用矽膠管柱層析法(乙酸乙酯/己烷)進行精製。於所獲得之(S)-3-((1-(第三丁氧基羰基)吡咯啶-2-基)甲氧基)異

唑-5-羧酸甲酯與甲醇(100mL)之混合物中添加硼氫化鈉(1.18g)。將反應混合物於室溫下攪拌4小時，添加水，利用乙酸乙酯進行萃取。利用飽和食鹽水洗淨有機層，利用無水硫酸鎂加以乾燥，將溶劑於減壓下蒸餾去除。於所獲得之(S)-2-(((5-(羥甲基)異

唑-3-基)氧基)甲基)吡咯啶-1-羧酸第三丁酯與THF(100mL)之混合物中添加甲磺醯氯(2.10mL)。將反應混合物於室溫下攪拌2小時，添加飽和碳酸氫鈉水溶液，利用乙酸乙酯進行萃取。利用飽和食鹽水洗淨有機層，利用無水硫酸鎂加以乾燥，將溶劑於減壓下蒸餾去除。將所獲得之(S)-2-(((5-(((甲基磺醯基)氧基)甲基)異

唑-3-基)氧基)甲基)吡咯啶-1-羧酸第三丁酯、7-(哌啶-4-基氧基)噻吩并[3,2-b]吡啶二鹽酸鹽(8.85g)、碳酸鉀(19.9g)、四丁基碘化銨(5.32g)及DMF(50mL)之混合物於室溫下攪拌16小時。於反應混合物中添加水與乙酸乙酯，利用乙酸乙酯進行萃取。利用水及飽和食鹽水洗淨有機層後，利用無水硫酸鎂加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(NH、乙酸乙酯/己烷)精製殘渣。於所獲得之(S)-2-(((5-((4-(噻吩并[3,2-b]吡啶-7-基氧基)哌啶-1-基)甲 基)異

唑-3-基)氧基)甲基)吡咯啶-1-羧酸第三丁酯與乙酸乙酯(20mL)之混合物中添加4M氯化氫/乙酸乙酯(40mL)。將反應混合物於室溫下攪拌1小時，將溶劑於減壓下蒸餾去除，而獲得標題化合物(8.03g)。 3-Hydroxyiso

Methyl oxadiazole-5-carboxylate (3.79 g), tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.84 g) and triphenylphosphine (6.94 g) were azeotroped in toluene. A 40% toluene solution of diethyl azodicarboxylate (14 mL) was added to the mixture of the residue and toluene (50 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour, and then the solvent was distilled off to half under reduced pressure. The product was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained (S)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)isopropylamine was added to the mixture.

Sodium borohydride (1.18 g) was added to a mixture of methyl oxadiazole-5-carboxylate and methanol (100 mL). The reaction mixture was stirred at room temperature for 4 hours, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained (S)-2-(((5-(hydroxymethyl)isocyanate

Methanesulfonyl chloride (2.10 mL) was added to a mixture of (S)-2-(((5-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester and THF (100 mL). The reaction mixture was stirred at room temperature for 2 hours, and a saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained (S)-2-(((5-(((methylsulfonyl)oxy)methyl)isobutyl ester was purified by centrifugation and purified by centrifugation.

A mixture of tert-butyl (( ...-((((((((((((((((((((((-((((((((((((((((((((-((((((((((((((-(((((((((((((-((((((((((((((-((((((((((((-((((((((((-(((((((((-((((((-(((((((-((((((-(((( The obtained (S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

To a mixture of tert-butyl (3-(4-oxazol-3-yl)oxy)methyl)pyrrolidine-1-carboxylate and ethyl acetate (20 mL) was added 4 M hydrogen chloride/ethyl acetate (40 mL). The reaction mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure to obtain the title compound (8.03 g).

MS: [M+H] ⁺ 415.2.

B) (S)-4-(5,6-difluoro-1H-indole-2-carbonyl)-3-methylpiperidin

-1-carboxylic acid tert-butyl ester

-1-羧酸第三丁酯(1.12g)、5,6-二氟-1H-吲哚-2-羧酸(1.00g)、DIEA(2.72mL)、及DMF(20mL)之混合物中添加HATU(2.89g)。將反應混合物於室溫下攪拌1小時，利用水與乙酸乙酯進行稀釋，利用乙酸乙酯進行萃取。利用無水硫酸鎂將有機層加以乾燥，將溶劑於減壓下蒸餾去除而獲得標題化合物(1.61g)。 (S)-3-Methylpiperidin

HATU (2.89 g) was added to a mixture of tert-butyl-1-carboxylate (1.12 g), 5,6-difluoro-1H-indole-2-carboxylic acid (1.00 g), DIEA (2.72 mL), and DMF (20 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 distilled off under reduced pressure to obtain the title compound (1.61 g).

MS: [M+H-tBu] ⁺ 324.2.

C) 2-(2-((S)-4-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)-2-methylpiperidin

-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid methyl ester

-1-羧酸第三丁酯(1.61g)、碳酸鉀(762mg)、2-溴乙酸甲酯(0.629mL)、及DMF(15mL)之混合物於室溫下攪拌16小時。於反應混合物中添加水與乙酸乙酯，利用乙酸乙酯進行萃取。利用無水硫酸鎂將有機層加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣。於所獲得之(S)-4-(5,6-二氟-1-(2-甲氧基-2-側氧乙基)-1H-吲哚-2-羰基)-3-甲基哌

-1-羧酸第三丁酯與乙酸乙酯(10mL)之混合物中添加4M氯化氫/乙酸乙酯溶液(21.2mL)。將反應混合物於室溫下攪拌1小時，將溶劑於減壓下蒸餾去 除。於所獲得之(S)-2-(5,6-二氟-2-(2-甲基哌

-1-羰基)-1H-吲哚-1-基)乙酸甲酯鹽酸鹽、(S)-2-((第三丁氧基羰基)胺基)-2-環己基乙酸(1.20g)、DIEA(3.0mL)及DMF(20mL)之混合物中添加HATU(3.22g)。將反應混合物於室溫下攪拌1小時，添加水與乙酸乙酯，利用乙酸乙酯進行萃取。利用無水硫酸鎂將有機層加以乾燥，將溶劑於減壓下蒸餾去除而獲得標題化合物(639mg)。 (S)-4-(5,6-difluoro-1H-indole-2-carbonyl)-3-methylpiperidin

-1-carboxylic acid tert-butyl ester (1.61 g), potassium carbonate (762 mg), methyl 2-bromoacetate (0.629 mL), and DMF (15 mL) were stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained (S)-4-(5,6-difluoro-1-(2-methoxy-2-oxoethyl)-1H-indole-2-carbonyl)-3-methylpiperidin

4M hydrogen chloride/ethyl acetate solution (21.2 mL) was added to a mixture of tert-butyl-1-carboxylate and ethyl acetate (10 mL). The reaction mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure.

To a mixture of (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid (1.20 g), DIEA (3.0 mL) and DMF (20 mL) was added HATU (3.22 g). The reaction mixture was stirred at room temperature for 1 hour, water and ethyl acetate were added, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (639 mg).

MS: [M+H] ⁺ 591.5.

D) 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)-2-methylpiperidin

-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid methyl ester

-1-羰基)-5,6-二氟-1H-吲哚-1-基)乙酸甲酯(639mg)與乙酸乙酯(3mL)之混合物中添加4M氯化氫/乙酸乙酯溶液(5mL)。將反應混合物於室溫下攪拌1小時，將溶劑於減壓下蒸餾去除。於所獲得之2-(2-((S)-4-((S)-2-胺基-2-環己基乙醯基)-2-甲基哌

-1-羰基)-5,6-二氟-1H-吲哚-1-基)乙酸甲酯鹽酸鹽、N-(第三丁氧基羰基)-N-甲基-L-丙胺酸(329mg)、DIEA(0.85mL)、及DMF(5mL)之混合物中添加HATU(616mg)。將反應混合物於室溫下攪拌1小時，添加水與乙酸乙酯，利用乙酸乙酯進行萃取。利用無水硫酸鎂將有機層加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣，而獲得標題化合物(450mg)。 2-(2-((S)-4-((S)-2-((tert-butyloxycarbonyl)amino)-2-cyclohexylacetyl)-2-methylpiperidin

To a mixture of methyl (5,6-difluoro-1H-indol-1-yl)-5,6-difluoro-1H-indol-1-yl)acetate (639 mg) and ethyl acetate (3 mL) was added 4 M hydrogen chloride/ethyl acetate solution (5 mL). The reaction mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The obtained 2-(2-((S)-4-((S)-2-amino-2-cyclohexylacetyl)-2-methylpiperidin

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

MS: [M+H] ⁺ 676.5.

E) 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)-2-methylpiperidin

-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid

-1-羰基)-5,6-二氟-1H-吲哚-1-基)乙酸甲酯(225mg)與甲醇(1.6mL)之混合物中添加2M氫氧化鈉水溶液(0.8mL)。將反應混合物於室溫下攪拌1小時，利用1M鹽酸製成酸性，利用乙酸乙酯進行萃取。利用無水硫酸鎂將有機層加以乾燥，將溶劑於減壓下蒸餾去除，而獲得標題化合物(221mg)。 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)-2-methylpiperidin

To a mixture of methyl (2-(4 ...

MS: [M+H] ⁺ 662.4.

F)((S)-1-(((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-羰基)-5,6-二氟-1H-吲哚-1-基)乙酸(336mg)、(S)-3-(吡咯啶-2-基甲氧基)-5-((4-(噻吩并[3,2-b]吡啶-7-基氧基)哌啶-1-基)甲基)異

唑三鹽酸鹽(319mg)、DIEA(0.53mL)、及DMF(3mL)之混合物中添加HATU(386mg)。將反應混合物於室溫下攪拌2小時，添加水，濾取析出物，利用矽膠管柱層析法(C18、乙腈/5mM乙酸銨水溶液)進行精製。於所獲得之化合物中添加乙酸乙酯與飽和碳酸氫鈉水溶液，利用無水硫酸鈉將有機層加以乾燥，將溶劑於減壓下蒸餾去除而獲得標題化合物(320mg)。 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)-2-methylpiperidin

-1-carbonyl)-5,6-difluoro-1H-indol-1-yl)acetic acid (336 mg), (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

HATU (386 mg) was added to a mixture of oxadiazole trihydrochloride (319 mg), DIEA (0.53 mL), and DMF (3 mL). The reaction mixture was stirred at room temperature for 2 hours, water was added, and the precipitate was filtered and purified by silica gel column chromatography (C18, acetonitrile/5 mM ammonium acetate aqueous solution). Ethyl acetate and saturated sodium bicarbonate aqueous solution were added to the obtained compound, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (320 mg).

MS: [M+H] ⁺ 1058.5.

G)(S)-N-((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)

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

唑-3-基)氧基)甲基)吡咯啶-1-基)乙基)-1H-吲哚-2-羰基)-3-甲基哌

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(320mg)與乙酸乙酯(2mL)之混合物中添加4M氯化氫/乙酸乙酯溶液(2mL)。將反應混合物於室溫下攪拌1個半小時，將溶劑於減壓下蒸餾去除。於殘渣中添加飽和碳酸氫鈉水溶液，濾取析出物而獲得標題化合物(216mg)。 ((S)-1-(((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)

To a mixture of tert-butyl (( ...))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))

¹ H NMR (300MHz, DMSO-d ₆ )δ 0.77-1.33(10H,m),1.40-2.24(19H,m),2.31-2.46(2H,m),2.58-3.49(8H,m),3.53-3 .70(3H,m),3.82-4.86(8H,m),5.01-5.48(2H,m),6.07-6.39(1H,m),6.67-6.81(1H,m ),7.05(1H,dd,J=5.6,1.9Hz),7.49(1H,dd,J=5.6,3.0Hz),7.62(1H,dd,J=10.9,8.1H z),7.68-7.83(1H,m),7.89(1H,t,J=9.4Hz),7.97-8.07(1H,m),8.49(1H,d,J=5.7Hz)

Example 9 (S)-N-((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)

-1-yl)-2-oxoethyl)-2-(methylamino)propionamide A) (S)-4-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetyl)-2-methylpiperidin

-1-Carboxylic acid benzyl ester

-1-羧酸苄酯鹽酸鹽(5.26g)、1-羥基苯并三唑(3.4g)、DIEA(10.2mL)及DMF(50mL)之混合物中添加1-乙基-3-(3-二甲胺基丙基)碳二醯亞胺鹽酸鹽(4.8g)。將反應混合物於室溫下攪拌2小時，添加冰水，利用乙酸乙酯對水層進行萃取。依序利用水、飽和碳酸氫鈉水溶液、飽和食鹽水洗淨有機層後，利用無水硫酸鈉加以乾燥，將溶劑於減壓下蒸餾去除而獲得標題化合物(6.7g)。 In the presence of (S)-2-((tert-butyloxycarbonyl)amino)-2-cyclohexylacetic acid (5 g), (S)-2-methylpiperidin

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.8 g) was added to a mixture of 1-benzyl-1-carboxylate hydrochloride (5.26 g), 1-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 with water, saturated sodium bicarbonate aqueous solution, and saturated brine in sequence, and then dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (6.7 g).

MS: [M+H] ⁺ 474.2.

B) (S)-4-((S)-2-amino-2-cyclohexylacetyl)-2-methylpiperidin

-1-Carboxylic acid benzyl ester hydrochloride

-1-羧酸苄酯(6.7g)與DCM(60mL)之混合物中添加4M氯化氫/二

烷溶液(30mL)。將反應混合物於室溫下攪拌3小時，將溶劑於減壓下蒸餾去除。利用DCM洗淨殘渣，而獲得標題化合物(6g)。 (S)-4-((S)-2-(((tert-butyloxy)carbonyl)amino)-2-cyclohexylacetyl)-2-methylpiperidin

To a mixture of benzyl-1-carboxylate (6.7 g) and DCM (60 mL) was added 4 M hydrogen chloride/dichloroethane.

The reaction mixture was stirred at room temperature for 3 hours, and the solvent was distilled off under reduced pressure. The residue was washed with DCM to obtain the title compound (6 g).

^1H NMR (400MHz, DMSO-d ₆ )δ 1.01-1.25(8H,m),1.59-1.70(6H,m),2.85-3.18(3H,m),3.77-4.28(5H,m),5.10(2H,s),7.33-7.37(5H,m ),8.06-8.04(3H,m).

C)(S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)-2-methylpiperidin

-1-Carboxylic acid benzyl ester

-1-羧酸苄酯鹽酸鹽(6g)、DIEA(10.3mL)、及HATU(7.3g)。將反應混合物於室溫下攪拌16小時，添加冰水，利用乙酸乙酯對水層進行萃取。依序利用水、飽和碳酸氫鈉水溶液、飽和食鹽水洗淨有機層，利用無水硫酸鈉加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣，而獲得標題化合物(6g)。 To a mixture of N-(tert-butoxycarbonyl)-N-methyl-L-alanine (3 g) and DMF (30 mL) was added (S)-4-((S)-2-amino-2-cyclohexylacetyl)-2-methylpiperidin

-1-carboxylic acid benzyl ester hydrochloride (6 g), DIEA (10.3 mL), and HATU (7.3 g). The reaction mixture was stirred at room temperature for 16 hours, ice water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate aqueous solution, and saturated brine in sequence, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (6 g).

MS: [M+H] ⁺ 559.1.

D)((S)-1-(((S)-1-cyclohexyl-2-((S)-3-methylpiperidin

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-羧酸苄酯(3.8g)與乙醇(50mL)之混合物中添加10%鈀碳(1g)。將反應混合物於常壓之氫氣環境下、室溫下攪拌16小時，並進行矽藻土過濾。將濾液於減壓下濃縮，而獲得標題化合物(2.3g)。 (S)-4-((S)-2-((S)-2-((tert-butyloxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)-2-methylpiperidin

10% palladium carbon (1 g) was added to a mixture of benzyl-1-carboxylate (3.8 g) and ethanol (50 mL). The reaction mixture was stirred at room temperature under a hydrogen atmosphere at normal pressure for 16 hours and filtered through celite. The filtrate was concentrated under reduced pressure to obtain the title compound (2.3 g).

MS: [M+H] ⁺ 425.2.

E) 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)-2-methylpiperidin

-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetic acid methyl ester

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(901mg)、5-氟-1H-吲哚-2-羧酸(380mg)、DIEA(1.14mL)、及DMF(12mL)之混合物中添加 HATU(1.21g)。將反應混合物於室溫下攪拌1小時，注入至水中，濾取析出物，於甲苯中共沸。將所獲得之((S)-1-(((S)-1-環己基-2-((S)-4-(5-氟-1H-吲哚-2-羰基)-3-甲基哌

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯、碳酸鉀(322mg)、2-溴乙酸甲酯(356mg)及DMF(12mL)之混合物於室溫下攪拌16小時。利用水與乙酸乙酯稀釋反應混合物，利用乙酸乙酯進行萃取。利用無水硫酸鎂將有機層加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣，而獲得標題化合物(979mg)。 ((S)-1-(((S)-1-cyclohexyl-2-((S)-3-methylpiperidin

HATU (1.21 g) was added to a mixture of ((S)-1-(((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1H-indole-2-carbonyl)-3-methylpiperidin-2-yl)-1- ...

A mixture of tert-butyl (( ...)))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))

MS: [M+H] ⁺ 658.4.

F) 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)-2-methylpiperidin

-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetic acid

-1-羰基)-5-氟-1H-吲哚-1-基)乙酸甲酯(979mg)與甲醇(8mL)之混合物中添加2M氫氧化鈉水溶液(3.72mL)。將反應混合物於室溫下攪拌1小時，添加1M鹽酸製成酸性，利用乙酸乙酯進行萃取。利用無水硫酸鎂將有機層加以乾燥，將溶劑於減壓下蒸餾去除而獲得標題化合物(915mg)。 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)-2-methylpiperidin

To a mixture of methyl (5-(2-(4-(4-fluoro-1-indol-1-yl)-5-fluoro-1H-indol-1-yl)acetate (979 mg) and methanol (8 mL) was added 2 M aqueous sodium hydroxide solution (3.72 mL). The reaction mixture was stirred at room temperature for 1 hour, acidified by adding 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (915 mg).

MS: [M+H] ⁺ 644.4.

G)((S)-1-(((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-羰基)-5-氟-1H-吲哚-1-基)乙酸(621mg)、(S)-3-(吡咯啶-2-基甲氧基)-5-((4-(噻吩并[3,2-b]吡啶-7-基氧基)哌啶-1-基)甲基)異

唑三鹽酸鹽(606mg)、DIEA(1.0mL)、及DMF(5mL)之混合物中添加HATU(734mg)。將反應混合物於室溫下攪拌2小時，添加水，濾取析出物，利用矽膠管柱層析法(C18、乙腈/5mM乙酸銨水溶液)進行精製。利用乙酸乙酯稀釋所獲得之化合物，利用飽和碳酸氫鈉水溶液洗淨有機層。利用無水硫酸鈉將有機層加以乾燥，將溶劑於減壓下蒸餾去除而獲得標題化合物(367mg)。 2-(2-((S)-4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionylamide)-2-cyclohexylacetyl)-2-methylpiperidin

-1-carbonyl)-5-fluoro-1H-indol-1-yl)acetic acid (621 mg), (S)-3-(pyrrolidin-2-ylmethoxy)-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

HATU (734 mg) was added to a mixture of oxadiazole trihydrochloride (606 mg), DIEA (1.0 mL), and DMF (5 mL). The reaction mixture was stirred at room temperature for 2 hours, water was added, and the precipitate was filtered and purified by silica gel column chromatography (C18, acetonitrile/5 mM ammonium acetate aqueous solution). The obtained compound was diluted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (367 mg).

MS: [M+H] ⁺ 1040.5.

H)(S)-N-((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)

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

唑-3-基)氧基)甲基)吡咯啶-1-基)乙基)-1H-吲哚-2-羰基)-3-甲基哌

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(367mg)與乙酸乙酯(2mL)之混合物中添加4M氯化氫/乙酸乙酯溶液(3mL)。將反應混合物於室溫下攪拌1個半小時，將溶劑於減壓下蒸餾去除。於殘渣中添加飽和碳酸氫鈉水溶液，濾取析出物而獲得標題化合物(249mg)。 ((S)-1-(((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)

To a mixture of tert-butyl (( ...))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))

¹ H NMR (300MHz, DMSO-d ₆ )δ 0.74-1.34(10H,m),1.38-2.25(19H,m),2.33-2.46(2H,m),2.60-3.5 0(8H,m),3.55-3.71(3H,m),3.79-4.94(8H,m),5.00-5.50(2H,m),6. 03-6.43(1H,m),6.61-6.82(1H,m),6.98-7.19(2H,m),7.26-7.71(3H,m),7.89(1H,t,J=9.7Hz),7.98- 8.13(1H,m),8.49(1H,d,J=5.5Hz).

Example 10 (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-(2-(2-(2-(2-(5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperidin

-1-yl)-2-oxoethyl)-2-(methylamino)propionamide hydrochloride A) 2-(Benzyloxy)-3,4-difluorobenzaldehyde

Potassium carbonate (6.56 g), benzyl bromide (4.51 mL) and sodium iodide (2.37 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 and filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (7.0 g).

¹ H NMR (400MHz, DMSO-d ₆ ): δ 5.33(2H,s),7.30-7.42(4H,m),7.45-7.47(2H,m),7.55-7.59(1H,m),10.04(1H ,s).

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

To a mixture of methyl azidoacetate (3.15 mL), 2-(benzyloxy)-3,4-difluorobenzaldehyde (2.0 g) and methanol (10 mL) was added dropwise a mixture of sodium methoxide (1.74 g) and methanol (10 mL) at -10°C under an atmosphere of hydrogen. 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 filtered to obtain the title compound (2.1 g).

¹ H NMR (400MHz, 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=6.9Hz).

C) 4-(Benzyloxy)-5,6-difluoro-1H-indole-2-carboxylic acid methyl ester

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

¹ H NMR (400MHz, DMSO-d ₆ ): δ 3.87(3H,s),5.41(2H,s),7.05(1H,m),7.26(1H,s),7.32-7.41(3H,m), 7.47-7.49(2H,m),12.19(1H,s).

D) 4-(Benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carboxylic acid methyl ester

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

MS: [M+H] ⁺ 332.1.

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

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

MS: [M+H] ⁺ 318.1.

F)((S)-1-(((S)-2-(4-(4-(Benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperidin

tert-butyl ((1-cyclohexyl)-2-oxoethyl)amino)-1-oxopropane-2-yl) (methyl) carbamate

-1-基)乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(1.81g)、HATU(2.52g)及DIEA(1.9mL)。將反應混合物於室溫下攪拌2小時，添加冰水，利用乙酸乙酯進行萃取。依序利用飽和碳酸氫鈉水溶液、水、飽和食鹽水洗淨有機層後，利用無水硫酸鈉加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣而獲得標題化合物(2.1g)。 To a mixture of 4-(benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carboxylic acid (1.4 g) and DMF (20 mL) was added ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperidin-

To the reaction mixture was added tert-butyl (1-(2-( ...

MS: [M+H] ⁺ 710.1.

G)((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-4-hydroxy-1-methyl-1H-indole-2-carbonyl)piperidin

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-基)-1-環己基-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(2.1g)與乙醇(50mL)之混合物中添加鈀碳(400mg)，於常壓之氫 氣環境下、室溫下攪拌2小時。將反應混合物進行矽藻土過濾，將濾液於減壓下濃縮，而獲得標題化合物(1.7g)。 ((S)-1-(((S)-2-(4-(4-(Benzyloxy)-5,6-difluoro-1-methyl-1H-indole-2-carbonyl)piperidin

Palladium carbon (400 mg) was added to a mixture of tert-butyl (( ...))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))

MS: [M+H] ⁺ 620.4.

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

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

MS: [M+H] ⁺ 439.2.

I) ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)-1H-indole-2-carbonyl)piperidin

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(450mg)與DMF(5mL)之混合物中添加碳酸銫(591mg)與4-甲基苯磺酸2-(2-(2-(2-(苄氧基)乙氧基)乙氧基)乙氧基)乙酯(573mg)。將反應混合物於室溫下攪拌16小時，添加冰水，利用乙酸乙酯進行萃取。利用水及飽和食鹽水洗淨有機層後，利用無水硫酸鈉加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣，而獲得標題化合物 (490mg)。 ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-4-hydroxy-1-methyl-1H-indole-2-carbonyl)piperidin

To a mixture of tert-butyl ((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((

MS: [M+H] ⁺ 886.4.

J)((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-4-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)-1-methyl-1H-indole-2-carbonyl)piperidin

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(490mg)與乙醇(15mL)之混合物中添加鈀碳(100mg)。將反應混合物於常壓之氫氣環境下、室溫下攪拌16小時後，進行矽藻土過濾，將濾液於減壓下濃縮，而獲得標題化合物(360mg)。 ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)-1H-indole-2-carbonyl)piperidin

Palladium carbon (100 mg) was added to a mixture of tert-butyl (( ...))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))

MS: [M+H] ⁺ 796.2.

K)((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-(2-(2-(2-(2-(5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperidin

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(20mg)、5-((4-(噻吩并[3,2-b]吡啶-7-基氧基)哌啶-1-基)甲基)異

唑-3-醇(12.4mg)、三苯基膦(32.9mg)及甲苯(2mL)之混合物中添加偶氮二羧酸二第三丁酯(17.3 mg)。將反應混合物於室溫下攪拌16小時，將溶劑於減壓下蒸餾去除。利用製備薄層層析法精製殘渣而獲得標題化合物(25mg)。 ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-4-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)-1-methyl-1H-indole-2-carbonyl)piperidin

tert-butyl 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isobutyl ester (20 mg),

To a mixture of oxazol-3-ol (12.4 mg), triphenylphosphine (32.9 mg) and toluene (2 mL) was added di-tert-butyl azodicarboxylate (17.3 mg). The reaction mixture was stirred at room temperature for 16 hours, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography to obtain the title compound (25 mg).

MS: [M+H] ⁺ 1109.8.

L)(S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-(2-(2-(2-(2-(5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperidin

-1-yl)-2-oxoethyl)-2-(methylamino)propionamide hydrochloride

唑-3-基)氧基)乙氧基)乙氧基)乙氧基)乙氧基)-1H-吲哚-2-羰基)哌

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(25mg)與DCM(1mL)之混合物中添加4M氯化氫/二

烷溶液(0.3mL)。將反應混合物於室溫下攪拌1小時，將溶劑於減壓下蒸餾去除，並利用二乙醚洗淨，而獲得標題化合物(17mg)。 ((S)-1-(((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-(2-(2-(2-(2-(5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperidin

To a mixture of tert-butyl (1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (25 mg) and DCM (1 mL) was added 4 M hydrogen chloride/dichloromethane.

The reaction mixture was stirred at room temperature for 1 hour, the solvent was distilled off under reduced pressure and washed with diethyl ether to obtain the title compound (17 mg).

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

Example 11 (S)-N-((S)-1-cyclohexyl-2-(4-(2-methyl-1-(2-(2-(2-(2-(5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperidin

-1-yl)-2-oxoethyl)-2-(methylamino)propionamide A)((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1H-indole-5-carbonyl)piperidin

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-基)乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(4g)與DMF(70mL)之混合物中添加2-甲基-1H-吲哚-5-羧酸(1.9g)、DIEA(6.8mL)、及HATU(4.45g)，並於室溫下攪拌16小時。利用水稀釋反應混合物，並利用乙酸乙酯對水層進行萃取。依序利用水、飽和食鹽水洗淨有機層後，利用無水硫酸鈉加以乾燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(乙酸乙酯/己烷)精製殘渣，而獲得標題化合物(4g)。 In ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-(piperidin

To a mixture of (4 g) (2-( ...

MS: [M+H] ⁺ 568.3.

B)((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1-(1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)-1H-indole-5-carbonyl)piperidin

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(2g)與DMF(30mL)之混合物中添加碳酸銫(2.87g)，並於室溫下攪拌5分鐘後，添加4-甲基苯磺酸2-(2-(2-(2-(苄氧基)乙氧基)乙氧基)乙氧基)乙酯(2.78g)，於80℃下攪拌16小時。利用水稀釋反應混合物，並利用乙酸乙酯對水層進行萃取。利用水、飽和食鹽水洗淨有機層後，利用無水硫酸鈉加以乾 燥，將溶劑於減壓下蒸餾去除。利用矽膠管柱層析法(NH、乙酸乙酯/己烷)精製殘渣，而獲得標題化合物(1.3g)。 ((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1H-indole-5-carbonyl)piperidin

To a mixture of tert-butyl (( ... The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to obtain the title compound (1.3 g).

MS: [M+H] ⁺ 834.4.

C)((S)-1-(((S)-1-cyclohexyl-2-(4-(1-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)-2-methyl-1H-indole-5-carbonyl)piperidin

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(1.3g)與乙醇(50mL)之混合物中添加10%鈀碳(250mg)，於常壓之氫氣環境下、25℃下攪拌16小時。將反應混合物進行矽藻土過濾，將濾液於減壓下濃縮，而獲得標題化合物(1.1g)。 ((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1-(1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)-1H-indole-5-carbonyl)piperidin

To a mixture of tert-butyl (( ...))))))))))))

MS: [M+H] ⁺ 744.3.

D)((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1-(2-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperidin

(1-yl)-2-oxoethyl)amino)-1-oxopropane-2-yl)(methyl)carbamic acid tert-butyl ester

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(20mg)、5-((4-(噻吩并[3,2-b]吡啶-7-基氧基)哌啶-1-基)甲基)異

唑-3-醇(10.6mg)、三苯基膦(35.2mg)及甲苯(2mL)之混合物中添加偶氮二羧酸二第三丁酯(24.7mg)，並於25℃ 下攪拌16小時。將反應混合物於減壓下濃縮，利用製備薄層層析法精製殘渣，而獲得標題化合物(17mg)。 ((S)-1-(((S)-1-cyclohexyl-2-(4-(1-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)-2-methyl-1H-indole-5-carbonyl)piperidin

tert-butyl 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isobutyl ester (20 mg),

To a mixture of oxazol-3-ol (10.6 mg), triphenylphosphine (35.2 mg) and toluene (2 mL) was added di-tert-butyl azodicarboxylate (24.7 mg), followed by stirring at 25° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography to obtain the title compound (17 mg).

MS: [M+H] ⁺ 1057.3.

E)(S)-N-((S)-1-cyclohexyl-2-(4-(2-methyl-1-(2-(2-(2-(2-(5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperidin

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

唑-3-基)氧基)乙氧基)乙氧基)乙氧基)乙基)-1H-吲哚-5-羰基)哌

-1-基)-2-側氧乙基)胺基)-1-側氧丙烷-2-基)(甲基)胺基甲酸第三丁酯(17mg)與DCM(1mL)之混合物中添加TFA(0.01mL)，並於25℃下攪拌1小時。將反應混合物於減壓下濃縮，利用製備HPLC(C18、流動相：乙腈/20mM碳酸氫銨水溶液)精製殘渣，而獲得標題化合物(4mg)。 ((S)-1-(((S)-1-cyclohexyl-2-(4-(2-methyl-1-(2-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperidin

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

MS: [M+H] ⁺ 957.8.

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

-1-羰基)-5,6-二氟-N,1-二甲基-N-(2-(2-(2-((5-((4-(噻吩并[3,2-b]吡啶-7-基氧基)哌啶-1-基)甲基)異

唑-3-基)氧基)乙氧基)乙氧基)乙基)-1H-吲哚-3-甲醯胺(2-(4-((S)-2-cyclohexyl-2-((S)-2- (methylamino)propanamido)acetyl)piperazine-1-carbonyl)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide)、

Example No. 1 (Compound 1): 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propionamido)acetyl)piperidin

-1-carbonyl)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

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

Salt type: HCl; MS value: 1006.6

-1-羰基)-6-甲氧基-1-甲基-N-(2-(2-(2-(4-((4-(噻吩并[3,2-d]嘧啶-4-基氧基)哌啶-1-基)磺醯基)苯氧基)乙氧基)乙氧基)乙基)-1H-吲哚-3-甲醯胺(2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-6-methoxy-1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide)、[化56]

Example No. 2 (Compound 2): 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propionamido)acetyl)piperidin

-1-carbonyl)-6-methoxy-1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide (2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)piperazine-1-carbonyl)-6-methoxy-1-methyl-N-(2-(2-(2-(4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenoxy)ethoxy)ethoxy)ethyl)-1H-indole-3-carboxamide), [Chemical 56]

Salt type: -; MS value: 1046.5

-1-基)-2-((2R,5R)-5-甲基-2-((2-(2-(2-((5-((4-(噻吩并[3,2-b]吡啶-7-基氧基)哌啶-1-基)甲基)異

唑-3-基)氧基)乙氧基)乙氧基)乙氧基)甲基)哌

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

Example No. 3 (Compound 3): 1-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperidin

-1-yl)-2-((2R,5R)-5-methyl-2-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperidin

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

Salt type: HCl; MS value: 909.7

唑-3-基)氧基)乙氧基)乙氧基)乙氧基)-1H-吲哚-2-羰基)哌

-1-基)-2-側氧乙基)-2-(甲基胺基)丙醯胺((S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide)、

Example No. 4 (Compound 4): (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperidin

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

Salt type: HCl; MS value: 966.4

唑-3-基)氧基)-6,9,12-三氧雜-3-氮雜十四烷基)-1H-吲哚-2-羰基)哌

-1-基)-2-側氧乙基)-2-(甲基胺基)丙醯胺((S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)-6,9,12-trioxa-3-azatetradecyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide)、

Example No. 5 (Compound 5): (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)-6,9,12-trioxa-3-aza-tetradecyl)-1H-indole-2-carbonyl)piperidin

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

Salt type: HCl; MS value: 1050.3

唑-3-基)氧基)甲基)吡咯啶-1-基)乙基)-1H-吲哚-2-羰基)哌

-1-基)-2-側氧乙基)-2-(甲基胺基)丙醯胺((S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1- yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide)、

Example No. 6 (Compound 6): (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperidin-1-yl)

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

Salt type: HCl; MS value: 944.2

唑-3-基)氧基)甲基)吡咯啶-1-基)乙基)-1H-吲哚-2-羰基)哌

-1-基)-2-側氧乙基)-2-(甲基胺基)丙醯胺((S)-N-((S)-1-cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide)、[化61]

Example No. 7 (Compound 7): (S)-N-((S)-1-cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperidin-1-yl)

-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S)-N-((S)-1-cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide), [Chemical 61]

Salt type: -; MS value: 926.1

唑-3-基)氧基)甲基)吡咯啶-1-基)乙基)-1H-吲哚-2-羰基)-3-甲基哌

-1-基)-2-側氧乙基)-2-(甲基胺基)丙醯胺((S)-N-((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide)、

Example No. 8 (Compound 8): (S)-N-((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)

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

Salt type: -; MS value: 958.4

唑-3-基)氧基)甲基)吡咯啶-1-基)乙基)-1H-吲哚-2-羰基)-3-甲基哌

-1-基)-2-側氧乙基)-2-(甲基胺基)丙醯胺((S)-N-((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide)、

Example No. 9 (Compound 9): (S)-N-((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)

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

Salt type: -; MS value: 940.4

唑-3-基)氧基)乙氧基)乙氧基)乙氧基)乙氧基)-1H-吲哚-2-羰基)哌

-1-基)-2-側氧乙基)-2-(甲基胺基)丙醯胺((S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-(2-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperazin-1-yl)-2-oxoethyl)-2- (methylamino)propanamide)、

Example No. 10 (Compound 10): (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-(2-(2-(2-(2-(5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperidin

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

Salt type: HCl; MS value: 1009.7,

and

唑-3-基)氧基)乙氧基)乙氧基)乙氧基)乙基)-1H-吲哚-5-羰基)哌

-1-基)-2-側氧乙基)-2-(甲基胺基)丙醯胺((S)-N-((S)-1-cyclohexyl-2-(4-(2-methyl-1-(2-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide)、[化65]

Example No. 11 (Compound 11): (S)-N-((S)-1-cyclohexyl-2-(4-(2-methyl-1-(2-(2-(2-(2-(5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperidin

-1-yl)-2-oxoethyl)-2-(methylamino)propanamide ((S)-N-((S)-1-cyclohexyl-2-(4-(2-methyl-1-(2-(2-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)isoxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperazin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide), [Chemical 65]

Salt type: -; MS value: 957.8

Experimental Example 1: Determination of XIAP binding inhibitory activity

The human XIAP binding inhibitory activity was measured by the Homogeneous Time Resolved Fluorescence (HTRF) method using a commercially available purified protein of the human XIAP_BIR3 region (R&D) and a Smac N-terminal peptide (AVPIAQK (SEQ ID NO: 1)) (hereinafter referred to as "b-Smac", PEPTIDE INSTITUTE Co., Ltd.) biotinylated at the C-terminus by conventional methods as a ligand.

The HTRF method is described in detail below.

The test compound diluted in reaction buffer (25 mM HEPES (4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid) buffer containing 100 mM NaCl, 0.1% BSA (Bovine Serum Albumin), 0.1% Triton X-100, pH 7.5) was added to a 384-well white shallow bottom plate (Greiner 784076) at 1 μL/well and flash centrifuged for 30 seconds. Then, human XIAP_BIR3 region purified protein was diluted to 90 nM using reaction buffer to obtain sample dilution, and the sample dilution was added to the above-mentioned white shallow bottom dish at 4.5 μL/well, and flash centrifugation was performed for 30 seconds. Then, b-Smac diluted to 90 nM using reaction buffer was added to the above-mentioned white shallow bottom dish at 4.5 μL/well, and flash centrifugation was performed for 30 seconds. Anti-6HIS-Cryptate (Eu ³⁺ Cryptate-conjugated mouse monoclonal antibody anti-6 Histidine, cisbio) and Streptavidin-XL ^ent! diluted 100 times using HTRF detection buffer (cisbio) (Highgrade XL665-conjugated streptavidin, cisbio) were mixed at a volume ratio of 1:1, and the obtained solution was added to the above-mentioned white light bottom plate at 10 μL/well, and flash centrifuged for 30 seconds. After that, the white light bottom plate was placed in a dark place at room temperature for more than 4 hours. The white light bottom plate after placement was used for the measurement of fluorescence intensity using EnVision (PerkinElmer) (excitation wavelength: 320nm, fluorescence wavelength: 665nm and 615nm).

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

The XIAP binding inhibition rate of the test compound was evaluated. The XIAP binding inhibition rate when the test compound concentration was 3μM was shown in the following table according to A≧75%, 75%>B≧50%, 50%>C≧25%, and D<25%, or the 50% inhibition concentration (IC50 value) was shown in the following table according to A<0.3μM, 0.3μM≦B<3μM, and 3μM≦C<30μM.

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

The above results show that the compounds of the present invention have excellent IAP (especially XIAP) binding (inhibition) activity.

Experimental Example 2: Determination of IRAK-M binding inhibitory activity

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

(Information value of the test compound - Information value of the positive control compound)/(Information value of the negative control compound - Information value of the positive control compound) × 100

Negative control compound = DMSO (100% Ctrl)

Positive control compound = control compound (0% Ctrl)

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

Experimental Example 3: Decomposition-inducing activity of target protein in vitro

The in vitro degradation-inducing activity of the example compounds on the target protein was evaluated by enzyme binding immunoassay (ELISA) according to the following analytical procedures. THP1 cells (ATCC, TIB-202) were cultured in RPMI (Roswell Park Memorial Institute)-1640 supplemented with 10% FBS (Fetal Bovine Serum), 1X sodium pyruvate, 1X HEPES, D-(+)-glucose and 1% penicillin/streptomycin. THP1 cells seeded at 1×10 ⁶ cells/well in a 24-well plate were treated with DMSO control and the test compounds and cultured for 24 hours. The cells were recovered and lysed on ice for 30 minutes using lysis buffer (PBS (Phosphate Buffered Saline) containing 0.1% Triton X-100) supplemented with a protease inhibitor cocktail (Roche, Cat# 11836170001). The lysate was ultrasonically disrupted for 10 cycles of 30 seconds on/30 seconds off (30sec ON/30sec OFF) and centrifuged at 13krpm for 10 minutes at 4°C. The protein concentration was determined by BCA (bicinchoninic acid) analysis (Sigma, Cat# QPBCA-1KT). ELISA analysis was performed using the Human IRAK3/IRAKM/IRAK-M ELISA Kit (LifeSpan BioSciences, Cat # LS-F35271) to assess the protein amount of IRAK-M according to the kit instructions. The protein degradation rate of IRAK-M by the test compound is shown in the following table as A≧75%, 50%≦B<75%, 25%≦C<50%, D<25% at a concentration of 1μM of the test compound, or as A<0.03μM, 0.03μM≦B<0.1μM, 0.1μM≦C<0.3μM, 0.3μM≦D<1μM at a concentration of 50% degradation (DC50 value).

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

Experimental Example 4: Anti-tumor effect in the mouse Lewis lung cancer cell inoculation model

Lewis lung carcinoma, LLC (ATCC, CRL-1642) cells were subcutaneously inoculated into the flank of C57BL/6 mice (Charles River Laboratories Japan, male, 7-8W) at 2×10 ⁴ cells/mouse together with matrix gel. The tumor size was measured using an electronic vernier caliper 7 days after inoculation, and the mice were divided into groups so that the size of each group was the same. The compound was administered starting 8 days later. The tumor size was calculated using the formula of tumor long diameter × short diameter × short diameter ÷ 2.

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

The daily changes in tumor size of each group in Examples 1, 6, 7, 8 and 9 are shown in Figure 1. Each compound used the salt shown in the figure. The figure represents the mean ± standard error.

The above results show that these compounds have the effect of inhibiting cancer growth.

Preparation Example 1

The medicine containing the compound of the present invention as an active ingredient can be prepared, for example, by the following formulation.

1. Capsules

Mix (1), (2), (3) and 1/2 of (4) and granulate. Add the rest of (4) and seal the whole into a gelatin capsule.

2. Tablets

Mix (1), (2), (3), 2/3 of (4) and 1/2 of (5) and granulate. Add the remaining (4) and (5) to the granules and press to form tablets.

Preparation Example 2

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

The above detailed description is a simple explanation of the purpose and object of the present invention, and does not limit the scope of the attached patent application. Practitioners understand that various changes and substitutions can be made to the described implementation forms according to the teachings recorded in this specification without departing from the scope of the attached patent application.

[Industrial availability]

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

Claims (13)

A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula (I):

The above IRAK-M conjugate (M) is represented by the following formula (II):

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

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

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

(herein, * indicates the position of bonding to A, ** indicates the position of bonding to the linking group), any group represented by, a C1-6 alkylene group which may be substituted, a C3-10 cycloalkylene group which may be substituted, a C6-14 arylene group which may be substituted, or a bonding bond, and the arrow indicates the bonding to the linking group (L)], wherein the linking group (L) is a group having 5 to 20 carbon atoms which may contain at least one heteroatom selected from N and O, and the E3 ligase conjugate (E) is represented by the following formula (IV):

[In the formula, R ₀₁ , R ₀₂ , R ₀₃ , R ₀₄ , R ₀₅ , R ₀₆ , R ₀₇ , and R ₀₈ each independently represent a hydrogen atom or a C1-6 alkyl group that can form a ring with each other, and D is the following formula (V)

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

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

(wherein R ₂₁ , R ₂₂ , and R ₂₃ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or an optionally substituted aminoformyl group; R ₂₅ and R ₂₆ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, an optionally substituted aminoformyl group, or a bond to the linking group (L); R ₂₄ represents a hydrogen atom, a methyl group, or a bond to the linking group (L); wherein the bond to the linking group (L) is any one of R ₂₄ , R ₂₅ or R ₂₆ ), or the following structural formula:

(wherein R represents a hydrogen atom, a C1-6 alkyl group, or is bonded to the linking group (L)), and either D or E is bonded to the linking group (L)]. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the IRAK-M conjugate (M) is represented by the following formula (III):

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

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

(Here, * indicates the position of bonding to A ⁰¹ , ** indicates the position of bonding to the linking group) any group represented by, the arrow indicates the bonding to the linking group (L)]. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the IRAK-M conjugate (M) is a valent group derived from a compound selected from the group consisting of: 5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

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

oxazol-3-ol (5-((4-((2-methylthieno[3,2-b]pyridin-7-yl)oxy)piperidin-1-yl)methyl)isoxazol-3-ol), 1-methyl-5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)-1H-pyrazol-3-ol), and 4-((4-(thieno[3,2-d]pyrimidin-4-yloxy)piperidin-1-yl)sulfonyl)phenol. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the linking group (L) is a structural formula described below:

(Here, * represents a group bonded to the IRAK-M conjugate (M)), *-(CH ₂ CH ₂ O)n(CH ₂ )m(NRCO)s(CH ₂ )t-* (n is a natural number of 1 to 5, m is 0, 1, or 2, s is 0 or 1, t is 0 or 1, R represents a hydrogen atom or a C1-6 alkyl group), or a bond. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the E3 ligase conjugate (E) is represented by the following formula (IV):

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

(wherein W ₁₁ represents methylene or difluoromethylene), or the following formula (VI-1)

(wherein Q represents a bond to the linker (L)), and E is the following formula (VII):

(wherein R ₂₁ , R ₂₂ , and R ₂₃ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a C1-6 alkoxy group; R ₂₅ and R ₂₆ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a bond to the linking group (L); R ₂₄ represents a hydrogen atom, a methyl group, or a bond to the linking group (L); wherein the bond to the linking group (L) is any one of R ₂₄ , R ₂₅ or R ₂₆ ), or the following structural formula:

(wherein R represents a hydrogen atom, a C1-6 alkyl group, or is bonded to the linking group (L)), and either D or E is bonded to the linking group (L)]. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the IRAK-M conjugate (M) is represented by the following formula (III):

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

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

(here, * represents a bond to the IRAK-M conjugate (M)), *-(CH ₂ CH ₂ O)n(CH ₂ )m(NRCO)s(CH ₂ )t-* (n is a natural number of 1 to 5, m is 0, 1, or 2, s is 0 or 1, t is 0 or 1, R represents a hydrogen atom or a C1-6 alkyl group), or a bond, the E3 ligase conjugate (E) is represented by the following formula (IV):

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

Or the following formula (VI-1):

(wherein Q represents a bond to the linker (L)), and E is the following formula (VII):

(wherein R ₂₁ , R ₂₂ , and R ₂₃ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a C1-6 alkoxy group; R ₂₅ and R ₂₆ each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a bond to the linking group (L); R ₂₄ represents a hydrogen atom, a methyl group, or a bond to the linking group (L); wherein the bond to the linking group (L) is any one of R ₂₄ , R ₂₅ or R ₂₆ ), or the following structural formula:

(wherein R represents a hydrogen atom, a C1-6 alkyl group, or is bonded to the linking group (L)), and either D or E is bonded to the linking group (L)]. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the following compounds 1 to 11: Compound 1: 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propionylamide)acetyl)piperidin

-1-carbonyl)-5,6-difluoro-N,1-dimethyl-N-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

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

Compound 2: 2-(4-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propionylamide)acetyl)piperidin

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

Compound 3: 1-((R)-4-(5,6-difluoro-1-methyl-1H-indole-2-carbonyl)-2-methylpiperidin

-1-yl)-2-((2R,5R)-5-methyl-2-((2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)methyl)piperidin

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

Compound 4: (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-3-(2-(2-(2-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperidin

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

Compound 5: (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(3-methyl-2-oxo-14-((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)-6,9,12-trioxa-3-aza-tetradecyl)-1H-indole-2-carbonyl)piperidin

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

Compound 6: (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperidin-1-yl)

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

Compound 7: (S)-N-((S)-1-cyclohexyl-2-(4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)piperidin-1-yl)

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

Compound 8: (S)-N-((S)-1-cyclohexyl-2-((S)-4-(5,6-difluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)

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

Compound 9: (S)-N-((S)-1-cyclohexyl-2-((S)-4-(5-fluoro-1-(2-oxo-2-((S)-2-(((5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethyl)-1H-indole-2-carbonyl)-3-methylpiperidin-1-yl)

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

Compound 10: (S)-N-((S)-1-cyclohexyl-2-(4-(5,6-difluoro-1-methyl-4-(2-(2-(2-(2-(5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-1H-indole-2-carbonyl)piperidin

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

and compound 11: (S)-N-((S)-1-cyclohexyl-2-(4-(2-methyl-1-(2-(2-(2-(2-(5-((4-(thieno[3,2-b]pyridin-7-yloxy)piperidin-1-yl)methyl)iso

(oxazol-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-indole-5-carbonyl)piperidin

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

A medicine comprising a compound as described in any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. For example, the medicine in claim 8 is an IRAK-M protein degradation inducer. If the medicine in claim 8 is a cancer preventive or therapeutic agent. For example, the medicine in claim 8 is used in combination with other anticancer agents. A use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for inducing the decomposition of IRAK-M protein. A use of a compound as claimed in any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the prevention or treatment of cancer.